search
for
 About Bioline  All Journals  Testimonials  Membership  News  Donations


Indian Journal of Medical Sciences
Medknow Publications on behalf of Indian Journal of Medical Sciences Trust
ISSN: 0019-5359 EISSN: 1998-3654
Vol. 60, Num. 10, 2006, pp. 427-437

Indian Journal of Medical Sciences, Vol. 60, No. 10, October, 2006, pp. 427-437

Practitioners section

Development of safer molecules through chirality

Manager Medical Services, Emcure Pharmaceuticals Ltd., 255/2, Rajiv Gandhi IT Park, Phase I, MIDC Hinjwadi, Pune - 57
Correspondence Address:Manager Medical Services, Emcure Pharmaceuticals Ltd., 255/2, Rajiv Gandhi IT Park, Phase I, MIDC, Hinjwadi, Pune - 57
Mudgal.Kothekar@emcure.co.in

Code Number: ms06065

Abstract

Many of the drugs currently used in medical practice are mixtures of enantiomers (racemates). Many a times, the two enantiomers differ in their pharmacokinetic and pharmacodynamic properties. Replacing existing racemates with single isomers has resulted in improved safety and/or efficacy profile of various racemates. In this review, pharmacokinetic and pharmacodynamic implications of chirality are discussed in brief, followed by an overview of some important chiral switches that have yielded safer alternatives. These include levosalbutamol, S-ketamine, levobupivacaine, S-zopiclone, levocetirizine, S-amlodipine, S-atenolol, S-metoprolol, S-omeprazole, S-pantoprazole and R-ondansetron. Few potential chiral switches under evaluation and some chiral switches that have not been successful are also discussed.

Keywords: Chiral switch, enantiomer, racemate, safety

Alternatives to existing molecules are developed with the ultimate objective of increasing efficacy and/or enhancing safety, in view of limitations of modern therapeutic agents. The quest for enhancing the efficacy and safety profile of modern therapeutic agents has made the medical fraternity witness an array of generations of drugs in almost all therapeutic areas. Drugs like thalidomide, cisapride, terfenadine had fallen back due to safety concerns despite their promising efficacy. From time to time, structural changes in existing drugs had opened up safer alternatives. One of the currently adapted modalities to enhance safety and/or efficacy of existing agents is the ′Chiral Switch.′ Switching from existing racemate to one of its isomers has provided safer alternatives to drugs ranging from antihistaminics like cetirizine to anesthetics like ketamine. The increasing availability of single-enantiomer drugs promises to provide clinicians with safer, better-tolerated and more efficacious medications for treating patients. It is incumbent upon the medical fraternity to be familiar with the newly introduced chiral switches and their rationale. This review discusses basics of chirality, its pharmacokinetic and pharmacodynamic implications and how chirality is used for development of safer alternatives to existing racemates.

Basics of chirality[1],[2],[3],[4]
Compounds can be chiral or achiral (non-chiral). Chiral compounds possess the property of handedness, i.e., they may be right-handed or left-handed. These two - left- and right-handed - forms of a chiral compound are identical in their structural formulas but differ in spatial arrangement so that one form is exactly a mirror image of the other but the two forms are not superimposable on one another. This is akin to pair of gloves, socks or hands. An achiral object exists only in one form and there is no possibility of left- or right-handedness. This existence of left- or right-handedness of a compound is referred to as chirality. Chirality or asymmetry can arise in several ways in a molecule but most commonly it is due to the presence of an asymmetric carbon (most common), nitrogen or sulfur in the molecule. An asymmetric carbon atom is one to which four different atoms or groups (ligands) are attached. This carbon atom exists in two different spatial orientations in a manner that ligands in one orientation are not superimposable on ligands of the other. Asymmetric carbon thus imparts left- or right-handedness to the molecule. [Figure - 1] depicts chiral structure of ibuprofen.

Each form (left- or right-handed) of a chiral compound is called an ′enantiomer′ or an ′isomer.′ The enantiomers are denoted as R or S according to ′absolute descriptor′ convention proposed by Cahn, Prelog and Ingold or they are denoted as dextro (+) or levo (-) depending on clockwise or anticlockwise rotation of plane-polarized light by them respectively. The two systems of nomenclature are mutually exclusive. R enantiomer of one compound may be dextrorotatory, while another compound may have its S enantiomer as dextrorotatory.

A collection containing only one enantiomeric form of a chiral molecule is called an optically pure, chirally pure or enantiomerically pure compound, while collection of equal amounts of the two enantiomeric forms is called a racemate [Figure - 2].

