Myocardial necrosis related to hydrochlorothiazide-induced hypokalemia in cynomolgus monkeys

摘要

Myocardial necrosis is a serious adverse effect that results from the administration of some medications; therefore, when it is observed during preclinical studies it becomes a major drug development concern. Although data from preclinical monkey studies are generally extrapolated to predict effects in humans, few reports have described any mechanism that might explain the occurrence of myocardial necrosis. For this reason, we examined the association between hypokalemia and myocardial necrosis in monkeys. Four female cynomolgus monkeys (Macaca fascicularis) were treated with 50 mg/kg/day hydrochlorothiazide (a thiazide diuretic used for antihypertensive therapy) for 1 or 2 weeks. Clinical, hematological, plasma biochemical, and pathological examinations were conducted. Two animals were kept in a hypokalemic state from day 3 of dosing on, and their mean plasma potassium levels were 2.52 +- 0.24 and 2.60 +- 0.24 mmol/l. These animals were necropsied after 1 week of dosing due to an aggravated general condition. A flattened T-wave was noted during electrocardiography. A transient increase in plasma cardiac-specific troponin-I and multifocal myocardial necrosis also occurred. The rest of the animals were occasionally hypokalemic, with mean plasma potassium levels of 3.13 +- 0.31 or 2.96 +- 0.30 mmol/1. These animals were necropsied after 2 weeks of dosing. One animal showed evidence of focal myocardial necrosis and a transient increase in plasma cardiac-specific troponin-L These data suggest that the severe hypokalemia induced by hydrochlorothiazide is likely to be associated with myocardial necrosis in monkeys.