association of physicians of india: position …fl v 65 fl december 2017 49 association of...

Journal of The Association of Physicians of India ■ Vol. 65 ■ December 2017 49

Association of Physicians of India: Position Statement on Role of Chirally Pure Molecules in Clinical PracticeMilind Y Nadkar1, Mangesh Tiwaskar2, Sanjay Kalra3, Siddharth N Shah4, BR Bansode5, Anjanlal Dutta6, Sarita Bajaj7, Sameer Aggarwal8, Yatan Pal Singh Balhara9, AK Das10, Puneet Dhamija11, YK Gupta12, Jubbin Jacob13, Sundeep Mishra14, SN Narasingan15, CK Ponde16, Ram Prabhoo17, Balakrishnan S18, Manisha Sahay19, RK Sahay20, I Sathyamurthy21, Shilpa Tiwaskar22, Agam Vora23

P O S I T I O N S T A T E M E N T

1Department of Medicine and Rheumatology, Seth GS Medical College, Mumbai, Maharashtra; 2Department of Medicine, Shilpa Medical Research Center, Mumbai, Maharashtra; 3Department of Endocrinology, Bharti Hospital, Karnal, Haryana; 4Department of Diabetology, Bhatia Hospital, Saifee Hospital, S.L. Raheja Hospital and Reliance H.N. Hospital, Mumbai, Maharashtra; 5Department of Medicine & Cardiology, Bharat Ratna Dr. Babasaheb Ambedkar Memorial Hospital, Mumbai, Maharashtra; 6Department of Cardiology, Peerless Hospital, Kolkata, West Bengal; 7Department of Medicine, MLN Medical College, Allahabad, Uttar Pradesh; 8Pt. Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Haryana; 9Department of Psychiatry, All India Institute of Medical Sciences, New Delhi; 10Department of Medicine and Endocrinology, Pondicherry Institute of Medical Sciences, Pondicherry; 11Department of Pharmacology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand; 12Department of Pharmacology, All India Institute of Medical Sciences, New Delhi; 13Endocrine and Diabetes Unit, Christian Medical College and Hospital, Ludhiana, Punjab; 14Department of Cardiology, All India Institute of Medical Sciences, New Delhi; 15Prof. M Vishwanathan Diabetes Research Center and SNN Specialties Clinic and Diagnostic Center, Chennai, Tamil Nadu; 16Department of Cardiology, P.D. Hinduja National Hospital, Mumbai, Maharashtra; 17Department of Orthopedics, Mukund Hospital, Mumbai, Maharashtra; 18Department of Pharmacology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh; 19Department of Nephrology, Osmania Medical College and Hospital, Hyderabad, Telangana; 20Department of Endocrinology, Osmania Medical College and Hospital, Hyderabad, Telangana; 21Department of Interventional Cardiology, Apollo Hospitals, Chennai, Tamil Nadu; 22Department of Anesthesiology, Bhaktivedant Hospital, Mumbai, Maharashtra; 23Department of Chest and Tuberculosis, Vora Clinic, Mumbai, MaharashtraReceived: 11.09.2017; Accepted: 20.09.2017

Abstract Chirally pure molecules or enantiomers are non-superimposable mirror images of each other with a chiral center (such as carbon, sulphur, nitrogen or phosphorous atom). An equimolar mixture of enantiomers forms a racemate. Chirally pure molecules (single enantiomers) are important in the field of drug discovery as the drug targets such as enzymes and receptors are enantioselective in nature. Clinical studies have demonstrated that chirally pure drugs exhibit different pharmacokinetic and metabolic profiles, reduced adverse events, improved safety profiles and similar therapeutic activity at lowered drug dosage as compared with the racemate in many therapeutic areas. However, since there is a low level of awareness on the advantages of chirally pure molecules among clinicians, pharmacists and patients in India, the Association of Physicians of India (API) developed this position statement to increase awareness on the concept of chirality and the associated advantages of using chirally pure drugs in certain therapeutic areas to maximize patient outcomes. This includes the clinical evidence associated with single enantiomers such as S-metoprolol, S-amlodipine, esomeprazole, escitalopram, levobupivacaine, cisatracurium, S-etodolac, dexketoprofen, levofloxacin in terms of efficacy and safety as compared with their racemates. In addition, the API also provides some tactical recommendations for clinicians, pharmacists, patients, regulatory body and pharmaceutical companies to increase awareness on chirally pure drugs and puts forth the need for expedited availability of chirally pure drugs in the Indian market.

Introduction

Chirality has gained considerable attention in pharmaceutical

drug development as there is a greater understanding on the implications of single-enantiomers in improving drug therapeutic profile.1 The global trend towards development of single enantiomers as new drugs for various diseases started in the late 1980s and chiral molecules comprised almost half the marketed drugs by 2000. 1 Between January 2010 to November 2014, 127 new molecular entities (NMEs) were approved by the United States Food and Drug

Journal of The Association of Physicians of India ■ Vol. 65 ■ December 201750

Administration (US FDA) of which 81 (64%) were chiral drugs with single enantiomers as a majority.2 Thus there is a trend towards the development of single enantiomers over racemic mixtures in drug development. Chiral drugs are also available in India but there is a need for generating awareness among clinicians (including academicians and researchers) , pharmacists and patients about the potential benefits of chirally pure drugs.

The word ‘chiral’ is derived from the Greek word ‘cheir’ which stands for ‘hand’ or handedness (Figure 1). Chiral molecules or enantiomers can be compared to the r ight and left hand i.e. the molecules cannot be superimposed on each other and comprise a chiral center (e.g., carbon, sulphur, nitrogen or phosphorous atom).3 Isomers are the molecules with similar molecular formula but different chemical structure. They are further classified into stereoisomers that di f fer in the spat ia l or three-d i m e n s i o n a l a r r a n g e m e n t o f atoms. Configurational isomers are stereoisomers that cannot be converted to one another by rotation around a single bond. Enantiomers are configurational isomers that are non-superimposable mirror images of one another. 3 Based on the standard nomenclature used, enantiomers are classified as rectus (R) or sinister (S) based on atomic mass and number (Figure 2) . A racemate is an optical ly inactive, equimolar mixture of two enantiomers and at times could have different properties than either of the pure enantiomers.3 Chirality is an integral part of nature, such as some naturally occurring flavonoids like pisatin, medicarpin, vestiton.4 Similarly, i n b i o l o g i c a l s y s t e m s , a m i n o acids, carbohydrates, nucleosides, proteins, enzymes, and hormones are chiral compounds.3 Receptors and enzymes are proteins (composed of amino acids), that bind their l igands in an enantioselect ive manner . 5 Hence , in des igning

Fig. 1: Chiral molecules

Fig. 2: Nomenclature in chiral chemistry


molecules for drug targets such as proteins or enzymes, chirality is increasingly important.

The concept of chiral separation was f irst introduced by Louis Pasteur in 1848, in separating enantiomers of sodium ammonium t a r t r a t e . 6 S i n c e t h e n , c h i r a l technology has made tremendous p r o g r e s s w i t h a d v a n c e s i n the synthesis , separation, and analys is o f pure enant iomers f rom racemates . 7 Chira l drug development includes development of a single enantiomer or switching over to a single enantiomer from an already existing racemate or the development of a fixed ratio of enantiomers.8 Single enantiomers or chiral ly pure drugs exhibit different pharmacological activity and metabol i sm as compared to the other enantiomer in the racemate.9,10 They may provide advantages of s imilar eff icacy at lower doses, improve safety and reduce the metabolic load if therapeutic activity is associated with one enantiomer.11

The importance of chiral i ty was evident in the thalidomide tragedy. Thalidomide, an anti-emetic prescribed for morning sickness in pregnant women, was a racemic mixture wherein the active

R-enantiomer was associated with efficacy and the S-enantiomer was responsible for teratogenicity. The racemate led to phocomelia (failure of limb development) in infants thus resulting in its withdrawal.12,13 This tragedy (1961-1962) made scientists reflect on the significance of s ingle enantiomers in drug development.

