THIRD INTERNATIONAL MEETING ON PHARMACY AND

PHARMACEUTICAL SCIENCES9-12 JUNE, 2010 ISTANBUL, TURKEY

ABSTRACT BOOK

CONTENTS

Introduction iii

Program v

Plenary Lectures 13

Oral Presentations 61

Poster Presentations 89

Authors Index 253

Dear Colleagues,

On behalf of the orginizing committee, we cordially invite you to attend the 3rd International Meeting on Pharmacy and Pharmaceutical Sciences (IMPPC-3) which will be organized by Marmara University, Fac-ulty of Pharmacy.

The upcoming meeting will be held in Istanbul, Turkey on June 9-12, 2010. With IMPPC-3, we want con-tinue the tradition of international meetings covering advances in all aspects of Pharmaceutical Sciences. This meeting will create an environment for focusing on the key role of the pharmacist in drug design, research and development, performed by academia and pharmaceutical industry, as well as the new clinical role from the respect of pharmaceutical care.

Istanbul is the most populous city in Europe and and richest financial and cultural center of Turkey. It is lo-cated on the Bosphorus peninsula and encompasses the natural harbor known as Haliç (the Golden Horn), in the northwest of the country.

The city is often referred as The City on Seven Hills because the historical part of the city, was built on seven hills, each of which bears a historic mosque. It is the only city in the world which is placed on two conti-nents as it extends both on the European and on the Asian (Anatolian) side of the Bosphorus. In its long history, Istanbul has been the capital of three major empires: the Romans, the Byzantines and the Ottoman Empires. Recently, the city of Istanbul was chosen as joint European Capital of Culture for 2010.

Due to the distinguishing features of ‹stanbul such as its geographic location, unique natural beauty, and the great historical and cultural heritage we strongly hope that this visit will give additional pleasure and unforgettable memories to our guests.

We look forward to seeing your active participation to this meeting in Istanbul, where continents and civi-lizations meet.

Prof. Dr. Sevim Rollas

Chairperson

iii

COMMITTEES

Organising CommitteeHonorary President Necla PUR, President of Marmara University Symposium ChairpersonProf. Sevim ROLLAS, Dean of Faculty of Pharmacy

İlkay KÜÇÜKGÜZEL, Secretary Ş.Güniz KÜÇÜKGÜZEL, Treasurer Göksel ŞENER Adile ÇEVİKBAŞ Semra ŞARDAŞ Güler YALÇIN Sinem GÖKTÜRK Mesut SANCAR Oya SİPAHİGİL Şermin TETİK Hale TOKLU Ali Demir SEZER Esra TATAR Social CommitteeDiren BEYOĞLU Filiz ARIÖZ ÖZDEMİR Kübra ELÇİOĞLU Özer ŞEHİRLİ Sevgi KARAKUŞ Şule APİKOĞLU RABUŞ Sevinç ŞAHBAZ Burçak GÜRBÜZ Neşe ERDİNÇ

Scientific CommitteeJülide AKBUĞA Feyza ARICIOĞLU Gül AYANOĞLU-DÜLGER Betül DORTUNÇ Emre DÖLEN Fikret Vehbi İZZETTİN A.Seza BASTUĞ Gülden OMURTAG Mürşit PEKİN Fikriye URAS Mert ÜLGEN Türkan YURDUN Ertan TUZLACI Murat TÜRKOĞLU Dilek EROL Günay SARIYAR Tayfun UZBAY Sevil ÜNAL Hüsnü Can BAŞER Fethi ŞAHİN Mehmet MELLİ Atilla HINCAL Afife MAT Yıldız ÖZSOY-ERGİNER Levent KABASAKAL Bedia KAYMAKÇIOĞLU Ümran SOYOĞUL GÜRER Azize ŞENER Kadir TURAN Leyla BİTİŞ

iv

SCIENTIFIC PROGRAM

WEDNESDAY, JUNE 09

13.00-16.30 REGISTRATION

Hall 1 SESSION I

Inaugural Lecture

16.30-17.30 OPENING CEREMONY Chairperson İlkay Küçükgüzel (Marmara University, Turkey)

17.30-18.30 PL-1

The antiviral drug era: Half a century after the synthesis of the first antiviral drug Erik De Clercq (Rega Institute, Katholieke Universiteit Leuven, Belgium)

18.30-21.00 WELCOME RECEPTION

THURSDAY, JUNE 10

HALL 1 SESSION II

Computational chemistry & molecular modeling

HALL 2 SESSION III

Natural products & phytotheraphy

Chairpersons : Sumru Özkırımlı(Istanbul University, Turkey) Salvatore Guccione (Catania University)

Chairpersons : Filiz Meriçli (İstanbul University, Turkey)

09.00-09.40 PL-2

Computer aided drug design studies on chemotherapeutically active heterocyclic compounds Esin Akı (Ankara University, Turkey)

09.00-09.40 PL-4

Scientific evaluation of Turkish folk remedies for wound healing Erdem Yeşilada (Yeditepe University, Turkey)

09.40-10.20 PL-3

De novo design of selective monoamine oxidase A and B inhibitors : evaluation of  novel pyrazoline  derivatives using molecular modeling techniques Kemal Yelekçi (Kadir Has University, Turkey)

09.40-10.20 PL-5

Developing herbal medicines: Can metabolomic approaches help in establishing their quality and safety? Michael Heinrich (University of London, UK)

10.20-10.40 C O F F E E B R E A K & E X H I B I T I O N

HALL 1 SESSION IV

Drug delivery & drug targeting

HALL 2 SESSION V

Drug safety & personalized medicine

Chairpersons : Atilla Hıncal (Hacettepe University, Turkey) Elizabeth Colbourn (Intelligensys Ltd., UK)

Chairpersons : Gül Dülger (Marmara University, Turkey) Véronique Michaud (Montréal University, Canada)

10.40-11.20 PL-6

Peptide drug delivery using phospholipid nanomicelles Hayat Önyüksel (University of Illinois, USA)

10.40-11.20 PL-9

The metabolomics revolution in drug metabolism Jeffrey R. Idle (Charles University, Czech Republic)

11.20-12.00 PL-7

Advances responsive and feedback-controlled nanoparticles for drug and protein delivery Nicholas Peppas (University of Texas, USA)

11.20-12.00 PL-10

Pharmacogenetics/genomics for predictive and personalized medicine in post genomic era Candan Hızel (Centre Jean Perrin Anti-cancereux-Clermont-frerand, France)

12.00-12.40 PL-8

Brain drug targeting Yılmaz Çapan (Hacettepe University, Turkey)

12.40-14.00 L U N C H

v

13.00-15.00

PROF. DR. MUSTAFA NEVZAT PISAK HALL Workshop on Pharmaceutical Care in Diabetes

Fikret Vehbi İzzettin, Mesut Sancar, Şule Rabuş, Betül Okuyan

HALL 1 SESSION VI

Proteins & peptidomimetics for future drugs

HALL 2 SESSION VII

Pharmacogenetics & cardiovascular disease

Chairpersons : Güler Yalçın (Marmara University, Turkey), Esin Akı (Ankara University, Turkey)

Chairpersons : Semra Şardaş (Marmara University, Turkey), Jeffrey R. Idle (Charles University, Czech Republic)

14.00-14.40 PL-11

Translating information about biochemical pathways into practical, small organic or peptidomimetic therapeutic agents Salvatore Guccione (Catania University, Italy)

14.00-14.40 PL-14

Pharmacogenetics and cardiovascular drugs Jacques Turgeon(Montréal University, Canada)

14.40-15.20 PL-12

Potential protein drugs: New vitamin K dependent proteins and their receptors Fikriye Uras (Marmara University, Turkey)

14.40-15.20 PL-15

The influence of pharmacogenetics for warfarine dose requirements Véronique Michaud (Montréal University, Canada)

15.20-16.00 PL-13

Understanding protein properties: essential for proteomics, quality control, binding assays and molecular modelling Hermann Wätzig (Technical University Braunschweig, Germany)

15.20-16.00    OP-1

Resistin gene expression in type 2 diabetic patients human adipose tissues: relationship with drug use: relationship with drug use Belgin Süsleyici Duman (Marmara University, Turkey)

PROF. DR. MUSTAFA NEVZAT PISAK HALL Clinical pharmacy and pharmaceutical care

Chairperson: Levent Kabasakal (Marmara University, Turkey)

15.00-15.20 OP-2

The effect of medication compliance on control of chronic diseases Feras Jassim Jirjees (Sharjah University, UAE)

15.20-15.40 OP-3

Old and new antiarrythmics medications: Current directions Muneera Albabtain (Prince Sultan Cardiac Center, Saudi Arabia)

15.40-16.00 OP-4

Cardiac rehabilitation: Measures and tools Fadwa Fadwa (Prince Sultan Cardiac Center, Saudi Arabia)

Chairperson: Azize Şener (Marmara University, Turkey)

16.20-16.40 OP-5

Some tacrolimus pharmacokinetic properties in Iranian liver transplant recipients. Simin Dashti - Khavidaki (Tehran University of Medical Sciences, Iran)

16.40-17.00 OP-6

Enhancement of the cytotoxicity of anticancer drugs by celecoxib is cell type-, drug- and sequence-dependent. Raafat El-Awady (Sharjah University, UAE)

16.00-16.20 C O F F E E B R E A K & E X H I B I T I O N

HALL 1 SESSION VIII

The use of ANN in pharmacy research

HALL 2 SESSION IX

Rational pharmacotherapy teaching in Turkey

Chairperson : Betül Dortunç (Marmara University, Turkey)

Chairperson : Berrak Yeğen (Marmara University, Turkey)

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16.20-17.00 PL-16

Machine learning technologies in pharmaceutical formulation Elisabeth Colbourn (Intelligensys Ltd., UK)

16.20-17.00 PL-17

PL-17a : Problem based Rational Pharmacotherapy Teaching : An Experience in a Medical School in Turkey Ersin Yarış (Karadeniz Technical University, Turkey) PL-17b : Problem based Rational Pharmacotherapy Teaching : An Experience in a Pharmacy School in Turkey Hale Z. Toklu (Marmara University, Turkey)

20:00 Concert Cihat Aşkın - Mehru Ensari

FRIDAY, JUNE 11

ORD. PROF. DR. REŞAT KAYNAR AUDITORIUM SESSION X Recent developments on antiviral & antituberculosis drug design

HALL 1 SESSION XI Oxidative damage & antioxidants

Chairpersons : Dilek Erol (Yeditepe University, Turkey) Adile Çevikbaş (Marmara University, Turkey),

Chairpersons : Göksel Şener (Marmara University, Turkey), Fikriye Uras (Marmara University, Turkey)

09.00-09.40 PL-18

Inhibitors of hepatitis C virus replication Neerja Kaushik – Basu (New Jersey MedicalSchool, USA)

09.00-09.40 PL-20

Melatonin:  mechanisms as an antioxidant and clinical applications Russel J. Reiter (University of Texas, USA)

09.40-10.20 PL-19

Prevention of HIV by means of microbicide formulations. Why does it take so long? Paul J. Lewi ( Janssen Pharmaceutica, Belgium)

09.40-10.20 PL-21

The roles of multidrug resistance transporter (Mdr)-1 and multidrug resistance-associated protein (Mrp)-1 in the treatment of stroke Ertuğrul Kılıç (Yeditepe University, Turkey)

10.20-10.40 C O F F E E B R E A K & E X H I B I T I O N

10.00-12.00

PROF. DR. MUSTAFA NEVZAT PISAK HALL Panel on Pharmacoeconomics

Moderator :Erdal Akalın Speakers : Mehtap Tatar, Aylin Sancar, Ömer Saka, Ali Edizer, Akif Akbulat

ORD. PROF. DR. REŞAT KAYNAR AUDITORIUM SESSION XII

New frontiers on the treatment of neoplastic diseases

HALL 1 SESSION XIII

New approaches for drug formulation

Chairpersons : Rolf W. Hartmann (Saarland University, Germany) Birsen Tozkoparan (Hacettepe University, Turkey)

Chairpersons : Gülgün Yener, (İstanbul University, Turkey) Yılmaz Çapan (Hacettepe University, Turkey)

10.40-11.20 PL-22

New potent inhibitors of human protein kinase CK2, a target in neoplastic diseases Joachim Jose (Heinrich Heine University)

10.40-11.20 PL-24

Dry powder inhalers: construction of antibiotic microparticles for lung infection treatment Paolo Colombo (University of Parma, Italy)

11.20-12.00 PL-23

Molecular Targeted Therapies In Cancer Medicine Emin Kansu (Hacettepe University, Turkey)

11.20-12.00 PL-25

The role of gamma scintigraphy in pharmaceutical product development Fiona McInnes (University of Strathclyde, UK)

12.00-13.30 L U N C H

13.00-13.30 POSTER SESSION

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ORD. PROF. DR. REŞAT KAYNAR AUDITORIUM SESSION XIV

Neuroscience & antipsychotic targets

HALL 1 SESSION XV

Biotechnology and Nanotechnology

Chairpersons : Kemal Yelekçi (Kadir Has University, Turkey)

Chairpersons : Jülide Akbuğa (Marmara University, Turkey) Ahmet Zeki Şengil (Marmara University, Turkey)

13.30-14.10 PL-26

Novel enzymatic pathways in Alzheimer's disease pathogenesis Domenico Praticò (Temple University, USA)

13.30-14.10 PL-29

Functional macromolecules for drug delivery Rana Sanyal (Boğaziçi University, Turkey)

14.10-14.50 PL-27

Glutamatergic system and its role in neurobiology of psychiatric disorders Feyza Arıcıoğlu(Marmara University, Turkey)

14.10-14.50 PL-30

An old material for new applications: Carbon nanotube carriers for drug delivery İ.Tuncer Değim  (Gazi University, Turkey)

14.50-15.30 PL-28

Design and synthesis of selective glutamate receptor agonists Rasmus P. Clausen (University of Copenhagen, Denmark)

14.50-15.30 PL-31

Human tooth germ stem cells (HTGSCs): A promising stem cell source Fikrettin Şahin(Yeditepe University, Turkey)

15.30-15.50 C O F F E E B R E A K & E X H I B I T I O N

PROF. DR. MUSTAFA NEVZAT PISAK HALL

Pharmaceutical analysis and formulation Chairperson : Adnan Aydın (Marmara University, Turkey)

Drug formulation Chairperson : Paolo Colombo (University of Parma, Italy)

13.30-13.50 OP-7

Development and validation of an UPLC method for the determination of atorvastatin and its impurities. Serap Odabaşı (Bilim Pharmaceuticals, Turkey)

14.30-14.50 OP-10

Orally fast disintegrating tablets: Developments, technologies and clinical studies Tansel Çomoğlu (Ankara University, Turkey)

13.50-14.10 OP-8

A stability-indicating UPLC method for the determination of levofloxacin and its related compounds. İlkay Küçükgüzel (Marmara University, Turkey)

14.50-15.10 OP-11

Preparation and characterization of vascular endothelial growth factor loaded poly (lactic-co-glycolic acid) microspheres Oya Sipahigil (Marmara University, Turkey)

14.10-14.30 OP-9

A novel accelerated in vitro release method for biodegradable coating of drug eluting stents: Insight to the drug release mechanisms. Marika Kamberi (Abbott Vascular Inc., USA)

16.10-16.30 OP-12

Formulation of herbal conditioner shampoo and evaluation of it’s physicochemical properties. Gholamreza Dehghan – Noudeh (Kerman University of Medical Sciences, Iran)

ORD. PROF. DR. REŞAT KAYNAR AUDITORIUM SESSION XVI

Drug discovery & development

HALL 1 SESSION XVII

Pharmaceutical care

Chairperson : Rasmus P. Clausen (University of Copenhagen, Denmark)

Chairperson : Türkan Yurdun (Marmara University, Turkey)

15.50-16.30 PL-32

From target identifcation, hit discovery to lead optimisation: recent examples from our research Rolf W. Hartmann (Saarland University, Germany)

15.50-16.30 PL-33

Development of clinical pharmacy and pharmaceutical Care in Turkey Fikret Vehbi İzzettin (Marmara University, Turkey)

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SATURDAY, JUNE 12

ORD. PROF. DR. REŞAT KAYNAR AUDITORIUM SESSION XVIII

Novel approaches for cosmetics

HALL 1 SESSION XIX

Drug metabolism & metabolite-induced toxicity

Chairpersons: Yıldız Özsoy-Erginer (İstanbul University, Turkey) Ayla Gürsoy (Marmara University, Turkey)

Chairpersons: Jacques Turgeon (Montréal University, Canada) Feyza Arıcıoğlu (Marmara University, Turkey)

09.00-09.40 PL-34

Usage of nanotechnology and biotechnology in cosmetology Gülgün Yener (İstanbul University, Turkey)

09.00-09.40 PL-37

Toxicity of Mycotoxins Gülden Z. Omurtag (Marmara University, Turkey)

09.40-10.20 PL-35

What are the novelties in cosmetic science: expectations and responses Yasemin Yazan (Anadolu University, Turkey)

09.40-10.20 PL-38

In vitro drug metabolism studies : What have we learned from biotransformation of amines? Mert Ülgen (Acıbadem University, Turkey)

10.20-11.00 PL-36

Development of dermal and oral products based on tea extracts Murat Türkoğlu (Marmara University, Turkey)

10.20-11.00 PL-39

Pharmacogenetics is the important component of pharmacovigilance Semra Şardaş (Marmara University, Turkey)

11.00-11.20 C O F F E E B R E A K & E X H I B I T I O N

PROF. DR. MUSTAFA NEVZAT PISAK HALL

Research on Pharmaceutical Chemistry Chairpersons : Fatma Gümüş - (Gazi University, Turkey)

Safiye Erdem (Marmara University, Turkey)

Rational Drug Design Chairperson : Esin Akı - (Ankara University, Turkey) Bedia Kaymakçıoğlu (Marmara University, Turkey)

09.00-09.20 OP-13

Synthesis and AChE/BuChE inhibitory and antimicrobial activities of 6-substituted-3(2H)-pyridazinone-2-propyl-3-(substituted/nonsubstituted benzal) hydrazones Mehtap Gökçe (Gazi University, Turkey)

10.00-10.20 OP-16

Synthesis and selective inhibitory activity against MAO of 3-substituted benzylidenehydrazine derivatives containing 2-benzoxazolinones and molecular docking studies Nesrin Gökhan Kelekçi (Hacettepe University, Turkey)

09.20-09.40 OP-14

Synthesis and evaluation of antiviral activity of some novel heterocyclic thiourea compounds Esra Tatar (Marmara University, Turkey)

10.20-10.40 OP-17

QSAR study of phenylalkylamine derivatives as monoamine oxidase inhibitors Safiye Erdem (Marmara University, Turkey)

09.40-10.00 OP-15

3,6-Disubstituted 7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines as novel analgesic/anti-inflammatory compounds Peri Aytaç (Hacettepe University, Turkey)

10.40-11.00 OP-18

Investigation of ligand recognition by beta-lactamases. Elif Özkırımlı Ölmez (Boğaziçi University, Turkey)

PROF. DR. MUSTAFA NEVZAT PISAK HALL

Diabetes and Cardiovascular Disease Chairperson:  Mesut Sancar (Marmara University, Turkey)

11.00-11.20 OP-19   

Diabetes Mellitus management and its implication to cardiovascular disease Muneera Albabtain (Prince Sultan Cardiac Center, Saudi Arabia)

11.20-11.40 OP-20  

Plasma matrix gla protein (mgp) levels in patients with coronary artery disease Erdem Yılmaz (Marmara University, Turkey)

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ORD. PROF. DR. REŞAT KAYNAR AUDITORIUM SESSION XX

HALL 1 SESSION XXI

Chairperson : Emre Dölen (Marmara University, Turkey) Chairperson : Fikret Vehbi İzzettin (Marmara University Turkey)

11.20-12.00 PL-40

New materials and technologies for enantioseparation of chiral drugs Bezhan Chankvetadze (Tbilisi State University, Georgia)

PL-41 Gender difference in science Berrak Yeğen (Marmara University, Turkey)

12.00-13.30 L U N C H

13.00-13.30 POSTER SESSION

ORD. PROF. DR. REŞAT KAYNAR AUDITORIUM SESSION XXII

Pharmaceutical Industry

HALL 1 SESSION XXIII

Therapeutic applications of immunology

Chairpersons : Fethi Şahin (Gazi University, Turkey) ; Mert Ülgen (Acıbadem University, Turkey)

Chairpersons : Fikrettin Şahin (Yeditepe University, Turkey)

13.30-14.10 PL-42

Drug discovery and development Esen Bellur(Zentiva Pharmaceuticals, API Plant, Turkey)

13.30-14.10 PL-44

Allergen specific immunotheraphy in allergic disease Tunç Akkoç(Marmara University, Turkey)

14.10-14.50 PL-43

The effects of patent protection in Turkish pharmaceutical industry Tuncer Arslan(Koçak Pharmaceuticals, Turkey)

   

PROF. DR. MUSTAFA NEVZAT PISAK HALL

New applications for pharmacy and hospital practice Chairperson : Şule Apikoğlu Rabuş (Marmara University, Turkey)

13.10-13.30 OP-21

Radiopharmacy applications in hospital practice Mine Silindir (Hacettepe University, Turkey)

13.30-13.50 OP-22

Fat Mass and Obesity Associated Gene Expression in Human Omental and Subctaneous Adipose Tissue Meliha Koldemir (Marmara University, Turkey)

13.50-14.10 OP-23

Relationship between eNOS Glu298asp Polymorphism in Acute Coronary Syndrome and Coronary Heart Disease Patients. Belgin Süsleyici Duman (Marmara University, Turkey)

14.10-14.30 OP-24

Assessment of the 5th grade pharmacy students’ opinions on the first-time held ‘Pharmacy Practice I’ course of the second cycle Betül Okuyan (Marmara University, Turkey)

14.30-14.50 OP-25

Does Phototherapy Cause Dna Damage in Psoriasis Patients ? Diren Beyoğlu (Marmara University, Turkey)

14.50-15.10 C O F F E E B R E A K & E X H I B I T I O N

15.10-16.00

ORD. PROF. DR. REŞAT KAYNAR AUDITORIUM CLOSING CEREMONY

xi

The organizers of IMPPS-3 thank to the sponsors of the 3rd International Meeting On Pharmacy and Pharmaceutical Sciences

Main Sponsors

BİLİM İLAÇ SAN. VE TİC. A.Ş.

ABDİ İBRAHİM İLAÇ SAN. VE TİC. A.Ş.

NOVARTIS

Sponsors

ARAŞTIRMACI İLAÇ FİRMALARI DERNEĞİ

ARGİS İLAÇ ARAŞTIRMA VE GELİŞTİRME

BAB GÖRÜNTÜ İŞLEME VE ANALİZ SİSTEMİ

BRISTOL-MYERS SQUIBB COMPANY

BURSA ECZACILAR KOOPERATİFİ

DEVA HOLDİNG

DR. F. FRİK İLAÇ A.Ş

FARGEM FARMASÖTİK ARAŞTIRMA VE GELİŞTİRME MERKEZİ SANAYİ VE TİC. A.Ş.

GALENOS ECZA DEPOSU

GILEAD

GLAXOSMITHKLINE İLAÇ SAN. TİC. A.Ş.

HEDEF ALLIANCE HOLDİNG A.Ş

İSTANBUL ECZACILAR KOOPERATİFİ

İSTANBUL ECZACI ODASI

LUNDBECK İLAÇ TİC. LTD. ŞTİ

MARMARA ÜNİVERSİTESİ

MARMARA ÜNİVERSİTESİ ECZACILIK FAKÜLTESİ MEZUNLARI DERNEĞİ

MEDSANTEK - LABORATUVAR MALZEMERİ SAN. VE TİC. LTD. ŞTİ.

MERCK SHARP DOHME İLAÇLARI LTD. ŞTİ.

MUSTAFA NEVZAT İLAÇ SANAYİ

ROCHE MÜSTAHZARLARI SANAYİ A.Ş.

SANOFI-AVENTIS

SELÇUK ECZA DEPOSU A.Ş.

SEM LABORATUAR CİHAZLARI A.Ş.

SERVIER İLAÇ VE ARAŞTIRMA A.Ş.

SOLGAR

*Sponsors are listed in alphabetical order.

xii

12

13

PLENARYLECTURES

14

15

PL1

THE ANTIVIRAL DRUG ERA: HALF A CENTURY AFTER THE SYNTHESIS OF THE FIRST ANTIVIRAL DRUG

Erik DE CLERCQRega Institute for Medical Research, K.U.Leuven, B-3000 Leuven, BelgiumE-mail : erik.declercq@rega.kuleuven.be ; Christiane.Callebaut@rega.kuleuven.be

Today, more than 50 years after the first antiviral drug [5-iodo-2’-deoxyuridine (IDU)] was described [to be later marketed for the topical treatment of herpetic keratitis], there are about 50 compounds formally approved for the treatment of viral infections, half of them for the treatment of AIDS. Most of these drugs are specifically targeted at the enzymes (i.e. DNA-dependent or RNA-dependent DNA polymerase, RNA polymerase, protease or neuraminidase) associated with virus replication, and thus focused on either her-pesviruses [i.e. herpes simplex virus (HSV)], retroviruses [i.e. human immunodeficiency virus (HIV)], he-padnaviruses [i.e. hepatitis B virus (HBV)], flaviviruses [i.e. hepatitis C virus (HCV)] or orthomyxoviruses (influenza virus).

16

PL2

COMPUTER AIDED DRUG DESIGN STUDIES ON CHEMOTHERAPEUTICALLY ACTIVE HETEROCYCLIC COMPOUNDS Esin AKI, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Tandoğan, Ankara, Turkey. İsmail YALÇIN, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Tandoğan, Ankara, Turkey. İlkay YILDIZ, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Tandoğan, Ankara, Turkey. Tuğba ERTAN-BOLELLİ, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Tandoğan, Ankara, Turkey. Kayhan BOLELLİ, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Tandoğan, Ankara, Turkey. Serap YILMAZ, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Tandoğan, Ankara, Turkey. E-mail : Esin.Sener@pharmacy.ankara.edu.tr The most effective therapeutically active drugs has been discovered and put into market by using the com-puter aided rational drug design methods including quantitative structure-activity relationships and mo-lecular modelling studies in the recent years. In the anticancer drug development, eukaryotic topoisom-erases is widely used that they are essential for several cellular processes such as replication, transcription and chromosome condensation. The formation of protein-concealed DNA strand breaks, resulting in the stabilization by the drug of an intermediary complex of the Topo II reaction is related to their antitumor activity. Our group have been working on the rational design of antitumoral active new heterocyclic com-pounds possessing benzoxazole, benzimidazole, benzothiazole and oxazolopyridine fused ring systems in their structures by testing their DNA Topoisomerase I and II inhibitory activities. COMFA (Comparative Molecular Field Analysis) and CoMSIA methods as the 3D-QSAR application for the lead optimisation to the training set of synthesized compounds given in Figure 1 using the Sybyl 6.6 Software in SGI work-station were used in our studies. The three-dimensional pharmacophore hypotheses generated by program Catalyst/HipHop from Accelrys in SGI Workstation were also used in our work. Molecules shown at Fig-ure 1 were edited using the Catalyst 2D/3D visualizer which Catalyst automatically generated conforma-tional models for each compound using the Poling Algortihm.

17

PL3

DE NOVO DESIGN OF SELECTIVE MONOAMINE OXIDASE A AND B INHIBITORS: EVALUATION OF NOVEL PYRAZOLINE DERIVATIVES USING MOLECULAR MODELING TECHNIQUES

Kemal YELEKÇİKadir Has University, Faculty of Arts and Sciences, Istanbul, Turkey. E-Mail : yelekci@khas.edu.tr

Monoamine oxidases (MAO, EC 1,4,3,4) are flavoenzymes bound to the mitochondrial outer membrane. There are two isozymes named as MAO-A and MAO-B. The basic difference in these two isozymes is in their selectivity for the oxidation of the various substrates and inhibitors. MAO-A oxidizes serotonin and norepinephrine and any compound selectively inhibits this isozyme possesses antidepressant activity. On the other hand, dopamine is the substrate for MAO-B and selective inhibition of MAO-B shows potent anti-Parkinson property. That is why, they are the well known target for antidepressant, Parkinson’s disease and neuroprotective drugs. Recently published crystallographic structures of MAO-A and MAO-B paved the way for computational modeling studies.

In this study, a series of new pyrazoline scaffolds were used hoping to increase both selectivity and potency toward MAO-A and MAO-B separately. De novo design method was used for the modifications and ad-ditions to a pyrazoline scaffold within a target binding site in order to enhance its binding affinity and selectivity to that isozyme. Several hundred compounds were screened in silico for prioritization of lead candidates before synthesis and experimental work in order to save money and time.

The best candidates showing high activity and selectivity against MAO-A and the MAO-B isoforms were determined. Their interaction in the active site of the isozyme will be presented in detail. for synthesis and experimental study.

This research was supported by The Scientific and Technological Research Council of Turkey with a grand number 108T232

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18

PL4

SCIENTIFIC EVALUATION OF TURKISH FOLK REMEDIES FOR WOUND HEALING

Erdem YEŞİLADAYeditepe University, Faculty of Pharmacy, İstanbul, Turkey.E-mail : yesilada@yeditepe.edu.tr

Wound is a breach in the normal tissue continuum, which arise due to injuries by physical, chemical or microbial factors, resulting in a variety of cellular and molecular sequela. Wound healing is a self-initiated process for the repairment of tissue damage and fundamentally connective tissue response. The process be-gins the moment tissue is injured with blood platelets aggregating at the point of contact with exposed col-lagen and clotting factors being release in the deposition of a fibrin clot at the site of injury. This initial acute inflammatory phase is followed by synthesis of collagen and other extracellular matrix to close the wound opening so that tissue damage and infections are minimized, nonviable tissue is debrided, tissue perfusion and oygenation are maximized and proper nutrition and a moist wound-healing environment are provided.

Wound is a common daily event particularly in the countryside and people use home-made natural reme-dies to accelerate and enhance the healing process of injuries. Ethnobotanical studies have revealed that sev-eral plant remedies, i.e. oily extracts of Hypericum perforatum (sarı kantaron) flowering herbs, Momordica charantia (kudretnarı) fruits, root barks of Alkanna tinctoria (havaciva otu) and several other Boraginaceae plants, Centaurea iberica (deligöz dikeni) aerial parts and poultice from leaves of Sambucus ebulus (cüce mürver) have been used traditionaly in Turkish folk medicine for wound healing.

In this study, results of in vitro and in vivo experimental and histopathological studies were carried out to prove the efficiency of these folk remedies will be discussed.

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PL5

DEVELOPING HERBAL MEDICINES: CAN METABOLOMIC APPROACHES HELP IN ESTABLISHING THEIR QUALITY AND SAFETY?

Michael HEINRICHCentre for Pharmacognosy and Phytotherapy, The School of Pharmacy, University of London, UK.E-mail : michael.heinrich@pharmacy.ac.uk

Metabolomics, in particular metabolomic fingerprinting is a fast developing area of research which offers a state of the art approach for analysing herbal medical products. NMR spectroscopy is a key analytical technique in this area and is very sensitive, non-selective, fast, offers a relatively high-throughput and an uncomplicated sample preparation. It has often been used to assess the composition of complex mixtures and in the area of herbal medicines the concomitant use of this technique with in vitro or in vivo pharma-cological studies is of particular interest (e.g. Liu et al, 2010; Modarai et al 2010).

We have used this tool in the evaluation of the variability of Cannabis cultivars and of the variability of extraction strategies especially for tinctures. Hot and cold water extracts as well as ethanol/water mixtures (tinctures) of cannabis were compared in order to better understand how these extracts differ in their over-all composition. NMR analysis and in vitro cell assays of crude extracts and fractions were used to better understand the link between phytochemical composition and in vitro NF-kappaB inhibitory and cytotoxic activity. Temperature and polarity of the solvents used for the extraction resulted to be two factors that affect the total amount of ∆9-THC in the extracts and its relative quantity with respect to ∆9-THC-acid and other metabolites. With this method it was possible, without any evaporation or separation step, to distinguish between tinctures from different cannabis cultivars (Politi et al 2008).

In a second study, we assessed the link between of in vitro CYP3A4 inhibition (as an indicator of an ex-tract’s interaction risk) and correlated this with the NMR metabolomic profiles of Echinacea preparations. Six Echinacea Liquid Preparations were studied in detail. PCA and partial least squares regression analysis were used to identify regions in the NMR spectra that are associated with CYP3A4 inhibitory activity. In parallel we analysed the alkylamide content of all ELPs to investigate whether particular alkylamides were associated with the more potent ELP. This approach enabled us to better understand the composition of the various preparations (Modarai et al 2010).

Overall, this approach offers opportunities to optimise plant extracts in terms of the composition of bioac-tive substances and to develop these extracts into ones with a more reproducible composition and of higher quality.

Liu, N. Q et al (2010) Metabolomic investigation of the ethnopharmacological use of Artemisia afra with NMR spectroscopy and multivariate data analysis. Journal of Ethnopharmacology 128, 230-235.

Modarai, M., et al. ( 2010) Metabolomic profiling of liquid Echinacea medicinal products inhibiting Cy-tochrome P450 3A4 (CYP3A4). Planta medica 76: 378–385.

Politi M., et al (2008) Cannabis water extracts and tinctures analysed by NMR spectroscopy; different strategies to reduce the content of ∆9-THC. Phytochemistry 69: 562–570.

20

PL6

PEPTIDE DRUG DELIVERY USING PHOSPHOLIPID NANOMICELLES

Hayat ÖNYÜKSELAdress : Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612-7231, USA.E-mail : hayat@uic.edu

Formulation and delivery of peptide drugs is challenging due to their in vitro and in vivo instability. Peptide molecules aggregate or hydrolyze in aqueous media, and subject to fast enzymatic degradation in the blood. In order to overcome these instability problems we have developed a novel approach to deliver amphiphilic peptide molecules using phospholipid micelles as carriers. These micelles are self assemblies of PEGylated phospholipid molecules with a nanometer size (15nm) that can circulate long hours in the blood without being taken up by reticuloendothelial system. Furthermore they are non toxic since PEGylated phospho-lipid we use is already approved in another product for human use by US FDA. When peptide drugs are incubated with phospholipid micelles they self associate with the micelle, change their conformation to alpha helix, become stabilized, and stay in the micelle until they reach their receptor. For example, we have shown that half life of a neuropeptide, vasoactive intestinal peptide (VIP) increased from 20minutes to 9.6hrs when delivered in micelles. VIP, as an anti-inflammatory agent, has shown similar effect at ten times less dose when delivered in micelles, compared to peptide in saline, on a collagen induced arthritis animal model. This is not only due to the increase in stability but also passive targeting of the drug to the inflamed tissues. Furthermore, side effect of the peptide, lowering blood pressure, is completely eliminated when de-livered in micelles. We propose that VIP in phospholipid micelles should be further developed to be used in the clinics as a targeted peptide nanomedicine against rheumatoid arthritis, which currently does not have a cure.

21

PL7

ADVANCES RESPONSIVE AND FEEDBACK-CONTROLLED NANOPARTICLES FOR DRUG AND PROTEIN DELIVERY

Nicholas A. PEPPAS Fletcher S. Pratt Chair in Engineering, Professor of Chemical Engineering, Biomedical Engineering, and Pharmacy, Chairman of the Department of Biomedical Engineering.Center on Biomaterials, Drug Delivery, Bionanotechnology and Molecular RecognitionThe University of Texas at Austin, USA.E-mail : peppas@che.utexas.edu

Engineering the molecular design of intelligent biomaterials by controlling recognition and specificity is the first step in coordinating and duplicating complex biological and physiological processes. We address design and synthesis characteristics of artificial molecular structures capable of specific

molecular recognition of biological molecules. Recent developments in protein delivery have been directed towards the preparation of targeted formulations for protein delivery to specific sites, use of environmental-ly-responsive polymers to achieve pH- or temperature-triggered delivery, usually in modulated mode, and improvement of the behavior of their mucoadhesive behavior and cell recognition. Molecular imprinting and microimprinting techniques, which create stereo-specific three-dimensional binding cavities based on a biological compound of interest can lead to preparation of biomimetic materials for intelligent drug deliv-ery, drug targeting, and tissue engineering. We have been successful in synthesizing novel glucose-binding molecules based on non-covalent directed interactions formed via molecular imprinting techniques within aqueous media.

22

PL8

BRAIN DRUG TARGETING

Yılmaz ÇAPANDepartment of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.E-mail : ycapan@hacettepe.edu.tr

Inhibition of programmed cell death is important in the treatment of acute and chronic neuronal diseases. Neuropeptides as basic fibroblast growth factor (bFGF) that inhibits this process and caspase inhibitors (caspases are important enzymes in the apoptotic process) as N-benzyloxycarbonil-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-flouromethyl ketone (Z-DEVD-FMK) play important roles in the apoptotic process. But these molecules cannot pass through the blood brain barrier (BBB) when they applied systematically. Thus, design of an effective drug carrier system is needed to reach the efficient active substance concentration that provides neuroprotection in the brain. Chitosan nanoparticles which are polyethylene glycole modi-fied, targeted to the type I transferrin receptor stated in the cerebral vessels by conjugating of a monoclo-nal antibody are developed. After the systemic application, transporting to the brain and their activity are investigated for the nanoparticles which have been loaded with different active substances following the characterization of nanoparticles. The detection of transporting to the brain has done with determining the penetration of nile red, a fluorescence dye, loaded nanoparticles to the brain parenchyma by intravital fluo-rescence microscopy as a function of time. Thus it is proved that the carrier system was passing through the brain. After the ischemia infarct volume analysis, the indicator of neuroprotection, was performed for the activity assay of the substances passing BBB. For that purpose, after the administration of nanoparticles that loaded with each of two active substances, the alteration of the ischemia infarct volume versus the experi-mental group was determined. As a result, the nanoparticles which penetrated to the brain, has the ability of carrying both of the active substances without losing their activity and it was found that the nanoparticle system developed in this study is a promising carrier system for brain delivery.

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PL10

PHARMACOGENETICS/GENOMICS FOR PREDICTIVE AND PERSONALIZED MEDICINE IN POST-GENOMIC ERA

Candan HIZELCentre Jean Perrin Anti-cancereux-Clermont-frerand, France, President of C2H-Vichy Genomics, Vichy, France.Marmara University Faculty of Pharmacy, Pharmacogenetics and Drug Safety Unit, Istanbul.E-mail : candan.hizel@gmail.com

The International Human Genome Project was completed in 2003, exactly 50 years after the discovery of DNA by Dr WATSON and Dr. CRICK. The first draft of human genome has been presented in spring 2000, in Canada, what has symbolically announced the beginning of post-genomic era in the third millen-nium. Due to completion and rapid development in the field of genetics, and molecular medicine which has accelerated the use of Predictive and Personalized Medicine in routine medical and pharmacy practise for more efficient treatment of individuals. In spite of this tremendous progress which has been done dur-ing last several years, today, the physicians, have to optimize a dosage regimen for an individual patient by “trail-and error” method. This kind of blind approach may cause many important adverse drug reactions, hospitalizing problem and many avoidable deaths. In addition, inefficient treatment cost a lot of money. Both drug safety and drug efficacy could be improved by personalized medicine, which would allow phar-macotherapy to be selected for individual patients according to their genetic profiles. Pharmacogenetics/genomics, the study of how genetic differences influence the variability in patients' responses to drugs, forms the cornerstone of predictive and personalized medicine. We are in post-genomic era, it is now time…. don’t miss out on this opportunity, make your genes work for you and take control of your health!

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PL11

TRANSLATING INFORMATIONS ABOUT BIOCHEMICAL PATHWAYS INTO PRACTICAL, SMALL ORGANIC OR PEPTIDOMIMETIC THERAPEUTIC AGENTS

Salvatore GUCCIONEDepartment of Pharmaceutical Sciences, University of Catania, 95123 Catania, Italy. E-mail: guccione@unict.it

The study of biochemical pathways in living species is of central importance in many disciplines of modern life sciences and can contribute an enormous value to address challenges in the areas of drug discovery .

Systems biology is a rapidly advancing field that combines experimental and computational techniques to gain understanding of complex biological and physiological phenomena making it possible for scientists to develop smarter therapeutic strategies – for example by disrupting two or three key intersections on a biochemical network. This could lead to significant advances in the treatment of disease and help with the shrinking pipeline of pharmaceutical companies using traditional reductionist approaches to drug discov-ery.

The new policy document, produced by the Life Sciences and Medical Sciences units of the Strasbourg-based European Science Foundation (ESF) calls for a co-ordinated strategy towards systems biology across Europe. The scientists have pinpointed several key disease areas (e.g. cancer, diabetes, inflammatory diseases and disorders of the central nervous system) that are ripe for a systems biology approach. Research is con-centrated on understanding the molecular and cellular biology exploiting the knowledge gained from basic research to develop new therapeutic approaches and targets.

Protein-protein interactions (PPI) are key players in many intercellular interactions and are involved in many diseases. They are considered as potential targets for drug intervention.

Adiponectin is a relatively abundant protein secreted from the circulating adipocytes in the micrograms per milliliter range. It acutely lowers blood glucose levels through suppression of hepatic glucose levels and chronically has potent insulin-sensitizing effects through reduction of hepatic lipids. Various diseases are associated with lower plasma adiponectin levels. Specifically, type 2 diabetic subjects and patients with early-stage cardiovascular disease have lower levels of adiponectin. Recently, heme oxygenase-2 (HO-2) -/- (knockout) mice were showed to exhibit low levels of adiponectin thus resulting in insulin resistance. Interestingly, pharmacological induction of heme oxygenase-1 (HO-1) restored adiponectin levels in heme oxygenase-2 -/- animals and rescued them from the diabetic condition suggesting that the heme oxygenase system can be involved in the secretory mechanisms of adiponectin. Based on our previously published results computational methods for protein interactions prediction were used to identify the possibility for both HO-1/adiponectin and HO-2/adiponectin complexes to form at the level of the monomeric adipo-nectin. These oxygenases show, in fact, extended regions that are complementary in shape and functions to corresponding areas in adiponectin, which reflects in the strongly favourable free binding energy. The modelled complexes were used to select the interacting portions of these proteins. An additional filtering procedure was applied to select a shortlist of fragments which are likely to keep the original structural in-tegrity. The corresponding coding regions are cloned and assayed in a Two Hybrid Yeast System for a direct evaluation of their binding potential and the design of drugs.

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PL12

POTENTIAL PROTEIN DRUGS: NEW VITAMIN K DEPENDENT PROTEINS AND THEIR RECEPTORS

Fikriye URASDepartment of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, Turkey. E-mail : furas@marmara.edu.tr

Vitamin K-dependent proteins (VKDPs) have in common the requirement to be post-translationally mod-ified by carboxylation of glutamic acid (Glu) residues in order to become biologically active. The most well-known VKDPs are the coagulant factors II, VII, IX, and X. The only known biological activity of vitamin K is as a cofactor for an enzyme that catalyzes the carboxylation of the glutamic acid residues, resulting in its conversion to gamma-carboxyglutamic acid (Gla). There are many other VKDPs with important physiologic roles. Protein C and protein S are anticoagulant proteins. Activated protein C (APC) plays an important role in coagulation homeostasis. Protein S forms a complex with C4b-binding protein that negatively regulates complement on the surface of apoptotic cells. VKD coagulation factors are synthesized in the liver but some other VKDPs are made outside the liver. The VKD carboxylation system is present in most cells and tissues isolated from eukaryotic organisms indicating that VKDPs play vital roles in a variety of physiological processes distinct from blood coagulation. The protein C system, besides its well-recognized role in anticoagulation, plays a crucial role in inflammation. Inflammation and coagulation are closely linked interdependent processes. Recombinant human APC, which inhibits clots and inflammation in the human body, is the only drug approved by the U.S. Food and Drug Administration for treating severe sepsis. Indeed, the protein C system is now emerging as a novel participant in the pathogenesis of acute and chronic inflammatory diseases, such as sepsis, asthma, inflammatory bowel disease, atherosclerosis, and lung and heart inflammation, and may emerge as unexpected therapeutic targets for intervention.

VKDPs have been isolated in organic matrix of bone: osteocalcin (OC), matrix Gla protein (MGP), pro-tein S, Gla rich protein (GRP), periostin. The physiologic role of the VKDPs in mineralized tissues is still a matter of debate. MGP also has important functions in vascular biology. It is produced by vascular smooth muscle cells and prevents vascular calcification. Its clinical importance is evidenced by the development of widespread and extensive vascular calcification in MGP knockout mice. Periostin is made by mesenchymal derived cells and that expression of periostin following injury or environmental perturbations can alter normal physiological interactions between fibroblasts and myocytes that can affect collagen, fibrosis and scar mechanics. Thus, by regulating extracellular or matricellular components, such as periostin, there is realistic potential for controlling the onset and/or progression of myocardial remodeling. Periostin and the pathway it regulates might provide a target for new strategies to treat heart failure and possibly congenital heart defects in children.

Interesting class of invertebrate Gla-proteins is formed by the conantokins (Con), produced by the fish-hunting snail Conus Geographus. These snails produce a neurotoxin containing a variety of Gla proteins. They were characterized as antagonists of the N-methyl-D-aspartate (NMDA) receptor class of ionotropic glutamate receptors. Four naturally occurring conantokins have been identified and characterized to date, con-G, -T, -R, and -L. Con-G is selective for subtypes of NMDA receptors containing the NR2B subunit. This pharmacological selectivity has raised general interest in several potential clinical applications that include developing conantokin peptides as drugs for neuroprotection, pain, epilepsy, stroke, Parkinson's disease, and probing mechanisms of drug addiction. Con-G (CGX-1007) has reached phase I clinical trials for both pain and epilepsy.

Gas6 gene was cloned in a screening for genes whose mRNA was increased under conditions of growth arrest in embryonic mouse fibroblasts, and sequenced. It was named “Growth Arrest-Specific gene 6” and its expression was found to be up regulated. Gas6 protein belongs structurally to the VKDPs. It has a high

26

structural homology with the natural anticoagulant protein S. Despite the similarity in protein structure, they differ in function. They are ligands for TAM family (Tyro3, Axl and Mer) in receptor tyrosine kinases (RTKs). Gas6 can function as a growth factor that activates the Axl and stimulates cell proliferation or pre-vents apoptosis in some cells. The TAM family plays pivotal roles in a number of major cellular processes: cell survival and proliferation, immunomodulation and phagocytosis. There has been a considerable expan-sion of our knowledge of the biology of TAM receptors that has lead to a clear picture of their importance in inflammation, haemostasis and cancer, making this system an interesting target in biomedicine. Gas6 has widespread physiologic roles, important in inflammation, renal disease, sepsis, and neoplasia. Gas6 is secreted by platelets, contributing to platelet degranulation and aggregation. Gas6-deficient mice seem to be protected from thromboemoblism but do not suffer from bleeding. The lack of increased bleeding in the treated mouse model suggests that blockade of the Gas6 system may be both an efficacious and safe means of anticoagulant therapy. The Gas6 pathway and soluble TAM receptors may be a promising new pharmacological target for the treatment of thrombosis. Recognizing the importance of VKDPs in vascular biology will stimulate new areas of research and offer potential therapeutic interventions.

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PL13

UNDERSTANDING PROTEIN PROPERTIES: ESSENTIAL FOR PROTEOMICS, QUALITY CONTROL, BINDING ASSAYS AND MOLECULAR MODELLING

Simone SCHRÖDER, Institute of Pharmaceutical Chemistry, University of Braunschweig, Germany.Xi DENG, Institute of Pharmaceutical Chemistry, University of Braunschweig, Germany.Adhitasari SURATMAN, Institute of Pharmaceutical Chemistry, University of Braunschweig, Germany.Deia EL HADY, Institute of Pharmaceutical Chemistry, University of Braunschweig, Germany.Sascha KÜHNE, Institute of Pharmaceutical Chemistry, University of Braunschweig, Germany.Lukas KAMINSKI, Institute of Pharmaceutical Chemistry, University of Braunschweig, Germany.Yuanhong XU, Institute of Pharmaceutical Chemistry, University of Braunschweig, Germany.Sabine REDWEIK, Institute of Pharmaceutical Chemistry, University of Braunschweig, Germany.Hermann WÄTZIG, Institute of Pharmaceutical Chemistry, University of Braunschweig, Germany.E-mail : h.waetzig@tu-bs.de

Gel electrophoresis (GE) is one of the major techniques in proteome research, due to its unrivalled selectiv-ity. However, it is still known for its often unsatisfactory precision. Percental relative standard deviations (RSD%) up to 60% have been reported. An improvement of precision and sensitivity is absolutely essen-tial here, for proteome research and particularly for the quality control of biopharmaceuticals. Our work reflects the remarkable and completely irregular changes of the background signal from gel to gel. This ir-regularity was identified as one of the governing error sources. Fortunately this is strongly reduced by using signal detection in the near-infrared (NIR) range. In order to further investigate variance components in GE, an experimental Plackett-Burman screening design was performed. Out of seven investigated param-eters, just four showed a significant effect on some proteins, namely destaining time, staining temperature, changes of detergent additives (SDS and LDS) in the sample buffer, and the age of the gels. Employing precise control of these parameters, we have now achieved RSD%s of 3 to 4% for spot areas in repetitive experiments under favourable circumstances.

For capillary isoelectric focussing (CIEF), reproducibility of migration time and peak area with RSD% less than 10% has been obtained in a long-term measurement (n = 86). A new rinsing procedure with 3M hydrochloric acid on linear polyacrylamide coated capillary using isoelectric focusing was employed here. After each run the capillaries were rinsed with hydrochloric acid for 5 minutes, followed with water for 20 minutes (∆p = 1030 mbar each). Myoglobin, ß-lactoglobulin and ovalbumin were used as model proteins. Further the avoidance of a complete stand still of liquid within the capillary proved to be important.

In order to achieve excellent precision in the estimation of binding constants by affinity capillary electro-phoresis (ACE), electroosmotic flow (EOF) stability is the key parameter as well, especially when using proteins in binding assays. Appropriate rinsing protocols are mandatory, too. Further improvements in pre-cision have been obtained again by avoiding a complete standstill of liquid within the capillary and flushing the capillary with buffer for 25 min after each 30 consecutive runs. The precision of measurements is further improved by the use of mobility ratios to report mobility changes (RSD% less than 0.5% in a long-term measurement, n = 300-600). Apart from the importance of a stable EOF, other ACE key parameters in-clude protein concentration, drug plug length, applied voltage, and the choice of the regression method. Protein interactions with e.g. glass vials and connecting tubes have also been investigated. These interac-tions are also relevant for other techniques to characterize proteins, such as size exclusion chromatography.

Further understanding of the unique properties of proteins should enable us to further improve the preci-sion in protein quantitation. Recently, tightly bounded solvent layers in the 10 nm range have been dis-cussed [1, 2]. These layers increase the real protein size, or at least its sphere of influence. Disturbances within these sphere, e.g. by hull ion exchanges, could impair reproducibility when working with proteins.

[1] Edward Yeung, presentation on HPLC 2009 in Dresden [2] Hanno Stutz, Electrophoresis 2009, 30, 2032–2061

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PL14

PHARMACOGENETICS OF CARDIOVASCULAR DRUGS

Jacques TURGEONFaculty of Pharmacy, University of Montréal, Montréal, Québec, Canada.E-mail : jacques.turgeon.chum@ssss.gouv.qc.ca

Pharmacogenetic factors explain in part intersubject variability in drug action. Polymorphisms in determi-nants of drug pharmacokinetics and pharmacodynamics can lead to wide variability in drug response. In the course of this conference, we will review the role of polymorphisms associated with enzymatic systems (CYP2D6) in the metabolism of drugs such as nebivolol, propafenone and carvedilol. We will demonstrate how a poor metabolism status may be associated with either a decrease, an increase or no change in drug efficacy. We will demonstrate using carvedilol, candersartan and losartan how polymorphisms at the ef-fector site can modulate drug action. The role of genetic polymorphisms in CYP3As and P-glycoprotein will be demonstrated using creatinine clearance as a marker of renal function in patients undergoing heart transplantation and treatment with tacrolimus. Finally, we will demonstrate how genetic polymorphisms in membrane transporters (ABCG2 and OATP1B1) can modulate the pharmacokinetic and cardiac toxicity of rosuvastatin.

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PL15

THE INFLUENCE OF PHARMACOGENETICS FOR WARFARIN DOSE REQUIREMENTS

Véronique MICHAUDDepartment of Clinical Pharmacology, Indianapolis University, Indianapolis, United States. E-mail : veronique.michaud@epfl.ch

Wide intersubject variability is observed in dose requirements for warfarin. Genetic factors such as CY-P2C9, CYP4F2 and VKORC1 polymorphisms have been proposed to explain intersubject variability in warfarin pharmacokinetics and effects. This presentation will review concepts involved in the transfer of knowledge developed in clinical studies to the clinical situation. For instance, several studies have been per-formed in healthy volunteers or in patients with multiple exclusion criteria. In this population, a genotypic approach may be predictive of dose. In the real clinical situation, patients take multiple drugs and cannot present with exclusion criteria. Hence the role of phenotypic and genotypic measures, alone or combined, will be compared. In brief, results obtained from various studies indicate that covariables such as age, BSA, CYP2C9, CYP4F2 and VKOR genotypes are major determinants of warfarin dose requirements. How-ever, a phenotypic measure such as determination of INR at Day 4 may be extremely valuable in real clinical settings with patients taking multiple drugs.

30

PL16

MACHINE LEARNING TECHNOLOGIES IN PHARMACEUTICAL FORMULATION

Elizabeth COLBOURNIntelligensys Ltd, Springboard Business Centre, Stokesley, North Yorkshire, United Kingdom. E-mail : colbourn@intelligensys.co.uk

Development of commercial pharmaceutical formulations and processes can involve extensive experimen-tation which generates a large amount of data. Understanding such data and discovering the key relation-ships within it can be a complex process which adds considerably to the time and expense taken to get a product to market. New computational techniques such as neural and evolutionary computing have the potential to accelerate the mining and modeling of data, and can be made readily accessible to the product formulator. This presentation outlines the basis of these technologies, focusing on neurofuzzy logic, deci-sion trees and gene expression programming, and discusses their use in pharmaceutical formulation and processing.

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PL17A

PROBLEM BASED RATIONAL PHARMACOTHERAPY TEACHING: AN EXPERIENCE IN A MEDICAL SCHOOL IN TURKEY

Ersin YARIŞ, Department of Pharmacology, School of Medicine, Karadeniz Technical University , Trabzon, Turkey.Mine KADIOĞLU DUMAN, Department of Pharmacology, School of Medicine, Karadeniz Technical University , Trabzon, Turkey.E-mail: eyaris@meds.ktu.edu.tr

Rational use of drugs (RUD) is a growing need throughout the world. Rational prescribing starts by order-ing the best treatment according to the criteria of efficacy, safety, suitability and cost. However, in most of the medical schools in Turkey pharmacotherapy courses are generally given as lectures by the pharmacolo-gists. Thus, medical students and physicians often face problems in implementing theoretical pharmaco-therapy knowledge to medical practice, probably because of the classical, non-interactive teaching methods. Some medical schools have developed new models (e.g. Groningen model) for pharmacotherapy education using novel teaching methods like “problem based learning”.

We have been using this method in our school of medicine since 2004, training intern students by a one week course; 638 intern students were trained since then. Their pharmacology knowledge and communica-tion skills in prescribing practice were evaluated by an examination called “OSCE” (objectively structured clinical examination) which is not generally used in medical schools in Turkey. In this pharmacotherapy course two different clinical modules (hypertension and non-complicated bacterial cystitis) were selected. The average OSCE scores (mean ± S.E.M) for hypertension and non-complicated bacterial cystitis were increased (29.18 ± 0.54 / 56.90 ± 0.65 and 33.41 ± 0.57 / 70.88 ± 0.56, respectively) by this interactive course. This increase included knowledge, attitude and behavior of the students who were educated in phar-macotherapy lectures in phase 2 and 3.

Our experience demonstrated the benefits of a problem based pharmacotherapy teaching in the medical schools.

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PL17B

PROBLEM BASED RATIONAL PHARMACOTHERAPY TEACHING: AN EXPERIENCE IN A PHARMACY SCHOOL IN TURKEY

Hale Z. TOKLU, Department of Pharmacology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey.Gül DÜLGER, Department of Pharmacology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey.E-mail : haletoklu@marmara.edu.tr

Rational use of medicines requires that "patients receive medications appropriate for their clinical needs, in doses that meet their individual requirements, for an adequate period of time, and at the lowest cost for them and their community". The changing role of the pharmacist as a patient counselor/educator to affect patient outcome in the ambulatory settings is essential for the rational use of drugs. The need for the quali-fied pharmacy services enforces improvement of teaching methods in pharmacotherapy.

In the pharmacy schools, Pharmacotherapy courses are generally given as lectures by the pharmacologists. However pharmacy students and pharmacists often face problems in implementing theoretical pharmaco-therapy knowledge to their pharmacy practice, probably because of the disadvantages of classical and non-interactive teaching methods. In order to solve such problems, in our School of Pharmacy we developed a new pharmacotherapy course using problem based learning methods for pharmacy students. For this purpose we prepared a model checklist for evaluating different components of the dispensing behavior of a pharmacist. This checklist is called “OSPE” (objective structured practical examination) and it is used in scoring of the performances of the students. This practical examination can be friendly used for evaluation of both under and post graduate level pharmacist’s practice.

This novel, interactive pharmacotherapy teaching method is applied in our School of Pharmacy since 2008. In this course asthma module was selected. The average OSPE scores (mean ± S.E.M) of the students were increased from 23.55 ± 1.4 to 56.17 ± 1.7 by this interactive course. This increase included knowledge, dispensing attitude and behavior of the students.

Besides the feedback obtained from the students, the improvement of the dispensing scores in the post test also demonstrates the effectiveness of a course structure d on a problem based pharmacotherapy teaching.

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PL18

INHIBITORS OF HEPATITIS C VIRUS REPLICATION

Neerja KAUSHIK-BASUDepartment of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, New Jersey, USA.E-mail : kaushik@umdnj.edu

Hepatitis C virus (HCV), a blood borne pathogen is a major public health problem affecting 200 mil-lion people worldwide. Persistent HCV infection is often associated with the development of malignant chronic liver disease with sequelae including fibrosis, cirrhosis, and hepatocellular carcinoma. There are no prophylactic vaccines against HCV and available therapies for hepatitis C infection have limited ef-ficacy and multiple side-effects thus posing treatment challenges. Therefore, the development of new and improved anti-HCV therapeutic agents is an area of high priority. Studies in our lab have focused on de-veloping small molecule inhibitors targeting HCV NS5B RNA-dependent RNA polymerase (RdRp), a crucial and unique component of the viral replication machinery with no functional equivalent in the host. These studies have been accomplished in collaboration with researchers from Turkey, Brazil, India, Italy and the United States. These investigations have led to the identification of novel HCV NS5B inhibitors with structurally diverse scaffolds such as coumestan, thiazolidinones, aurintricarboxylic acid (ATA) and rhodanine. While both members of the coumestan and thiazolidinone families exhibited excellent correla-tion between their structures and activities, the coumestans exhibited greater potency, inhibiting NS5B in the low micromolar range. Further investigation of their kinetic, biochemical and binding characteristics suggested that these molecules functioned as NS5B non-nucleoside inhibitors (NNI). These parameters included noncompetitive inhibition with respect to nucleoside triphosphate (rNTP) substrates, a mixed mode of inhibition towards the nucleic acid template, and interference at the step of NS5B–RNA binary complex formation. Further, molecular docking of the most potent compound from the coumestan and thiazolidinone series within the NS5B allosteric site yielded significant correlation between their IC50 values and calculated binding energies. Studies on the thiazolidinone scaffold were further extended to synthesize novel 2,3-diaryl-1,3-thiazolidin-4-one derivatives with substantially improved NS5B inhibitory activity. Studies with ATA yielded equipotent inhibition of recombinant NS5B and HCV replicase com-plex in the submicromolar range. Importantly, ATA treatment ablated HCV RNA replication in cell cul-ture (EC50=74.8 nM) with concomitant decrease in NS5B protein synthesis, with no apparent cytotoxic effect. This study was the first to demonstrate the unique property of ATA to inhibit NS5B with a bimodal mechanism with characteristics of pyrophosphate mimics and non-nucleoside inhibitors. This aspect was supported by kinetic, biochemical, competition displacement studies and molecular modeling approach. In ongoing investigations, we have discovered novel small molecule NNI of NS5B, through application of virtual screening of ChemBridge compound database against the crystal structure of NS5B in complex with a tetracyclic indole inhibitor, resulting in the identification of two lead molecules bearing the rhoda-nine scaffold and displaying micromolar range of NS5B inhibition. We propose to follow up these leads by systematically optimizing this scaffold to develop new analogs. In addition, we have been studying HCV NS5B-host interactions towards understanding HCV replication and pathogenesis. These studies may pro-vide a new paradigm for antiviral therapy.

34

PL19

PREVENTION OF HIV BY MEANS OF MICROBICIDE FORMULATIONS. WHY DOES IT TAKE SO LONG?

Paul J. LEWIVice President, Center for Molecular Design, Janssen Pharmaceutica NV, retired.Visiting Professor; Universities of Brussels, Leuven and Antwerp; Consultant for Johnson & Johnson.E-mail : paul.lewi2@telenet.be

Prevention of infection by HIV is more effective than life-time treatment of HIV/AIDS by antiviral medi-cines, especially in regions where family budgets are less than 500 USD per year. Epidemiologists have computed that a preventive agent which is 60 percent effective could reduce infections in poor-resource regions by about 800,000 per year.

An effective defense against the spread of HIV would be vaccination. But after several unsuccessful trials there still is no effective vaccine in development today.

The classical approach to prevention is ABC, which stands for abstinence (A), being faithful to one partner (B) and condom use (C). This approach demands extensive promotion and counseling. Its acceptance is often hampered by traditional and cultural differences between regions.

Pre-exposure prophylaxis (PreP) is intended to protect non-infected persons with anti-HIV medicines when they are exposed to the virus during sexual activity or by intravenous injection. This can be achieved by injection at regular intervals of a long-acting formulation of an anti-HIV medicine. Several PreP studies on uninfected volunteers with the antiviral drug tenofovir are in course.

Administration of anti-HIV drugs to mother and child before, during and after delivery is now an effective means of preventing Mother to Child (MTC) transmission of HIV.

A highly promising preventive approach is the administration of microbicides, especially to women at high risk of infection, such as commercial sex-workers. HIV-microbicides are products that are applied topically in order to kill viruses before they enter an organism. Several HIV-microbicide formulations have being tested over the past ten years for use by women that otherwise have little control over the way to protect themselves from infection by their male partner(s). The most studied types of formulations are gels and intravaginal rings (IVR). The IVR has the advantage that it can provide protection during several months without the need for replacement. Several classes of a-specific compounds have been tested for microbicide activity, ranging from detergents, anionic polymers and pH stabilizers. Rather predictably, all of these have failed in large scale clinical trials. Preliminary studies are now in course with highly specific antiviral com-pounds, including tenofovir (PMPA) and dapivirine (TMC120). But clinical development of a specific microbicide compound is hampered by considerations regarding safety, possible selection for resistant virus and manufacturer liability.

While experts are debating these issues, millions of people are dying from AIDS which is killing a large part of the productive population in countries that are already in a vulnerable economical situation. It took only 4 years to develop penicillin and 3 years to develop the first effective polio vaccine. Why does it take more than 10 years to develop an effective HIV-microbicide? Some answers to this question will be presented and discussed.

