Leflunomide对实验性IgA肾病大鼠肾脏TGF-β_1、MCP-1表达的影响

目的:分别从基因和蛋白水平研究leflunomide对实验性IgA肾病(IgAN)大鼠肾组织转化生长因子(TGF-β1)、单核细胞趋化因子(MCP-1)水平的影响,了解其作用机制。方法:建立IgAN大鼠模型,随机分成leflunomide组、强的松组、模型对照组,并同时设立正常对照组。用免疫组化、RT-PCR的方法分别检测和比较各组肾组织TGF-β1、MCP-1蛋白和基因的表达水平。结果:Leflunomide组TGF-β1、MCP-1表达均明显低于模型对照组(P<0.05);leflunomide组与激素组相比,TGF-β1、MCP-1表达无明显差异。结论:Leflunomide可通过下调TGF-β1、MCP-1在肾脏的表达,减少局部炎症反应,延缓肾脏纤维化的进程,从而保护肾脏。

Leflunomide对异种肾移植(豚鼠/大白鼠)超急排斥反应的抑制效果

目的：观察Ｌｅｆｌｕｎｏｍｉｄｅ对异种肾移植超急排斥反应的抑制效果。方法：用已经建立的异种异位肾移植超急排斥反应模型。术前１，３，５，７天开始分别给５组受鼠口服Ｌｅｆｌｕｎｏｍｉｄｅ１０ｍｇ／（ｋｇ·ｄ）。观察超急排斥反应发生的时间。结果：术前服药时间少于３天的受鼠，其超急排斥反应发生的时间与对照组相比无明显变化；术前服药５天和７天的受鼠，移植肾的持续泌尿时间分别为９５８±２０９ｍｉｎ和２７２５±７６３ｍｉｎ，显著长于对照组。结论：Ｌｅｆｌｕｎｏｍｉｄｅ作为免疫抑制剂，在异种（豚鼠→大白鼠）肾移植实验研究中，可推迟、但不能消除异种超急排斥反应。

Leflunomide对实验性IgA肾病大鼠肾脏病理及MCP-1表达的影响

目的观察leflunomide对实验性IgA肾病(IgAnephropathyIgAN)大鼠肾脏病理及肾组织单核细胞趋化因子(monocytechemoattractivepeptide1,MCP-1)表达的影响,了解其作用机制。方法建立IgAN大鼠模型,随机分成leflunomide组,强的松组,模型对照组,并同时设立正常对照组。行免疫荧光、光镜检查,并用免疫组化和RT-PCR方法分别检测肾组织MCP-1蛋白和基因水平的表达。结果与模型对照组相比,leflunomide组免疫复合物在肾脏的沉积明显减少,系膜区基质增生程度显著减轻(P<0.01);Leflunomide在基因和蛋白水平均能够有效抑制MCP-1在肾组织的表达(P<0.05)。结论Leflunomide能够减少免疫复合物在肾脏的沉积,减轻系膜区基质增生,并且下调MCP-1在肾脏的表达,减少局部炎症反应,减轻肾脏损害,保护肾脏。

Leflunomide对结肠癌细胞增殖及凋亡的影响

目的:检测Leflunomide对结肠癌细胞增殖和诱导凋亡作用。方法:实验采用结肠癌细胞株SW260,与不同浓度的Leflunomide药物(0、5、10、20、40、80μg/ml)共同培养,以MTT方法和流式细胞仪技术检测细胞的增殖状态,用TUNEL染色和流式细胞仪技术检测细胞的凋亡。结果:Leflunomide在对结肠癌细胞增殖具有双重影响,即在低浓度下(5μg/ml和10μg/ml)有轻度的促进结肠癌细胞SW620增殖的作用,而提高浓度后(>40μg/ml)则表现为明显的抑制细胞的增殖作用,并随着剂量增加和作用时间延长,抑制作用更为明显,即存在着时相性和量-效依赖性。结论:Leflunomide可抑制结肠癌细胞增殖和诱导凋亡。可能对结肠癌病人有潜在的治疗作用。