Chiral drugs are available in India and with the aim to increase awareness on these drugs among clinicians (including academicians and researchers), pharmacists and patients, a panel meeting was held under the aegis of the Association of Physicians of India (API) to discuss chirally pure drugs in different therapeutic areas and the regulatory considerations followed by other countries on chiral drugs (2 nd July , 2017 , Mumbai) . The panel of 23 members comprised of anesthesiologist, cardiologists, endocrinologists, orthopedician, nephrologist, pharmacologists, p h y s i c i a n s , p u l m o n o l o g i s t , psychiatrist, and rheumatologist practicing in different regions across India. The discussion was based on chiral drug development and associated challenges, the regulatory cons iderat ions for chiral drugs in different countries and the advantages of some of

the chiral ly pure drugs in the therapeutic areas based on the clinical expertise of the panelists. This position statement provides recommendations on generating awareness on the potential benefits of chiral ly pure drugs among regulatory bodies, pharmaceutical companies, clinicians, pharmacists, a n d p a t i e n t s . T h i s p o s i t i o n statement puts forth the need for expedited availability of these drugs in the Indian market.

Chiral Switching and Advantages of Chirally Pure Drugs

Chiral or racemic switching is the development of single enantiomers from previously approved and marketed racemic mixtures or mixtures of diastereomers.14 Single enantiomers developed from the racemate, have different qualitative and quantitative, pharmacodynamic and pharmacokinetic properties.15 A large number of “old” racemic mixtures have been re-examined for their potential to be developed a s s i n g l e e n a n t i o m e r s w i t h more se lec t ive and enhanced therapeutic profiles (Figure 3) and possibly for newer indications. However for many racemic drugs the stereospecificity is yet to be evaluated.

L e v o c e t i r i z i n e , a s i n g l e -enantiomer of cetirizine (racemate), is an anti-histamine used in the alleviation of allergy symptoms.16 It demonstrates higher H1 receptor a f f in i ty , i s s tereoisomerica l ly stable in vivo, and has low renal c l e a r a n c e a s c o m p a r e d w i t h dextrocetirizine.17 Less sedation has been reported with levocetirizine leading to a better s ide effect profile as compared with cetirizine, consequently advancing its use in therapy.18 Thus single enantiomers may also display reduced adverse effects in comparison to racemic mixtures.

An active enantiomer may also demonstrate similar therapeutic activity with better safety profiles

Fig. 3: Chiral switch


at lowered drug dosage. Ibuprofen, a non-steroidal anti-inflammatory drug, is commonly prescribed as an analgesic and antipyretic in adults and children.19,20 Dexibuprofen, the S-enantiomer of ibuprofen, has demonstrated similar efficacy at half the dose of ibuprofen. Its potential advantages include less toxicity, lowered variability in therapeutic effects as well as r e d u c e d r e n a l a n d m e t a b o l i c load on the body. Additionally, dexibuprofen does not demonstrate cardiac toxicity associated with R-enantiomer thus providing an improved safety profile.21-23

Additional advantage of chirally p u r e d r u g s i n c l u d e l o we r e d d r u g - d r u g i n t e r a c t i o n s . 2 2 , 2 4 A stereoselective interaction was observed between metronidazole a n d S - w a r f a r i n ; w h e r e i n metronidazole inhibits cytochrome P450 2C9 isozyme (CYP2C9) that is primarily responsible for the metabol i sm of S -warfar in . 25-27 Interactions between warfarin and metronidazole can be prevented by using R-warfarin instead of the commonly used racemic mixture.

E n a n t i o m e r s a l s o e x h i b i t d i f f e r e n t p h a r m a c o l o g i c a l mechanism of action and therefore can be used potentially for different therapeutic indications. For e.g., quinine has antimalarial activity while quinidine (stereoisomer of quinine) has an anti-arrhythmic property, levomethorphan is a potent opioid analgesic while

dextromethorphan is an ant i -tussive.28,29

S i n g l e e n a n t i o m e r s o f a chiral drug often demonstrate d i s c r e t e d i f f e r e n c e s i n t h e i r pharmacokinetic and metabolic profiles both quantitatively and qualitatively. Thus prospective d i s c r i m i n a t i o n b e t w e e n t h e metabolites of enantiomers at each pharmacokinetic stage is easier with single enantiomers (Figure 4).7,11

Development of Chirally Pure Drugs and Associated Challenges

Single enantiomers are purified from racemic mixtures by utilizing classical resolution techniques or other modern technologies. C l a s s i c a l r e s o l u t i o n s u t i l i z e a c i d - b a s e r e a c t i o n s l e a d i n g t o s e p a r a t i o n o f t h e s i n g l e enantiomers from the mixture. Further separation is carried out by crystallization of the two salts, by filtration of the soluble salt from the insoluble one or by liquid chromatography. Kinetic resolution utilizing biological catalysts (e.g., yeasts, molds, bacteria) to degrade one enantiomer and hence separate the other that remains in solution is another classical method for chiral separation.30

C o m m o n l y u s e d m o d e r n technologies for chiral separation include high performance liquid chromatography (HPLC) with

ch i ra l s ta t ionary phases tha t d i r e c t l y s e p a r a t e t h e s i n g l e enantiomers. Simulated moving bed chromatography and chiral cata lysts are a lso ut i l ized for chiral separat ion. For c l inical chemical analysis of biosamples, HPLC and gas chromatography are used. For bioanalysis of the chiral drug, HPLC, gas chromatography, supercritical fluid chromatography, and capillary electrophoresis are performed. Chiral immunoassays c a n a l s o b e p e r f o r m e d t o analyze the quantity of s ingle e n a n t i o m e r f r o m b i o l o g i c a l samples.3 Challenges associated w i t h d e v e l o p m e n t o f s i n g l e enantiomers include development and standardization of processes for separation and characterization of single enantiomers, scale-up of a synthetic route of separation for the continuous production of the single enantiomer, requirement of pure enantiomer and racemate to initiate the process, and development of sensitive and specific analytical assays to differentiate enantiomers from racemic mixtures throughout t h e p r e c l i n i c a l , c l i n i c a l , a n d production cycle of the drug.8

Regulatory Considerations for Developing Chirally Pure DrugsUnited States Food and Drug Administration guidelines

The US FDA published their pol icy on the development of new stereoisomeric or chirally pure drugs in 1992 (Table 1). 31 This pol icy focusses on some general as well as specific issues including chemistry, methodology a n d s p e c i f i c a t i o n o n d r u g s , pharmacology, pharmacokinetics, toxicology and the permissible impuri ty l imits in re lat ion to chirally pure drugs. The policy requires that for all chiral drugs, the quantitative isomeric composition of the material be identified early on in the drug development process and the information specif ied during the drug approval process.