35

PL20

MELATONIN: MECHANISMS AS AN ANTIOXIDANT AND CLINICAL APPLICATIONS.

Russel J. REITERDepartment of Cellular & Structural Biology, The UT Health Science Center, San Antonio, Texas, USA.E-mail : reiter@uthscsa.edu

My lecture will consider the functional relevance of the endogenously-produced antioxidant, melatonin, in protecting the brain against deterioration during diseases of aging. The lecture will especially discuss the importance of melatonin in reducing free radical-mediated neuronal loss in ischemia/reperfusion injury (stroke) and other conditions where toxic radical products are generated in the central nervous system.

36

PL21

THE ROLES OF MULTIDRUG RESISTANCE TRANSPORTER (MDR)-1 AND MULTIDRUG RESISTANCE – ASSOCIATED PROTEIN (MRP)-1 IN THE TREATMENT OF STROKE

Ertuğrul KILIÇDepartment of Physiology, Faculty of Medicine, Yeditepe University, Istanbul, Turkey.E-mail : kilic44@yahoo.com

Neuroprotection therapies have made limited progress in recent years. Several compounds shown to be effi-cacious in animals were tested in humans in cost-expensive trials. Unfortunately none of these studies were able to demonstrate efficacy under clinical conditions in patients. In order to establish treatments that are of benefit not only in animals but also humans, new strategies are clearly needed, comprising (i) new factors mimicking intrinsic mechanisms that the brain itself makes use of, (ii) novel delivery techniques allowing drugs to pass the blood-brain barrier more efficaciously than before, (iii) better, functionally relevant read-outs of brain recovery and (iv) strategies that are of usefulness not only in the acute, but also post-acute stroke phase. In this presentation, our recent studies, including Mdr-1 and Mrp-1 will be reviewed.

37

PL22

NEW POTENT INHIBITORS OF HUMAN PROTEIN KINASE CK2, A TARGET IN NEOPLASTIC DISEASES

Joachim JOSEInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University, Düsseldorf, Germany.E-mail : Joachim.Jose@uni-duesseldorf.de

Human protein kinase CK2 is an emerging drug target in neoplastic diseases. Upregulated CK2 activity can be found in a variety of tumors. This increased activity is assumed to suppress the induction of apoptosis and therefore contributes to neoplasia. Small molecules that would bring CK2 activity down to a non-pathogenic level could help to treat such diseases. Protein kinase CK2 is a heterotetrameric enzyme (α2β2) and a major bottleneck in inhibitor testing is the availability of the human enzyme.

In a first approach, we provided a new access to human CK2 by displaying its subunits on the surface of E. coli by Autodisplay. Whole cells of E. coli displaying CK2 could be used for inhibitor testing and IC50 values determined thereby in the standard radiometric assay were identical to those obtained with the free purified enzyme as used before.

In a second approach, we developed two novel CK2 inhibition tests to replace the radiometric assay, which exhibited some limitations when used for the determination of reaction parameters. A first assay was based on a FRET-effect between a fluorophor (EDANS) and a quencher (DABCYL) coupled to the CK2 sub-strate peptide RRRDDDSDDD. Phosphorylation of the substrate results in the blocking of cleavage by porcine elastase, and the FRET-effect is maintained. Accordingly, the EDANS based fluorescence is in-versely correlated to CK2-activity. Inhibition of CK2 by the known inhibitors Emodin or TBB was easily detectable in this FRET-based assay. A second assay was based on the quantification of the phosphorylated product peptide RRRDDDSpDDD is by capillary electrophoresis (CE)1. The phosphate group leads to a difference in charge between substrate and product and enables electrophoretic separation. Substrate and product concentrations can be quantified by UV absorption. The CE-based test was validated as well by determining the IC50 values of TBB and Emodin.

Finally, we used this assay to screen a large series of compounds including indenoindoles, benzofurans, and oxazinocarbazoles for inhibition of CK2 and identified new inhibitors with IC50 values in the nanomolar range. The most potent inhibitor was compound TF with an IC50 value of 30 nM. Treatment of prostate carcinoma cell line LNCaP with TF led to an inhibition of endogenous CK2 activity and a decrease in cell viability. Furthermore, TF was able to induce apoptosis in these cells. Selectivity profiling with 63 human protein kinases confirmed its selectivity for human protein kinase CK2.

1Gratz A, Götz, C, Jose J (2010) Electrophoresis, 31:634-640.

38

PL23

MOLECULAR TARGETED THERAPIES IN CANCER MEDICINE

Emin KANSUFACP, Institute of Oncology, Hacettepe University Ankara, Turkey.E-mail : ekansu@ada.net.tr

In recent years there has been a significant progress in the field of cancer cell biology and molecular oncol-ogy. Many researchers outlined very important processes of tumorogenesis, tumor growth, invasion and metastasis. As a result of this progress a large number of molecular abnormalities that are specific to malig-nant cells and are believed to be critical features of cancer phenotype have been described. Tumour cells acquire the ability to proliferate uncontrollably, resist apoptosis, sustain angiogenesis and evade immune surveillance.

These advances over the past decade have led to a new era in cancer therapeutics and several strategies directed to selective molecular targetsin the malignant cells. This new class of anticancer agents has been named as “targeted therapies”, because these structures target specific cellular molecules. Different from conventional chemotherapeutic agents, which mainly kill proliferating cells by interacting with general cellular processes, targeted agents are expected to affect only cells in which the specific molecular altera-tion is present, induce predominantly antiproliferative effects, and be specific for cancer cells versus normal tissues. In this context, there have been very significant progress in the anti-cancer “targeted molecules” including inhibitors for Protein Kinases including Tyrosine Kinase, and Angiogenesis, modulators of cell matrix interactions, agents that interact with the cell cycle , cell death (apoptosis), as well as inhibitors for mTOR Pathway, Transfer factors,protein trafficking regulators and recently discovered microRNAs or siR-NAs.

Several of these new therapeutic agents are showing promise in the clinic and many more are being devel-oped. The RAS proteins control signalling pathways that are key regulators of several aspects of normal cell growth and malignant transformation. They are aberrant in most human tumours due to activating muta-tions in the RAS genes themselves or to alterations in upstream or downstream signalling components. Rational therapies that target the RAS pathways might inhibit tumour growth, survival and spread. The p53 is an attractive therapeutic target in oncology because its tumour-suppressor activity can be stimulated to eradicate tumour cells. Inhibiting the p53–MDM2 interaction is a promising approach for activating p53, because this association is well characterized at the structural and biological levels. MDM2 inhibits p53 transcriptional activity, favours its nuclear export and stimulates its degradation, so inhibiting the p53–MDM2 interaction with synthetic molecules should lead to p53-mediated cell-cycle arrest or apoptosis in p53-positive stressed cells.

Angiogenesis inhibitors are a new class of drugs, for which the general rules involving conventional che-motherapy might not apply. The successful translation of angiogenesis inhibitors to clinical application depends partly on the transfer of expertise from scientists who are familiar with the biology of angiogenesis to clinicians.

Monoclonal antibodies have become the most rapidly expanding class of pharmaceuticals for treating a wide variety of human diseases, including cancer. Six antibodies including Trastuzumab (Herceptin), Rituximab (Mabthera), Alemtuzumab (Campath), Cetuximab, Gefinitib and Bevacizumab(Avastin) are now approved for cancer therapy.

Coupled antibodies to toxins or radionuclides is the most widely investigated means for increasing their antitumour activity. Two anti-CD20 radioimmunoconjugates, Bexxar (tositumomab; 131iodine) and Ze-valin (ibritumomab tituxetan; 90Yyttrium),and Mylotarg ( anti-CD33-calicheamicin conjugate) are ap-proved for cancer therapy and currently in clinical practice.

39

PL24

DRY POWDER INHALERS: CONSTRUCTION OF ANTIBIOTIC MICROPARTICLES FOR LUNG INFECTION TREATMENT.

Paolo COLOMBODepartment of Pharmacy, Università degli Studi di Parma, Parma, Italy.E-mail: farmac2@unipr.it

Oral drug therapy is standard in case of lung infections such as tuberculosis. However, poor patient compli-ance and adverse effects on long-term pushes to explore alternative routes. Inhalation dosage forms, intro-ducing formulation into airways by means of inhaled aerosols, is the most direct approach for antitubercu-lar drug administration to the target site. These dosage forms are unique since the combined formulation and delivery device constitute the inhalation product, both affecting the bioavailability of inhaled drug.

The known biopharmaceutical constraints of orally administered drug products could be less stringent with inhalation preparations, which introduce though other constrains, i.e., delivery and lung deposition. Par-ticle deposition precedes their dissolution and permeation processes and depends on the formulation and the device, this last determining the right amount of drug delivered and inhaled.

Thus, the main requirement of a pulmonary product is the respirability, determined by the capacity of the drug formulation to be metered, aerosolized and deposited by inhalation into the lung. This depends strongly on the aerodynamic diameter of the particles composing the aerosol.

Respirable microparticles can be prepared using constructive techniques such as spray drying, with the aim to control their aerodynamic behavior and targeting the deposition to active site. Dry powder inhalers con-taining microparticles with large payloads and prolonged release of anti-tuberculosis drugs can also target alveolar macrophages.

Here, focusing on the aerodynamic behavior of the generated aerosol, dry powder inhalers for dosing and aerosolizing fine powders for lung drug delivery are described. Respirable microparticles of aminoglycoside antibiotics and ciprofloxacin are illustrated and discussed in regard to pharmaceutics and biopharmaceutics aspects and formulation characteristics.

40

PL25

THE ROLE OF GAMMA SCINTIGRAPHY IN PHARMACEUTICAL PRODUCT DEVELOPMENT

Fiona MCINNES Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Scotland, UK. E-mail : fiona.mcinnes@strath.ac.uk

In the development of pharmaceutical products, pharmacokinetic studies provide useful information on the rate and extent of drug absorption in vivo, but do not explain what happens to the dosage form itself. The presentation will outline the reasons why gamma scintigraphy is a useful imaging tool for development of pharmaceutical formulations, along with a brief summary of the general technique. The main focus will be a series of specific case studies on pharmaceutical formulations where the use of gamma scintigraphy has provided critical insight into behaviour in vivo, with a particular emphasis on oral modified release tech-nologies. Examples will include the use of gamma scintigraphy both in clinical and pre-clinical studies, and correlation of in vitro data with in vivo performance.

41

PL26

NOVEL ENZYMATIC PATHWAYS IN ALZHEIMER'S DISEASE PATHOGENESIS

Domenico PRATICÒDepartment of Pharmacology, School of Medicine, Temple University, USA.E-mail : praticod@temple.edu

The enzyme 5-lipoxygenase (5-LO) catalyzes the conversion of arachidonic acid to 5-hydroxy-peroxy-eico-satetraenoic acid (5-HPETE) and subsequently to 5-hydroxy-eicosatetraenoic acid (5-HETE), which are then metabolized into different leukotrienes. The 5-LO is widely expressed in the central nervous system (CNS), where it localizes mainly in neuronal cells. Its presence has been documented in various regions of the brain, including hippocampus and cerebellum, where significant changes in its levels have been as-sociated with aging (1). Since aging is one of the strongest risk factors for developing neurodegenerative diseases such as Alzheimer’s disease (AD), it has been suggested that this pathway may be involved in its pathogenesis. To this end, we showed that 5-LO is up-regulated in the brain of a mouse model of AD-like amyloidosis, Tg2576 mice, and that AD brains had higher 5-LO protein levels than healthy controls (2). Further, we investigated the effect of 5-LO-targeted gene disruption on the brain amyloid b (Ab) pathol-ogy of the Tg2576 mice, by crossing them with 5-LO-deficient mice. In that study, we found that the ge-netic absence of 5-LO resulted in a significant reduction in their brain Ab levels and deposition (2). These changes were not associated with alterations in amyloid-b precursor protein (APP) levels or its processing via the a- or the b-secretase pathways, suggesting a possible involvement of the g-secretase. Recently, in an effort to further elucidate the neurobiology of 5-LO, we describe a novel molecular mechanism underlying the effect of 5-LO on the Ab metabolic pathway(s). First, we show that over-expression or pharmacologi-cal blockade of 5-LO results in an elevation or reduction of Ab formation, respectively. These phenomena associate with correspondent changes in the steady state levels of the g-secretase complex. Direct exposure of neuronal cells to the main 5-LO metabolic product, i.e. 5-HETE, results in a significant elevation of Ab, and protein and mRNA levels of the g-secretase complex. Additionally, it induces a significant elevation in the cAMP-response element binding protein (CREB) levels and activity. Pharmacological blockade of protein kinase A (PKA), which activates CREB, or use of dominant negative CREB mutants suppresses the 5-HETE-dependent effect on Ab and g-secretase. In vivo 5-LO inhibition or its genetic absence results in a significant reduction of CREB levels. Finally, compared with wild type littermates 5-LO knock-out mice had significant less endogenous Ab levels, a significant reduction of CREB and the g-secretase complex levels.

Taken together, these data provide the first experimental evidence for a novel biological role of 5-LO in the CNS as an endogenous modulator of Ab formation through a mechanism that involves transcription of the g-secretase complex via activation of CREB.

42

PL27

GLUTAMATERGIC SYSTEM AND ITS ROLE IN NEUROBIOLOGY OF PSYCHIATRIC DISORDERS.

Feyza ARICIOĞLUDepartment of Pharmacology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey.E-mail : feyza.aricioglu@gmail.com

Although psyciatric disorders are common in the society, very limited is known about their neurobiology. Several neurotransmitter systems have been implicated in the pathophysiology of these disorders are poorly understood but is likely to involve alterations in excitatory glutamatergic signaling molecules in several areas of the brain. Clinical and experimental evidence has shown that glutaminergic synapse appear to be dysregulated in psyciatric disorders. It has been suggested that depression, schizophrenia and some other disorders involve molecular changes in the glutamatergic pathways that mediate excitatory communication between multiple brain regions. The fascinating capacity that the central nervous system (CNS) has for encoding and retaining memories is thought to be based on activity-dependent forms of synaptic plastic-ity. Recent data also implicate abnormalities in cellular functions such as receptor trafficking and synaptic targeting, pointing that plastic changes in neurons, neurotrophic factors and cytokines were important molecules. Preclinical and clinical studies demonstrate that these factors might play a critical role. The CNS and the immune systems are known to be engaged in an intense bidirectional crosstalk, and glial cells are viewed as a crucial third element of the synapse. In addition to the pre- and the post-synaptic neurons, these cells actively contribute to neurotransmission, neuronal excitability, and several forms of synaptic plasticity, such as long-term potentiation (LTP). Such changes may contribute to the cognitive deficits common in schizophrenia. Two major forms of synaptic plasticity, LTP and long-term depression (LTD) are cellular processes involved in learning and memory. Although they produce opposite effects on synaptic excitabil-ity, both LTP and LTD can occur at the same synapse in response to different patterns of activation of NMDA receptors. Other recent evidences for abnormal expression and regulation of the NMDA receptor and its interacting molecules of the postsynaptic density (PSD), reduction in presynaptic dysbindin-1 in schizophrenia populations, an inversely correlated increase in vesicular glutamate transporter-1 (VGluT-1) and D-amino acid oxidase (DAO). The number and subunit composition of synaptic NMDA are not stat-ic, but cell- and synapse-specific changes or dysregulations can contribute to neuropsychiatric disorders.

43

ON

(S)CO2H

H2NOH

O NNN

N N

OH NNOH

(R)

CO2H

H2N(S)

H2N

CO2H

8-Me-4-AHCP Bn-Tet-AMPA Pr-NHP5G

PL28

DESIGN AND SYNTHESIS OF SELECTIVE GLUTAMATE RECEPTOR AGONISTS

Rasmus Prætorius CLAUSENDepartment of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Denmark.E-mail : rac@farma.ku.dk

This presentation will cover our recent development of subtype discriminating glutamate receptor ligands emphasizing the application of structure-based methods for design and understanding structure activity relationships. Design, synthesis and activity aspects will be covered as well as future strategies.

Glutamate (Glu) is the major neurotransmitter in the central nervous system (CNS), and the glutamate receptors (GluRs) mediating the response of glutamate are fundamentally involved in the normal functions of the CNS and in various disorders of the brain.

Glu activates both G-protein coupled receptors (metabotropic GluRs) and ligand gated ion channels (ionotropic GluRs). Compounds that interact with these receptors in a selective manner are important tools for understanding the physiological role of the highly heterogeneous group of receptors and the thera-peutic potential. However, it has proven difficult to develop highly subtype selective ligands, in particular agonists.

We have recently reported 8-Me-4-AHCP1, Bn-tet-AMPA2,3 and Pr-NHP5G4 that can discriminate cloned subtypes within the three major groups of ionotropic glutamate receptors called kainic acid, AMPA and NMDA receptors, respectively. X-ray crystallographic and molecular modeling studies were applied in the design of the compounds, but also for understanding the activity of the compounds.

[1] Clausen, R. P. et al. J.Med.Chem. 2009, 52, 4911.[2] Jensen, A. A et al J.Med.Chem. 2007, 50, 4177.[3] Vogensen, S. B. et al J. Med. Chem. 2007, 50, 2408.[4] Clausen, R. P. et al J.Med.Chem. 2008, 51,4179.

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PL29

FUNCTIONAL MACROMOLECULES FOR DRUG DELIVERY

Rana SANYALDepartment of Chemistry, Bogaziçi University, 34342 İstanbul, TurkeyE-mail : Rana.sanyal@boun.edu.tr

Synthesis of polymers with reactive functional groups is an active area of research with applications in three-dimensional scaffolds for cell growth and tissue engineering as well as drug delivery purposes [1]. This talk will highlight synthesis and utilization of dendron-polymer-dendron systems where the end-groups of the dendrons are reactive. These reactive groups can be used to conjugate drug molecules or to obtain hy-drogels. Biocompatible dendron-polymer conjugates are synthesized via copper catalyzed [3+2] Huisgen `click` reaction [2]. These macromolecules are converted into hydrogels using either the Huisgen `click` reaction or UV irradiation. Left over reactive functional groups within these hydrogel scaffolds are cova-lently functionalized with biologically relevant molecules and dye molecules for proof of concept, the final products being triple “click-click-click” hydrogels in the former case [3]. Microcontact printing techniques were employed to obtain micro patterns of the UV-hydrogels that can be conveniently functionalized.

[1] Quaglia, F. Int. J. Pharm. 2008, 364, 281.[2] Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004.[3] Altin, H.; Kosif, I., Sanyal, R. Macromolecules 2010, 43, 3801.

45

PL30

AN OLD MATERIAL FOR NEW APPLICATIONS: CARBON NANOTUBE CARRIERS FOR DRUG DELIVERY

İ. Tuncer DEĞİM, Department of Pharmaceutical Technology, Faculty of Pharmacy, Gazi University, Ankara, TURKEY.Sibel İLBASMIŞ TAMER, Department of Pharmaceutical Technology, Faculty of Pharmacy, Gazi University, Ankara, TURKEY.

Nanotechnology is rapidly developing field in especially engineering and medical sciences. Carbon nano-tubes (CNTs) are one of the most studied nanomaterials in material sciences and physics but not in medical sciences and pharmacy. Althoguh CNTs were first introduced to the market in 19911 they did not studied well enough in the area of pharmacy and they have not been used in any medical formulations. If CNTs are able to penetrate through skin layers or if they can be able to provide drug molecules on to the skin surface they can be used to deliver active substances for therapeutic purposes but exploration of their pharmaceuti-cal applications remains at a very early stage2. Recently it has been also noticed that single-walled carbon nanotubes (SWNTs) and multi walled carbon nanotubes (MWNTs) can be internalized by living cells and can pass across the skin cell membranes in cell culture studies3,4.

Therefore adsorption and desorption properties of carbon nanotubes were investigated for ibuprofen, naproxen, oxaliplatin and paclitaxel in this study. Multiwalled carbon nanotubes were also PEGylated and the effect of PEGylation was investigated.

Skin penetration experiments using CNTs and drug complexes were also done and higher penetrations were observed. Higher penetrations were observed when drugs were provided with CNTs. The physical ap-pereance of MWCNTs were determined using AFM and TEM. The tubular shapes of CNTs were clearly seen. On the figure tubular and branches of CNTs and carbon particles were observed.

As a conclusion to prepare CNTs-drug mixture is possible and it is resulted in drug adsorption. CNTs can adsorp drug molecule on their surface and it can deliver the drug and even they can release the drug by subsequent desorption. CNTs were found to be suitable material for drug transport having higher surface area and being an adsorptive material. PEGylation process was found to be effective and useful technique for further studies.

References

[1] S. Iijima, Nature 354:56 (1991).[2] C.R. Martin, P. Kohli, Nat. Rev. Drug Discov. 2:29 (2003).[3] L. Lacerdaa et al., Nanotoday 2:38 (2007).[4] A. N. Monterio-Riviere et al., Nanotoxicology 1:293 (2005).

46

PL31

HUMAN TOOTH GERM STEM CELLS (HTGSCS): A PROMISING STEM CELL SOURCE

M.E. YALVAÇ, Department of Genetics and Bioengineering, College of Engineering and Architecture, Yeditepe University, Istanbul, Turkey.D. MERCAN, Department of Genetics and Bioengineering, College of Engineering and Architecture, Yeditepe University, Istanbul, Turkey.S. AYDIN, Department of Genetics and Bioengineering, College of Engineering and Architecture, Yeditepe University, Istanbul, Turkey.A. DOĞAN, Department of Genetics and Bioengineering, College of Engineering and Architecture, Yeditepe University, Istanbul, Turkey.AA RIZVANOV, Department of Genetics and Bioengineering, College of Engineering and Architecture, Yeditepe University, Istanbul, Turkey.Department of Genetics, Faculty of Biology and Soil Sciences, Kazan State University, RussiaF. ŞAHİN, Department of Genetics and Bioengineering, College of Engineering and Architecture, Yeditepe University, Istanbul, Turkey.E-mail : fsahin@yeditepe.edu.tr

Use of stem cells in cellular therapy of neurodegenerative diseases is considered to be an alternative treat-ment. Mesenchymal stem cells (MSCs) were shown to have therapeutic effects after brain ischemia, Amyo-trophic lateral sclerosis (ALS) and spinal cord injury. It was suggested that MSCs are exerting their heal-ing function by inducing neurogenesis, vasculogenesis, and regulating immune responses in damaged area rather than replacing the diseased region of nervous system. Among MSCs sources, Bone Marrow Stem Cells (BMSCs) have been primary source so far. On the other hand, stem cells derived from third molars of tooth germs have been shown to be very proliferative and multipotent stem cell source. In a previous study, we isolated human tooth germ stem cells (HTGSCs) with MSCs characteristics from young adults (aged 11-13 years old) and immortalized them using Human telomerase reverse transcriptase (hTERT). In this study, we tested neuroprotective effects of both non-immortalized and immortalized HTGSCs on SH-SY5Y cells (a neuroblastoma cell line) and primary cortical neurons derived from mice under stress condi-tions caused by hydrogen peroxide and paclitaxcel. The results showed that MSCs` conditioned medium treatment increased viability of SH-SY5Y cells and primary neurons reducing the expression of apoptotic markers caspase3 and Annexin V suggesting that HTGSCs might be a potential stem cell source in cellular therapy of neurodegenerative diseases.

47

PL32

FROM TARGET IDENTIFICATION, HIT DISCOVERY TO LEAD OPTIMISATION: RECENT EXAMPLES FROM OUR RESEARCH

Rolf W. HARTMANN Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Germany.E-mail : rwh@mx.uni-saarland.de

The review is focussed on four steroidogenic enzymes: aldosterone synthase (CYP11B2) and cortisol syn-thase (CYP11B1) as well as the 17β-hydroxysteroid dehydrogenases 1 and 2 (17βHSD1 and 17βHSD2), all of them novel, innovative drug targets. Different strategies will be presented leading to highly potent and selective inhibitors. CYP11B2 was first propagated by our group as a target for the

treatment of congestive heart failure and myocardial fibrosis. The most potent and selective compounds discovered so far will be presented. Until now no selective CYP11B1 inhibitors have been described. The first rather potent and selective a compounds will be shown, potential therapeutics for the treatment of Cushing’s syndrome and eventually metabolic syndrome. In contrast to the mentioned CYP enzymes, the 17βHSDs do not unfold their activity on an endocrine level, they act

within the target cell (intracrine mechanism). Very potent and selective 17βHSD1 inhibitors – potential therapeutics for the treatment of breast cancer and endometriosis – will be introduced as well as up to now unpublished 17βHSD2 inhibitors for the treatment of osteoporosis.

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PL33

DEVELOPMENT OF CLINICAL PHARMACY AND PHARMACEUTICAL CARE IN TURKEY

Fikret Vehbi İZZETTİNDepartment of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey.E-mail: fvizzettin@hotmail.com

The American College of Clinical Pharmacy defines clinical pharmacy as the area of pharmacy concerned with the science and practice of rational medication use [1]. On the other hand, the activities and services of the clinical pharmacist are described as the development and promotion of the rational and appropriate use of medicinal products and devices by the European Society of Clinical Pharmacy [2]. Thus, the clinical pharmacist is a pharmacist who deals not only with dispensing and compounding, but also has expanded her/his role on rational practice of pharmacotherapy. Pharmaceutical care which is regarded as a part of clinical pharmacy at the pharmacist/patient interface can be practiced in any health care setting [3]. In order to practice pharmaceutical care, new pharmacy graduates need to be equipped with relevant clini-cal knowledge and skills. The formal clinical pharmacy education in Turkey started first in the Marmara University in 1990-91. My experience in implementation of clinical pharmacy education in Marmara Uni-versity began with the introduction of the clinical pharmacy lectures within the biochemistry courses in 1991 and improved by gradual placement of clinical pharmacy education in the syllabus through graduate and undergraduate courses. By 2010 more than 53 pharmacist received MSc degrees (23 with thesis and 30 without thesis) and 4 pharmacists received PhD degrees in Clinical Pharmacy from Marmara Univer-sity. These clinical pharmacy specialists are now providing pharmacy services promoting the rational use of drugs both at the community and hospital settings, as well as the pharmaceutical industry. Today, clinical pharmacy and/or pharmaceutical care courses are a part of the curriculum at almost all pharmacy facul-ties. The continuing education programs coordinated by different organizations offer continuing updated clinical pharmacy education to pharmacists from the whole country. Another accomplishment is that the Ministry of Health opened new positions for clinical pharmacy specialists to be employed in state hospitals. Our experience of implementation of clinical pharmacy might be a good model for pharmacy faculties in need of offering clinical pharmacy and pharmaceutical care courses to their students.

References

[1] American College of Clinical Pharmacy. The definition of clinical pharmacy. Pharmacotherapy 2008;28:816–817. [2] Description of clinical pharmacy on the website of ESCP www.escpweb.org [Accessed 20.10.09][3] ESCP News 2010;147:2.

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PL34

USAGE OF NANOTECHNOLOGY AND BIOTECHNOLOGY IN COSMETOLOGY

Gülgün YENERDepartment of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul, Turkey.E-mail : gulyen@superonline.com

Nanoparticles are defined as particles in the atomic, molecular or macromolecular levels ranging in size from 1-100 nm. The use of nanotechnology in cosmetics is not new, dates back to 1961 with the advent of lipo-some technology use to market some moisturizing creams.The cosmetic industry leads all other industries in the number of patents for nanoparticles, which have the potential to enhance sunscreens, shampoos and conditioners, lipsticks, eye shadows, moisturizers, deodorants, after-shave products, perfumes and tooth-pastes. As the commercial application of nanotechnology have increased over the past several years, there has also been an increase in the potential uses of nanoparticles in cosmetic products regulated by FDA. Us-age of nanotechnology in cosmetology especially found place in anti-aging products and sunscreens. Since skin is the first point of contact and the first line of defense for newly manufactured nanomaterials, derma-tologists have concerns about the potential health risks posed by nanotechnology. The challenge is that a standard has not been set yet to evaluate the safety and efficacy of topical products that contain nanosized particles. Existing scientific and legal regulations are considered sufficient to support the use of nanomateri-als in cosmetics. Today, there is shortcomings in legislation of nanomaterials and nanotechnology of FDA. FDA needs the legal authority which will enable its access to private information regarding to products and technologies under its supervision whenever needed.

Biotechnologists have been working with the cosmetics industry for 40 years. Plant cell cultures, fermenta-tion and enzyme reactions are used to produce new active ingredients and additives that can be incorpo-rated into cosmetic products. Moisturizers, anti-aging agents, de-pigmentation ingredients, exfoliating, anti-film foaming agents, emulsifiers and encapsulating agents are among these. Oligosaccharides, polysac-charides, proteins, lipids, enzymes and phenol derivatives are ingredients derived from biotechnological processes used in cosmetology. Preservatives, texture and encapsulation agents, surfactants, aromas can be counted as additives regarding to biotechnology in cosmetology. Artificial skins produced by biotechno-logical processes are also used for innocuousness tests of cosmetic products instead of animal testing which was banned. Biotechnology is a part of our daily life and the possibilities it offers are still far from being exhausted.

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PL35

WHAT ARE THE NOVELTIES IN COSMETIC SCIENCE: EXPECTATIONS AND RESPONSES

Yasemin YAZANDepartment of Pharmaceutical and Cosmetic Technology, Faculty of Pharmacy, Anadolu University, Eskişehir, Turkey E-mail : yyazan@anadolu.edu.tr

Cosmetic science is motivated by consumer expectations and acceptance. The favorable issue by both the young and old consumers is to look young. Understanding the mechanism of skin aging is the leading knowledge in the reduction and slowing of aging signs. Several of the recent studies claim 90% effect of environmental conditions (eg wind, chemicals, smoking, UV radiation) on skin aging while the remaining 5% is the chronological aging including genetic characteristics. Skin aging is believed to begin in early ages but appear at 40s. Skin thickness, facial frame, barrier function and inflammatory properties of skin com-pletely changes upon aging. In a wide European survey, expectations from an antiaging cosmetic product were found to be skin tonicity and brilliance rather than an anti-wrinkle effect.

Prescriptacosmetics/cosmeceuticals do not only change the characteristics of skin but also its structure and function. The need for regulations regarding this class of cosmetics will gain great importance since more and more cosmeceuticals enter the market every day.

Technical advances in molecular and synthetic biology lead to developments in the peptide field which is involved in the moisturization and elasticity of skin. The issue of peptide dermal delivery is of cosmetic concern and many researchers work on penetration of high-molecular weight peptides.

Misfunctioning of mitochondri leading to decrease in cellular energy ends up with cell damage or even death. Cosmetic technology is focused on cellular energy improver creatine and creatine kinase for their properties of skin moisturizing, tightening and elasticity and cell turn-over rate enhancing. Skin damage may be reduced, repaired or even prevented by creatine and its derivatives.

Cosmetic science is aiming to maintain the turn-over of skin cells. Increase in the rate of turn-over is the second step in this concept. Calcium, AHAs, retinol, some natural ingredients (eg resveratrol, colorless caretenoids, natural vitamin E) are some examples to materials presenting cell turn-over.

Some other materials which are regarded as the center of cosmetic attraction and promising ingredients for facial care are human growth factors, growth hormones, cosmetic analgesics, muscle relaxants, BHAs and some naturals. However, existence of such ingredients is not sufficient enough for the efficacy of products. New delivery technologies should also be made available to target skin cells or cell compartments.

Neurocosmetics, preparation of products by applicators, home and self-designed cosmetics, nutricosmet-ics, multipurpose cosmetics, advanced peptide research, cosmetic nanotechnology, luxurious products, sunscreening matducts and allocosmetics are the concepts in the future to meet the demands of cosmetic expectations and science.

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PL36

DEVELOPMENT OF DERMAL AND ORAL PRODUCTS BASED ON TEA EXTRACTS

Murat TÜRKOĞLUDepartment of Pharmaceutical Technology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyE-mail : turkoglu@marmara.edu.tr

Tea (camellia sinensis) is a valuable plant. The tea plant grows in high altitudes and therefore contains spe-cific chemicals against the UV. Its health benefits are countless and the current scientific literature concen-trates on the effects of locally applied tea products on the skin and on its systemic preventive effects against diseases including some cancers. Tea can be studied as tea leaves directly from the plant, fully fermented black tea, partially fermented oolong tea, and unfermented green tea. Tea chemistry is a popular area to uncover the elusive chemical structure of thearubigins (TR’s) and also to study the metabolism and phar-macokinetics of TR’s, theaflavins (TF’s), and the other catechins such as EGCG in man. There is strong evidence in the literature that tea extracts protect the skin against UV radiation. The TR’s and TF’s in black tea are large and hydrophilic molecules, their absorption through human skin is unlikely. Therefore, the mechanism of protection against UV must be studied further. In an in vivo study, we showed that a black tea gel protected the skin of six volunteers against UVC, UVB, and UVA from an artificial UV source. No erythema was found on the treatment sites and a total protection was achieved. The practical conclusion of this study would be that a dermal products containing tea extracts could prevent sunburn and protect against cummulative damage in skin that could lead to skin cancers. Furthermore, in the long term, the tea extracts would also prevent skin aging and wrinkles which result from the UVA exposure. There is a need for dermal products containing tea extracts. Those products must be manufactured and be made available for the public for their protection against skin cancer and premature skin aging. Black or green tea extracts can be obtained using different methods. Freeze-drying is the process of choice for manufacturing tea ex-tracts which contain polyphenols such as EC, EGC, EGCG, TF, TR, and caffeine as a partial representative of the active substances of the tea leaves. On the other hand, spray drying is more feasible and convenient alternative. The UV and IR scans and antioxidant capacity tests must be performed as the quality control tests for the extracts. There is evidence that caffeine contributes significantly to the health benefits of tea, especially for dermal protection. Caffeine shows a strong UV absorption in tea extracts between 250-300 nm that exactly corresponded to the maximum DNA damage and human erythema spectrum. For systemic administration, per oral tea tablets were formulated. Each tablet will contain a minimum of 500 mg tea extract. Administration of 1-2 tablets a day would provide the antioxidant benefits even for preventing prostate cancer.

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PL37

TOXICITY OF MYCOTOXINS

Gülden Z. OMURTAGDepartment of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey.E-Mail: gomurtag@hotmail.com

Mycotoxins are found agricultural crops such as dried fruits, cereals, feedstuffs and animal products such as milk and milk products, meat and meat products and eggs. They are potent toxic, carcinogenic, teratogenic and mutagenic chemical compounds.

The most important mycotoxins in agricultural products can be cited, such as, aflatoxins (AFs), ochratoxin A (OTA), citrinin, fumonisins, zearalenone (ZEA), sterigmatocystin and trichothecenes (TCs), such as, T-2 toxin, deoxynivalenol (DON, vomitoxin), nivalenol (NIV) and diacetoxyscirpenol (DAS, anguidine).The International Agency for Research on Cancer (IARC) has placed AFB1 on their list of probable human carcinogen as Group I. Fumonisins and TCs, are as a group of naturally occurring contaminants of foods and feedstuffs. FBs and TCs are hazardous for human and animal health and they are the most abundant in naturally contaminated agricultural products such as cereals and feed. IARC has declared F. moniliforme toxins as potentially carcinogenic to humans (class 2B carcinogens). FB1 is a cancer promoter and together with other mycotoxins may play an important role in carcinogenesis in humans.

All food analyses for the entire food chain are very important for human and animal health. Studies in this field will be useful in developing both guidelines for mycotoxins and preventing their toxic effects. Agri-cultural products are very important in Turkey’s economy, since they are consumed not only in Turkey but exported all around the world. In Turkey, the current guideline are for mycotoxins (in foods, feedstuffs, spices) aflatoxins, ochratoxin A, patulin, deoxynivalenol, zearalenone and fumonisins. The mycotoxin anal-yses offer a simple and reliable way of reducing or eliminating the risk of great economic loss in industry and the threat to human and animal health due to exposure to them.

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PL38

IN VITRO DRUG METABOLISM STUDIES: WHAT HAVE WE LEARNED FROM BIOTRANSFORMATION OF AMINES?

Mert ÜLGEN Acıbadem University, The School of Associated Health Sciences, Maltepe, Istanbul.E-mail : mert.ulgen@acibadem.edu.tr

Amines are important class of compounds used as drugs, cosmetics, additives and nutrients. They also exist in the air pollution and enviromental products. Depending on the spesific compound, the amine metabo-lism may result in either detoxication or activation. Metabolism leads in some cases to loss of carcinogenic activity while oxidation of some compounds may promote activation. The metabolites of amines can fur-ther rearrange either enzymically or chemically to give the corresponding toxic products. In the present study, we have focused on in vitro biotransformation of amines which is selected from in vitro liver micro-somal studies of my group and Prof. J W Gorrod’s group during the past 20 years. The chemical formation mechanisms and structures of metabolites from nitrogenous substrates and the final conclusions from the related papers will be discussed. In addition, the importance of the log P and pKa of the nitrogen in the metabolic processes and the chemical artifacts observed during metabolism and work-up procedures will be discussed.

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PL39

PHARMACOGENETICS IS THE IMPORTANT COMPONENT OF PHARMACOVIGILANCE

Semra ŞARDAŞ Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey.E-Mail: semrasardas@gmail.com

With growing technological advances, newer and more effective drugs are being developed and used on an ever-growing scale for people with various medical conditions. Yet early detection of population signals pertaining to drug toxicity or treatment resistance has been problematic. Oftentimes, such signals are de-tected far too late and thus markedly risk population health. A meta-analysis study has suggested that ad-verse drug reactions (ADRs) were responsible for over 100,000 deaths making them between the fourth to sixth commonest cause of death, not far behind the deaths caused by cancer and heart disease. ADRs have been a major clinical problem, accounting for increased length of stay in hospitals as well as being a drain on health resources. Serious ADRs (SADRs) reported to the US Food and Drug Administration (FDA) from 1998 through 2005 showed 2.6-fold marked increase. Less common ADRs (e.g., <0.1%) are typically detected after introduction of a new medication for routine clinical use. Epidemiology of ADRs noted above underscores the importance of this public health problem and highlights the need for improved “early warning systems” to manage the risks of prescription drugs. Both pharmacogenomics and pharma-covigilance, in essence, aim to understand "heterogeneity" and population substructure in the distribution of drug efficacy and safety signals. Despite this undeniable conceptual and practical synergy, these two disciplines and their interest groups have not converged appreciably to date. In this regard, it is notable that drugs that are frequently cited in ADR studies (59%) are reportedly metabolized by at least one enzyme with a variant genetically polymorphic allele known to be associated with altered drug metabolism. The new "hybrid" term "pharmacogenovigilance", defined as pharmacovigilance activities informed and guided by accompanying pharmacogenomics analyses. Those who engaged in pharmacogenovigilance should be considered as an integral component of the healthcare teams charged to identify the pharmacoepidemiol-ogy signals for drug toxicity and resistance with new medications. Not surprisingly, the literature is now providing the early signposts that the time has come for pharmacovigilance to take interest in pharmacoge-nomics, and vice versa . The idea of pharmacogenovigilance implementation in the therapeutic contexts will be discussed during the presentation.

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PL40

NEW MATERIALS AND TECHNOLOGIES FOR ENANTIOSEPARATION OF CHIRAL DRUGS

Bezhan CHANKVETADZEInstitute of Physical and Analytical Chemistry, School of Exact and Natural Sciences, Tbilisi State University, Chavchavadze Ave §, 0179 Tbilisi, Georgia.E-mail : jpba_bezhan@yahoo.com

The major current trend in enantioseparations is to leave the classical column size and separation scale in two opposite directions: On the one hand chromatography is becoming a valuable tool for obtaining of enantiomerically pure drugs on preparative and production scale. On the other hand, the techniques for analytical-scale enantioseparations are continuously miniaturized and microtechnologies, such as capillary and nano-liquid chromatography (CLC), capillary electrophoresis (CE) and capillary electrochromatog-raphy (CEC) are gaining importance in this field. This presentation summarizes new developments for preparation of effective chiral stationary phases for liquid phase enantioseparations as well as the innova-tions from the viewpoint of applied separation technologies.

Microanalytical techniques such as CLC, CE and CEC are progressing very rapidly. CLC and nano-LC rely on the same separation principle as HPLC but offers the advantages of miniaturisation compared to the latter one. In particular, nano-LC requires less amount of the packing material, mobile phases and samples. It is cost-effective and environmentally friendly technique and offers also the advantage of higher sensitivity when coupled to mass spectrometer.

CE offers higher peak efficiency compared to HPLC. In addition, chiral CE provides almost unlimited possibility from the viewpoint of adjustment of separation factor. Together with aforementioned concep-tual advantages CE offers some favourable technical characteristics for achieving high separation selectivity. This in combination with the inherently high separation efficiency makes chiral CE a very powerful tech-nique for enantioseparations [1-3].

Thus, in the coming years separation science may turn from the workhorse HPLC with standard size chro-matographic columns to microanalytical techniques (CLC, CE, CEC) for enantiomeric purity determina-tion of chiral drugs.

References:

1. B. Chankvetadze, Capillary Electrophoresis in Chiral Analysis, 555pp; 1997, Wiley&Sons, Chichester, UK.2. K. Lomsadze, A. B. Martinez-Giron, M. Castro-Puyana, L. Chankvetadze, A. L. Crego, A. Salgado, M. L. Marina, B. Chankvetadze, Electrophoresis, 2009, 30, 2803-2811.3. B. Chankvetadze, Electrophoresis, 2009, 30, S211-S221.

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PL41

GENDER DIFFERENCE IN SCIENCE

Berrak Ç. YEĞENDepartment of Physiology, Faculty of Medicine, Marmara University, Haydarpaşa 34668 İstanbul, Turkey.E-mail : byegen@marmara.edu.tr

It has been reported worldwide that women make up half the student population and may even be the ma-jority of graduates in some scientific disciplines. Although women are equally presented in the beginning of all scientific careers, statistics show that women then disappear or appear in disproportionate numbers at each stage of the academic ladder. In the European Union (EU) countries, only 18 % of full professors are women and 13 % of institutions in the higher education sector are headed by women and only 9 % of uni-versities have a female head. This phenomenon, which is named as the “leaky pipeline”, appears to be con-stant across national boundaries and across discipline boundaries. Similarly, the representation of women in leadership positions in scientific and professional societies, and honorary organizations is low relative to the numbers of women qualified to hold these positions. Since 1903, the Nobel Prize Assembly has awarded more than 700 men, but only 35 women. Previous studies have stated that gender discrimination originates from two major reasons: 1) social stereotypes due to certain psychological characteristics and social roles to genders (e.g. responsibility for childcare or other dependents’ care), and 2) organizational practices, which fail to promote women. Several countries, primarily the EU countries and Australia, have implemented proactive policies to tackle gender imbalance, which is not self-correcting. As Mustafa Kemal Atatürk, the founder of Turkish Republic, has emphasized the role of women in population in 1925, “Human society is comprised of two genders. Is it possible to propagate a mass, while one part of it is in inertia? Is it possible for an object to rise in the sky, while the other half of the object is bound to the land with chains?”

1. Rees T. The Helsinki Group on Women and Science: National policies on women and science in Europe. European Commission, 2002.2. A. Lawler, Beyond bias and barriers: Fulfilling the potential of Women in Academic Science and Engineering” National Academy Press. National Science Board, 2006.3. She Figures 2009: Statistics and Indicators on Gender Equality in Science, European Commission, 2009.

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PL42

DRUG DISCOVERY AND DEVELOPMENT

Esen BELLUR ATICIZentiva Chemical Products (API Plant) – Part of the Sanofi-Aventis Group, Tekirdağ, Turkey.E-mail : esen.bellur@zentiva.com.tr

In the past, man has found by trial, error or luck, which berries, roots, leaves and barks could be used for “medicinal purposes” to alleviate symptoms of illness. In the modern world, how are drugs discovered and developed? The process of drug development is difficult, complicated, risky, bureaucratic, lengthy, and costly and the end result is never guaranteed. It includes drug discovery / product development, pre-clini-cal research (microorganisms/animals) and clinical trials (on humans). Literally hundreds and sometimes thousands of chemical compounds must be prepared and tested in an effort to find one that can achieve a desirable result. According to a study published in 2006 the cost to bring a new drug, one with a new chem-ical entity (NCE), to the market ranged from 500 million to 2 billion US dollars. Consequently, much of the focus of new drug development is on chronic or serious diseases with large populations of potential users (e. g. coronary artery disease, hypertension, diabetes or hyperlipidemias.

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PL43

THE EFFECTS OF PATENT PROTECTION ON TURKISH PHARMACEUTICAL INDUSTRY

Tuncer ASLANDepartment of Research and Development, Koçak Pharmaceuticals, Çerkezköy-Tekirdağ, Turkey.E-mail: tuncerarslan2009@hotmail.com

How pharmaceutical industry affected from patent protection is explained with special examples. The ex-amples include novel processes for the preparation of Sildenafil Citrate, Sodium Alendronate Trihydrate, Lisinopril Dihydrate, Valacyclovir Hydrochloride, Losartan Potassium, Irbesartan, Candesartan Cilexetil, Zoledronic acid and Sodium Ibandronate Monohydrate. Most of the works on these drug substances are patented and for some of them, patent applications are in progress.

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PL44

ALLERGEN SPECIFIC IMMUNOTHERAPY IN ALLERGIC DISEASE

Tunç AKKOÇFaculty of Health Sciences, Marmara University, Cevizli, Kartal 34865 İstanbul, Turkey.E-mail : tuncakkoc@marmara.edu.tr

The essential role of the immune system is the ability to distinguish self from non-self while still responding to and neutralizing pathogens. The physiopathology of immune tolerance-related diseases, such as allergy, asthma or autoimmune diseases is complex and influenced by several factors. These include genetic suscep-tibility, the nature of the antigen that initiates the disease (antigen dose, time of exposure, route of exposure, and its structural characteristics) and possible co-exposure with innate immune response stimulating sub-stances, such as infections and flora bacteria 1

Since allergy is predominantly Th2 type of immune disorder, the essential mechanism to overcome atopic pathology is allergen-SIT that involves repeated administration of the sensitizing allergens by injection or mucosal route. The induction of peripheral tolerans to sensitized allergen is the main target in allergen-SIT. After successful immunotheraphy allergen-specific T regulatory cell (Treg) are generated and they suppress proliferative and cytokine responses against allergens. Also antibody class-switching occur in B cells to se-crete allergen specific IgG4 which has allergen-blocking capacity. IL-10 that is secreted by Treg cells during allergen-SIT, counter regulates antigen specific-IgE and simultaneously increase IgG4 production.

Peripheral T-cell tolerance is the key immunologic mechanism in the healthy immune response to self and non-infectious, non-self antigens. Induction of peripheral T cell tolerans by T regulatory cells is the main aim of successful allergen-SIT. It is characterized by the presence of Treg cells, suppressive cytokines such as IL-10 and also non-inflammatory Ab isotypes IgG4 and IgA are essential to overcome allergic state in immune system. Knowledge of this molecular basis is pivotal in understanding the equilibrated regulation of the immune response and anergy to immunologic agents and their possible therapeutic applications. A crucial area for the future studies is the identification of drugs, cytokines, or costimulatory molecules that induced peripheral T cell tolerance to environmental allergens.

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ORALPRESENTATIONS

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63

OP1

RESISTIN GENE EXPRESSION IN TYPE 2 DIABETIC PATIENTS HUMAN ADIPOSE TISSUES: RELATIONSHIP WITH DRUG USE

Belgin SÜSLEYİCİ DUMAN, Department of Biology, Faculty of Science and Arts, Marmara University, İstanbul, Turkey.Melek ÖZTÜRK, Department of Medical Biology, Cerrrahpaşa Medical Faculty, İstanbul University, İstanbul, Turkey.Figen Esin KAYHAN, Department of Biology, Faculty of Science and Arts, Marmara University,İstanbul, Turkey.Kağan ZENGİN, Department of Surgery, Cerrrahpaşa Medical Faculty, İstanbul University, İstanbul, Turkey.Fatma KAYA DAĞISTANLI, Department of Medical Biology, Cerrrahpaşa Medical Faculty, İstanbul University, İstanbul, Turkey.Meliha KOLDEMİR, Department of Biology, Faculty of Science and Arts, Marmara University,İstanbul, Turkey.Penbe ÇAĞATAY, Department of Biostatistics, Faculty of Science and Arts, Marmara University,İstanbul, TurkeyMustafa TAŞKIN, Department of Surgery, Cerrrahpaşa Medical Faculty, İstanbul University, İstanbul, Turkey .

Resistin, mainly expressed in adipocytes antagonizes insulin action. The exact role of resistin in the patho-genesis of type 2 diabetes mellitus (T2DM) is unknown. The aim of this study was to demonstrate site-specific adipose tissue (visceral and subcutaneous) resistin gene expression differences in individuals with and without T2DM. The relationship between conventional drug therapy (anti-hypertensive, anti-obesity, oral anti-diabetics) and adipose tissue resistin expression was also determined. Paired visceral and subcu-taneous human adipose tissues were excised during elective surgery in n=10 subjects (six with T2DM, age and sex matched). All metabolic parameters were measured in fasting state. Adipose tissue mRNA gene expression was determined by quantitative PCR (LightCycler 2.0). Transcript quantitation was performed in a Lightcycler 2.0 (Roche, USA) using the LightCycler® TaqMan® Master kit (Roche, USA) according to the manufacturer\'s instructions. Resistin expression level was also determined by immunocytochemis-try and results correlated to q-PCR results. Two different endogenous control genes were used beta-gluc-uronidase (GUSB) and TATA-binding protein (TBP). Subjects subcutaneous and visceral adipose tissue mRNA expression levels were not significantly different among T2DM and non-diabetic controls. The T2DM patients and non-diabetic controls omental resistin expression levels were found to be 0.35±0.67 and 0.17±0.2 respectively (TBP as reference gene). The T2DM patients subcutaneous resistin gene expres-sion wasn\'t observed, whereas 0.11±0.15 in non-T2DM individuals (TBP as reference gene). Resistin gene expression was not observed in both study groups subcutaneous adipose tissues when GUSB refer-ence gene was used. Omental resistin gene expression was found to be nonsignificantly (p>0.05) higher in T2DM compared to non-T2DM group (0.86±1.67 versus 0.07±0.09) with GUSB reference gene. Resistin gene expression was not found to differ significantly neither in visceral nor in subcutaneous adipose tissues with respect to any drug use. In conclusion, conventional drug therapy was found to be ineffective over site-specific resistin gene expression.

Pharmacogenetics & cardiovascular disease

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Clinical Pharmacy and Pharmaceutical CareOP2

THE EFFECT OF MEDICATION COMPLIANCE ON CONTROL OF CHRONIC DISEASES

Feras Jassim JIRJEES, College of Pharmacy, Sharjah University, UAE.Osama Mohameed IBRAHIM, College of Pharmacy, Sharjah University, UAE.

Medication non-compliance is an ignored health problem in developing countries, which have an alarm-ing average of less than 50% of patients complying with medication instructions. Such non-compliance is considered a major challenge to effective management of most chronic diseases such as diabetes mellitus, hypertension, and dyslipidemia. This problem may lead to failure of national medical plans and a rise in the cost of treatment, especially for long-term therapies for chronic diseases. Many factors contribute to the pervasiveness of this problem, such as polypharmacy, cultural differences, side effects, and so on.

Objective: To evaluate the medication compliance of patients with chronic diseases (diabetes mellitus, hy-pertension and/or dyslipidemia) and its effect on their diseases control.

Method: A cross-sectional study will be conducted for 100 patients with chronic diseases who are followed up at Al-Qassimi Hospital, Sharjah, United Arab Emirates. A validated data collection form and question-naire will be used to collect patients’ demographics, degree of knowledge about their medications and con-current diseases. Patients will be selected based on inclusion and exclusion criteria which include chronic diseased adult patients who have one or more of the major chronic conditions confirmed in the patients’ medical file (not on their initial appointment). Participants should have an active prescription for without changes for at least 90 days at the time of study entry. The study will exclude patients who have recently changed their prescription medications and patients whose medications are used for short term

Result: Data will be analyzed statistically to correlates patients’ knowledge about their medications and compliance. Also, relevant correlations between patient demographics and level of compliance and control of chronic diseases will be investigated. Results and conclusion will be presented in the conference.

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Clinical Pharmacy and Pharmaceutical CareOP3

OLD AND NEW ANTIARRYTHMICS MEDICATIONS: CURRENT DIRECTIONS

Muneera ALBABTAINPharmacy Services Department, Prince Sultan Cardiac Center, Saudi Arabia.

Cardiac arrhythmias are associated with significant morbidity and mortality. In recent years, the limited efficacy and proarrhythmic potential of classic antiarrhythmic drugs have focused attention on nonphar-macologic approaches to treatment of cardiac arrhythmias. Despite the current success of ablative therapy and implantable defibrillators, the need is still pressing for new antiarrhythmic drugs. In the last decade evolving knowledge about the molecular mechanisms of cardiac arrhythmias provides innovative strategies for discovering new cardiac antiarrhythmic drugs. Some of these have already led to the development of new compounds on the verge of clinical use, and others hold great promise for future drug development. The success of such agents depends critically on their electrophysiological selectivity, freedom from cardiac adverse effects, and general safety. This talk reviews the current evidence-based position of antiarrythmic drugs and discusses potential innovative approaches to new antiarrhythmic drug development, including the upstream therapy for prevention of electrical and structural remodeling of cardiac arrhythmia.

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Clinical Pharmacy and Pharmaceutical CareOP4

CARDIAC REHABILITATION: MEASURES AND TOOLS

Fadwa FADWA Pharmacy Services Department, Prince Sultan Cardiac Center, Saudi Arabia.

Coronary heart disease is the leading cause of death worldwide among men and women. It is also a major cause of physical disability, particularly in the rapidly growing population of elderly persons. The preven-tion of subsequent coronary events and the maintenance of physical functioning in such patients are ma-jor challenges in preventive care. Cardiac-rehabilitation (CR) programs were first developed in the 1960s, once the benefits of ambulation during prolonged hospitalization for coronary events had been recognized. Over the past 40 years, CR programs has evolved into comprehensive rehabilitation and secondary pre-vention service, delivered by multidiscipilinary staff, and based on scientific and clinical evidence. CR is now recognized as an important element in the continuum of care for patients with cardiovascular disease. The contemporary definition of cardiac rehabilitation is \'services are comprehensive, long term programs involving medical evaluation, prescribed exercise, cardiac risk factor modification, education, and counsel-ing. CR is indicated for patients who have received a diagnosis of acute myocardial infarction, those who have undergone coronary revascularization, and those with chronic stable angina. It is also appropriate for patients with chronic heart failure and those who have undergone cardiac transplantation. The goals of cardiac rehabilitation and secondary prevention are to prevent disability resulting from coronary disease, particularly in elderly persons and those with occupations that involve physical exertion, and to prevent subsequent coronary events, subsequent hospitalization, and death from cardiac causes through a program of prescribed exercise and interventions designed to modify coronary risk factors, including drug therapy.

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Clinical Pharmacy and Pharmaceutical CareOP5

SOME TACROLIMUS PHARMACOKINETIC PROPERTIES IN IRANIAN LIVER TRANSPLANT RECIPIENTS

Simin DASHTI-KHAVIDAKI, Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, IRAN.Zahra NASIRI-TOOSI, Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, IRAN.Shirin-Sadat BADRI, Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, IRAN.Sima SADRAI, Department of Pharmaceutical Sciences, Tehran University of Medical Sciences , Tehran, IRAN.Hossein KHALILI, Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, IRAN.Mohsen NASIRI-TOOSI, Department of Gastroenterology, Tehran University of Medical Sciences , Tehran, IRAN.Ali JAFARIAN, Department of Surgery, Tehran University of Medical Sciences , Tehran, IRAN.

Objectives: Tacrolimus has been used as the cornerstone of immunosuppressive regimen in most liver trans-plantation protocols. This study was designed to determine some pharmacokinetic properties of orally ad-ministered tacrolimus in Iranian adult liver transplant recipients.

Methods: Tacrolimus doses and steady state whole blood trough concentrations as well as patient demo-graphic and clinical data were obtained retrospectively using the 11 included patients’ medical records. Drug apparent clearance (CL/F) and elimination half life (t½β) were calculated.

Results: The administered dose of tacrolimus to the patients ranged 0.006 to 0.153 mg/kg/day. Tacrolimus trough concentrations varied widely within the range of 1.7 to 19.2 ng/mL. The median values of CL/F and t½β were found to be 0.42 L/h/kg and 5.9 hours, respectively.

Conclusion: The median of apparent tacrolimus clearance and elimination half life in these recipients were comparable to reported values for Asian liver transplant patients; and more than 70% of obtained tacroli-mus trough concentrations were within desired range.

68

Treatment of Several DiseasesOP6

ENHANCEMENT OF THE CYTOTOXICITY OF ANTICANCER DRUGS BY CELECOXIB IS CELL TYPE-, DRUG- AND SEQUENCE-DEPENDENT

Raafat EL-AWADY, Department of Pharmacology, Faculty of Pharmacy, University of Sharjah, UAE. Marwa EZZ, Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, EGYPT. Ekram SALEH, Department of Biochemistry, Faculty of Pharmacy, Cairo University, EGYPT.

Non-steroidal anti-inflammatory drugs (NSAID) are used since long time as analgesic-antipyretic and anti-inflammatory agents. Their role in prevention of some types of cancer such as colon cancer have been extensively studied and reported by many investigators. In addition, many studies have reported a role for NSAID in increasing the tumour killing effects of many anticancer drugs by a mechanism non-related to their anti-inflammatory action. In the present study we tested the effect of the selective COX2 inhibitor celecoxib on the cytotoxic activity of many anticancer drugs. We used a panel of tumour cell lines from different histological origins (colon, cervix, breast, brain and liver) and four anticancer drugs acting by dif-ferent mechanisms (5-FU, etoposide, cis-platin and doxorubicin). The selective COX2 inhibitor was added before, along with or after treatment of the cells with the different anti-cancer drugs. Our investigation showed that the sensitizing effect of celecoxib is cell type-, drug- and sequence dependent.

69

Pharmaceutical Analysis OP7

DEVELOPMENT AND VALIDATION OF A UPLC METHOD FOR THE DETERMINATION OF ATORVASTATIN AND ITS IMPURITIES

Naciye ARSLAN, Department of Research & Development, Bilim Pharmaceuticals, Gebze 41480 Kocaeli, Turkey Serap ODABAŞI, Departmnet of Research & Development, Bilim Pharmaceuticals, Gebze 41480 Kocaeli, Turkey İlkay KÜÇÜKGÜZEL, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey.

The objective of the current study was to develop a simple, sensitive, precise and rapid reversed-phase UPLC method and subsequent validation using ICH suggested approach for the quantitative determination of atorvastatin in the presence of its related substances and degradants in raw materials and pharmaceuti-cal dosage forms. Chromatographic separation of the analytes was achieved with good resolution on an Acquity C18 (100 x 2.1 mm, 1.7 μm particle size) UPLC column, which were maintained at 30oC±1oC. Detection of the peaks were achieved using a TUV detector at 246 nm. The optimized mobile phase was consisted of a phosphate buffer, acetonitril, THF and methanol in gradient mode. Total run time was 25 min within which API and 10 related compounds (process impurities and degradants) were separated. The described method has been extensively validated in terms of specifity, linearity, range, accuracy, precision, limits of detection (LOD) and quantification (LOQ), robustness, solution stability and system suitability. The proposed method provided linear responses within the reported concentration range for all compo-nents. The precision of the method was demonstrated using repeatability and intermediate precision by the assay RSD values which were less than 5.0 % in all instances. Stability indicating potential was established by stress tests and separation of known degradation products. Accelerated degradation studies were per-formed on API and tablets of atorvastatin according to ICH suggested stress conditions using acid, base, oxidative, thermal stress and photolytic degradation. Results showed that the developed method was able to determine the API in the presence of process impurities and degradants.

NHOHOH

O

F

O

OHN

70

Pharmaceutical Analysis OP8

A STABILITY-INDICATING UPLC METHOD FOR THE DETERMINATION OF LEVOFLOXACIN AND ITS RELATED COMPOUNDS

Hayriye İÇİN, Department of Research & Development, Bilim Pharmaceuticals, Gebze 41480 Kocaeli, TurkeySerap ODABAŞI, Department of Research & Development, Bilim Pharmaceuticals, Gebze 41480 Kocaeli, Turkeyİlkay KÜÇÜKGÜZEL, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey Esra TATAR, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

The objective of the current study was to develop a simple, sensitive, precise and rapid reversed-phase UPLC method and subsequent validation using ICH suggested approach for the quantitative determina-tion of levofloxacin in the presence of its related substances and degradants in raw materials and pharma-ceutical dosage forms. Chromatographic separation of the analytes was achieved with good resolution on a Acquity UPLC BEH C18 (50 x 2.1 mm, 1.7 μm particle size) column using UV detection at 294 nm. The optimized mobile phase was consisted of a pH 7.0 Monobasic Potassium Phosphate buffer– acetonitrile (95:5 and 78:22, v/v). Total run time was 12 min within which API and 4 (imp A, imp B, imp C, major un-known impurities) other known and major unknown impurities were separated. The described method has been extensively validated in terms of specifity, linearity, accuracy, precision, limits of detection (LOD) and quantification (LOQ), robustness, solution stability and system suitability. The proposed method provided linear responses within the reported concentration range for all components. Correlation coefficients (r) of the regression equations for the analytes were greater than 0.975 in all cases. The precision of the method was demonstrated using repeatability and intermediate precision by the assay RSD values which were less than 5.0 % in all instances. Stability indicating capability was established by forced degradation experi-ments and separation of known degradation products. Accelerated degradation studies were performed on API and tablets of levofloxacin according to ICH suggested stress conditions using acid, base, oxidative, thermal stress and photolytic degradation. During forced degradation studies, one major product was de-tected, synthesized and characterized as levofloxacin N-oxide using IR, 1H NMR, 13C NMR and mass spectral techniques.

71

Drug Delivery Systems OP9

A NOVEL ACCELERATED IN VITRO RELEASE METHOD FOR BIODEGRADABLE COATING OF DRUG ELUTING STENTS: INSIGHT TO THE DRUG RELEASE MECHANISMS

Marika KAMBERI Analytical Chemistry, Abbott Vascular Inc. ,3200 Lakeside Drive, Santa Clara, CA 95054, USA.

The major objective of the present study was to develop an accelerated in vitro release method for evero-limus/poly(lactic-co-glycolic acid) (PLGA) biodegradable DES that reflects and discriminates between many different sources of variations in the manufacturing process by introducing organic solvents in the release medium. To get further insight into the underlying drug release mechanisms, alongside release stud-ies, the surface changes of the coated stents and the molecular weight changes of the polymer upon im-mersion in the selected release media were examined by scanning electron microscopy and size exclusion chromatography. The incorporation of acetonitrile in the release medium resulted in an increase in the drug release rate due to an increment in total porosity of the matrices. The developed method reflected and discriminated between different sources of variations in the manufacturing process and correlated with the real-time release. Over 80% of everolimus release occurred within 24h. The molecular and gravimetric weights of PLGA remained unchanged throughout the dissolution period, suggesting that the polymer does not undergo degradation through cleavage of its backbone ester linkages. It is likely that the drug release occurred mainly through its diffusion. The method can be employed as a rapid quality control test during development or commercial manufacturing.

72

Drug Formulation OP10

ORALLY FAST DISINTEGRATING TABLETS: DEVELOPMENTS, TECHNOLOGIES AND CLINICAL STUDIES

Tansel ÇOMOĞLUDepartment of Pharmaceutical Technology, Faculty of Pharmacy , Ankara University, Tandoğan, Ankara.

