来氟米特在风湿免疫性疾病及肾脏疾病中的临床应用

来氟米特作为一种新型免疫抑制剂,最初主要用于类风湿关节炎治疗.近年基础和临床研究表明,本品对其他风湿免疫性疾病和肾脏疾病等治疗具有较好的临床疗效.本文综述来氟米特相关临床应用研究.     

复方玄驹胶囊联合来氟米特治疗类风湿关节炎的疗效观察

目的 观察复方玄驹胶囊联合来氟米特片治疗类风湿关节炎患者的临床疗效和安全性.方法 选择2019年6月～2020年12月在盘锦市中心医院收治的90例类风湿关节炎患者采用随机对照的临床研究方法,将按标准纳入的患者分为三组:复方玄驹胶囊、来氟米特片以及联合治疗组(复方玄驹胶囊+来氟米特片).分别记录治疗前和治疗8周后的晨僵时...     

来氟米特不良反应并文献分析

目的探讨来氟米特的安全性,为临床更加安全有效地使用该药提供有价值的信息。方法通过维普资讯《中国科技期刊数据库》,检索2005-2010年发表的有关来氟米特的临床研究文献。筛选用药中进行不良反应监测的文献,进行汇总分析。结果获得符合条件的病例报道45篇,涉及病例2540例。发生不良反应的病例147例,占全部病例的5.79%。来氟米特的不良反应以皮肤疾病以及腹泻腹痛、肝功能障碍发生率较高,分别是25.85%、20.40%、12.24%。结论来氟米特主要不良反应是皮肤疾病、腹泻腹痛和肝功能障碍,临床安全性较好。     

来氟米特凝胶剂的制备与质量控制

目的制备来氟米特凝胶剂，并建立其质量控制方法。方法以壳聚糖为凝胶材料制备来氟米特凝胶剂，采用高效液相色谱法测定来氟米特含量。结果来氟米特质量浓度在10～100μg／mL范围内与峰面积线性关系良好，平均回收率为100．3％，RSD为0．67％（n=6）。结论制备工艺合理、简单，含量测定方法可行，制剂质量稳定。     

来氟米特脂质体的工艺优化

目的：制备来氟米特脂质体。方法：采用旋转薄膜－超声法制备来氟米特脂质体,以高效液相色谱法测定来氟米特的含量,用均匀设计法优化来氟米特脂质体的处方和制备工艺。结果：来氟米特脂质体的质量比为胆固醇,抗氧化及药物与磷脂的比依次为１０：１００,１：１００,５：１００。结论：来氟米特脂质体呈均一单型,有效粒径１０６ｎｍ,包封率６９．２０％。     

来氟米特治疗过敏性紫癜性肾炎的疗效观察

目的 探讨免疫抑制剂——来氟米特治疗过敏性紫癜性肾炎的疗效，并与雷公藤疗效比较。方法 选择我院过敏性紫癜同时伴有血尿和蛋白尿的患儿75例，将患几分为雷公藤组（32例）和来氟米特组（43例）。雷公藤组给予雷公藤多甙1mg,／kg口服，疗程3—6月；来氟米特组给予来氟米特1mg,／kg，用3d，以后以0．35mg／kg维持治疗3—6个月，同时2组患儿均给予强的松1mg／kg，口服4周，然后逐渐减量，疗程6个月。观察尿常规、24h尿蛋白定量、血常规、肝功能、肾功能、皮肤紫癜或肾炎复发次数及药物不良反应。结果 来氟米特组3、6个月时尿红细胞及1、3、6个月时尿蛋白明显少于雷公藤组（均P〈0．01）。雷公藤组复发率为31．25％，来氟米特组复发率为11．62％，来氟米特组复发率明显低于雷公藤组（P〈0．05）。结论 来氟米特对过敏性紫癜的血尿和蛋白尿均有良好的疗效。     

来氟米特可致严重肝损伤

2010年7月13日，FDA发布来氟米特（leflunomide）可导致严重肝损伤的安全通报。来氟米特临床用于治疗活动性类风湿性关节炎。     

来氟米特治疗IgA肾病的应用

作为一种新型的免疫抑制药,来氟米特已运用到IgA肾病的治疗中,但是对于来氟米特治疗IgA肾病的疗效尚不确切。该文综述来氟米特治疗IgA肾病的进展。     

来氟米特药物代谢酶和转运体的基因组学研究进展

来氟米特是一种用于治疗免疫系统疾病的免疫调节剂,但由于存在药物不良反应,超过50%的患者在用药1年后停用该药。目前,药物遗传学研究表明单核苷酸多态性（SNPs）对来氟米特血药浓度有一定的影响,与类风湿性关节炎（RA）患者的有效性和耐受性存在潜在相关。体外研究表明,细胞色素P450酶CYP1A2、CYP2C19和CYP3A4参与来氟米特在机体内的代谢,CYP1A2*1F等位基因可能与RA患者的来氟米特不良反应相关。此外,二氢乳清酸脱氢酶（DHODH）基因rs3213422（19C>A）的C等位基因和雌激素受体（ESR1/2）的基因多态性可能与来氟米特的不良反应和治疗效果相关。本文总结了参与来氟米特体内过程相关代谢酶及转运体的基因多态性与来氟米特及其活性代谢物特立氟胺血药浓度、临床疗效以及药物不良反应的相关性,为深入研究来氟米特临床合理用药提供参考信息。     

