CYP3A4、3A5基因多态性对肾移植患者术后他克莫司浓度/剂量比值的影响

摘 要 目的:探讨CYP3A4*18B(82266G>A,rs2242480)、CYP3A5*3(6986A>G,rs776746)位点的基因多态性对肾移植术后服用他克莫司（FK506）用药的指导作用。方法: 采用PCR RFLP(聚合酶链反应 限制性片段长度多态性)方法对280名肾移植患者进行CYP3A4*18B、CYP3A5*3基因型检测,利用化学发光微粒子免疫分析技术（CMIA）检测肾移植患者FK506血浓度,比较不同基因型患者之间FK506血药谷浓度/剂量*体质量(C₀/D)比值。 结果:280例肾移植患者中,CYP3A4*18B和CYP3A5*3基因型的突变频率分别为29.1%和69.3%。CYP3A4*18B/*18B基因型肾移植患者术后1个月,3个月FK506的C₀及C₀/D值显著低于CYP3A4*1/*1、CYP3A4*1/*18B基因型（P<0.05）。CYP3A5*3/*3基因型肾移植患者术后7日,1个月FK506的C₀及C₀/D值显著高于CYP3A5*1/*1、CYP3A5*1/*3基因型（P<0.05）。将CYP3A4*18B和CYP3A5*3进行单倍体基因型组合分析,用药后15 d、1个月,GG-GG基因型组的C₀明显高于AA-GG基因型组（P<0.05）;用药后6月,GG-GG、GA-GG、GA-AG基因型组的C₀均明显高于AA GG基因型组（P<0.05）。结论: CYP3A4*18B和CYP3A5*3基因多态性对肾移植患者的FK506血药浓度及其C₀/D值有一定影响,患者在使用FK506前进行CYP3A4*18B和CYP3A5*3基因型检测,对预测FK506用药剂量有一定的指导作用。     

ABCC2 1249G>A基因多态性与肾移植患者术后吗替麦考酚酯所致不良反应的相关性研究

摘 要 目的:探究肾移植受者ABCC2 1249G>A基因多态性是否与吗替麦考酚酯（MMF）所致相关不良反应有关。方法：对236例患者按不良反应类型分为骨髓抑制组、胃肠道反应组、感染组和对照组,并对患者的肾源、年龄、性别、身高、质量、BMI值、透析时间、移植年月等临床资料以及患者移植术后3,6,12,24,36个月时的MMF剂量进行统计学分析;采用高效液相 荧光检测器法测定肾移植受者的霉酚酸(MPA)血药浓度;采用限制性片段长度多态性（PCR-RFLP）法检测236例患者的ABCC2 1249G>A位点多态性。结果：36例骨髓抑制,15例胃肠道反应,26例感染。ABCC2 1249G>A基因突变频率为12.08%,术后12月时GG基因型组的谷浓度显著高于GA基因型组（P<0.05）,GG基因型组与GA基因型组在BMI值上的差异有统计学意义（P＜0.01）。Logistic回归模型显示,用药时间、术后3月的MMF谷浓度是肾移植术后发生MMF所致骨髓抑制毒性的危险因素。结论：ABCC2 1249G>A位点的多态性与肾移植术后MMF所致相关不良反应无关。     

术中iv维生素C对心脏手术患者术后肺部并发症的影响

目的 观察术中iv维生素C对心肺转流下行心脏手术患者术后肺部并发症的影响。方法 选取2018年12月—2019年8月在徐州医科大学附属医院择期在心肺转流下行心脏手术最终的70例患者为研究对象,采用随机序列法将患者分为对照组（37例）和维生素C组（33例）。维生素C组患者分别在麻醉诱导后10 min、体外循环后并行开始前10 min、胸骨完全闭合后予iv维生素C注射液,1 g用生理盐水稀释至10 mL,总量3 g。对照组患者在同等时间静脉注射10 mL生理盐水。记录患者术后肺部并发症发生率、严重度评分及种类。分别于插管后10 min（T₀）、胸骨完全闭合后（T₁）、术后第1天（T₃）、术后第3天（T₃）记录患者氧合指数（PaO₂/FiO₂）、肺泡动脉血氧分压差（A-aDO₂）。并于T₀、T₁记录肺动态顺应性（Cd）、肺静态顺应性（Cs）。观察患者术后其他并发症发生情况。结果 与T₀时刻比较,两组T₁~T₃时刻PaO₂/FiO₂、A-aDO₂明显降低（P<0.01）;两组T₁时刻Cd、Cs明显升高（P<0.05）。维生素C组术后肺部并发症发生率为12.12%,显著低于对照组的29.73%（P<0.05）。与对照组相比,维生素C组患者术后肺部评分显著降低（P<0.01）。术后患者其他并发症以房颤最常见,但两组间差异无统计学意义。结论 术中iv维生素C能够降低心脏手术患者术后肺部并发症评分,减少术后肺部并发症发生率,改善患者的肺功能。     

