Alan S Bass

Merck, White House Station, New Jersey, United States

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Publications (27)62.42 Total impact

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    ABSTRACT: Professor Gerhard Zbinden recognized in the 1970s that the standards of the day for testing new candidate drugs in preclinical toxicity studies failed to identify acute pharmacodynamic adverse events that had the potential to harm participants in clinical trials. From his vision emerged the field of safety pharmacology, formally defined in the International Conference on Harmonization (ICH) S7A guidelines as "those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above." Initially, evaluations of small-molecule pharmacodynamic safety utilized efficacy models and were an ancillary responsibility of discovery scientists. However, over time, the relationship of these studies to overall safety was reflected by the regulatory agencies who, in directing the practice of safety pharmacology through guidance documents, prompted transition of responsibility to drug safety departments (e.g., toxicology). Events that have further shaped the field over the past 15 years include the ICH S7B guidance, evolution of molecular technologies leading to identification of new therapeutic targets with uncertain toxicities, introduction of data collection using more sophisticated and refined technologies, and utilization of transgenic animal models probing critical scientific questions regarding novel targets of toxicity. The collapse of the worldwide economy in the latter half of the first decade of the twenty-first century, continuing high rates of compound attrition during clinical development and post-approval and sharply increasing costs of drug development have led to significant strategy changes, contraction of the size of pharmaceutical organizations, and refocusing of therapeutic areas of investigation. With these changes has come movement away from dedicated internal safety pharmacology capability to utilization of capabilities within external contract research organizations. This movement has created the opportunity for the safety pharmacology discipline to come "full circle" and return to the drug discovery arena (target identification through clinical candidate selection) to contribute to the mitigation of the high rate of candidate drug failure through better compound selection decision making. Finally, the changing focus of science and losses in didactic training of scientists in whole animal physiology and pharmacology have revealed a serious gap in the future availability of qualified individuals to apply the principles of safety pharmacology in support of drug discovery and development. This is a significant deficiency that at present is only partially met with academic and professional society programs advancing a minimal level of training. In summary, with the exception that the future availability of suitably trained scientists is a critical need for the field that remains to be effectively addressed, the prospects for the future of safety pharmacology are hopeful and promising, and challenging for those individuals who want to assume this responsibility. What began in the early part of the new millennium as a relatively simple model of testing to assure the safety of Phase I clinical subjects and patients from acute deleterious effects on life-supporting organ systems has grown with experience and time to a science that mobilizes the principles of cellular and molecular biology and attempts to predict acute adverse events and those associated with long-term treatment. These challenges call for scientists with a broad range of in-depth scientific knowledge and an ability to adapt to a dynamic and forever changing industry. Identifying individuals who will serve today and training those who will serve in the future will fall to all of us who are committed to this important field of science.
    No preview · Article · Jun 2015 · Handbook of experimental pharmacology
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    ABSTRACT: Evaluating whether a new medication prolongs QT intervals is a critical safety activity that is conducted in a sensitive animal model during nonclinical drug development. The importance of QT liability detection has been reinforced by nonclinical (ICH S7B) and clinical (ICH E14) regulatory guidance from the International Conference on Harmonization. A key challenge for the cardiovascular safety community is to understand how the finding from a nonclinical in vivo QT assay in animals predicts the outcomes of a clinical QT evaluation in humans. The HESI Pro-Arrhythmia Working Group performed a literature search (1960-2011) to identify both human and non-rodent animal studies that assessed QT signal concordance between species and identified drugs that prolonged or did not prolong the QT interval. The main finding was the excellent agreement between QT results in humans and non-rodent animals. Ninety-one percent (21 of 23) of drugs that prolonged the QT interval in humans also did so in animals, and 88% (15 of 17) of drugs that did not prolong the QT interval in humans had no effect on animals. This suggests that QT interval data derived from relevant non-rodent models has a 90% chance of predicting QT findings in humans. Disagreement can occur, but in the limited cases of QT discordance we identified, there appeared to be plausible explanations for the underlying disconnect between the human and non-rodent animal QT outcomes. This article is protected by copyright. All rights reserved.
