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

Abstract

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 dierences 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 ineective 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.

Select Dietary Phytochemicals Function as Inhibitors of COX-1 but Not COX-2

“…However, pharmacokinetic data analysis revealed that at this dose, aspirin might mainly targets COX-1 rather than COX-2, because the maximal serum concentration achieved was well below the reported whole blood COX-2 IC 50 values [31,32]. In this study, we confirmed that most natural product-based compounds were COX-1, rather than COX-2 selective inhibitors.…”

A New Combined Test with Flowcytometric Basophil Activation and Determination of Sulfidoleukotrienes Is Useful for in vitro Diagnosis of Hypersensitivity to Aspirin and other Nonsteroidal Anti-Inflammatory Drugs

“…These authors clearly showed that the use of several NSAIDs, in particular diclofenac, in addition to ASA markedly improved sensitivity (up to 72%), while not impairing a rather high specificity of 96%. Publications [58,59,60] recently quoted [1] as disproving the earlier reports on the diagnostic value of the CAST are in fact not using the same conditions; in particular, they do not include IL-3 and/or use much lower ASA concentrations. This also applies to the recent negative report of Kowalski et al [40] concerning the LTC 4 release in blood of ASA-hypersensitive patients.…”

Mechanisms of aspirin-sensitive asthma

“…Consequently, the evidence that aspirinsensitive asthmatics are deficient in PGE 2 synthesis, or that this process is more susceptible to aspirin inhibition in aspirin-sensitive patients, is currently limited. Furthermore, the hypothesis that PGE 2 deficiency is a fundamental problem in aspirin-sensitive asthma does not sit well with the observation that selective COX-2 inhibitors, which presumably also reduce PGE 2 production, 48 do not appear to increase leukotriene production and bronchospasm in these patients. 49 As an alternative to the deficient production of PGE 2 , an alternative hypothesis is that these patients may show a deficiency of PGE 2 receptor expression on target leukocytes and other tissues, which may result in deficient PGE 2 'braking' of cysteinyl leukotriene production at baseline, which is further exaggerated by COX-1 inhibition.…”