右美托咪定联合七氟醚对老年患者腹腔镜下胃肠肿瘤切除术后血流动力学、认知功能及谵妄的影响

目的 探究右美托咪定对老年腹腔镜下胃肠肿瘤切除术患者的作用效果。方法 选择2017年6月—2018年5月我院收治的择期行腹腔镜下胃肠肿瘤切除术患者80例为研究对象,按照随机数字表法分为观察组（n=40）和对照组（n=40）。对照组采用七氟醚麻醉,观察组在对照组的基础上加用右美托咪定麻醉,比较两组患者在五个不同时刻［术前（T₀）、右美托咪定泵注10 min后（T₁）、气管插管后即刻（T₂）、气腹时（T₃）、气管拔管后即刻（T₄）］的平均动脉压（MAP）、心率（HR）、简易智力状态检查量表（MMSE）评分以及术后谵妄的发生率。结果 T₁、T₂、T₃、T₄时刻,观察组患者MAP、HR均明显低于对照组（P<0.05）;术后两组患者MMSE评分均明显低于术前（P<0.05）,但观察组明显高于对照组（P<0.05）;观察组患者术后谵妄的发生率明显低于对照组（P<0.05）。结论 右美托咪定能有效稳定老年腹腔镜胃肠肿瘤切除术患者的血流动力学指标,减少认知功能障碍和谵妄的发生。     

布托啡诺联合右美托咪定用于TURP术后镇痛的效果及安全性

目的 观察布托啡诺联合右美托咪定用于经尿道前列腺切除术（TURP）术后镇痛的效果及安全性。方法 选取2017年4月至2018年10月滁州市第一人民医院84例行择期TURP术治疗的患者为研究对象,采用随机数字表法分为对照组及观察组,各42例。对照组给予布托啡诺自控静脉镇痛（PCIA）干预,观察组予以布托啡诺+右美托咪定PCIA干预。比较两组术后4小时（T₁）、术后12小时（T₂）、术后24小时（T₃）、术后48小时（T₄）疼痛程度[视觉模拟评分（VAS）]、镇静程度[Ramsay镇静评分（RSS）]、膀胱痉挛次数、生命体征指标[平均动脉压（MAP）、心率（HR）、血氧饱和度（SpO₂）、呼吸频率（RR）]差异,并比较两组患者术后48小时PCIA按压次数、术后镇痛满意度及不良反应发生情况的差异。结果 两组患者术后VAS评分组间、时间序列及组间与时间序列的交互效应差异均有统计学意义（P<0.05）;两组患者术后RSS评分组间、时间序列差异有统计学意义（P<0.05）,但组间与时间序列的交互效应差异无统计学意义（P>0.05）;两组术后膀胱痉挛次数组间、时间序列及组间与时间序列的交互效应差异均有统计学意义（P<0.05）。两组术后MAP、HR、SpO₂、RR组间、时间序列及组间与时间序列的交互效应差异均无统计学意义（P>0.05）。术后48 h,观察组PCIA按压次数及不良反应总发生率低于对照组（P<0.05）,且镇痛满意度高于对照组（P<0.05）。结论 布托啡诺联合右美托咪定应用于TURP术后镇痛效果显著,并减少术后膀胱痉挛发生。     

