chirality booklet inner 4 col final - chiralemcure.com booklet.pdf · arranged in 3-dimensional...

History 2

Basics of Chiral Chemistry 3

Chirality rules in Nature 6

USFDA’s policy statement 7

Commercial impact of Chirality 11

Chirality – Today and Tomorrow’s way of Treatment 12

Differential properties of enantiomers 18

Chirality and Cardiovascular drugs 23

Chirality and NSAIDs 25

R-Sibutramine in Obesity Management ....................... 44

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Chirally pure proton pump inhibitors 48

Latest update 50

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1

Contents

Chirality is part of life

and chirally pure

molecules support life

through treatment of

diseases. This booklet

introduces the exciting

science of Chirality, its

regulatory and

pharmacological

significance along with its

applications in the

management of pain, acid

peptic disorders, obesity

and cardiovascular

disorders.

CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment

‘Chiral' is derived from the Greek name "kheir" meaning "hand" and apparently

was coined by Lord Kelvin in his Baltimore lectures on Molecular Dynamics

and the Wave Theory of Light in which he stated ..."I call any geometrical figure,

or group of points, chiral, and say it has chirality, if its image in a plane mirror,

ideally realized, cannot be brought to coincide with itself."

Chirality of a molecule was first reported in 1815 by a French Physician Jean

Baptist Biot and in 1835 he discovered the rotation of the polarization of light in

sugar solution. Following Kekule's recognition in 1858 that carbon has a

valency of 4, van’t Hoff and Le Bel independently recognized that when four

different groups are attached to a carbon atom, arrayed at the corners of a

tetrahedron, then the arrangements can be in two different forms. The

concepts of "asymmetry" were developed by J.H. van't Hoff and J.A. Le Bel in

1874 following the resolution by Louis Pastuer of a mixture of tartaric acid salt

isomers during the period 1848-1853, in which he picked out the differing

crystal types by hand - doing so on the basis of the differing physical

appearance of the salt crystals. Pastuer recognized that two of the isomers

polarized light differently (one to the left and the other to the right) and that this

must be due to an asymmetric grouping of atoms in the optically active

molecules. Emil Fischer in 1902 showed how nature is exquisitely sensitive to

chirality when he established detailed stereochemistry of the sugars and the

amino acids.

Techniques for studying optical activity did not progress as rapidly. Major

advances in the form of chiral High-Performance Liquid Chromatography

(HPLC) were developed as recently as 1980.

Stereoisomerism in molecules can occur because the component atoms are

arranged in 3-dimensional space rather than being restricted to a linear array

or a 2-dimensional plane. It is of importance since the interaction between

biologically active sites and substrate molecules, e.g. drug-receptor site

interaction, are highly stereoselective. Stereoisomerism is sub-categorized

into enantiomerism and diastereoisomerism. A pair of stereoisomers that are

related as non-superimposable mirror images are called enantiomers while

those that are not so related are diastereoisomers. The absolute

configurations of enantiomers and diastereoisomers are described by the R, S

convention.

The phenomenon whereby a single molecular formula can represent more

than one compound is called isomerism.

In recent years, there has been considerable interest in the biological activity,

both pharmacological and toxicological, of the enantiomers of chiral drugs.

This interest in drug stereochemistry has resulted from the considerable

advances in the synthesis, analysis and separation of chiral molecules,

together with an increased appreciation of the potential significance of the

differential biological properties of the enantiomers of chiral drugs

administered as racemates.

Isomerism

Stereoisomerism

Stereoisomerism occurs in molecules with identical structures, by which is

meant they have the same order of attachment of atoms but differ in

their spatial arrangement. The phenomenon can further be divided into two

categories, enantiomerism and diasteroisomerism.

History

2 3

Basics of Chiral Chemistry


Enantiomerism

Chirality

Optical activity

A Carbon atom that is bound to 4 different

atoms is referred to as an asymmetric carbon.

The configuration of such molecular unit is

chiral and structure may exist as right-handed

configuration or left-handed configuration. This

type of configurational stereisomerism is termed enantiomerism and the non-

identical, mirror image pair of stereoisomers that result are called enantiomers.

A molecule which is not superimposable on its mirror image is said to be chiral.

Chiral is derived from Greek name 'Kheir' meaning 'hand' i.e. it possesses the

property of handedness, our left hand is the mirror image of our right hand but

two hands are not superimposable. An achiral object is identical with

(superimposable on) its mirror image.

Objects like gloves and shoes come in pairs, a right and a left; golf clubs and

scissors are chiral objects. Objects that do not have a handedness like a

baseball bat, a plain round ball, a pencil, a T-shirt or a nail are achiral objects.

Chirality or asymmetry can arise in several ways in a molecule but by far the

most common is through the presence of a chiral or asymmetric carbon in the

molecule. A chiral carbon atom is one to which 4 different atoms or groups

(ligands) are attached. In fig.1 the carbon atom marked with the * is chiral,

ibuprofen therefore exists in two non-superimposable mirror image forms.

A chiral molecule is described as optically active because it rotates plane-

polarised light. A molecule is dextrorotatory if it rotates polarized light to the

right, symbolized by 'd' or (+), or levorotatory if it rotates polarized light to the

left, symbolized by 'l' or (-). A 1:1 mixture of the 'd' and 'l' forms of an optically

active compound is called a racemate and will display no optical activity

because of mutual cancellation of rotation. A racemate may be prefixed by the

symbol (±)- or 'dl'.

The actual orientation in space of the 4 ligands in each of the enantiomers of

ibuprofen (in fig. 2) constitutes its absolute configuration. For many molecules,

such configuration is determined by X-ray crystallography or by known

stereospecific synthetic transformations.

Once known, the description of this spatial arrangement of atoms around the

chiral centre is then made by using the symbols 'R' (Latin,rectus, right) or 'S'

(Latin, sinister, left) according to a convention proposed by Cahn, Prelog and

Ingold (Gunstone, 1975). This obviates the need to draw stereoformulae such

as those of Fig. 2. It should be noted, however, that there is no correlation

between the symbols (R,S), which depict the absolute configuration of a

molecule according to a set convention, and the symbols (+, -), which denote

the experimentally determined direction of polarised light rotation. Thus an R

configuration is not always associated with levorotation (-) nor is S always

dextrorotatory (+). However, once it is known that an enantiomer of a

compound is R(+), then the other enantiomer must be S(-) e.g. R(+)-

propranolol and S(-)-propranolol.

Absolute configuration: R,S convention

4 5

COOH

XC

HOOCCH3

H

S(+)- ibuprofen_R( )-ibuprofen

CCH3 CH2

CH3

H

X =

C

H

COOHCH3

Fig. 2

The 3-dimensional representation (absolute configuration) of the two enantiomers of ibuprofen

( ----- in plane of paper, ((((((( behind plane of paper, out of plane of paper)

X

CCH3 CH2

CH3

H

C* COOH

H

CH3

Fig. 1

Ibuprofen

The structure shows only the bonding pattern and not the

stereochemistry of the molecule. The carbon with the * is

the chiral or asymmetric carbon atom.


Chirality is very much a part of life. In cells, all amino acids need to be levoform

enantiomers, whilst all nucleotides need to be dextroform, otherwise protein

synthesis as programmed by DNA will fail, and DNA itself could not be formed

(http://www.iscid.org/encyclopedia/Chirality). The sweet smell of oranges and

lemons is due to S-limonene while R-limonene would render a disagreeable

turpentine-like odor. Quinine that we get from the cinchona bark is chirally

pure. Even the poppy plant knows that only the levo form of morphine is

analgesic. Have you ever wondered why we infuse 'dextrose' and not the levo

form? It is because our body metabolizes only the dextro form. Chirality plays

an important part in the working of penicillin too! Penicillin's activity is

stereoselective. The antibiotic works only on peptide links of D-alanine that

occur in the cell walls of bacteria - but not in humans. The antibiotic can kill only

the bacteria, and not us, because we humans do not have these D-amino

acids.

Source

Introduction

: FDA's policy statement for the development of new stereoisomeric

drugs. http://www.fda.gov/cder/guidance/stereo.htm (accessed June 5, 2008).

USFDA recognized the growing importance of chirality in drugs when it

published its policy statement for the development of new stereoisomeric

drugs in the year 1992.

Stereoisomers are molecules that are identical in atomic constitution and

bonding, but differ in the three-dimensional arrangement of the atoms. Such

stereoisomers usually require specialized chiral techniques for their correct

identification, characterization, separation and measurement. They are often

readily distinguished by biological systems, however, and may have different

pharmacokinetic properties (absorption; distribution, biotransformation. and

excretion) and quantitatively or qualitatively different pharmacologic or

toxicologic effects. Now that technological advances (large scale chiral

separation procedures or asymmetric syntheses) permit production of many

single enantiomers on a commercial scale, it is appropriate to consider what

FDA's policy with respect to stereoisomeric mixtures should be. Development

of racemates raises issues of acceptable manufacturing control of synthesis

and impurities, adequate pharmacologic and toxicologic assessment, proper

characterization of metabolism and distribution, and appropriate clinical

evaluation.

For product development following information should be considered.

1. Appropriate manufacturing and control procedures should be used to assure

stereoisomeric composition of a product, with respect to identity, strength,

quality and purity. Manufacturers should notify compendia of these

specifications and tests.

2. Pharmacokinetic evaluations that do not use a chiral assay will be

Chirality rules in Nature

6 7

FDA's policy statement for the development of new stereoisomeric drugs

Nature is Chirally oriented

S-Limonene sweet smell of oranges / lemons

R-Limonene turpentine like odour→→

Quinine is chirally pure

Natural Quinineextracted from the

bark of thecinchona tree is

single enantiomer

(R)-(5-ethenyl-1-

azabicyclo[2.2.2]oct-2-yl)-(6-

methoxyquinolin-4-yl) -methanol


misleading if the disposition of the enantiomers is different. Therefore,

techniques to quantify individual stereoisomers in pharmacokinetic samples

should be available early. If the pharmacokinetics of the enantiomers are

demonstrated to be the some or to exist as a fixed-ratio in the target population,

an achiral assay or an assay that monitors one of the enantiomers may be

used, subsequently.

The stereoisomeric composition of a drug with a chiral center should be known

and the quantitative isomeric composition of the material used in

pharmacologic, toxicologic, and clinical studies known. Specifications for the

final product should assure identity; strength, quality, and purity from a stereo

chemical viewpoint.

Pharmacokinetic evaluation should be done. Unless it proves particularly

difficult, the main pharmacologic activities of the isomers should be compared

in vitro systems, in animals and/or in humans. Toxicological study should be

carried of the isomers. If, however, there are toxic findings other than those that

are natural extensions of the pharmacologic effects of the drug, and especially

if they are unusual or occur near the effective dose in animals or near the

planned human exposure, toxicologic evaluation of the individual isomers in

the study where the toxicity was detected should be undertaken.

All information developed by the sponsor or available from the literature that is

relevant to the chemistry, pharmacology, toxicology, or clinical actions of the

stereoisomers should be included in the IND and NDA submissions.

To develop a single stereoisomer from a mixture that has already been studied

non-clinically, an abbreviated, appropriate pharmacology/toxicology

evaluation could be conducted to allow the existing knowledge of the racemate

Policy in general

Developing a Single Stereoisomer after the Racemate is studied

available to the sponsor to be applied to the pure stereoisomer. Ongoing

studies would usually include the longest repeat-dose toxicity study conducted

(up to 3 months), and the reproductive toxicity segment II study in the most

sensitive species, using the single enantiomer. These studies should include a

positive control group consisting of the racemate. If there is no difference

between the toxicological profile of the single stereoisomeric product and the

racemate, no further studies would be needed. If the single enantiomer is more

toxic, the explanation should be sought and the implications for human dosing

considered.

