Source:http://linkedlifedata.com/resource/pubmed/id/15879003
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
2
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| pubmed:dateCreated |
2005-7-18
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| pubmed:abstractText |
We have previously shown that complement factor 5a (C5a) plays a role in the pathogenesis of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats by using the selective, orally active C5a antagonist AcF-[OP(d-Cha)WR]. This study tested the efficacy and potency of a new C5a antagonist, hydrocinnamate (HC)-[OP(d-Cha)WR], which has limited intestinal lumenal metabolism, in this model of colitis. Analogs of AcF-[OP(d-Cha)WR] were examined for their susceptibility to alimentary metabolism in the rat using intestinal mucosal washings. One metabolically stable analog, HC-[OP(d-Cha)WR], was then evaluated pharmacokinetically and investigated at a range of doses (0.03-10 mg/kg/day p.o.) in the 8-day rat TNBS-colitis model, against the comparator drug AcF-[OP(d-Cha)WR]. Using various amino acid substitutions, it was determined that the AcF moiety of AcF-[OP(d-Cha)WR] was responsible for the metabolic instability of the compound in intestinal mucosal washings. The analog HC-[OP(d-Cha)WR], equiactive in vitro to AcF-[OP(d-Cha)WR], was resistant to intestinal metabolism, but it displayed similar oral bioavailability to AcF-[OP(d-Cha)WR]. However, in the rat TNBS-colitis model, HC-[OP(d-Cha)WR] was effective at reducing mortality, colon edema, colon macroscopic scores, and increasing food consumption and body weights, at 10- to 30-fold lower oral doses than AcF-[OP(d-Cha)WR]. These studies suggest that resistance to intestinal metabolism by HC-[OP(d-Cha)WR] may result in increased local concentrations of the drug in the colon, thus affording efficacy with markedly lower oral doses than AcF-[OP(d-Cha)WR] against TNBS-colitis. This large increase in potency and high efficacy of this compound makes it a potential candidate for clinical development against intestinal diseases such as inflammatory bowel disease.
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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/AcPhe(ornithine-Pro-cyclohexylamine-...,
http://linkedlifedata.com/resource/pubmed/chemical/Complement C5a,
http://linkedlifedata.com/resource/pubmed/chemical/Peptides, Cyclic,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Complement,
http://linkedlifedata.com/resource/pubmed/chemical/Trinitrobenzenesulfonic Acid
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| pubmed:status |
MEDLINE
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| pubmed:month |
Aug
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| pubmed:issn |
0022-3565
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:volume |
314
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| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
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| pubmed:pagination |
811-7
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| pubmed:dateRevised |
2005-11-17
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| pubmed:meshHeading |
pubmed-meshheading:15879003-Animals,
pubmed-meshheading:15879003-Biological Availability,
pubmed-meshheading:15879003-Biotransformation,
pubmed-meshheading:15879003-Complement C5a,
pubmed-meshheading:15879003-Digestive System,
pubmed-meshheading:15879003-Eating,
pubmed-meshheading:15879003-Edema,
pubmed-meshheading:15879003-Female,
pubmed-meshheading:15879003-Humans,
pubmed-meshheading:15879003-Inflammatory Bowel Diseases,
pubmed-meshheading:15879003-Intestinal Mucosa,
pubmed-meshheading:15879003-Peptides, Cyclic,
pubmed-meshheading:15879003-Rats,
pubmed-meshheading:15879003-Rats, Wistar,
pubmed-meshheading:15879003-Receptors, Complement,
pubmed-meshheading:15879003-Trinitrobenzenesulfonic Acid,
pubmed-meshheading:15879003-Ulcer,
pubmed-meshheading:15879003-Weight Loss
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| pubmed:year |
2005
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| pubmed:articleTitle |
Increased potency of a novel complement factor 5a receptor antagonist in a rat model of inflammatory bowel disease.
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| pubmed:affiliation |
Promics Pty. Ltd., The University of Queensland, Brisbane, QLD 4072 Australia.
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| pubmed:publicationType |
Journal Article
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