Pharmacokinetic and pharmacodynamic implications of chirality
All the pharmacokinetic processes, viz, absorption, distribution, metabolism and excretion may be influenced by chirality. Active transport processes may discriminate between the enantiomers, with implications on bioavailability - e.g., esomeprazole is more bioavailable than racemic omeprazole.[5] The volume of distribution of levocetirizine has been shown to be significantly smaller than that of its dextro enantiomer, which is a positive aspect in terms of both safety and efficacy.[6] Drug metabolizing enzyme systems are also subject to stereoselective influences. Two isomers of a drug are often metabolized at different rates. This may result in accumulation of the inactive enantiomer or rapid elimination of the active one and vice versa. Two isomers of a drug also induce or inhibit the cytochrome enzymes stereoselectively.

The phenomenon of ′Chiral Inversion′ adds to the complexity. Chiral inversion is conversion of one enantiomer into its mirror image. For example, the S form of ibuprofen is active but significant R (inactive enantiomer) to S inversion takes place in the body.[7] Therefore, a certain amount of S-ibuprofen is theoretically expected to be less effective than the racemate containing similar amount of S-ibuprofen. Clinical studies have however shown a superior efficacy and enhanced safety with S-enantiomer as compared to that of the racemate containing similar amount of S-ibuprofen.[8] Harmful intermediates are released during R-to-S conversion upon administration of racemate, whereas administration of S-ibuprofen results in no such release of intermediates as it does not undergo chiral inversion. This is thought to be the reason of enhanced safety of S-ibuprofen over the racemate.[9] S-thalidomide exhibits teratogenic effect whereas R thalidomide is sedative. However, the individual enantiomers of thalidomide are both inverted rapidly to the racemic mixture in the liver. Hence the claims that R-thalidomide could be safer and that the thalidomide tragedy could have been prevented by using single R-enantiomer of thalidomide are not valid.[10] Many drugs, however, do not undergo chiral inversion, e.g., S-amlodipine.[11] The single active enantiomers hold promise only if it is proved that they don′t undergo chiral inversion to a significant extent.

Pharmacodynamic implications of chirality could be easily understood with the example of a drug-receptor model as depicted in [Figure - 3]. As the two isomers of a drug have different spatial configurations, their complementary binding sites are also expected to be different. One isomer may bind precisely to the target sites (receptor, enzyme, etc.), while the other may have an imprecise binding. This inactive isomer (commonly referred to as ′distomer′) may bind precisely to other sites that are not the intended targets. In this way, whenever a drug exists as a racemate, the one isomer may be active while the other isomer may have:

  1. No activity.
  2. Some activity.
  3. Antagonistic activity.
  4. A completely separate beneficial activity.
  5. A completely separate adverse activity.

Putting chirality to work for drug safety
Pharmacokinetic differences result in different spectra of interactions for the two isomers. Pharmacokinetic differences may also result in one isomer being retained more in poor metabolizers than its counterpart. Activity at undesired targets is a pharmacodynamic mechanism of adverse effects due to the distomer. The idea of investigating single stereoisomers following the observation of unacceptable adverse effects with the racemate is not new. D-penicillamine, dextromethorphan and levodopa are well-known examples where the other isomer is associated with adverse effects and hence not used. Following are some recent examples where single isomers have enhanced safety profile over the racemate.

Levosalbutamol: Salbutamol salvaged from its antagonist
The bronchodilator activity of racemic salbutamol resides in its levorotatory R enantiomer and the dextrorotatory S enantiomer has been found to be virtually inactive at therapeutic concentrations.[12] To add to this, later studies have found that the S enantiomer is not completely inert; it rather induces airway hyper-reactivity, eventually contributing to increased morbidity and mortality in patients with asthma.[13],[14] Clinical studies have shown that it is at least twice as potent as the racemate.[15],[16]

Esketamine: Anesthesia with smoother recovery
In vitro and in vivo anesthetic and analgesic pharmacological studies have shown that S-ketamine is two to three times more potent than racemic ketamine.[17],[18] Furthermore, S-ketamine is eliminated more rapidly as a single enantiomer than as a component of the racemate since R-ketamine inhibits the elimination of S-ketamine.[19] Thus the recovery time after S-ketamine is shorter than that after the racemate, which is a favorable property for an anesthetic agent. In clinical studies, use of S-ketamine was associated with a remarkably smoother emergence period, a profound postoperative analgesia and a more rapid recovery of cerebral functions. The incidence of psychotomimetic phenomena was negligibly less after S-ketamine in comparison to racemic ketamine.[20]

