ArticleBritish journal of pharmacology2008
Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea-pig model.
Article in British journal of pharmacology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 75 citations in OpenAlex.
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- The effect of sex and age on ex vivo cardiac electrophysiology: insight from a guinea pig model.American journal of physiology. Heart and circulatory physiology · 2023Article
- Abnormal dopamine receptor signaling allows selective therapeutic targeting of neoplastic progenitors in AML patients.Cell reports. Medicine · 2021Article
- Drug-induced cholestasis assay in primary hepatocytes.MethodsX · 2020Article
- On the potential of in vitro organ-chip models to define temporal pharmacokinetic-pharmacodynamic relationships.Scientific reports · 2019Article
- Development of (6 R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5 H-imidazo[2,1- b][1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis.Journal of medicinal chemistry · 2018Article
- Towards Bridging Translational Gap in Cardiotoxicity Prediction: an Application of Progressive Cardiac Risk Assessment Strategy in TdP Risk Assessment of Moxifloxacin.The AAPS journal · 2018Article
- Modulation of the heart's electrical properties by the anticonvulsant drug retigabine.Toxicology and applied pharmacology · 2017Article
- 7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis.Journal of medicinal chemistry · 2017Article
- Ionic mechanisms underlying the negative chronotropic action of propofol on sinoatrial node automaticity in guinea pig heart.British journal of pharmacology · 2015Article
- The novel benzimidazole derivative BRP-7 inhibits leukotriene biosynthesis in vitro and in vivo by targeting 5-lipoxygenase-activating protein (FLAP).British journal of pharmacology · 2014Article
- Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: a study to assess the drug's cardiac ion channel profile.Toxicology and applied pharmacology · 2013Article
- Age and gender dependent heart rate circadian model development and performance verification on the proarrhythmic drug case study.Theoretical biology & medical modelling · 2013Article
- The electro-mechanical window in anaesthetized guinea pigs: a new marker in screening for Torsade de Pointes risk.British journal of pharmacology · 2012Article
- Wild type and K897T polymorphisms of the hERG gene: modeling the APD in Caucasians.Bioinformation · 2012Article
- Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug development.British journal of pharmacology · 2010Review
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeDrug-induced prolongation of the QT interval can lead to torsade de pointes, a life-threatening ventricular arrhythmia. Finding appropriate assays from among the plethora of options available to predict reliably this serious adverse effect in humans remains a challenging issue for the discovery and development of drugs. The purpose of the present study was to develop and verify a reliable and relatively simple approach for assessing, during preclinical development, the propensity of drugs to prolong the QT interval in humans. EXPERIMENTAL APPROACH: Sixteen marketed drugs from various pharmacological classes with a known incidence -- or lack thereof -- of QT prolongation in humans were examined in hERG (human ether a-go-go-related gene) patch-clamp assay and an anaesthetized guinea-pig assay for QT prolongation using specific protocols. Drug concentrations in perfusates from hERG assays and plasma samples from guinea-pigs were determined using liquid chromatography-mass spectrometry. KEY
resultsVarious pharmacological agents that inhibit hERG currents prolong the QT interval in anaesthetized guinea-pigs in a manner similar to that seen in humans and at comparable drug exposures. Several compounds not associated with QT prolongation in humans failed to prolong the QT interval in this model. CONCLUSIONS AND IMPLICATIONS: Analysis of hERG inhibitory potency in conjunction with drug exposures and QT interval measurements in anaesthetized guinea-pigs can reliably predict, during preclinical drug development, the risk of human QT prolongation. A strategy is proposed for mitigating the risk of QT prolongation of new chemical entities during early lead optimization.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.