Where little difference is observed in activity and disposition of the

enantiomers, racemates may be developed. In some situations, development

of a single enantiomer is particularly desirable (e.g., where one enantiomer

has a toxic or undesirable pharmacologic effect and the other does not). A

signal that should trigger further investigation of the properties of the individual

enantiomers and their active metabolites is the occurrence at clinical doses of

toxicity with the racemate that is not clearly expected from the pharmacology of

the drug or the occurrence of any other unexpected pharmacologic effect with

the racemate. These signals might be explored in animals but human testing

may be essential.

It should be appreciated that toxicity or unusual pharmacologic properties

might reside not in the parent isomer, but in an isomer-specific metabolite. In

general, it is more important to evaluate both enantiomers clinically and

consider developing only one when both enantiomers are pharmacologically

active but differ significantly in potency, specificity, or maximum effect, than

when one isomer is essentially inert. Where both enantiomers are fortuitously

found to carry desirable but different properties, development of a mixture of

the two, not necessarily the racemate, as a fixed combination might be

reasonable.

Clinical and Biopharmaceutical

8 9


If a racemate is studied, the pharmacokinetics of the two isomers should be

studied in Phase 1. Potential interconversion should also be examined. Based

on Phase 1 or 2 pharmacokinetic data in the target population, it should be

possible to determine whether an achiral assay or monitoring of just one

enantiomer where a fixed ratio is confirmed will be sufficient for

pharmacokinetic evaluation.

If a racemate has been marketed and the sponsor wishes to develop the single

enantiomer, evaluation should include determination of whether there is

significant conversion to the other isomer, and whether the pharmacokinetics

of the single isomer are the same as they were for that isomer as part of the

racemate.

In an analysis of all single enantiomer drugs launched as a percentage of chiral

molecules, the ratio increased from 31.6% in 1985-1988 to 89.8% in 2001-

2004 (Fig. 4). It is estimated that sales of unichiral drugs could reach $200

billion in 2008. A number of factors have contributed to the introduction and

popularity of unichiral products since 1980 and more so 1992 onwards. These

are : introduction of enantioselective analytical methods, new synthetic

methods for unichiral molecules, chromatographic methods for separation and

more importantly USFDA’s statement in 1992 stating that development of

racemates would require justification for inclusion of both the isomers.

According to data from ORG-IMS, out of the 15 top cardiovascular molecules

sold in India, seven are single enantiomers; these are S(-)amlodipine,

telmisartan, diltiazem, enalapril, losartan, ramipril and atorvastatin.

Fig. 4. Commercial impact of chirality

10 11

NIFEDIPINE

NICORANDIL

S-AMLODIPINE

PRAZOSIN

GLY.TRINIT./NITROGLY

TELMISARTAN

DILTIAZEM

ENALAPRIL

ISMN

METOPROLOL

ATENOLOL

LOSARTAN

RAMIPRIL

AMLODIPINE

ATORVASTATIN

0 50 100 150 200 250 300 350Yearly sales in Crores

7 out of the top 15CVS molecules in

India are chirally pure

100908070605040302010

0

1985-1988

1989-1992

1993-1996

1997-2000

2001-2004

%

Single enantiomer drugslaunched as % of chiralmolucules

Commercial impact of Chirality


Reprinted from- The future lies in chiral purity: A perspective. J Indian Med Assoc. 2007; 105(4):177-8.

1Dr. Mukund Gurjar Director - R&D,Emcure Pharmaceuticals Limited

Stereoisomers are compounds made up of the same atoms connected by the

same sequence of bonds, but having different three dimensional structures.

Enantiomers are mirror image stereoisomers. A chiral object is not

superimposable on its mirror image. Chiral molecules possess either: an

asymmetrically substituted atom (mainly carbon) or other asymmetry

elements imparting an overall chiral shape. The Cahn-Ingold-Prelog system is

commonly used in designating the absolute configuration of a chiral compound

as R (rectus) or S (sinister) isomers. Enantiomers can rotate the plane of the

polarized light either in a clockwise direction (dextrorotatory/ (+)-enantiomer)

or anticlockwise direction (levorotatory/ (-)- enantiomer). An equimolar mixture

of R and S enantiomers is called a racemate.

Many pharmaceutical compounds are marketed as racemates. Some of them

need to be used as racemates for optimum activity e.g. labetalol and nebivolol.

Many racemates need to be separated into single enantiomers or chirally pure

components prefixed as R or S enantiomers. It is demonstrated that each

enantiomer by virtue of three dimensional structure can interact with binding

sites of enzymes and receptors differently and one with strong binding provide

pronounced pharmacological action. Hence the pharmacological differences

caused by enantiomers can be pharmacokinetic or pharmacodynamic in

nature.

The pharmacokinetic implications of chiral drugs are exemplified by the

bioavailability of R-verapamil which is twice that of S-verapamil and attributed

to the reduced hepatic first-pass metabolism. Similarly R-pantoprazole and R-

metoprolol are subjected to much higher variability than their S-counterparts in

extensive/poor metabolizers. Overall, the single enantiomer provides less

complex pharmacokinetics, reduced metabolic load over the enzymatic

system and finally, offer less interaction potential.

The pharmacodynamic implications of the concept of chirality in drug activity

stem from the fact that the beneficial effects of a drug can reside in one

enantiomer. Its counterpart enantiomer having either no activity or less activity

or antagonist activity against the active enantiomer or completely separate

beneficial or adverse activity from the active enantiomer. The active and

inactive enantiomers are referred to as "eutomer" and "distomer" respectively.

Examples of drug candidates in which one enantiomer is 'active', while the

other enantiomer is "inactive" are S-atenolol - beta blocking property resides in

its S-form, levocetirizine - antihistaminic profile is associated with the R-

enantiomer (levo) while the S-enantiomer (dextro) being essentially inactive;

and levofloxacin - antibacterial activity resides in the S-enantiomer only.

Examples where one isomer is more potent than the other are (R, R)-

methylphenidate - approximately ten fold more potent than (S, S)-

methylphenidate; R-ondansetron - more potent than the S-enantiomer; S-

pantoprazole - more potent than the R-enantiomer; and esomeprazole - more

potent than the R-enantiomer.

Examples where beneficial effects reside in one enantiomer, the other

enantiomer having antagonistic activity are: salbutamol whose bronchodilator

activity resides with (S)-salbutamol, the latter is indirectly involved in

antagonizing the benefits of (R)-salbutamol and may have proinflammatory

effects; R-lipoic acid is responsible for most of the beneficial effects while the

corresponding S-form can oppose the action of its R-form.

The literature indicates many examples where enantiomers have entirely

different therapeutic possibilities. For example: R-fluoxetine is useful for

depression while S-fluoxetine is envisaged for migraine treatment; S-

propranolol has beta-blocking and membrane stabilizing property, its

12 13

Chirality - Today and Tomorrow's Way of Treatment

1. Ex Deputy Director & Head - Organic Chemistry Technology, National Chemical Laboratory, Pune (India


counterpart, R-propranolol, has membrane stabilizing and spermicidal

properties and may be useful in hyperthyroidism; R-sibutramine metabolite is

under evaluation for the treatment of depression while the S-sibutramine

metabolite may be useful for the treatment of erectile and ejaculatory

dysfunction. These possibilities need research, development, and validation.

Examples of beneficial effects in one enantiomer whilst the other enantiomer

has adverse activity are: S-amlodipine is a calcium channel blocker (CCB)

while R-amlodipine is inactive as CCB and is thought to be responsible for

pedal edema observed with racemic amlodipine; the post-anaesthetic

emergence reactions (hallucinations and agitation) are predominantly

associated with R-ketamine and not with S-ketamine, the latter being used for

dissociative anaesthesia; levo-bupivacaine is a safe drug while cardiotoxicity

is predominantly associated with its R-enantiomer; beta-1 selectivity of S-

metoprolol is similar to that of racemic metoprolol, while the R-enantiomer is

almost non-selective and may cause adverse effects related to additional beta-

2 blockade; S-oxybutynin has equivalent antispasmodic activity with lower

incidence of antimuscarinic side-effects than seen with racemate oxybutynin.

As a result of the appreciation of differences between enantiomers, the USFDA

(United States Food and Drug Administration) issued guidelines in 1992 and

again in 1995. The guidelines strongly encourage the development of single

isomers and discourage the commercialisation of racemic mixtures. Approval

can not be granted for a drug containing more than one isomer unless the

pharmacokinetic and pharmacodynamic properties of each could be

described and, more importantly, justified.

Some drugs are developed as pure enantiomers and defined as new single

isomer chemical entity (NSCE) such as enalapril, ramipril, diltiazem,

atorvastatin, simvastatin, pravastatin, clopidogrel, L-carnitine, levodopa, d-

penicillamine, levetiracetam, and rivastigmine. Chiral switches involve

development of unichiral version of the racemic drug already marketed. For

example escitalopram, esomeprazole, dexibuprofen, dexketoprofen, S-

ketamine, levocetirizine, levofloxacin, (R, R)-methylphenidate, levo-

leucovorin, levo-bupivacaine, and eszopiclone are the examples of chiral

switches because these drugs were initially marketed as racemic mixtures.

Some of the chiral switches under development are: dexloxiglumide, S-

doxazosin, R- and S- fluoxetine, R-lipoic acid and S-oxybutynin.

Chiral switch has been proposed to be a means of obtaining safer alternatives

to existing racemates. Switching from existing racemate to one of its isomers

has provided safer alternatives to drugs ranging from antihistamines like

cetirizine to anaesthetics like ketamine. Some recent chiral switches have

yielded safer and/or more effective alternatives to the existing racemates.

These include levosalbutamol, S-ketamine, levobupivacaine, S-zopiclone,

levocetirizine, S-amlodipine, S-atenolol, S-metoprolol, S-omeprazole, S-

pantoprazole, and R-ondansetron. More chiral switches are expected to

replace the racemates with safer options, making drug therapy more effective

and safer.

In India, Emcure Pharmaceuticals Limited, Pune has taken the lead in

developing several single enantiomer (unichiral) drugs, e.g. S-amlodipine, S-

atenolol, S-metoprolol, S-pantoprazole, and R-ondansetron. The advantages

of these unichiral drugs are briefly enumerated below:

: provision of the active CCB component only, longer half-life

of S-isomer, consistent pharmacokinetics due to less inter-subject variability of

S-isomer compared to R-isomer, half the racemate dose, less metabolic load,

prevention of accumulation of R-amlodipine in elderly, negligible pedal edema,

while retaining the ancillary properties of the racemate.

: provision of the active beta-1 blocker component only, half the

racemate dose, and lesser side-effects on switch-over from racemate to

eutomer.

(I) S-amlodipine

(ii) S-atenolol

14 15


(iii) S-metoprolol

(iv)S-pantoprazole

(v) R-ondansetron

Clearly, the future lies in chiral purity.

: provision of the beta-1 blocker component only, half the

racemate dose, avoiding the beta-2 blocking component, can be administered

at high doses without causing beta-2 receptor medicated side effects, safer in

poor metabolizers of CYP2D6, and avoids many drug-drug interactions.

: provision of more potent PPI and cytoprotective

component, half the racemate dose, consistent pharmacokinetics, safer than

racemate in poor metabolizers, and lesser potential for drug interactions.

: clinically more potent component, half the racemate

dose, does not prolong QTc interval, safer in children and elderly, and lesser

side-effects.

