Effects of non-steroidal anti-inflammatory drugs on cyclo-oxygenase and lipoxygenase activity in whole blood from aspirin-sensitive asthmatics vs healthy donors.
1. Cyclo-oxygenase (COX) and lipoxygenase (LO) share a common substrate, arachidonic acid. Aspirin and related drugs inhibit COX activity. In a subset of patients with asthma aspirin induces clinical symptoms associated with increased levels of certain LO products, a phenomenon known as aspirin-sensitive asthma. The pharmacological pathways regulating such responses are not known. 2. Here COX-1 and LO activity were measured respectively by the formation of thromboxane B(2) (TXB(2)) or leukotrienes (LT) C(4), D(4) and E(4) in whole blood stimulated with A23187. COX-2 activity was measured by the formation of prostaglandin E(2) (PGE(2)) in blood stimulated with lipopolysaccharide (LPS) for 18 h. 3. No differences in the levels of COX-1, COX-2 or LO products or the potency of drugs were found in blood from aspirin sensitive vs aspirin tolerant patients. Aspirin, indomethacin and nimesulide inhibited COX-1 activity, without altering LO activity. Indomethacin, nimesulide and the COX-2 selective inhibitor DFP [5,5-dimethyl-3-(2-isopropoxy)-4-(4-methanesulfonylphenyl)-2(5H)-furanone] inhibited COX-2 activity. NO-aspirin, like aspirin inhibited COX-1 activity in blood from both groups. However, NO-aspirin also reduced LO activity in the blood from both patient groups. Sodium salicylate was an ineffective inhibitor of COX-1, COX-2 or LO activity in blood from both aspirin-sensitive and tolerant patients. 4. Thus, when COX activity in the blood of aspirin-sensitive asthmatics is blocked there is no associated increase in LO products. Moreover, NO-aspirin, unlike other NSAIDs tested, inhibited LO activity in the blood from both aspirin sensitive and aspirin tolerant individuals. This suggests that NO-aspirin may be better tolerated than aspirin by aspirin-sensitive asthmatics.
Gray
P A
PA
Department of Cardiac, Vascular and Inflammation Research, St Bartholomew's and The Royal London School of Medicine & Dentistry, Charterhouse Square, London EC1M 6BQ, UK.
Warner
T D
TD
Vojnovic
I
I
Del Soldato
P
P
Parikh
A
A
Scadding
G K
GK
Mitchell
J A
JA
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000008:administration & dosage; D001249:Asthma / Q000097:blood* / Q000139:chemically induced / Q000201:enzymology; D001555:Benzene Derivatives / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D007527:Isoenzymes / Q000097:blood / Q000187:drug effects; D015289:Leukotrienes / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008084:Lipoxygenase / Q000097:blood / Q000187:drug effects*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology; D013929:Thromboxane B2 / Q000097:blood
C404485:3-2(-propyloxy)-(4-methylsulfonylphenyl)-(5,5-dimethyl)furanone; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001555:Benzene Derivatives; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005663:Furans; D007476:Ionophores; D007527:Isoenzymes; D015289:Leukotrienes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D013449:Sulfonamides; D000001:Calcimycin; D013929:Thromboxane B2; D008084:Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D001241:Aspirin; C012655:nimesulide; D007213:Indomethacin