N EW E T T

( Volume 20 No 1 )

( January 2010 )

E R

Asomex® by EmcureAsomex® S(-)amlodipine is the world's first chirally pureanti-hypertensive. Emcure - putting stereochemistry intomedicine.

Chirality and enantiomersChiral drugs have two structurally similar forms that canbehave very differently in biological systems due to theirdifferent shapes in three dimensional space. The two mirrorimages of a chiral molecule are termed enantiomers and thetwo enantiomers of a given chiral drug should be consideredas two different drugs.Like hands, enantiomers come in pairs. Both molecules ofan enantiomer pair have the same chemical composition andcan be drawn the same way in two dimensions (drug structureon package insert) but in chiral environments, such as on thereceptors or enzymes in the body, they can behave differ-ently. A racemate or racemic mixture is a mixture of equalamounts of both enantiomers of a chiral drug.Chirality is defined as the geometric property of a rigidobject (like a molecule or drug) which is incapable of beingsuperimposed on its mirror image. Molecules that can besuperimposed on their mirror images are achiral (not chiral).Chirality is a property of matter found throughout biologicalsystems in amino acids, carbohydrates and lipids. The des-ignations D and L (note the upper case) are used for sugarsand amino acids but are specific to these molecules and arenot generally applicable to other compounds. The terms dor dextro and I or levo are considered obsolete and should beavoided. Instead, the RlS system for absolute configurationand the +/- system for optical rotation should be used. Thetwo enantiomers of a chiral drug are best identified on thebasis of their absolute configuration or their optical rotation.The absolute configuration at a chiral centre is designatedas R or S to unambiguously describe the three dimensionalstructure of the molecule. R is from the Latin rectus mean-ing to the right (clockwise) and S is from sinister for theleft (counter-clockwise). A chiral drug may have more thanone chiral centre and therefore it is necessary to assign anabsolute configuration to each centre. Optical rotation isoften used for a given enantiomer pair, one enantiomer canbe designated (+) and the other as (-) based on the directionthey rotate polarized light.Racemates can be designated as (R,S) or ( + )

Chiral drugs in biological systemsEnantiomers of a chiral drug have identical physical andchemical properties in an achiral environment. However, ina chiral environment, one enantiomer may display differentchemical and pharmacological behaviour from the otherenantiomer. Because living systems are themselves chiral,each of the enantiomers of a chiral drug can behave very dif-ferently in vivo. In other words, the R-enantiomer of a drugwill not necessarily behave the same way as the S-enantiomerof the same drug when taken by a patient. For a given chiraldrug, two enantiomers should be considered as two separatedrugs with different properties unless proven otherwise.

Importance of chirality in drugsIn the marketplace, about 50% of drugs are chiral and ofthese about half are mixtures of enantiomers rather thansingle enantiomers. It is critical to distinguish the singleenantiomer drug from the racemic form because they maydiffer in their dosages, efficacies, side effect profiles or evenindicated use.The two enantiomers of a chiral drug may also differ signifi-cantly in their bioavailability, rate of metabolism, metabolites,excretion, potency, receptor selectivity and toxicity. The useof single-enantiomer drugs can potentially lead to simpler andmore selective pharmacologic profiles, improved therapeuticindices, and decreased side effects.

Asomex® S(-)amlodipineAmlodipine is a widely prescribed calcium channel blockingantihypertensive (CCB) agent. However, arnlodipine is aracemate with an equal proportion of two enantiomers SandR, thus patients receiving arnlodipine are in fact taking twodifferent drugs S-Amlodipine and R-Amlodipine which donot have the same level of antagonistic effect on the calciumchannel receptor. The S-enantiomer of amlodipine is activeand the R-enantiomer is inactive in terms of calcium channelblocking activity.S( -)Amlodipine has 1000 fold stronger calcium channelblocking activity than R-Amlodipine. S(-)Amlodipine istherefore responsible for all of the CCB-mediated pharma-codynamic action of amlodipine including its anti-anginalactivity.Asomex® S(-)amlodipine 2.5 and 5 mg (iOs) by Emcure

Asomex® 5(-) amlodipine

Asomex®is the world's first chirally pure antihypertensive.S-Amlodipine is the only vasoactive enantiomer ofamlodipine. The R-Amlodipine accumulates in the elderlyand may contribute to the side-effects seen with the racemate,such as pedal edema. Randomised controlled trials of S-AmIodipine for the treatment of hypertension administeredat half the dose of racemate has been shown to be as effectiveas racemate but with reduced incidence of peripheral edema.S-Amlodipine is also safe and effective in elderly hyperten-sion, isolated systolic hypertension and in treatment of an-gina. Thus, in S-Amlodipine, drug action is stereo-specificand it is this enantiomer which best fits the receptor and hasthe highest therapeutic activity.

Asomex® S(-)Amlodipine is indicated for the treatment of:AnginaEssential hypertensionHypertension in the elderlyIsolated systolic hypertension

Side effects: On the basis of clinical data, only minor sideeffects have been reported with the use of S-Amlodipine.Caution should be exercised when administeringS-Amlodipine to hepatic and renally impaired patients.