Levobupivacaine: The active bupivacaine with less CNS and cardiac toxicity
Bupivacaine has been the most widely used local anesthetic for years. In vitro animal studies show that levobupivacaine has less cardiotoxic effects and less toxic effects on the CNS in comparison with both dextrobupivacaine and bupivacaine itself.[21] Studies in human volunteers confirmed these results. Equal potency of levo- and racemic bupivacaine as determined by MLAC (Minimum Local Analgesic Concentration) in labor analgesia and reduced toxicity of levobupivacaine provide wider safety margin to levobupivacaine, making it a better alternative in daily clinical practice.[22] The levorotatory derivative of bupivacaine, ropivacaine, is also a safer alternative to bupivacaine.[23]

Eszopiclone: Hypnosis with fewer hangovers
Eszopiclone (S-zopiclone), a nonbenzodiazepine hypnotic agent, is the dextrorotatory enantiomer of racemic zopiclone. Preclinical studies have demonstrated that S-zopiclone is more active than R-zopiclone at the benzodiazepine receptor complex and is responsible for most of the hypnotic activity of the racemic compound.[24],[25] Eszopiclone has a shorter duration of action, which could minimize or prevent residual hangover effects.[26] Preclinical data also suggest a significantly lower propensity for its anticholinergic effects than that of the R-enantiomer.[25]

Levocetirizine: Cetirizine made more selective and less sedative
Levocetirizine, the active R-enantiomer of cetirizine - with its smaller volume of distribution, smaller even than that of cetirizine - confers improved safety because of low hemato-encephalic barrier passage and low cerebral receptor binding.[27],[28],[29] Exclusion of the S-enantiomer leads not only to enhanced peripheral receptor binding compared with that of cetirizine but also improves overall selectivity specific to the H 1 receptor.[30] Gandon JM and Allain H analyzed the effects of single and multiple doses of levocetirizine on CNS using integrated measures of cognitive as well as psychometric performance in 19 healthy male volunteers and concluded that levocetirizine does not produce any deleterious effect on these functions.[31] Though pharmacokinetic studies indicate improved safety profile of levocetirizine, data on head-to-head comparison of safety of levocetirizine versus the racemate is sparse. A study in 20 healthy volunteers found that both levocetirizine and racemic cetirizine were free from psychomotor and cognitive impairment.[32] In view of the inactive nature of the dextro enantiomer and the favorable pharmacokinetics of levocetirizine, the switch form cetirizine to levocetirizine is expected to be safer; large-scale comparative studies are, however, warranted to address the issue.

S-amlodipine: The safer and longer-acting amlodipine
Vasodilating property of amlodipine resides in its S-enantiomer.[33],[34] The R-enantiomer, although inactive as a calcium channel blocker, may not be completely inert. Clinical studies have shown that lower extremity edema associated with amlodipine was resolved in most of the patients when they were shifted to S-amlodipine.[35],[36] Overall incidence of edema with S-amlodipine has been reported to be 1.39% as against the reported incidence ranging from 1.7 to 32% with racemic amlodipine.[36],[37] This indicates that R-amlodipine component of amlodipine is mainly responsible for blunting of precapillary postural vasoconstrictor reflex and for other local changes responsible for peripheral edema due to amlodipine. Plasma half-life of S-amlodipine is also reported to be longer than that of racemic amlodipine. Longer duration of action of S-amlodipine is expected to further reduce the chances of reflex tachycardia.[11],[38] Moreover, the clearance of S-amlodipine is subjected to much less inter-subject variation than R-amlodipine.[11] S-amlodipine is thus a safer and longer-acting alternative to the existing racemate.

S-atenolol and S-metoprolol: Beta blockers with improved beta-1 selectivity
Although beta blockers are clinically used for their selective beta-1-antagonist effect, the majority actually appear to have rather poor beta-1/beta-2 selectivity.[39] Cardioselectivity of beta blockers is compromised at higher doses, resulting in adverse effects of beta-2 blockade which are particularly of concern in asthmatics, smokers, COPD patients and diabetics.[40] As with most of the beta blockers, cardiac beta-blocking activity of atenolol and metoprolol resides predominantly in their S-enantiomers.[41] R-enantiomers of beta blockers have been shown to possess relatively stronger activity in blocking beta-2 receptors.[42] This higher affinity of R-enantiomer for beta-2 receptors may be a cause of loss of cardioselectivity at higher doses.

