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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
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
(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.”
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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.
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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:
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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:
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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
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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
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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
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• 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.
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• 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.
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• 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
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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
CHIRALITY... Today & Tomorrow’s way of treatment CHIRALITY... Today & Tomorrow’s way of treatment
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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