Chronic Toxicity and Carcinogenicity Studies with the {beta}-Adrenoceptor Antagonist Levobunolol

The chronic toxicity and carcinogenicity of levobunolol, a nonselectiveß-adrenoceptor antagonist, was evaluated in Swissmice and Wistar rats. The drug was administered in the dietto mice at 0, 12, 50, and 200 mg/kg/day for 80 weeks and torats at 0, 0.5, 2, 5, 30, and 180 mg/kg/day for 2 years. Inmice, uterine leiomyomas were present in 4 of 50 females at200 mg/kg but not in any other group. The incidences of othertumor types, as well as pathologic findings, were comparableamong groups. In rats, significant body weight gain suppressionoccurred at 5, 30, and 180 mg/kg. Brown discoloration of perianalfur and steel-gray discoloration of hairless skin were evidentin high-dose rats. A generalized steel-gray discoloration ofinternal organs and tissues occurred in the 30 and 180 mg/kggroups. No other differences between treated and control groupswere evident. The clinical relevance of the increased incidenceof uterine leiomyoma in mice is questionable because it occurredonly in one species at more than 200 times the projected therapeuticdose.