Oral delivery is currently the gold standard in the pharmaceutical industry where it is regarded as the saf-est, most convenient and most economical method of drug delivery having the highest patient compli-ance. Tablets are the most widely utilised oral dose format. A novel tablet concept which offers ease of oral administration and benefits of increased patient compliance is the fast disintegrating/dissolving tab-lets (FDTs). FDTs have received ever-increasing demand during the last decade, and the field has become a rapidly growing area in the pharmaceutical industry. Upon introduction into the mouth, these tablets dissolve or disintegrate in the mouth in the absence of additional water for easy administration of active pharmaceutical ingredients. There have been some methods to prepare the FDTs. Many attemps having fast disintegrating behavior have been reported by lyophilizing or molding, and compressing wet powders to construct highly porous structure. However, these methods required the particular machines and the time consuming techiniques, moreover, the hardness of the products was not enough to stand up to process of packing and transportation. The tablets manufactured by any of the mentioned methods are usually com-posed of the drug and saccharides, which disintegrate in a small amount of water or saliva in the oral cavity within about 30s. Direct compression is the most convenient method because no special manufacturing facilities or granulation process is required. A major claim of FDTs is increased bioavailability compared to traditional tablets. Because of dispersion in saliva while still in the oral cavity, there can be pre-gastric absorption from some formulations in those cases where the drug dissolves quickly. Buccal, pharyngeal and gastric regions are all areas of absorption of the many formulations. However, other formulations show nearly identical plasma-concentration profiles. In this presentation some advantages, production methods and clinical studies of FDTs are summarized.

73

Drug Delivery Systems OP11

PREPARATION AND CHARACTERIZATION OF VASCULAR ENDOTHELIAL GROWTH FACTOR LOADED POLY(LACTIC-CO-GLYCOLIC ACID) MICROSPHERES

Oya SİPAHİGİL, Department of Technology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey.Emine ALARÇİN, Department of Technology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey.Murat TÜRKOĞLU, Department of Technology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey.Betül DORTUNÇ, Department of Technology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey.Hüseyin KARAGÖZ, Department of Plastic Surgery, GATA Educational Hospital, Haydarpaşa 34668 İstanbul, Turkey.Ersin ÜLKÜR, Department of Plastic Surgery, GATA Educational Hospital, Haydarpaşa 34668 İstanbul, Turkey.

Introduction: PLGA and its derivatives have been used for developing nano/microparticles encapsulating VEGF in controlled release (CR) applications (1), due to their advantages that include extended release rates up to days, weeks or months, in addition to their biocompatibility and biodegradability. In this work, we aimed to develop formulations of VEGF loaded PLGA microspheres by using the method of water-in-oil-in-water emulsification, characterize the microspheres by particle size distribution and surface morphology.

Experimental Methods: VEGF was encapsulated into PLGA microspheres using a water-in-oil-in-water emulsification method, following a protocol previously described (2). The composition of the formulations are listed in Table 1. Particles were sized by laser diffractometry using a Malvern 2000 laser sizer (Malvern Instruments Ltd., Malvern, UK). The surface morphology of the microspheres was determined by a scan-ning electron microscobe ( JEOL/JSM-6335F) after coating the microspheres with 10 nm palladium/gold on an aluminium stub.

Results:The mean particle size of free PLGA microspheres and VEGF loaded PLGA microspheres were found to be at the range of 8 µm and 159 µm. Free PLGA microspheres were found to be spherical in shape and exhibited a smooth surface morphology. VEGF loaded PLGA microspheres were also spheri-cal in shape but they exhibited porous surface morphology. Finally, it can be concluded that the VEGF loaded microspheres were successfully prepared and their physical properties showed that the microspheres could be used for further in vitro and in vivo experiments. Acknowledgements This work was supported by TÜBİTAK (Turkish Scientific and Technological Research Council) Project No: 107S219 (SBAG-3713).

References: 1.Patil, S.D., Papadmitrakopoulos, F., Burgess, D. Concurrent delivery of dexamethasone and VEGF for localized inflammation control and angiogenesis. J. Control. Rel. 117, 68-79, 2007. 2.Kim, T., Burgess, D. Pharmacokinetic characterization of 14C-vascular endothelial growth factor controlled release microspheres using a rat model. J. Pharm. and Pharmacol. 54, 897-905, 2002.

Table 1. Free and VEGF Loaded PLGA Microspheres

Formulation codes VEGF (µg) PLGA (g) RSA (mg) CH2Cl2(ml) 1. PVA (ml) MgOH(mg) 2. PVA(ml) F1 - 0.5 50 4 10 (1%) 20 150 (0.1%) F2 - 0.5 50 4 10 (2%) 20 150 (0.1%)

FV1 5 0.5 50 4 10 (2%) 20 150 (0.1%) FV2 10 0.5 50 4 10 (2%) 20 150 (0.1%) FV3 5 0.5 50 4 10 (1%) 20 150 (0.1%) FV4 10 0.5 50 4 10 (1%) 20 150 (0.1%)

74

Drug Formulation OP12

FORMULATION OF HERBAL CONDITIONER SHAMPOO AND EVALUATION OF IT’S PHYSICOCHEMICAL PROPERTIES

Gholamreza DEHGHAN NOUDEH, Pharmaceutics Research Centre, Kerman University of Medical Sciences, Kerman, Iran. Fariba SHARIFIFAR, Department of Pharmacognosy, Kerman University of Medical Sciences, Kerman, Iran. Reza JAHANBAKHSH, Department of Pharmacognosy, Kerman University of Medical Sciences, Kerman, Iran.

Nowadays the hair preparations and conditioner such as shampoos have been interested. Hair tonic and conditioner formulations containing plant extracts such as fenugreek can prevent from hair loss and retain hair conditioning. At the first the seeds of fenugreek after identification were extracted with 50% ethanol by maceration method, obtained extracts were freeze dried and stored in refrigerated. After formulation, some physicochemical properties such as pH, foam formation, viscosity, conditioning and wettability were evaluated and they compared with those of some marketing products such as Nivea, Panten, Mas and Natel. The pH of the formulated shampoo was determined 6.6. The results of its rheogram showed good thixotro-py property. High foam production and stability were observed; this may be due to the existence of saponin in the Fenugreek seeds extract. On the basis of wettability and conditioning results, formulated shampoo can represent an attractive and suitable product to marketing shampoos. The pH of formulated shampoo was determined to 6.6 which is in the acceptable range of 6-8. The formulated shampoo has also shown the better foaming effect and thixotrop activity which shows suitable viscosity. Regarding the wetting effect of shampoo in 3-5 minute indicate the fine quality of shampoo in comparison to other market shampoos. In all in the basis of wettability and conditioning data, can conclude that the formulated shampoo has the good quality for introducing to market.

75

Drug Synthesis OP13

SYNTHESIS AND AChE/BUChE INHIBITORY AND ANTIMICROBIAL ACTIVITIES OF 6-SUBSTITUTED-3(2H)-PYRIDAZINONE-2-PROPYL-3-(SUBSTITUTED/NONSUBSTITUTEDBENZAL) HYDRAZONES

A.Berna ÖZÇELİK, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Etiler, YeniMahalle, Ankara, Turkey.Mehtap GÖKÇE, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Etiler, YeniMahalle, Ankara, Turkey.İlkay ORHAN, Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330 Etiler, YeniMahalle, Ankara, Turkey.Fatma KAYNAK, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Gazi University, 06330 Etiler, YeniMahalle, Ankara, Turkey.M.Fethi ŞAHİN, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Etiler, YeniMahalle, Ankara, Turkey.

Despite an enormous amount of work, many aspects of both the etiology and physiological pathways of the disease still remain unclear. To date, the majority of current drug therapeutic approaches to Alzheimer’s disease (AD) follow the cholinergic hypothesis [1-3]. The acetylcholinesterase (AChE) has received impor-tant attention as a drug design target for the palliative treatment of the AD. On this basis, acetylcholines-terase inhibitors (AChEIs) have become the leading strategy for the development of anti-AD agents. In this study thirteen new 6-Substituted-3(2H)-pyridazinone-2-propyl-3-(substituted/-nonsubstituted benzal)hydrazone V derivatives were synthesized as acetylcholinesterase and butyrylcholinesterase inhibitors. The structures of compounds V were elucidated by IR, 1H-NMR and MASS spectra. The acetylcholinesterase (AChE) and butyrylcholinesterase (BChe) inhibitory activity of V derivatives was measured using Ellman’s method. Also antimicrobial activity of the synthesized compounds have been evaluated. The minimum inhibition concentration (MIC) values of the compounds were determined by the Microdilution method using two Gram positive bacteria (Staphylococcus aureus, Enterecoccus faecalis ) two Gram negative bacte-ria (Escherichia coli, Pseudomonas aeruginosa) and their clinical isolates and two yeast like fungi (Candida albicans, Candida krusei).

References: 1) M.F. Siddiqui, A.I. Levey, Drugs Future 24 (1999) 417-424. 2) A. Nordberg, A.L. Svensson, Drug Saf. 19 (1998) 465-480. 3) M.L. Bolognesi, A. Minarini, V. Tumiatti, C. Melchiorre, Expert Opin.Ther. Pat. 16 (2006) 811-823.

76

Drug Synthesis OP14

SYNTHESIS AND EVALUATION OF ANTIVIRAL ACTIVITY OF SOME NOVEL HETEROCYCLIC THIOUREA COMPOUNDS

Esra TATAR, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey.İlkay KÜÇÜKGÜZEL, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey.Ş.Güniz KÜÇÜKGÜZEL, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey.Sevgi KARAKUŞ, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey.Erik DE CLERCQ, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.Graciela ANDREI, Rega Institute for Medical Research, Katholieke Universiteit Leuve, Belgium. Robert SNOECK, Rega Institute for Medical Research, Katholieke Universiteit Leuve, Belgium. Christophe PANNECOUQUE, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.

Although combination therapies have been proven to decrease HIV-related mortality, there is still a need for development of novel antiretroviral agents due to the emergence of multi-drug resistance, which is a ma-jor challenge to successful therapy for individuals infected with HIV. An essential step for the replication of the virus involves reverse transcription of retroviral RNA to proviral DNA by the enzyme reverse tran-scriptase (RT). Non-nucleoside reverse transcriptase inhibitors (NNRTIs) exhibit their action by binding to a specific allosteric site, thereby resulting in non-competetive inhibition of this enzyme. Examples of such non-nucleoside inhibitors of HIV-1 RT may include widely diverging chemical classes such as di-pyridodiazepinone, bis-heteroarylpiperazines, benzoxazinones, TIBO derivatives, 1-[(2-hydroxyethoxy)-methyl]-6-phenylthio)thymine, α-anilinophenylacetamides and phenylethylthiazolylthiourea (PETT) de-rivatives (LY73497 and trovirdine). Many PETTs and analogous thiourea derivatives have been identified as NNRTIs. Based on the literature about thioureas [1, 2], a certain degree of flexibility might be required for binding to HIV-1 RT. Following these observations, we designed and synthesized a series of thioureas in which a heterocycle (1,3,4-thiadiazole or 4H-1,3,4-triazole-5-thione) is combined with the thiourea moiety, in which more flexibility is ascertained by characteristics of starting compounds or isothiocyanate adducts. Antiviral activity and cytotoxicity of the synthesized compounds were assessed by using HIV-1, HIV-2, some other selected viruses, in various cell culture systems, in the Rega Institute for Medical Re-search, Katholieke Universiteit Leuven.

77

Drug Synthesis OP15

3,6-DISUBSTITUTED 7H-1,2,4-TRIAZOLO[3,4-b]-1,3,4-THIADIAZINES AS NOVEL ANALGESIC/ANTI-INFLAMMATORY COMPOUNDS

Peri AYTAC, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye, Ankara, Turkey.Özgür GÖKTAS, Departmnet Pharmacology, Faculty of Pharmacy, İnönü University, Malatya, Turkey.Songül ÜNÜVAR, Departmnet Pharmacology, Faculty of Pharmacy, İnönü University, Malatya, Turkey.Göknur AKTAY, Departmnet Pharmacology, Faculty of Pharmacy, İnönü University, Malatya, Turkey.Birsen TOZKOPARAN, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye, Ankara, Turkey.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most useful clinical therapies for the treat-ment of pain, inflammation and inflammation-related disorders. But these drugs exhibit unwanted adverse effects including gastrointestinal PUB (perforation, ulceration and bleeding) and renal toxicity. Thus there is still a necessity to develop safer analgesic/anti-inflammatory compounds . Over the last fifteen years, we have prepared many compounds containing a 1,2,4-triazole skeleton and screened them for their analgesic/anti-inflammatory activities. In the literature survey, some 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine deriva-tives have paid attention as analgesic/anti-inflammatory compounds. We therefore considered it worth-while to design and synthesize a novel series of 4-amino-3-substituted-1,2,4-triazole-5-thiones (I) and their corresponding condensed 3,6-disubstituted 7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine derivatives (II). The starting compounds, 4-amino-3-substituted-1,2,4-triazole-5-thiones (I) were obtained by the reaction of carboxylic acids with thiocarbohydrazide at the melting temperature (160-170 ºC). 1,2,4-Triazolo[3,4-b]-1,3,4-thiadiazine derivatives (II) were synthesized by reacting them with appropriate phenacyl halo-genes in dry ethanol. All compounds were characterised by their melting points, elementary analysis, IR, 1H-NMR and mass spectra. All of the synthesized compounds were screened for their anti-inflammatory and analgesic activities. In addition, gastric toxicity and antioxidant activity on acute administration of the compounds were tested. Most of the synthesized compounds showed high activity in both carrageenan-induced oedema and acetic acid-induced writing tests with negligible ulcerogenic action. This study is sup-ported by Hacettepe University Scientific Research Fund (07-01-301-001).

Compounds

78

Drug Synthesis OP16

SYNTHESIS AND SELECTIVE INHIBITORY ACTIVITY AGAINST MAO OF 3-SUBSTITUTED BENZYLIDENEHYDRAZINE DERIVATIVES CONTAINING 2-BENZOXAZOLINONES AND MOLECULAR DOCKING STUDIES.

Nesrin GÖKHAN KELEKÇİ, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye, Ankara, Turkey.Umut SALGIN GÖKŞEN, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye, Ankara, Turkey.Samiye YABANOĞLU, Department Biochemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye, Ankara, Turkey.Gülberk UÇAR, Department of Biohemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye, Ankara, Turkey.Kemal YELEKÇİ, The Faculty of Arts and Sciences, Kadir Has University, İstanbul, Turkey.

Depression is one of the most common neuropsychiatric conditions, with a lifetime prevalence approach-ing 17%1. Compounds that inhibit monoamine oxidase have shown therapeutic value in a variety of condi-tions including affective disorders and neurodegenerative diseases2. MAO-A and MAO-B have essential roles in vital physiological processes and are involved in the pathogenesis of various human diseases. In par-ticular, selective MAO-A inhibitors are used as antidepressant and antianxiety drugs, while selective MAO-B inhibitors can be used either alone or in combination with L-DOPA, in the treatment of PD. Elevated levels of the isoform B have also been assayed in plaque-associated astrocytes of brains from Alzheimer’s patients3. Also numerous compounds among the great variety of substituted hydrazines behave as MAO inhibitors. A common structural feature of substrates and inhibitors is an amino or imino group that is assumed to play an essential role in orientation and complex formation at the active site of the enzyme4. Prompted by these findings and in continuation of our efforts in synthesizing various bioactive molecules, we have combined 5-methyl-2-benzoxazolinone with 3-substituted benzaldehydes to obtain hybride mol-ecules, and investigated the eventual role of the of the hydrazone subunit on the selective MAO inhibitor activities. Synthesized compounds showed high activity against both the MAO-A/MAO-B isoforms. It was suggested that all compounds increased the inhibitory effect and selectivity toward MAO-B. The in-hibition profile was found to be competetive and reversible for all compounds. A series of experimentally tested compounds was docked computationally to the active site of the MAO-A and MAO-B isoenzyme.

References

[1] Holtzheimer, P. E., et al, NeuroTherapeutics 3, 42-56 (2006).[2] Youdim, M. B. H., et al, Nat. Rev. Neurosci. 7, 295-309. (2006).[3] Mai, A., et al, Arkivoc 5, 32-43 (2004).[4] Chimenti, F., et al, J. Med. Chem. 50, 707-712 (2007).

This study was supported by the Novartis

79

Rational Drug DesignOP17

QSAR STUDY OF PHENYLALKYLAMINE DERIVATIVES AS MONOAMINE OXIDASE INHIBITORS*

Mustafa KÖKTÜRK, Department of Chemistry,Faculty of Arts and Sciences, Marmara University, 34722 Göztepe, İstanbul, Turkey.Safiye (SAĞ) ERDEM, Department of Chemistry,Faculty of Arts and Sciences, Marmara University, 34722 Göztepe, İstanbul, Turkey.Melek TÜRKER SAÇAN, Institute of Environmental Sciences, Bogazici University, 34342 Bebek, İstanbul, Turkey.

Monoamine Oxidase (MAO, EC 1.4.3.4) is a flavoenzyme bound to the mitochondrial outer membranes of the cells and is responsible for the oxidative deamination of neurotransmitter and dietary amines. It has two distinct isozymic forms, designated MAO-A and MAO-B, each displaying different substrate and inhibitor specificities. They are the well-known target for antidepressant, Parkinson’s disease and neuro-protective drugs. Phenylalkylamines are studied as seratonergic agents and a series of phenylalkylamines have been shown to be selective MAO-A inhibitors. The purpose of this work is to develop QSAR models for 32 phenylalkylamine derivatives whose MAO-A inhibitory activities pIC50 are listed in the literature. In the present study, structures of 42 phenylalkylamine were optimized with Density Functional Theory (B3LYP/6-31G*) and E-HOMO, E-LUMO, dipole moments were calculated using Spartan04 software. In addition, 1273 and 151 descriptors were obtained from Dragon 5.4 and Codessa2.2 software, respec-tively. Heuristic algorithm running in Codessa 2.2 was used to decrease the number of descriptors. The descriptors appearing in 4-parameter linear model are: R7m, H3u, Mor07v, E3s. Statistical parameters of the developed model are: n=32, r2 = 0.861, F=41.75, .S.E. =0.384. To test the validity of the model, data set was divided into training (25 molecules) and test set (7 molecules). Training set model with the same descriptors had a high correlation (r2 = 0.851, F=28.46, S.E.=0.402). For test set the plot of calculated versus experimental values had also a high correlation coefficient (r2 = 0.909). The developed model can be used to predict the MAO inhibitory activity of the phenyl alkyl amines whose pIC50 values are not avail-able. *We acknowledge TUBITAK-ARRS for the financial support o project no:108Y119.

80

Rational Drug DesignOP18

INVESTIGATION OF LIGAND RECOGNITION BY BETA-LACTAMASES

Pinar KANLIKILIÇER, Department of Chemical Engineering, Boğaziçi University, İstanbul, Turkey.Nilay BUDEYRİ, Department of Bioengineering, Marmara University, İstanbul, Turkey.Berna SARIYAR AKBULUT, Department of Bioengineering, Marmara University, İstanbul, Turkey. Elif OZKIRIMLI ÖLMEZ, Department of Chemical Engineering, Boğaziçi University, İstanbul, Turkey.

Bacterial production of beta-lactamase is a major cause of antibiotic resistance, which is a growing health threat especially in hospital infections, and therefore beta-lactamase inhibition is an important area of re-search. Beta-lactamases confer resistance to their host organism by hydrolyzing the beta-lactam ring of beta-lactam antibiotics such as penicillin. There are more than 700 types of beta-lactamases, which share a common fold, and TEM-1 and SHV-1 beta-lactamases are the two most prevalent. Here, we report molec-ular dynamics simulations and in vitro kinetic studies on beta-lactamase ligand recognition. As a first step in deciphering the ligand recognition mechanism of TEM-1 and SHV-1 beta-lactamase and to describe the observed difference in their affinity to the beta lactamase inhibitor protein (BLIP), the structural and ener-getic aspects of TEM-1 and SHV-1 in complex with BLIP are examined using molecular dynamics simula-tions. The binding affinity and inhibitory potential of various BLIP derived peptides are investigated by repeating the simulations on TEM-1 - peptide complexes. Finally, the binding kinetics of the peptides and their inhibitory potential are investigated using in vitro experiments. Funding by TUBITAK(108M644, 109M229) and Bogazici University BAP (09HA504P) are gratefully acknowledged.

TEM-1 beta-lactamase correlations

81

Treatment of Several Diseases OP19

DIABETES MELLITUS MANAGEMENT AND ITS IMPLICATION TO CARDIOVASCULAR DISEASE

Muneera ALBABTAINPharmacy Services Department, Prince Sultan Cardiac Center, Saudi Arabia.

Diabetes mellitus is becoming more prevalent in the Saudi Arabian population. The estimated number of patients with diabetes, presently about 170 million people, is expected to increase by 50-70% within the next 25 years. Diabetes is responsible for acceleration and worsening of atherothrombosis. Major cardiovas-cular events cause about 80% of the total mortality in diabetic patients. Results of the 10-year follow-up of the UKPDS suggest that tight glycemic control of younger, newly diagnosed patients with type II diabetes may have CV benefits many years later. Although past epidemiological studies have shown a relationship between high glycated hemoglobin levels and CV events in patients with type 2 diabetes, recent large ran-domized clinical trials have found that intensive glycemic control either has no impact on CV outcomes or even worsens them. On the other hand, the American Diabetes Association made recommendations that diabetes patients at a high risk of cardiovascular events should be on a low-dose aspirin regimen. However, more recent data show that aspirin has no clinical benefit to the diabetic patient as compared with a control group. Finally, lifestyle modifications and antihyperglycemics play a vital role in controlling diabetes and increasing the insulin sensitivity of tissues and thus decreasing the cardiovascular risk factor of diabetes. Much of the information presented in this lecture demonstrates current recommendations in the era of primary prevention of CVD in diabetic patients as well as the need for more and better worldwide efforts to be implemented for the primary prevention of cardiovascular events in prediabetic and type II diabetes patients.

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New Biomarkers for Prediction of Diseases OP20

PLASMA MATRIX GLA PROTEIN (MGP) LEVELS IN PATIENTS WITH CORONARY ARTERY DISEASE

Erdem YILMAZ, Department of Biochemistry,Faculty of Pharmacy, Marmara University, 34722 Göztepe, İstanbul, Turkey.Abdullah Kemal TUYGUN, Cardiovascular Surgery, Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital, İstanbul, Turkey.Ozlem OZAKPINAR, Department of Biochemistry,Faculty of Pharmacy, Marmara University, 34722 Göztepe, İstanbul, Turkey.Fikriye URAS, Department of Biochemistry,Faculty of Pharmacy, Marmara University, 34722 Göztepe, İstanbul, Turkey.

Background/Aims: In Europe every year approximately 700.000 cardiac arrrest is ocurring. Matrix Gla Pro-tein (MGP), which is a vitamin K–dependent protein, has been expressed in lung, kidney, heart, cartilage and arterial walls. Biochemical and genetic studies have established MGP as an inhibitor of calcification in cartilage and blood vessels. The protective effects of MGP in arterial calcification were demonstrated in studies with warfarin-treated rats and MGP knockout mice. Our aim is to examine that if MGP is a pre-venting factor for coronary artery disease.

Material and Methods: Plasma MGP levels were determined by ELISA kit from Biomedica (Vienna, Aus-tria) in 48 patient who are preop bypass with coronary artery disease and 42 healthy subjects. Mann-Whit-ney U test was performed to assess whether observed differences between groups were statistically signifi-cant (P<0.05). Results: The plasma levels of MGP (22.03±3.89 nM ) were significantly lower in patients with preop by-pass than those of the control group (17.59±5.43 nM ) (P<0.001).

Conclusion and Discussion : We obtained the preliminary results indicating that plasma MGP levels were significantly lower in patients with coronary artery disease. As a result, MGP might be an atherosclerosis preventing factor. Further studies will reply the question whether there is a relationship between MGP and coronary artery disease.

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Clinical Pharmacy and Pharmaceutical CareOP21

RADIOPHARMACY APPLICATIONS IN HOSPITAL PRACTICE

Mine SİLİNDİR, Department of Radiopharmacy, Faculty of Pharmacy,Hacettepe University, 06100 Sıhhiye, Ankara, TurkeyA. Yekta ÖZER, Department of Radiopharmacy, Faculty of Pharmacy,Hacettepe University, 06100 Sıhhiye, Ankara, Turkey

With the development in imaging modalities, it is needed to develop special target spesific contrast agents for obtaining better images. However, some conventional but cheap and effective radiopharmaceuticals like kits are also used in hospital practice. Technetium (Tc-99m) labeled kits are frequently used depending on the ideal radionuclidic properties. These kits are used for many purposess like bone scintigrapy, kidney im-aging, lymph node imaging, cardiac perfusion studies, brain imaging etc. Blood volume measurement, ery-trocyte and leucocyte labeling also have been studied commonly in Nuclear Medicine Departments of hos-pitals. Radiopharmacy discipline joins the practices of pharmaceutical technology and nuclear radiation for the preparation, dispending and control of radiopharmaceuticals that can be used for imaging, metabolic and functional studies for diagnosis, therapy and/or staging diseases. Radiopharmaceuticals should be pre-pared and released by the permission of qualified person (radiopharmacist) in hospitals. Radiopharmacist have to know working rules in a hot lab (GRP), labeling procedures of kits, quality control (QC), release of radiopharmaceuticals and radiation protection rules. Depending on the administration to human, it is very essential to do some QC tests on radiopharmaceuticals in hospitals. QC tests indicate some properties of radiopharmaceuticals such as purity, potency, definition of the product, biological safety anf efficacy and besides depending on the activity some additional tests like radionuclidic purity, radiochemical purity and radioassay have to be implemented. Depending on the frequently use of kits and radionuclides having short half-life like Tc-99m in routine hospital preparations, some of these tests have to be completed after the release of the radiopharmaceuticals.

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New Biomarkers for Prediction of Diseases OP22

FAT MASS AND OBESITY ASSOCIATED GENE EXPRESSION IN HUMAN OMENTAL AND SUBCTANEOUS ADIPOSE TISSUE

Belgin SÜSLEYİCİ DUMAN, Department of Biology, Faculty of Science and Arts, Marmara University, İstanbul, Turkey.Kağan ZENGİN, Department of Surgery, Cerrrahpaşa Medical Faculty, İstanbul University, İstanbul, Turkey.Figen Esin KAYHAN, Department of Biology, Faculty of Science and Arts, Marmara University,İstanbul, Turkey.Meliha KOLDEMİR, Department of Biology, Faculty of Science and Arts, Marmara University,İstanbul, Turkey.Penbe ÇAĞATAY, Department of Biostatistics, Faculty of Science and Arts, Marmara University,İstanbul, Turkey.Mustafa TAŞKIN, Department of Surgery, Cerrrahpaşa Medical Faculty, İstanbul University, İstanbul, Turkey.

Fat mass and obesity (FTO) associated gene has been shown to strongly correlated with obesity in humans. The function of FTO protein has not been studied experimentally. Our aim was to investigate the FTO gene expression in subcutaneous and intra-abdominal adipose tissues from morbidly obese (BMI>40) T2DM and non-T2DM individuals. Although, all individuals were morbid obese only 3 were using an-ti-obesity drugs. Paired intraabdominal and subcutaneous were excised during elective surgery in n=10 subjects (six with T2DM, age and sex matched). All metabolic parameters were measured in fasting state. Adipose tissue mRNA gene expression was determined by quantitative PCR (LightCycler 2.0). Transcript quantitation was performed in a Lightcycler 2.0 (Roche, USA) using the LightCycler® TaqMan® Master kit (Roche, USA) according to the manufacturer\'s instructions. Beta-glucuronidase (GUSB) was used as endogenous control gene. Subcutaneous and visceral adipose tissue expression levels were found to differ significantly (p=0.002) among T2DM and non-diabetic controls. The T2DM patients and non-diabetic controls omental-subcutaneous resistin expression levels were found to be 31.99±62.09/2.63±0.58 and 2.53±1.02/4.24±2.16 respectively (GUSB as reference gene). The anti-hypertensive (p=0.035) and anti-diabetic (p=0.02) drug use was found effective, whereas antiobesity drugs didn’t change FTO gene expres-sion. As a result, FTO may be a candidate gene for T2DM acting via obesity.

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New Biomarkers for Prediction of Diseases OP23

RELATIONSHIP BETWEEN ENOS GLU298ASP POLYMORPHISM IN ACUTE CORONARY SYNDROME AND CORONARY HEART DISEASE PATIENTS

Belgin SÜSLEYİCİ DUMAN, Department of Biology, Faculty of Science and Arts, Marmara University, İstanbul, Turkey.Yurdanur ÇEBİ, Department of Medical Biology and Genetics, Medical Faculty, İstanbul Bilim University, İstanbul, Turkey.Melike ERSÖZ, Department of Biology, Medical Faculty, İstanbul Bilim University, İstanbul, Turkey.Penbe ÇAĞATAY, Department of Biostatistics, Medical Faculty, İstanbul University,İstanbul, Turkey.Mehtap KILIÇGEDİK, Department of Cardiology, Medical Faculty, İstanbul Bilim University, İstanbul, Turkey.Çavlan ÇİFTÇİ, Department of Cardiology, Medical Faculty, İstanbul Bilim University, İstanbul, Turkey.

The objective of this study was to evaluate the effects of eNOS Glu298Asp polymorphism over acute coro-nary syndrome (ACS) and coronary heart disease (CHD) for the first time in a Turkish study group. We have analyzed the genotype frequencies of the Glu298Asp polymorphism of the eNOS gene in 17 ACS patients (10 men, 7 women), 13 CHD patients (8 men, 5 women), and 47 controls (13 men, 34 women), who were angiographically proven to have normal coronaries. The demographic, biochemical and left ven-tricule systolic dysfunction data of the ACS, CHD patients and controls were analyzed as a function of eNOS Glu298Asp genotypes. The eNOS gene Glu298Asp polymorphism frequencies for Glu/Glu, Glu/Asp and Asp/Asp genotypes were respectively 70.6%, 23.5%, 5.9% in subjects with ACS; 76.9%, 15.4%, 7.7% in subjects with CHD and 17%, 51.1%, 31.9% in the control group. Significant difference was ob-served in genotype frequencies between the study groups for Glu298Asp polymorphism (p≤0.001). The Asp/Asp genotype frequency was found to be the lowest in both ACS and CHD patients. Whereas in the controls the Glu/Asp genotype frequency was found to be significantly higher than Glu/Glu and Asp/Asp genotypes (p≤0.001). The genotype frequency distributions (86.4% Asp298Asp versus 13.6% Glu298Glu) were found to be significantly different among angiotensin receptor blocker users (p≤0.05).

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Clinical Pharmacy and Pharmaceutical CareOP24

ASSESSMENT OF THE 5TH GRADE PHARMACY STUDENTS’ OPINIONS ON THE FIRST-TIME HELD ‘PHARMACY PRACTICE I’ COURSE OF THE SECOND CYCLE

Basak SOYDEĞER CARLI, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.Yakup KASAP, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.Betul OKUYAN, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.Sule APIKOGLU RABUŞ, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.Mesut SANCAR, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.Fikret Vehbi İZZETTİN, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.

Background: After reassessment of the undergraduate pharmacy curriculum according to the Bologna agreement for educational equivalence across Europe, the undergraduate program is now 5-years, since 2005. The second cycle of the pharmacy education in Marmara University Faculty of Pharmacy covers the “Pharmacy Practice I & II” courses. In the 2009-2010 fall semester 5th year pharmacy students’ attended to the “Pharmacy Practice I” course for the first time. This study aimed to assess the 5th year students’ opin-ions and suggestions about this course, in order to act as a guide for quality education.

Methods: During the “Pharmacy Practice I” course the students attended to practical courses at communi-ty pharmacy (2 days/wk; 6 weeks) and at various hospital wards (2 days/wk; 6 weeks). A self-administered survey questioning the students’ opinions on “Pharmacy Practice I” course that was structured at the Clini-cal Pharmacy Department was handled to all 5th year pharmacy students (n=110).

Results: The pharmacy students reported that the owner pharmacist of the study-pharmacy was helpful to them during the course. Most of the students (68%) thought that the course positively changed their atti-tudes towards pharmacy profession. Most of students pointed out that their expectations from “Pharmacy Practice I” were fulfilled. Of the students 77% had ‘finance, management and professional competence-related’ concerns regarding their professional future. Majority (69%) of the students claimed that their pharmacist provided clinical pharmacy services such as patient profiling and to a lesser extent, patient edu-cation and drug information. All of the students appreciated the service provided by the instructors and teaching assistants of this course. Of the students, 95% thought that this course contributed to their future professional life.

Conclusion: The results of this survey yielded that the “Pharmacy Practice I” course coordinated under the auspices of the Clinical Pharmacy Department was very beneficiary for the students.

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New Biomarkers for Prediction of Diseases OP25

DOES PHOTOTHERAPY CAUSE DNA DAMAGE IN PSORIASIS PATIENTS ?

Diren BEYOĞLU, Department of Toxicology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.Zehra AŞIRAN SERDAR, Department of Dermatology, Haydarpasa Numune Training and Research Hospital, İstanbul, Turkey İlkin ZİNDANCI, Department of Dermatology, Göztepe Training and Research Hospital, İstanbul, Turkey Gülden Z. OMURTAG, Department of Toxicology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.Semra SARDAŞ, Department of Toxicology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.

Psoriasis is a common, chronic, multifactorial and inflammatory disease characterized by T-cell mediated hyperproliferation of keratinocytes. Epidemiological studies from around the world have estimated the prevalence of psoriasis to be anywhere from 0.6-4.8%. When topical treatment are inadequate or more than 5% of the body surface area is involved, phototherapy constitutes are preferred as treatment before considering other systemic treatments in psoriasis. The combination of oral 8-methoxypsoralen followed by UVA (PUVA) used as an effective therapy against psoriasis has been reported to cause mutagenic and carcinogenic effect. Therefore, narrowband UVB (N-UVB) phototherapy is widely used as efficient thera-peutic option to moderate-severe psoriasis. Recent reports about safety and efficacy of N-UVB and other treatment options (wide-spectrum UVB and PUVA) have been widely discussed for efficacy and clinical consequences. However, there are few studies on the genotoxic effect of these treatments. The present study was aimed to evaluate the possible DNA damage in psoriasis patients (n=13) before and after 20 sessions of N-UVB treatment by using alkaline comet assay. Mean tail %DNA for each cell was calculated as 100-Head %DNA. The mean tail %DNA damage increased highly after 20 sessions of N-UVB treatment (13.59 ± 1.57) as compared with the pre-treatment values of psoriasis patients (8.62 ± 1.11).

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POSTERPRESENTATIONS

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PP1

PREPARATION AND EVALUATION OF THE ANTIBACTERIAL ACTIVITY OF NITROARYL THIADIAZOLE-GATIFLOXACIN HYBRIDS

Mohammad Hassan MOSHAFI, Department of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, Tehran University of Medical Sciences, Tehran, Iran.Alireza FOROUMADI, Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Tehran University of Medical Sciences, Tehran, Iran.Hamid FOROUTANFAR, Department of Biotechnology, Faculty of Pharmacy and Pharmaceutical Sciences, Tehran University of Medical Sciences, Tehran, Iran.

During recent years much attention has been devoted to the synthesis of new fluoroquinolones and to their antibacterial activity. Antibacterial resistance is now well documented for many pathogens, and stud-ies with a variety of bacteria indicate that resistance can develop within just a few years. Resistance against many members of fluoroquinolones, particularly older ones, such as ciprofloxacin 1, is increasing. Further advances in quinolone field are likely to provide better compounds capable of dealing with the resistant strains. In our continuing efforts to find new quinolone nitroarylthiadiazole hybrids, a number of gatifloxa-cin analogues containing a 5-(nitroaryl)-1,3,4-thiadiazole moiety attached to the piperazine ring at C-7 position were prepared and evaluated in vitro by the conventional agar dilution method against a panel of Gram-positive and Gram-negative bacteria . Among synthesized compounds, nitrofuran analog contain-ing a [5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl] moiety exhibited more potent inhibitory activity against Gram-positive bacteria including S. epidermidis (MIC = 0.0078 µg/mL), B. subtilis (MIC = 0.0039 µg/mL), E. feacalis (MIC = 0.125 µg/mL) and M. luteus (MIC = 0.125 µg/mL), respect to other synthesized compounds and reference drug gatifloxacin.

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PP2

IMPACT OF PERSONALIZED MEDICINE ON CLINICAL STUDIES

Latif ÖZBAY, GCP/GLP Center, Yeditepe University, Acıbadem, İstanbul, Turkey. Durişehvar ÖZER ÜNAL, Faculty of Pharmacy, Yeditepe University, Kayışdağı, İstanbul, Turkey.

Genetic differences between people contribute to inter-individual variations in the response to many com-monly used drugs. The main goal of personalized medicine is to improve clinical outcomes such as drug safety and efficacy. Most drugs are lipophilic compound that are mainly metabolized by oxidation catalyzed by the cytochrome P450 (CYP) enzymes in the liver. Drug metabolizing enzymes have polymorphisms. Polymorphism is distinguished by phenotype and genotype. Individuals having normal metabolic activity are called extensive metabolizer and defective individuals are called poor metabolizer. Individual genotype and phenotype information will inform us to whether the patient is at risk for non response or drug associa-teted toxicities. Identification of genetic polymorphisms will help clinicians to improve responses of drug and decrease toxicity. Individual genetic variability effects on pharmacokinetic parameters and metaboliza-tion will discussed in this study.

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PP3

EFFECT OF VITAMIN D RECEPTOR GENE POLYMORPHISM ON BONE MINERAL DENSITY IN TURKISH POSTMENOPAUSAL WOMEN

Özlem KURT, Department of Biochemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, Turkey.Hülya YILMAZ AYDOĞAN, Department of Molecular Medicine, Institute for Experimental Medicine, Istanbul University, İstanbul, Turkey.Turgay İSBİR, Department of Medical Biology, Medical Faculty, Yeditepe University, İstanbul, Turkey.Mehmet UYAR, Department of Phsycial Medicine and Rehabilitation, Uskudar State Hospital, İstanbul, Turkey. Ayşe CAN, Department of Biochemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, Turkey.

Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Vitamin D receptor (VDR) gene has been suggested as possibly implicated in reduced bone mineral density (BMD) in osteoporosis. The present study investigated the relation between FokI and TaqI polymorphisms of VDR gene and BMD in postmenopausal women from Turkey through RFLP-PCR technique. BMD was measured at the lumbar spine and hip (femoral neck, trochanter and Ward’s triangle) by dual-energy X-ray absorptiometry (DXA). 53 control, 112 osteopenic and 81 osteopo-rotic postmenopausal women were recruited. The BMD, the body mass index (BMI) values and the ratio of dietary protein intake were found to be lower in osteopenic and osteoporotic women as compared to healthy women (p<0,001; p<0,001; p<0,01, respectively). Statistical analysis revealed no difference in the VDR genotype frequencies within three groups (p>0,05). Subjects with VDR FokI FF genotype had lower BMD values at the femoral neck compared to subjects with Ff genotype, and the presence of \'f\' allel was associated with a significantly higher BMD values at the femoral neck than the values of non-carriers in osteoporotic women (p<0,05). In osteopenic women, subjects with ff genotype had higher BMD values at the lumbar spine and femoral neck compared to the values of subjects with FF genotype and Ff genotype; however, the differences were not statistically significant (p>0,05). No significant effect of the VDR TaqI genotypes on BMD values was found at any site in study groups (p>0,05). Our results suggest that VDR FokI poymorphism may contribute to the determination of BMD in Turkish postmenopausal women.

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PP4

THE EFFECT OF ACTIVE SITE TYROSINE ORIENTATION ON BINDING OF NEW PYRAZOLINE DERIVATIVES TO MAO-B: MOLECULAR DOCKING AND DYNAMIC SIMULATIONS *

Seyhan TÜRKKAN, Department of Chemistry,Faculty of Arts and Sciences, Marmara University, 34722 Göztepe, İstanbul, Turkey.Safiye ERDEM, Department of Chemistry,Faculty of Arts and Sciences, Marmara University, 34722 Göztepe, İstanbul, Turkey.Kemal YELEKÇİ, Department of Chemistry, Kadir Has University, İstanbul, Turkey.Demet AKTEN, Department of Chemistry, Kadir Has University, İstanbul, Turkey.Nesrin GÖKHAN, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye Ankara, Turkey.

Monoamine Oxidase is a flavoenzyme bound to the mitochondrial outer membranes of the cells and is responsible for the oxidative deamination of neurotransmitter and dietary amines. The crystal structures of MAO-A and MAO-B show that in both enzymes, two aromatic tyrosine residues are situated in an ap-proximately parallel orientation in re-face of FAD. Previous studies showed that this aromatic cage plays an important role in MAO catalysis. Molecular dynamic simulations have been widely used to obtain differ-ent states of the target receptor including the real bioactive conformation. In this study, we used NAMD v2.63 software as our MD simulation tool. MD simulation was performed at constant NPT at 310 K using Langevin dynamics for all non-hydrogen atoms, with a Langevin damping coefficient of 5 ps-1. Prior to Molecular Dynamics, the system was subjected to 10,000 steps of energy minimization using conjugate gradient algorithm, followed by a total of 10 ns of Molecular Dynamics simulation. It was observed that Tyr398 residue fluctuates between perpendicular and parallel orientations with respect to Tyr435 in MD simulation. Two MD frames having nearly parallel or perpendicular orientation were selected from the production phase of the trajectory and used for molecular docking applications of four chiral pyrazoline derivatives. Autodock 4.2 was employed to perform molecular docking. The molecular docking results showed that the binding mode of the ligands is closely related to the orientation of the Tyrosine rings such that when Tyr398 is perpendicular, all ligands bind the enzyme at the si-face of the FAD cofactor which suggests that the perpendicular conformation of Tyr398 retards the ligand binding to re-face of FAD. On the other hand, in the case where tyrosines are nearly parallel as in the x-ray structure, all four ligands bind to the re-face of FAD.

*The authors acknowledge TÜBİTAK for the support of the project no108T232

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PP5

ANTIAPOPTOTIC AND ANTIOXIDATIVE EFFECTS OF NESFATIN IN EXPERIMENTAL SUBARACHNOID HEMORRHAGE

Derya ÖZSAVCI, Department of Biochemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.Mehmet ERSAHİN, Department of Neurosurgery, Haydarpasa Numune Education and Research Hospital, Haydarpaşa, İstanbul, Turkey.Azize ŞENER, Department of Biochemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.Özlem ÖZAKPINAR, Department of Biochemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.Hale TOKLU, Department of Pharmacology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyGoksel SENER , Department of Pharmacology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.Berrak YEĞEN, Department of Physiology, School of Medicine, Marmara University, , Department of Pharmacology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.

Objectives: There is substantial evidence to suggest that oxidative stress plays a significant role in the devel-opment of acute brain injury following subarachnoid hemorrhage (SAH). This study investigated the an-tiapoptotic, antioxidative and anti-inflammatory effects of nesfatin, an endogenous peptide, in a rat model of SAH.

Materials-Methods: Male Wistar albino rats were divided as saline- and nesfatin(10μ/kg, ip)-treated con-trol and SAH groups. To induce SAH, rats with 0.3 mL blood was injected into their cisterna magna. Forty-eight hours after SAH induction, neurological examination scores were measured and the rats were decapitated. Brain tissue samples were taken for determination of apoptotic and oxidative stress markers or blood brain barrier (BBB) permeability and brain water content.

Results: The neurological examination scores were increased in SAH groups on the second day of SAH induction while SAH caused a significant increase in the BBB, and edema, along with increase in the levels of tissue proinflammatory cytokines (TNF-α, IL-1β, IL-6), malondialdehyde, protein carbonyl contents, myeloperoxidase activity, glutatyon and antioxidant enzymes (catalase, superoxide dismutase, g-glutamyl transferase) and nitric oxide, (p<0.05-0.001). On the other hand, in the nesfatin-treated SAH group these alterations were significantly reversed. Furthermore SAH induced apoptosis, measured by caspase-3, is also significantly reduced (p<0.01) with nesfatin treatment. CONCLUSION: The present study suggests that nesfatin exerts neuroprotection through antiapoptotic, antioxidative and anti-inflammatory properties.

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PP6

SYNTHESIS AND CHARACTERIZATION OF NOVEL SUBSTITUED THIOUREA DERIVATIVES INCLUDING 1,2,4-TRIAZOLE

Ahmet Özgür ÇELEN, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey Bedia KOÇYİĞİT KAYMAKÇIOĞLU, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey

Synthesis of substitued thiourea derivatives is important due to their antituberculosis, anticonvulsant, an-tibacterial, antifungal and especially anti-HIV activity[1]. Furthermore, most of these compounds include heterocyclic rings as oxadiazole, thiadiazole, triazole and pyrazole. From these ring systems, 1,2,4-triazoles are determined for their anticonvulsant, bronchodilator, anticancer[2], antiinflammatory[3], antibacterial and antifungal activity[4]. All of these data made it exciting to study for novel thiourea derivatives includ-ing 1,2,4-triazole. New thioureas are synthesized by the reaction of (4-aminophenyl)acetic acid with dif-ferent isothiocyanates. And then, treatment of these compounds with thiocarbohydrazide, gave us new thiourea derivatives that including 1,2,4-triazole. All new compounds are characterized by various spectro-scopic methods (IR, 1H-NMR, MS).

References: [1] Koçyiğit Kaymakçıoğlu B, Rollas S, Körceğez E, Arıcıoğlu F. Synthesis and biological evaluation of new N-substituted-N-(3,5-di/1,3,5-trimethylpyrazole-4-yl)thiourea/urea derivatives. Eur J. Pharm. Sci., 26(1):97-103, 2005. [2] Sztanke K, Tuzimski T, Rzymowska J, Pasternak K, Kandefer-Szerszeń M. Synthesis, determination of the lipophilicity, anticancer and antimicrobial properties of some fused 1,2,4-triazole derivatives. Eur J. Med Chem, 43(2):404-419, 2008 [3] Tozkoparan B, Aktay G, Yeşilada E. Synthesis of some 1,2,4-triazolo[3,2-b]-1,3-thiazine-7-ones with potential analgesic and antiinflammatory activities. Il Farmaco, 57(2):145-152, 2002. [4] Vikrant S. Palekar, Amey J. Damle, S.R. Shukla. Synthesis and antibacterial activity of some novel bis-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles and bis-4-thiazolidi-none derivatives from terephthalic dihydrazide. Eur J. Med Chem, 44 (12):5112-5116, 2009

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PP 7

MICROWAVE ASSISTED SYNTHESIS AND BIOLOGICAL EFFECTS OF NOVEL HYDRAZIDE-HYDRAZONES STARTING FROM FLURBIPROFEN

Sevil AYDIN, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyŞ.Güniz KÜÇÜKGÜZEL, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyNeerja KAUSHIK-BASU, Department of Biochemistry and Molecular Biology, Biomedical Sciences New Jersey Medical School, UMDNJ, USA.Payal ARORA, Biochemistry and Molecular Biology, Biomedical Sciences, New Jersey Medical School UMDNJ, USA.Mehmet AKKURT, Departmant of Physics, Faculty of Arts And Sciences, Erciyes University, Kayseri, Turkey. İsmail ÇELİK, Department of Physics, Faculty of Arts And Sciences, Cumhuriyet University, Sivas, Turkey. Orhan BÜYÜKGÜNGÖR, Department of Physics, Faculty of Arts and Sciences, Ondokuz Mayıs University,Samsun, Turkey.

The synthesis of new hydrazide-hydrazone derivatives has been appreciated based on the data that these derivatives are less toxic than their starting compounds-hydrazides, due to blockage of the -NH[sb2]group. Our data on various hydrazide-hydrazones synthesized in our laboratory is consistent with this param-eter of overall lower toxicity of this class of compounds. This factor motivated us to design and synthesis new hydrazide-hydrazones. Microwave aided synthesis, also known as Green Chemistry has advantages of low solvent consumption, time and energy saving, and in addition is established as a conservation-minded chemical method of gaining new compounds. In the present study, twenty new hydrazide-hydrazone de-rivatives were synthesized by using Microwave aided synthesis starting from Flurbiprofen, an antiinflamma-tory drug. The characterization of compounds was accomplished by employment of UV, IR, [sp1]H-NMR and EI-Mass spectral data, while their purities was established by elemental analysis and TLC. The molecu-lar structure of compound 3s was determined by X-ray crystallographic analysis. The anticancer activity of the selected compounds was elucidated at NIH (National Institutes of Health) and the Hepatitis C virus NS5B polymerase enzyme inhibition efficacy of all compounds was evaluated in the Department of Bio-chemistry and Molecular Biology, UMDNJ- New Jersey Medical School.

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PP8

SYNTHESIS AND BIOLOGICAL ACTIVITY OF (±)-2-(2-FLUORO-4-BIPHENYLYL) PROPANOIC ACID HYDRAZIDE DERIVATIVES

Esra TATAR, Departmant of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.Pelin ÇIKLA, Departmant of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.Ş. Güniz KÜÇÜKGÜZEL, Departmant of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.İlkay KÜÇÜKGÜZEL, Departmant of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.Fikrettin ŞAHİN, Department of Genetics and Bioengineering, Faculty of Engineering and Architecture , Kayışdağı, İstanbul, Turkey.Dilşad YURDAKUL, Department of Genetics and Bioengineering, Faculty of Engineering and Architecture , Kayışdağı, İstanbul, Turkey.Neerja KAUSHIK-BASU, Department of Biochemistry and Molecular Biology, New Jersey Medical School, UMDNJ, USA.Ramalingam KRISHNAN, Department of Biochemistry and Molecular Biology, New Jersey Medical School, UMDNJ, USA.

Despite there is no preventive vaccination against Hepatitis C virus, it is one of the most important hu-man patogens that threatens world population with chronic hepatitis, cirrhosis, hepatocellular carcinoma and other chronic liver diseases and can not be cured prosperously by using α-interferon and ribavirine combination therapy because of the severe adverse effects. Compounds having different chemical struc-tures have been synthesized and elucidated for anti-HCV activity and it is known that the compounds with 4-thiazolidinone moiety, as an example 2[ge],4[ge]-difluoro-4-hydroxybiphenyl-3-carboxylic acid[2-(2-fluorophenyl)-4-thiazolidinone-3-yl]amide (SGK-46), demonstrate hepatitis-C (HCV) NS5B poly-merase inhibition. By the help of all these knowledge and the literature giving notice of the antitumor activity of ([pm]-2-(2-fluoro-4-biphenylyl) propanoic acid (Flurbiprofen) ; that reduces the proliferation of human MG63 osteocarcinoma cells up to a concentration besides its non-steroidal antiinflammatory ac-tivity; Flurbiprofen hydrazide derivatives were also designed as dual acting antimicrobial / antiviral agents, possesing antiinflammatory properties against pain and inflammatory events due to the cell damage arising from cancer, hepatitis-C and accompanying infectious diseases, via their potential metabolite-Flurbiprofen. The anticancer activity of the selected compounds was elucidated in NCI (National Institutes of Cancer) and the HCV NS5B polimerase enzyme inhibition efficacy of all compounds was laboured in the Depart-ment of Biochemistry and Molecular Biology of New Jersey Medical School- UMDNJ.

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PP9

ANTIMICROBIAL ACTIVITIES OF MANNICH BASES OF CHLOROKOJIC ACID DERIVATIVES

Mutlu D. AYTEMİR,Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University , 06100 Sıhhiye, Ankara, Turkey.Gülşah DEMİRYÜREK, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University , 06100 Sıhhiye, Ankara, Turkey.Berrin ÖZÇELİK, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Gazi University, 06330 Etiler, Yeni Mahalle , Ankara, Turkey.

Bacteria and fungi are developing resistance rapidly to the existing drugs, so it poses a major threat to the public health. Design and synthesis of novel antimicrobial agents which have a broad spectrum of activity against the resistant microorganisms is vital for use. Some Mannich bases of 3-hydroxy-6-hydroxymethyl/methyl-4H-pyran-4-one derivatives were synthesized and investigated for their antimicrobial, antiviral and anticonvulsant activities1,2. Literatures suggest that chlorokojic acid (2-chloromethyl-5-hydroxy-4H-py-ran-4-one) also have remarkable antifungal effect3. The structures of 6-chloromethyl-3-hydroxy-2-substi-tuted 4H-pyran-4-one derivatives were identified by IR, 1H-NMR, ESI-MS and elemental analysis data. Compounds were screened for their in-vitro antibacterial and antifungal activities by microbroth dilution method used for the determination of minimum inhibitory concentration. Standard strains of E. coli, P. aeruginosa, P. mirabilis, K. pneumoniae, A. baumannii, S. aureus, E. faecalis, and B. subtilis with their pathogens from clinical isolates as well as fungi (C. albicans, C. parapsilosis, C. tropicalis, C. krusei) were used to ascertain the antimicrobial activity. Compound which is bearing nonsubstituted phenyl piperazine ring showed significant antibacterial activity against all Gram-negative bacteria (MIC: 8-16 µg/ml) and only S. aureus among Gram-positive bacteria when compared with the other synthesized compounds and chlorokojic acid. Additionally, the same compound showed high antifungal activity. In particular, it was found to have a better inhibition against C. krusei than flukonazole. Important outcome of the exhaustive screening of all candidates in the present experiment was that the introduction of piperazine containing Mannich groups at 6-position of chlorokojic acid nucleus significantly improved the biological activity. This study is supported by Hacettepe University Scientific Research Fond. References 1. Aytemir MD et. al. Archiv Pharm Pharm Med Chem, 337, 281-8 (2004). 2. Aytemir MD et. al. Med Chem Res, DOI 10.1007/s00044-010-9338-x. 3. Brtko J et. al. Cent Eur J Publ Health, 12, 16-8 (2004).

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PP10

SYNTHESIS OF 4-AMINO-2-HYDROXY-N\' [(SUBSTITUTED PHENYL)METHYLIDENE] BENZOHYDRAZIDES AS POSSIBLE ANTITUBERCULOUS DRUGS

Tuğba ÖZKAN, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, TurkeyAydin SALMAN, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, Turkey

As the consequence of the occurance of new strains, the treatment of tuberculosis became more complicat-ed. This situation led us to synthesize new molecules having antituberculous activity[1-3]. Two of the drugs used for the treatment of tuberculosis are Isoniazid (INH) and p-Aminosalicylic acid (PAS). Kakimoto and co-workers prepared PAS hydrazide and examined its antitubercular action and found that it is more effec-tive than Isoniazid against to Mycobacterium tuberculosis[4]. In 1954 it is introduced in clinic by Reale[5]. On the other hand antituberculous activity of hydrazide hydrazones of some acids and also PAS were tested and found less active than the parent hydrazides[6]. Novel 4-amino-2-hydroxy-N'-[(substituted phenyl) methylidene]benzohydrazides we synthesized wherein PAS molecule is in the form of hydrazide derivatives and can be converted into PAS molecule by metabolic hydrolysis. These compounds are expected to show antimycobacterial activity in either hydrazone form or metabolic degradation form, PAS. The structures of the synthesized compounds have been confirmed by spectral (UV, IR, 1H-NMR, 13C-NMR, HMBC and MS) analysis.

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PP11

SYNTHESIS AND EVALUATION OF PYRIDINE-3-CARBOHYDRAZIDE DERIVATIVES

Hale DEMİR, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, TurkeySumru ÖZKIRIMLI, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, Turkey

Development of new active compounds for viral infections is a high priority goal. Use of antiviral com-pounds may be limited because of rapid onset of resistance and hypersensitivity reactions. Therefore, there is still an existing need for new antiviral agents. A number of diverse chemical structures have been shown to be potent RTIs. Amongst them, nicotinamide is gaining attention for its cytoprotective and antiviral properties (1). Furthermore, 3-pyridinecarboxamide derivatives with antitumor (2), anti- HIV and antivi-ral properties have been reported. 4-Thiazolidinones exhibit antiviral (3) activities. Here, we combine these two moities as a part of an ongoing project directed towards the design and synthesis of bioactive mol-ecules bearing 4-thiazolidinone and pyridine-3-carboxamide scaffolds together. To this end, we prepared new N-[2-(substituted phenyl)-4-oxo-1,3-thiazolidine-3-yl]pyridine-3-carboxamides (Ia,b) and N-[2-(substituted phenyl)-5-methyl-4-oxo-1,3-thiazolidine-3-yl]pyridine-3-carboxamides (IIa,b) to investigate their antiviral and anticancer potency. The structures of the synthesized compounds have been confirmed by spectral (UV, IR, 1H-NMR, 13C-NMR, HMBC and MS) analysis.

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PP12

NEW [6-(4-CHLOROPHENYL)IMIDAZO[2,1-b]THIAZOLE]DERIVATIVES: SYNTHESIS AND ANTICANCER ACTIVITY

Berin KARAMAN, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, TurkeyNuray ULUSOY GÜZELDEMİRCİ, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, Turkey

Recently much interest has been focused on the chemistry and the biological activity of imidazo[2,1-b]thiazoles and their derivatives. The imidazo[2,1-b]thiazole derivatives have been reported in the literature as antitumor [1-3] agents. New [6-(4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl]acetic acid hydrazide hy-drazones (4a-e) were synthesized by reacting [6-(4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl]acetic acid hydrazide with various aromatic aldehydes. The chemical structures were elucidated by elemental analyses and UV, IR, 1H-NMR, 13C-NMR (APT, DEPT) HSQC and EI MS data. The synthesized compounds 4b and 4e were selected for one dose assay and tested at a single high dose (10-5 M) in the full National Cancer Institute’s 60 cell panel. Compound 4b, [6-(4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl]acetic acid 2-hydroxybenzyliden hydrazide which passed the criteria for activity in this assay were scheduled automati-cally for the five dose assay and demonstrated the most marked effects on an ovarian cancer cell line (OV-CAR-3, log10 GI50 value -6,44).

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PP13

SYNTHESIS , ANTIOXIDANT AND ANTICANCER ACTIVITY OF NEW 1H-INDOLE-2-CARBOHYDRAZIDES

Sumru ÖZKIRIMLI, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, TurkeyFüsun KAZAN, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, TurkeyNurten ÖZSOY, Department of Biochemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, TurkeyAyşe CAN, Department of Biochemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, Turkey

Oxidative stress caused by free radicals plays an important role in many human diseases such as cancer, atherosclerosis, neurodegenaration and diabetes[1]. As a result, antioxidants have gained increased inter-est as drugs. Indolamine derivatives such as tryptamine, serotonine, melatonine are radical scavenging an-tioxidants. Due to the great structural diversity of biologically active indoles, the indole ring system has become an important scaffold for pharmaceutical research. Some naturally occuring indoles, vincristine, vinblastine and mytomycine are currently being used in cancer treatment. Indole-2- carboxamides were reported as apoptosis inducing compounds [2]. The thiazolidinone nucleus is another important chemical moiety used in diverse therapeutic areas. Substituted thiazolidinones are under investigation as antibacte-rial [3], antifungal [4], antiviral [5] agents. In order to take advantage of the properties of the indole ring and the thiazolidinone nucleus, we prepared 3-phenyl-5-iodo/chloro- N-[4-substituted phenylmethylene]- 1H- indole-2-carbohydrazides (I), and 3-phenyl-5-iodo/chloro- N-[4-oxo-2-substituded phenyl-1,3-thia-zolidine-3-yl]- 1H- indole-2-carboxamides (II) to investigate their antioxidant and anticancer properties. [1] Herraiz T., Galisteo J. Free radical Research 2004, 38, 323-331 [2] Zhang H. Z., Drewe J., Tseng B., Kasibhatla S., Cai, S. X. Bioorganic and Medicinal Chemistry 2004, 12, 3649- 3655 [3] Ur,F., Cesur N., Birteksöz, S., Otuk G. Arzneim.-Forsch./Drug Res 2004, 45, 125-129 [4] Capan G., Ulusoy N., Ergenc N., Kiraz M. Monatsch Chem 1999, 130, 1399-1407 [5] Rao A., Balzarini J., Carbone A., Chimirri A., Clerck E., Monforte A.M., Monforte P., Pannecouque C., Zappala M. Farmaco 2004, 59, 33-39

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SYNTHESIS OF SOME NEW N-(1-THIA-4-AZASPIRO[4,5]DECANE-4-YL)CARBOXAMIDES AS POSSIBLE INHIBITORS OF INFLUENZA VIRUS FUSION

Pınar TAS, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, TurkeyMerve TANSUYU, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, Turkey Füsun UR, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, Turkey Zafer CESUR, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, TurkeyNesrin CESUR, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, Turkey

Currently available drugs for the prevention and treatment of influenza virus infections are the M2 ion channel blockers (amantadine and rimantadine) and the neuraminidase (NA) inhibitors (oseltamivir and zanamivir). The M2 ion channel blockers inhibit only influenza A virus replication and are associated with neurological side effects. NA inhibitors are favored clinically, since they are effective against all NA sub-types. However, it is not clear whether these antivirals will be sufficient to deal with larger influenza epi-demics, so there is a need to develop new antivirals that act on novel influenza virus targets. An alternative strategy is to block virus entry into the host cell, a process in which the viral hemagglutinin (HA) plays a key role. Influenza virus is a negative strand enveloped RNA virus which invades cells by means of receptor-mediated endocytosis. In the endosomes viral components are disassemble and low pH-triggered confor-mational changes in the HA causes the formation of pores through which the genetic viral materials are de-livered into the host cytoplasm. During the last decades some compounds influencing the low-pH induced HA conformational change by direct interaction with the HA protein have been reported. In our recent paper we reported the identification of some new influenza A virus fusion inhibitors (1 and 2) that have similar backbone structure as the reported fusion inhibitors, consisting of an aromatic system linked to a nonaromatic cyclic system via an amide bridge. In this study some new N-(1-thia-4-azaspiro[4,5]decane-4-yl)carboxamides (3 and 4) were synthesized with variations in the aromatic system in order to explore the structure-activity relationship of the new inhibitors of influenza virus fusion.

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PP15

SYNTHESIS AND EVALUATION OF CYTOTOXIC ACTIVITIES OF SOME 2,5-DISUBSTITUTED 1,3,4-THIADIAZOLES AND 3,4-DISUBSTITUTED-1,2,4-TRIAZOLE-5-THIONES

Işıl ÇORUH, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey. Suna ÖZBAŞ TURAN, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey. Jülide AKBUĞA, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey. Sevim ROLLAS, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.

Among the increasing number of heterocyclic sulphur and nitrogen containing compounds, which are be-ing pursued in both industry and academia, 1,3,4-thiadiazole and 1,2,4-triazole-5-thione derivatives are sig-nificant targets for drug desing due to their use in medicine. In this study, a series of novel 2,5-disubstituted 1,3,4-thiadiazoles and 3,4-disubstituted-1,2,4-triazole-5-thiones were synthesized from 1,4-disubstitued-thiosemicarbazides obtained by benzilic acid hydrazide and several isothiocyanates. Synthesized thiosemi-carbazides underwent ring-closing rearrangement to give 1,3,4-thiadiazoles I(a-d) and 1,2,4-triazole-5-thiones II(a-c), when treated with concentrated sulfuric acid and 2N NaOH solution, respectively. The structures of these substances were elucidated using IR, 1H-NMR, and mass spectral techniques. Cytotoxic activities of the compounds have been investigated.

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PP16

SYNTHESIS AND EVALUATION OF CYTOTOXIC ACTIVITIES OF SOME SUBSTITUTED ISOXAZOLONE DERIVATIVES

Şila KOKYAN, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey. Suna ÖZBAŞ TURAN, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey. Jülide AKBUĞA, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey. Sevim ROLLAS, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.

