OA12054A - Novel use of ppar gamma agonist. - Google Patents

Description

1 1 2054

This invention relates to a method of treatment, in particular to a method forthe treatment of diseases or conditions associated with increased numbers ofneutrophils and/or over-activation of neutrophils.

European Patent Application, Publication Number 0,306,228 relates to certainthiazolidinedione dérivatives disclosed as having antihyperglycaemic andhypolipidaemic activity. One particular thiazolidinedione disclosed in EP 0306228 is5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione(hereinafter 'Compound (I)'). WO94/05659 discloses certain salts of Compound (I)including the maleate sait at example 1 thereof.

Compound (I) is an example of a class of anti-hyperglycaemic agents knownas "glitazones" or "thiazolidinedione".

European Patent Applications, Publication Numbers: 0008203,0139421,0032128, 0428312,0489663,0155845, 0257781,0208420, 0177353, 0319189,0332331,0332332,0528734,0508740; International Patent Application, PublicationNumbers 92/18501, 93/02079, 93/22445 and United States Patent Numbers 5104888and 5478852, also disclose certain thiazolidinediones.

The contents of the above mentioned publications aie incorporated herein byreference.

It is known that the γ-isoform of peroxisome proliferator-activated receptor(herein after PPARy) is member of a nuclear receptor superfamily that includesreceptors for the steroid, thyroid and retinoid hormones( Evans, Science 240, 889-895,(1988)). It, is also known from Chawla et al that PPARy is expressed early during thedifférentiation of adipocytes (Endocrinology 135,798-800, 1994).

It is known from J. Biol. Chem., 270,12963-12966 that thiazolidinediones such asCompound (I) are PPARy agonists.

We hâve now demonstrated that PPARy expression is significantly up-regulated in activated neutrophils. Thus, PPARy agonists are expected to inhibitactivated neutrophil function and therefor to hâve potential use in diseases andconditions where suppression of neutrophil activity or numbers would be of benefit.Such disorders include those listed herein including: goût, arthritis, asthma, chronicobstructive pulmonary disease, irritable bowel syndrome, psoriasis and acné.

Also neutrophils are a major cell type infiltrating the skin dermis andepidermis layer following moderate to server UV sun exposure. These cells hâvethe capability to cause tissue damage and in certain severe circumstances delayedhealing of the skin. Thus PPARy agonists are considered to be useful in preventingand/or treating damage to the skin dermis and/or epidermis layers caused by excess 2 1 2 05 4 ultra violet radiation or sun-light exposure. They are also considered to aid healingof the skin following such damage.

Accordingly, the invention provides a method for the treatment of a diseaseor condition associated with increased numbers of neutrophils and/or neutrophil over-activation in a mammal such as a human, which method comprises administering aneffective, non-toxic and pharmaceutically acceptable amount of a PPARy agonist,such as Compound (I), to a mammal in need thereof.

In an alternative aspect the invention provides a use of a PPARy agonist, suchas Compound (I), for the manufacture of a médicament for the treatment of a diseaseor condition associated with increased numbers of neutrophils and/or neutrophil over-activation in a mammal such as a human.

Suitable diseases or conditions associated with increased numbers ofneutrophils and/or neutrophil over-activation include diseases or conditions of therespiratory tract, bone and joints, skin, gastrointestinal tract, other tissues andsystematic diseases, allograft rejections and certain cancers. In particular a disease orof the respiratory tract. In particular a disease or condition of the bone and joints. Inparticular a disease or condition of the skin. In particular a disease or condition of thegastrointestinal tract. In particular a diseases or condition of other tissues andsystematic diseases. In particular conditions associated with allograft rejections. Inparticular certain cancers.

