RESUMO
ICH established S7B and E14 guidelines in 2005 to prevent drug-induced torsade de pointes (TdP), effectively preventing the development of high-risk drugs. However, those guidelines unfortunately hampered the development of some potentially valuable drug candidates despite not being proven to be proarrhythmic. In response, Comprehensive In Vitro Proarrhythmia Assay (CiPA) and Exposure-Response Modeling were proposed in 2013 to reinforce proarrhythmic risk assessment. In 2022, ICH released E14/S7B Q&As (Stage 1), emphasizing a "double negative" nonclinical scenario for low-risk compounds. For "non-double negative" compounds, new Q&As are expected to be enacted as Stage 2 shortly, in which more detailed recommendations for proarrhythmia models and proarrhythmic surrogate markers will be provided. This review details the onset mechanisms of drug-induced TdP, including IKr inhibition, pharmacokinetic factors, autonomic regulation and reduced repolarization reserve. It also explores the utility of proarrhythmic surrogate markers (J-Tpeak, Tpeak-Tend and terminal repolarization period) besides QT interval. Finally, it presents various in silico, in vitro, ex vivo and in vivo models for proarrhythmic risk prediction, such as CiPA in silico model, iPS cell-derived cardiomyocyte sheet, Langendorff perfused heart preparation, chronic atrioventricular block animals (dogs, monkeys, pigs and rabbits), acute atrioventricular block rabbits, methoxamine-sensitized rabbits, and genetically engineered rabbits for specific long QT syndromes. Those models along with the surrogate markers can play important roles in quantifying TdP risk of new compounds, impacting late-phase clinical design and regulatory decision-making, and preventing adverse events on post-marketing clinical use. Significance Statement Since ICH S7B/E14 guidelines unfortunately hampered the development of some potentially valuable compounds with unproven proarrhythmic risk, Comprehensive In Vitro Proarrhythmia Assay and Exposure-Response Modeling were proposed in 2013 to reinforce proarrhythmic risk assessment of new compounds. In 2022, ICH released Q&As (Stage 1) emphasizing "double negative" nonclinical scenario for low-risk compounds, and new Q&As (Stage 2) for "non-double negative" compounds are expected. This review delves into proarrhythmic mechanisms with surrogate markers, and explores various models for proarrhythmic risk prediction.
RESUMO
An injectable anti-influenza drug peramivir has been reported to induce QT-interval prolongation in some phase III studies, although its thorough QT/QTc study was negative. We investigated the discrepancy among those clinical studies using isoflurane-anesthetized beagle dogs (n = 4). Peramivir in doses of 1 mg/kg/10 min (sub-therapeutic dose) followed by 10 mg/kg/10 min (clinically-relevant dose) was intravenously administered. Peramivir prolonged QT interval/QTcV and Tpeak-Tend, and tended to delay ventricular repolarization in a reverse-frequency dependent manner, indicating IKr inhibition in vivo. Meanwhile, peramivir did not alter P-wave duration, PR interval or QRS width, indicating a lack of impact on cardiac conduction via Na+ or Ca2+ channel inhibition in vivo. Peramivir prolonged Tpeak-Tend and tended to prolong terminal repolarization period, which would develop substrates for initiating and maintaining spiral reentry, respectively. Meanwhile, peramivir did not prolong J-Tpeakc, which could not induce early afterdepolarization, a trigger inducing torsade de pointes. Thus, our results support that clinical dose exposure of peramivir can delay the ventricular repolarization in influenza patients. Peramivir has only a small potential to induce torsade de pointes in patients with the intact hearts, but caution should be paid on its use for patients formerly having the trigger for torsade de pointes.
