The primary prostaglandins such as PGE2, as well as the breakdown products of prostacyclin and TxA2, have all been detected in elevated levels at sites of acute and chronic inflammation. The most abundant cyclo-oxygenase product is usually PGE2, but this depends on the nature and location of the inflammatory response. For example, in conditions where mast cell degranulation is central to the pathology, such as in systemic mastocytosis, PGD2 and its metabolites can be detected in high amounts in plasma and urine. The enzymatic source of prostaglandins depends on the chronicity of the lesion. The early production (within minutes) of prostaglandins which ocurs in acute pain models (zymosan-induced writhing in mice, for example) is likely to be solely due to the activity of the constitutive COX 1 while the delayed, cytokine-dependent production of prostaglandins is dependent upon the induction of COX 2.
Prostaglandins produced at a site of injury contribute to the signs and symptoms of inflammation. Prostaglandin E, and prostacyclin can sensitize nerve endings to painful chemical and mechanical stimuli, a process termed hyperalgesia. Consequently, inhibition of prostaglandin biosynthesis in inflamed tissues by NSAIDs accounts for the analgesic activity of this class of compound. Prostaglandin E2 and prostacyclin are also potent vasodilators and are responsible in many circumstances for the increased flow of blood to sites of inflammation.
Prostaglandins are not chemotactic for neutrophils nor do they directly induce vascular permeability, but the increased blood flow may potentiate leukocyte accumulation and edema formation. The ability of NSAIDs to suppress edema formation has been attributed to inhibition of prostaglandin synthesis, but the doses required to inhibit edema formation are much higher than required to inhibit the production of prostaglandins in many circumstances. Furthermore, it is well recognized that the antiedema or 'anti-inflammatory' doses of NSAIDs are much higher than the analgesic doses. It is puzzling why the doses of NSAIDs required to inhibit these end points should differ if inhibition of prostaglandin synthesis is responsible for both effects. Differences in site of action, degree of inhibition required to inhibit each end-point or COX1/2 selectivity may explain the divergent potencies of NSAIDs as analgesic compared to anti-inflammatory agents.
Reduction in the tissue concentrations of vasodilator and cytoprotective prostaglandins also explain why NSAIDs cause gastrointestinal ulceration and kidney damage. These side-effects can be serious, particularly in the elderly population, and limit the dose of NSAID which can be used. Since inhibition of the constitutive COX 1 is likely to be responsible for the side-effects there has been a large effort in recent years to identify novel agents which selectively inhibit COX 2 in the hope that gastrointestinal and renal toxicity will be reduced while anti-inflammatory efficacy will be retained. Several companies have been successful in identifying such compounds and COX 2 inhibitors, a potentially new class of NSAID, are in the late stages of development. Preclinically, COX 2 inhibitors have shown efficacy in reducing edema and suppressing adjuvant arthritis but, unlike traditional NSAIDs, COX 2 inhibitors do not cause gastrointestinal ulceration. The results of clinical trials with COX 2 inhibitors are awaited with interest. It is possible that reduced side-effects may enable the doses to be increased to achieve more profound anti-inflammatory activity. On the other hand, COX 1 may contribute to prostaglandin production in inflamed tissues and/or spinal cord in some circumstances.
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