The Experts below are selected from a list of 8676 Experts worldwide ranked by ideXlab platform
Icilio Cavero - One of the best experts on this subject based on the ideXlab platform.
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Comprehensive in vitro Proarrhythmia Assay (CiPA): Pending issues for successful validation and implementation
Journal of Pharmacological and Toxicological Methods, 2016Co-Authors: Icilio Cavero, Jean-michel Guillon, Veronique Ballet, Mike Clements, Jean-frédéric Gerbeau, Henry HolzgrefeAbstract:Introduction: The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a nonclinical Safety Pharmacology paradigm for discovering electrophysiological mechanisms that are likely to confer Proarrhythmic liability to drug candidates intended for human use. Topics covered: Key talks delivered at the ‘CiPA on my mind’ session, held during the 2015 Annual Meeting of the Safety Pharmacology Society (SPS), are summarized. Issues and potential solutions relating to crucial constituents [e.g., biological materials (ion channels and pluripotent stem cell-derived cardiomyocytes), study platforms, drug solutions, and data analysis] of CiPA core assays are critically examined. Discussion: In order to advance the CiPA paradigm from the current testing and validation stages to a research and regulatory drug development strategy, systematic guidance by CiPA stakeholders is necessary to expedite solutions to pending and newly arising issues. Once a study protocol is proved to yield robust and reproducible results within and across laboratories, it can be implemented as qualified regulatory procedure.
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13th Annual Meeting of the Safety Pharmacology Society: focus on novel technologies and safety pharmacology frontiers.
Expert Opinion on Drug Safety, 2014Co-Authors: Icilio CaveroAbstract:Introduction: The 13th Annual Meeting of the Safety Pharmacology (SP) Society discussed novel therapeutic areas, recent regulatory developments, emerging biology technologies and non-pharmaceutical dairy products that may need SP evaluations for ensuring their human safety.Areas covered: The meeting honored Willem Einthoven, the father of electrocardiography. The Comprehensive in vitro Proarrhythmia Assay (CiPA) is an under-discussion proposal for replacing the International Conference on Hamonization (ICH) S7B guideline strategy. Drugs targeting epigenetic mechanisms (e.g., histone deacetylase inhibitors) have the potential to produce Proarrhythmic safety liabilities by dysregulating the synthesis of cardiac ion channel proteins as well as the intracellular machinery, moving them to sarcolemmal residence. Novel frontiers of regulatory SP investigations are functional food and probiotic (microorganisms) preparations.Expert opinion: The CiPA initiative is a unique opportunity for concerned stakeholders to ...
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comprehensive in vitro proarrhythmia assay a novel in vitro in silico paradigm to detect ventricular Proarrhythmic liability a visionary 21st century initiative
Expert Opinion on Drug Safety, 2014Co-Authors: Icilio Cavero, Henry HolzgrefeAbstract:Introduction: The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a novel safety screening proposal intended to replace the 2005 regulatory strategy recommended by the International Conference of Harmonization S7B guideline. Areas covered: CiPA consists of three components. The first assay evaluates candidate drug effects on key cardiac ion channels. Then, simulations test whether the channel dataset yields Proarrhythmic markers on a computationally reconstructed human ventricular cardiomyocyte action potential. Finally, the relevance of in silico conclusions is verified by determining the electrical activity of human stem cell-derived ventricular cardiomyocytes. Expert opinion: The CiPA initiative is intended to move safety pharmacology from a predominantly traditional pharmacodynamics approach to in silico and in vitro drug toxicity assessment. In practice, CiPA assays will have to be compliant with regulatory safety pharmacology tenets. The latter will necessitate international consensus on assay ...
Jagmeet P Singh - One of the best experts on this subject based on the ideXlab platform.
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cardiac resynchronization therapy and its potential Proarrhythmic effect
Clinical Cardiology, 2007Co-Authors: Indranill Basu Ray, Lahn Fendelander, Jagmeet P SinghAbstract:Cardiac resynchronization therapy (CRT) has become an established adjunctive treatment to optimal pharmacologic therapy in patients with advanced chronic heart failure (CHF), diminished left ventricular (LV) function and intraventricular conduction delay. Although CRT has been shown to improve ventricular hemodynamics, quality of life and exercise capacity, there is some evidence that it may rarely potentiate ventricular arrhythmias. As CRT is considered for an expanded population of CHF patients, and left-sided pacing is considered as an option for pacemaker-indicated patients (potentially without defibrillator backup), the effect of these pacing modalities on the incidence of ventricular tachyarrhythmia must be systematically studied and mechanistically understood. Strategies to prospectively predict the Proarrhythmic potential of LV epicardial pacing need to be developed, and therapy accordingly individualized. This review attempts to summarize the current information on proarrhythmia in resynchronization therapy.