Assuntos
Ácidos Carbocíclicos , Guanidinas , Influenza Humana , Isoflurano , Síndrome do QT Longo , Torsades de Pointes , Humanos , Cães , Animais , Isoflurano/efeitos adversos , Influenza Humana/tratamento farmacológico , Coração/fisiologia , Síndrome do QT Longo/induzido quimicamente , EletrocardiografiaRESUMO
Risperidone is a second-generation antipsychotic for treating schizophrenia and bipolar disorder. It can potently inhibit IKr, but is classified into conditional risk for torsade de pointes (TdP) by CredibleMeds®. Our previous studies using chronic atrioventricular block dogs showed that risperidone alone did not induce TdP, and that dl-sotalol (ß-adrenoceptor blockade plus IKr inhibition) induced TdP three times more frequently than d-sotalol (IKr inhibition alone). Since risperidone can block α1-adrenoceptor and decrease blood pressure, the resulting reflex-mediated increase of sympathetic tone on ß-adrenoceptor might protect the heart from its IKr inhibition-associated TdP. To validate this hypothesis, risperidone was administered to chronic atrioventricular block dogs after ß-adrenoceptor blocker atenolol infusion with monitoring J-Tpeak and Tpeak-Tend, which are proarrhythmic surrogate markers of "substrate" and "trigger" toward TdP, respectively. Atenolol alone induced TdP in 1 out of 5 dogs; moreover, an additional infusion of risperidone induced TdP in 3 out of 4 dogs. Risperidone prolonged QT interval, J-Tpeak and Tpeak-Tend in animals that induced TdP. These findings indicate that ß-adrenoceptor blockade can diminish repolarization reserve to augment risperidone's torsadogenic potential, thus advising caution when using ß-adrenoceptor blockers in patients with IKr inhibition-linked labile repolarization.
Assuntos
Antagonistas Adrenérgicos beta , Antipsicóticos , Atenolol , Risperidona , Torsades de Pointes , Risperidona/farmacologia , Animais , Cães , Atenolol/farmacologia , Antipsicóticos/farmacologia , Antipsicóticos/efeitos adversos , Antagonistas Adrenérgicos beta/farmacologia , Torsades de Pointes/induzido quimicamente , Bloqueio Atrioventricular/induzido quimicamente , MasculinoRESUMO
Cardio-stimulatory actions of aciclovir have been considered to primarily depend on the sympathetically-mediated reflex resulting from its hypotensive effect. To further clarify onset mechanisms of the cardio-stimulatory actions, we initially studied them using isoflurane-anesthetized dogs under thorough ß1-adrenoceptor blockade with atenolol (1 mg/kg, i.v.) (n = 4). Aciclovir (20 mg/kg/10 min, i.v.) decreased mean arterial blood pressure by 10 mmHg, whereas it increased heart rate by 10 bpm and maximum upstroke velocity of ventricular pressure by 928 mmHg/s, and shortened AH interval by 2 ms, indicating that cardio-stimulatory actions were not totally abolished by ß1-adrenoceptor blockade. Then, unknown mechanisms of cardio-stimulatory action were explored. Since aciclovir has a similar chemical structure to theophylline, in silico molecular docking simulation was performed, indicating aciclovir as well as theophylline possesses strong likelihood of interactions with phosphodiesterase 1A, 1C and 3A. Indeed, aciclovir inhibited phosphodiesterase 1A derived from the bovine heart (n = 4), moreover it exerted positive chronotropic action on the atrial tissue preparation of rats along with an increase of tissue cyclic AMP concentration (n = 4). These results indicate that cardio-stimulatory actions of aciclovir could result from not only hypotension-induced, reflex-mediated increase of sympathetic tone but also its inhibitory effects on phosphodiesterase in the heart.
