Protective effects of leflunomide on renal lesions in a rat model if diabetic nephropathy

Diabetic nephropathy is one of the most common chronic complications of diabetes with poor efficacy of clinical treatment. This study investigated the protective effects of leflunomide, a new immunosuppressant, on tubulointerstitial lesions in a rat model of diabetic nephropathy. Diabetes was induced with streptozotocin (STZ, 50?mg/kg) by intraperitoneal injection in male Wistar rats. Two weeks after STZ injection, diabetic rats were treated daily for 8 weeks with low (5?mg/kg) and high dose (10?mg/kg) of leflunomide, and benazepril hydrochloride (4?mg/kg) as a positive control. In diabetic rats, the 24-h urine volume, urine protein and microalbumin, blood creatinine and urea nitrogen significantly increased, which were attenuated by leflunomide treatment in a dose-dependent manner (all p?leflunomide treatment. Immunohistochemistry study and real-time polymerase chain reaction results demonstrated that osteopontin (OPN), transforming growth factor beta 1 (TGF-β1), α-smooth muscle actin and CD68 expression in the renal tubulointerstitial region were significantly increased in the diabetic rats, while these increases were inhibited by leflunomide treatment. These findings suggest that leflunomide protects the kidney injury of diabetic rats might through its inhibition of OPN/TGF-β1 mediated extracellular matrix deposition and tubulointerstitial fibrosis, as well as its inhibition on tubular epithelial-myofibroblast transdifferentiation.     

Proposals for leflunomide use to avoid lung injury in patients with rheumatoid arthritis

Abstract

Among the 5,043 consecutive patients registered in the postmarketing surveillance for leflunomide, 61 were reported to have lung injury and 24 died from it. The adjusted multivariate logistic regression analysis of the risk factors showed that preexisting interstitial lung disease posed the greatest risk, as well as loading dose, smoking history, and low body weight of 40 kg or less with odds ratios of 8.17, 3.97, 3.12, and 2.91, respectively. In 12 patients, lung injury developed even 2 months after leflunomide withdrawal. When patients with (n = 9) and without (n = 13) fatal outcome were compared, eight out of the former, and six out of the latter had preexisting interstitial lung disease; the former showed severe hypoxemia, high serum C-reactive protein level, hypoalbuminemia, and continuous lymphocytopenia, and required mechanical ventilation. On the basis of these results and literature review, the committee proposes that leflunomide should only be recommended as a second-line drug, should not be administered to patients with preexisting interstitial lung disease, should also not be administered to patients with smoking history or those with low body weight, and should be administered without loading dose. Careful monitoring is necessary, and when lung injury develops, leflunomide elimination using colestyramine is mandatory.     

来氟米特致外周神经病变2例并文献复习

目的提高临床医生对来氟米特致外周神经病变的认识。方法报道2例风湿病患者服用来氟米特后出现外周神经病变并复习文献,对发生机制、危险因素、预防、治疗措施及预后进行总结。结果 1例60岁女性类风湿关节炎和1例61岁男性重叠综合征患者分别在服用来氟米特治疗后2个月及4年后逐渐出现双手、足麻木、疼痛及双足下垂表现,在排除了风湿性疾病自身继发外周神经病变以及其他药物致外周神经病变可能后,及时停用来氟米特后上述症状迅速好转,确定此2例患者外周神经受累症状病因与来氟米特治疗相关。结论来氟米特导致的外周神经病变在30d内停药可改善患者临床预后。     

活血化瘀法联合来氟米特片、美洛昔康分散片治疗类风湿关节炎临床疗效观察

目的：通过观察活血化瘀法联合来氟米特片、美洛昔康分散片治疗类风湿关节炎的临床疗效,探讨中西医结合治疗类风湿关节炎的优势。方法：对确诊的159例患者随机分为两组,对照组服用来氟米特片和美洛昔康分散片治疗,治疗组在此基础上加服自拟活血化瘀中药方剂治疗。两组均连续服用3个月为1个疗程,1个疗程后观察并统计疗效。结果：治疗组总有效率为87.5%,显著高于对照组的74.68%。治疗组治疗后RF、ESR、补体C3等指标改善程度明显,统计学有显著性差异（P〈0.05）。结论：活血化瘀法联合来氟米特片、美洛昔康分散片治疗类风湿关节炎疗效较好,且较单纯西医治疗效果显著。     

The side‐effects and efficacy of leflunomide in Japanese patients with rheumatoid arthritis

