Rothwell C E, McGuire E J, Martin R A, De la Iglesia F A
Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105-2430.
Fundam Appl Toxicol. 1992 Apr;18(3):353-9. doi: 10.1016/0272-0590(92)90133-3.
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.
对非选择性β-肾上腺素能受体拮抗剂左布诺洛尔的慢性毒性和致癌性在瑞士小鼠和Wistar大鼠中进行了评估。该药物以饮食方式给予小鼠，剂量分别为0、12、50和200毫克/千克/天，持续80周；给予大鼠的剂量分别为0、0.5、2、5、30和180毫克/千克/天，持续2年。在小鼠中，200毫克/千克剂量组的50只雌性中有4只出现子宫平滑肌瘤，而其他组未出现。其他肿瘤类型的发生率以及病理结果在各组之间具有可比性。在大鼠中，5、30和180毫克/千克剂量组出现明显的体重增加抑制。高剂量大鼠出现肛周毛发棕色变色和无毛皮肤钢灰色变色。30和180毫克/千克剂量组的内脏器官和组织出现全身性钢灰色变色。治疗组和对照组之间没有其他明显差异。小鼠子宫平滑肌瘤发生率增加的临床相关性值得怀疑，因为它仅在一个物种中出现，且剂量超过预计治疗剂量的200倍以上。
