12th Congres SRFTTC

Congress PresidentProf. Dr. Victor Voicu University of Medicine and Pharmacy Bucharest, Fellow of the Romanian Academy

Congress Honorary Presidents:Prof. Dr. Folke Sjoqvist, Prof. Dr. Florian Popa Professor Emeritus of Clinical Pharmacology, Karolinska Institute in Stockholm, Sweden Rector of University of Medicine and Pharmacy, Carol Davila, Bucharest Romania

Congress Honorary Vice-Presidents and International Scientific CommiteeProf. Dr. Jiri Bajgar, Czech Republic Prof. Dr. Kim Brsen, Denmark Prof. Dr. Svein Dahl, Norway Prof. Dr. Hege Christensen, Norway Prof. Dr. Jaime Kapitulnik, Israel Prof. Dr. Franz Kerek, Germany Prof. Dr. Edward Krenzelok, USA Prof. Dr. Momir Mikov, Serbia Prof. Dr. Jose de Leon, USA Prof. Dr. Olavi Pelkonen, Finland Dr. Christos Potsides, Greece Dr. Stanislav Yanev, Bulgaria Prof. Dr. Horst Thiermann, Germany

Organizing CommitteeProf. Dr. Victor A. Voicu PresidentDr. Vlad Negulescu Dr. Flavian Rdulescu Dr. Ec. Luminia Horhot

Scientific CommitteeProf. Victor Voicu PresidentProf. Dr. Anca Buzoianu Dr. Gabriela Cioca Prof. Dr. Rodica Cinc Assoc. Prof. Dr. Dana Goa Prof. Dr. Ioan Lascr Prof. Dr. Sorin Leucua Prof. Dr. Florica Popescu Dr. Flavian Rdulescu Prof. Dr. Liviu Safta

Prof. Dr. Valentin Crlig

Prof. Dr. Oana Andreia Coman Prof. Dr. Iosefina C. Corciovei Prof. Dr. Carmen Cristescu Prof. Dr. Barbu Cuparencu Prof. Dr. Maria T. Dogaru Prof. Dr. Ioan Fulga Prof. Dr. Aurelia Nicoleta Cristea

Prof. Dr. Ctlina Lupuoru Prof. Dr. Radu Macovei Assoc. Prof. Dr. Ioan Magyar

Prof. Dr. Ionel Sinescu

Prof. Dr. Adrian Streinu-Cercel Prof. Dr. Vlaicu andor Assoc. Prof. Dr. Bogdan erb Assoc. Prof. Dr. Andrei Tica Prof. Dr. Coriolan Ulmeanu Prof. Dr. Gheorghe arlung Assoc. Prof. Dr. Daniel Vasile

Prof. Dr. Andrei Medvedovici Dr. Dalia Miron

Prof. Dr. Constantin Mircioiu Assoc. Prof. Dr. Cristina Mogoan Prof. Dr. Ostin Mungiu Prof. Dr. Mihai Nechifor

Prof. Dr. Victor Dumitracu Prof. Dr. Virginia Gligor

Prof. Dr. Mircea Pavelescu

Assoc. Prof. Dr. Aurelian Zugravu

Journal published in cooperation with:

National Institute of Infectious Diseases "Prof. Dr. Matei Bal"

Romanian Society of Pharmacology, Therapeutics and Clinical Toxicology Romanian Academy of Medical Sciences University of Medicine and Pharmacy "Carol Davila"

Academic Medical DatabaseCNCSIS Category: B+ Code: 605 NLM (National Medical Library) EBSCOhost IndexCopernicus getCITED

Vol. XV

Supplement II

June 2011

Founders Emanoil Manolescu

Mircea Angelescu

Liviu Ioan Miclea

Editor-in-Chief Therapeutics Adrian Streinu-Cercel (Professor, Member of Academy of Medical Science, Head of Department of Infectious Diseases, National Institute ofInfectious Diseases "Prof. Dr. Matei Bal", University of Medicine and Pharmacy Carol Davila Bucharest)

Editor-in-Chief Clinical Pharmacology and Toxicology Victor A. Voicu (Professor, Member of Romanian Academy, Head of Department of Pharmacology, Toxicology and Clinical Psychopharmacology,University of Medicine and Pharmacy Carol Davila Bucharest)

International Scientific BoardLaure Aurelian (Professor, Senior Associate, The Johns Hopkins School of Public Health), d Hege Christensen (Professor, School of Pharmacy, University of Oslo, Norway), d Jaime Kapitulnik (Professor, The Hebrew University of Jerusalem, Israel), d Momir Mikov (Senior Lecturer, School of Pharmacy, University of Otago, New Zealand), d Stanislav Yanev (Professor, Head of Department Drug and Toxicology, Bulgarian Academy of Science, Bulgaria), d Olavi Pelkonen (Professor, Head of the Department of Pharmacology and Toxicology, University of Oulu, Finland), d Olivier Patey (Professor, Chef de service des maladies infectieuses et tropicales CHI, Villeneuve-Saint Georges, France), d George C. Rodgers (Professor of Pediatrics, Pharmacology and Toxicology, University of Louisville, Kentucky, USA), d Robert Smith (Professor, Brown Medical School, U.K), d Jean Paul Stahl (Professor, Rdacteur en chef de Mdecine et Maladies Infectieuses, Elsevier Maison, Grenoble, France), d Michel Urbain (Chief of Research Department, Societe de Etude et de Research Biologique, Paris, France), d Andrei Iagru (Department of Nuclear Medicine, Stanford University, USA) d Serafim Kastanakis (Professor, University of Crete, Greece)

Romanian Scientific Board Ioana Alina Anca (Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Eduard Apetrei (Professor, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Romanian Academy of Medical Science), d tefan Sorin Aram (Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Constantin Arion (Professor, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Romanian Academy of Medical Science), d Anca Buzoianu (Professor, University of Medicine and Pharmacy Iuliu Haieganu Cluj-Napoca) d Eugen Ciofu (Professor, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Academy of Medical Science), d Carmen Dorob (Professor, University of Medicine and Pharmacy Gr.T. Popa, Iassy), d Constantin Dumitrache (Professor, Member of Romanian Academy, University of Medicine and Pharmacy Carol Davila Bucharest), d Leonida Gherasim (Professor, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Romanian Academy of Medical Science), d Ioan Hulic (Professor, Member of Romanian Academy, University of Medicine and Pharmacy Gr.T. Popa, Iassy), d Daniela Ion (Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Ion Fulga (Professor, Head of Department of Pharmacotherapy and Pharmacology, University of Medicine and Pharmacy Carol Davila Bucharest), d Sorin Leucua (Professor, University of Medicine and Pharmacy Oradea), d Radu Macovei (Professor, Head of Department of ICU-Toxicology, University of Medicine and Pharmacy Carol Davila Bucharest), d Alina Manolescu (researcher, ICSMCF), d Nicolae Miu (Professor, University of Medicine and Pharmacy Iuliu Haieganu Cluj-Napoca), d Ostin C. Mungiu (Professor, Head of Department of Pharmacology and Clinical Toxicology, University of Medicine and Pharmacy Gr.T. Popa, Iassy), d Lucian Negruiu (Professor, University of Medicine and Pharmacy Victor Babe Timioara), d Dumitru Oreanu (Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Florian Popa (Professor, Chancellor of University of Medicine and Pharmacy Carol Davila Bucharest), d Irinel Popescu (Professor, Head

of Department of Surgery and Liver Transplant, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Academy of Medical Science), d Laureniu Mircea Popescu (Professor, Member of Romanian Academy, Head of Department of Celular Biology, University of Medicine and Pharmacy Carol Davila Bucharest), d Valeriu Popescu (Professor, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Romanian Academy of Science), d Florica Stniceanu (Professor, Univeristy of Medicine and Pharmacy Carol Davila Bucharest), d Dan Tulbure (Professor, Head of Department of ICU, University of Medicine and Pharmacy Carol Davila Bucharest), d Doina ulescu (Professor, University of Medicine and Pharmacy Iuliu Haieganu Cluj-Napoca), d Coriolan Ulmeanu (Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Doina Velican (Researcher, Member of Romanian Academy of Medical Science), d Florin Cruntu (Associate Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Adrian Gabriel Popescu (Associate Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Paraschiva Postolache (Associate Professor, University of Medicine and Pharmacy Gr.T. Popa, Iassy), d Alexandru Rafila (Associate Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Adriana Hristea (Lecture, University of Medicine and Pharmacy Carol Davila Bucharest), d Gabriela Leanu (Lecture, University of Medicine and Pharmacy Carol Davila Bucharest) d Ion Lic (Lecture, University of Medicine and Pharmacy Carol Davila Bucharest), d Raluca Papacocea (Lecture, University of Medicine and Pharmacy Carol Davila Bucharest), d George Jugulete (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Voichia Lzureanu (Assistant Professor, University of Medicine and Pharmacy Victor Babe Timioara), d Anca Macovei (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Anca Streinu-Cercel (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest), d Andrei Tica (Associate Professor, University of Medicine and Pharmacy Craiova) d Mihail Tudosie (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest)

General Registrar of Editorial BoardPharmacy Carol Davila Bucharest)

Editorial Office

Victoria Aram (Associate Professor, University of Medicine and Issue Editor Elisabeta Otilia Benea (Associate Professor, University of Medicineand Pharmacy Carol Davila Bucharest) Monica Luminos (Associate Professor, University of Medicine and Pharmacy Carol Davila Bucharest)

Institutul Naional de Boli Infecioase Prof. Dr. Matei Bal, Pavilionul IV, Etaj 4 Dr. Calistrat Grozovici, Nr. 1, Sect. 2, Bucureti, C.P. 021105, O.P. 10 Email: [email protected] [email protected] Published by Editura Rp.