卡泊芬净联合万古霉素治疗肾移植术后肺部感染的疗效观察

目的 评价卡泊芬净联合万古霉素治疗肾移植术后肺部感染患者的疗效。方法 选取西安交通大学第一附属医院2018年8月-2019年10月收治的肾移植术后肺部感染患者122例为研究对象,按照随机数表法将患者分为对照组和观察组,每组各61例。对照组患者静脉滴注注射用盐酸去甲万古霉素,250 mg/次,采用0.9%氯化钠注射液250 mL溶解,滴注时间>1 h,12 h/次。用药3 d后,根据血药浓度谷峰值调整给药剂量。观察组患者在对照组的基础上静脉滴注注射用醋酸卡泊芬净,首次给药剂量为70 mg,使用200 mL葡萄糖溶液溶解,第2天开始以维持剂量为50 mg治疗,1次/d。两组疗程均为14 d。观察两组患者的临床疗效,比较两组治疗前后的肾功能指标、肺功能指标及血气指标水平。结果 治疗后,观察组治疗后总有效率为91.80%,显著高于对照组的77.05%,两组总有效率比较差异具有统计学意义（P<0.05）;治疗后,观察组细菌完全清除率为34.43%,显著高于对照组的14.75%,两组细菌完全清除率比较差异有统计学意义（P<0.05）。两组患者治疗后尿微量白蛋白/肌酐比值（ACR）、血肌酐（Scr）、尿β2-微球蛋白均显著升高（P<0.05）,组间比较观差异无统计学意义。两组患者治疗后肺功能指标第1秒用力呼气容积用力呼气容积（FEV₁）、第1秒用力呼气容积占预计值百分比（FEV₁% pred）和FEV₁/FVC均显著升高（P<0.05）,治疗后,观察组肺功能指标水平显著高于对照组,差异具有统计学意义（P<0.05）。治疗后,两组患者的动脉血氧饱和度（SaO₂）、动脉血氧分压（pO₂）和氧合指数（OI）均显著升高,动脉血二氧化碳分压（pCO₂）显著降低,同组治疗前后比较差异具有统计学意义（P<0.05）;治疗后,观察组患者的SaO₂、pO₂、OI显著高于对照组,pCO₂明显低于对照组（P<0.05）。结论 卡泊芬净联合万古霉素治疗肾移植术后肺部感染具有可靠的应用价值,能够有效抑制患者肺部感染,卡泊芬净与万古霉素联合应用起效迅速,但仍需根据患者实际情况合理选择用药。     

右美托咪定复合舒芬太尼对心脏手术快通道麻醉术后镇痛效果及血清C反应蛋白的影响

目的 评价右美托咪定复合舒芬太尼对婴幼儿心脏手术快通道麻醉术后镇痛效果及血清C反应蛋白（CRP）的影响。方法 选择2017年1月至2018年1月在河南科技大学第一附属医院行先天性心脏病房缺和室缺修补术的患儿60例,采用随机数字表法分为右美托咪定复合舒芬太尼镇痛组（Ⅰ组）和舒芬太尼镇痛组（Ⅱ组）,每组30例。Ⅰ组患儿于缝皮前20 min开始静脉泵注右美托咪定1 μg/（kg·h）,至手术结束,Ⅱ组患儿给予等容量生理盐水。术后镇痛泵药液配方：Ⅰ组为右美托咪定37.5 μg/kg+舒芬太尼2.5 μg/kg+托烷司琼0.1 mg/kg,Ⅱ组为舒芬太尼2.5 μg/kg+托烷司琼0.1 mg/kg,均加生理盐水至100 mL,泵速2 mL/h。记录术毕（T₁）、苏醒（T₂）、拔管（T₃）、术后第6小时（T₅）、术后第24小时（T₆）、术后第48小时（T₇）的心率（HR）、平均动脉压（MAP）;记录术后4 h （T₄）、T₅、T₆、T₇疼痛行为量表（FLACC）评分和Ramsay镇静评分;记录术前（T₀）、T₅、T₆、T₇的血清CRP水平;记录术后48 h内不良反应的发生情况。结果 Ⅱ组患儿在T₂、T₃、T₅、T₆时点的MAP和HR均高于Ⅰ组（MAP：F_组间=10.105,P=0.034;HR：F_组间=10.830,P=0.030）;Ⅰ组患儿在T₄、T₅、T₆时点FLACC评分低于Ⅱ组（F_组间=23.091,P=0.001）,Ramsay镇静评分高于Ⅱ组（F_组间=21.534,P=0.002）;Ⅱ组患儿T₆、T₇时点血清CRP水平高于I组（F_组间=14.981,P=0.018）。与Ⅱ组比较,Ⅰ组患儿术后48 h内恶心、呕吐发生率降低,差异有统计学意义（P<0.05）。结论 右美托咪定复合舒芬太尼用于婴幼儿心脏手术快通道麻醉,术后镇痛安全有效,不良反应少,术后应激反应减轻。     