The success of unichiral products (expected sales = $200 billion by 2008), US

FDA regulations and scarcity of blockbuster new entities indicate that in the

foreseeable future the pharmaceutical industry will be placing increasing

emphasis on the development of chiral drugs as single enantiomers and to

carry out racemic switches in all areas of therapeutics. This will be significant

step towards offering rational, safer and more effective therapies.

16 17

50% impurity is not acceptable

“The development of “hybrid” drugs, presented as astep forward in medicinal chemistry, tends to be step backward in therapy.”

EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 1984, 26, 663-8

“Too often, and even without it being noticed, data in the scientific literature on mixture of stereoisomers, racemates, are presented as if only one compound were involved. The neglect of stereochemical aspects of drug action .... degrades many pharmacokinetic studies to expensive “highly sophisticated pseudoscientific nonsense.”


Reprinted from: J Indian Med Assoc. 2007; 105(4):173-4, 176.

Dr. Vinay GulatiMD (Medicine),Assistant Professor, Department of MedicineAll India Institute of Medical Sciences, Delhi (India)

Many of the drugs used in clinical practice are chiral, and are administered as

racemate, a 50:50 mixture of complementary enantiomers. Alternatives to

existing racemates are developed with the ultimate objective of increasing

efficacy and/or enhancing safety, in view of limitations of racemates. 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/unichiral drug). Unichiral drugs are increasingly available and

promises to provide clinicians with safer, better-tolerated and more efficacious

medications for treating patients. It is therefore important for the clinicians to be

familiar with the important properties of individual enantiomers of the

racemates used in clinical practice. Table 1 describes the important differential

properties of R and S enantiomers of some of the commercially available

racemates.

18 19

Differential properties of enantiomers of commercially available racemates

Ketamine

Salbutamol

Zopiclone

Cetirizine

Amlodipine

Atenolol

Esketamine

Levosalbutamol

Eszopiclone

Levocetirizine

S-Amlodipine

S-Atenolol

1Inhibits the elimination of S-ketamine in the racemate

5Bronchodilator activity

8More propensity for anticholinergic effects.

Smaller volume of distribution, smaller even than that of cetirizine - confers improved safety because of low hemato-encephalic barrier passage and low cerebral receptor

11,12,13binding. Enhanced peripheral receptor binding and improved overall selectivity specific to the H1 receptor than the

1 4 racemate. Pharmacokinetic studies indicate improved safety profile.

Inactive as a calcium channel blocker but may not be completely inert.Mainly responsible for blunting of precapillary postural vasoconstrictor reflex and for other local changes responsible for peripheral

15edema due to racemic amlodipine.

Relatively stronger activity in blocking beta-2 1 6 receptors than beta-1 receptors.

Responsible for loss of cardioselectivity at higher doses of racemate

Two to three times more potent than racemic 2,3ketamine. Eliminated more rapidly as a

single enantiomer than as a component of the racemate. Incidence of psychotomimetic phenomena is negligibly less with S-ketamine in comparison to racemic

4ketamine.

5Inactive as bronchodilator but not completely inert and can induce airway hyper-reactivity, eventually contributing to increased morbidity and mortality in patients

6,7with asthma.

More active than R-zopiclone at the benzodiazepine receptor complex and is responsible for most of the hypnotic activity

8,9of the racemic compound. Shorter duration of action, which could minimize or prevent

10residual hangover effects.

Inactive nature (large-scale comparative studies are however, warranted to address the issue).

Only vasoactive enantiomer of amlodipine Longer plasma half-life. Lesser intersubject variability in the clearance. Negligible incidence of peripheral oedema than the

15racemate.

Predominantly responsible for cardiac beta-17blocking activity.

Properties of S-enantiomerProperties of R-enantiomerRacemateUnichiral drugsapproved for use

Table 1. Important properties of R and S enantiomers of the commercially available racemates


Although synthetic chemistry has enhanced the ability of the pharmaceutical

industry to develop single enantiomer/unichiral drugs, many drugs are still

used clinically as racemates. It is therefore important from the clinician point of

view to recognize the differential properties of enantiomers of these racemates

when they are placed in a biological environment as these differing properties

can impact the clinical outcome of patients positively or negatively. For this

reason regulatory authorities like US-FDA now encourages the development

of single isomers. Rather than using chiral synthetic drugs as racemates in the

first instance, the activities and toxicities of the enantiomers are now needed to

be tested individually. Unichiral drugs of racemates discussed above have

provided safer and/or more effective alternatives to the existing racemates.

Several other available and investigational unichiral drugs are expected to

provide safer and or more effective therapeutic options over the racemates.

20 21

Properties of S-enantiomerProperties of R-enantiomerRacemateUnichiral drugsapproved for use

Metoprolol

Omeprazole

Pantoprazole

Ondansetron

Bupivacaine

S-Metoprolol

Esomeprazole

S-Pantoprazole

R-Ondansetron

Relatively stronger activity in blocking beta-2 1 6receptors than beta-1 receptors.

Responsible for loss of cardioselectivity at higher doses of racemate.Clearance is s lower than S-metoprolol in poor metabo l i zers , resu l t ing in h igher concentrations of the non-selective R-

18,19enantiomer if a racemate is administered.

Predominantly responsible for cardiac beta-17blocking activity. Ensures cardioselectivity

even in poor metabolizers as concentrations of only the beta-1-selective component would be increased. Avoids some harmful drug-interactions with some drugs like paroxetine, cimetidine, ciprofloxacin and verapamil, which selectively increase the concentrations of non-selective R-

20-23metoprolol.

Exhibits greater variability than S-isomer in poor versus extensive metabolizers of CYP2C19 substrates.More dependent on CYP2C19. 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

24, 25hyperplasia.

Exhibits greater variability than their S-isomers in poor versus extensive metabolizers of CYP2C19 substrates. More dependent on CYP2C19. 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-

24, 25like cell hyperplasia.

Could be metabolized by alternative pathways l ike CYP3A4 and sulfo-transferases. Clinically more effective than

26-28the racemate.

Could be metabolized by alternative p a t h w a y s l i k e C Y P 3 A 4 a n d sulfotransferases Clinically more effective

26-28than the racemate.

29 No QTc prolongation. Less cardiotoxic than e i ther S-ondanse t ron o r racemic

30ondansetron. More potent than the S 31isomer.

29, 30Causes QTc prolongation.

Cardiotoxic effects and toxic effects on the 32CNS.

Less cardiotoxic effects and less toxic effects on the CNS in comparison with both

32 dextrobupivacaine and bupivacaine itself.33Wider safety margin than the racemate.

Levobupivacaine


References

22 23

1. 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.

2. 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.

3. Adams HA. Mechanisms of action of ketamine. Anaesthesiol Reanim 1998;23:60-3.

4. Himmelseher S, Pfenninger E. The clinical use of S-(+)-ketamine-a determination of its place. Anasthesiol Intensivmed Notfallmed Schmerzther 1998;33:764-70.

5. Waldeck B. Enantiomers of bronchodilating b-2adrenoceptor agonists: Is there a cause for concern? J Allergy Clin Immunol 1999;103:742-8.

6. Handley DA, McCullough JR, Cowther SD, Morley J. Sympathomimetic enantiomers and asthma. Chirality 1998;10:262-72.

7. Page CP, Morley J. Contrasting properties of albuterol stereoisomers. J Allergy Clin Immunol 1999;104:S31-41.

8. Georgiev V. (S)- Zopiclone sepracor. Curr Opin Invest Drugs 2001;2:271-3.

9. McMahon LR, Jerussi TP, France CP. Steroselective discriminative stimulus effects of zopiclone in rhesus monkeys. Psychopharmacology 2003;165:222-8.

10. 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.

11. 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.

12. 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.

13. Tillement JP, Testa B, Bree F. Compared pharmacological characteristics in humans of racemic cetirizine and levocetirizine, two histamine H1-receptor antagonists. Biochem Pharmacol 26. 2003;66:1123-6.

14. 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.

15. Patil P.A, Kothekar M. A. Development of safer molecules through chirality. Indian J Med Sci 2006; Vol. 60, No. 10.

16. 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.

17. Mehvar R, Brocks D. Stereospecific pharmacokinetics and pharmacodynamics of â-adrenergic blockers in humans. J Pharm Pharmaceut Sci 2001;4:185-200.

18. 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.

19. 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.

20. 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.

21. 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.

22. Waite NM. Disposition of the (+) and (-) isomers of metoprolol following ciprofloxacin treatment. Pharmacotherapy 1990;10:236.

23. 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.

24. 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.

25. 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.

26. Baker DE. Esomeprazole magnesium (Nexium). Rev Gastroenterol Disord 2001;1:32-41.

27. 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.

28. 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.

29. Bodhankar SL, Maurya OP. Effect of racemate ondansetron and its isomers on QT interval in rats. Pharmacology. Data on file 2006.

30. Rubin PD, Barberich TJ. Methods for treating apnea and apnea disorders using optically pure R(+) ondansetron downloaded from http:// patft.uspto.gov.

31. Shinde J. R-Ondansetron-A novel antiemetic. Gastroenterol Today 2005;IX:132-3.

32. 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.

33. Ivani G, Borghi B, van oven H. Levobupivacaine. Minerva Anestesiol 2001;67:20-3.

Unichiral drug development is important for successful development and

clinical use of cardiovascular drugs and their therapeutic applications. This is

because there are several cardiovascular drugs in which

pharmacokinetic/pharmacodynamic properties of the enantiomers are

distinctly different. Most common examples are beta-blockers such as

atenolol, metoprolol and calcium channel blocker (CCB) such as Amlodipine.

Among the commonly used anti-hypertensives, the ACE-inhibitors like

enalapril and ramipril are unichiral drugs. Chirality has therefore been

visualized as an important factor in cardiovascular research. The fact that

seven out of the top 15 cardiovascular molecules used in India are unichiral

(Source: ORG-IMS) emphasizes the benefits of using chirally pure

therapeutics in clinical practice.

Here we discuss two important unichiral cardiovascular drugs, S-amlodipine

and S-metoprolol, with their important pharmacological properties and clinical

profile.

Chirality and cardiovascular drugs

Chirally Pure CVS products

Beta adrenergic Antagonists: S(-)Metoprolol, S(-)Atenolol

Calcium Channel Antagonists: S(-)Amlodipine, Diltiazem

Antiarrhythmic Drugs: Quinidine

ACE Inhibitor: Captopril, Enalapril, Ramipril, Lisinopril, Benazepril, Fosinopril, Perindopril

Statins: Atorvastatin .Simvastatin, Pravastatin, Lovastatin,Rosuvastatin

Anti-platelet: Clopidogrel

Centrally acting antihypertensive: Methyldopa


24 25

Unichiral CCBs : Focus on S-Amlodipine

Among the calcium channel blockers (CCBs), Amlodipine has an outstanding

pharmacokinetic and pharmacodynamic profile. Amlodipine is a racemic

mixture, composed of S and R enantiomers in equal proportion. But the

calcium channel-blocking activity is confined only to S-amlodipine; R-

amlodipine being 1000-fold less active than its S-counter part. Studies in

spontaneously hypertensive rats have shown that R-amlodipine does not

lower the blood pressure at all while S-amlodipine lowers the blood pressure

effectively. The R-enantiomer which is inactive as a calcium channel blocker

thus constitutes an impurity and causes an increased metabolic load on the

body when racemic Amlodipine is used in clinical practice.