Cristina Negulescu Oana Streinu-Cercel Ana-Maria Tudor Publishing Editor

CUI RO9954898, RC J40/7184/1997

Address: Str. Drumul Murgului nr. 2 sector 3, Bucureti, Tel/Fax: 031.80..40.513 E-mail: [email protected] Web: www.terapeutica.ro ISSN 2066-0170

Vlad Negulescu (Assistant Professor, University of Medicine andPharmacy Carol Davila Bucharest)

12-th International Congress of the Romanian Society of Clinical Pharmacology, Therapeutics and Toxicology 7-11 June 2011, Bucharest, Romania Copyright reserved 2011

CONGRESS PROGRAMME

7-th June 2011 Crowne Plaza Hotel19.00 Welcome Concert, Crowne Plaza Hotel, Ballroom Piano Recital by Horia Mihail, concert soloist of the Romanian Radio Symphonic Orchestras Welcome Cocktail, Crowne Plaza Hotel, Ballroom

20.00

8-th June 2011 Crowne Plaza Hotel - Conference Room A8.30 9.00 Opening Ceremony Prof. Dr. Victor A. Voicu, Prof. Dr. Edward P. Krenzelok, Prof. Dr. Hege Christensen, Prof. Olavi Pelkonen, Prof. Dr. Jaime Kapitulnik, Prof. Dr. Svein G. Dahl, Prof. Dr. Horst Thiermann, Prof. Dr. Jose de Leon, Prof. Dr. Franz Kerek, Prof. Dr. Momir Mikov, Prof. Dr. Stanislav Yanev, Prof. Dr. Christos Potsides, Prof. Dr. Mircioiu Constantin, Prof. Dr. Andrei Medvedovici

9.00-10.30

Conference Room A Chairs: Prof. Jaime Kapitulnik, Prof. Svein G. Dahl, Prof. Hege Christensen Toxokinetics as a key to the integrated toxicity risk assessment based primarily on nonanimal approaches Olavi Pelkonen A profile of acetaminophen (paracetamol) toxicity in the United State Edward P. Krenzelok Synergic effect of hyperglycemia and bilirubin on apoptosis of microvascular endothelial cells of the blood-brain barrier Clara Benaim, Shlomo Sasson, Jaime Kapitulnik Discussions Coffee break

Session I - Invited Speakers Lectures

9.00-9.30 9.30 - 10.00 10.00 - 10.30 10.30 - 10.45 10.45-11.00

XV, Vol.15, Supplement II/2011

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12-th International Congress of Romanian Society of Clinical Pharmacology, Therapeutics and Toxicology

11.00-13.00

Conference Room A Chairs: Prof. Olavi Pelkonen, Prof. Jose de Leon, Prof. Constantin Mircioiu The future (or lack of future) of personalized prescription in psychiatry. Jose de Leon Molecular structure and ligand binding of monoamine trasporter proteins Svein G. Dahl Mechanisms involved in the pharmacokinetic interaction between atorvastatin and cyclosporine A Hege Christensen, Rune Amundsen, Anders Asberg Discussions Lunch

Session II - Invited Speakers Lectures

11.00-11.30 11.30-12.00 12.00-12.30 12.30- 12.45 13.00-14.00

14.00-15.30

Conference Room A Chairs: Prof. Edward P. Krenzelok, Prof. Stanislav Yanev, Prof. Andrei Medvedovici Prediction of the biological fate of oximes Victor A. Voicu, Flavian Rdulescu Why do patients die from intentional OP-insecticide poisoning in spite of proper use of antidotes? Horst Thiermann, Thomas Zilker, Florian Eyer, Franz Worek Host-guest inclusion of some cation type aldoximes on macrocyclic cavities: ESI/MS approach for fast screening Victor A. Voicu, Andrei Medvedovici, Florin Albu Disscusions Coffee break

Session III - Invited Speakers Lectures

14.00 14.30 14.30 15.00 15.00 15.30 15.30 - 15.45 15.30-15.45

15.45-19.00

Conference Room A Chairs: Prof. Franz Kerek, Prof. Horst Thiermann, Prof. Momir Mikov Drug absorbtion from the gastrointestinal tract and the influence of probiotics Momir Mikov, Hani Al-Salmi, Svetlana Goloorbin-Kon Counterfeit drugs: cure or threat Svetlana Goloorbin-Kon Immune system and drug metabolism interactions Stanislav Yanev Targeting the innate imune receptors, as promising approach for drug-discovering Franz Kerek, Victor A. Voicu Newer developments in enviromental risk assessment according to EU legislation Christos Y. Potsides Research concerning inclusion of DTPA Zn in microemulsions for improving its bioavailability and efficacy as decontaminant in managing radiological terrorist incidents Constantin Mircioiu, Victor A. Voicu, Marilena Jiquidi, Otilia Cintez, Eugen Reviu, Manuela Spiroiu, Flavian Rdulescu In vitro drug release methodologies for topical semisolid dosage forms Flavian Radulescu, Dalia Miron, Victor Voicu, Constantin Mircioiu DisscusionsTherapeutics, Pharmacology and Clinical Toxicology

Session IV - Invited Speakers Lectures

15.45 16.00 16.00 - 16.15 16.15 16.45 16.45 17.15 17.15 - 17.45 17.45 - 18.15

18.15 - 18.30 18.30 - 19.006

12-th International Congress of the Romanian Society of Clinical Pharmacology, Therapeutics and Toxicology

9-th June 2011 Crowne Plaza Hotel, Conference Rooms A Session V - Experimental Pharmacology

9.00-11.00

Conference Room A Chairs: Prof. Mihai Nechifor, Prof. Oana Andreia Coman

9.00 - 9.15

9.15 -9.30 9.30 - 9.45 9.45 - 10.00 10.00 - 10.15 10.15 - 10.30 10.30 - 10.45 10.45 - 11.00 11.00-11.15

Research about the plasma and saliva concentrations of bivalent cations in patients with oral malignant tumors Mihai Nechifor, Elena Luca, Irina Gradinaru, Eugenia Popescu, Mihaela Baican, Diana Ciubotariu, Florina Crivoi, Cristina Gales Influence of ceftazidime and moxifloxacin on sperm motility Elena Antohi, Cristina Gales, Mihai Nechifor Manganese influence on morphine physical dependence and brain reward system in rats Diana Ciubotariu, Ileana Palamaru, Mihai Nechifor Possible cannabinomimetic effects for high doses of metamizole sodium in mice H. Punescu, Eugenia Panaitescu, Isabel Ghi, Oana Andreia Coman, I. Fulga Possible potentiation between high doses of acetaminophen and FAAH inhibitors in central analgesia Oana Andreia Coman, H. Punescu, Isabel Ghi, I. Fulga The antioxidant N-acetylcysteine effect in physical effort to Race Horses Nicoleta Taus, Monica Potrovita, Valentin Necula, Antonela Diana Hirceaga Screening of oxime efficacy in the neurotoxic organophosporous compounds poisoning Cristina Sarbulescu Secara, B. Patrinichi, Rodica Alexandrescu, C Draghici, V.. A. Voicu Disscusions Coffee break

11.15-13.00

Conference Room A Chairs: Prof. Ctlina Elena Lupuoru, Prof. Vlaicu andor Paracetamol analgesia. cannabinoid connection andor Vl Amphetamine- myorelaxant agents interactions in an experimental model Cuparencu B, Albu Silvia, Safta L, andor Vl. Calcitonin in ulcer treatment andor Vl Cimetidine in experimental CCL4-induced hepatitis andor Vl The effects of novel copolymeric matrices for indomethacin in experimental somatic nociception Liliana Taru, Andra Sabina Valeanu, Loredana Ni, Aurica Chiriac Biocompatibility evaluation and investigation of magnesium soft mater vesicles effects on the cognitive processes in rats Liliana Tartau, Catalina Elena Lupusoru, Diana Ciubotariu, Viorel Melnig Features, mechanisms and morphometric correlation of endothelium-dependent relaxation, as revealed by time-course analysis and the use of different precontraction agents Hogas MM, Serban IL, Oprisa C, Tucaliuc ES, Hurjui L, Nechifor M, Serban DN Lunch7

Session VI - Experimental Pharmacology

11.15 - 11.30 11.30 - 11.45 11.45 - 12.00 12.00 - 12.15 12.15 - 12.30 12.30 - 12.45 12.45 - 13.00

13.00-14.00XV, Vol.15, Supplement II/2011

7-11 June 2011, Bucharest, Romania

9.00-10.15

Conference Room B Chairs: Prof. Coriolan Ulmeanu, Prof. Florin Popescu Acute liver failure in acute poisoning in children Coriolan Ulmeanu, Gabriela Viorela Niescu, Elena Mdlina Petran Crystalluria - The prevalence in pediatric poisoning Gabriela Viorela Niescu, Alexandru Ulmeanu, Coriolan Ulmeanu Toxic and hypersensitivity reactions to contact with Cnidarians Florin-Dan Popescu, Vieru Mariana, Adriana Mihaela Tudose, Florica Popescu Antidote versus non-specific treatment of acute poisoning in children Ioan Magyar, Alina Maghiar, Adriana Moldovan, Carmen Pantis, Mohamed Bouyakhrichan Lead poisoning caused by boilers used to plum brandy distillation Mitrut Anca Oana, Gofita Eliza, Mitrut Paul, Calina Daniela Disscusions Coffee break

Session VII - Clinical Toxicology

9.00 - 9.15 9.15 - 9.30 9.45 - 10.00 10.00 - 10.15 10.15 - 10.30 10.15 - 10.30 10.30-10.45

10.45-13.00

Session VIII - Pharmacogenetics and Clinical PharmacologyConference Room B Chairs: Prof. Anca Dana Buzoianu, Prof. Florica Popescu

10.45 - 11.00

11.00 - 11.15 11.15 - 11.30 11.30 - 11.45 11.45 - 12.00 12.00 - 12.15 12.15 - 12.30 12.30 - 12.45 12.45 - 13.00 13.00-14.00