    Full-text · Article · May 2015 · British Journal of Pharmacology

  • No preview · Article · Nov 2014 · Journal of Pharmacological and Toxicological Methods
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    ABSTRACT: Inhibitors based on a benzo-fused spirocyclic oxazepine scaffold were discovered for stearoyl-coenzyme A (CoA) desaturase 1 (SCD1) and subsequently optimized to potent compounds with favorable pharmacokinetic profiles and in vivo efficacy in reducing the desaturation index in a mouse model. Initial optimization revealed potency preferences for the oxazepine core and benzylic positions, while substituents on the piperidine portions were more tolerant and allowed for tuning of potency and PK properties. After preparation and testing of a range of functional groups on the piperidine nitrogen, three classes of analogs were identified with single digit nanomolar potency: glycine amides, heterocycle-linked amides, and thiazoles. Responding to concerns about target localization and potential mechanism-based side effects, an initial effort was also made to improve liver concentration in an available rat PK model. An advanced compound 17m with a 5-carboxy-2-thiazole substructure appended to the spirocyclic piperidine scaffold was developed which satisfied the in vitro and in vivo requirements for more detailed studies.
    No preview · Article · Dec 2012 · Bioorganic & medicinal chemistry letters
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    ABSTRACT: A consortium of scientific, regulatory and medical research representatives formed to assess the concordance between non- clinical repolarization assays and clinical QT interval measures (Trepakova et al., 2009). Bioinformatics and text mining tools enabled a thorough review of the literature to identify nonclinical and clinical QTc examples to assess concordance. This exercise focussed on published literature on drugs that exhibited (or lacked) QTc prolongation risk, and were developed before implementation of ICH S7B and E14 guidance. Initial review identified 123 compounds that were subjected to in-depth secondary review by a panel of scientific experts. Of these, 28 drugs meet inclusion criteria and were evaluated. A central finding of this analysis was that the majority (88%) of agents that caused QTc prolongation in humans also demonstrated a positive QTc signal in an experimental non-rodent animal model (i.e., 15 of 17 agents). Likewise, of the 11 human agents devoid of any effect on QTc intervals, most did not alter QTc intervals in animals (10; 91%). To gain some understanding of non-concordance, the 28 drugs were tested in hERG potency and trafficking assays. This qualitative evaluation suggested that non-rodent models are useful for predicting QTc findings in human studies, but discordance can occur. In the few cases of discordance, there appears to be a plausible explanation for the underlying disconnect between the animal and human QTc outcomes. While these findings are compelling, the findings from this literature-based analysis may be limited by reporting bias and missing agents.
    Full-text · Article · Sep 2012 · Journal of Pharmacological and Toxicological Methods
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    ABSTRACT: In recognition of the tenth anniversary of the Safety Pharmacology Society (SPS), this review summarizes the significant events of the past 10years that have led to the birth, growth and evolution the SPS and presents a roadmap to the immediate-, intermediate- and long-term future of the SPS. The review discusses (i) the rationale for an optimal non-clinical Safety Pharmacology testing, (ii) the evolution of Safety Pharmacology over the last decade, (iii) its impact on drug discovery and development, (iv) the merits of adopting an integrated risk assessment approach, (v) the translation of non-clinical findings to humans and finally (vi) the future challenges and opportunities facing this discipline. Such challenges include the emergence of new molecular targets and new approaches to treat diseases, the rapid development of science and technologies, the growing regulatory concerns and associated number of guidance documents, and the need to train and educate the next generation of safety pharmacologist.
