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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。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。已知红霉素可使健康志愿者的心率校正EKG QT间期（QTc）平均延长20 msec。肝硬化患者的基线QTc间期较非肝硬化患者的基线QTc间期延长，延长幅度与疾病的严重程度相关。我们的初步数据显示，属于Child A、B或C类的心律失常患者的平均QTc间期分别为419、438和463毫秒，而健康志愿者的平均QTc间期为394毫秒。与健康志愿者相比，肝硬化已知会降低肝细胞色素P450 3A 4（CYP 3A 4）酶活性。与年龄、性别、病因学、Child-Pugh分级匹配的无TIPS患者和健康志愿者相比，经颈静脉肝内门体分流术（TIPS）患者的肠道CYP 3A 4活性显著降低。红霉素的清除部分由CYP 3A 4介导，并随多次给药而降低。因此，口服CYP 3A底物（如红霉素）在健康受试者中几乎不引起QTc延长，但在肝硬化和TIPS患者中可能引起明显的QTc延长。先前已表明，红霉素的药代动力学在肝硬化患者中发生改变（半衰期延长和肝脏固有清除率降低）。这增加了口服红霉素可能导致肝硬化患者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、肝硬化患者和肝硬化伴TIPS患者校正QT间期的影响。在红霉素给药后定期进行心电图检查，并使用Fridericia方法计算心率校正的QTc间期（QTc = QT/（RR）1/3）。

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 hepatic 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).