Further, S-Amlodipine has less pharmacokinetic variability and longer duration

of action than the racemate. A pharmacokinetic study of Amlodipine after single

oral administrations of 20 mg racemic Amlodipine to 18 healthy volunteers

demonstrated that oral clearance of S-Amlodipine is subjected to much less

inter-subject variation than that of the R-enantiomer with coefficient of

variations of 25% and 52% for clearance of S and R enantiomers respectively.

R-Amlodipine is more rapidly eliminated from plasma than S-Amlodipine, with

mean terminal half-lives of 34.9 hours (R) and 49.6 hours (S). Thus the

attribute of long duration of action of Amlodipine is dependent on its S-

enantiomer. Use of S-Amlodipine alone will thus provide a further longer

duration of action than the racemate. S-Amlodipine maintains rather reinforces

the pharmacokinetic advantages of amlodipine (higher bioavailability, longer

half-life, lipophilicity, vascular selectivity etc).

Emcure Pharmaceuticals Ltd has

developed S-amlodipine (Asomex, S-

Numlo), which is commercially

available in various countries for the

treatment of hypertension and angina

at half the dose of racemic amlodipine.

Randomized, controlled studies of S-

amlodipine at half the dose of

amlodipine have shown that S-

amlodipine was equivalent in efficacy

in the management of hypertension

compared to racemate. This implies

that half the dose of the racemate as S-

amlodipine lowers the metabolic load, avoids the impurity and provides the

right medication and equal efficacy. The efficacy of S-amlodipine has also been

proven in the African population and also through studies in Ukraine, Korea

and Philippines. In post-marketing surveillance studies (SESA studies,

n=5140), the incidence of pedal edema with S-amlodipine has been

seen to be much lesser (mean 1.36%) than that reported with the racemate

(usually about 16-20%). SESA studies have also shown that majority of

patients with edema due to racemate when switched to S-amlodipine, showed

resolution of their edema. This finding provides clinical evidence that the R-

enantiomer of racemate, although inactive as a calcium channel blocker, may

not be completely inert and may be responsible for edema seen with racemate.

A pilot clinical study in patients with mild to moderate hypertension showed that

S-amlodipine exhibits a trend towards better ambulatory blood pressure

control in the night-time as compared to Amlodipine. S-Amlodipine has also

been shown to be effective and safe in elderly hypertensives, isolated systolic

hypertension patients and normotensive patients with angina.

S-amlodipine (Asomex) is available in over 31 countries world-wide.


26 27

• Seong-Jin Baek, Ah-Young Lim. Comparative antihypertensive effects of R/S, S(-) and R(+) Amlodipine besylate in the spontaneously

hypertensive rat (SHR) model. Study No: B05199. Data on File.

• Katarzyna Kulig, Piotr Nowicki, Barbara Malawska. Influence of the absolute configuration on pharmacological activity of antihypertensive and antiarrhythmic drugs. Pol. J. Pharmacol, 2004; 56: 499-508.

• Luksa J, Josic D, Kremser M, Kopitar Z, Milutinovic S. Pharmacokinetic behaviour of R-(+) and S-(-)-amlodipine after single enantiomer administration. J Chromatogr B Biomed Sci Appl. 1997; 703(1-2):185-93.

• Laufen H, Leitold M. Enantioselective disposition of oral amlodipine in healthy volunteers. Chirality 1994; 6(7):531-6.

• Pathak L, Hiremath MS, Kerkar PG, Manade VG. 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. JAPI 2004, 52: 197-202.

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

• The SESA-II Study: Safety and Efficacy of S(-)Amlodipine in the treatment of Hypertension; SESA Study group,India: Indian Medical Gazette 2005; Vol. CXXXIX, No. 12:.529-533.

• MICRO-SESA-1 - Safety and Efficacy of S (-) Amlodipine in the treatment of isolated systolic hypertension; SESA study group India; Indian Medical Gazette 2005; Vol.C39, No.6: 243-250.

• MICRO-SESA-II - Safety and Efficacy of S(-)Amlodipine in the Treatment of Hypertension in Elderly Patients, SESA Study group,India; Indian Medical Gazette 2005; Vol. XXXIX, No.8: 353-358.

• Hiremath JS. The SESA-Angina Study - Safety and Efficacy of S-Amlodipine in Angina. Indian Medical Gazette 2005; CXXXIX, No 9: 403-8.

• SESA-III Study Group. Multicentre Clinical Evaluation of a Fixed-Dose Combination of S-Amlodipine and Atenolol in the Treatment of Mild to Moderate Hypertension. Indian Medical Gazette 2006; Vol CXL, No. 10: 464-466.

• Basu D. Comparative study to evaluate the effect of S-Amlodipine versus Amlodipine on office and ambulatory blood pressure in mild to moderate hypertensives. Indian Medical Gazette, December 2007; Vol./ CXLI, No.12: pg. 493-497.

All the beta-blockers are racemic mixtures of two enantiomers, R and S. Both

these isomers may exhibit differing pharmacological properties and so

currently used racemic beta-blockers are actually fixed-dose combinations of

two pharmacokinetically and pharmacodynamically different isomers. The

cardiac beta-blocking activity of the racemic beta-blockers resides in their S-

enantiomers, while in-vitro studies suggest that the R-isomer is more selective

for beta 2 receptors. This may explain the loss of cardioselectivity of racemates

at higher doses. Further, it has recently been shown that the generally

considered cardioselective racemic drugs like atenolol and metoprolol have

poor beta 1: beta 2 selectivity; suggesting that there is considerable potential

for developing more selective beta blockers for clinical use, thereby reducing

the side-effects arising due to poor cardioselectivity. Cardioselectivity is

preferable for high-risk groups like diabetics, patients with peripheral arterial

disease and COPD patients.

Metoprolol is a widely used cardioselective beta-blocker. It is a racemic mixture

of R and S isomers. The beta 1 blocking activity (cardioselectivity) of

Metoprolol resides in S-isomer while R-isomer exhibits beta 2 blocking activity.

The needless administration of the non beta-1-blocking R-enantiomer that

makes up 50% of racemate actually puts the patient at an increased risk of

side-effects, drug interactions and loss of cardioselectivity with up-titration of

dosing.

S-Metoprolol (Metpure-XL) is a chirally pure form of Metoprolol developed by

Emcure Pharmaceuticals Ltd. The cardiac ß-blocking activity of S-Metoprolol

is greater than R-isomer with S: R activity ratio=33:1. The beta 1 receptor

affinity of the S-form is about 500 times greater than that of R-form. R-

enantiomer has rather strong activity in blocking beta 2 receptors with the S: R

ratio being 1:10.

Unichiral beta-blockers : Focus on S-Metoprolol

References:


28 29

There are differences in the metabolism of Metoprolol isomers that leads to

stereoselectivity observed in the plasma concentrations of racemic

Metoprolol. The plasma concentrations of racemic Metoprolol in poor

metabolizers (PM) are 6 times higher than those in extensive metabolizers

(EM). EM have greater ability to eliminate R-Metoprolol than S-Metoprolol; in

PM however, the clearance of R-Metoprolol is equal to or less than that for S-

Metoprolol. Therefore, the same concentrations of the racemate would contain

less of the active S isomer and higher concentration of R isomer in poor

metabolizers, shifting the ß-blockade effect-concentration relationship to the

right. This can lead to loss of cardioselectivity and side-effects associated with

beta-blockade such as diminished pulmonary function in patients with asthma

or COPD as indicated by reduction in FEV1, FVC, and peak expiratory flow

rate (PEFR). Use of chirally pure S-Metoprolol will therefore ensure safety as

well as efficacy in patients irrespective of their metaboliser status. Further, R-

Metoprolol has been shown to exhibit pharmacokinetic variability when

racemate metoprolol is administered concomitantly with drugs that inhibit

CYP2D6 enzyme. Use of S-isomer alone would therefore render less

interaction potential especially in patients taking CYP2D6 inhibitors or in

patients with heart failure or hepatic insufficiency.

Randomized, controlled studies (SMART-trials) and post-marketing

surveillance studies have shown that chirally pure S-Metoprolol at half the

dose of racemate is as effective as racemate in the treatment of patients with

hypertension and/or angina. S-Metoprolol has also been shown to be effective

and well-tolerated in patients with co-existing diabetes (SMART-Dimension

Study), COPD, hyperlipidemia and CHF (SMART-CHF Study). These studies

thus provide clinical evidence of higher cardioselectivity of S-Metoprolol.

• Vasant V Ranade, John C Somberg . Chiral cardiovascular drugs: an overview. Am J Ther. ;12 (5):439-59.

• Stoschitzky K, Zernig1 G, Lindner W. Racemic beta-blockers - fixed combinations of different drugs. Journal of Clinical and Basic Cardiology 1998; 1 (1): 15-19.

• Baker JG. The selectivity of ß-adrenoceptor antagonists at the human ß1, ß2 and ß3 adrenoceptors. British Journal of Pharmacology 2005; 144: 317-322.

• Wahlund G, Nerme V, Abrahamsson T, Sjoquist PO. The ß 1- and ß 2-adrenoceptor affinity and ß 1-blocking potency of S- and R-metoprolol. Br J Pharmacol. 1990; 99(3):592-.

• Nathanson JA. Stereospecificity of ß adrenergic antagonists: R-enantiomers show increased selectivity for ß-2 receptors in ciliary process. J Pharmacol Exp Ther 1988; 245:94-101.

• Murthy SS; Shetty U; Nelson WL; Jackson PR; Sennard MS. Enantioselective and diastereoselective aspects of the oxidative metabolism of Metoprolol. Biochem Pharmacol 1990: 40:1637-1644.

• 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.

• 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(1):222-43.

• Kim M; Shen D, Eddy A, Nelson W. Inhibition of the enantioselective oxidative metabolism of Metoprolol by verapamil in human liver microsomes. Drug Metab Dispos 1993; 21:309-317.

• Hemeryck A, Lefebvre RA, Vriendt CD, Belpaire FM. Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharmacol Ther 2000; 67: 283-91.

• 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.

• The SMART Trial Study Group. The SMART Trial (S-Metoprolol Assessment in Hypertension Trial). Cardiology Today 2005; IX (4): 222 - 229.

• SMART-II Study Group. Results of SMART-II study on efficacy and safety of S-Metoprolol extended release tablet. Indian Medical Gazette 2006; CXL(2): 72-75.

• Aneja P, Srinivas A, Janardhan G. Efficacy and safety of S-Metoprolol extended release tablets in the management of Hypertension - Results of multicentric, prospective, clinical study. Indian Medical Gazette 2005; Vol. CXXXIX(11): 485-487.

• Singh TSD. Efficacy and Safety of a fixed dose combination of S-Metoprolol 25 mg and Hydrochlorothiazide 12.5 mg Tablet in the Treatment of Mild to Moderate Hypertension. Indian Medical Gazette 2006; Vol. CXL(7):.314-317.

• Mandora VP. Safety and Efficacy of S-Metoprolol Succinate Extended Release tablet in the Treatment of Hypertension Coexisting with COPD - An Open-label, Non-comparative, Prospective Clinical Study. Indian Medical Gazette 2006, CXL(1):.28-32.

• Talwalkar PG. Safety & Efficacy of S-Metoprolol in the Treatment of Patients with Diabetes Mellitus and Hypertension (SMART-DIMENSION Study). Indian Medical Gazette 2007; CXLI(4): 139-144.

• Aneja P, Srinivas A, Das Biswas A. 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. International Journal of Clinical Pharmacology and Therapeutics 2007; 45(5): 253-258.

• SMART-HF study. Indian Medical Gazette (in press).