Dosage and administration: The usual recommendeddosage is 2.5 mg for the treatment of hypertension. Ifrequired, the dose may be increased to 5 mg once daily.Supplied as Aso1TU!XfY2.5 and 5 mg in blister strips of 10tablets by Emcure.

The common coldThe cold and flu season has arrived. Many patientscurrently suffering from a cold will turn to a pharmacist fortreatment. What should pharmacists be recommending?There is no cure for the common cold, but symptom reliefshould be offered. Analgesics such as paracetamol, aspirinand ibuprofen relieve fever, chills, sore throats, headachesand sinus pain. After analgesics, topical decongestants helpto relieve the nasal congestion associated with colds. Coughsyrups can also be recommended for relieving the coughcommonly associated with respiratory conditions. Carlisleproduces a wide range of cough preparations to treat thesymptom complex with which the patient presents. Is theresome truth in the pearls of wisdom passed down through theages "feed a cold, starve a fever?" A few small scale studiessuggest that this represents sound medical advice. Therationale may be that eating and drinking helps the bodygenerate heat during a cold, while reducing food intake helpsto relieve the inner heat produced during a fever.

HDL in diabetics differs but improves with Niacin

Researchers are learning more about the protective effectsof HDL. Besides removing cholesterol from plaque andbringing it to the liver, leading to a regression of atheros-clerosis, research suggests that HDL's direct effects on nitric-oxide (NO) production are also important. Previous studieshave shown that HDL cholesterol has endothelial protectiveeffects, such as stimulating NO production and endothelial-dependent vasomotion. In addition, some studies also suggestthat HDL has antioxidant effects, while others have shownthat it promotes endothelial-progenitor-cell (EPC) mediatedendothelial repair. Most of these studies, however, wereperformed using HDL isolated from healthy subjects orreconstituted HDL.

In a recent study, done at the Hannover Medical School,Germany, the researchers isolated HDL cholesterol from 10healthy subjects and 33 individuals with diabetes and lowHDL-cholesterollevels. They then measured the effects ofHDL on endothelium-dependent vasodilation and EPC-mediated endothelial repair.

Compared with healthy subjects, the endothelial protectiveproperties of HDL from diabetic patients were markedlyimpaired. The HDL from healthy subjects stimulatedendothelial NO production and reduced endothelialoxidant stress. HDL also improved endothelium-dependentvaso-dilation and improved early EPC-mediated endothelialrepair. These benefits were not observed in diabeticpatients.

Diabetic patients with low HDL-cholesterollevels and thosemeeting the criteria for metabolic syndrome are regularlytreated with HDL-raising therapies. Thus, a group ofresearchers wanted to evaluate whether niacin altered thequality of their HDL. They randomized the diabetic patientsto niacin extended-release 1500 mg/day or placebo for threemonths.

Treatment with niacin increased HDL-cholesterollevels, butmore importantly, also improved the endothelial protectiveeffects compared with the HDL from healthy subjects. Inthose diabetics treated with niacin, endothelial-cell NOproduction and EPC-mediated endothelial repair wasstimulated. Niacin also reduced the amount of myelo-peroxidase-induced antioxidant damage to HDL.

The quality of the HDL was better after niacin. It not onlyraised HDL, which has been known for some time, but thequality of the HDL, the vasoprotective effects were improvedand this may be more important than simply raising HDL-cholesterol levels.Heartwire, fan 4,2010.

Bleeding in genetically susceptible individual

A 90-year-old woman was hospitalized for gastrointestinalbleeding. Although she had been receiving only warfarin 5mg/day, her international normalized ratio (INR) was 66.Warfarin was discontinued and her INR fell to 3.7 aftertransfusion of fresh-frozen plasma. However, it rose againspontaneously to 7.5. Eleven days after the last dose of war-farin had been administered, it was still detectable in thepatient's plasma, indicating that impaired warfarin clearancemay have caused an enhanced anticoagulation effect.Genetic analysis of the cytochrome P450 (CYP) isoenzyme2C9, which mediates the major deactivating pathway ofS-warfarin, revealed that the patient was a compoundheterozygote carrying two variant alleles: CYP2C9*2 andCYP2C9*3. The patient's enhanced sensitivity to warfarin 5mg/day can be ascribed to decreased clearance of S-warfarinsecondary to genetic alteration of the gene encoding CYP2C9,resulting in a life-threatening bleeding complication.Warfarin is administered as a racemate containing equalamounts of Rand S enantiomers. Most of its anticoagulantactivity is attributed to the S-enantiomer which is four-foldas active as the R-enantiomer. The major deactivating path-way of warfarin is mediated predominantly by CYP2C9.About 20% of Caucasian patients carry a single CYP2C9allelic variant (CYP2C9*2 or CYP2C9*3), and approxi-mately 1% carry two mutated alleles. Carriers of thesedefective alleles metabolize S-warfarin more slowly than doindividuals who lack an allelic variant for CYP2C9. Thus,they may exhibit excessive anticoagulation and enhancedbleeding diathesis if treated with the usual warfarin dosage.Reducing the warfarin dosage in such individuals maysignificantly enhance the safety of long-term therapy. Incontrast, CYP2C9*2 is present in 4% of African-Americans,and this allele is extremely rare among Japanese individuals.Pharmacotherapy. 2002;22(1).