Fig. 4: Advantages of chirally pure drugs


The FDA may guide the sponsors on developing a single enantiomer o r t h e r a c e m a t e . A l t h o u g h , the final decision lies with the sponsor company, the rationale for developing either enantiomer or racemate must be clarified in the drug approval application.31 European Medicines Agency Guidelines

T h e E u r o p e a n M e d i c i n e s A g e n c y ( E M A ) g u i d e l i n e s (1994)32 in addition to the FDA guidelines recommend that a single enantiomer drug developed from an approved racemic mixture would be considered as a new application, wherein the rationale behind the development should b e m e n t i o n e d ( Ta b l e 1 ) . T h e enantiomeric purity of the single enantiomer should be defined and the possibility of inversion in vivo should be considered.International Conference on Harmonization of Technical Requirements Guidelines 6QA

The International Conference on Harmonization (ICH) of Technical Requirements guidelines (1999) 6QA for the ‘Test procedures and acceptance criteria for new drug substances and new drug products: chemical substances’ is followed by many countries (Table 1) . 33 These guidelines like the others, r e c o m m e n d e n a n t i o s e l e c t i v e determination of drug substance u t i l i z i n g c h i r a l a s s a y s a n d

c o n t r o l l i n g f o r e n a n t i o m e r i c impurities. The efficacy and safety must be analyzed by a chiral assay that is able to distinguish between the two isomers. Health Canada guidelines

The Health Canada guidelines (2000)34 also lets the sponsor decide whether a racemic mixture or single enantiomer is to be developed but recommends that the decision be driven by safety, efficacy, quality and risk-benefit assessment data. The recommendations are similar to those proposed by the FDA (Table 1). Regulatory Considerations followed by India

The Central Drug Standard Control Organization (CDSCO) of India has published a “Guidance for the industry on the preparation of common technical document for import/manufacture and marketing approval of new drugs for human use” that is based on the ICH Harmonised Tripartite Guideline on “Organisation of the Common Te c h n i c a l D o c u m e n t f o r t h e Registration of Pharmaceuticals for Human Use” M4, Step 4 (2004).33,35 India follows these guidelines for the approval of new drugs. For chiral drugs, the guideline recommends that the spec i f ic stereoisomer be mentioned in the characterization of drug and also if the final product intended for

marketing is the same stereoisomer that has been investigated in the non-clinical and clinical studies. Additionally, if the molecule is a racemate or a single enantiomer t h e n t h e i m p l i c a t i o n s o f a n y difference between the compound invest igated and intended for marketing should be clarified in the documents.35 There are no special guidelines recommending the drug approval processes of chirally pure drugs in India.

In India, the registration pattern for approval of single enantiomers (with efficacy and safety established in other countries) is similar to that of new drugs. All the studies done for new drugs in the Indian subpopulation are also required for chiral drug approval in India even though they have been approved by other countries. Since the Indian regulatory requirements for chirally pure drugs are extensive, there may be a delay in their availability to Indian patients.

Therapeutic Areas Currently Employing Chirally Pure Drugs

C h i r a l l y p u r e d r u g s a r e prescribed as therapy in the areas of cardiology, gastroenterology, neuropsychiatry, rheumatology, etc. (Table 2). Some of them are briefly discussed below as a part of this review.

Table 1: Regulatory guidelines on single enantiomer drug development

United States Food and Drug Administration guidelines, 1992

European Medicines Agency guidelines, 1994

International Conference on Harmonization of Technical Requirements guidelines 6QA, 1999

Health Canada guidelines, 2000

Focusses on chemistry, methodology and specification of drugs, pharmacology, pharmacokinetics, toxicology of single enantiomers

Single enantiomer from racemate will be a new application

Enantioselective determination of drug substance utilizing chiral assays and controlling for enantiomeric impurities

Enantioselective tests to be performed for identification and purity of single enantiomer

Stereospecific activity to be identified in early drug development utilizing stereospecific identity or a stereochemically selective assay method

Reproductive toxicity studies to include pre and post-natal treatment effects from conception

Chirally pure drug to comprise limited amount of second enantiomer (considered an impurity)

Enantiomer stability in vivo and also in stability studies for the shelf life testing of the drug

For switching to single enantiomer, bridging studies are to be conducted that include the longest repeat-dose toxicity studies and reproductive toxicity studies

Bioinversion to be considered Chiral specific assays for safety and efficacy studies

Metabolism of enantiomer to be followed enantioselectively from pre-clinical studies to phase 1.

Rationale for developing single enantiomer must be clarified in the drug approval application.


Cardiology

Hypertension, a risk factor for stroke and other cardiovascular diseases, is treated with beta-blockers , some of which exist as R- and S-enantiomers having different pharmacokinetic and pharmacodynamics properties.36-38

The S-enantiomer of metoprolol possesses higher affinity towards t h e b1 r e c e p t o r a s c o m p a r e d with the R-enantiomer (S:R=33:1, beta blocking act ivi ty) , hence S-metoprolol may be preferred in the treatment of hypertension.38 In a double-blind, randomized c l i n i c a l t r i a l , S - m e t o p r o l o l (50 mg, extended-release [ER]) demonstrated a 13.6% increase in responders (>20 mm Hg reduction in sys to l i c b lood pressure or reduction of >10 mm Hg in diastolic b lood pressure) on day 21 as compared with racemic metoprolol (100 mg) with comparable safety.39 Similarly, in another prospective trial , S-metoprolol (25 mg and 50 mg ER) was wel l tolerated with a responder rate of 80% (on day 28) in the treatment of hypertension.40 An open-label , prospective, comparative study reported that the response rate was higher with S-metoprolol (74%, 50 mg ER) as compared with metoprolol (61%, 100 mg ER) in hypertensive patients with angina. There was no significant difference in frequency and severity of adverse events between groups.41 Another open- labe l , prospect ive , non-comparative study reported that the S-metoprolol succinate (6.25-50

mg, ER tablet) was effective in reducing the blood pressure, heart rate and improving symptoms in hypertensive pat ients with congestive heart failure (CHF). The side effects were fatigue and dyspnea , which were mi ld in nature.42 Another similar study r e p o r t e d t h a t S - m e t o p r o l o l succinate (50 mg, ER) was safe and effective in the treatment of hypertension in pat ients with chronic obstructive pulmonary disease.43 S-metoprolol was also e f f icac ious in reducing blood pressure in Indian patients with co-existing illnesses such as chronic obstructive pulmonary disease, angina, angina co-existent with diabetes mellitus, and CHF without major safety concerns.44

A p h a s e 3 , m u l t i c e n t e r , r a n d o m i z e d s t u d y i n K o r e a n patients with mild to moderate h y p e r t e n s i o n d e m o n s t r a t e d a r e s p o n s e r a t e o f 9 2 . 7 % f o r blood pressure reduction with S-amlodipine (2 .5 mg, a long acting L-type calcium channel b locker ) as compared to 88% r e s p o n d e r s w i t h a m l o d i p i n e besylate (5 mg). Thus S-amlodipine was therapeutically equivalent and non-inferior to amlodipine besylate.45 Similar results were reported in Indian hypertensive patients.46 A prospective study in Indian hypertensive patients using S-amlodipine (2.5-5 mg) therapy reported low incidence of pedal edema (0.75%) which is a common side-effect of calcium channel blockers.47 In a post marketing study (n=1076), pedal edema was

reported in 51% (300/589) patients using amlodipine. Upon initiation of S-amlodipine (2.5 mg or 5 mg), edema resolved in 95.67% (287/300) patients. Post 30 days of therapy, edema was observed in 1 .77% patients compared to 31.88% before therapy (p<0.0001).48 S-atenolol (25 mg) has demonstrated efficacy s imilar to atenolol (50 mg) in patients with hypertension.49 Thus, the S-enantiomers of metoprolol, a m l o d i p i n e a n d a t e n o l o l demonstrated similar efficacy at half the dose of the racemate and they are currently marketed in India.38

Gastroenterology

D i s e a s e s s u c h a s gastroesophageal reflux disease (GERD) , Barre t t ’ s esophagus , Zollinger-Ellison syndrome and peptic ulcers are treated using proton-pump inhibitors (PPIs) that block H, K-ATPase thereby inhibit gastric acid secretion.50 The PPIs belong to the class of substituted benzimidazoles with a chiral sulphur. S-omeprazole (also known as esomeprazole), was the first chirally pure PPI which was developed due to its higher metabolic stability (chiral stability i . e . res i s tant to invers ion , as observed in humans). It has higher bioavai labi l i ty and less inter-patient variability as compared to omeprazole in clinical studies.51,52

