The acute and subchronic toxicity of BRB-I-28, a novel class Ib antiarrhythmic agent, in CD-1 mice

The acute and subchronic toxic effects of BRB-I-28 (7-benzyl-3-thia-7-azabi cyclo[3.3.1]nonane HCl), a novel class Ib antiarrhythmic agent, were invest igated in male and female mice. The estimated oral LD50 for BRB-I-28 was 12 8 mg/kg (male mice) and 131 mg/kg (female mice). In subchronic oral studies , four groups of mice (15/sex/group/dose) were fed daily with diets contain ing BRB-I-28 for 90 consecutive days. The equivalent daily doses mere appro ximately 0, 16, 32, 76 (male) and 0, 18, 37, 89 mg/kg (female). All mice su rvived. Food consumption per day was decreased, but mater consumption per d ay was increased (in a non-dose-dependent manner). However, both mean body weight and mean body weight gain were not significantly changed as sere tru e for hematological and clinical chemistry profiles, except for serum Na+ c oncentration (male) and serum KC concentration in male and female mice (hig h dose levels). Hepatocellular necrosis occurred in male and female mice (i n a dose-dependent fashion). Renal cortical vacuoles and myocardial necrosi s with low numbers of lymphocytic infiltrations were present in female mice (middle and high doses). Lesions in the liver, kidney and heart mere mild with (very small) changes in serum biochemical values. These data suggest t hat BRB-I-28 has limited toxic potential, and coupled with low proarrhythmi c and other desirable cardiovascular effects, makes BRB-I-28 worthy of furt her development. (C) 2000 Elsevier Science Ltd. All rights reserved.