Analyses of the onset mechanisms of cardio-stimulatory action by aciclovir.

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.

Characterization of cardiovascular profile of anti-influenza drug peramivir: A reverse-translational study using the isoflurane-anesthetized dog.

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.

INCIDENCE AND CHARACTERISTICS OF NEOVASCULAR AGE-RELATED MACULAR WITH OVER A 12-MONTH REMISSION AFTER THREE MONTHLY AFLIBERCEPT ADMINISTRATION: 60 Months Results of a Pro Re Nata Regimen.

PURPOSE: To investigate the characteristics of patients with over a 12-month remission after 3 monthly intravitreal aflibercept injections followed by a pro re nata regimen for exudative age-related macular degeneration (AMD). METHODS: One hundred forty-four eyes with exudative AMD were included. All patients received 3 monthly intravitreal aflibercept injections as a loading dose, followed by an as-needed regimen for 60 months. Patients were classified into the remission and recurrence groups depending on the presence or absence of a 12-month remission. ARMS2 A69S and CFH I62V were genotyped in all cases. RESULTS: During the study, 82 eyes (56.9%) showed 12 months or more remission at least once. The cumulative incidence rate of a 12-month remission showed a plateau pattern and converged to 60% (y = -166.26x-2.172 + 0.6, R2 = 0.8168). Patients in the remission group were younger than those in the recurrence group (P < 0.001) and had less risk allele frequency of the ARMS2 gene than the recurrence group (P < 0.001). The longer the remission interval was prolonged, the better visual acuity was achieved at the 60-month visit (P < 0.001). CONCLUSION: Fifty-seven percent of patients showed a 12-month remission or more at least once during a 60-month follow-up, suggesting that patients with no reactivation can prolong the treatment interval.

Excess heat production of the pair annihilation of ionic vacancies in a copper redox reaction using a double bipolar MHD electrode.

Through a copper double bipolar magnetohydrodynamic (MHD) electrode (MHDE) producing twice the amounts of ionic vacancies than a conventional single MHDE, the molar excess heat of the pair annihilation of ionic vacancies, 702 kJ mol-1 at 10 T on average was obtained in a copper redox reaction. It was about twice as large as that of a single MHDE, 387 kJ mol-1 at the same magnetic field. This result strongly suggests that a multi-channel bipolar MHDE will produce much greater excess heat. To conserve the linear momentum and electric charge during electron transfer in an electrode reaction, ionic vacancies are created, storing the solvation energy in the polarized core of the order of 0.1 nm, and the pair annihilation of the vacancies with opposite charges liberates the energy as excess heat. The promoted excess heat by the double bipolar MHDE with a diffuser at 10 T was 710 ± 144 kJ mol-1, whereas as mentioned above, 702 ± 426 kJ mol-1 was obtained by the same electrode without such a diffuser. From the theoretical excess heat of 1140 kJ mol-1, the collision efficiencies in pair annihilation were 0.623 ± 0.126 and 0.616 ± 0.374, respectively. From these results, the reproducibility of the thermal measurement was experimentally validated. At the same time, it was concluded that at magnetic fields beyond 10 T, the concentration of ionic vacancy and the collision efficiency take constant uppermost values.

Cardiovascular safety pharmacology of ivermectin assessed using the isoflurane-anesthetized beagle dogs: ICH S7B follow-up study.

Antiparasitic ivermectin has been reported to induce cardiovascular adverse events, including orthostatic hypotension, tachycardia and cardiopulmonary arrest, of which the underlying pathophysiology remains unknown. Since its drug repurposing as an antiviral agent is underway at higher doses than those for antiparasitic, we evaluated the cardiovascular safety pharmacology of ivermectin using isoflurane-anesthetized beagle dogs (n=4). Ivermectin in doses of 0.1 followed by 1 mg/kg was intravenously infused over 10 min with an interval of 20 min, attaining peak plasma concentrations of 0.94 ± 0.04 and 8.82 ± 1.25 µg/mL, which were 29-31 and 276-288 times higher than those observed after its antiparasitic oral dose of 12 mg/body, respectively. The latter peak concentration was > 2 times greater than those inhibiting proliferation of dengue virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and hepatitis B virus in vitro. Ivermectin decreased heart rate without altering mean blood pressure, suggesting that ivermectin does not cause hypotension or tachycardia directly. Ivermectin hardly altered atrioventricular nodal or intraventricular conduction, indicating a lack of inhibitory action on Ca2+ or Na+ channel in vivo. Ivermectin prolonged QT interval/QTcV in a dose-related manner and tended to slow the repolarization speed in a reverse frequency-dependent manner, supporting previously described its IKr inhibition, which would explain Tpeak-Tend prolongation and heart-rate reduction in this study. Meanwhile, ivermectin did not significantly prolong J-Tpeakc or terminal repolarization period, indicating torsadogenic potential of ivermectin leading to the onset of cardiopulmonary arrest would be small. Thus, ivermectin has a broad range of cardiovascular safety profiles, which will help facilitate its drug repurposing.