It is well known that compounds containing 1, 3, 4-thiadiazole and 1, 2, 4-triazole rings have been reported to possess antimicrobial, anticancer and antitubercular activities. Therefore, there is a need for new drugs of novel structural classes. In this research, starting from substituted 1, 3, 4-thiadiazole and 1, 2, 4-tri-azole-3-thione derivatives, several isoxazolones were synthesized. In the first part of study, the diazonium salts of 2-(4-aminophenyl)-5-alkyl/arylamino-1, 3, 4-thiadiazoles and 5-(4-aminophenyl)-4-substitude-2, 4-dhydro-3H-1, 2, 4-triazole-3-thiones were coupled with ethyl acetoacetate. In the second part, the ob-tained products were reacted with hydroxylamine hydrochloride and sodium acetate in ethanolic medium to give 3-methyl-4-[4-(5-alkyl/arylamino-1,3,4-thiadiazole-2-yl)phenylhydrazino]-5-isoxazolone (1) and 3-methyl-4-[4-(4-alkyl/aryl-1,3,4-triazole-3-thion)phenylhydrazino)-5-isoxazolone (2). The structures of the synthesized compounds have been elucidated using IR, 1H-NMR, mass spectral data and elemental analysis. Cytotoxic activities of the compounds have been investigated.

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PP17

SYNTHESIS, STRUCTURE DETERMINATION AND ANTICONVULSANT ACTIVITY STUDIES ON SOME 2-PYRAZOLINES DERIVED FROM CHALCONES

Nagihan BEYHAN, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey Bedia KOÇYİĞİT-KAYMAKÇIOĞLU, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey E. Elçin ORUÇ-EMRE, Department of Chemistry, Faculty of Arts and Sciences, Gaziantep University, Gaziantep, Turkey Hale Zerrin TOKLU, Department of Pharmacology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey Salih GÜMRÜ, Department of Pharmacology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey Feyza ARICIOĞLU, Department of Pharmacology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey

Epilepsy is a common and serious chronic neurological disorder characterized by recurring seizures [1]. But available epileptic drugs are not effective in any epileptic occasion and the drug researches in medicinal chemistry are still proceeding to study on potential compounds. Among these compounds, 2-pyrazolines are promising structure as anticonvulsant agents. In the present study, a series of chalcones were prepared by Claisen Schmidt condensation as starting compounds and 2-pyrazoline derivatives have been synthesized by the reaction of chalcones with thiosemicarbazide [2,3]. The structures of the synthesized compounds have been confirmed by IR, 1H-NMR spectral data and elemental analysis. 2-Pyrazolines have been tested for anticonvulsant activity by using pentylenetetrazole induced seizure and maximal electroshock seizure tests.

Ar: 2-pyrrolyl, 5-bromo-2-thienyl, 2-thienyl, 5-chloro-2-thienyl, 2-furyl, 4-pyridyl, phenyl Ar’: 4-pyridyl

References

[1] Acharya MM, Hattiangady B, Shetty AK. Progress in Neuroprotective Strategies for Preventing Epilepsy. Progress in Neurobiology. 84(4):363-404, 2008.[2] Özdemir A, Turan-Zitouni G, Kaplancıklı ZA, Revial G, Güven K. Synthesis and antimicrobial activity of 1-(4-aryl-2-thiazolyl)-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives. Eur J Med Chem. 42(3):403-409, 2007.[3] Chimenti F, Carradori S, Secci D, Bolasco A, Bizzarri B, Chimenti P, Granese A, Yáñez M, Orallo F. Synthesis and inhibitory activity against human monoamine oxidase of N1-thiocarbamoyl-3,5-di(hetero)aryl-4,5-dihydro-(1H)-pyrazole derivatives. Eur J Med Chem. 45(2):800-804, 2010.

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PP18

SYNTHESIS AND BIOLOGICAL ACTIVITY STUDIES OF HETEROCYCLIC THIOSEMICARBAZONE DERIVATIVES AND THEIR PT(II), PD(II) COMPLEXES

Demet TAŞDEMİR, Department of Chemistry, Faculty of Arts and Sciences, Gaziantep University, Gaziantep, Turkey Ayşegül KARAKÜÇÜK-İYİDOĞAN, Department of Chemistry, Faculty of Arts and Sciences, Gaziantep University, Gaziantep, Turkey Emine Elçin ORUÇ EMRE, Department of Chemistry, Faculty of Arts and Sciences, Gaziantep University, Gaziantep, Turkey Osman ERKMEN, Faculty of, Food Engineering, Gaziantep University, Gaziantep, Turkey

Thiosemicarbazone derivatives and their transition metal complexes were possessed important biological activity such as antiviral, antimalarial, antituberculosis, anticancer, antifungal and antimicrobial, so that it is interested in many research groups [1-4]. This study consists of two parts. In the first part, 4-substituted isothiocyanates were synthesized and these compounds were treated with hydrazine monohydrate and con-verted to 4-substituted N-phenylhyhidrazinecarbothioamide derivatives. Then, these thiosemicarbazide derivatives in methanol were reacted with 5-substituted-2-thiophene carboxaldehydes in order to obtain thiosemicarbazone derivatives (I). In the second part, thiosemicarbazone derivatives used as ligand were treated with K2PtCl4 and K2PdCl4 in presence of water/ethyl alcohol. Thus their Pt(II) and Pd(II) metal complexes (II) were obtained. The structure of the new synthesized thiosemicarbazones derivatives have been elucidated by using IR, 1H NMR, 13C NMR, mass spectroscopy and elemental analysis. Thiophene-2-carboxaldeyde-N-(4-nitrophenyl)-3-thiosemicarbazone and its Pt(II), Pd(II) complexes were selected as prototype for antimicrobial activity against Saccharomyces cerevisiae, Aspergillus niger, Listeria monocy-togenes, Stafilococcus aureus, Escherichia coli using microdilution method and studies on the anticancer activity of these compounds are in progress.

[1] Quenelle, D.C., Keith, K.A., Kern, E.R. (2006). Antiviral Research, 71, 24-30.[2] Afrasiabi, Z., Sinn, E., Padhye, S., Dutta, S., Newton, C., Anson, C., Powell, A. (2003). Journal of Inorganic Biochemistry, 95, 306–314.[3] Oliveira, R., Souza-Fagundes, E.M., Soares, R.P., Andrade, A.A., Krettli, A.U., Zani, C.L. (2008). European Journal of Medicinal Chemistry, 43, 1983-1988.[4] Cocco, A., Cenzo Congiu, C., Onnis, V., Pellerano, M. (2002). Bioorganic & Medicinal Chemistry, 10, 501–506.

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PP19

SYNTHESIS OF SOME NOVEL HYDRAZONES FROM ETHYL 2-AMINO-3-SULFANYLPROPANOATE

Yusuf SICAK, Department of Chemistry, Faculty of Arts and Sciences, Gaziantep University, Gaziantep, Turkey Emine Elçin ORUÇ EMRE, Department of Chemistry, Faculty of Arts and Sciences, Gaziantep University, Gaziantep, Turkey Ayşegül KARAKÜÇÜK İYİDOĞAN, Department of Chemistry, Faculty of Arts and Sciences, Gaziantep University, Gaziantep, Turkey Bedia KOÇYİĞİT KAYMAKÇIOĞLU, Departmant of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.

The hydrazones possess a wide range of pharmacological properties including antibacterial, antifungal, analgesic, antiinflammatory, antitubercular, anticancer activities [1-5]. In present research with the aim of obtaining new antimicrobial agents, novel series of 4-substituted-N-{1-[2-(4-substituted benzylidene)hydrazinyl]-1-oxo-3-sulfanylpropan-2-yl}benzamide derivatives were synthesized. These derivatives have been obtained by the condensation with 4-substitued benzaldehyde and hydrazides, which were synthe-sized by reaction of ethyl 2-{[(4-substituted phenyl)carbonyl]amino}-3-sulfanylpropanoate derivatives and hydrazine monohydrate. The structure of the new synthesized hydrazide-hydrazones derivatives have been evaluated by using UV, IR, 1H NMR spectroscopy and elemental analysis. Antimicrobial activity of these compounds are screened.

[1] Koçyiğit-Kaymakçıoğlu, B., Oruç, E., Unsalan, S., Kandemirli, F., Shvets, N., Rollas, S., Dimoglo, A., European Journal of Medicinal Chemistry, 41(11), 1253-1261, 2006.[2] Bhandari S.V., Bothara K.G., Raut M.K., Patil A.A., Sarkate A.P., MokaleV.J., Bioorganic & Medicinal Chemistry 16, 1822-1831, 2008.[3] Zheng L.W., Wub L.L., Zhao B.X., Dong W.L., Miao J.Y., Bioorganic & Medicinal Chemistry 17, 1957-1962, 2009.[4] Raparti V., Chitre T., Bothara K., Kumar V., Dangre S., Khachane C., Gore S., Deshmane B., European Journal of Medicinal Chemistry 44, 3954-3960, 2009.[5] Koçyiğit-Kaymakçıoğlu, B., Oruç, E.E., Unsalan, S., Rollas, S., Medicinal Chemistry Research, 18, 277-286, 2009.

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PP20

5-ARYLIDENE-4-THIAZOLIDINONES : AN APPROACH TO THE DISCOVERY OF NEW ANTIVIRAL AGENTS

Gökhan SATILMIŞ, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkeyİlkay KÜÇÜKGÜZEL, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyEsra TATAR, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyErik DE CLERCQ, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium. Graciela ANDREI, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium. Robert SNOECK, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium. Christophe PANNECOUQUE, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.

There are many targets for anti–HIV drug development due to the unique nature of the replication of HIV–1. Of these target macromolecules, reverse transcriptase (RT) plays an essential role in the replica-tive cycle of HIV–1. A key step for the replication and spread of the virus is the reverse transcription of the retroviral RNA to proviral DNA by the enzyme reverse transcriptase (RT). Non-nucleoside reverse transcriptase inhibitors (NNRTIs) interact with an allosteric site of the enzyme resulting in alteration of its function and therefore achieving suppression of HIV–1 replication with high selectivity. Ongoing studies for discovery of new antiviral agents gave rise to novel types NNRTIs which include 1H,3H-thiazolo[3,4-a]benzimidazoles (TBZs) and recent studies on molecular modification of TBZs revealed that dismantling of the imidazole nucleus led to the design of new 1,3-thiazolidin-4-one derivatives maintaining molecular requirements for enzyme inhibition. Since 5-arylidene-4-thiazolidinones have been identified as ligands for important proteins and enzymes1, synthesis of new 5-arylidene-2-[[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]imino]-1,3-thiazolidine-4-one derivatives were carried out through Knoevenagel’s reaction procedure. In the knowledge that halogens can influence ligand binding interactions through different means, including van der Waals and electrostatic interactions, halogen substituted aryl aldehydes were cho-sen to react with 2-[[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]imino]-1,3-thiazolidine-4-ones in or-der to gain the desired compounds. Antiviral activity and cytotoxicity of the synthesized compounds were assessed by using HIV-1, HIV-2 and some other selected viruses in various cell culture systems.

References

1. Carlson E.E., May J.F., Kiessling L.L. : Chemical Probes of UDP-Galactopyranose Mutase, Chemistry &Biology 13 (8) : 825-837, 2006.

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IN VITRO CYTOTOXIC ACTIVITIES OF PLATINUM(II) AND PLATINUM(IV) COMPLEXES BEARING BENZIMIDAZOLE LIGANDS AGAINST HRT-18 CELL LINE

Semra UTKU, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mersin University, Mezitli, Mersin, Turkey. Taner KARAOĞLU, Department of Virology, Faculty of Veterinary Medicine, Ankara University, Ankara, Turkey.Fatma GÜMÜŞ, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Etiler, Yeni Mahalle, Ankara, Turkey.

Platinum-based drugs such as cisplatin, carboplatin, and oxaliplatin are widely used against various solid tu-mors including genitourinary, colorectal, and non small cell lung cancers [1]. In general, the platinum-based drugs suffer from two main disadvantages: chemoresistance to the drugs can occur and second they are non selective toward cancer cells which lead to severe toxic side effects, primarily kidney toxicity and neurotox-icity [2]. In addition to square-planar Pt(II) complexes, an attempt has also been made recently to octahe-dral Pt(IV) complexes, since, some of these complexes are toxic to tumors that are resistant to cisplatin [3]. Although no platinum(IV) complex is an approved drug yet, some Pt(IV) complexes have shown sufficient promise to enter clinical trials: Iproplatin, tetraplatin, and satraplatin, have been tested in clinical trials [4]. In a previous paper, with the aim to determine the effect of axial and equatorial ligand variation on the cytotoxic activities of the Pt(II) and Pt(IV) complexes, we synthesized some Pt(II) and Pt(IV) complexes with the structures of [PtL2Cl2] (C1), [PtL2I2] (C2), [PtL2Cl2(OH)2] (C3), [PtL2Cl2(OCOCH3)2] (C4), and [PtL2Cl4] (C5) (L= benzimidazole as carrier ligands) and tested for their preliminary in vitro cytotoxic activities against the human MCF-7 breast, HeLa cervix, and HEp-2 larynx carcinoma cell lines [5]. In the present paper, to determine whether cytotoxic activities of the Pt(II) and Pt(IV) complexes C1-C5 were cell-type dependent we tested their preliminary in vitro cytotoxic activities against the HRT-18 rectal adenocarcinoma cell line.

References

[1] Jung Y, Lipard SJ., Chem. Rev., 2007;107:1387-1407.[2] Rabik CA, Dolan ME., Cancer Treat. Rev., 2007;33:9-23.[3] Reedijk, J. Chem. Commun., 1996;7:801-806.[4] Abu-Surrah AS, Kettunen M. Current. Med. Chem., 2006;13:1337-1357.[5] Utku S, Gümüş F, Tezcan S, MS Serin, Ozkul A., J. Enzym Inhib. Med. Chem., 2010 (Accepted Manuscript).

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ACETYLCHOLINESTERASE AND BUTYRYLCHOLINESTERASE INHIBITORY ACTIVITIES OF NOVEL 6-SUBSTITUTED-3(2H)-PYRIDAZINONE-2-ACETYL-2-(SUBSTITUTED/-NONSUBSTITUTED BENZAL)HYDRAZONES

Semra UTKU, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mersin University, Mezitli, Mersin, TurkeyMehtap GÖKÇE, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Etiler, Yeni Mahalle, Ankara, Turkeyİlkay ORHAN, Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330 Etiler, Yeni Mahalle, Ankara, TurkeyM. Fethi ŞAHİN, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Etiler, Yeni Mahalle, Ankara, Turkey

Alzheimer’s disease (AD) is a neurodegenerative disorder of the central nervous system, characterized by loss of cognitive ability and severe behavior abnormalities, which ultimately results in degradation of intel-lectual and mental activities [1]. Three main stages Despite an enormous amount of work, many aspects of both the etiology and physiological pathways of the disease still remain unclear. To date, the majority of current drug therapeutic approaches to AD follow the cholinergic hypothesis [2]. The acetylcholinesterase (AChE) has received important attention as a drug design target for the palliative treatment of the AD. On this basis, AChE inhibitors have become the leading strategy for the development of anti-AD agents. Some anti-AChE agents, such as tacrine, donepezil, rivastigmine, and ensaculin, show a modest induce of the im-provement in memory and cognitive functions [2] and have been used to treat AD clinically for a long time. In this study thirteen 6-Substituted-3(2H)-pyridazinone-2-acetyl-2-(substituted/-nonsubstituted benzal)hydrazone V derivatives (R= H, 4-Br, 3-Cl, 4-Cl, 4-F, 4-C2H5, 4-OC2H5, 4-CH3, 3-OCH3, 4-OCH3, 4-OH and 3-OCH3, 4-N(CH3)2, 4-NO2) were synthesized as AChE and BChE inhibitors. The struc-tures of compounds V were elucidated by IR, 1H-NMR and MASS spectra. The AChE and BChE in-hibitory activity of V derivatives was measured using Ellman’s method. While some of the 6-Substituted-3(2H)-pyridazinone-2-propyl-3-(substituted/-nonsubstituted benzal)hydrazone V derivatives exhibited significant AChE inhibitory activity, none of the compounds have been shown BChE inhibitory activity. These results indicate that V derivatives were AChE inhibitors with AChE/ BChE selectivity.

References

[1] Frank RA, Galasko D, Hampel H, Hardy J, de Leon M J, Mehta PD, Rogers J, Siemers E, Trojanowski QJ. Neurobiol Aging. 2003;24:521-536.[2] Pakaski M, Kalman J. Neurochem Internation. 2008; 53:103-111.[3] Reale M, Iarlori C, Gambi F, Feliciani C, Isabella L, Gambi D. Neuropharmacol. 2006;50:606-613.

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SYNTHESIS AND ANTIVIRAL EVALUATION OF 2-[4-BENZYL-5-SUBSTITUTED-4H-1,2,4-TRIAZOL-3-YL]SULFANYL]-N-(SUBSTITUTED PHENYL)ACETAMIDE DERIVATIVES

Necla KÜÇÜKYILDIZ, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkeyİlkay KÜÇÜKGÜZEL, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyEsra TATAR, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyErik DE CLERCQ, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium. Graciela ANDREI, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium. Robert SNOECK, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium. Christophe PANNECOUQUE, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.

Effective treatment of tuberculosis in HIV-patients are critical for their avarage life span further minimiz-ing the negative effects of tuberculosis on the course of HIV. Interruption of transmission of Mycobac-terium tuberculosis to the others in community have to be throughly considered. Although the use of rifampin with protease inhibitors and non-nucleoside reverse transcriptase inhibitors is contraindicated, a tuberculosis treatment regimen that includes rifabutin instead of rifampin can be applied concurrently with antiretroviral therapy. Bearing these goals in mind we initiated a synthetic approach for altering the nature of the thioacetanilide core which is reported to be an alternate scaffold for non-nucleoside reverse transcriptase inhibitor (NNRTI) activity [1, 2 ]. According to our synthetic procedure ring cyclization of the thiosemicarbazides led to the corresponding triazoles and the linkers were obtained by condensing ap-propriate anilines with chloroacetyl chloride; then these two fragments were reacted in DMF in order to gain the desired target compounds with potential antiretroviral and antitubercular activities. 2-[4-Benzyl-5-substituted-4H-1,2,4-triazol-3-yl]sulfanyl]-N-(substituted phenyl)acetamide derivatives were assesssed in terms of their wide spectrum antiviral activity by using HIV-1, HIV-2, herpes simplex virus [HSV-1, HSV-2], varicella-zoster virus (VZV), cytomegalovirus (CMV), vaccinia virus (VV), vesicular stomatitis virus (VSV), Coxsackie virus B4, Respiratory syncytial virus (RSV), Parainfluenza-3 virus, Sindbis virus, and Punta Toro virus, in various cell culture systems, in the Rega Institute for Medical Research, Katho-lieke Universiteit Leuven. References: [1] Zhan P., Liu X., Cao Y., Wang Y., Pannecouque C., De Clercq E : 1,2,3-Thiadiazole thioacetanilides as a novel class of potent HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem. Lett., 18 (20), 5368-5371, 2008. [2] Zhan P., Liu X., Zhu J., Fang Z., Li Z., Pannecouque C., De Clercq E. : Synthesis and biological evaluation of imidazole thioacetanilides as novel non-nucleoside HIV-1 reverse transcriptase inhibitors. Bioorg. Med. Chem. Lett., 17 (16), 5775-5781, 2009.

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PP24

SYNTHESIS AND BIOLOGICAL ACTIVITIES OF HYDRAZIDE HYDRAZONES AND THEIR CORRESPONDING 3-ACETYL-2,5-DISUBSTITUTED-1,3,4-OXADIAZOLINES

Bedia KOÇYİĞİT KAYMAKÇIOĞLU, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyE.Elçin ORUÇ-EMRE, Department of Chemistry, Gaziantep University, Faculty of Arts and Sciences, Gaziantep, Turkey Seda ÜNSALAN, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyNurhayat TABANCA, Department of Agriculture, Agricultural Research Service, Natural Products Utilization Research Unit, The University of Mississippi, USA.David E. WEDGE, Department of Agriculture, Agricultural Research Service, Natural Products Utilization Research Unit, The University of Mississippi, USA. Shabana I. KHAN, National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, The University of Mississippi, USA. Fatih DEMİRCİ, Department of Pharmacognsy, Faculty of Pharmacy, Anadolu University, Eskişehir, Turkey Sevim ROLLAS, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey

The five membered 1,3,4-oxadiazole heterocycles have gained importance due to their application in pharmaceutical chemistry in recent years. Therefore several 1,3,4-oxadiazole derivatives exhibited broad spectrum of biological activities such as antimicrobial, antituberculosis, analgesic, antiinflammatory and anticancer activities [1-4]. Many synthesis methods are reported about the cyclization of 1,3,4-oxa-diazole derivatives. In this research, 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazolines (11-20) were synthesized by cyclization of hydrazide-hydrazones (1-10) with acetic anhydride. Compounds 1-20 were evaluated for antiinflammatory (inhibition of NF-κB and iNOS), antioxidant and cytotoxic activ-ities through a panel of in vitro assays involving mammalian cells. Compounds, 1-[5-(4-fluorophenyl)-2-(4-hydroxyphenyl)-1,3,4-oxadiazol-3(2H)-yl]ethanone and 1-[5-(4-fluorophenyl)-2-(3-hydroxy-4-methoxyphenyl)-1,3,4-oxadiazol-3(2H)-yl]ethanone showed significant inhibition of NF-κB (IC50 5.5 and 0.9 µg/mL) and iNOS (IC50 0.3 and 4 µg/mL) activities in PMA induced SW1353 and LPS induced RAW264.7 cells, respectively. Antioxidant activity (inhibition of reactive oxygen species (ROS) genera-tion) was observed with IC50s in the range of 0.7-0.9 µg/mL. No cytotoxicity was observed towards any of the cell lines. All compounds were further evaluated for antifungal activity against plant pathogens (C. fragariae, C. gloeosporioides, C. acutatum, Botrytis cinerea, Fusarium oxysporum, Phomopsis obscurans, and Phomopsis viticola) in in vitro dose-response studies.

References

[1] S. Rollas, N. Gulerman, H. Erdeniz, Farmaco 57 (2002) 171-174.[2] F. Macaev, G. Rusu, S. Pogrebnoi, A. Gudima, E. Stingaci, L. Vlad, N. Shvets, F. Kandemirli, A. Dimoglo, R. Reynoldsd. Bioorganic & Medicinal Chemistry 13 (2005) 4842–4850.[3] V. Padmavathi, G.S. Reddy, A. Padmaja, P. Kondaiah, A. Shazia. European Journal of Medicinal Chemistry 44 (2009) 2106–2112.[4] D. Kumar, S. Sundaree, E.O. Johnson, K. Shah. Bioorganic & Medicinal Chemistry Letters 19 (2009) 4492–4494.

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PP25

CYTOTOXICITY AND DNA INTERACTIONS OF SOME PLATINUM(II) COMPLEXES WITH BENZIMIDAZOLE LIGANDS

A. Berna ÖZÇELİK, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Etiler, Yeni Mahalle, Ankara, Turkey.Semra UTKU, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mersin University, Mezitli, Mersin, TurkeyAyten ÇELEBİ KESKİN, Department of Biology, Faculty of Art and Science, Kırıkkale University, Yahşihan, Kırıkkale, Turkey Leyla AÇIK, Department of Biology, Faculty of Art and Science, Kırıkkale University, Yahşihan, Kırıkkale, TurkeyŞükran YILMAZ, Department of Cell and Virus Bank, Foot and Mouth Disease Institute, Ankara, Turkey. Adeviye ÖZGÜNGÖR, Department of Cell and Virus Bank, Foot and Mouth Disease Institute, Ankara, Turkey. Fatma GÜMÜŞ, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Etiler, Yeni Mahalle, Ankara, Turkey.

Cisplatin has become one of the most commonly used compounds for the treatment of a various types of cancer such as testicular,overian and bladden carcinomas.1 Unfortunately, cisplatin has several major drawbacks. Serious toxicities; such as nephrotoxicity, gastrointestinal toxicity, ototoxicity and neurotoxic-ity.2 Therefore, several research groups have interested in therapeutic activity of cisplatin and its analogues againts cancer studying the relation between the drug structure and biological activity, in order to optimize the active principle both in efficiency and safety.3 Although there is some evidence to suggest that other biological targets may be important in the mechanism, it is generally accepted that DNA is the primary bio-logical target of the drug.4 Bonds between PtII and guanine N7, which is readily accessible in major groove of DNA, are very strong, and intrastrand crosslinking of two adjacent guanines by square-planar PtII results in bending and unwinding of the DNA.5 It is generally believed that biological activity of cisplatin is as-sociated with the recognition of its DNA adducts by cellular poteins such as repair enzymes, transcription factors, histones, and high mobility group (HMG) domain proteins.6 Design of new platinum antitumor drugs has been introduced on the basis of preventing resistance by enhancing this mechanism using more hydrophobic platinium compounds.7 In the present study, five PtII complexes with bulky, near-planer, hy-drophobic amine ligands 2-ethyl/or benzyl/or p-chlorobenzyl/or p-methoxybenzyl/or 2-phenoxymethyl benzimidazole were synthesized and evaluated for their in vitro cytotoxic activities on HeLa, MCF-7 and MDA-MB-231 cell lines. The plasmid DNA interactions and inhibition of BamH1 restriction enzyme activity of the complexes were also studied.

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PP26

ANTIOXIDANT ACTIVITY OF SPIROINDOLINONES INCORPORATING A 5-CHLOROBENZOTHIAZOLINE MOIETY

Görkem ERMUT, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, TurkeyNurten ÖZSOY, Department of Biochemistry, , Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, TurkeyNilgün KARALI, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, TurkeyAyşe CAN, Department of Biochemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, Turkey

Free radicals are constantly formed as a result of normal organ functions or excessive oxidative stres. High levels of free radicals can cause damage to biomolecules such as lipids, proteins, enzymes and DNA in cells and tissues, resulting in mutations that can lead to malignancy. The discovery of the role of free radicals in cancer, diabetes, cardiovascular diseases, autoimmune diseases, neurodegenerative disorders, aging and other diseases has led to new medical insight. Minimizing oxidative damage may be an important approach to the primary prevention or treatment of these diseases, since antioxidants may stop the free-radical forma-tion, or interrupt an oxidizing chain reaction. In recent years, many publications have covered the antioxi-dant and cytotoxic roles of several indole derivatives. The results indicated that the indol ring is the reac-tive center dealing with oxidants due to its high resonance stability and very low activation energy barrier towards free radical reactions. A large number of 2-arylbenzothiazoles have been prepared because of their wide pharmacological potency. Interestingly fact, this important class of compounds has significant anti-cancer and antioxidant properties. In the light of these findings, 2,3-dihydro-5-chloro-1,3-benzothiazole-2-spiro-3’-1’,3’-dihydro-2’H-indole-2’-ones 1-7 were synthesized from treatment of 1H-indole-2,3-diones with 2-amino-4-chlorothiophenol in ethanol. All compounds were tested in vitro for their abilities to in-hibit lipid peroxidation, induced by Fe3+/ascorbate system, scavenge DPPH•, ABTS•+ and superoxide radicals, and reducing power. The results presented in this study showed that all of the tested compounds possess high degrees of potency in inhibiting lipid peroxidation and demonstrate scavenging activities against the DPPH•, ABTS•+ and superoxide radicals, indicating their possible value as antioxidants in medicine and industry. Compounds 1, 4 and 5 were selected for screening anticancer and all compounds were found to be cytotoxic against leukemia cell lines (K-562 and RPMI-8226), prostate cancer cell line (PC-3) and breast cancer cell lines (MCF7 and T-47D) in the primary screen.

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PP27

SYNTHESIS OF 1, 4-DISUBSTITUTED PIPERAZINE DERIVATIVES DESIGNATED AS NOVEL ANTIPSYCHOTIC CANDIDATES

İrem KARAMELEKOĞLU, Department of Pharmaceutical Chemistry, Faculty f Pharmacy, Yeditepe University, Kayışdağı, Turkey.Hilal YUGAÇ, Department of Pharmaceutical Chemistry, Faculty f Pharmacy, Yeditepe University, Kayışdağı, Turkey.Hülya AKGÜN, Department of Pharmaceutical Chemistry, Faculty f Pharmacy, Yeditepe University, Kayışdağı, Turkey.

Schizophrenia, the most serious psychotic disease is a devastating mental illness. It affects approximately 1% of the population. Numbers of genetic and environmental factors are responsible for triggering the disease [1]. Although etiology and mechanistic basis for schizophrenia is not completely understood, it is known that currently marketed drugs effect via interference with central dopaminergic pathways [2]. Halo-peridol, olenzapine, clozapin, and risperidon are some important second generation atypical antipsychotic agents. [3]. In 2002, aripirazol introduced into clinic as D2 agonist/5-HT2A antagonist [4]. In this work, synthesis of 1,4-disubstituted piperazines were synthesized . Structure elucidation of the final compounds were determined by IR, 1H-NMR and MS techniques. Pharmacological activity of the compounds will be elucidated further.

References

1. Nikam SS, Awasthi KA, Current Opionion in investional Drugs, 9/1 37-46, 2008.2. Werkman TR, Glennon JC, Wadmen WJ, McCreary AC, CNS NeurolDisord Dreug Targets, 5/13-23 2006.3. Babtista T, CRC press LLC, Boca Raton, Fl, USA 69-83 2004.4. Stahl SM, J. Clin Psychiatry , 62/9 670-671, 2001.

General Formula

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PP28

SYNTHESIS OF NEW DICLOFENAC DERIVATIVES AS POSSIBLE ANTIVIRAL AGENTS

Ayşe KOCABALKANLI, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, Turkey Gültaze ÇAPAN, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, Turkey

Viruses affect practically all living organisms including humans. Although some of the viruses are self-lim-iting, they remain significant human pathogens causing a diverse set of diseases ranging from cold sores to life-threatening illness. Even the most benign infections pose serious danger in immunocompromised individuals, such as in AIDS or chemo-suppressed organ transplant patients. Current antiviral treatment has been seriously complicated by drug resistance resulting from mutant strains. Both vertical and horizon-tal transmission of drug-resistant variants has been demonstrated and as more people have begun antiviral therapy, the transmission of drug-resistant and multiple drug-resistant strains has increased. Thus, there is an urgent need to design, screen, and identify new agents for antiviral chemotherapy. Recent studies showed that the third position of various groups of 4-thiazolidinones complied with the human immuno-deficiency virus type 1 reverse transcriptase (HIV-1 RT), the major target of AIDS drugs. A class of com-pounds with a thiazolidinone core structure was also identified as an inhibitor of hepatitis C virus (HCV) replication. Very recently, N-(3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl)carboxamide derivatives, which may be regarded as spiro analogs of 4-thiazolidinones, were found to effectively inhibit influenza virus hem-agglutinin-mediated membrane fusion. Furthermore, congeners of 1, prepared in a previous work were found to exhibit activity against Coxsackie B-4 virus in VERO cells. Prompted by these findings, we pre-pared new 2-[2-(2,6-dichloroanilino)phenyl]-N’-(4-(un)substituted cyclohexylidene) acetohydrazides (1) and 2-[2-(2,6-dichloroanilino) phenyl]-N-(3-oxo-8-(un)substituted-1-thia-4-azaspiro[4.5]dec-4-yl)acet-amides (2,3) starting from the well known antiinflammatory drug diclofenac to test their antiviral potency.

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PP29

EVALUATION OF NOVEL INDOLE-3-IMINE-2-ON DERIVATIVES AS SRC KINASE AND MAMMALIAN GLUTATHIONE S-TRANSFERASE INHIBITORS

Doğuş AYDIN, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, 06100 Tandoğan, Ankara. Belgin İŞGÖR, Chemistry Group, Atılım University, 06836 Gölbaşı, Ankara. Yasemin İŞGÖR, Nanomedicine and Advanced Technologies Research Center, Gazi University, Ankara.Süreyya ÖLGEN, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, 06100 Tandoğan, Ankara.

Src ( pp60c-Src), a member of Src family kinases, has important functions in malignant cells, including regulation of cell division, growth factor signaling, and movement. Recent studies have provided renewed interest in Src as a molecular target for cancer therapy. Therefore, investigating new small molecule inhibi-tors of Src is important to discover and develop novel therapeutics for cancer and metastasis. Moreover, some of the small molecule inhibitors that do not qualify for therapeutic use may become very useful tool to explore the role of Src kinase in normal cells as well as in a variety of disease models. Glutathione S-trans-ferases (GST, EC 2.5.1.18) are multifunctional enzymes and highly expressed in the various mammalian tissues. They have capacity to recognize diverse chemical structures, catalyze their conjugation to glutathi-one, and hence reduce cytotoxic reactivity of those chemicals. The increased activity levels of GSTs have been correlated with human cancers and the anticancer drug resistance. Similarly, Src has been reported in many cancers including breast, colon, lung, and skin with relatively high catalytic activity. Therefore, the in-hibition of both GSTs and Src may enhance the therapeutic efficacy of chemotherapeutics by increasing the sensitivity of cancer cells to those agents. In this present work, a series of novel indole-3-imine-2-on deriva-tives were synthesized and evaluated for their inhibitory activity against GSTs and Src (Figure 1). Among them 3-[(4-chlorophenyl)imino]-1,3-dihydro-2H-indole-2-on and its N-benzyl derivative, compounds N-benzyl-5-chloro-3-[(3-chloro-4-fluorophenyl) imino]-1,3-dihydro-2H-indole-2-on and N-benzyl-5-chloro-3-[(4-chlorophenyl) imino]-1,3-dihydro-2H-indole-2-on showed both Src and GST inhibitory properties. [sb1]

Figure 1. Indole-3-imine-2-on derivatives

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PP30

SYNTHESIS AND CYTOTOXIC ACTIVITY OF SOME SULFONYLTHIOUREA DERIVATIVES

Kübra YURT, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeySevgi KARAKUŞ, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeySuna ÖZBAŞ TURAN, Pharmaceutical Biotechnology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyJülide AKBUĞA, Pharmaceutical Biotechnology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey

Substituted sulfonylthioureas are important for pharmacological activity. These compounds show anticon-vulsant, antidiabetic and cytotoxic activities [1-3]. In this research, a series of sulfonylthiourea derivatives have been synthesized and evaluated for their cytotoxic activity. Structures of the novel compounds were characterized by various spectroscopic methods ( IR, 1H-NMR, MS ). Cytotoxicity of these compounds were evaluated by using HeLa ( ATCC CCL-2 ) cell line according to procedures of MTT [ 3-(4,5-di-methylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide ] Assay [ Cell Proliferation Kit I (MTT) Roche-Germany ].

References

[1] Rostom S.A.F. Synthesis and in vitro antitumor evaluation of some indeno[1,2-c]pyrazol(in)es substituted with sulfonamide, sulfonylurea (-thiourea) pharmacophores, and some derived thiazole ring systems. Bioorganic & Medicinal Chemistry. 14(19):6475-6485, 2006.[2] Masereel B, Wouters J, Pochet L, Lambert D. Design, synthesis, and anticonvulsant activity of 1-(pyrid-3-ylsulfonamido)-2-nitroethylenes. J. Med. Chem. 41 (17): 3239–3244, 1998.[3] Soliman R, Feid-Allah HM, Mohamed HF. Preparation and antidiabetic activity of cyclic sulfonylthiourea derivatives. J Pharm Sci. 70(8):952-6, 1981.

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PP31

SYNTHESIS AND EVALUATION OF NOVEL 5-(3,4-DICHLOROPHENYL)-3-SUBTITUTEDPIPERAZINOMETHYL-1,3,4-OXADIAZOLE-2-ONES AS POTENTIAL ANTIMICROBIAL AGENTS

İrem ÖZKAN, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Yeditepe University, Kayışdağı, Turkey.Meriç KÖKSAL, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Yeditepe University, Kayışdağı, Turkey.Mine YARIM, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Yeditepe University, Kayışdağı, Turkey.Fikrettin ŞAHİN, Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, Kayışdağı, Turkey.Dilek DEMİR EROL, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Yeditepe University, Kayışdağı, Turkey.

Significant rise in microbial resistance against known agents triggerred scientists to explore novel drug can-didates [1]. In regard to literature data, 1,3,4-oxadiazole derivatives posses antibacterial, antifungal, anti-mycobacterial, antiviral, anticonvulsant, antiinflammatory and insectisidal properties [2-5]. In the present investigation, 1,3,4-oxadiazole derivatives were synthesized as potential antimicrobial agents. As a result, novel 5-(3,4-dichlorophenyl)-3-subtitutedpiperazinomethyl-1,3,4-oxadiazole-2-one derivatives evaluated for their antimicrobial activities. Identification of the compounds were done by elemental analyses, IR and 1H-NMR spectra. Activity screening of compounds were tested by disc-diffusion and MIC dilution meth-ods against Aspergillus spp., Fusarium oxysporium, Botrytis cinerea, Penicillium spp., B. meg, E. coli, S. aureus and P. aeroginosa strains.

General Formula of Novel Drug Candidates

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PP32

QUANTITATIVE DETERMINATION OF THE HEAVY METALS ( LEAD, ZINC AND MANGANESE ) IN WHITE CHEESE PRODUCED IN ERGENE BASIN BY USING ATOMIC ABSORBTION SPECTROPHOTOMETR

Aysen KURT CÜCÜ, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyHülya DEMİRCAN DEMİR, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyMustafa YAVUZ, Department of Analytical Chemistry, Graduate Studies in Pure and Applied Sciences, İstanbul, Turkey.

It’s known that hard metals are harmful for human being health. Such kind of harmful effects for each metal appear after spesific concantrations. This study is made for examining the quantity of hard metals in cheese that is produced in milk producers whichare in Ergene riverbasin. Milk producers around the Ergene river were searched and suitable ones were stabilized. It was very important to get the example because the re-sults could be effected directly. As a result of the experimental datas, upon the cheese which is produced in Ergene river basin and includes hard metals were prepared. These prepared cheese stock solutions into the atomic absorbtion spectrophotometer were determined the amount of Lead, Zinc and Manganese and the results were compared with the excepted scientific data and the evaluation was made. Analysis results of cheese produced in Ergene river basin were compared with literature results. For Lead, Zinc and Manga-nese results are found in acceptable limits (1,2,3,4,5,6,7).

References

1-Johnson, H. A.; Webb, H. B.; Alford,A. J.: “ Fundamentals of Dairy Chemistry “, The Avi Publishing Comp. Inc., Westport, Connecticut, USA, (1971), 24-28.2-Carmen, M.H.; Lourdes, A.: “Lebensm Unters Forsch”, 194, Spain, (1992) 541-544.3-World Health Organization, “Technical Report Series”, No:751, Evaluation of Certain, Food Additivies and Contaminants, Geneva, (1987).4-World Health Organization, “Technical Report Series”, No:505, Food Additivies and Contaminants, Geneva, (1972) 16-17.5-Allen, E. S.; Grimshaw, M.H.; Parkinson, J. A.; Quarmby, C.: “Chemical Analysis Ecological Materials”, John Wiley and Sons., New York, (1974).6-Skurikhin, I. M.: “Methods of Analysis Elements in Food Products 3. Limit of Determination of Methods for Assuring Safety”, J. Assoc. Off. Anal. Chem., Vol. 72, (1989).7-Bayraktaroğlu, G.:”Trakya Bölgesinde Üretilen Peynirlerde Bazı Ağır Metal İçeriklerinin Araştırılması”, Yüksek Lisans Tezi, Trakya Üniversitesi Fen Bilimleri Enstitüsü, Edirne, (1993).

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SPECTROPHOTOMETRIC AND SPECTROFLUORIMETRIC DETERMINATION OF PRAMIPEXOLE IN BULK DRUG AND DOSAGE FORMS

Armağan ÖNALDepartment of Analytical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, Turkey

Two new, sensitive and selective spectrofluorimetric and spectrophotometric methods have been developed for the determination of the pramipexole (PRM) in bulk drug and tablet. Methods are based on derivatiza-tion with the secondary amino group of PRM with 7-chloro-4-nitrobenzofurazon (NBD-Cl) in borate buffer of pH 8.5 where a yellow colored reaction product was obtained and measured spectrophotometri-cally at 474 nm. The same product could be measured spectrofluorometrically at 529 nm after excitation at 470 nm. Beer’s law was obeyed within a concentration range of 10–60 μg mL−1 spectrophotometrically and 0.3–3.0 μg mL−1 fluorimetrically. All the variables were studied to optimize the reaction conditions. The validity of both methods in terms of specificity, linearity, accuracy, precision and robustness, was evalu-ated. Good recoveries were obtained ranging from 99.30-101.47 %, indicating that no interference is ob-served from concomitants usually present in dosage forms. The described methods can be easily applied to quality control laboratories for the routine analysis of PRM in raw materials and pharmaceutical formula-tions.

Fig.1. Proposed reaction pathway between Pramipexole and NBD

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FORMULATION OF AN HAIR TONIC HERBAL LOTION AND EVALUATION ITS STABILITY

Gholamreza DEHGHAN, Pharmaceutics Research Center, Kerman University of Medical Sciences, Kerman, Iran. Fariba SFARIFIFAR, Pharmaceutics Research Center, Kerman University of Medical Sciences, Kerman, Iran. Khadije SHARIFIYAN, Pharmaceutics Research Center, Kerman University of Medical Sciences, Kerman, Iran.

Nowadays, Lotions are the most frequently prescribed treatment to the hair. Hair tonic and conditioner formulations include a large part of cosmetic products. They are may contain plant extracts and they most commonly used as means of conditioning hair and scalp. In this study extracts of three plants (Zingiber of-ficinalis roots and rhizomes, Arctium lappa roots and Vitis vinifera seeds) were prepared using maceration, and then lyophilized. In this study transparent o/w emulsion was prepared with nonionic surfactants in wide extensive HLB. Transparent o/w emulsions have been prepared using isopropyl myristate as oil phase and blend of non- ionic surfactants an emulsifier, by establishment of phase diagrams at different HLB values. The refractive index of aqueous phase was approached to oil phase by adding various polyols i.e., glycerin, propylene glycol and ethylene glycol. The most stable o/w transparent emulsions can be formed with blend of tween 80 and span 60. Glycerin has been found the more suitable polyol to form the transpar-ent o/w emulsions. Stability tests were performed at various temperatures (4oC, 25oC, 55oC) followed by centrifugation at 1500 rpm for 45 minutes. So, it has been concluded that the transparent o/w emulsions were stable over a period of 6 month. On the basis of results, formulated lotion can represent an attractive and suitable product to marketing cosmetic.

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NEW AND SENSITIVE SPECTROFLUORIMETRIC METHOD FOR THE DETERMINATION OF NON-STEROIDAL ANTI INFLAMMATORY DRUGS, ETODOLAC AND DICLOFENAC SODIUM IN PHARMACEUTICAL PREPARATIONS

Sevgi TATAR ULUDepartment of Analytical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, Turkey

Simple, rapid and highly sensitive spectrofluorimetric method is presented for the determination of non-steroidal anti-inflammatory drugs, etodolac and diclofenac sodium, in pharmaceutical preparations. Pro-posed method is based on the derivatization of two drugs with 4-fluoro-7-nitrobenzofurazan (NBD-F) in borate buffer of pH 8.5 to yield a yellow product. The optimum experimental conditions have been studied carefully. Beer’s law is obeyed over the concentration range 40–600 ngmL−1 for etodolac, 25–500 ngmL−1 for diclofenac sodium, respectively. The detection limits were found to be 0.071 ngmL−1 for etodolac, 0.055 ngmL−1 for diclofenac sodium. Intra-day and inter-day relative standard deviation and relative mean error values at three different concentrations were determined. The low relative standard de-viation values indicate good precision and high recovery values indicate accuracy of the proposed methods. The method is highly sensitive and specific. The results obtained are in good agreement with those obtained by the official method.

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DETERMINATION OF COMPLEXES OF ETHAMBUTOL - L -ASPARAGINE AND ETHAMBUTOL -L-GLUTAMIC ACID WITH CU(II) AND ZN(II)

Gülbin ERDOĞAN, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyDilek BİLGİÇ ALKAYA, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeySerap KARADERİ, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey

Ethambutol is an antimycobacterial agent that is most commonly used in combination with other drugs in the treatment of tuberculosis. It is also used as part of a combination regimen in the therapy of Mycobac-terium avium complex (MAC) infections in patients with or without concomitant infection with human immunodeficiency virus (HIV). Formation constants for copper(II) and zinc(II) complexes of ethambutol with aminoacids have been measured potentiometrically at 25° C I = 0.1 moldm-3 (NaCIO4). In this reason firstly binary and ternary complexes were measured by spectrophotometric method, the condition of binary complexes formation were examined by Job method. Stability constants were determinated and then as a first step, binary complexes of ethambutol with Zn(II) and Cu(II) were investigated by potentio-metric method using Irving-Rossotti procedure. As a second step, ternary complexes with aminoacids were determinated. In this paper, we review the stability constant of ternary complexes of etambutol with Zn(II), Cu(II) and with aminoacids, L-asparagine and L-glutamic acid, will be important from the point of being data for further studies on these complexes.

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MIXED LIGAND COMPLEXES OF PYRAZINAMIDE - L -ASPARAGINE AND PYRAZINAMIDE -L-GLUTAMIC ACID WITH CU(II) AND ZN(II)

Serap KARADERİ, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyGülbin ERDOĞAN, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyDilek BİLGİÇ ALKAYA, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey

Almost one third of the world’s population is infected with Mycobacterium tuberculosis which is treat-able with a six -month course of antibiotics. (PZA) is an important first-line drug for tuberculosis (TB) and appears to be the most important drug in killing latent Mycobacterium tuberculosis The emergence of strains resistant to PZA represents an important public health problem, as both primary and secondary line treatment schemes include PZA. PZA is coordinated to M(II) through the oxygen atom of the carbonyl group. Figure 1: Pyrazinamid Figure 2 : L - asparagine Figure 3: L-glutamic acid Formation constants for copper(II) and zinc(II) complexes of pyrazinamid with aminoacids have been measured potentiometrically at 25° C I = 0.1 moldm-3 (NaCIO4). In this reason firstly binary and ternary complexes were measured by spectrophotometric method , the condition of binary complexes formation were examined by Job method. Stability constants were determinated binary complexes of pyrazinamide with Zn(II) and Cu(II) by poten-tiometric method using Irving-Rossotti procedure. Also mixed ligand complexes with aminoacids were de-terminated. In the present paper, we report on the stability constant of ternary complexes of pyrazinamide with Zn(II), Cu(II) and with aminoacids, L-asparagine and L-glutamic acid.

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INVESTIGATION OF COMPLEXES OF ISONIAZID – L –ASPARAGINE AND ISONIAZID -L-GLUTAMIC ACID WITH CU(II) AND ZN(II)

Dilek BİLGİÇ ALKAYA, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey Serap KARADERİ, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyGülbin ERDOĞAN, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey

Isoniazid is an antitubercular drug which has been classified as a first line drug in spite of it is toxicity. The most common adverse reaction during antituberculous treatment is hepatic toxicity, other undesirable side effect observed during treatment is copper and zinc imbalances. Figure 1: Isoniazid Figure-2 : L - Aspara-gine Figure 3: L-Glutamic Acid Formation constants for copper(II) and zinc(II) complexes of isoniazid with aminoacids have been measured potentiometrically at 25° C and I = 0,1 moldm-3 (NaCIO4). In this reason firstly binary and ternary complexes were measured by spectrophotometric method, the condition of binary complexes formation were examined by Job method. Stability constants were determinated and then as a first step, binary complexes of isoniazid with Zn(II) and Cu(II) were investigated by potentiomet-ric method using Irving-Rossotti procedure. As a second step, ternary complexes with aminoacids were de-terminated. This study suggests that isoniazid toxicity can be lessened via complex formation and increased mycobactericidial action of isoniazid and copper(II) and zinc(II) binding by aminoacids may be account for a number of side effect of isoniazid treatment. As it seen from our investigation the stability constant of ternary complexes of isoniazid with Zn(II), Cu(II) and with aminoacids, L-Asparagine and L-Glutamic Acid, will be important from the point of being data for further studies on these complexes.

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HIGH-PERFORMANCE LIQUID CHROMATOGRAPHIC DETERMINATION OF FREE CISPLATIN IN PLASMA AFTER ADMINISTRATION OF CISPLATIN

Songül BUTUR, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyFiliz ÖZDEMİR, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyFikret Vehbi İZZETTİN, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey

Cisplatin is an antineoplastic agent used for treatment of different cancer types. Nephrotoxicity is a dose-limiting serious adverse effect of cisplatin. Plasma concentrations of nonprotein-bound (free) cisplatin is primarily responsible for nephrotoxicity that can be pharmacokinetically monitored. In this study the de-termination of free cisplatin has been studied in ultrafiltrate plasma (plasma samples were obtained from patients who had different cancer types and treated with cisplatin based chemotherapy) in the presence of nickel chloride as internal standard. Cisplatin (CDDP) and internal standard were chelated by exchange with diethyldithiocarbamate. After derivatization, the mixture was dissolved with methanol and directly injected into the coloumn. HPLC method was performed on C18 coloumn and methanol: water (80:20) were used as the mobile phase; flow rate was 1mL/min. The eluent measured spectrophotometrically at 254 nm for CDDP and the internal standard. The peak area of CDDP to the internal standard varied linearly with concentration over the range 0.1-2 µg/mL. Precision and reproductibility were both excellent and the limit of quantification was 0.05 µg/mL using only 0.5 mL of ultrafiltrate. This method can be suitable for therapeutic drug monitoring in patients receiving CDDP.

References: 1-Gerald K. McEvoy, Pharm.D. AHFS Drug Information, s. 979-984. 2006. 2-Augey V, Co-ciglio M, Galtier M, Yearoo R, Pinsani V, Bressolle F. High-performance liquid chromatographic deter-mination of cis-dichlorodiammineplatinum(II) in plasma ultrafiltrate.J Pharm Biomed Anal. 13:1173-8.1995. 3-Lopez-Flores A, Jurado R, Garcia-Lopez P. A high-performance liquid chromatographic assay for determination of cisplatin in plasma, cancer cell, and tumor samples. J Pharmacol Toxicol Methods. 52:366-72. 2005.

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EVALUATION OF DIFFERENT WORLD TEAS FOR ORAL AND DERMAL PRODUCTS

Gülşah GEDİK, Department of Pharmaceutical Technology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.Murat TÜRKOĞLU, Department of Pharmaceutical Technology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.

Introduction: Tea is a beverage obtained from the leaves of Camellia sinensis. It has been reported that tea extracts have antibacterial, antiviral, antidiabetic, antioxidative, anticarcinogenic and skin protective activi-ties against UV radiation. Because of these reasons, the importance of tea is increasing rapidly on pharma-ceutical field. The purpose of this study was to evaluate different world teas based on their polyphenol con-tents and UV-IR absorbing properties. Completion of this study will contribute to a better understanding of tea chemistry and correlating the health benefits with the tea quality.

Methods: Five green and 11 black tea samples were investigated. Two grams of tea samples were infused in 300 ml of boiling distilled water. The solution was cooled and further tests were carried out. The soluble fraction and moisture content of teas were determined using a gravimetric method. The infusions were prepared as 40 µg/ml in a flask and the absorbances between 200-1200 nm was measured using a UV-VIS spectrophotometer. The tea leaves and their freeze-dried forms were scanned in IR. Caffeine content of the samples were also measured.

Results and Discussion: The water soluble fraction of studied tea samples ranged between 24 - 43 %. The moisture content changed between 0.54 – 3.60 % and the caffeine content between 0.97 – 5.77 %, the pH of the infusions ranged between 5.2 -5.8 depending on the tea quality. There is a significant difference among the tea samples, in return the products made from tea extracts would differ in their expected biologi-cal effects.

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MODIFICATION AND OPTIMIZATION OF A HIGH PERFORMANCE LIQUID CHROMATOGRAPHIC METHOD FOR ASSAY OF BETAHISTINE

Sevinç SAHBAZ, Department of Pharmaceutical Technology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.Betül DORTUNÇ, Department of Pharmaceutical Technology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.

Betahistine (BH) is a drug used in the treatment of diseases accompanied by impaired peripheral circula-tion, e.g. Meniere’s syndrome and most of the patients have to take this drug three times a day. BH is a good candidate for transdermal delivery because of its low molecular weight, short elimination half life and low daily dosage range (1). Transdermal formulations containing BH will be prepared and evaluated by using in vitro, ex vivo and in vivo tests. For the ex vivo studies excised human epidermis and Franz diffusion cells containing 0,85% NaCl-10mM phosphate buffer pH 7.4 as a receptor fluid will be used. Aliquots of the receptor fluid will be withdrawn periodically for 24 hours, then be analysed. The aim of this study is to de-velop a suitable HPLC method for this analysis of transdermal therapeutic systems containing betahistine. Method is developed by modifying the methods used in the literature (2,3). The sample medium and the amount of ion-pairing agent were modified. The mobile phase was methanol- 0,025 M KH2PO4 (pH:3,0) (25:75) containing 5mM sodium 1- heptanesulfonate (1g/L). The retention time was increased about 3 minutes but a more symmetric and sharp peak was obtained. The peaks obtained with the previous and the modified method can be seen as Image 1-2.

References

1. Martindale The Extra Pharmacopoeia, 34th Edition, The Pharmaceutical Press, London, 2005.2. A. Khedr, M. Sheha, Stress degradation studies on betahisine and development of a validated stability- indicating assay method, J. Chrom. B, 869, 111-117, 2008.3. T. Ogiso, N. Niinaka, M. Iwaki, Mechanism for Enhancement Effect of Lipid Disperse System on Percutaneous Absorption, J. Pharm Sci., 85, 1, 57-64, 1996.

The peak obtained with the new method

The peak obtained with the new method

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DETERMINATION OF TRIMETAZIDINE FROM HUMAN PLASMA BY HIGH PERFORMANCE LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY

Elif AKSU, GLP Laboratory, Yeditepe University, Acıbadem, İstanbul, Turkey Z. Irem DILER, GLP Laboratory, Yeditepe University, Acıbadem, İstanbul, TurkeyDürişehvar ÖZER ÜNAL, GLP Laboratory and GCP Clinics, Yeditepe University, Acıbadem, İstanbul, TurkeyDilek DEMİR EROL, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Yeditepe University, Kayışdağı, İstanbul.

Trimetazidine [1-(2,3,4-trimethoxybenzyl) piperazine dihydrochloride] is a clinically effective anti-anginal agent. By switching energy substrate preference from fatty acid oxidation to glucose oxidation and, it has a direct anti-ischaemic effect on the myocardium without affecting myocardial oxygen consumption and cor-onary blood flow [1]. A simple and sensitive high performance liquid chromatographic method with MS detection (HPLC-MS) for the determination of trimetazidine from plasma was developed and validated. Liquid-liquid extraction was used for extracting trimetazidine from plasma. (Ethlyacetate:İsoamylalcohol) (98:2) was used as extraction solvent. The chromatographic separation of trimetazidine and lidocaine (IS) was carried out using reverse phase Zorbax Eclipse XDB-C18 (4.6×150 mm, 5µm) with mobile phase of Methanol:Water:TFA (40:60:%0.1) (v/v)]. The flow rate of mobile phase was 0.6 ml/min, injection vol-ume was 5 µl. The mass spectrometric parameters were optimized to obtain maximum sensitivity at unit resolution. Atmospheric pressure ionization-electrospray mode(API-ES) was used at positive ionization. Data was collected by selected ion monitoring (SIM). The ions used to quantify were selected as m/z 267.2 for trimetazidine, m/z 235.1 for IS. The calibration curve was linear within the concentration range 2.5-200 ng/ml for trimetazidine. The limit of quantification was 2.5 ng/ml trimetazidine with good accuracy and precision. The stability was assesed under a variety of conditions and found that appropriate for the quantification. The method developed can be used for bioequivalence and pharmacokinetic studies.

References

1. Y. Jiao et al. / Journal of Pharmaceutical and Biomedical Analysis 43 (2007) 1804–18072. Guidance for Industry, Bioanalytical Method Validation, FDA, May 2001

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CAPILLARY ELECTROPHORESIS METHOD FOR THE DETERMINATION OF LACTULOSE AND MANNITOL FOR ESTIMATING INTESTINAL PERMEABILITY

Ebru TÜRKÖZ ACAR, Faculty of Pharmacy, Yeditepe University, Kayışdağı, İstanbul. Durişehvar ÖZER ÜNAL, GLP Laboratory and GCP Clinics, Yeditepe University, Acıbadem, İstanbul, TurkeyMehmet KOÇ, Department of Internal Medicine, Faculty of Medicine, Marmara University, Altunizade, İstanbul, TurkeyDilek DEMİR EROL, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Yeditepe University, Kayışdağı, İstanbul.

The evaluation of changes in intestinal permeability and monitoring the intestinal mucosa integrity is mea-sured by lactulose to mannitol ratio in urine. The lactulose-mannitol ratio test is highly sensitive test for the screening of the diseases such as Crohn’ s disease, atopic dermatitis, cow’ s milk proteins intolerance, cystic fibrosis, diarrhea, HIV infection and diabetes. The test is based on the oral administration of both lactulose and mannitol and determination of their excreation rate in urine. In this study, sensitive and specific capil-lary electrophoresis method developed for the determination of lactulose and mannitol from urine. For CE analysis Agilent 3D Capillary Electrophoresis system with DAD detector was used. In this method reversed polarity mode was used and LAC and MAN were monitored by indirect UV detection using sorbic acid. The background electrolyte (BGE) consisted of 6 mmol/L sorbic acid, 1.25mmol/L hexadecy-ltrimethylammoniumbromide (HDTMA), 50 mmol/L LiOH (pH 12.5) .Urines were pruified prior to analysis with solid phase extraction. The linear ranges for lactulose and mannitol from urine were 0.02-0.4 mg/ml and 0.3-2.0 mg/ml respectively. The developed method can be applied successfuly to patients who are tested intestinal permeability by lactulose to mannitol ratio in urine.

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VALIDATION AND DETERMINATION OF MONTELUKAST FROM HUMAN PLASMA USING HIGH PERFORMANCE LIQUID CHROMATOGRAPHY - FLOURESCENCE DETECTION

Reyhan CEYHAN, GLP Laboratory and GCP Clinics, Yeditepe University, Acıbadem, İstanbul, TurkeyDurişehvar ÖZER ÜNAL, GLP Laboratory and GCP Clinics, Yeditepe University, Acıbadem, İstanbul, TurkeyDilek DEMİR EROL, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Yeditepe University, Kayışdağı, İstanbul.

Montelukast is a potent and selective antagonist of the cyteinyl leukotriene receptor used for the treatment of asthma. A simple and sensitive high performance liquid chromatographic method with fluorescence detec-tion (HPLC-FLD) for the determination of Montelukast from plasma was developed and validated. Liquid-liquid extraction was used for extracting Montelukast from plasma. (Ethlyacetate:İsoamylalcohol) (98:2) was used as extraction solvent. The chromatographic separation of Montelukast and Loratadin(IS) was car-ried out using reverse phase Altima C18 (4.6×150 mm, 3µm) with mobile phase of Acetonitrile:Ammonium Acetate ( 10 mM, pH: 3.0)(70:30) (v/v)]. The flow rate of mobile phase was 1.0 ml/min, injection volume was 20 µl. The fluorescence detector was set to excitation and emission wavelengths of 350 and 400 nm for the determination of montelukast and 290 and 360 nm for the determination of Loratadine respectively. The calibration curve was linear within the concentration range 5-1000 ng/ml for Montelukast. The limit of quantification was 5 ng/ml with good accuracy and precision. The stability was assesed under a variety of conditions and found that appropriate for the quantification. The method developed can be used for bioequivalence and pharmacokinetic studies.

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DETERMINATION OF ALUMINIUM(III) AND COPPER(II) COMPLEXES OF QUERCETIN BY HPLC

Deniz ÇIKLA YILMAZ, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyMürşid PEKiN, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyEmre DÖLEN, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey

Quercetin is one the most common flavonol present in nature that has attacted the attention of many researchers because of its biological and pharmaceutical properties. It is a strong antioxidant and a major dietary flavononoid fonund in many food apple, tea, onion, berries and vegetables (1). Furhermore flavo-noids are metal ion chelators. Antioxidant activity of cobalt–quercetin complex (2), antitumor properties of copper-quercetin complex (3), zinc- quercetin complex (4), rare earth (III)-quercetin complexes (5)were investigated. A reversed phase high pressure liquid chromatographic method was developed for the determination aluminium and copper complexes of quercetin. Mobile phase was 0.01 M HCLO4 / 8.33 x 10-5 M quercetin in methanol (40/60), column was XTerra RP18, 5 μm, 4.6 x 150 mm, detector was Diode Array Detector at λ = 373 ve 420 nm (band width 4nm). For quercetin - aluminium(III) peak retention time was 3.706 and tailing factor was 0.957. For quercetin - copper(II) peak retention time was 3.606 and tailing factor was 1.303.

References

1- Erlund I. (2004). Nutrition Research. 24:851-874.2- Bukhari SB, 1, Memon S, Tahir MM, Bhanger MI. (2008). Journal of Molecular Structure, 892:39–463- Tan J, Wang B, Zhu L. (2009). Journal of Biol Inorg Chem, 14:727–739.4- Zhou J, Wang L, Wang J, Tang N. (2001). 26:57-63.5- Zhou J, Wang L, Wang L, Wang J, Tang N. (2001). Journal of Inorganic Biochemistry, 83:41-48.

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RAPID QUANTIFICATION OF LEVETIRACETAM IN HUMAN PLASMA AND TABLETS BY LIQUID CHROMATOGRAPHY

Armağan ÖNAL, Department of Analytical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, Turkey Sena ÇAĞLAR, Department of Analytical Chemistry, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, Turkey

Epilepsy is a common comorbidity among developmentally disabled patients, and special considerations apply to its treatment. Levetiracetam (LEV), [(S)-α-ethyl-2-oxo-pyrrolidine acetamide] is a novel anti-epi-leptic drug mechanistically and structurally unrelated to the existing anti-epileptics [1,2]. A simple reverse-phase high-performance liquid chromatographic method for the determination of LEV in human plasma and tablets has been developed and validated. The assay of the drug was performed on a C18 column (5 μ, 250 x 4.6 mm i.d.) with UV detection at 205 nm. The mobile phase consisted of phosphate buffer (pH:6): acetonitrile mixture in the ratio of 90:10, and a flow rate of 1.0 mL-1 min was maintained. The standard curve was linear over the range of 2.0-50 µg mL-1 (r2=0.9997). The limit of detection was found to be 0.5 µg mL-1 in human plasma samples. The inter-day precision was from 2.97 to 5.02 % and the intra-day pre-cision ranged from 3.24 to 5.78 % for plasma. The average absolute recovery from spiked plasma samples were 95.89±0.91. This method could be used without any interference from tablet matrix and endogenous substance from the plasma samples. The applicability of the method to the plasma and tablet analysis was also studied. The method can easily be applied to drug monitoring.

References

1. Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Loiseau P, Perucca E, (1999) Epilepsy Research. 34, 1–41.2. Hovinga CA, (2001) Pharmacotherapy 21, 1375–1388.  

