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Effects of moxifloxacin on the proarrhythmic surrogate markers in healthy Filipino subjects: Exposure-response modeling using ECG data of thorough QT/QTc study

Effects of moxifloxacin on QTc as well as proarrhythmic surrogate markers including J-Tpeakc, Tpeak-Tend and short-term variability (STV) of repolarization were examined by using both standard E14 time-based evaluation and exposure-response modeling. The study was conducted with a single-blind, randomized, single-dose, placebo-controlled and two-period cross-over design in healthy Filipino subjects. QT interval was corrected by Fridericias formula (QTcF). In the E14 time-based evaluation of ECG data, the largest ΔΔQTcF with 90% confidence interval was 14.1xa0ms (11.2-16.9) with Cmax of 3.39xa0μg/mL at 3xa0h post-dose (nxa0=xa069; male: 35, female: 34), indicating a positive effect on the QTcF. Moxifloxacin significantly increased the ΔΔJ-Tpeakc and ΔΔTpeak-Tend, whereas the ΔΔSTV was not altered. Meanwhile in the exposure-response modeling of the same ECG data, the slope of moxifloxacin plasma concentration-ΔΔQTcF relationship was 4.84xa0ms per μg/mL and the predicted ΔΔQTcF with 90% confidence interval was 13.8xa0ms (13.1-15.1) at Cmax, also indicating a positive effect on the QTcF. Importantly, results in each proarrhythmic surrogate marker obtained by the exposure-response modeling also showed high similarity to those obtained by the E14 statistical evaluation. Thus, these results of moxifloxacin may become a guide to estimate proarrhythmic potential of new chemical entities.

Analysis of torsadogenic and pharmacokinetic profile of E-4031 in dogs bridging the gap of information between in vitro proarrhythmia assay and clinical observation in human subjects

We analyzed torsadogenic and pharmacokinetic profile of E-4031 using chronic atrioventricular block dogs. E-4031 in intravenous doses of 0.03, 0.1 and 0.3xa0mg/kg over 10xa0min prolonged QT/QTc, and increased short-term variability of QT in a dose-related manner (nxa0=xa04), resulting in onset of torsade de pointes in 1 animal after the middle dose and 4 animals after the high dose, while it attained peak plasma concentrations of 16.5, 60.5 and 182.5xa0ng/mL at 10xa0min after their start of administration, respectively (nxa0=xa02). These results bridge the gap of information between inxa0vitro proarrhythmia assay and clinical observation in human subjects.

Electropharmacological characterization of microminipigs as a laboratory animal using anti-influenza virus drug oseltamivir

We analyzed electropharmacological characteristics of microminipigs under halothane-anesthesia using anti-influenza virus drug oseltamivir, which has been known to possess multi-channel blocking properties, including Na+, Ca2+ and K+ channels (n = 4). Oseltamivir in doses of 0.3, 3 and 30 mg/kg was intravenously infused over 10 min with an interval of 20 min, which provided peak plasma concentrations 1.4, 7.4 and 125.5 µg/mL, respectively. The low dose did not alter any of the cardiovascular variables. The middle dose decreased the heart rate at 30 min after the start of the infusion. The high dose transiently returned the heart rate toward the baseline for 10-15 min, but decreased it for 20-60 min; decreased the mean blood pressure for 5-60 min; prolonged the PR interval for 10-60 min, and the QRS width for 10-20 min; but shortened the QT interval for 10-30 min, and the QTc for 5-60 min. Thus, oseltamivir can suppress the sinus automaticity, and atrioventricular nodal and intraventricular conduction; and decrease the mean blood pressure, extents of which were greater in microminipigs than in beagle dogs in our previous observation in spite of similar plasma concentrations, reflecting higher sensitivity of microminipigs for Na+ and Ca2+ channel inhibition than that of beagle dogs. In contrast to beagle dogs, oseltamivir shortened the repolarization period in microminipigs, indicating that oseltamivir can more potently inhibit the inward currents than the outward ones in the hearts of microminipigs. This information may help improve utilizatione of microminipigs as a laboratory animal.