Henry Holzgrefe - One of the best experts on this subject based on the ideXlab platform.
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Comprehensive in vitro Proarrhythmia Assay (CiPA): Pending issues for successful validation and implementation
Journal of Pharmacological and Toxicological Methods, 2016Co-Authors: Icilio Cavero, Jean-michel Guillon, Veronique Ballet, Mike Clements, Jean-frédéric Gerbeau, Henry HolzgrefeAbstract:Introduction: The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a nonclinical Safety Pharmacology paradigm for discovering electrophysiological mechanisms that are likely to confer Proarrhythmic liability to drug candidates intended for human use. Topics covered: Key talks delivered at the ‘CiPA on my mind’ session, held during the 2015 Annual Meeting of the Safety Pharmacology Society (SPS), are summarized. Issues and potential solutions relating to crucial constituents [e.g., biological materials (ion channels and pluripotent stem cell-derived cardiomyocytes), study platforms, drug solutions, and data analysis] of CiPA core assays are critically examined. Discussion: In order to advance the CiPA paradigm from the current testing and validation stages to a research and regulatory drug development strategy, systematic guidance by CiPA stakeholders is necessary to expedite solutions to pending and newly arising issues. Once a study protocol is proved to yield robust and reproducible results within and across laboratories, it can be implemented as qualified regulatory procedure.
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comprehensive in vitro proarrhythmia assay a novel in vitro in silico paradigm to detect ventricular Proarrhythmic liability a visionary 21st century initiative
Expert Opinion on Drug Safety, 2014Co-Authors: Icilio Cavero, Henry HolzgrefeAbstract:Introduction: The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a novel safety screening proposal intended to replace the 2005 regulatory strategy recommended by the International Conference of Harmonization S7B guideline. Areas covered: CiPA consists of three components. The first assay evaluates candidate drug effects on key cardiac ion channels. Then, simulations test whether the channel dataset yields Proarrhythmic markers on a computationally reconstructed human ventricular cardiomyocyte action potential. Finally, the relevance of in silico conclusions is verified by determining the electrical activity of human stem cell-derived ventricular cardiomyocytes. Expert opinion: The CiPA initiative is intended to move safety pharmacology from a predominantly traditional pharmacodynamics approach to in silico and in vitro drug toxicity assessment. In practice, CiPA assays will have to be compliant with regulatory safety pharmacology tenets. The latter will necessitate international consensus on assay ...
Lars Eckardt - One of the best experts on this subject based on the ideXlab platform.
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Proarrhythmic Effect of Acetylcholine-Esterase Inhibitors Used in the Treatment of Alzheimer’s Disease: Benefit of Rivastigmine in an Experimental Whole-Heart Model
Cardiovascular Toxicology, 2020Co-Authors: Christian Ellermann, Patrick Leitz, Michael Fehr, Dirk G. Dechering, Simon Kochhäuser, Lars Eckardt, Alix Coenen, Philipp Niehues, Gerrit FrommeyerAbstract:Several studies suggest QT prolongation and torsade de pointes with acetylcholine-esterase inhibitors. We therefore examined the electrophysiologic profile of donepezil, rivastigmine, and galantamine in a sensitive whole-heart model of proarrhythmia. 34 rabbit hearts were isolated and retrogradely perfused employing the Langendorff setup. Hearts were treated either with donepezil, rivastigmine, or galantamine in rising concentrations and electrophysiologic studies were performed. In the presence of donepezil and galantamine, spatial dispersion of repolarization was amplified. Cardiac repolarization (QT interval and action potential duration) was prolonged with donepezil but not with galantamine. Remarkably, both drugs induced triggered activity (early afterdepolarizations and torsade de pointes tachycardia). Despite a pronounced prolongation of repolarization with rivastigmine, no increase in spatial dispersion of repolarization and thus no triggered activity was observed. In the present study, donepezil and galantamine provoked triggered activity, whereas rivastigmine did not have Proarrhythmic effects. Spatial dispersion of repolarization but not duration of cardiac repolarization was associated with increased risk of drug-induced proarrhythmia with acetylcholine-esterase inhibitors. Consequently, QT interval duration might be insufficient to estimate the risk of proarrhythmia with acetylcholine-esterase inhibitors. Our findings emphasize the need for further electrocardiographic risk predictors.
