氨磷汀预防化疗致周围神经毒性疗效与安全性的系统评价

目的:系统评价氨磷汀预防化疗致周围神经毒性(CIPN)的疗效和安全性,为临床提供循证参考。方法:计算机检索PubMed、EMBase、Cochrane图书馆、中国期刊全文数据库、万方数据库和中文科技期刊数据库,收集氨磷汀联合化疗(试验组)对比单纯化疗(对照组)用于肿瘤患者的随机对照试验(RCT),资料提取并采用改良的Jadad评分量表评价质量后,采用RevMan 5.3统计软件进行Meta分析。结果:共纳入20项RCT,合计1 552例患者。Meta分析结果显示,试验组患者CIPN总发生率[RR=0.57,95%CI(0.45,0.72),P<0.001]、严重CIPN发生率[RR=0.47,95%CI(0.32,0.69),P<0.001]显著低于对照组,恶心发生率[RR=1.31,95%CI(1.03,1.67),P=0.03]、呕吐发生率[RR=2.28,95%CI(1.14,4.54),P=0.02]及低血压发生率[RR=28.29,95%CI(10.53,76.04),P<0.001]显著高于对照组,差异均有统计学意义;两组患者客观缓解率比较,差异无统计学意义[RR=1.08,95%CI(0.98,1.19),P=0.14]。结论:氨磷汀能有效预防肿瘤患者化疗致CIPN的发生,且不影响化疗疗效,但会加重患者化疗后恶心、呕吐的发生,并易诱发低血压。     

艾塞那肽治疗2型糖尿病疗效及安全性的Meta分析

目的:评价人胰高血糖素样肽-1(GLP-1)抑制剂艾塞那肽治疗2型糖尿病的疗效及安全性。方法:计算机检索EMBase、PubMed、Coehrane、中国期刊网数据库(CNKI)、万芳数据库(VIP)、中国生物医学文献数据库(CBM)数据库,纳入相关随机对照试验(RCT),对纳入的RCT进行质量评价并提取相关资料。应用RevMan 5.2软件进行Meta分析,计算均数差(MD)、相对风险度(RR)和95%置信区间(CI)。结果:共纳入8个RCT进行分析。Meta分析结果显示:艾塞那肽组在改善2型糖尿病患者糖化血红蛋白和空腹血糖水平方面显著优于安慰剂[MD=-0.86,95%CI(-0.95,-0.77),P<0.01;MD=-1.06,95%CI(-1.52,-0.59),P<0.01]。在不良反应发生率方面,艾塞那肽组发生恶心和呕吐的相对风险度显著增高[RR=3.91,95%CI(2.36,6.47),P<0.01;RR=3.73,95%CI(1.67,8.34),P=0.01]。合用磺酰脲类治疗时,艾塞那肽组发生低血糖的相对风险度较安慰剂显著增高[RR=3.55,95%CI(1.55,8.16),P<0.01];未合用磺酰脲类治疗时,则与安慰剂组无显著性差异[RR=1.03,95%CI(0.74,1.43),P=0.87]。结论:艾塞那肽可显著改善2型糖尿病患者糖化血红蛋白和空腹血糖水平,但恶心和呕吐不良反应发生风险增高,同时与磺酰脲类药物合用可能会增加低血糖风险。     