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SEPERATION OF MOLLUSCAN INDIGOID DYES BY HPLC WITH DIODE-ARRAY DETECTION

Çağlar DEMIRBAĞ USTA, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyEmre DÖLEN, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey

Indigotin, indirubin and their brominated derivatives are natural dyes which derived exclusively from ma-rine shellfish of the Muricidae and Thaisidae families. This molluscan dyes has been known since pre-Ro-man times and in the Mediterranean region there is evidence for the industry around 13th century B.C. (1,2) Indirubin is an active ingredient of Danggui Longhui Wan, a traditional Chinese medicine recipe used to treat chronic diseases such as leukemias. A variety of indirubins were identified as a powerful in-hibitors of glykogen synthase kinase-3 (GSK-3). GSK-3 has a clear implication in various human diseases like diabetes, cancers, Alzheimer’s disease.(3,4) In this study a high performance liquid chromatography (HPLC) method is developed for the seperation of seven indigoid natural dye compounds. HPLC is com-bined with diode-array detector and the mobile phase consisted of a water/ acetonitrile gradient with 0.1% trifluoroacetic acid. Despite similarity of molecular structures of indigoid compounds a good seperation was achieved with this method according to other studies.(5,6)

References

1. McGovern PE., Michel R.H.(1985). Anal Chem, 57:1514-1522.2. Cooksey CJ. (2001). Molecules, 6: 736-769.3. Meijer L., Skaltsounis AL., Magiatis P., Polychronopoulos P., Knockaert M., Leost M., Ryan XP., Vonica C.A., Brivanlou A., Dajani R., Crovae C., Tarricone C., Musacciho A., Roe SM., Pearl L., Greengard P.(2003). Chem Bio, 10: 1255-1266.4. Zhang N., Jiang Y., Zou J., Zhang B., Jin H., Wang Y., Yu Q.(2006). Eur J Med Chem, 41: 373-378.5. Karapanagiotis I., Villemereuil V. (2006). J Liq Chromatogr R T, 29:1491-1502.6. Koren ZC.(2006). Indirubin, the red shade of indigo. Life in progress Editions, Roscoff, France, 5:45-53.

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ANALYSIS OF COLOR DIFFERENCE OF TEA INFUSIONS

Gülşah GEDİK, Department of Pharmaceutical Technology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeySerap AYAZ, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

The infusion color difference analysis was carried out in a spectrocolorimeter (Konica Minolta CM 2300 d, Japan). The white little cup supplied by the spectrocolorimeter was used as background. To diminish the errors arising from different determination conditions, such as different equipment , depth, reflection and the infusion colour difference indicators of Δ L, Δ a, Δ b and Δ E, which represent the light–dark (Δ L), red–green (Δ a), yellow–blue (Δ b) and total color differences (ΔE) in the three dimensional color co-ordinate system among the tea infusions . Soluble fraction content of caffeine, pH, chemical composition, color differences of tea infusions and their relationships were analysed. Although it is possible to find many studies related to black or green tea, our study is going to contribute to tea research, since the teas used in the literature were not evaluated based on colorimetric studies. In this study, we have tested many regional tea samples to characterize their infusions specific color.

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PP49

THE IMPROVEMENT OF AN ISOLATION METHOD FOR GENISTEIN IN A NON-GENETICALLY MODIFIED SOYBEAN SPECIES BY ACCELERATED SOLVENT EXTRACTION

Güler YALÇIN, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyElif SARAYOĞLU, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

Introduction: Soybean isoflavone Genistein (GS) has been considered as an antioxidant in preventing tu-mour initiation, promotion and oxidative damage (1). The isolation conditions of GS was improved and optimized in a non-genetically modified soybean species by accelerated solvent extraction (ASE) and the amount of the GS in soybean was found in this study. ACCELERATED SOLVENT EXTRACTION AND CHROMATOGRAPHIC PROCEDURE The soybean samples were grinded, dried, sieved in cer-tain conditions. Soybean powder and diatome earth were wrapped with a filter paper and transferred into extraction cell. Extraction solvent: 90 % (v/v) aqueous methanol, temperature: 100°C, static cycle: 3, static time: 10 min., flush volume: 60 %, pressure: 1500-1600 psi, purge time: 90 sec. were used. Reverse Phase-HPLC method of Mitani, K et al was used (2). Injection sample: The supernatants were evaporated to dry-ness at 60°C. The residue was dissolved in the 10 ml of the mobile phase and filtered. Retention time of GS: 6.9 min. The reproducibility of the peak areas was found as 1.99 % RSD. Recovery procedure: Standard solutions in three different concentrations were spiked to the samples. The recoveries was found 90.66 % with the RSD % of 4.70. Calibration Graph: y=320,49 x + 1.93 was found for three measurements. The amount of genistein in dried soybean was found 0.068 mg g-1 .

Results and Discussion: The developed extraction method is reproducible, easy and fast for determining the GS. It can be applied all the solid commercial products in the market.

Acknowledgements

We would like to thank to Marmara University Research Fund, Istanbul, Turkey for its financial support.

References

1- Caragay, A. B., Cancer-preventive foods and ingredients, Food Technol. 1992; 46: 65-68.2- Mitani K., Narimatsu S., Kataoka H., J. of Chromatography A, 2003; 986: 169-177.

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PP50

INVESTIGATION OF THE IMPURITIES OF ELLAGIC ACID FROM CHESTNUT TREE BARK BY CHROMATOGRAPHIC METHODS

Güler YALÇIN, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyLevent ÖZGÜL, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyBerna İŞYAPAN, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

Introduction: Ellagic Acid (EA) is a polyphenolic compound which exists in higher plants (1). EA have antiviral, antimutagenic, antioxidant, anticarcinoenic effects (2). The aim of this study is to investigate the impurities of the powder of EA from chestnut tree bark (95%) in the market. RP-HPLC CONDITIONS Elution Profile: The gradient profile was given in the Table 1. , Column: Luna 5µm C18 (2) 250 x 4.6 mm, Mobil phase: A: 0.02 M KH2PO4 pH = 3.0, B: Acetonitrile, Detection: DAD, λ=255 nm. Ellagic Acid RtEA :15.99 min. Two main unknown impurities (X, Q) resolved with Rt,X of 14.43 min, and Rt,Q of 27.46 min. The peak purity was 995.95 and tailing factor was 1.136. TWO DIMENTIONAL THIN LAYER CHROMATOGRAPHY Stationary phase: Silicagel 60 F254 Merck, Mobil phase I: Toluene: THF: Formic Acid-MeOH ( 3:3:0.8:0.2 v/v), Mobil phase II: Toluene: THF: NH3: MeOH (3:3:0.8:0.2 v/v). Retention Factors: Ellagic Acid Rf, EA : 0.79 and the unknown impurity X Rf,Y: 0.18

Results And Discussion: Two main impurities have been detected by HPLC. The less apolar one, compar-ingly to EA, has Rt,X = 14. 43 min. Whereas, just one impurity has been detected by two dimentional TLC. The spot of the impurity detected by TLC has Rf,y of 0.18. It is planned to identify two impurities by spectroscopic methods and check if these two are the same ones.

Acknowledgements: We would like to thank to Marmara University Research Fund, Istanbul, Turkey for its financial support.

References

1. Hakkinen, S.H, Karenlampi, S.O.,Mykkanen,H.M., Heinonen, I.M., Törrönen, A.R. (2000) Ellagic acid content in berries: influence of domestic processing and storage, European Food Research and Technology, 212, 75-80.2. Bala, I, Bhardwaj, V., Hariharan, S., Kumar, M.N.V.R., (2006) Analitical methods for assay of ellagic acid and its solubility studies, Journal of Pharmaceutical and Biomedical Analysis,40, 206-210.

Table 1: Gradient profile of the RP-HPLC system

Time %B Flow Rate (mL/min) 0.00 7.00 1.000 8.00 7.00 1.000

13.00 40.00 1.000 18.00 50.00 1.000 23.00 7.00 1.000

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PP51

INVESTIGATIONS ON MOUTH & TOOTH PRODUCTS

Sema ALTAN, Department of Pharmaceutical Technology, Faculty of Pharmacy, Ankara University, 06100 Tandoğan, Ankara.Nefise ÖZLEN ŞAHİN, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ankara University, 06100 Tandoğan, Ankara

The most important problem is the lack of studies focused on investigating the pharmaceutical and micro-biological aspects of cosmetic products in literature. In this study, it was aimed to investigate the mouth and tooth products collected from the markets, pharmacy stores and spice shops with respect to pharmaceuti-cal and microbiological aspects. 8 out of the 11 tested products were non-used whereas 3 products were collected following a month of use by consumers. Therefore, it would be possible to determine the micro-biological contamination because of consuming the product. The products under investigation were in-vestigated using conventional microbiological tests and pharmaceutical quality control tests. No pathogen microorganism should exist in a cosmetics product and the number of live microorganism in the products to be used in or around the mouth shouldn’t exceed 100 per gram or mililiter as stated in the guidelines of Turkish Standard Isntitute. In addition, total number of live microorganisms was calculated and also, pharmaceutical quality control tests were carried out. Microbiological test were conducted on both groups prior to and after the accelerated stability study. Result of the tests, 3 consumed products showed microbio-logical contamination with the detection of microorganisms more than 10³ per gram or milliliter. However, only one of the nonused products indicated microbial contamination higher than the acceptance limits. Pathogen microorganisms were detected in some of the consumed and nonused products even though they claim to have antimicrobial agents in their formulae. Accelerated stability test was also conducted at 4[ord]C and 30[ord]C for 90 days. Change in pH and viscosity were determined after the stability study. Mouth wash products subjected to high temperature showed loss of volume. Phase separation was found in semi-solid products. All products undergone stability study was tested for microbiological contamination after 90days. No change was observed.

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PP52

DEVELOPMENT OF VARIOUS TYPES OF SURFACE MODIFIED TITANIUM DIOXIDE FORMULATIONS BASED ON NANOSTRUCTURED LIPID CARRIERS (NLC) FOR UV PROTECTION

Melike ÜNER, Department of Pharmaceutical Technology, Faculty of Pharmacy, İstanbul University, 34116 Bayezit, İstanbul, TurkeyRainer H. MÜLLER, Department of Pharmaceutics, Biopharmaceutics and NutriCosmetics, Freie Universität Berlin, Germany.

Decrease in the ozone layer causes greater incidences of skin cancer and various disorders. Physical sun-screens such as TiO2 are can be prefered since molecular sunscreens can penetrate into the skin and cause side effects. However, TiO2 dye the skin by increasing particle size. Additionally, there is an reverse rela-tionship between its UV reflecting effect and particle size. TiO2 in nanometer size range introduces an alternative to overcome to these problems. However, TiO2 in 10-20 nm size range can also be disscussed since such small particles can penetrate into the skin via the skin channels approximately in 50 nm diam-eter. Therefore, there is a need to develop sunscreen formulations avoiding undesired effects. This could be achieved by incorporation of TiO2 into the solid particle matrix of NLC. The particles are retained in the lipid nanoparticle due to higher particle size of NLC than diameters of skin channels. NLC also provides a “prolonged release system” which delays the release of TiO2 to the skin for 6-8 hours. Surface modified TiO2 types including UV-TITAN M160, UV-TITAN M170 and UV-TITAN X195 were formulated with various types of lipids and surface active agents by using high pressure homogenization method. Par-ticle size analysis were performed by photon correlation spectroscopy (PCS) for particles in 3 nm-3 µm size range, and laser diffraction (LD) for particles in 100 nm-2000 µm size range by volume (D50, D90 and D99). It was observed that UV-TITAN X195 was not suitable to formulate with carnauba wax and Tween® 80. D50 values of all NLC dispersions of UV-TITAN M160, UV-TITAN M170 were lower than 0.5 μm. Polydispersity index between 0.23 and 0.46 obtained from PCS measurements were supported this obser-vation indicating particle size range in 267 nm-436 nm for TITAN M160 and UV-TITAN M170 loaded NLC dispersions.

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PP53

PREPARATION, CHARACTERIZATION AND BIOAVAILABILITY ASSESSMENT OF PIROXICAM TOPICAL DRUG DELIVERY SYSTEM

Abdelazim ZAGHLOUL, Department of Pharmaceutics, Faculty of Pharmacy, Kuwait University, KuwaitFathy ABDALLAH, Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt Hamdy DAWABA, Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt Ahmad SAMY, Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt

Objectives: this study aimed to increase the solubility and availability of a poorly soluble drug; piroxicam through preparation of thermodynamically stable microemulsion (ME) formulations. Characterization, stability and in-vivo bioavailability studies were performed.

Methodology: included investigating the solubility of piroxicam in different oils, surfactants (S) and cosur-factants (CoS). The ingredients showing high solubility were used to prepare different ME formulations. Triangular phase diagrams were plotted to outline the areas of ME formation upon dilution with water. Formulations showing good emulsifications were evaluated for their particle size and shape, drug solubi-lization, viscosity, electric conductivity and in-vitro drug release. The accelerated and shelf-life stability of selected formulations was evaluated. The passed formulations were subjected to bioavailability study in albino rats. Results: indicated that oleic acid (solvent), Tween 80 (S), and propylene glycol (CoS) have high solubility of piroxicam and used to prepare pre-ME. The triangular Phase diagrams showed 10% oil, 30-70% S, 20-60% CoS and 0.5% drug loading led to stable ME formulations on dilution with 50% water. The particle size ranged from 100 to 500nm of nearly spherical shape, the viscosity ranged from 10000 to 45000 cp and the highest drug solubility (5.87 mg/ml) was obtained when the ratio of CoS:S was 0.29:1. The electric conductivity showed O/W ME type upon dilution with water up to 400% of the preME. The highest percent drug released (74.2%) was observed in ME composed of 10% oil, 60% S and 30% CoS. The tested formulations showed stability towards accelerated and shelf-life stability. The analgesic and anti-inflammatory effects of these formulations were comparable to the market formulation (Feldine gel®).

Conclusions: the incorporation of piroxicam in ME led to improvement in its solubility and in-vitro avail-ability. The prepared formulations were stable and have high potential for analgesic anti-inflammatory ef-fects on topical application.

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PP54

PREPARATION AND CHARACTERISATION OF NANOPARTICLE FORMULATIONS CONTAINING DOXYCYCLINE

Çiğdem YÜCEL, Department of Pharmaceutical Technology, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey Zeliha Gül DEĞİM, Department of Pharmaceutical Technology, Faculty of Pharmacy, Gazi University, 06330 Etiler, Yeni Mahalle , Ankara, Turkey.

Doxycycline is a semi-synthetic antibiotic, derived from tetracycline. It has been used to overcome various type of infections.1,2 Nanoparticles are solid and their size vary 10nm to 1000nm. The par-ticles with a therapeutic agent of interest encapsulated within the polymeric matrix or conjugated onto the surfaces. 3,4 In this study, nanoparticle formulations of doxycycline were developed. Nanoparticles were prepared with different amount of polymer(Eudragit-RS-100) using Ultraturrax® applying various rates(8000,9500,13500rpm). The size of particles and zeta potentials were determined using Malvern Zeta-sizer Nano series. Eudragit-RS-100 was used as a polymer. The polymer(1000-2000mg) was dissolved in methanol at the room temperature then it was injected slowly(0.5 mL.min-1) into aqueous phases contain-ing Doxycycline and 0.4% PVA(polyvinilalcohol). The mixture was stirred at 8000,9500 and 13500rpm by Ultraturrax® for 5 minutes. Particle sizes and zeta potentials were determined. Nanoparticle sizes were determined to be 68nm±0.001 to 307nm±0.001 depending on stiring rate and amount of the polymer used. Similarly zeta potentials were measured to be 3.5±0.226mV to 6.45±2.56mV. The encapsulation ef-ficiency was found to be 54.6% for 8000rpm, 36.1% for 9500rpm, 20% for 13500rpm when 1000mg. polymer was used. It was 83.4% for 8000rpm, 60.4% for 9500rpm, 49.1% for 13500rpm when 2000mg. polymer was used. Polydispersity index of formulations were evaluated to be 0.315, 0.392, 0.54 and 0.314, 0.341, 0.371 for 8000, 9500, 13500rpm when 1000mg or 2000mg polymer was used respectively. As a result, formulations were selected for futher experiments considering higher encapsulation efficiency and smaller polidispersity index.

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PP55

FORMULATION AND CHARACTERIZATION OF FUCOSPHERES CONTAINING OFLOXACIN

Ali Demir SEZER, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyJülide AKBUĞA, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey

Ofloxacin, second-generation fluoroquinolone, is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. It is used in pneumonia, urethritis and urinary tract infections, cervicitis, acute pelvic inflammatory disease, and prostatitis. Despite these effects; ofloxacin has a short biological half life, is not to stable in serum conditions and it requires frequent usage during the treat-ment. Being a sustained release dosage form, microspheres allow ofloxacin to exhibit improved release and absorption profiles. The objectives of this study were to prepare ofloxacin encapsulated fucoidan-chitosan (fucosphere) and chitosan microspheres and to investigate the effect of the formulation parameters on the properties of the prepared microspheres. Ofloxacin encapsulated fucospheres were prepared by polyion complexation of fucoidan with chitosan and chitosan microspheres were prepared by precipitation meth-od. The effect of polymers, drug and cross-linking agent concentrations and chitosan molecular weight on particle size and charge, encapsulation capacity and release properties of the microspheres were the investigated parameters. Fucospheres and chitosan microspheres size range are 0.61-1.48 [mic]m and 1.05 – 2.08 [mic]m. The zeta potential values of the microspheres were between 5.6 – 28.0 mV (fucospheres) and 22.3 – 42.4 mV (chitosan microspheres). The encapsulation capacity of fucospheres were between 63.9 and 96.3 % depending on the fucoidan concentrations and chitosan molecular weight used in the formula-tion. All formulation parameters affected the particle size, encapsulation capacity and release profiles of the microspheres. The cumulative in vitro release of ofloxacin from the particles was found to retard the release of drug. The release mechanism of microspheres was proposed to be zero order kinetic model, and to be controlled by the Mw and the cross-linking density of shell. It can be concluded that ofloxacin encapsulated fucospheres might be a potential delivery system for antibiotics application.

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PP56

A STUDY ON SOLUBILIZATION OF THEOPHYLLINE BY [BET] -CYCLODEXTRIN

Sinem GÖKTÜRK, Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey. Neşe ERDİNÇ, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.

Cyclodextrins can increase the apparent solubility and dissolution rate of poorly water soluble drug candi-dates improving their biopharmaceutical performance. The most commonly used α-,β- and γ-cyclodextrins consist of six to eight glucopyranose units, respectively, and possess hydrophilic exterior and hydrophobic internal cavity. Placing inside the cyclodextrin molecular cavity the substrate can considerably improve physico-chemical and pharmacological properties (solubility, stability, bioactivity, etc.). β-Cyclodextrin (β-CD) has an amphiphilic character due to an apolar cavity that shows a certain degree of selectivity in binding organic and inorganic compounds and a hydrophilic annulus consisting of a number of hydroxyl groups. In the present study Theophylline (1,3-dimethylxanthine, TP) has been chosen a model drug to study the interaction with β-CD in aqueous media. TP is a poorly water soluble purine alkaloid and widely used in medicine (1-3). The interaction and inclusion complex formation of TP with β-CD has been stud-ied by means of UV-vis spectroscopy. Aqueous solutions of TP containing wide concentration range of β-CD have been prepared and the absorbance spectra recorded. The changes of absorbance were observed as a function of the concentration of β-CD added. Properties of inclusion complex between TP and β-CD such as aqueous solubility and the association constants of this complex have been determined. The phase-solubility diagrams have been drawn from UV spectral measurements. The water solubility of TP was in-creased by inclusion complexation with β-CD. The binding constants (Kb) and fraction of bound TP to β-CD were calculated by means of the Benesi-Hildebrand Equation. The results show that β-CD addition is promising approach for enhancing the solubility of TP.

References

1. Venkatramana M. Raoa, M. Nerurkar, S. Pinnamaneni, F. Rinaldi, K. Raghavan , International Journal of Pharmaceutics. 2006; 319: 98–106.2. Szente L, Szejtli J. Adv Drug Deliv Rev.1999; 36:17-38.3. Loftsson T, Brewester M. J Pharm Sci.1996;85:1017-1025.

147

PP57A COMPERATIVE SOLUBILITY ENCHANCEMENT OF POORLY SOLUBLE DRUGS WITH SODIUMDODECYLSULFATE MICELLES AND [BET] -CYCLODEXTRIN

Sinem GÖKTÜRK, Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyElif ÇALIŞKAN, Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyR.Yeşim TALMAN, Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyÜmran VAR, Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey

Many researchers are interested in the development of an appropriate dissolution medium for such drugs to overcome solubility problems. One approach to improving dissolution was to use a large amount of dissolu-tion medium. A co-solvent method was also used to increase drug solubility. Other researchers have used surfactants to increase drug solubility. Of the various methods investigated, the use of media containing surfactants was proposed as a suitable method for solubilizing such drugs, because various surfactants are present in the gastrointestinal fluid, e.g., bile salts, lecithin, cholesterol and its esters. Recently, Cyclodex-trins have received increasing interest in the pharmaceutical field because of their ability to solubilize and in some instances stabilize, poorly water-soluble drug candidates enabling both oral and parenteral formu-lation (1-4). In this work two poorly soluble drugs i.e. Sulfamethoxazole (SM) and Trimetoprim (TMP) were chosen model drugs to study their solubilization behaviour by [bet]-CD and Sodiumdodecyl sulfate (SDS) micelles. Interactions between two types of drugs and anionic surfactant SDS and [bet]-CD were studied by measuring UV spectra of each drug. The studied drugs of binding constants to SDS micelles and [bet]-CD were calculated using Benesi-Hildebrand Equation. Solubility of drugs in various media and the partition coefficients of drugs into micelles were found to depend on drug characteristics.

References

1.M.A. El-Massik, I.A. Darwish, E.E. Hassan and L.K. El-Khordagui, Int. J. Pharm. 1996: 140;69–76. 2.Maggi, M.L. Torre, P. Giunchedi and U. Conte, Int. J. Pharm. 1996: 135; 73–79.3.Kawakami K, Naohiko O., Miyoshi K., Funaki T., Ida Y. European Journal of Pharmaceutical Sciences 2006:28; 7–14.4.Corrigan O.I., Drug Dev. Ind. Pharm. 1991:17; 695–708.

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PP58

SOLUBILIZATION BEHAVIOUR OF PHENOTHIAZINE WITH COMBINED USE OF SURFACTANTS AND COSOLVENT: RELEVANCE IN DRUG DELIVERY

Sinem GÖKTÜRK, Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyÜmran VAR, Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey

Poor aqueous solubility is a common concern in the pharmaceutical sciences. Surfactants are amphiphilic molecules, consisting of both hydrophilic and hydrophobic regions. These substances are known to play a vital role in many processes of interest in both fundamental and applied sciences. One important property of surfactants is the formation of colloidal-sized clusters in solutions, known as micelles which have par-ticular significance in pharmacy because of their ability to increase the solubility of poorly soluble drugs in water, thus increasing their bioavailability. Therefore, the utilization of aqueous micellar solutions for drug solubilization can be advantageous for drug delivery purposes, with the possibility of increasing water solu-bility of poorly soluble drugs, improving bioavailability, reducing toxicity and other side effects, enhanc-ing permeability across the physiological barriers, and substantial change in drug distribution. Cosolvent solubilization is also particularly important for parenteral dosage forms where it is desirable to incorporate the required dose as a true solution in the smallest volume of liquid as possible (1-2). This work deals with the solubilization behavior of a poorly soluble model drug, phenothiazine (PHT), under combined use of anionic and nonionic surfactants (sodium dodecyl sulfate (SDS), TritonX-100). The influence of ethanol (EOH) on micellar solubilization of PHT was also studied. Solubilization capacity determined with spectrophotometry has been quantified in terms of molar solubilization ratio, micelle–water partition coefficient and locus of solubilization. The solubility of PHT in the aqueous surfactant solutions increased linearly with increase of the surfactant concentration. When various amounts of ethanol (v/v) were added to the aqueous surfactant solutions, its effect on the solubility depended on the combination of the surfac-tant and the cosolvent.

References

1. Torchilin, V.P. J. Control. Rel., 2001:73;137-172.2. Atwood, D., Florence, A.T. Physicochemical principles of pharmacy. 3rd ed. London: The MacMillan Press, 2003.

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PP59

EX VIVO DIFFUSION OF CAPTOPRIL FROM SINGLE AND DOUBLE LAYERED MATRIX TRANSDERMAL THERAPEUTIC SYSTEMS

Oya SİPAHİGİL, Department of Pharmaceutical Technology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyEbru KESKİN, Department of Regulatory Affairs, Actavis Pharmaceuticals, İstanbul, Turkey. Betül DORTUNÇ, Department of Pharmaceutical Technology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey

Introduction: Captopril is the first orally effective angiotensin converting enzyme inhibitor developed and marketed. It is used in the chronical treatment of hypertension, congestive heart failure and left ventricular dysfunction post-myocardial infarction as first agent because of the absence of side effects in the majority of the patients. It has a relatively short elimination half life in plasma (2 h) and low oral bioavailability (60-75%) (1). The aim of our study was to develop a captopril containing transdermal therapeutic system (TTS) and to evaluate the ex vivo diffusion profiles of captopril from these formulations using human skin.

Experimental Methods: Captopril containing TTSs were prepared according to a previous study (2). Gen-eral appearance, transparency, color, softness, homogeneity, flexibility as well as thickness and captopril content of the TTSs were evaluated (Table 1). Ex vivo diffusion experiments were conducted using Franz diffusion cells. Excised human skin from a female volunteer (40 years old), who had undergone abdominal plastic surgery, was used as the diffusion surface.

Results: Ex vivo diffusion studies conducted with TTS formulations containing captopril by using human epidermis showed that effective concentration of capropril can be obtained (Figure 1). It can be concluded that the captopril containing TTSs were successfully prepared and that captopril can be administered via skin. Animal studies should be carried out to assess these results before going into clinical trial.

Acknowledgements : This study was supported by Marmara University Research Fund (Project no: SAG-YLS-120707-0127). References 1. Bhattacharya, M., L. Alper, S., Pharmacology of Volume Regulation. In Principles of Pharmacology. Golan, D.E., pp. 345-365, Lippincott Williams & Wilkins, China, 2008. 2. Sipahigil, O., Keskin, E., Dortunç, B. “Diffusion of Captopril from a Matrix Type Trandermal Therapeutic System”, 7th Central European Sysmposium on Pharmaceutical Technology and Biodelivery Systems, Sep-tember 18-20, 2008, Ljubljana, Slovenia.

Table 1.TTS Formulations, Thickness and Captopril Content

Code Eud. RL 100 (g)

Eud. RS 100 (g)

PEG 400 (%)

Captopril (%)

PIB (g) Thickness (mm±SD)

Captopril con-tent (%±SD)

F1 1,3 0,7 20 20 0,2 1.160±0.107 99.729±0.847 *F2a/b 1,0/1,0 -/- 20/20 20/10 -/0,2 1.030±0.049 100.108±1.123 *F3a/b 1,0/1,0 -/- 20/20 20/10 -/- 0.960±0.062 101.275±0.419

* Double layered systems a: lower layer b: upper layer

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PP60

SOLUTION BEHAVIOUR OF AMPHIPHILIC PHENOTHIAZINE DRUG THIORIDAZINE HYDROCHLORIDE IN ANIONIC MICELLAR ENVIRONMENT

Neşe ERDİNÇ, Department of Analytical Chemistry, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeyElif ÇALIŞKAN, Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, TurkeySinem GÖKTÜRK, Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey

Surfactants are vital components in biological systems, and belong to pharmaceutical excipient series. Sur-factant micelles and lamellar phases also have been used as mimetics for biomembranes, because one of the major components of membranes, lecithins, are in fact themselves surface active materials. The physi-cal chemical interactions of drugs with surfactant micelles can be visualized as an approximation for their interactions with biological surfaces. This provides an insight into more complex biological processes, such as the passage of drugs through cell membranes(1-3). In this study the interaction of amphiphilic phe-nothiazine drug Thioridazine hydrochloride (THCl), used in treatment of mental illness, with various anionic surfactants has been reported. The effect of hydrophobicity on micellar binding of THCl with sodiumdodecyl sulfate, sodiumtetradecyl sulfate, sodiumhexadecyl sulfate and sodiumoctadecyl sulfate has been studied spectrophotometrically in submicellar and micellar concentration range. Going from aqueous solution to the more hydrophobic micellar environment the maximum absorbance of THCl shifted to a higher wavelength in its absorption maxima. The binding constant values of THCl to anionic micelles were calculated by means of Benesi–Hildebrand Equation. Binding constants values and the absorption maxima of THCl in the presence of micelles showed that hydrophobic interaction plays a major role in binding process of THCl to anionic micelles.

References

1. D. Myers, Surfactant Science and Technology, John Wiley & Sons, New Jersey, 2006.2. S.R.W. Louro, O.R. Nascimento, M. Tabak, Biochim. Biophys. Acta. 1994: 1190; 319.3. Erdinç N., Göktürk S., Tunçay M. J Pharm Sci.2003; 93(6):1566-1576.

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PP61

DESIGNING AND DEVELOPMENT OF IM DEPOT INJECTION OF POLYLACTIC ACID MICROSPHERES CONTAINING LAMOTRIGINE FOR ONCE A WEEK DELIVERY

Sushma DRABU, Maharaja Surajmal Institute of Pharmacy, Guru Gobind Singh Indraprastha University, Delhi,India. Smriti KHATRI, Maharaja Surajmal Institute of Pharmacy, Guru Gobind Singh Indraprastha University, Delhi,India.Sheveta BABU, Maharaja Surajmal Institute of Pharmacy, Guru Gobind Singh Indraprastha University, Delhi,India.

In mental illness, the main cause of failure of oral dosage form is patient noncompliance. Drug adverse effects and pessimistic tendency about the likelihood of improvement of disease and difficulty in remem-bering the dose are the main reasons for not taking their medication. Lamotrigine is an antipsychotic drug and is used mainly in the management of mental illness and it is also used in the treatment of various forms of epilepsy. Depot formulation can be the only way to solve all these problems. Such medication is very useful in overcoming the problem of patient non-compliance and minimizes the incidence and severity of adverse side effect as with oral tablet dosage form. Microspheres are one of the multiparticulate delivery systems and are prepared to obtain prolonged or controlled drug delivery to improve bioavailability or stability and to target drug to specific sites. The aim of this study was to prepare and evaluate polylactic acid microspheres containing lamotrigine. Microspheres were prepared by solvent evaporation method us-ing methylene chloride solvent. The influence of formulation factors (stirring speed, polymer: drug ratio, stabilizer: drug ratio) on particle size, encapsulation efficiency and in vitro release characteristics of the mi-crospheres were investigated. The yields of preparation and the encapsulation efficiencies were high for all formulations. Particle size changed by changing the polymer: drug ratio or the stirring speed of the system. The increased amount of the polymer ensured the formation of spherical particles while the amount of the drug and volume of the solvent remained constant. Lamotrigine microspheres were prepared successfully showing controlled release without initial peak levels were achieved. These microspheres assured reduced dosing frequency, decreased side effects and better patient compliance

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INVESTIGATIONS ON PHYSICOCHEMICAL AND RHEOLOGICAL CHARACTERISTICS OF SELECTED INDIAN HONEYS.

Sheveta BABU, Maharaja Surajmal Institute of Pharmacy, Guru Gobind Singh Indraprastha University, Delhi,India.Kakasaheb MAHADIK, Department of Pharmaceutical Chemistry, Bharati Vidyapeeth Deemed University, Poona College of Pharmacy, Erandawane, Pune-411038, Maharashtra State, IndiaAnant PARADKAR, Institute of Pharmaceutical Innovation, University of Bradford, United Kingdom Sushma DRABU, Maharaja Surajmal Institute of Pharmacy, Guru Gobind Singh Indraprastha University, Delhi,India.Smriti KHATRI, Maharaja Surajmal Institute of Pharmacy, Guru Gobind Singh Indraprastha University, Delhi,India.

The physicochemical properties of four different varieties of honeys, viz. Forest honey(FH), Mustard honey(MH), Litchi honey(LH) and Sunflower honey(SH), were studied according to the procedures list-ed by Bureau of Indian Standards. Rheological studies were performed on pure honey samples and honey samples blended with 4 formulation excipients in different concentrations (citric acid 0.5-2.5%, glycerine 2-12%, gelatin 0.4-4% and glyceryl mono-oleate {GMO} 0.7-7.7%) using a stress controlled Rheometer. The samples were subjected to Oscillation Stress sweep to determine their linear viscoelastic region. The parameters measured included elastic modulus(G’), viscous modulus(G”) and loss tangent(δ). Frequency sweep tests were performed to determine resistance of samples towards structural changes besides Creep recovery test to determine viscoelastic properties. Addition of citric acid did not alter complex rheologi-cal properties of honey in a concentration dependent manner, but concentration did alter elastic character indicating increased rigidity. Addition of glycerin resulted in increased rigidity and decrease in viscous character. Gelatin showed no effect at lower concentrations, but at higher concentrations both G’ and G” increased. Addition of GMO, at all concentrations, increased G’ values but G” increased only at higher concentrations. Frequency dependent increase in G” indicates that honey behaves more like a viscous fluid due to molecular relaxation process associated with structural organization of carbohydrate molecules. Topical preparations can be prepared using lower glycerin concentrations. Value added products involv-ing citric acid can also be worked out successfully without significantly affecting its rheological properties. Gelatin can be incorporated to prepare spreadable or extrudable forms of honey. Honey and GMO gels can be utilised to formulate liquid crystalline based drug delivery systems as the cubic phase of GMO remains uniformly dispersed in honey without any phase separation. Thus, physiochemical and rheological charac-terization will serve as a guideline in formulation and processing industry for honey.

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ABT- 492: A NOVEL POTENT ANTIBACTERIAL FLUOROQUINOLONE

Smriti KHATRI, Maharaja Surajmal Institute of Pharmacy, Guru Gobind Singh Indraprastha University, Delhi,India.Sheveta BABU, Maharaja Surajmal Institute of Pharmacy, Guru Gobind Singh Indraprastha University, Delhi,India.Sushma DRABU, Maharaja Surajmal Institute of Pharmacy, Guru Gobind Singh Indraprastha University, Delhi,India.

There has been a remarkable progress in the prevention; control and even eradication of infectious diseases with improved hygiene and development of antimicrobials and vaccines. However, infectious diseases still remain a leading cause of global disease burden with high morbidity and mortality especially in the devel-oping world. Furthermore, there have been threats of new diseases during the past three decades due to the evolution and adaptation of microbes and the re-emergence of old diseases due to the development of an-timicrobial resistance and the capacity to spread to new geographic areas. The impact of the emerging and re-emerging diseases in India has been tremendous at socioeconomic and public health levels. Their control requires continuing surveillance, research and training, better diagnostic facilities and improved public health system. Emerging and reemerging zoonotic, food borne and waterborne diseases and diseases caused by multi resistant organisms constitute the major threats in India. This review of bacterial diseases is of critical importance to pharmacists’ microbiologists, clinicians, public health personnel and policy makers in the field of health science. The role of high antibiotic usage environments is indicated. The implication of the wide use of antibiotics in animals has been pointed out. Steadily increasing antibiotic resistance and decreasing numbers of newer antibiotics appear to point to a post-antibiotic period during which treatment of infections would become increasingly difficult. This article attempts to review the global antimicrobial resistance scene and juxtaposes it to the Indian experience.

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DEVELOPMENT AND IN VITRO EVALUATION OF FLOATING TABLETS OF TRIKATU

Smriti KHATRI, Maharaja Surajmal Institute of Pharmacy, Guru Gobind Singh Indraprastha University, Delhi,India.Sushma DRABU, Maharaja Surajmal Institute of Pharmacy, Guru Gobind Singh Indraprastha University, Delhi,India.Farhan JALEES, Faculty of Pharmacy, Hamdard University, Delhi,IndiaSheveta BABU, Maharaja Surajmal Institute of Pharmacy, Guru Gobind Singh Indraprastha University, Delhi,India.

Trikatu is a classical Ayurvedic formulation comprising of a 1:1:1 ratio of dried fruits of Piper nigrum, Piper longum, with dried rhizomes of Zingiber officinale, which is widely used for gastric and abdominal discomfort, to enhance the bioavaibility of other formulations. Reported investigations about formulation of floating Matrix tablets of TRIKATU, a major herbal preparation, which enhances bioavailabilities of some drugs are very promising. In case of conventional formulation rapid gastrointestinal transit may result incomplete drug release from the dosage form leading to diminished efficacy of the administered dose. Present investigation deals with the development of floating matrix tablets of Trikatu, which were prolong gastric residence time, and hence increase bioavailability. The tablets were prepared by the direct compres-sion technique, using matrix forming polymer HPMC K4M, NaHCO3 as gas generating agent and Trika-tu extract with additives. The effervescent-based floating drug delivery is a promising approach to achieve in vitro buoyancy by using gel-forming polymer HPMC K4M and gas-generating agent sodium bicarbonate.

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EVALUATION OF TRAMADOL HYDROCHLORIDE SUPPOSITORY AND RECTAL GEL IN ANIMAL MODEL

Wantana REANMONGKOL, Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University, ThailandNattha KAEWNOPPARAT, Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Thailand Chaveewan RATANAJAMIT, Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Thailand

The rectal tramadol hydrochloride preparation was developed in two dosage forms, rectal suppository and rectal gel. Two different bases were used in each dosage form. For rectal suppository, Witepsol H15 as fatty suppository base and polyethylene glycol as water-soluble suppository base were used. For rectal gel, poloxamer, non-ionic surfactant and hydroxyethylcellulose, non-ionic cellulose ethers derivative were used as gel base. The analgesic activity of rectal tramadol hydrochloride using hot plate test was evaluated in rats. Administration of tramadol hydrochloride suppository (2, 4 and 8 mg/ 2 g) using Witepsol H15 as base, significantly prolonged the latency of nociceptive response in rats. When using polyethylene glycol as base, it was slightly pronounced analgesic effect than that of Witepsol H15 as base in rats. For rectal gel, using poloxamer or hydroxyethylcellulose as base, it (2, 4 and 8 mg/ 0.2 ml) exerted markedly increase of the no-ciceptive response latency in rats. In the present study, tramadol hydrochloride suppository and rectal gel with different bases prolonged latency of nociceptive response in vivo experiment. Rectal administration of tramadol may be an alternative route in addition to oral and intravenous administration.

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FORMULATION OF AN HERBAL LOTION AGAINST PITYROSPORUM OVALE AND PITYROSPORUM ORBICULAR BY USING THREE MEDICINAL PLANTS

Gholamreza DEHGHAN, Department of Pharmaceutics Research, Kerman University of Medical Sciences, Kerman, Iran. Fariba SHARIFIFAR, Department of Pharmaceutics Research, Kerman University of Medical Sciences, Kerman, Iran Behzad KAHNAMOOEI, Department of Pharmaceutics Research, Kerman University of Medical Sciences, Kerman, Iran

Nowadays, antifungal Lotions are the most frequently prescribed treatment to the scalp. They are may con-tain plant extracts and they most commonly used a means of scalp. In this study extracts of three (Fumaria parviflora of aerial parts, Salvia rhytidea of aerial parts and Matricaria aurea of flowering tops) were prepared using maceration, and then the antifungal activity (MIC) against Pityrosporum ovale and Pityrosporum orbicular were evaluated. In this study transparent o/w emulsion was prepared with nonionic surfactants in wide extensive HLB. Transparent o/w emulsions have been prepared using isopropyl myristate as oil phase and blend of non- ionic surfactants (Tween 60, Tween 80, span 60, span80 …..) an emulsifier, by establish-ment of phase diagrams at different HLB values. The refractive index of aqueous phase was approached to oil phase by adding various polyols i.e., glycerin, propylene glycol and ethylene glycol. The most stable o/w transparent emulsions can be formed with blend of Tween 80 and span 60. Glycerin has been found the more suitable polyol to form the transparent o/w emulsions. Stability tests were performed at various temperatures (4oC, 25oC, 55oC) followed by centrifugation at 1500 rpm for 45 minutes. So, it has been concluded that the transparent o/w emulsions were stable over a period of 6 month.

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STUDY OF BIOLOGICAL PROPERTIES OF TWO CHALCONES: CHALCONE, 3-(4-TRIFLUOROMETHYL-BENZYLIDENE)–CHROMAN-4 ON AND 3-(2, 3-DIMETHOXY-BENZYLIDENE)–CHROMAN

Golamreza DEHGHAN, Department of Pharmaceutics Research, Kerman University of Medical Sciences, Kerman, Iran. Ali DEHGHAN, Department of Life Sciences, Anglia Ruskin University, East Road, Cambridge, CB1 1PT, UK Mohammad Hassan MOSHAFI, Department of Pharmaceutics Research, Kerman University of Medical Sciences, Kerman, Iran. Alireza FOROMADI, Pharmaceutics Research Centre, Tehran University of Medical Sciences, Tehran, Iran

In the present study antibacterial and anti-tumour activities of two synthetic compounds of Chalcone, 3-(4-trifluoromethyl-benzylidene)–chroman-4-On, and 3-(2,3-dimethoxy-benzylidene)– chroman-4-On was investigated. To study the antibacterial activity of these two synthetic compounds, agar dilution method was used. To investigate anti-tumour activity of the compounds, Potato Disc Method was used. Different dilutions of anti-tumour component in were applied. When 3-(4-trifluoromethyl-benzylidene)–chroman-4-On was applied in its highest dilution (50 µg/disk), it showed 70.86 % anti-tumour effect. In the case of the other component, 3-(2,3-dimethoxy-benzylidene)– chroman-4-On, 54.41 % of anti-tumour effect was observed in dilution of 50 µg/disk. There was a significant difference between these two components for their anti-tumour activities. IC50 values (the concentration at which 50 % inhibitory was observed) was calculated and it was 11.74 mg/ml for 3-(4-trifluoromethyl-benzylidene)–chroman-4-On, and 35.92 mg/ml for 3-(2, 3-dimethoxy-benzylidene)– chroman-4-On. The most observed anti-tumour effect was 70.86 % with IC50 when 11.54 mg/ml of 3-(4-trifluoromethyl-benzylidene)–chroman-4-On was applied. The anti-tumour effect of these two components shows that they have a high potentiality in inhibition of tu-mours in vivo. The anti-bacterial experiments show that 3-(2,3-dimethoxy-benzylidene)– chroman-4-On, has more anti-bacterial effects in comparison with 3-(4-trifluoromethyl-benzylidene)–chroman-4-On.

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PP68

DETERMINATION OF PROTEOLYTIC AND LIPOLYTIC ACTIVITIES OF SOME PSEUDOMONAS BACTERIA

Tuba ÇAYLAK, Department of Biology, Faculty of Science and Arts, Niğde University, Niğde, TurkeyBerrak ALTINSOY, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyGökçen YUVALI ÇELİK, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey.

In this study, a total of fifteen strains belonging to Pseudomonas fluorescens ssp. indologenes, Pseudomonas vesicularis, Pseudomonas luteola, Pseudomonas aeruginosa were analysed. Strains were isolated from the raw milk and identified by using Analytical Profile Indeks (API 20 NE). Antibiotic susceptibility tests of Pseudomonas spp. strains to ampicillin (10 μg), amikacine (30 μg), gentamicine (10 μg), oflaxacine (5 μg), tetracikline (30 μg), chloramphenicol (30 μg), cephuroxime (30 μg) were determined by using the disk diffusion method. The results were described according to NCCLS standards. It was determined that 57% of Pseudomonas strains were susceptibility, 35% were resistant and 7% were intermediate susceptibility against fifteen antibiotics tested. Proteolytic activities of Pseudomonas strains were tested in Skim Milk Agar (SMA) medium and fourteen strains were determined that had a proteolytic activities. Proteolytic activities of these strains were found between 8.0 and 55.0 mm with an average 28.1 mm zone diameter. The highest proteolytic activity 55.0 mm was found in P. fluorescens ssp. indologenes T7 strain. In this study, lipolytic activities of Pseudomonas strains were tested in Tributirin Agar (TA) medium. Thirteen strains were determined that had a lipolytic activities. Lipolytic activities of these strains were found between 5.3 and 29.3 with an average 15.4 mm zone diameter. Zone diameter of the highest lipolytic activity 29.3 mm was found in P. fluorescens ssp. indologenes T8 strain. Our research in this sense, purification and eco-nomic benefits of microbial enzymes, which are used in the pharmaceutical industry, sheds light

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CHITOSAN-BASED CARRIERS FOR GENE TRANSFER INTO THE SKIN

Suna ÖZBAS TURAN, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.Emine SALVA, Department of Pathology, Vocational Health School, Marmara University, İstanbul, Turkey. Jülide AKBUĞA, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.

The skin is an attractive and the largest organ for local and systemic drug applications. In present study, chitosan-based carriers were investigated for nucleic acid delivery into the skin. In this study, three differ-ent pharmaceutical forms including hydrogels, nanoparticles, liposomes were prepared for gene delivery. Physico-chemical properties and in vitro / in vivo transfection characteristics of these formulations were investigated. It was observed that three dosage forms protected DNA from enzymatic degradation. After the control and characterization of these forms, in vitro and in vivo transfection experiments were made. Mouse fibroblastic NIH 3T3 cell line and primary human dermal fibroblasts were used for in vitro transfec-tion studies. Transfection efficiency of formulations was monitored by measuring of β-galactosidase activity expressed by β-Gal reporter plasmid. The higher transfection efficiency and reporter gene expression was obtained with liposome formulations than that of other forms. Pups and young adult Sprague–Dawley rats were used for in vivo transfection studies. By using enzyme assays and histological techniques, it was shown that the reporter gene expression in dermis and hypodermis layers of skin sustained for 7 days. As a result, chitosan-based delivery systems including hydrogels, nanoparticles, and liposomes can be efficiently used for DNA transfer through the skin.

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THIRTY YEARS OF THE DARK AGOUTI (DA) RAT IN DRUG METABOLISM – WHAT HAVE WE LEARNED?

Sabah AL-DABBAGH, College of Pharmacy, Mosul University, Iraq. Jeffrey IDLE, Institute of Pharmacology, Charles University, Praha, Czech Republic

The authors began working together in 1979, two years after the report of the debrisoquine 4-hydroxyl-ation polymorphism. By 1980, they had uncovered an animal model for the human EM and PM pheno-types of what is now known as the CYP2D6 polymorphism. Dark Agouti (DA) female rats had a relative deficiency of debrisoquine 4-hydroxylation. The question was, could the DA rat serve as a model for the human PM phenotype? Work by the Gonzalez laboratory indicated that impaired metabolism in DA rats was due to an allelic variant of CYP2D1. In the intervening 30 years, many scientific developments have built on the hydroxylation-deficient DA rat. Firstly, hypercholesterolaemia and defective bile acid transport were reported in DA rats. Secondly, clues regarding genetic susceptibility to Parkinson’s disease emerged from studies with the neurotoxins tetrahydroisoquinoline and MPTP. Thirdly, the DA rat has been used to investigate aflatoxin B1 and ochratoxin A metabolism as a model for susceptibility to endemic diseas-es. Finally, various amphetamines, opiate analgesics and antitussives have been investigated in the DA rat model, establishing their likely pharmacology in the human PM phenotype. Uncritical use of the DA rat model may lead to erroneous interpretation of laboratory data. CYP2D1 is not the only enzyme with dif-ferential activity in the DA rat. For example, hepatic expression of the nuclear receptor CAR is greater in DA rats than in other strains, leading to elevated expression of CYP3A1, 3A2, and 2B1, and the enhanced 8-hydroxylation of caffeine in DA rats, a CYP3A activity. DA rats express a high hepatic epoxide hydratase activity, which probably explains their reduced susceptibility to aflatoxin B1 hepatotoxicity, rather than im-paired CYP2D1 activity and aflatoxin B1 epoxide formation. We have learned that the DA rat has served us well, providing prudence is exercised before enthusiasm.

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COMPARISON OF BIOAVAILABILITY OF IMMEDIATE RELEASE AND MODIFIED RELEASE FORMULATION OF TRIMETAZIDINE

Latif ÖZBAY, GLP Laboratory and GCP Clinics, Yeditepe University, Acıbadem, İstanbul, TurkeyUrun GÜNEY TUNÇ, GLP Laboratory and GCP Clinics, Yeditepe University, Acıbadem, İstanbul, TurkeyDurişehvar ÖZER ÜNAL, GLP Laboratory and GCP Clinics, Yeditepe University, Acıbadem, İstanbul, TurkeyDilek DEMİR EROL, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Yeditepe University, Kayışdağı, İstanbul

Trimetazidine is an anti-ischemic (anti-anginal) metabolic agent, which improves myocardial glucose utili-zation through inhibition of fatty acid metabolism. Modified release (MR) Trimetazidine was developed to maintain effective plasma concentrations. MR trimetazidine ( 35 mg) and Immediate release (IR) trimeta-zidine ( 20 mg )were administrated single oral tablet orally. Blood sampling was performed over 48 and 72 hours post dose for the determination of pharmacokinetic profiles of trimetazidine IR ad MR tablets respectively. Time of peak plasma concentration (tmax) was longer for MR tablets. MR trimetazidine pro-duces sustained plasma levels compared to IR with resulting enhancement of pharmacodynamic effects. The initial absorption phase of Trimetazidine IR formulation was similar to that of MR tablets, with mean tmax values of 1.9 and 5.2 hours for IR and MR formulation respectively. Cmax was higher for MR tablet than IR tablet. Cmax/AUC ratio is recommended for assessing absorption rates. Both formulations gave similar results and were well tolarated. The findings indicate that MR formulation of Trimetazidin provides a sustained pattern of plasma concentrations which is evident in the 3 to 10 hour period.

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EFFECTS OF VALPROIC ACID TREATMENT ON PLASMA L-CARNITINE LEVELS

Mohamed Hachem SAADAOUI, Biochemistry and Toxicology Laboratory, University Hospital of Monastir, Tunisia. Hajer MABROUK, Biochemistry and Toxicology Laboratory, University Hospital of Monastir , TunisiaNawel KARMANI, Biochemistry and Toxicology Laboratory, University Hospital of Monastir, Tunisia Anouar MECHRI, Research Laboratory “Vulnerability to Psychotic Disorders”, University Hospital of Monastir, Tunisia Fadoua NEFFATI, Biochemistry and Toxicology Laboratory, University Hospital of Monastir , TunisiaWahiba DOUKI, Biochemistry and Toxicology Laboratory, University Hospital of Monastir, Tunisia Lotfi GAHA, Research Laboratory “Vulnerability to Psychotic Disorders”, University Hospital of Monastir, TunisiaMohamed Fadhel NAJJAR, Biochemistry and Toxicology Laboratory, University Hospital of Monastir, Tunisia

Introduction: We determined plasma L-carnitine levels at patients treated by valproic acid (VPA) at thera-peutic doses in the aim to study the influence of VPA treatment on this parameter.

Materials and Methods: The population studied included 22 patients treated by VPA for bipolar disorders, from Psychiatry department of the University Hospital of Monastir (17–50 years of age, mean age 34.57 ± 9.96; 19 males and 3 females), and 13 control healthy subjects (20–50 years of age, mean age 33.23 ± 10.68; 7 males and 6 females). Plasmatic VPA was measured by FPIA on AxSYM TM analyzer (Abbott). Plasmatic L-carnitine was determined by enzymatic colorimetric method on Konélab 30TM.

Results: L-carnitine levels were lower at patients than control group (mean = 59.62 ± 7.01 µmol/L in pa-tients versus 86.30 ± 5.00 µmol/L in control group; p = 0.002). It was also significantly lower in women treated with VPA than men. No correlation between plasmatic L-carnitine and age or BMI (Body Mass In-dex) was found in both groups. No significant variation of the mean plasmatic L-carnitine levels according to VPA concentrations was noted. However, we found a decrease of plasmatic L-carnitine concentrations in patients negatively correlated with VPA dosage (r = 0.92). This decrease is predominantly observed with doses greater than 1500 mg/day. Moreover, the longer the treatment is the lower plasmatic L-carnitine gets. This is mostly observed when the duration of treatment exceeds 7 years (mean L-carnitine concentrations = 47.56 ± 10.61 µmol/L in patients with treatment duration more than 7 years versus 60.67 ± 17.53 µmol/L in other patients; p = 0.05).

Conclusion: High doses of VPA may decline plasmatic L-carnitine levels. This justifies the determination of L-carnitine concentration in patients treated by VPA in order to avoid metabolic consequences of this decrease.

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STUDY OF CHOLINESTERASE ACTIVITY IN SCHIZOPHRENIC PATIENTS

Hajer MABROUK, Biochemistry and Toxicology Laboratory, University Hospital of Monastir, Tunisia Haythem MECHRIA, Research Laboratory «Vulnerability to Psychotic Disorders», University Hospital of Monastir , Tunisia Anouar MECHRI, Research Laboratory «Vulnerability to Psychotic Disorders», University Hospital of Monastir, Tunisia Fadoua NEFFATI, Biochemistry and Toxicology Laboratory, University Hospital of Monastir, Tunisia Wahiba DOUKI, Biochemistry and Toxicology Laboratory, University Hospital of Monastir , Tunisia Lotfi GAHA, Research Laboratory «Vulnerability to Psychotic Disorders», University Hospital of Monastir, Tunisia Mohamed Fadhel NAJJAR, Biochemistry and Toxicology Laboratory, University Hospital of Monastir, Tunisia

Introduction: The objective of the present study was to assess the cholinesterase activity in schizophrenic patients.

Materials and Methods: This study included 60 patients with chronic schizophrenia according DSMIV criteria from Psychiatry departments of the University Hospital of Monastir (43 males and 17 females, mean age = 37.52 ± 10.01 years) and 30 healthy controls (27 males and 3 females, mean age = 26.43 ± 5.81 years). Cholinesterase activity was determined by enzymatic method on Integra 400 plus analyzerTM (Roche Diagnostics).

Results: No significant difference was observed between schizophrenic patients and controls (mean = 8913 U/L in patients versus 8612 U/L in controls; p = 0.45). In patients, cholinesterase activity was higher in female than male without significant difference (mean = 9314 U/L in female versus 8754 U/L in male; p = 0.41). In the controls we found an increase only in the male. A significant difference was noted between female patients and controls (mean = 9314 U/L in patients versus 7386 U/L in controls; p = 0.02). Cho-linesterase activity was significantly higher in patients treated by antipsychotic than those treated by anti-cholinergic drugs (mean = 10099 U/L in antipsychotic versus 8319 U/L in anticholinergic; p = 0.02). No significant difference was noted according the tabagic status.

Conclusion: In the schizophrenia cholinesterase activity is not affected but its increase in female patients and patients treated by antipsychotics requires more investigations.

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INCIDENCE AND RISK FOR NEUTROPENIA/AGRANULOCYTOSIS AMONG CLOZAPINE USERS: A RETROSPECTIVE COHORT STUDY

Chaveewan RATANAJAMIT, Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Thailand. Chutima MUSAKOPAS, Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Thailand. Sorayut VASIKNANONTE, Department of Psychiatry, Faculty of Medicine, Prince of Songkla University, Thailand. Wantana REANMONGKOL, Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University , Thailand.

Objective: To estimate the incidence and the risk of neutropenia or agranulocytosis (the outcome) associ-ated with clozapine use (the exposure), and to identify risk factors.

Methods: All data were derived from the computerized database of a medical teaching hospital. Adult psychiatric patients were identified, and 95 incident clozapine users and 884 non-clozapine users were in-cluded in this retrospective cohort study. The cumulative incidence of developing the outcome for each group was calculated. Cox proportional hazards regression was used to estimate the hazards ratio (HR) of developing the outcome after clozapine use adjusted for confounding factors. The interaction between clozapine and valproic acid was assessed a posteriori.

Results: Throughout the 24-month follow-up, the incidence of neutropenia was 6.3% in the clozapine group and 5.8% in the non-clozapine group. One agranulocytosis was found in the non-clozapine group. The HR (95% CI) for neutropenia were: clozapine 1.33 (0.54-3.25); age > 45 years 2.99 (1.63-5.48); and lithium 0.15 (0.02-1.09). Valproic acid might positively modify the clozapine-associated neutropenia (HR 5.10, 95% CI 0.70-37.12).

Conclusion: Clozapine might slightly increase the risk of neutropenia in psychiatric patients. Concerning clozapine-associated neutropenia, older patients are at increased risk and use of valproic acid concurrently with clozapine should be avoided.

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ACETYLATION OF PRIMARY AMINE CONTAINING DRUGS IN THE PRESENCE OF ASPIRIN

İrem SET, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyMert ÜLGEN, Faculty of Health Sciences, Acıbadem University, İstanbul, Turkey

Amines are important class of compounds used as drugs, cosmetics, additives and nutrients. Acetylation of amines in the organism forms acetyl derivatives which may change the pharmacological and toxicological characteristics of amines. Aspirin (acetylsalicylic acid) is known to acetylate some drugs bearing primary amine function in the solid state and has also been reported to acetylate various endogenous compounds in vitro and in vivo. In the present study, the primary amines ie. aniline, p-toluidine, p-chloroaniline and p-aminophenol (as model compounds) and amlodipine, a well known calcium-channel bloker used in the treatment of angina and hypertension (as a drug molecule) were used to find out the possible acetylated derivatives in the presence of aspirin. In the first part of the study the acetyl derivatives of amines were prepared and analysed on a reversed phase HPLC using UV detection. All model primary amines and am-lodipine were then incubated with aspirine in a non-enzymatic media in the physiological conditions. After incubation, the incubates were extracted with DCM, evaporated to dryness and the extracts obtained were analysed using the HPLC system developed and the results were reported.

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INTERFERENCE OF TOBACCO SMOKE WITH IMMUNO-CHROMATOGRAPHY ASSAY FOR URINARY DRUG DETECTION

Dhouha HAJ MOUHAMED, Laboratory of Biochemistry-Toxicology, University Hospital of Monastir, Tunisia. Asma EZZAHER, Laboratory of Biochemistry-Toxicology, University Hospital of Monastir, Tunisia, Hajer MABROUK, Laboratory of Biochemistry-Toxicology, University Hospital of Monastir, Tunisia, Mohamed Hachem SÂADAOUI, Laboratory of Biochemistry-Toxicology, University Hospital of Monastir, Tunisia.Wahiba DOUKI, Laboratory of Biochemistry-Toxicology, University Hospital of Monastir, Tunisia.Mohamed Fadhel NAJJAR, Laboratory of Biochemistry-Toxicology, University Hospital of Monastir, Tunisia.

Objective: This study aimed to evaluate the interference of tobacco smoke with immuno-chromatography assay for urinary drug detection and to investigate the correlation between urinary cotinine, plasma thio-cyanates and false positive results. Study design: The initial study was conducted with 256 subjects, 143 were non-smokers aged 44. 20 ± 15.81 years and 113 were current smokers aged 38.02 ± 17.49 years.

Methods: Subjects were classified into smokers, or non-smokers based on a questionnaire. Cotinine was measured by enzymatic colorimetric method on Konelab 30™ and SCN- by selective electrode. Urinary drug was detected by immuno-chromatography assay. A second analytical method must be used for all posi-tive results to obtain a confirmed result.

Results: We showed a false positive result for benzodiazepines, which is frequent in smokers compared with non smokers (76.92% Vs 27.58%; χ² = 16.42, p < 0.001). For smokers, the number of smoked cigarettes was significantly higher in subject with falsely positive result for benzodiazepine compared to subject with negative result (32 ± 11 Vs 20 ± 10; p = 0.04). Between these two groups, we established a significant difference for urinary cotinine (345.23 ± 211.12 Vs 116.57 ± 53.92 µg/µmol; p < 10-10) and for plasma thiocyanates concentrations (101.59 ± 3.40 Vs 98.80 ± 2. 1 3 µmol/L; p = 0.001).

Conclusion: For smokers, multi-parametric tests of urinary drug detection by immuno-chromatography were often falsely positive for benzodiazepines; therefore, all subjects must be questioned about their smok-ing status to avoid these false results .

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PP77

HYPERHOMOCYSTEINEMIA IN TUNISIAN BIPOLAR I PATIENTS

Asma EZZAHER, Laboratory of Biochemistry-Toxicology, University Hospital of Monastir, TunisiaDhouha HAJ MOUHAMED, Laboratory of Biochemistry-Toxicology, University Hospital of Monastir, Tunisia Mohamed Hachem SAADAOUI, Laboratory of Biochemistry-Toxicology, University Hospital of Monastir, Tunisia Anwar MECHRI, Department of Psychiatry, University Hospital of Monastir, Monastir , Tunisia, Asma OMEZZINE, Laboratory of Biochemistry, CHU Sahloul Sousse, TunisiaWahiba DOUKI, Laboratory of Biochemistry-Toxicology, University Hospital of Monastir, Tunisia, Ali BOUSLAMA, Laboratory of Biochemistry, CHU Sahloul Sousse, TunisiaLotfi GAHA, Department of Psychiatry, University Hospital of Monastir, TunisiaMohamed Fadhel NAJJAR, Laboratory of Biochemistry-Toxicology, University Hospital of Monastir, Tunisia.

Objective: Hyperhomocysteinemia has been suggested to be associated with bipolar disorder but this as-sociation is controversed among studies. The aim of this study is to investigate the hyperhomocysteinemia frequence in Tunisian bipolar I patients according to MTHFR C677T polymorphism and to folatemia and.vitamin B12 levels.

Patients and methods: Our study included 130 patients with bipolar disorder diagnosed according to the DSM IV, and 171 control subjects aged respectively 37.9 ± 12.1 and 44.9 ± 14.2 years. Homocysteine, folic acid and vitamin B12 were measured by an immunoassay method. 677CT polymorphisms in MTHFR were determined by polymerase chain reaction-restriction fragment length polymorphism.

Results: Bipolar patients had significantly higher levels of homocysteine (15.76 ± 8.95 Vs 9.68 ± 4.52; p < 0.001) than controls. Moreover, we found that patients had the significantly highest frequencies of hyper-homocystenemia. Genotypes for C677T polymorphism were in Hardy–Weinberg equilibrium and were similarly distributed between patients and controls. After adjustment to MTHFR C677T genotype and to potential confounder parameters, OR of hyperhomocysteinemia associated with bipolar disorder remained significative (OR = 5.1, CI 95%: [2.8-9.2]; p < 10-3). So, hyperhomocysteinemia in bipolar patients seems to be independent of C677I genotype, but it is probably dependant of hypofolatemia. In fact, we’ve noted lower levels of folate in patients compared with controls with an OR = 5.4, CI 95% [3.3-8.8]; p < 0.001) Hyperhomocysteinemia, hyfolatemia and hypovitamin B12 were not related to duration and episode of illness. Only hypofolatemia was significantly associated with drug usage. Indeed, all patients under lithium had hypofolatemia.

Conclusion: Hyperhomocystenemia was more frequent in bipolar I patients but was not associated with C677T polymorphism. Patients had reduced levels of folate that modulate homocysteine metabolism. In-deed, this finding may reflect that a supplementation of folate may be appropriate in bipolar patients with hyperhomocysteinemia.

168

PP78

THE INVESTIGATION OF THE NEW BETA-LACTAMASE INHIBITORS

Yağmur TUNALI, Department of Pharmaceutical Microbiology, Anadolu University, Eskişehir, Turkey. Hülya KARACA, Department of Pharmaceutical Microbiology, Anadolu University, Eskişehir, Turkey.Zerrin CANTÜRK, Department of Pharmaceutical Microbiology, Anadolu University, Eskişehir, Turkey.Seval KORKMAZ, Abdi ibrahim İlaç Sanayii, İstanbul, Turkey. Yusuf ÖZTÜRK, Department of Pharmacology, Anadolu University, Eskişehir, Turkey.