Use of single S-isomers of atenolol and metoprolol is expected to preserve cardioselectivity even at high doses as the beta-2-blocking R-isomer is absent. Genetic polymorphism in the metoprolol-metabolizing enzyme CYP2D6 increases the chances of loss of cardioselectivity in poor metabolizers even at normal doses.[43],[44] Interestingly, clearance of R-metoprolol is slower than S-metoprolol in poor metabolizers, resulting in higher concentrations of the non-selective R-enantiomer if a racemate is administered.[45],[46] Use of single S-enantiomer is expected to ensure cardioselectivity even in poor metabolizers as concentrations of only the beta-1-selective component would be increased. Use of S-metoprolol also avoids some harmful drug-interactions with some drugs like paroxetine, cimetidine, ciprofloxacin and verapamil, which selectively increase the concentrations of non-selective R-metoprolol.[47],[48],[49],[50]

S-atenolol and S-metoprolol have been found to be as effective as double-dosed racemates in reducing blood pressure and heart rate.[51],[52],[53],[54]

Esomeprazole and S-pantoprazole: Safety potentially enhanced through pharmacokinetic consistency
S-enantiomers of omeprazole and pantoprazole are found to be more effective than the corresponding racemates,[5],[55],[56] though marked differences have not been observed in the safety profile of the single isomer and racemate preparations. However, R-enantiomers of both the proton pump inhibitors exhibit greater variability than their S-isomers in poor versus extensive metabolizers of CYP2C19 substrates. R-enantiomers of both the drugs are more dependent on CYP2C19, whereas the S-enantiomers could be metabolized by alternative pathways like CYP3A4 and sulfotransferases . This results in the less active R-enantiomer achieving higher concentrations in poor metabolizers, which may in the long term cause adverse effects like gastric carcinoids and enterochromaffin-like cell hyperplasia.[57],[58]

R-ondansetron: Free of QTc-prolonging potential of racemate
Significant QTc prolongation has been reported with 5-HT 3 receptor antagonists including ondansetron. Although the recorded QTc interval is less than that deemed to pose a risk of cardiovascular death, it is reasonable to assume that co-administration of ondansetron with medications that also prolong this interval would produce additive prolongation of QTc interval, increasing the risk.[59] In an experimental study in dogs, it was found that QTc was very prolonged among animals receiving S-ondansetron and racemic ondansetron and least prolonged among animals receiving R-ondansetron.[60] Significantly, two of the four dogs receiving S-ondansetron died during or shortly after the experiment, whereas all the dogs receiving the R-stereoisomer or the racemate survived. R-ondansetron was thus shown to have less cardiotoxicity than either S-ondansetron or racemic ondansetron. One more recent study conducted in rats demonstrated that S-enantiomer of ondansetron is responsible for QTc prolongation and R-ondansetron produced no QTc prolongation.[61] It may be noted that R-ondansetron is clinically more potent than the S isomer and clinical studies have found that the effective dose is half of the racemate in treatment of nausea and vomiting.[62] Thus a switch-over to its single R isomer from racemic ondansetron provides a potentially safer antiemetic alternative.

Safer single-isomer alternatives under evaluation
S-doxazosin
Dizziness and fainting due to hypotensive episodes are adverse effects of doxazosin, an alpha-1 adrenoceptor antagonist used for treatment of benign prostatic hyperplasia. S-doxazosin is thought to be selective for prostate receptors and at the same time expected to have lower incidence of hypotension.

S-oxybutynin
Racemic oxybutynin is used clinically to treat urinary incontinence and reportedly undergoes N-deethylation to metabolites R- and/or S-desethyloxybutynin. RS- and R-oxybutynin and RS- and R-desethyloxybutynin exhibit high antimuscarinic activity relative to their antispasmodic activity, while S-oxybutynin and S-desethyloxybutynin exhibit relatively weak antimuscarinic activity. S-oxybutynin deserves consideration for development as a single-enantiomer drug for the treatment of urinary incontinence with a lower incidence of antimuscarinic side effects.[63]

Dexnorcisapride
The dextrorotatory enantiomer of norcisapride, an active metabolite of cisapride, is a potentially safer alternative to cisapride, as preliminary studies have indicated that the former is devoid of various adverse effects seen with cisapride.[64]

