WO1993020809A1

WO1993020809A1 - Arylalkanoic acid s enantiomer for reducing adverse side effects

Info

Publication number: WO1993020809A1
Application number: PCT/US1993/003041
Authority: WO
Inventors: Timothy J. Barberich; James W. Young
Original assignee: Sepracor Inc.
Priority date: 1992-04-13
Filing date: 1993-03-31
Publication date: 1993-10-28
Also published as: AU3971993A

Abstract

The adverse side effects associated with the administration of arylalkanoic acid derivative drugs such as the arylpropionic acid derivatives ibuprofen, ketoprofen, or flurbiprofen are reduced by administering the S enantiomer of these drugs. In particular, the adverse side effects of gastrointestinal toxicity or irritation and of kidney toxicity are reduced. The S enantiomer drug compositions are also disclosed.

Description

ARYLALKANOIC ACID S ENANTIOMER FOR REDUCING ADVERSE SIDE EFFECTS

Description

Background of the Invention

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used as pharmacological compositions to alleviate the symptoms of pain, inflammation and fever. Thus, they are categorized as analgesic, anti-inflammatory, antipyretic compounds. Aspirin is the best known compound exhibiting the therapeutic properties of this group of drugs. Since aspirin is the prototypical example of this group, the compounds are known as 'aspirin-like' drugs.

The NSAIDs are further classified according to their chemical structure. These structures have been grouped into families of compounds based on the fundamental organic structure from which members of the families are derived. The NSAID families include the salicylates (of which aspirin is a member) , the pyrazolons, the para-aminophenols, and the arylal- kanoic acid derivatives. The arylalkanoic acid derivatives include etodolac as well as compounds known as arylpropionic acid derivatives. Among the arylpropionic acid derivatives are ibuprofen (α-methyl-4-(2-methyl propyl)-benzeneacetic acid), ketoprofen (3-benzoyl-α-methyl-benzeneacetic acid) , r flurbiprofen (2-fluoro-α-methyl-[l,l -biphenyl]- 4-acetic acid) , naproxen, fenoprofen, tiaprofenic acid, carprofen, indoprofen, pirprofen, cicloprofen, clindanac and loxoprofen. These arylpropionic acid derivatives have become more commonly prescribed and consumed than the other NSAIDs because the arylpro- pionic acid derivatives are usually better tolerated by their users.

Although the NSAIDs, including the arylpropionic acid derivatives, are pharmacologically useful as analgesic, anti-inflammatory, antipyretic agents, there are undesired side effects associated with their administration. Most NSAIDs have as an un¬ desired side effect gastrointestinal irritation to varying degrees. Other specific side effects which are known to be associated with NSAID drugs may or may not be general for the entire class. For example, administration of racemic ibuprofen has been shown to be associated with adverse side effects such as kidney dysfunction. Two other NSAID drugs, sulindac and piroxicam, were found to also have adverse effects on kidney function.

It is readily apparent that the undesired side effects observed with the administration of these agents should be minimized while retaining the beneficial effects these agents provide. A recog- nized goal of pharmaceutical formulation is the achievement of maximum benefit to the user with as little adverse effect as possible.

Summary of the Invention

The present invention pertains to a method of providing a therapeutic effect while at the same time reducing adverse side effects that accompany the administration of an arylalkanoic acid derivative drug (AAA) . This invention is achieved by adminis¬ tering the S enantiomer of the AAA. The present invention also relates to compositions useful in the method of providing therapeutic effects while reducing adverse side effects. In particular, the present invention is a method of reducing adverse effects associated with the administration of an AAA that is an arylpropionic acid derivative, such as ibuprofen, ketoprofen, or flurbiprofen, by administering the S enantiomer of that drug. The present method is useful, for example, in reducing gastrointestinal toxicity or irritation and for reducing kidney dysfunction which has been shown to be associated with the consumption of AAAs. The method is also useful for reducing gastrointestinal toxicity or irritation or kidney dysfunction in patients who take the drugs on a prolonged or chronic basis, e.g., for relief of pain from rheumatoid or osteoarthritis. In the method of the present invention, the S enantiomer of at least one AAA is administered, either alone or in combination with another drug, other drugs, and/or inactive substances such as carriers or fillers.

