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

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          Abstract

          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), MAP 90(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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          Most cited references 25

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          Do existing measures of Poincaré plot geometry reflect nonlinear features of heart rate variability?

          Heart rate variability (HRV) is concerned with the analysis of the intervals between heartbeats. An emerging analysis technique is the Poincaré plot, which takes a sequence of intervals and plots each interval against the following interval. The geometry of this plot has been shown to distinguish between healthy and unhealthy subjects in clinical settings. The Poincaré plot is a valuable HRV analysis technique due to its ability to display nonlinear aspects of the interval sequence. The problem is, how do we quantitatively characterize the plot to capture useful summary descriptors that are independent of existing HRV measures? Researchers have investigated a number of techniques: converting the two-dimensional plot into various one-dimensional views; the fitting of an ellipse to the plot shape; and measuring the correlation coefficient of the plot. We investigate each of these methods in detail and show that they are all measuring linear aspects of the intervals which existing HRV indexes already specify. The fact that these methods appear insensitive to the nonlinear characteristics of the intervals is an important finding because the Poincaré plot is primarily a nonlinear technique. Therefore, further work is needed to determine if better methods of characterizing Poincaré plot geometry can be found.
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            Increased short-term variability of repolarization predicts d-sotalol-induced torsades de pointes in dogs.

            Identification of patients at risk for drug-induced torsades de pointes arrhythmia (TdP) is difficult. Increased temporal lability of repolarization has been suggested as being valuable to predict proarrhythmia. The predictive value of different repolarization parameters, including beat-to-beat variability of repolarization (BVR), was compared in this serial investigation in dogs with chronic AV block. In anesthetized dogs with electrically remodeled hearts, the dose-dependent difference in drug-induced TdP (d-sotalol, 2 and 4 mg/kg IV over 5 minutes, 25% and 75% TdP, respectively) could not be accounted for by prolongation of QT(c) (410+/-37 to 475+/-60 versus 415+/-47 to 484+/-52 ms, respectively). BVR was quantified by Poincare plots at baseline and immediately before onset of d-sotalol-induced extrasystolic activity. TdP occurrence was associated with an increase in short-term variability (STV) of the left ventricular monophasic action potential duration (3.5+/-1.5 to 5.5+/-1.6 versus 3.0+/-0.7 to 8.6+/-3.8 ms, respectively), which was reversible when TdP was abolished by I(K,ATP) activation. The absence of TdP despite QT(c) prolongation after chronic amiodarone treatment could also be explained by an unchanged STV. In experiments with isolated ventricular myocytes, STV increased after I(Kr) block and was highest in cells that subsequently showed early afterdepolarizations. Proarrhythmia is not related to differences in prolongation of repolarization but corresponds to BVR, here quantified as STV of the left ventricle. STV could be a new parameter to predict drug-induced TdP in patients.
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              An improved method to correct the QT interval of the electrocardiogram for changes in heart rate.

              The adequacy of the Bazett formula to correct for heart rate-induced changes in the QT interval of the electrocardiogram has been frequently questioned. In the present study, a simple linear equation was derived, which in anesthetized dogs corrects more adequately for changes in heart rate than the Bazett formula. Regression analysis of experimental data yielded the following equation: QTc = QT - 0.087 (RR - 1000) = QT - 87 (60/HR - 1). The reliability of this equation was investigated in experiments on anesthetized dogs with different cardioactive drugs with a known mechanism of action.
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                Author and article information

                Contributors
                keando@cis.ac.jp
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                20 January 2020
                20 January 2020
                2020
                : 10
                Affiliations
                [1 ]ISNI 0000 0004 1793 0095, GRID grid.443455.7, Department of Pharmacology, , Faculty of Pharmacy, Chiba Institute of Science, ; 15-8 Shiomi-cho, Choshi, Chiba 288-0025 Japan
                [2 ]ISNI 0000 0004 0569 1541, GRID grid.482669.7, Department of Cardiology, , Juntendo University Urayasu Hospital, ; 2-1-1 Tomioka, Urayasu, Chiba 279-0021 Japan
                [3 ]ISNI 0000 0001 0376 205X, GRID grid.411304.3, Acupuncture and Tuina School/Third Teaching Hospital, , Chengdu University of Traditional Chinese Medicine, ; No. 37 Shierqiao Road, Jinniu District, Chengdu, Sichuan 610075 China
                Article
                57601
                10.1038/s41598-020-57601-x
                6971088
                31959820
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001691, MEXT | Japan Society for the Promotion of Science (JSPS);
                Award ID: 16K08559
                Award Recipient :
                Funded by: the Advancement of Science in commemoration of Toho University’s 60th anniversary
                Categories
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                © The Author(s) 2020

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