There are three different clinically used inhibitors which irreversible inhibit beta-lactamase; these are clavu-lanic acid, sulbactam and tazobactam which are called suicidal inhibitors. Although they do not exibit any antibacterial effect alone when applied in combination they add to the benefits of penicillins and cephalo-sporins. In this study, the possible antibacterial activity of epigallocatechin gallate, catechin, catechin gal-late and epicatechin which are tea polyphenols were investigated. For this study, Echerichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Pseudomanas aeruginosa and Enterobacter faecalis which are serious infection agents and have the beta-lactamase enzyme have been preffered, and while testing tea polyphenols effectiveness, the methods taking place in Clinical and Laboratory Standards Institute (CLSI, 2006) have been used. In addition, it is also used Neutral Red Uptake and MTT methods to evaluate cytotoxic effect on NIH3T3 (mouse fibroblast cell line) with tea polyphenol compounds.

169

PP79

DYESTUFF ANALYSIS OF HEMP-DYED WOOL AND HEMP DATISCA CANNABINA L. BY HPLC-DAD

Ozan DEVEOĞLU, Department of Chemistry, Faculty of Arts and Sciences, Marmara University, İstanbul, Turkey. Emine TORGAN, Research and Development Laboratory for Natural Dyes, Turkish Cultural Foundation, İstanbul, Turkey. Recep KARADAĞ, Laboratory for Natural Dyes, Marmara University, İstanbul, Turkey.

Since prehistoric times, natural dyestuffs have been used for many purposes such as the coloring of natu-ral fibers wool, cotton and silk as well as fur and leather [1-2]. High performance liquid chromatography technique provide high-resolution seperation for the identification of natural dyestuffs [3]. In this study, the wool sample was mordanted via alum (KAl(SO4)2.12 H2O) solution. Then, the mordanted sample was dyed in the dye bath including the aerial parts of hemp (Datisca cannabina L.). The extraction of dye-stuffs form hemp plant were achieved by hydrochloric acid/methanol/water (2:1:1; v/v/v) and methanol/water (2:1; v/v) solution. The yellow dyestuffs extraction from the dyed wool sample was provided with hydrochloric acid/methanol/water (2:1:1; v/v/v) solution. Reversed phase high performance liquid chro-matography (RP-HPLC) with diode array detection (DAD) method was utilized for the identification of dyestuffs present in the dyed wool sample. HPLC analysis shows that datiscetin was identified in the acid hydrolysed hemp extract, the acid hydrolysed wool sample extract and the non-hydrolysed hemp extract. The structure of datiscetin compound is presented in figure 1.

References

[1] Karadag, R. Dogal Boyamacılık, T.C. Kültür ve Turizm Bakanlığı, Ankara (2007)[2] Cristea, D.; Vilarem, G. Dyes and Pigments 70 (2006) 238-245.[3] Deveoglu, O.; Karadag, R.; Yurdun, T. Jordan Journal of Chemistry Vol. 4 No.4, (2009) 377-385.

Figure 1: Structure of datiscetin compound

170

PP80FOLK MEDICINAL PLANTS OF BAYRAMİÇ (ÇANAKKALE-TURKEY)

Gizem BULUT, Department of Pharmaceutical Botany, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey. Ertan TUZLACI, Department of Pharmaceutical Botany, Faculty of Pharmacy, Marmara University, 34668 Haydarpaşa, İstanbul, Turkey.

In this study, the folk medicinal plants of Bayramiç (Çanakkale) were researched. For this purpose, the center of Bayramiç and all of the 76 villages have been visited between April 2004-June 2007. During the field works, the information were obtained from local healers, experienced adults and patients by personal interviews and the specimens of the plants were collected. According to the results of the identifications of the specimens, 90 plant taxa are used in therapy in Bayramiç. These are presented in a table in the text. Among them 72 taxa are wild and 18 taxa are cultivated plants. The folk medicinal plants are mostly used for stomach ailments, cold, rheumatism, hemorrhoids, eczema and bronchitis.

171

PP81

EVALUATING THE SURFACE PROPERTIES AND TOXICITY OF AQUEOUS EXTRACT OF THREE MEDICINAL PLANTS ON CELL MEMBRANE– PERMEABILITY

Effat BEHRAVAN, Department of Pharmacodynamy and Toxicology, Faculty of Pharmacy, Mashhad University of Medical Sciences, Iran.Vahid ALINIA, Department of Pharmacodynamy and Toxicology, Faculty of Pharmacy, Mashhad University of Medical Sciences, Iran.

Surface active agents have been used in pharmaceutical formulations for several aims, so the study of the effect of these agent on biological membranes is necessary. The aim of this study is the evaluation of the ef-fect of three aqueous extract of Tribulus terrestris L, Trigunella foenum-graecum L and Echium amoenum Fisch, on red blood cells (RBC) as a model for biological membranes. Also in this study some of physi-cochemical properties including Emulsification index (E24), Foam producing activity (Fh) and Critical Micelle Concentration (cmc) were studied. The extracts solution were prepared in McIvan’s buffer. 0.2 ml of RBC (hematocrit: %12) were added to 0.2 ml of each sample extract solution, incubated in two different temperatures (25°C & 37°C) for two different times (15 min & 30 min). The absorbance of the samples were determined by UV spectrophotometer. All of the aqueous extracts showed hemolysis. In comparison of the in three studied extracts, Tribulus terrestris L, have shown the highest hemolytic effect (12.45% in 37°C & 30 min). The values of emulsification Index (E24) and foam formation activity (Fh) showed for each extract the properties of surface activity. Nowadays there are a great deal of research is being carried on concerning the effect of surfactants on absorption since natural surfactants show less toxicity in contrast with chemical surfactants and according to the results of the present study extracts with different hemolytic effect, when consider the health of consumer, the use of aqueous extract of Heracleum persicum Desf, with low hemolytic effect is preferred in pharmaceutical preparation but if the hemolytic effect were considered, the use of aqueous extract of Artemisia dracunculus L, with great hemolythc effect in compare two other extract is preferred.

172

PP82

ANTIOXIDNT ACTIVITY POTENTIAL OF SIX SALVIA SPECIES WITH TOTAL PHENOLIC AND FLAVONOID CONTENT

Mehmet BOĞA, Department of Analytical and General Chemistry, Faculty of Pharmacy Istanbul University, Istanbul,Turkey.Mehmet ÖZTÜRK, Department of Chemistry, Faculty of Art & Science, Muğla University, Muğla, TurkeyFatemeh BAHADORI, Department of Chemistry, Faculty of Science & Letters Istanbul Technical University, Istanbul, TurkeyUfuk KOLAK, Department of Analytical and General Chemistry, Faculty of Pharmacy Istanbul University, Istanbul, Turkey.Gülaçtı TOPÇU, Department of Chemistry, Faculty of Science & Letters, Istanbul Technical University, Istanbul, Turkey

Salvia L. is one of the largest genera of the family Lamiaceae (Labiatae) which is widespread throughout the world by about 900 species. Salvia species have been used as culinary herbs and teas as well as to treat many disorders including colds, bronchitis, tuberculosis, menstrual and digestive disorders. Salvia species are a rich source of bioactive compounds including abietane diterpenoids, triterpenoids, flavonoids and other phenolics [1]. There are about 90 Salvia species in Turkey, and half of them are endemic [2]. Metha-nol extracts of six Anatolian Salvia species, S. aucheri var. aucheri, S. syriaca, S. eriophora [3], S. pilifera [4], S. staminea, S. verticillata subsp. amasiaca were evaluated using seven different antioxidant tests, namely lipid peroxidation inhibitory, DPPH free radical scavenging, superoxide anion radical scavenging, ABTS cation radical scavenging, ferric reducing power, cupric reducing power (CUPRAC), and metal chelating activities [5-7]. Total phenolic and total flavonoid contents of the extracts were determined. Among the extracts, the methanol extract of S. verticillata subsp. amasiaca displayed the highest activity in four assays: in the radical scavenging assays of DPPH and ABTS, and in reducing power tests of ferric and cupric ions. The high activity results of the methanol extract of S. verticillata subsp. amasiaca are correlated its high phenolic content and high flavonoid content. In b-carotene/linoleic acid assay, S. pilifera, S. staminea, and S. eriophora extracts showed better activity than the other extracts. S. staminea and S. pilifera extracts also displayed the highest activity in superoxide anion radical scavenging assay.

173

PP83

FOLK MEDICINAL PLANTS OF OVACIK (TUNCELİ-TURKEY)

Ahmet DOĞAN, Department of Pharmaceutical Botany, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyErtan TUZLACI, Department of Pharmaceutical Botany, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, Turkey

This study was made to reveal the plants used as traditional folk medicine in Ovacık (Tunceli). For this purpose, the field works have been done between May 2007-May 2008 in April, May, June and July lasting for 30 days, in total. During this research all the settlement centers (including 33 villages) have been visited, the specimens of the plants used as folk remedies have been collected and the information such as local names, ailments treated or therapeutic effects, plant parts used, method of administration, dosage, duration of treatment have been recorded. The collected plant specimens are kept in the Herbarium of the Faculty of Pharmacy, Marmara University (MARE). As a result of identification of 76 plant specimens, 67 species used as a traditional folk medicine, have been determined. Among them 65 species are wild and 2 species are cultivated plants. These plants and their local usage in treatment are presented in a table in the text. The plants recorded in Ovacık are mostly used for cold, wound and diabetes.

174

PP84IN VIVO EVALUATION OF BLACK AND GREEN TEA DERMAL PRODUCTS AGAINST UV RADIATION

Gülşah GEDİK, Department of Pharmaceutical Technology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyMurat TÜRKOĞLU, Department of Pharmaceutical Technology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, Turkey

Introduction: Tea (Camellia sinensis) extracts have protective activities against UV radiation. Application of green tea extract before UVA / UVB radiation to the skin and their protective activities against these ra-diation have been investigated in human volunteers. Similar studies were performed by using black tea. The protective activity of black tea gels against an artificial UV source was shown in our department. Preparing dermal products containing green or black tea extracts would protect the skin against sunburn, premature aging, and skin cancers.

Methods: In this study, 10 % aqueous extracts of black and green teas were obtained. The infusions were frozen at -18°C before further processing. The tea infusions were placed in a freeze-drier. After obtaining freeze-dried extracts carbomer gels were made for skin application. The dermal products were designed and manufactured and they were tested in the forearms of six human volunteers using an artifical UV source for 2.5 minutes at 50 cm distance to produce a visible erythema on a control site.

Results and Discussion: No UV erythema was observed on the black and green tea gel sites in any of the subjects. The UV erythema was always present in caffeine, carbomer gel, and the control sites. Therefore, tea extracts were found to have a great potential against the UV radiation. These products has great potential for protecting the skin against erythema, premature aging, and skin cancers.

175

PP85

ANTIOXIDANT ACTIVITY OF DİFFERENT EXTRACTS OF PAPAVER RHOEAS L. LEAVES

Şebnem SELEN İŞBİLİR, Department of Chemistry, Faculty of Art & Science, Trakya University, Edirne, TurkeyAyten SAĞIROĞLU, Department of Chemistry, Faculty of Art & Science, Trakya University, Edirne,Turkey

The role of free radicals and reactive oxygen species (ROS) in the pathogenesis of human diseases, including cancer, aging, atherosclerosis, neurological damage, has been recognised. Antioxidants, exogenous and es-pecially endogenous, are vital substances which possess the ability to protect the body from possible harms caused by the free radical induced oxidative stress and are necessary to balance ROS in human body. Hence, the antioxidants are the important elements for human nutrition, and so pharmaceutical and food indus-tries. In recent years, there has been an increasing interest in natural antioxidants present in medicinal and dietary plants. Papaver rhoeas L., commonly known as “corn poppy”, is traditionally used as a herbal medicine against coughing, bronchitis, sore throat, minor sleep problems and possesses a sedative effect. However its young leaves have been extensively used as garniture in salads. In this study, the possible an-tioxidant properties of water, ethanol and acetone extracts of corn poppy leaves have been investigated by using different antioxidant tests including total antioxidant activity in linoleic acid system, DPPH• scav-enging activity, reducing power, chelation activity and hydrogen peroxide scavenging activity. In addition, the amount of total phenolics has also been determined. The water and ethanol extracts have been found to have different levels of antioxidant potential in the test models used. Therefore, the leaves of the plant can be used as an easily accessible source of natural antioxidant and, can have important applications for the pharmaceutical and food industries.

176

PP86

ANTICHOLINESTERASIC ACTIVITY OF ASTRAGALUS GOMBIFORMIS POMEL EXTRACTS

Hassen TEYEB, Range Ecology Laboratory, Arid Land Institute of Medenine Hajer MABROUK, Biochemistry and Toxicology Laboratory, University Hospital of Monastir, TunisiaMohamed NEFFATI, Range Ecology Laboratory, Arid Land Institute of Medenine, Tunisia.Wahiba DOUKI, Biochemistry and Toxicology Laboratory, University Hospital of Monastir, TunisiaMohamed Fadhel NAJJAR, Biochemistry and Toxicology Laboratory, University Hospital of Monastir, Tunisia

To adapt to the climatic conditions, the plants produce infinity of substances which their permit to fight against the different types of anxiety and to defend itself against the microorganisms. This natural phenom-enon allowed obtaining various bioactive molecules. The present work aims to evaluate the anticholines-terasic activity of some extracts of Astragalus gombiformis Pomel. The aerial dried part was extracted by dichlomethane, ethyle acetate and methanol using the soxhlet. The vegetable powder was also macerated by water at room temperature and the aqueous extract was lyophilised. The anticholinesterasic activity of different extracts was measured by the colorimetric method of Ellman and al., (1961) using Konélab® 30 (Thermo Electron Corporation). The human plasma was used as enzyme source. The effects of the time of incubation and temperature also were studied. Our results showed that the ethyle acetate extract of (18.75 % yield) is the most active with an IC50 of 110 µg/ml. For all extracts, the activity is better after an incubation of 15 min. The temperature of 37 °C seems to be more adequate for the evaluation of anticho-linesterasic activity. The suppressants of cholinesterase have various possible applications. They can be used as insecticides and in the treatment of certain diseases such as Alzheimer. Astragalus gombiformis can be a source of such compounds. Thus, this study represents a contribution to the investigation of the Tunisian flora species and should be completed by the characterization of the substances of the active extract.

177

PP87

NEW BACTERIAL STRAINS FOR FUNGI CONTROL

Dilşad YURDAKUL, Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, İstanbul, Turkey.Fikrettin ŞAHİN, Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, İstanbul, TurkeySami AGUŞ, Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, İstanbul, Turkey.İskender KARALTI, Department of Medical Microbiology, Yeditepe University,İstanbul, Turkey.Arzu ALA GÖRMEZ, Department of Plant Protection, Faculty of agriculture , Atatürk University, Erzurum, Turkey.

Natural products, which are the substances produced by living organisms, are widely used in new drug discovery. Penicillins and aminoglycosides are the mostly known antibacterial agents that are produced by microorganisms. There are strong attempts to search novel microbial metabolites which may be used for fungi control. Therefore, our aim in this study was to assess fungicidal activity of bacterial strains that were isolated from environmental samples ( soil, plant and insects). Clinical fungi such as Fusarium spp., Mi-crosporum spp., Trichophyton rubrum, Aspergillus fumigatus and two Aspergillus flavus isolates that were obtained from patients, and plant pathogenic fungi such as Acremonium spp., Papulaspora spp., Fusarium spp. and two NRRL (Agricultural Research Service Culture Collection) isolates of Aspergillus parasiticus were included in the study. Fungi isolates were stained with lactophenol cotton blue stain and were identi-fied by microscopic examination. Fungicidal activity test was performed by inoculating bacteria (n=8) and fungi (n=11) on the same Potato Dextrose Agar plate, after two weeks of incubation at room temperature, fungicidal activity was evaluated by observing the clear zones around the bacterial strains. Four (OSU142, DYCF1, DYCF2, BA7) of the eight bacterial strains tested were found highly effective on Microsporum, Trichophyton and Aspergillus isolates whereas DYCF1 was effective on Fusarium spp. Three of the bacte-rial strains effective on fungi were identified as Bacillus subtilis, and one was identified as Burkholderia cepacia based on FAME analysis by Microbial Identification System (MIS). Also Bacillus cereus was effec-tive on T.rubrum. This result suggests that secondary metabolites from bacterial strain with antifungal ac-tivities may be used as potential antifungal agents. Acknowledgement: The authors are thankful to Prof. Dr. Gülden Yılmaz, Yeliz Demirci, Esen Eberliköse from University of Yeditepe, Prof. Dr. İsmet Hasenekoğlu from University of Atatürk and Dr. Zülal Kesmen from University of Erciyes.

178

PP88

BIOACTIVE ENT-KAURANES FROM SIDERITIS CONGESTA

Abdülselam ERTAŞ, Department of Analytical and General Chemistry, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey.Mehmet BOĞA, Department of Analytical and General Chemistry, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey.Mehmet ÖZTÜRK, Department of Chemistry, Faculty of Art&Science, Muğla University,Muğla, Turkey.Tuncay DİRMENCİ, Department of Biology, NecatiBey Faculty of Education, Balıkesir University, Balıkesir, Turkey.Gülaçtı TOPÇU, Department of Chemistry, Faculty of Science&Letters, Istanbul Technical University, Istanbul, Turkey.

As one of the Lamiaceae family plants Sideritis genus is represented by 46 species consisting of 34 endemic species [1]. Sideritis plant extracts and constituents were found to have antiinflammatory, antirheumatic, antiulcer, insecticidal, antifeedant, antimicrobial, antioxidant and cytotoxic activities [2]. Sideritis species are commonly used as herbal teas and for some medicinal purposes and flavouring agents in Turkey [3]. In this study a new and seven known ent-kaurene diterpenes were isolated from petroleum ether and acetone extracts of whole plant of Sideritis congesta P.H. Davis & Hub.-Mor. Their structures were elucidated as the new ent-3β,7α-dihydroxy,18-acetoxy-15β,16β-epoxykaurane (1) and the known kaurenes sideroxol (2), 7-epi-candicandiol (3), sideridiol (4), foliol (5), linearol (6), sidol (7) and siderol (8) based on IR, 1D- and 2D NMR techniques and HRMS [4,5]. Antioxidant potential of the extracts was investigated by four methods including β-carotene bleaching method, DPPH free radical scavenging activity, superoxide anion radical scavenging activity and metal chelating activity [6]. Acetone extract of S. congesta was found to be more active than standards α-tocopherol and butylated hydroxy toluene (BHT) in β-carotene bleaching method while both acetone and methanol extracts of S. congesta have shown stronger activity than BHT in DPPH free radical and superoxide anion radical scavenging activity tests. Some of the isolated kaurane di-terpenoids have been investigated for their anticholinesterase activity and they exhibited moderate AChE/BChE activity.

179

PP89

EVALUATION OF ANTIOXIDANT ACTIVITY AND CHEMICAL COMPOSITION OF BLACK AND GREEN TEAS

Gülşah GEDİK, Department of Pharmacutical Technology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey.Murat TÜRKOĞLU, Department of Pharmacutical Technology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey.A. Mine YILMAZ, Department of Biochemistry, Faculty of Medicine, Marmara University, İstanbul, Turkey.A.Süha YALÇIN, Department of Biochemistry, Faculty of Medicine, Marmara University, Istanbul, Turkey.

Catechins are the most important polyphenols in tea. Besides catechins, the secondary phenolic substances produced by oxidation such as theaflavine monogallat also possesses antioxidant properties. Freeze dried samples (100 mg) were dissolved in 1 mL ultra-pure water. After vortex mixing samples were kept at 37oC for 2 hours , centrifuged at 9000 g for 2 minutes, the supernatants were diluted 100 times and used for an-tioxidant activity measurements. The cupric ion reducing antioxidant capacity were determined using the assay where 0.2 ml of 10 mM CuCl2 , 0.2 ml of 7.5 mM neocuproine and 0.2 ml of 1 M ammonium acetate were added to a test tube. After vortex mixing, a 20 or 50 μl sample and ultra-pure water were added and the absorbance at 450 nm was read after 30 minutes. The trolox equivalent antioxidant capacity was cal-culated using a calibration curve obtained by a serial dilution of 1 mM tr (TR=1.67x mol/l/cm). The free radical scavenging activity of samples was measured with DPPH. The DPPH was dissolved in ethanol (4 mg/100 ml) and 100 μl of this solution was added to an equal volume of samples. The mixture was shaken ,the absorbance decrease was measured at 515 nm after 30 minutes. Water was used as control. Antioxidant activities of black and green teas, high quality black tea, and l-ascorbic acid samples were found to be strong and comparable as 0.48, 0.50, 0.82, and 1.32 mM TR/mg. The free radical scavenging activity: 26.3, 18.4, 26.5, 41.8 (% inhibition) and the teas’ water soluble fractions: 27.34, 34.95, and 34.7 % ; caffeine contents: 2.21, 1.65, 5.16 % ; pH’s : 5.3, 5.2, 5.4. The data were evaluated by the ANOVA.

180

PP90

ANTINOCICEPTIVE AND ANTIPYRETIC ACTIVITIES OF PUTRANJIVA ROXBURGHII WALL. LEAVES EXTRACT IN EXPERIMENTAL ANIMALS

Wantana REANMONGKOL, Department of Clinical Pharmacy, Prince of Songkla University, Thailand.Tassanee NOPPAPAN, Department of Clinical Pharmacy, Prince of Songkla University, Thailand.Sanan SUBHADHIRASAKUL, Department of Pharmacognosy and Pharmaceutical Botany, Prince of Songkla University, Thailand.

The effects of the ether extract from the leaves of Putranjiva roxburghii (P. roxburghii) Wall. were assessed on nociceptive responses using writhing, hot plate and formalin tests in mice and the antipyretic activity in yeast-induced fever in rats. It was found that the ether extract (100, 200 and 400 mg/kg, p.o.) of P. rox-burghii dose dependently produced analgesic activity on acetic acid-induced writhing in mice. The extract had no significant effect on nociceptive response induced by heat in mice. At the dose of 400 mg/kg, the extract significantly suppressed the licking activity in the late phase of formalin test in mice and decreased fever induced by yeast in rats. The results indicated that the ether extract of P. roxburghii leaves possesses the analgesic and antipyretic activities.

181

PP91

CHOLINESTERASE INHIBITORY ACTIVITY OF A SERIES SALVIA SPECIES

Mehmet ÖZTÜRK, Department of Chemistry, Faculty of Art & Science, Muğla University, Muğla, Turkey.Mehmet BOĞA, Department of Analytical and General Chemistry, Faculty of Pharmacy, Istanbul University, Istanbul, TurkeyDemet DINÇEL, Department of Chemistry, Faculty of Science & Letters , Istanbul Technical University, Istanbul, Turkey.Seda Damla HATIPOĞLU, Department of Chemistry, Faculty of Science & Letters, Istanbul Technical University, Istanbul, Turkey.Fatemeh BAHADORI, Department of Chemistry, Faculty of Science & Letters , Istanbul Technical University, Istanbul, Turkey.Ufuk KOLAK, Department of Analytical and General Chemistry, Faculty of Pharmacy , Istanbul University, Istanbul, Turkey.Gülaçtı TOPÇU, Department of Chemistry, Faculty of Science & Letters, Istanbul Technical University, Istanbul, Turkey.

Salvia L. is one of the largest genera of the family Lamiaceae (Labiatae) which is widespread every part of the world, especially in the three districts, Mediterranean region, South-East Asia, Central and South America [1]. Salvia (sage) is one of the most investigated genera for various biological activities, and has been held in high regard throughout history for both culinary and medicinal properties [2]. In fact, sage has been also known as an outstanding memory enhancer and used in the treatment of cerebrovascular diseases and depression for over hundreds years [3-5]. Anticholinesterase activity of alcohol extracts of the aerial parts of thirteen Salvia species growing in Turkey were investigated against acetylcholinesterase (AChE) and butyryl-cholinesterase (BChE) enzymes by modified Ellman method [6]. The investigated plant extracts were S. aucheri, S. bracteata, S. eriophora, S. heldreichiana, S. kronenburgii, S. macrochlamys, S. pilifera, S. poculata, S. recognita, S. staminea, S. syriaca, S. verticillata subsp. amasiaca, and S. wiedemannii. Among them, the most active extract at 200 μg/mL was found to be S. staminea with the inhibition of %55,17 and 79,75 against enzymes AChE and BChE, respectively which is well correlated with its antioxidant activity results.

182

PP92

BIOACTIVE CONSTITUENTS OF SALVIA TRILOBA

Gülaçtı TOPÇU, Department of Chemistry, Faculty of Science & Letters, Istanbul Technical University, Istanbul, Turkey.Aslı BARLA, Department of Analytical and General Chemistry, Faculty of Pharmacy,Istanbul University, Istanbul, Turkey.Tuba KUŞMAN, Department of Chemistry, Faculty of Science & Letters, Istanbul Technical University, Istanbul, Turkey.Mehmet ÖZTÜRK, Department of Chemistry, Faculty of Art & Science, Muğla University, Muğla, Turkey.Mehmet BOĞA, Department of Analytical and General Chemistry, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey.Ufuk KOLAK, Department of Analytical and General Chemistry, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey.

From antiquity, Salvia species have been used as antiseptic, antibacterial, and in the treatment of some menopause problems as well as sedative and memory enhancer, traditionally. In the last fifty years, extracts of Salvia species and their constituents have been studied for antibacterial, antioxidant, cytotoxic/antitu-mor, antiviral and anti-Alzheimer activities [1-3]. From the methanol extract of Salvia triloba (syn:S. fru-ticosa ), three triterpenoids oleanolic acid, ursolic acid and a new triterpen 3-penta-decanoyl-ursolic acid were isolated, and their structures were elucidated based on 1H-NMR, 13C-NMR and mass spectroscopic techniques. Besides triterpenoids, two diterpenoids carnosic acid-12-methylether and manool were also isolated as well as some other compounds which were not identified yet. Structure elucidation studies on the unidentified compounds are going to be completed. In the last about 30 years, we have investigated over 60 Salvia species for their active constituents [1, 2, 4-6]. In this study, antioxidant and anticholinesterase activity of the methanol extract of S. triloba were investigated. The antioxidant activity was searched by six tests including β-caroten bleaching method, DPPH free radical scavenging, super oxide anion radical scavenging, ferric reducing power assay, CUPRAC and metal chelating assay, and the extract was found to be highly active in all assays.The anticholinesterase activity was investigated against AChE and BChE enzymes.The activity studies for the isolated compounds are still under investigation.

3-penta-decanoyl-ursolic acid

183

Sclareol

PP93

BIOLOGICAL ACTIVITIES AND COMPOSITION OF SALVIA CHRYSOPHYLLA

Burcu ÇULHAOĞLU, Department of Chemistry, Faculty of Science & Letters, Istanbul Technical University, Istanbul, Turkey.Mehmet BOĞA, Department of Analytical and General Chemistry, Faculty of Pharmacy, Istanbul University Istanbul, Turkey.Gönül YAPAR, Department of Chemistry, Faculty of Science & Letters, Istanbul Technical University, Istanbul, Turkey.Gülaçtı TOPÇU, Department of Chemistry, Faculty of Science & Letters, Istanbul Technical University, Istanbul, Turkey.

Salvia L. as one of the largest genera of Lamiaceae is composed of over 900 species and distrubuted exten-sively in three regions of the world: Central and South America (500 spp.), western Asia (200) and South-ern Asia(100). Turkey is home to 95 Salvia species and 49 (52%) of which are endemic [1]. Salvia species are used in traditional medicine all around the world, possesing antioxidant, antidiabetic, antibacterial, anti-tumor, antiplasmodial and anti-inflammatory effects [2, 3]. In our continuing studies on bioactive constituents of Salvia species, anticholinesterase activity of methanol and dichloromethane extracts of the aerial parts of Salvia chrysophylla were investigated against acetylcholinesterase (AChE) and butyrylcho-linesterase (BChE) enzymes by modified Ellman method [4-6]. Total phenolic and total flavonoid contents of Salvia chrysophylla extracts were determined, and they were also screened for free radical scavenging capacity by DPPH assay and lipid peroxidation inhibitory activity by β-carotene-linoleic acid assay. Di-chloromethane extract showed higher anticholinesterase activity while methanol extract showed higher antioxidant activity. In this study, four terpenic compounds and a flavonoid have been isolated, and their structures were elucidated as sclareol, oleanolic acid, ursolic acid, β-sitosterol and salvigenin by NMR and mass spectroscopic techniques. Structure elucidation and activity studies on the other isolated constituents have been continuing.

184

PP94

INVESTIGATION OF THE RELATIONSHIP BETWEEN SIALIC ACID LEVEL AND TISSUE FACTOR ACTIVITY IN EXPERIMENTAL HYPERLIPIDEMIA

Şehkar OKTAY, Department of Biochemistry,Faculty of Dentistry, Marmara University, Nişantaşı, İstanbul, TurkeyBenun KILIÇ, Department of Biochemistry,Faculty of Dentistry, Marmara University, Nişantaşı, İstanbul, TurkeyEbru Işık ALTURFAN, Department of Biochemistry,Faculty of Dentistry, Marmara University, Nişantaşı, İstanbul, TurkeyAli ŞAHİN, Department of Biochemistry,Faculty of Dentistry, Marmara University, Nişantaşı, İstanbul, TurkeyNesrin EMEKLİ, Department of Biochemistry,Faculty of Dentistry, Marmara University, Nişantaşı, İstanbul, Turkey

Introduction: Sialic acid (SA) participates in multiple physiological functions, such as cell to cell interac-tions, cell migration and proliferation. Serum SA has been proposed as a marker of an acute-phase response in different diseases. Although the importance of tissue factor (TF) in coagulation has been known, the mechanism of the system remains unclear. In recent days, literatures show that inhibition of TF activition may play an important role in development of new treatment procedures. Free radicals cause lipid peroxida-tion (LPO) and malondialdehite occurs as a lipid peroxidation product. Glutathione (GSH) is an impor-tant antioxidant molecule.

Materials and Methods: The study group consisted of 24 female C57BL/6 mice divided into 2 groups. The control group was fed with standart fodder while the hyperlipidemic group was fed with hyperlipidemic fodder for 3 months. SA levels were determined by the thiobarbituric acid method, TF activities were de-termined by the Quick method , GSH and LPO levels were determined by chemical methods.

Results: When compared to control group we found significant differences between TF activity, SA, GSH and LPO levels in hyperlipidemic group ( respectively p<0.001, p< 0.01, p<0.05, p<0.001).

Discussion: It was shown that SA is a strong predictor of cardiovascular mortality and may also reflect the existence or activity of an atherosclerotic process. SA has an important role in protecting the integrity of the blood vessel structure whereas TF is necessary for blood coagulation therefore, we aimed to investigate the possible relation between TF and SA in experimental hyperlipidemia. According to the results of this study, antioxidant balance was disturbed which in turn caused LDL oxidation. As a result, controlling the oxidant-antioxidant balance is important in hyperlipidemia.

185

PP95

STUDY MUTAGENICITY PROPERTY OF THREE MEDICINAL PLANTS EXTRACTS

Gholamreza DEHGHAN, Pharmaceutics Research Center, Kerman University of Medical Sciences, Kerman, Iran Fariba SHARIFIFAR, Pharmaceutics Research Center, Kerman University of Medical Sciences Kerman, IranMohammadhassan MOSHAFI, Pharmaceutics Research Center, Kerman University of Medical Sciences, Kerman, IranReza GHARAEEI, Pharmaceutics Research Center, Kerman University of Medical Sciences Kerman, Iran

Some plants are traditionally used for the treatment of many diseases. In this research we surveyed muta-genicity effects of Zataria multiflora, Stachys inflata and Achillea wilhelmsii. Conducting the Ames test, we used Salmonella typhimurium, which has mutated histidine operan and depends on histidine for its growth. The tester strains used were, TA98 and TA100, which can determine point mutations including frame shift and base pair substitution mutations. These strains can also grow and produce colonies in the presence of mutagen substances in minimal glucose agar medium. The extracts of plants were prepared in different volumes such as 10, 20, 50, 100, 200, 250 and 300 microliter and were exposed to TA98 and TA100 strains. TA98 and TA100 were cultured in media with minimum glucose agar; and the produced colonies were counted after 48 hours. The mean of revertant colonies in each group was compared with the mean of each corresponding control revertant colony. Using evaluation indices, the rates of mutation was calculated and dose-response curve plotted. These extracts in many applied volumes can revert TA98 and TA100. It can establish point mutations including frame shift and base pair substitution mutation. How-ever, in order to obtain higher certainty, other mutagenicity tests must be performed.

186

PP96

THE BIOCHEMICAL ASSESSMENT OF THE EFFECTS OF NIGELLA SATIVA OIL ON CUTANEOUS WOUND HEALING IN RATS

Halil AKSOY, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey Sule APİKOĞLU-RABUŞ, Department of Clinical Pharmacy, Faculty of Pharmacy , Marmara University, Haydarpaşa 34668 İstanbul, Turkey Mesut SANCAR, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyBetul OKUYAN, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey Fikriye URAS, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyFikret Vehbi İZZETTİN, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

Background: There is evidence that topical application of Nigella sativa oil together with or without in-traperitoneal Nigella sativa oil administration accelerates cutaneous wound healing in rats. This positive effect might be attributable to thymoquinone -an active substance of Nigella sativa oil- which possesses antioxidant properties. Thus, in this study we aimed to identify the involvement of an antioxidant mecha-nism through assessment of the biochemical effects of Nigella sativa oil on cutaneous wound healing in rats.

Methods: This study was conducted using a total of nine groups of male Sprague-Dawley rats, receiving three different treatments: (i) topical normal saline, (ii) topical Nigella sativa oil, (iii) intraperitoneal Ni-gella sativa oil. The three-group design was repeated for three different time frames where the rats were sac-rificed on the 3rd, 7th and 14th days. There were six rats in each group. Two round, full-thickness excision wounds, 0.6 mm in diameter, were created with a punch biopsy instrument on the dorsal thoracic area of each rat. The wounds were left open throughout the study. After the wound excision, test and control solu-tions were applied to each wound once daily until the end of experiment. At the day of sacrification, samples were taken from each wound site. After the biopsy samples were homogenized, glutathione peroxidase and malondialdehyde levels were measured. Hidroxyproline and superoxide dismutase levels, as well as catalase activity were also measures.

Results: Both topical and intraperitoneal administration of Nigella sativa oil caused varying effects on glu-tathione peroxidase, malondialdehyde, superoxide dismutase and hidroxyproline levels as well as and cata-lase activity measured at the wound samples taken at the 3rd, 7th and 14th days. Further studies are needed to explain these varying results.

187

PP97

EFFECT OF THE CREAMS BEARING APRICOT SEED OIL ON THE SKIN MOISTURE AND SEBUM

Soner SOYTOPRAK, Department of Pharmacutical Technology, Faculty of Pharmacy, MersinUniversity, Mersin, Turkey.Altan YÜKSEL, Department of Pharmacutical Technology, Faculty of Pharmacy, MersinUniversity, Mersin, Turkey

Recently, apricot oil has gained importance in Turkey and the rest of the world as a popular natural product that has been used to reduce wrinkles while moisturizing skin. Although there exist many cosmetic creams prepared with apricot oil in the local market, no significant study conducted to determine the efficacy of such product was found in literature. In this study, both marketed products and the formulae developed with apricot oil in our laboratory were compared. Seven different brand names of creams bearing apricot oil were selected from the local market. In addition, apricot creams were prepared with various concentra-tion of apricot oil (% 0.5 – 3.0 w/w) in our laboratory. At first, salon tests were carried out on volunteers to determine the effect of apricot oil bearing creams on skin moisture and sebum. Also, suitability tests for the purpose of use and microbiological test were conducted on both marketed products and the formulae developed in our laboratory. In the end of our study, it was determined that most of the marketed products affect skin moisture in a positive way. However, no significant effect of apricot oil bearing creams was found on the sebum

188

PP98

ANTİOXİDANT ACTİVİTY OF SEVERAL PARTS OF TRACHYSTEMON ORIENTALIS (L.) G.DON

Nurten ÖZSOY, Department of Biochemistry, Faculty of Pharmacy, Istanbul University, Istanbul, TurkeyTurgut TAŞKIN, Department of Pharmacognosy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyLeyla BİTİŞ, Department of Pharmacognosy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

The genus Trachystemon D.Don belongs to the family Boraginaceae is represented by only this species in Turkey. T. orientalis (L.) G.Don. is distributed in East Bulgaria, West Caucasia and the Black Sea region in Turkey. The plant known as Hodan, Galdirek, Kaldırık, Ispıt names in Turkey(1,2) This species known with 20-60 cm herbaceous and perennial plant with tuberous blackish rhizome(1) The flowering branches, rhizomes, leaves and petioles of the plant are consumed as vegetables in Istanbul and some locations of the Black Sea region. Moreover, the roots and petioles are used for preparing pickle. This plant is known as diuretic and plasmapheresis. It is used as diaphoretic, laxative and antipyretic.(2) This study was conducted to evaluate the antioxidant activities of methanolic extracts of the different parts of T. Orientalis, including leaves, petioles, aerial parts and rhizomes. It was concluded that all the extracts showed inhibitory effect against the formation of thiobarbituric acid reactive substances (TBARS) in a phosphatidylcholine lipo-some model system, strong scavenging effect on DPPH• radical, as well as marked reducing power. As a conclusion, all of the extracts have antioxidant activity and the antioxidant activity results also showed well correlations with total phenolic and flavonoid contents.

References

1. Davis, P.H., ‘’Flora of Turkey and the East Aegean Islands’’ Vol. 6., Edinburgh University Press, Edinburgh(1978).2. Baytop, T., ‘’Türkiye’de Bitkiler ile Tedavi’’, Nobel Kitabevleri, 2. Baskı, İstanbul, s. 184-185 (1999)

189

PP99

ANTIOXIDANT, ANTIBACTERIAL AND ANTIFUNGAL ACTIVITIES OF SEVERAL EXTRACATS FROM SAMBUCUS EBULUS LEAVES

Zehra İlke MERİÇ, Department of Pharmacognosy, Faculty of Pharmacy, Marmara University Haydarpaşa 34668 İstanbul, TurkeyBurçak GÜRBÜZ, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyÜmran SOYOĞUL GÜRER, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyLeyla BİTİŞ, Department of Pharmacognosy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

There are two Sambucus species (Caprifoliaceae) in Turkey; Sambucus ebulus L. and Sambucus nigra L. Both plants have been used to treat various ailments in Turkish folk medicine. Several pharmacological effects have been reported for Sambucus species. In our previous study, phenolic content and antioxidant activity of leaves have been found higher than fruits and flowers in S.ebulus. In this reason we decided to study on the leaves of S.ebulus. Air dried leaves have been extracted with petroleum eter and with etha-nol in a soxhlet aparatus. The concentrated ethanol was diluted with water and fractionated with toluen, chloroform and ethyl acetate respectively. The ethyl acetate fraction contains high amount of flavonoids. Antioxidant activity of Sambucus ebulus was determined with DPPH method using BHT and ascorbic asit as standards. Ethyl asetat extracts showed higher antioxidant activity than other extracts. The total phenolics content was determined according to the colorimetric Folin–Ciocalteu method with gallic acid as a standard compound. The total phenolic contents were higher in ethyl asetat extracts than the others. All extracts of Sambucus ebulus were investigated for their antibacterial and antifungal activities against Staphylococcus aureus (ATCC 25923), Staphylococcus epidermidis (ATCC 12228), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), Proteus vulgaris (ATCC 13315), Klebsiella pneumoniae (ATCC 4352), Candida albicans (ATCC 90028), Candida glabrata (ATCC 90030), Candi-da guilliermondii (KUEN 998), Candida tropicalis (KUEN 1021), Candida parapsilosis (ATCC 90018), and Candida krusei (ATCC 6258). In conclusion, the ethyl acetate extract of S. ebulus has been found to be the most effective extract against tested bacteria.

190

PP100

ANTIOXIDANT AND ANTIMICROBIAL ACTIVITIES OF METHANOL EXTRACTS OF SOME ACHILLEA SPECIES

Mehmet Zahid UYANIK, Department of Pharmacognosy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey Burçak GÜRBÜZ, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey Ümran SOYOĞUL GÜRER, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyGizem BULUT, Department of Pharmaceutical Botany, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey Leyla BİTİŞ, Department of Pharmacognosy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

42 Achillea L. species (Asteraceae) (48 taxons) grow wildly in Turkey and 27 taxons of them are endemic in Turkey. Aerial parts of Achillea species are used for their antispasmodic, diuretic, appetizer, carminative, cholagogue, emmenagogue, antiinflammatory and wound healing (especially for haemorrhoids) properties in Turkish folk medicine. In this study, antimicrobial and antioxidant activities of methanolic extracts of Achillea multifida (DC.) Boiss., Achillea crithmifolia Waldst. & Kit., Achillea setacea Waldst. & Kit., Ach-illea wilhelmsii C. Koch, Achillea nobilis L. subsp. neilreichii (Kerner) Formánek species were investigated. The total phenolic content of this species were determined according to the colorimetric Folin–Ciocalteu method, gallic acid was used as a standard. Also, antioxidant capacity was assayed by DPPH method us-ing BHT and askorbic acid as standards. Our result clearly demonstrate that all of the extracts have anti-oxidant capacity and Achillea crithmifolia has higher antioxidant activity than the other Achillea species. The antimicrobial activity of five different Achillea species against Staphylococcus aureus (ATCC 25923), Staphylococcus epidermidis (ATCC 12228), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), Proteus vulgaris (ATCC13315), Klebsiella pneumoniae (ATCC 4352), Candida albi-cans (ATCC 90028), Candida glabrata (ATCC 90030), Candida guilliermondii (KUEN 998), Candida tropicalis (KUEN 1021), Candida parapsilosis (ATCC 90018), and Candida krusei (ATCC 6258) were investigated. Agar well diffusion method was used in the antimicrobial activity test. Minimal inhibition concentration (MIC) was determined by broth macrodilution method according to Clinical and Labora-tory Standarts Institute (CLSI) Meropenem for bacteria, Amphotericin B for Candida were used as control substance. The results showed that all methanolic extracts have antibacterial activity against S. aureus and S. epidermidis. The solvent (methanol) used as control, did not show any antibacterial and antifungal activity.

191

PP101

ANTISPASMODIC ACTIVITY OF SEVERAL PARTS OF SAMBUCUS EBULUS

Zehra İlke MERİÇ, Department of Pharmacognosy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyLevent KABASAKAL, Department of Pharmacology, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyLeyla BİTİŞ, Department of Pharmacognosy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

There are two Sambucus species (Caprifoliaceae) in Turkey; Sambucus. ebulus L. and Sambucus nigra L. Both plants have been used to treat various ailments in traditional medicine such as, abdominal pain and asthma. Extracts obtained from the plant have shown antiinflammatory, wound healing, antinociceptive, diuretic, hypotensive, anti-Helicobacter pylori, and antioxidative properties. In this study, the leaves, flow-ers and fruits of S.ebulus L. have been extracted with methanol at room temperature. Previously we found that the leaves of S.ebulus have higher phenolic content than fruits and flowers. According this result, we also prepared ethyl acetate extract from S.ebulus leaves by fractionation. The aim of the present study was to investigate the spasmolytic activity of methanol methanol extracts of leaves, fruits, flowers and ethyl asetat extracts of the leaves of S. ebulus on duodenum of Wistar rat. Contraction changes in the duodenum of rat were monitored using a force displacement transducer amplifier connected to a Grass Polgraph 7E. All pro-cedures concerning animals were carried out in an ethically proper way by following guidelines as set by the WHO. The approval was also obtained from Marmara University Local Animal Ethical Committee. In the rat duodenum, cumulative dose-response curves to acetylcholine (Ach) were obtained in the absence and presence different doses of the extract. The extract has exhibited an inhibitory effect on the dose-response curves induced by Ach on rat duodenum and significantly reduced the maximal response in a concentra-tion dependent manner. This is the first study that describes the spasmolytic effect of the leaves, flowers and fruits of S. ebulus. Observed spasmolytic activity of S. ebulus has been attributed to the flavonoids. It is well known that some flavonoids can act as spasmolytic agents by relaxing smooth muscles in various parts of the mammalian body.

192

PP102

COMPARISON OF ANTIMICROBIAL AND ANTIOXIDANT ACTIVITIES OF AERIAL PARTS OF FIVE CENTAUREA L. SPECIES

Ali ŞEN, Department of Pharmacognosy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyLeyla BİTİŞ, Department of Pharmacognosy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeySeher BİRTEKSÖZ, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Istanbul University, İstanbul, TurkeyGizem BULUT, Department of Pharmaceutical Botany, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

The genus Centaurea L.(Asteraceae) are represented by 205 taxon in Turkey(1,2,3). In traditional medi-cine, they are used for fever, menstrual disorders, vaginal candidiasis ,the treatment of liver, kidney and ulcer diseases, as antidiarrheal, stomachic, tonic, appetitive, antidiabetic, antipyretic, also as a diüretic and expectorant (4,5). In this study, methanol extracts obtained by maceration from aerial parts ( except for capitulum) of 5 Centaurea species were investigated to antioxidant, antimicrobial activities and total phe-nolic contents. The total phenolic contents of the species were determined according to the colorimetric Folin–Ciocalteu method with gallic acid as a Standard (6). According to our study, The total phenol con-tents of the plant extracts are in the following order: C. stenolepis > C. kilaea> C. iberica > C. cuneifolia > C. solstitialis subsp. solstitialis Antioxidant activity was assayed by DPPH method using BHT and Ascor-bic acid standards (7). Also, the scavenging effects of methanol extracts and standards are in the following order : Ascorbic acid > C. Stenolepis > BHT > C. kilaea > C. solstitialis subsp. solstitialis > C.cuneifolia > C. iberica. As a result, Centaurea stenolepis showed significant antioxidant activity when compared with BHT. Antimicrobial activity was assayed by disc diffusion and microbroth dilution methods. Antimicrobial activities of methanol extracts were determined against Staphylococcus aureus ATCC 6538, Staphylococ-cus epidemidis ATCC 12228 Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 4352 Pseudo-monas aeruginosa ATCC 27853, Proteus mirabilis ATCC 14153, Salmonella typhi, Shigella flexneri and Candida albicans ATCC 10231 . All of the extracts except Centaurea solstitialis subsp. solstitialis exhibited moderate activity against Candida albicans. Centaurea kilaea and Centaurea solstitialis subsp. solstitialis possessed moderate activity against Pseudomonas aeruginosa. On the other hand, Centaurea cuneifolia showed low activity against Staphylococcus aureus.

193

PP103

IN VITRO ANTIOXIDANT AND ANTIMICROBIAL ACTIVITIES OF VARIOUS EXTRACTS OF CENTAUREA STENOLEPIS KERNER

Ali ŞEN, Department of Pharmacognosy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyBurçak GÜRBÜZ, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyÜmran SOYOĞUL GÜRER, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyLeyla BİTİŞ, Department of Pharmacognosy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

Oxidation is essential to many living organisms for the production of energy to fuel biological processes. However, oxygen-centred free radicals and other reactive oxygen species (ROS), which are continuously produced in vivo, result in cell death and tissue damage. There is an increasing interest in natural antioxi-dants, e.g., polyphenols, present in medicinal and dietary plants, which might help prevent oxidative dam-age (1). Centaurea stenolepis Kerner (Asteraceae) is one of the 205 taxon of the genus Centaurea growing wild in Turkey (2,3,4). The aim of the present work is to investigate the antioxidant and antimicrobial prop-erties of different extracts of Centaurea stenolepis. Dried aerial parts ( except for capitulum) of Centaurea stenolepis were extracted with petroleum eter and then ethanol in a Soxhlet aparatus. The concentrated ethanol was diluted with water and fractionated with toluen, chloroform, ethyl acetate, respectively. The antioxidant acitivities of four different extracts (toluene, chloroform, ethyl acetate, aqueous) have been determined by using 1,1-diphenyl-2-picrylhydrazyl (DPPH) as well as their phenolic contents by using Folin-Ciocalteu reagent (1,5) The ethyl acetate extract was the most potent one on antioxidant activity and total phenolic content. Also, the ethyl acetate extract was more effective than BHT being used as a posi-tive control. The Petroleum ether, toluene, chloroform, ethyl acetate, aqueous extracts were screened for antimicrobial activity against Staphylococcus aureus (ATCC 25923), Staphylococcus epidermidis (ATCC 12228), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), Proteus vulgaris (ATCC 13315), Klebsiella pneumoniae (ATCC 4352), Candida albicans (ATCC 90028), Candida gla-brata (ATCC 90030), Candida guilliermondii (KUEN 998), Candida tropicalis (KUEN 1021), Candida parapsilosis (ATCC 90018), and Candida krusei (ATCC 6258). Agar well diffusion method was employed for both the antibacterial and the antifungal activity tests. The results showed that the ethyl acetate extract had significant activity against all of the tested microorganisms. Key words: DPPH,Total phenol, Antimi-crobial activity

194

PP104

A CANDIDATE THERAPEUTIC TARGET FOR DIABETIC NEPHROPATHY: GAS6

Aybala EREK, Department of Clinical Biochemistry, Bezm-i Alem Valide Sultan Vakif Gureba Training and Research Hospital, Istanbul, TurkeyÖzlem ÖZAKPINAR, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyZeynep KARACA, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyFikriye URAS, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyAhmet Riza URAS, Department of Clinical Biochemistry, Bezm-i Alem Valide Sultan Vakif Gureba Training and Research Hospital, İstanbul, Turkey

Objective: Growth arrest-specific gene 6 protein (Gas6) is a vitamin K-dependent growth factor for me-sangial cells that plays a key role in the progression of various kidney diseases. Diabetes mellitus is the most important cause of end-stage renal diseases in many countries. The mechanism of diabetic nephropathy, however, remains incompletely understood. We research into the effect of Gas6 in the pathogenesis of diabetic nephropathy.

Methods: In this study, 32 diabetic patients with nephropathy, 34 diabetic patients without nephropathy and 34 healthy control subjects were recruited as three comparing groups. Plasma Gas6 levels were de-termined by ELISA kit from R&D Systems. Whole blood samples for hemoglobin A1c (HbA1c), serum samples for C reactive protein (CRP), plasma samples for fibrinogen; 24 hour urine samples for microalbu-minuria were analyzed by Primus PDQ, Beckman Coulter Immage 800, STA Compact, Roche Cobas In-tegra 800 Analyzer, respectively. Statistical difference of Gas 6 among three groups and correlation between Gas 6 with microalbuminuria, CRP and fibrinogen was investigated by using SPSS (Statistical Package for Social Sciences) for Windows 17.0.

Results: There was statistically significant difference among three groups for Gas6 by using Kruskal Wallis Test (p=0,035). Gas6 plasma levels were higher in diabetic patients with nephropathy (23,5 ± 10,1 ng/ml) comparing those with diabetic patients without nephropathy (18,5 ± 6,6 ng/ml). Also there was a significant positive correlation between Gas6 and microalbuminuria (p=0,003). Moreover the correlation between microalbuminuria and CRP, microalbuminuria and fibrinogen, microalbuminuria and HbA1c was significant (p<0,05).

Conclusions: Inhibition of Gas6 would be an attractive therapeutic target for slow down the progression of diabetic nephropathy. Further investigations on the role of the Gas6 in human kidney diseases and the development of specific antagonists targeting the pathway are needed.

195

PP105

INVESTIGATION OF DNA DAMAGE AND DNA REPAIR CAPACITY IN PATIENTS WITH COLORECTAL CANCER AND THEIR FIRST DEGREE RELATIVES

Ayfer BECEREN, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyGülden Z. OMURTAG, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyKerem TOLAN, Department of General Surgery, Faculty of Medicine, Marmara University , Istanbul, TurkeyÖznur SENKESEN, Department of Radiation Oncology, Kozyatağı Acıbadem Hospital , Istanbul, TurkeyCumhur YEGEN, Department of General Surgery, Faculty of Medicine,Marmara University , Istanbul, TurkeySemra ŞARDAŞ, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

Studies in all over the world have reported that genetic susceptibility and environmental factors play an important role in the formation of colorectal cancer. The aim of our study was to investigate the potential DNA damage using by comet assay and chromosomal aberrations (CAs), measurement of DNA repair capacity by using challenge assay as biomarkers of susceptibility in peripheral lymphocytes of colorectal cancer patients and their first degree relatives. For this purpose, peripheral blood samples were taken from untreated patients diagnosed with colorectal cancer and their first degree relatives and this study is still continuing to increase the number of subjects. A total of 50 individual cells were screened per sample (from each slide). An undamaged cell resembles an intact nucleus without a tail and a damaged cell has the ap-pearance of a comet. The length of the DNA migrated in the comet tail, which is an estimate of DNA dam-age, was measured with image analysis system. Mean tail %DNA for each cell was calculated as 100-Head %DNA. No difference in CAs between colorectal cancer patients (n:15) and their first degree relatives (n:15) were observed. The Mean %DNA in tail was calculated as (10.36±1.37) in colorectal cancer patients (n:39) and as (9.89±1.39) in their first degree relatives (n:33). However DNA repair capacity was assessed as (45.06±4.78) in colorectal cancer patients and as (48.24±7.61) in their first degree relatives (p<0.05). DNA repair capacity of each individual will be presented as a separate table. Our study is ongoing by in-crease the number of patients.

196

PP106

EVALUATION OF GENOTOXICITY THROUGH CYTOKINESIS BLOCK MICRONUCLEUS ASSAY IN OFFSET PRINTING WORKERS

Diren BEYOĞLU, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyLale DONBAK, Department of Biology, Faculty of Art & Sciences, Kahramanmaras Sutcu Imam University, Kahramanmaraş, TurkeyBehzat ÇİMEN, Department of Biochemistry, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyGülden Z. OMURTAG, Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeySemra ŞARDAŞ, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

Offset printing workers are exposed to a various complex chemical mixtures, including polycyclic aromatic hydrocarbons (PAHs), benzene, lead, toluene, cobalt, hydroquinone, thinner, organic solvents and printing dyes. An increased risk of cancer at various sites has been reported among workers in the printing industry. In 1996, an IARC (International Agency for Research on Cancer) working group evaluated occupational exposures in printing process as possibly carcinogenic to humans (Group 2B), based on limited epidemio-logic evidence. Genotoxic analyses are sensitive methods in the field of biomonitoring of human exposure in industry, and play a significant role in the prevention of DNA damage to human health. In this study, cytokinesis block micronucleus assay (CBMN) was applied in peripheral blood lymphocyte cells of offset printing workers (n=40), in order to evaluate the genotoxic risk by comparing with unexposed controls (n=20). The number of micronuclei (MN) in 1000 binucleate (BN) cell were scored and the frequency of MN per 1000 BN cell were calculated. The mean (±SD) of baseline MN frequencies (‰) of offset print-ing workers (3.75 ± 2.64) were significantly higher than that of controls (0.75 ± 1.16) (p<0.001). Since smoking is a confounding factor in genotoxicity studies, individuals were evaluated accordingly. The MN in 1000 BN lymphocytes of smoker printing workers (4.42 ± 2.33) were slightly higher than the MN observed for non smokers (2.50 ± 2.82) (p<0.05). In conclusion, offset printing workers seem to have an occupational risk. Therefore, it is important that necessary precautions should be taken into account in the process of offset printing.

197

PP107

ASSESMENT OF DNA DAMAGE AND DNA REPAIR CAPACITY IN PATIENTS WITH RHEUMATOID ARTHRITIS

Gülden Z. OMURTAG, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyDiren BEYOĞLU, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeySelin OĞUZ, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyNevsun İNANÇ, Department of Rheumatology, Faculty of Medicine, Marmara University, İstanbul, TurkeyHaner DİRESKENELİ, Department of Rheumatology, Faculty of Medicine, Marmara University, İstanbul, Turkey Semra ŞARDAŞ, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by invasion of synovial tissue into cartilage and bone. The development of RA includes risk factors such as; genetic, environmental, hor-monal, gender, infection, personal and life style factors. Although the pathophysiological basis of RA is not yet fully understood, reactive oxygen species have been implicated in its pathogenesis. The aim of our study was to investigate the DNA damage and DNA repair capacity in patients with RA, therefore RA patients were classified into 3 groups;

Group 1: Patients who were newly diagnosed with RA (n=9),

Group 2: RA patients who were receiving methotrexate and folic acid treatment for at least 1-2 years (n=20),

Group 3: RA patients who were being treated with anti-TNF for 1-2 years (n=20). The DNA damage was evaluated in peripheral lymphocytes by alkaline comet assay, which detects DNA strand breaks, alkali labile. The challenge assay which is able to detect difference of repair competence of human lymphocytes under various conditions has been used to evaluate DNA repair process after H2O2 induction. The mean percentage of DNA in tail (%DNAT) for each cell was calculated as 100-Head %DNA for both assays. The assessed mean %DNAT of basal DNA damage for group 1, 2 and 3 were 8.36±0.99, 8.90±1.42, 9.26±0.81, respectively. The mean %DNA repair capacity varied as 50.98±6.01 (Group 1), 45.79±10.69 (Group 2), 41.46±8.82 (Group 3) in studied groups. DNA repair capacities will be presented with individual param-eters in a separate table by taking the confounding factors such as life style and demographical characteris-tics of all included subjects.

198

PP108

THE ROLE OF PLATELET-DERIVED NITRIC OXIDE ON PLATELET OXIDANT STATUS

Azize ŞENER, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyGözde EGEMEN, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyÖzge ÇEVİK, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyBanu AYÇA, Department of Sports and Health Sciences, Faculty of Physical Education and Sports, Marmara University, İstanbul, Turkey

Nitric oxide (NO) is an important endogenous inhibitor of platelet activation and hemostasis. NO is gen-erated by the enzymatic oxidation of L-arginine into L-citrulline through the action of NO synthase. In vitro and ex vivo studies have shown that L-arginine reduces platelet aggregation. However, effects of L-arginine on platelet oxidative modifications have been poorly investigated. Dramatic changes in platelet redox status occur during normal platelet aggregation. In the present work, the dose-dependent effects of L-arginine on platelet NO production and platelet redox status were investigated in activated platelets. Platelets were incubated with ADP for 30 min at 37 º C with or without L-arginine (0.5-1 mmol/L). Then platelet NO, lipid peroxidation (LPO), protein carbonyl (PCO) contents, reduced glutathione (GSH) and protein-reduced thiols (p-SH) levels were measured. Protein nitrotyrosine (NT) levels was quantified by the competitive ELISA L-arginine caused a marked increase in platelet NO production. After L-arginine incubation, LPO, PCO and protein NT levels of activated platelets significantly decreased compared to the control group. p-SH levels of L-arginine- treated platelets significantly increased. The GSH values of L-arginine group increased by 34 % compared to the control group, but this was not statistically significant. Stimulation of endogenous NO release via L-arginine treatment in in vitro may protect platelets from oxi-dative modifications. This effect of L-arginine may provide additional benefits in its clinical applications.

199

PP109

EVALUATION OF ANTIGENOTOXIC EFFECT OF 7-HYDROXY COUMARIN AND 7-ISOPENTENYLOXY COUMARIN ON HUMAN PERIPHERAL LYMPHOCYTES EXPOSED TO OXIDATIVE STRESS

Effat BEHRAVAN, Department of Pharmacodynamy & Toxicology, Faculty of Pharmacy, Mashhad University of Medical Science, IranRamin REZAEE, Department of Pharmacodynamy & Toxicology, Faculty of Pharmacy, Mashhad University of Medical Science, IranMehrdad IRANSHAH, Department of Pharmacogenosy, Faculty of Pharmacy, Mashhad University of Medical Science, IranJavad BEHRAVAN, Department of Biotechnology, Faculty of Pharmacy, Mashhad University of Medical Science, IranFatemeh SOLTANI, Department of Biotechnology, Faculty of Pharmacy, Mashhad University of Medical Science, Iran

Coumarins are a large class of natural derivatives mainly found in the families Umbelliferae and Ruta-ceae. DNA damage and oxidative stresses are accepted to be major factors in many degenerative diseases and in the aging process.Single-cell electrophoresis(also known as Comet assay)is a sensitive, rapid and reliable method for evaluation of genotoxic effects.Protective properties of two preny:lated coumarins: \"7-isopentenyloxy coumarin\" and \"7-hydroxy coumarin\" were tested on human peripheral lymphocytes DNA lesions after exposure to H2O2-induced oxidative stress using the single-cell gel electrophoresis tech-nique under alkaline condition.Lymphocytes were isolated from healthy volunteers blood samples. The lymphocytes were incubated with 7-isopentenyloxy coumarin(10,25,50,100,200 ìM) alone or with 7-iso-pentenyloxy coumarin (10,25,50,100,200 ìM) in the presence of H2O2(25 ìM).The same procedure were done for 7-hydroxy coumarin(10,25,50,100,200 ìM). In this study, ascorbic acid(10,25,50,100,200 ìM) and H2O2(25 ìM) were considered as known antioxidant agent and positive control, respectively.Lym-phocytes which were treated by PBS only, were assumed as the negative control.The extent of DNA migra-tion was analyzed with \"TriTek comet score 1.5\" software and the DNA damage was expressed as DNA tail percentage.As it was observed in this experiment, 7-isopentenyloxy coumarin and 7-hydroxy coumarin both exhibited significant antigenotoxic effect via decreasing DNA migration in comparison with non-treated group. It must be mentioned that antigenotoxic effect of 7-hydroxy coumarin was greater than that of 7-isopentenyloxy coumarin.It is suggested that antigenotoxic properties of these substances is of great pharmacological importance and might be beneficial for cancer prevention.

200

PP110

S-NITROSOGLUTATHIONE PROTECTS PLATELET AGANIST APOPTOSIS/NECROSIS AND MITOCHONDRIAL POLARIZATION ALTERATION ASSOCIATED WITH APOPTOSIS

Azize ŞENER, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyGözde EGEMEN, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyÖzge ÇEVİK, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyRabia OBA, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyGülderen YANIKKAYA-DEMIREL, Department of Immunulogy-Microbiology, Faculty of Medicine, Yeditepe University, İstanbul, Turkey

Nitric oxide (NO) is an important signal molecule of platelet activation and recruitment. NO inhibits platelet activation and prevents thrombosis. Impaired platelet NO responsiveness is to be independent predictor of increased mortality and cardiovascular morbidity in patients with acute coronary syndromes. NO generates by nitric oxide synnthase or releases from an endogenous S-nitrosothiols. At the same time, S-nitrosothiols are also an important class of NO donor drugs. S-nitrosoglutathione (GSNO) as a nitroso-thiol has more potent antioxidant than the classical antioxidant GSH. Although considerable evidence is available as to the inhibition of platelet activation by GSNO, GSNO's effects on platelet apoptosis have not yet been investigated. In the present study, we demonstrate that GSNO also markedly inhibits apoptosis/necrosis and especially mitochondrial apoptosis in human washed platelets. In this study, after stimulation with ADP (50 µM), washed platelets incubated with GSNO at 37ºC for 30 min. Then, platelet mitochon-drial membrane potential (ΔΨm), were assessed using 5,5',6,6'-tetrachloro 1,1',3,3'-tetraethyl benzimidazol carbocyanine iodide ( JC-1) dye, phosphatydylserine translocation, propidium iodide staining and P-selec-tin (CD62-P) expression were detected by flow cytometry. GSNO (1-100 µM) concentration-dependently inhibited platelet aggregation stimulated by ADP. GSNO (100 µM) inhibited dissipation of the platelet ΔΨm, activation of caspase-3, and increases in platelet early apoptosis and late apoptosis/necrosis phases mediated ADP. GSNO treatment resulted in a increase the percentage of viable cells We concluded that GSNO prevents platelet aggregation and platelet destruction. The inhibiting effect of platelet destruction may be a new useful therapeutic property of GSNO.