    No preview · Article · Jun 2011 · Journal of pharmacological and toxicological methods

  • No preview · Article · Sep 2010 · Journal of Pharmacological and Toxicological Methods

  • No preview · Chapter · Mar 2010
  • Alan S. Bass · Laurie A. Hanson · Terry A. Jackson
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    ABSTRACT: ObjectiveDrug-induced torsades de pointes (TdP) arrhythmia is a serious public health concern that has significantly slowed the advancement of promising new therapeutic agents to the marketplace. Modeling for the potential to produce TdP has relied in part on the surrogate biomarker QT interval prolongation, measured in vivo in animals and in the clinic in man. This study was a comparison of the effects of PNU-142093, a selective 5HT1D-serotonin receptor agonist, on QT interval prolongation under restraint and non-restraint conditions in conscious cynomolgus non-human primates.MethodsLead II electrocardiograms (ECG) were collected following an oral single-dose (non-restraint conditions using radio-telemetry) and single- and multiple-doses for 14 days (restraint conditions using electrodes applied to the surface) at doses of 0, 5, 15, and 25 mg/kg. ECG were collected from non-restrained animals predose and for up to 5 hrs, and again at 7 hrs, postdose on 4 different days in a Latin-square crossover design; N=4/sex/dose level. ECG were collected from restrained animals on days 1, 7, and 13, predose and at approximately 4 hrs postdose; N=2/sex/group.ResultsNon-restrained animal heart rate ranged from 159±22.1 to 168±21.4 beats/minute when compared to restrained animal heart rate (ranging from 242±17.2 to 246±11.5 beats/minute), suggesting that non-restrained animals were under less stress. In non-restrained animals, PNU-142093 produced a non-dose related decrease in heart rate, associated with a dose-related increase in QT and QTc (QT interval corrected for changes in heart rate) intervals, which was accompanied by alterations in T-wave morphology (e.g., widening and notching of the T wave). In restrained non-human primates, PNU-142093 had no effect on heart rate or ECG morphology on any day of dosing and no statistically significant effect on QT or QTc intervals on days 1 or 7 of dosing. By day 13 there were statistically significant increases in QT and QTc intervals at 15 and 25 mg/kg. The increase in QTc interval in restrained animals on day 13 was 29±12 and 30±19 msec at 15 and 25 mg/kg/day, respectively, and that in non-restrained animals was 65±23 and 73±28 msec.DiscussionThese data demonstrate an ability to detect problematic drugs in conscious cynomolgus non-human primates using both restraint and non-restraint procedures. They further show that the sensitivity of these assays to identify this signal of cardiac risk is significantly improved under the condition of non-restraint.
    No preview · Article · Jul 2009 · Journal of pharmacological and toxicological methods
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    ABSTRACT: Testing for possible cardiovascular side effects of new drugs has been an essential part of drug development for years. A more detailed analysis of the electrocardiogram (ECG) to detect effects on ventricular repolarization (effects on the QT interval), as a marker for possible proarrhythmic potential has been added to that evaluation in recent years. State-of-the art evaluation of drug-induced effects on the QT interval have evolved, but due to the complexity of the assessment, the trend in safety pharmacology studies has been to collect large numbers of high quality ECGs to allow for a robust assessment including the influence of heart rate on the QT interval apart from possible drug-induced effects. Since an assessment of the ECG is often included in toxicological studies, one can consider making such an assessment using ECG data from routine toxicological studies. This review summarizes various aspects of both safety pharmacology and toxicology studies with regards to their impact on the quality and quantity of ECG data that one can reasonably derive. We conclude that ECG data from toxicological studies can offer complementary ECG data that can strengthen a risk assessment. However, for the great majority of standard toxicity studies conducted, the ECG data collected do not permit an adequate assessment of drug-induced effects on the QT interval with the sensitivity expected from the ICH S7B guidelines. Furthermore, sponsors should be discouraged from performing any analyses on low quality ECGs to avoid generating misleading data. Substantial improvements in ECG quality and quantity are available, thereby making a QT interval assessment within the context of a standard toxicological study feasible, but these methods may require a larger commitment of resources from the sponsor. From the viewpoint of risk mitigation and limiting the attrition of promising new therapies, a commitment of resources to insure ECG data quality in either toxicology or safety pharmacology studies may be well justified.
