its variants include plaque , bullous , linear , frontoparietal , subcutaneous , generalized and pan - sclerotic morphea of childhood . eosinophilic fasciitis was recently included in the disease spectrum.1 it is considered to be an auto - immune disease possibly related to microchimerism of fetal cells.2 abnormal tryptophan metabolism has been reported in other sclerosing cutaneous diseases.3 l - tryptophan supplementation was responsible for an outbreak of eosinophilia myalgia syndrome , which resulted in cutaneous sclerosis resembling eosinophilic fasciitis.4 although initially reported in association with contaminated l - tryptophan , later reports linked the condition to l - tryptophan from other suppliers.5 abnormalities in l - tryptophan metabolism were also reported in the toxic oil syndrome reported in spain from contaminated rapeseed ( canola ) oil.6 this resulted in cutaneous sclerosis similar to eosinophilic fasciitis . several drugs known to act on the kynurenine pathway have been reported to produce cutaneous sclerosis as side - effects . l - tryptophan is an inducer of tryptophan2 , 3 di - oxygenase,7 the first enzyme in the hepatic kynurenine pathway . benserazide is a potent inhibitor of the enzyme kynurenase8 and a component of levodopa containing preparations used to treat parkinsonism . several cases of scleroderma - like illnesses have been reported during treatment of parkinsonism with l-5-hydroxytryptophan and levodopa / benserazide combinations.9 aromatic hydocarbons have also has been reported to precipitate scleroderma - like illnesses,10 and these are ligands for the aryl hydrocarbon receptor . kynurenine is a natural ligand for the aryl hydrocarbon receptor.11 manipulation of this pathway may provide additional therapeutic options to supplement the traditional immunosuppressive modalities known to have efficacy in this disorder ( corticosteroids , methotrexate , mycophenylate mofetil and phototherapy).12 an ideal candidate agent would have known safety , approval for use in human subjects and anecdotal reports of efficacy in this group of disorders . tranilast is an agent approved in japan and korea for the management of allergic disorders . it is known to inhibit the release of mast cell mediators.13 more recently , it was demonstrated to inhibit the release of transforming growth factor beta 114 and it is now approved for the management of keloids and hypertrophic scars . 15 it is a derivative of 3- hydroxyanthralinic acid , which is a known stimulator of tgf beta production,16 suggesting that it is acting as an antagonist . the aim of this study was to evaluate whether tranilast had a direct effect on the kynurenine pathway under conditions of tryptophan loading . l tryptophan was obtained from bioeva australia ( biovea , hurstville nsw 2220 australia ) . tranilast was obtained from ebiochem ( pudong , shanghai , china ) , weighed and capsulated . early morning urine specimens were obtained , frozen and transported in laboratory - supplied kits . organic acid profiles were performed at the great plains laboratory ( lenaxa ks ) via gas chromatography / mass spectrometry . a healthy 56-year - old male with no significant co ethical approval for this research was obtained , and the subject gave his written , informed consent to participate . urinary organic acid profiles were performed commercially at a clia certified laboratory ( great plains laboratory lenaxa ks ) via gas chromatography / mass spectroscopy . 3 values were obtained at baseline and under conditions of l tryptophan loading 2 grams daily , with 4 values obtained for l tryptophan 2 grams daily with tranilast 1 gram daily . tryptophan loading was commenced 10 days prior to the collection of the initial specimen and continued throughout the trial period . mean baseline value for kynurenic acid and quinolinic acid were 1.1 and 2.1 mmol / mol creatinine , respectively . this rose to 5.6 and 3.8 mmol / mol creatinine , respectively , under conditions of l tryptophan loading 2 grams daily . adding 1 gram of tranilast daily lowered the values to 2.0 and 2.9 mmol / mol creatinine , respectively . a 2 tail , 2 sample equal variance t test indicated statistical significance ( p < 0.05 ) for all values . although reaching statistical significance in this individual , the results may not automatically be applicable to a larger population . as drugs known to promote cutaneous sclerosis as an adverse reaction would be anticipated to increase kynurenine levels , any potential therapeutic agent needs to be shown to produce statistically significant lowering of both kynurenine and quinolinic acid , presumably by acting at the level tdo / ido . the data does not allow us to determine which enzyme or both is being acted on . from a therapeutic perspective , the aim is to lower levels of kynurenine as the evidence suggests this is the most relevant metabolite . the agent initially used to demonstrate the role of the kynurenine pathway in the maintenance of immunological tolerance during pregnancy , 1-methyl - d - tryptophan , 17 is undergoing trials in patients with advanced malignancy.18 until these are available , there remains little data on its use in human subjects . expression varies at the body site , being maximal in interface areas19 including the gastrointestinal tract , lung and skin where exposure to foreign antigens occurs , in the spleen and thymus where it presumably plays a role in the regulation of self - antigens , and in the epididymis and prostate where it presumably has a protective role against intracellular infectious organisms . as it inhibits tgf beta activity , which is normally enhanced by 3 hydroxyanthranilic acid , it would appear to be acting as an antagonist to 3 hydroxyanthranilic acid . these data suggest that tranilast may act as a competitive inhibitor at the level of tryptophan 2 , 3 di - oxygenase / indoleamine 2 , 3-dioxygenase .
the pathogenesis of morphea and other cutaneous sclerosing disorders remain poorly understood . 
 although they are considered to be autoimmune disorders , abnormal tryptophan metabolism may be involved . 
 current therapy is directed to supressing the autoimmune response . 
 demonstration of a therapeutic response to manipulation of the kynurenine pathway would both support a role for abnormal tryptophan metabolism and offer additional targets for therapy . 
 tranilast is a 3-hydroxyanthranilic acid derivative known to target the kynurenine pathway . 
 the aim of this study was to see if tranilast lowered the urinary excretion of the kynurenine metabolites kynurenic and quinolinic acid under condition of l tryptophan loading in a volunteer . 
 mean baseline value for kynurenic acid and quinolinic acid were 1.1 and 2.1 mmol / mol creatinine , respectively . 
 this rose to 5.6 and 3.8 mmol / mol creatinine respectively under conditions of l tryptophan loading 2 grams daily . adding 1 g of tranilast daily lowered the values to 2.0 and 2.9 mmol / mol creatinine , respectively . 
 these data suggest that tranilast acts as a competitive inhibitor of either indoleamine 2 , 3-dioxygenase ( ido ) , tryptophan 2 , 3-di - oxygenase ( tdo ) or both . as it involved only 1 subject , the results may not be representative of the larger population and must be considered preliminary .