Source:http://linkedlifedata.com/resource/pubmed/id/19043284
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
5
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| pubmed:dateCreated |
2008-12-1
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| pubmed:abstractText |
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 microg/ml, but shortened action potential duration (APD) in isolated guinea pig papillary muscles at 10 and 100 microg/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 Ca(2+) channel because MA-2029 inhibited the Ca(2+) current in isolated guinea pig myocytes. MA-2029 at 100 microg/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 Ca(2+) channel blockade. The plasma concentration at 4 hr after 30 mg/kg administration was 2.10 microg/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.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Cisapride,
http://linkedlifedata.com/resource/pubmed/chemical/MA-2029,
http://linkedlifedata.com/resource/pubmed/chemical/Oligopeptides,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Gastrointestinal Hormone,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Neuropeptide,
http://linkedlifedata.com/resource/pubmed/chemical/motilin receptor
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| pubmed:status |
MEDLINE
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| pubmed:month |
Dec
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| pubmed:issn |
1880-3989
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| pubmed:author | |
| pubmed:issnType |
Electronic
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| pubmed:volume |
33
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
631-9
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| pubmed:meshHeading |
pubmed-meshheading:19043284-Action Potentials,
pubmed-meshheading:19043284-Animals,
pubmed-meshheading:19043284-Blood Pressure,
pubmed-meshheading:19043284-Cell Line,
pubmed-meshheading:19043284-Cisapride,
pubmed-meshheading:19043284-Dogs,
pubmed-meshheading:19043284-Electric Stimulation,
pubmed-meshheading:19043284-Electrocardiography,
pubmed-meshheading:19043284-Guinea Pigs,
pubmed-meshheading:19043284-Heart Rate,
pubmed-meshheading:19043284-Humans,
pubmed-meshheading:19043284-Irritable Bowel Syndrome,
pubmed-meshheading:19043284-Male,
pubmed-meshheading:19043284-Oligopeptides,
pubmed-meshheading:19043284-Papillary Muscles,
pubmed-meshheading:19043284-Patch-Clamp Techniques,
pubmed-meshheading:19043284-Receptors, Gastrointestinal Hormone,
pubmed-meshheading:19043284-Receptors, Neuropeptide,
pubmed-meshheading:19043284-Telemetry
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| pubmed:year |
2008
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| pubmed:articleTitle |
Cardiovascular safety profile of MA-2029, a novel motilin receptor antagonist.
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| pubmed:affiliation |
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan. tabomty@chugai-pharm.co.jp
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| pubmed:publicationType |
Journal Article,
In Vitro
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