Assuntos
Hipotensão , Teofilina , Animais , Bovinos , Ratos , Cães , Teofilina/farmacologia , Aciclovir/farmacologia , Simulação de Acoplamento Molecular , Pressão Sanguínea , Átrios do Coração , Frequência Cardíaca , Diester Fosfórico Hidrolases , Receptores AdrenérgicosRESUMO
To characterize utility of atrioventricular block (AVB) dogs as atrial fibrillation (AF) model, we studied remodeling processes occurring in their atria in acute (<2 weeks) and chronic (>4 weeks) phases. Fifty beagle dogs were used. Holter electrocardiogram demonstrated that paroxysmal AF occurred immediately after the production of AVB, of which duration tended to be prolonged in chronic phase. Electrophysiological analysis showed that inter-atrial conduction time and duration of burst pacing-induced AF increased in the chronic phase compared with those in the acute phase, but that atrial effective refractory period was hardly altered. Echocardiographic study revealed that diameters of left atrium, right pulmonary vein and inferior vena cava increased similarly in the acute and chronic phases. Histological evaluation indicated that hypertrophy and fibrosis in atrial tissue increased in the chronic phase. Electropharmacological characterization showed that i.v. pilsicainide effectively suppressed burst pacing-induced AF with increasing atrial conduction time and refractoriness of AVB dogs in chronic phase, but that i.v. amiodarone did not exert such electrophysiological effects. Taken together, AVB dogs in chronic phase appear to possess such pathophysiology as developed in the atria of early-stage AF patients, and therefore they can be used to evaluate drug candidates against early-stage AF.
Assuntos
Fibrilação Atrial , Remodelamento Atrial , Bloqueio Atrioventricular , Modelos Animais de Doenças , Átrios do Coração , Animais , Cães , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/etiologia , Bloqueio Atrioventricular/fisiopatologia , Átrios do Coração/fisiopatologia , Átrios do Coração/patologia , Remodelamento Atrial/fisiologia , Masculino , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Ecocardiografia , Amiodarona/farmacologiaRESUMO
We simultaneously assessed electropharmacological effects of anti-atrial fibrillatory drug vernakalant and its potential risk toward torsade de pointes. Vernakalant hydrochloride in doses of 0.3 and 3 mg/kg/10 min was intravenously administered to isoflurane-anesthetized beagle dogs without (n = 5) and with (n = 4) α-adrenoceptor blockade. Its vascular effect was analyzed using the rat aortae (n = 12). Vernakalant increased total peripheral vascular resistance and preload to left ventricle, leading to transient elevation of mean blood pressure indirectly via non-adrenergic pathway. Vernakalant suppressed sinus automaticity, ventricular contractility and intra-atrial/atrioventricular nodal/intraventricular conductions, and decreased cardiac output. Moreover, vernakalant prolonged atrial/ventricular effective refractory period by 53/55 ms, respectively, whereas it delayed ventricular repolarization in a reverse frequency-dependent manner. The extent of prolongation in early/late ventricular repolarization and electrically vulnerable period was 26/32 and 9 ms, respectively when QT-interval prolongation was the greatest. We compared them with those of known anti-atrial fibrillatory drugs; ranolazine, amiodarone, dronedarone, dl-sotalol and bepridil. The magnitude of vernakalant to alter those variables was the greater among those drugs except that the atrial selectivity was the lesser of those. Thus, vernakalant is expected to be efficacious against atrial fibrillation, but caution should be excised on its use for patients having labile ventricular function and repolarization.
Assuntos
Fibrilação Atrial , Isoflurano , Torsades de Pointes , Cães , Animais , Ratos , Fibrilação Atrial/tratamento farmacológico , Torsades de Pointes/induzido quimicamente , Isoflurano/efeitos adversos , Antiarrítmicos/farmacologiaRESUMO
Since information is still limited whether atrial IK,ACh may become a potential therapeutic target to terminate persistent atrial fibrillation (AF), we assessed it by using the persistent AF canine model with representative IK,ACh inhibitor AVE0118 and class I drugs. AVE0118 (6 mg/kg, n = 7), disopyramide (3 mg/kg, n = 7) and cibenzoline (3 mg/kg, n = 6) terminated the AF in 3/7, 1/7 and 2/6 animals, respectively, whereas aprindine (3 mg/kg, n = 6) did not suppress it. These findings suggest that IK,ACh inhibition in addition to open-state INa suppression with slow dissociation kinetics can synergistically exert potent antiarrhythmic action against persistent AF.