Aims: To investigate the efficacy and safety of leflunomide, including the side‐effects, we assessed 84 rheumatoid arthritis (RA) patients who received leflunomide treatment. Methods: We analyzed the C‐reactive protein (CRP), white blood cell count (WBC), KL‐6, and visual analogue scale (VAS) scores, modified Stanford Health Assessment Questionnaire (MHAQ) score, American Rheumatism Association score (ACR20 and ACR50) within a time course after treatment with leflunomide. We treated 84 RA patients, 12 male and 72 female from 28 to 81‐years‐old, with an average age of 63.5 years. The patients were divided into three groups: a group consisting of 38 patients who received 100 mg/day of leflunomide for 3 days followed by 20 mg/day thereafter; a second group of 11 patients who received a no‐loading dose of 10 mg/day; and a third group of 35 patients who received a no loading dose of 20 mg/day. Results: The 50% decrease of CRP seen in 2 weeks was 52% of the total of 84 patients. The WBC score did not change significantly after the medication was given. The KL‐6 score did not change significantly, either. The VAS pain score improved 4 weeks later, and then further improved 8 weeks later. Therefore, RA patients using leflunomide obtained pain relief 4 weeks after commencing medication. The MHAQ score did not change significantly until 8 weeks after the patients started the medication. ACR20 was 62% and ACR50 was 38% at 8 weeks after treatment. The side‐effects of leflunomide observed in our patients were rash, respiratory infection, diarrhea, nausea, alopecia, muscle pain, headache, dizziness and general fatigue. Twenty‐three out of 84 patients experienced side‐effects (27%), and 48/84 (57%) experienced withdrawal. In our hospital, there were no patients who developed severe interstitial pneumonia (IP) or who died after taking leflunomide; however, the incidence of side‐effects of the 100 mg/day loading dose (42.1%) was 2.5 times higher than in the patients who received 20 mg/day (17.1%) of a no‐loading dose. Conclusion: Because of this, it is possible that a 100 mg/day loading dose is a relatively high risk dose in terms of causing side‐effects, especially for severely ill RA patients with a high CRP level.     

联合使用糖皮质激素和来氟米特治疗幼年Cogan综合征1例报告并文献复习

目的探讨联合使用糖皮质激素和来氟米特治疗Cogan综合征的疗效和预后。方法对1例12岁男性Cogan综合征患儿应用甲基泼尼松龙合并来氟米特治疗并进行长期随访,分析临床疗效。结果患儿治疗24周状态良好,无疾病复发迹象。结论幼年时期特发性关节炎患儿出现眼耳症状时需要注意鉴别Cogan综合征,大剂量糖皮质激素联合来氟米特可以达到长期控制Cogan综合征的疗效。     

正清风痛宁治疗幼年类风湿性关节炎的临床观察

目的探讨正清风痛宁等多种中西药联合治疗幼年类风湿性关节炎的疗效。方法将32例多关节型幼年类风湿性关节炎病人,按随机、双盲原则分为治疗组和对照组。对照组16例予来氟米特,甲氨蝶呤(MTX),尼美舒利,泼尼松;治疗组16例在对照组治疗基础上加用正清风痛宁60~120 mg。观察关节肿胀数(SJC)、关节压痛数(TJC)、晨僵时间、血沉(ESR)、C-反应蛋白(CRP)、类风湿因子(RF)水平、抗环胍氨酸肽抗体(CCP)等指标,以总改善百分率对疗效进行综合评估。疗程1年。结果除治疗组1例末坚持治疗,对照组1例失访外,两组患儿的临床症状、体征及实验室指标都有所改善,关节肿胀数、关节压痛数、晨僵时间减少,ESR、CRP、RF均较治疗前有显著的改善(P<0.01);治疗组的疗效优于对照组。用药1年后治疗组的总有效率为93.3%,对照组的总有效率为86.7%,两组差异有统计学意义(P<0.05)。两组的主要不良反应表现为乏力、头晕、皮疹、轻度食欲不振、轻度恶心、白细胞下降、转氨酶升高。治疗组不良反应的发生率为20.0%,对照组不良反应发生率为12.3%。结论正清风痛宁联合甲氨蝶呤和来氟米特等多种中西药治疗幼年类风湿性关节炎,效果显著,安全性较好。     

来氟米特对氟康唑体外抗耐药白色念珠菌增效作用研究

目的：研究来氟米特与氟康唑在体外合用对耐药白色念珠菌的抗真菌效果。方法：采用棋盘式微量稀释法测定来氟米特联合氟康唑对15株临床耐药白色念珠菌的最小抑菌浓度MIC₈₀。时间-杀菌曲线验证两药联用对耐药白色念珠菌生长的抑制作用。结果：来氟米特单药对实验所用白色念珠菌均无抗菌活性（MIC₈₀>320μg·mL^-1）。来氟米特联合氟康唑可产生协同抗菌作用,协同指数（FICI）<0.25。用药24h后,时间-杀菌曲线上联合用药组比单用氟康唑组平均降低了3.9log₁₀CFU/mL,证实两药具有协同抑菌作用。结论：来氟米特与氟康唑在体外对耐药白色念珠菌具有良好的协同抗真菌活性。