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Stanat, Scott J.C.; Carlton, Carol G.; Crumb, William J.; Agrawal, Krishna C.; Clarkson, Craig W.

doi:10.1023/a:1027309703313

Cited by 83 publications

(19 citation statements)

References 22 publications

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“…Indeed, moxifloxacin is the standard positive-control drug in human QTc prolongation studies (7, 10, 25). Similarly, macrolides have also been known to inhibit hERG channel activity and have the potential to cause QTc prolongation (12, 13). Revised product labeling to include a warning of sudden death due to cardiac arrhythmias was required for azithromycin on the basis of reports to the U.S. Food and Drug Administration (FDA) (26).…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline

Tanaka

Villano

2016

Antimicrob Agents Chemother

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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 g/ml (179.5 M), with a 25% inhibitory concentration of 166 g/ml (298.0 M). 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. Omadacycline is a first-in-class aminomethylcycline antibiotic (1) with broad-spectrum microbiological activity, including potent activity against Gram-positive and atypical bacteria and good activity against Gram-negative and anaerobic bacteria (2-4).Results from clinical studies indicate that omadacycline can be administered as once daily oral or intravenous (i.v.) therapy; the bioavailability of the oral tablet formulation currently in use is 35% (5, 6). Clinical development is proceeding to evaluate omadacycline for the treatment of serious infections, including community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI).An important component of the development of novel pharmacologic compounds is an evaluation of the potential for cardiovascular toxicity (7). A variety of drugs, including those belonging to the macrolide, ketolide, and fluoroquinolone classes of antibiotics, are well-known to block the cardiac potassium channel encoded by the human ether-a-go-go-related gene (hERG), which causes prolonged cardiac repolarization with the attendant potential for an increased risk for ventricular arrhythmias (8)(9)(10)(11)(12)(13)(14).A series of nonclinical in vitro and in vivo studies was undertaken with omadacycline with the objective of evaluating the potential for cardiovascular toxicity. These studies investigated the affinity of omadacycline binding to mammalian pharmacologic receptors, binding activity on hERG channels, ex vivo effects on the sinoatrial (SA) node, and in vivo effects on cardiovascular function and physiology in the cynomolgus monkey. MATERIALS AND METHODSReceptor binding. Standard radiolabeled ligand binding assays were performed with omadacycline at a concentration of 10 M (5.57 g/ml) and 59 pharmacologically relevant ...

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Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline

Tanaka

Villano

2016

Antimicrob Agents Chemother

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“…In stably transfected human kidney embryonic (HEK) cells, the IC50 for erythromycin-induced HERG/ I Kr -block was 38.9 µM [31] and 0.008 µM for E-4031 [32]. Thus, likely, E-4031, which is used in a concentration of up to 13x IC50 in the perfusion solution, reaches a sufficient concentration in the cardiac tissue to elicit a complete HERG/ I Kr -block, while erythromycin, used in a concentration of up to 8x IC50, may not necessarily exert a complete block at highest concentration explaining why genotype-specific differences in the susceptibility – with a higher susceptibility in LQT1 rabbits – were obvious only at high concentrations of erythromycin.…”

Section: Discussionmentioning

confidence: 99%

Pronounced Effects of HERG-Blockers E-4031 and Erythromycin on APD, Spatial APD Dispersion and Triangulation in Transgenic Long-QT Type 1 Rabbits

et al. 2014

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BackgroundProlongation of action potential duration (APD), increased spatial APD dispersion, and triangulation are major factors promoting drug-induced ventricular arrhythmia. Preclinical identification of HERG/IKr-blocking drugs and their pro-arrhythmic potential, however, remains a challenge. We hypothesize that transgenic long-QT type 1 (LQT1) rabbits lacking repolarizing IKs current may help to sensitively detect HERG/IKr-blocking properties of drugs.MethodsHearts of adult female transgenic LQT1 and wild type littermate control (LMC) rabbits were Langendorff-perfused with increasing concentrations of HERG/IKr-blockers E-4031 (0.001–0.1 µM, n = 9/7) or erythromycin (1–300 µM, n = 9/7) and APD, APD dispersion, and triangulation were analyzed.ResultsAt baseline, APD was longer in LQT1 than in LMC rabbits in LV apex and RV mid. Erythromycin and E-4031 prolonged APD in LQT1 and LMC rabbits in all positions. However, erythromycin-induced percentaged APD prolongation related to baseline (%APD) was more pronounced in LQT1 at LV base-lateral and RV mid positions (100 µM, LQT1, +40.6±9.7% vs. LMC, +24.1±10.0%, p<0.05) and E-4031-induced %APD prolongation was more pronounced in LQT1 at LV base-lateral (0.01 µM, LQT1, +29.6±10.6% vs. LMC, +19.1±3.8%, p<0.05) and LV base-septal positions. Moreover, erythromycin significantly increased spatial APD dispersion only in LQT1 and increased triangulation only in LQT1 in LV base-septal and RV mid positions. Similarly, E-4031 increased triangulation only in LQT1 in LV apex and base-septal positions.ConclusionsE-4031 and erythromycin prolonged APD and increased triangulation more pronouncedly in LQT1 than in LMC rabbits. Moreover, erythromycin increased APD dispersion only in LQT1, indicating that transgenic LQT1 rabbits could serve as sensitive model to detect HERG/IKr-blocking properties of drugs.

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“…hERG inhibition was measured at 37°C using a stably transfected HEK cell line at expressing the hERG mRNA. 33 For routine screening, compounds were tested in replicate at 30 and 300 lM. For measurement of the IC 50 of 1, 3, and 7a, duplicate measurements were made at 1, 3, 10, 50, 100, and 300 lM.…”

Section: In Vitro Assaysmentioning

confidence: 99%

“…hERG is a potassium ion channel found in the heart, which if inhibited can lead to prolongation of the QT interval and potentially fatal cardiac arrhythmia. [32][33][34][35] By alkylation to form 9-O-acetamides the potency was improved and the antibacterial activity reduced. 36 Further the acetamides also reduced the ability of the molecules to inhibit hERG.…”

Section: Introductionmentioning

confidence: 99%