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

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Nano Research 2024年第4期17卷 2628-2637页

作者： Dingyue Sun Ming Peng Taijin Wang Longju Yi Shizuo Zhang Feng Liu Gary J.Cheng The Institute of Technological Sciences Wuhan UniversityWuhan 430072China School of Power and Mechanical Engineering Wuhan UniversityWuhan 430072China School of Industrial Engineering Purdue UniversityWest LafayetteIN 47906USA

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.

关键词： Leflunomide additive engineering defect passivation perovskite

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Inhibitory effect of Leflunomide on hepatic fibrosis induced by CCl4 in rats

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Acta Pharmacologica Sinica 2004年第7期25卷 69-74页

作者： Hong-wei YAO2,3, Jun LI3,4, Ji-qiang CHEN2, Shu-yun XU3 2 Zhejiang Respiratory Drugs Research Laboratory of State Drugs Administration of China, School of Medicine, Zhejiang University, Hangzhou 310031 3Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China 浙江大学国家食品药品监督管理局呼吸药物研究实验室 Hangzhou 310031 Institute of Clinical Pharmacology Anhui Medical University Hefei

AIM: To study the effect of Leflunomide on CCl4-induced hepatic fibrosis in rats. METHODS: Hepatic fibrosis was induced by subcutaneous injection with 50 % CCl4 in Sprague-Dawley rats. The amount of CCl4 administered was 1 mg/kg. The alanine aminotransferase (ALT), aspartate aminotransferase (AST), nitric oxide (NO) levels in plasma and hydroxyproline (Hyp) contents in liver tissue were assayed by spectrophotometry. The hyaluronic acid (HA) and procollagen III (PC III) were assessed by radioimmunoassay. The transforming growth factor-β1 (TGF-β1) in serum was determined by ELISA. The nuclear factor-kappa B (NF-κB) in liver tissue was examined by immunohistochemistry. Liver samples collected after 12 weeks of CCl4 treatment were stained with hematoxy- lin and eosin. RESULTS: Leflunomide (1, 3, and 9 mg/kg) significantly decreased indices of liver and spleen, the serum transaminase (AST, ALT) activities, HA and PC III levels, and Hyp contents in liver tissue in rats of hepatic fibrosis. Histopathological examination showed Leflunomide had inhibitory effect on fibrogenesis and formation of pseudolobulus. Furthermore, Leflunomide significantly inhibited NF-κB expression in liver tissue, and reduced elevated serum TGF-β1 and NO levels in rats of hepatic fibrosis. CONCLUSION: Leflunomide showed inhibitory action on hepatic fibrosis induced by CCl4 in rats.

关键词： Leflunomide hepatic fibrosis nuclear factor-kappa B transforming growth factor-beta nitric oxide

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Efficacy of Leflunomide, Telmisartan, and Clopidogrel for Immunoglobulin A Nephropathy： A Randomized Controlled Trial

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Chinese Medical Journal 2016年第16期129卷 1894-1903页

作者： Jie Wu Shu-Wei Duan Xue-Feng Sun Wen-Ge Li Ya-Ping Wang Wen-Hu Liu Jian-Rong Zhang Li-De Lun Xue-Mei Li Chun-Hua Zhou Ji-Jun Li Shu-Wen Liu Yuan-Sheng Xie Guang-Yan Cai Lu Ma Wen Huang Hua Wu Qiang Jia Xiang-Mei Chen Department of Nephrology Chinese People's Liberation Army General Hospital Chinese People's Liberation Army Institute of Nephrology State Key Laboratory of Kidney Diseases National Clinical Research Center for Kidney Diseases Beijing 100853 China Department of Nephrology China-Japan Friendship Hospital Beijing 100029 China Department of Nephrology PLA Army General Hospital Beijing 100700 China Department of Nephrology Beijing Friendship Hospital Capital Medical University Beijing 100050 China Department of Nephrology General Hospital of Chinese People's Armed Police Forces Beijing 100039 China Department of Nephrology Air Force General Hospital of People's Liberation Army Beijing 100142 China Department of Nephrology Peking Union Medical College Hospital Chinese Academy of Medical Sciences Beijing 100730 China Department of Nephrology Navy General Hospital Beijing 100048 China Department of Nephrology First Affiliated Hospital of General Hospital of People's Liberation Army Beijing 100048 China Treatment Center for Kidney Disease No. 281 Hospital of Beijing Military Region Qinhuangdao Hebei 066100 China Department of Nephrology Beijing Tongren Hospital Capital Medical University Beijing 100730 China Department of Nephrology Beijing Hospital Beijing 100730 China Department of Nephrology Xuanwu Hospital Capital Medical University Beijing 100053 China