3种溶剂对来氟米特离体皮肤渗透的影响

目的：研究溶剂对来氟米特离体皮肤渗透的影响,方法：采用改良Franz扩散池,以离体小鼠皮肤为渗透屏障,渗透速率为指标,HPLC法测定来氟米特浓度,结果：乙醇对来氟米特皮肤渗透有一定的促进作用,丙二醇和低浓度1,3－二甲基2－咪唑啉酮（DMI）对来氟米特的皮肤渗透影响不大,结论：3种溶剂都可用于来氟米特皮肤局部用制剂。     

Clinical pharmacokinetics of leflunomide

Leflunomide is the first disease-modifying antirheumatic drug to be approved for rheumatoid arthritis in the past 10 years. Orally administered leflunomide is almost completely converted into its active metabolite A77 1726 (hereafter referred to as M1). M1 displays linear pharmacokinetics at the dosages of leflunomide used in clinical practice. It has a long elimination half-life (approximately 2 weeks), reaching a steady state after approximately 20 weeks. M1 is highly bound to plasma proteins. The pharmacokinetics of M1 are not affected by food intake, and dosage requirements are not influenced by age or gender. Approximately 90% of a single dose of leflunomide is eliminated, 43% in urine, primarily as leflunomide glucuronides and an oxalinic acid derivative of M1, and 48% in faeces, primarily as M1. Elimination can be dramatically increased by using charcoal or cholestyramine. In vitro studies have shown no major influence of leflunomide on the metabolism of analgesics, nonsteroidal anti-inflammatory drugs and methotrexate, drugs usually used in the treatment of rheumatoid arthritis. In clinical studies with a limited number of patients using these drugs concomitantly, no safety problems appeared. Nonspecific inducers of cytochrome P450 (CYP) and some drugs metabolised by CYP2C9 affect the metabolism of M1, and caution should be used in patients cotreated with them. Additional in vitro and in vivo pharmacokinetic studies are needed to better understand the nonenzymatic and enzymatic metabolism of leflunomide. Additional clinical trials should be performed in order to find new indications for leflunomide in other autoimmune diseases, and new combination therapeutic strategies in rheumatoid arthritis. This review is a summary of current knowledge of the pharmacokinetics of leflunomide, focusing primarily on humans and in particular on patients with rheumatoid arthritis.     

新型免疫调节剂—来氟米特

来氟米特是一个新型的免疫调节剂。其作用机制独特 ,血浆蛋白结合率高 ,目前主要用于治疗类风湿关节炎、系统性红斑狼疮、抗移植排斥反应等。本文对来氟米特的作用机制、药动学及临床应用进行综述。     

Leflunomide for the treatment of rheumatoid arthritis in clinical practice: incidence and severity of hepatotoxicity.

OBJECTIVE: Leflunomide is a novel disease modifying antirheumatic drug (DMARD). Because of reports on possible hepatotoxicity and adaptations in the recommendations for monitoring liver function during leflunomide treatment, we conducted a study to evaluate the incidence and severity of hepatotoxicity. METHODS: We included consecutive rheumatoid arthritis patients starting treatment with leflunomide in the region of Friesland (The Netherlands) between January 2000 and January 2002. During follow-up patient characteristics, disease characteristics, and clinical and laboratory data on liver functions were registered. Severity of hepatotoxicity was categorised using the National Cancer Institute Common Toxicity Criteria, as moderate (grade 2), severe (grade 3) or life threatening (grade 4). RESULTS: One hundred and one patients were followed for a median period of 10 months (range 0.5-12). Grade 2 or 3 elevations in any liver function blood test were recorded in a total of nine patients (8.9%). No grade 4 elevations were recorded. Four patients (4%) showed grade 2-3 aminotransferase elevations. Due to grade 2 hepatotoxicity one patient (1%) was withdrawn from leflunomide treatment, and one patient continued leflunomide at a reduced dose. In eight of nine patients with grade 2-3 liver function blood tests, these elevated liver function tests occurred within 6 months after starting leflunomide. None of the patients with grade 2 or 3 toxicity had a history of hepatic disease, eight patients concomitantly used potential hepatotoxic co-medication. Eight (8%) patients used leflunomide in combination with methotrexate, and one of these patients developed hepatotoxicity. No clinical signs of serious hepatotoxicity were recorded during follow-up. DISCUSSION: In 8.9% of the patients, grade 2 or 3 hepatotoxicity was recorded within the first year after the start of leflunomide therapy based on liver enzyme determinations. In the majority of the patients liver enzyme elevations occurred within the first 6 months of therapy and resolved during continued follow-up. None of the patients showed clinical signs of hepatotoxicity. CONCLUSION: Under continued monitoring of liver functions hepatotoxicity during leflunomide use does not seem to be a major problem in our population.     

