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Precise safety pharmacology studies of lapatinib for onco-cardiology assessed using in vivo canine models.

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机构: [1]Department of Pharmacology, Faculty of Pharmacy, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba, 288-0025, Japan. [2]Department of Cardiology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu, Chiba, 279-0021, Japan. [3]Acupuncture and Tuina School/Third Teaching Hospital, Chengdu University of Traditional Chinese Medicine, No. 37 Shierqiao Road, Jinniu District, Chengdu, Sichuan, 610075, China.
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Cancer chemotherapies have improved prognosis in cancer patients, resulting in a large and rapidly increasing number of cancer survivors. "Onco-cardiology" or "cardio-oncology" is a new discipline for addressing the unanticipated cardiac side effects of newly developed cancer drugs. Lapatinib, a tyrosine kinase inhibitor suppressing the epidermal growth factor receptor and ErbB2, has been used in advanced or metastatic breast cancer treatment. Reportedly, lapatinib has induced cardiovascular adverse events including QT-interval prolongation and heart failure. However, they have not been predicted by preclinical studies. Hence, a new method to assess the tyrosine kinase inhibitor-induced adverse effects needs to be established. Here, we intravenously administered lapatinib to halothane-anaesthetised dogs, evaluating cardiohemodynamic, electrophysiological, and echocardiographic profiles for pharmacological safety assessments. We intravenously administered lapatinib to chronic atrioventricular block beagle dogs to assess its proarrhythmic potential. The therapeutic concentration of lapatinib significantly increased total peripheral vascular resistance, QT, QTc, monophasic action potential (MAP)90(sinus), MAP90(CL400), effective refractory period, and plasma concentration of cardiac troponin I (cTnI), suggesting that lapatinib prolonged the ventricular repolarization without inducing lethal ventricular arrhythmia. Careful monitoring of plasma cTnI concentration and an electrocardiogram could be supportive biomarkers, predicting the onset of lapatinib-induced cardiovascular adverse events.

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出版当年[2020]版:
大类 | 3 区 综合性期刊
小类 | 3 区 综合性期刊
最新[2023]版:
大类 | 2 区 综合性期刊
小类 | 2 区 综合性期刊
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第一作者机构: [1]Department of Pharmacology, Faculty of Pharmacy, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba, 288-0025, Japan.
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