Genotype-phenotype correlations between the alleles of the CYP2C19 polymorphism and pharmacokinetic parameters in romanian epileptic patients Buzoianu Anca Dana, Bocan Ioana Corina, Maier Codruta, Trifa AP, Militaru Claudia, Major Z What are the essential Pharmacological knowledge, skills and attitudes for medical students ? Buzoianu Anca Dana Pharmacogenetics of the side effects concerning atypical antipsychotic medication Popescu Florica, Mitrulescu Bianca, Popescu F.D, Nicoli Elena Raluca, Ionete Oana Mariana The influence of pharmacogenetics studies on individualized cancer chemotherapy Elena-Raluca Nicoli, Florica Popescu, Alina Cimpoeru, Gabriela Avram, Mihai Ioana CETP Inhibitors: a new therapy in atherosclerotic cardiovascular disease Lavinia Codrua Gligor, Rzvan Gligor, erban Gligor, Virginia Gligor Study of the sensitivity to antibiotics of Staphylococcus aureus strains isolated from genital infections Mitrut Anca, Calina Daniela, Gofita Eliza, Rosu Lucica, Mitrut Paul The management of acute bacterial pneumonia in elderly patients Mitrut Anca Oana, Calina Daniela Mitrut Paul, Gofita Eliza Research on Ceftazidime - induced neurotoxicity in in-patients with renal diseases Buleandra Carmen, Georgescu Costinela, Nechifor Mihai Disscusions Lunch

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Therapeutics, Pharmacology and Clinical Toxicology

12-th International Congress of the Romanian Society of Clinical Pharmacology, Therapeutics and Toxicology

14.00-16.00

Session IX- Clinical Pharmacology and TherapeuticsConference Room A Chairs: Assoc. Prof. Daniel Vasile, Prof. Radu Spineanu

14.00 - 14.15 14.15 - 14.30 14.30 - 14.45 14.45 - 15.00

15.00 - 15.15

15.15 - 15.30

15.30 - 15.45 15.45 - 16.00 15.15 - 15.30

Spider bites causing cutaneous adverse reactions Mariana Vieru, Florin-Dan Popescu, Florica Popescu Pharmacotoxicological aspects related to Latrodectism Florica Popescu, Florin-Dan Popescu, Mariana Vieru Confirming Gilbert Syndrome by Rifampin Test Spineanu Radu, Cheregi Simona, Heredea Liliana, Szilgyi Ariana, Szilgyi Gheorghe Role of extracellular contrast agents in hepatocarcinoma evaluation Cristiana Iulia Dumitrescu, Daniela Dumitrescu, Anca Berbecaru Iovan, Maria Bogdan, Mihaela Burlacu, Alexandru Ciobanu, Popescu Florica The role of contrast agents in computed tomography to detect and characterize focal liver disease Cristiana Iulia Dumitrescu, Daniela Dumitrescu, Sergiu Cazacu, Anca Berbecaru Iovan, Maria Bogdan, Mihaela Burlacu, Cornel Tambura, Popescu Florica 25 years of fluoxetine: how far are we from an optimal treatment for depression? Nicolae Florin Taina, Daniel Vasile, Octavian Vasiliu, Andrei Gabriel Mangalagiu, Beatrice Stanescu Nightmare pharmacologic treatment in posttraumatic stress disorder- a systematic literature review Nicolae Florin Taina, Daniel Vasile, Octavian Vasiliu, Andrei Gabriel Mangalagiu Disscusions Coffee break


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BIOGRAPHY

OLAVI PELKONEN

Olavi Pelkonen has MD (1973) and PhD degrees (1973). He was a post-doctoral fellow at the National Institutes of Health, Bethesda, Maryland (1976-1977) and 1978-2010 been Associate and Full Professor of Pharmacology as well as Head of the Department in Oulu, Finland. He has been as a visiting professor in Spain, UK and Australia. He has been participating, also as a working group leader, in European Union COST Actions (since 1986, the latest Action B25 Physiologically based Pharmacokinetic and Pharmacodynamic Modelling in 2005-2009) and in Framework Programme consortia (since 1991, also as a coordinator of the project EUROCYP Integration of in vitro approaches to study drug metabolism and drug interaction in drug development in human). He has >300 original and review articles in international scientific journals, mainly on various aspects of drug and carcinogen metabolism, especially by cytochrome P450 enzymes, and its regulation by genetic and environmental factors and he is a HighlyCited Researcher in pharmacology and toxicology (ISI-Thomson). His current interests include the development of in vitro and in silico methods for drug development and chemical risk assessment. In this respect, he has been participating in multi-year Pharma projects in Finland, with the support from The Academy of Finland, Finnish Technology Research Centre and Drug Industry. He has expert roles at ECVAM and EMA (a co-opted member in toxicology), among others, and advisory roles in Finnish drug development service entities. In 2003, he gave The Oswald Schmiedeberg Lecture at the University of Tartu. In 2007, he was awarded The Bo Holmstedt Memorial Lecture Award by EUROTOX and he was a plenary lecturer in IUPHAR WorldPharma2010 Congress in Copenhagen in 2010.

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INVITED SPEAKERS LECTURES

TOXICOKINETICS AS A KEY TO THE INTEGRATED TOXICITY RISK ASSESSMENT BASED PRIMARILY ON NON-ANIMAL APPROACHESOlavi Pelkonen University of Oulu Department of Pharmacology and Toxicology, Finland

Abstract. Toxicity risk assessment is moving away from descriptive animal toxicity studies towards mechanistic in vitro screening systems and their integration with various types of computational approaches, including modelling and simulation. The use of omics techniques and high-throughput screening are some of the emerging tools to ensure predictive toxicity risk assessment. Toxicokinetics (TK) is the endpoint that informs about the penetration into and fate within the body of a toxic substance, including the possible emergence of metabolites, and their absorption, distribution, metabolism and excretion (ADME). Currently, when there is an increasing reliance on non-animal testing approaches, toxicokinetics has been identified as a key element to integrate the results fron in silico, in vitro and in vivo studies. There are several crucial contributions from TK knowledge in integrated risk assessment. TK is needed to estimate the range of target organ doses that can be expected from realistic external exposure scenarios. This information is crucial for determining the dose range that should be used for in vitro testing. TK is necessary to convert the in vitro results, generated at tissue/cell or sub-cellular level, into dose response or potency information relating to the entire target organism, i.e. the human body. For the optimal use of TK knowledge it is imperative that in all in vitro toxicity testing systems the behaviour of the compound under study is investigated, to produce data on disposition (biotransformation and transport) and concentration-response relationships. In silico approaches such as QSARs, read across etc, allow further quantitation of specific processes needed for the prediction of TK in vivo. Physiologically based toxicokinetic modelling (PBTK) is currently regarded as the most adequate approach to simulate the fate of compounds in the human body and can be used to estimate the relevant exposure at organism level from measured in vitro concentrations, and vice versa. However, validation is currently a bottleneck and novel approaches are needed to ensure that mechanistic and integrative risk assessment could be employed to a full extent.


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BIOGRAPHY

EDWARD P. KRENZELOK

Dr. Krenzelok is Director of the Pittsburgh Poison Center and the Drug Information Center at the University of Pittsburgh Medical Center, a Professor of Pharmacy and Pediatrics at the University of Pittsburgh and the Dr. Gordon J Vanscoy Endowed Chair in Pharmacy. He received his Bachelor of Science degree in Pharmacy from the University of Wisconsin in 1971 and his Doctor of Pharmacy degree from the University of Minnesota in 1974. Dr. Krenzelok is active in numerous professional toxicology and medically related societies and associations and is a Past-President of the American Academy of Clinical Toxicology. He is board-certified in clinical toxicology by the American Board of Applied Toxicology and has been awarded the distinction of being a Fellow in the American Academy of Clinical Toxicology. In 2009 Dr. Krenzelok received the American Academy of Clinical Toxicology Career Achievement Award. Dr. Krenzelok is former member of the Board of Directors of the American Association of Poison Control Centers. He is a former Chair of the United States Pharmacopeia Clinical Toxicology and Substance Abuse Committee, a former member of the Food and Drug Administration Nonprescription Drug Advisory Committee, a consultant to the FDA Drug Safety and Risk Management Advisory Committee, on the editorial boards and review panels of numerous medical and toxicology journals and is the author of several hundred scientific publications and book chapters and the editor of three books.

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A PROFILE OF ACETAMINOPHEN (PARACETAMOL) TOXICITY IN THE UNITED STATESEdward P Krenzelok Pittsburgh Poison Center and Drug Information Center, University of Pittsburgh Medical Center

Abstract. Over 25 billion doses of acetaminophen (paracetamol) and in excess of 200 million prescriptions for acetaminophen-opioid combination products are sold in the United States every year. As a consequence of its ubiquitous presence, acetaminophen toxicity is a common problem. While acetaminophen is a safe pharmaceutical when used properly, the ingestion of an excessive amount results in the depletion of glutathione and the potential development of hepatotoxicity. Furthermore, the abuse of combination products that contain acetaminophen and an opioid (e.g., oxycodone, hydrocodone) is rampant and a leading cause of accidental death in adults. Acute ingestions account for 85% of all acetaminophen exposures. However, nearly 21% of the acetaminophen-opioid combination exposures have a supratherapeutic chronic component which creates treatment decision challenges. With regard to gender, females are implicated in approximately 59% of the ingestions. In children less than six years of age, 74% of the exposures involve acetaminophen alone compared to less than 10% of the exposures in adults over 20 years of age where the ingestion of acetaminophen-opioid combination products predominates. Ninety-three percent of the fatalities occur in adults over 20 years of age and only 0.8% in children less than six years of age. Since acetaminophen overdosage is responsible for such a high percentage of acute liver failure cases in the United States, the U.S. Food and Drug Administration has proposed a number of strategies to reduce the incidence of acetaminophen-related hepatotoxicity. The first enacted strategy is to establish a maximum acetaminophen dose of 325 mg in all acetaminophen-opioid combination products. Several recommendations have been proposed for consideration.


