本文選題：苯妥英鈉 + 個體化給藥　； 參考：《安徽醫(yī)科大學》2014年碩士論文

【摘要】：苯妥英鈉（Phenytoin），又名苯妥英、大倫丁鈉，是癲癇大發(fā)作時的首選藥物。華法林（Warfarin）作為香豆素類口服抗凝藥，目前廣泛用于治療心臟瓣膜置換術、深靜脈血栓、肺栓塞、房顫等。這兩種藥物的治療窗均較窄，血藥濃度個體差異大，易受多種因素影響，因此對其實施個體化給藥尤為必要。本研究分為以下兩個部分： 第一部分以基因導向和NONMEM為基礎探討苯妥英鈉劑量個體化給藥方案 目的：以基因導向和NONMEM為基礎，建立苯妥英鈉群體藥動學模型，優(yōu)化初始給藥劑量，進一步獲得苯妥英鈉劑量個體化給藥方案，為臨床合理使用苯妥英鈉提供參考依據。 方法：收集顱內腫瘤切除術后口服苯妥英鈉以預防術后癲癇發(fā)作的112例病人的272個苯妥英鈉血藥濃度點和CYP2C9、CYP2C19基因分型及相關臨床數據。應用非線性混合效應模型(nonlinear mixed effect model, NONMEM)軟件求算藥動學參數，建立基礎模型和最終模型，并以最終模型設計其劑量個體化方案進行臨床應用。 結果：經NONMEM法對數據進行群體藥動學分析，獲得最終模型公式為：①CYP2C9*1/*1合并CYP2C19*1/*1或*1/*2或*1/*3時, Vmax=23.8×(WT/66.07)0.856×1.16(mg·h-1)，Km=5.84×0.731(mg·L-1)；②CYP2C9*1/*1合并CYP2C19*2/*2或*2/*3或*3/*3時，Vmax=23.8×(WT/66.07)0.856×0.874(mg·h-1)，Km=5.84×0.659(mg·L-1)；③CYP2C9*1/*3合并CYP2C19*1/*1或*1/*2或*1/*3或*2/*2或*2/*3或*3/*3時，Vmax=23.8×(WT/66.07)0.856×0.796(mg·h-1)，Km=5.84×0.291(mg·L-1)。采用Bootstrap法進行內部驗證，，結果顯示模型穩(wěn)定、可靠。臨床應用中，13例患者中有9例患者的苯妥英鈉血藥濃度在服藥7天后達到有效治療濃度水平（10~20mg·L-1）。 結論：以基因導向和NONMEM為基礎可獲得顱內腫瘤切除術后患者體內苯妥英鈉的群體藥動學模型，內部驗證結果顯示該模型穩(wěn)定可靠，可為臨床設計苯妥英鈉劑量個體化方案提供參考。 第二部分以基因導向為基礎，以meta分析法探討華法林劑量的個體化給藥方案 目的：用meta分析方法探討CYP2C9和VKORC1-1639GA不同基因型組合對華法林平均日劑量(Mean daily warfarin dose, MDWD)影響的定量關系，為臨床設計華法林劑量個體化給藥方案提供參考。 方法：計算機檢索相關期刊論文(CNKI)、中國生物醫(yī)學文獻數據庫(CBM)、萬方數據庫、PubMed (2004.1~2013.7)，根據納入標準對文獻進行篩選和評估，采用RevMan5.1軟件及Stata12.0軟件對數據進行Meta分析。 結果：共納入包括998名患者在內的9篇研究，其中中文3篇，英文6篇。結果顯示，與*1/*1+AA組相比，*1/*1+GG組、*1/*1+GA組和*1/*3+GA組MDWD分別升高1.01(95%CI:0.38,1.65, P=0.002)、0.41(95%CI:0.15,0.68, P=0.002)和0.06個標準單位(95%CI:－0.06,0.18, P=0.31)；*1/*3+AA組和*3/*3+AA組MDWD分別降低0.29(95%CI:－0.45,－0.13, P=0.0004)和0.38個標準單位(95%CI:－0.59,－0.17,P=0.0003)。敏感性分析表明，結果穩(wěn)定。 結論：本meta分析得到CYP2C9和VKORC1-1639GA不同基因型組合對華法林平均日劑量的影響的定量結果，該結果可對華法林個體化給藥提供參考。
[Abstract]:In this study , it is especially necessary for the treatment of heart valve replacement , deep vein thrombosis , pulmonary embolism , atrial fibrillation , etc . The study is divided into two parts :