Detailed Description of the Invention

This invention pertains to a method of providing a therapeutic effect while reducing undesired or adverse side effects that occur when arylalkanoic acid derivative drugs are administered to an individual by administering the S enantiomer of the drugs. The individual to whom the S enantiomer of an arylalkanoic acid derivative drug is administered is a member of any animal species, including human, which responds in a therapeutic manner to such administration. This invention also relates to compositions useful in the method of reducing the undesired or adverse side effects.

In the following discussion, a description of organic compound stereochemistry, particularly as related to arylalkanoic acid derivative drugs is first given. This is followed by a detailed descrip- tion of the present invention.

Enantio ers are organic compounds that exist as stereoisomers with non-superimposable mirror image symmetry. The spatial configuration of the atoms that constitute organic molecules allows these molecules to exist as stereoisomers, i.e. as mole¬ cules that differ from each other only by the spatial orientation of their atoms while retaining the specificity of bonding between the particular atoms. If these stereoisomers exist as mirror images of each other but are not superimposable on each other, no matter how they are rotated in space, they are enantiomers. (If they are superimposable, they are indistinguishable from each other and are considered to be identical) .

Enantiomers, as a consequence of their non- superimposable mirror image symmetry, are optically active. That is, enantiomers can rotate impinging plane polarized light. This rotation can be either to the right (clockwise) when observing the polarized light source through the enantiomeric sample, or to the left (counterclockwise) . • These rotations are respectively designated as dextrorotatory or (+) and levorotatory or (-) . Thus, the enantiomers are designated as (+) or (-) depending on the direction of optical activity the enantiomer exhibits.

When both enantiomers of an organic molecule exist together in a volume, they form what is termed a racemic mixture of the (+) and (-) enantiomers. Organic compounds that can exhibit optical activity usually exist as racemic mixtures because customary organic synthesis routes do not distinguish between enantiomers and do not use optically pure starting compounds. Such racemic mixtures are optically inactive, since equal quantities of both enantiomers are present. Optical activity is manifested when the racemic mixture is separated into its enantiomeric components.

An attribute of organic compounds that causes them to be enantiomers is the presence of an asymmetric carbon atom. Such a carbon atom has four different chemical substituents covalently bonded to it. The geometrical interrelationship of these four chemical substituents bonded to the carbon atom is what confers the enantiomeric property and optical activity to these compounds. Arylalkanoic acid derivative drugs of this invention, such as ibuprofen, ketoprofen and flurbiprofen, have asym¬ metric carbon atoms in their chemical structure. Racemic mixtures of these drugs include the two enantiomers that occur as a result of the non- superimposable mirror image symmetry of the four chemical substituents covalently bonded to their asymmetric carbon-atoms. Another aspect of the stereochemistry of organic compounds arises as a consequence of the existence of asymmetric carbon atoms. This aspect is known as the configuration of these compounds. As previously stated, each asymmetric carbon atom has four different chemical substituents covalently bonded to it. Each of these chemical substituents can be assigned priority values depending on the atomic number of each atom bonded to the asymmetric carbon atom. In instances where two or more atoms with the same atomic number are covalently bonded to the asymmetric carbon atom, priority is based on the atomic number of the next bonded atom progressing outward from the asymmetric carbon atom. The covalent bond type is also considered in this latter assessment. The configuration is assigned by visualizing the asymmetric carbon atom and its four chemical substituents in space such that the asym¬ metric carbon atoms and the lowest priority chemical substituent are aligned and this lowest priority chemical substituent is directly behind the asymmet¬ ric carbon atom, i.e. the lowest priority chemical substituent is masked by the asymmetric carbon atom. The other three chemical substituents then form a circle around the asymmetric carbon atom hub as these remaining chemical substituents are visualized in turn. Starting with the highest priority chemical substituent, if the next highest priority chemical substituent is the next chemical substituent in a clockwise rotation, the asymmetric carbon atom is said to have an R configuration. If the next highest priority chemical substituent is the next chemical substituent in a counterclockwise rotation from the highest priority chemical substituent, the asymmetric carbon atom is said to have an S configuration. The enantiomers of the nonsteroidal anti- inflammatory drugs which possess analgesic, anti- inflammatory or antipyretic activity have the S configuration. That is, the enantiomers of ibupro¬ fen, ketoprofen, flurbiprofen, fenoprofen, tiapro- fenic acid, carprofen, indoprofen, pirprofen, ciclo- profen, clindanac, loxoprofen and etodolac which possess analgesic, anti-inflammatory or antipyretic activity have S configuration asymmetric carbon atoms. The specific enantiomers of the present inven¬ tion may be obtained by a method which utilizes the enantioselectivity of certain protease enzymes on specific derivatives of the subject compounds including ibuprofen, ketoprofen, and flurbiprofen. The method of synthesis of the specific enantiomers can be described by the generalized equations indicated below. This method is described in detail in PCT Patent Application WO 89/09765 (19.10.89).