Suitable diseases or conditions of the respiratory tract include those in the listconsisting of: obstructive airways diseases including chronic obstructive pulmonarydisease (COPD); asthma, such as bronchial, allergie, intrinsic, extrinsic and dustasthma, particularly chronic or inveterate asthma (eg late asthma and airways hyper-responsiveness); bronchitis; acute allergie, atrophie rhinitis and chronic rhinitisincluding rhinitis caseosa, hypertrophie rhinitis, rhinitis purulenta, rhinitis purulenta,rhinitis sicca and rhinitis medicarmenrosa; membranous rhinitis including croupous,fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitisincluding rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoiosis, farmer's lungand related diseases, fibreie lung and idiopathic interstitial pneumonia. A particulardisease or condition of the respiratory tract is considered to be each individualmember of the preceeding list not including any other member of the said list.

Suitable diseases or conditions of the bone and joints include those in the listconsisting of: rheumatoid arthritis, séronégative spondyloarthropathis (includingankylosing spondylitis, psoriatic arthritis and Reiter’s disease), Behcet's disease,Sjogren's syndrome and systemic sclerosis. A particular disease or condition of thebone and joints is considered to be each individual member of the preceeding list notincluding any other member of the said list. 3 , 1 2054

Suitable diseases or conditions of the skin include those in the iist consistingof: psoriasis, atopical dermatitis, contact dermatitis and other eczmatous dermitides,seborrcetic dermatitis, Lichan planus, Pemphigus, bullous Pemphigus, Epidermolysisbullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, 5 uveitis, Alopecia areata and vemal conjunctivitis. A particular disease or condition ofthe skin is considered to be each individual member of the preceeding list notincluding any other member of the said list.

Suitable diseases or conditions of the gastrointestinal tract include those in thelist consisting of: Coeliac disease, proctitis, eosinopillic gastro-enteritis, 10 mastocytosis, Crohn'd disease, ulcerative colitis, food-related allergies which hâveeffects remote from the gut e.g. migraine, rhinitis and eczema. A particular disease orcondition of the gastrointestinal tract is considered to be each individual member ofthe preceeding list not including any other member of the said list.

Suitable diseases of other tissues and systematic diseases include those in the 15 list consisting of: multiple sclerosis, atherosclerosis, Acquired Immundeficiency

Syndrome (AIDS), lupus erythematosus, systemic lupus, erythtmatosus, Hashimoto'sthyroiditis, myasthenia gravis, type I diabètes, nephrotic syndrome, eosinophiliafascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathicthrombocytopenia pupura. A particular disease or condition of other tissues and 20 systematic diseases is considered to be each individual member of the preceeding listnot including any other member of the said list.

Suitable conditions associated with allograft rejection include those associatedwith the list consisting of: acute and chronic conditions following transplantation ofkidney, heart, liver, lung, bone marrow, skin and comea; and chronic graft versus host 25 disease. A particular condition associated with allograft rejection is considered to beeach individual member of the preceeding list not including any other member of thesaid list.

Suitable cancers include those in the list consisting of: non-small cell lungcancer (NSCLC) and squamous sarcoma. A particular cancer is non-small cell lung 30 cancer (NSCLC). A particular cancer is squamous sarcoma

In a further aspect, there is included the conditions ordiseases in the list consisting of: cystic fibrosis, stroke, re-perfusion injury in the heart, brain,peripheral limbs and sepsis, goût, arthritis, asthma, chronic obstructive pulmonarydisease, irritable bowel syndrome, psoriasis and acné. A particular condition or 35 disease is considered to be each individual member of the preceeding list notincluding any other member of the said list.

As indicated above, a further condition of the skin associated with increasednumbers of neutrophils and/or neutrophil over-activation is damage to the skin dermis 4 . 1 2054 and/or epidermis layers caused by excess ultra violet radiation or sun-lightexposure. Accordingly, the invention also provides a method for preventing and/ortreating damage to the skin dermis and/or epidermis layers caused by excess ultraviolet radiation or sun-light exposure in a mammal such as a human, which methodcomprises administration, preferably topical administration, of an effective, non-toxicand pharmaceutically acceptable amount of a PPARy agonist, such as Compound (I),to a mammal in need thereof.

