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首页> 外文期刊>Cardiovascular therapeutics >Sunitinib, a receptor tyrosine kinase inhibitor, increases blood pressure in rats without associated changes in cardiac structure and function
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Sunitinib, a receptor tyrosine kinase inhibitor, increases blood pressure in rats without associated changes in cardiac structure and function

机译：舒尼替尼，一种酪氨酸激酶受体抑制剂，可增加大鼠的血压，而心脏结构和功能没有相关变化

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Background: Sunitinib, a multi-tyrosine kinase inhibitor has demonstrated clinical activity in advanced renal cell carcinoma and imatinib-resistant/intolerant gastrointestinal stromal tumor. It has been associated with manageable hypertension and other unique toxicities. Aims: Two nonclinical studies were conducted to determine if sunitinib has direct/indirect effects on cardiac structure/function that may be related to hypertension at clinically relevant exposures. Materials & Methods: Rats received once-daily vehicle or sunitinib 1 or 10 mg/kg/day (n = 10/group) orally for 4 weeks, followed by 2 weeks off treatment then a 2-week rechallenge. Blood pressure (BP) and heart rate (HR) were continuously acquired and echocardiograms were obtained weekly. Effects of sunitinib and its metabolite (0.003-0.3 μM) were also evaluated in guinea pig isolated Langendorff-perfused hearts (n = 4-6 hearts/group). Results: Sunitinib 10 mg/kg/day produced significant (P < 0.05) hemodynamic changes: 24 h average BP increased during initial dosing/rechallenge, with rebound hypotension during the off-treatment period; 24 h average HR increased during the off-treatment period, and decreased during rechallenge; no changes in cardiac structure/function were observed. In guinea pig isolated hearts, neither sunitinib nor its metabolite had direct effects on contractility, HR or left ventricular pressure. Discussion & Conclusion: These studies demonstrate that sunitinib/metabolite had no direct effects on cardiac function ex vivo, and that therapeutically relevant concentrations of sunitinib dosed on a "clinical schedule" increased BP in rats without adverse changes in cardiac structure/function.
机译：背景：舒尼替尼，一种多酪氨酸激酶抑制剂，已证明在晚期肾细胞癌和伊马替尼耐药/不耐受胃肠道间质瘤中具有临床活性。它与可控制的高血压和其他独特的毒性有关。目的：进行了两项非临床研究，以确定舒尼替尼对临床相关暴露是否与高血压相关的心脏结构/功能有直接/间接影响。材料与方法：大鼠接受口服媒介物或舒尼替尼1或10 mg / kg /天（n = 10 /组），每天口服一次，持续4周，然后停药2周，再挑战2周。连续获取血压（BP）和心率（HR），每周获取超声心动图。还对豚鼠离体的Langendorff灌注心脏（n = 4-6个心脏/组）也评估了舒尼替尼及其代谢产物（0.003-0.3μM）的作用。结果：舒尼替尼10 mg / kg / day产生显着（P <0.05）的血流动力学变化：初始给药/再攻击期间24 h平均BP升高，在非治疗期间出现反弹性低血压;在治疗结束后的24小时内，平均HR升高，而在再挑战期间则下降;没有观察到心脏结构/功能的改变。在豚鼠离体心脏中，舒尼替尼或其代谢物均未直接影响收缩力，HR或左心室压力。讨论与结论：这些研究表明舒尼替尼/代谢产物对离体心脏功能没有直接影响，并且以“临床时间表”给药的舒尼替尼的治疗相关浓度可增加大鼠的BP，而不会对心脏结构/功能产生不利影响。

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