Polyphloretin phosphate (PPP) antagonists of prostaglandin action also inhibit prostaglandin biosynthesis in-vitro.

Several polyphloretin phosphate (PPP) fractions (low mol. wt LC1259; high mol. wt LC1261; crude mixture, LC101) were confirmed in their established property as antagonists of the pharmacological actions of prostaglandins in a preparation of guinea-pig isolated ileum stimulated by prostaglandin (PG)E2. Further samples of the same material were then compared in-vitro with indomethacin in their ability to inhibit prostaglandin biosynthesis from arachidonic acid by a microsomal enzyme preparation. All three PPP fractions potently inhibited prostaglandin generation, with the rank order of potency LC1259 = LC101 = indomethacin greater than LC1261. The oral LD50 in mice was 25 mg kg-1 for indomethacin and greater than 1 g kg-1 for LC101. PPP fractions (especially LC101) may therefore have therapeutic potential as anti-inflammatory agents.

Anti-hypertriglyceridaemic activity of some phenylethylamine anorectic compounds.

In rats allowed access to food, and in food-deprived rats, fenfluramine (20 and 100 mg kg-1) and amphetamine (10 and 20 mg kg-1) provoked a hypotriglyceridaemic effect. No changes in plasma cholesterol concentration were observed. The time course of the absorption of a lipid load differed according to the nutritional status of the animals; being bellshaped under fed, and curvilinear under fasted, conditions. However, absorption under both nutritional conditions was inhibited by amphetmine and fenfluramine. When rats which had received the test compounds were administered glycerol trioleate containing a tracer dose of glycerol [1-14C]-trioleate or [2-3H]-glycerol trioleate, there was an inhibition in the increase of plasma radioactivity only in the case when the fatty acid contained the radioactive label. The net effect of lipid absorption was a transfer of dietary lipid from the gut to adipose tissue stores. There was never more than 5 per cent of the administered load in the liver. These observations indicate that amphetamine and fenfluramine may have acute effects in reducing circulating triglycerides, separate from the effects on lipid absorption from the gut. In this latter, the palmitoyl-CoA monooleinacyltransferase enzyme probalby plays a key role and appears a major target of the overall anti-obesity of fenfluramine.

Permissive effects on adipose tissue lipolysis of a plasmatic factor which inhibits prostaglandin biosynthesis.

Plasma obtained from fasted rats provoked a dose-dependent stimulation of fat cell glycerol release and was able to inhibit also generation of prostaglandins E2 and F2 alpha from arachidonate, in vitro, over a very similar range of doses. It is proposed, therefore, that a plasmatic fat-mobilizing factor may act as an endogenous inhibitor of adipose tissue prostaglandin biosynthesis, mediating in the acute (long-term not precluded) regulation of adipose tissue lipolysis. The proposed mechanism of permissive effects of the plasmatic factor in reducing the effects of endogenously-generated inhibitory prostaglandins may be implicated in the development of obesity by reduced availability of the factor and thus reduced ability to utilize fat stores.