Background： The efficacy and safety of telmisartan combined with clopidogrel, Leflunomide, or both drugs for immunoglobulin A nephropathy （IgAN） are unclear. This study was designed to evaluate the efficacy and safety of telmisartan combined with clopidogrel, Leflunomide, or both drugs for IgAN. Methods： It is a multicenter, prospective, double-dummy randomized controlled trial. Primary IgAN patients were recruited in 13 renal units across Beijing, China, from July 2010 to June 2012. After a 4-week telmisartan （80 mg/d） wash-in, 400 patients continuing on 80 mg/d telmisartan were randomly assigned to additionally receive placebo （Group A）, 50 mg/d clopidogrel （Group B）, 20 mg/d Leflunomide （Group C）, or 50 mg/d clopidogrel and 20 mg/d Leflunomide （Group D）. The 24-week intervention was completed by 360 patients. The primary endpoint was change in 24-h proteinuria at 24 weeks. A linear mixed-effect model was used to analyze the changes at 4, 12, and 24 weeks. Generalized estimating equations were used to evaluate changes in hematuria grade. This trial was registered at the Chinese Clinical Trial Registry. Results： The effects oftelmisartan combined with Leflunomide on changes in proteinuria （0.36 [95% confidence interval （CI） 0.18 0.55] g/d, P 〈 0.001）, in serum uric acid （76.96 [95% CI 57.44-96.49] μmol/L, P 〈 0.001）, in serum creatinine （9.49 [95% CI 6.54-12.44]μmol/L, P 〈 0.001）, and in estimated glomerular filtration rate （-6.72 [95% CI-9.46 to -3.98] ml.min -1. 1.73 m -2, p 〈 0.001） were statistically significant, whereas they were not statistically significant on changes in systolic and diastolic blood pressure and weight （P 〉 0.05）.Telmisartan combined with clopidogrel had no statistical effect on any outcome, and there was no interaction between the interventions. No obvious adverse reactions were observed. Conclusions： Telmisartan combined with Leflunomide, not clopidogrel, is safe and effective for decreasing proteinuria in certain IgAN patients.

关键词： Clopidogrel Immunoglobulin A Nephropathy Leflunomide Randomized Controlled Trial

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A Small-Scale Medication of Leflunomide as a Treatment of COVID-19 in an Open-Label Blank-Controlled Clinical Trial

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Virologica Sinica 2020年第6期35卷 725-733页

作者： Ke Hu Mengmei Wang Yang Zhao Yunting Zhang Tao Wang Zhishui Zheng Xiaochen Li Shaolin Zeng Dong Zhao Honglin Li Ke Xu Ke Lan Department of Respiratory and Critical Care Medicine Renmin Hospital of Wuhan UniversityWuhan 430060China Shanghai Key Laboratory of New Drug Design State Key Laboratory of Bioreactor EngineeringSchool of PharmacyEast China University of Science and TechnologyShanghai 200237China State Key Laboratory of Virology College of Life SciencesWuhan UniversityWuhan 430072China Frontier Science Center for Immunology and Metabolism Wuhan UniversityWuhan 430072China

We recently reported that inhibitors against human dihydroorotate dehydrogenase(DHODH)have broad-spectrum antiviral activities including their inhibitory efficacies on SARS-CoV-2 replication in infected cells.However,there are limited data from clinical studies to prove the application of DHODH inhibitors in Coronavirus disease 2019(COVID-19)patients.In the present study,we evaluated Leflunomide,an approved DHODH inhibitor widely used as a modest immune regulator to treat autoimmune diseases,in treating COVID-19 disease with a small-scale of patients.Cases of 10 laboratory-confirmed COVID-19 patients of moderate type with obvious opacity in the lung were included.Five of the patients were treated with Leflunomide,and another five were treated as blank controls without a placebo.All the patients accepted standard supportive treatment for COVID-19.The patients given Leflunomide had a shorter viral shedding time(median of5 days)than the controls(median of 11 days,P=0.046).The patients given Leflunomide also showed a significant reduction in C-reactive protein levels,indicating that immunopathological inflammation was well controlled.No obvious adverse effects were observed in Leflunomide-treated patients,and they all discharged from the hospital faster than controls.This preliminary study on a small-scale compassionate use of Leflunomide provides clues for further understanding of Leflunomide as a potential antiviral drug against COVID-19.