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BIOGRAPHY

JAIME KAPITULNIK

Born in Buenos Aires, Argentina. After completing his high school studies, and following one year of studies at the Faculty of Medicine of the Universidad of Buenos Aires, he immigrated to Israel in 1963. He studied at the Hebrew University of Jerusalem (Faculty of Science), and received his PhD in Biochemistry (Faculty of Medicine) in 1974. After a two-year post-doctoral period in the USA (at Hoffmann-LaRoche, Nutley, New Jersey), he returned to the Hebrew University of Jerusalem and joined the Department of Pharmacology of the Faculty of Medicine and the Division of Pharmacology of the Faculty of Dental Medicine. He chaired the Department of Pharmacology (1994-2000), was Director of the Adolf and Clara Brettler Research Center in Molecular Pharmacology and Therapeutics of the School of Pharmacy (2000-2007), Vice-Dean for Special Projects at the Faculty of Medicine (2002-2006), and Provost of the Rothberg International School of the Hebrew University of Jerusalem (2004-2007). Since 1994 he is a member of the Executive Committee of the Drug Metabolism Section of IUPHAR (1998-2002: Secretary; 2002-2006: Vice-President; 2006-2010: President). He was also a member of the Management Committees of COST B15 and B25 Actions of the European Union (representing Israel). He was a Visiting Scientist at the Laboratory of Molecular Carcinogenesis (National Cancer Institute, NIH, Bethesda, Maryland), the Department of Pharmacology of the Biocentrum (University of Basel), and the Department of Molecular and Cell Biology of the Karolinska Institute (Stockholm). He teaches undergraduate courses of Pharmacology for students of Medicine, Dental Medicine and Veterinary Medicine, and delivers an advanced graduate course in Drug Metabolism for MSc and PhD students. Since 2010 he is the Specialty Chief Editor of Frontiers in Drug Metabolism and Transport. Research activities: effects of oxidative stress on the regulation of cytochrome P450 gene expression; the cytoprotective role of bilirubin as an endogenous antioxidant and its capacity to activate the Aryl hydrocarbon receptor in the absence of UDP-glucuronosyl transferase; effects of bilirubin on glucose transport in the blood-brain barrier.

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SYNERGISTIC EFFECT OF HYPERGLYCEMIA AND BILIRUBIN ON APOPTOSIS OF MICROVASCULAR ENDOTHELIAL CELLS OF THE BLOOD-BRAIN BARRIERClara Benaim, Shlomo Sasson and Jaime Kapitulnik Department of Pharmacology, Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem Abstract. The bloodbrain barrier (BBB) is a physical and functional barrier that regulates the entrance of many drugs and chemicals into brain cells regardless of their molecular size. Carrier-mediated transport systems in the BBB, that are active in the efflux of drugs and chemicals, include the P-glycoprotein pump (Pgp/MDR1/ABCB1) and non-Pgp multidrug-resistance proteins (MRPs). These transporters limit the influx of these compounds, thus protecting the brain from their toxic effects. Very importantly, they also affect the efflux of endogenous compounds, as is the case with bilirubin (BR), a neurotoxic catabolite of heme. Thus, BRdrug competition for BBB-mediated efflux may affect the entrance of both BR and drugs into the brain. Diabetes causes changes in BBB transport which may affect drug and glucose delivery to the brain. Glucose transporter 1 (GLUT1) is the major transporter responsible for the entry of glucose into the brain. We have previously shown in vascular endothelial cells (VEC) that BR significantly augmented the rate of glucose transport, GLUT1 expression, and plasma membrane localization of GLUT1 in these cells. BR also reversed the high glucose (23 mM)-induced downregulation of the glucose transport system in VEC. Pathological concentrations of BR in the vascular compartment (jaundice) may thus influence the cellular handling of glucose in diabetes, including its delivery to the brain. We now show that BR increases dose-dependently the apoptosis of bEnd.3 cells, a line of microvascular endothelial cells derived from the BBB. Switching these cells from a low glucose (5.5 mM) to a high glucose (23 mM) containing medium increased the magnitude of BR-mediated apoptotic events in a synergistic fashion.


15


BIOGRAPHY

JOSE DE LEON

A native of Bilbao, Spain, Dr. Jose de Leon received his medical training at the University of Navarra in Spain. He came to the United States in 1987 to hone his research skills in psychiatry. He completed fellowships in clinical research and clinical psychopharmacology in Philadelphia. In 1991 was named Research Assistant Professor in the Department of Psychiatry at the Medical College of Pennsylvania and Hahnemann University. In 1995, he was promoted to Research Associate Professor. He and his family moved to Lexington, Kentucky, in 1996 where Dr. de Leon progressed from Associate Professor to Professor in the Colleges of Medicine and Pharmacy, University of Kentucky (UK). He has directed the Mental Health Research Center at Eastern State Hospital (ESH) for 15 years, and served as ESH staff physician for the treatment-refractory unit for 8 years. He no longer manages patients, but as a state consultant for the Department for Mental Health, Developmental Disabilities and Addiction Services, he assists clinicians caring for patients with complex psychiatric illnesses at public facilities all over Kentucky by sharing his psychiatric and medical expertise with psychiatrists at state mental health and mental retardation facilities. He investigates deaths and recommends specific interventions for improving care standards; and is working on developing specialized pharmacological guidelines for mental retardation facilities. The pharmacological guidelines are being published in the journal Research in Developmental Disabilities. His ongoing work with UK psychiatric residents and pharmacists at ESH has resulted in several articles, and special recognition awards by the residents. An expert in schizophrenia, psychopharmacology and pharmacogenetics, Dr. de Leons research career has been prolific. He has received grants from the NIMH, NARSAD and the industry. To date, he has published more than 210 peer-reviewed letters and articles in scientific journals included in PubMed. They include one letter in Science, 30 publications in the Journal of Clinical Psychiatry, 21 publications in Schizophrenia Research and 19 publications in the Journal of Clinical Psychopharmacology. The SCI (Science Citation Index) and the SSCI (Social Science Citation Index) are indexes developed by the Institute of Scientific Information (ISI) to reflect the number of times that articles are cited and are used to calculate the impact factor of journals. According to a computer search in the ISI Web of Science in February 2011, Dr. de Leons scientific publications have been cited in the literature more than 4000 times. Hirsch (PNAS 102:16569-72, 2005) proposed the h index to summarize a researchers articles. Dr. de Leons h index is 36 (he has at least 36 articles with 36 citations). His three-year risperidone pharmacogenetic study of 560 Kentucky subjects which focused on the cytochrome P450 2D6 (CYP2D6) gene laid the groundwork for his most ambitious study. From 2003 through 2007, over 4500 subjects were recruited at three state hospitals, identifying subjects with unusual CYP2D6 and CYP2C19 genetic profiles. The first article of this study was published in January 2009. He has collaborated with several research groups in Spain and has facilitated the career development of Spanish researchers who have become internationally known in the areas of schizophrenia, bipolar disorder and suicide. Since 1998, Dr. de Leon has been a Visiting Professor at the Federico Oloriz Neuroscience Institute, Medical School, University of Granada, Granada, Spain. He often combines family visits to Spain with lectures and teaching opportunities in order to educate Spanish physicians in the latest developments in pharmacogenetics and psychopharmacology, and inspire them to conduct psychiatric research. From 2003 to 2009, he has been a Voluntary Professor at the Department of Statistics, Science School, Universidad Nacional, Medellin, Colombia. Dr. de Leon is often invited to lecture in other countries. He has been a member of the advocacy group, the National Alliance for the Mentally Ill (NAMI) since 1989. He has spoken at NAMI state and local meetings several times and is always happy to advocate on behalf of persons and families challenged with mental illness and/or mental retardation issues.

16




THE FUTURE (OR LACK OF FUTURE) OF PERSONALIZED PRESCRIPTION IN PSYCHIATRYJose de Leon University of Kentucky, Mental Health Research Center at Eastern State Hospital

Abstract. Rapid technological advances in genetics have created conceptual chaos regarding the genetics of drug response. Terms for differing concepts are used interchangeably: pharmacogenetics with pharmacogenomics, personalized medicine with personalized prescription. Biomarker has many definitions. The author prefers the concept of personalized prescription and uses it with implications beyond pharmacogenetics by considering all scientific information valid for prescribing medication. Genetics may not be crucial for all drugs. In this comprehensive view, clinicians must consider genetic, environmental and personal variables when prescribing medication and incorporate some basic pharmacological principles: (1) safety and efficacy, (2) pharmacokinetics and pharmacodynamics, (3) therapeutic window and prescriber's role, and (4) idiosyncratic and dose-related adverse drug reactions. Personalized prescription in the clinical environment can be expressed in two main ways: as personalized selection of the drug and as personalized dosing. The future, or lack of future, of personalized drug selection and of personalized dosing in psychiatry is reviewed. Currently, the author thinks that, in psychiatry, pharmacogenetic tests have some potential in two areas: (1) excluding some drugs for some unusual patients (HLA-B*1502 genotyping in Asians for carbamazepine), and (2) using pharmacokinetic genes for personalizing dosing in narrow therapeutic window drugs. In the short term, there is dubious potential for other pharmacogenetic tests and no potential for pharmacogenetic testing to ascertain the best drug for each patient. Personalized dosing has immediate application if one understands it as the use of our current scientific knowledge of genetic, environmental and personal variables to determine dosing; its sole requirement is well-trained psychiatrists.