A s y s t e m a t i c a n a l y s i s h a s d e m o n s t r a t e d a s i g n i f i c a n t l y higher odds of maintaining the gastric pH >4 with esomeprazole as compared with omeprazole (odds

Table 2: Commonly utilized chirally pure drugs

Cardiology Gastroenterology Neuropsychiatry Endocrinology Anaesthesia Rheumatology, pain and inflammation

Pulmonology Infectious diseases

Anti-anginal Esomeprazole Anti-convulsants/ Sedatives/Hypnotics

Levothyroxine S-etomidate S-penicillamine Levosalbutamol Levofloxacin [S-ofloxacin]

S-amlodipine S-pantoprazole S-fluoxetine S-ketamine S-etodolac LevocetirizineAntihypertensive Dexrabeprazole S-zopiclone Levobupivacaine Dexketoprofen

[S-ketoprofen]R-formoterol

S-metoprolol Anti-Parkinson Ropivacaine Dexibuprofen [S-ibuprofen]

S-atenolol Levodopa CisatracuriumS-amlodipine Anti-depressant

Escitalopram


ratio=1.57; CI=1.04, 2.38; p=0.03).53 In three studies, S-omeprazole also demonstrated superiority as compared to omeprazole in the treatment of GERD (odds ratio=1.18; CI=1.01,1.38; p=0.04).53 Since 3% of Caucasians and 15% of the Asian population are poor metabolizers of the P450 cytochrome system, the metabolites of the racemic mixture are intrinsically cleared three times slower as compared to the chirally pure esomeprazole. This is the primary cause for the plasma concentration variability of the racemic mixture in patients but is advantageous for esomeprazole as i t e l iminates the need for dose adjustment in patients with mild-moderately severe hepatic impairment.54

In a multi-center, double-blind, randomized study, S-pantoprazole ( 2 0 m g , S - e n a n t i o m e r o f p a n t o p r a z o l e ) d e m o n s t r a t e d efficacy and safety similar to that of pantoprazole (40 mg) at half the dose, in patients with GERD.55 In another study conducted in patients from India with GERD, on day 28, S-pantoprazole (20 mg) therapy led to improvement in symptoms of acid regurgitation (relat ive r isk reduction [RRR] 13%), heart burn (RRR 15%) and bloating (RRR 13%) as compared with pantoprazole.56 Additionally, S-pantoprazole also demonstrated efficacy in GERD patients with or without predominant nocturnal symptoms and peptic ulcer patients (gastric ulcer/duodenal ulcer ).57 Similarly, dexrabeprazole (10 mg, the S-enantiomer of rabeprazole), l e d t o l o w e r i n c i d e n c e s o f regurgitation, residual esophagitis and improved healing as compared with the racemate rabeprazole (20 mg) in patients with GERD.58

Neuropsychiatry

Citalopram, a selective serotonin reuptake inhibitor, is commonly used in psychiatric practice for the treatment of major depressive and anxiety disorders. Escitalopram, S-enantiomer of citalopram, is 30 times more potent as compared to

the R-enantiomer (also counteracts the activity of the S-enantiomer).59 An expert opinion article reviewing data from multiple clinical trials reported that escitalopram has demonstrated evidence of efficacy as early as 2 weeks, reduced risk of re lapse over 36 weeks and reduced symptoms of depression.60 Escitalopram has reduced affinity f o r p o s t - s y n a p t i c r e c e p t o r s , which reduces the possibility of adverse events associated with other psychotropic molecules.60 A pooled analys is compar ing esc i ta lopram with c i ta lopram demonstrated higher number of responders with escitalopram at different time points.61 A meta-analysis of randomized clinical trials demonstrated better response (odds ratio=1.44, 95% CI=1.18; 1 .75 , p=0.0003) and remiss ion (odds ratio=1.86, 95% CI=1.46; 2.36, p <0.0001) with escitalopram as compared with citalopram.62 Additionally, the QTc interval prolongation of escitalopram was half (4.5 ms at 10 mg) as compared with citalopram (8.5 ms at 20 mg).63

S-fluoxetine, an enantiomer of fluoxetine (racemate) used as an anti-depressant, demonstrated a rapid onset of action, higher efficacy and lower rate of adverse e ve n t s i n a p h a s e 2 t r i a l f o r migraine as compared with the racemate.64 R-fluoxetine reported s i g n i f i c a n t p r o l o n g a t i o n o f cardiac repolarization at higher doses.65 S-zopiclone, a sedative h y p n o t i c h a s d e m o n s t r a t e d e f f i c a c y i n t h e t r e a t m e n t o f primary chronic insomnia, with no added requirement of dose adjustment in patients with renal failure.66 The anxiolytic effect of S-zopiclone was not associated with substantial central nervous system depression as reported for the racemate zopiclone.67 The racemate 3 , 4 - d i h y d r o x y p h e n y l a l a n i n e (Dopa) was replaced by levodopa, the L-enantiomer, due to side-effects such as granulocytopenia.68 O x a z e p a m , a n a n x i o l y t i c , i s a racemic mixture with rapid

interconversion amongst the two enantiomers that is faster than the time required for onset of drug action at ambient temperature. Separation of the enantiomers i s n o t p o s s i b l e a s o x a z e p a m presents a unique case of a rapidly interconverting chiral molecule.69

Endocrinology

Levothyroxine (an enantiomer o f t h y r o x i n e ) i s c o m m o n l y prescribed for the treatment of hypothyroidism. A dose of 150 µg of levothyroxine is equipotent to 4000 µg of dextrothyroxine i n r e d u c i n g s e r u m t h y r o i d stimulating hormone, triglycerides, cholesterol , and phospholipid levels in hypothyroid patients.70

Po lycys t i c ovary syndrome (PCOS) is commonly reported cause of infertility in women of reproductive age. Insulin resistance is one of the common reasons for abnormal ovarian function.71 Myo-inositol (MI) and D-chiroinositol (DCI) (both isomers of inositol), u s e d a s i n s u l i n s e n s i t i z e r s , demonstrated beneficial effects at metabolic, hormonal, and ovarian level as therapy for PCOS.72,73 The most abundant natural isoform of inositol is MI whereas DCI is formed by epimerization of MI to DCI. Both isomers exhibit different functions i.e. MI improves ovarian function and DCI reduces hyperinsulinemia.72,73 Thus, the combined administration of MI with DCI synergistically aids in correcting hormonal and metabolic imbalance in PCOS patients.74 Anesthesia

E t o m i d a t e , a s h o r t - a c t i n g anesthetic drug induces sedation by modulating the gamma amino butyric acid (GABA) receptors. It contains a single chiral carbon atom and studies have established that the R-etomidate has 10 to 20 fold greater potency as compared with S-etomidate thus leading to R-etomidate being developed as a single enantiomer anesthetic.75 S-ketamine, the S-enantiomer of ketamine demonstrated higher


ef f i cacy as an anes thet ic and analgesic as compared with the racemate and also produces fewer psychomimetic adverse effects as compared with R-ketamine and the racemate.76 Hence, S-ketamine is emerging as a potential replacement for ketamine as an analgesic.77