    No preview · Article · Jun 2009 · Journal of pharmacological and toxicological methods
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    ABSTRACT: Identification of novel new molecules which hold the greatest promise of safe and effective therapies remains a continuous challenge to the pharmaceutical industry. This has led the industry to implement strategies for identification of the most promising candidates during the discovery phase and for their safe and expeditious advancement through development. Testing for potential liable properties in the discovery phase has included the evaluation of major areas of pharmaceutics that have led to failure such as its physical and pharmaceutical properties, drug metabolism and pharmacokinetic characteristics, various safety endpoints including pre-development safety pharmacology, general toxicology and genetic toxicology and interrogation of counter-screen data to identify off-target affinities (i.e., receptors, ion channels, transporters, kinases, etc.) that pose a concern. Amongst the many important areas of concern is the potential for toxicities of the major organ systems. To mitigate this concern, a strategy pursued is to identify the prominent toxicological properties of the candidate prior to its recommendation for development. The results of these studies in discovery allow exclusion of the candidate before the expenditure of resources and time typical of development. In addition, the discovery phase toxicology studies serve to address key questions that may have arisen from the study of another molecule, the phenotypic profile from pre-clinical models where the therapeutic target has been genetically modified or concerns that have been raised as a result of other investigations. Importantly, the results of the exploratory drug safety studies will be used by the sponsor to judge the potential risks associated with continued pursuit of a potential development candidate. In many ways, pre-clinical toxicological investigations in discovery serve the important objective of identifying the most promising candidates to progress into development and onto registration.
    No preview · Article · Jun 2009 · Journal of pharmacological and toxicological methods
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    ABSTRACT: IntroductionThe objectives of this survey were to obtain a global information update regarding current industry perspectives that describe Safety Pharmacology programs as they relate to the ICH S7A and S7B regulatory guidelines but also to obtain a broader perspective of other practises practices in the field currently used by companies. Preliminary findings were presented at the 7th Annual Meeting of the Safety Pharmacology Society (SPS) (Edinburgh, Scotland, Sept 19–21, 2007).MethodsThe survey was distributed by the SPS to 125 pharmaceutical companies. Survey topics included (a) an update on ICH S7A and S7B practices, (b) frontloading Safety Pharmacology studies prior to selection of candidate drugs, (c) abuse and dependence-liability studies and (d) an extended evaluation of industry practises practices as assessed by Contract Research Organizations (CROs).ResultsRespondents (> 94%) include GLP core battery (CV, CNS and respiratory) studies in the drug package submitted to regulatory agencies, and ∼ 40% also submit studies on gastrointestinal and renal function. Respondents to the ICH S7B aspects indicate ∼ 98% include the hERG assay and QT interval (in vivo) data in submissions, 63% include APD in vitro data and another 23% APD in vivo and other cardiac channel data (26%). SP frontloading is performed by 78% of all responding companies. Respondents indicate that 39% of these non-GLP CV studies are conducted before lead optimization (LO) and 85% during LO and before candidate drug selection. The hERG, CNS selectivity binding screens and rodent behavioral studies are frontloaded by 100%, 90% and 74% of respondents. Responding CROs (26) were surveyed on the services offered including Irwin or Functional Observational Battery (FOB) tests (70%), respiratory studies (85%), in vivo telemeterized dogs (69%) and in vitro CV studies (50%). Only 38% of SP studies are combined with toxicology studies at the CROs.DiscussionThe survey results indicate that ICH S7A core battery studies are implemented by most of the responding companies with a clear trend of an enhanced submission of renal and GI studies. The impact of ICH S7B is clear since, all respondents assess cardiac repolarization using cellular hERG (IKr) and whole animal (QT interval) assays as a component of their safety assessment. Responses indicate a diversity of approaches for conducting abuse liability studies, which primarily use the methods of self-administration and drug discrimination. While early SP frontloading of studies seems to vary, the methods used appear to be generic to some extent and include in vitro ‘off-target’ evaluations and in vivo tests to determine the potential for CNS and cardiovascular issues.
