RESUMO
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.
Assuntos
Antineoplásicos/efeitos adversos , Arritmias Cardíacas/induzido quimicamente , Lapatinib/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Troponina I/sangue , Animais , Arritmias Cardíacas/diagnóstico , Biomarcadores/sangue , Modelos Animais de Doenças , Cães , Eletrocardiografia , Proteínas Tirosina Quinases/antagonistas & inibidores , SegurançaRESUMO
Tyrosine kinase inhibitors are known to clinically induce various types of cardiovascular adverse events; however, it is still difficult to predict them at preclinical stage. In order to explore how to better predict such drug-induced cardiovascular adverse events, we tried to develop a new protocol by assessing acute electrophysiological, cardiohemodynamic, and cytotoxic effects of dasatinib in vivo and in vitro. Dasatinib at 0.03 and 0.3 mg/kg was intravenously administered to the halothane-anesthetized dogs for 10 min with an interval of 20 min between the dosing (n = 4). Meanwhile, that at 0.1, 0.3, and 1 µM was cumulatively applied to the human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) (n = 7). In the dogs, the low and high doses provided peak plasma concentrations of 40 ± 5 (0.08) and 615 ± 38 ng/mL (1.26 µM), respectively. The low dose decreased the heart rate, impaired the left ventricular mechanical function, and prolonged the ventricular effective refractory period. The high dose prolonged the repolarization period, induced hemorrhagic tendency, and increased plasma cardiac troponin I level in addition to enhancement of the changes observed after the low dose, whereas it neither affected the cardiac conduction nor induced ventricular arrhythmias. In the hiPSC-CMs, dasatinib prolonged the repolarization and refractory periods like in dogs, while it did not induce apoptotic or necrotic process, but that it increased the conduction speed. Clinically observed major cardiovascular adverse events of dasatinib were observed qualitatively by currently proposed assay protocol, which may become a useful guide for predicting the cardiotoxicity of new tyrosine kinase inhibitors.
Assuntos
Antineoplásicos/toxicidade , Arritmias Cardíacas/induzido quimicamente , Dasatinibe/toxicidade , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Inibidores de Proteínas Quinases/toxicidade , Disfunção Ventricular Esquerda/induzido quimicamente , Função Ventricular Esquerda/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Cardiotoxicidade , Células Cultivadas , Cães , Relação Dose-Resposta a Droga , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Terapia de Alvo Molecular/efeitos adversos , Miócitos Cardíacos/metabolismo , Período Refratário Eletrofisiológico , Medição de Risco , Fatores de Tempo , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
PURPOSE: Cancer chemotherapies have improved the prognosis of cancer patients in recent years; however, their side effects on the cardiovascular systems have emerged as a major concern in the field of both cardiology and oncology. In particular, multi-targeted tyrosine kinase inhibitors are known to induce various types of cardiovascular adverse events including hypertension, QT-interval prolongation and heart failure, but their underlying mechanisms remain elusive. To explore how to better predict such drug-induced cardiovascular adverse events, we assessed the electropharmacological effects of sunitinib using the halothane-anesthetized dogs (n = 5), while plasma concentrations of cardiac enzymes including aspartate aminotransferase, lactate dehydrogenase, creatinine kinase and cardiac troponin I were measured. METHODS: Sunitinib was intravenously administered at 0.01 and 0.1 mg/kg for 10 min with 20 min interval. RESULTS: Sunitinib decreased the amplitude of maximum downstroke velocity of the left ventricular pressure, prolonged the isovolumic relaxation time and increased the left ventricular end-diastolic pressure in a dose-related manner without affecting the other cardiohemodynamic and electrophysiological variables. More importantly, sunitinib significantly elevated cardiac troponin I level for 30-60 min after the high dose without altering the other biomarkers. CONCLUSIONS: Monitoring of the cardiac diastolic function together with cardiac troponin I after the start of sunitinib administration may become a reliable measure to predict the onset of sunitinib-induced cardiovascular adverse events.
Assuntos
Sunitinibe/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Fascículo Atrioventricular/efeitos dos fármacos , Diástole/efeitos dos fármacos , Cães , Eletrocardiografia/efeitos dos fármacos , Técnicas Eletrofisiológicas Cardíacas , Feminino , Sístole/efeitos dos fármacosRESUMO
A beverage made of red wine vinegar and grape juice (Yamanashi-no-megumi™) was developed as a supplemental fluid containing polyphenols, which has been clinically shown to enhance the colonic transit. In this study, we assessed the mechanism of its prokinetic action by analyzing the effects on both the colonic phosphodiesterase activity of rats (n=4) and the isolated colonic strip preparation of guinea pigs (n=4). The 7% (v/v) solution of the beverage significantly decreased the phosphodiesterase activity by 9% (n=4). The beverage in concentrations of 0.7, 2.1 and 7% (v/v) relaxed the colonic strips pre-contracted by 1 µmol/L of carbachol in a concentration-related manner with 50, 58 and 79%, each response of which was diminished to 11, 19 and 46%, respectively in the presence of 100 µmol/L of L-nitro-arginine methyl ester. These results obtained by biochemical, functional and pharmacological analyses suggest that the beverage could relax the colon through both cAMP-associated and nitric oxide-dependent pathways, which may partly explain clinically observed prokinetic effect of the beverage.
