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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.


Related in: MedlinePlus

Concentration-response relationship for the effect of omadacycline on the hERG tail current. Data are corrected for mean vehicle breakdown. *, P < 0.01 versus the vehicle-treated group.
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Figure 1: Concentration-response relationship for the effect of omadacycline on the hERG tail current. Data are corrected for mean vehicle breakdown. *, P < 0.01 versus the vehicle-treated group.

Mentions: In vehicle-treated cells (n = 4), approximately 10 min of exposure to 100% bath solution produced a residual tail current of 91.1% ± 5.0% of the control values. Omadacycline at 100, 250, 500, and 1,000 μg/ml inhibited the hERG tail current in a concentration-dependent manner, and the inhibition began to plateau at higher concentrations. A significant inhibition of the tail current was observed at concentrations of 250 μg/ml and above (P < 0.01) compared with the results obtained with the vehicle-treated group. When the results for the omadacycline- and vehicle-treated groups were compared, omadacycline at 100 μg/ml had no significant inhibitory effect on the hERG tail current. The IC25 value for omadacycline was 166 μg/ml (Fig. 1). When administered to vehicle-treated cells, approximately 10 min of exposure to the K+ channel blocker E-4031 (100 nM; n = 2 cells) produced a residual tail current of 9.8% or a decrease in the tail current of 90.2%.


In Vitro and In Vivo Assessments of Cardiovascular Effects with Omadacycline
Concentration-response relationship for the effect of omadacycline on the hERG tail current. Data are corrected for mean vehicle breakdown. *, P < 0.01 versus the vehicle-treated group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Concentration-response relationship for the effect of omadacycline on the hERG tail current. Data are corrected for mean vehicle breakdown. *, P < 0.01 versus the vehicle-treated group.
Mentions: In vehicle-treated cells (n = 4), approximately 10 min of exposure to 100% bath solution produced a residual tail current of 91.1% ± 5.0% of the control values. Omadacycline at 100, 250, 500, and 1,000 μg/ml inhibited the hERG tail current in a concentration-dependent manner, and the inhibition began to plateau at higher concentrations. A significant inhibition of the tail current was observed at concentrations of 250 μg/ml and above (P < 0.01) compared with the results obtained with the vehicle-treated group. When the results for the omadacycline- and vehicle-treated groups were compared, omadacycline at 100 μg/ml had no significant inhibitory effect on the hERG tail current. The IC25 value for omadacycline was 166 μg/ml (Fig. 1). When administered to vehicle-treated cells, approximately 10 min of exposure to the K+ channel blocker E-4031 (100 nM; n = 2 cells) produced a residual tail current of 9.8% or a decrease in the tail current of 90.2%.

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.


Related in: MedlinePlus