Cytoprotective prostaglandins

NSAIDs also inhibit production of cytoprotective prostaglandins in the gastric mucosa, accounting for their tendency to cause gastrointestinal irritation, although the incidence is much lower with ibuprofen than aspirin. 

Older NSAIDs, such as aspirin and ibuprofen, inhibit both COX-1 and -2, but a newer class of NSAIDs, called coxibs, are selective for inhibition of COX-2. By sparing production of cytoprotective prostaglandins by mucosal COX-1, coxibs have fewer problems with irritation and ulceration in the upper GI tract. 

There are two forms of COX, COX-1 and COX-2. COX-1 is a primarily constitutive isoform found in most normal cells and tissues, while cytokines and inflammatory mediators that accompany inflammation induce COX-2 production. However, COX-2 also is constitutively expressed in certain areas of kidney and brain, and is induced in endothelial cells by laminar shear forces. Importantly COX-1, but not COX-2, is expressed as the dominant, constitutive isoform in gastric epithelial cells and is the major source of cytoprotective prostaglandin formation. Inhibition of COX-1 at this site is thought to account largely for the gastric adverse events that complicate therapy with tNSAIDs, thus providing the rationale for the development of NSAIDs specific for inhibition of COX-2. 

NSAlDs also are very frequently associated with peptic ulcers (in up to 60% of patients, particularly those with complications such as bleeding). Topical injury by the luminal presence of the dmg appears to play a minor role in the pathogenesis of these ulcers, as evidenced by the fact that ulcers can occur with very low doses of aspirin (10 mg) or with parenteral administration of NSAlDs. The effects of these drugs are instead mediated systemicaUy the critical element is suppression of COX-1 in the mucosa and decreased production of the cytoprotective prostaglandins PGE and PGI. ... 

The prostaglandin Ei and E2 analogues showing antisecretory and cytoprotective activities49,50 had to be deuterium or tritium labelled for preclinical studies. The tritiated or deuteriated title compounds 61, 62 and 63 have been synthesized51 by the methods outlined in equations 25, 26 and 27. Compounds 61 and 62, with hydrogen at 7-position... 

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