左氧氟沙星联合常规四联化疗方案治疗复治涂阳肺结核疗效及安全性的Meta分析

目的 采用Meta分析法评价左氧氟沙星联合常规四联化疗方案治疗复治涂阳肺结核的疗效及安全性。方法 计算机检索中国知网、万方数据知识服务平台、维普网等中文数据库中公开发表的左氧氟沙星联合常规化疗方案治疗复治涂阳肺结核的相关文献,时间限定为建库起至2022年8月。对照组采用利福平+异烟肼+吡嗪酰胺+乙胺丁醇常规化疗方案,试验组在对照组基础上加用左氧氟沙星。提取纳入文献的资料,采用Cochrane评价法评价纳入文献的质量,采用Stata MP 15及RevMan 5.3软件进行Meta分析。结果 最终纳入23篇文献,共包含1 793例患者,各文献的选择偏倚均为低风险。Meta分析结果显示,试验组总有效率[RR=3.66,95%CI(2.78,4.82)]、痰菌转阴率[RR=1.33,95%CI(1.25,1.41)]、空洞闭合率[RR=1.50,95%CI(1.31,1.71)]、病灶总吸收率[RR=1.28,95%CI(1.21,1.36)]高于对照组(P<0.05),不良反应发生率低于对照组[RR=0.46,95%CI(0.34,0.60),P<0.05]。漏斗图结果显示,报...     

华蟾素注射液联合化疗药物治疗中晚期非小细胞肺癌的Meta 分析

目的根据现有临床资料系统评价华蟾素注射液联合化疗作为中晚期非小细胞肺癌(NSCLC)治疗方案的疗效及安全性。方法电子检索Medline(1966～2011)、Cochrane Library(2011年第11期)、CNKI(1978～2011)、维普(1989～2011)、万方(1988～2011)、CBMdisc(1978～2011)等数据库,对符合纳入标准的随机对照试验(RCT),采用RevMan5.0.2软件进行Meta分析。结果通过阅读文题、摘要及全文后,最终共纳入7个RCT,共498例患者。Meta分析结果显示:试验组和对照组在近期(6个月)疗效[RR=1.29,95%CI(1.07,1.56)]、治疗前后卡氏评分[RR=1.86,95%CI(1.14,3.05)]、体重增加[RR=1.56,95%CI(1.20,2.03)]、胃肠道反应[RR=0.72,95%CI(0.53,0.99)]、白细胞减少[RR=0.70,95%CI(0.54,0.91)]、血小板减少[RR=0.53,95%CI(0.38,0.75)]、肾功能异常[RR=0.37,95%CI(0.17,0.79)]等反面差异具有统计学意义,在肝功能异常[RR=0.59,95%CI(0.26,1.34)]、神经毒性[RR=0.74,95%CI(0.32,1.75)]等方面差异无统计学意义。结论华蟾素注射液联合化疗适于晚期NSCLC的治疗,能提高近期疗效,提高卡氏评分,增加体重,并且减少胃肠道反应、白细胞减少、血小板减少等毒副作用。     

基于随机对照试验的儿童利奈唑胺抗感染治疗有效性和安全性的Meta 分析

目的:评价利奈唑胺在儿科感染患者中应用的有效性和安全性。方法:检索Pumed、EMBase、the Cochrane Library、中国知网(CNKI)、万方数据库和中国生物医学文献数据库(CBM),检索时限均从建库至2017年7月。纳入利奈唑胺治疗儿科感染患者的相关随机对照试验(RCT),应用RevMan 5.3 软件进行Meta 分析。结果:共纳入2篇RCT文献,包括815例患儿。对照组为万古霉素等其他抗革兰阳性菌有效的阳性对照药物。有效性研究显示,试验组临床有效性[OR= 1.39,95% CI(0.98,1.98),P=0.07]和微生物有效性[OR=1.12,95%CI(0.61,2.03),P=0.72]与对照组比较差异无统计学意义(P>0.05);亚组分析显示,利奈唑胺治疗耐甲氧西林金黄色葡萄球菌(MRSA)[OR=1.20,95%CI(0.18,7.92),P=0.85]和甲氧西林敏感金黄色葡萄球菌(MSSA)[OR =1.05,95%CI(0.48,2.30), P=0.90]疗效与对照组比较差异无统计学意义( P>0.05)。安全性研究显示,试验组与对照组腹泻[RR=0.86,95%CI(0.51,1.45),P=0.58]、恶心[RR=1.31, 95%CI(0.54,3.18),P=0.55]、呕吐[RR=0.56,95%CI(0.25,1.22),P =0.14]和中性粒细胞减少[RR =1.34,95%CI(0.73,2.49),P=0.35]发生率比较差异无统计学意义(P>0.05)。结论:基于目前的RCT 研究,利奈唑胺治疗儿科患者感染性疾病的有效性较好,但与其他抗菌药物的有效性和安全性比较无显著优势,有待更大规模的临床试验进一步深入研究。     

