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, fou...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.展开更多
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 ...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.展开更多
A 27-year-old male patient with rheumatoid arthritis was diagnosed with acute liver failure when he was taking leflunomide, a new immunosuppressant. This case illustrates the risk that leflunomide may lead to severe h...A 27-year-old male patient with rheumatoid arthritis was diagnosed with acute liver failure when he was taking leflunomide, a new immunosuppressant. This case illustrates the risk that leflunomide may lead to severe hepatotoxicity.展开更多
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 ...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.展开更多
<strong>Background: </strong>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 manageme...<strong>Background: </strong>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. <strong>Objective: </strong>To evaluate the outcome of leflunomide in the treatment of proliferative lupus nephritis compared to cyclophosphamide. <strong>Method: </strong>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.<strong> Result:</strong> 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). <strong>Conclusion:</strong> 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.展开更多
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 rando...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.展开更多
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...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.展开更多
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 ...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.展开更多
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...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.展开更多
基金University Grants Commission,New Delhi,India,for providing financial assistance to carry out the study(F.No.:37-323/2009(SR))
文摘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.
文摘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.
文摘A 27-year-old male patient with rheumatoid arthritis was diagnosed with acute liver failure when he was taking leflunomide, a new immunosuppressant. This case illustrates the risk that leflunomide may lead to severe hepatotoxicity.
基金Supported by National Natural Science Foundation of China(No.81401362)Scientific Research Foundation of Sichuan Provincial Health and Family Planning Commission(No.140080)Doctoral Foundation of Sichuan Provincial People's Hospital(No.30305030564)
文摘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.
文摘<strong>Background: </strong>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. <strong>Objective: </strong>To evaluate the outcome of leflunomide in the treatment of proliferative lupus nephritis compared to cyclophosphamide. <strong>Method: </strong>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.<strong> Result:</strong> 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). <strong>Conclusion:</strong> 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.
基金Science and Technology Research and Development Program of Affiliated Hospital of Yan'an University(2018PT-09).
文摘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.
文摘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.
文摘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.
文摘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.
