Preclinical toxicologic evaluation of nadolol, a new β-adrenergic antagonist☆

Abstract Nadolol, 2,3- cis -5-[3-[)1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,2,3,4-tetrahydro-2,3-naphthalenediol, is a potent new β-adrenergic blocking agent that has undergone extensive safety evaluation in animals. In 1-month parenteral studies, no signs of toxicity were observed in rats given as much as 25 mg of nadolol/kg daily ip or in dogs given 12.5 mg/kg daily iv. Nadolol did not produce signs of toxicity in monkeys given daily oral doses of up to 250 mg/kg for 3 months. Mice and rats given daily doses of 500 and 1000 mg/kg, respectively, in the diet in 2-year studies showed no evidence of toxicity or carcinogenicity. In a 1-year oral study in dogs, nadolol was administered at daily doses of 24, 60, and 150 mg/kg. The only significant effect observed was a slight, dose-related decrease in tolerance to an intravenous glucose load. Nadolol produced no significant changes in a fertility and reproductive study in rats and in teratologic studies in rats and hamsters at daily doses of up to 300 mg/kg. In rabbits, nadolol was embryotoxic and fetotoxic at 100 and 300 mg/kg, but not at 50 mg/kg. No significant effects were noted in an oral perinatal and postnatal study in rats with doses of up to 1800 mg/kg. There were no indications of teratogenicity resulting from the administration of nadolol to any of the species studied. The results of these studies indicate that nadolol has a low order of toxicity and lacks teratogenic and carcinogenic potential in the species studied.