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Published on: March 2, 2020
Electrophysiological safety of DW-286a, a novel fluoroquinolone antibiotic agent
Eun-Joo Kim1, Ki-Suk Kim, Won-Ho Shin
1Department of Pharmacology and National Research Laboratory, Korea Institute of Toxicology, Yuseong, Daejeon, Korea. ejkim@kitox.re.kr
Abstract:
Inhibition of the potassium current I(Kr) and QT prolongation has been known to be associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. We investigated the cardiac electrophysiological effects of DW-286a, a new class of fluoroquinolone antibiotics reported to prolong the QT interval. To investigate the electrophysiological safety of DW-286a, we used conventional microelectrode recording techniques in isolated guinea pig papillary muscles, whole-cell patch clamp techniques in human ether-à-go-go related gene (hERG)-transient transfected Chinese hamster ovary cells, and in vivo electrocardiogram (ECG) measurements in Sprague-Dawley (SD) rats by the use of a telemetry system. DW-286a at 300 microM significantly (P<0.01) prolonged action potentials at 50% repolarization (APD50) and 90% repolarization (APD90). For IHERG, the IC50 value was 89.00+/-37.85 microM with a Hill coefficient (nH) of -0.97+/-0.49. However, when DW-286a was orally administered to conscious SD rats at a high dose (1000 mg/kg), no significant effect on ECG in vivo was detected. From a previous study, we know that concentration at 19.8 microM is the antimicrobial end-point of DW-286a. Therefore, our data suggest that in the electrophysiological aspect, it can be thought that the effective concentrations of DW-286a are between 19.8 and 100 microM (concentration in serum).
Insights
This study assessed the cardiac safety of DW-286a, a fluoroquinolone antibiotic. While high concentrations prolonged action potentials in vitro, no significant in vivo cardiac effects were observed in rats, suggesting a good safety profile at therapeutic doses.
Area of Science:
- Pharmacology
- Cardiology
- Electrophysiology
Background:
- Drug-induced torsades de pointes (TdP) and sudden cardiac death are linked to potassium channel inhibition and QT prolongation.
- DW-286a is a novel fluoroquinolone antibiotic with reported QT interval prolongation concerns.
Purpose of the Study:
- To evaluate the cardiac electrophysiological effects and safety of DW-286a.
- To determine the in vitro and in vivo effects of DW-286a on cardiac repolarization.
Main Methods:
- Conventional microelectrode recordings in guinea pig papillary muscles.
- Whole-cell patch clamp on hERG-transfected cells to assess IHERG inhibition.
- In vivo electrocardiogram (ECG) measurements in Sprague-Dawley rats via telemetry.
Main Results:
- DW-286a (300 microM) significantly prolonged action potential duration (APD50 and APD90) in guinea pig papillary muscles.
- The IC50 for DW-286a inhibition of IHERG was 89.00+/-37.85 microM.
- No significant in vivo ECG changes were observed in rats after oral administration of DW-286a at 1000 mg/kg.
Conclusions:
- DW-286a exhibits in vitro electrophysiological effects at concentrations exceeding its antimicrobial endpoint.
- In vivo studies indicate no significant cardiac electrophysiological adverse effects at high doses.
- The therapeutic concentrations of DW-286a appear to be within a range considered electrophysiologically safe.
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