百令对他克莫司药代动力学影响及特发性膜性肾病典型病例用药分析

发布时间：2018-01-19 04:23

本文关键词： 他克莫司膜性肾病五酯胶囊百令胶囊中西医结合治疗　出处：《河北医科大学》2017年硕士论文　论文类型：学位论文

【摘要】：膜性肾病是肾病综合征主要的病理类型之一,膜性肾病主要分为特发性膜性肾病和继发性膜性肾病,不同类型的膜性肾病治疗方案不同,继发性膜性肾病的治疗主要针对于病因,特发性膜性肾病多采用钙调磷酸酶抑制剂、烷化剂、来氟米特、雷公藤多苷等联合激素治疗、吗替麦考酚酯、利妥昔单抗、依库丽单抗、静脉注射大剂量免疫球蛋白、促肾上腺皮质激素、咪唑硫嘌呤和中西医结合等治疗方案。钙调磷酸酶抑制剂代表药为他克莫司和环孢素A,两者相比,他克莫司对细胞免疫和体液免疫的抑制作用是Cs A的10~100倍,并且肝毒性较小。他克莫司是大环内酯类的新型免疫抑制剂其作用机制为通过与细胞质内的他克莫司结合蛋白相结合形成的复合物,主要通过竞争性地抑制钙调磷酸酶,从而阻止一系列淋巴细胞的转录特异性抑制T细胞活化和B淋巴细胞增殖。特发性膜性肾病中他克莫司联合泼尼松治疗过程较长,其过程中用药较多。本课题拟追踪一例典型病例,对其方案的疗效和安全性分析。治疗膜性肾病临床常见他克莫司与泼尼松的方案,以及联合用药为厄贝沙坦和百令胶囊。加用百令胶囊后可改善临床症状与尿蛋白水平,提升临床疗效。部分膜性肾病患者发展为终末期肾脏病,而采取肾移植术,对肾移植治疗临床常见应用他克莫司与百令胶囊合用。百令胶囊为发酵冬虫夏草菌粉[Cs—C—Q80],中华被毛孢Hirsutella sinensis Liu,Yu—er Zeng(1989)经液体深层发酵所得菌丝体的干燥粉末制成的胶囊。冬虫夏草成分丰富,其主要成分对肾脏及免疫有调节作用。他克莫司主要是通过肠黏膜上皮细胞P-糖蛋白转运,绝大部分经肝脏酶CYP3A4代谢,其中有些药物通过抑制P-糖蛋白或CYP3A4而影响他克莫司的血药浓度。经文献检索,未发现他克莫司与百令胶囊药物的相互作用。本课题拟研究百令胶囊对比格犬体内他克莫司药代动力学的影响,以期为临床合理用药提供参考。第一部分百令对他克莫司的药代动力学的影响目的:探讨百令对比格犬体内他克莫司的药代动力学的影响;方法:百令对比格犬体内他克莫司的药代动力学的影响。采用自身前后对照法。对照组:(n=6)将比格犬口服他克莫司胶囊前(0h)及服药1mg后0.167h,0.333h,0.5h,0.667h,0.833h,1h,1.5h,2h,3h,4h,6h,8h,12h,24h采静脉血2m L。置EDTA-K2抗凝管中。采用化学发光微粒子免疫法监测他克莫司的血药浓度。清洗期为一周。实验组:口服他克莫司联合百令胶囊,采血时间、测定方法等同上。采用DAS(2.1.1版)软件计算得到主要的药代动力学参数。应用SPSS 21.0统计软件,对数据进行配对t检验。结果:联合服用他克莫司(1mg)与百令(2粒)与单服他克莫司(1mg)相比,比格犬体内他克莫司各采血点血药浓度,药-时曲线下面积,消除半衰期、达峰时间、表观分布容积、清除率等差异均无统计学意义。达峰浓度差异有统计学意义结论:比格犬单服他克莫司1mg和他克莫司1mg与百令胶囊1g(2粒)联合应用后,他克莫司的药-时曲线下面积,消除半衰期、达峰时间、、表观分布容积、清除率均无统计学意义。达峰浓度差异有统计学意义。但百令胶囊与他克莫司合用对人体的药代动力学有待进一步研究。第二部分特发性膜性肾病典型病例用药分析目的:对特发性膜性肾病典型病例治疗方案和安全性进行分析,以期为临床合理用药提供参考。方法:特发性膜性肾病典型病例用药分析。追踪一例典型特发性膜性肾病患者,结合患者临床症状、检验指标包括尿蛋白、生化指标、血常规、他克莫司血药浓度等以及药品不良反应等情况。对其治疗方案的疗效和安全性以及联合用药情况进行分析,以期为临床合理用药提供参考。结果:1患者的病理结果为膜性肾病一期,治疗方案为他克莫司(1mg,2/d)联合泼尼松(10mg,1/日)治疗,15天后患者24小时尿蛋白量由原来的6.58g/d降低到5.57g/d。联合应用五酯胶囊为(2粒,3/d)15天后以后,他克莫司的血药浓度由服用五酯前的3.2 ng/ml增加到11.7ng/m L,24小时尿蛋白的量则从5.57g/d减少到1.22g/d且血浆白蛋白值由之前的30.21g/L升高到33.40g/L。当五酯胶囊减少为(2粒,2/d)他克莫司血药浓度降低为10.9ng/m L,24小时尿蛋白降低到1.17g/d,白蛋白升高到41.10g/L。五酯胶囊为(2粒,2/d),他克莫司减为(0.5mg,2/d)时其血药稳态谷浓度达到8.0 ng/m L,24小时尿蛋白量降低为0.47g/d,白蛋白升高到45.10g/L。患者24小时尿蛋白,生化指标达正常范围并且稳定一段时间后,停用他克莫司和激素,单服厄贝沙坦。患者24小时尿蛋白指标出现异常后调整用药为他克莫司(0.5mg,2/d)厄贝沙坦(0.3g,2/d)24小时尿蛋白量不在升高。2中西医结合治疗具体方案为他克莫司(0.5g,2/d),厄贝沙坦(0.15g,2/d)中药为独活、桑寄生、积雪草、茯苓、川芎、灵芝、炒僵蚕、生黄芪、生甘草、续断、烫狗脊、当归、熟地黄、酒萸肉。患者应用此方案后腰膝酸软,易困乏力,体虚潮热症状得到改善。精神状态得到提高,24小时尿蛋白量由之前的1.10g/d降低到0.17g/d。3患者饭前口服他克莫司产生恶心,干呕,平时常见头晕。调整为饭后服用。激素的副作用主要表现为骨质疏松,加用骨化三醇软胶囊,并注射伊班膦酸但其易导致肌肉酸痛。双嘧达莫不良反应常为头晕,改为阿司匹林。卡托普利引起刺激性干咳,改换为厄贝沙坦。结论:1他克莫司联合泼尼松的治疗的方案产生了一定的治疗效果,患者服用五酯胶囊可以提高他克莫司的血药浓度。建议患者可根据24小时尿蛋白转归及生化指标情况调整他克莫司和五酯胶囊的剂量。在达到治疗的目的前提下,减少药物品种,降低药物剂量。2中西医结合治疗对患者的机体起到了很好的调理作用,并且降低了尿蛋白。如患者精神状态不佳,身体不适,西药的作用不明显可考虑中西医结合治疗。3膜性肾病一般需长期治疗。结合典型病例对治疗期间药品不良反应、作息时间、饮食等情况给出一些建议。口服他克莫司产生恶心,干呕,平时常见头晕。建议改为饭后服用他克莫司,服药前20分钟监测他克莫司血药浓度。而头晕则提醒患者平时开车等情况需注意。而激素的不良反应主要为骨质疏松,可服用骨化三醇,维D钙咀嚼片,以及注射伊班膦酸钠,其不良反应是肌肉酸痛,但几天后会消失。对于防止血栓栓塞可服用阿司匹林,双嘧达莫的不良反应为头晕。此外服用卡托普利后干咳的患者,可调药为厄贝沙坦。建议其他患者作息规律,保持积极的心态,饮食清淡,食用低脂蛋白。
