Phenylbutazone confirmation

Phenylbutazone was recognised to potentiate the anticoagulant effect of warfarin as long ago as 1959. As subsequent in vitro studies confirmed that phenylbutazone displaced warfarin from its protein binding site, it was assumed that any non-steroidal antiinflammatory drug (NSAID) would enhance warfarin s anticoagulant effect in this way. However it is now known that the interaction is due instead to a stereoselective inhibition of the metabolism of warfarin. Warfarin is available as a racemic mixture of two enantiomers R and S), and of these the S enantiomer is five times more potent as an anticoagulant. Phenylbutazone inhibits the metabolism of the... 

Table 1 (48a,b) shows the 24 hr results of the test described above on phenylbutazone. Copper degraded phenylbutazone both as a salt and as acetyl acetonate. Iron was less aggressive, and the free salt was stronger than the complex. The degradation products were 4-hydroxy- and 4-hydroperoxy-phenylbutazone, the known oxidation impurities. The susceptibility of phenylbutazone to metal oxidation can be attributed to activation of the hydrogen on C-4 by the adjacent carbonyls. Selegiline hydrochloride, a stable compound, was not oxidized under the same conditions. This confirms the discriminating power of the experimental conditions. 

By far the greatest number of reports have referred to the anti-inflammatory activity found for a variety of 1,2-benzothiazines.15 An initial report by Lombardino et al.9 indicated that potent anti-inflammatory activity was present in a series of 4-hydroxy-2H-l,2-benzothiazine-3-carboxanilide 1,1-dioxides. Antiedema activity in a rat model indicated that carboxanilide 132 (CP-14, 304) was twice as potent as the standard anti-inflammatory agent phenylbutazone. This observation on compound 132 was later confirmed and extended by others.17,85 Studies of the metabolism of compound 132 in animals indicated that a major metabolite resulted from hydroxylation of the carboxanilide moiety.86 The plasma half-life of compound 132 was found to be 21 hours in man.86... 

A quantitative difference exists in the responsiveness of various types of oedema formalin oedema responds more readily than dextran oedema in the same animal. Lorenz found kaolin oedema in rats to be far more susceptible than egg-white or formalin oedema to phenylbutazone in oral doses of 3 to 50 mg/kg. Wagner-Jauregg, Jahn and Biich confirmed that kaolin oedema is the most sensitive of the rat-paw tests. In their hands, 100 mg/kg of phenylbutazone orally inhibited swelling by 36 per cent. Cohen and Got , giving phenylbutazone intraperitoneally in a dose of 100 mg/kg, obtained a very marked response in kaolin oedema, and found, moreover, that the response is less at low room temperatures. Varga, Mehes, Par and Ronai showed that phenylbutazone in a dose of 50 mg/kg intraperitoneally inhibits oedema of the rat s paw caused by kaolin, dextran, 5-hydroxytryp-tamine and formalin. 

In various analgesic tests phenylbutazone is active, though less so than amidopyrine . Clinically, however, it is of little value as an analgesic in pain of non-inflammatory origin . Randall and Selitto demonstrated a clear cut analgesic effect in inflammatory pain as measured by tolerance of pressure applied to the yeast-inflamed foot, a result which was confirmed by Crepax and Silvestrini . ... 

Two other studies confirm this interaction with oxyphenbutazone. One of them found no interaction with phenylbutazone. ... 

In 5 healthy subjects the half-life of a single 6-mg/kg dose of phenylbutazone was reduced by 38% after pretreatment with phenobarbital 2 to 3 mg/kg daily for 3 weeks. Other studies confirm that phenobarbital increases the clearance of phenylbutazone. ... 

The absorption of a single 400-mg dose of phenylbutazone in 4 depressed women was considerably delayed (time to maximum level, 4 to 10 hours compared with 2 hours), but the total amount absorbed (measured by the urinary excretion of oxyphenbutazone) remained unchanged when they were pretreated with desipramine 75 mg daily for 7 days. In another 5 depressed women the half-life of oxyphenbutazone was found to be unaltered by 75 mg of desipramine or nortriptyline dailyAnimal studies have confirmed that the absorption of phenylbutazone and oxyphenbutazone are delayed by the tricyclic antidepressants, probably because their antimuscarinic effects reduce the motility of the gut, - but there seems to be no direct clinical evidence that the antirheumatic effects of either drug are reduced by this interaction. No particular precautions appear to be needed. 

