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Cardiovascular safety profile of MA-2029, a novel motilin receptpr antagonist.
- Source :
-
Journal of Toxicological Sciences . Dec2008, Vol. 33 Issue 5, p631-639. 9p. 2 Diagrams, 2 Charts, 2 Graphs. - Publication Year :
- 2008
-
Abstract
- The aim of this study was to assess the cardiovascular effect of MA-2029, a selective motilin receptor antagonist highly expected for the treatment of irritable bowel syndrome (IBS). MA-2029 inhibited the human ether-a-go-go-related gene (hERG) current at 100 μg/ml, but shortened action potential duration (APD) in isolated guinea pig papillary muscles at 10 and 100 μg/ml and the corrected QT (QTc) interval after oral administration of 30 and 300 mg/kg in conscious telemetered dogs. The discrepancy was probably caused by blockade of the Ca2+ channel because MA-2029 inhibited the Ca2+ current in isolated guinea pig myocytes. MA-2029 at 100 μg/ml also decreased the maximum rising velocity and action potential amplitude in the action potential study, indicating that MA-2029 has Na+ channel blocking potential. In the cardiovascular study, MA-2029 at 30 mg/kg induced slight cardiovascular changes such as hypotension, QTc shortening, and PR prolongation possibly caused by Ca2+ channel blockade. The plasma concentration at 4 hr after 30 mg/kg administration was 2.10 μg/ml, 200-fold higher than the effective concentration of MA-2029 as a motilin receptor antagonist. These results suggest that MA-2029 has sufficient cardiovascular safety although it inhibits multiple ion channels at supra-effective concentrations. On the other hand, cisapride, an effective IBS drug, showed clear hERG inhibition and APD prolongation at 100 ng/ml. Cisapride exhibited a narrow safety margin because it caused QT prolongation potential even at the therapeutic concentration. In conclusion, MA-2029 is a novel drug highly expected for the treatment of IBS with lower cardiovascular risk than cisapride. [ABSTRACT FROM AUTHOR]
- Subjects :
- *CARDIOVASCULAR diseases
*MOTILIN
*MUSCLE cells
*SWINE
*HYPOTENSION
*CISAPRIDE
Subjects
Details
- Language :
- English
- ISSN :
- 03881350
- Volume :
- 33
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- Journal of Toxicological Sciences
- Publication Type :
- Academic Journal
- Accession number :
- 36085189
- Full Text :
- https://doi.org/10.2131/jts.33.631