[Abstract]:Membranous nephropathy nephrotic syndrome is one of the main pathological type, membranous nephropathy mainly divided into idiopathic membranous nephropathy and membranous nephropathy, different treatment of different types of membranous nephropathy, membranous nephropathy treatment mainly for the etiology of idiopathic membranous nephropathy with calmodulin phosphatase inhibitors, alkylating agents, leflunomide, Tripterygium Glycosides combined with hormone therapy, mycophenolate mofetil, rituximab, according to finds mAb, intravenous immunoglobulin, adrenocorticotropic hormone, azathioprine and combining traditional Chinese and Western medicine therapy. Compared with calcineurin inhibitors representative drug tacrolimus and cyclosporin A, the inhibitory effect of tacrolimus on cellular immunity and humoral immunity is 10~100 times of Cs A, and liver toxicity is small. Tacrolimus is the mechanism of new immunosuppressive macrolides for With the FK506 binding protein in the cytoplasm of the combination of complex formation, mainly by competitive inhibition of calcineurin, thereby preventing a series of lymphocyte specific transcription inhibition of T cell activation and proliferation of B lymphocytes. Idiopathic membranous nephropathy in tacrolimus combined with prednisone in the treatment of a long process, in the process of drug use is more. This paper intends to follow a typical case, analysis the efficacy and safety of the scheme. The common clinical treatment of idiopathic membranous nephropathy of tacrolimus and prednisone, and combination therapy of irbesartan and bailing capsule. Combined with Bailing capsule can improve the clinical symptoms and levels of urinary protein, improve clinical curative effect. The development section patients with membranous nephropathy to end-stage renal disease, and renal transplantation, renal transplantation for the treatment of common clinical application of tacrolimus and bailing capsule combined with Bailing Capsule for fermentation in winter. The summer insects bacteria powder - C - Q80] [Cs Hirsutella sinensis, the Chinese hirsutella Liu, Yu - er Zeng (1989) capsule by dry powder liquid fermentation of the mycelium Cordyceps made. Its main ingredients are rich ingredients, regulating effect on kidney and immune. Tacrolimus mainly through the intestinal epithelial cells of P- glycoprotein transport, most of the liver enzyme of CYP3A4 metabolism, including some drugs by inhibiting P- or CYP3A4 glycoprotein affect the blood concentration of tacrolimus. Through literature retrieval, not tacrolimus and bailing capsule drug interactions. This project intends to study the effect of Bailing Capsule on tacrolimus pharmacokinetics in beagle dogs, in order to provide the reference for the clinical rational use of drugs. The first part of Bailing on tacrolimus pharmacokinetics Objective: To study the effects of Bailing on beagle dogs of tacrolimus pharmacokinetics. Effect; methods: effects of Bailing on beagle dogs of tacrolimus pharmacokinetics. Using self controlled method. The control group: (n=6) the Beagle Tacrolimus Capsules (0h) and oral medication after 1mg 0.167h, 0.333h, 0.5h, 0.667h, 0.833h, 1H, 1.5h, 2h, 3h, 