Effect of carprofen and indomethacin on gastric function, mucosal integrity and generation of prostaglandins in men.

The effects of indomethacin and carprofen on gastric secretion, serum gastrin level, electropotential difference, gastric microbleeding, DNA loss, mucosal blood flow and the production of mucosal prostaglandins (PGs) were investigated in a double-blind cross-over study in 18 healthy volunteers after one week of treatment. We did not observe any significant changes in basal and pentagastrin-stimulated gastric secretory parameters, serum gastrin level and electro-potential difference before and after treatment with these drugs. Mucosal blood flow was significantly reduced following indomethacin treatment. The most pronounced differences were found in endoscopic score studies of gastric mucosa. After indomethacin all subjects developed multiple erosions, submucosal haemorrhages, and half of them showed diffuse antral erythema. These effects were accompanied by a significant increase in both gastric microbleeding and DNA loss, and significant decrease in the production of PGE2. We concluded that carprofen, in contrast to indomethacin, did not alter gastric mucosal integrity and production of PGE2. This study indicates that the gastric mucosal damage by non-steroid anti-inflammatory compounds (NOSAC) depends upon the suppression of PGE2 biosynthesis, and that endogenous PGE2 is involved in the control of mucosal blood flow and mucosal integrity.

Distribution of prostaglandins in gastric and duodenal mucosa of healthy subjects and duodenal ulcer patients: effects of aspirin and paracetamol.

The distribution of mucosal PGE2-like activity was determined by bioassay technique in the body and antrum of the stomach and in the duodenum of healthy subjects and duodenal ulcer patients before and after administration of aspirin, paracetamol, or histamine. In healthy subjects, the oxyntic, antral and duodenal mucosa was found to be capable of generating large amounts of PGE2, which were not significantly different from those found in duodenal ulcer patients. No correlation was found between the generation of PGE2 and gastric acid secretory status or serum gastrin level. Aspirin-and to a much lesser extent, paracetamol-caused a dramatic reduction in the ability of the gastric mucosa to biosynthesis PGE2 and this was accompanied by marked side-effects and injury to the gastric mucosa. Administration of histamine caused small but significant reduction in the biosynthesis of PGE2 but it was accompanied by marked mucosal damage. This study indicates that the gastric and duodenal mucosa is capable of generating PGE2-like activity which may be involved in the mechanism that protects the mucosa against the damage caused by aspirin.

Antioxidants as agents potentiating the antiinflammatory action of indomethacin.

Nordihydroguaiaretic acid inhibits prostaglandin (PG) biosynthesis in vitro (ID50=228 muM), with a slope of dose-response curve high (b=209) as compared with indomethacin (ID50=0.1 muM, b=72.1). Butylated hydroxyanisole, in contrast to inactive butylated hydroxytoluene, inhibits PG biosynthesis (ID50=107 muM, b=63). Only norihydroguaiaretic acid (100 mug, s.p.) inhibited the postcarrageenin edema of rat paw. Butylated hydroxyanisole (10 mug, s.p.) given together with a subthreshold (1 mug) dose of indomethacin inhibited the paw edema by 35%, while butylated hydroxytoluene and nordihydroguaiaretic acid produced a similar effect only when given at 10-fold higher doses. The results suggest the possibility of potentiation and prolongation of the anti-inflammatory effect of indomethacin by its simultaneous administration with an antioxidant, butylated hydroxyanisole.