关键词： DHODH inhibitors Leflunomide Coronavirus disease 2019(COVID-19) Viral shedding time Inflammation

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Leflunomide,a new disease-modifying drug for treating active rheumatoid arthritis in methotrexate-controlled phase Ⅱ clinical trial

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Chinese Medical Journal 2003年第8期116卷 1228-1234页

作者：鲍春德陈顺乐顾越英劳志英倪立青於强徐建华李向培刘嘉玲孙凌云何培根马骥良徐淑云丁长海 Department of Clinical Immunology Shanghai Renji Hospital Shanghai Second Medical University Shanghai 200001 China Department of Rheumatology Shanghai Guanghua Hospital Shanghai 200000 China Department of Rheumatology Shanghai Zhongshan Hospital Shanghai Medical University Shanghai 200032 China Department of Clinical Immunology Affiliated Hospital of Anhui Medical University Hefei 230022 China Department of Rheumatology Anhui Provincial Hospital Hefei 230001 China Department of Rheumatology Affiliated Hospital of Nanjing Medical University Nanjing 210029 China Department of Rheumatology Nanjing Gulou Hospital Nanjing 210008 China Department of Rheumatology Tongji Hospital Tongji Medical University Wuhan 430003 China Department of Rheumatology Beijing Friendship Hospital Beijing 100050 China Institute of Clinical Pharmacology Anhui Medical University Hefei 230022 China

Objective To evaluate the efficacy and safety of Leflunomide in comparison with methotrexate (MTX) on patients with rheumatoid arthritis (RA) in China.Methods Five hundred and sixty-six patients with active rheumatoid arthritis were randomly assigned to receive Leflunomide at 20 mg once daily or MTX at 15 mg once weekly in a controlled trial. Five hundred and four patients completed the 12-week treatment and some patients continued the treatment for 24 weeks. Results Both Leflunomide and MTX could improve the symptoms,signs,and joint function,but there were no changes in X-ray observations of patients with rheumatoid arthritis. In the Leflunomide group,the overall rates of effectiveness at 12 weeks and 24 weeks were 86.94% and 92.31% respectively; the rates of remarkable improvement were 64.95% and 79.81% respectively. In the MTX group,the overall rates of effectiveness at 12 weeks and 24 weeks were 84.04% and 83.15% respectively; the rates of remarkable improvement were 56.81% and 75.28% respectively. According to intent-to-treat analysis,the ACR 20% response rates at 12 weeks and 24 weeks in the Leflunomide group were 62.54% and 67.18% respectively,compared with 60.08% and 61.32% respectively in MTX group. No statistical differences were shown in the efficacy between the two groups ( P >0.05). The adverse events in the Leflunomide group were gastrointestinal symptoms,skin rash,alopecia,nervous system symptoms,decreased leukocyte count,and elevation of alanine aminotransferase (ALT). Most of these side effects were mild and transient. The incidence of adverse events in the Leflunomide group was 16.84%,significantly lower than that in MTX group (28.17%,P =0.002).Conclusions Leflunomide is effective in the treatment of RA with less adverse events than MTX. Its efficacy is similar to MTX,but the incidence of adverse events and the rate of withdrawal due to adverse events were lower in the Leflunomide group than in MTX group.

