Cardiotoxicity of Ma Huang/caffeine or ephedrine/caffeine in a rodent model system.

Ma Huang (equivalent to 0, 12.5, 25, or 50 mg/kg ephedrine) or ephedrine (0, 6.25, 12.5, 25 mg/kg) were administered as one bolus oral dose to male F344 rats with and without caffeine. The herbal medicine Ma Huang (ephedra) in combination with caffeine caused rapid clinical signs of toxicity including salivation, hyperactivity, ataxia, and eventually lethargy, and failure to respond to stimuli. When this syndrome of clinical signs emerged, animals were moribund sacrificed, and a histological analysis for heart lesions performed. Cardiotoxicity included hemorrhage, necrosis, and degeneration in the ventricles or interventricular septum within 2-4 hours after treatment with Ma Huang (ephedra)/caffeine or ephedrine (the principal active component in Ma Huang)/caffeine. There was a steep dose response curve for cardiotoxicity with minimal toxicity seen at levels of Ma Huang (equivalent to 12.5 mg/kg ephedrine) with caffeine. However, cardiotoxic lesions occurred in 28% of animals with Ma Huang dosages equivalent to 25 mg/kg ephedrine with 15 or 30 mg/kg caffeine, and in 90% of animals at Ma Huang exposures equivalent to 50 mg/kg ephedrine with 15 or 30 mg/kg caffeine. Cardiotoxic lesions occurred in 47% of animals in the 25 mg/kg ephedrine groups with caffeine at 7.25, 15, or 30 mg/kg. There was no statistical difference in the occurrence of cardiotoxic lesions when 15 or 30 mg/kg caffeine was combined with Ma Huang equivalent to 25 or 50 mg/kg ephedrine; likewise there was no statistical difference in the occurrence of cardiotoxic lesions when 7.25, 15, or 30 mg/kg caffeine was combined with 25 mg/kg ephedrine. These results show that the cardiotoxic effects of the herbal medicine, Ma Huang, are similar to that of ephedrine, the principal active ingredient in the herbal medicine. The combination of Ma Huang or ephedrine with caffeine enhanced the cardiotoxicity over that with the herbal medicine or the active ingredient alone.

Toxicity of p-chloroaniline in rats and mice.

p-Chloroaniline (PCA) was administered as PCA hydrochloride in water by gavage to groups of ten Fischer 344 rats and ten B6C3F1 mice of each sex for 13 wk. The doses, calculated as PCA rather than the hydrochloride salt, were 0, 5, 10, 20, 40 or 80 mg PCA/kg body weight/day for rats and 0, 7.5, 15, 30, 60 or 120 mg/kg body weight/day for mice. The vehicle controls were given deionized water by gavage. All male rats survived to the end of the studies. One of the ten female rats that received 80 mg PCA/kg died from unknown causes. The final body weights of rats that received 80 mg/kg were 16% lower than those of vehicle controls in the case of males and 4% lower in females. In mice, there was no mortality related to PCA administration. The final body weights of treated mice were similar to those of vehicle controls. In both rats and mice, no treatment-related effects on organ weights were observed at autopsy, except for a dose-related increase in spleen weight. The proportion of haemoglobin in the form of methaemoglobin was increased in dosed groups in both species and resulted in a secondary anaemia, the severity of which was dose related. Compound-related lesions observed histologically in rats and mice, included pigmentation (haemosiderin) in the kidney, spleen and liver and increased haematopoiesis in the liver and spleen and in the bone marrow (in rats but not mice), reflecting the response to the haemolytic anaemia and methaemoglobinaemia induced by PCA. It is concluded that the haematopoietic system is a target of PCA toxicity.