In a study in 3 subjects and one patient, phenylbutazone 200 mg three times daily and twice daily, respectively, given for 11 to 19 days before and 11 days after a single dose of warfarin, markedly increased the prothrombin time, but decreased the half-life of warfarin, and the warfarin AUC. In another study that gave the enantiomers of warfarin separately, it was found that phenylbutazone inhibited the clearance of 5-warfarin, but increased the clearance of7 -warfarin. This was confirmed in other studies, were the AUC of7 -warfarin was decreased by 41% and the AUC of 5-warfarin increased by 18%. ... 

Information seems to be limited to these studies, whieh await confirmation. A similar interaction with phenytoin has been reported with phenylbutazone, which has a very close chemical relationship with sulfinpyiazone (see Phenytoin + Aspirin or NSAIDs , p.551). Thus what is known suggests that concuncnt use should be monitored and suitable phenytoin dosage reductions made where necessary. 

A patient (who was very sensitive to levodopa) found that he was only able to prevent the involuntary movements of his tongue, jaw, neck and limbs caused by levodopa, by taking frequent small doses (125 mg) of levodopa. He was able to suppress the levodopa adverse effects with phenylbutazone. However, the phenylbutazone also lessened the therapeutic effect of the levodopa. The reason is not understood. This interaction has not been confirmed, and its general importance is not known. 

UK manufacturer lists carbamazepine (see also Clozapine + Anti epileptics , p.744), chloramphenicol, cytotoxics, penicillamine, pyrazolone analgesics (e.g. phenylbutazone), sulphonamides (e.g. co-trimoxazole) and, because they cannot be stopped if an adverse reaction occurs, they advise against the use of depot antipsychotics. There are several cases that confirm the clinical significance of these predicted interactions. 

Oestradiol-17 and estrone are metabolized by hepatic microsomes to a mixture of polar metabolites most of which are hydroxylated (2-, 18-, 16 a-, 16i3-posi-tions) and the rate of the conversion is increased by repeated administration of chlordane or phenobarbital to female rats. Accordingly, the increases in uterine weight caused by the administration of physiological doses of oestradiol-17 P or estrone to immature female rats are abolished by pretreatment with phenobarbital, chlordane, chlorcyclizine, phenylbutazone or DDT. These results appear to confirm older observations that chronic exposure of female animals to chlordane or DDT produces alterations in the estrus cycle and in ovarian and vaginal cytology which are associated with oestrogen deficiency. 

The close association of fibrin d osition and inflammatory response is further supported by several recent experiments. The carrageenin-edema in the rat paw is inhibited by agents such as pival and heparin which affect the formation and resolution of fibrin.xhe moderate vitro fibrinolytic activity of antiinflammatory drugs has been confirmed and attributed to their binding to the fibrin molecule and possibly the release of a fibrinolytic activator. Salicylate and phenylbutazone also inhibit platelet aggregation and adhesion induced by fibrin and collagen fragments. 

Matsuda et al [146] provided evidence, via DTA, of the polymorphic transformation in spray dried phenylbutazone encouraged by varying the inlet temperature from 30° to 120°C. Importantly and indicative of its use, TGA was utilised to confirm that there was no residual solvent in the sample, in the form of a solvate. Two or three crystal forms were present. At 120°C the 5-form was produced, at 80° and 100°C, a mixture of two forms was formed and a third form was apparent at 70°C [146]. Mixtures containing two forms contained the P- and 8-form, and when three forms were present, they corresponded to the P-, 5- and s-forms. A single DTA endotherm was found in samples prepared at 100° and 120°C with an endothermic peak at 103°C, equivalent to the 5-form. Melting endotherms at 91-92°C were found for samples obtained at 70°C and 80°C. In these samples a recrystallisation exotherm at 93°C, corresponding to the 5-form was found again the 5-form subsequently melted as an endotherm at 103°C [146]. 

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