右美托咪定对体外循环下心脏瓣膜置换术患者的脑保护作用

目的 研究右美托咪定对体外循环（CPB）下心脏瓣膜置换术患者的脑保护作用。方法 以2015年1月-2015年12月于郑州市第七人民医院择期进行CPB下心脏瓣膜置换手术的患者80例为研究对象,根据实施手术的时间顺序分为观察组和对照组,每组40例,观察组在麻醉诱导前及手术中使用右美托咪定,对照组给予相同剂量的生理盐水,比较两组的麻醉诱导前（T₀）、升主动脉开放时（T₁）、CPB结束后10 min（T₂）以及术后6 h时（T₃）4个时间点的动脉-静脉血氧含量差（Da-jvO₂）、颈内静脉血氧饱和度（SjvO₂）以及脑氧摄取率（CERO₂）、血浆髓鞘碱性蛋白（MBP）、血清神经元特异性烯醇化酶（NSE）和S100β蛋白水平;手术前及手术后5 d的简易智力量表（MMSE）评分及认知功能障碍（POCD）发生率。结果 T₀和T₃时,两组的SjvO₂、Da-jvO₂和CERO₂比较,差异无统计学意义;T₁时,两组的SjvO₂较T₀时升高（P<0.05）,Da-jvO₂和CERO₂较T₀时降低（P<0.05）;T₁和T₂时,观察组的SjvO₂高于对照组,Da-jvO₂和CERO₂低于对照组（P<0.05）;T₂、T₃时,观察组和对照组的MBP水平均高于T₀时（P<0.05）,且观察组MBP水平低于对照组（P<0.05）;T₁、T₂、T₃时,观察组和对照组的NSE和S100β水平均较T₀时显著升高（P<0.05）,观察组的NSE水平在T₁、T₂、T₃时均低于对照组（P<0.05）,S-100β水平在T₂、T₃时均低于对照组（P<0.05）;术后5 d,观察组的MMSE评分与术前比较,差异无统计学意义（P<0.05）,对照组的MMSE评分显著低于术前（P<0.05）;观察组术后7 d的MMSE评分高于对照组,POCD发生率低于对照组（P<0.05）。结论 CPB下心脏瓣膜置换术患者术中使用右美托咪定可显著改善患者的脑缺血缺氧状态,减轻脑损伤。     

超声联合神经刺激器引导下腰丛-腘窝坐骨神经阻滞在大隐静脉曲张手术中的应用效果

目的 观察超声联合神经刺激器引导下的腰丛联合腘窝坐骨神经阻滞在单侧大隐静脉曲张手术中的麻醉效果。方法 选择2015年1月至2015年12月在安徽医科大学附属省立医院择期行单侧大隐静脉曲张手术患者60例,ASA分级Ⅰ~Ⅱ级,采用随机数字表法将其分为神经阻滞组（NB组,30例）和硬膜外麻醉组（EA组,30例）。记录两组麻醉前（T₀）、麻醉后10分钟（T₁）、30分钟（T₂）、60分钟（T₃）的收缩压、舒张压及心率;记录两组感觉阻滞起效时间、感觉阻滞维持时间、术中麻黄碱使用情况、麻醉效果及术后随访情况（恶心呕吐及尿潴留）。结果 与EA组相比,NB组T₂时的收缩压（SBP）及舒张压（DBP）高于EA组（P<0.05）;NB组感觉阻滞起效时间小于EA组（P<0.05）,阻滞维持时间大于EA组;NB组术中麻黄碱使用例数小于EA组（P<0.05）;两组在麻醉优良率方面差异无统计学意义（P>0.05）,尿潴留NB组中的发生率低于EA组,差异有统计学意义（P<0.05）,而恶心呕吐方面比较,两组发生率的差异无统计学意义（P>0.05）。结论 超声联合神经刺激器引导下腰丛-腘窝坐骨神经阻滞用于单侧大隐静脉曲张手术的麻醉效果与硬膜外麻醉相似,且具有血流动力学影响小、术后并发症少等优点。     

