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In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline
Omadacycline is a first-in-class aminomethylcycline antibiotic with a broad spectrum of activity against Gram-positive and Gram-negative aerobes and anaerobes and atypical bacterial pathogens. A series of nonclinical studies, including mammalian pharmacologic receptor binding studies, human ether-a-...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997885/ https://www.ncbi.nlm.nih.gov/pubmed/27324778 http://dx.doi.org/10.1128/AAC.00320-16 |
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author | Tanaka, S. Ken Villano, Stephen |
author_facet | Tanaka, S. Ken Villano, Stephen |
author_sort | Tanaka, S. Ken |
collection | PubMed |
description | Omadacycline is a first-in-class aminomethylcycline antibiotic with a broad spectrum of activity against Gram-positive and Gram-negative aerobes and anaerobes and atypical bacterial pathogens. A series of nonclinical studies, including mammalian pharmacologic receptor binding studies, human ether-a-go-go-related gene (hERG) channel binding studies, studies of the effects on ex vivo sinoatrial (SA) node activity, and studies of in vivo effects on cardiovascular function in the cynomolgus monkey, was undertaken to assess the cardiovascular risk potential. Omadacycline was found to bind almost exclusively to the muscarinic subtype 2 acetylcholine receptor (M(2)), and in the SA node model it antagonized the effect of a pan-muscarinic agonist (carbamylcholine) in a concentration-dependent manner. Omadacycline exhibited no effect on hERG channel activity at 100 μg/ml (179.5 μM), with a 25% inhibitory concentration of 166 μg/ml (298.0 μM). Omadacycline had no effect on QTc in conscious monkeys at doses up to 40 mg/kg of body weight. Overall, omadacycline appears to attenuate the parasympathetic influence on the heart rate but has a low potential to induce cardiac arrhythmia or to have clinically significant cardiovascular toxicity. |
format | Online Article Text |
id | pubmed-4997885 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-49978852016-09-13 In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline Tanaka, S. Ken Villano, Stephen Antimicrob Agents Chemother Mechanisms of Action: Physiological Effects Omadacycline is a first-in-class aminomethylcycline antibiotic with a broad spectrum of activity against Gram-positive and Gram-negative aerobes and anaerobes and atypical bacterial pathogens. A series of nonclinical studies, including mammalian pharmacologic receptor binding studies, human ether-a-go-go-related gene (hERG) channel binding studies, studies of the effects on ex vivo sinoatrial (SA) node activity, and studies of in vivo effects on cardiovascular function in the cynomolgus monkey, was undertaken to assess the cardiovascular risk potential. Omadacycline was found to bind almost exclusively to the muscarinic subtype 2 acetylcholine receptor (M(2)), and in the SA node model it antagonized the effect of a pan-muscarinic agonist (carbamylcholine) in a concentration-dependent manner. Omadacycline exhibited no effect on hERG channel activity at 100 μg/ml (179.5 μM), with a 25% inhibitory concentration of 166 μg/ml (298.0 μM). Omadacycline had no effect on QTc in conscious monkeys at doses up to 40 mg/kg of body weight. Overall, omadacycline appears to attenuate the parasympathetic influence on the heart rate but has a low potential to induce cardiac arrhythmia or to have clinically significant cardiovascular toxicity. American Society for Microbiology 2016-08-22 /pmc/articles/PMC4997885/ /pubmed/27324778 http://dx.doi.org/10.1128/AAC.00320-16 Text en Copyright © 2016 Tanaka and Villano. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Mechanisms of Action: Physiological Effects Tanaka, S. Ken Villano, Stephen In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline |
title | In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline |
title_full | In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline |
title_fullStr | In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline |
title_full_unstemmed | In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline |
title_short | In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline |
title_sort | in vitro and in vivo assessments of cardiovascular effects with omadacycline |
topic | Mechanisms of Action: Physiological Effects |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997885/ https://www.ncbi.nlm.nih.gov/pubmed/27324778 http://dx.doi.org/10.1128/AAC.00320-16 |
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