Endoscopic evaluation of etodolac and naproxen, and their relative effects on gastric and duodenal prostaglandins

Abstract

Etodolac has been shown to have a favorable safety profile in short-term and long-term studies in both osteoarthritis (OA) and rheumatoid arthritis (RA). Two studies were conducted to further assess the gastrointestinal (GI) safety profile of this drug. These studies were designed to compare the therapeutic efficacy and upper GI effects of etodolac (600 mg/day) and naproxen (1000 mg/day) administered over 4 weeks in patients with active rheumatoid arthritis. In addition, the relative effects of the drugs on prostaglandin levels in the stomach and duodenum were assayed in one study. Fifteen patients were included in each study and received either 300 mg b.i.d. of etodolac or 500 mg b.i.d. of naproxen. In both studies, endoscopic examinations were performed on day 1 of the study and again 4 weeks later. In the second study, at the time of each endoscopy, samples of gastric and duodenal mucosa were taken for histologic study and prostaglandin assay. Endoscopy results from the first study showed significant differences in favor of etodolac between the two treatment groups. In the second study more naproxen-treated patients had abnormal endoscopy results than did etodolac-treated patients. Results from prostaglandin assays in gastric and duodenal mucosa showed no overall suppression of gastric or duodenal prostaglandin levels for etodolac-treated patients in contrast to naproxen-treated patients, who showed suppression of PGE2 and PGI2. The results of these studies show that etodolac therapy caused less gastric and duodenal injury than naproxen and also support the theory that the GI safety of etodolac may be due to selective sparing of cytoprotective prostaglandins.

Experimental models used to investigate the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2 by non-steroidal anti-inflammatory drugs

“…However, in an endoscopy study in patients with rheumatoid arthritis, 1000 mg naproxen, but not 600 mg etodolac, appeared to suppress gastric and duodenal PGE 2 and PGI 2 levels in mucosal biopsy specimens, suggesting a COX-1-sparing effect, at least for the dose tested. However, there was no correlation between PGE 2 /PGI 2 levels and gastrointestinal damage in the individual patients [44,55].…”

Overview of COX-2 in inflammation: from the biology to the clinic

“…In a 4 week endoscopic study in patients with RA, 1000 mg naproxen, but not 600 mg etodolac appeared to suppress gastric and duodenal PGE 2 and PGI 2 levels in mucosal biopsy specimens, and naproxen also caused more mucosal lesions than etodolac. However, there was no correlation between PGEiPGI 2 levels and gastrointestinal damage in individual patients [178,188]. In microbleeding studies, etodolac in doses ranging from 600 to 1200 mg for 1 to 4 weeks did not produce clinically significant bleeding in healthy volunteers or in arthritic patients, although in some studies faecal blood loss was significantly higher than in the placebo run-in period [179].…”

Clinical experience with cyclooxygenase-2 inhibitors

“…There are no published reports of etodolac being tested in these COX-1 sparing studies, measuring either serum TxB 2 , platelet aggregation or urinary PGE 2 excretion. However, some COX-1 sparing data was obtained from an endoscopy study described below [58,59].…”

“…Etodolac was tested in four endoscopy studies [59,[65][66][67]. In one study, volunteers received doses of 600 and 1000 mg (12 volunteers/group) for one week as compared to 200 mg indomethacin, 1000 mg naproxen and 2400 mg ibuprofen.…”