右美托咪定对妇科腹腔镜手术患者围术期炎症因子及应激反应的影响

目的 探讨右美托咪定对妇科腹腔镜手术患者围术期炎症因子及应激反应的影响。方法 选择180例妇科腹腔镜手术患者,随机分为两组,每组90例。对照组患者静脉输注0.5 μg/kg舒芬太尼、1.8 mg/kg丙泊酚、0.6 mg/kg罗库溴铵进行麻醉诱导,术中吸入七氟醚行麻醉维持,并间断静脉推注顺苯磺阿曲库铵维持肌松。观察组麻醉诱导前静脉泵注0.5 μg/kg右美托咪定负荷剂量,之后以0.5 μg/（kg·h）输注至术毕前10 min,其余麻醉方法与对照组相同。观察麻醉诱导前10 min（T₀）、气管插管后即刻（T₁）、建立气腹时（T₂）、气腹建立30 min后（T₃）、手术结束时（T₄）5个时间点的血流动动力学变化情况,使用酶联免疫吸附法检测炎症指标,以及血管紧张素Ⅱ、皮质醇及醛固酮等应激反应指标。结果 与T₀时间点比较,观察组T₁～T₃ 心率（HR）均明显下降（P<0.05）,对照组T₁～T₃ HR均明显上升（P<0.05）,对照组发生心动过速1例,观察组未发生;与T₀时间点比较,观察组T₁～T₄有创平均动脉压（MAP）未发生明显变化,对照组T₁～T₄ MAP明显上升,组间比较差异明显（P<0.05）;与T₀时间点比较,两组的IL-6、IL-10及TFN-α均明显上升,而对照组上升程度明显高于观察组（P<0.05）;与T₀时间点比较,两组的血管紧张素Ⅱ、皮质醇及醛固酮均明显上升,且对照组上升程度明显高于观察组（P<0.05）。结论 麻醉诱导前静脉泵注0.5 μg/kg右美托咪定负荷剂量,之后以0.5 μg/（kg·h）输注至术毕前10 min,可以维持妇科腹腔镜手术围术期的血流动力学稳定,抑制围术期炎症反应及应激反应。     

五酯胶囊对肝移植受者他克莫司浓度的影响

目的评价五酯胶囊对肝移植受者术后服用他克莫司血药浓度的影响。方法选取60例肝移植受者,随机分成2组,试验组32例,口服他克莫司的同时,加服五酯胶囊;对照组28例,服用他克莫司,未服五酯胶囊,连续服药6个月,比较2组他克莫司的用量、血药浓度及肝肾功能生化指标。结果服用五酯胶囊后,试验组他克莫司血药浓度升高,相应减少服用量,试验组每日服用他克莫司剂量比对照组显著降低(P<0.01);但术后1,2,3,4,6月复查,2组他克莫司血药浓度及肾功能(Cr)无明显差异(P>0.05);试验组与对照组比较,肝功能(ALT)有所改善,差异有统计学意义(P<0.05)。结论五酯胶囊能明显提高肝移植受者他克莫司全血浓度,同时减少他克莫司服用量,降低患者医疗费用。     

Physicochemical,Pharmacokinetic and Pharmacodynamic Evaluation of Liposomal Tacrolimus (FK 506) in Rats