复方苦参注射液联合含奥沙利铂化疗方案治疗大肠癌疗效与安全性的系统评价

目的:系统评价复方苦参注射液联合含奥沙利铂化疗方案治疗大肠癌的疗效和安全性,为临床提供循证参考。方法:计算机检索中国期刊全文数据库、万方数据库、中国生物医学文献数据库、中文科技期刊数据库、PubMed、Cochrane图书馆,收集复方苦参注射液联合含奥沙利铂化疗方案(试验组)对比常规化疗方案(对照组)治疗大肠癌的随机对照试验(RCT),提取资料并依据改良的Jadad量表进行质量评价后,采用RevMan 5.3统计软件进行Meta分析。结果:最终纳入33项RCT,合计2 801例患者。Meta分析结果显示,试验组患者近期有效率[RR=1.34,95%CI(1.24,1.46),P<0.001]、功能状态(KPS)评分改善率[RR=1.87,95%CI(1.65,2.14),P<0.001]、CD4~+/CD8~+[WMD=0.49,95%CI(0.26,0.72),P<0.001]、CD4~+水平[WMD=10.34,95%CI(7.00,13.69),P<0.001]、CD3~+水平[WMD=5.85,95%CI(4.07,7.62),P<0.001]、自然杀伤细胞水平[WMD=3.52,95%CI(1.76,5.27),P<0.001]、白细胞介素(IL)-2水平[WMD=12.96,95%CI(10.39,15.53),P<0.001]显著高于对照组,CD8~+水平[WMD=-5.89,95%CI(-11.39,-0.40),P=0.04]、IL-10水平[WMD=-21.04,95%CI(-29.15,-12.94),P<0.001]、恶心呕吐发生率[RR=0.72,95%CI(0.67,0.78),P<0.001]、白细胞减少发生率[RR=0.52,95%CI(0.45,0.61),P<0.001]、肝功能异常发生率[RR=0.63,95%CI(0.53,0.74),P<0.001]、周围神经毒性发生率[RR=0.77,95%CI(0.64,0.92),P=0.005]显著低于对照组,差异均有统计学意义。结论:复方苦参注射液联合含奥沙利铂化疗方案治疗大肠癌疗效优于单纯化疗,可以提高患者生存质量,改善免疫功能,降低化疗引起的不良反应。     

参附注射液联合化学治疗对非小细胞肺癌疗效的Meta分析

目的评价参附注射液联合化学治疗(简称化疗)对非小细胞肺癌(NSCLC)的有效性和安全性。方法采用Cochrane系统评价方法,检索Cochrane Library,PubMed,EMbase,CBM,VIP,CNKI及万方数据库,检索时间从各数据库建库至2013年7月。纳入参附注射液联合化疗方案治疗NSCLC的随机对照试验(RCT),根据Cochrane Handbook 5.0进行质量评价并对同质研究采用RevMan 5.2软件进行Meta分析。结果共纳入7个RCT,包括421例患者。Meta分析结果显示,与单纯化疗方案相比,参附注射液联合化疗可提高功能状态卡氏(KPS)评分[加权均数差(WMD)=8.27,95%CI(5.27,11.27),P<0.000 01]、减少白细胞下降[RR=0.59,95%CI(0.39,0.90),P=0.01]和血小板下降[RR=0.63,95%CI(0.40,0.98),P=0.04],降低恶心呕吐[RR=0.60,95%CI(0.42,0.85),P=0.004]及腹泻发生率[RR=0.54,95%CI(0.30,0.96),P=0.03],而在有效率[RR=1.10,95%CI(0.75,1.63),P=0.62]、肝功能损害[RR=1.03,95%CI(0.47,2.24),P=0.95]、肾功能损害[RR=0.68,95%CI(0.21,2.19),P=0.52]方面的差异无统计学意义。结论评价结果初步显示,参附注射液联合化疗治疗非小细胞肺癌可提高KPS评分、降低不良反应,但由于纳入研究少,上述结果尚有待高质量大样本的随机双盲对照试验验证。     