抗排斥反应的新型免疫抑制剂──Leflunomide

Ｌｅｆｌｕｎｏｍｉｄｅ是一种新型的免疫抑制剂，具有明显的抗急、慢性免疫排斥反应的作用。其作用机制可能与以下三个方面有关：抑制Ｔ、Ｂ淋巴细胞增殖，影响细胞因子及其受体的表达；抑制蛋白酪氨酸激酶的活性；抑制二清乳氢酸脱氢酶的活性。

抗排斥反应的新型免疫抑制剂——Leflunomide

Leflunomide(Lef),又称HWA486,暂译名为雷抑素),是一种新型免疫抑制剂,属异恶唑类衍生物。1979年由德国Hoechst A.G药厂首先合成,初步证实能有效防治MRL小鼠系统性红斑狼疮及慢性移植物抗宿主病和大鼠肾小管间质性肾炎等一系列自身免疫性疾病。此外。

Leflunomide在器官移植中的应用

Leflunomide(Lef)是一种异恶唑类化合物 ,它的应用范围较广 ,目前的研究发现 ,Lef作用于免疫反应的多个环节 ,具有强大的抗排斥反应作用 ,同时Lef具有独特的抗巨细胞病毒感染的作用 ,因此受到移植界的重视。本文对Lef在器官移植抗排斥反应中的应用研究作一综述。

Isolation and characterization of a degradation product in leflunomide and a validated selective stability-indicating HPLC-UV method for their quantification

Leflunomide （LLM） is subjected to forced degradation under conditions of hydrolysis, oxidation, dry heat, and photolysis as recommended by International Conference on Harmonization guideline Q1A（R2）. In total, four degradation products （I-IV） were formed under different conditions. Products I, II and IV were formed in alkaline hydrolytic, acidic hydrolytic and alkaline photolytic conditions. LLM and all degradation products were optimally resolved by gradient elution over a C18 column. The major degradation product （IV） formed in hydrolytic alkaline conditions was isolated through column chromatography. Based on its IH NMR, IR and mass spectral data, it was characterized as a British Pharmacopoeial impurity B. The HPLC method was found to be linear, accurate, precise, sensitive, specific, rugged and robust for quantification of LLM as well as product IV. Finally, the method was applied to stability testing of the commercially available LLM tablets.

The Active Metabolite of Leflunomide A771726 Inhibits Corneal Neovascularization

The effects of A771726, the active metabolite of leflunomide, on experimental rat corneal neovascularization （NV） in vivo and on cultured human umbilical vein endothelial cells in vitro were studied. The corneal NV was induced by alkali burn in 40 SD rats. The rats were randomly divided into 4 groups with 10 rats in each group. Group A was treated with 0.9% sodium chloride （control group）, and group B, group C and group D were given different concentrations of A771726 eye drops （0.5%, 1.0%, 2.0% respectively） 4 times daily during days 0--28. The occurrence and development of corneal NV were observed at 4, 7, 14, 21 and 28 day after alkali burn by a slit lamp microscope. The cultured human umbilical vein endothelial cells （ECV-304） were incubated with A771726 solution at different concentrations （20, 40, 80, 160, 320 μmol/L） for 36 h. The proliferation of cells was assessed by methyl thiazolyl tetrazolium （MTT）, and the expression of proliferating cell nuclear antigen （PCNA） in cells was detected by using immunofluorescence under the laser confocal microscope. The rat model showed that the onset of corneal NV was delayed and progression of corneal NV was inhibited in the groups C and D. The corneal NV areas in groups C and D were significantly smaller than in groups A and B （P〈0.01）. No significant difference was found in corneal NV areas between groups C and group D （P〉0.05）. A771726 solution （940 μmol/L） could inhibit proliferation of human umbilical vein endothelial cells and decrease the expression of PCNA in cells significantly, A771726, as the active metabolite of leflunomide, strongly prevented corneal NV induced by alkali burn in the in vivo model, and inhibited proliferation of human umbilical vein endothelial cells in the in vitro model. Therefore, A771726 may serve as an angiogenic inhibitor in the treatment of corneal NV.