Examples where the chiral switch was no safer
Fenfluramine is a racemic drug used as an appetite suppressant. ′Fen-phen,′ the combination of fenfluramine and the achiral anti-obesity drug phentermine, was widely used for weight loss. When dexfenfluramine, the S-enantiomer, came to the U.S. market in 1996, Fen-phen also came to mean the combination of dexfenfluramine and phentermine. Vigorous prescription of this new compound with the belief that the dextro isomer would be safer concealed the fatal adverse effects of fenfluramine which were retained in the dextro isomer. Both fenfluramine and dexfenfluramine were withdrawn from the market in 1997.[65]

The single S-isomer of sotalol increased mortality in patients with myocardial infarction. It should however be noted that S-isomer of sotalol is the non-beta-blocking isomer possessing class II anti-arrhythmic activity.[66]

Development of single beta-blocking R,R-stereoisomer, named dilevalol, of labetalol was terminated due to adverse effects associated with hepatotoxicity.[67] However, there are two chiral centers and hence four isomers in labetalol.

Pharmaceutical industry′s role in chiral switches
Pharmaceutical companies are in the forefront of pharmaceutical research and are responsible for providing chirally pure products for clinical use. However, the acceptance of any molecule (including chiral switches) would depend solely on its advantages vis-à-vis already existing products. Launching of chirally pure products from the racemate that has been already promoted requires considerable amount of time and monetary investments on its chemical separation and clinical evaluation. Obviously, industry would ensure its returns on investments. Successful emergence of a safer and more efficacious chiral switch is a welcome innovation in the health care system and merits incentives in the form of patents.

Conclusion

Clinical use of racemic mixtures has been the accepted practice since years. This has been partly caused by an early general ignorance about the role of chirality in pharmacology and later by the expense required to separate the stereoisomers on a large scale. With increasing knowledge about advantages of stereoselectivity, better methods have been developed to simplify the separation and preparation of stereoisomers. This has coincided with the regulatory authorities, like US-FDA, encouraging the development of single isomers.[68] Rather than using chiral synthetic drugs as racemates in the first instance, the activities and toxicities of the enantiomers now need to be tested individually. It is now the responsibility of the innovator to show why a drug should not be used as the single active enantiomer by comparing its efficacy and toxicity with the racemate. Some recent chiral switches discussed above have provided safer and/or more effective alternatives to the existing racemates. Putting chirality to work for development of safer molecules has yielded successful results. Several more chiral switches are expected to replace the racemates with safer options, making drug therapy more effective and safer.