Protease enzyme

S-enantiomer

Chemical hydrolysis

S-ena^ήtiomer where n = e.g., 1-3

j ^for ketoprofen

and for flurbiprofen

In this method, a charged, water-soluble ester of the racemic mixture form of one of the drugs is first prepared. The racemic water-soluble ester is then subjected to enantioselective enzymatic hydroly- sis by the action of, e.g. the enzyme Prozyme 6 from Aspergillus oryzae as sold by A ano Chemical Company. The resulting hydrolysis product mixture contains, for example, the R-enantiomer of the subject drug and the S-enantiomer of the subject drug as the ester derivative, which is not hydrolyzed by the enantio¬ selective enzyme. The two products are readily separated on the basis of different physical proper¬ ties (solubility, crystallization properties, etc.) by means which are described in the above reference. Alternatively, the subject compounds may be resolved by conventional techniques such as by fractional crystallization of diastereomeric derivatives and salts which are formed upon the addition of chiral resolving agents (e.g. chiral amines in the case of the AAAs) . Such resolution methods are well known in the art. See, for example Jacques et al., Enantiomers, Racemates, and Resolutions, John Wiley & Sons, New York, 1981.

Arylalkanoic acid derivative drugs are usually administered to relieve the symptoms of pain, inflammation, or fever because these drugs have analgesic, anti-inflammatory, and anti-pyretic properties. Unfortunately, the administration of these drugs to relieve undesired symptoms is often accompanied by undesired or adverse side effects. Among the adverse side effects associated with the administration of arylalkanoic acid derivative drugs are gastric or intestinal ulceration, renal or kidney toxicity, anemia, the prolongation of labor in pregnant females, and male infertility. These adverse side effects can be reduced, i.e., lessened or avoided, through the use of the present method.

One of the adverse side effects associated with the administration of arylalkanoic acid derivative drugs is gastrointestinal toxicity. This toxicity is clinically manifested as ulceration, necrosis and/or peritonitis. Erosion of the gastrointestinal tract often occurs and, ultimately, perforation of the GI tract wall may happen. Another side effect of arylalkanoic acid deriva¬ tive drug therapy of particular note is gastro¬ intestinal irritation. With this adverse side effect, the afflicted individual experiences dyspepsia, heartburn or a variety of other states of uncomfortableness. Symptoms may be mild or even non-evident on casual observation, e.g. the only sign may be local irritation of the stomach lining or an increase in the amount of blood excreted in the stool. In other cases, or at a more advanced stage, severe gastrointestinal ulceration evident by pain and overt bleeding can occur. In a study reported in 1990 (Scrip, #1518/9, p 30, June 1, 1990) the incidence of gastrointestinal lesions was reported to be 37% for arthritis patients taking ibuprofen, 45.7% for flurbiprofen, and 61% for ketoprofen. Kidney toxicity is an adverse side effect of some concern because it signals a reduction or loss of kidney function which may be due to changes in renal hemodynamics such as renal plasma flow or glomerular filtration rate or to an irreversible breakdown and loss of kidney tissue. Such changes as papillary necrosis or the necrotic syndrome with interstitial nephritis may occur gradually in association with the prolonged use of arylalkanoic acid derivative drugs. Kidney toxicity is progressive in nature and is usually not detectable by overt symptoms until pathological damage has occurred. As used herein, the term "kidney toxicity" means the partial or complete loss of kidney function, whether reversible or irreversible.

The adverse side effects associated with the administration of the specified arylalkanoic acid derivative drugs, i.e. ibuprofen, ketoprofen, flurbiprofen, fenoprofen, tiaprofenic acid, carprofen, indoprofen, pirprofen, cicloprofen, clindanac, loxoprofen or etodolac, are due, at least in part, to the fact that, until now, these drugs have been administered as racemic mixtures. Such mixtures, of course, contain the therapeutically efficacious S enantiomer as well as the opposite member R enantiomer.