Purpose. Tacrolimus (FK 506) is a new potent immunosuppressant. Because of poor water solubility, the conventional intravenous dosage forms of FK 506 (C-FK 506) contain surfactants such as HCO-60 which may cause adverse effects. We sought a liposomal formulation of FK 506 (L-FK 506) containing endogenous phospholipids to target drug to the spleen, a major organ controlling the immune system. Methods. L-FK 506, consisting of 0.1 µm diameter vesicles of phosphatidylcholine and phosphatidylglycerol (molar ratio 9:1) and 7.5 mole% drug, was evaluated for in vitro stability. The intravenous disposition profile, spleen distribution, and immunosuppression of L-FK 506 was compared with that of C-FK 506 in the rat after single doses of 0.3 mg/kg. Results. The L-FK 506 showed good in vitro stability. L-FK 506 exhibited an increased volume of distribution at steady-state (V_ss) (from 3.41 to 14.71 L/kg) and increased mean residence time (MRT) (from 2.83 to 16.07 hr). FK 506 concentrations in spleen were increased by 40% at 10 hr after administration of the liposomal formulation. The pharmacodynamics of L-FK 506, evaluated by the extent of inhibition of splenocyte proliferation, was comparable to that of C-FK 506. Conclusions. Liposomal FK 506 may be an improved dosage form for parenteral use.     

P-Glycoprotein-Dependent Disposition Kinetics of Tacrolimus: Studies in mdr la Knockout Mice

Purpose. This study was performed to evaluate the involvement of P-glycoprotein in disposition kinetics of tacrolimus (FK506), a substrate of P-glycoprotein, in the body. Methods. The blood and tissue concentrations of FK506 after i.v. or p.o. administration (2 mg/kg) to normal andmdrla knockout mice were measured by competitive enzyme immunoassay. Results. The blood concentrations in knockout mice were significantly higher than those in normal mice. The value of the total clearance (CL_tot) for knockout mice (19.3 mL/min/kg) was about 1/3 of that for normal mice (55.8 mL/min/kg)(P < 0.001), although there was no significant difference in the distribution volume at the steady-state (Vd_ss) (about 4.6 L/kg) between both types of mice. FK506 rapidly penetrated the blood-brain barrier and the brain concentration reached a maximum, which was about 10 times higher in knockout mice than in normal mice, 1 hr after administration. The brain concentration in normal mice thereafter decreased slowly, whereas in knockout mice, an extremely high concentration was maintained for 24 hr. Conclusions. The pharmacokinetic behavior of FK506 in the tissue distribution is related with the function of P-glycoprotein encoded by themdr la gene. The brain distribution of FK506 is dominated by the P-glycoprotein-mediated drug efflux and presumably also by the binding to FK-binding proteins (immunophilins) in the brain.     

造血干细胞移植儿童体内伏立康唑与钙调神经磷酸酶抑制剂的相互作用

目的:评价接受造血干细胞移植(HSCT)患儿中伏立康唑与钙调神经磷酸酶抑制剂环孢素(CsA)或他克莫司(FK506)之间的相互作用.方法:采用前瞻性队列研究方法评估31例接受稳定剂量CsA或FK506并开始使用伏立康唑的同种异体HSCT患儿.在伏立康唑用药前和用药后5～8d测定CsA或FK506的血药浓度,并在稳态下测定伏立康唑的血药浓度,评估伏立康唑给药前后CsA及FK506的血药浓度变化情况.结果:伏立康唑给药后,CsA的浓度/剂量(C/D)值增加了215.75％(10.16％～706.35％),FK506的C/D增加了239.24％(89.66％～615.00％)(P均＜0.01).伏立康唑对CsA和对FK506血药浓度的影响程度相当(P＞0.05).伏立康唑血药浓度与CsA的C/D增幅之间无相关性(P＞0.05),而与FK506的C/D增幅呈正相关(P＜0.05).结论:HSCT患儿联用伏立康唑后,CsA与FK506的血药浓度明显增加,且增加幅度存在显著个体差异.     

Single synchronous delivery of FK506-loaded polymeric microspheres with pancreatic islets for the successful treatment of streptozocin-induced diabetes in mice

Immune rejection after transplantation is common, which leads to prompt failure of the graft. Therefore, to prolong the survival time of the graft, immunosuppressive therapy is the norm. Here, we report a robust immune protection protocol using FK506-loaded microspheres (FK506_M) in injectable hydrogel. Pancreatic islets were codelivered with the FK506_M into the subcutaneous space of streptozocin-induced diabetic mice. The islets codelivered with 10?mg/kg FK506_M maintained normal blood glucose levels during the study period (survival rate: 60%). However, transplantation of islets and FK506_M at different sites hardly controlled the blood glucose level (survival rate: 20%). Immunohistochemical analysis revealed an intact morphology of the islets transplanted with FK506_M. In addition, minimal number of immune cells invaded inside the gel of the islet-FK506_M group. The single injection of FK506_M into the local microenvironment effectively inhibited immune rejection and prolonged the survival time of transplanted islets in a xenograft model.     

