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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.

Oral administration of 3-methyl salicylic acid (3MS) to diabetic and non-diabetic patients in modest doses (0.9–1.8 g/day) over several months produced a significant increase in plasma insulin levels, one hour after a glucose load. In 2 diabetic subjects, acute doses had a similar effect. — Improvement in glucose tolerance after chronic administration of 3 MS to diabetic patients was inconsistent, and could not be conclusively related to the action of the drug. Although acute doses of 3 MS caused a fall in plasma FFA after 3–6h, chronic treatment gave no predictable change in fasting plasma FFA levels. — Because of side effects, 3 MS was not considered suitable for introduction as a therapeutic agent. The results, however, are of academic interest since it is the first demonstration of increased plasma insulin after an oral salicylate.

Summary Ethionine inhibits protein synthesis in the intestinal mucosa of female rats and interferes with the intestinal transport of triglycerides containing long-chain fatty acids presumably by reducing chylomicron formation. The absorption of triglycerides containing medium-chain fatty acids is unaffected. In contrast to its effects on the liver, ethionine does not lead to decreases in intestinal ATP levels and administration of ATP to the animals does not protect against the inhibitory effects of ethionine. The intestinal activity of methionine-activating enzyme is about one-sixth that of liver. This may account for the failure of ethionine to reduce intestinal ATP concentrations since with low activating enzyme levels in the intestine relatively little adenine would be trapped in the form of S -adenosythionine. It is suggested that the inhibitory effect of ethionine on intestinal protein synthesis must involve a mechanism unrelated to reductions in cellular ATP levels.

IT has recently been shown that the fatty liver produced in rats by ethionine administration is associated with a decrease in hepatic adenosine triphosphate (ATP) levels and that injections of ATP are able to prevent both the fatty liver and the drop in ATP1,2. We have observed that a variety of agents which produce a fatty liver lead to decreased ATP concentrations in the liver and that the protective effects of ATP administration are not limited to ethionine toxicity.

Administration of large doses of adenosine triphosphate (ATP) can protect rats against the fatly liver produced by ethionine1,2,3 carbon tetrachloride3 (CCl4), azaserine3, ethanol4 and puromycin5. In considering the possible mechanisms involved in this protection, Hyams et al 3. suggested that suppression of free fatty acid (FFA) mobilisation was a major factor, but the possibility that hypothermia played a part, at least in the case of CCl4 toxicity, could not be excluded.

The use of anion exchange resins for the treatment of type II hyperlipoproteinemia is now well established, and one such resin, cholestyramine, has received considerable attention (1, 2). This class of drug acts by preferentially binding bile acids in the intestine and facilitating their increased excretion. Since cholesterol is the precursor of bile acids in the liver, total body cholesterol decreases and there is a subsequent fall in plasma cholesterol. Cholestyramine is found to be only moderately effective because the liver compensates by synthesizing more cholesterol from acetate (3). Also, the proportion of bile acids sequestered in the intestine is small (about 5–10%) compared with the total available (4). For these reasons, effective treatment is obtained with only large doses (12–35 g/day) of the resin. In type II hypercholesterolemic patients even 32 g/day gives a mean decrease of only 22% (5).

A comparison was made of the effect of DEAE (diethylaminoethyl) Sephadex (an anion exchange resin) and cholestyramine (Questran) with and without the addition of clofibrate in normal and hypercholesterolaemic patients. DEAE Sephadex (12-15 g/day) alone appeared to be as effective as cholestyramine in lowering the plasma cholesterol by 12-15%. Clofibrate acted synergistically with DEAE Sephadex and increased the activity of the latter by over twofold. This combination proved superior to that of clofibrate and cholestyramine and has the greatest potential use in the treatment of type II pattern hyperlipoproteinaemia.