The adverse side effects that accompany the administration of arylalkanoic acid derivative drugs originate from one or more of three possible sources. One of these sources is the S enantiomer of the arylalkanoic acid derivative, which, in addition to being the therapeutically efficacious enantiomer, may also interact with physiological systems to cause an adverse effect or reaction. Another of these sources is the R enantiomer of the arylalkanoic acid derivative, which, rather than being an inocuous passenger in the racemic mixture, may interact with physiological systems in such a manner that adverse effects are produced. In these instances, the R enantiomer is a causative agent of some or all of the adverse effects and may be devoid of any beneficial, therapeutic attributes. Finally, the S and R enantiomers may produce the adverse effect in a combinatorial manner. That is, the S and R enantio- mers may interact with physiological systems to produce adverse effects which may or may not occur in the absence of one of the enantiomers. The combina¬ torial ef ect of the S and R enantiomers may produce an adverse effect of a different type than the adverse effect(s) caused by either of the enantiomers individually. Alternatively, this enantiomer combination may enhance an adverse effect produced by either of the enantiomers individually. For example, for substances of the present invention, the presence of the R enantiomer amplifies an adverse effect which occurs when the S enantiomer is present alone. That is, an effect of the R enantiomer is to amplify or enhance the adverse effect which occurs when the S enantiomer is present. A feature of this enhancement situation is that the magnitude of the adverse effect produced when both enantiomers are present can be larger than the magnitude of the adverse effect which would be expected by simply adding the magnitudes of the effects of the two individual enantiomers when present at the same quantities. That is, the adverse effects are not simply additive but, rather, the resultant effect is of greater magnitude.

Thus, the reduction in side effects which occurs with the present invention is only partially due to the elimination of the adverse side effects specifically associated with the non-therapeutic R-enantiomer which is removed from the racemic drug. Also of significance is the apparent interaction between the R and S enantiomers. This interaction can evoke and exacerbate certain adverse side effects. These adverse side effects are lessened in the present invention when the same dose of the S enantiomer as was present as a component of the racemic mixture is administered without the R enantiomer. The severity of these side effects is not solely attributable to the quantity of S enantiomer or, alternatively, to the R enantiomer but, rather, to an enhancement effect ascribable to the presence of the R enantiomer. In this invention, the S enantiomer of the arylalkanoic acid derivative drug is administered since this enantiomer produces the therapeutic effects of, for example, analgesia, anti- inflammation, and antipyrexia (cessation of fever) . Preferably, the opposite member R enantiomer is not incorporated in the administered drug because it is not therapeutically active and places a burden on the body's metabolic and excretory systems and, more importantly, because it produces or contributes to an adverse biological effect. However, when the S enantiomer of an arylalkanoic acid derivative drug is produced, it may also contain some of the opposite member R enantiomer. The quantity of opposite member R enantiomer will generally not exceed 10% of the total amount of arylalkanoic acid derivative drug. Preferably, the quantity of opposite member R enantiomer does not exceed 5%, and more preferably 1% of the total amount of arylalkanoic acid derivative drug. That is, the S enantiomer will generally be at least 90%, preferably 95%, and more preferably 99% of the total amount of arylalkanoic acid derivative drug. As used herein, the term "substantially only the S enantiomer" means the composition contains at least 90% S isomer, and at most 10% R isomer of the amount of the arylalkanoic acid derivative drug. If the quantity of arylalkanoic acid derivative drug contains more than 10% of the opposite member R enantiomer, it is considered to be a mixture of the R and S enantiomers. If the quantity of arylalkanoic acid derivative drug contains 50% of the opposite R enantiomer it is considered to be a racemic mixture. As previously stated, administration of the S enantiomer of an arylalkanoic acid derivative drug reduces, i.e. lessens or avoids, adverse side effects that occur when the racemic mixture of the aryl- alkanoic acid derivative drug is administered. The term reduced adverse side effects refers to either fewer or less intense adverse side effects than are seen when a racemic mixture of the arylalkanoic acid derivative drug is administered. If the incidence or severity of adverse side effects is lessened or delayed when an amount of the S enantiomer of an arylalkanoic acid derivative drug is administered in comparison to when the same amount of the S enantiomer is administered in the racemic mixture form of this drug, the adverse side effects are said to be reduced. The total absence of an adverse side effect constitutes a complete reduction -or avoidance of this side effect.