Bupivacaine, a local anesthetic agent has demonstrated cardiotoxic effects and levobupivacaine, the S-enantiomer, has been developed as a safer alternative. Despite higher concentrations of levobupivacaine reported in plasma, it has less effect on mean stroke index. The cardiac arrhythmias induced by bupivacaine may be a result of the R-enantiomer interacting more potently with the sodium channels. Levobupivacaine displays lower potency in inhibiting the sodium channels thus leading to lower cardiotoxicity.78 Ropivacaine is the pure S-enantiomer of propivacaine and is used as a regional anesthetic in surgeries and has displayed lower incidence of motor block, reduced CNS toxicity and reduced cardiotoxicity as compared with bupivacaine.79 Cisatracurium, an R-enantiomer of atracurium, also demonstrated higher potency and lowered release of histamine and laudanosine (an epileptogenic c o m p o u n d ) a s c o m p a r e d t o atracurium and hence is preferred in therapy.80

Rheumatology, Pain and Inflammation

Penicillamine (racemic mixture) a n d R - p e n i c i l l a m i n e h a v e demonstrated optic neuritis as an associated adverse event. However, this adverse event does not occur with S-penicillamine use, hence it is preferred for the treatment of rheumatoid arthritis. The toxicity of R-penicillamine may be due to its ability to utilize pyridoxine in some enzymatic reactions leading to its incorporation into the proteins. In contrast, due to its isomeric form, S -pen ic i l l amine cannot undergo reactions thus avoiding its incorporation in proteins.81 Etodolac, an anti-inflammatory and analgesic, is a cyclooxygenase-2

i n h i b i t o r t h a t i s u s e d i n t h e m a n a g e m e n t o f r h e u m a t o i d ar thr i t i s and os teoar thr i t i s . 82 S - e t o d o l a c ( S - e n a n t i o m e r o f etodolac) demonstrated 2.6 times more potency as compared with the racemic mixture.83 S-etodolac at 300 mg demonstrated bioequivalence to etodolac at 600 mg.83,84 A double-blind, randomized, comparative study reported that the S-etodolac (300 mg, ER tablet) was equally e f f e c t i ve i n t h e t r e a t m e n t o f osteoarthritis in Indian patients in comparison to etodolac (600 mg, ER tablet). Few adverse events were reported and none of them were serious adverse events.85

Dexketoprofen, an analgesic commonly prescribed for relief from post-surgical dental pain and dysmenorrhea, is the S-enantiomer of ketoprofen. A double-blind, r a n d o m i z e d , c l i n i c a l t r i a l demonstrated that dexketoprofen (25 mg) had a faster onset of act ion and ef f icacy s imilar to ketoprofen (50 mg) at half the dose and hence may be used in the treatment of postsurgical dental pain. 86 Dexketoprofen (25 mg) also resulted in similar efficacy, safety and tolerability in women with primary dysmenorrhea when compared with twice the dose of ketoprofen (50 mg).87

Pulmonology

S a l b u t a m o l ( a l s o k n o w n as albuterol), a short-acting b2 a d r e n e r g i c r e c e p t o r a g o n i s t , i s a c o m m o n l y p r e s c r i b e d bronchodilator for relief in the symptoms of asthma and chronic obstructive pulmonary disease.88 Its enantiomers are stereoselective at the β2-receptor with a 68-fold greater potency for R-salbutamol.89 The R-enantiomer metabolizes 12 times faster, leading to higher concentrations of S-salbutamol in the body.90 Since, S-salbutamol is e l iminated s lowly from the body, it indirectly antagonizes the benefits of R-salbutamol.91,92 Symptom control is achieved by the R-enantiomer at lower doses, thus reducing metabolic load and

hence may be preferred in therapy as compared with the racemate.90,91

One of the active metabolites of terfenadine is fexofenadine and is used preferentially in the treatment of rhinitis and urticaria since it has reduced cardiotoxic and sedative effects.93,94 The concentration of S-fexofenadine in human plasma was reported to be higher than R - f e x o f e n a d i n e . I t wa s a l s o observed that R-fexofenadine is metabolized via efflux transporters such as P-glycoprotein, that may be chirally selective and not by the usual CYP450 metabol ism pathway. Thus, R-fexofenadine may probably have the advantage of lowered drug-drug interactions and also predictable efficacy as compared with the S-enantiomer.95 R-formoterol, the enantiomer of formotero l adminis tered as a nebul izer (exhibi ted two fold higher affinity for the β2-receptor) h a s d e m o n s t r a t e d e f f i c a c y as a bronchodilator in chronic obstructive pulmonary disease.96,97 Levocetirizine, an antihistamine, is also preferentially prescribed over the racemate cetirizine as it has demonstrated lesser side effects such as sedation.98 Infectious Diseases

O f l o x a c i n , a q u i n o l o n e derivative, is a specific inhibitor of DNA gyrase and possesses a broad spectrum antibiotic activity against both gram posi t ive and gram negative bacteria.99 Levofloxacin, the S-enant iomer of of loxacin is the act ive enant iomer with the anti-bacterial activity. In a randomized, double-blind clinical trial of patients with complicated u r i n a r y t r a c t i n f e c t i o n s , levofloxacin (300 mg) exhibited anti-bacterial activity and safety comparable to that of ofloxacin (600 mg).100 Levofloxacin (0.5%) also demonstrated superior microbial eradication rates as compared to ofloxacin (0.3%) in patients with bacterial conjunctivitis.101 In addition, in a multidrug regimen used for the treatment of multidrug-resistant tuberculosis, levofloxacin


a lso repor ted h igher e f f i cacy as compared with oflaxacin. 102 Thus, levofloxacin established an improved safety and efficacy profile compared with ofloxacin.

Chirally Pure Drugs: Recommendations for India

The exposure of patients to multiple concomitant drugs has increased due to various co-existing diseases. Hence, it is important that in addition to safety and efficacy, the metabolic load due to the drugs be given due consideration. Reduction in metabolic load may be achieved with the use of chirally pure drugs in place of racemates. The advantages of utilizing chirally pure drugs in certain therapeutic areas as compared with racemic

mixtures is a lso evident from various clinical trials. However, to bridge the gap in awareness on the therapeutic uses of chirally p u r e d r u g s , a n e x p e r t p a n e l delineated issues requiring focus for all the stakeholders (including regulatory body, pharmaceutical companies, clinicians, pharmacists, pat ients) and outl ined certain recommendations (Table 3). There was a unanimous consensus in the panel on the importance of educating the clinicians, pharmacists, and patients regarding the efficacy, safety profile, and benefits of using chirally pure molecules.

Awareness on chiral ly pure drugs can be increased amongst physicians by continued medical education and dissemination of information on related clinical trials and real-world clinical experience.

A larger patient population may be potential ly benefitted from available chirally pure drugs if physicians prefer these drugs in their clinical practice. Pharmacists should be advised to adhere to the physician’s prescription and substitution between racemate and chirally pure drugs at the pharmacy level should be strongly discouraged. Patients could be made aware of the potential advantages of chirally pure drugs via physician counsel l ing. Addit ional ly , the regulatory bodies may consider the need to expedite the approval o f c h i r a l l y p u r e d r u g s w i t h established efficacy and safety and thus accelerating their availability. Overall, increased awareness on the concept of chirality will translate in to maximum benefits to the patients and optimize the outcomes.

Table 3 Chiral drugs-recommendations for India

Stakeholders Regulatory body Pharmaceutical companies

Clinicians Pharmacists Patients

Issues to focus on Awareness on different policies in different countries for chiral drugs

Making chiral drugs available in the market

Understanding the principle of chirality in drugs

Understanding the difference between racemates and chiral drugs as well as related health-outcomes

Education on the concept of ‘chirally pure drugs’

Expedited approval process to be considered for chiral drugs basis clinical evidence

Knowledge on efficacy, safety and potency of chiral drugs in clinical practice

Awareness on the perils of drug substitution

Awareness on safety and efficacy of chiral drugs

Recommendations to resolve issues

To conduct round table meeting or panel discussions with regulatory board for framing expedited approval guidelines for chiral drugs

To abide by the concerned regulatory requirements for the discovery and development of chirally pure drugs whenever possible.