References:


30 31

Although not all of the NSAIDs are chiral, most of them possess a chiral center.

The chiral NSAIDs are one of the most studied classes for chirality. This class

includes the Ibuprofen, Ketoprofen, Fenoprofen, Flurbiprofen, Tiaprofenic

acid, Carprofen, Pirprofen, Benoxaprofen, Naproxen, Etodolac and Ketorolac.

For NSAIDs, it is the enantiomer possessing the S configuration that almost

exclusively possesses the ability to inhibit prostaglandin activity. Of the chiral

NSAIDs, all are traditionally administered in racemic form except Naproxen,

which is given as the single S enantiomer. The NSAIDs have been intensively

studied from the perspective of stereoselectivity in pharmacokinetics.

Here we discuss the recently introduced single enantiomer NSAIDs -

Dexibuprofen, Dexketoprofen and the soon to be introduced molecule S(+)

Etodolac.

Racemic Ibuprofen, which contains equal quantities of R(-)Ibuprofen and

S(+)Ibuprofen, has been used as an anti-inflammatory and analgesic agent for

over 30 years. R-Ibuprofen and Dexibuprofen differ in their physicochemical,

pharmacological and metabolic properties. S-Ibuprofen or Dexibuprofen is the

pharmacologically active enantiomer of racemic Ibuprofen. Dexibuprofen

inhibits both COX-1 and COX-2 enzymes (Mayer and Testa, 1997).

Dexibuprofen is the S(+)(dextrorotatory)-enantiomer of Ibuprofen and

accounts for virtually all pharmacodynamic (analgesic, antiinflammatory,

antipyretic) activities of the racemic compound (Kaehler et al, 2003; Mayer and

Testa, 1997). In vitro, Dexibuprofen is over 100 times as potent as the R-

enantiomer as an inhibitor of prostaglandin biosynthesis (Mayer and Testa,

1997). In therapy, potential advantages of Dexibuprofen over racemic

Ibuprofen include lesser toxicity, greater clinical efficacy and/or less variability

in therapeutic effects achieved, and easier dose optimization, all at half the

dose of Ibuprofen. Several clinical trials and post marketing surveillance

studies have been performed to elucidate the efficacy and safety of

Dexibuprofen [S(+)Ibuprofen]

Dexibuprofen. More than 12,000 patients were studied in 31 clinical trials till

2003 (Kaehler et al, 2003).

In vivo, the R-enantiomer of racemic Ibuprofen undergoes unidirectional

enzymatic chiral inversion to S-enantiomer. This occurs to the extent about

65%, whereas there is no bioinversion of S- to R-Ibuprofen (Gabard et al, 1995;

Kelley et al, 1992). Although this would favour use of racemic Ibuprofen, since

most of its inactive enantiomer is converted to active form, conversion of

racemic Ibuprofen to S-Ibuprofen results in variability of clinical response,

including delayed onset of activity, and difficulty in achieving an optimal dose;

also the formation of coenzyme A (CoA) thioester during bioinversion of R- to

S-Ibuprofen may result in toxic effects (eg, interference of lipid

anabolism/catabolism). In addition, R-Ibuprofen bioactivation is susceptible to

biological factors and certain drugs (Gabard et al, 1995; Mayer and Testa,

1997).

Many clinical studies have evaluated the efficacy and tolerability of

Dexibuprofen. The findings from these studies demonstrate that Dexibuprofen

is effective and very well tolerated in patients with osteoarthritis and dental

pain. These effects are comparable to Diclofenac, Celecoxib and double dose

of racemic Ibuprofen (Dionne and McCullagh, 1998; Hawel et al, 1997; Hawel

et al, 2003; Mayrhofer, 2001; Singer et al, 2000).

Dexibuprofen 200 or 400 mg as a single dose was effective in the treatment of

acute pain following third-molar extraction in a double-blind, placebo-

controlled study. Effective pain relief compared to placebo was evident for up to

6 hours following the 400-mg dose (Dionne and McCullagh, 1998). When

given for acute pain following third-molar extraction, single doses of

Dexibuprofen 200 and 400 mg provided pain relief statistically superior to that

of racemic Ibuprofen 400 mg and placebo during the first hour post-ingestion;

Dexibuprofen 400 mg (but not 200 mg) remained statistically superior to

Ibuprofen 400 mg at 2 and 3 hours, whereas all regimens provided similar

Chirality and NSAIDs


32 33

analgesia during hours 4 to 6. The incidence of adverse effects did not differ

between groups (Dionne and McCullagh, 1998).

Dexibuprofen, 300 mg orally three times daily for 15 days was as effective as

diclofenac sodium 50 mg orally three times daily in a randomized, double-

blind, parallel-group trial of 110 patients with osteoarthritis of the knee. All

patients had a baseline Lequesne index score of at least 8. Improvement in the

Lequesne index score averaged 5.9 and 7.4 points after 8 and 15 days,

respectively, for the Dexibuprofen group compared with 5.5 and 7.3 points for

the diclofenac group. In physician assessment at study end, Dexibuprofen

treatment was judged to be 'very good' or 'good' in 90.9% of patients versus

86.5% of diclofenac patients; in patient self-assessment, Dexibuprofen was

judged to be 'very good' or 'good' in 89.1% of the cases versus 82.7% for

diclofenac. Dexibuprofen was better tolerated, with 4 patients (7.3%)

discontinuing treatment due to adverse effects compared with 8 patients

(14.5%) for diclofenac. Further studies of longer duration and placebo-

controlled, crossover design are needed (Hawel et al, 1997).

A randomized, parallel-group, double-blind, active controlled clinical trial

aimed to assess the relative therapeutic efficacy and tolerability/safety of

Dexibuprofen and the selective COX-2 inhibitor celecoxib in adults with

osteoarthritis of the hip (Hawel et al, 2003). 148 inpatients were randomly

assigned to Dexibuprofen 800 mg or celecoxib 200 mg daily. Evaluation of the

WOMAC osteoarthritis index proved that Dexibuprofen 400 mg b.i.d. is not

inferior to celecoxib 100 mg b.i.d. with the Mann-Whitney estimator equal to

0.5129 and the corresponding lower boundary of the 95% confidence interval

equal to 0.4409. The overall incidence of adverse drug reactions was 12.16%

in the Dexibuprofen group and 13.51% in the celecoxib group. 8.1% of patients

on Dexibuprofen and 9.5% on celecoxib suffered from gastrointestinal

disorders. This shows that Dexibuprofen has at least equal efficacy and a

comparable safety/tolerability profile as celecoxib in adult patients suffering

from osteoarthritis of the hip.

An efficacy study was performed to prove the equivalent efficacy of

Dexibuprofen compared to the double dose of racemic Ibuprofen and to show

a clinical dose-response relationship of Dexibuprofen. The 1-year tolerability

study was carried out to investigate the tolerability of Dexibuprofen (Mayrhofer,

2001). In the efficacy study 178 inpatients with osteoarthritis of the hip were

assigned to 600 or 1200 mg of Dexibuprofen or 2400 mg of racemic Ibuprofen

daily. The primary end-point was the improvement of the WOMAC

osteoarthritis index. A 1-year open tolerability study included 223 outpatients

pooled from six studies. The main parameter was the incidence of clinical

adverse events. In the efficacy study the evaluation of the improvement of the

WOMAC osteoarthritis index showed equivalence of Dexibuprofen 400 mg

t.i.d. compared to racemic Ibuprofen 800 mg t.i.d., with Dexibuprofen being

borderline superior (P = 0.055). The comparison between the 400 mg t.i.d. and

200 mg t.i.d. doses confirmed a significant superior efficacy of Dexibuprofen

400 mg (P = 0.023). In the tolerability study the overall incidence of clinical

adverse events was 15.2% (GI tract 11.7%, CNS 1.3%, skin 1.3%, others

0.9%). The active enantiomer Dexibuprofen proved to be an effective NSAID

with a significant dose-response relationship. Compared to the double dose of

racemic Ibuprofen, Dexibuprofen was at least equally efficient, with borderline

superiority over Dexibuprofen (P = 0.055). The tolerability study in 223 patients

on Dexibuprofen showed an incidence of clinical adverse events of 15.2% after

12 months. The results of the studies suggest that Dexibuprofen is an effective

NSAID with good tolerability.

A double-blind randomized trial (Singer et al, 2000) was conducted to compare

the isolated active enantiomer Dexibuprofen with the double dose of racemic

Ibuprofen and to show a dose-response relationship of Dexibuprofen in painful

osteoarthritis of the hip. 178 patients were randomly assigned to Dexibuprofen

600/1,200 mg or racemic Ibuprofen 2,400 mg daily. The evaluation of the


34 35

WOMAC osteoarthritis index showed statistically significant equivalence of

Dexibuprofen 400 mg t.i.d. compared with racemic Ibuprofen 800 mg t.i.d. by a

Mann-Whitney statistic of 0.578 and the corresponding lower bound of the

95% confidence interval of 0.498. The test for superiority of Dexibuprofen was

borderline significant with p = 0.055. Dexibuprofen 400 mg t.i.d. and

Dexibuprofen 200 mg t.i.d. showed a statistically significant dose-response

relationship in improving the WOMAC OA index (p = 0.023). Patients suffered

from adverse drug reactions, mainly gastrointestinal disorders, 13.34% on

Dexibuprofen 200 mg, 15.25% on Dexibuprofen 400 mg and 16.94% on

racemic Ibuprofen 800 mg. Thus, the active enantiomer Dexibuprofen proved

to be an effective non-steroidal anti-inflammatory drug. Compared with

racemic Ibuprofen half of the daily dose of Dexibuprofen shows at least

equivalent efficacy. The additional administration of R-Ibuprofen in form of

racemate does not contribute to the clinical efficacy of racemic Ibuprofen.

Dexketoprofen [S(+)Ketoprofen] Trometamol

Racemic Ketoprofen is a 50:50 mixture of S(+)- and R(-)-enantiomers

(Barbanoj et al, 1998). Most or all COX inhibitory activity of Ketoprofen is

attributed to the S(+)-enantiomer (Dexketoprofen) (Mauleon et al, 1996).

Dexketoprofen has been demonstrated to be an inhibitor of COX-1 and COX-2

activities in experimental animals and humans (Mauleon et al, 1996). The R-

enantiomer is 30 to 5000 times less potent as an inhibitor of COX-1 and about

100 times less potent as an inhibitor of COX-2 (Cooper et al, 1998). Although

R-Ketoprofen has produced some degree of analgesic activity in animal

models and in patients with dental pain (after high doses), this appears related

to bioinversion to the S-enantiomer (Barbanoj et al, 1998; Cooper et al, 1998;

Mauleon et al, 1996). Between 10 and 13% bioinversion of R to S occurs in

humans (Cooper et al, 1998; Jerussi et al, 1998; Rudy et al, 1998). In contrast,

there is no inversion of S-Ketoprofen to R-Ketoprofen (Mauleon et al, 1996;

Rudy et al, 1998;). In addition, S-Ketoprofen has been found to be significantly

less ulcerogenic in the rat gastrointestinal tract as compared to the racemic

Ketoprofen and that the R-enantiomer may contribute to the pathogenesis of

intestinal ulcers (Cabre et al, 1998). This effect was also dose-dependant

(Nieto et. al, 2002).