关键词： Leflunomide rheumatoid arthritis·methotrexate·clinical trial

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Combination regimen of Leflunomide plus methylprednisolone in a female patient with reactive arthritis and concomitant IgA nephropathy

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Chinese Medical Journal 2010年第3期123卷 375-378页

作者： CHEN Yi-zhi ZHAO Xue-zhi WU Jun MEI Chang-lin Kidney Institute of Chinese People's Liberation Army Shanghai Kidney Disease Quality Control Center Division of Nephrology Shanghai Changzheng Hospital Second Military Medical University Shanghai 200003 China

Spondyloarthropathies （SpAs） include five categories： ankyloslng spondyllns （AS）, reactive arthritis （ReA）,psoriatic arthritis （PsA）, enteropathic arthritis （EA） and undifferentiated spondyloarthropathy （USpA）.2 ReA is an aseptic arthritis occurring after extra-articular infections, particularly genitourinary （GU） or gastrointestinal （GI） tracts. When arthritis is accompanied by conjunctivitis and urethritis, the diagnosis of Reiter syndrome will be suitable for this clinical triad; however, the term ＂ReA＂ has been proposed to substitute for Reiter syndrome.

关键词： arthritis, reactive glomerulonephritis, IgA female Leflunomide methylprednisolone

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Arsenic Trioxide Combining Leflunomide Activates Nrf2-ARE-HO-1 Signaling Pathway and Protects Heart Xenografts

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Chinese Journal of Integrative Medicine 2021年第10期27卷 760-766页

作者： WANG Teng-da XU Song-lin YU Zheng-yi Nl Shao-bin ZHANG Cheng JIAO Zhi-xing Department of Urology The First Affiliated Hospital of Harbin Medical UniversityHarbin(150000)China

Objective:To investigate the molecular mechanisms underlying the effects of arsenic trioxide(As_(2)0_(3))in combination with Leflunomide on the hamster-to-rat heart xenotransplant.Methods:Transplantation of LVG hamster hearts to Lewis rats was performed by anastomosis of vessels in the neck using end-to-end anastomosis with a non-suture cuff technique.Four groups of recipient rats(n=6 in each)were treated with normal saline(control),As_(2)0_(3)[5 mg/(kg*day)intraperitoneally],Leflunomide[5 mg/(kg*d)orally],or Leflunomide[5 mg/(kg.d)+As_(2)0_(3)5 mg/(kg.d)]in combination.Donor hearts and/or rat spleens were harvested and analyzed 4 days after transplantation.Quantitative reverse-transcription polymerase chain reaction and Western blot analysis were performed to detect the expression of the nuclear factor erythroid-derived factor 2-related factor(Nrf2)and its target gene heme oxygenase-1(HO-1),Treg cell marker fork-head Box P3(FOXP3),apoptosis-associated proteins Bcl-2,Bax,and cleaved caspase-3.Immunohistochemical staining was used to detect the levels of inflammatory natural killer cell and macrophage infiltration,intercellular cell adhesion molecule-1(ICAM-1)and complement C3.Results:Expression of Nrf2-ARE-HO-1 signaling pathway was upregulated in heart xenografts in rats treated with As_(2)0_(3) plus Leflunomide compared with control rats or rats treated with either drug alone(PLeflunomide treatment(PLeflunomide protected hamster heart-xenografts in recipient rats.

关键词： arsenic trioxide Leflunomide Nrf2-ARE-HO-1 signaling pathway inflammation infiltration xenotransplantation

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The Active Metabolite of Leflunomide A771726 Inhibits Corneal Neovascularization

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2008年第3期28卷 364-368页

作者：张明昌郝念边芳 Department of Ophthalmology Union HospitalTongji Medical CollegeHuazhong University of Science and Technology

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.

关键词： A771726 Leflunomide corneal neovascularization human umbilical vein endothelial cells proliferating cell nuclear antigen

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

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Journal of Pharmaceutical Analysis 2015年第3期5卷 207-212页

作者： Balraj Saini Gulshan Bansal Department of Pharmaceutical Sciences and Drug Research Punjabi University

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.

关键词： Leflunomide Characterization Forced degradation Degradation product HPLC-UV

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Leflunomide对IgA肾病大鼠肾脏保护作用的机制研究

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中国危重病急救医学 2008年第5期20卷 283-286,321页

作者：汤颖娄探奇王成彭晖刘迅唐骅中山大学附属第三医院肾内科广东广州510630

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... 详细信息

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。

关键词： Leflunomide IgA肾病实验性转化生长因子-β1 单核细胞趋化因子-1

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