Leflunomide抑制大鼠角膜移植免疫排斥反应的研究

目的 研究 L eflunomide对大鼠角膜移植排斥反应的防治作用。方法 建立大鼠穿透性角膜移植排斥反应的动物模型 ,观察 L eflunomide对大鼠角膜植片存活和排斥反应指数 (RI)的影响 ,并与阴性对照组和 Cs A治疗组相比较。结果 阴性对照组角膜植片存活时间为 12 .375 d± 1.76 8d,而 Cs A组为 17.375 d± 1.40 8d,L eflunom ide组为 18.2 5 0 d±1.35 6 d,均比阴性对照组显著延长 (P<0 .0 1)。结论 L eflunomide能抑制大鼠穿透性角膜移植免疫排斥反应 ,显著延长角膜植片的存活时间。

Flare up of rheumatoid arthritis associated with VogtKoyanagi-Harada syndrome treated with leflunomide

Dear Editor,We present a case of"Flare up of rheumatoid arthritis associated with Vogt-Koyanagi-Harada(VKH)syndrome treated with leflunomide".To our knowledge,this is the first case of uveitis and arthritis inflammation active at the same time and no treatment for this condition has been described in the literature.

Outcome of Leflunomide in the Treatment of Proliferative Lupus Nephritis Compared to Cyclophosphamide

Background: Lupus nephritis (LN) is one of the most common presentations of Systemic lupus erythematosus (SLE). Cyclophosphamide is one of the key immunosuppressive agents for the management of LN. Leflunomide is an isoxazole immunomodulatory agent has been shown to be safe, well tolerated and effective in SLE and LN. Objective: To evaluate the outcome of leflunomide in the treatment of proliferative lupus nephritis compared to cyclophosphamide. Method: This randomized clinical trial was held in Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from July 2017 to August 2019. A total of 66 patients of proliferative lupus nephritis who need induction therapy were enrolled in this study. Leflunomide 100 mg/day for consecutive 3 days followed by 0.5 mg/kg/day in divided dose was given in experimental group (n = 32) and intravenous cyclophosphamide 0.5 gm/m2 of body surface area monthly pulse was given in control group (n = 34). All study patients have received prednisolone and hydroxychloroquine according to KDIGO guideline then followed up monthly for 6 months. Outcomes were measured at 6th month by renal function [S. Creatinine, 24 hours urinary total protein (24-hr UTP)], changes in SELENA-SLEDAI score, anti-ds DNA level, serum complement levels (serum C3 & C4), remission (complete/partial) and adverse drug responses. Result: In experimental group, remission occurred in 18 (56.3%) patients and no remission in 14 (43.7%) patients. In control group, remission occurred in 24 (70.6%) patients and no remission in 10 (29.4%) patients. Adverse effects in experimental group were: elevated ALT (6.3%), hypertension (12.5%), infection (6.3%) and amenorrhea (12.5%). In control group, adverse effects were mainly leucopenia (5.9%), infection (17.7%) and amenorrhea (29.4%). Intergroup analysis for treatment responses and adverse effects showed no significant difference (p > 0.05). Conclusion: Leflunomide combined with prednisolone is effective in the induction treatment of proliferative lupus nephritis in Bangladeshi patients in terms of response rate and adverse effects.

Clinical efficacy of tocilizumab combined with leflunomide in the treatment of rheumatoid arthritis

