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In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline

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ABSTRACT

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 (M2), 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.

No MeSH data available.


Quantitative effects of increasing omadacycline concentrations on the spontaneous beating frequency (left) and percent reversal of carbamylcholine effects (right) in isolated rabbit sinoatrial node. Carba, carbamylcholine. *, P < 0.01 versus the control group. The four connected symbols in each figure (from left to right, respectively) represent the results for the following treatments: 200 nM carbamylcholine and 0.008 nM (4.6 μg/ml) omadacycline, 200 nM carbamylcholine and 0.024 nM (13.8 μg/ml) omadacycline, 200 nM carbamylcholine and 0.093 nM (51.8 μg/ml) omadacycline, and 200 nM carbamylcholine and 0.39 nM (217 μg/ml) omadacycline. **, P < 0.01 versus the carbamylcholine-treated group.
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Figure 4: Quantitative effects of increasing omadacycline concentrations on the spontaneous beating frequency (left) and percent reversal of carbamylcholine effects (right) in isolated rabbit sinoatrial node. Carba, carbamylcholine. *, P < 0.01 versus the control group. The four connected symbols in each figure (from left to right, respectively) represent the results for the following treatments: 200 nM carbamylcholine and 0.008 nM (4.6 μg/ml) omadacycline, 200 nM carbamylcholine and 0.024 nM (13.8 μg/ml) omadacycline, 200 nM carbamylcholine and 0.093 nM (51.8 μg/ml) omadacycline, and 200 nM carbamylcholine and 0.39 nM (217 μg/ml) omadacycline. **, P < 0.01 versus the carbamylcholine-treated group.

Mentions: Because omadacycline was found to inhibit the binding activity of the muscarinic M2 receptor, carbamylcholine (a pan-muscarinic receptor agonist) was also evaluated in these experiments. Carbamylcholine (200 nM) markedly increased the cycle length of spontaneous activity in the rabbit pacemaker SA node by decreasing the diastolic slope, leading to reduced pacemaker activity (the spontaneous beating rate was reduced by 32% ± 3% compared with the value for the control) (Fig. 4). Omadacycline reversed the effects of carbamylcholine (200 nM) on pacemaker activity. Omadacycline at 8 μM (4.6 μg/ml) significantly counterbalanced the decrease in pacemaker activity induced by carbamylcholine at 200 nM by 45% ± 4.4% (Fig. 4). This reversal was concentration dependent and reached a maximum at 93 μM (51.8 μg/ml) and 390 μM (217.1 μg/ml), which resulted in the nearly total reversal of the carbamylcholine effect (by 99% ± 9% and 108% ± 17%, respectively).


In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline
Quantitative effects of increasing omadacycline concentrations on the spontaneous beating frequency (left) and percent reversal of carbamylcholine effects (right) in isolated rabbit sinoatrial node. Carba, carbamylcholine. *, P < 0.01 versus the control group. The four connected symbols in each figure (from left to right, respectively) represent the results for the following treatments: 200 nM carbamylcholine and 0.008 nM (4.6 μg/ml) omadacycline, 200 nM carbamylcholine and 0.024 nM (13.8 μg/ml) omadacycline, 200 nM carbamylcholine and 0.093 nM (51.8 μg/ml) omadacycline, and 200 nM carbamylcholine and 0.39 nM (217 μg/ml) omadacycline. **, P < 0.01 versus the carbamylcholine-treated group.
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Related In: Results  -  Collection

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Figure 4: Quantitative effects of increasing omadacycline concentrations on the spontaneous beating frequency (left) and percent reversal of carbamylcholine effects (right) in isolated rabbit sinoatrial node. Carba, carbamylcholine. *, P < 0.01 versus the control group. The four connected symbols in each figure (from left to right, respectively) represent the results for the following treatments: 200 nM carbamylcholine and 0.008 nM (4.6 μg/ml) omadacycline, 200 nM carbamylcholine and 0.024 nM (13.8 μg/ml) omadacycline, 200 nM carbamylcholine and 0.093 nM (51.8 μg/ml) omadacycline, and 200 nM carbamylcholine and 0.39 nM (217 μg/ml) omadacycline. **, P < 0.01 versus the carbamylcholine-treated group.
Mentions: Because omadacycline was found to inhibit the binding activity of the muscarinic M2 receptor, carbamylcholine (a pan-muscarinic receptor agonist) was also evaluated in these experiments. Carbamylcholine (200 nM) markedly increased the cycle length of spontaneous activity in the rabbit pacemaker SA node by decreasing the diastolic slope, leading to reduced pacemaker activity (the spontaneous beating rate was reduced by 32% ± 3% compared with the value for the control) (Fig. 4). Omadacycline reversed the effects of carbamylcholine (200 nM) on pacemaker activity. Omadacycline at 8 μM (4.6 μg/ml) significantly counterbalanced the decrease in pacemaker activity induced by carbamylcholine at 200 nM by 45% ± 4.4% (Fig. 4). This reversal was concentration dependent and reached a maximum at 93 μM (51.8 μg/ml) and 390 μM (217.1 μg/ml), which resulted in the nearly total reversal of the carbamylcholine effect (by 99% ± 9% and 108% ± 17%, respectively).

View Article: PubMed Central - PubMed

ABSTRACT

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 (M2), 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 &mu;g/ml (179.5 &mu;M), with a 25% inhibitory concentration of 166 &mu;g/ml (298.0 &mu;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.

No MeSH data available.