Comparison of electropharmacological effects between terfenadine and its active derivative fexofenadine using a cross-over study in halothane-anesthetized dogs to analyze variability of pharmacodynamic and pharmacokinetic profiles of terfenadine and torsadogenic risk of fexofenadine

In order to better understand the variability of pharmacodynamic and pharmacokinetic profiles of terfenadine between the previous studies as well as to qualitatively and quantitatively examine the proarrhythmic potential of its major active metabolite fexofenadine in comparison with that of terfenadine, we directly compared their electropharmacological effects with halothane-anesthetized dogs (n = 3). For this purpose, we adopted a cross-over design, which can directly compare the effects of terfenadine and fexofenadine under the identical metabolic condition. Terfenadine in doses of 0.03 and 0.3 mg/kg increased the mean blood pressure, but that of 3 mg/kg decreased it. Terfenadine also increased the heart rate and ventricular contractility in a dose-related manner; but delayed the atrioventricular nodal and intraventricular conductions as well as repolarization suggesting its proarrhythmic potential. Meanwhile, fexofenadine in the same dose increased the mean blood pressure in a dose-related manner without affecting any of the electrophysiological variables in the same animals that proarrhythmic risk of terfenadine was confirmed, indicating its lack of proarrhythmic risk. Peak plasma concentrations for fexofenadine were 3.7, 8.1 and 11.2 times greater than for terfenadine at each matching dose, indicating terfenadine may be metabolized much faster than fexofenadine. Taken together, after the low and middle doses of terfenadine, vasopressor effect of a metabolite fexofenadine could be greater than the depressor effect of parent compound terfenadine, but its reverse would be correct after the high dose. Thus, the cross-over analysis can be an effective way to better understand drug-induced cardiovascular responses.

Application of human induced pluripotent stem cell-derived cardiomyocytes sheets with microelectrode array system to estimate antiarrhythmic properties of multi-ion channel blockers

We examined electrophysiological indices of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) sheets in order to quantitatively estimate Na+, K+ and Ca2+ channel blocking actions of bepridil and amiodarone using microelectrode array system in comparison with that of E-4031. We analyzed the field potential duration, effective refractory period, current threshold and conduction property using a programmed electrical stimulation protocol to obtain the post repolarization refractoriness and coefficient a of the relationship between the pacing cycle length and field potential duration. Electropharmacological profile of each drug was successfully characterized; namely, 1) the changes in the current threshold and conduction property provided basic information of Na+ channel blocking kinetics, 2) the relationship between pacing cycle length and field potential duration reflected drug-induced inhibition of human ether-à-go-go-related gene (hERG) K+ channel, 3) the post repolarization refractoriness indicated the relative contribution of these drugs to Na+ and K+ channel blockade, and 4) L-type Ca2+ channel blocking action was more obvious in the field potential waveform of the hiPSC-CMs sheets than that expected in the electrocardiogram in humans. Thus, this information may help to better utilize the hiPSC-CMs sheets for grasping the properties and net effects of drug-induced Na+, Ca2+ and K+ channel blockade.

Changes of electrocardiogram and hemodynamics in response to dipyridamole: In vivo comparative analyses using anesthetized beagle dogs and microminipigs

Microminipigs are expected as a novel animal model for cardiovascular pharmacological experiments. Since inherent vulnerability of coronary circulation of microminipigs has not been characterized, we performed dipyridamole-stress test to both microminipigs and beagle dogs, and compared the results. Dipyridamole in doses of 0.056 and 0.56xa0mg/kg were intravenously infused over 10xa0min (nxa0=xa04 for each animal). Dipyridamole decreased the systolic/diastolic blood pressures and double product in dogs as well as in microminipigs; but it did not significantly alter the heart rate or the global balance between the myocardial oxygen demand and supply in either animal. While organic coronary arterial stenosis was not detected in either animal, dogs have well-developed epicardial intracoronary networks unlike microminipigs. Like in humans, dipyridamole did not affect the ST segment of microminipigs, whereas it substantially depressed that in dogs. The results indicate the onset of subendocardial ischemia by dipyridamole in dogs may be partly associated with their well-developed native coronary collateral channels. Microminipigs would be more useful to evaluate the drugs which may affect the coronary circulation in the pre-clinical study than dogs.

Use of microminipigs for unveiling unknown mechanisms of azithromycin-induced cardiovascular death

Although azithromycin can suppress cardiac INa, IKr, IKs, ICa,L and IK1, its onset mechanisms for cardiovascular death have not been fully investigated. We examined electropharmacological effects of azithromycin in intravenous doses of 0.3, 3 and 30xa0mg/kg using microminipigs under the halothane anesthesia (nxa0=xa04), which provided plasma concentrations of 3.1, 11.2 and 120.4xa0μg/mL, respectively. The low dose did not alter any of the cardiohemodynamic or electrocardiographic variables. The middle dose significantly shortened QT interval for 10-20xa0min and QTc for 10-30xa0min. The high dose significantly decreased mean blood pressure for 5-60xa0min, prolonged QRS width at 20xa0min, but shortened QT interval for 15-20xa0min and QTc for 15-30xa0min (nxa0=xa03). Cardiohemodynamic collapse occurred in 1 animal after the start of the high dose infusion, which might be associated with the cardiovascular death in patients with vasomotor dysfunction. Prolongation of QRS width indicates that azithromycin may suppress ventricular INa inxa0vivo, which may unmask latent type of Brugada electrocardiographic genotype. Meanwhile, abbreviation of the QTc might cause potentially lethal, short QT-related, cardiac arrhythmia syndrome. These findings with microminipigs suggest the possible entry point for analyzing the mechanisms of cardiovascular death clinically seen with this antibiotic.