Assuntos
Ácido Acético/química , Bebidas , Colo/fisiologia , Músculo Liso/fisiologia , Polifenóis/administração & dosagem , Vinho/análise , Ácido Acético/efeitos adversos , Animais , Bebidas/efeitos adversos , Agonistas Colinérgicos/farmacologia , Colo/efeitos dos fármacos , Colo/enzimologia , Colo/fisiopatologia , Constipação Intestinal/enzimologia , Constipação Intestinal/fisiopatologia , Constipação Intestinal/prevenção & controle , Inibidores Enzimáticos/farmacologia , Feminino , Sucos de Frutas e Vegetais/efeitos adversos , Sucos de Frutas e Vegetais/análise , Cobaias , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/enzimologia , Músculo Liso/fisiopatologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Polifenóis/efeitos adversos , Polifenóis/uso terapêutico , Ratos Sprague-Dawley , Vitis/efeitos adversos , Vitis/química , Vinho/efeitos adversosRESUMO
Fatal cases with the use of atypical antipsychotic drug paliperidone have been reported; however, there was no clinical report describing paliperidone-induced torsade de pointes. In this study we assessed its electropharmacological effects together with its proarrhythmic potential in intravenous doses of 0.03, 0.3 and 3 mg/kg using the halothane-anesthetized dogs (n = 5), which could provide approximately 2, 20 and 200 times higher peak plasma drug concentrations than its therapeutic level, respectively. Paliperidone exerted potent vasodilator effect resulting in hypotension, which may be largely explained by its α1-adrenoceptor blocking action. In vivo electrophysiological results suggest that paliperidone may inhibit human ether-à-go-go-related gene K+ channel in a dose-related manner and modestly suppress Na+ channel in the in situ heart. The high dose of paliperidone may have some potential to induce early afterdepolarization that can trigger lethal ventricular arrhythmias, whereas the low and middle doses lack such proarrhythmic possibility, indicating that at least 20 times higher plasma concentration may be considered to be safe.
Assuntos
Anestesia por Inalação , Anestésicos Inalatórios , Antipsicóticos/efeitos adversos , Arritmias Cardíacas/induzido quimicamente , Halotano , Palmitato de Paliperidona/efeitos adversos , Antagonistas de Receptores Adrenérgicos alfa 1 , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/sangue , Cães , Relação Dose-Resposta a Droga , Técnicas Eletrofisiológicas Cardíacas , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Feminino , Infusões Intravenosas , Miocárdio/metabolismo , Palmitato de Paliperidona/administração & dosagem , Palmitato de Paliperidona/sangue , Palmitato de Paliperidona/farmacologia , Bloqueadores dos Canais de Sódio , VasodilatadoresRESUMO
Using moxifloxacin and terfenadine, which are known to induce benign and malignant QT interval prolongation, respectively, we analysed whether halothane-anaesthetized microminipigs are an appropriate model for assessing the risk of drug-induced long QT syndrome. Moxifloxacin (0.03, 0.3 and 3 mg/kg) and terfenadine (0.03, 0.3 and 3 mg/kg) were intravenously infused over 10 min. with a pause of 20 min. to the halothane-anaesthetized microminipigs (n = 4 for each drug). Moxifloxacin decreased the heart rate, whereas it increased the blood pressure in a dose-related manner. It also prolonged the PR interval and QT/QTc in a dose-related manner without altering the QRS width. Terfenadine decreased the heart rate and blood pressure, whereas it prolonged the PR interval, QRS width and QT/QTc in a dose-related manner. Terfenadine significantly prolonged the beat-to-beat variability of QT interval reflecting its pro-arrhythmic potential, which was not observed with moxifloxacin. The peak plasma concentrations of moxifloxacin and terfenadine after doses of 3 mg/kg were 4.81 and 10.15 µg/mL, respectively, which were both 1.5 times less in microminipigs than those previously reported in dogs. These results indicate that halothane-anaesthetized microminipigs would be useful for detecting drug-induced cardiovascular responses as well as differentiating benign from malignant QT interval prolongation like dogs, although there may be some differences in pharmacokinetic profile between these animals.