References

1.McConathy J, Owens MJ. Stereochemistry in drug action. Prim Care Companion J Clin Psychiatry 2003;5:70-3.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Virtual textbook of organic chemistry. Downloaded from: http://www.cem.msu.edu/~reusch/VirtualText/intro1.htm;   Back to cited text no. 2    
3.March J. Advanced organic chemistry: Reactions, mechanism and structure. 4th ed. Wiley: New York; 1992.  Back to cited text no. 3    
4.Sokolov. Introduction to theoretical stereochemistry. Gordon and Breach: New York; 1991.  Back to cited text no. 4    
5.Baker DE. Esomeprazole magnesium (Nexium). Rev Gastroenterol Disord 2001;1:32-41.  Back to cited text no. 5    
6.Baltes E, Coupez R, Giezek H, Voss G, Meyerhoff C, Strolin Benedetti M. Absorption and disposition of levocetirizine, the eutomer of cetirizine, administered alone or as cetirizine to healthy volunteers. Fundam Clin Pharmacol 2001;15:269-77.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Cheng H, Rogers JD, Demetriades JL, Holland SD, Seibold JR, Depuy E. Pharmacokinetics and bioinversion of ibuprofen enantiomers in humans. Pharm Res 1994;11:824-30.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Mayrhofer F. Efficacy and long-term safety of dexibuprofen [S(+)-ibuprofen]: A short-term efficacy study in patients with osteoarthritis of the hip and a 1-year tolerability study in patients with rheumatic disorders. Clin Rheumatol 2001;20:S22-9.  Back to cited text no. 8  [PUBMED]  
9.Dexibuprofen. Drug evaluation monograph. Micromedex (R) Healthcare Series 2006;128.  Back to cited text no. 9    
10.Agranat I, Caner H, Caldwell J. Putting chirality to work: The strategy of chiral switches. Nat Rev Drug Discovy 2002;1:753-68.  Back to cited text no. 10    
11.Laufen H, Leitold M. Enantio selective disposition of oral amlodipine in healthy volunteers. Chirality 1994;6:531-6.  Back to cited text no. 11    
12.Waldeck B. Enantiomers of bronchodilating b-2-adrenoceptor agonists: Is there a cause for concern? J Allergy Clin Immunol 1999;103:742-8.  Back to cited text no. 12    
13.Handley DA, McCullough JR, Cowther SD, Morley J. Sympathomimetic enantiomers and asthma. Chirality 1998;10:262-72.  Back to cited text no. 13    
14.Page CP, Morley J. Contrasting properties of albuterol stereoisomers. J Allergy Clin Immunol 1999;104:S31-41.  Back to cited text no. 14    
15.Milgrom H, Skoner DP, Bensch G, Kim KT, Claus R, Baumgartner RA, et al . Low-dose levalbuterol in children with asthma: Safety and efficacy in comparison with placebo and racemic albuterol. J Allergy Clin Immunol 2001;108:938-45.  Back to cited text no. 15    
16.Nelson HS. Clinical experience with levalbuterol. J Allergy Clin Immunol 1999;104:S77-84.  Back to cited text no. 16    
17.Zeilhofer HU, Swandulla D, Geisslinger G, Brune K. Differential effects of ketamine enantiomers on NMDA receptor currents in cultured neurons. Eur J Pharmacol 1992;213:155-8.  Back to cited text no. 17    
18.Adams HA. Mechanisms of action of ketamine. Anaesthesiol Reanim 1998;23:60-3.  Back to cited text no. 18    
19.Ihmsen H, Geisslinger G, Schüttler J. Stereoselective pharmacokinetics of ketamine: R (-)-ketamine inhibits the elimination of S (+)-ketamine. Clin Pharmacol Ther 2001;70:431-8.  Back to cited text no. 19    
20.Himmelseher S, Pfenninger E. The clinical use of S-(+)-ketamine-a determination of its place. Anasthesiol Intensivmed Notfallmed Schmerzther 1998;33:764-70.  Back to cited text no. 20    
21.Bardsley H, Gristwood R, Baker H, Watson N, Nimmo W. A comparison of the cardiovascular effects of levobupivacaine and rac-bupivacaine following intravenous administration to healthy volunteers. Br J Clin Pharmacol 1998;46:245-9.  Back to cited text no. 21    
22.Ivani G, Borghi B, van oven H. Levobupivacaine. Minerva Anestesiol 2001;67:20-3.  Back to cited text no. 22    
23.Casati A, Baciarello M. Enantiomeric local anesthetics: Can ropivacaine and levobupivacaine improve our practice? Curr Drug Ther 2006;1:85-9.  Back to cited text no. 23    
24.McMahon LR, Jerussi TP, France CP. Steroselective discriminative stimulus effects of zopiclone in rhesus monkeys. Psychopharmacology 2003;165:222-8.  Back to cited text no. 24    
25.Georgiev V. (S)- Zopiclone sepracor. Curr Opin Invest Drugs 2001;2:271-3.  Back to cited text no. 25    
26.Leese P, Maier G, Vaickus L. Esopiclone: Pharmacokinetic and pharmacodynamic effects of a novel sedative hypnotic after daytime administration in healthy subjects (abstract 061.C). Sleep 2002;25:A45.  Back to cited text no. 26    