Analysis of Safety Margin of Lithium Carbonate Against Cardiovascular Adverse Events Assessed in the Halothane-Anesthetized Dogs

Lithium is one of the classical drugs that have been widely used for treating bipolar disorder. However, several cardiac side effects including sick sinus syndrome, bundle branch block, ventricular tachycardia/fibrillation, non-specific T-wave abnormalities in addition to Brugada-type electrocardiographic changes have been noticed in patients who were given antidepressant, anticonvulsant, and/or antipsychotic drugs besides lithium. In this study, we assessed cardiohemodynamic and electrophysiological effects of lithium carbonate by itself to begin to analyze onset mechanisms of its cardiovascular side effects. Lithium carbonate in intravenous doses of 0.1, 1, and 10xa0mg/kg over 10xa0min was cumulatively administered with an interval of 20xa0min to the halothane-anesthetized beagle dogs (nu2009=u20094), which provided peak plasma Li+ concentrations of 0.02, 0.18, and 1.79xa0mEq/L, respectively, reflecting sub-therapeutic to toxic concentrations. The low and middle doses prolonged the ventricular effective refractory period at 30xa0min and for 5–30xa0min, respectively. The high dose decreased the heart rate for 45–60xa0min, delayed the intraventricular conduction for 15–20xa0min and the ventricular repolarization at 45xa0min, and prolonged the effective refractory period for 5–60xa0min. No significant change was detected in the other cardiovascular variables. Thus, lithium alone may have a wide safety margin against hemodynamic adverse events; however, it would directly and/or indirectly inhibit Na+ and K+ channels, which may synergistically increase the ventricular refractoriness from the sub-therapeutic concentration and decrease the heart rate at the supra-therapeutic one. These findings may partly explain its clinically observed various types of arrhythmias as well as electrocardiographic changes.

In vivo Analysis of the Anti-atrial Fibrillatory, Proarrhythmic and Cardiodepressive Profiles of Dronedarone as a Guide for Safety Pharmacological Evaluation of Antiarrhythmic Drugs

Anti-atrial fibrillatory, proarrhythmic and cardiodepressive profiles of dronedarone were analyzed using the halothane-anesthetized beagle dogs (nxa0=xa04) to create a standard protocol for clarifying both efficacy and adverse effects of anti-atrial fibrillatory drugs. Intravenous administration of dronedarone hydrochloride in doses of 0.3 and 3xa0mg/kg over 30xa0s attained the peak plasma concentrations of 61 and 1248xa0ng/mL, respectively, reflecting sub- to supra-therapeutic ones. The low dose decreased the left ventricular contraction and mean blood pressure, which were enhanced at the high dose. The high dose also decreased the heart rate and cardiac output, but increased the total peripheral resistance and left ventricular end-diastolic pressure, showing its potent cardiodepressive profile. Moreover, the high dose delayed the atrioventricular nodal and intraventricular conductions in addition to the ventricular repolarization, suggesting its inhibitory action on the Ca2+, Na+ and K+ channels in the in situ heart, respectively. The high dose also prolonged the effective refractory period 1.9 times greater in the atrium than in the ventricle, explaining its clinically demonstrated efficacy against the atrial arrhythmias. Dronedarone significantly prolonged the Tpeak–Tend in a dose-related manner with a tendency to prolong the terminal repolarization period and J–Tpeakc, indicating considerable risk to induce torsade de pointes. No significant change was detected in the P-wave duration by either dose, indicating the lack of effect on the atrial Na+ channel in vivo. The current experimental protocol and the results of dronedarone can be used as a guide for safety pharmacological evaluation of new anti-atrial fibrillatory drugs.

Sunitinib does not acutely alter left ventricular systolic function, but induces diastolic dysfunction

PurposeCancer 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 (nu2009=u20095), while plasma concentrations of cardiac enzymes including aspartate aminotransferase, lactate dehydrogenase, creatinine kinase and cardiac troponin I xa0were measured.MethodsSunitinib was intravenously administered at 0.01 and 0.1xa0mg/kg for 10xa0min with 20xa0min interval.ResultsSunitinib 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 30–60xa0min after the high dose without altering the other biomarkers.ConclusionsMonitoring 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.