The S enantiomer of an arylalkanoic acid derivative drug is administered by any route that allows a sufficient quantity of the drug to be introduced into the body. That is, it can be admin¬ istered orally, rectally, topically, or by injection. The delivered form of the arylalkanoic acid derivative drug is determined by the route by which it is given. That is, it can be in the form of a capsule, tablet or oral liquid suspension, supposi¬ tory, cream or ointment, or injectable liquid suspen¬ sion.

The most common form of these drugs is as a capsule or tablet. In this form, administration is achieved by swallowing one or more capsules or tablets. This can be followed by further adminis¬ tration at designated time intervals, e.g. every 4 hours as the need for such a drug's effect is de¬ sired.

The higher potency of the drug in enantio-. merically pure form also makes this form more suit- able for sustained release dosage forms, e.g. includ¬ ing, but not limited to, capsules, coated tablets, and transdermal patch formulations.

The S enantiomer of an arylalkanoic acid derivative drug can be administered alone or in combination with another drug or drugs as well as with inactive materials such as fillers, preserva¬ tives, encapsulating materials, etc. commonly used in the pharmaceutical industry. For example, the S enantiomer of one arylalkanoic acid derivative drug can be combined with one or more other arylalkanoic acid derivative drugs or with some other drug or drugs. If the other drug is an arylalkanoic acid derivative drug, it can be the S enantiomer or a racemic mixture of enantiomers of this drug. The combination of drugs provide the advantage of a wider spectrum of similarly acting pharmaceutical agents applied to a common symptom or set of symptoms, as well as a grouping of different drugs that are individually active against different symptoms. The administration of the S enantiomer of an arylalkanoic acid derivative drug with inactive materials is for purposes of storage, packaging, or ease of formu¬ lation or administration.

The reduction in gastrointestinal irritation resulting from use of the pure enantiomer form of arylalkanoic acid derivative drugs can be supple¬ mented by combining the method of the present invention with other methods for reducing arylalkanoic acid derivative drug-induced G. I. irritation. For example, it has been shown that misoprostol, a prostaglandin derivative, helps prevent gastric and duodenal ulcers associated with arylalkanoic acid derivative drugs without affecting the therapeutic effects of the arylalkanoic acid derivative drugs. The use of S-enantiomer arylalkanoic acid derivative drugs can therefore be combined with agents such as misoprostol or its enantiomer and such combination therapies are in¬ cluded as part of the present invention. Such combination therapies can be carried out with fixed dosage combination formulations or by independent administration of the two agents.

Another advantage of this invention occurs as a result of the therapeutically effective component being the S enantiomer of an arylalkanoic acid derivative drug rather than the racemic mixture of this drug. Since the racemic mixture has equal portions of the S enantiomer and the opposite member enantiomer, only one-half of the racemic drug mixture is therapeutically effective. The other half is therapeutically ineffective, is a contributory agent of the adverse side effects and may interfere with or slow the absorption or action of the therapeutically efficacious isomer. Thus, with this invention, the amount of drug administered at a specific time may be one-half or less of the amount administered before this invention. For example, instead of adminis¬ tering 400 mg of the arylalkanoic acid derivative drug, 200 mg or less of the S enantiomer may be administered. There is, advantageously, a reduction in the amount of the arylalkanoic acid derivative drug administered as well as a reduction in the adverse side effects associated with the administra¬ tion of the racemic mixture. In addition, due to the reduction in adverse side effects with the present invention, it is possible to administer larger doses of the therapeutically efficacious isomer than have been previously administered. Such an administration can effectuate a quicker, more effective or longer lasting therapeutic effect. This possibility exists since it is not necessary to limit the amount of administered drug because of adverse side effects associated with or exacerbated by the presence of the R isomer. This is an important attribute of the present invention.

The amount of the S enantiomer of a an arylal¬ kanoic acid derivative drug that is therapeutically effective depends upon the symptom(s) to be allev- iated as well as the individual to whom the drug is administered. There are variations in drug efficacy and tolerance between individuals which must be taken into account when the drug is administered. In addition, the symptoms occur at different, unpredict able intensities when they are present. The therapeutically effective amount of the S enantiomer of an arylalkanoic acid derivative drug is empiri¬ cally determined and is based upon these variations between individuals as well as upon the intensity of the individual's symptom(s) , e.g. of pain, inflam¬ mation, or fever. Usually, the dosage of the S enantiomer of the arylalkanoic acid derivative drug administered will be in the range of 400 to 600 milligrams per day for S ibuprofen, 75 to 150 milli- grams per day for S ketoprofen, and 75 to 150 milli¬ grams for S flurbiprofen.