Assuntos
Fibrilação Atrial , Potenciais de Ação , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Compostos de Bifenilo , Cães , Átrios do CoraçãoRESUMO
Since information of antiviral drug oseltamivir on the anti-atrial fibrillation (AF) property is still limited, we assessed it using the canine paroxysmal AF model. Oseltamivir in doses of 3 and 30 mg/kg/10 min was intravenously infused to the isoflurane-anesthetized, chronic atrioventricular block dogs (n = 6) with monitoring hemodynamic and electrophysiological variables, in which AF was induced by 10 s of burst pacing on atrial septum. Oseltamivir decreased AF incidence and AF duration, and prolonged AF cycle length in a dose-dependent manner. The low and high doses attained the peak plasma drug concentrations of 9.7 and 96.5 µg/mL, which were approximately 100 and 1000 times greater than those observed in human clinical cases, respectively. The low dose of oseltamivir decreased mean blood pressure without altering sinoatrial or idioventricular rate, whereas its high dose reduced each of them. Oseltamivir delayed inter-atrial conduction in dose- and frequency-dependent manners, whereas it prolonged atrial effective refractory period in dose-dependent but frequency-independent manners. The high dose prolonged ventricular effective refractory period, which was not detected with the low dose. These findings can be used for repurposing oseltamivir as an anti-AF drug candidate.
Assuntos
Antiarrítmicos , Antivirais/farmacologia , Antivirais/farmacocinética , Fibrilação Atrial/prevenção & controle , Fibrilação Atrial/fisiopatologia , Reposicionamento de Medicamentos , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Oseltamivir/farmacologia , Oseltamivir/farmacocinética , Animais , Fibrilação Atrial/metabolismo , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Feminino , Infusões Intravenosas , Oseltamivir/administração & dosagemRESUMO
Imatinib has been reported to induce heart failure and/or QTc prolongation. To better understand their underlying mechanisms, we assessed its effects on cardiohemodynamic, electrocardiographic and echocardiographic variables along with biomarkers of myocardial damage. Imatinib mesylate in doses of 1 and 10 mg/kg was intravenously administered to the halothane-anesthetized beagle dogs (n = 4). Effects of imatinib on each phase of isovolumetric contraction, ejection, isovolumetric relaxation and filling were studied, whereas its electrophysiological effects on early and late repolarization were analyzed by measuring J-Tpeak and Tpeak-Tend, respectively. The low and high doses of imatinib provided peak plasma concentrations of 3.23 and 17.39 µg/mL, reflecting clinically-relevant and supratherapeutic concentrations, respectively. Neither lethal ventricular tachyarrhythmia nor cardiohemodynamic collapse was observed. Imatinib decreased amplitude of peak -dP/dt, indicating suppression of isovolumetric relaxation, whereas no significant change was detected in the other phases. Imatinib prolonged QTc and J-Tpeakc without altering Tpeak-Tend, indicating increase of net inward current, which leads to intracellular Ca2+ overload. Thus, imatinib suppressed ventricular active relaxation and early repolarization, which may suggest the association of mitochondrial dysfunction-associated inhibition of ATP production. Since those findings were also reported for dasatinib, sunitinib and lapatinib, they could be common cardiac phenotype of tyrosine kinase inhibitors in vivo.
