A characterization of the acute cardiopulmonary toxicity of fenfluramine in the rat

Abstract

Fenfluramine (FN) is a potent serotonin-releasing drug used primarily as an anorectic agent. The symptomatology of its acute lethality has been well documented in animal models such as the rat. A very prominent feature of this lethality profile is hypoxia, as demonstrated by the onset of severe cyanosis just prior to death. It is not clear in the literature whether this hypoxia is the result of a direct pulmonary effect or is secondary to cardiac injury. To further characterize this aspect of FN's toxicity, respiratory and electrocardiographic measurements were taken in anaesthetized rats subjected to high doses of FN (129.6 mg/kg, i.p.). Death occurred in these animals within 15 min of drug administration, apparently as the result of abrupt respiratory cessation, followed by cardiac ischaemia. No significant gross or histopathological lesions were evident in these animals. In other trials, prior treatment with diethylcarbamazine (DEC) was found to potentiate the lethality of FN, while cyproheptadine (CHP) pretreatment attenuated FN's toxic effects. Necropsies, conducted 24 h after FN administration, revealed widespread alveolar and pulmonary interstitial haemorrhage in the CHP-pretreated animals. The data suggest that high doses of FN directly result in pulmonary hypertension, which secondarily induces ischaemic cardiac injury.