Objective:To study the clinical efficacy of tocilizumab combined with leflunomide in the treatment of rheumatoid arthritis.Methods:114 patients with rheumatoid arthritis admitted from May 2015 to April 2018 were randomly divided into control group(n=57)and observation group(n=57).The control group was treated with leflunomide.On the basis of this,the observation group was treated with tocilizumab for 12 weeks.Functional indicators,erythrocyte sedimentation rate(ESR),rheumatoid factor and inflammatory factors were evaluated and adverse reactions were recorded.Results:The total treatment efficiency of the observation group(89.47%)was significantly higher than that of the control group(75.44%)(P<0.05).Morning stiffness time,joint pain score,joint swelling score,ESR,serum C-reactive protein(CRP),rheumatoid factor(RF),tumor necrosis factor(TNF-α),and interleukin-1 were observed in the observation group and the control group.The levels of IL-1),IL-6,IL-8 and other indicators were lower than those before treatment.The indexes of the observation group were significantly lower than those before treatment(P<0.05),and after treatment The morning stiffness time,joint pain score,joint swelling score,ESR,CRP,RF,TNF-α,IL-1,IL-6,IL-8 and other indicators in the observation group were significantly lower than those in the control group(P<0.05).The incidence of adverse reactions in the observation group was 14%,and the incidence of adverse reactions in the control group was 17.54%.Toltuzumab combined with leflunomide in the treatment of rheumatoid arthritis did not increase the probability of adverse reactions.Conclusion:The use of tocilizumab combined with leflunomide in the treatment of rheumatoid joints has good efficacy and safety.This may be related to a significant reduction in inflammatory factors TNF-α,IL-1,IL-6,IL-8 and the like.

Effect of leflunomide combined with losartan potassium therapy on renal function and glomerular podocyte injury in patients with diabetic nephropathy

Objective:To study the effect of leflunomide combined with losartan potassium therapy on renal function and glomerular podocyte injury in patients with diabetic nephropathy.Methods:A total of 82 patients with diabetic nephropathy (CKDIIIa, IIIb stage) who were treated in our hospital between June 2013 and May 2016 were selected as the research subjects, random number table was used to divide them into leflunomide (LEF) group and control group who received leflunomide combined with losartan potassium therapy and losartan potassium monotherapy respectively. Before treatment and 8 weeks after treatment, serum contents of renal function indexes, RAAS molecules and inflammatory factors as well as urine contents of podocyte damage proteins were determined.Results:8 weeks after treatment, serum Scr, BUN, CysC, PRA, AT-II, ALD, IL-1β, IL-6 and TNF-α contents, urine ACR levels as well as podocalyxin, nephrin, CA2AP and podocin contents of both groups of patients were significantly lower than those before treatment, and serum Scr, BUN, CysC, IL-1β, IL-6 and TNF-α contents, urine ACR level as well as podocalyxin, nephrin, CA2AP and podocin contents of LEF group were significantly lower than those of control group, serum PRA, AT-II, ALD contents had no significant difference with control group.Conclusion:Leflunomide combined with losartan potassium therapy can improve the renal function of patients with diabetic nephropathy, and inhibit the inflammatory response injury to glomerular podocyte.

类风湿性关节炎药物Leflunomide治疗干癣性关节炎

《临床类风湿学期刊》(Journal of Clinical Rheuma-tology 2001,7:366-370.)的最新研究报告指出,类风湿性关节炎治疗药物 leflunomide,或许可用来治疗多年不愈的牛皮癣或干癣性关节炎。 截至目前,leflunomide(商品名:Arava)在治疗牛皮癣及干癣性关节炎方面的效果还有待细探。该药目前主要的用途是治疗风湿性关节炎。研究人员针对 12名经常发作干癣性关节炎的患者,每位受测者都曾经对至少一种抗风湿药物的作用失去疗效反应。

消炎镇痛药—Leflunomide

ATT1726，Leflunomide的活性代谢物，是一种能抑制活动性类风湿关节炎病人的活动淋巴细胞中增殖的免疫调节物。由于ATT1726有较长的半衰（≈2周），口服Leflunomide的开始负荷剂量是一天一次100mg，连服3天；然后再继续一天一次20mg的剂量。