Assuntos
Halotano , Inibidores de Proteínas Quinases , Trifosfato de Adenosina , Animais , Biomarcadores , Dasatinibe , Cães , Halotano/farmacologia , Mesilato de Imatinib/farmacologia , Lapatinib , Inibidores de Proteínas Quinases/efeitos adversos , SunitinibeRESUMO
We investigated how a lack of placebo control affects the interpretation of results of thorough QT/QTc (TQT) study. Results of TQT study in 48 healthy Japanese subjects assessing the effects of 480 and 960 mg of carotegrast methyl (test drug) and 400 mg of moxifloxacin (positive control) on the time-matched changes in corrected QT from baseline (ΔQTcF) and the placebo-adjusted ΔQTcF (ΔΔQTcF) were analyzed with central-tendency and concentration-response analyses. In central-tendency analysis, moxifloxacin prolonged ΔQTcF and ΔΔQTcF with the largest mean values (90% confidence interval) of 12.1 ms (9.3, 14.8) and 15.4 ms (12.6, 18.1), respectively. Meanwhile, carotegrast methyl hardly altered ΔQTcF and ΔΔQTcF with the largest mean values of 0.8 ms (-2.3, 3.9) and 2.1 ms (-0.7, 4.8) for the low dose, and -0.2 ms (-3.4, 3.0) and 1.6 ms (-0.9, 4.2) for the high dose, respectively. In concentration-response analysis, moxifloxacin attained the estimated mean values for ΔQTcF and ΔΔQTcF of 11.4 ms (8.5, 14.4) and 16.7 ms (14.0, 19.4) at the mean Cmax, whereas carotegrast methyl provided those of -4.6 ms (-7.3, -1.9) and 0.7 ms (-1.4, 2.8), respectively. Thus, lack of placebo control did not influence the interpretation of TQT study with either of the analysis in line with updated E14/S7B Q&As.
Assuntos
Fluoroquinolonas , Síndrome do QT Longo , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia , Voluntários Saudáveis , Frequência Cardíaca , Humanos , Integrina alfa4/farmacologia , Japão , Moxifloxacina/farmacologia , Fenilalanina/análogos & derivados , QuinazolinonasRESUMO
Although NMDA receptor antagonist memantine is considered to be better tolerated than cholinesterase inhibitors on treating Alzheimer's disease, several types of cardiovascular adverse events have been associated with memantine treatment, including hypertension, myocardial infarction, severe bradycardia and QT-interval prolongation. In order to clarify how memantine induces these cardiovascular adverse events, we assessed its electropharmacological effects using the halothane-anesthetized dogs (n = 4). Memantine hydrochloride was intravenously administered in doses of 0.01, 0.1 and 1 mg/kg over 10 min, providing subtherapeutic, clinically-relevant and supratherapeutic concentrations, respectively. The low to high doses increased the mean blood pressure and left ventricular contraction and enhanced the atrioventricular nodal conduction, suggesting an increase of sympathicotonic output from the central nervous system similarly to donepezil, which might induce myocardial ischemia in patients with coronary artery disease. Meanwhile, the high dose suppressed the intra-atrial conduction and the low to high doses inhibited the intra-ventricular conduction, indicating potential to induce severe bradycardic adverse event by advanced cardiac conduction block in susceptible patients. Memantine alone did not induce repolarization delay, indicating lack of risk for inducing torsade de pointes. Thus, these in vivo experimental findings may provide basic information to better understand the clinically observed adverse events of memantine.
Assuntos
Halotano , Síndrome do QT Longo , Animais , Arritmias Cardíacas/induzido quimicamente , Cães , Halotano/efeitos adversos , Ventrículos do Coração , Humanos , Síndrome do QT Longo/induzido quimicamente , Memantina/efeitos adversosRESUMO
Elevation of the head and expiratory negative airway pressure (ENAP) ventilation can both significantly alter cardiovascular hemodynamics. The impact of head-up tilt (HUT) position on mechanically regulated ENAP ventilation-induced hemodynamics was assessed in microminipigs under halothane anesthesia (n = 4) in the absence and presence of adrenergic blockade. Supine ENAP ventilation increased cardiac output, but decreased mean right atrial, systolic pulmonary arterial, and mean left atrial pressures without significantly altering heart rate or aortic pressure. With HUT, the magnitude of ENAP ventilation-induced reduction in right and left atrial pressures was attenuated. HUT minimally altered ENAP ventilation-induced increase in cardiac output and reduction in pulmonary arterial systolic pressure. In addition, with up to 10 cm of HUT there was a significant increase in mean right atrial pressure with and without the ENAP ventilation, whereas HUT did not alter the other hemodynamic variables irrespective of ENAP ventilation. These observations suggest that head elevation augments venous return from the brain irrespective of the ENAP ventilation. Additional studies with pharmacological adrenergic blockade revealed that ENAP ventilation-induced increases in cardiac output and decreases in pulmonary systolic pressure were minimally altered by sympathetic nerve activity, irrespective of the head position. However, the observed ENAP ventilation-induced decreases in right and left atrial pressures were largely dependent upon adrenergic activity. These experimental findings may provide insight into future clinical application of HUT and ENAP for patients with head injury and hypotension.
