本文關(guān)鍵詞： 他克莫司 膜性腎病 五酯膠囊 百令膠囊 中西醫(yī)結(jié)合治療　出處：《河北醫(yī)科大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：膜性腎病是腎病綜合征主要的病理類型之一,膜性腎病主要分為特發(fā)性膜性腎病和繼發(fā)性膜性腎病,不同類型的膜性腎病治療方案不同,繼發(fā)性膜性腎病的治療主要針對于病因,特發(fā)性膜性腎病多采用鈣調(diào)磷酸酶抑制劑、烷化劑、來氟米特、雷公藤多苷等聯(lián)合激素治療、嗎替麥考酚酯、利妥昔單抗、依庫麗單抗、靜脈注射大劑量免疫球蛋白、促腎上腺皮質(zhì)激素、咪唑硫嘌呤和中西醫(yī)結(jié)合等治療方案。鈣調(diào)磷酸酶抑制劑代表藥為他克莫司和環(huán)孢素A,兩者相比,他克莫司對細胞免疫和體液免疫的抑制作用是Cs A的10~100倍,并且肝毒性較小。他克莫司是大環(huán)內(nèi)酯類的新型免疫抑制劑其作用機制為通過與細胞質(zhì)內(nèi)的他克莫司結(jié)合蛋白相結(jié)合形成的復(fù)合物,主要通過競爭性地抑制鈣調(diào)磷酸酶,從而阻止一系列淋巴細胞的轉(zhuǎn)錄特異性抑制T細胞活化和B淋巴細胞增殖。特發(fā)性膜性腎病中他克莫司聯(lián)合潑尼松治療過程較長,其過程中用藥較多。本課題擬追蹤一例典型病例,對其方案的療效和安全性分析。治療膜性腎病臨床常見他克莫司與潑尼松的方案,以及聯(lián)合用藥為厄貝沙坦和百令膠囊。加用百令膠囊后可改善臨床癥狀與尿蛋白水平,提升臨床療效。部分膜性腎病患者發(fā)展為終末期腎臟病,而采取腎移植術(shù),對腎移植治療臨床常見應(yīng)用他克莫司與百令膠囊合用。百令膠囊為發(fā)酵冬蟲夏草菌粉[Cs—C—Q80],中華被毛孢Hirsutella sinensis Liu,Yu—er Zeng(1989)經(jīng)液體深層發(fā)酵所得菌絲體的干燥粉末制成的膠囊。冬蟲夏草成分豐富,其主要成分對腎臟及免疫有調(diào)節(jié)作用。他克莫司主要是通過腸黏膜上皮細胞P-糖蛋白轉(zhuǎn)運,絕大部分經(jīng)肝臟酶CYP3A4代謝,其中有些藥物通過抑制P-糖蛋白或CYP3A4而影響他克莫司的血藥濃度。經(jīng)文獻檢索,未發(fā)現(xiàn)他克莫司與百令膠囊藥物的相互作用。本課題擬研究百令膠囊對比格犬體內(nèi)他克莫司藥代動力學(xué)的影響,以期為臨床合理用藥提供參考。第一部分百令對他克莫司的藥代動力學(xué)的影響目的:探討百令對比格犬體內(nèi)他克莫司的藥代動力學(xué)的影響;方法:百令對比格犬體內(nèi)他克莫司的藥代動力學(xué)的影響。采用自身前后對照法。對照組:(n=6)將比格犬口服他克莫司膠囊前(0h)及服藥1mg后0.167h,0.333h,0.5h,0.667h,0.833h,1h,1.5h,2h,3h,4h,6h,8h,12h,24h采靜脈血2m L。置EDTA-K2抗凝管中。采用化學(xué)發(fā)光微粒子免疫法監(jiān)測他克莫司的血藥濃度。清洗期為一周。實驗組:口服他克莫司聯(lián)合百令膠囊,采血時間、測定方法等同上。采用DAS(2.1.1版)軟件計算得到主要的藥代動力學(xué)參數(shù)。應(yīng)用SPSS 21.0統(tǒng)計軟件,對數(shù)據(jù)進行配對t檢驗。結(jié)果:聯(lián)合服用他克莫司(1mg)與百令(2粒)與單服他克莫司(1mg)相比,比格犬體內(nèi)他克莫司各采血點血藥濃度,藥-時曲線下面積,消除半衰期、達峰時間、表觀分布容積、清除率等差異均無統(tǒng)計學(xué)意義。達峰濃度差異有統(tǒng)計學(xué)意義結(jié)論:比格犬單服他克莫司1mg和他克莫司1mg與百令膠囊1g(2粒)聯(lián)合應(yīng)用后,他克莫司的藥-時曲線下面積,消除半衰期、達峰時間、、表觀分布容積、清除率均無統(tǒng)計學(xué)意義。達峰濃度差異有統(tǒng)計學(xué)意義。但百令膠囊與他克莫司合用對人體的藥代動力學(xué)有待進一步研究。