Toxicity and Fate of the Lethal Effect of Theophyllinated Scillaridin ∗ in the Cat

Abstract

Riseman and London 1 have recently described some of the properties of a substance which is obtained by condensing a disodium salt of a mixture of genins isolated from Squills (presumably scillaridin A and B) with 2 molecules of theophylline. They demonstrated by electrocardiographic studies that the substance so obtained differs in its action from either a mechanical mixture of theophylline with the genins, or from the original glycosides, thus giving physiological confirmation for a discrete compound. Since this appears to be the first report of an attempt to modify the action of a cardiac glycoside by chemical combination with a xanthine derivative, it seemed to be of considerable interest to determine the toxicity of the substance and the fate of the lethal effect of sublethal doses in the cat. The ratio of genins present in the compound has not been determined, but the empirical formula may be approximated as C₂₄H₂₈O₃ (C₇H₇O₂N₄)₂ 2H₂O. It should be pointed out however, that by the method of preparation used, structural rearrangement of the genin may well have taken place. The influence of structure on physiological action is discussed further by Lendle. 2

The preparation was assayed by the original Hatcher and Brody procedure using a 1:714 solution in normal saline and a rate of infusion such that the animals died within 30 to 90 minutes. The geometric mean lethal dose on the basis of 10 cats was found to be 21.4 mg per kg (or 28.2 micromoles per kg) and the standard deviation was 4.2. By comparison, the lethal doses 3 of Scillaridin A and of Scillarin A are respectively 0.150 and 1.72 mg per kg (0.217 and 4.73 micromoles per kg).