17


BIOGRAPHY

SVEIN G. DAHL

Svein G. Dahl has worked 7 years in the pharmaceutical industry, including 3 years as the Director of Reseach at Jouveinal/Parke Davis, Paris, France. He has been a Professor of Pharmacology at the Faculty of Medicine, University of Troms, Norway, since 1982, and is the head of their Medical Pharmacology and Toxicology Research Group. He is a member of the Council of Scientists of the Human Frontier Science Program (HFSP), the Governing Board of the International Neuroinformatics Coordinating Facility (INCF), the steering group for the Norwegian Research Councils Nevro Nor initiative, and of the Board of directors of Orthogenics AS (Norway). He has served as a board member of Jouveinal/Parke Davis (France), COST Action B15 (EU), European College of Neuropsychopharmacoloy, Scandinavian College of Neuropsychopharmacoloy, Lytix Biopharma (Norway), and other international professional organizations. An important part of his research has been related to the clinical and basic pharmacology of CNSactive drugs. He was the first in the world to demonstrate how combined computational and molecular graphics techniques could be used to make a three-dimensional model of a drug target (the dopamine D2 receptor, 1989), and to simulate the molecular dynamics of drug-receptor interactions. Such methods are now used in virtually all pharmaceutical companies and research institutions in the world. The group has since focused on studies of the molecular structure and mechanisms of drugs, receptors and transporter proteins. He was honored with election as a foreign corresponding fellow of the American College of Neuropsychopharmacology (ACNP) in 1990, included in the ACNPs Pioneers in Psychopharmacology gallery in 2007, and elected as the Norwegian Portrait of Science by the European Federation of Pharmaceutical Industries and Associations (EFPIA) in 2008. His most recent publications (2008 - 2010) are on modeling of different physiological, pharmacokinetic and pharmacodynamic systems, and of molecular targets for antidepressant drugs.

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MOLECULAR STRUCTURE AND LIGAND BINDING OF MONOAMINE TRANSPORTER PROTEINSSvein G. Dahl Medical Pharmacology and Toxicology Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Troms, Norway Abstract. Transporter proteins in biological membranes may be divided into channels, which function as selective pores that open in response to a chemical or electrophysiological stimulus, and active carrier proteins using an energy producing process to translocate a substrate against a concentration gradient. Secondary active transporters use the movement of a solute down a concentration gradient to drive the translocation of another substrate across a membrane and against a concentration gradient. The secondary transporters include the neurotransmitter:sodium symporters (NSS family), glucose transporters, and the Escherichia coli lactose permease symporter (Lac Permease). Secondary transporters are very distinct in terms of sequence and function, and transport a wide variety of substances including the monoamine neurotransmitters dopamine, serotonin and noradrenalin. Members of the NSS family are the target of many currently used psychotropic drugs and several substances of abuse. The serotonin transporter (5HTT) and the norepineprine transporter (NET) are the main sites of action of antidepressant drugs, and the dopamine transporter (DAT) is the main site of action of cocaine and other substances of abuse. The rational design of novel drugs interfering with monoamine reuptake is limited by the scarcity of structural information about these transporter proteins. We and others have therefore used molecular modeling techniques to generate 3-dimensional (3D) models of monoamine transporters, based on homology with bacterial membrane transporters and information obtained from site directed mutagenesis studies. 3D modeling of monoamine transporters relies on the availability of experimental 3D structures that may be used as templates. When the crystal structure of a bacterial homologue of the human monoamine neurotransmitter transporters from Aquifex aeolicus (LeuTAa) was reported in 2005, this represented a breakthrough in the structural/functional analysis of monoamine transporters, and provided the possibility of using a homology modeling approach to generate 3D molecular models of NSS family members. These models have demonstrated how transporters may undergo substantial conformational changes during the transport cycle. When performing docking studies on such models, the structural flexibility of transporters should therefore be considered. The conformational flexibility of membrane transporters suggest that different transporter inhibitors may bind to different conformations of the transporter. Computational methods based on accurate molecular transporter models represent a useful tool in the discovery of safer and more efficient drugs acting on membrane transporters.


19


BIOGRAPHY

HEGE CHRISTENSEN

Current appointment: Professor in Pharmacology, School of Pharmacy, Department of Pharmaceutical Biosciences, University of Oslo, Norway (since 2007) Previous appointments: Scientific assistent, School of Pharmacy, University of Oslo, Norway (1985-1986) Drug consultant, Lvens kemiske Fabrik, Norway (1986-1987) Ph.D. research fellow, Norwegian Defence Research Establishment, Kjeller, Norway (1988-1991) Senior Scientist at ICIT (The International Cardiology Research Institute), Oslo, Norway (1991-1992)

Associate professor, School of Pharmacy, Department of Pharmaceutical Biosciences, University of Oslo, Norway (1992-2007)

Sabbatical 2004-2005: University of Sheffield, Section of Molecular Pharmacology and Pharmacogenetics, Sheffield, U.K. Research activities: The research area is pharmacokinetics with special focus on processes involved in determining bioavailability, distribution and elimination of drugs. A main area is optimisation of drug therapy based on interindividual variability in cytochrome P450-mediated drug metabolism and drug transport, which appears to be of major importance for variability in drug response between individuals. Several projects are related to drug metabolism and transport studies and drug interaction studies, both in vitro in human liver cells and microsomes and by in vitro-in vivo extrapolations. Publications: 33 full papers, 1 book chapter, > 55 abstracts. Teaching Undergraduate and postgraduate teaching for Pharmacy students, School of Pharmacy, University of Oslo (from 1992 until now): Basic pharmacology (Neurobiology, CNS and Cardiovascular Pharmacology) Pharmacokinetics (including laboratory courses in drug metabolism) Pharmacotherapy Several courses in Continuing Education for Pharmacists: Pharmacotherapy in Psychiatric diseases, Neurology and Cardiovascular diseases Pharmacokinetics (drug-drug interactions) Other relevant activities: Delegate in Management Committee in COST ACTION B25 Physiologically based Pharmaco-Toxicokinetics and Dynamics (2005-2009) Member of the Programme Committee and Co-chair of the Pharmaceutical Sciences World Congress (3rd World Congress of the Board of Pharmaceutical Sciences of FIP), Amsterdam, 22-25 April 2007

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MECHANISMS INVOLVED IN THE PHARMACOKINETIC INTERACTION BETWEEN ATORVASTATIN AND CYCLOSPORINE AHege Christensen, Rune Amundsen and Anders sberg Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway Abstract. Due to a high incidence of dyslipidaemia following solid organ transplantation, HMG-CoA reductase inhibitors (statins) are frequently used in transplant recipients, and concomitant use of the calcineurin inhibitor cyclosporine A (CsA) increases systemic exposure of statins. CsA has been shown to increase the systemic exposure of atorvastatin severalfold, while another calcineurin inhibitor tacrolimus (Tac) did not show such an effect. The mechanism behind the interaction between atorvastatin and CsA has been discussed to be primarily due to inhibition of membrane transport, but it has also been proposed that CYP3A4 inhibition is involved. CsA has been reported to inhibit CYP3A4, P-glycoprotein, organic anion transporting polypeptide 1B1 (OATP1B1) and some other uptake transporters. The aim of the present study was to investitate the potential of CsA and Tac to inhibit the OATP1B1-mediated uptake of atorvastatin in an in vitro model and to explore to what extent CsA and Tac inhibit CYP3A-mediated metabolism. In vitro-in vivo extrapolations (IVIVE) were performed in order to elucidate which mechanisms might be of most importance in an in vivo setting. The inhibitory effect of CsA and Tac on cellular uptake of atorvastatin via OATP1B1 was investigated in an in vitro over expression whole cell model (HEK293 cells). Inhibition of OATP1B1 mediated uptake of atorvastatin by CsA was about 90-fold more potent than inhibition by Tac, and inhibition constants (Ki) obtained were 0.014 and 1.30 M, respectively. Co-incubation as compared with pre-incubation with CsA showed a 20-fold lower inhibitory capacity. The IVIVE showed that clinically obtainable concentrations of CsA, but not Tac, inhibit OATP1B1 transport of atorvastatin. CsA inhibition ranged from 28 to 77 % within a dosing interval, while it was below 1 % for Tac, considering free concentrations and assuming competitive inhibition. This does not fully explain the clinically observed interaction with CsA, suggesting that a more complex inhibitory mechanism may be present. This study provides evidence that OATP1B1 inhibition is a relevant mechanism for the interaction observed between CsA and atorvastatin. In the literature inhibition of CYP3A-mediated metabolism of atorvastatin has also been proposed to be involved in the interaction with CsA, thus in the present study the possible inhibitory effect of CsA and Tac on CYP3A4 and CYP3A5 metabolism in vitro was investigated. The experiments were performed with the CYP3A probe substrate midazolam and the inhibitory effect of CsA and Tac on the formation of 1-OH midazolam in insect microsomes expressing CYP3A4 or CYP3A5 and in human liver microsomes (HLM) were studied. CsA was shown to be a competitive inhibitor of CYP3A4 with a Ki of 0.9 M, and CsA did not inhibit CYP3A5. Tac showed a time-dependent inhibition of CYP3A4 and CYP3A5 in insect microsomes, but interestingly in HLM the inhibitory effect of Tac was less pronounced and the effect was not time-dependent. The maximum unbound plasma concentration of CsA and Tac will be much lower than the Ki values found in this study. Thus the clinical relevance of CYP3A4 inhibition by CsA will most certainly be limited. However, the IVIVE indicated that inhibition with CsA and Tac might play a moderate role on CYP3A4-mediated intestinal metabolism.