27.Devalia JL, De Vos C, Hanotte F, Baltes E. A randomized, double-blind, crossover comparison among cetirizine, levocetirizine and ucb28557 on histamine-induced cutaneous responses in healthy adult volunteers. Allergy 2000;56:50-7.  Back to cited text no. 27    
28.Wang DY, Hanotte F, De Vos C, Clement P. Effect of cetirizine, levocetirizine and dextrocetirizine on histamine-induced nasal response in healthy adult volunteers. Allergy 2001;56:339-43.  Back to cited text no. 28    
29.Tillement JP, Testa B, Bree F. Compared pharmacological characteristics in humans of racemic cetirizine and levocetirizine, two histamine H1-receptor antagonists. Biochem Pharmacol 2003;66:1123-6.  Back to cited text no. 29    
30.Gillard M, van Der Perren C, Moguilevsky N, Massingham R, Chatelain P. Binding characteristics of cetirizine and levocetirizine to human H(1) histamine receptors: Contribution of Lys(191) and Thr(194). Mol Pharmacol 2002;61:391-9.  Back to cited text no. 30    
31.Gandon JM, Allain H. Lack of effect of single and repeated doses of levocetirizine, a new antihistamine drug, on cognitive and psychomotor functions in healthy volunteers. Br J Clin Pharmacol 2002;54:51-8.  Back to cited text no. 31    
32.Hindmarch I, Johnson S, Meadows R, Kirkpatrick T, Shamsi Z. The acute and sub-chronic effects of levocetirizine, cetirizine, loratadine, promethazine and placebo on cognitive function, psychomotor performance and weal and flare. Curr Med Res Opin 2001;17:241-55.  Back to cited text no. 32    
33.Goldmann S, Stoltefuss J, Born L. Determination of the absolute configuration of the active amlodipine enantiomer as (-)-S: A correction. J Med Chem 1992;35:3341-4.  Back to cited text no. 33    
34.Zhang XP, Loke KE, Mital S, Chahwala S, Hintze TH. Paradoxical release of nitric oxide by an L-type calcium channel antagonist, the R+ enantiomer of amlodipine. J Cardiovasc Pharmacol 2002;39:208-14.  Back to cited text no. 34    
35.SESA study group, India. Safety and efficacy of S-Amlodipine. JAMA-India 2003;289:87-92.  Back to cited text no. 35    
36.SESA-II study group, India. Safety and efficacy of S(-)Amlodipine in the treatment of hypertension. Indian Med Gazette 2005;529-33.  Back to cited text no. 36    
37.Blankfield RP. Fluid matters in choosing antihypertensive therapy: A hypothesis that the data speak volumes. J Am Board Fam Pract 2005;18:113-24.  Back to cited text no. 37    
38.Cogolludo A, Perez-Vizacaino F, Tumargo J. New insights in the pharmacological therapy of arterial hypertension. Curr Opin Nephrol Hypertens 2005;14:423-7.  Back to cited text no. 38    
39.Baker JG. The selectivity of beta-adrenoceptor antagonists at the human beta-1, beta-2 and beta-3 adrenoceptors.Br J Pharmacol 2005;144:317-22.  Back to cited text no. 39    
40.Dart RA, Gollub S, Lazar J, Nair C, Schroeder D, Woolf SH. Treatment of systemic hypertension in patients with pulmonary disease: COPD and asthma. Chest 2003;123:222-43.  Back to cited text no. 40    
41.Mehvar R, Brocks D. Stereospecific pharmacokinetics and pharmacodynamics of β-adrenergic blockers in humans. J Pharm Pharmaceut Sci 2001;4:185-200.   Back to cited text no. 41    
42.Nathanson JA. Stereospecificity of beta adrenergic antagonists: R-enantiomers show increased selectivity for beta-2 receptors in ciliary process. J Pharmacol Exp Ther 1988;245:94-101.  Back to cited text no. 42    
43.Benny K, Adithan C. Genetic polymorphism of CYP2D6. Indian J Pharmacol 2001;33:147-69.  Back to cited text no. 43    
44.Lennard MS. Genetic polymorphism of sparteine/debrisoquine oxidation: A reappraisal. Pharmacol Toxicol 1990;67:273-83.   Back to cited text no. 44    
45. Lennard MS, Tucker GT, Silas JH, Freestone S, Ramsay LE, Woods HF. Differential stereoselective metabolism of metoprolol in extensive and poor debrisoquin metabolizers. Clin Pharmacol Ther 198;34:732-7.  Back to cited text no. 45    
46.Lennard MS, Silas JH, Freestone S, Ramsay LE, Tucker GT, Woods HF. Oxidation phenotype-A major determinant of metoprolol metabolism and response. N Engl J Med 1982;307:1558-60.  Back to cited text no. 46    
47.Hemeryck A, Lefebvre RA, De Vriendt C, Belpaire FM. Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharmacol Ther 2000;67:283-91.  Back to cited text no. 47    
48.Toon S, Davidson EM, Garstang FM, Batra H, Bowes RJ, Rowland M. The racemic metoprolol H2-antagonist interaction. Clin Pharmacol Ther 1988;43:283-9.  Back to cited text no. 48    
