Chronic toxicity and carcinogenicity studies with the beta-adrenoceptor antagonist levobunolol.
The chronic toxicity and carcinogenicity of levobunolol, a nonselective beta-adrenoceptor antagonist, was evaluated in Swiss mice and Wistar rats. The drug was administered in the diet to mice at 0, 12, 50, and 200 mg/kg/day for 80 weeks and to rats at 0, 0.5, 2, 5, 30, and 180 mg/kg/day for 2 years. In mice, uterine leiomyomas were present in 4 of 50 females at 200 mg/kg but not in any other group. The incidences of other tumor types, as well as pathologic findings, were comparable among groups. In rats, significant body weight gain suppression occurred at 5, 30, and 180 mg/kg. Brown discoloration of perianal fur and steel-gray discoloration of hairless skin were evident in high-dose rats. A generalized steel-gray discoloration of internal organs and tissues occurred in the 30 and 180 mg/kg groups. No other differences between treated and control groups were evident. The clinical relevance of the increased incidence of uterine leiomyoma in mice is questionable because it occurred only in one species at more than 200 times the projected therapeutic dose.
Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105-2430.
C E
CE
Rothwell
E J
EJ
McGuire
R A
RA
Martin
F A
FA
De la Iglesia
D000319:Adrenergic beta-Antagonists / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D005260:Female; D007889:Leiomyoma / Q000139:chemically induced / Q000473:pathology; D002040:Levobunolol / Q000633:toxicity*; D051379:Mice; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains; D014594:Uterine Neoplasms / Q000139:chemically induced / Q000473:pathology
D000319:Adrenergic beta-Antagonists; D002273:Carcinogens; D002040:Levobunolol