Cardiohemodynamic and Arrhythmogenic Effects of the Anti-Atrial Fibrillatory Compound Vanoxerine in Halothane-Anesthetized Dogs

Hagiwara-Nagasawa, Mihoko; Kambayashi, Ryuichi; Goto, Ai; Nunoi, Yoshio; Izumi-Nakaseko, Hiroko; Takei, Yoshinori; Matsumoto, Akio; Sugiyama, Atsushi

doi:10.1007/s12012-020-09612-3

Cited by 8 publications

(7 citation statements)

References 23 publications

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“…For clinical data, this includes new clinical drug studies, 62–69 comparison of different measurement algorithms, 70–73 improved heart rate assessment correction, 74 and multiple studies from independent groups re‐analyzing the FDA clinical trial data 70,71,75,76 . For nonclinical studies, this includes drugs overlapping with clinical study drugs and many interesting drugs without clinical data 35,77–82 . For example, a recent nonclinical in vivo study focused on vanoxerine, 80 an interesting drug with large QTc prolongation that has multi‐ion channel effects, and was hypothesized by a sponsor to be of relatively low risk for TdP 83 .…”

Section: Figurementioning

confidence: 99%

“…However, in a phase III trial for atrial fibrillation, 3 of the first 26 patients developed TdP 84 . A nonclinical in vivo ECG biomarker study demonstrated that vanoxerine prolonged J‐Tpeakc with the same J‐Tpeakc vs. Tpeak‐Tend pattern as other high‐risk drugs (bepridil, sotalol, and E‐4031), whereas amiodarone did not prolong J‐Tpeakc 80 . This suggests that the J‐Tpeakc biomarkerwould have identified vanoxerine as a predominant hERG blocker consistent with high TdP risk.…”

Section: Figurementioning

confidence: 99%

“…70,71,75,76 For nonclinical studies, this includes drugs overlapping with clinical study drugs and many interesting drugs without clinical data. 35,[77][78][79][80][81][82] For example, a recent nonclinical in vivo study focused on vanoxerine, 80 an interesting drug with large QTc prolongation that has multi-ion channel effects, and was hypothesized by a sponsor to be of relatively low risk for TdP. 83 However, in a phase III trial for atrial fibrillation, 3 of the first 26 patients developed TdP.…”

Section: Reviewmentioning

confidence: 99%

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Translational Models and Tools to Reduce Clinical Trials and Improve Regulatory Decision Making for QTc and Proarrhythmia Risk (ICH E14/S7B Updates)

Strauss

et al. 2021

Clin Pharma and Therapeutics

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After multiple drugs were removed from the market secondary to drug‐induced torsade de pointes (TdP) risk, the International Council for Harmonisation (ICH) released guidelines in 2005 that focused on the nonclinical (S7B) and clinical (E14) assessment of surrogate biomarkers for TdP. Recently, Vargas et al. published a pharmaceutical‐industry perspective making the case that “double‐negative” nonclinical data (negative in vitro hERG and in vivo heart‐rate corrected QT (QTc) assays) are associated with such low probability of clinical QTc prolongation and TdP that potentially all double‐negative drugs would not need detailed clinical QTc evaluation. Subsequently, the ICH released a new E14/S7B Draft Guideline containing Questions and Answers (Q&As) that defined ways that double‐negative nonclinical data could be used to reduce the number of “Thorough QT” (TQT) studies and reach a low‐risk determination when a TQT or equivalent could not be performed. We review the Vargas et al. proposal in the context of what was contained in the ICH E14/S7B Draft Guideline and what was proposed by the ICH E14/S7B working group for a “stage 2” of updates (potential expanded roles for nonclinical data and details for assessing TdP risk of QTc‐prolonging drugs). Although we do not agree with the exact probability statistics in the Vargas et al. paper because of limitations in the underlying datasets, we show how more modest predictive value of individual assays could still result in low probability for TdP with double‐negative findings. Furthermore, we expect that the predictive value of the nonclinical assays will improve with implementation of the new ICH E14/S7B Draft Guideline.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

See 1 more Smart Citation

Translational Models and Tools to Reduce Clinical Trials and Improve Regulatory Decision Making for QTc and Proarrhythmia Risk (ICH E14/S7B Updates)

