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In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline

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 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 spontaneous frequency (left) and on resting membrane potential and Vmax (right) in isolated rabbit SA nodes. **, P < 0.01.
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Figure 2: Quantitative effects of increasing omadacycline concentrations on spontaneous frequency (left) and on resting membrane potential and Vmax (right) in isolated rabbit SA nodes. **, P < 0.01.

Mentions: Increasing concentrations of omadacycline of 0.05, 0.126, 0.422, 1.5, and 5 mM (27.8, 70.1, 235, 835, and 2,783 μg/ml, respectively; n = 6 SA node preparations) had no effect on the cycle length (the time between 2 beats) or AP parameters up to a concentration of 0.422 mM (235 μg/ml). At 1.5 mM (835 μg/ml) and 5 mM (2,783 μg/ml), omadacycline markedly depolarized SA node tissue due to cytotoxicity, making the diastolic potential more positive and leading to a reduced amplitude, an increased duration, and an increased cycle length (Fig. 2). Increasing concentrations of omadacycline did not significantly modify APD50 or APD90 up to 1.5 mM (835 μg/ml) (Fig. 3). At a concentration of 2,783 μg/ml, APD50 and APD90 were significantly increased (+32% and +18%, respectively, compared with the values for the control), again likely reflecting the cytotoxicity of this concentration.


In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline
Quantitative effects of increasing omadacycline concentrations on spontaneous frequency (left) and on resting membrane potential and Vmax (right) in isolated rabbit SA nodes. **, P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4997885&req=5

Figure 2: Quantitative effects of increasing omadacycline concentrations on spontaneous frequency (left) and on resting membrane potential and Vmax (right) in isolated rabbit SA nodes. **, P < 0.01.
Mentions: Increasing concentrations of omadacycline of 0.05, 0.126, 0.422, 1.5, and 5 mM (27.8, 70.1, 235, 835, and 2,783 μg/ml, respectively; n = 6 SA node preparations) had no effect on the cycle length (the time between 2 beats) or AP parameters up to a concentration of 0.422 mM (235 μg/ml). At 1.5 mM (835 μg/ml) and 5 mM (2,783 μg/ml), omadacycline markedly depolarized SA node tissue due to cytotoxicity, making the diastolic potential more positive and leading to a reduced amplitude, an increased duration, and an increased cycle length (Fig. 2). Increasing concentrations of omadacycline did not significantly modify APD50 or APD90 up to 1.5 mM (835 μg/ml) (Fig. 3). At a concentration of 2,783 μg/ml, APD50 and APD90 were significantly increased (+32% and +18%, respectively, compared with the values for the control), again likely reflecting the cytotoxicity of this concentration.

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.