Effects of non‐steroidal anti‐inflammatory drugs on cyclo‐oxygenase and lipoxygenase activity in whole blood from aspirin‐sensitive asthmatics vs healthy donors

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. Here COX‐1 and LO activity were measured respectively by the formation of thromboxane B2 (TXB2) or leukotrienes (LT) C4, D4 and E4 in whole blood stimulated with A23187. COX‐2 activity was measured by the formation of prostaglandin E2 (PGE2) in blood stimulated with lipopolysaccharide (LPS) for 18 h. 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. 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. British Journal of Pharmacology (2002) 137, 1031–1038. doi:10.1038/sj.bjp.0704927