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additive Proarrhythmic effect of combined treatment with qt prolonging agents
Cardiovascular Toxicology, 2018Co-Authors: Gerrit Frommeyer, Christina Fischer, Michael Fehr, Dirk G. Dechering, Simon Kochhäuser, Christian Ellermann, Philipp Lange, Kristina Wasmer, Lars EckardtAbstract:Drug combinations may elevate the risk of proarrhythmia. The aim of the present study was to investigate whether combinations of non-cardiovascular agents induce an additive increase in the Proarrhythmic risk. In 12 female rabbit hearts, a drug combination of cotrimoxazole (300 µM), ondansetron (5 µM) and domperidone (1 µM) was infused after obtaining baseline data. In another 13 hearts, a combination of cotrimoxazole (300 µM), ondansetron (5 µM) and erythromycin (300 µM) was infused. Monophasic action potentials and ECG displayed a significant QT prolongation in all groups. This was accompanied by a significant increase in action potential duration. Of note, addition of each drug resulted in a further increase in the QT interval. Furthermore, a significant elevation of spatial dispersion of repolarization was observed. Lowering of potassium concentration in bradycardic AV-blocked hearts provoked early afterdepolarizations and torsade de pointes (TDP) in both study groups. Under baseline conditions, no episodes of TDP recorded. After administration of the first agent, TDP occurred in 5 of 12 hearts (37 episodes) and 5 of 13 hearts (26 episodes), respectively. After additional infusion of the second drug, TDP were recorded in 7 of 12 hearts (55 episodes) and 8 of 13 hearts (111 episodes). After additional infusion of the third drug, TDP occurred in 11 of 12 hearts (118 episodes) and 9 of 13 hearts (88 episodes). Combined treatment with several non-cardiovascular QT-prolonging agents resulted in a remarkable occurrence of proarrhythmia. An additive and significant prolongation of cardiac repolarization combined with an increased spatial dispersion of repolarization represents the underlying electrophysiological mechanism.
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severe Proarrhythmic potential of risperidone compared to quetiapine in an experimental whole heart model of proarrhythmia
Naunyn-schmiedebergs Archives of Pharmacology, 2016Co-Authors: Gerrit Frommeyer, Florian Reinke, Philipp S Lange, Dirk G. Dechering, Kristina Wasmer, Benedict Brucher, Julia Kobe, Christian Pott, Gerold Monnig, Lars EckardtAbstract:In several case reports, Proarrhythmic effects of antipsychotic drugs have been reported. The aim of the present study was to investigate if application of risperidone or quetiapine has the potential to provoke polymorphic ventricular tachycardia in a sensitive model of proarrhythmia. In 24 isolated rabbit hearts, risperidone (5 and 10 μM, n = 12) or quetiapine (5 and 10 μM, n = 12) was infused after obtaining baseline data. Eight endocardial and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant QT prolongation after application of risperidone as compared with baseline (5 μM: +29 ms, 10 μM: +35 ms, p < 0.01) accompanied by an increase of action potential duration. Administration of risperidone also significantly increased spatial dispersion of repolarization (5 μM: +16 ms, 4 μM: +19 ms; p < 0.05) as well as temporal dispersion of repolarization. Lowering of potassium concentration in bradycardic AV-blocked hearts provoked early afterdepolarizations (EADs) in 8 of 12 hearts and polymorphic ventricular tachycardia resembling torsade de pointes in 6 of 12 hearts (10 μM, 49 episodes). The results were compared with hearts treated with quetiapine (5 and 10 μM). Quetiapine led to an increase in QT interval (5 μM: +10 ms; 10 μM: +28 ms; p < 0.05) and a similar increase of APD90. However, treatment with quetiapine did not result in significant alterations of spatial and temporal dispersion of repolarization. No ventricular arrhythmias were observed in this group. In the present study, quetiapine demonstrated a safe electrophysiologic profile despite significant QT prolongation. In contrast, risperidone led to a more marked prolongation of myocardial repolarization combined with a more marked increase of dispersion of repolarization.