201

PP111

PLATELET-BOUND GAMMA-GLUTAMYLTRANSFERASE CAN PROMOTE OXIDATIVE REACTIONS

Azize ŞENER, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyÖzge ÇEVİK, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey Derya ÖZSAVCI, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyGülderen YANIKKAYA DEMİREL, Department of Immunilogy-Microbiology, Faculty of Medicine, Yeditepe University, İstanbul, Turkey

Gamma-glutamyltransferase (GGT), a key enzyme of GSH metabolism, is a cell plasma membrane and serum circulating enzyme. GGT activity during the catabolism of GSH originates the thiol dipeptide cyste-inylglycine, whose–SH group is provided in particular with a much stronger iron-reducing ability. Several studies indicate that increased serum GGT activity could be used as a marker for increased oxidative stress in human. GGT activity is also found in platelets. However, the effect of platelet GGT activity on its redox enviroment is unknown. Platelets play an important role in hemostasis and redox reactions may modify platelet functions. The objective of the present work is to determine, in presence of Fe(III), whether the platelet-bound GGT activity initiates oxidative modifications and apoptotic stimuli via determination of phosphatidylserine (PS) exposure and propidium iodide staining, markers of apoptosis/necrosis, caspase-3 activation, lipid peroxidation, protein oxidation and GSH levels. In this study, we used gel filtrated plate-lets. Stimulation of platelet GGT activity with GSH and glcylglycine (for 1 h) in the presence of Fe(III) did not change caspase 3 activation but caused an increase in PS exposure and mild decrease in cell viability. A significant increase in lipid and protein oxidation and decrease in GSH levels were also observed. Inhibiton of GGT activity was effective in the normalization of oxidative markers and PS externalization. Platelet GGT/GSH/Fe(III) system can induce oxidative modifications and PS externalization on human platelets. Thus, platelet GGT activity may contribute to the increase of ROS in its microenviroment and promote atherosclerosis and coronary artery disease.

202

PP112

DETERMINATION OF SERUM COPPER AND ZINC LEVELS AND EVALUATION OF DNA DAMAGE IN END-STAGE RENAL DISEASE PATIENTS

Seher KARSLI CEPPİOĞLU, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyTürkan YURDUN, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyMustafa CANBAKAN, Division of Nephrology, Haydarpasa Numune Education and Research Hospital, İstanbul, Turkey

In spite of the precautions to optimize dialysis treatment, high ratios of mortality in patients with end stage renal disease (ESRD) have been consistently demonstrated. Chronic kidney disease (CKD) is highly asso-ciated with cardiovascular risk; however traditional cardiovascular risk factors are not fully responsible for this circumstance. Proteinuria, altered calcium and phosphorus metabolism, inflammation, uremic toxins and oxidative stress are considered as extra renal risk factors. In this study, we aimed to investigate oxidative stress and oxidative DNA damage status of ESRD and CKD patients. For this purpose, we evaluated serum Cu and Zn levels which are one of the most important elements of antioxidant defense mechanism. Blood samples of 39 ESRD, 43 CKD patients and 36 controls were collected and measured by using flame atom-ic absorption spectrophotometry. Moreover, to detect DNA damage at the single-cell level, we evaluated genotoxicity with alkaline comet assay and the DNA damage as total comet scores (TCS) of ESDR (n=41) and CKD (n=43) patients were compared with healthy control group (n=34). It is observed that, serum Cu levels are significantly high in CKD patients (0.2185±0.0297 mg/L) when compared with ESRD pa-tients (0.2095±0.0306 mg/L, p=0.045), but not different from control group (0.2216±0.0389 mg/L). Se-rum Zn levels are similar with CKD patients (0.1684±0.0497 mg/L) and controls (0.1550±0.0302 mg/L) however, significantly low in ESDR patients (0.1211±0.0240 mg/L, P=0.0001). The TCS frequency ob-served in ESRD patients (30.44±20.61) is higher than the TCS of control group (18.82±8.81) and this difference is statistically significant (P=0.039). Besides, the frequencies of undamaged or migrated cells in the CKD patients (23.37±16.40) versus controls are insignificant. As a conclusion, serum zinc levels and oxidative DNA damage are involved in oxidative mechanisms in ESDR patients and tightly following these parameters could result in remedies to improve poor clinical outcomes in ESRD and CKD.

203

PP113EVALUATION OF COAGULATION ABNORMALITIES IN TYPE 2 DIABETIC CORONARY ARTERY DISEASE.

Şermin TETİK, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyEnver ÇIRACI, Department of Biochemistry, Faculty of Pharmacy, Marmara University Haydarpaşa 34668 İstanbul, TurkeyKoray AK, Department of Cardiovascular Surgery, Faculty of Medicine, Marmara University, İstanbul, TurkeySelim İŞBİR, Department of Cardiovascular Surgery, Faculty of Medicine, Marmara University, İstanbul, TurkeyTuray YARDIMCI, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

Objective: To evaluate the role of coagulation abnormalities in patients with type 2 diabetic coronary artery disease in terms of the results of trombin-antithrombin complex (TAT), C-reactif protein (CRP), Low-Density Lipoprotein (LDL), Hemoglobin A1c (HbA1c) and oxide-Low density lipoprotein (ox-LDL) pathogenesis and therapeutic approach.

Patients and Methods: In this study, biochemical results of TAT complex and ox-LDL levels in the plasma of 10 control grup (Group 1) and 19 patient (Group 2) were assessed by ELISA method.

Results: A significant difference was not detected between control (Group 1; 272.63±32.26 mm3) and pa-tient plasma (Group 2; 294.27±46.51 mm3) in terms of platelet levels (p>0.05). A significant difference has been detected control (Group 1; 76.12±10.63 mg/dL) and patient plasma (Group 2; 164.26±27.74 mg/dL ) in terms of LDL (p<0.001). By using ELISA method, TAT and ox-LDL levels were assed. At the end of the assesment, the levels of TAT complex in plasma collected from control (Group 1; 29,27±24.14 ng/mL) and patients (Group 2; 10.12±3.62 ng/mL) were different significantly (p<0.001). In addition to this, a significant difference has not been detected between the oxidized LDL values of control (Group 1; 123.26±17.18 pg/mL) and patient plasma (Group 2; 122.87±27.13 pg/mL) (p>0.05). Moreover, C-reactif protein (CRP) and fibrinogen levels were assed in the plasma of 19 patient and 10 control groups in Marmara University Cardiovascular medicine department. A significant difference has been detected between the CRP values of control (Group 1; 1.78±0.34 mg/ml) and patient plasma (Group 2; 6.18±0.56 mg/ml) (p=0.001). In addition to this, a significant difference has been detected between fibrinogen levels of control ( Group 1; 289.71±63 mg/dl) and patient plasma ( Group 2; 347.25±57 mg/dl). HbA1c levels in both group were observed meaningful difference between control (Group 1; 5.35±0.42%) and patient plasma (Group 2; 7. 82±0.73) (p<0.001).

204

PP114

EVALUATION OF ASSOCIATION BETWEEN SYSTEMIC INFLAMMATION CONDITION AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Şermin TETİK, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyGizem GÜRGEN, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyTuray YARDIMCI, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

Aim: This study was planned to investigate the relationship between inflammation and chronic obstructive pulmonary disease.

Methods: 10 healthy donors (Group 1) and a total of 17 consecutive patients with chronic obstructive pul-monery disaese (Group 2) were included in this study. Pulmonary function test, plasma hemoglobin (Hb) level, platelet number, CRP level in patient plasma were measured with conventional methods. Plasma lev-els of interleukin (IL)-6, IL-10 and tumor necrosis factor (TNF)-α were measured with the use of enzyme immunoassay ELISA.

Results: FEV1: 1.17±1.14 L, FVC: 2.131±1.12 and the ratio of FEV1/FV: 56.43±23.18% were recorded in the pulmonary function test. CRP level in patient plasmas were found high in significant level compared to control group (Group 1: 1.98±0.58 mg/mL, Group 2: 39.74±120.05 mg/mL, p<0.001). A significant difference was not detected between groups in terms of Hb levels (Group 1: 15±3.4, Group 2: 13.7±3.6) and platelet number (Group 1: 275.64±183.425 mm3, Group 2: 263.176±192.824 mm3, p>0.05). The plasma IL-6 and IL-10 levels in Group1 and Group2 were 3.63±0.03 ng/mL vs 3.63±0.06 ng/mL for IL-6, and 2.94±0.01 ng/mL vs 2.93±0.01 ng/mL for IL-10 respectively. The differences weren’t significant (p>0.05). TNF-α level in the plasma collected from control (Group 1; 3.7±0.10 ng/mL) and patients (Group 2; 4.0±0.70 ng/mL) were significantly different (p<0.05).

Conclusion: High levels of TNF-α probably cause acute attack in patients with chronic obstructive pul-monary disease. Cytokine IL-10 is an anti-inflammatory agent and it controls TNF-α level. Low plasma IL-10 levels can create high TNF-α level . This parametric results can contribute different therapeutic approaches.

205

PP115

POLYGONUM COGNATUM MEISSN EXTRACT PREVENTS OXIDATIVE DAMAGE IN COLONIC TISSUES OF RATS WITH ULCERATIVE COLITIS

Özge CEVİK, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyAzize ŞENER, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyZarife Nigar ÖZDEMİR, Department of Physiology, Faculty of Medicine, Marmara University, İstanbul, TurkeyAyhan ALTINTAŞ, Department of Pharmacognosy, Faculty of Pharmacy, Anadolu University, Eskişehir, TurkeyBerrak C YEĞEN, Department of Physiology, Faculty of Medicine, Marmara University, İstanbul, TurkeyAysen YARAT, Department of Biochemistry, Faculty of Dentistry , Marmara University, İstanbul, Turkey

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by bleeding of the colonic mucosa and its etiology remains unclear. Previous studies have suggested an increasing use of complemen-tary and alternative medicine in patients with IBD. Polygonum cognatum Meissn (PC), locally name as Madimak, is an endemic plant and is widely consumed as food in Sivas, Turkey. No studies regarding the therapeutic use of this plant are found in the literature. The aim of our study was to evaluate the antioxidant effect of aqueous extract of PC, which were collected from several locations in Sivas and screened phyto-chemically, on the colonic tissue. UC was induced under anaesthesia by giving intracolonic acetic acid (4%, 1ml) in rats. PC aqueous extract (2g/kg) was orally administered once a day as pre-treatment for 10-days before the induction of colitis. Following UC pre-treatment, two groups of rats were administered to saline for 3- or 10-consecutive days (pre-treatment groups) and other two groups of rats were given PC extract for 3- or 10-consecutive days (pre-post-treatment groups).Oxidant damage and antioxidant status in colonic tissue were than evaluated. Major components of PC extracts were found as sterols, triterpene, tanens, reduced compounds of carbohydrate, polyuronides (pectins, mucilages, gums) and saponines . PC extract treatment of UC rats significantly increased colonic glutathione levels, catalase and superoxide dismutase activities and decreased malondialdhyde levels, myeloperoxidase and gamma-glutamyl transferase activities compared with the UC groups. Without a significant of difference between 3- and 10-days treatment, treat-ment with PC extract given before and after UC was more effective in blocking oxidant damage than the only post-treatment. PC, exerting antioxidant effects, may eliminate the oxidative colonic damage in UC. Thus, it can be an alternative therapeutic or preventive choice in diminishing the inflammatory responses.

206

PP116

PROTECTIVE EFFECTS OF MELATONIN AND NATIVE HDL ON GLYCATED LIPOPROTEIN INDUCED PLATELET RESPONSE

Derya ÖZSAVCI, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyAydan DAĞTEKİN, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyÖzlem BINGÖL- ÖZAKPINAR, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyAzize ŞENER, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyGülderen YANIKKAYA DEMIREL, Department of Immunology-Microbiology, Faculty of Medicine, Yeditepe University, İstanbul, TurkeyBirgul VANIZOR- KURAL, , Department of Biochemistry, Faculty of Medicine, Karadeniz Technical University, Trabzon, TurkeyTuray YARDIMCI, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyGöksel ŞENER, Department of Pharmacology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

Modified lipoproteins directly affect several cell functions such as stimulating foam cell formation, oxida-tive cell damage and apoptosis. Increased platelet activation and apoptosis can cause thrombotic risk related to cardiovascular events. It is known melatonin is a direct free radical scavenger and native high density lipoprotein (HDL) has cardioprotective effects. The aim of this study is to investigate the in vitro effects of glycated low density lipoprotein (LDL) and HDL on platelet features such as apoptosis, activation, and also to investigate the effects of melatonin and native HDL on altering platelet response with glycated li-poproteins. LDL and HDL were isolated from plasma by discontinuous ultracentrifugation. Isolated LDL and HDL were glycated by glucose. After pre-incubation with or without melatonin and/or native HDL, glycated LDL (G-LDL) and G-HDL was added to ADP induced washed platelets. Early and late apopto-sis of platelets and CD62-P expression were determined by flow cytometry. Platelet caspase 3-9 activities were measured with ELISA reader. Paraoxanase (PON) activity of G-HDL and native HDL was also de-tected. Following incubation with G-LDL and GHDL, platelet P-selectin, Annexin-V expressions, caspase 3-9 activity, propidium iodide positivity were significantly increased. After melatonin and/or native HDL, elevated levels of P-selectin Annexin-V, caspase 3-9 and propidium iodide positivity were significantly re-duced. PON activity of G-HDL was significantly lower than native HDL. These observations suggest that abnormalities like increased apoptosis and activation process induced by glycated lipoproteins in platelets may elevate thrombotic risk and may play an important role in the development of atherosclerosis in pa-tients with diabetes mellitus. Both melatonin and native HDL protect platelets from G-HDL and G-LDL induced apoptosis and activation triggering signals.

207

PP117

EFFECT OF STATIN TREATMENT ON PROTEIN MODIFICATION IN PATIENTS WITH SEVERE CORONARY ARTERY DISEASE

Şermin TETİK, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyYücel ŞAHİN, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeySelim İŞBİR, Department of Cardiovascular Surgery, School of Medicine, Marmara University, Istanbul, Turkey Turay YARDIMCI, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

Aim : Hyperlipidemia and Atherosclerosis are the main sources of oxidative stress and contribute systemic modification. This study was planned to investigate the effects of short term treatment (one week) on pro-tein modification.

Methods: Fifteen hyperlipidemic patients with severe coronary artery disease (all had triple vessels disease confirmed by coronary angiography) and 10 healthy donors (control group) were included into the study. All hyperlipidemic patients had a fixed dose of atorvastatin therapy (20 mg daily) for the one week. Plasma protein, plasma carbonyl and thiol were determined spectrophotometrically and ox-LDL, ox-LDL-Ab and Lp(a) determinations were done with ELISA technique in blood samples taken before (group 1) and at the 7th day of statin therapy (group 2).

208

PP118

SENSITIVITY IN DNA DAMAGE DETECTION WITH CONVENTIONAL ALKALINE COMET ASSAY, ENDO III, FPG ENZYMES AND THE CHALLENGE ASSAY.

Tuğçe YEŞİL, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeySemra ŞARDAŞ, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

Electrophoretic microgel technique, developed by Ostling and Johanson (1) was modified in 1988, by performing the electrophoresis at alkaline pH to allow the detection of DNA single strand breaks, alkali labile sites and DNA cross-linking (2). The next version of the assay was developed by Collins et al. by the use of lesion specific ezymes; endonucleas III (endo III) and formamidopyrmidine gylcosylase (Fpg) to detect oxidised DNA bases. Endo III and Fpg are restriction enzymes that involve in base excision repair, recognize and remove oxidized pyrimidines and oxidized purines respectively from DNA to form apry-midinic and apurinic sites. (3).The challenge assay to detect repair competence after H2O2 induction has been introduced recently (4). Our aim was to compare detection sensitivity between these assays (H2O2 concentrations, duration of lysis, alkali unwinding and electrophoresis are adapted to an individual cell) .Peripheral lymphocytes were isolated and treated with hydrogen peroxide for DNA damage. At the end of the incubation periods aliquots were taken to check the cell viability. To measure the DNA repair ca-pacity; cells are incubated at 37oC to repair. Endo III and Fpg were administered. Slides were treated at alkaline condition to unwind and electrophoresis, stained with etidium bromide. Data were scored using image analysis system. %DNA in the tail was used as a measure of basal genetic damage the %tail DNA with buffer alone was 26.84%, 32.58% while Fpg demonstrated 37.32% and 37.52% with Endo III treat-ment. Untreated cells compared to 50µl and 100µl H2O2 demonstrated %tail DNA 29.18%, 33.91% and 36.08% respectively. Duration of electrophoresis, lysis and other confounding factors will be presented and discussed with the ongoing findings.

References: 1. Ostling and Johanson, Biochem Biophys Res Commun. 1984, 123:291-298 2. Singh et al., Exp Cell Res. 1988, 175:184-91 3. Collins et al., Carcinogenesis. 1993, 14:1733-35 4. Au WW, Environ. Health Perspect. 1993,101:303-8

209

PP119

INFLUENCE OF POMEGRANATE EXTRACT ON THE OXIDATIVE STRESS LEVEL OF CIGARETTE SMOKERS

Özge ŞAHİN, Department of Pharmaceutical Technology, Faculty of Pharmacy, Mersin University, Mersin, TurkeyMehmet BERKÖZ, Department of Pharmaceutical Technology, Faculty of Pharmacy, Mersin University, Mersin, TurkeyNefise Özlen ŞAHİN, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Mersin University, Mersin, TurkeyDilek BATTAL, Department of Pharmaceutical Toxicology, Faculty of Pharmacy,Mersin University, Mersin, TurkeySerap YALIN, Department of Biochemistry, Faculty of Pharmacy, Mersin University, Mersin, Turkey

Pomegranate is one of the oldest edible fruits growing in tropical and subtropical countries. Recently, the number and the consumption of the products containing pomegranate extract in the market increased as they reduce the risk of developing some serious diseases. Capsules of pomegranate extract as nutraceuticals have formed a rapidly increasing market segment. One of the most important effects of these products is antioxidant activity. In literature, it was reported that cigarette smoking reduces antioxidant levels. In this study, the acute effect of pomegranate containing capsules on the lipid peroxidation and antioxidant levels of cigarette smokers were investigated following 15 days of treatment. For this purpose, blood samples were collected from both the control (non-smokers) and the test groups (cigarette smokers) prior to and after the treatment with pomegranate capsules. Lipid peroxidation and antioxidant levels were measured in se-rum. Lipid peroxidation was determined in terms of malondialdehit (MDA) levels. Antioxidant levels were measured based on superoxide dismutase and catalase activities. The data were statistically analyzed using SPSS v16.0 program. Based on the data obtained in this study, MDA levels decreased in the control group following the treatment (p<0.05), whereas, no significant difference was found among the data for pre- and post-treatment in the test group (p>0.05). The results of SOD activity measurements showed treatment de-pendent increase in both groups and catalase activity increased in both groups following the treatment, but this increasing wasn't found significant, statistically. Based on these data, the short term use of pomegranate increases the antioxidant levels. Although this effect leads to reduction in lipid peroxidation levels of the subjects in the control group, it doesn’t cause any significant change in the group of cigarette smokers. That can be suggested that long term consumption of pomegranate extract might reduce oxidative stress.

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PP120

INVESTIGATION OF PARAOXANASE AND ARYL ESTERASE ACTIVITIES ON WATER-PIPE USERS

Mehmet BERKÖZ, Department of Pharmaceutical Technology, Faculty of Pharmacy, Mersin University, Mersin, TurkeyEbru Derici EKER, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Mersin University, Mersin, TurkeyNefise Özlen ŞAHİN, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Mersin University, Mersin, TurkeyEwelina JAROCH, Department of Pharmaceutical Technology, Faculty of Pharmacy, Mersin University, Mersin, Turkey

Tobacco consumption causes upper and lower respiratory tract cancers, cardiovascular diseases, stroke, chronic obstructive lung disease and related deaths. Among different ways of using tobacco; chewing, snuff, pipe, cigar, cigarette and water pipe are the most well-known. Recently, the use of water pipe has become popular among youngsters. Nicotine, tar, and heavy metals in the smoke of water pipes cause serious ir-reversible damage in the body. Main task of paraoxanase and aryl esterase is to prevent the oxidation of low density lipoprotein (LDL). The activity levels of these enzymes decrease upon nicotine consumption and hence, lead to cardiovascular diseases. Although there are several studies indicating the reduction of paraoxanase enzyme activity due to cigarette smoking, no such study dealing with the effect of water pipe is found in literature. In this study, it was aimed to investigate the effect of water-pipe consumption on the activities of paraoxanase and aryl esterase enzymes. 24 water pipe users (experimental group) and 25 nonsmokers (control group) were included to the study (nT = 49). All subjects were selected among the people without a habit of smoking or any other use of tobacco. Paraoxanase and aryl esterase activities were determined in the serum samples collected from both groups before taking any food in the morning. Eck-erson’s modified method was applied. The data obtained for two groups were compared statistically using SPSS v16.0 and Independent T-Test.In conclusion, in this study, paraoxanase and aryl esterase activities of water-pipe smokers were found to be lower than the control group (p<0.05). In other words, water pipe consumption reduces paraoxanase and aryl esterase activities as cigarette smoke and hence, causes increase in the risk of developing cardiovascular diseases.

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PP121

PROTECTIVE EFFECTS OF CURCUMIN AGAINST LEARNING AND MEMORY DEFICITS INDUCED BY ALUMINUM IN MICE

Rebai OUAFA, Biology, Laboratory of Microbiology and Vegetal Biology, University of Mostaganem, Mostaganem, AlgeriaDjebli NOUR EDDINE, Biology, Laboratory of Microbiology and Vegetal Biology, University of Mostaganem, Mostaganem, AlgeriaDouichene SALIMA, Biology, Laboratory of Microbiology and Vegetal Biology, University of Mostaganem, Mostaganem, Algeria

Amongst the various hypotheses concerning Alzheimer diseases (AD), the one implicating aluminum (Al) as a possible environmental etiologic factor is of considerable interest. Increasing evidence suggests thera-peutic properties of curcumin in AD. In this study, we observed the memory improving properties of cur-cumin in mice. METHODS: Albino mice were randomly assigned to one control group and two Alumi-num-poisoned groups orally administered 50 mg/kg/day of Aluminum chloride (AlCl3) in drinking water for a period of 90 days. From day 40 curcumin (200 mg/kg) was administrated orally for 50 days. After cessation of treatment, forced swimming, black and white test box and Morris water maze were evaluated to assess anxiety, responses to stress and learning memory of animals. RESULTS: All tests indicated deficits in mice spatial learning and memory induced by aluminium. Curcumin treatment dose-dependently pro-tected against the development of aluminium-induced spatial learning and memory deficits. The brains of AD mice, studied by optical microscopy, have revealed damage in the hippocampus and cortex, including neurofibrillary degeneration. Consecutive administration of curcumin attenuated these neuropathological changes in the hippocampus. CONCLUSIONS: This study demonstrates that curcumin is effective in im-proving the spatial learning and memory of AD mice. These findings strongly implicate that curcumin has potential to protect brain from oxidative damage resulting from aluminium toxicity.

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PP122

TRANSFECTION OF HUMAN TOOTH GERM STEM CELLS (HTGSC) BY USING INVITROGEN NEON TRANSFECTION SYSTEM

Mehmet Emir YALVAÇ, Department of Genetics and Bioengineering, Yeditepe University, Istanbul, TurkeyAysu YILMAZ, Department of Genetics and Bioengineering, Yeditepe University , Istanbul, TurkeyDilek MERCAN, Department of Genetics and Bioengineering, Yeditepe University , Istanbul, TurkeySafa AYDIN, Department of Genetics and Bioengineering, Yeditepe University, Istanbul, TurkeyAysegül DOĞAN, Department of Genetics and Bioengineering, Yeditepe University, Istanbul, Turkey Fikrettin SAHİN, Department of Genetics and Bioengineering, Yeditepe University, Istanbul, Turkey

Recent studies revealed that human tooth germs (hTGs) contain MSCs which can be easily isolated and it was seen that HTGSCs (Human Tooth Germ Stem Cells) have the ability to differentiate into neuron like cells that can be used in cellular therapy of neurodegenerative diseases such as Parkinson and Alzheimer. It has been shown that HTGSCs immortalized by telomerase reverse transcriptase (hTERT) have neuropro-tective effects on oxidative stress induced SH-SY5Y (neuroblastoma cell line) and GT1-7 (Gonadotropin-Releasing Hormone Neurons) cells. There are plenty of studies reporting the efficient use of electroporation for transfecting MSCs from different sources to insert some genes into the cells. In this study, the electro-poration conditions were optimized for HTGSCs and transfection efficiency of Neon Transfection System was tested. Firstly, the cells were trypsinized and suspended in PBS. 5 different conditions (C1 990 V 40ms 1 pulse,C2 1100V 40ms 1 pulse, C3 1100 V 30 ms 1 pulse, C4 990V 30ms 2 pulses,C5 990V 20ms 2 pulses) were tested to electroporate the cells using special buffer and tips of Neon Transfection System. After electroporations the cells were incubated for 24 hours and checked for transfection efficiency by using flow cytometry and fluorescence microscope. As a result, the efficiency could reach only 11%. Therefore, it can be said that this system hardly transfects MSCs. Instead of Neon Transfection reagent, a much more effective method is available and by using this, it can be reached up to 30% transfection efficiency.

213

PP123INVESTIGATION OF THE BACTERICIDAL EFFECTS OF FIVE ANTISEPTICS AND ONE DISINFECTANT ON NOSOCOMIAL ESCHERICHIA COLI ISOLATES

Müjde ERYILMAZ, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Ankara University, Ankara, TurkeyAhmet AKIN, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Ankara University, Ankara, TurkeyÖzay ARIKAN AKAN, Central Laboratory, Ankara University, Ibn-i Sina Hospital , Ankara, Turkey

Objective: Nosocomial infections can be defined as: Infections occuring in a patient in a hospital or other health care facilities in whom the infection was not present or incubating at the time of admission. Esch-erichia coli (E.coli), the predominant nosocomial pathogen, is the major cause of infection in the urinary tract and is also common in other body sites. Disinfection and antisepsis are of primary importance in controlling outbreaks of E. coli, a pathogen that frequently shows multiple antibiotic resistance. Consider-ing the importance of the prevention of nosocomial infections, the aim of this study was to evaluate the bactericidal activity of five hospital antiseptics and one disinfectant against nosocomial E. coli isolates.

Methods: The bactericidal effects of chlorhexidine gluconate (4% wt/vol), glutaraldehyde (2% wt/vol), 2-propanol (70% vol/vol), polyvinylpyrrolidone (7,5% wt/vol), polyvinylpyrrolidone (10% wt/vol), hy-drogen peroxide (3% wt/vol) against 26 E. coli isolates were assessed by the quantitative suspension test at contact times of 3-5-10 minutes. The E. coli included in the study were randomly selected among nosoco-mial isolates, obtained from clinical specimens sent to Ankara University, School of Medicine, Ibn-i Sina Hospital, Central Microbiology Laboratory. E. coli ATCC 25922 was used as a control strain and sterile distilled water was used as a diluent and disinfectant control.

Results: All the isolates were susceptible to chlorhexidine gluconate, glutaraldehyde, 2-propanol, polyvinyl-pyrrolidone (7,5% wt/vol), polyvinylpyrrolidone (10% wt/vol) at contact times of 3-5-10 minutes. How-ever, only 4 isolates were found to be susceptible to hydrogen peroxide at contact times of 3-5-10 minutes, 7 isolates were found to be susceptible at contact times of 5-10 minutes and 11 isolates were found to be susceptible at contact time of 10 minutes. Four isolates were resistant to hydrogen peroxide at all contact times. Due to differences between hospital environments, each hospital should define its own disinfectant usage policy.

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PP124

EFFECTS OF CERTAIN NATURAL PHENOLIC COMPOUNDS ON EXPERIMENTAL DIABETES AND RESPONSE IN SMOOTH MUSCLES OF STZ-DIABETIC RATS GASTRIC FUNDUS

Nurcan BEKTAŞ, Department of Pharmacology, Faculty of Pharmacy , Anadolu University, Eskişehir, TurkeyYusuf ÖZTÜRK, Department of Pharmacology, Faculty of Pharmacy, Anadolu University, Eskişehir, Turkey

Diabetic smooth muscle complications developed in isolated gastric fundus obtained from 6-week strepto-zotocin (STZ)-diabetic rats and effects of treatment with 10 mg/kg p-OH benzoic acid, protocatechic acid and gallic acid, which have antioxidant activities with increasing potency order related to their hydroxyl number, were investigated on the development of these complications by using isolated organ bath. STZ-diabetic rats demonstrated characteristic symptoms of diabetes such as hyperglycemia, polyuria, polydip-sia, polifaji and weight loss. In diabetic animals, responses of gastric fundus to serotonin were observed to be decreased while responses to acetylcholine unchanged. It was found that the in vivo administration of p-OH benzoic acid, protocatechic acid and gallic acid inhibited, unchanged or promoted the changes occurred in smooth muscles, and sometimes, they caused alterations in unchanged smooth muscle activity due to diabetes relative to control animals. According to these datas, it was concluded that by p-OH ben-zoic acid, protocatechic acid and gallic acid exhibit the positive or negative effects in a manner independent of their antioxidant power and from diabetic complications and they may exhibit prooxidant activities in the experimental conditions applied.p-

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PP125

POSSIBLE INVOLVEMENT OF ADRENERGIC MECHANISMS IN THE ANALGESIA OF SOME NSAI DRUGS AS EXAMINED BY HOT PLATE TEST Rana ARSLAN, Department of Pharmacology, Faculty of Pharmacy, Anadolu University, Eskişehir, TurkeyNurcan BEKTAŞ, Department of Pharmacology, Faculty of Pharmacy, Anadolu University, Eskişehir, TurkeyBüşra ÖZTÜRK, Department of Pharmacology, Faculty of Pharmacy, Anadolu University, Eskişehir, Turkey

Objectives: Non-steroidal anti-inflammatory drugs (NSAIDs) are most commonly used for the treatment of pain, fever and inflammation. It is known that analgesic effects of NSAI drugs are due to inhibition of PG synthesis. Recent studies have been suggested that for some of these agents, centrally mediated anal-gesia may also be achieved by additional mechanism(s), which are independent of prostaglandin synthesis inhibition. In addition, the adrenergic system is involved at spinal and supraspinal levels. In the present study, we aimed to examine the role of adrenergic mechanisms in the analgesic effects of some NSAI drugs (diclofenac, etodolac and indomethacin) in hot plate test.

Material and Methods: The antinociceptive effects of three NSAI drugs were assessed by intraperitoneal administration in the hot plate test in mice. Thermal stimulus was measured using a Hot Plate Analgesia Meter from Ugo Basile Instruments. Diclofenac, etodolac and indomethacin were injected at same doses (10 mg/kg, i.p.). Prazosin (1 mg/kg; i.p., 30 min. before testing) was also tested.

Results: In the present study, diclofenac (p<0.01), etodolac and indomethacin (p<0.001) showed signifi-cantly antinociceptive activities in hot plate test when compared with control group. Prazosin antagonized significantly antinociceptive effect of indomethacin (p<0.001) only.

Conclusion: Hot plate is an acute nociceptive thermal model and model of somatic pain. It is believed that NSAIDs are not effective in this model. Several studies have indicated that antinociceptive effects of NSAIDs cannot be explained entirely by inhibition of prostaglandins. In our experiments, diclofenac, etodolac and indomethacin exhibited statistically significant antinociceptive activities in hot plate test. The noradrenergic system has a role in spinal and supraspinal nociception. In this context, we examined the antinociceptive effects of these NSAIDs (diclofenac, etodolac, indomethacin) in noradrenergic system. Ac-cording to our results, only indomethacin was antagonized by prazosin (p<0.001). In the further studies we will examine other noradrenergic antagonists in order to clarify the antinociceptive mechanism of these NSAIDs.

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PP126

INVESTIGATION OF THE INFLUENCE OF AMPHOTERICIN B IN MICE INFECTED WITH CANDIDA ALBICANS BY MEANS OF CHRONOTHERAPY

Yeşim TAHMAZ, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyAdile ÇEVİKBAŞ, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyUmran SOYOĞUL GÜRER, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyBurcak GÜRBÜZ, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyUgur ÇEVİKBAŞ, Department of Pathology, Faculty of Medicine, Istanbul University, İstanbul, Turkey

Our research determined the effect of AmB treatment by means of chronobiology on mice kidney’s whose infection and pathogenesis were infected by Candida. The animals were placed in light and dark periods. Test and control mice were infected with Candida albicans (1× 108 CFU/ml) and divided into 3 groups. After infection at 24 h, light and dark periods the 1st group control mice were treated with saline, the 2nd group test mice were treated with AmB (0.5 mg/kg/day) and the 3rd group test mice were treated with AmB (1 mg/kg/day) for three days. After being treated with AmB at 24 h, the mouse’s kidneys from all groups were examined by microbiologic and histopathologic methods. The 4th group healthy test mice were administrated with AmB (5 mg/kg/day) in lighting and dark for investigation by means of nephro-toxicity, histopathology and biochemistry. Mice which were treated in a dark period with AmB (0.5 mg/kg/day) significantly decreased number of Candida in their kidneys when compared with a light group (p=0.009). Mice which were treated with AmB (1 mg/kg/day) was no statistically significant difference be-tween in dark and light groups however their histopatological values significantly decreased in a dark group when compared with a light group (p<0.05). Healthy mice which were administrated in a dark period for four days with high doses of AmB showed significantly lower level of BUN, creatin level in their blood and histopathological values when compared with a light group (p= 0.001, p<0.05, p<0.001). Our research de-termined that fungi infections treated in a dark period with AmB (0.5 mg/kg/day) significantly decreased infection but both of doses significantly decreased AmB toxicity. Considering all test results and human biorhythm, we believe that treatment using chronotherapy might obtain more successful results than using conventional medical therapy but more research needs to be done.[sb1]

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PP127

ETANERCEPT TREATMENT PROTECTS AGAINST THERMAL TRAUMA IN RATS

Burcu ÜNLÜ, Faculty of Pharmacy,Yeditepe University, İstanbul, TurkeyÖzer ŞEHİRLİ, Department of Pharmacology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyGöksel ŞENER, Department of Pharmacology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

Thermal trauma may cause damage to multiple organs distant from the original burn wound and may lead to multi organ failure. In the present study, we investigated whether the TNF-α blocker etanercept is pro-tective against burn-induced injury of the lung. Under brief ether anesthesia, dorsum of the rats was shaved, exposed to 90o C water bath for 10 s, which resulted in a second-degree burn involving 30 % of the total body surface area. Etanercept (1 mg/kg) or saline was administered intraperitoneally immediately after and at 24th hour burn injury. The same protocol was applied in the control group, except that the dorsum was dipped in a 25oC water bath for 10 s. In both saline- and etanercept-treated burn groups, rats were decapitated at 6 h and 48 h following burn injury. After decapitation, trunk blood was collected, to assay pro-inflammatory cytokines (TNF-α and IL-1β), and LDH activity. In order to evaluate the presence of oxidant injury in the distant organ, lung tissue samples were taken and stored at -80oC for the determina-tion of MDA, and GSH levels, MPO and Na+-K+ ATPase activities. Severe skin scald injury (30% of total body surface area) caused a significant increase in serum samples cytokines TNF-α, IL-1β, LDH caused significant increase in MDA levels and MPO activity of lung tissue. On the other hand, burn injury caused depletion of GSH and decreased in Na+-K+ ATPase activity. Treatment of rats with etanercept (1 mg/kg) significantly elevated the reduced GSH levels and Na+-K+ ATPase activity while it decreased tissue MDA and MPO activity as well as decreased plasma levels of TNF-α, IL-1β, LDH. According to the findings of the present study, TNF-α inhibitor etanercept could be protective against burn induced distant organ damage.

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PP128

EFFECT OF CIPROFLOXACIN ON NEUTROPHIL FUNCTIONS AND MPO ACTIVITY, GSH AND MDA LEVELS OF PATIENTS WITH DIABETES MELLITUS, ALLERGIC ASTHMA AND HEALTHY VOLUNTEERS

Pervin RAYAMAN, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey Erkan RAYAMAN, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyA. Özer ŞEHİRLİ, Department of Pharmacology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey Adile ÇEVİKBAŞ, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyÜmran SOYOĞUL GÜRER, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyRefik DEMİRTUNÇ, Department of Internal Medicine, Haydarpaşa Numune Training and Research Hospital, İstanbul, Turkey Ş. Gül KESKİN, Department of Pneumology, Haydarpaşa Numune Training and Research Hospital, İstanbul, Turkey Göksel ŞENER, Department of Pharmacology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

This study was designed to compare the polymorphonuclear leukocyte (PMN) functions (phagocytosis and intracellular killing) of patients and healthy volunteers and to assess the myeloperoxidase (MPO) ac-tivity, glutathione (GSH) and malondialdehyde (MDA) levels in PMN of both groups. Furthermore the effect of ciprofloxacin on PMN functions, and MPO, MDA and GSH levels in PMN were also compared with patients and healthy volunteers. The effect of ciprofloxacin (2.5 µg/ml) on PMN functions of patients and healthy volunteers was investigated in vitro. PMN's (1×107 cells/ml) were isolated from venous blood by ficoll-hypaque gradient centrifugation method. Phagocytosis and intracellular killing activity were as-sayed by modified Alexander's method. MPO activities were assayed by modified o-diasinidin method. GSH and MDA levels were determined by Ellman's and Beuge's methods, respectively. Phagocytic and in-tracellular killing activity (p=0.003, p=0.009) in the non-treated PMN of both patient groups significantly (p<0.001) decreased when compared with healthy volunteers. There was no statistically significant differ-ence between PMN's MPO activity, GSH and MDA levels of patients and healthy volunteers. Ciprofloxa-cin treatment of the PMN significantly increased the phagocytic and intracellular killing activity (p<0.05 and p<0.0001, respectively), MPO (p<0.001, p<0.01) activity and GSH (p<0.001) levels in healthy vol-unteers when compared with that of both patient groups. Furthermore ciprofloxacin did not significantly change the PMN's MDA levels. Ciprofloxacin treatment in the patients group significantly increased the PMN functions (p<0.001, p<0.001), MPO activity (p<0.001) and MDA (p<0.001) levels while GSH levels (p<0.001) were decreased when compared with that of non-treated values. In conclusion, antibiotics with immunomodulatory effect such as ciprofloxacin increase the PMN functions and MPO activity in immunocompromised patients with depressed immun system and this treatment approach provides more successful therapy.

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PP129

ANTI-INFLAMMATORY EFFECTS OF POLYGONUM COGNATUM MEISS EXTRACT TREATMENT IN RATS WITH ULCERATIVE COLITIS

Özge CEVİK, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyAzize ŞENER, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyŞule CETİNEL, Department of Histology, Faculty of Medicine, Marmara University, İstanbul, TurkeyZarife Nigar ÖZDEMİR, Department of Physiology, School of Medicine, Marmara University, İstanbul, TurkeyErtan TUZLACI, Department of Pharmaceutical Botany, , Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyBerrak C. YEĞEN, Department of Physiology, Faculty of Medicine, Marmara University, İstanbul, TurkeyAysen YARAT, Department of Biochemistry, Faculty of Dentistry, Marmara University, Nişantaşı, İstanbul, Turkey

In recent years the consumption of certain herbs as a folk remedy for ulcerative colitis (UC) has increased, and particularly because they promise oral treatment, these plants have stimulated considerable interests. Polygonum cognatum Meiss (PC), called Madimak, is a widely grown plant and consumed as vegetable in Anatolian. No studies regarding the therapeutic use of this plant are found in the literature. UC is a chron-ic, relapsing, inflammatory and immunologically mediated disorder which is used to generally nonspecific and based on the anti-inflammatory agents in treatment. The aim of our study was to evaluate the anti-inflammatory effects of aqueous extract of PC in UC. Taxonomic characteristics of PC were determined and deposited at the Herbarium. Sprague–Dawley rats of both sexes randomly were divided into groups: control; colitis; pre-treatment; pre-post-treatment; post-treatment. UC was induced by giving intracolonic acetic acid (4%, 1ml) in rats. PC aqueous extract (2g/kg) was given orally to rats and they were sacrificed on the 3rd or 10th day of the experiment and colonic tissues were taken for histological analysis. Cardiac blood samples were collected and serum TNF-α and IL-6 levels were determined as a marker of inflammation. Serum IL-6 and TNF-α levels were significantly decreased in pre-and/or post-treatment groups compared with the UC groups. Light microscopic evaluation demonstrated that severe necrotic degeneration with ac-cumulation of inflammatory cells dominantly polymorphonuclear leukocytes were present in colitis group when compared with the control groups. PC treated colitis groups showed remarkable regression in the density of inflammation via decrease in both edema and congestion of blood vessels. Pre-treatment groups demonstrated better morphology regarding the invasion of inflammation. The data indicate that the use of PC may be effective in preventing inflammation in UC and it may be included in daily diet to treat or prevent the disease.

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PP130PHOSPHOLIPASE AND PROTEINASE ACTIVITY OF CANDIDA ALBICANS ISOLATES BRIEF EXPOSURED TO SUB-THERAPEUTIC CONCENTRATIONS OF THREE MOUTHRINSES

Banu UYGUN CAN, Department of Microbiology, Faculty of Dentistry, Marmara University, Nişantaşı, İstanbul, TurkeyTanju KADİR, Department of Microbiology, Faculty of Dentistry, Marmara University Nişantaşı, İstanbul, TurkeyAdile ÇEVİKBAŞ, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

Objectives: One of the most important virulence factors of C. albicans is extracellular phospholipase and the other one is aspartic proteinase. It is generally recorded that some oral antiseptic agents including chlorhexidine gluconate (0.2%), hexetidine (0.1%) and triclosan (0.045%) are used in the management of oral candidiasis. However, the intraoral concentrations of these antiseptics fluctuate considerably due to the diluent effect of saliva and the cleansing effect of the oral musculature, thereafter the drugs concen-tration are likely to be sub-therapeutic, thus compromising their therapeutic efficacy. The behaviours and enzymatic activity of Candida under these conditions have been little known. So the aim of this study was to investigate the effect of brief exposure (30 min) to four different sub-therapeutic concentrations (1/150, 1/200, 1/250, and 1/300) of above oral antiseptics on the extracellular phospholipase and proteinase pro-duction of 20 C.albicans isolates derived from Candida-associated denture stomatitis.

Methods: An in vitro phospholipase production was done by plate assay method using an egg yolk-agar medium and proteinase production on agar plates containing bovine serum albumin.

Results: We found that limited exposure of C.albicans isolates to each concentration of three antiseptics highly significant (p<0.001) reduce their phospholipase and proteinase activities when compared with unexposed controls. However, there was no statistically significant difference among all antiseptics on their effect on enzymatic production of C.albicans.

Conclusion: The results of this study imply that sub-therapeutic levels of chlorhexidin, hexetidine and tri-closan may modulate candidal phospholipase and proteinase activities, thereby suppressing pathogenicity of C. albicans.

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PP131

DEFINITION OF RELATIONSHIP BETWEEN INFECTION AND, PRE-AND POST-TRANSPLANTATION LEVELS OF SERUM HEPCIDIN, IL-6 AND TNF-ALPHA LEVELS OF PEDIATRIC PATIENTS SUBJECT

Bahar GÖKER, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyMeral AKBIYIK, Department of Hematologic Oncology, Istanbul Medical Faculty, Istanbul University , Istanbul, TurkeySema ANAK, Department of Hematologic Oncology, Istanbul Medical Faculty, Istanbul University, İstanbul, Turkey

Bone marrow transplantation is used in managament of many malignant and benign disorders. Disordered bone marrow causes anemia, leukopenia and trambocytopenia. In treatment-aimed bone marrow trans-plantation, within the duration in which tranplated stem cells are engrafted into bone marrow and begin to renewing hematopoesis, bleeding and infections may be appeared due to trombocytopenia and leukopenia, respectively. Since immune system of patient is suppressed before transplantation, severe infections migth occur in this period. The aim of bone marrow transplantation is to ensure engrafment and to avoid GvHD (Graft versus Host Disease). TNF-alpha is an impotant cytokine which triggers systemic inflammation. TNF-alpha was shown to stimulate IL-6 production and IL-6 was shown to increase hepcidin expression in hepatocytes. We suppose that, in addition to IL-6 and TNF-alpha, hepcidin has important role as well, in infections which occur in patients subject to bone marrow transplantation. In this purpose, we measured serum levels of prohepcidin, TNF-alpha and IL-6 from one pre-transplantation and three post-transplan-tation periods of patients subject to transplantation. We considered urine prohepcidin levels and standard biochemical parameters from each period of the patients. As a preliminary study, results of our study has demonstrated that serum prohepcidin level was significally increased through post-transplantation periods, and this increasment was related to CRP level. This relationship suggests that serum prohepcidin level might be an important parameter for transplantation patients. Verification of these results by the next stud-ies in which homogenous patient group and more specific measurements are used, will support the clinical importance of hepcidin.

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PP132

RESVERATROL PROTECTS AGAINST ISOPROTERENOL-INDUCED MYOCARDIAL INFARCTION IN RATS

Özer ŞEHİRLİ, Department of Pharmacology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, Turkey Ömer YIĞINER, Department of Cardiology, Gülhane Military Medical Academy , İstanbul, TurkeyŞermin TETİK, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey Şule ÇETİNEL, Department of Histology&Embryology, Faculty of Medicine, Marmara University, Istanbul, TurkeyMustafa AKKIPRIK, Department of Medical Biology, Faculty of Medicine, Marmara University, Istanbul, Turkey Ayşe ÖZER, Department of Medical Biology, Faculty of Medicine, Marmara University, Istanbul, TurkeyBerrak Ç. YEĞEN, Department of Physiology, Faculty of Medicine, Marmara University, Istanbul, TurkeyGöksel ŞENER, Department of Pharmacology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

Ischemia-reperfusion injury, which occurs as a result of sympathetic hyperactivity, plays an important role in acute myocardial infarction (AMI). Resveratrol (RVT), present mainly in grape skin, is thought to have antiatherogenic, antioxidant and vasodilatory effects. In this study, we investigated whether RVT protects against AMI. In Wistar albino rats, AMI was induced by intraperitoneal isoproterenol (ISO, 5 mg/kg) injection for 30 days and during this period half of the rats were treated with saline while the other half were given RVT (10 mg/kg/day). At the end of this period, blood pressure (BP), heart rate (HR) and echo-cardiographic measurements were recorded and the rats were decapitated to obtain plasma and cardiac tis-sue samples. Lactate dehydrogenase (LDH), creatine kinase (CK), lysosomal enzymes (β-D-glucuronidase, β-galactosidase, β-D-N-acetyl-glucosaminidase, acid phosphatase and cathepsin-D) were studied in plasma samples, while malondialdehyde (MDA) and glutathione (GSH) levels and Na+,K+-ATPase and myelo-peroxidase (MPO) activities were determined in the cardiac samples. In the saline-treated AMI group, cardiotoxicity resulted in decreased BP and HR along with decreased cardiac Na+,K+-ATPase activities, GSH contents, while plasma LDH, CK and lysosomal enzyme activities and cardiac MDA and MPO activities were increased (p<0.05-0.001). On the other hand, RVT treatment reversed all the functional and biochemical changes (p<0.01-0.001). The present results demonstrated that RVT ameliorates iso-protrenol–induced myocardial infarction in rats. These observations highlight that RVT is a promising supplement for improving defense mechanisms in the heart against oxidative stress caused by myocardial infarction.

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PP133

NIGELLA SATIVA TREATMENT IMPROVES CARDIOVASCULAR FUNCTION AND PROTECTS AGAINST OXIDATIVE DAMAGE IN RATS WITH RENOVASCULAR HYPERTENSION

Nur TAŞAR, Department of Pharmacology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyÖzer ŞEHİRLİ, Department of Pharmacology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyÖmer YIĞINER, Department of Cardiology, Gülhane Military Medical Academy, Istanbul, TurkeyŞule ÇETİNEL, Department of Histology & Embryology, Faculty of Medicine, Marmara University, Istanbul, TurkeyBerrak Ç. YEĞEN, Department of Physiology, Faculty of Medicine, Marmara University, Istanbul, TurkeyGöksel ŞENER, Department of Pharmacology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, Turkey

Angiotensin II (Ang II) maintains early renal cortical blood flow and renal oxygenation in 2-kidney, 1-clip (2K1C) Goldblatt hypertensive rats. While the involvement of Ang II declines during the progression of 2K1C, oxidative stress becomes the effective factor. Nigella sativa L. (family Ranunculaceae) and its active component thymoquinone have been known as sources of antioxidants. In this study, we investigated the protective effect of nigella sativa in a renovascular hypertension model induced by placing a renal artery clip in Wistar albino rats (n=8), while sham rats (n=8) had no clip placement. Starting on the 3rd week after the operation, rats received nigella sativa (10 mg/kg/day) or vehicle for the following 6 weeks. At the end of the 9th week, blood pressure (BP) and echocardiographic measurements were recorded, plasma sam-ples were obtained to assay lactate dehydrogenase (LDH), creatine kinase (CK) activity. Malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) and Na+,K+-ATPase activities in the re-nal and cardiac tissues were determined. 2K1C caused increased BP and left ventricular (LV) dysfunction, while plasma LDH and CK activities were increased in these hypertensive animals. Moreover, hyperten-sion caused a significant decrease in tissue Na+,K+-ATPase activities and GSH content, while MDA levels and MPO activity were increased in both tissues. On the other hand, nigella sativa treatment significantly reduced BP, attenuated oxidative injury and improved LV function. In conclusion, nigella sativa protected against hypertension-induced renal and cardiac damage and improved cardiovascular function via its an-tioxidant and antihypertensive actions, suggesting a therapeutic potential of nigella sativa in renovascular hypertension.

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PP134NESFATIN PREVENTS SUBARACHNOID HEMORRHAGE INDUCED VASOSPASM OF THE BASILARY ARTERY IN RATS

Dilek AKAKIN, Department of Histology and Embriyology, Faculty of Medicine, Marmara University , Istanbul, TurkeyMehmet ERŞAHİN, Department of Neurosurgery, Haydarpasa Numune Education and Research Hospital , Istanbul, TurkeyHale TOKLU, Department of Pharmacology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyGöksel ŞENER, Department of Pharmacology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyBerrak YEĞEN, Department of Physiology, Faculty of Medicine , Marmara University, Istanbul, Turkey

Objectives: There is substantial evidence to suggest that oxidative stress plays a significant role in the de-velopment of acute brain injury following subarachnoid hemorrhage (SAH). This study investigated the putative neuroprotective effect of nesfatin, an endogenous peptide, in a rat model of SAH.

Materials and Methods: Male Wistar albino rats were divided as saline- and nesfatin (10 μg/kg, i.p.)-treated control and SAH groups. To induce SAH, rats with 0.3 mL blood was injected into their cisterna magna. Forty-eight hours after SAH induction, brain tissue samples containing basilar arteries were obtained for histological examination and processed for transmission electron microscopical evaluation.

Results: Toluidine blue (TB) staining of semi-thin sections showed that basilar artery of SAH group had irregular lumen, reflecting vasoconstriction, compared to that of control group. In nesfatin-treated group, the vessel wall structure had nearly normal appearance. Electron microscopical examinations showed that basilar artery of SAH group had degenerative ultrastructural alterations. The internal elastic lamina was partially separated from the tunica media layer. The appearance of nuclei of smooth muscle cells in the tunica media and the nuclei of endothelial cells was irregular. Intercellular widening between the smooth muscle cells was apparent. In nesfatin-treated group, the cellular alterations considering vasospasm showed regression. The general vessel ultrastructure was almost similar to that of controls.

Conclusion: The present study suggests that nesfatin prevented the vasospasm and morphological changes of the basilar artery which is a major pathology in SAH.

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PP135

THE EFFECT OF HAZELNUT ADDED TO THE DIETS ON LIPOPRITEIN PROFILE OF PATIENTS WITH CARDIOVASCULAR DISEASE

Aylin YILMAZ, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyŞermin TETİK, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyDerya ÖZSAVCI, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyK.Turay YARDIMCI, Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

Coronary cardiovascular diseases take place among the prior reasons of death in most of the countries in the world. Triglyceride (TG), low density lipoprotein cholesterol (LDL) and total cholesterol levels in blood, low levels of high density lipoprotein cholesterol (HDL) are the important risk factors of coronary heart disease. The fact that diets low in saturated fatty acids and high in monounsaturated fatty acids (MUFA) can control blood lipid levels shown us in many investigations. This positive effect lowers the risk of coro-nary heart disease. High levels of mono (MUFA) and poly (PUFA) unsaturated fatty acids are included in nuts and they lower the level of LDL Cholesterol. The subjects who takes place in our study consist of 13 men 6 women. Blood samples were collected in the beginning and in the 12 weeks. Serum total cholesterol, triglyceride, LDL and sub groups, HDL and sub groups, total lipid, lipoprotein (a) and homocysteine lev-els were. The results of this study consisted of two groups, Mediterrenean diet and 30gr/d Hazelnut plus Mediterrenean Diet; In the group consuming hazelnut with Mediterrenean diet have significant decline in body fat mass, fat percentage (%) and weight (p=0.018). In biochemical mesurements; Total Cholesterol and LDL (mg/dl) decreased significantly (p=0.028). LDL-1 (mg/dl) value is also decreased (p=0.043). In the subjects consuming Mediterrenean diet, fat mass and fat percentage (%) also decreased significantly (p=0.002). Body mass index (kg/ m²), weight (kg) (p=0.003) and blood values, especially LDL (mg/dl) (p=0.021) and LDL-1 (mg/dl) (p=0.045) decreased significiantly.

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PP136

INVIVO ANTIDIABETIC POTENTIAL OF INFUSION OF VACCINIUM ARCTOSTAPHYLOS L. IN STREPTOZOTOCIN-INDUCED-DIABETIC MODEL RATS

Cenk SESAL, Department of Biology, Faculty Art and Science, Marmara University, Istanbul, TurkeySeza TETİKKURT, Department of Pathology, Taksim First Aid Hospital, İstanbul, TurkeyKübra ELÇIOĞLU, Department of Pharmacology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyFigen CILOĞLU, Genlab Medical Diagnostics and Research Laboratory, Istanbul University, Istanbul, TurkeyTuğba KOTIL, Department of Histology and Embryology, Istanbul University, Istanbul, TurkeyNazan DENIZ YÖN, Department of Biology, Sakarya University, Kocaeli, Turkey

Diabetes mellitus is one of the most important diseases of the 21st century. The worldwide burden is pre-dicted to reach 300 million people at 2025. Ethnobotanical field studies in Turkey have revealed that a number of plant remedies such as the dried fruit of Vaccinium arctostaphylos is used to alleviate the symp-toms of diabetes, however, only a few have been scientifically evaluated to confirm the claimed activity. The aim of our study is to investigate the hypoglycemic and end-organ effect on kidneys, liver and testis of hydrophilic extracts from leaves of Vaccinium arctostaphylos (Ericaceae) in streptozotocin (STZ)-induced diabetic rats to scientifically confirm the claimed activity and find the appropriate effective concentration. Five days after injecting the Wistar rats with streptozotocin (STZ), the animals with glucose level above 180 mg/dl were considered to be diabetic and used in the experiment. A total of 54 rats in 9groups were used. After 14 days of supplementing with extract, blood samples were tested for glucose, insulin, total cholesterol, triglyceride, urea, uric acid, creatinin, aspartate amino transferase (AST) and alanine amino transferase (ALT). The organ samples from the kidneys, liver, and testis were examined histopathologically by electron and light microscopes The data was analyzed statistically using student t-test According to the results, blood glucose levels were not affected by infusion of Vaccinium arctostaphylos (Ericaceae) L. in Streptozotocin –induced diabetic model rat. However, histological results showed that in the rats receiving 100 mg/kg infusion., the kidneys were less damaged and in the rats receiving 200 mg/kg infusion, the liver and testis seemed to be healthier as compared with un-treated rats. This gives us hope that while not nor-malizing blood glucose levels, Vaccinium arctostaphylos (Ericaceae) L may have a protective effect against the damages of diabetes mellitus on vital organs and deserves to be further studied.

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PP137

THE EFFECTS OF ANTIDEPRESSANT DRUGS ON POLYMORPHONUCLEAR LEUKOCYTE FUNCTIONS AND LEVELS OF FOLIC ACID, VITAMIN B12, ZINC AND COPPER IN MAJOR DEPRESSION

Dilşad YURDAKUL, Department of Genetics and Bioengineering, Faculty of Engineering and Architecture Yeditepe University , Istanbul, TurkeyÜmran SOYOĞUL GÜRER, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, Turkey Erkan RAYAMAN, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyErol ERÇAĞ, Department of Analytical Chemistry, Faculty of Engineering, İstanbul University, Istanbul, TurkeyGoncagül HAKLAR, Department of Biochemistry, , Faculty of Medicine, Marmara University, Istanbul, TurkeyAdile ÇEVİKBAŞ, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyAylan GIMZAL GÖNENTÜR, Department of Psychiatry, Faculty of Medicine, Marmara University, Istanbul, Turkey

In this study our aim was to investigate the effect of antidepressant drugs on polymorphonuclear leukocyte (PMN) functions, serum folic acid, vitamin B12, zinc, copper levels, hemogram parameters of patients with major depression (MD). PMNs were isolated by Ficoll-Hypaque gradient centrifugation method. Phago-cytosis and intracellular killing activity were assayed by modifying Alexander’s method. White blood cell (WBC), neutrophil counts (NE) significantly increased after 2 months of antidepressant drug treatment (p<0,05). The phagocytic activity of PMN of MD patients was found in the same level as healthy volun-teers, the intracellular killing activity was found lower than that of healthy volunteers. The PMN’s phago-cytic activity after one and two months of antidepressant drug treatment insignificantly increased when compared with those before treatment. The intracellular killing activity also insignificantly increased after one month of treatment. Within the reference values, the level of folic acid insignificantly increased where-as the levels of vitamin B12, zinc insignificantly decreased. Level of copper was not affected. This study showed that WBC, NE counts in patients with MD significantly increased in the reference value intervals after antidepressant drug treatment (p<0,05). We conclude that antidepressant drugs have not deleterious effects on PMN functions, serum folic acids, vitamin B12, zinc, copper levels of patients with MD.

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PP138

GENOTYPING OF PROPIONIBACTERIUM ACNES ISOLATED FROM ACNE PATIENTS AND INVESTIGATION OF ANTIBIOTIC SUSCEPTIBILITY PATTERNS OF STRAINS

N. ÖZEL, Department of Microbiology, Faculty of Medicine, Marmara University, Istanbul, TurkeyN. ÜLGER (Toprak), Department of Microbiology, Faculty of Medicine, Marmara University, Istanbul, TurkeyZ. DEMİRÇAY, Department of Dermatology, Faculty of Medicine, Marmara University, Istanbul, Turkey I. USTA, Department of Dermatology, Faculty of Medicine, Marmara University, Istanbul, Turkey G. SÖYLETİR, Department of Microbiology, Faculty of Medicine, Marmara University, Istanbul, Turkey

Propionibacterium acnes, a member of skin flora, is the most commonly encountered microorganism in acne vulgaris and can be found in various systemic or disseminated opportunistic infections. Although three genotypes of P. acnes have been described, there are few epidemiological investigations of their roles in severity of infections and antimicrobial susceptibility pattern.

This study determined the antibiotic susceptibility patterns of P. acnes isolated from patients with acne vul-garis and to investigate the relationship between the genotype of P.acnes and the antimicrobial resistance.

Fifty-eight patients (36 females, 22 males) who attempt to Marmara University Hospital, Department of Dermatology and 62 healthy people (43 females, 19 males) as controls were enrolled in the study. The sam-ples obtained from the acne lesions and from facial skin of control group were cultured. Propionibacterium acnes was isolated from all patients and control group and identified by conventional methods. Genotypic analysis was made by PCR using specific primers to genotypes. Susceptibility tests were performed accord-ing to recommendations of CLSI agar dilution technique and the breakpoints recommended by EUCAST for the following antibiotics: erythromycin, azithromycin, roxithromycin, clindamycin, fusidic acid, tetra-cycline and doxycycline.

A total of 89 isolates (n:47 patient, n:42 control) showed genotype IA PCR bands, followed by type IB (n:5 patient, n:8 control) and type II (n:4 patient, n:7 control). No type III P.acnes has been detected. The resistance ratio among the acne patients group is found higher than the control group. In the group of acne patients, clindamycin, erythromycin and tetracyclin resistant P.acnes strains were recovered in 37%, in 46% and in 5%, respectively while in group of control the incidence of resistant strains against these antibiotics was 26%, 29% and 4%, respectively. No significant correlation existed between the genotype of P.acnes and antimicrobial resistance.

As a conclusion, the risk of increased resistance of P.acnes must be considered when treating acne patients with antibiotics.

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PP139

NUTRITIONAL PARAMETERS OF IRANIAN HIV POSITIVE INDIVIDUALS

Hossein KHALILI, Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, IranSimin DASHTI-KHAVIDAKI, Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Iran

Background/Objectives: HIV-infected individuals are prone to malnutrition due to increased energy re-quirements, enteropathy, and increased catabolism. The goal of this study was to evaluate nutritional pa-rameters of Iranian HIV-infected patients.

Subjects/Methods: Nutritional parameters were evaluated in 65 HIV infected patients and 65 healthy in-dividuals based on clinical assessment, anthropometric parameters and serum albumin.

Results: The most route of HIV infection was injection drug abuse and the main cause of hospital referral was bacterial infection. Severe, moderate and mild malnutrition detected in 15.4%, 38.5% and 24.6% of HIV infected patients respectively. Route of HIV infection, duration of illegal injection, homeless, smok-ing, history of prison, and fungal infection were risk factors for malnutrition. Conclusions: Malnutrition were prevalent in HIV-infected individuals in Iran, due to that most of these patients are injection drug users.

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PP140

THE COMPRATIVE EVALUEATION OF RESPONSE AND SIDE EFFECTS OF CINNOVEX, REBIF, AVONEX AND BETAFERON IN IRANIAN MULTIPLE SCLEROSIS PATIENTS

Seyed Mojtaba SOHREVARDI, Department of Clinical Pharmacy, Pharmaceutiacal Research Center, Kerman University of Medical Sciences, IranEbrahim SALEHIFAR, Department of Clinical Pharmacy, Faculty of Pharmacy , Mazandaran University of Medical Sciences, Sari, IranMahmud ABEDINI, Department of Neurology, Sari Faculty of Medicine, Iran Behnaz SEDIQI, Department of Neurology, Kerman Faculty of Medicine, Iran

Introduction: Different &#946;-interferons (IFNS &#8211;&#946;) are the most important agents in treatment of Multiple Sclerosis (MS) patients. The main purpose of this study was to evaluate the efficacy and safety profile of different IFNS &#8211;&#946; preparations available in our market.

Methods: This study has been conducted in two manners including a 2 years of retrospective and 1 year of prospective study to evaluate the efficacy and side effects of four brands of INFS-&#946; in MS patients. Patients received one of the four treatments for 12 months and were compared with each other. In observa-tional, multicenter retrospective study, patient data were evaluated by interview and questionnaires.