来氟米特片联合肾易通颗粒治疗系膜增生性肾小球肾炎临床疗效分析

目的分析来氟米特片联合肾易通颗粒治疗系膜增生性肾小球肾炎的临床效果。方法采用病例对照分析研究,将65例患者随机分为来氟米特组(25例)、来氟米特加肾易通组(20例)、肾易通组(20例)。观察临床症状、体征以及尿常规、尿红细胞计数、24 h尿蛋白定量、血清白蛋白(ALB)、血常规、血尿素氮、血肌酐(Ser)、谷丙转氨酶、谷草转氨酶的变化以及用药期间不良反应。结果来氟米特组各疗程有效率虽较肾易通组高,但差异无显著性(P>0.05);来氟米特加肾易通组治疗6个月后的疗效(100%)不仅优于肾易通组(P<0.05),而且优于来氟米特组(P<0.05)。结论来氟米特联合肾易通颗粒对系膜增生性肾小球肾炎患者具有疗效好、不良反应少的特点,值得临床推广。     

来氟米特致周围神经病变2例简

1 例64 岁和1 例46 岁女性类风湿关节炎患者,在服用来氟米特后出现双手麻木、痛觉过敏、足下垂等症状,排除其他因素引起的神经病变后,及时停药,上述症状好转;并对来氟米特致周围神经病变进行文献复习,总结其发生特点、诊断、危险因素等,-旦明确是由于药物导致的外周神经病变后,应立即停药,改善患者的临床预后.     

Association of DHODH haplotype variants and response to leflunomide treatment in rheumatoid arthritis

Aim: Leflunomide is a disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis. Not all patients respond to leflunomide and, as it has potentially serious side effects, targeting only those most likely to benefit would address a clinical need. We aimed to determine whether variations in the gene encoding DHODH, the molecular target of leflunomide, might include biomarkers that could be used to rationalize provision of this drug. Materials & methods: We analyzed six haplotype-tagging SNPs in DHODH in 56 patients with rheumatoid arthritis treated with leflunomide. Clinical response was determined by assessing the change in 28 joint disease activity score over the first 3 months of treatment. Results & conclusion: Carriage of a six-marker DHODH haplotype was associated with a reduced treatment response (p = 0.008). This suggests that a functional variant in strong linkage disequilibrium with this haplotype may predispose to reduced leflunomide efficacy. Original submitted 2 April 2012; Revision submitted 13 July 2012.     

中药溻渍结合西药对强直性脊柱炎化验指标临床研究

目的观察中药溻渍结合来氟米特治疗强直性脊柱炎的临床疗效。方法选取本院2011年4月～2012年4月强直性脊柱炎患者80例,随机分两组,中药溻渍结合来氟米特治疗患者40例为观察组,仅用来氟米特治疗患者40例为对照组,疗程60d。治疗后分析临床指标与临床疗效。结果治疗组有效率95％,对照组有效率84％,差异具有统计学意义（P〈0．05）,治疗组在改善疼痛和功能活动,炎症指标血沉,C反应蛋白降低方面优于对照组（P〈0．05）。结论中药溻渍结合来氟米特治疗强直性脊柱炎在改善疼痛和功能活动有所好转,炎症指标血沉,C反应蛋白降低。     

来氟米特在中国健康人群中的群体药动学研究

目的：建立来氟米特口服给药在中国健康受试者体内的群体药动学模型,探讨其药动学特征及可能的影响因素。方法：21名健康男性受试者参与本次研究,应用Phoenix NLME（Vision 8.0）软件中的群体模块分析来氟米特口服给药后其代谢产物的血药浓度数据,估算相关药动学参数及其变异情况。结果：来氟米特活性代谢产物特立氟胺在健康志愿者中符合一级吸收的一室模型。吸收速率常数K_a、分布容积V、药物清除率CL的群体典型值分别为0.691 h^-1、12.843 L和0.031 L·h^-1。协变量筛选结果显示,BMI对分布容积V有显著影响（P<0.01）。结论：本研究成功建立了来氟米特在中国健康人群中的群体药动学模型,最终模型可对个体药代参数做出精确的估计,BMI对分布容积V有显著影响。