CYP3A4*18B基因多态性与他克莫司血药浓度的相关性研究

目的:探讨中国汉族肾移植患者CYP3A 4* 18B基因型对术后1个月内他克莫司谷浓度的影响.方法:采用限制性片段长度多态性技术分析了30例汉族患者CYP3A4* 18B基因型,采用酶增强免疫测定技术测定患者他克莫司谷浓度.将血药浓度标准化后对不同基因型患者剂量调整谷浓度差异进行t检验.结果:测得CY P3A 4*18B等位基因频率为0.333,符合Hardy-Weinberg平衡.将患者分成*1/*1型慢代谢组和*1/*18B合并*18B/*18B型快代谢组,两组标准化谷浓度分别为(98.02±18.56) ng·kg·mL-1· mg-1和(62.91±18.15) ng· kg· mL-1· mg-1 (P＜0.01),慢代谢组的FK506剂量调整谷浓度显著高于快代谢组.结论:CYP3A 4* 18B基因多态性与他克莫司剂量调整谷浓度显著相关,该突变可能导致CYP3A4酶活性的提高.     

Lymphocyte-sensitivity to glucocorticoid correlates with the sensitivity to cyclosporin A and tacrolimus in chronic renal failure patients

AIMS: Association between lymphocyte-sensitivity to immunosuppressants in transplant recipients in vitro and clinical outcomes has been demonstrated. In general, renal transplant recipients are treated with a combination of immunosuppressants such as either glucocorticoid/cyclosporin A (CsA) or glucocorticoid/tacrolimus (FK506) but the pharmacological complementarity of these drugs is still controversial. We examined relationships between the lymphocyte-sensitivities to these immunosuppressants. METHODS: We examined lymphocyte-sensitivities to prednisolone (PSL), CsA, and FK506 in vitro in a total of 190 chronic renal failure (CRF) patients and 140 healthy subjects. The lymphocyte-sensitivity was evaluated from the IC50 value against mitogen-stimulated lymphocyte-blastogenesis in vitro. RESULTS: Statistically significant correlations of the IC50 values in CRF patients between the following pairs of drugs were observed: PSL and CsA (P<0.0001; n=129, r=0.419), PSL and FK506 (P<0.001; n=54, r=0. 441), and CsA and FK506 (P<0.0001; n=45, r=0.608).Similar correlations were also observed in lymphocytes from healthy subjects. The population of CRF patients who exhibited high IC50 values (low sensitivities) to PSL and FK506 was significantly larger than that of healthy subjects (P<0.05). CONCLUSIONS: Patients who showed low lymphocyte-sensitivity to either of the drugs also may exhibit low sensitivity to the others, and thus they may have a high risk of unsatisfactory outcome under combination therapy after renal transplantation. To overcome this risk, the selection of immunosuppressants is recommended to be restricted according to individual lymphocyte-sensitivities to these drugs in vitro, or alternatively, by addition of other drugs with different mechanisms for immunosuppression.     

Co-administration of grapefruit juice increases bioavailability of tacrolimus in liver transplant patients: a prospective study