The following Examples illustrate the invention. They are not meant to be limiting of the invention in any way.

EXAMPLE 1 - Determination of Toxicity of Racemic Flurbiprofen and Its Enantiomers

This study compares the gastrointestinal toxicity of S, R,S and R-flurbiprofen in a thirty-day period. In order to examine the potential GI and renal toxicities of the APA-class NSAIDs, flurbi¬ profen was chosen as a model due to its enantiomeric stability in the rat.

Approximately 2-month-old female rats (Harlan Sprague Dawley; mean weight 220 g) were treated daily with either R (> 99% ee: 25, 6.3 or 2.5 mg/kg) S

(> 99% ee: 6.3 or 2.5 mg/kg) or RS-flurbiprofen (12.5 or 5 mg/kg) . The drugs were suspended in 1% CMC/H_0 and administered orally by gavage daily for 30 days. The animals were singly caged and allowed free access to water and a pelleted commercial diet. They were maintained on a 12-hours-on, 12-hours-off light cycle. Clinical observations were recorded daily, and body weights were obtained on days 1, 15, 22, and 29 with the drug dose adjusted thereby. The animals were sacrificed on day 30 by cardiac exsanguination under anesthesia followed by necropsy. Kidneys were examined grossly and weighed. Kidney weights were consistent with body weights in all groups. The GI tract was opened, rinsed and examined. GI lesions were described and ulcers counted.

Daily clinical observations of the groups suggested that the high dose (12.5 mg/kg RS) animals were highly compromised with the first death at day 4 (diarrhea) . All members of this group appeared more sluggish compared to the vehicle control throughout the experiment. Two died on day 17 and two more became moribund and were sacrificed on days 22 and 23 respectively. There were no other observations except that single animals from the 6.3 S, 2.5 S and 6.3 mg/kg R groups were found dead on days 16, 18 and 17 respectively with bleeding characteristic of lung puncture during gavage. Table 1 summarizes the rather remarkable clinical observations at necropsy. TABLE 1

CLINICAL OBSERVATIONS (GI) AT NECROPSY

12.5 mg/kg RS 5/10 died (peritonitis) 25 mg/kg R 5/6 NR ascites and/or adhesions 1/6 fatty bodies 8/10 numerous necrotic ulcers in kidney and urine sediment

6.3 mg/kg S 9/10 thickened walls 6.3 mg/kg R 5/6 NR

4/10 some mottling of jejunum 1/6 died*

4/10 1-3 ulcers

1/10 died* I

5 mg/kg RS 5/6 multiple ulcers and 2.5 mg/kg R NR thickened intestinal walls

3/6 mottled jejunum and necrotic lesions

2.5 mg/kg S NR Vehicle

1/6 died * Controls NR

NR = Nothing Remarkable Apparently not treatment related

The supposed therapeutically equivalent dose pairs

(12.5 RS vs 6.3 mg/kg S) and (5 RS vs 2.5 mg/kg S) , if one assumes the S enantiomer is the therapeuti¬ cally efficacious isomer, did not exhibit equivalent clinical effects. The racemic (RS) drug groups exhibited much greater GI toxicity. Additionally, and unexpectedly, the 6.3 S group exhibited less pathology than the 5 RS group! None of the groups receiving R-flurbiprofen exhibited significant life-threatening toxic effects by the presence of the nontherapeutic R-flurbiprofen.

This study demonstrates that, though the R- isomer is without apparent significant gastrointes¬ tinal toxicity, at therapeutically equivalent doses the racemic drug (RS) exhibits significantly more toxicity (ulcers, peritonitis, and death) than the S-isomer. Thus it appears that the toxicity of the S-isomer is enhanced by the presence of the R-isomer. The clinical implications of these findings are of great potential importance.

The racemic (RS) AAAs are widely employed in chronic treatment of arthritis, gout, dysmenorrhea, fever and pain in human medicine. The results in this example suggest a superior therapeutic index for the pure S-isomers of these substances. (Therapeutic index is conventionally defined as the ratio of the concentration of a drug that gives toxic effects to the concentration of that drug that gives therapeutic effects, i.e. LD /ED₅₀.) This superiority is also expected to hold even for those AAAs where there is metabolic conversion of the R enantiomer to the S enantiomer. In addition, these results demonstrate the unexpected superiority of the use of the S enantiomer in alleviating toxic side effects associated with the racemic mixture but not exhibited by the R enantiomer alone.