    Full-text · Article · Sep 2008 · Journal of pharmacological and toxicological methods
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    ABSTRACT: Biological therapeutic agents (biologicals), such as monoclonal antibodies (mAbs), are increasingly important in the treatment of human disease, and many types of biologicals are in clinical development. During preclinical drug development, cardiovascular safety pharmacology studies are performed to assess cardiac safety in accord with the ICH S7A and S7B regulations that guide these studies. The question arises, however, whether or not it is appropriate to apply these guidelines, which were devised primarily to standardize small molecule drug testing, to the cardiovascular evaluation of biologicals. We examined the scientific literature and formed a consensus of scientific opinion to determine if there is a rational basis for conducting an in vitro hERG assay as part of routine preclinical cardiovascular safety testing for biologicals. We conclude that mAb therapeutics have very low potential to interact with the extracellular or intracellular (pore) domains on hERG channel and, therefore, are highly unlikely to inhibit hERG channel activity based on their targeted, specific binding properties. Furthermore, mAb are large molecules (> 140,000 Da) that cannot cross plasma membranes and therefore would be unable to access and block the promiscuous inner pore of the hERG channel, in contrast with typical small molecule drugs. Consequently, we recommend that it is not appropriate to conduct an in vitro hERG assay as part of a preclinical strategy for assessing the heart rate corrected QT interval (QTc) prolongation risk of mAbs and other types of biologicals. It is more appropriate to assess QTc risk by integrating cardiovascular endpoints into repeat-dose general toxicology studies performed in an appropriate non-rodent species. These recommendations should help shape future regulatory strategy and discussions for the cardiovascular safety pharmacology testing of mAbs as well as other biologicals and provide guidance for the preclinical cardiovascular evaluation of such agents.
    Full-text · Article · Sep 2008 · Journal of pharmacological and toxicological methods
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    ABSTRACT: The effects of dofetilide were studied in monkeys and dogs. Pharmacokinetic data were generated together with the monitoring of cardiovascular changes in order to compare effects relative to human exposure. Beagle dogs and cynomolgus monkeys were telemetered to collect arterial blood pressure, heart rate and ECG for 6 h after selected oral doses of dofetilide. Pharmacokinetic parameters were determined for each dose. Dogs: increases in the QT(c) interval reached 56 ms in dogs dosed with 0.3 mg kg(-1) of dofetilide. Premature ventricular contractions and right bundle branch block were evident at this dose, without changes in cardiovascular parameters. The mean C(max) values were 3.35 and 60.15 ng mL(-1) at doses of 0.03 and 0.3 mg kg(-1), respectively. Monkeys: increases in QT(c) intervals reached 40-50 ms after 0.03 mg kg(-1). T-wave changes were observed after 0.03 mg kg(-1) without changes in cardiovascular parameters. The mean C(max) values following oral doses of 0.01 and 0.03 mg kg(-1) were 0.919 ng mL(-1) and 1.85 ng mL(-1), respectively. Despite dofetilide exposure comparable to that in humans, QT(c) responses in dogs were greater than those reported in humans. A comparable human dose used in the monkey achieved only half of the exposure but was associated with twofold greater increases in QT(c). Our data support the view that safety risk assessments of new drugs in animal models should ensure that the clinical therapeutic range of exposure is achieved and any untoward effects interpreted accordingly.
    Preview · Article · Aug 2008 · British Journal of Pharmacology
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    ABSTRACT: Knowledge of the cardiac safety of emerging new drugs is an important aspect of assuring the expeditious advancement of the best candidates targeted at unmet medical needs while also assuring the safety of clinical trial subjects or patients. Present methodologies for assessing drug-induced torsades de pointes (TdP) are woefully inadequate in terms of their specificity to select pharmaceutical agents, which are human arrhythmia toxicants. Thus, the critical challenge in the pharmaceutical industry today is to identify experimental models, composite strategies, or biomarkers of cardiac risk that can distinguish a drug, which prolongs cardiac ventricular repolarization, but is not proarrhythmic, from one that prolongs the QT interval and leads to TdP. To that end, the HESI Proarrhythmia Models Project Committee recognized that there was little practical understanding of the relationship between drug effects on cardiac ventricular repolarization and the rare clinical event of TdP. It was on that basis that a workshop was convened in Virginia, USA at which four topics were introduced by invited subject matter experts in the following fields: Molecular and Cellular Biology Underlying TdP, Dynamics of Periodicity, Models of TdP Proarrhythmia, and Key Considerations for Demonstrating Utility of Pre-Clinical Models. Contained in this special issue of the British Journal of Pharmacology are reports from each of the presenters that set out the background and key areas of discussion in each of these topic areas. Based on this information, the scientific community is encouraged to consider the ideas advanced in this workshop and to contribute to these important areas of investigations over the next several years.British Journal of Pharmacology (2008) 154, 1491–1501; doi:fn8
    Full-text · Article · Jul 2008 · British Journal of Pharmacology
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    A S Bass · B Darpo · J-P Valentin · P Sager · K Thomas
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    ABSTRACT: Drug-induced torsades de pointes (TdP) remains a significant public health concern that has challenged scientists who have the responsibility of advancing new medicines through development to the patient, while assuring public safety. As a result, from the point of discovering a new molecule to the time of its registration, significant efforts are made to recognize potential liabilities, including the potential for TdP. With this background, the ILSI (HESI) Proarrhythmia Models Project Committee recognized that there was little practical understanding of the relationship between drug effects on cardiac ventricular repolarization and the rare clinical event of TdP. A workshop was therefore convened at which four topics were considered including: Molecular and Cellular Biology Underlying TdP, Dynamics of Periodicity, Models of TdP Proarrhythmia and Key Considerations for Demonstrating Utility of Pre-Clinical Models. The series of publications in this special edition has established the background, areas of debate and those that deserve scientific pursuit. This is intented to encourage the research community to contribute to these important areas of investigation in advancing the science and our understanding of drug-induced proarrhythmia.
