Bilasy Shymaa E, Essawy Soha S, Mandour Mohamed F, Ali Eman A I, Zaitone Sawsan A
Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
Department of Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
Pharmacol Rep. 2015 Feb;67(1):102-14. doi: 10.1016/j.pharep.2014.08.009. Epub 2014 Aug 23.
Safety of the combination of leflunomide and methotrexate was examined in several studies with inconclusive results. The present study was designed to compare the efficacy and safety of the combination of leflunomide and methotrexate in adjuvant-induced arthritis (AIA) in rats focusing on immunosuppressive and hepatotoxic effects.
Eighty four rats were divided into seven groups. Group 1: Sham control, group 2: the vehicle control, group 3: methotrexate group, group 4-5: leflunomide (5 and 10mg/kg/day) groups, group 6-7: combination 1 and 2 [methotrexate+leflunomide (5 and 10mg/kg/day)] groups, respectively.
The current results indicated that combination therapies improved the ankle circumference and clinical scores compared to monotherapies; histopathological examination confirmed these findings. The myelosuppressive effect of leflunomide (10mg/kg/day) was comparable to that produced by methotrexate as indicated by the complete blood count and bone marrow cellularity; however their combination resulted in greater toxicity. Furthermore, methotrexate greatly affected the splenic histopathology compared to leflunomide and the combination therapy produced a greater effect compared to leflunomide not methotrexate. Differently, assessment of the hepatotoxic potential of the two drugs highlighted that leflunomide induced a dose-dependent increase in the fibrosis score which was higher in their magnitude than that induced by methotrexate. Leflunomide (10mg/kg/day) and combination 2 groups showed the greatest degree of liver fibrosis.
In rats with AIA, current drug combinations provided higher therapeutic benefit compared to monotherapies, however, greater toxicities were observed. Therefore, continuous monitoring of hematologic parameters and liver function will be recommended in clinical settings.
在多项研究中对来氟米特与甲氨蝶呤联合用药的安全性进行了检验，但结果尚无定论。本研究旨在比较来氟米特与甲氨蝶呤联合用药对佐剂诱导性关节炎（AIA）大鼠的疗效和安全性，重点关注免疫抑制和肝毒性作用。
84只大鼠分为7组。第1组：假手术对照组，第2组：赋形剂对照组，第3组：甲氨蝶呤组，第4 - 5组：来氟米特（5和10mg/kg/天）组，第6 - 7组：联合用药1组和2组[甲氨蝶呤 + 来氟米特（5和10mg/kg/天）]。
当前结果表明，与单一疗法相比，联合疗法改善了踝关节周长和临床评分；组织病理学检查证实了这些发现。全血细胞计数和骨髓细胞计数表明，来氟米特（10mg/kg/天）的骨髓抑制作用与甲氨蝶呤相当；然而，它们联合使用会产生更大的毒性。此外，与来氟米特相比，甲氨蝶呤对脾脏组织病理学影响更大，联合疗法与来氟米特相比产生更大影响，而非与甲氨蝶呤相比。不同的是，对两种药物肝毒性潜力的评估突出显示，来氟米特诱导纤维化评分呈剂量依赖性增加，其幅度高于甲氨蝶呤诱导的增加幅度。来氟米特（10mg/kg/天）组和联合用药2组显示出最大程度的肝纤维化。
在患有AIA的大鼠中，与单一疗法相比，当前的药物联合疗法提供了更高的治疗益处，然而，观察到了更大的毒性。因此，建议在临床环境中持续监测血液学参数和肝功能。