Assuntos
Halotano , Hipertensão Pulmonar , Adrenérgicos , Pressão Sanguínea/fisiologia , Halotano/farmacologia , Frequência Cardíaca/fisiologia , Hemodinâmica/fisiologia , HumanosRESUMO
BACKGROUND: Effects of rapid electrical defibrillation and ß-blockade on coronary ischemia/reperfusion-induced ventricular fibrillation (VF) during cardiopulmonary resuscitation (CPR) remain unknown.MethodsâandâResults:After induction of VF by 30 min of ischemia followed by reperfusion, animals were treated with defibrillation alone (Group A, n=13), 2 min of open-chest cardiac massage followed by defibrillation (Group B, n=11), or the same therapy to Group B with propranolol (1 mg/kg, i.v.) treatment before ischemia/reperfusion (Group C, n=11). If return of spontaneous circulation (ROSC) was not attained, each therapy was repeated ≤3 times (Set-1). When ROSC was not obtained within Set-1, cardiac massage was applied to all animals followed by defibrillation, which was repeated ≤3 times (Set-2). ROSC after Set-1 was 8% in Group A, 82% in Group B and 82% in Group C, whereas that after Set-2 was 62% in Group A, 100% in Group B and 82% in Group C. Each animal with ROSC in Groups A (n=8) and B (n=11) showed sinus rhythm, whereas those in Group C (n=9) had sinus rhythm (n=5), atrial fibrillation (n=1), accelerated idioventricular rhythm (n=2) and atrioventricular block (n=1). Post ROSC heart rate and mean arterial pressure were significantly lower in Group C. CONCLUSIONS: Cardiac massage increased the likelihood of ROSC vs. rapid defibrillation, but ß-blocker pretreatment may worsen hemodynamics and electrical stability after ROSC.
Assuntos
Reanimação Cardiopulmonar , Parada Cardíaca , Animais , Modelos Animais de Doenças , Cães , Cardioversão Elétrica , Parada Cardíaca/terapia , Massagem Cardíaca , Humanos , Isquemia , Reperfusão , Fibrilação Ventricular/terapiaRESUMO
We assessed concentration-dependent effects of halothane or isoflurane inhalation on the electrocardiographic and hemodynamic variables using a cross-over design in intact beagle dogs (n = 4). Elevation of inhaled halothane from 1.0% to 2.0% or isoflurane from 1.5% to 2.5% decreased the mean blood pressure and prolonged the QRS width without significantly altering the heart rate, PR interval or QT interval. However, the observed changes disappeared after regressions of both anesthetic conditions to their initial settings. These results indicate that hypotension-induced, reflex-mediated increase of sympathetic tone may have counterbalanced the direct negative chronotropic, dromotropic and repolarization slowing effects of the anesthetics.
Assuntos
Anestésicos/farmacologia , Eletrocardiografia/efeitos dos fármacos , Halotano/administração & dosagem , Halotano/farmacologia , Hemodinâmica/efeitos dos fármacos , Isoflurano/administração & dosagem , Isoflurano/farmacologia , Administração por Inalação , Animais , Pressão Sanguínea/efeitos dos fármacos , Estudos Cross-Over , Cães , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Masculino , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
We compared dl-sotalol-induced electrocardiographic responses in intact dogs using a repeated-measures design among 1% halothane anesthesia, 1.5% isoflurane anesthesia with nitrous oxide (N2O), and conscious state to clarify influences of the anesthetics (n = 4). Basal PR interval was longer in halothane than either in isoflurane with N2O or in conscious state, reflecting sympathetic nerve suppression for the atrioventricular node by halothane. Both anesthetics exhibited longer basal QRS width than conscious state, suggesting their ventricular INa inhibition. Also, both anesthetics showed longer basal QT interval, QTcF and Tpeak-Tend than conscious state, indicating their ventricular IKr inhibition. Meanwhile, dl-sotalol prolonged PR interval similarly in isoflurane with N2O and in conscious state, which was less great in halothane, suggesting further sympathetic nerve suppression for the atrioventricular node might be limited in halothane. dl-Sotalol prolonged QT interval and QTcF >3 times greater in either of the anesthetics than in conscious state; moreover, dl-sotalol prolonged Tpeak-Tend similarly in both anesthetics, but hardly altered it in conscious state; indicating isoflurane with N2O as well as halothane may have reduced the repolarization reserve to increase the sensitivity of ventricle toward IKr suppression. Thus, isoflurane with nitrous oxide could be useful for in vivo IKr assay like halothane.