Also provided is a method for promoting or aiding healing of the skinfoliowing such damage, which method comprises administration, preferably topicaladministration, of an effective, non-toxic and pharmaceutically acceptable amount ofa PPARy agonist, such as Compound (I), to a mammal in need thereof. A suitable PPARy agonist is Compound (I) or a pharmaceutically acceptabledérivative thereof.

Other suitable PPARy agonists include (+) -5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-l-benzopyran-2-yl)methoxyjphenyl]methyl]-2,4-thiazoîidinedione (or troglitazone; 5-[4-[(l-methylcyclohexyl)methoxy)benzyl] thiazolidine-2,4-dione (or ciglitazone);5-[4-[2-(5-ethyîpyridin-2-yl)ethoxy]benzyl] thiazolidine-2,4-dione (or pioglitazone);and 5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl)thiazolidine-2,4-dione (orenglitazone); or a pharmaceutically acceptable dérivative thereof.

It will be understood that the PPARy agonist, such as Compound (I), isadministered in a pharmaceutically acceptable form including pharmaceuticallyacceptable dérivatives.

Suitable pharmaceutically dérivatives include pharmaceutically acceptablesalts, esters and solvatés, as appropriate to the relevant PPARy agonist.

Suitable pharmaceutically acceptable salted and or solvated forms ofCompound (I) include those described in EP 0306228 and WO94/05659. A preferredpharmaceutically acceptable sait of Compound (I) is a maleate. A preferredpharmaceutically acceptable solvaté of Compound (I)is a hydrate.

Other pharmaceutically acceptable dérivatives are those disclosed in standardreference texts such as the British and US Pharmacopoeias, Remington'sPharmaceutical Sciences (Mack Publi,shing Co.) and Martindale The ExtraPharmacopoeia (London, The Pharmaceutical Press) or the above mentionedpublications.

The PPARy agonists may be prepared using known methods, for examplethose disclosed in the above mentioned publications. ti 1 2 05 4

Compound (I) and pharmaceutically acceptable forms thereof may beprepared using known methods, for example those disclosed in EP 0306228 andWO94/05659 publications.

Compound (I) may exist in one of several tautomeric forms, ail of which areencompassed by the term Compound (I) as individual tautomeric forms or as mixturesthereof. Compound (I) contains a chiral carbon atom, and hence can exist in up to twostereoisomeric forms, the term Compound (I) encompasses ail of these isomeric formswhether as individual isomers or as mixtures of isomers, including racemates.

As used herein the term 'pharmaceutically acceptable' embraces both humanand veterinary use: for example the term 'pharmaceutically acceptable' embraces aveterinarily acceptable compound.

For the avoidance of doubt, when reference is made herein to scalar amounts,including mg amounts, of Compound (I) in a pharmaceutically acceptable form, thescalar amount referred to is made in respect of Compound (I) per se·. For example 2mg of Compound (I) in the form of the maleate sait is that amount of maleate saitwhich contains 2 mg of Compound (I).

Neutrophil activation may be demonstrated using conventional methodologysuch as that disclosed in Current Protocols in Immunology, Vol I, Suppl 1, Unit6.12.3., the disclosure of which is incorporated herein by reference.

Neutrophils may be isolated from human blood as described in CurrentProtocols in Immunology Vol I, Suppl 1 Unit 7.23.1, the disclosure of which isincorporated herein by reference.

In the method of the invention, the active médicaments are preferablyadministered in pharmaceutical composition form.

Accordingly, in one aspect the invention provides a pharmaceuticalcomposition for use in the treatment of a disease or condition associated withincreased numbers of neutrophils and/or neutrophil over-activation in a mammal, suchas a human, which composition comprises a PPARy agonist, such as Compound (I),and a pharmaceutically acceptable carrier therefor.

The compositions may be adapted for any suitable mode of administration,for example oral administration, parentéral administration, sublingual or transdermaladministration.

The compositions may be in the form of tablets, capsules, powders, granules,lozenges, suppositories, reconstitutable powders, or liquid préparations, such as oralor stérile parentéral solutions or suspensions.