21


BIOGRAPHY

VICTOR A. VOICU

Fellow of Romanian Academy; General Secretary of Romanian Academy (2002-2006). Professor, Head of Department of Clinical Pharmacology, Toxicology and Psychopharmacology, Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest. The medical studies performed as a military student at the Faculty of General Medicine in Bucharest, completing his M.D. degree in 1962; in 1970 he defended the PhD thesis on Homeostasis and pharmacodynamic reactivity of vegetative nervous system in acute irradiation syndrome. He has been assistant professor at the Department of Pharmacology in Bucharest (1963-1966), researcher at the Center for Radiobiology and Molecular Biology (1964-1970), head of Laboratory of Pharmacodynamics, Army Center for Medical Research (1970), professor (from 1972) and head of Department of Pharmacology, Faculty of Medicine, Craiova (from 1973); from 1974 is senior physician and, starting from 1985, commander (director) of Army Center for Medical Research; Major General and head of Medical Directorate of National Defense Ministry (1990-1995); from 1993, professor of toxicology at the Faculty of Medicine in Bucharest; he founded the first Department of Pharmacology in the Faculty of Medicine Craiova and the first Department of Clinical Pharmacology, Toxicology and Psychopharmacology in the Romanian medical school (University of Medicine and Pharmacy Carol Davila Bucharest). Some original research topics are to be mentioned: he described and defined the cholinergic muscarinic mechanism of OP-induced hypothermia (1976), the potentiating synergism between antimuscarinics and tricyclic antidepressants and its value in OP compounds antidotism (1974), PK/PD or TK/TD correlations as fundamental tools for identification and anticipation of the safety, efficacy and / or toxicity profiles of drugs or toxicants etc. Another field is represented by the epigenetic mechanisms for effects of chronic treatment with antipsychotics and their consequences on therapeutics, as well as defining some criteria and mechanisms in the evaluation of drugs with active metabolite (including the transport across membranes, blood-brain barrier etc.), essential aspects for treatment individualization in major pathology frames. He is co-author of the finite interactions theory dealing with drug-receptor interactions as an interaction between a molecule and a given biological structure, having essentially the properties of a continuous structure. The results of his research activity are found in more than 330 paper published in Romania or abroad, monographs, and books e.g.: The enzymatic mechanisms in pharmacodynamics (1977); Pharmacology (1980); The pharmacology of ergot alkaloids (1981); Elements of clinical pathopharmacology (1987); The therapy of ocular pathologies (1989); Pharmacological mechanisms at membranar interfaces, paper awarded with the Daniel Danielopolu prize by the Romanian Academy (1994); Clinical toxicology (1997); The psychopharmacology and clinical toxicology of drugs of abuse (2005). The results of his recent research from the field of PD/PK and TD/TK correlations and their consequences on pharmacotherapeutics were published in Basic and Clinical Pharmacology and Toxicology (2010), Analit.Letter (2010), J.Pharm. Biomed.Analysis (2010) etc. These works are added to the 25 patents, referring especially to new drug preparations, the majority of them applied (Atox, drug for counteracting and treating the toxic effects of OP compounds; Dixidextetracaina 70, drug for sub-arachnoid hyperbaric anesthesia; Composition for drug with antispastic action; analgesic-antispastic; antihypertensive; collagenic bandage for treatment of wounds and burns etc.). President of the Romanian Society for Clinical Pharmacology, Therapeutics and Toxicology SRFTTC (from 1991), member of the Academy of Medical Sciences, Romania, President of the Scientific Council of National Medicine Agency (from 1998), member of the Council of European Association of Clinical Pharmacology and Therapeutics (1997), member of the Working Group of European Association of Antitoxic Centers and of Clinical Toxicologists for Certification of Antitoxic Centers; elected member of American College of Clinical Pharmacology, of American Chemical Society etc. As president of SRFTTC, he organized the 12 national and international editions of the Congress of Clinical Pharmacology, Therapeutics and Toxicology.

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PREDICTION OF THE BIOLOGICAL FATE OF OXIMES

Victor A Voicu, Flavian Radulescu University of Medicine and Pharmacy Carol Davila Bucharest, Department of Clinical Pharmacology, Toxicology and Psychopharmacology, Bucharest, Romania.

Abstract. Although oximes represent one of the major antidotal tools of the atropine-oxime-anticonvulsant triad, generally, their current use in the experimental and clinical research reveals some essential aspects: the oximes are not equally active against OP, especially against the nerve agents and there is no broadspectrum reactivator. the differences between the oximes, on one side, and their kinetic behaviour versus nerve agents, on the other side, are illustrated by the PK/PD (oximes) and TK/TD (OP) correlations (Voicu VA et al, 2010), difference that finally explains their reduced efficacy against the neurotoxicity of OP nerve agents. the increase of lipophilicity, the decrease of the polar character of oximes, respectively, leads to an increase of their acute toxicity (Lorke et al, 2009), aspect anticipated by Bodor et al (1975), Pro-2-PAM having a good BBB permeability, but also a consequent neurotoxicity. The therapeutic effects of the compounds with high lipophilicity dont seem to be significantly higher compared to the reference oximes. In this context, the authors have performed an analysis of available literature data for the most studied oximic compounds (with PK evaluations), based on the ADME predictions performed with various specialized software (ADMET Predictor, PreADMET on-line platform, ChemAxon). These predictions have been focused on the most relevant molecular descriptors. Last but not least, these molecular descriptors have been correlated with the biological fate for the analyzed compounds. It has been confirmed the direct correlation between the logP and the acute toxicity (1/LD50), relevant for both oral route (the bioavailability being an essential element), and parenteral routes, mainly percutaneous one. Also, there is a good correlation between logP and the apparent volume of distribution Vd, this time a relation of proportionality. The direct correlation is also valid between the acute toxicity (1/LD50) and Vd for the analyzed compounds. There are some non-homogeneity for the transfer across BBB, suggesting the implication of other forms of transport than the passive diffusion. This type of analysis performed on a large number of compounds allows a more relevant evaluation of structure activity relationship, focusing mainly on the molecular descriptors determinants of their kinetic behavior and their correlation with a series of biological parameters, essential for their specific therapeutic efficacy.


23


BIOGRAPHY

HORST THIERMANN

Horst Thiermann studied medicine at the University of Regensburg (Germany) and at the Technical University Munich (Germany) where he finished his doctoral thesis (MD) in 1988. From 1987 to 1989 he worked at the Bundeswehr Hospital Munich in the departments of anesthesiology and surgery and joined the Bundeswehr Institute of Pharmacology and Toxicology, Munich in 1989. Towards his qualifications as a Pharmacologist and Toxicologist (1996) and as a Clinical Pharmacologist (2002) he was working in research fellowships at the Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig Maximilians-University Munich and at MDS Pharma Services, Hhenkirchen-Siegertsbrunn, Germany. In 2005 Horst Thiermann has hablitated (postdoctoral university lecturing qualification) at the Technical University of Munich as an external scientist and pursues his venia legendi (Privatdozent, University Lecturer) in Pharmacology and Toxicology at the same university. Since 2006 he is heading the Bundeswehr Institute of Pharmacology and Toxicology. This institute is the German national competence centre on medical aspects against chemical warfare agents. The scientific focus is directed towards the improvement of medical countermeasures (e.g. therapeutic strategies) against poisoning by chemical warfare agents as well as the verification of exposure to such toxicants.

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WHY DO PATIENTS DIE FROM INTENTIONAL OP-INSECTICIDE POISONING IN SPITE OF PROPER USE OF ANTIDOTES?Horst Thiermann1, Thomas Zilker2, Florian Eyer2, Franz Worek11. 2.

Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany, Department of Clinical Toxicology, II. Medical Clinic, Technical University, Munich, Germany

Abstract. Objective: For optimal therapy of organophosphorus pesticide (OP) poisoning administration of antimuscarinic compounds, e.g. atropine, and oximes is suggested. Atropine should be applied according to signs and symptoms and oximes should be given as long as reactivation of inhibited acetylcholinesterase is possible (1,2). Although this strategy, together with advanced intensive care treatment should result in good outcome, lethality is still high. Therefore, the cause of death in patients, who were treated accordingly was analysed. Methods: During a clinical study in Germany, patients were treated with obidoxime (250 mg i.v. followed by infusion of 750 mg/24 h), atropine according to demand, and the necessary supportive care. The clinical course of the patients was assessed and the conditions associated with lethal outcome analysed in detail. Results: Almost all patients ingested OP pesticides for suicidal purpose. Although therapeutic strategies were directed to achieve optimal reactivation of inhibited acetylcholinesterase 7 out of 34 patients died (2). In poisoning with diethyl-OP compounds unconsciousness and severe circulatory insufficiency dominated the early phase of the very fast developing cholinergic crisis. In contrast, in poisoning with dimethyl-OP compounds several patients were able to communicate when the emergency physician arrived on the spot and critical situations developed more frequently not until several hours after poison intake. The patients needed antidotes for 3.6 days (median (throughout), 1.2 28.3 days) in case of diethyl-OP and for 5.2 days (0.8 17.7 days) in case of dimethyl-OP poisoning. Artificial ventilation was necessary for 16.0 (3.6 37.6 days) and 6.7 (0.8 22.8 days) in diethyl- and dimethyl OP-poisoning. The frequency and patterns of complications were quite similar in both types of poisoning. Only two patients died during cholinergic crisis (death on day 21 and 16 after ingestion). Both of them had ingested extremely high amounts of parathion and no reactivation was possible. Finally they died due to severest respiratory dysfunction. Four patients, in whom initially reactivation was achieved, died 18, 23, 19 or 38 days after poison ingestion from complications that were no longer related to cholinergic crisis (peritonitis from a stress ulcer, lung embolism, pneumonia). In one other patient with oxydemeton methyl poisoning clinical conditions on admission were already deleterious. Here neither antidotes nor advanced intensive care could improve conditions nor restore health. Conclusion: While optimized antidotal treatment together with advanced intensive care is usually effective in treatment of cholinergic signs and symptoms in most patients with OP-poisoning. However, severe non-cholinergic complications may be responsible for high death rates.