Assuntos
Anestesia/métodos , Estado de Consciência/efeitos dos fármacos , Eletrocardiografia/efeitos dos fármacos , Halotano , Isoflurano , Óxido Nitroso , Sotalol/farmacologia , Animais , Estado de Consciência/fisiologia , Cães , Halotano/farmacologia , Isoflurano/farmacologia , Masculino , Óxido Nitroso/farmacologiaRESUMO
Lamotrigine has been used for patients with epilepsy and/or bipolar disorder, overdose of which induced the hypotension, elevation of the atrial pacing threshold, cardiac conduction delay, wide complex tachycardia, cardiac arrest and Brugada-like electrocardiographic pattern. To clarify how lamotrigine induces those cardiovascular adverse events, we simultaneously assessed its cardiohemodynamic and electrophysiological effects using the halothane-anesthetized dogs (n = 4). Lamotrigine was intravenously administered in doses of 0.1, 1 and 10 mg/kg/10 min under the monitoring of cardiovascular variables, possibly providing subtherapeutic to supratherapeutic plasma concentrations. The low or middle dose of lamotrigine did not alter any of the variables. The high dose significantly delayed the intra-atrial and intra-ventricular conductions in addition to the prolongation of ventricular effective refractory period, whereas no significant change was detected in the other variables. Lamotrigine by itself has relatively wide safety margin for cardiohemodynamics, indicating that clinically reported hypotension may not be induced through its direct action on the resistance arterioles or capacitance venules. The electrophysiological effects suggested that lamotrigine can inhibit Na+ channel in the in situ hearts. This finding may partly explain the onset mechanism of lamotrigine-associated cardiac adverse events in the clinical cases. In addition, elevation of J wave was induced in half of the animals, suggesting that lamotrigine may have some potential to unmask Brugada electrocardiographic genotype in susceptible patients.
Assuntos
Anestesia Geral/métodos , Doenças Cardiovasculares/induzido quimicamente , Eletrocardiografia , Halotano/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Anestésicos Inalatórios/farmacologia , Animais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Modelos Animais de Doenças , Cães , Sistema de Condução Cardíaco/fisiopatologia , Lamotrigina/toxicidadeRESUMO
To characterize in vivo anti-atrial fibrillatory potential and pharmacological safety profile of ranolazine having INa,L plus IKr inhibitory actions in comparison with those of clinically available anti-atrial fibrillatory drugs; namely, dronedarone, amiodarone, bepridil and dl-sotalol in our previous studies, ranolazine dihydrochloride in sub-therapeutic (0.3 mg/kg) and supra-therapeutic (3 mg/kg) doses was intravenously infused over 10 min to the halothane-anesthetized dogs (n = 5). The low dose increased the heart rate, cardiac output and atrioventricular conduction velocity possibly via vasodilator action-induced, reflex-mediated increase of adrenergic tone. Meanwhile, the high dose decreased the heart rate, ventricular contraction, cardiac output and mean blood pressure, indicating that drug-induced direct actions may exceed the reflex-mediated compensation. In addition, it prolonged the atrial and ventricular effective refractory periods, of which potency and selectivity for the former were less great compared with those of the clinically-available drugs. Moreover, it did not alter the ventricular early repolarization period in vivo, but prolonged the late repolarization with minimal risk for re-entrant arrhythmias. These in vivo findings of ranolazine suggest that INa,L suppression may attenuate IKr inhibition-associated prolongation of early repolarization in the presence of reflex-mediated increase of adrenergic tone. Thus, ranolazine alone may be less promising as an anti-atrial fibrillatory drug, but its potential risk for inducing torsade de pointes will be small. These information can be used as a guide to predict the utility and adverse effects of anti-atrial fibrillatory drugs having multi-channel modulatory action.