In order to obtain consistency of administration it is preferred that acomposition of the invention is in the form of a unit dose. 1 2054

Unit dose présentation forms for oral administration may be tablets andcapsules and may contain conventional excipients such as binding agents, for examplesyrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, forexample lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine;tabletting lubricants, for example magnésium stéarate; disintegrants, for examplestarch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose;or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.

The compositions are preferably in a unit dosage form in an amountappropriate for the relevant daily dosage based upon such factors as the particularcompound chosen and the nature and severity of the disease or condition.

Suitable dosages including unit dosages of the PPARy agonist, such asCompound (I), include the known dosages and unit doses for these compounds asdescribed or referred to in reference texts such as the British and US Pharmacopoeias,Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The ExtraPharmacopoeia (London, The Pharmaceutical Press) or the above mentionedpublications.

In the treatment of the invention the PPARy agonist may be administered inaccordance with know regimens described or referred to in reference texts such as thethose referred to above or in the above mentioned publications.

In the treatments the médicaments may be administered frorn 1 to 6 times aday, but most preferably 1 or 2 times per day.

The solid oral compositions may be prepared by conventionalmethods of blending, filling or tabletting. Repeated blending operations may be usedto distribute the active agent throughout those compositions employing largequantities of fillers. Such operations are of course conventional in the art. The tabletsmay be coated according to methods well known in normal pharmaceutical practice,in particular with an enteric coating.

Oral liquid préparations may be in the form of, for example, émulsions,syrups, or élixirs, or may be presented as a dry product for reconstitution with wateror other suitable vehicle before use. Such liquid préparations may containconventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulosè, aluminium stéarategel, hydrogenated edible fats; emulsifying agents, for example ldcithin, sorbitanmonooleate, or acacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, fractionated coconut oil, oily esters such as esters of glycérine,propylene glycol, or ethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouringagents. ·! 7 1 2054

For parentéral administration, fluid unit dosage forms are prepared utilizingthe compound and a stérile vehicle, and, depending on the concentration used, can beeither suspended or dissolved in the vehicle. In preparing solutions the compound canbe dissolved in water for injection and filter sterilized before filling into a suitable vialor ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, apreservative and buffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial and the waterremoved under vacuum. Parentéral suspensions are prepared in substantially the samemanner, except that the Compound (I)s suspended in the vehicle instead of beingdissolved, and sterilization cannot be accomplished by filtration. The compound canbe sterilized by exposure to ethylene oxide before suspending in the stérile vehicle.Advantageously, a surfactant or wetting agent is included in the composition tofacilitate uniform distribution of the compound.

Compositions may contain from 0.1% to 99% by weight, preferably from10-60% by weight, of the active material, depending upon the method ofadministration.

As indicated the PPARy agonist can also be administered in apharmaceutically acceptable form suitable for topical application.

Topical application of the PPARy agonist is particularly suited to thetreatment of diseases or conditions of the skin, including those in the list mentionedabove and the prévention and/or treatment of damage to the skin dermis and/orepidermis layers caused by excess ultra violet radiation or sun-light exposure.

Psoriasis is a particular diseases or conditions of the skin.

Accordingly, in a further aspect, the invention also provides a pharmaceuticalcomposition adapted for topical administration, especially for the treatment ofdiseases or conditions of the skin, comprising a PPARy agonist and apharmaceutically acceptable carrier.

Suitable pharmaceutically acceptable carriers adapted for topical applicationinclude any substance compatible with the active compound which can safely be usedfor topical or transdermal administration to human or non-human mammals andincludes solvents, diluents, preservatives, pénétration enhancers, polymers, buffers,perfumes, thickeners, gelling agents, surfactants and emulsifiers. Such substances aredisclosed in standard reference texts such as the British and US Pharmacopoeias,Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The ExtraPharmacopoeia (London, The Pharmaceutical Press) Harry's Cosmeticology (LeonardHill Books) and Drugs and Pharmaceutical Sciences, Vol 18, DermatologicalFormulations " Percutaneous Absorption" by Brian W Barry, pub Marcel Deker(ISBN 0/8247/1729/5).or the above mentioned publications. 8. 12054

The active ingrédient may comprise, for topical administration, from 0.001%to 10% w/w, for instance from 1% to 2% by weight of the formulation. It mayhowever comprise as much as 10% w/w but preferably will comprise less than 5%w/w, more preferably from 0.1% to 1% w/w of the formulation.

