High-pressure liquid chromatographic evaluation of cyclic paracetamol-acetylsalicylate and its active metabolites with results of a comparative pharmacokinetic investigation in the rat.

Like benorilate, its correlated open ester, MR 897, a cyclic ester between acetylsalicylic acid and paracetamol, gives rise to acetylsalicylic acid, salicylic acid and paracetamol by enzymatic hydrolysis. An analytical method was developed, which detects parent drugs and active metabolites, in order to compare the pharmacokinetic and metabolic behaviour of the two products. The method was specifically validated for quantitative analysis of salicylic acid and paracetamol, which are the main systemic metabolites of both MR 897 and benorilate. Extraction from plasma or tissue homogenate was carried out in two steps with diethyl ether and acetate. Recovery of the analytical substances ranged from 82.7% for paracetamol to 98.5% for salicylic acid. The results of a comparative pharmacokinetic investigation of MR 897 and benorilate in the rat confirm higher bioavailability and a more favourable plasma level profile with MR 897.

Effect of etersalate on human platelet responsiveness. A study in healthy volunteers.

Ex vivo antiplatelet properties of 2-(p-acetamido-phenoxy)ethyl-o-acetoxybenzoate (etersalate, Daital) and its effects on serum thromboxane A2 (TXA2) levels and prostaglandin I2 (PGI2) generation were studied in human volunteers at two levels of oral dosing. Etersalate inhibited at the lower dosage platelet function and decreased TXA2 levels, but PGI2 generation from rat aortic rings was stimulated when incubated with plasma from etersalate-treated donors. Blood coagulation parameters remained within normal values. It is suggested that etersalate administration could act on platelet arachidonate metabolism at a different level than that of the cyclooxygenase pathway.

The metabolism of the anti-inflammatory drug eterylate in rat, dog and man.

Oral doses of 14C-eterylate were well absorbed by rat and man and excreted mainly in the urine (94% dose by rat in three days and 91% by man in five days). Oral doses to dogs were excreted in similar proportions in both the urine and faeces, although faecal 14C was probably derived in part, from biliary-excreted material. Peak plasma 14C and drug concn. were generally reached between one and three hours after oral doses. In humans, only two metabolites, salicylic acid and 4-acetamido-phenoxyacetic acid, were detected in plasma. The latter was cleared more rapidly than the former and hence plasma salicyclate concn. reached a peak (10.9 and 19.8 micrograms/ml in Subjects 1 and 2, respectively) and initially declined with a half-life of about two-three hours. Plasma 4-acetamidophenoxyacetic acid concn. reached a peak (4.3, 10.0 micrograms/ml, respectively) and declined with a half-life of about one hour. Tissue concn. of 14C were generally greater in dogs than in rats. Highest conc. occurred at three hours in dogs and at one hour in rats. Apart from those in the liver and kidneys, tissue concn. were lower than those in the corresponding plasma. Unchanged drug was not detected in urine or plasma of any species and was rapidly metabolized in human plasma. The major 14C components in human urine were identified as salicyluric acid and 4-acetamidophenoxyacetic acid; minor metabolites were salicylic acid, gentisic acid and paracetamol. These metabolites were also detected in rat urine albeit in different proportions to those in human urine. Dog urine contained less of these metabolites and a major proportion of the 14C was associated with relatively non-polar components. Although salicylic acid and 4-acetamidophenoxyacetic acid were the only major circulating metabolites in man and rat, dog plasma also contained the non-polar urine metabolites.

Synthesis and pharmacological properties of eterylate, a new derivative of acetylsalicylic acid.

A description is given of the synthesis and main physical and chemical properties of a new derivative of acetylsalicylic acid which we have called eterylate and which is 2-(p-acetamidophenyloxy)-ethyl-o-acetoxy-benzoate. The anti-inflammatory and analgesic action of the preparation was studied and found to be comparable to that of acetylsalicylic acid and benorylate. Nevertheless, eterylate is tolerated better than the latter product, as is shown by toxicity tests and studies of the digestive system.

Immunogenicity of aryl esters of salicylic or acetylsalicylic acid in guinea pigs.

A variety of derivatives of acetylsalicylic and salicylic acid have been investigated for their immunogenic properties in guinea pigs including salicylsalicylic acid (SSA), acetylsalicylsalicylic acid (ASSA), disalicylide (DI), trisalicylide (TRI), acetylsalicylic acid paracetamol ester (ASPE) and acetylsalicylic acid guajacol ester (ASGE). Contact sensitivity could be elicited by the sensitizing agent, however, with acetylsalicylic acid anhydride (ASAN) a more pronounced contact reaction could consistently be observed. Systemic anaphylactic reactions elicited by intravenous injection of N-salicyloyl bovine serum albumin could only be induced by ASAN, DI, TRI and ASSA, whereas SSA, ASPE and ASGE did not induce an anaphylactic state at a comparable dose level. From these results it is anticipated that all aryl esters of acetylsalicylic or salicylic acid are immunogenic when applied intradermally, leading to a N-salicyloyl specific immune response.

[Phototoxic and photoallergic reactions of the skin (author's transl)]. / Phototoxische und photoallergische Reaktionen der Haut

Phototoxic and photoallergic reactions of the skin are certainly not very common, but, on the other hand, the complete list of medicinal substances which are accused of causing them is extremely extensive. For this reason, dispensing with many details, an attempt is made to present the basis of such reactions. After irradiation with longwave ultra-violet light, which alone would not have produced inflammation, a reaction occurred through the agency of many drugs which can proceed according to a toxic or allergic mechanism.