In vivo analysis of acute eletropharmacological effects of proton pump inhibitors using halothane-anesthetized dogs: a translational study of cardiovascular adverse events.

Long-term use of proton pump inhibitors (PPIs) is known to clinically induce hypomagnesemia, increasing the risk toward QT-interval prolongation and lethal ventricular arrhythmias, whereas PPIs can directly modulate cardiac ionic currents in the in vitro experiments. In order to fill the gap between those information, we assessed acute cardiohemodynamic and electrophysiological effects of sub- to supra-therapeutic doses (0.05, 0.5 and 5 mg/kg/10 min) of typical PPIs omeprazole, lansoprazole and rabeprazole, using halothane-anesthetized dogs (n = 6 for each drug). The low and middle doses of omeprazole and lansoprazole increased or tended to increase the heart rate, cardiac output and ventricular contraction, whereas the high dose plateaued and decreased them. Meanwhile, the low and middle doses of omeprazole and lansoprazole decreased the total peripheral vascular resistance, whereas the high dose plateaued and increased it. Rabeprazole decreased the mean blood pressure in a dose-related manner; moreover, its high dose decreased the heart rate and tended to reduce the ventricular contractility. On the other hand, omeprazole prolonged the QRS width. Omeprazole and lansoprazole tended to prolong the QT interval and QTcV, and rabeprazole mildly but significantly prolonged them in a dose-related manner. High dose of each PPI prolonged the ventricular effective refractory period. Omeprazole shortened the terminal repolarization period, whereas lansoprazole and rabeprazole hardly altered it. In effects, PPIs can exert multifarious cardiohemodynamic and electrophysiological actions in vivo, including mild QT-interval prolongation; thus, PPIs should be given with caution to patients with reduced ventricular repolarization reserve.

Comparison of one-year outcomes between as-needed brolucizumab and aflibercept for polypoidal choroidal vasculopathy.

PURPOSE: To compare the one-year visual and anatomic outcomes of an as-needed regimen of brolucizumab and aflibercept for polypoidal choroidal vasculopathy (PCV). STUDY DESIGN: A retrospective comparative study. METHODS: A retrospective medical chart review was performed for consecutive 56 eyes from 56 patients with PCV initially treated with thee monthly intravitreal aflibercept (n = 33, 2.0 mg/0.05 ml) or brolucizumab (n = 23, 6.0 mg/0.05 ml) followed by as-needed administration, followed up for at least 12 months. All patients were followed up monthly, and fluorescein and indocyanine green angiography (ICGA) were performed at baseline, 3-month, and 12-month visits. RESULTS: At the 12-month visit, best-corrected visual acuity significantly improved from 0.30 ± 0.31 to 0.21 ± 0.29 (p = 0.042) in the brolucizumab-treated group and from 0.24 ± 0.25 to 0.14 ± 0.25 (p = 7.7×10-3) in the aflibercept-treated group, suggesting comparable visual improvement in both groups. Central retinal thickness and subfoveal choroidal thickness decreased by 38.4% and 14.2%, respectively, in the brolucizumab-treated group and by 34.8% and 13.9%, respectively, in the aflibercept-treated group at the 12-month visit. The mean number of additional injections was significantly higher in the aflibercept-treated group (2.9 ± 2.7) than in the brolucizumab-treated group (1.3 ± 1.2, p = 0.045). The complete resolution of polypoidal lesions on ICGA was higher in the brolucizumab-treated group than in the aflibercept-treated group (3-month visit: 56.5% vs 30.3%, 12-month visit: 56.5% vs 30.3%). CONCLUSIONS: In treatment-naïve eyes with PCV, the as-needed administration regimen of brolucizumab was comparable to aflibercept in terms of visual and anatomical outcomes, with fewer additional injections during the 12-month follow-up.

Characterization of the electrocardiogram of microminipig in comparison with that of Clawn miniature swine: impacts of miniaturization of body size on electrocardiographic indices.