    Full-text · Article · Jul 2008 · British Journal of Pharmacology
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    Full-text · Article · May 2008 · Journal of Pharmacological and Toxicological Methods
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    ABSTRACT: The Health and Environmental Sciences Institute of the International Life Sciences Institute (ILSI/HESI) Cardiovascular Safety Subcommittee outlined a set of in vivo telemetry studies to determine how well this preclinical model identified compounds known to cause torsades de pointes (TdP) and prolong QT interval in humans. In the original analysis of these data, QT, QTcB (Bazett model), QTcF (Fridericia model), and QTcQ (animal-specific model) were evaluated. We further evaluate the statistical properties of these measurements, using a method that can properly account for the sources of variability in the dataset. The ILSI/HESI telemetry studies were conducted as a double Latin square design where eight dogs each received a vehicle control and three dose levels of a compound on four separate dosing days. We statistically analyzed the QT/QTc intervals using a repeated measures analysis of covariance and evaluate the powers for QT, QTcF and QTcQ based on simulations. The analyses for QTcF and QTcB intervals show that all six compounds which were known to cause TdP in humans were identified as positive and all six compounds known to be free of TdP events in their clinical use had no statistically significant treatment-related effects, while the analyses for QTcQ identified all positive compounds except pimozide. The power analysis shows that the method can detect a 7% increment of QT, a 5% increment of QTcF, and a 4% increment of QTcQ, with greater than 80% of power when n=8. We describe a repeated measures procedure to perform statistical analysis of covariance on Latin square designs and show that it can be used to detect meaningful changes in the analysis of QT/QTc intervals.
    No preview · Article · Sep 2007 · Journal of Pharmacological and Toxicological Methods
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    ABSTRACT: Introduction Regulatory Guidelines Governing Safety Pharmacology In Vivo Cardiovascular Safety Pharmacology In Vitro Cardiac Safety Pharmacology (Cardiac Electrophysiology) Respiratory Safety Pharmacology Central Nervous System (CNS) Safety Pharmacology Acknowledgments References
    No preview · Article · Aug 2007
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    ABSTRACT: Drugs that delay cardiac repolarization pose potential safety risks to patients and cause serious regulatory concern because of the link between QT interval prolongation and the potentially fatal arrhythmia torsades de pointes (TdP). Predicting which drugs will cause TdP is an inexact and difficult science. The utility of non-clinical assays was not well understood due in part to variability in methods, species, and consistency in the assays reported in the literature. The Health and Environmental Sciences Institute of the International Life Sciences Institute (ILSI/HESI) outlined a set of studies to determine how well selected commonly used non-clinical assays identified compounds known to cause TdP and prolong QT interval in humans. Compounds known to prolong ventricular repolarization and compounds considered safe by years of clinical use were tested in three assays: HERG ionic current, Purkinje fiber repolarization, and in vivo QT studies in conscious telemeterized dogs. The data from each of these assays demonstrate that compounds that may pose a proarrhythmia risk for patients can be distinguished from those that are considered safe. Taken collectively, the in-vitro and in-vivo preclinical results can be integrated to develop an accurate preclinical risk assessment to support clinical safety.
    Full-text · Article · Sep 2006 · Journal of Pharmacological and Toxicological Methods