ORAL ERYTHROMYCIN ON QT INTERVAL IN HEALTHY SUBJECTS, PATIENTS WITH CIRRHOSIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 红霉素是一种抗生素，用于治疗各种细菌感染，如喉咙痛、肺炎和皮肤感染。众所周知，红霉素可以使健康志愿者的心率校正后的EKG QT间期(QTC)平均增加20毫秒。与非肝硬变患者相比，肝硬变患者的基线QTC间期较长，延长的幅度与疾病的严重程度相关。我们的初步数据显示，肝硬变患者Child‘s A、B或C级的平均QTC间期分别为419、438和463毫秒，而健康志愿者为394毫秒。与健康志愿者相比，肝硬变患者的细胞色素P450 3A4(CYP3A4)酶活性降低。有经颈静脉肝内门体分流术(TIPS)的肝硬变患者的肠道细胞色素P3A4活性明显降低，与年龄、性别、病因、Child-Pugh分级匹配的无TIPS的肝硬变患者和健康志愿者有关。红霉素的清除作用部分由细胞色素P3A4介导，并随多次给药而减少。因此，口服CYP3A底物(如红霉素)对健康人的QT间期有轻微的延长作用，对肝硬变和TIPS患者则可能引起明显的QT间期延长。以往的研究表明，红霉素在肝硬变患者体内的药代动力学发生了改变(半衰期延长，肝脏固有清除量降低)。这增加了口服红霉素可能导致肝硬变患者QTC间期进一步延长的可能性。因此，我们计划进行一项前瞻性研究，以确定单剂量和多剂量口服红霉素对健康受试者、肝硬变患者和TIPS患者校正的QT间期的影响。给红霉素后每隔一定时间做一次心电图，用Fridericia法(QT_c=QT/(RR)1/3)计算心率校正后的QT_c间期。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Erythromycin is an antibiotic, which is used to treat various bacterial infections such as sore throat, pneumonia, and skin infections. Erythromycin is known to increase the heart rate corrected EKG QT interval (QTc) by an average of 20 msec in healthy volunteers. Patients with liver cirrhosis experience a greater baseline QTc intervals relative to non-cirrhotics and the magnitude of the prolongation is correlated with the severity of the disease. Our preliminary data showed that cirrhotics belonging to Child's class A, B, or C had a mean QTc interval of 419, 438 and 463 msecs, respectively compared to a 394 msec in healthy volunteers. Liver cirrhosis is known to reduce heptaic Cytochrome P450 3A4 (CYP3A4) enzyme activity, compared to healthy volunteers. The intestinal CYP3A4 activity is markedly diminished in cirrhotics with transjugular intrahepatic portasystemic shunts (TIPS), relative to age, gender, etiology, and Child-Pugh class matched cirrhotics without TIPS and healthy volunteers. The clearance of erythromycin is mediated in part by CYP3A4 and decreases with multiple dosing. Therefore, orally administered CYP3A substrates (such as erythromycin) that cause little prolongation of QTc in healthy subjects may cause marked QTc prolongation in patients with cirrhosis and TIPS. It previously has been shown that pharmacokinetics of erythromycin are altered in patients with cirrhosis (prolongation of half-life and decrease hepatic intrinsic clearance). This raises the possibility that orally administered erythromycin could lead to further prolongation of QTc interval in patients with cirrhosis. Therefore, we plan to conduct a prospective study to determine the effects of single dose and multiple doses of oral erythromycin on the corrected QT interval in healthy subjects, patients with cirrhosis, and patients with cirrhosis and TIPS. An electrocardiogram will be performed at regular intervals following erythromycin administration and heart rate corrected QTc interval will be calculated using method of Fridericia (QTc = QT/(RR)1/3).