Preclinical safety evaluation of the nadolol/bendroflumethiazide combination in mice, rats, and dogs.
Nadolol, a beta-adrenergic antagonist, and bendroflumethiazide, a thiazide diuretic, were administered orally alone and in combination to animals in acute and 6-month toxicity studies and in a rat teratology study. The two drugs in combination showed no evidence of potentiation of acute toxicity in mice. Nadolol and/or bendroflumethiazide were administered orally to rats at daily doses of 1000 or 160 mg/kg of nadolol and 125 or 20 mg/kg of bendroflumethiazide and to dogs at daily doses of 160 or 40 mg/kg of nadolol and 20 or 5 mg/kg of bendroflumethiazide for 6 months. The two drugs, alone and in combination, caused only minor changes in clinical-laboratory tests and no major gross or histopathologic changes. Many of the changes noted were expected pharmacologic effects of the individual agents. The drugs, alone or in combination, produced no evidence of embryotoxicity, fetotoxicity, or teratogenicity in rats. The results of these studies indicate that nadolol and bendroflumethiazide have a low order of toxicity individually, and when given in combination show no additional or potentiated toxicity.