CT imaging and cancer risk

The use of computed tomographic (CT) scans has increaseddramatically over the last few decades. Irrespective of therecognised benefits from the radiologic definitions achievedwith this technology, there is growing concern about radiationexposure associated with CT imaging, particularly with thelifetime attributable risk for radiation-related secondarycancer development. The potentially harmful consequencesof ionizing radiation are divided into deterministic andstochastic effects. Deterministic effects of ionizing radiationresult from cell and tissue death. Such changes occur onlyat doses above a certain threshold and are proportional to thedose given. Radiation doses from medical diagnosticprocedures are usually far below this threshold, but adverseeffects, such as skin burns have been reported afterinterventional procedures that use fluoroscopy. Stochasticradiation effect refers to irradiated cells that are modifiedrather than killed. Modified cells may develop into cancerafter a latency period of years. In principle, stochastic effectshave no threshold. Exposed individuals do not incur illeffects but they have a higher statistical chance for toxicityincluding cancer. These doses delivered in diagnosticprocedures are large enough to cause stochastic radiationeffects and the probability increases with the magnitude ofthe dose.Although exact risk estimates related to low doses ofradiation exposure are difficult to ascertain, the ionizingradiation exposure from a single abdominal or chest CT scanmay be associated with elevated risk for DNA damage andcancer formation. The seventh National Academy of Sciencereport on Biological Effects of Ionizing Radiation estimatedthat a single dose of 10 Sv produces a lifetime risk ofdeveloping a solid cancer or leukemia of 1 in 1000.Therefore, it may be time for a paradigm shift in the wayclinicians approach the use of CT imaging and balance therisk-benefit profile for the patient.Arch Intern Med 2009;22:207/.

Skin patches and steroid spraySome patients complain of skin redness or itching afterapplying Duragesic® and other skin patches. Prescribing acorticosteroid nasal spray or inhaler to use on the site beforeapplying the patch will prevent rashes.The sprays are used because of concerns that the emollientsin steroid creams and ointments will affect patch adhesion.The metered dose inhaler also allows for easy delivery.Advise patients that they can also minimize irritation byalternating sites and not applying the patch to skin that isalready irritated.

How to manage· coughs and colds

When a patient is miserable with a fever, cough, congestionor a runny nose, there are many choices for managing theirsymptoms. The preparation of choice depends upon thepatient's age, duration and frequency of cough, type andonset of cough and the characteristics of the sputum. Thepatient's accompanying symptoms, smoking habits and anymedications (Rx, OTe, herbal) must also be evaluated.Carlisle Laboratories offers a full range of cough and coldmedications for the entire family. Following are someselection guidelines:Tuscosed Linctus, a cough suppressant for treating anon-productive, dry, irritating cough. It may be sedating,thus it is suitable for night-time dosing. Histatussin DMLiquid, a cough suppressant for a persistent, non-productivecough which is accompanied by nasal congestion. Suitablefor a cough associated with a post-nasal drip. Sucrose-free.Histal DM Liquid is a non-drowsy, day-time coughsuppressant. Sucrose free. Histatussin Liquid is indicatedfor the relief of cold symptoms, runny nose and chestiness.Sucrose free. Histal Ex Liquid stimulates expectorationin colds and bronchitis. Sucrose free. Distal DC Liquidis for congestion associated with colds, allergies and sinusitis.Histal DC tablet is the tablet formulation for congestionassociated with colds, allergies and sinusitis.

New Drugs/Devices

Novartis Consumer Health is a world leader in self-medication products for the treatment and prevention ofself-limiting conditions.Excedrin® a triple combination of acetaminophen, aspirinand caffeine is an analgesic known for its potency and strongpositioning for relief as the 'headache medicine.' Unti12005,it was manufactured by Bristol-Myers Squibb, but in July2005 it was purchased by Novartis, along with other productsfrom BMS's over the counter business. Following is theirselection of products based on headache type and severity.Excedrin®caplets 24sExcedrin® Extra Strength 45 x 2sExcedrin® Migraine caplets 50sExcedrin® Sinus Headache caps 24sExcedrin® tension caps 24s

Procto-Glyvenol® 400 mg Suppository is indicated forrelief of the unpleasant symptoms of internal and externalhemorrhoids (pain, itching). The suppositories should beinserted rectally morning and evening or simply once dailyat night and Procto-Glyvenol® cream applied in themorning.

Supplied as Procto-Glyvenol@ 400 mg suppository 5s andProcto-Glyvenol@ cream 15g by Novartis

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