Repercussions of pharmacologic reduction in ionic currents on action potential configuration in rabbit Purkinje fibers: Are they indicative of proarrhythmic potential?

Dumotier, Bérengère; Adamantidis, M. M.; Puisieux, François; Bastide, Michèle; Dupuis, B

doi:10.1002/(sici)1098-2299(199906)47:2<63::aid-ddr2>3.0.co;2-5

Cited by 28 publications

(12 citation statements)

References 51 publications

(59 reference statements)

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“…action potential for the evaluation of cardiac safety. 9,10) The European Federation of Pharmaceutical Industries and Associations has performed a survey on the methodology within the pharmaceutical industry relating to the detection of undesired cardiac effects of active new compounds. 33) The most commonly used tissue for in vitro electrophysiology was Purkinje fibers.…”

Section: Fig 2 Effects Of Terfenadine On Herg Channel Current Exprementioning

confidence: 86%

“…[9][10][11][12][13][14] The maximum concentration of terfenadine examined (20 mM) was higher than the maximum clinically approachable plasma concentration of the drug in hepatic compromise or coadministration with drugs affecting its metabolism. [20][21][22] A lack of APD prolongation by terfenadine in tissue has also been reported in guinea pig ventricle, 15) and canine, 23,24) and porcine Purkinje fiber.…”

Section: Discussionmentioning

confidence: 98%

“…Purkinje fibers are known to be highly sensitive to the APD-prolonging effect of drugs, [9][10][11][12][13][14] and some researchers have recommended the use of rabbit Purkinje fiber 134 Vol. 27, No.…”

Section: Discussionmentioning

confidence: 99%

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Lack of Action Potential-Prolonging Effect of Terfenadine on Rabbit Myocardial Tissue Preparations

Masumiya

Saito

Ito

et al. 2004

Biological & Pharmaceutical Bulletin

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It is well recognized that both cardiovascular and noncardiovascular drugs may promote arrhythmia.1) Clinical treatment with class I and class III antiarrhythmic agents as well as non-cardiovascular drugs such as terfenadine, cisapride, and haloperidol has been associated with QT prolongation and serious ventricular arrhythmia including torsades de pointes.2-6) Studies with animal myocardium have demonstrated that these drugs are able to prolong action potential duration (APD) through inhibition of the rapid component of the delayed rectifier potassium current (IKr). 2,7,8) Since then, the assessment of the risks incurred with noncardiovascular therapeutic agents for cardiac function has received great attention. Some researchers and organizations have postulated that analysis of APD in rabbit Purkinje fibers is the most adequate method for evaluation.9) This appeared reasonable because rabbit Purkinje fibers had been shown to be highly sensitive to drugs with APD-prolonging activity.

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Section: Fig 2 Effects Of Terfenadine On Herg Channel Current Exprementioning

confidence: 86%

Section: Discussionmentioning

confidence: 98%

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Lack of Action Potential-Prolonging Effect of Terfenadine on Rabbit Myocardial Tissue Preparations

Masumiya

Saito

Ito

et al. 2004

Biological & Pharmaceutical Bulletin

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“…Furthermore, the use of the hERG assay can lead to incorrect conclusions on cardiac risk, as a partial inhibition of hERG current does not result in prolongation of the DPA-90 because of the compensatory effects of other cardiac ion channels. Thus, to properly evaluate the integrated cardiac risk, further studies should be considered, especially those designed to investigate the electrophysiological properties of the test article, such as evaluation of AP duration using different pro-arrhythmic models (73). …”

Section: Safety Studiesmentioning

confidence: 99%

Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies

Andrade¹,

Bento²,

Cavalli³

et al. 2016

Braz J Med Biol Res

114

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The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose.

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“…Variations on the AP shape are indicative of the potential effects of the substance on the main cardiac ionic currents such as the rapid sodium current (I Na ) responsible for the rapid cell depolarization (phase 0 of the AP) and involved in cell electrical conductance, the transient outward potassium current (I Kto ) responsible for the notch specific to the Purkinje fiber AP (phase 1 of the AP), the slow calcium current (I CaL ) partly responsible for the maintaining of the AP plateau (phase 2 of the AP) and involved in the contractile properties of the cardiomyocytes, the slow and rapid components of the delayed rectifier potassium current (I Ks and I Kr ) mainly responsible for the cell late repolarization (phase 3 of the AP), and the inward rectifier potassium current (I K1 ) that helps in the maintenance of the cardiac cell hyperpolarization at rest (phase 4 of the AP). Most of Purkinje fiber studies are conducted in rabbit or dog preparations either because of the high sensitivity of the rabbit cardiac preparation to AP duration variations [22,23] or because comparison of ex vivo and in vivo data (QT interval on dog ECG) are facilitated by use of the same animal species [24,25]. Some scientists claim that the rabbit Purkinje fiber is too much sensitive to AP duration lengthening to be accurately predictive for human and that it would present a high risk of false positive, particularly when Purkinje fibers are removed from females that have been shown as more sensitive than males to such effects [26].…”

Section: Ex Vivo Multicellular Studies On Surrogate Biomarkers Of Promentioning

confidence: 99%

Supplemental Studies for Cardiovascular Risk Assessment in Safety Pharmacology: A Critical Overview

et al. 2011

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Safety Pharmacology studies for the cardiovascular risk assessment, as described in the ICH S7A and S7B guidelines, appear as being far from sufficient. The fact that almost all medicines withdrawn from the market because of life-threatening tachyarrhythmias (torsades-de-pointes) were shown as hERG blockers and QT interval delayers led the authorities to focus mainly on these markers. However, other surrogate biomarkers, e.g., TRIaD (triangulation, reverse-use-dependence, instability and dispersion of ventricular repolarization), have been identified to more accurately estimate the drug-related torsadogenic risk. In addition, more attention should be paid to other arrhythmias, not related to long QT and nevertheless severe and/or not self-extinguishing, e.g., atrial or ventricular fibrillation, resulting from altered electrical conduction or heterogeneous shortening of cardiac repolarization. Moreover, despite numerous clinical cases of drug-induced pulmonary hypertension, orthostatic hypotension, or heart valvular failure, few safety investigations are still conducted on drug interaction with cardiac and regional hemodynamics other than changes in aortic blood pressure evaluated in conscious large animals during the core battery mandatory studies. This critical review aims at discussing the usefulness, relevance, advantages, and limitations of some preclinical in vivo, in vitro, and in silico models, with high predictive values and currently used in supplemental safety studies.

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Repercussions of pharmacologic reduction in ionic currents on action potential configuration in rabbit Purkinje fibers: Are they indicative of proarrhythmic potential?

Cited by 28 publications

References 51 publications

Lack of Action Potential-Prolonging Effect of Terfenadine on Rabbit Myocardial Tissue Preparations

Lack of Action Potential-Prolonging Effect of Terfenadine on Rabbit Myocardial Tissue Preparations

Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies

Supplemental Studies for Cardiovascular Risk Assessment in Safety Pharmacology: A Critical Overview

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