Leflunomide可作为治疗严重异位性皮炎的新选择

Background: Based on the increasing knowledge of T cellmediated pathogenesis in atopic dermatitis (AD). systemic immunosuppressive drugs are increasingly applied. The chronic, relapsing course of severeADnecessitates a drug, both efficacious and safe in long term application. Leflunomide is a pyrimidine de novo synthesis inhibiting immunosuppressant exhibiting an extremely long in vivo half life of its active metabolite. Objectives: To evaluate the efficacy of leflunomide in long term treatment of AD. Methods: As a proof of principle, we treated two patients with severe AD, recalcitrant to different systemic treatment modalities, for 20 months with leflunomide (loading dose 100 mg daily during 3 days; maintenance dose 20 mg daily). At regular visits physical examination, eczema area and severity index (EASI), visual analogue scale (VAS) for itching, and laboratory findings were assessed with according adjustment of the leflunomide dose. Results: At the initiation of leflunomide therapy, both patients presented with almost erythrodermic AD (patient 1, EASI 40.0, VAS 10; patient 2, EASI 43.0, VAS 8). Partial remission was observed within 4 and 7 weeks, respectively, and maintained over 20 months (patient 1, median EASI 4.2, median VAS 2; patient 2, median EASI 8.4, median VAS 2) except for one episode of exacerbation in each case. In one patient, remissionwas stable even after cessation of drug dosing. Severe adverse eventswere ot observed. Conclusions: Leflunomide was efficient in the long term treatment of recalcitrant AD. Controlled studies will be necessary to evaluate the subset of severe AD patients benefitingmost from this drug.

Leflunomide: A versatile additive for defect reduction, enhanced optoelectronic properties and environmental stability of perovskite films

The development of perovskite photoelectric devices with excellent performance is largely dependent on the defects in the perovskite films.To address this issue,a specific drug,leflunomide(LF,C_(12)H_(9)F_(3)N_(2)O_(2)),was incorporated into the perovskite to reduce defects and improve its photoelectric properties.It is believed that the C=O bond on LF molecule can interact with the uncoordinated Pb2+of the perovskite,thereby reducing non-radiative recombination.This novel approach of incorporating LF into perovskite films has the potential to revolutionize the development of high-performance perovskite photoelectric devices.The trifluoromethyl functional(–CF_(3))group on LF can form a protective layer on the surface of the perovskite film,shielding it from water erosion.Moreover,LF can be utilized to alter the nucleation position of perovskite,thus minimizing the number of defects and optimizing the film quality.Consequently,the LF-doped perovskite film displays low trap density and high photoelectric performance.The LF-doped perovskite film showed a trap density of 8.28×10^(11),which is notably lower than the 2.04×10^(12) of the perovskite film without LF.The responsivity and detectivity of the LF-doped perovskite photodetector were 0.771 A/W and 2.81×10^(11) Jones,respectively,which are much higher than the 0.23 A/W and 1.06×10^(10) Jones of the LF-undoped perovskite photodetector.Meanwhile,the LF-doped photodetector maintained an initial photocurrent of 86%after 30 days of storage in air,indicating drastically increased environmental stability.This strongly suggests that LF is an effective additive for perovskites utilized in optoelectronic devices with high performance.

leflunomide对IgA肾病大鼠肾脏保护作用的机制研究

目的观察leflunomide对实验性IgA肾病（IgAN）大鼠肾脏病理及肾组织转化生长因子-β1（TGF-β1）、单核细胞趋化因子1（MCP-1）表达的影响。方法建立IgAN大鼠模型，随机分成模型组、泼尼松组、leflunomide组，同时设立正常对照组。用免疫荧光和光镜观察免疫复合物在肾脏的沉积及系膜区基质增生程度；用免疫组化和逆转录-聚合酶链反应（RT-PCR）方法分别检测肾组织TGF-β1、MCP-1的蛋白和基因表达水平。结果与模型组比较，leflunomide组免疫复合物在肾脏的沉积明显减少，系膜区基质增生程度显著减轻（P均〈0．01）；leflunomide在基因和蛋白水平均能够有效抑制TGF-β1和MCP-1在肾组织中的表达（P〈0．05或P〈0．01）。结论leflunomide能减少免疫复合物在肾脏的沉积，并且下调TGF-β1、MCP-1在肾脏的表达，减少局部炎症反应，减轻系膜区基质增生，延缓肾脏纤维化的进程，保护肾脏。