乌苯美司联合化疗用于恶性肿瘤的系统评价

目的:系统评价乌苯美司联合化疗用于恶性肿瘤的疗效和安全性,为临床提供循证参考。方法:计算机检索Central、PubMed、中国期刊全文数据库、中文科技期刊数据库、万方数据库,收集乌苯美司联合化疗(试验组)对比单纯化疗(对照组)用于恶性肿瘤的随机对照试验(RCT),筛选文献、提取资料并采用Cochrane系统评价员手册5.1.0提供的偏倚风险评价标准评价纳入研究质量,采用Rev Man 5.3统计软件进行Meta分析。结果:共纳入12项RCT,包括762例患者。Meta分析结果显示,试验组患者近期有效率[RR=1.24,95%CI(1.08,1.43),P=0.002]、生存质量(KPS)评分改善率[RR=1.69,95%CI(1.46,1.95),P<0.001]显著高于对照组,胃肠道毒性发生率[RR=0.74,95%CI(0.57,0.94),P=0.02]和白细胞抑制发生率[Ⅰ°～Ⅳ°(用药≤3个月):RR=0.54,95%CI(0.37,0.79),P=0.002;Ⅲ°～Ⅳ°:RR=0.44,95%CI(0.29,0.68),P<0.001]显著低于对照组,差异均有统计学意义。结论:乌苯美司联合化疗用于恶性肿瘤,可以提高患者的近期疗效,改善生存质量,降低胃肠道毒性和骨髓毒性。     

罗氟司特对亚洲慢性阻塞性肺疾病患者肺功能影响的Meta分析

目的:系统评价罗氟司特对亚洲慢性阻塞性肺疾病(COPD)患者肺功能的影响,为临床合理用药提供循证参考。方法:计算机检索Cochrane图书馆、PubMed、Embase、中国生物医学文献数据库、中国知网、维普数据库和万方数据库,收集罗氟司特或罗氟司特联合常规治疗或安慰剂(试验组)对比常规治疗或安慰剂治疗(对照组)治疗亚洲人群COPD的随机对照试验(RCT)。筛选文献,提取资料并按照Cochrane偏倚风险评估工具评价文献质量后,采用Rev Man 5.2软件进行Meta分析。结果:共纳入6项RCT,包括1 494例患者。Meta分析结果显示,试验组患者支气管扩张药使用前第1秒用力呼气容积[MD=75.19,95%CI(53.21,97.17),P<0.000 01]、支气管扩张药使用后第1秒用力呼气容积[MD=56.60,95%CI(27.56,85.63),P=0.000 1]、用力肺活量[MD=43.67,95%CI(15.91,71.43),P=0.002]、支气管扩张药使用后25%～75%用力肺活量的平均流速[MD=14.58,95%CI(8.43,20.73),P<0.001]、腹泻发生率[RR=5.06,95%CI(1.26,20.27),P=0.02]、呼吸道感染发生率[RR=1.94,95%CI(1.30,2.90),P=0.001]、食欲下降发生率[RR=7.43,95%CI(2.94,18.79),P=0.001]、体质量下降发生率[RR=5.46,95%CI(2.12,14.03),P=0.001]、头痛发生率[RR=7.73,95%CI(1.42,42.16),P=0.02]、头晕发生率[RR=3.44,95%CI(1.28,9.27),P=0.01]、胃炎发生率[RR=5.09,95%CI(1.49,17.45),P=0.01]、厌食症发生率[RR=5.06,95%CI(1.97,13.00),P=0.001]均显著高于对照组;圣乔治呼吸问卷总评分[MD=-5.82,95%CI(-7.77,-3.87),P<0.001]、呼吸症状评分[MD=-1.67,95%CI(-2.51,-0.84),P<0.001]、活动受限评分[MD=-1.55,95%CI(-2.14,-0.97),P<0.001]、疾病影响评分[MD=-2.59,95%CI(-3.40,-1.79),P<0.001]均显著低于对照组。结论:罗氟司特可改善亚洲COPD患者的肺功能及呼吸困难症状,但会增加不良反应的发生风险。     

