Pharmacological studies of lumisantonin derivatives, with special reference to anti-inflammatory effect and to histamine-release inhibitory action

A number of derivatives and related compounds of lumisantonin were submitted to evaluatien for the action of histamine-release inhibition and antiinflammatory effect, as they structurally resemble guaiazulene in which these actions had been proved. Nineteen compounds of these suppressed 50 per cent or more of the increase in urinary excretion of histamine due to ovomucoid injection. Five of them markedly inhibited all the edemas in the rat hind paws induced by local inoculation of dextran, hyaluronidase, histamine, and 5-hydroxytryptamine. Among these compounds, #32(methyl pyrophotosantoninate) showed a superior effect of inhibition than guaiazulene on all of these edemas, although the effects of two drugs were comparable in the case of oral administration. The members showing the edema inhibition likewise evidently protected passive cutaneous anaphylaxis in guinea pigs by the intraperitoneal administration; the effect of #32 was more marked than guaiazulene. This effect could be observed when applied to the skin with an ointment containing the compouhd in a concentration of more than 0.03 per cent 24 hours before. In vitro histamine releases from the minced lung tissue of sensitized guinea pig elicited by antigen and sinomenine were both inhibited by these compounds. These findings indicate that the main sites of the histamine-release inhibition and of the anti-inflammatory effect of these compounds are in the local tissue. Compound #32 failed to show any analgesic effect in mice, but possessed a considerable antipyretic action in rats. Some of the compounds in the tests depressed guinea-pig ileal strip while guaiazulene increased peristalsis, but any of these actions was not recognized with #32 even in a high concentration. Most of the members effective in inhibiting edemas as well as histamine release proved to be less toxic than guaiazulene. #32 was well tolerated in the doses of 6g/kg orally and of 4g/kg intraperitoneally by mice. The growth curves for three weeks of rats practically did not deviate from that of the controls by daily administration of 1g/kg of #32 by stomach tube and there were no gross and microscopical abnormalities in the main organs and blood.