第二部分特發(fā)性膜性腎病典型病例用藥分析目的:對特發(fā)性膜性腎病典型病例治療方案和安全性進行分析,以期為臨床合理用藥提供參考。方法:特發(fā)性膜性腎病典型病例用藥分析。追蹤一例典型特發(fā)性膜性腎病患者,結(jié)合患者臨床癥狀、檢驗指標(biāo)包括尿蛋白、生化指標(biāo)、血常規(guī)、他克莫司血藥濃度等以及藥品不良反應(yīng)等情況。對其治療方案的療效和安全性以及聯(lián)合用藥情況進行分析,以期為臨床合理用藥提供參考。結(jié)果:1患者的病理結(jié)果為膜性腎病一期,治療方案為他克莫司(1mg,2/d)聯(lián)合潑尼松(10mg,1/日)治療,15天后患者24小時尿蛋白量由原來的6.58g/d降低到5.57g/d。聯(lián)合應(yīng)用五酯膠囊為(2粒,3/d)15天后以后,他克莫司的血藥濃度由服用五酯前的3.2 ng/ml增加到11.7ng/m L,24小時尿蛋白的量則從5.57g/d減少到1.22g/d且血漿白蛋白值由之前的30.21g/L升高到33.40g/L。當(dāng)五酯膠囊減少為(2粒,2/d)他克莫司血藥濃度降低為10.9ng/m L,24小時尿蛋白降低到1.17g/d,白蛋白升高到41.10g/L。五酯膠囊為(2粒,2/d),他克莫司減為(0.5mg,2/d)時其血藥穩(wěn)態(tài)谷濃度達到8.0 ng/m L,24小時尿蛋白量降低為0.47g/d,白蛋白升高到45.10g/L。患者24小時尿蛋白,生化指標(biāo)達正常范圍并且穩(wěn)定一段時間后,停用他克莫司和激素,單服厄貝沙坦。患者24小時尿蛋白指標(biāo)出現(xiàn)異常后調(diào)整用藥為他克莫司(0.5mg,2/d)厄貝沙坦(0.3g,2/d)24小時尿蛋白量不在升高。2中西醫(yī)結(jié)合治療具體方案為他克莫司(0.5g,2/d),厄貝沙坦(0.15g,2/d)中藥為獨活、桑寄生、積雪草、茯苓、川芎、靈芝、炒僵蠶、生黃芪、生甘草、續(xù)斷、燙狗脊、當(dāng)歸、熟地黃、酒萸肉�；颊邞�(yīng)用此方案后腰膝酸軟,易困乏力,體虛潮熱癥狀得到改善。精神狀態(tài)得到提高,24小時尿蛋白量由之前的1.10g/d降低到0.17g/d。3患者飯前口服他克莫司產(chǎn)生惡心,干嘔,平時常見頭暈。調(diào)整為飯后服用。激素的副作用主要表現(xiàn)為骨質(zhì)疏松,加用骨化三醇軟膠囊,并注射伊班膦酸但其易導(dǎo)致肌肉酸痛。雙嘧達莫不良反應(yīng)常為頭暈,改為阿司匹林。卡托普利引起刺激性干咳,改換為厄貝沙坦。結(jié)論:1他克莫司聯(lián)合潑尼松的治療的方案產(chǎn)生了一定的治療效果,患者服用五酯膠囊可以提高他克莫司的血藥濃度。建議患者可根據(jù)24小時尿蛋白轉(zhuǎn)歸及生化指標(biāo)情況調(diào)整他克莫司和五酯膠囊的劑量。在達到治療的目的前提下,減少藥物品種,降低藥物劑量。2中西醫(yī)結(jié)合治療對患者的機體起到了很好的調(diào)理作用,并且降低了尿蛋白。如患者精神狀態(tài)不佳,身體不適,西藥的作用不明顯可考慮中西醫(yī)結(jié)合治療。3膜性腎病一般需長期治療。結(jié)合典型病例對治療期間藥品不良反應(yīng)、作息時間、飲食等情況給出一些建議。口服他克莫司產(chǎn)生惡心,干嘔,平時常見頭暈。建議改為飯后服用他克莫司,服藥前20分鐘監(jiān)測他克莫司血藥濃度。而頭暈則提醒患者平時開車等情況需注意。而激素的不良反應(yīng)主要為骨質(zhì)疏松,可服用骨化三醇,維D鈣咀嚼片,以及注射伊班膦酸鈉,其不良反應(yīng)是肌肉酸痛,但幾天后會消失。對于防止血栓栓塞可服用阿司匹林,雙嘧達莫的不良反應(yīng)為頭暈。此外服用卡托普利后干咳的患者,可調(diào)藥為厄貝沙坦。建議其他患者作息規(guī)律,保持積極的心態(tài),飲食清淡,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.

【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R96

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