EXAMPLE 2 - Determination of Renal Toxicity of R- Flurbiprofen

Female Sprague-Dawley rats weighing approxi¬ mately 200g were anesthetized with ether and surgi- cally catheterized in both femoral veins, one femoral artery and in the urinary bladder. After a 2 hour recovery period, isotonic saline was intra¬ venously infused into the restrained animal at a rate of 1 mL/hr. Measurement of urine volume, urine sodium, urine potassium and glomerular filtration rate (GFR) was initiated every 20 minutes (one period) . The mean arterial pressure was monitored continuously through the intraarterial line. The GFR was measured by monitoring the clearance rate of

14C-ιnulιn which was infused continuously through the second intravenous line.

As soon as the GFR stabilized (3 periods) ,

R-flurbiprofen was administered (10 mg/mL in 1.2% sodium bicarbonate solution) by intravenous infusion, in place of the saline, at a rate of 1 mL/hr.

Infusion of the drug was continued for four hours.

At the end of this time, 200 mg/kg had been infused into the animal. Drug infusion was stopped and the 1 mL/hr saline infusion was resumed. Measurements of renal function were continued for another 2 hours (6 periods) .

Table 2 shows the results for the GFR measurements for each animal. The subscripts denote the period in which the GFR measurement was taken.

The administration of R- lurbiprofen significantly diminishes renal function as measured by the GFR, as can be seen by comparison of the GFR and GF values. The ability of the kidneys to clear inulin is notably impaired. Although there is a partial recovery of GFR renal function during the recovery time, normal clearance rates have not been achieved in the animals after two hours.

These results demonstrate that R-flurbiprofen affects renal function. That is, there is kidney toxicity associated with the administration of R-flurbiprofe . Equivalents

Persons skilled in the art will recognize, or be able to ascertain, using no more than routine experi¬ mentation, many equivalents to the specific embodi- ments of the invention described herein. Such equivalents are intended to be encompassed within the scope of the following claims.

Claims

The invention claimed is:CLAIMS

1. Use of the S enantiomer of either ketoprofen or flurbiprofen, substantially free of its R enantiomer, 5 for the manufacture of a medicament for providing a therapeutic effect while reducing adverse side effects associated with the administration of racemic ketoprofen or flurbiprofen.

2. Use of substantially only the S enantiomer of an 0 arylalkanoic acid derivative drug for the manufacture of a medicament for providing a therapeutic effect while reducing adverse side effects associated with the administration of the racemic form of.the arylalkanoic acid derivative drug, wherein the S

15 enantiomer is associated with a greater therapeutic index for the adverse side effects when compared to the racemic form.

3. The use of Claim 2 wherein the adverse side effect is gastrointestinal toxicity or irritation.

2₀4. The use of Claim 2 wherein the adverse side effect is kidney toxicity.

5. Use of the S enantiomer of an arylalkanoic acid derivative drug for the manufacture of a medicament for producing an analgesic, anti-inflammatory or 25 antipyretic effect accompanied by a lesser amount of gastrointestinal toxicity or irritation when compared to the administration of a racemic mixture of the arylalkanoic acid derivative drug.

6. Use of the S enantiomer of an arylalkanoic acid derivative drug for the manufacture of a medicament for producing an analgesic, anti-inflammatory or antipyretic effect accompanied by a lesser amount of kidney toxicity when compared to the administration of a racemic mixture of the arylalkanoic acid derivative drug.

7. The S enantiomer of an arylalkanoic acid derivative drug which is both therapeutically efficacious and adverse side effects-reducing, wherein the adverse side effects are those associated with the administration of a racemic mixture of the arylalkanoic acid derivative drug.

8. The composition of Claim 7 wherein the adverse side effect is gastrointestinal toxicity or irritation.

9. The composition of Claim 7 wherein the adverse side effect is kidney toxicity.

10. The composition of Claim 7 additionally including at least one inactive filler, preservative or encapsulating material.

11. The composition of Claim 7 additionally including at least one other nonsteroidal anti-inflammatory or other drug.

12. The composition of Claim 11 wherein the other drug is selected to prevent gastrointestinal toxicity or irritation.

13. The composition of Claim 12 wherein the other drug is misoprostol or its active enantiomer.