To create awareness via continued medical education or concept based panels to discuss the benefits of chiral drugs over racemates

To conduct policy campaigns on ‘no substitution on prescription’ for pharmacists

To utilize mass media for conducting campaigns such as advertisements relating chiral drugs mentioning safety and efficacy benefits. This could be achieved via health slogans (e.g. ‘purity counts’), storylines with messages, advertisement boards

To update the decision makers (government representatives, health ministry, state bodies and DCGI) on chirality through guideline recommendations and position statements.

To conduct round table meetings, focussed group meetings and position statements would help to educate clinicians on differential benefits of chirally pure molecules

To conduct camps on chirality and chiral drugs to educate pharmacists

To conduct patient education programs to explain purity, safety, quality of chiral drugs via individual or group instruction

To provide global perspective by generating awareness on guidelines governing the approval process in different countries so that informed decisions can be made in drafting approval guidelines for chiral drugs

To include clinicians in clinical trials for chiral molecules and disseminate the findings of clinical trials for the Indian population to increase awareness among clinicians

To provide counselling services to pharmacists by clinicians to explain the non-equivalence of drugs and prescription sanctity in order to discourage substitution with racemates

To encourage healthcare providers to share their knowledge and experience with patients on using chirally pure drugs


Conclusions

The evidence in certain thera-peutic areas clearly demonstrates similar efficacy at lower doses, improved safety, and reduced metabolic load associated with chirally pure molecules in compari-son with racemates. However, there is a need for increased awareness on the advantages of chirally pure drugs among cl inicians, phar-macists, and patients. Efforts in this direction are warranted for patients to benefit from therapy with chirally pure molecules.Acknowledgments

D r . S o n i a P h i l i p o s e ( S I R O Clinpharm Pvt. Ltd.) provided writing assistance. Dr. Sangita Patil, CMPP (SIRO Clinpharm Pvt. Ltd.) and the Medical Team of Emcure Pharmaceutical Ltd. provided additional editorial support for this manuscript. Author Contributions

All authors met ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors provided direction and comments on the manuscr ipt , made the f inal decision about where to publish the manuscript, and approved submission to the journal.Conflict of Interest

Emcure Pharmaceutical Ltd. provided the educational grant.

References1. Agranat I, Caner H, Caldwell J. Putting

chirality to work: the strategy of chiral switches. Nat Rev Drug Discov 2002; 1:753-768.

2. Shen Z, Lv C, Zeng S. Significance and challenges of stereoselectivity assessing methods in drug metabolism. J Pharm Anal 2016; 6:1-10.

3. Nguyen LA, He H, Pham-Huy C. Chiral Drugs: An Overview. Int J Biomed Sci 2006; 2: 85-100.

4. Yanez JA, Andrews PK, Davies NM. Methods of analysis and separation of chiral flavonoids. J Chromat B 2007; 848:159-181.

5. Brooks WH, Guida WC, Daniel KG. The significance of chirality in drug design and development. Curr Top Med Chem 2011;

11:760-770.

6. Gal J. Louis Pasteur, language, and molecular chirality. I. Background and dissymmetry. Chirality 2011; 23:1-16.

7. Burke D, Henderson DJ. Chirality : a blueprint for the future. Br J Anaesth 2002; 88: 563-576.

8. Srinivas NR, Barbhaiya RH, Midha KK. Enant iomer ic drug development : issues, considerations, and regulatory requirements. J Pharm Sci 2001; 90:1205-1215.

9. Kasprzyk-Hordern B. Pharmacologically active compounds in the environment and their chirality. Chem Soc Rev 2010; 39: 4466-4503.

10. Maher TJ, Johnson DA. Review of chirality and its importance in pharmacology. Drug Dev Res 1991; 24:149-156.

11. McConathy J, Owens MJ. Stereochemistry in drug action. Prim Care Companion. J Clin Psychiatry 2003; 5:70-73.

12. Kim JH, Scialli AR. Thalidomide: the tragedy of birth defects and the effective treatment of disease. Toxicol Sci 2011; 122: 1-6.

13. Vargesson N. Thalidomide -induced teratogenesis: History and mechanisms. Birth Defects Research Part C, Embryo Today: Reviews. 2015; 105:140-156.

14. Agranat II, Caner H. Intellectual property and chirality of drugs. Drug Discov Today 1999; 4:313-321.

15. Hutt A, Valentova J. The chiral switch: the development of single enantiomer drugs from racemates. In: Universitatis C o m e n i a n a e . A c t a F a c u l t a t i s Pharmaceuticae 2003; 50:7-23.

16. Hair PI, Scott LJ. Levocetirizine: a review of its use in the management of allergic rhinitis and skin allergies. Drugs 2006; 66:973-996.

17. Tillement J-P, Testa B, Brée F. Compared pharmacological characteristics in humans of racemic cetirizine and levocetirizine, two histamine H 1-receptor antagonists. Biochem Pharmacol 2003; 66:1123-1126.

18. De Vos C, Mitchev K, Pinelli M-E, Derde M-P, Boev R. Non-interventional study comparing treatment satisfaction in patients treated with antihistamines. Clin Drug Inves 2008; 28:221-230.

19. Autret E, Breart G, Jonville A, Courcier S, Lassale C, Goehrs J. Comparative efficacy and tolerance of ibuprofen syrup and acetaminophen syrup in children with pyrexia associated with infectious diseases and treated with antibiotics. Eu Clin Pharmacol 1994; 46:197-201.

20. Moore RA, Derry S, Aldington D, Wiffen PJ. Single dose oral analgesics for acute postoperative pain in adults-an overview of Cochrane reviews. The Cochrane Library 2015:CD008659.

21. Kollenz C, Phleps W, Kaehler S. ADIDAC trial: analgesia with dexibuprofen versus ibuprofen in patients suffering from primary dysmenorrhea: a crossover trial. Gynecol Obstet Investig 2009; 67:25-31.

22. Yoon JS, Jeong DC, Oh JW, Lee KY, Lee HS, Koh YY, et al. The effects and safety of dexibuprofen compared with ibuprofen in febrile children caused by upper respiratory tract infection. Br J Clin Pharmacol 2008; 66:854-860.

23. Evans AM. Pharmacodynamics and pharmacok inet ics of the profens: enantioselectivity, clinical implications, and special reference to S (+)-ibuprofen. J Clin Pharmacol 1996; 36(12 Suppl): 7S-15S.

24. Kollenz C, Phleps W, Kaehler ST. ADIDAC trial: analgesia with dexibuprofen versus ibuprofen in patients suffering from primary dysmenorrhea: a crossover trial. Gynecol Obstet Invest 2009; 67: 25-31.

25. Wingard LB, Levy G. Drug interactions with warfarin enantiomers-a different perspective. Br J Clin Pharmacol 1978; 6:434-436.

26. O’Reilly RA. The Stereoselective Interaction of Warfarin and Metronidazole in Man. New Eng J Med 1976; 295:354-357.

27. Bungard TJ, Yakiwchuk E, Foisy M, Brocklebank C. Drug interactions involving warfarin: practice tool and practical management tips. Can Pharm J/Revue des Pharmaciens du Canada 2011; 144:21-25. e9.

28. Lyon AF, DeGraff AC. Antiarrhythmic drugs Part I. Mechanism of quinidine action. Am Heart J 1965; 69:713-715.

29. Wang SC, Chou DT, Wallenstein MC. Studies on the potency of various antitussive agents. Agents Actions 1977; 7: 337-340.