The first part , based on the genetic guidance and NONMEM , was used to study the dosage of sodium phentoylide .

Objective : To establish a pharmacokinetic model of phentolamine based on the genetic guidance and NONMEM , to optimize the initial dose of administration , to further obtain a dose - individualized dosing regimen of Phenylide , and to provide a reference for clinical rational use of sodium phentolamine .

Methods : 272 patients with epilepsy after resection of intracranial tumor were collected for prevention of post - operative epilepsy , and 272 patients with epilepsy were divided into two groups . The pharmacokinetic parameters were calculated by nonlinear mixed effect model ( NONMEM ) software , the basic model and the final model were established , and their dosage regimens were designed in the final model for clinical application .

RESULTS : The data were analyzed by NONMEM method . The formula of the final model was as follows : ( 1 ) Vmax = 23.8 脳 ( WT / 66.07 ) 0.856 脳 1.16 ( mg 路 h - 1 ) , Km = 5.84 脳 0.731 ( mg 路 L - 1 ) .
( 2 ) Vmax = 23 . 8 脳 ( WT / 66.07 ) 0.856 脳 0.874 ( mg 路 h - 1 ) , Km = 5.84 脳 0.659 ( mg 路 L - 1 ) ;
In clinical application , 9 out of 13 patients received effective treatment concentration ( 10 ~ 20mg 路 L - 1 ) after 7 days of administration .

Conclusion : Based on the gene guidance and NONMEM , the pharmacokinetic model of phentolamine in patients with intracranial tumor resection is obtained . The results of internal verification show that the model is stable and reliable , which can provide a reference for clinical design of sodium phentolamine dosage regimens .

The second part is based on gene guidance , and the individual dosage regimen of warfarin dosage is discussed by meta - analysis .

Objective : To study the quantitative relationship between the effects of different genotype combinations on mean daily warfarin dose ( MDWD ) and mean daily warfarin dose ( MDWD ) by meta - analysis .

Methods : The Chinese Journal Full - Text Database ( CNKI ) , Chinese Biomedical Literature Database ( CBM ) , Wanfang Database ( 2004 . 1 - 2013 . 7 ) were searched and the literature was screened and evaluated according to the inclusion criteria , and the data were analyzed by RevMan5.1 software and Stata12.0 software .

Results : Nine studies including 998 patients were included , including 3 Chinese and 6 in English . Results showed that MDWD increased 1.01 ( 95 % CI : 0.38 , 1.65 , P = 0.002 ) , 0.41 ( 95 % CI : 0.15 , 0.68 , P = 0.002 ) and 0.06 standard units ( 95 % CI : - 0.06 , 0.18 , P = 0.31 ) compared with the * 1 / * 1 + AA group .
* 1 / * 3 + AA group and * 3 / * 3 + AA group MDWD decreased 0.29 ( 95 % CI : - 0.45 , - 0.13 , P = 0.0004 ) and 0.38 standard units ( 95 % CI : - 0.59 , - 0.17 , P = 0.0003 ) , respectively . The sensitivity analysis shows that the results are stable .

Conclusion : This meta - analysis results in the quantitative results of the effects of different genotypes on the mean daily dose of warfarin . The results can provide reference for individual administration of warfarin .
【學位授予單位】：安徽醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R969.1

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