The pharmacokinetic profile of Ketoprofen and its enantiomers has been

assessed in several animal species and in human volunteers (Barbanoj,

2006). The absorption of S-enantiomer from racemic Ketoprofen and

Dexketoprofen trometamol has been found to be equivalent. Dexketoprofen

trometamol, given as a tablet, is rapidly absorbed, with a time to maximum

plasma concentration (t ) between 0.25 and 0.75 hours after administration of max

Dexketoprofen trometamol 12.5 and 25 mg, respectively. This fast absorption

could account for the suitability of Dexketoprofen in the management of acute

pain. No R-Ketoprofen has been isolated in the urine of volunteers indicating

that inversion from R- to S-enantiomer is unidirectional (Barbanoj, 2006).

DEXIBUPROFEN : PLACE IN THERAPY

Potential advantages of dexibuprofen over racemic ibuprofen include

• Lesser toxicity,• Greater clinical efficacy• Less variability in therapeutic effects achieved• Easier dose optimization• Half the dose of ibuprofen.• Dexibuprofen has a faster onset of action, making it

an attractive option in management of acute pain


36 37

Clinical studies performed on several pain models have demonstrated that

Dexketoprofen has analgesic, anti-inflammatory and antipyretic activities

while R-Ketoprofen weakly demonstrate these effects after conversion to the

S-enantiomer. Dexketoprofen is as effective as twice the dose of racemate

(Cooper et al, 1998; Rudy et al, 1998).

Several clinical trials conducted with orally administered Dexketoprofen

trometamol in patients affected by acute and chronic pain have confirmed its

high analgesic potency and good tolerability profile. The trials have also

investigated the analgesic efficacy of oral Dexketoprofen trometamol in

comparison with enantiomerically equivalent doses of the racemic compound

Ketoprofen. In patients with dental pain, osteoarthritis and dysmenorrhea,

Dexketoprofen showed comparable analgesic efficacy and tolerability but a

faster onset of action than Ketoprofen.

In patients with extraction of impacted third molar, the level of analgesia

produced by Dexketoprofen 25 mg was similar to that produced by Ketoprofen

50 mg with more rapid onset of action (McGurk et al, 1998). Dexketoprofen

trometamol 25 mg has efficacy and tolerability comparable to Rofecoxib 50 mg

in patients after third molar extraction (Jackson et al, 2004). Similarly,

Dexketoprofen trometamol 5 to 20 mg offered pain relief comparable to

Ibuprofen 400 mg following third-molar extraction. The onset of analgesia was

more rapid with Dexketoprofen trometamol (50% pain reduction in 0.9 versus

2.1 hours) (Gay et al, 1996).

The results of a multi-centric, randomized, comparative clinical trial to evaluate

the efficacy and safety of Dexketoprofen trometamol 25 mg t.i.d. versus

Ketoprofen 50 mg t.i.d. in the treatment of pain due to dental surgery shows

that the Dexketoprofen trometamol 25 mg is equally effective as compared to

Ketoprofen 50 mg in decreasing pain due to dental extraction in the first 8 hours

of therapy. Dexketoprofen has a better analgesic effect at 24 hours and on the

second and third day of therapy as compared to Ketoprofen. In this study,

Dexketoprofen provided significant analgesia within 1 hour of dosing whereas,

though Ketoprofen decreased the pain intensity at 1 hour, statistically

significant analgesia was observed only after 8 hours of therapy with

Ketoprofen (Data on file 1).

Dexketoprofen has been studied in acute and chronic management of

osteoarthritis and related symptoms. In osteoarthritis patients, 3 week

treatment with Dexketoprofen trometamol 25 mg t.i.d. was found to be more

efficacious than Ketoprofen 50 mg t.i.d. In addition, 75% of the Dexketoprofen

group had improved compared with 50% of the Ketoprofen patients. There

were fewer adverse events in the Dexketoprofen treatment group (Beltran et

al, 1998). Morning stiffness in osteoarthritis of the hands is a troublesome

symptom that deserves attention in many patients. In such patients,

Dexketoprofen-trometamol (50 mg) administered early in the morning rapidly

reduced the degree of morning stiffness in thirty-five patients compared with

nineteen controls (Rovetta et al, 2001). Dexketoprofen 50 mg IV has also been

found to have the equivalent analgesic activity and better tolerability compared

to Ketoprofen 100 mg IV in the management of postoperative pain after

orthopedic surgery (Zippel and Wagenitz, 2006).

In patients with a history of primary dysmenorrhea Dexketoprofen 12.5 and 25

mg and racemic Ketoprofen 50 mg significantly reduced pain intensity

compared with placebo from 1 h after dose to 4-6 h after dose. There were no

significant effects of any treatment on activities of daily living, menstrual flow, or

associated symptoms. Dexketoprofen was shown to be effective, well

tolerated, and did not show any difference in the incidence of adverse events

compared to Ketoprofen or placebo (Ezcurdia et al, 1998).

The results of a multi-centric, randomized, comparative clinical trial to evaluate

the efficacy and safety of Dexketoprofen trometamol 25 mg t.i.d. versus

Ketoprofen 50 mg t.i.d. in the treatment dysmenorrhoea shows that the

Dexketoprofen trometamol 25 mg is equally effective as compared to


38 39

Ketoprofen 50 mg in decreasing pain of dysmenorrhoea. Both the drugs have

similar onset of action and are safe and well-tolerated in this indication (Data

on file 2).

Dexketoprofen trometamol is an effective and rapidly acting analgesic for the

treatment of acute musculoskeletal injuries. In patients with acute lower limb

injury 25 mg oral Dexketoprofen trometamol was found to be more effective in

reducing pain score at 15, 30, 45, and 60 minutes as compared to Diclofenac

sodium 50 mg (Leman et al, 2003).

Animal studies have demonstrated that addition of sub-therapeutic doses of

Dexketoprofen improves the activity of opioid analgesics like Fentanyl (Gaitán

and Herrero, 2002). In patients undergoing elective hip arthroplasties,

Dexketoprofen 25 mg t.i.d., peri-operative and post-operative, markedly

improved analgesia and reduced opioid requirement and side effects such as

nausea, vomiting and sedation (Iohom et al, 2002). Thus, synergistic drug

combinations should be helpful in improving efficacy of pharmacological

treatment of pain while simultaneously minimizing drug specific adverse

effects (Miranda et al, 2007).

Dexketoprofen trometamol (25 mg and 50 mg) is a good analgesic for the

treatment of moderate to severe pain due to renal colic, comparable to

dipyrone (2g) but with significantly greater analgesic efficacy soon after

administration, suggesting a faster onset of action of Dexketoprofen

trometamol (Sánchez-Carpena et al, 2007).

S(+)Etodolac

S-Etodolac is a chirally pure, pharmacologically active form of Etodolac

containing only S(+)enantiomer. The racemate Etodolac has analgesic,

antipyretic, and anti-inflammatory properties (Joubert et al, 1982). The drug

has been shown to inhibit formation of prostaglandin endoperoxides from

arachidonic acid (Ferdinandi et al, 1982). Etodolac is more selective for

induced COX-2 (associated with inflammation) over COX-1 (cytoprotective)

(Glaser et al, 1995). In experimental models of inflammation, Etodolac was

demonstrated more potent than Phenylbutazone, Sulindac and Naproxen but

less potent than Indomethacin (Joubert et al, 1982). However, in clinical trials,

Etodolac has shown comparable efficacy and better gastrointestinal

tolerability when compared with non-selective NSAIDs (Liang and Hsu, 2003).

Etodolac possesses a more favorable therapeutic index between anti-

inflammatory effects and gastric irritation as compared to other NSAIDs (Chen

et al, 2008; Martel and Klicius, 1982)

It is the S-enantiomer of Etodolac that possesses almost all of the anti-

inflammatory activity while R-Etodolac is almost inactive. S-Etodolac is 2.6

times more potent than the racemate and 100 times more potent than R-

enantiomer (Demerson et al, 1983). S-Etodolac achieves greater

concentrations in synovial fluid than plasma (SF: plasma ratio = 1.98 +/- 0.8)

compared to R-Etodolac (SF: plasma = 0.91 +/- 0.3) (Brocks and Jamali,

1991).

S-Etodolac has a favorable pharmacokinetic profile compared to R-Etodolac.

S-Etodolac rapidly attains the peak plasma concentration and is rapidly

cleared from plasma compared to R-Etodolac. The pharmacologically inactive

R-Etodolac has higher plasma concentration compared to S-Etodolac. The

pharmacokinetic differences are attributed to the greater extent of plasma

protein binding of R-Etodolac, and to preferential conjugation and biliary

excretion of S-Etodolac (Brocks and Jamali, 1990; Shi et al, 2004). In addition,

findings from human serum albumin (HSA) study suggest that R- and S-

Etodolac interact mainly with site II of HSA and are displaced by each other

DEXKETOPROFEN - PLACE IN THERAPY1• Single isomer

1• Simplifies pharmacokinetics1

• Allows 50% reduction in dosage1

• Reduces metabolic and renal load• Reduced incidence of gastro duodenal ulcerations• 1

Tromethamine salt faster absorption→•

2Earlier onset of analgesic efficacy vs. diclofenac•

3Greater analgesic efficacy in the first hour vs. ibuprofen •

4More rapid onset of action compared to ketoprofen1 2 3 4Acute Pain (2003) 5, 57—62. Emerg. Med. J. 2003;20;511-513 Med Oral 2004;9:138-48. J. Clin. Pharmacol. 1998; 38; 46


40 41

(Mignot et al, 1996). Using both the isomers simultaneously (i.e. racemate

Etodolac) thus leads to significant interactions between the isomers for

competitive binding to HSA. Thus, it is justified to use a single active, potent

enantiomer with the anti-inflammatory activity i.e. S-Etodolac.

Emcure Pharmaceuticals Limited received the license to manufacture and

market S(+) Etodolac extended release tablets for the first time in the world nd

from the Drug Controller General of India on 2 June 2008.

A clinical study showed that extended release S-Etodolac tablet, at a single

daily dose of 300 mg is as effective as extended release Etodolac tablet at a

single dose of 600 mg/day thereby further confirming that the S-enantiomer of

Etodolac is the active NSAID.

It is now clear that the S and R enantiomers of all NSAIDs that are currently

used in clinical practice have different pharmacological properties. It is the S-

enantiomer of chiral NSAIDs that possesses the anti-inflammatory and

analgesic activity. R-enantiomer lacks such activity and has a completely

different activity. The needless administration of the R-enantiomers that make

up 50% of racemic NSAID contributes to an increase in dose, pharmacokinetic

variability, metabolic load and enantiomer interactions. Thus, it is a rationale

approach to perform the chiral switch, i.e., to replace the currently used

racemic NSAIDs by the optically pure S-enantiomers in order to avoid potential

harm to patients. The development of Dexketoprofen, Dexibuprofen and S-

Etodolac are the positive steps in this direction.

• Barbanoj MJ, Gich I, Artigas R, et al: Pharmacokinetics of dexketoprofen trometamol in healthy volunteers after single and repeated oral doses. J Clin Pharmacol 1998; 38:33S-40S.

• Barbanoj MJ. Clinical pharmacokinetics of dexketoprofen trometamol: recent studies. Methods Find Exp Clin Pharmacol. 2006 Jun;28 Suppl A:3-5.

• Beltran J, Martin-Mola E, Figueroa M, et al: Comparison of Dexketoprofen trometamol and Ketoprofen in the treatment of osteoarthritis of the knee. J Clin Pharmacol 1998; 38:74S-80S.

• Brocks DR, Jamali F. Enantioselective pharmacokinetics of Etodolac in the rat: tissue distribution, tissue binding, and in vitro metabolism. J Pharm Sci. 1991 Nov;80(11):1058-61.