Effects of body size reduction on electrocardiographic indices were examined using microminipigs in comparison with Clawn miniature swine (Clawn). Electrocardiogram was recorded using Holter electrocardiograph in conscious state for 24 hr for microminipigs (male: 11.6 ± 0.1 kg, 12-17 months, n=5; and female: 9.9 ± 0.4 kg, 6 months, n=5) and Clawn (female: 20.3 ± 0.4 kg, 8-9 months, n=8). Microminipig had shorter PR interval and QRS width than Clawn, whereas no significant difference was detected in JTcF/QTcF between them. Ratios of PR interval, QRS width, and body weight cubic root for microminipigs to Clawn ranged between 0.713 and 0.830. These findings indicate that PR interval and QRS width will depend on distance for excitatory current propagation, whereas JTcF/QTcF may be governed by local electrical activities.

Characterization of electropharmacological profile of an anti-atrial fibrillatory drug vernakalant along with potential risk toward torsade de pointes: Translational studies using isoflurane-anesthetized dogs and isolated rat aortic preparations.

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.

Electropharmacological Characterization of Licorice Using the Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Sheets and the Chronic Atrioventricular Block Dogs.

Licorice has been traditionally prescribed for palpitation, whereas its overdose has caused lethal arrhythmias including torsade de pointes. Licorice contains glycyrrhizic acid of ≥ 2% (w/w), which is hydrolyzed to glycyrrhetinic acid (GRA) in the intestine. Since their cardiac electropharmacological properties are not fully understood, we assessed them to ask mechanism of licorice-induced torsade de pointes. GRA at 0.1, 1 and 10 µg/mL was cumulatively applied to the human induced pluripotent stem cell-derived cardiomyocytes sheets (n = 6). GRA shortened spontaneous activation interval and repolarization period, and decreased maximum contraction velocity, indicating Ca2+ channel blockade. It prolonged effective refractory period and post-repolarization refractoriness with a steep frequency-dependency, whereas it delayed conduction with a modest use-dependency, resembling lidocaine in the mode of Na+ channel-blocking action. Meanwhile, Kanzoto containing a decoction of licorice alone in a dose of 2 or 6 g/body/day was orally administered to the conscious chronic atrioventricular block dogs for 3 days (n = 4). Kanzoto prolonged QT interval with increasing its temporal dispersion, suggesting K+ channel suppression, and slightly decreased the plasma K+ concentration without inducing torsade de pointes. Moreover, it significantly suppressed atrial and idioventricular rates, leading to sinus arrest along with the onset of ventricular fibrillation in one animal, possibly due to Na+ channel blockade. These results indicate that electropharmacological profile of licorice can be explained by Na+, Ca2+ and K+ channels blockade, which may be associated with low torsadogenic risk, but might contribute to the onset of other types of lethal ventricular arrhythmias.

A Treat-and-Extend Regimen of Intravitreal Brolucizumab for Exudative Age-Related Macular Degeneration Refractory to Aflibercept: A 12-Month Result.

We aimed to investigate whether a treat-and-extend regimen of intravitreal brolucizumab (6.0 mg/0.05 mL) is effective for eyes with exudative age-related macular degeneration (AMD) refractory to aflibercept for 12 months. Sixty eyes from 56 patients receiving brolucizumab for exudative AMD refractory to aflibercept were included. Patients received a mean of 30.1 aflibercept administrations for a mean 67.9-month follow-up. All patients exhibited exudation on optical coherence tomography (OCT) despite regular 4-8 weeks of aflibercept administration. Visit 1 was scheduled at the same interval from the last aflibercept injection to the baseline. The treatment interval was extended or shortened by 1-2 weeks depending on the presence or absence of exudation on OCT. After switching to brolucizumab, the follow-up interval significantly extended at 12 months (before switching: 7.6 ± 3.8 weeks vs. at 12 months: 12.1 ± 6.2 weeks, p = 1.3 × 10-7). Forty-three percent of the eyes achieved a dry macula at 12 months after switching. However, the best-corrected visual acuity did not improve at any visit. Morphologically, the central retinal thickness and subfoveal choroidal thickness significantly decreased from baseline at 12 months (p = 3.6 × 10-3 and 1.0 × 10-3, respectively). Switching to brolucizumab can be considered to extend the treatment interval in eyes with exudative AMD refractory to aflibercept.

Both osmolality-dependent and independent mechanisms are associated with acute hyperglycemia-induced cardiovascular adverse reactions: Analysis of the mutual interactions leading to cardiovascular phenotypes in dogs.