The compositions of the invention adapted for topical administration may beformulated in any convenient dosage form suitable for topical application, forexample as a lotion, Intiment, gel, cream, ointment, drops, solution or spray usingmethods disclosed in the reference texts mentioned above.

Lotions or liniments for application to the skin may also include an agent tohasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizersuch as glycerol or an oil such as castor oil or arachis oil.

Creams, ointments or pastes according to the présent invention are semi-solidformulations of the active ingrédient for extemal application. They may be made bymixing the active ingrédient in finely-divided or powdered form, alone or in solutionor suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery,with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard,soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of naturalorigin such as almond, corn, arachis, castor or olive oil; wool fat or its dérivatives or afatty acid such as steric or oleic acid together with an alcohol such as propylene glycolor a macrogel. The formulation may incorporate any suitable surface active agentsuch as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or apolyoxyethylene dérivative thereof. Suspending agents such as natural gums,cellulose dérivatives or inorganic materials such as silicaceous silicas, and otheringrédients such as lanolin, may also be included.

Drops according to the présent invention may comprise stérile aqueous or oilysolutions or suspensions and may be prepared by dissolving the active ingrédient in asuitable aqueous solution of a bactericidal and/or fungicidal agent and/or any othersuitable preservative, and preferably including a surface active agent. The resultingsolution may then be clarified by filtration, transferred to a suitable container which isthen sealed and sterilized by autoclaving or maintaining at 98-100°C. for half an hour.Altematively, the solution may be sterilized by filtration and transferred to thecontainer by an aseptie technique. Examples of bactericidal and fungicidal agentssuitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%),benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solventsfor the préparation of an oily solution include glycerol, diluted alcohol and propyleneglycol.

In the topical treatments the médicaments may be applied from 1 to 6 times aday, but most preferably 1 or 2 times per day. 9 . 1 2054

The présent invention also provides a pharmaceutical composition adaptedfor topical administration comprising a PPARy agonist and a pharmaceuticallyacceptable carrier adapted for topical application, for use as an active therapeuticsubstance. 5 Compositions may, if desired, be in the form of a pack accompanied by written or printed instructions for use.

The compositions are formulated according to conventional methods, such asthose disclosed in standard reference texts, for example the British and USPharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.) and 10 Martindale The Extra Pharmacopoeia (London The Pharmaceutical Press) (forexample see the 3 lst Edition page 341 and pages cited therein) and Harry'sCosmeticology (Leonard Hill Books) or as disclosed in the above-mentionedpublications.

No adverse toxicological effects hâve been established for the compositions or 15 methods of the invention in the above mentioned dosage ranges.

The following example illustrâtes the invention but does not limit it in any way. ΙΟ- 1 2054 DEMONSTRATION OF EFFECTThe résulte shown in Figure 1 demonstrate: (Figure 1 A): That PPARgamma mRNA is rapidly and significantly increased during5 (data taken at 1 and 4 hours) human neutrophil attachment to culture dishes and is further enhanced by treatment with GM-CSF, (Figure 1 A). (Figure IB): That the increase in Gélatinase B mRNA expression observed 4 hoursafter neutrophil attachment was reduced by treatment with 1 μΜ of Compound (I).Time zéro (TO) refers to expression in naïve human neutrophils prior to attachment. -11- 1 2054

Figure 2: Inhibition of MMP-9 release by Compound (I)

