thromboxane-b2 and Duodenal-Ulcer

The objective of this endoscopic study was to compare the effects on the gastroduodenal mucosa of healthy volunteers of different doses and dosing regimens of AZD3582, a cyclooxygenase-inhibiting nitric oxide donator (CINOD), with equimolar doses of naproxen.. Healthy volunteers were enrolled in a single-centre, randomized, double-blind, crossover trial consisting of two 12-day treatment periods and employing six sequences. The groups were: AZD3582 750 mg daily versus 375 mg twice daily (n=25), AZD3582 375 mg twice daily versus 750 mg twice daily (n=25) and naproxen 250 mg twice daily versus 500 mg twice daily (n=25).. Gastroduodenal tract damage was similar with AZD3582 375 mg twice daily and 750 mg twice daily (mean number of erosions and ulcers+/-SD: 2.88+/-3.95 versus 3.08+/-2.80, respectively; p=0.824; 1 ulcer counted as 10 erosions). There was an indication of decreased gastroduodenal toxicity with AZD3582 750 mg daily compared with 375 mg twice daily (0.92+/-2.08 versus 2.71+/-4.75, respectively; p=0.068). Gastroduodenal toxicity was significantly lower with AZD3582 375 mg twice daily than with naproxen 250 mg twice daily (2.88+/-3.95 versus 6.16+/-9.36; p<0.05), and with AZD3582 750 mg twice daily versus naproxen 500 mg twice daily (3.08+/-2.80 versus 6.68+/-6.97; p<0.05). Equimolar twice-daily doses of AZD3582 and naproxen resulted in similar naproxen plasma levels and serum thromboxane B(2) inhibition.. AZD3582 has an improved gastroduodenal safety profile compared with equimolar doses of naproxen. The gastroduodenal effects of AZD3582 375 mg and AZD3582 750 mg twice daily are similar. A once-daily regimen of AZD3582 might be less gastrotoxic than a twice-daily regimen.

Topics: Adult; Cross-Over Studies; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Duodenal Ulcer; Endoscopy, Gastrointestinal; Female; Humans; Intestinal Mucosa; Male; Naphthalenes; Naproxen; Reference Values; Stomach Ulcer; Thromboxane B2; Treatment Outcome

In 13 patients with endoscopically proven duodenal ulcer, biopsies were obtained from the stomach body and antrum and from the duodenal bulb before and, in 10, after 4 weeks of cimetidine treatment (1 g/day). The specimens were organ-cultured for 90 min, and prostanoid accumulation in the medium was determined by radio-immunoassay. After 4 weeks of cimetidine treatment, prostaglandin E2 and 6-keto-prostaglandin F1 alpha synthesis by cultured specimens obtained from the body of the stomach (1304 +/- 197 and 497 +/- 124, no. +/- 10) was significantly higher than their respective synthesis before therapy (734 +/- 90 and 222 +/- 26; no. = 13) (X +/- SE, pg/mg wet wt/90 min). Prostanoid synthesis by cultured specimens from the antrum and duodenum was not significantly different before and after cimetidine treatment. It is therefore suggested that cimetidine, in addition to its antisecretory effects, accelerates ulcer healing also by induction of endogenous gastric prostanoid synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Cimetidine; Dinoprostone; Duodenal Ulcer; Duodenum; Fatty Acids; Female; Gastric Mucosa; Humans; Intestinal Mucosa; Male; Prostaglandins E; Prostanoic Acids; Thromboxane B2

Cultured duodenal mucosa obtained from normal subjects synthesized and secreted significantly less prostaglandin E2 (PGE2), 6-keto-PGF1 alpha, and thromboxane B2 (TXB2) than cultured gastric mucosa obtained from the same subjects. Accumulation of PGE2, 6-keto-PGF1 alpha, and TXB2--the stable metabolites of prostacyclin I2 and thromboxane A2, respectively--by cultured gastric mucosa obtained from 21 untreated patients with active duodenal ulcer was significantly lower than their respective accumulation by cultured gastric mucosa obtained from 14 normal subjects. Accumulation of all three prostanoids by cultured duodenal mucosa obtained from patients with active duodenal ulcer and from normal subjects was not significantly different. PGE2, 6-keto-PGF1 alpha, and TXB2 accumulation was five to six times higher than their respective content in fresh tissue before culture and was inhibited by flufenamic acid. These results suggest that a decrease in endogenous gastric prostanoid synthesis may have a role in the pathogenesis of peptic ulcer disease.

Topics: 6-Ketoprostaglandin F1 alpha; Culture Techniques; Dinoprostone; Duodenal Ulcer; Duodenum; Female; Gastric Mucosa; Humans; Intestinal Mucosa; Male; Prostaglandins E; Thromboxane B2; Thromboxanes