30. Mohan SJ, Mohan EC, Yamsani MR. Chirality and its importance in pharmaceutical field-an overview. Int J Pharmaceut Sci Nanotechnol 2009; 1:309-316.

31. Development of New Stereoisomeric Drugs. c2014 [updated 2014 Dec 7; cited 2017 Jun 21]. Available from: https://www.fda.gov/drugs/guidance complianceregulator yinformation/guidances/ucm122883.htm.

32. Investigation of chiral active substances. c1993 [updated 1993; cited 2017 Jun 21]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000706.jsp&mid=WC0b01ac0580028bfd.

33. ICH Q6A. c1999 [updated 1999 Oct 6; cited 2017 Jun 21]. Available from: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/CTD/M4_R4_Organisation/M4_R4__Granularity_Document.pdf.

34. Guidance for Industry: Stereochemical Issues in Chiral Drug Development. c2000 [updated 2000 Feb 14; cited 2017 Jun 21].


Available from: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance -documents/chemical - ent i t y-produc ts- qual i t y/guidance-industry-stereochemical-issues-chiral-drug-development.html.

35. Organization CDSC. Guidance for industry on preparation of common technical document for import/manufacture and marketing approcal of new drugs for human use (new drug application-NDA). c2010 [updated 2010 Oct 28; cited 2017 Jun 21]. Available from: http://www.cyclonepharma.com/Guideline/India.pdf.

36. Opari l S , Zaman MA, Calhoun DA. Pathogenesis of hypertension. Annals of Int Med 2003; 139:761-776.

37. Law M, Wald N, Morris J. Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy. Int Tech Assess in Health Care 2005; 21:144-150.

38. Dasbiswas A, Dasbiswas D. Chirally pure S-metoprolol-place in therapy. Ind Heart J 2010; 62:143-145.

39. Jayaram S, Kaul U, Pai V, Pandit A, Pathak L, Shinde S. The SMART Trial (S-metoprolol assessment in hypertension trial). Cardiol Today 2005; 9:222-229.

40. SMART-II Study Group. Results of SMART-II study on efficacy and safety of S-Metoprolol extended release tablet. Ind Med Gaz 2006; CXL(2): 72-75.

41. Aneja P, Srinivas A, Biswas AD. Comparative clinical study of the efficacy and safety of a S-metoprolol ER tablet versus a racemate metoprolol ER tablet in patients with chronic stable angina. Int J Clin Pharmacol Therap 2007; 45:253-258.

42. SMART-HF Study Group. Efficacy and safety of S-metoprolol extended release tablet in the management of congestive heart failure. Ind Med Gaz 2008; CXLII(5) 194-197.

43. Mandora V. Safety and eff icacy of S-metoprolol succinate extended release tablet in the treatment of hypertension coexisting with COPD-an open label, non-comparitive, prospective clinical study. Ind Med Gazette 2006: CXL(1): 28-32.

44. Mohan JC, Shah SN, Chinchansurkar S, Dey A, Jain R. Rediscovering Chirality–Role of S-Metoprolol in Cardiovascular Disease Management. J Assoc Physicians of India 2017; 65:74-79.

45. Kim SA, Park S, Chung N, Lim D-S, Yang J-Y, Oh B-H, et al. Efficacy and safety profiles of a new S-amlodipine nicotinate formulation versus racemic amlodipine besylate in adult Korean patients with mild to moderate hypertension: An 8-week, multicenter, randomized, double-blind, double-dummy, parallel-group, phase III, noninferiority clinical trial. Clin Therap 2008; 30:845-857.

46. Pathak L, Kerkar P, Manade V. Multicentric, clinical trial of S-Amlodipine 2.5 mg versus Amlodipine 5 mg in the treatment of mild to moderate hypertension--a randomized, double-blind clinical trial. J Assoc Physicians of India 2004; 52:197-202.

47. SESA Study Group. Safety and Efficacy of S-Amlodipine. JAMA-India 2003;2(8): 87-92.

48. SESA IV Study Group. SESA IV: Results of a multicentric post-marketing surveillance study on safety and efficacy of S-amlodipine in the treatment of hypertension. Cardiol Today 2007; XI(5): 1-4.

49. Pathak LT, H; Jayaram, S; Sharma, S; Mannik ar, J ; Apte D. Randomized, double-blind, parallel-group, multicentric clinical trial of S-atenolol 25 mg versus racemic atenolol 50 mg in stage 1 and 2 hypertension. JAMA-India 2004; 3:71-75.

50. Shin JM, Sachs G. Pharmacology of proton pump inhibitors. Curr Gastroenterol Rep 2008; 10:528-534.

51. Andersson T, Weidolf L. Stereoselective disposition of proton pump inhibitors. Clin Drug Inves 2008; 28: 263-279.

52. Lindberg P, Keeling D, Fryklund J, Andersson T, Lundborg P, Carlsson E. Esomeprazole-enhanced bio-availability, specificity for the proton pump and inhibition of acid secretion. Alim Pharmacol Therap 2003; 17:481-488.

53. Asghar W, Pittman E, Jamali F. Comparative efficacy of esomeprazole and omeprazole: Racemate to single enantiomer switch. DARU J Pharm Sci 2015; 23:50-57.

54. Kendall M. Review article: Esomeprazole-the first proton pump inhibitor to be developed as an isomer. Alimen Pharmacol Therap 2003; 17(S1): 1-4.

55. Cho YK, Choi M-G, Bak Y-T, Rhee P-L, Kim SG, Jung H-Y, et al. Efficacy of S-pantoprazole 20 mg compared with pantoprazole 40 mg in the treatment of reflux esophagitis: a randomized, double-blind comparative trial. Dig Dis Sci 2012; 57:3189-3194.

56. Pai VG, Pai NV, Thacker HP, Shinde JK, Mandora VP, Erram SS. Comparative clinical trial of S-pantoprazole versus racemic pantoprazole in the treatment of gastro-esophageal reflux disease. World J Gastroenterol 2006; 12:6017-6020.

57. S-Pantoprazole Study Group. Results of an Open-label, Prospective, Noncomparative Study to Assess Safety and Efficacy of S-Pantoprazole in Clinical Practice. Ind Med Gaz 2006; CXL(6): 285-289.

58. Pai V, Pai N. Randomized, double-blind, comparative study of dexrabeprazole 10 mg versus rabeprazole 20 mg in the treatment of gastroesophageal reflux disease. World J Gastroenterol 2007; 13:4100-4102.

59. Sánchez C, Bøgesø KP, Ebert B, Reines EH, Braestrup C. Escitalopram versus

citalopram: the surprising role of the R-enantiomer. Psychopharmacol 2004; 174:163-176.

60. Burke WJ. Escitalopram. Exp Opin on Invest Drugs 2002; 11:1477-1486.

61. Gorman JM, Korotzer A, Su G. Efficacy co m p a r i s o n o f e s c i t a l o p ra m a n d citalopram in the treatment of major depressive disorder: pooled analysis of placebo-controlled trials. CNS Spectrums 2002; 7(S1):40-44.

62. Montgomery S, Hansen T, Kasper S. Efficacy of escitalopram compared to citalopram: a meta-analysis. Int J Neuropsychopharmacol 2011; 14:261-268.

63. US Food and Drug Administration. FDA Drug Safety Communication: Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses. c2011 [updated 2011 Aug 24; cited 2017 Jun 21]. Available from: https://www.fda.gov/Drugs/DrugSafety/ucm297391.htm

64. Steiner T, Ahmed F, Findley L, MacGregor E, Wilkinson M. S-fluoxetine in the prophylaxis of migraine: a phase II double-blind randomized placebo-controlled study. Cephalalgia 1998; 18:283-286.

65. Owens MJ, Knight DL, Nemeroff CB. S econd- generat ion SSRIs : human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biologic Psych 2001; 50:345-350.