Neutrophils were isolated by countercurrent centrifugal élutriation to a purity of atleast 98 % and were maintained in RPMI1640 plus 1 % BSA. Cells were cultured 5 in 48 well plates and attached to the wells within 1 hour of plating. Compound (I)(referred to as "BRL49653" in Figure 2) was included from the beginning of theexperiment. After 4 hours the media was removed and a human MMP-9 ELISAassay (Amersham) was performed. Data (from 4 different individuals) were notsuitable for pooling directly, so for the purposes of the figure they were normalised 10 to percentage of no compound control. Asterisks dénoté p < 0.05 using a pairedStudent's t-test performed on the raw data prior to normalisation. IC50 for theinhibition by Compound (I) of MMP-9 release was 10.6 nM (calculated by fitting a4-parameter logistic curve using Statistica).

Claims (11)

1. -12- 1 2054 ' Claims:

   1. A use of a PPARy agonist for the manufacture of a médicament for thetreatment of a disease or condition associated with increased numbers of neutrophilsand/or neutrophil over-activation in a mammal
2. 2. A use according to claim 1, wherein the diseases or conditions associatedwith increased numbers of neutrophils and/or neutrophil over-activation is selectedfrom: diseases or conditions of the respiratory tract, bone and joints, skin,gastrointestinal tract, other tissues and systematic diseases, allograft rejections andcertain cancers.
3. 3. A use according to claim 1 or claim 2, wherein the diseases or conditions ofthe respiratory tract are those in the list consisting of: obstructive airways diseasesincluding chronic obstructive pulmonary disease (COPD); asthma, such as bronchial,allergie, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma;bronchitis; acute allergie, atrophie rhinitis and chronic rhinitis including rhinitiscaseosa, hypertrophie rhinitis, rhinitis purulenta, rhinitis purulenta, rhinitis sicca andrhinitis medicarmenrosa; membranous rhinitis including croupous, fîhrinous andpseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis includingrhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoiosis, farmer’s lung andrelated diseases, fibricic lung and idiopathic interstitial pneumonia.
4. 4. A use according to any ope of claims 1 to 3, wherein the diseases or conditionsof the bone and joints are those in the list consisting of: rheumatoid arthritis,séronégative spondyloarthropathis, Behcet's disease, Sjogren's syndrome and systemicsclerosis.
5. 5. A use according to any one of claims 1 to 3, wherein the diseases or conditionsof the skin are those in the list consisting of: psoriasis, atopical dermatitis, contactdermatitis and other eczmatous dermitides, seborrcetic dermatitis, Lichan planus,Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas,vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia areata and vemalconjunctivitis.
6. 6. A use according to any one of claims 1 to 3, wherein the diseases or conditionsof the gastrointestinal tract are those in the list consisting of: Coeliac disease, -13- 1 2 05 4 proctitis, eosinopillic gastro-enteritis, mastocytosis, Crohn'd disease, ulcerative colitisand food-related allergies which hâve effects remote from the gut.
7. 7. A use according to any one of claims 1 to 3, wherein the diseases of othertissues and systematic diseases are those in the list consisting of: multiple sclerosis,atherosclerosis, Acquired Immundeficiency Syndrome (AIDS), lupus erythematosus,systemic lupus, erythtmatosus, Hashimoto’s thyroiditis, myasthenia gravis, type Idiabètes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatousleprosy, sezary syndrome and idiopathic thrombocytopenia pupura.
8. 8. A use according to any one of claims 1 to 3, wherein the conditions associatedwith allograft rejection are those associated with the list consisting of: acute andchronic conditions following transplantation of kidney, heart, liver, lung, bonemarrow, skin and comea; and chronic graft versus host disease.
9. 9. A use according to any one of claims 1 to 3, wherein the cancers are those inthe list consisting of: non-small cell lung cancer (NSCLC) and squamous sarcoma.
10. 10. A use according to any one of claims 1 to 9, wherein the PPARy agonist is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione("Compound (I)") or a pharmaceutically acceptable dérivative thereof.
11. 11. A use according to any one of claims 1 to 9, wherein the PPARy agonist 5-[4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl] thiazolidine-2,4-dione (or pioglitazone).