Strauss

et al. 2021

Clin Pharma and Therapeutics

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“…In COR-ART, no ventricular proarrhythmia was noticed [ 148 ], while RESTORE SR was prematurely terminated due to increased incidence of torsades de pointes ventricular tachyarrhythmia in the vanoxerine arm [ 149 ]. A recent pharmacodynamics study highlights that vanoxerine possesses poor atrial selectivity, prolongs ventricular repolarization, and increases intracellular calcium overload risk, thus rendering future investigations unlikely [ 150 ].…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

Molecular Insights in Atrial Fibrillation Pathogenesis and Therapeutics: A Narrative Review

et al. 2021

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The prevalence of atrial fibrillation (AF) is bound to increase globally in the following years, affecting the quality of life of millions of people, increasing mortality and morbidity, and beleaguering health care systems. Increasingly effective therapeutic options against AF are the constantly evolving electroanatomic substrate mapping systems of the left atrium (LA) and ablation catheter technologies. Yet, a prerequisite for better long-term success rates is the understanding of AF pathogenesis and maintenance. LA electrical and anatomical remodeling remains in the epicenter of current research for novel diagnostic and treatment modalities. On a molecular level, electrical remodeling lies on impaired calcium handling, enhanced inwardly rectifying potassium currents, and gap junction perturbations. In addition, a wide array of profibrotic stimuli activates fibroblast to an increased extracellular matrix turnover via various intermediaries. Concomitant dysregulation of the autonomic nervous system and the humoral function of increased epicardial adipose tissue (EAT) are established mediators in the pathophysiology of AF. Local atrial lymphomononuclear cells infiltrate and increased inflammasome activity accelerate and perpetuate arrhythmia substrate. Finally, impaired intracellular protein metabolism, excessive oxidative stress, and mitochondrial dysfunction deplete atrial cardiomyocyte ATP and promote arrhythmogenesis. These overlapping cellular and molecular alterations hinder us from distinguishing the cause from the effect in AF pathogenesis. Yet, a plethora of therapeutic modalities target these molecular perturbations and hold promise in combating the AF burden. Namely, atrial selective ion channel inhibitors, AF gene therapy, anti-fibrotic agents, AF drug repurposing, immunomodulators, and indirect cardiac neuromodulation are discussed here.

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“…12 J-Tpeak can estimate the net balance between inward INa,L plus ICa,L and outward IKs plus IKr during Phase 2 of the action potential, and a prolongation in J-Tpeak may predict the onset of Ca 2+ overload, governing the "trigger" of premature ventricular contractions. 13 Meanwhile, Tpeak-Tend may indicate the extent of IKr inhibition, with a prolongation in Tpeak-Tend possibly reflecting an increase in transmural dispersion of the repolarization period, which also plays an important role as a "substrate" for perpetuating spiral re-entry. 12,14 Intravenous administration of 1 mg/kg donepezil hydrochloride over 10 min, which provided an approximate 30-fold greater plasma…”

mentioning

confidence: 99%

Measurement of Early and Late Repolarization Periods in Addition to QT Interval to Help Predict the Torsadogenic Risk of Donepezil Based on Reverse Translational Animal Research on Its Proarrhythmic Potential

et al. 2021

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Cardiohemodynamic and Arrhythmogenic Effects of the Anti-Atrial Fibrillatory Compound Vanoxerine in Halothane-Anesthetized Dogs

Cited by 8 publications

References 23 publications

Translational Models and Tools to Reduce Clinical Trials and Improve Regulatory Decision Making for QTc and Proarrhythmia Risk (ICH E14/S7B Updates)

Translational Models and Tools to Reduce Clinical Trials and Improve Regulatory Decision Making for QTc and Proarrhythmia Risk (ICH E14/S7B Updates)

Molecular Insights in Atrial Fibrillation Pathogenesis and Therapeutics: A Narrative Review

Measurement of Early and Late Repolarization Periods in Addition to QT Interval to Help Predict the Torsadogenic Risk of Donepezil Based on Reverse Translational Animal Research on Its Proarrhythmic Potential

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