4h, 6h 8h, 12h, 24h, 2m L. EDTA-K2 venous blood anticoagulant tube. The blood concentration of chemiluminescent microparticle immunoassay of tacrolimus. The cleaning period is one week. The experimental group: oral tacrolimus combined with Bailing capsule, blood sampling time, the determination method of equivalent. Using DAS (2.1.1 version) software to calculate the main pharmacokinetic parameters. Using SPSS 21 statistical software, the data was analyzed by paired t test. Results: the combined use of tacrolimus (1mg) and 100 (2 tablets) and oral tacrolimus (1mg) in beagle dogs collected blood tacrolimus blood concentration, area under concentration time curve, eliminationhalf ring During the peak time, the apparent volume of distribution and clearance rate. There were no significant differences in peak concentration difference was statistically significant. Conclusion: oral tacrolimus Beagle 1mg and tacrolimus 1mg and bailing capsule 1g (2 tablets) combined tacrolimus concentration time curve of the product, elimination half-life, as the peak time, the apparent volume of distribution and clearance rate were not statistically significant. There are statistically significant differences. But the peak concentration of Bailing Capsule and tacrolimus combination on human pharmacokinetics needs further study. The second part of idiopathic membranous nephropathy in typical case analysis of the use of objective analysis of the idiopathic membrane treatment and the safety of typical cases of nephropathy, so as to provide reference for clinical rational drug use. Methods: analysis of idiopathic membranous nephropathy. Typical cases of drug tracking a typical case of idiopathic membranous nephropathy patients with clinical symptoms of patients, Test indicators include urine protein, biochemical index, blood routine, blood drug concentration of tacrolimus and adverse drug reactions. The treatment efficacy and safety and combined medication were analyzed, in order to provide reference for clinical rational use of drugs. Results: 1 patients with pathological results as membranous nephropathy stage, treatment for tacrolimus (1mg, 2/d) and prednisone (10mg, 1/) 15 days after treatment, 24 patients with urinary protein was reduced from 6.58g/d to five for the combined application of 5.57g/d. ester capsules (2 capsules, 3/d) 15 days later, blood concentration increased by taking him Kmos before the 3.2 ng/ml five ester 11.7ng/m L, 24 hour urine protein quantity is reduced from 5.57g/d to 1.22g/d and plasma albumin value from 30.21g/L increased to 33.40g/L. when reduced to five ester capsules (2 capsules, 2/d) tacrolimus concentration reduced to 10.9ng/m L, 24 hour urine To reduce the protein 1.17g/d, albumin increased to 41.10g/L. five for ester capsules (2 capsules, 2/d), tacrolimus (0.5mg, 2/d) for reducing the blood drug concentration reached 8 ng/m L steady-state trough, 24 hour urine protein decreased 0.47g/d, albumin increased to 45.10g/L. patients 24 hours urine protein, biochemical index of