利奈唑胺对比糖肽类抗菌药物治疗MRSA相关性院内获得性肺炎的疗效和安全性的Meta分析

目的:系统评价利奈唑胺对比糖肽类抗菌药物治疗耐甲氧西林金黄色葡萄球菌(MRSA)相关性院内获得性肺炎的疗效和安全性。方法:计算机检索Medline、EMBase、OVID、中国生物医学文献数据库、中国期刊全文数据库、维普及万方数据库,查找利奈唑胺对比糖肽类抗菌药物治疗MRSA相关性院内获得性肺炎的随机对照试验(RCT)。对符合条件的RCT进行资料提取和质量评价后,采用Rev Man 5.1统计软件进行Meta分析。结果:共纳入8项RCT,合计1 966例患者。Meta分析结果显示,利奈唑胺治疗MRSA相关性院内获得性肺炎的临床治愈率[RR=1.10,95%CI(1.01,1.20),P=0.03]、微生物清除率[RR=1.14,95%CI(1.03,1.27),P=0.01]均高于糖肽类抗菌药物;而两者的病死率[RR=0.86,95%CI(0.68,1.08),P=0.20]和不良反应发生率[RR=1.05,95%CI(0.94,1.16),P=0.41]比较差异无统计学意义。结论:利奈唑胺较糖肽类抗菌药物治疗MRSA相关性院内获得性肺炎可以提高患者的临床治愈率和微生物清除率,但是不能改善患者病死率及不良反应发生率。限于研究的设计及报告质量,该结论仍有进一步评价的必要。     

Role of glutathione in reduction of arsenate and of gamma-glutamyltranspeptidase in disposition of arsenite in rats

Arsenate (AsV), the environmentally prevalent form of arsenic, is converted sequentially in the body to arsenite (AsIII), monomethylarsonic acid (MMAsV), monomethylarsonous acid (MMAsIII), and dimethylarsinic acid (DMAsV) and some trimethylated metabolites. Although the biliary excretion of arsenic in rats is known to be glutathione (GSH)-dependent, involving transport of arsenic-GSH conjugates, the role of GSH in the reduction of AsV to the more toxic AsIII in vivo has not been defined. Therefore, we studied how the fate of AsV is influenced by buthionine sulfoximine (BSO), which depletes GSH in tissues. Control and BSO-treated rats were given AsV (50 micromol/kg, i.v.) and arsenic metabolites in bile, urine, blood and tissues were analysed by HPLC-HG-AFS. BSO increased retention of AsV in blood and tissues and decreased appearance of AsIII in blood, bile (by 96%) and urine (by 63%). The biliary excretion of MMAsIII was also nearly abolished, the appearance of MMAsIII and MMAsV in the blood was delayed and the renal concentrations of these monomethylated arsenicals were decreased by BSO. Interestingly, appearance of DMAsV in blood and urine remained unchanged and the concentrations of this metabolite in the kidneys and muscle were even increased in response to BSO. To test the role of gamma-glutamyltranspeptidase (GGT) in arsenic disposition, the effect of the of the GGT inhibitor acivicin was investigated in rats injected with AsIII (50 micromol/kg, i.v.). Acivicin lowered the hepatic and renal GGT activities and increased the biliary as well as urinary excretion of GSH, but failed to alter the disposition (i.e. blood and tissue concentrations, biliary and urinary excretion) of AsIII and its metabolites. In conclusion, shortage of GSH decreases not only the hepatobiliary transport of arsenic, but also reduction of AsV and the formation of monomethylated arsenic, while not hindering the production of dimethylated arsenic. While GSH plays an important role in the disposition and toxicity of arsenic, GGT, which hydrolyses GSH and GSH conjugates, apparently does not influence the fate of the GSH-reactive trivalent arsenicals in rats.     