• Brocks DR, Jamali F. The pharmacokinetics of Etodolac enantiomers in the rat. Lack of pharmacokinetic interaction between enantiomers. Drug Metab Dispos. 1990 Jul-Aug;18(4):471-5.

• Chen YF, Jobanputra P, Barton P, Bryan S, Fry-Smith A, Harris G, Taylor RS. Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (Etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation. Health Technol Assess. 2008 Apr;12(11):1-178.

• Cooper SA, Reynolds DC, Reynolds B, et al: Analgesic efficacy and safety of (R)-ketoprofen in postoperative dental pain. J Clin Pharmacol 1998; 38:11S-18S.

• Data on File 1. A Multicentric, Comparative, Randomized, Parallel Group Clinical Trial to Evaluate the Efficacy and Safety of Dexketoprofen trometamol in the Treatment of Dental Pain.

• Data on File 2. A Multicentric, Comparative, Randomized, Parallel Group Clinical Trial to Evaluate the Efficacy and Safety of Dexketoprofen trometamol in the Treatment of Dysmenorrhea.

• Data on File 3. A Multicentric, Randomized, Comparative Clinical Trial to Evaluate the Efficacy and Safety of S-Etodolac in the Treatment of Osteoarthritis.

• Demerson CA, Humber LG, Abraham NA, Schilling G, Martel RR, Pace-Asciak C. Resolution of Etodolac and antiinflammatory and prostaglandin synthetase inhibiting properties of the enantiomers. J Med Chem. 1983 Dec;26(12):1778-80.

• Dionne RA and McCullagh L: Enhanced analgesia and suppression of plasma beta-endorphin by the S(+)-isomer of ibuprofen. Clin Pharmacol Ther 1998; 63(6):694-701.

• Ezcurdia M, Cortejoso FJ, Lanzon 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.

• Ferdinandi ES, Cayen MN, and Pace-Asciak C: Disposition of Etodolac, other anti-inflammatory pyranoindole-1-acetic acids and furobufen in normal and adjuvant arthritic rats. J Pharmacol Exp Ther 1982; 220:417.

• Gabard B, Nirnberger G, Schiel H, et al: Comparison of the bioavailability of dexibuprofen administered alone or as part of racemic ibuprofen. Eur J Clin Pharmacol 1995; 48(6):505-511.

• Gaitán G, Herrero JF. Subeffective doses of dexketoprofen trometamol enhance the potency and duration of fentanyl antinociception. Br J Pharmacol. 2002 Jan;135(2):393-8.

• Gay C, Planas E, Donado M, et al: Analgesic efficacy of low doses of Dexketoprofen in the dental pain model. Clin Drug Invest 1996; 11(6):320-330.

• Glaser K, Sung ML, O'Neill K et al: Etodolac selectively inhibits human prostaglandin G/H synthase 2 (PGHS-2) versus human PGHS-1. Eur J Pharmacol 1995; 281: 107-111.

• Hawel R, Klein G, Mitterhuber J et al: Double-blind comparative study of the effectiveness and tolerance of 900 mg dexibuprofen and 150 mg diclofenac sodium in patients with painful gonarthrosis. Wien Klin Wochenschr; 109(2):53-59. German, 1997.

• Hawel R, Klein G, Singer F, Mayrhofer F, Kahler ST.Comparison of the efficacy and tolerability of dexibuprofen and celecoxib in the treatment of osteoarthritis of the hip. Int J Clin Pharmacol Ther. 2003 Apr;41(4):153-64.

• Iohom G, Walsh M, Higgins G, Shorten G.Effect of perioperative administration of dexketoprofen on opioid requirements and inflammatory response following elective hip arthroplasty.Br J Anaesth. 2002 Apr;88(4):520-6.

• Jackson ID, Heidemann BH, Wilson J, Power I, Brown RD. Double-blind, randomized, placebo-controlled trial comparing rofecoxib with dexketoprofen trometamol in surgical dentistry. Br J Anaesth. 2004 May;92(5):675-80.

• Jerussi TP, Caubet J-F, McCray JE, et al: Clinical endoscopic evaluation of the gastroduodenal tolerance to (R)-ketoprofen, (R)-flurbiprofen, racemic ketoprofen, and paracetamol: a randomized, single-blind, placebo-controlled trial. J Clin Pharmacol 1998; 38:19S-24S.

• Joubert L, Mullane JF, Merlo M, et al: Clinical pharmacological profile of Ultradol(R), a new nonsteroidal anti-inflammatory drug. Curr Ther Res 1982; 32:74-88.

• Kaehler ST, Phleps W, Hesse E. Dexibuprofen: pharmacology, therapeutic uses and safety. Inflammopharmacology. 2003;11(4):371-83.

• Kelley MT, Walson PD, Edge JH, et al: Pharmacokinetics and pharmacodynamics of ibuprofen isomers and acetaminophen in febrile children. Clin Pharmacol Ther 1992; 52(2):181-189.

• Leman P, Kapadia Y, Herington J. Randomised controlled trial of the onset of analgesic efficacy of dexketoprofen and diclofenac in lower limb injury. Emerg Med J. 2003 Nov;20(6):511-3.

• Liang TH, Hsu PN. Double-blind, randomised, comparative trial of Etodolac SR versus diclofenac in the treatment of osteoarthritis of the knee. Curr Med Res Opin. 2003;19(4):336-41.

• Martel R and Klicius J: Comparison of the anti-inflammatory and ulcerogenic effects of Etodolac with several clinically effective anti-inflammatory drugs. Agents Actions 1982; 12(3):1.

References

S(+) ETODOLAC - PLACE IN THERAPY

• S-Etodolac is the active NSAID component of Etodolac (J Med Chem. 1986, May;29(5):871- 4.)• S-Etodolac has potency at least twice that of racemate (J. Med. Chem. 1983,26, 1778-1780).• The pharmacokinetics of the enantiomers of Etodolac are highly stereoselective in humans (J Clin Pharmacol 1992;32:982-989).• Therapeutically active S-Etodolac has greater concentrations in synovial fluid than plasma (Clin Pharmacol 1991;31:741-746)• Avoids isomer interactions in binding to albumin (Chirality. 1996;8(3):271-80.)• Administration of half the dose of racemate • Less metabolic load


42 43

• Mauleon D, Artigas R, Garcia L, et al: Preclinical and clinical development of dexketoprofen. Drug 1996; 52(suppl 5):24-46.

• Mayer JM and Testa B: Pharmacodynamics, pharmacokinetics and toxicity of ibuprofen enantiomers. Drugs Fut 1997; 22(12):1347-1366.

• 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 Nov;20 Suppl 1:S22-9.

• McGurk M, Robinson P, Rajayogeswaran V, et al: Clinical comparison of Dexketoprofen trometamol, Ketoprofen, and placebo in postoperative dental pain. J Clin Pharmacol 1998; 38:46S-54S.

• Mignot I, Presle N, Lapicque F, Monot C, Dropsy R, Netter P. Albumin binding sites for Etodolac enantiomers. Chirality. 1996;8(3):271-80.

• Miranda HF, Puig MM, Dursteler C, Prieto JC, Pinardi G.Dexketoprofen-induced antinociception in animal models of acute pain: synergy with morphine and paracetamol.Neuropharmacology. 2007 Feb;52(2):291-6.

• Nieto AI, Cabré F, Moreno FJ, de la Lastra CA. Mechanisms Involved in the Attenuation of Intestinal Toxicity Induced by (S)-(+)-Ketoprofen in Re-Fed Rats. Dig Dis and Sci 2002 Apr;47(4):905-13.

• Rovetta G, Monteforte P, Brignone A, Molfetta L, Buffrini L. Early-morning administration of dexketoprofen-trometamol in morning stiffness induced by nodal osteoarthritis of the hands. Int J Tissue React. 2001;23(2):63-6.

• Rudy AC, Liu Y, Brater C, et al: Stereoselective pharmacokinetics and inversion of (R)-ketoprofen in healthy volunteers. J Clin Pharmacol 1998; 38:3S-10S.

• Sánchez-Carpena J, Domínguez-Hervella F, García I, Gene E, Bugarín R, Martín A, Tomás-Vecina S, García D, Serrano JA, Roman A, Mariné M, Mosteiro ML; Dexketoprofen Renal Colic Study Group.Comparison of intravenous dexketoprofen and dipyrone in acute renal colic.Eur J Clin Pharmacol. 2007 Aug;63(8):751-60.

• Shi JM, Lai SG, Xu CJ, Duan GL, Li D. Pharmacokinetic difference between S-(+)- and R-(-)-Etodolac in rats. Acta Pharmacol Sin. 2004 Aug;25(8):996-9.

• Singer F, Mayrhofer F, Klein G, Hawel R, Kollenz CJ. Evaluation of the efficacy and dose-response relationship of dexibuprofen (S(+)-ibuprofen) in patients with osteoarthritis of the hip and comparison with racemic ibuprofen using the WOMAC osteoarthritis index. Int J Clin Pharmacol Ther. 2000 Jan;38(1):15-24.

• Zippel H, Wagenitz A. Comparison of the efficacy and safety of intravenously administered dexketoprofen trometamol and ketoprofen in the management of pain after orthopaedic surgery: A multicentre, double-blind, randomised, parallel-group clinical trial. Clin Drug Investig. 2006;26(9):517-28.

Introduction

Obesity is the excessive accumulation of the body fat to the extent that the

health of the individual may be impaired. Obesity results from the imbalance

between the energy intake and energy expenditure. When people are

overweight or obese, they are more likely to develop health problems such as

ischaemic heart disease, hypertension, other cardiovascular diseases,

diabetes, cancer, arthritis and psychiatric illnesses. The management of

obesity involves prevention of weight gain, promotion of weight maintenance,

management of obesity comorbidities and promotion of weight loss.

The treatment is recommended for patients with a body mass index (BMI) of > 2

27 kg/m or a waist circumference > 88 cm in women and > 102 cm in men

along with presence of two or more risk factors (i.e., hypertension,

dyslipidemia, coronary heart disease, type 2 diabetes and sleep apnea). The 2

treatment is also indicated for patients with a BMI > 30 kg/m regardless of risk

factors. Lifestyle measurements involving diet and exercise are of paramount

importance in the obesity management. Moderate weight loss (approximately

5-10% of body weight) by lifestyle changes improves obesity-related

comorbidities. Unfortunately, this medical approach is not long lasting and

weight regain is often seen. Drugs that prevent weight regain appear

necessary in obesity treatment (Public Health Nutrition. 2007;10(10A), 1156-

63). Currently approved drugs for the obesity management are Sibutramine,

Orlistat and Rimonabant. Orlistat causes clinically significant gastrointestinal

side effects such as, increased defecation, fatty/oily stools, leaking of oil from

the rectum, faecal urgency and faecal incontinence. It has shown to reduce the

absorption of fat soluble vitamins D, E and K (Pharmacotherapy. 2002

Jul;22(7):814-22). Rimonabant is not approved by US FDA as it causes

depression as found in Phase III trials (Rimonabant Briefing Information,

2007). Sibutramine is a combined norepinephrine and serotonin reuptake

inhibitor approved for the treatment of obesity.

R-Sibutramine in Obesity Management


44 45

Sibutramine

R-Sibutramine

Sibutramine enhances satiety and decreases caloric intake in the body. It has

shown marked thermogenic properties in preclinical studies. Racemic

Sibutramine is a mixture containing equal amounts of R and S isomers.

Sibutramine works by preventing the reuptake of the neurotransmitters-

serotonin and norepinephrine at the presynaptic membrane. Thus, there is the

excess neurotransmitter left in the synaptic cleft resulting in satiety (hunger

satisfaction); so the individual doesn't feel hungry and eats less (appetite

suppression). This behavior results in weight- loss.