Assuntos
Anestésicos Inalatórios/farmacologia , Halotano/farmacologia , Síndrome do QT Longo/induzido quimicamente , Animais , Arritmias Cardíacas/induzido quimicamente , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fluoroquinolonas/efeitos adversos , Fluoroquinolonas/sangue , Fluoroquinolonas/farmacocinética , Frequência Cardíaca , Síndrome do QT Longo/epidemiologia , Masculino , Moxifloxacina , Reprodutibilidade dos Testes , Medição de Risco , Sensibilidade e Especificidade , Suínos , Porco Miniatura , Terfenadina/efeitos adversos , Terfenadina/sangue , Terfenadina/farmacocinéticaRESUMO
Since astemizole in an oral dose of 50 mg/kg/day was recently reported to exert anti-cancer effect in mice, we evaluated its proarrhythmic potential using the atrioventricular block dogs in order to clarify its cardiac safety profile. An oral dose of 3 mg/kg prolonged the QT interval without affecting the QTc (n = 4), whereas that of 30 mg/kg increased the short-term variability of repolarization and induced premature ventricular contractions in each animal, resulting in the onset of torsade de pointes in 1 animal (n = 4). Thus, proarrhythmic dose of astemizole would be lower than anti-cancer one, limiting its re-profiling as an anti-cancer drug.
Assuntos
Antineoplásicos/efeitos adversos , Astemizol/efeitos adversos , Torsades de Pointes/induzido quimicamente , Animais , Bloqueio Atrioventricular , Modelos Animais de Doenças , Cães , Feminino , MasculinoRESUMO
Direct vasodilator effects of nitroglycerin, nifedipine, cilnidipine and diltiazem on human skeletonized internal mammary artery graft harvested with ultrasonic scalpel were assessed in the presence of 0.1 or 0.2 µM of noradrenaline. Ring preparations were made of distal end section of the bypass grafts, and those dilated by acetylcholine were used for assessment. Each drug dilated the artery in a concentration-related manner (0.01-10 µM, n = 6 for each drug) with a potency of nitroglycerin > nifedipine = cilnidipine > diltiazem. These results indicate that nitroglycerin can be useful for treating internal mammary artery spasm, that clinical utility of diltiazem may not depend on its vasodilator effect on the bypass graft, and that cilnidipine as well as nifedipine will have anti-spastic action which is in the middle between those of nitroglycerine and diltiazem.
Assuntos
Artéria Torácica Interna/efeitos dos fármacos , Nifedipino/farmacologia , Nitroglicerina/farmacologia , Vasodilatadores/farmacologia , Ponte de Artéria Coronária , Di-Hidropiridinas/farmacologia , Diltiazem/farmacologia , Humanos , Técnicas In Vitro , Artéria Torácica Interna/cirurgia , Vasoconstrição/efeitos dos fármacosRESUMO
The in vitro effects of 2 representative mycotoxins, T-2 toxin and deoxynivalenol (DON), of trichothecene group on the electron transport system (ETS) of mitochondria in rat cardiomyocytes were investigated by measuring oxygen consumption rates (OCR). The ATP-linked OCR and the reserve capacity (RC) of the mitochondria ETS were quantified by a "mitochondria stress test" which was estimated by the OCR responses to oligomycin and carbonyl cyanide-p-trifluoromethoxyphenylhydrazone, with an extracellular flux analyzer. The basal OCR was significantly inhibited by the application of T-2 toxin at concentrations of 6 × 10⻹ to 6 × 10â»5 µM and DON at concentrations of 0.78 to 100 µM for 24 hr. The threshold of cardiomyocyte toxicity was estimated to be between 6.0 × 10â»6 and 6.0 × 10â»5 µM for T-2 toxicity on both ATP-linked OCR and RC and between 0.39 and 0.78 µM on ATP-linked OCR or between 1.56 and 3.13 µM on RC for DON. The decrease in OCR of cardiomyocytes exposed to T-2 toxin with a concentration of 6.0 × 10⻳ and 6.0 × 10â»4 µM was significantly inhibited by antioxidants, catalase and vitamin C. In conclusion, the present study demonstrated, through the direct and real-time measurement of respiratory function in mitochondria, that a marked inhibition of mitochondrial ETS function in cardiomyocytes was induced by T-2 toxin and DON and that the mitochondrial dysfunction by T-2 toxin was largely associated with oxidative stress.
Assuntos
Transporte de Elétrons/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Miócitos Cardíacos/ultraestrutura , Consumo de Oxigênio/efeitos dos fármacos , Toxina T-2/toxicidade , Tricotecenos/toxicidade , Trifosfato de Adenosina/fisiologia , Animais , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Catalase/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Ratos Sprague-Dawley , Toxina T-2/antagonistas & inibidores , Tricotecenos/antagonistas & inibidoresRESUMO
Whereas nausea and emesis are burdensome side effects that lead to poor treatment compliance especially in chemotherapy, it is difficult to predict the emetic potential of agents in rats and mice because rodents do not vomit. We examined the effect of emetics on gastric retention and role of serotonin (5-hydroxytryptamine, 5-HT)