49.Waite NM. Disposition of the (+) and (-) isomers of metoprolol following ciprofloxacin treatment. Pharmacotherapy 1990;10:236.  Back to cited text no. 49    
50.Kim M, Shen D, Eddy A, Nelson W, Roskos LK. Inhibition of the enantioselective oxidative metabolism of metoprolol by verapamil in human liver microsomes. Drug Metab Dispos 1993;21:309-17.  Back to cited text no. 50    
51.McCoy RA, Clifton D, Clementi WA, Smith MD, Garvey TQ, Wermeling DP, et al . Pharmacodynamics of racemic and S(-)-atenolol in humans. J Clin Pharmacol 1994;34:816-22.  Back to cited text no. 51    
52.Stoschitzky K, Egginger G, Zernig G, Klein W, Lindner W. Stereoselective features of (R)- and (S)-atenolol: Clinical pharmacological, pharmacokinetic and radioligand binding studies. Chirality 1993;5:15-9.  Back to cited text no. 52    
53.Pathak L, Thacker H, Jayaram S, Sharma S, Mannikar J, Apte D. Randomized, double blind, parallel group, multicentric clinical trial of Atpure (S-atenolol 25 mg) versus racemic atenolol 50 mg in stage 1 and 2 hypertension. JAMA-India 2004;3:71-5.  Back to cited text no. 53    
54.Jayaram S, Kaul U, Pai V, Pandit A, Pathak L, Shinde SN, et al . The SMART Trial (S-metoprolol assessment in hypertension trial). Cardiol Today 2005;9:222-9.  Back to cited text no. 54    
55.Cao H, Wang M, Jia J, Wang Q, Cheng M. Comparison of the effects of pantoprazole enantiomers on gastric mucosal lesions and gastric epithelial cells in rats. J Health Sci 2004;50:1-8.  Back to cited text no. 55    
56.Cao H, Wang M, Sun L, Ikejima T, Hu Z, Zhao W. Pharmacodynamic comparison of pantoprazole enantiomers: Inhibition of acid related lesions and acid secretion in rats and guinea-pigs. J Pharm Pharmacol 2005;57:923-7.  Back to cited text no. 56    
57.Tybring G, Bottiger Y, Widen J, Bertilsson L. Enantioselective hydroxylation of omeprazole catalyzed by CYP2C19 in Swedish white subjects. Clin Pharmacol Ther 1997;62:129-37.  Back to cited text no. 57    
58.Tanaka M, Ohkubo T, Otani K, Suzuki A, Kaneko S, Sugawara K, et al . Stereoselective pharmacokinetics of pantoprazole, a proton pump inhibitor, in extensive and poor metabolizers of S-mephenytoin. Clin Pharmacol Ther 2001;69:108-13.  Back to cited text no. 58    
59.Goodin S, Cunningham R. 5-HT3 receptor antagonists for the treatment of nausea and vomiting: A reappraisal of their side-effect profile. Oncologist 2002;7:424-36.  Back to cited text no. 59    
60.Rubin PD, Barberich TJ. Methods for treating apnea and apnea disorders using optically pure R(+) ondansetron downloaded from http://patft.uspto.gov.  Back to cited text no. 60    
61.Bodhankar SL, Maurya OP. Effect of racemate ondansetron and its isomers on QTc interval in rats. Pharmacology. Data on file 2006.  Back to cited text no. 61    
62.Shinde J. R-Ondansetron-A novel antiemetic. Gastroenterol Today 2005;IX:132-3.  Back to cited text no. 62    
63.Smith ER, Wright SE, Aberg G, Fang Y, McCullough JR. Comparison of the antimuscarinic and antispasmodic actions of racemic oxybutynin and desethyloxybutynin and their enantiomers with those of racemic terodiline. Arzneimittelforschung 1998;48:1012-8.  Back to cited text no. 63    
64.Peeters OM, Blaton NM. (+)-(3S,4R)-Norcisapride hydrogen (2R,3R)-tartrate monohydrate. Acta Cryst 2002;E58:o1169-71.  Back to cited text no. 64    
65.Rouhi M. Chirality at work: Drug developers can learn much from recent successful and failed chiral switches. CEN 2003;81:56-61.  Back to cited text no. 65    
66.Waldo AL, Camm AJ, deRuyter H, Friedman PL, MacNeil DJ, Pauls JF, et al . Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet 1996;348:7-12.  Back to cited text no. 66    
67.Hutt AJ, Valentovα J. The chiral switch: The development of single enantiomer drugs from racemates. Acta Facult Pharm Univ Comenianae 2003;50:7-23.  Back to cited text no. 67    
68.FDA's policy statement for the development of new stereoisomeric drugs. http://www.fda.gov/cder/guidance/stereo.htm.  Back to cited text no. 68    

Copyright 2006 - Indian Journal of Medical Sciences


The following images related to this document are available:

Photo images

[ms06065f1.jpg] [ms06065f3.jpg] [ms06065f2.jpg]
Home Faq Resources Email Bioline
© Bioline International, 1989 - 2019, Site last up-dated on 15-Ago-2019.
Site created and maintained by the Reference Center on Environmental Information, CRIA, Brazil
System hosted by the Internet Data Center of Rede Nacional de Ensino e Pesquisa, RNP, Brazil