微透析取样技术在中药体内分析中的应用研究进展

本文综述了微透析取样技术在中药体内分析中的应用,介绍微透析取样技术的原理、组成、探针类型、特点,重点阐述了微透析取样技术在测定脑、血液、皮肤等组织器官中中药有效成分浓度的应用实例。表明微透析取样技术在中药药效研究中具有广阔的前景。     

应用PASS系统分析我院2010年住院医嘱

目的:了解我院2010年住院患者的合理用药情况,探讨如何利用合理用药监测系统( PASS)提高合理用药水平.方法:利用PASS对我院2010年15 966例住院患者的1 184 997条用药医嘱进行监测,以黑色警示医嘱为依据,收集不合理用药信息,并对监测结果进行统计、分析.结果:不合理用药医嘱50 261条,发生率为4.24％.绝对禁止黑色医嘱5441条,主要为药物相互作用(66.54％)、注射液体外配伍(17.86％)、用法用量(15.46％)、儿童警告(1.14％).结论:应用PASS系统能有效监测医嘱中的不合理用药情况,有利于提高临床合理用药水平,但PASS系统尚存在局限性,有待进一步完善.     

Changes in levels of dependency and predictors of mortality in elderly people in institutional care in Dunedin

The 1983 study of dependency of subjects in institutional care in Dunedin was repeated two years later. A significant increase in levels of dependency in residential homes, particularly in the Religious and Welfare sector was found. In 1983 there were 29 high dependency residents and 73 medium dependency residents in residential homes. In 1985 these numbers had increased to 55 and 86 respectively. There was no change in the number of low dependency residents. In 1983, 6 high dependency residents had been admitted to residential home care in the year prior to the study. In 1985 the number of high dependency residents recently admitted had increased to 23. There had also been a significant increase in the dependency of patients in Religious and Welfare continuing care hospitals. Of the 933 subjects in institutional care in 1983 who were able to be followed, 354 (37.9%) died in the following 2 years. Mortality rate was higher for those in hospital care (48.1%) than for those in residential home care (29.6%). Mortality rates were higher in more dependent subjects and this was evident for each measure of dependency.     

应用PASS系统对我院2008年住院医嘱的分析

目的监测分析2008年我院住院患者用药情况。方法将PASS系统嵌入医生工作站、临床药学工作站等子系统,构建合理用药计算机网络系统,对住院医嘱进行及时监测,将监测结果向医生反馈,并对其进行统计、分析。结果2008年共监测医嘱3 620 241条,不合理医嘱908条,占0.02%。不合理医嘱中,配伍禁忌(381条)占41.96%,用法用量(381条)占41.96%,药物相互作用(108条)占11.89%,儿童用药(38条)占4.19%。经与医生沟通后,更改不合理医嘱856条,占94.27%。结论PASS系统可有效监测医嘱中的不合理用药,通过与医生交流,大大减少药物不良事件的发生,值得临床推广应用,也为临床药师开展工作带来了极大的便利。但PASS系统尚存在局限性,有待进一步完善。     

Role of desacetylation in the detoxification of cephalothin in renal cells in culture