25


BIOGRAPHY

ANDREI VALENTIN MEDVEDOVICI

Present position: a. Professor at the University of Bucharest, Faculty of Chemistry, Department of Analytical Chemistry b. Scientific Director, LaborMed Group Key qualifications: Teaching skills; Skills in operating HPLC, SFC, GC, MS equipments, including hyphenation; Experience in environmental analysis, food chemistry, pharmaceutical formulations, clinical analysis; Experience in analytical method development and validation, qualification of analytical methods and equipments. Editorial board member: Journal of Liquid Chromatography & Related Technologies (Taylor & Francis Group, U.S.A.) ISSN 1082-6076 (paper) Bioanalysis (Future Science Ltd., U.K.) ISSN 1757-6199; Advisory board member for journals: Analytical and Bioanalytical Chemistry; Journal of Chromatography A; Journal of Chromatography B; Journal of Pharmaceutical and Biochemical Analysis; Chromatographia; Analytical Letters; Revue Roumaine de Chimie; Revista de Chimie; Evaluation board member: CNCSIS; RENAR; ARACIS Publications: ISI publications: 92 (80 in journals abroad Romania); Non-ISI publications: 13 (11 in journals abroad); Journals: J. Chromatogr. A; J. Chromatogr. B; Talanta; Water Research; Chirality; Chromatographia; J. High Resolut. Chromatogr.;J. Appl. Toxicol.;J. Incl. Phen. Macrocycle Chem.; J. Sep. Science; J. Pharm. Biomed. Anal.; J. Liq. Chromatogr. & Rel. Tehnol.; J. Chemometrics; J. Chem. Inf. & Computer Sci.; Chem. Eur. J.; J. Microcol. Sep; Microchem. J.; Sep. Sci. & Technol.; Biomed. Chromatogr.; J. Catalysis; Eur. J. of Drug Metab. and Pharmacokinetics; Eur. Pharm. Rev.; Analli di Chimica; Chemia Analityczna; Arzneimittel Forschung; Comptes Rendues Chimie; LC-GC International; Int. Env. Technol.; Anal. Letters; Bioanalysis; Rev. Roum. Chimie; Analele Univ. Bucureti; Southern Brazilian J. of Chem.; Proceedings Int. Sympos. Capillary Chromatogr. (Riva de Garda, 1993, 1994, 1996). Books/Chapters in books & encyclopedias: 25 (14 in publications abroad); Membership of professional bodies: Romanian Analytical Chemical Society; Awards: C.D. Nenitescu Award of the Romanian Academy, December 2009. Posters > 40 (16 to congresses/ symposia abroad); Plenary lectures, Keynotes: > 70 (15 abroad); Cumulated Impact Factor: 160.34 Cumulates Citation Index: 541 (419 without self-citations); h-Index: 12

26




HOST-GUEST INCLUSION OF SOME CATION TYPE ALDOXIMES IN MACROCYCLIC CAVITIES: ESI/MS APPROACH FOR FAST SCREENINGVictor Voicu1,2, Andrei Medvedovici3, Florin Albu4 University of Medicine and Pharmacy Carol Davila, Department of Pharmacology, Toxicology and Clinical Psychopharmacology, 2. Romanian Army Center for Medical Research 3. University of Bucharest, Faculty of Chemistry, Department of Analytical Chemistry 4. Bioanalytical Laboratory, SC Labormed Pharma SA1.

Abstract. Inclusion of active ingredients in macrocyclic cavities is widely used to enhance on the stability of the host compound in physiological media or for an increased absorption (transfer through biological barriers). Usually, hydrophobic compounds are included in externally hydrophilic cavities for increasing their solubility in aqueous media, thus controlling their release from the formulation and consequently enhancing their bioavailability. Contrarily, cation type aldoximes used as AChE reactivators are highly polar compounds, their in-vivo transport through biological membranes being seriously affected by means of such a molecular characteristic. It may be of a real practical interest to study the possibility of inclusion of cationic type aldoximes in macrocyclic cavities in order to reduce their solubility in water, to improve their absorption and to increase their stability in physiological media. Advances in the construction of novel hosts with applications in supramolecular chemistry have generated an increasing demand of new analytical techniques for studying their binding properties with minimal sample consumption. The binding properties of a host and the characterization and evidence of the host-guest formation in solution have been obtained from many conventional methods including nuclear magnetic resonance, UV-Vis and fluorescence spectrometry, circular dichroism, X-ray diffraction, light scattering, calorimetry, conductometry, scanning tunneling or atomic force microscopy, and computer simulations. Mass spectrometry is an additional quite recent tool for studying non-covalent interactions in the gas phase and probing molecular recognition. In the present work, our interest was focused on the possibility of a fast screening of the interaction ability of different cation type aldoximes in macrocyclic cavities as crown ethers and functionalized calixarenes by means of electrospray mass spectrometry. The mixture of the host and guest congeners in a liquid aqueous/polar organic solvent phase is directly introduced in an atmospheric pressure electrospray ion source, followed by the MS or MS/MS analysis of the resulting ions. Formation of the complexes is supported by the observation of host-guest cluster ions. The method may be used only for fast screening of the interaction between hosts and guest. Deep insights about inclusion/non-inclusion features in the cavity and type of interactions are then obtained through detailed structural investigation techniques such 1H and 13C NMR or FTIR.


27


BIOGRAPHY

MOMIR MIKOV

Member of: Serbian Medical Society, Serbian Pharmacological Society (Member of the board), Section of Toxicology- Serbian Medical Society (Member of the board), International Society for the Study of Xenobiotics, Controlled Release Society New Zealand , Australian Pharmaceutical Sciences Association 2006-, Head of Clinical pharmacology Section of Serbian Medical Society 2009Positions: Professor in Pharmacology and Toxicology University of Novi Sad, Medical Faculty and University Pristina Kosovska Mitrovica (Medicine and Dentistry and English Medical Studies in Novi Sad), Professor in Pharmacology and Toxicology Medical Faculty University of Banja Luka,, Professor in Pharmacology and Toxicology Pharmaceutical Technology group University of Novi Sad, School of Pharmacy, Medical Faculty, University of Novi Sad, Serbian Poison regulatory committee member, Senior Lecturer School of Pharmacy, University of Otago, New Zealand, Professor Pharmacy Faculty, University of Monenegro Postdoctoral research: UK, London, St Marys Hospital Medical School, Department of Biochemical Pharmacology Imperial College, 1986-1989 Collaboration: Department of Pharmacology, Medical Faculty University of Banja Luka (Bosnia and Herzegovina), Department of Pharmacology and Toxicology, Medical Faculty University of Skopje (Macedonia), Department of Pharmacology Medical Faculty University of Podgorica (Montenegro), Bulgarian Academy of Sciences, Institute of Physiology, Toxicology Department, Research Activities Research on drug metabolism in vivo and in vitro, Development of analytical methods for metabolic studies, Inventor of bile acids as new antidiabetic agents, Study director/principal investigator/clinical investigator on more than 60 bioequivalence and controlled clinical trials Supervisior of more than 20 PhD amd MSci postgraduate students nationally and internationally Distinctions: Award for Science Serbian Medical Society, Award For Contribution and Education in the field of Xenobiotic Metabolism and Toxicity in Balkan Countries, Award Military Pharmaceutical Laboratories of Greek Army, Author of more than 100 publications: books, journal articles, invited lectures and 4 patents

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DRUG ABSORPTION FROM THE GASTROINTESTINAL TRACT AND THE INFLUENCE OF PROBIOTICSMikov M.1, Al-Salmi H.2, Golocorbin-Kon S.11. 2.

Department of Pharmacology and Toxicology, Medical Faculty Novi Sad Serbia Biomedical Engineering, Medical School, McGill University, Montreal, Canada

Abstract. Drug absorption across the gastrointestinal tract occurs by a combination of passive diffusion and active transport. Barriers to absorption include enterocyte tight junctions, the mucus layer, efflux transporters and the metabolic barrier consist of intestinal mucosa and gut flora. The absorption, metabolism and systemic availability of some orally administered drugs can be influenced by the metabolic activity of gut microflora and modified by disease and probiotics. Probiotics are live, ingestible microorganisms that provide benefits to the health and well-being of the host. They have been shown to be beneficial in a wide range of conditions including infections, allergies, and metabolic disorders such as diabetes. Combinations of different bacterial strains can be used as probiotics but the mixture of Lactobacillus and Bifidobacteria is a most common choice. Recently, the Ussing chamber has been used to investigate drug permeation through different tissues and the transporters involved. In our work it was used to investigate the effect of probiotics on permeation of antidiabetics like glicalazide and bile acid derivatives. We have also investigated the influence of probiotics on absorption in healthy and diabetic animals on the absorption of bile acid derivative, gliclazide and sulphasalazine metabolism. In our experiments probiotic pre-treatment in healthy animals decreased the permeation of gliclazide but the same treatment in diabetic animals improved the drug permeation which was impaired in diabetic subjects without any probiotic treatment Probiotic treatment decreased bile acid derivative (monoketocholic acid MKC) absorption and lowered blood glucose in healthy and diabetic rats. The reduction of MKC absorption in probiotic treated healthy and diabetic rats results most likely from the induction of presystemic elimination of MKC by gut bacteria. It was found also that probiotic treatment significantly increased sulphasalazine degradation in mucus of the ileum and colon and that probiotics alter the enzymatic activities of bacteria in gut contents in different manner than in gut mucus. The modification of gut flora with probiotics is one of important factors influencing drug absorption and metabolism. Acknowledgement: This project has been supported by the Ministry of Science of the Republic of Srpska Research Grant 2010-2011.