Acute hyperglycemia causes various cardiovascular responses; however, the underlying pathophysiology in vivo is myriad and complex, of which mutual interactions remain poorly understood. We analyzed the cardiovascular effects of acute hyperglycemia in comparison with those of hyperosmolality alone. Three g/kg of D-glucose (n = 4) or D-mannitol (n = 4) was intravenously infused to isoflurane-anesthetized intact dogs. Glucose infusion increased plasma glucose level and osmolality, whereas mannitol infusion similarly changed osmolality to glucose infusion but decreased glucose level. Glucose infusion decreased total peripheral vascular resistance, but increased heart rate, left ventricular contraction, left ventricular preload and cardiac output without altering mean blood pressure. Mannitol infusion likewise changed them, but its positive chronotropic and inotropic effects were less potent than those of glucose infusion. Glucose infusion prolonged PR interval, QRS width and QTcV. Mannitol infusion similarly changed them, but its QTcV prolongation was smaller than that of glucose infusion. Glucose infusion-induced cardiovascular responses would be basically attributed to osmolality-dependent mechanisms, whereas its positive chronotropic and inotropic effects along with repolarization delay may be enhanced by osmolality-independent mechanisms, including hyperglycemia by itself and insulin release.

DISTINCT CHARACTERISTICS OF SIMPLE VERSUS COMPLEX CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To compare the clinical and genetic characteristics of simple and complex central serous chorioretinopathy using central serous chorioretinopathy international group criteria. METHODS: Patients with idiopathic central serous chorioretinopathy were included. Depending on the presence or absence of retinal pigment alterations greater than 2-disc areas in either eye, patients were classified into complex or simple types. Demographic factors and clinical findings were compared between groups. CFH variants, including rs800292 and rs1329428, were genotyped using TaqMan technology. RESULTS: A total of 319 consecutive patients were evaluated at the initial presentation. Of them, 53 (16.6%) had the complex type. The complex type was exclusively seen in men (100% vs. 79.0%, P = 2.0 × 10 -4 ) and demonstrated a significantly higher proportion of bilateral involvement (75.5% vs. 17.7%, P = 6.2 × 10 -18 ) and descending tract(s) (83.0% vs. 0%, P = 1.2 × 10 -57 ) than the simple type. Increased choroidal thickness (425 ± 131 vs. 382 ± 110, P = 0.02) and decreased central retinal thickness (274 ± 151 vs. 337 ± 136, P = 2.9 × 10 -4 ) were observed for the complex versus simple type. The risk allele frequencies of both variants were significantly higher in the complex versus simple type (rs800292: 61.3% vs. 48.7%, P = 0.018; rs1329428: 65.1% vs. 54.3%, P = 0.04). CONCLUSION: In this new classification system, the complex type has distinct genetic and clinical characteristics compared with the simple type.

Characterization of pathological remodeling in the chronic atrioventricular block cynomolgus monkey heart.

We studied time course of pathological remodeling occurring in the cynomolgus monkey hearts against persistent atrioventricular block condition (n = 10). The atrioventricular block induced the ventricular and atrial dilation followed by the ventricular hypertrophy. Interstitial fibrosis in the ventricle was also observed along with gradual increases in the plasma angiotensin II and aldosterone concentrations. These adaptations were associated with the changes in gene expression profiling reflecting fibrosis and hypertrophy. Atrioventricular block reduced the ventricular rate and cardiac output, but the ejection fraction and stroke volume increased, whereas the cardiac output was gradually restored to its basal level. Systolic/diastolic blood pressure after the atrioventricular block was kept equal to or lower than that before the block, according with lack of increase in the plasma catecholamine levels. Chronic atrioventricular block gradually prolonged the QRS width and JT interval, leading to the QT interval prolongation in conscious state. 10 mg/kg of dl-sotalol hydrochloride induced torsade de pointes (TdP) in 6 out of 10 animals by 15 months. Animals showing longer QTcF under anesthesia after the atrioventricular block developed dl-sotalol-induced TdP earlier. No marked difference was observed in pharmacokinetics of dl-sotalol between 1 and 7 months after the atrioventricular block. Each TdP spontaneously terminated, reflecting a monkey's relatively small "effective size of the heart (=∛(left ventricular weight)/wavelength of reentry)". These fundamental knowledge will help better utilize the chronic atrioventricular block monkeys as an in vivo proarrhythmia model for detecting drug-induced TdP.

Peripheral Regulation of Central Brain-Derived Neurotrophic Factor Expression through the Vagus Nerve.

