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9365818

Source:http://linkedlifedata.com/resource/pubmed/id/9365818

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pubmed-article:9365818pubmed:abstractTextTwo forms of cyclooxygenase (COX) activity are involved in the synthesis of prostaglandins, prostacyclins, and thromboxanes in mammalian cells. There is now convincing evidence, obtained with a number of structurally distinct inhibitors, that selective COX-2 inhibitors possess anti-inflammatory effects with an improved gastrointestinal tolerability compared with conventional nonsteroidal anti-inflammatory drugs (NSAIDs) affecting both COX-1 and COX-2. As more selective COX-2 inhibitors are being developed, assays with a high degree of sensitivity to inhibition are needed to compare the relative effects of compounds on COX-1 activity. In the present report, we describe a sensitive assay for the inhibition of human COX-1 based on the production of prostaglandin E2 by microsomes from U937 cells incubated with a subsaturating concentration of arachidonic acid. More than 45 NSAIDs and selective COX-2 inhibitors were tested in this assay. IC50 values ranged from 1 nM for flunixin and flurbiprofen to about 200-500 microM for salicylate and acetaminophen. Potent and nonselective NSAIDs such as sulindac sulfide, diclofenac, and indomethacin showed IC50 values of < 20 nM. Among the compounds that have been reported to show selectivity for COX-2, the rank order of potency against COX-1 was DuP 697 > SC-58451 > celecoxib > nimesulide-meloxicam-piroxicam-NS-398-RS-57067 > SC-57666 > SC-58125 > flosulide > etodolac > L-745,337 > DFU-T-614, with IC50 values ranging from 7 nM to 17 microM. A good correlation was obtained between the IC50 values for the inhibition of microsomal COX-1 and both the inhibition of TXB2 production by Ca2+ ionophore challenged platelets and the inhibition of prostaglandin E2 production by CHO cells stably expressing human COX-1. However, the microsomal assay was more sensitive to inhibition than cell-based assays and allowed the detection of inhibitory effects on COX-1 for all NSAIDs and selective COX-2 inhibitors examined with discrimination of their potency under conditions of limited availability of arachidonic acid.lld:pubmed
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pubmed-article:9365818pubmed:dateRevised2006-11-15lld:pubmed
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pubmed-article:9365818pubmed:year1997lld:pubmed
pubmed-article:9365818pubmed:articleTitleComparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays.lld:pubmed
pubmed-article:9365818pubmed:affiliationMerck Frosst Centre for Therapeutic Research, Kirkland, QC, Canada.lld:pubmed
pubmed-article:9365818pubmed:publicationTypeJournal Articlelld:pubmed
pubmed-article:9365818pubmed:publicationTypeComparative Studylld:pubmed
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