The value in rheumatism therapy of salicylic acid was recognized as early as 1876 and cinchophen (phenylcinchoninic acid; atophan) was introduced in gout treatment in 1908. Several of the many clinical observations are of great interest to the biochemist, e.g. the effect of these substances on the excretion of uric acid, their ability to. promote the secretion of bile etc. More recent chemical studies were mainly concerned with attempts to isolate from urine products of salicylate detoxication such as salicyluric acid and salicylglucuronide. Chemical work on cinchophen dates back to the time of Skorczewski & Sohn [1911] and Dohrn [1912], who isolated various oxidation products of cinchophen from human urine.However, information is far from complete with regard to the actual mechanism in which salicylate and cinchophen exert their beneficial in4uence on the diseases of the joint. Continuing the work on problems connected with the tissues which make up the joint [Lutwak-Mann, 1940;, a study was made of the effect of salicylate and cinchophen, first on the in vitro activity of isolated tissues and enzyme systems, and secondly on certain metabolic processes in the intact animal (rat).
A. EXPERIMENTS IN VITRORespiration and anaerobic acid production Rat liver and kidney cortex, in the form of slices, extracts and pulp, were used in experiments which were carried out at 380 in Barcroft differential manometers for the measurement of the O2-uptake and the anaerobic acid production. The tissue slices were suspended in Ringer-phosphate pH 7*2 for the measurement of respiration and in Ringer-bicarbonate for the C02-evolution due to anaerobic acid production. The results recorded below give values (p,l./02 g. fresh tissue) for the first 20-30 min. when the reactions proceeded at a steady rate; but readings were always continued for another 30-60 min. Salicylate and cinchophen (Na salt), as well as certain benzoic acid derivatives other than salicylic acid, were added in various concentrations to tissue slices respiring either alone or in the presence of certain substrates. Table 1 shows that M/100 salicylate had little effect on the 02-uptake of the liver slices; M/100 cinchophen had, a slight inhibitory effect which increased markedly at M/50 concentration. In M/20 salicylate the respiration was well below the control and M/10 salicylate caused a considerable inhibition. This effect, however, varied from one animal to another. Table 1 gives also results obtained with M/10 benzoate, o-aminobenzoate (anthranilate) and o-cresotinate. Of these, only o-cresotinate inhibited the O2-uptake to a degree comparable with that of salicylate, while the others had little effect. On the other hand, M/12 cinchophen almost completely stopped the respiration of liver slices.Experiments of this kind were repeated with livers from starved rats and also from rats which received an excess of glucose for one or more days before the experiment, in addition to their ration. With M/10 salicylate it was found that the respiration in the starved tis...