Department of Pharmacology, Therapeutics and Toxicology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria.
Department of Pharmacology, Faculty of Pharmaceutical Sciences, University of Jos, Jos, Nigeria.
Pharmacol Res Perspect. 2018 Feb;6(1). doi: 10.1002/prp2.381.
This study investigated the protective effects of carvedilol alone and coadministered with prednisolone and diltiazem on doxorubicin (DOX) and 5-fluorouracil (5-FU)-induced toxicity. Each of 2 pools of 70 female rats were randomly allotted into 10 groups of 7 animals each and treated as follows: Group 1: normal saline (10 mL/kg); Group 2: normal saline and DOX (40 mg/kg)/5-FU (20 mg/kg) alone; Group 3: gallic acid (200 mg/kg) and DOX/5-FU; Group 4: carvedilol (0.075 mg/kg) and DOX/5-FU; Group 5: carvedilol (0.15 mg/kg) and DOX/5-FU; Group 6: carvedilol (0.30 mg/kg) and DOX/5-FU; Group 7: diltiazem (3.43 mg/kg) and DOX/5-FU; Group 8: diltiazem (3.43 mg/kg), carvedilol (0.15 mg/kg), and DOX/5-FU; Group 9: prednisolone (0.57 mg/kg) and DOX/5-FU; and Group 10: prednisolone (0.57 mg/kg), carvedilol (0.15 mg/kg), and DOX/5-FU. Treatments were done p.o. for 16/14 days for the DOX/5-FU models. DOX/5-FU was administered i.p. to the rats in Groups 2-10 on day 14/10-14. On day 17/15 (DOX/5-FU), blood samples were collected, and liver and kidneys of rats were harvested for antioxidant and histopathological assessments. Carvedilol alone and coadministered with prednisolone significantly (P < .05) decreased alanine aminotransferase level compared with administration of DOX alone. Carvedilol alone and coadministered with diltiazem significantly (P < .05) decreased creatinine level compared with administration of DOX/5-FU alone. Carvedilol alone and coadministered with diltiazem and prednisolone significantly (P < .05) increased the level of hepatic superoxide dismutase and catalase, and decreased malondialdehyde compared with DOX administration alone. Histopathological observations correlated with results of biochemical and antioxidant analyses. Carvedilol administered alone and coadministered with diltiazem and prednisolone reduced the effect of DOX/5-FU-induced hepatic and renal toxicities due to enhanced in vivo antioxidant activity. The protective effect was more prominent in the doxorubicin model compared with the 5-fluorouracil test. Coadministration of carvedilol with either diltiazem or prednisolone did not show better protection relative to carvedilol alone.
本研究旨在探讨卡维地洛单独使用以及与泼尼松龙和地尔硫卓联合使用对多柔比星（DOX）和 5-氟尿嘧啶（5-FU）诱导的毒性的保护作用。将两池 70 只雌性大鼠随机分为 10 组，每组 7 只，分别进行如下处理：第 1 组：生理盐水（10 mL/kg）；第 2 组：生理盐水和 DOX（40 mg/kg）/5-FU（20 mg/kg）单独给药；第 3 组：没食子酸（200 mg/kg）和 DOX/5-FU；第 4 组：卡维地洛（0.075 mg/kg）和 DOX/5-FU；第 5 组：卡维地洛（0.15 mg/kg）和 DOX/5-FU；第 6 组：卡维地洛（0.30 mg/kg）和 DOX/5-FU；第 7 组：地尔硫卓（3.43 mg/kg）和 DOX/5-FU；第 8 组：地尔硫卓（3.43 mg/kg）、卡维地洛（0.15 mg/kg）和 DOX/5-FU；第 9 组：泼尼松龙（0.57 mg/kg）和 DOX/5-FU；第 10 组：泼尼松龙（0.57 mg/kg）、卡维地洛（0.15 mg/kg）和 DOX/5-FU。DOX/5-FU 模型的治疗通过口服给药进行 16/14 天。第 14 天/第 10 天，第 2-10 组大鼠腹腔内注射 DOX/5-FU。第 17 天/第 15 天（DOX/5-FU），采集血样，并采集大鼠的肝和肾进行抗氧化和组织病理学评估。与单独给予 DOX 相比，卡维地洛单独给药和与泼尼松龙联合给药显著（P <.05）降低了丙氨酸氨基转移酶水平。与单独给予 DOX/5-FU 相比，卡维地洛单独给药和与地尔硫卓联合给药显著（P <.05）降低了肌酐水平。与单独给予 DOX 相比，卡维地洛单独给药和与地尔硫卓和泼尼松龙联合给药显著（P <.05）增加了肝超氧化物歧化酶和过氧化氢酶的水平，并降低了丙二醛水平。组织病理学观察与生化和抗氧化分析结果一致。卡维地洛单独给药和与地尔硫卓和泼尼松龙联合给药通过增强体内抗氧化活性，减轻了 DOX/5-FU 诱导的肝和肾毒性的作用。与 5-FU 试验相比，卡维地洛单独给药和与地尔硫卓或泼尼松龙联合给药对 DOX 模型的保护作用更为显著。与卡维地洛单独给药相比，卡维地洛与地尔硫卓或泼尼松龙联合给药并未显示出更好的保护作用。