The toxicity of three cephalosporin antibiotics to rabbit kidney cells in culture was compared to their known nephrotoxic potential in vivo (cephaloridine greater than cefazolin greater than cephalothin). While cephalothin is considered to be a relatively nonnephrotoxic cephalosporin when administered to many species including humans and rabbits, in several in vitro systems involving rabbit renal tissue, cephalothin was comparatively more toxic than anticipated based on in vivo data. Cephalothin is extensively desacetylated in rabbits to a less microbiologically active metabolite, desacetylcephalothin. When a microsomal S9 fraction from rabbit kidney was added to the in vitro assay in cultured rabbit renal cells, cephalothin was desacetylated and its toxicity to kidney cells was reduced. The addition of S9 in vitro provided a toxicity ranking of the cephalosporins that correlated with their known in vivo nephrotoxic potentials (cephaloridine greater than cefazolin greater than cephalothin). The in vitro detoxification of cephalothin by S9 was blocked by the coadministration of the esterase inhibitor, aminocarb. Desacetylcephalothin was relatively nontoxic to rabbit renal tissue in vitro. These results suggest that the desacetylation of cephalothin in vivo represents a previously unrecognized mechanism of detoxification of this cephalosporin antibiotic. Furthermore, this mechanism of detoxification may be applicable to other acetylated cephalosporins.     

2009年某院住院患者抗真菌药用药调查

目的:分析讨论某院抗真菌药使用的合理性,为临床安全有效地使用抗真菌药提供参考。方法:回顾性统计分析某院2009年住院患者抗真菌药用药信息。结果:2009年某院住院患者抗真菌药DDDs排名前3名分别为:氟康唑、制霉菌素和伊曲康唑;使用金额排名前3名分别为:氟康唑、米卡芬净及卡泊芬净;更换一种抗真菌药进行治疗的患者数为176人,在全部患者中占13.4%。结论:应进一步强化用药指征的意识,提高标本送检率,同时改善某些抗真菌用药不合理更换的现象,以避免耐药性发生,从而更好更长远地体现抗真菌药的治疗价值。     

Kinetics of in vitro metabolism of methoxyphenamine in rats

1. Methoxyphenamine (MP) was metabolized in vitro by rat liver preparations to O-desmethylmethoxyphenamine (O-desmethyl-MP), N-desmethylmethoxyphenamine (N-desmethyl-MP) and 5-hydroxymethoxyphenamine (5-hydroxy-MP). These metabolic pathways were inhibited by SKF 525-A and carbon monoxide, which indicates that these reactions were mediated at least partly by an NADPH-dependent cytochrome P-450 system. 2. Strain differences in the metabolism of this drug in vitro were observed in female Lewis and Dark Agouti (DA) rats, which are proposed models for human debrisoquine phenotypes. Methoxyphenamine O-demethylase and 5-hydroxylase activity in DA rats were lower than those in Lewis rats. 3. The metabolic transformation of methoxyphenamine in vitro to O-desmethyl-MP was inhibited competitively by debrisoquine and sparteine. This indicates that the cytochrome P-450 isoenzyme mediating the metabolism of MP to O-desmethyl-MP is similar to that mediating metabolism of debrisoquine and sparteine. However, no inhibition was observed with methenytoin.     

Comparison of in vitro cell models in predicting in vivo brain entry of drugs

Although several in vitro models have been reported to predict the ability of drug candidates to cross the blood-brain barrier, their real in vivo relevance has rarely been evaluated. The present study demonstrates the in vivo relevance of simple unidirectional permeability coefficient (P(app)) determined in three in vitro cell models (BBMEC, Caco-2 and MDCKII-MDR1) for nine model drugs (alprenolol, atenolol, metoprolol, pindolol, entacapone, tolcapone, baclofen, midazolam and ondansetron) by using dual probe microdialysis in the rat brain and blood as an in vivo measure. There was a clear correlation between the P(app) and the unbound brain/blood ratios determined by in vivo microdialysis (BBMEC r=0.99, Caco-2 r=0.91 and MDCKII-MDR1 r=0.85). Despite of the substantial differences in the absolute in vitro P(app) values and regardless of the method used (side-by-side vs. filter insert system), the capability of the in vitro models to rank order drugs was similar. By this approach, thus, the additional value offered by the true endothelial cell model (BBMEC) remains obscure. The present results also highlight the need of both in vitro as well as in vivo methods in characterization of blood-brain barrier passage of new drug candidates.