Effects of two different inhibitors of the arachidonic acid metabolism on platelet sequestration in endotoxic shock

Abstract

Metabolites of arachidonic acid are known to play an important part in the pathogenesis of organ injury in endotoxic shock. We compared the effects of the classical cyclooxygenase inhibitor aspirin with that of the dual cyclooxygenase and lipoxygenase inhibitor ketoprofen on the behavior of platelets tagged with 111In-labeled oxine in multiple organs during endotoxin shock. Three groups of sheep (n = 7 in each) were anesthetized before being subjected to endotoxin shock. Group E had no drug treatment (shock controls), group KET received ketoprofen and group ASP received aspirin treatment. In the lungs and in the liver of group E there was a marked sequestration of platelets, which started in both organs immediately after administration of endotoxin and continued throughout the study. In the treated groups, however, the response to endotoxin was both delayed and reduced compared with the untreated shock controls. The first changes in platelet activity were noted after more than 1 h in the treated groups. Four hours after administration of endotoxin, platelet activity (sequestration) had increased in the lungs by 102 +/- 14% in group E, 53 +/- 11% in group ASP and 20 +/- 13% in group KET (P < 0.01, P < 0.01 and P < 0.05 respectively compared to baseline). Corresponding values for the liver were 52 +/- 16% in group E, 22 +/- 19% in group ASP and -2 +/- 12% in group KET (P < 0.01, P < 0.01 and P > 0.05 respectively compared with baseline).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of pre- versus post-incision administration of intraplantar indomethacin and MK886 in a rat model of postoperative pain

“…Ketoprofen differs from other non-steroidal antinflammatory drugs because, in addition to inhibiting cyclooxygenase, it also inhibits the 5-lipoxygenase-activating protein, thus preventing the generation of both prostaglandins and leukotrienes (14). Leukotrienes produce hyperalgesia in animals (15,16) and human beings (17), and seem to play an important role in the maintenance of a longlasting nociceptive response (18).…”

Coagulopathy as a Therapeutic Target for TRALI: Rationale and Possible Sites of Action

“…[43] In addition, in both in vivo and in vitro models of LAI, blocking TXA2 by aspirin or a thromboxane receptor antagonist protects against ALI. [43,[76][77][78][79][80][81] Anti-platelet therapy is associated with a reduced incidence of ALI/ARDS in a recent cohort study of critically ill patients, even when adjusting for confounding variables. [14] Side-effects of anticoagulant therapies…”

Prevention of sepsis and multiple organ failure in critically ill patients

“…Pentoxifylline, a TNF inhibitor has been shown to have several beneficial respiratory and haemodynamic effects both in experimental and clinical illnesses (53)(54)(55) and recently it was shown to decreased anorexia, loss of body weight and muscle protein and partially prevented reduction in muscle protein synthesis induced by sepsis (56). Drugs influencing the arachidonic acid cascade such as phospholipase A, inhibitors, prostaglandin E, , prostacyclin, defibrotide, cyclooxygenase inhibitors, lipoxygenase inhibitors, thromboxane A, synthetase and receptor blockers have shown impressive effects on endotoxemia, sepsis and ARDS in various experimental models (49,(57)(58)(59)(60). It is not unlikely that in the future specific indications may be defined for some of these agents in critical illness.…”