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divergent electrophysiologic profile of fluconazole and voriconazole in an experimental whole heart model of proarrhythmia
European Journal of Pharmacology, 2016Co-Authors: Gerrit Frommeyer, Christina Fischer, Philipp S Lange, Patrick Leitz, Michael Fehr, Peter Milberg, Harilaos Bogossian, Lars EckardtAbstract:In several case reports a prolongation of the QT-interval and even Proarrhythmic effects of fluconazole and voriconazole were reported. The aim of the present study was to investigate if application of fluconazole or voriconazole has the potential to provoke polymorphic ventricular tachycardia in a sensitive model of proarrhythmia. In female rabbits, fluconazole (10, 30 and 50 µM, n=6) and voriconazole (10, 30 and 50 µM, n=6) were infused after obtaining baseline data. Eight endocardial and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant QT prolongation after application of fluconazole as compared with baseline (10 µM:+12 ms, 30 µM:+22 ms, 50 µM:+37 ms; P<0.05) accompanied by an increase of action potential duration (APD90). Administration of voriconazole also induced QT prolongation (30 µM:+10 ms, 50 µM:+20 ms, P<0.05). Spatial dispersion of repolarization remained stable in voriconazole-treated hearts while fluconazole induced a significant increase (30 µM:+15 ms, 50 µM:+16 ms; P<0.05). Lowering of potassium concentration in bradycardic AV-blocked hearts did not provoke any early afterdepolarizations (EADs) or polymorphic ventricular tachycardia in voriconazole-treated hearts. Application of fluconazole led to the reproducible induction of EADs in 4 of 6 hearts and polymorphic ventricular tachycardia in 3 of 6 hearts (36 episodes). In the present study, voriconazole demonstrated a safe electrophysiologic profile despite significant QT prolongation. In contrast, fluconazole led to a more marked prolongation of myocardial repolarization combined with a more marked increase of dispersion of repolarization. These results imply that application of fluconazole might be torsadogenic and the QT-interval should be closely monitored.
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vernakalant in an experimental model of pacing induced heart failure lack of proarrhythmia despite prolongation of repolarization
Journal of Cardiac Failure, 2014Co-Authors: Gerrit Frommeyer, Jochen Schulze Grotthoff, Florian Reinke, Christina Fischer, Michael Fehr, Peter Milberg, Dirk G. Dechering, Simon Kochhäuser, Harilaos Bogossian, Lars EckardtAbstract:Abstract Background The present ESC guidelines on atrial fibrillation have introduced vernakalant (VER) for pharmacologic cardioversion of atrial fibrillation. The aim of the present study was to investigate possible Proarrhythmic effects of vernakalant in an experimental model of heart failure (HF). Methods and Results In 12 female rabbits, HF was induced with the use of 4 weeks of rapid ventricular pacing. Twelve rabbits were sham operated. Isolated hearts demonstrated a significant prolongation of myocardial repolarization after induction of HF. Vernakalant caused a concentration-dependent (10 μmol/L and 30 μmol/L) increase of action potential duration (APD 90 ) and QT interval without affecting spatial and temporal dispersion of repolarization. The increase in APD 90 was accompanied by a greater increase in refractory period resulting in a significant increase in post-repolarization refractoriness. In control conditions, programmed ventricular stimulation and burst pacing led to ventricular fibrillation (VF) in 2 of the 12 sham (4 episodes) and in 3 of the 12 HF (24 episodes) subjects. In the presence of 30 μmol/L vernakalant, VF was no longer inducible in both groups (0 episodes). In the presence of low K + concentration, neither sham nor HF vernakalant-treated subjects developed early after-depolarizations or ventricular tachyarrhythmias. Conclusion In the present study, application of vernakalant led to a significant prolongation of myocardial repolarization and increased post-repolarization refractoriness but did not induce early after-depolarization and therefore did not cause proarrhythmia in failing hearts.
David G. Strauss - One of the best experts on this subject based on the ideXlab platform.
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cipa challenges and opportunities from a non clinical clinical and regulatory perspectives an overview of the safety pharmacology scientific discussion
Journal of Pharmacological and Toxicological Methods, 2018Co-Authors: Rob Wallis, Yasunari Kanda, David G. Strauss, Charles Enso, Orje Darpo, Gary A Ginta, Krishna Prasad, Jeanpierre ValentiAbstract:The Safety Pharmacology Society organized a scientific session at its annual conference in 2017 to discuss the challenges and opportunities of the Comprehensive In-Vitro Proarrhythmia Assay (CiPA) paradigm. Our intention was to raise awareness of this initiative with its members and also to gauge the extent to which safety pharmacologists have incorporated the CiPA testing strategy within the pharmaceutical industry. CiPA offers many potential opportunities including 1) a focus on Proarrhythmic risk (as opposed to QTc prolongation), 2) providing scientific rationale to support the continued development of compounds that may have a poor selectivity over hERG whilst also blocking other inward currents and 3) reducing the extent of ECG monitoring in clinical trials with a greater influence of the non-clinical studies. Such opportunities may speed drug development and reduce costs. However, there are also challenges for CiPA implementation. For example, the mixed ion channel paradigm does not easily lend itself to a prospective drug discovery strategy although testing for such effects can be achieved with assays with good throughput. However, it should also be recognized that compounds with a mixed ion channel profile might also have properties that are undesirable to treat non-life threatening indications. All components of CiPA (nonclinical and clinical) require validation, particularly as a composite package to impact drug development and evaluation. One of the significant discussion points was that the existing regulatory guidance supports the use of components of CiPA through follow-up studies. A survey of the conference audience showed that the level of awareness of CiPA is quite high and that companies are already conducting some testing against a wider panel of cardiac ion channels beyond hERG. However, the adoption of other technologies (stem cell derived cardiac myocytes and in silico modeling) is less well developed. Taken together, the session demonstrated the potential advantages of CiPA, but also some significant challenges.
