3-methyl salicylic acid: A long acting salicylate which decreases free fatty acid mobilisation and plasma cholesterol

A comparative study has been made of the action of 3-methyl salicylic acid, a derivative which has a much longer half-life than salicylic acid in man, on free fatty acid mobilisation and plasma cholesterol in the rat, rabbit, baboon and man. 3-Methyl salicylic acid decreased plasma free fatty acids in rats exposed to conditions of increased mobilisation, such as fasting, cold, and treatment with noradrenaline and ACTH. Evidence was obtained that a dose equivalent to salicylic acid given shortly before test was more effective. As for salicylate, 3-methyl salicylate decreased the in vitro production of FFA and glycerol liberated in vitro by the incubated rat epididymal fat pad. Administration of 3-methyl salicylic acid (100 mg/kg, body weight) reduced plasma cholesterol from 7 to 45% in baboons given an atherogenic, cholesterol-containing diet for one month. In acute experiments, the drug caused a marked choleresis in which the volume and excretion of bile acids but not cholesterol was increased. In the rabbit, the drug (100 mg/kg) caused a decrease in fasting FFA for up to four hours, followed by a large elevation. Inclusion of the drug in the diet of animals given a semi-synthetic diet of low cholesterol content did not reduce hypercholesterolaemia or the extent and severity of atherosclerotic lesions in the aorta. Administration of 0.9 g orally to fasting patients caused a 50% reduction in elevated plasma FFA after four hours and even after twelve hours the values were still subnormal. A double-blind control trial of nine hypercholesterolaemic and eight normal patients was conducted over twelve to eighteen months. Subjects in the hypercholesterolaemic group on chronic dosage (0.9–1.8 g per day) showed a fall of 25% in the mean plasma cholesterol, but there was no change in normal patients. Side effects, the chief of which were drowsiness and vomiting precluded the use of 3-methyl salicylate as a therapeutic agent in man.