Assuntos
Anestesia por Inalação/métodos , Fibrilação Atrial/tratamento farmacológico , Halotano/farmacologia , Átrios do Coração/fisiopatologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Ranolazina/administração & dosagem , Potenciais de Ação/efeitos dos fármacos , Anestésicos Inalatórios/farmacologia , Animais , Fibrilação Atrial/fisiopatologia , Débito Cardíaco/efeitos dos fármacos , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Eletrocardiografia/efeitos dos fármacos , Feminino , Átrios do Coração/efeitos dos fármacos , Sistema de Condução Cardíaco/fisiopatologia , Infusões Intravenosas , Bloqueadores dos Canais de Sódio/administração & dosagemRESUMO
It has been difficult to experimentally reproduce synergistic effects of ketoconazole on terfenadine-induced torsade de pointes. We assessed proarrhythmic effects of terfenadine (30 mg/kg, p.o.) with/without ketoconazole (100 mg/kg, p.o.) pretreatment using the chronic atrioventricular block cynomolgus monkeys with repeated-measured design (n = 4). Terfenadine with ketoconazole pretreatment repeatedly induced non-sustained torsade de pointes in each animal, although terfenadine alone did not induce it at all. Thus, the chronic atrioventricular block cynomolgus monkeys can be used for studying drug interaction-associated torsade de pointes, providing a non-clinical strategy to circumvent untoward drug interactions in patients specially under polypharmacy.
Assuntos
Bloqueio Atrioventricular , Modelos Animais de Doenças , Sinergismo Farmacológico , Cetoconazol/efeitos adversos , Terfenadina/efeitos adversos , Torsades de Pointes/induzido quimicamente , Animais , Doença Crônica , Cetoconazol/administração & dosagem , Macaca fascicularis , Polimedicação , Terfenadina/administração & dosagemRESUMO
Since microminipig is becoming attractive model for various cardiac electropharmacological applications, which may meet consideration of 3Rs. We characterized microminipigs by analyzing how multi-ionic channel inhibitor bepridil may affect their in situ hearts in comparison with dogs. Bepridil in doses of 0.3 and 3.0 mg/kg were intravenously administered over 10 min under halothane anesthesia (n = 4). Microminipigs may be less sensitive for ICaT inhibition of bepridil, whereas they are more responsive to INa, IKr and IKs suppression than dogs. This information would help predict cardiovascular effects of a drug in patients with the remodeled hearts having similar electrophysiological profile to microminipigs.
Assuntos
Animais de Laboratório , Bepridil/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Modelos Animais de Doenças , Porco Miniatura , Animais , Bepridil/administração & dosagem , Bloqueadores dos Canais de Cálcio/administração & dosagem , Cães , Relação Dose-Resposta a Droga , Infusões Intravenosas , SuínosRESUMO
We assessed torsadogenic action of risperidone, which can potently inhibit IKr as well as α1-adrenoceptor. A toxic dose of 3 mg/kg of risperidone was intravenously administered over 10 min to chronic atrioventricular block dogs without anesthesia with monitoring Holter electrocardiogram (n = 4). Risperidone increased atrial/ventricular rate for 1-12 h/1-6 h and prolonged QTcF at 6 h after its administration, whereas it did not increase short-term variability of repolarization or induced torsade de pointes. These results suggest that α1-adrenoceptor blockade-dependent, hypotension-induced, reflex-mediated increase of sympathetic tone by risperidone might play a role in protecting the heart from IKr inhibition-associated torsade de pointes.