66. Monti JM, Pandi-Perumal S. Eszopiclone: its use in the treatment of insomnia. Neuropsych Dis Treat 2007; 3:441-453.

67. C a r l s o n J N , H a s k e w R , W a c k e r J, Maisonneuve IM, Glick SD, Jerussi TP. Sedative and anxiolytic effects of zopiclone’s enantiomers and metabolite. Eu J Pharmacol 2001; 415:181-189.

68. Drayer DE. Pharmacodynamic and pharmacokinetic differences between drug enantiomers in humans: an overview. Clin Pharmacol Therap 1986; 40:125-133.

69. Reist M, Testa B, Carrupt P-A. Drug racemization and its significance in pharmaceutical research. Stereochem Aspects of Drug Action Dispos 2003: 91-112.

70. Gorman CA, Jiang N-S, Ellefson RD, Elveback LR. Comparative effectiveness of dextrothyroxine and levothyroxine in correcting hypothyroidism and lowering blood lipid levels in hypothyroid patients. J Clin Endocrinol Metabol 1979; 49:1-7.

71. Nestler JE, Strauss JF 3rd. Insulin as an effector of human ovarian and adrenal steroid metabolism. Endocrinol Metabol Clini North Am 1991; 20:807-823.

72. Colazingari S, Treglia M, Najjar R, Bevilacqua A. The combined therapy myo-inositol plus D-chiro-inositol, rather than D-chiro-inositol, is able to improve IVF outcomes: results from a randomized controlled trial.


Arch Gynecol Obstet 2013; 288:1405-1411.

73. Nordio M, Proietti E. The combined therapy with myo-inositol and D-chiro-inositol reduces the risk of metabolic disease in PCOS overweight patients compared to myo-inositol supplementation alone. Eur Rev Med Pharmacol Sci 2012; 16:575-581.

74. Kalra B, Kalra S, Sharma J. The inositols and polycystic ovary syndrome. Ind J Endocrinol and Metabol 2016; 20:720-724.

75. Forman SA. Clinical and molecular pharmacology of etomidate. J Am Soc of Anesth 2011; 114:695-707.

76. Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI. Ketamine: a review of clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy. Clin Pharmacok 2016; 55:1059-1077.

77. Andrade C. Ketamine for Depression, 3: Does Chirality Matter? J Clin Psychiatry 2017; 78: e674-e677.

78. Mitra S, Chopra P. Chirality and anaesthetic drugs: A review and an update. Ind J Anaesth 2011; 55:556-562.

79. Kuthiala G, Chaudhary G. Ropivacaine: A review of its pharmacology and clinical use. Ind J Anaesth 2011; 55:104-110.

80. Joyce JA. A pathway toward safer anesthesia: stereochemical advances. AANA J 2002; 70:63-67.

81. Kean W, Howard-Lock H, Lock C. Chirality in antirheumatic drugs. The Lancet 1991; 338:1565-1568.

82. Demerson CA, Humber LG, Abraham NA, Schi l l ing G, Mar tel RR, Pace -Asciak C. Resolution of etodolac and antiinflammatory and prostaglandin synthetase inhibiting properties of the enantiomers. J Med Chem 1983; 26:1778-1780.

83. Menon S, Kadam N, Gursale A, Gokarn V, Palekar A. A randomized, crossover study to determine bioequivalence of S-Etodolac ER tablets versus Etodolac ER tablets in healthy Indian subjects. J Appl Res 2009; 9:57-64.

84. Babhulkar A. S-etodolac-the chirally pure

NSAID. J Ther Adv 2011; 2:22-26.

85. Sancheti P, Hardikar M, Karne N, Panse J, Singh S, Maria A, et al. A multicentric, randomized, comparative clinical trial to evaluate the efficacy and safety of S-etodolac in the treatment of osteoarthritis in Indian patients. Int J Clin Pharmacol Therap 2010; 48:429-434.

86. McGurk M, Robinson P, Rajayogeswaran V, De Luca M, Casini A, Artigas R, et al. Clinical comparison of dexketoprofen trometamol, ketoprofen, and placebo in postoperative dental pain. J Clin Pharmacol 1998; 38(12 Suppl):46S-54S.

87. Ezcurdia M, Cortejoso FJ, Lanzón R, Ugalde FJ, Herruzo U, Artigas R, et al. Comparison of the efficacy and tolerability of dexketoprofen and ketoprofen in the treatment of primary dysmenorrhea. J Clin Pharmacol 1998; 38:65S-73S.

88. Slattery D, Wong S, Colin A. Levalbuterol hydrochloride. Ped Pulmonol 2002; 33:151-157.

89. Brittain RT, Farmer JB, Marshall RJ. Some observations on the β-adrenoceptor agonist properties of the isomers of salbutamol. Br J Pharmacol 1973; 48:144-147.

90. B o u l t o n D W , F a w c e t t J P. T h e pharmacokinetics of levosalbutamol: what are the clinical implications? Clin Pharmacokinet 2001; 40:23-40.

91. Handley DA, Mor ley J , Vaickus L . Levalbuterol hydrochloride. Expert Opin Investig Drugs 1998; 7:2027-2041.

92. Boulton DW, Fawcett JP. Pharmacokinetics and pharmacodynamics of single oral doses of albuterol and its enantiomers in humans. Clin Pharm Therapeut 1997; 62:138-144.

93. Terrien M-H, Rahm F, Fellrath J-M, Spertini F. Comparison of the effects of terfenadine with fexofenadine on nasal provocation tests with allergen. J Allergy Clin Immunol 1999; 103:1025-1030.

94. Chen C. Some pharmacokinetic aspects of the lipophilic terfenadine and zwitterionic fexofenadine in humans. Drugs RD 2007;

8:301-314.

95. Miura M, Uno T. Clinical pharmacokinetics of fexofenadine enantiomers. Exp Opin Drug Metabol Toxicol 2010; 6:69-74.

96. Baumgartner RA, Hanania NA, Calhoun WJ, Sahn SA, Sciarappa K, Hanrahan JP. Nebulized arformoterol in patients with COPD: a 12-week, multicenter, randomized, double-blind, double-dummy, placebo-and active-controlled trial. Clin Ther 2007; 29:261-278.

97. Hanrahan JP, Hanania NA, Calhoun WJ, Sahn SA, Sciarappa K, Baumgartner RA. Effect of nebulized arformoterol on airway function in COPD: results from two randomized trials. COPD: J Chron Obstruct Pulmon Dis 2008; 5:25-34.

98. 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; 17:241-255.

99. Morrissey I, Hoshino K, Sato K, Yoshida A, Hayakawa I, Bures MG, et al. Mechanism of differential activities of ofloxacin enantiomers. Antimicrobl Agents Chemother 1996; 40:1775-1784.

100. Peng M. Randomized, double-blind, comparative study of levofloxacin and ofloxacin in the treatment of complicated urinary tract infections. J Microbiol Immunol Infect 1999; 32:33-39.

101. Schwab IR, Friedlaender M, McCulley J, Lichtenstein SJ, Moran CT, Group LBCACS. A phase III clinical trial of 0.5% levofloxacin ophthalmic solution versus 0.3% ofloxacin ophthalmic solution for the treatment of bacterial conjunctivitis. Ophthalmol 2003; 110:457-465.

102. Yew WW, Chan CK, Leung CC, Chau CH, Tam CM, Wong PC, et al. Comparative roles of levofloxacin and ofloxacin in the treatment of multidrug-resistant tuberculosis: preliminary results of a retrospective study from Hong Kong. Chest J 2003; 124:1476-1481.

association of physicians of india: position …fl v 65 fl december 2017 49 association of...

Documents