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uncertainty quantification reveals the importance of data variability and experimental design considerations for in silico proarrhythmia risk assessment
Frontiers in Physiology, 2017Co-Authors: Kelly C Chang, Sara Dutta, Gary R Mirams, Kylie A Beattie, Jiansong Sheng, Phu N Tran, Min Wu, Wendy W Wu, Thomas Colatsky, David G. StraussAbstract:The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a global initiative intended to improve drug proarrhythmia risk assessment using a new paradigm of mechanistic assays. Under the CiPA paradigm, the relative risk of drug-induced Torsade de Pointes (TdP) is assessed using an in silico model of the human ventricular action potential (AP) that integrates in vitro pharmacology data from multiple ion channels. Thus, modeling predictions of cardiac risk liability will depend critically on the variability in pharmacology data, and uncertainty quantification (UQ) must comprise an essential component of the in silico assay. This study explores UQ methods that may be incorporated into the CiPA framework. Recently, we proposed a promising in silico TdP risk metric (qNet), which is derived from AP simulations and allows separation of a set of CiPA training compounds into Low, Intermediate, and High TdP risk categories. The purpose of this study was to use UQ to evaluate the robustness of TdP risk separation by qNet. Uncertainty in the model parameters used to describe drug binding and ionic current block was estimated using the non-parametric bootstrap method and a Bayesian inference approach. Uncertainty was then propagated through AP simulations to quantify uncertainty in qNet for each drug. UQ revealed lower uncertainty and more accurate TdP risk stratification by qNet when simulations were run at concentrations below 5× the maximum therapeutic exposure (Cmax). However, when drug effects were extrapolated above 10× Cmax, UQ showed that qNet could no longer clearly separate drugs by TdP risk. This was because for most of the pharmacology data, the amount of current block measured was <60%, preventing reliable estimation of IC50-values. The results of this study demonstrate that the accuracy of TdP risk prediction depends both on the intrinsic variability in ion channel pharmacology data as well as on experimental design considerations that preclude an accurate determination of drug IC50-values in vitro. Thus, we demonstrate that UQ provides valuable information about in silico modeling predictions that can inform future Proarrhythmic risk evaluation of drugs under the CiPA paradigm.
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Evolving regulatory paradigm for Proarrhythmic risk assessment for new drugs.
Journal of electrocardiology, 2016Co-Authors: Jose Vicente, Norman Stockbridge, David G. StraussAbstract:Fourteen drugs were removed from the market worldwide because their potential to cause torsade de pointes (torsade), a potentially fatal ventricular arrhythmia. The observation that most drugs that cause torsade block the potassium channel encoded by the human ether-a-go-go related gene (hERG) and prolong the heart rate corrected QT interval (QTc) on the ECG, led to a focus on screening new drugs for their potential to block the hERG potassium channel and prolong QTc. This has been a successful strategy keeping torsadogenic drugs off the market, but has resulted in drugs being dropped from development, sometimes inappropriately. This is because not all drugs that block the hERG potassium channel and prolong QTc cause torsade, sometimes because they block other channels. The regulatory paradigm is evolving to improve Proarrhythmic risk prediction. ECG studies can now use exposure-response modeling for assessing the effect of a drug on the QTc in small sample size first-in-human studies. Furthermore, the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a new in vitro paradigm for cardiac safety evaluation of new drugs that provides a more accurate and comprehensive mechanistic-based assessment of Proarrhythmic potential. Under CiPA, the prediction of Proarrhythmic potential will come from in vitro ion channel assessments coupled with an in silico model of the human ventricular myocyte. The preclinical assessment will be checked with an assessment of human phase 1 ECG data to determine if there are unexpected ion channel effects in humans compared to preclinical ion channel data. While there is ongoing validation work, the heart rate corrected J-Tpeak interval is likely to be assessed under CiPA to detect inward current block in presence of hERG potassium channel block.