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BIOGRAPHY

FRANZ KEREK

Education Chemistry, Babes-Bolyai University of Cluj (Romania) Doctoral Thesis, Stereochemistry of Carbodiimides (1972), Prof. G. Ostrogovich Alexander von Humboldt post-doctoral fellowship 1973-5, University of Bochum (Germany) Natural Products Chemistry, (Prof. Gnther Snatzke) Carrier University Politehnica Timisoara (Romania) Assoc. Prof. Organic Chemistry -> 1975 Research Institute for Chemistry of the Romanian Academy (Timisoara) Head of the Department for Natural Products Chemistry ->1988 Max-Planck-Institute for Biochemistry Martinsried, 1992-> present Managing Director of the DoNatur and SiNatur GmbH in Munich 1997-> present Scientific achievements -First optically active cyclo-phosphorus compounds (chiral catalysis) -Method to disclose the absolute configuration of natural substances by Circular Dichroism spectra of their mono-dentate metal ion complexes -Permethylation of carbohydrates (very high citation index paper) Discoveries, patents Isolation and structural disclose of the novel drug substance MCS with characterization of its analgesic and immunosuppressive mechanism (1996-2009) Preclinical and clinical development of the novel anti-rheumatic drug MCS-Injection with successful Phase II clinical study in the treatment of osteoarthritis (2002-2008) Discovery of the novel Cysteine-rich plant proteins hellethionins (2003) Discovery and characterization of the Sub-nano-Silicic-Acid SNSA the first biologically active silicon compounds (2005-2008)

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TARGETING THE INNATE IMMUNE RECEPTORS, AS PROMISING APPROACH FOR DRUG-DISCOVERYFranz Kerek1, Victor A. Voicu21. 2.

Max-Planck-Institute for Biochemistry and DoNatur, Martinsried, Germany University of Medicine and Pharmacy Carol Davilla, Bucharest, Romania Abstract. Identification of the Toll-like Receptors (TLRs) and the cognate RAGE and NOD receptorfamilies opened new insights into the mechanism of the innate immune system that detects pathogens and mounts their efficient annihilation. Innate immunity plays a crucial role in modulation of the adaptive immunity including the malfunction of this system as manifested e.g. in the autoimmune diseases. This novel insight suggests therapeutic interventions in inflammatory diseases and autoimmune pathologies already at the level of the innate immunity. Despite of considerable efforts to develop novel drugs for the modulation of the innate immune response, so far no synthetic drug substance was authorised in this field for the human therapy. One possible reason of the failures with single-molecule drug-substances is that the receptors of the innate system such as TLRs, NOD etc., did not work according to the classical lock-key model. Conversely to the single molecular ligand mechanism of the classical pharmacology the innate immune receptors are activated in nature by substance mixtures (e.g. LPS for TLR-4) comprising only common structural elements such as the Pathogen or Damage associated molecular patterns (PAMP; DAMP). It seems therefore a more promising approach to investigate substance mixtures instead of a single molecule antagonist in suppressing the over-activation of the innate immune response. However, this strategy with drug substance mixtures faces major problems, such as to assure the reproducible composition and rigorous quality control of these very complex mixtures. Possible management of these difficulties is either by applying of sophisticated analytical techniques or by providing adequate methods for the quantitative assay of the immune-specific structural patterns in the complex mixture. The therapeutic potential of the innate immune approach and the connected difficulties are illustrated by own experience of the authors. Development of the MCS-substances for the therapy of arthritis pain, with an already successful Phase II clinical trial is a successful example to treat pain and inflammatory diseases by adequate substance mixtures able to down-regulate the pathological over-activation of the innate immune response.


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BIOGRAPHY

CHRISTOS. Y. POTSIDES

Dr. Christos. Y. Potsides obtained his BSc in Biochemical Pharmacology, MSc in General and Medical Microbiology from University College London, Postgraduate Diplomas in Electron Microscopy, Biotechnology from Birckbeck College London, Immunology from Kings College London and Toxicology from the University of Athens Medical School. In 1993 he received his Ph D in Pharmacology and in 1997 his DSc in Pharmaceutical Microbiology from the University of Novi Sad. He has worked for 25 years in the Pharmaceutical Industry, mainly in QC, Manufacturing and Regulatory Affairs. Since 2003 he works as an Assessor in the National Organization for Medicines, Athens, Greece. He has published 52 articles in International and National Journals, his work has been cited in numerous publications and books, and has organized seminars in Pharmacy and Pharmacology, is a member of various Scientific committees and represents Greece in various EU institutions. Membership of societies Greek Society of Medicinal Chemistry (President 1994-1998), EDCTP Founding Member (HIV, Malaria, TB), 2000, Convocation of the University of London, ECDC Scientific Advisor 2007- present, Panhellenic Association of Pharmacists (h.m) Honorary vice presidentships : 2 Scientific boards Greek Representative of the Military Pharmaceutical Laboratories - Scientific Sector, 1993-2000, Greek Representative of the Ministry of Development Scientific Sector, 2000-2003 Greek Representative (Assessor) of the Ministry of Health and Social Solidarity Medicinal Products Sector, 2003- present, Expert- European Union- Brussels, 2000- present Expert- Council of Ministers of the European Union, Consilium- Brussels,2009- present. Scientific participations Round Table member: 14, Plenary Lectures: 19 Visiting Professor: 2 Universities Member of international editorial board: 1

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NEWER DEVELOPMENTS IN ENVIRONMENTAL RISK ASSESSMENT ACCORDING TO EU LEGISLATIONChristos. Y. Potsides National Organization for Medicines

Abstract. Research on the fate and effects of pharmaceuticals in the environment is now a very important issue and has progressed significantly over the past years. Over 100 pharmaceuticals have been identified in rivers, lakes, and coastal waters throughout Europe and the United States in concentrations of parts per billion to parts per trillion. Work in the EU so as to provide a legislative process for investigating this issue begun about two decades ago resulting in the provision of the EMEA Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use namely EMEA/CHMP/SWP/4447/00. This guideline was further refined, largely through the efforts of the EMEA safety Working Group as well as Experts in Academia and Industry and incorporates recent developments, eg. the fate of antibiotics and hormones, and has been officially in force since December 2006. The guidance applies only to potential environmental risks that are a consequence of people storing, taking, and excreting medicines. It involves the preparation of a Risk protocol through the process of Risk Assessment which is defined as the determination of the quantitative or qualitative value of risk related to a concrete situation and a recognized threat. The EMEA risk assessment protocol is a tiered process that begins with a rough calculation of the aquatic predicted environmental concentration (PEC) of the new drug. The risk assessment is divided into a Phase I exposure assessment and a Phase II analysis of fate and effects. Generic products are not exempted from an ERA. About 50 new drugs are granted Marketing Authorization in the United States each year. Roughly a dozen of those are predicted to occur above the trigger concentration requiring them to undergo the first level, or Tier A, of risk assessment testing. The use of the Guideline up to March 2011, in a pan European level has proved to be most effective and it is seen as an appropriate response to an emerging issue which includes possible risks not just from pharmaceuticals but also from personal care products.


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BIOGRAPHY

CONSTANTIN MIRCIOIUCareer: I. Didactic: Professor of Applied Mathematics and Biostatistics, University of Medicine and Pharmacy, 1990 II. Professional Pharmacist in a Laboratory for production of solid and semisolid drugs, 1982-1984. Chief of the Department of Medical Computing of the Radiobiology Laboratory at Fundeni Clinical Hospital,1975-1982. Positions: Head of the Dept. of Applied Mathematics and Biostatistics, University of Medicine and Pharmacy "Carol Davila", Dean of the Faculty of Pharmacy, Bucharest, 2004-2008, Chancellor 2008 Head of Dept. of Biopharmacy, Army Center for Medical Research , European Center for Validation of Alternative Methods Scientific Advisory Committee, Ispra Fields of Specialisation Main field biopharmacy and pharmacokinetics Other fields pharmaceutical technology, biostatistics Current research activities Fundamental research concerning the physicochemical component of the action mechanism of drug molecules at the membranar interfaces; Mathematical methods applied in biopharmacy, pharmacokinetics, toxokinetics and clinical pharmacy; Applied research in pharmaceutical technology in antidote design, dissolution, bioanalytics and bioequivalence of drugs. Director for Bioequivalence studies at Biopharmacy & Pharmacol Res S. A. Part of research published (70 in scientific journals and volumes), books ("Pharmacological mechanisms at membranar interfaces", Romanian Academy Publ. House, 1994; Mathematics Applied in Pharmacy, 2000, Biostatistics 2005, associated editor for NBC Risks. Current Capabilities and Future Perspectives for Protection, NATO Science Series, Kluwer Academic Publishers, Dordrecht/Boston/London, 1999) , Biostatistics, Fundamental Pharmacokinetics etc Affiliations: Member of the Academy of Medical Sciences American Association of Pharmaceutical Scientists Awards: Prize "Daniel Daniepolu" of Romanian Academy, 1994

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RESEARCH CONCERNING INCLUSION OF DTPA ZN IN MICROEMULSIONS FOR IMPROVING ITS BIOAVAILABILITY AND EFFICACY AS DECONTAMINANT IN MANAGING RADIOLOGICAL TERRORIST INCIDENTSConstantin Mircioiu1,3, Victor A. Voicu2,3, Marilena Jiquidi3, Otilia Cinteza4, Eugen Reviu3, Manuela Spiroiu4, Flavian Radulescu1 1. Department of Applied Mathematics and Biostatistics, Faculty of Pharmacy 2. Department of Clinical Pharmacology, Toxicology and Psychopharmacology, Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, Romania. 3. Army Center for Medical Research, Bucharest, Romania. 4. Department of Physical Chemistry, Faculty of Chemistry, University of Bucharest, Romania.

Abstract. Background. The aim of the present study was to develop a bioavailable and efficient DTPA microemulsion formulation designed for decorporation of internal contamination with radionuclides. Methods. Model microemulsions containing sodium bis (2-ethylhexyl) sulfosuccinate (AOT) as surfactant and isopropyl myr

12th Congres SRFTTC

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