Laboratory of Inflammation, Department of Pharmacy and Pharmacology, University of Maringá, 87.020.900 Maringá, Paraná, Brazil.
Fundam Clin Pharmacol. 2012 Dec;26(6):722-34. doi: 10.1111/j.1472-8206.2011.00976.x. Epub 2011 Jul 31.
In this study, simvastatin, atorvastatin, ezetimibe, and ezetimibe + simvastatin combination were administered to arthritic rats, first to determine their effects on the inflammatory response, employing a low-dose adjuvant-induced arthritis model in rats. Arthritis was induced by the subcutaneous injection of a suspension of Mycobacterium tuberculosis (100 μg) in mineral oil [complete Freund's adjuvant used (CFA)] into the plantar surface of the hind paws. Simvastatin(40 mg/kg), atorvastatin(10 mg/kg), ezetimibe(10 mg/kg), ezetimibe(10 mg/kg) + simvastatin(20 mg/kg or 40 mg/kg) were given intragastrically and the treatment began on the day of CFA injection and continued daily up to the 28th day after arthritis induction. The ezetimibe + simvastatin combination was more effective in reducing the inflammatory response in arthritic rats than in atorvastatin, simvastatin, or ezetimibe monotherapy. The observed effect seems to be cholesterol-independent as there were no changes in plasma cholesterol levels. In spite of the benefits on joint lesions, treatment with ezetimibe + simvastatin combination caused a marked increment in liver, kidneys, spleen size, and plasma transaminases activities. Therefore, animals treated with the ezetimibe(10 mg/kg) + simvastatin(40 mg/kg) combination were also submitted to liver perfusion experiments. In this regard, ezetimibe + simvastatin did not improve the liver metabolic alterations seen in control arthritic rats, on the contrary, a worsening was observed in liver production of glucose from alanine, as well as in oxygen uptake. All of these metabolic changes appear to be induced by treatment with ezetimibe + simvastatin combination, as the same metabolic effects were observed in normal and treated arthritic animals.
在这项研究中，给关节炎大鼠分别给予辛伐他汀、阿托伐他汀、依折麦布和依折麦布+辛伐他汀联合治疗，首先在大鼠低剂量佐剂诱导关节炎模型中确定它们对炎症反应的影响。关节炎通过向跖足底皮下注射结核分枝杆菌（100μg）悬浮液（矿物油[完全弗氏佐剂]）来诱导。辛伐他汀（40mg/kg）、阿托伐他汀（10mg/kg）、依折麦布（10mg/kg）、依折麦布（10mg/kg）+辛伐他汀（20mg/kg 或 40mg/kg）灌胃给药，治疗于 CFA 注射当天开始，持续至关节炎诱导后第 28 天。与阿托伐他汀、辛伐他汀或依折麦布单药治疗相比，依折麦布+辛伐他汀联合治疗更能有效减轻关节炎大鼠的炎症反应。观察到的效果似乎与胆固醇无关，因为血浆胆固醇水平没有变化。尽管对关节病变有好处，但依折麦布+辛伐他汀联合治疗导致肝脏、肾脏、脾脏大小和血浆转氨酶活性显著增加。因此，用依折麦布+辛伐他汀（10mg/kg）联合治疗的动物还进行了肝脏灌注实验。在这方面，依折麦布+辛伐他汀并没有改善对照关节炎大鼠肝脏代谢改变，相反，观察到从丙氨酸产生葡萄糖以及耗氧量的肝脏代谢恶化。所有这些代谢变化似乎都是由依折麦布+辛伐他汀联合治疗引起的，因为在正常和治疗性关节炎动物中观察到了相同的代谢效应。