The brain-derived neurotrophic factor (BDNF) is an extensively studied neurotrophin es sential for both developing the brain and maintaining adult brain function. In the adult hippocampus, BDNF is critical for maintaining adult neurogenesis. Adult hippocampal neurogenesis is involved not only in memory formation and learning ability, but also mood regulation and stress responses. Accordingly, decreased levels of BDNF, accompanied by low levels of adult neurogenesis, occurs in brains of older adults with impaired cognitive function and in those of patients with major depression disorder. Therefore, elucidating the mechanisms that maintain hippocampal BDNF levels is biologically and clinically important. It has been revealed that signalling from peripheral tissues contribute to the regulation of BDNF expression in the brain across the blood-brain barrier. Moreover, recent studies indicated evidence that neuronal pathways can also be a mechanism by which peripheral tissues signal to the brain for the regulation of BDNF expression. In this review, we give an overview of the current status in the regulation of central BDNF expression by peripheral signalling, with a special interest in the regulation of hippocampal BDNF levels by signals via the vagus nerve. Finally, we discuss the relationship between signalling from peripheral tissues and age-associated control of central BDNF expression.

Characteristics of intermediate age-related macular degeneration with hyperreflective foci.

Hyperreflective foci (HRF) are the findings observed in optical coherence tomography (OCT) in several retinal diseases and are believed to be associated with the increased risk of atrophy in eyes with age-related macular degeneration (AMD). In this study, we investigated the clinical and genetic characteristics of intermediate AMD with HRF. We reviewed the medical charts for 155 patients with intermediate AMD, in whom macular neovascularization (MNV) was observed in the contralateral eye. The presence or absence of an HRF was evaluated using a spectral-domain OCT volume scan spanning the macular region. Patients were followed longitudinally for at least 12 months, and the maximum follow-up period was 60 months. Genotyping of ARMS2 A69S and CFH I62V was performed in all participants. Of the 155 patients (mean age: 77.8 ± 7.6 years, male/female: 103/52), HRF was observed in 53 eyes (34.2%) and was significantly associated with type-3 MNV (p = 1.0 × 10-5) in the contralateral eye, pseudodrusen (p = 5.0 × 10-4), thinner subfoveal choroidal thickness (p = 0.013), and risk of ARMS2 A69S (p = 0.023). During follow-up (40.8 ± 17.5), 38 eyes (24.5%) developed advanced AMD. The mean time to the onset of advanced AMD was 29.8 ± 12.9 months in eyes with intermediate AMD. HRF was associated with MNV (p = 1.0 × 10-3), but not with atrophy.

Site-directed deuteration of dronedarone preserves cytochrome P4502J2 activity and mitigates its cardiac adverse effects in canine arrhythmic hearts.

Cytochrome P4502J2 (CYP2J2) metabolizes arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic acids (EETs). Dronedarone, an antiarrhythmic drug prescribed for treatment of atrial fibrillation (AF) induces cardiac adverse effects (AEs) with poorly understood mechanisms. We previously demonstrated that dronedarone inactivates CYP2J2 potently and irreversibly, disrupts AA-EET pathway leading to cardiac mitochondrial toxicity rescuable via EET enrichment. In this study, we investigated if mitigation of CYP2J2 inhibition prevents dronedarone-induced cardiac AEs. We first synthesized a deuterated analogue of dronedarone (termed poyendarone) and demonstrated that it neither inactivates CYP2J2, disrupts AA-EETs metabolism nor causes cardiac mitochondrial toxicity in vitro. Our patch-clamp experiments demonstrated that pharmacoelectrophysiology of dronedarone is unaffected by deuteration. Next, we show that dronedarone treatment or CYP2J2 knockdown in spontaneously beating cardiomyocytes indicative of depleted CYP2J2 activity exacerbates beat-to-beat (BTB) variability reflective of proarrhythmic phenotype. In contrast, poyendarone treatment yields significantly lower BTB variability compared to dronedarone in cardiomyocytes indicative of preserved CYP2J2 activity. Importantly, poyendarone and dronedarone display similar antiarrhythmic properties in the canine model of persistent AF, while poyendarone substantially reduces beat-to-beat variability of repolarization duration suggestive of diminished proarrhythmic risk. Our findings prove that deuteration of dronedarone prevents CYP2J2 inactivation and mitigates dronedarone-induced cardiac AEs.

Imatinib induces diastolic dysfunction and ventricular early-repolarization delay in the halothane-anesthetized dogs: Class effects of tyrosine kinase inhibitors.

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.