Result: After 1 year, 83.3% of patients receiving Betaferon® and 87.5% of patients receiving Avonex® and Rebif ® remained relapse-free compared with 93.1% of those given Cinnovex®. Expanded Disability Status Scale (EDSS) decreased by 0.5 U in Cinnovex® treated patients, by 0.46 U in Rebif ® treated patients, by 0.58 U in Betaferon® treated patients. Mazandaran retrospective study results showed percentage of pa-tients with new relapse was 38.5% in Avonex® treated patients, 22.7% in Cinnovex® treated patients, 50% in Rebif ® treated patients and 44% in Betaferon® treated patients (P=0.066). In Kerman retrospective study, changing the treatment from Avonex® to Cinnovex® wasn';t tolerated because of significant disease worsen-ing in 22.8%. We observed variable side effects in our study.

Conclusion: Our results suggest that four brands of IFN- &#946; were all effective but there were small differences among them in adverse event and efficacy.

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PP141

QUALITY OF LIFE ASSESSMENT IN METASTATIC LUNG CANCER PATIENTS

Beril KIVRAK, Department of Clinical Pharmacy, Faculty of Pharmacy, Yeditepe University, İstanbul, TurkeyÇağlar MACİT, Department of Clinical Pharmacy, Faculty of Pharmacy, Yeditepe University, İstanbul, TurkeyYağmur ÖZKAN, Department of Clinical Pharmacy, Faculty of Pharmacy, Yeditepe University, İstanbul, TurkeySude CETIN, Department of Clinical Pharmacy, Faculty of Pharmacy, Yeditepe University, İstanbul, TurkeyTaflan SAHLEPCİ, Oncologist, Kartal Lutfi Kırdar Education & Research Hospital, Istanbul, Turkey Philip CLARK, Department of Clinical Pharmacy, Faculty of Pharmacy, Yeditepe University İstanbul, Turkey

Background: The 5-year survival rate of lung cancer patients improved only modestly from 13.8% to 17% between 1974 and 2001. Besides high mortality, lung cancer is associated with high morbidity including chest pain, cough, hemoptysis and dyspnea. Against this background, evaluation and improvement in qual-ity of life (QOL) assumes great importance.

Objectives: The aims of the study were to investigate: possible changes in QOL during chemotherapy; which factors might affect QOL; and any relationship between QOL and performance status. Setting and Patients: The study was conducted at the oncology clinics of Dr Lutfi Kirdar Kartal Teaching and Research Hospital, Istanbul, Turkey. Seventeen patients diagnosed with advanced small-cell lung cancer or stage IV non-small cell lung cancer were enrolled in the study. All patients were to receive platinum-based chemo-therapy. Methods: After collecting demographic data, the QOL EORTC core questionnaire QLQ–C30 (version 3.0) and the lung cancer module QLQ-LC13 were conducted on four separate occasions, pre-treatment and before the second, third and fourth cycles of chemotherapy. Data related to the patients’ clinical and performance status (KPS and ECOG) were recorded throughout the study.

Results: With treatment, significant increases in chemotherapy related side-effects and in symptom scales related both to adverse drug reactions and disease progression were recorded. This trend ran parallel with significant decreases in global health status and functional scales. A strong, significant, negative correlation (r = -0.71, p< 0.05) between ECOG performance and all domains of EORTC QLQ-C30 was found, simi-lar to that between KPS and EORTC QLQ-C30 (r = -0.74, p< 0.05).

Conclusion: This research may indicate lack of benefit from platinum-based chemotherapy; however, rou-tine QOL assessment may encourage the development of treatment programs which minimize chemo-therapy side-effects, while maximizing patients’ well being. This study also confirms the prognostic value of performance status in patients with advanced disease.

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PP142

EVALUATION OF DIETARY SUPPLEMENT CONSUMPTION AT COMMUNITY PHARMACY SETTING

Betul OKUYAN, Department of Clinical Pharmacy , Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey Elif KAYA, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyMesut SANCAR, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey Şule APİKOĞLU RABUŞ, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey Başak SOYDEĞER ÇARLI, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey Fikret Vehbi İZZETTİN, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, Turkey

The aim of this study was to identify knowledge and perceptions of subjects towards dietary supplements and also assess participants’ points of view about pharmacists’ role in counseling on dietary supplement consumption. The study was carried out at a community pharmacy located in Etiler distinct of Istanbul. A self-administered questionnaire was handled out to clients who accepted to participate in the study (n= 154). Of the study subjects, 58% were female and the mean age was 36.5. The participants were of a high education level. While, 65.0% of participants thought that dietary supplements were beneficial, 41.5% of them declared that dietary supplements were not harmful. 56.5% of participants mentioned that some of dietary supplements can cause side effects and drug-interactions. The most commonly used dietary sup-plements were multivitamins (17.1%), supplements for cardiovascular disorders (15.49%), antioxidants (14.0%) and supplements for enhancing immune system (11.4%). The sources for supplying dietary supple-ments were pharmacy (62.3%), herbalist (8.4%), internet (5.2%), and supermarket (1.9%). 81% of the sub-jects who consumed dietary supplements notified that their health outcomes were enhanced with dietary supplements; while, 19% mentioned to observe no difference in their health status. Some of the reasons for dietary supplement consumption were mentioned to be increasing the body’s ability to fight the disease (41.5%), improving physical well-being (41.2%) and supporting disease management (35.7%). Only half of the participants mentioned that they would take dietary supplements with pharmacist advice. Of the sub-jects who consumed dietary supplements, 11% mentioned side effects and 65% told that their pharmacists provided counseling about dietary supplements. 86% of participants were pleased about the pharmacists’ counseling service about dietary supplements. Taking into account relatively high percent of dietary supple-ment consumption and consumers’ lack of information, pharmacists must take an active role in counseling, safety use, and patient education regarding dietary supplements.

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PP143

EVALUATION OF THE ANALGESIC USE OF PATIENTS WHO WERE DISPENSED ANALGESICS IN THE COMMUNITY PHARMACIES IN ISTANBUL

Basak DÖNERTAŞ, Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Marmara University, İstanbul, TurkeyÇiğdem ŞİMŞEK, Faculty of Medicine, Marmara University, İstanbul, TurkeyHatice BOZKURT, Faculty of Medicine, Marmara University, İstanbul, TurkeyÇağatay ÖZYALÇIN, Faculty of Medicine, Marmara University, İstanbul, TurkeyHale TOKLU, Department of Pharmacology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyAhmet AKICI, Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Marmara University, İstanbul, Turkey

Although the analgesics are required by law to be sold with prescription only, they are dispensed in the pharmacies without prescription. The present study was conducted to evaluate the analgesic use habits of the patients. For this purpose, 202 patients (who bought analgesics in the community pharmacies located by the hospitals in Kadikoy, Bakirkoy and Kucukcekmece districts of Istanbul) were asked for their analge-sic use habits by a face to face questionnaire.

The results showed that the mean (standard deviation) age was 39.5 ±13 and 68.8% of the respondents were female.

The majority (80.7%) of the respondents reported that they bought the drugs for themselves. On the other hand 18.8% confessed that they did not recall the number of drugs they bought. Sixteen percent of the patients bought the analgesics without prescription and only 24.2% of them consulted the pharmacist. Of these, 54% told that they did not understand the drug information leaflets and 95.5% told that they used analgesics in the past 6 months. Also 5.2% told that they experienced adverse effects (mainly gastrointesti-nal disturbances) while taking these drugs.

A similar study conducted in the past had reported approximately 40% analgesic dispensing without pre-scription. This rate was reduced in the present study. However, if we take into consideration that more than half of the patients did not understood the drug information leaflets; it seems that effective public educa-tion about rational use of drugs is still needed.

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PP144

AN EVALUATION OF THE ATTITUDES OF THE PHARMACISTS, PRESCRIBERS AND PATIENTS TOWARDS GENERIC DRUG USE

Mustafa GANNEMOĞLU, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyAslihan YETİM, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyHasim GÜNEŞ, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyMehrad SERADJI, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyHale TOKLU, Department of Pharmacology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeyGül DÜLGER, Department of Pharmacology, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 İstanbul, TurkeySeyhan HIDIROĞLU, Department of Public Health, Faculty of Medicine, Marmara University, İstanbul, TurkeyAhmet AKICI, Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Marmara University, İstanbul, Turkey

The use of generic medication has increased significantly in recent years. Since generic drugs are available at a lower cost, they provide an opportunity for savings in drug expenditure. Thus, use of generic drugs is encouraged especially in developing countries. There are only a few studies concerning the perceptions and attitudes of the healthcare providers and patients towards generic drug use. Therefore the present study was conducted by a face to face questionnaire in the Kadikoy district of Istanbul in 2010. 55 pharmacists, 53 prescribers and 80 patients consented to participate in the study. Respectively 35 and 34 % of the pharma-cists and prescribers told that they believed that the generics did not differ from the original, whereas only 16% of the patients believed so. 60 % of the pharmacists and 81% of the prescribers told that they were unsure about the bioequivalence of the generics. 8 % of the patients claimed that they immediately accept generic substitution by the pharmacist, while 28% accepted if it was substituted by the prescriber. Cost was the most important factor taken into consideration about generic substitution (88% for pharmacists, 93% for patients and 95% for prescribers). In conclusion, our findings showed that healthcare providers as well as the public should be better educated with respect to generic substitution.

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PP145

INFLUENZA A/H1N1 VACCINATION EXPERIENCE OF HEALTHCARE WORKERS AND UNIVERSITY STUDENTS

Nefize TURAN, , Faculty of Medicine, Marmara University, İstanbul, TurkeyAydın GÜNDOĞMUŞ, Faculty of Medicine, Marmara University, İstanbul, TurkeyEmre KAYA, Faculty of Medicine, Marmara University, İstanbul, TurkeyBaşak DÖNERTAŞ, Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Marmara University, İstanbul, TurkeyAhmet AKICI, Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Marmara University, İstanbul, Turkey

Introduction: The pandemic alert level of Influenza A/H1N1 was raised to Phase VI by WHO, and vac-cination is accepted to be the most effective way of preventing the spread of H1N1 virus and reducing the morbidity and mortality associated with it. Vaccination programs have been started along with the public discussions about the vaccine’s safety. Our aim was to investigate the attitudes and experiences of healthcare workers and university students about the vaccination programs.

Methods: A face-to-face survey was conducted on a total of 247 healthcare workers (125 physicians, 122 other workers) from Marmara University Hospital and 253 students (163 medical students, 90 other stu-dents) from Marmara University Haydarpasa Campus during March 2010.

Results: About half of the participants (47.7%) were men and 48% of the participants have been vacci-nated, and their main reason (73%) was “the fear of catching H1N1’’. Contrarily, the major cause to refuse vaccination (41.1%) was ‘’worries about being used as an experimental subject on a vaccine trial’’. A total 88.4% of the vaccine-taker subjects have been vaccinated before flu symptoms; nevertheless, 15.5% of them caught flu after the vaccination. Physicians have the highest immunization rates, followed by the other healthcare workers and medical students. Approximately 34% of the vaccine-takers reported mild adverse effects, of which fatigue, muscle ache, and fever were the most frequent. The percentage of people intending to accept a similar pandemic vaccine in the future was 31.9%, and physicians and medical students showed greater tendency to accept vaccination compared to the other groups.

Conclusion: Physicians and medical students showed greater positive attitude towards pandemic vacci-nation when compared to other healthcare workers and students. In general, it can be deduced that the last vaccination program had a negative effect on pandemic vaccination campaigns although the situation among the physicians seems better.

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CHARACTERISTICS OF THE DRUG-DISEASE INFORMATION SERVICE DEMANDED FROM THE COMMUNITY PHARMACIST

Sibel GÜNEŞDOĞDU, Sibel Eczanesi, Istanbul,TurkeyŞule APİKOĞLU RABUŞ, Department of Clinical Pharmacy Department, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyMesut SANCAR, Department of Clinical Pharmacy Department, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyFikret V. İZZETTİN, Department of Clinical Pharmacy Department, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, Turkey

Background: Besides dispensing, the pharmacist conducts various professional services at the community pharmacy setting. The most common cognitive service provided at a typical community pharmacy in Tur-key is provision of drug/disease information. The study aimed to assess the characteristics of a “drug/disease information” service demanded directly from the pharmacist at a community pharmacy. Setting: A com-munity pharmacy in Umraniye District of Istanbul. The location f the pharmacy is urban; however, the patients served are of rural origin from a not-very-favorable socioeconomic class, with relatively lower-levels of health awareness. Methods: All questions directed by the clients only to the pharmacist were recorded for 10 work-days. Only the questions asked by the patients and the relatives/friends of the patients which are directed to the pharmacist were recorded. The questions that were directed to the pharmacy staff and those spontaneously generated during a routine patient education were excluded. Results: During the 10 days period, 465 questions (queries) from 329 individuals were directed to the pharmacist. 73% of these individuals were women while 27% were men. The majority (60.3%) of the individuals were between 21-40 years of age. About half of the questions were drug-related. The classification of the drug-related ques-tions was as follows: adverse-effect (30%), indication (20%), dosage (19.7%), drug use in pregnancy and lactation (9.6%), intoxication (0.8%), interactions (5.8%), questions about regulatory/reimbursement pro-cesses not necessitating pharmaceutical knowledge (13.8%). The distribution of the questions other than drug-related ones were as follows: information about various disease states (27%), point-of-care measure-ments (23%), new-born/infant care and nutrition (11%), contraception methods (9%), interpretation of biochemistry/pathology laboratory data (6%). Conclusion: The intensity of queries and the characteristics of the questions documented in this study suggest that there is an extensive public demand for the “drug/disease information” service provided at the community pharmacy by the pharmacist.

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PP147

GENERAL SATISFACTION OF HEALTHY VOLUNTEERS WHO ARE INVOLVED IN CLINICAL BIOEQUIVALANCE STUDIES

Latif ÖZBAY, GCP Manager, Faculty of Pharmacy, Yeditepe University, Istanbul, TurkeyNazlı ŞENCAN, Department of Pharmacy Management, Faculty of Pharmacy, Yeditepe University, Istanbul, TurkeyDurişehvar Özer UNAL, GLP Manager, Faculty of Pharmacy, Yeditepe University , Istanbul, TurkeyÜrün Güney TUNÇ, Quality Assuarance Manager, Faculty of Pharmacy, Yeditepe University, Istanbul, Turkey

As it is known, phase I and bioequivalence studies are conducted with healthy clinical trial volunteers to determine pharmacokinetical properties and safety profile of a drug.

In"Yeditepe University GCP Clinic", since 2005 many studies had been conducted. As it should be, a study design about volunteers (number of subjects, selection of volunteers) is standardized according to ICH-GCP (International Conference on Harmonisation - Good Clinical Practice) guidelines with the approval of ethical committee. So as to improve the quality of the service, to define the participant';s profile, and ensure quality assurance, since the beginning of 2010 a new approach has been being considered.

Satisfaction of healthy volunteers is measured via a survey, which is formed by the researchers. At the end of each trial, the surveys are given to participants at the same time. Demographic variables, knowledge about the whole research process, the reason of attendance, degree of satisfaction with the information given, interest of health professionals, efficiency of the facility and other items are questioned. The answers given are tabulated and discussed with future considerations.

This satisfaction surveys are a part of our quality assurance system and a part of our respect to the volun-teers. This is not a part time study. This will continue as long as the"Yeditepe University GCP Clinic" exists. It is obvious that GCP guideline can only be useful and effective, as more as volunteers are carefully and intimately followed up.

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PP148

WOMEN PHARMACISTS: A CULTURAL STATUS OF PATIENT’S CHOICE

Nazlı ŞENCAN, Pharmacy Management, Faculty of Pharmacy, Yeditepe University , Istanbul, Turkey

Cultural issues and status are very important parts of health care management. Patients'; choice of their health care givers and pharmacists are affected by culture.

Pharmaceutical care model is directly under the influence of population diversity. With this study, research-ers tried to understand how public thinks about pharmacists gender.

A focus group research was conducted. Two different socioeconomic groups were formed. One was under-educated, low-income social group. The other was formed from young academic staff. Both groups consist-ed of male and female participants. Each interview lasted more than an hour. The meetings were recorded by audio and image recorder with the permission of the participants.

The records are translated to words and interpreted. It is understood that in general people declared that they did not differ gender and they did not choose men or women pharmacists. However, at the end of long-deep talk, it is understood that in special health-related problems, people tended to ask and felt free consulting to pharmacists of their own gender.

It should be concluded that, pharmacists'; way of communication and interaction is always more considered than anything including gender preference.

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PP149

OUTCOMES OF DIABETES RISK-TESTING PERFORMED AT COMMUNITY PHARMACY SETTING

Şule APİKOĞLU RABUŞ, Department of Clinical Pharmacy Department, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyZehra TÜRE, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyMesut SANCAR, Department of Clinical Pharmacy Department, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyBetül OKUYAN, Department of Clinical Pharmacy Department, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyBaşak SOYDEĞER CARLI, Department of Clinical Pharmacy Department, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyFikret Vehbi İZZETTİN, Department of Clinical Pharmacy Department, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, Turkey

Background: International Diabetes Federation recommends the use of brief patient questionnaires to help healthcare professionals to quickly identify people who may be at a higher risk. This study aimed to evalu-ate the outcomes of a program testing diabetes risk of the clients, performed at the community pharmacy setting.

Setting: A community pharmacy located at Erenkoy District of Istanbul, Turkey.

Methods: The Turkish version of the Finnish Type 2 Diabetes Risk Assessment Form, providing a measure of the probability of developing type 2 diabetes over the following 10 years was used as the questionnaire. The clients who were seemingly over-weight and older than 45 years of age were invited to the study and the study was carried on those accepting to participate.

Results: A total of 109 clients participated in the study. Fifty-nine percent of the participants were female and the mean (SEM) age was 54.3 (1.3). The mean (SEM) body mass index was 29.3 (0.3) kg/m2. Of the participants, 43% were hypertensive and 16.5% were found to have higher than normal blood glucose levels. Majority (94%) of the participants had abdominal obesity. The risk of developing type 2 diabetes within 10 years was found to be moderate for 31%, high for 24% and very high for 5.5% of the participants. Those at the moderate risk group were advised to consider their physical activity and eating habits. Those in the high and very-high risk group were advised to have their blood glucose levels measured to determine if they have diabetes without symptoms. All these three risk groups were referred to a physician for further guidance.

Conclusion: Even a simple diabetes risk test performed at the community pharmacy can help to identify the patients at high risk and help the prevention/delay of developing diabetes.

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PP150

EFFICACY OF PHOSPHATE BINDING AGENTS IN HEMODIALYSIS PATIENTS

Esra ZEYTİN, Department of Clinical Pharmacy, Faculty of Pharmacy, Yeditepe University, Istanbul, TurkeyBurçin KARATAŞ, Department of Clinical Pharmacy, Faculty of Pharmacy, Yeditepe University, Istanbul, TurkeyÇağlar MACİT, Department of Clinical Pharmacy, Faculty of Pharmacy, Yeditepe University, Istanbul, TurkeyYağmur ÖZKAN, Department of Clinical Pharmacy, Faculty of Pharmacy, Yeditepe University, Istanbul, TurkeySude ÇETİN, Department of Clinical Pharmacy, Faculty of Pharmacy, Yeditepe University, Istanbul, TurkeyPhilip CLARK, Department of Clinical Pharmacy, Faculty of Pharmacy, Yeditepe University, Istanbul, Turkey

Background: Chronic renal failure can result in hyperphosphatemia and secondary hyperparathyroidism. Dietary phosphorus restriction and hemodialysis may fail to control serum phosphorus levels, in which case phosphate binders are employed.

Objective: The aim of the study was to evaluate the efficacy of phosphate binders alone and in combina-tion. Setting and Patients: The study was performed at the Dialysis Unit of Goztepe Teaching and Research Hospital, Istanbul, Turkey. 76 patients who had undergone hemodialysis were included in the study.

Method: A retrospective study of patients who attended the dialysis unit between January and May 2009 was carried out. Patients were receiving the following phosphate binding therapies: calcium acetate, sevelamer, calcium acetate + vitamin D (combination), and sevalemar + sucralfate (combination). In addi-tion, some patients were taking other alternative treatment choices, while some did not receive any treat-ment. Measures of renal function and in particular phosphate (P) and calcium (Ca) levels were recorded for each of the months. An ANOVA analysis of the Calcium - Phosforus Product (Ca x P), and the difference between P values for each month was conducted, in order to compare the different treatment options over a four month period.

Results: No significant differences were found between treatment options for either Ca x P or P levels (p> 0.05). On the other hand, when any of the treatment options was compared with no treatment for P during the entire study period, and for Ca x P during most of the study period, significant statistical differences (p< 0.05) were found.

Discussion/conclusion: Our study shows that no one treatment option is superior, but all have phosphate binding efficacy when compared with phosphate levels of patients who are not receiving any drug therapy. Our study may have important pharmacoeconomic implications both for patients and for the health sys-tem.

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PP151

MONITORING OF THEOPHYLLINE LEVELS IN PATIENTS WITH ACUTE EXACERBATION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Başak SOYDEĞER CARLI, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyFikret Vehbi İZZETTİN, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, Turkey Betul OKUYAN, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, Turkey Mesut SANCAR, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyTuran KARAGÖZ, Sureyyapasa Center for Chest Diseases and Thoracic Surgery, Maltepe, Istanbul, Turkey

The aim of the study was to monitor serum theophylline concentrations in patients with acute exacerbation of Chronic Obstructive Pulmonary Disease (COPD) and treated with continuous intravenous infusions of theophylline. Patients who are currently receiving theophylline with same dose at least 4 half life along after starting the continuous IV infusion were included in this study. Blood samples were collected one hour after intravenous administration. The theophylline serum levels were analyzed by with a fluorescence-polarisation immunoassay. 10-20 µg/mL was taken as reference levels for serum theophylline levels. Twenty patients (16 male) with a mean age of 65.7±2.13 years were included in this study. The severity of COPD were evaluated according to The Global Initiative for Chronic Obstructive Lung Disease (GOLD; FEV1 and FEV1/FVC levels) and six patients were found to be at stage 2 and nine patients were at stage 3 and five patients were at stage 4. The average theophylline level was 11.40±0.69 μg/mL. Forty percent of the patients had subtherapeutic levels, 60% had therapeutic levels, and toxic levels were not observed. Determi-nation and monitoring of theophylline levels in patients would prevent theophylline induced side effects and drug interactions and improve health outcomes in long term COPD management. Also theophylline serum level monitoring would be a good indicator for a need to clinical pharmacist in providing patient oriented services in COPD management.

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PP152

COMMUNITY PHARMACISTS’ PRACTICES ON THE MANAGEMENT OF PSEUDOALLERGY TO NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS)

Wilawan THONGRAUNG, Department of Clinical Pharmacy, Faculty of Pharmacy, Price of Songkhla University, Thailand Chaveewan RATANAJAMIT, Department of Clinical Pharmacy, Faculty of Pharmacy, Price of Songkhla University , Thailand

Background: Allergic to NSAIDs can be classified as true allergy and pseudoallergy. A drug causing pseu-doallergy acts pharmacologically to produce the direct release of inflammatory mediators from mast cells rather than through cell-bound IgE mechanism. Patients with pseudoallergic to NSAIDs should not be prescribed all classical NSAIDs. In Thailand, NSAIDs are available as over-the-counter (OTC) drugs. Therefore, community pharmacists should have adequate knowledge, to identify type of allergy, and good practice skills to take patients’ history sufficiently in order to select an appropriate medication and to give related advice to patients. Objectives: To investigate the practices of community pharmacists on the man-agement of pseudoallergy to NSAIDs. Setting: 131 community pharmacies were selected by simple ran-dom sampling from 248 community pharmacies in a province in southern Thailand.

Methods: Data collection was done independently by 2 senior, well-trained, female pharmacy students. Each data collector, with allergic history (urticaria and angioedema) to diclofenac and mefenamic acid, pre-sented at the assigned pharmacy to seek medicine for her muscle sprain. She experienced these cutaneous adverse drug reactions after the first dose of each NSAIDs. If the presented pharmacists could not identify the pseudoallergy, the client would ask them about this issue. The practices of pharmacists were recorded in a standardized data collection form.

Results: Of 131 pharmacists, 93 (71.0%) asked signs and symptoms of drug allergy, 23.7% asked history of taking NSAIDs. More than half (58.7%) of pharmacists dispensed NSAIDs. Moreover, 37.4% dispensed classical NSAIDs that were inappropriate drugs. About the explanation on pseudoallergy, most pharma-cists (77.4%) had incorrect explanation, 12.7% had no explanation and 9.9% had correct explanation.

Conclusion: History taking for essential information on pseudoallergy to NSAIDs is inadequate. Inappro-priate drugs (classical NSAIDs) were dispensed. There is a need to increase awareness in appropriate care.

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PP153A DRUG PROFILE STUDY ON PATIENTS WITH EYE DISORDERS IN A HOSPITAL SETTING

Mesut SANCAR, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyBaşak KIZILCADAĞ, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyFikret Vehbi İZZETTİN, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, Turkey

The aim of this study was to determine the type and frequency of medication used in common eye disorders in hospitalized patients. The study was designed as a retrospective drug profile study. Data were collected from medical records of patients who admitted to one of the ophthalmic training and research hospitals located in Istanbul. The study was conducted on randomly selected 300 patients admitted to the hospital during December. Total of 300 patients’ (164 male) medical records was evaluated in this study. The mean age was 53.84 years. The most common seen eye disorders in patients were as follows; diabetic retinopa-thy (115), age-related macular degeneration (43), cataracts (43), strabismus (28) and glaucoma (15). 66% of patients had history of diabetes. Hypertension (21% of the patients) was the second most common disease seen in these patients. The most frequently prescribed drugs were antibiotics (145 patients), anti-inflammatory drugs (113) and analgesics (49). The most commonly used eye drops in these patients were prednisolone acetate (66 patients), tobramycin (54 patients) and ketotifen (34 patients). The results of this study showed that long-term, uncontrolled diabetes leads to serious eye problems. Most of these complica-tions and number of drugs used in eye disorders can be minimized by patient education and monitoring. The clinical pharmacist can have an important role in diabetic patient care by providing counselling and monitoring such as early referral to ophthalmologist by pharmacist. Proper use of eye drops/ointments is a critical part of treatment. Pharmacist should be counselled the patients with eye problems about rational use of these medication.

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PP154

COMMUNITY PHARMACISTS' PERCEPTIONS OF MANAGEMENT SKILLS

Özlem Nazan ERDOĞAN, Technical College, Kocaeli University, Kocaeli, TurkeyMehmet SARPER ERDOĞAN, Department of Public Health, Istanbul University, Istanbul, TurkeyOnur GÜNAY, HEALTH, Şırnak Provincial Health Department, Şırnak, TurkeySerdar ERKUŞ, Health, Amasya Provincial Health Department, Amasya, Turkey

Introduction: Community pharmacies are the business organizations. In these organizations, pharmacists are to use pharmacies resources by effective planning and evaluating, in order to create patient’s quality-of-life. This requires some management skills for pharmacists. The aim of this study was to know how being perceived of management skills, that community pharmacists are supposed to have, by pharmacist.

Material and method: The survey was conducted between December 2007 and January 2008, in Bingöl and Amasya. 62,2 % pharmacies in the center of Amasya (28/45) and 55,3 % (21/38) in Bingöl were reached. A face-to-face questionnare was applied under the observation. Pharmacists evaluated 26 management skills determined according to the scientific health literature, as a manager of their pharmacies. Each skills were marked from 1 (the least important) to 5 (the most important) by pharmacists. SPSS program was used for all data entry and to evaluate data statistically. Mean and standard deviation of study variables with numeric and categorical variables are shown in percentage and frequency distributions.

Results: The average age of the participants was 39,63±1,18 (min 24 years, max 63 years). The average year of service of community pharmacists was 162,6 ±124,6 months (min.4 months, max 420 months). The first 5 skills, evaluated by community pharmacists, are presented below. 1. Exhibit ethical behavior in all aspects of pharmacy practice (4,60±0,84) 2. To ensure effective communication when talking or writing (4,47±0,82) 3. The effective use of computer on drug information, sales, investment, and labeling (4,27±1,11) 4. To use effective communication techniques while performing the mission of the pharmacy to motivate staff (4,25±0,94) 5. To meet customer needs and expectations and to listen effectively (4,22±0,97)

Conclusion: It is understood that ethics, communication, technology, motivation, and patient (customer) orientation were important issues of pharmacy and the priorities of the pharmacists. Also management skills in these areas were perceived as important by pharmacists.

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PP155

THE CLINICAL SUBJECTS OF COMMUNITY PHARMACY SERVICES

Özlem Nazan ERDOĞAN, Technical College, Kocaeli University, Kocaeli, Turkey Mehmet SARPER ERDOĞAN, Department of Public Health, Istanbul University Onur GÜNAY, Health, Şırnak Provincial Health Department, Şırnak, TurkeySerdar ERKUŞ, Health, Amasya Provincial Health Department, Amasya, Turkey

Introduction: The term clinical, which means directly interact with patients, has been made much progress since 1970’s when it was firstly defined. The aim was to reveal the knowledge and attitudes of pharmacist regarding clinical issues of community pharmacy subjects. The survey was conducted between December 2007 and January 2008, in Bingöl and Amasya. 62,2 % pharmacies in the center of Amasya (28/45) and 55,3 % (21/38) in Bingöl were reached. A face-to-face questionnare was applied under the observation. It was questioned socio-demographic data and counseling provided by pharmacists within a dedicated private area exists at the first part of the poll. In the second part, general topics of health education and drug use, and also pharmacist\'s opinions on these issues were evaluated. SPSS program was used for data entry and to evaluate data. Mean and standard deviation of study variables with numeric and categorical variables are shown in percentage and frequency distributions.

Results: The average age of the participants was 39,63±1,18 (min 24 years, max 63 years)). The average year of service of community pharmacists was 162,6±124,6 months (min.4 months, max 420 months). Community pharmacists they feel themselves most effectively among clinical issues, the first 5 issues are presented below.

1. Information on drug administration route and type to patients or relatives (4,5 ± 0,7) 2. Information on drug dose and schedule to patients or relatives (4,4 ± 0,81) 3. Information on drug storage conditions to patients or relatives (4,39 ± 0,90) 4. Information on the duration of drug use to patients or relatives (4,38 ± 0,91) 5. Warning about the use of drugs to patients or relatives to do (4,30 ± 0,86)

Conclusion: Presence of a place for consultation in 25 % of pharmacies is pointing out that pharmacists can develop better service quality to patients by improving their knowledge on several clinical issues including health promotion.

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PP156

KNOWLEDGE AND ANTIBIOTIC USE IN UPPER RESPIRATORY INFECTION IN THE THAI GENERAL POPULATION

Woranuch SAENGCHAROEN, Department of Clinical Pharmacy, Prince of Songkla University, ThailandSanguan LERKIATBUNDIT, Department of Pharmacy Administration, Prince of Songkla University, Thailand

Objectives: To investigate public knowledge and behavior regarding antibiotic use for upper respiratory infection (URI) in Thailand.

Method: A questionnaire survey was conducted in people age 16 or older who were Thai residents in south-ern Thailand.

Results: A total of 654 respondents participated in the study. Sixty one per cent of respondents agreed that common cold were caused by viruses and only 40% believed that it resolved on its own. One fourth believed that antibiotics could reduce the duration and prevent complications. Only 44% had completed the anti-biotic treatment course for URI. Higher education level and family income were related to the adequate knowledge. However, public knowledge was not significantly different in term of gender.

Conclusions: Misconceptions on the appropriate antibiotic use for URI are predictive of increased drug resistance. Targeted educational interventions should be developed for the Thai general public.

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PP157

DETERMINATION OF ANEMIA FREQUENCY IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Mesut SANCAR, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyYasemin ŞİRİNOĞLU, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyTuran KARAGÖZ, Chest Diseases Clinic, Sureyyapasa Center for Chest Diseases and Thoracic Surgery, Istanbul, TurkeyFikret Vehbi İZZETTİN, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, Turkey

Anemia of chronic disease is a potential complication of chronic obstructive pulmonary disease (COPD). If present in COPD, anemia could worsen dyspnea and limit exercise tolerance. The aim of the study was to investigate the frequency of anemia in patients with COPD utilizing hemoglobin levels as an indicator. The medical records of 452 (403 of male) COPD patients that was treated in Sureyyapasa Center for Chest Diseases and Thoracic Surgery, Istanbul from 2002-2006 were investigated. Other disease states for which anemia is a known complication were excluded. Anemia was defined by the World Health Organization criteria. Mean age was 63.10±9.39 (range 29-87). A total of 127 (28.1%) patients had anemia with mean hemoglobin of 11.7±0.98 g/dL. There was a correlation between the age and hemoglobin levels of the pa-tients (rho= -0,202; p<0.001). As a conclusion we can suggest that determination and treatment of anemia in COPD is an important entity which will help in the management of COPD.

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PP158

PERCEIVED JOB SATISFACTION OF TURKISH PHARMACISTS

Şule APIKOGLU RABUŞ, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, Turkey Mustafa İsmet KONCAGÜL, Faculty of Pharmacy, Marmara University, Istanbul, Turkey Betul OKUYAN, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyMesut SANCAR, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, Turkey Başak SOYDEĞER CARLI, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, Turkey Fikret Vehbi İZZETTİN, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, Turkey

Background: Today, the pharmacy profession in Turkey is undergoing a dynamic process necessitating the pharmacists to keep updated about the continuously-renewing regulatory procedures. This vigorous pro-cess seems to affect the pharmacists not only economically but also humanistically. This study aimed to assess the job satisfaction of Turkish pharmacists.

Methods: A questionnaire consisting of questions addressing the most common issues of job dissatisfac-tion was structured and sent to all members of the Society of Clinical Pharmacy in Turkey. All completed questionnaires were further analyzed.

Results: A total of 131 questionnaires were analyzed. Of the respondents, 77% were community pharma-cists, while 21% were hospital pharmacists; 51% were practicing pharmacy in Istanbul. While, 69% had chosen to be pharmacists with their own will, a similar rate does not want their children to become phar-macists now. Slightly more than a half of the respondents frequently/very frequently think that they did not perform their carrier in the best way; while, 79% reported that due to excessive stationary work-load they had no time left for professional activities such as patient education and drug information. In general the pharmacists were not satisfied with the working hours and thought that they did not have enough time for vacations (77%), for themselves (71%) and for their families (66%). The respondents reported that they would be more satisfied with their jobs, if they had the chance to deal less with stationary work (98%). Other factors associated with a higher job satisfaction were reported as: more frequent provision of clinical pharmacy services (94%), more flexible working hours (86.2%), more professional knowledge (76.8%) and a higher financial income (68.1%).

Conclusion: Most of the community pharmacists seem dissatisfied with their present professional status. The practice of delegation in pharmacy management can help the pharmacists soundly pass through ex-hausting periods of time.

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PP159

TURKISH CERTIFIED PHARMACY TECHNICIANS’ COUNSELING PRACTICES AND ATTITUDES REGARDING EMERGENCY CONTRACEPTIVE PILLS

Şule APIKOĞLU RABUŞ, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, Turkey Mesut SANCAR, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, TurkeyBetul OKUYAN, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, Turkey Fikret Vehbi İZZETTİN, Department of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Haydarpaşa 34668 Istanbul, Turkey

Background: In Turkish community all PTs can dispense both prescription and non-prescription drugs incuding the emergency contraception pills (ECPs); however, the pharmacist is the ultimate responsible person. The aim of this study is to assess the pharmacy technicians’ counseling practices and attitudes re-garding ECPs.

Methods: The survey tool was structured to question demography, professional experience, counseling practices and attitudes regarding ECP. Attitudes were measured under four domains: reproductive health; information and availability; risk behavior and regulatory restrictions. The questionnaires were adminis-tered to 145 certified PTs. Certified PTs are PTs who completed at least eleven years of formal school edu-cation and a 330 hours of professional education.

Results: Mean [SEM] age of the pharmacy technicians was 25.3 [0.4] and the mean [SEM] practice time was 5.4 [0.4] years. About half of the technicians were female and 89% were practicing in a community pharmacy. Of the technicians, 60.5% reported to be comfortable about ECP counseling with customers; while, 29% were comfortable with the same gender. An insufficent percent of technicians perported that they often/always counseled on timeframes (68%), dosage (67%), efficacy (51%), pregnancy test (45%), mechanism of action (30%), methods of contraception (26%) and side-effects (20%). In general, the tech-nicians were negative towards the items suggesting that the ECPs should be sold only to women and only on prescription; while 75% were positive towards the item suggesting age limitation (>18) to ECP sales. Majority of the technicians favored improved availability and knowledge regarding ECPs; while, they dis-played concern regarding risky sexual behavior by enhanced availability of ECPs.

Conclusion: Despite their positive attitude towards the ECPs, PTs provide insufficient ECP counseling to clients. Organization of continuing education programs on reproductive health and ECPs for the PTs could help to increase the quality of ECP counseling provided by the PTs.

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PP160

THE EFFECT OF TRAINING ON URINARY N-ACETYL-BETA-D-GLUCOSAMINIDASE LEVELS OF KARATE-DO PLAYERS

Banu AYÇA, Department of Sports and Health Sciences, Faculty of Physical Education and Sports Marmara University, İstanbul, TurkeySait BURUNCU, Acıbadem Labmed Clinical Laboratories, İstanbul, TurkeyAytekin SOYKAN, Department of Physical Education and Sports Teaching, Faculty of Physical Education and Sports Marmara University, İstanbul, Turkey

Karate is martial arts sport. All body parts uses as a means of defence and and attack. Karate involves rhyhtm,smoothness,agility,concentration and coordination.All techniques perform with power and quick move-ments.

Post-exercise proteinuria and increased urinary enzymes levels can be indicative of exercise-induced renal damage . The degree of this proteinuria depends on the type,intensity and duration of exercise. As N-acetyl-beta-D-glucosaminidase(NAG) and gamma-glutamyl transferase (GGT) are most important urinary in-dicator enzymes.

We aimed to asses the presence of exercise-induced in urinary NAG levels with protein, creatinine and uric acid levels in karate players.

The study was performed 7 male national karate players. After 10 minutes warm up athletes were training for 45 minutes and training were completed with 5 minutes cool down.

The spot urine samples were collected pre training and 1 hour post training. All samples were stored at -20º C till the day of the analysis.

The 1 hour post training urinary NAG and protein levels were significantly higher than the pre training levels(p<0.05). The 1 hour post training urinary creatinine and uric acid levels were higher than the pre training levels,but these increases are not statistically significant (p>0.05).

As a results,karate training by male players was to cause a enzyme and protein excretion.

251

PP161

COMPARATIVE STUDY OF CONVENTIONAL AND MICROWAVE INDUCED SYNTHESIS OF SOME OXIME ESTERS

Mehmet A. ALAGÖZ, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İnönü University, 44280 Malatya, TurkeyGülnihan ONAR, Departmet of Organic Chemistry, Faculty of Science and Arts, İnönü University, 44280 Malatya, TurkeyArzu KARAKURT, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İnönü University, 44280 Malatya, TurkeyBülent ALICI, Departmet of Organic Chemistry, Faculty of Science and Arts, İnönü University, 44280 Malatya, TurkeySevim DALKARA, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Turkey

Nafimidone is the representative of (arylalkyl)azole anticonvulsant. Derivatives have anticonvulsant and antimicrobial activities [1-3]. The oxime ester derivatives of nafimidone have synthesized new potential anticonvulsant and antimicrobial compounds.

Microwave induced synthesis can reduce the time of chemical reaction from hours to minutes. In this study we synthesized some ester derivatives by both conventional and microwave methods[4]. We found that the reaction rate of microwave induced synthesis 10-50 times compared to that by the conventional methods.

The compounds have been synthesized according to the reaction pathways given below and chemical struc-ture of the compounds were confirmed by spectral data.

O

CH3Br2

O

CH2Br

N

N

H O

CH2 NN

NH2OH

N

CH2 NN

OH N

CH2 NN

OC R

O

RCOOH

R= (CH2)3CH3CH2CH3 ,

1. Walker KAM, Wallach BM, Hirschfeld RD. 1-(Naphthylalkyl)-1H-imidazole derivatives, a new class of anticonvulsant agents. J Med Chem 24: 67-74, 1981.

2. Karakurt A, Dalkara S, Özalp M, Özbey S, Kendi E, Stables JP. Synthesis of some 1-(2-naphthyl)-2-(imidazole-1-yl)ethanone oxime and oxime ether derivatives and their anticonvulsant and antimicrobial activities. Eur J Med Chem 36: 421-433, 2001.

3. Karakurt A., Özalp M., Işık Ş., Stables J.P., Dalkara S.: Synthesis, anticonvulsant and antimicrobial activi-ties of some new 2-acetylnaphthalene derivatives, Biorg. Med Chem., 18, 2902–2911, 2010.

4. C.O. Kappe: Controlled Microwave Heating in Modern Organic Synthesis, Angew. Chem. Int. Ed., 43, 6250-6284, 2004.

252

PP162

ANTIRADICAL ACTIVITIES OF ALCHEMILLA MOLLIS

Gökçe Şeker KARATOPRAK, Department of Pharmacognosy, Faculty of Pharmacy, Erciyes University, 38039, Kayseri, Turkey.Müberra KOŞAR, Department of Pharmacognosy, Faculty of Pharmacy, Erciyes University, 38039, Kayseri, Turkey.S. ERTÜRK, Department of Pharmacognosy, Faculty of Pharmacy, Erciyes University, 38039, Kayseri, Turkey.

The European Pharmacopoeia includes the Alchemilla monograph(A.xanthoclora).Alchemilla species are rich in tannins.Tannins have good potentials as natural antioxidants and antimicrobials.Turkey has some Alchemilla species.In this study Alchemilla mollis (Buser) Rothm.(Rosaceae ) was researched as antiradical activities.Alchemilla mollis herb was extracted with different solvents such as methanol,50% methanol.Wa-ter extract was also prepared from Alchemilla mollis by reflux.Deodorized water extract also prepared using Clevenger apparatus.Methanol,50 % methanol,water and deodorised water extracts were tested in in vitro antioxidant assays.Oxidative stress and free radicals have role in cell damages and related various disorders.In order to evaluate the antioxidants properties of polar extracts from A.mollis were screened for their free radical scavenging activity using DPPH. and ABTS+. methods.All extracts scavenged the both of radicals with their phenolic compounds especially tannins.

253

PP163SCHIFF BASE OF 4,6-DISUBSTITUTED-3(2H)-PYRIDAZINONE DERIVATIVES: SYNTHESIS AND ANTIMICROBIAL ACTIVITY

M. SUKUROGLU, aGazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry T. ONKOL, Gazi University, Faculty of Pharmacy, Department of Pharmaceutical ChemistryF. KAYNAK, Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Microbiology, 06330 Ankara-TurkeyM. F. SAHIN, Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry

Heterocycles compounds which contain the 3(2H)-pyridazinone ring system have been reported to exhibit wide spectrum of biological activities. In addition, compounds having hydrazine and hydrazone moiety have been showed to possess different biological activity such as analgesic-antiinflamatory, antimicrobial, antiplatelet, antituberculosis and anticancer activities. Prompted by these investigations, in this study, we synthesized ten new derivatives of [4-phenyl-6-(morpholine-4-yl)-3(2H)-pyridazinone-2-yl]acetohydra-zide. Structures of the compounds have been elucidated by spectroscopic data and TOF-MS. The synthe-sized compounds were tested against two Gram-positive (S. aureus, E. faecalis) and two Gram-negative (E. coli P. aeruginosa) bacteria species and clinical isolates for in vitro antibacterial activities. In vitro antifungal activities of compounds were evaluated against C. albicans, C. krusei. The assessment of the antimicrobial activities of the synthesized compounds was performed using the broth microdilution test. Compounds showed the MIC values between 32-256 μg/ml.

R = H, 4-CH3, 4-Cl, 4-F, 2-F, 4-OCH3, 4-OC2H5, 4-CF3, 4-C(CH3)3

N

N

N

O

O

NHN

O

R

254

PP164AN INVESTIGATION ON ARCHAEOSOMES AS DNA CARRIER INTO THE MAMMALIAN CELLS

Azade ATTAR, Department of Bioengineering, Faculty of Chemistry and Metallurgy, Yıldız Technical University, Istanbul-TurkeyKadir TURAN, Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Marmara University, Istanbul-Turkey Ayşe OGAN, Department of Chemistry, Faculty of Science, Marmara University, Istanbul, TurkeyMeral BİRBİR, Department of Biology, Faculty of Science, Marmara University, Istanbul, TurkeyHuriye KUZU, Department of Bioengineering, Faculty of Chemistry and Metallurgy, Yıldız Technical University, Istanbul, Turkey

Archaeosomes are liposomes made from natural lipids found in Archaea. In this study we investigated the DNA delivery potential of archaeosomes prepared from Haloarcula hispanica to mammalian cells.

The archaeal lipids were extracted from H. hispanica isolated by Birbir et al. (2004). H. hispanica was grown in Brown medium. Lipids were extracted using methanol/chloroform/water (2:1:0.8,v/v), and the total polar lipid fraction was collected by cold acetone precipitation. The polar lipids were dried by rotary evaporation and the lipid film was hydrated in 10 mM HEPES buffer. pEGFP-N1 and pSV-β-Gal plasmid vectors were used. The formation of archaeosome-DNA complexes were achieved by adding plasmid DNA to archaeosomes at different concentrations and incubating at room temperature for 20 minutes. DNA encapsulated archaeosomes were prepared by the addition of plasmid DNA during hydration process of the lipid film. The archaeosome-DNA complex formation was monitored by agarose gel electrophoresis. The surface charge density of archaeosomes was measured by Zeta-Sizer Nano-ZS. HEK293 cell line was used for transfection experiments. The DNA transfection efficiency was determined by β-Galactosidase assay or examined under fluorescence microscope (Turan&Nagata, PDT,11,503-512,2006).

The agarose gel electrophoresis results of the archaeosome-DNA formulations indicated that archaeosomes and plasmid DNA form insufficient amount of complex. DNA encapsulated samples showed higher ability of DNA binding. The archaeosomes were found to be electronegative by the zeta potential analysis. The pEGFP-N1 transfection studies resulted in higher GFP expression in archaeosome samples when compared to naked DNA. However, the expression level is frequently low when compared to conventional transfec-tion reagents. The results were parallel with samples prepared with pSV-β-Gal plasmid. As a conclusion, the electronegativity of archaeosomes results in low DNA binding capacity and transfection efficiency. Further studies are still necessary to improve the DNA delivery capacity of archaeosomes by introducing electro-positive molecules such as chitosan, DOTAP and polybren.

Keywords: Archaea, Archaeosome, Gene delivery, Transfection

255

PP165SPECTROFLUORIMETRIC DETERMINATION OF GABAPENTIN INPHARMACEUTICAL PREPARATIONS

Elif KEL, Department of Analytical Chemistry, Faculty of Pharmacy, Istanbul University, Istanbul, 34452, TurkeySevgi Tatar ULU, Department of Analytical Chemistry, Faculty of Pharmacy, Istanbul University, Istanbul, 34452, Turkey

Gabapentin (brand name Neurontin) is a GABA analogue. It was originally developed for the treatment of epilepsy, and currently, gabapentin is widely used to relieve pain, especially neuropathic pain [1]. A sensitive and specific spectrofluorimetry method was developed and validated for the quantification of gabapentin in pharmaceutical preparations. The method is based on the fluorescent enhancing reaction of Gabapentin with 7-fluoro-4-nitrobenzofurazan(NBD-F; derivatization reagent), in borate buffer of pH 9.5 to yield a yellow, fluorescent product. Under these experimental conditions, the derivatized product of Gabapentin had excitation and emission wavelength maxima at 458 and 521 nm, respectively.The linear range of this method was 10–100 ng/mL. Intra-day and inter-day RSD and RME values at three different concentra-tions were determined. The results demonstrate that the method has linearity, acceptable precision/accu-racy and robust. The method is highly sensitive and specific. The results obtained are in good agreement with those obtained by the official method.

References

1. Baillie, J Kenneth; Ian Power, Current Opinion in Investigational Drugs, 2000, 7 (1): 33

256

Authors Index

ABDALLAH, FathyABEDINI, Mahmud AÇIK, Leyla AGUŞ, SamiAK, KorayAKAKIN, Dilek AKBIYIK, MeralAKBUĞA, JülideAKGÜN, Hülya AKI, EsinAKICI, Ahmet AKIN, Ahmet AKKIPRIK, MustafaAKKOÇ, Tunç AKKURT, Mehmet AKSOY, HalilAKSU, Elif AKTAY, GöknurAKTEN, DemetALA GÖRMEZ, Arzu ALAGÖZ, Mehmet A. ALARÇİN, EmineALBABTAIN, MuneeraAL-DABBAGH, SabahALICI, Bülent ALINIA, VahidALTAN, Sema ALTINSOY, BerrakALTINTAŞ, AyhanALTURFAN, Ebru IşıkANAK, Sema ANDREI, GracielaAPİKOĞLU RABUŞ, ŞuleARICIOĞLU, FeyzaARIKAN AKAN, Özay ARORA, PayalARSLAN, NaciyeARSLAN, Rana ASLAN, Tuncer AŞIRAN SERDAR, ZehraAYAZ, Serap AYÇA, Banu AYDIN, S. AYDIN, SevilAYDIN, Doğuş AYDIN, SafaAYTAÇ, Peri AYTEMİR, Mutlu D.

A

BBABU, ShevetaBADRI, Shirin SadatBAHADORI, FatemehBARLA, AslıBATTAL, Dilek BECEREN, AyferBEHRAVAN, EffatBEHRAVAN, JavadBEKTAŞ, NurcanBELLUR ATICI, EsenBERKÖZ, MehmetBEYHAN, NagihanBEYOĞLU, DirenBİLGİÇ ALKAYA, Dilek BİNGÖL ÖZAKPINAR, Özlem BİRTEKSÖZ, SeherBİTİŞ, LeylaBİTİŞ, Zehra İlkeBOĞA, MehmetBOLELLİ, KayhanBOUSLAMA, Ali BOZKURT, HaticeBUDEYRİ, Nilay BULUT, GizemBURUNCU, SaitBUTUR, SongülBÜYÜKGÜNGÖR, Orhan

CCAN, AyşeCANBAKAN, MustafaCANTÜRK, ZerrinCESUR, ZaferCESUR, NesrinCEYHAN, ReyhanCHANKVETADZE, BezhanCILOĞLU, FigenCLARK, Philip CLAUSEN, Rasmus PraetoriusCOLBOURN, ElizabethCOLOMBO, Paolo

ÇÇ. YEĞEN, BerrakÇAĞATAY, PenbeÇAĞLAR, SenaÇALIŞKAN, Elif ÇAPAN, YılmazÇAPAN, GültazeÇAYLAK, Tuba

ÇEBİ, YurdanurÇELEBİ KESKİN, AytenÇELEN, Ahmet ÖzgürÇELİK, İsmail ÇETİN, Sude ÇETİNEL, ŞuleÇEVİK, ÖzgeÇEVİK, Ş. GülÇEVİK, ÖzgeÇEVİKBAŞ, AdileÇEVİKBAŞ, UğurÇIKLA, PelinÇIKLA YILMAZ, DenizÇIRACI, EnverÇİFTÇİ, CavlanÇİMEN, BehzatÇOMOĞLU, TanselÇORUH, Işıl ÇULHAOĞLU, Burcu

DDAĞTEKİN, AydanDALKARA, Sevim DASHTI KHAVIDAKI, SiminDAWABA, HamdyDE CLERCQ, Erik DEGHAN, GolamrezaDEGHAN, AliDEĞİM, İ. TuncerDEĞİM, Zeliha GülDEHGHAN NOUDEH, Gholamreza DEMİR, Hale DEMİR EROL, DilekDEMİRBAĞ USTA, ÇağlarDEMİRCAN DEMİR, Hülya DEMİRCİ, Fatih DEMİRÇAY, ZDEMİRTUNÇ, RefikDEMİRYÜREK, GülşahDERİCİ EKER, Ebru DEVEOĞLU, OzanDILER, Z. IremDINÇEL, DemetDİRESKENELİ, HanerDİRMENCİ, TuncayDOĞAN, A. DOĞAN, AhmetDOĞAN, AyşegülDONBAK, LaleDORTUNÇ, BetülDOUKI, WahibaDÖLEN, Emre

DÖNERTAŞ, Başak DRABU, SushmaDÜLGER, Gül

EEGEMEN, GözdeEL AWADY, RafaatEL HADY, DeiaELÇİOĞLU, KübraEMEKLİ, NesrinERÇAĞ, ErolERDEM, SafiyeERDİNÇ, NeşeERDOĞAN, GülbinERDOĞAN, Özlem NazanERDOĞAN, Mehmet Sarper ERDOĞAN, Özlem NazanEREK, AybalaERKMEN, OsmanERKUŞ , Serdar ERMUT, GörkemERSAHİN, MehmetERSÖZ, Melike ERŞAHİN, MehmetERTAN BOLELLİ, Tuğba ERTAŞ, AbdülselamERTÜRK, S. ERYILMAZ, MüjdeEZZ, MarwaEZZAHER, Asma

FFADWA, FadwaFOROUMADI, AlirezaFOROUTANFAR, Hamid

GGAHA, LotfiGANNEMOĞLU, Mustafa GEDİK, GülşahGHARAEEI, Reza GIMZAL GÖNENTÜR, Aylan GÖKÇE, MehtapGÖKER, BaharGÖKHAN, NesrinGÖKHAN KELEKÇİ, NesrinGÖKTAŞ, ÖzgürGÖKTÜRK, Sinem GUCCIONE, SalvatoreGÜMRÜ, SalihGÜMÜŞ, FatmaGÜNAY, Onur

GÜNAY, Onur GÜNDOĞMUŞ, Aydın GÜNEŞ, HasimGÜNEŞDOĞDU, Sibel GÜNEY TUNÇ, Urun GÜRBÜZ, Burçak GÜRGEN, Gizem

HH. MÜLLER, RainerHAKLAR, GoncagülHARTMANN, Rolf W. HATIPOĞLU, Seda DamlaHEINRICH, MichaelHIDIROĞLU, SeyhanHIZEL, Candan

II. KHAN, ShabanaIBRAHIM, Osama MohameedIDLE, JeffreyIRANSHAH, Mehrdad

İİÇİN, HayriyeİLBASMIŞ TAMER, Sibel İNANÇ, NevsunİSBİR, TurgayİŞBİLİR, Şebnem SelenİŞBİR, SelimİŞGÖR, Belgin İŞGÖR, Yasemin İŞYAPAN, Berna İZZETTİN, Fikret VehbiİZZETTİN, Fikret Vehbi

JJAFARIAN, AliJAHANBAKHSH, RezaJALEES, FarhanJAROCH, Ewelina JIRJEES, Feras JassimJOSE, Joachim

KKABASAKAL, LeventKADIOĞLU DUMAN, Mine KADİR, TanjuKAEWNOPPARAT, NatthaKAHNAMOOEI, BehzadKAMBERI, Marika KAMINSKI, Lukas

KANLIKILIÇER, Pınar KANSU, EminKARACA, Hülya KARACA, ZeynepKARADAĞ, Recep KARADERİ, Serap KARAGÖZ, HüseyinKARAGÖZ, Turan KARAKURT, Arzu KARAKUŞ, SevgiKARAKÜÇÜK İYİDOĞAN, AyşegülKARALI, NilgünKARALTI, İskenderKARAMAN, BerinKARAMELEKOĞLU, İremKARAOĞLU, TanerKARATAŞ, BurçinKARMANI, NawelKARSLI CEPPİOĞLU, SeherKAUSHIK BASU, NeerjaKAYA, EmreKAYA, ElifKAYA DAĞISTANLI, FatmaKAYHAN, Figen EsinKAYNAK, FatmaKAZAN, FüsunKESKİN, EbruKHALILI, HosseinKHATRI, SmritiKILIÇ, Ertuğrul KILIÇ, BenunKILIÇGEDİK, Mehtap KIVRAK, BerilKIZILCADAĞ, Başak KOCABALKANLI, AyşeKOÇ, MehmetKOÇYİĞİT KAYMAKÇIOĞLU, Bedia KOKYAN, Şila KOLAK, UfukKOLDEMİR, MelihaKONCAGÜL, Mustafa İsmet KORKMAZ, SevalKOŞAR, Müberra KOTİL, TubaKÖKSAL, MeriçKÖKTÜRK, MustafaKRISHNAN, RamalingamKURT, ÖzlemKURT CÜCÜ, Aysen KUŞMAN, TubaKÜÇÜKGÜZEL, İlkay

KÜÇÜKGÜZEL, Ş. GünizKÜÇÜKYILDIZ, NeclaKÜHNE, Sascha

LLERKIATBUNDIT, Sanguan LEWI, Paul J.

MMABROUK, HajerMACİT, Çağlar MAHADIK, KakasahebMCINNES, Fiona MECHRI, AnouarMECHRI, AnwarMECHRIA, HaythemMERCAN, D. MERCAN, Dilek MERİÇ, Zehra İlkeMICHAUD, VeroniqueMOSHAFI, Mohammad HassanMOUHAMED, Dhoua HajMUSAKOPAS, Chutima

NNAJJAR, Mohamed Fadhel NASIRI TOOSI, ZahraNASIRI TOOSI, Mohsen NEFFATI, FadouaNOPPAPAN, TassaneNOUR EDDINE, Djebli

OOBA, RabiaODABAŞI, Serap OĞUZ, Selin OKTAY, ŞehkarOKUYAN, BetulOMEZZINE, AsmaOMURTAG, Gülden Z.ONAR, Gülnihan ORHAN, İlkay ORUÇ EMRE, Emine ElçinOUAFA, RebaiOZAKPINAR, ÖzlemOZKIRIMLI ÖLMEZ, Elif

ÖÖLGEN, SüreyyaÖNAL, ArmağanÖNYÜKSEL, HayatÖZAKPINAR, Özlem

ÖZBAŞ TURAN, SunaÖZBAŞ TURAN, SunaÖZBAY, LatifÖZBAY, Latif ÖZÇELİK, A. BernaÖZÇELİK, Berrin ÖZDEMİR, FilizÖZDEMİR, Zarife NigarÖZEL, N.ÖZER, A. YektaÖZER, AyşeÖZER ÜNAL, DurişehvarÖZGÜL, LeventÖZGÜNGÖR, AdeviyeÖZKAN, Tuğba ÖZKAN, İremÖZKAN, Yağmur ÖZKIRIMLI, SumruÖZLEN ŞAHİN, NefiseÖZSAVCI, Derya ÖZSOY, NurtenÖZTÜRK, Melek ÖZTÜRK, YusufÖZTÜRK, MehmetÖZTÜRK, BüşraÖZYALÇIN, Çağatay

PPANNECOUQUE, ChristophePARADKAR, AnantPEKİN, MürşitPEPPAS, Nicolas A. PRATICO, Domenico

RRATANAJAMIT, ChaveewanRAYAMAN, ErkanRAYAMAN, PervinREANMONGKOL, WantanaREDWEIK, SabineREITER, Russel J. REZAEE, RaminRIZANOV, A. A.ROLLAS, Sevim

SSAADAOUI, Mohamed HachemSADRAI, SimaSAENGCHAROEN, Woranuch SAĞ ERDEM, SafiyeSAĞIOĞLU, AytenSAHLEPCİ, Taflan

SALEH, EkramSALEHIFAR, Ebrahim SALGIN GÖKŞEN, Umut SALIMA, DouicheneSALMAN, AydinSALVA, EmineSAMY, AhmadSANCAR, MesutSANCAR, MesutSANYAL, Rana SARAYOĞLU, ElifSARIYAR AKBULUT, Berna SATILMIŞ, GökhanSCHRÖDER, Simone SEDIQI, Behnaz SENER, GokselSENKESEN, ÖznurSERADJI, Mehrad SESAL, CenkSET, İremSEZER, Ali DemirSHARIFIFAR, FaribaSHARIFIYAN, KhadijeSICAK, YusufSİLİNDİR, Mine SİPAHİGİL, OyaSNOECK, RobertSOHREVARDI, Seyed MojtabaSOLTANI, FatemehSOYDEĞER CARLI, BaşakSOYDEĞER CARLI, BaşakSOYKAN, Aytekin SOYOĞUL GÜRER, ÜmranSOYTOPRAK, SonerSÖYLETİR, G.SUBHADHIRASAKUL, Sanan SURATMAN, AdhitasariSÜSLEYİCİ DUMAN, Belgin

ŞŞAHBAZ, SevinçŞAHİN, FikrettinŞAHİN, M. FethiŞAHİN, Nefise ÖzlenŞAHİN, ÖzgeŞAHİN, YücelŞAHİN, AliŞARDAŞ, SemraŞEHİRLİ, ÖzerŞeker KARATOPRAK, Gökçe ŞEN, AliŞENCAN, Nazlı

ŞENER, AzizeŞENER, GökselŞİMŞEK, ÇiğdemŞİRİNOĞLU, Yasemin

TTABANCA, NurhayatTAHMAZ, YeşimTALMAN, R. YeşimTANSUYU, MerveTAŞ, Pınar TAŞAR, NurTAŞDEMİR, DemetTAŞKIN, MustafaTAŞKIN, TurgutTATAR, Esra TATAR ULU, Sevgi TETİK, Şermin TETİKKURT, SezaTEYEB, HassenTHONGRAUNG, Wilawan TOLAN, KeremTOPÇU, GülaçtıTORGAN, EmineTOZKOPARAN, BirsenTUNALI, YağmurTUNÇ, Ürün GüneyTURAN, Nefize TURGEON, JacquesTURKKAN, SeyhanTUYGUN, Abdullah KemalTUZLACI, ErtanTÜRE, ZehraTÜRKER SAÇAN, Melek TÜRKOĞLU, MuratTÜRKÖZ ACAR, Ebru

UUÇAR, GülberkULUSOY GÜZELDEMİRCİ, NurayUNAL, Durişehvar Özer UR, FüsunURAS, FikriyeURAS, Ahmet RizaUSTA, IUTKU, Semra UYANIK, Mehmet ZahidUYAR, MehmetUYGUN CAN, Banu

ÜÜLGEN, Mert

ÜLGER, NÜLKÜR, Esin ÜNER, MelikeÜNLÜ, BurcuÜNÜVAR, Songül

VVANIZOR KURAL, Birgül VAR, ÜmranVASIKNANONTE, Sorayut

WWATZIG, HermannWEDGE, David E.

XXU, Yuanhong

YYABANOĞLU, SamiyeYALÇIN, İsmail YALÇIN, GülerYALÇIN, A. SühaYALIN, SerapYALVAÇ, M. E. YALVAÇ, Mehmet EmirYANIKKAYA DEMİREL, GülderenYAPAR, Gönül YARAT, AysenYARAT, AysenYARDIMCI, TurayYARIM, Mine YARIŞ, ErsinYAVUZ, Mustafa YAZAN, Yasemin YEGEN, CumhurYEĞEN, Berrak Ç.YELEKÇİ, Kemal YENER, GülgünYEŞİL, TuğçeYEŞİLADA, ErdemYETİM, Aslihan YIĞINER, ÖmerYILDIZ, İlkayYILMAZ, SerapYILMAZ, Erdem YILMAZ, ŞükranYILMAZ, A. MineYILMAZ, AylinYILMAZ, AysuYILMAZ AYDOĞAN, Hülya YÖN, Nazan Deniz

YUGAÇ, HalilYURDAKUL, DilşatYURDUN, TürkanYURT, KübraYUVALI ÇELİK, GökçenYÜCEL, ÇiğdemYÜKSEL, Altan

ZZ. TOKLU, Hale ZAGHLOUL, AbdelazimZENGİN , KağanZEYTİN, Esra ZİNDANCI, İlkin