normal the scope and stability after a period of time, and discontinuation of tacrolimus, single oral irbesartan. Patients with 24 hours urine protein index abnormal after medication adjustment for tacrolimus (0.5mg, 2/d) Maher Bbe Chatain (0.3g, 2/d) 24 hour urine protein quantity not in increased. Treatment of specific plans for tacrolimus binding 2 (0.5g, 2/d), irbesartan (0.15g, 2/d) for the Chinese angelica, Loranthaceae, Centella asiatica, Poria, Rhizoma Chuanxiong, Ganoderma lucidum, fried silkworm, astragalus, licorice, angelica, Radix dipsaci, Cibotium barometz, Radix Rehmanniae Preparata, Fructus Corni. This scheme is applied in patients after Yaoxisuanruan, easily trapped weakness, weak tide Heat symptoms improved. The mental state improved, 1.10g/d urine protein of 24 hours from the previous reduced to 0.17g/d.3 patients before oral tacrolimus produce nausea, retching, usually common dizziness. Adjusted for the meal. The side effects of hormone mainly for osteoporosis, combined with ossification in three alcohol soft capsule and injection of ibandronate but it is easy to cause muscle soreness. Dipyridamole adverse reactions often dizziness, instead of aspirin. Kato Pury caused by irritating cough, changed to irbesartan. Conclusion: 1 tacrolimus combined with prednisone therapy has certain curative effect, patients taking five ester capsule can improve the blood concentration of tacrolimus. Patients may suggest the adjustment according to the outcome of 24 hours urine protein and biochemical indexes of tacrolimus and five ester capsule dose to achieve the purpose of treatment. In the premise of reducing drugs, reduce drug Physical treatment dose. A good conditioning effect on the patient's body with 2, and reduce the urinary protein. If the patients with poor mental state, physical discomfort, western medicine has no obvious effect on considering the treatment of membranous nephropathy.3 generally requires long-term treatment of traditional Chinese medicine and Western medicine. Combining with typical cases of adverse drug treatment period the reaction time, etc., are eating some advice. Oral tacrolimus produce nausea, retching, usually common dizziness. The author suggests to take 20 minutes before taking tacrolimus, monitoring the blood concentration of tacrolimus is provided. And dizziness should pay attention to wake up and so on. Patients usually drive and adverse reaction of hormone for osteoporosis, can taking ossification in three alcohol, vitamin D chewable tablets, and the injection of ibandronate and its adverse reaction is muscle soreness, but after a few days will disappear. To prevent thromboembolism may be taking aspirin, double The adverse reaction of pyridamole is dizziness. In addition, the patients with dry cough after taking Kato Pury can be adjusted to irbesartan. It is suggested that other patients should have a positive mental attitude, keep a light diet and eat low-fat protein.

【学位授予单位】：河北医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R96

【参考文献】