The efficacy and safety of Sibutramine in obesity management was proven by

STORM study (Sibutramine Trial of Obesity Reduction and Maintenance) that

demonstrated its utility on weight reduction as well as on weight loss

maintenance (Lancet 2000; 356: 2119-25). Similarly the efficacy and

tolerability has been proven in patients with cardiovascular disease (SCOUT

trial, Eur Heart J. 2007 Dec;28(23):2915-23) and in diabetics (Diabetes Care

2005; 28: 942-9).

Racemate Sibutramine is 1:1 mixture of R-Sibutramine and S-Sibutramine. R-

isomer being more potent than S-isomer in decreasing food intake and in

decreasing body weight. S-isomer has no effect on food intake (Eur J

Pharmacol. 2000;397:93-102). As a result, R-isomer has a greater anorexic

effect than S-isomer or racemate. The dopaminergic activity of Sibutramine is

attributable to the S-isomer, while R-isomer lacks such activity. The

dopaminergic activity may be responsible for the side effects of Sibutramine,

mainly hypertension (Eur J Pharmacol. 2000;397:93-102). In addition, R-

Sibutramine shows increased locomotor activity as compared to racemate

Sibutramine, but S-Sibutramine does not show effect on locomotor activity

(Indian J Physiol Pharmacol. 2007; 51(2): 175-178). S-Sibutramine is not

effective for reducing weight. S-Sibutramine, in fact, increases weight in animal

model (Indian J Physiol Pharmacol. 2007; 51(2): 175-178) and may be

responsible for the side-effects associated with Sibutramine. In vitro studies

have shown that, incubation of R-Sibutramine in rat microsomes leads to the

formation of M1 and M2 metabolites only, while the incubation of S -

Sibutramine or racemate (to a lesser extent) results in four major metabolites

(M1, M2, M3 and M4) and 2 or 3 minor metabolites. Thus, R-Sibutramine

represents the more advantageous Sibutramine enantiomer from the

pharmacological standpoint (J Pharm Pharmacol. 2005;57(3): 405-410).

To examine the safety and efficacy of R-Sibutramine in the clinical

management of weight loss in overweight and obese subjects an open label,

randomized, comparative, multicentric clinical trial was conducted in India

(Indian Medical Gazette, November 2007). A total of 241 patients with BMI > 27 2kg/m were enrolled in the study. All patients received either R-Sibutramine

(2.5/5 mg) or racemate Sibutramine (5/10 mg) for a period of 12 weeks. Total

201 patients (104 in R-Sibutramine group and 97 in Sibutramine group)

completed the study. Total 25 patients in Sibutramine and 15 patients in R-

Sibutramine group dropped out. After 12 weeks of treatment, there was a

significant reduction in weight, BMI, waist circumference, hip circumference,

waist to hip ratio in both the treatment groups (p<0.0001). There was also

significant improvement in appetite and satiety scores in both the groups

(p<0.0001). There was no significant difference between R-Sibutramine and

Sibutramine groups for these parameters. The most frequently reported

adverse events in both the groups were hypertension, headache, dry mouth,

constipation and musculoskeletal pain. There were more drop-outs in

Sibutramine group than R-Sibutramine group. No significant changes were

observed in laboratory parameters. Thus, R-Sibutramine was found to be

effective and safe in the treatment of obesity with equal efficacy and better

Indian Clinical Experience with R-Sibutramine


46 47

tolerability compared to Sibutramine. This study supports the clinical use of R-

Sibutramine for management of obesity.

R-Sibutramine has the advantages over the racemate and S-Sibutramine in

terms of more potency in weight reduction, less metabolic load and less

potential to cause side effects. Hence, R-Sibutramine is an ideal drug in the

management of obesity.

Conclusion

Dr. Vikas PaiMD. FIACM, FCHU (USA), Consultant in Internal MedicinePai Clinic & Endoscopic Center, Pune.

Dr. Nitin PaiM.D., D.M. Consultant GastroenterologistPai Clinic & Endoscopic Center, Pune.

Excerpted from JIMA, Aug 2007

Proton Pump Inhibitors (PPIs) inhibit gastric acid secretion by inhibiting the

final step of acid synthesis, the hydrogen-potassium-ATPase pump, in the

parietal cell canaliculi. In the parietal cell canaliculus, PPIs get protonated to

form the active sulfenamide moiety, which is achiral. This sulfenamide

molecule binds to the cysteine residues of the proton pumps and causes

irreversible inhibition of the H+K+ ATPase pump. Chemically, PPIs are

substituted benzimidazoles and chiral compounds, i.e. their spatial orientation

is asymmetrical with a sulphur atom as the chiral centre, in most cases. These

drugs are currently available as racemic mixtures of the (R) - and (S) -

enantiomers in equal proportions.

The development of chiral molecules in proton pump inhibitors has been

criticised because the actual activated form of all proton pump inhibitors, which

finally inhibits the H+K+ATPase pumps, is the sulfenamide moiety, an achiral

molecule. However, actual availability of the sulfenamide at the site of action is

dependant on the pharmacodynamic (PD) and pharmacokinetic (PK)

properties of the prodrug molecule and its enantiomers. Hence the relevance

of chirally pure PPI is not dependent on achiral sulfenamide. The individual isomers show variations in PK, PD properties and differences in

safety, toxicity profiles and can prove to be superior to their racemic

counterparts as has been demonstrated with the development of

esomeprazole, S-pantoprazole and recently dexrabeprazole.

The S-isomer of pantoprazole (developed by Emcure Pharmaceuticals Ltd,

Recent advances in chirally pure proton pump inhibitors

Parietal Cell

Proton PumpInhibitor(PPI)

Proton Pump

Acetylcholine Gastrin Histamine


48 49

Pune, India) was found to be better at inhibiting acid related lesions because of

its stronger inhibition of acid secretion in the pylorus ligation induced ulcer and

histamine induced ulcer model in rats and guinea pigs.

A randomized, double-blind, multicentric, parallel group, comparative clinical

trial (n=369) evaluated S(-)pantoprazole 20 mg versus racemic pantoprazole

40 mg in patients with gastro-oesophageal reflux disease (GERD). A

statistically significant between-group difference was demonstrated in the

proportion of patients showing improvement in acid regurgitation and bloating

on day 14 and day 28 of treatment, and heartburn on day 28, with

S(-)pantoprazole than with racemic pantoprazole. Absolute risk reductions for

heartburn, acid regurgitation, and bloating were approximately 15% on day 14

and 10% on day 28. The relative risk reductions were 26 -33 % on day 14 and

15% on day 28. S (-) pantoprazole was well-tolerated (World Journal

Gastroenterology 2006, 12, 37, 6017-20).

Rabeprazole is available as a racemic mixture of two isomers, R (+) isomer and

S (-) isomer in 1:1 proportion. The chirally pure R(+) rabeprazole known as

Dexrabeprazole has been developed by Emcure Pharmaceuticals Ltd, Pune,

India. A study done on Wister rats demonstrated that R (+)-rabeprazole (10

mg/kg) was more effective than S (-)-rabeprazole (10 mg/kg) and racemate

rabeprazole (10 mg/kg), in preventing acid related gastric lesions (Indian

Journal Pharmacology, 2006, 38, 5, 357-8).

A randomised, double blind clinical study was conducted on 50 patients with

endoscopically confirmed GERD. Patients randomly received either

dexrabeprazole 10 mg or rabeprazole 20 mg each once daily. Efficacy was

assessed by improvement in visual analog scale (VAS) scores of heart-burn

and regurgitation. Adverse events, if any, were recorded to monitor the safety

of treatment in both the arms. Laboratory investigations and upper gastro-

intestinal endoscopy was conducted at baseline and after 28 days of therapy.

The demographic data for the two groups did not differ significantly. Both

groups reported a significant reduction in the VAS score of heartburn and

regurgitation (P<0.0001) from baseline to day 14 with further reduction on day

28 of the therapy respectively. However, a higher proportion of patients in the

dexrabeprazole (10 mg) group (p =0.002) showed at least 50% improvement in

symptoms of regurgitation (96%) as against the rabeprazole 20 mg group

(60%). Symptoms improved earlier (p<0.05) with dexrabeprazole than with

rabeprazole. The dexrabeprazole group showed a higher incidence of

improvement/healing of esophagitis (P=0.036) as compared to the

rabeprazole group. No adverse drug reaction was seen in either group. Thus,

dexrabeprazole 10 mg was shown to be better than rabeprazole 20 mg in the

treatment of GERD with regards to improvement/healing of endoscopic

lesions and relief from symptoms of regurgitation (World Journal

Gastroenterology, 2007, 13, 30, 4100-2).

Racemic drugs represent a combination of two different molecules, which

differ from each other only because of their stereochemistry. Administration of

a racemate is equivalent to administering two different molecular identities

which may significantly differ from each other with respect to

pharmacodynamic, pharmacokinetic and therapeutic properties. The proton

pump inhibitors are vital components in the management of acid-related

disorders. Isomers of the existing group have further added advantages in

terms of metabolism and bioavailability, thus resulting in better disease and

symptom control. This has been clearly demonstrated in the case of

esomeprazole, the absorption and efficacy of which is better and metabolism

less varied as compared to the racemic omeprazole. Half dose of S-

pantoprazole has demonstrated equivalent therapeutic potential, thus offering

the advantage of a lesser metabolic load on the body. Dexrabeprazole has also

demonstrated a promising therapeutic advantage over racemic rabeprazole.

Thus, it is rational to prescribe chirally pure PPIs in place of racemates.

CONCLUSION


50 51

We are happy to inform that the famous textbook of Pharmacology -

Dr. K. D. Tripathi's

ISBN : 8184480857 Year Of Publication : 2008 Edition : Sixth

- Now includes (for the first time) a section on Chirality and discusses S-amlodipine, S-metoprolol, S-atenolol & S-pantoprazole.

Essentials of

Medical Pharmacology

Latest Update

Disclaimer

This monograph and /or document contain information available in public domain and published literature as cited, and also as per research data available on file with Emcure Pharmaceuticals Limited (Emcure). This information should not be construed as medical advice, a medical opinion or diagnosis. Emcure shall not be liable for any such interpretation and any action taken on the basis of such interpretation and consequences arising therefrom. As medical information and treatment guidelines are constantly evolving and changing, the prescriber is requested to update his/her information regularly before prescribing. Emcure shall not be liable for any consequence due to lack of such updation. Emcure shall not be held liable for any damage or injury or liability or compensation or claim arising from any unauthorized or improper or un-advised or off-label or mis-diagnosed use of products mentioned in this monograph or for any adverse effects arising out of any use, whether or not such reactions are documented in the published literature or prescribing information or are unexpected and not published hitherto including carcinogenicity, mutagenicity, any effect on fertility or pregnancy, any effect on pregnant women, nursing mothers, pediatric or geriatric patients. Emcure shall not be held liable for any adverse consequences of improper storage of the product by the doctor, patient, pharmacies or any other distribution partners. All possible proprietary trademarks, copyrights and patents related to any product(s) mentioned in this monograph rest with their respective owners and no possible infringement is intended or foreseen to be caused. Emcure Pharmaceuticals Limited holds copyright in this monograph and/or associated document(s), and all research data generated by Emcure on its products is the exclusive property of Emcure and is not to be used for any commercial purpose by any other person unless previously authorized in writing by Emcure. Unauthorized use or publication or duplication or copying or usage in any form of Emcure's proprietary data will constitute violation of copyright and be liable for penal action.

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