Cyclo-oxygenase inhibitors

Hall and Wolf [217] have proposed a hypothesis, concerning the pathogenesis of post-traumatic central nervous system ischaemia, which integrates an injury-induced rise in intracellular Ca2+, the increased synthesis of vasoactive prostanoids and progressive microvascular lipid peroxidation. The model used anaesthetised cats with a contusion injury to the lumbar spinal cord. Antioxidants, vitamin E and selenium, were compared with various Ca2 + antagonists, cyclo-oxygenase inhibitors, a thromboxane synthetase inhibitor and the stable prostacyclin analogue. The most impressive preservation of post-traumatic spinal cord blood flow was provided by the antioxidants. 

Flunixin Cyclo-oxygenase inhibitor Anti-inflammatory analgesia antipyresis... 

Metamizole (Dipyrone) Cyclo-oxygenase inhibitor ( Similar to other NSAIDs)... 

Antagonistic effects of cyclo-oxygenase inhibitors (indo-metacin or aspirin) have been repeatedly reported both in hypertension and in heart failure, strongly suggesting that there may be prostaglandin participation in the clinical response to ACE inhibitors (103,104). In animals, although not in all experimental models, aspirin can attenuate the beneficial effects of ACE inhibitors on ventricular remodelling after myocardial infarction. 

As expected with a cyclo-oxygenase inhibitor, the adverse effects most frequently reported by patients taking tenidap sodium were gastrointestinal serious gastrointestinal events occurred in 2.1% (1). 

Cameron NE, Cotter MA, Dines KC, Robertson S, Cox D. The effects of evening primrose oil on peripheral nerve function and capillarization of in streptozotocin-diabetic rats modulation by the cyclo-oxygenase inhibitor flurbiprofen. Br J Pharmacol 1993 109 972-979. 

Anti-inflammatory (MlAl) 219 Cyclo-oxygenase inhibitor (OX-C-) 60... 

Figure 4.8 PAF (10 ng) bolus injection causes vasodilation in isolated rat lungs perfused with blood at constant flow. This vasodilation is inhibited by CV3988 (I0 molL ) a PAF receptor antagonist but not by the cyclo-oxygenase inhibitor, indomethacin...

Unlike Tx synthetase inhibitors and receptor antagonists, NSAIDs given alone or with other adjunctive therapy (discussed below) improve survival or survival time in the rat model of sepsis . The beneficial action of the cyclo-oxygenase inhibitors in these sepsis modelis must therefore be attributed to inhibition of other prostanoid metabolites, e.g. PGE2, id... 

EFAD rats also exhibit prolonged survival time to acute intra-abdominal sepsis compared with normal rats Additionally, conjoint therapy with the aminoglycoside antibiotic, gentamicin, of EFAD rats following faecal peritonitis resulted in an improvement in overall survival at 48 h that was not seen with the antibiotic or EFA-deficiency alone. These observations and the beneficial actions of cyclo-oxygenase inhibitors suggest a deleterious effect of these arachidonic acid metabolites in endotoxaemia and sepsis. 

Studies conducted in our laboratories examined the effects of such conjoint therapy with antibiotics on eicosanoid levels and survival in septic shock. In the rat faecal peritonitis model, improved survival time was observed with early treatment with steroids. However, this protection appears to be independent of inhibition of arachidonic acid metabolism. Corticosteroid pretreatment effected no more than a 30 and 40% inhibition of plasma levels of iTxB2 and i6-keto-PGFi3( respectively, compared with 100% inhibition with the cyclo-oxygenase inhibitors. Conjoint steroid and NSAID treatment improved survival time compared with each drug employed individually. The combination of steroid, NSAID and gentamicin produced the most significant effect on survival. 

Almqvist, P.M., Kuenzig, M. and Schwartz, S.I. (1984). Treatment of experimental canine endotoxin shock with ibuprofen, a cyclo-oxygenase inhibitor. Circ. Shock, 13, 227-232 Gryglewski, R.J. (1978). Screening for inhibitors of prostaglandin and thromboxane biosynthesis. Adv. Lipid Res., 16, 327-44... 

Ogletree, M.L. and Brigham, K.L. (1982). Effects of cyclo-oxygenase inhibitors on pulmonary vascular responses to endotoxin in unanesthetized sheep. Prostagl Leak. Med., 8, 489-502... 

In patients with essential hypertension, indomethacin, given by in intramuscular injection at 1 mgkg increases blood pressure and total peripheral vascular resistance associated with diminution of cardiac output". However, reports that indomethacin, given orally at 75-200 mg day for 4-7 days, increases blood pressure in patients with untreated, uncomplicated, essential hypertension contrasts with reports that it does not . Cyclo-oxygenase inhibitors, indomethacin and ibuprofen, were also without effect on blood pressure in patients with renovascular hypertension . Yet, in two siblings with renin-dependent hypertension and aldosteronism, the administration of indomethacin at 250 mg day for 16 days was found to lower blood pressure and plasma renin activity, despite promoting slight retention of salt and water ... 

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