Purpose  The interactions between grapefruit juice (GFJ) and tacrolimus (FK506) metabolism remain obscure. The aim of this prospective study was to explore the effect of GFJ on the blood concentration of FK506 in liver transplant patients. Methods  Thirty liver transplant patients were enrolled in the study 1 month post-transplant and randomly divided into three equal-sized groups. Group A patients were treated with the standard FK506-based immunosuppressant regimen only and therefore served as the control; group B and C patients were treated with the standard FK506-based immunosuppressant regimen as well as one of two different kinds of GFJ, respectively. The blood concentrations of FK506 on the seventh day after GFJ intake were compared within each group and among groups. The dose of FK506 was adjusted depending on the valley concentration measured to a treatment window. Results  The blood concentration of FK506 in both group B and group C patients was significantly enhanced, by 1.56 ± 0.95 and 10.33 ± 5.59 ng/ml, respectively, following the administration of GFJ for 1 week (compared with the concentration at the start of the experiment in each group; p < 0.05). However, at the end time point, the blood concentration of FK506 in group C patients was significantly increased (p < 0.05) relative to that of the control patients, while this was not the case in group B patients (p > 0.05). Group C patients could be treated with a smaller dose of FK506 (decreased by 2.3 ± 1.3 mg/day for all patients; p = 0.011), amounting to a decrease in drug costs of approximately $8.70 ± 5.60/day (p = 0.011). Conclusion  In the setting of a controlled clinical study, the co-administration of GFJ with FK506 increased the bioavailability of FK506. However, the concentration of tacrolimus should be closely monitored and the dose adjusted to the treatment window.     

Implication of nitric oxide synthase activity in the genesis of water immersion stress-induced gastric lesions in rats: the protective effects of FK506

Background: Nitric oxide (NO) is a potent cytoprotective substance of gastric mucosa. FK506, an immunosuppressive drug, shows anti-gastric ulcer effects equivalent to famotidine, an H₂ blocker, in rats. This study was designed to evaluate the cytoprotective mechanism of FK506 on gastric mucosa in relation to the changes in NO synthase activity. Methods: Gastric lesions were induced in rats by water immersion stress. Changes in NO synthase activity during water immersion stress treatment, and effects of FK506 on NO synthase activity were determined enzymatically. Gastric mucosal interleukin (IL)-1β and IL-2 were measured by immunoradiometric assay. Gastric mucosal blood flow was measured by hydrogen gas clearance technique. Results: FK506 mitigated gastric lesions developed by water immersion stress. Stress-induced lesions were exacerbated by N^G-monomethyl-L -arginine (L -NMMA), a specific inhibitor of NO synthase, while sodium nitroprusside, a NO donor, mitigated the lesions. Water immersion stress increased NO synthase activity in the early phase (0.5 h after stress treatment) and decreased it in the late phase (6 h after). Decrease in NO synthase activity in the late phase was significantly mitigated by FK506, though it did not affect changes in NO synthase activity in the early phase. Water immersion stress increased gastric mucosal IL-1β and IL-2 contents 6 h after stress treatment, and these increases were prevented by FK506. FK506 itself did not affect gastric mucosal blood flow. L -NMMA treatment significantly decreased gastric mucosal blood flow. In contrast, gastric mucosal blood flow was significantly increased by sodium nitroprusside. Conclusions: Increase in NO synthase activity might contribute to cytoprotection, and a decrease in activity might be a harmful factor for the gastric mucosa. Preservation of NO synthase activity by FK506 might be involved in FK506's protective effects on the gastric mucosa.     

Effects of FK506 on an experimental model of colitis in rats

Aim: To assess the effects of FK506, a newly developed immunosuppressant, on experimental colitis in rats. Methods: Experimental colitis was induced by a single colonic instillation of hapten 2,4,6-trinitrobenzene sulphonic acid (TNB) in anaesthetized rats. Rats received 30 mg TNB dissolved in 0.25 mL of 50% ethanol, and were sacrificed on day 5 following 4 days dosing with FK506 (0.25, 0.5, 1.0, 2.0 mg/kg, s.c.) or vehicle. Mucosal prostanoid concentrations were determined using high performance liquid chromotography. Tissue myeloperoxidase activities were measured. The effects of FK506 on superoxide radical formation by neutrophils in both rats and humans were also estimated in vitro. Results: Administration of FK506 significantly reduced the colonic damage in a dose-dependent manner. Activities of myeloperoxidase and concentrations of 6-keto-prostaglandin Fl_1α (6-keto-PGF_1α, PGF_2α and PGE₂ in colonic tissue increased significantly following induction of experimental colitis, however, FK506 did not affect these changes. FK506 reduced stimulant-induced superoxide radical formation by neutrophils in rats and humans. Conclusion: FK506 decreased superoxide radical generation by neutrophils, which might contribute to the lessening of colonic damage in this model.