thromboxane-b2 and Peptic-Ulcer

In a pilot study, 26 rheumatoid arthritic patients taking continuous, stable dosage regimens of nonsteroidal anti-inflammatory drugs and with developed gastric and duodenal lesions were administered sucralfate 1 g four times per day (14 patients) or cimetidine 400 mg twice daily (12 patients) in a single-blind regimen for six weeks. Eleven of the patients given sucralfate and eight of the patients taking cimetidine had improved lesion scores. The lesion score of 10 of the 14 patients taking sucralfate and four of the 12 patients taking cimetidine improved by 50 percent or better (not significant). The antrum and body of the gastric mucosa and the mucosa of the duodenum synthesized prostanoids and thromboxane A2, and there was no significant difference in the synthesis of individual prostanoids at entry to the trial in the groups assigned to sucralfate or cimetidine. After six weeks of administration of sucralfate, prostaglandin E2 (PGE2) synthesis by the antrum and body, but not the duodenum, was significantly greater than observed in the biopsy specimens at entry despite continuation of non-steroidal anti-inflammatory drug therapy. After six weeks of cimetidine treatment, no change in PGE2 synthesis was noted in any biopsy specimens when compared with the synthesis at entry. No change in the synthesis of PGF2 alpha, 6-oxo-PGF1 alpha, or thromboxane B2 was noted in gastric or duodenal biopsy specimens in any treatment group. Sucralfate and cimetidine administration resulted in improved gastroduodenal lesion scores in rheumatoid arthritic patients continuing with nonsteroidal anti-inflammatory drug therapy.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Cimetidine; Duodenum; Female; Gastric Mucosa; Humans; Intestinal Mucosa; Male; Middle Aged; Peptic Ulcer; Pilot Projects; Prostaglandins; Random Allocation; Sucralfate; Thromboxane B2

Prostaglandin E2 (PGE2), one of the terminal products in the cyclooxygenase pathway, plays an important role in various inflammatory responses. To determine whether selective inhibition of PGE2 may relieve these inflammatory symptoms, we synthesized a selective PGE2 synthesis inhibitor, compound A [1-(6-fluoro-5,7-dimethyl-1,3-benzothiazol-2-yl)-N-[(1S,2R)-2-(hydroxymethyl)cyclohexyl]piperidine-4-carboxamide], then investigated the effects on pyrexia, arthritis and inflammatory pain in guinea pigs. In LPS-stimulated guinea pig macrophages, compound A selectively inhibited inducible PGE2 biosynthesis in a dose-dependent manner whereas enhanced the formation of thromboxane B2 (TXB2). Compound A suppressed yeast-evoked PGE2 production selectively and enhanced the production of TXB2 and 6-keto PGF1αin vivo. In addition, compound A relieved yeast-induced pyrexia and also suppressed paw swelling in an adjuvant-induced arthritis model. The effect on gastrointestinal (GI) ulcer formation was also evaluated and compound A showed a lower GI adverse effect than indomethacin. However, compound A failed to relieve yeast-induced thermal hyperalgesia. These results suggest that selective inhibition of PGE2 synthesis may have anti-pyretic and anti-inflammatory properties without GI side effect, but lack the analgesic efficacy.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Benzothiazoles; Depression, Chemical; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fever; Guinea Pigs; Imidazoles; Indomethacin; Inflammation; Macrophages; Pain; Peptic Ulcer; Phenanthrenes; Piperidines; Stimulation, Chemical; Thromboxane B2

Despite the increasing importance of biomarkers as predictors of drug effects, toxicology protocols continue to rely on the experimental evidence of adverse events (AEs) as a basis for establishing the link between indicators of safety and drug exposure. Furthermore, biomarkers may facilitate the translation of findings from animals to humans. Combined with a model-based approach, biomarker data have the potential to predict long-term effects arising from prolonged drug exposure. Here, we used naproxen as a paradigm to explore the feasibility of a biomarker-guided approach for the prediction of long-term AEs in humans.. An experimental toxicology protocol was set up for evaluating the effects of naproxen in rats, in which four active doses were tested (7.5, 15, 40 and 80 mg·kg(-1) ). In addition to AE monitoring and histology, a few blood samples were also collected for the assessment of drug exposure, TXB2 and PGE2 levels. Non-linear mixed effects modelling was used to analyse the data and identify covariate factors on the incidence and severity of AEs.. Modelling results showed that besides drug exposure, maximum PGE2 inhibition and treatment duration were also predictors of gastrointestinal ulceration. Although PGE2 levels were clearly linked to the incidence rates, it appeared that ulceration severity is better predicted by measures of drug exposure.. These results show that the use of a model-based approach provides the opportunity to integrate pharmacokinetics, pharmacodynamics and toxicity data, enabling optimization of the design, analysis and interpretation of toxicology experiments.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Dinoprostone; Dose-Response Relationship, Drug; Male; Models, Biological; Naproxen; Peptic Ulcer; Rats; Thromboxane B2

Peptic ulcers due to nonsteroidal anti-inflammatory drug (NSAID) use may have contributed to the static prevalence of ulcer disease in Asia.. We aimed to determine the current etiology of peptic ulcer disease in Singapore.. Consecutive patients undergoing esophagogastroduodenoscopy who had not been exposed to antibiotics, or antiulcer therapy within the past 6 months, and in whom peptic ulcers were found, were prospectively studied. Before endoscopy, patients were interviewed regarding the use of NSAID or aspirin. During endoscopy, antral biopsies were obtained for urease test and histology. Serum thromboxane B2 levels were compared with those of healthy volunteers.. Peptic ulcers were detected in 600 patients during a 2-year period. The ulcers were negative for Helicobacter pylori in 212 patients (35.3%) and these H. pylori negative ulcers were related to NSAID use in 68.9% of cases. On the basis of serum thromboxane B2 levels, 30.8% of the patients with non-H. pylori non-NSAID were considered to have consumed NSAID.. H. pylori negative peptic ulcer makes up a significant proportion of peptic ulcer in Singapore. Most of these ulcers were related to NSAID use. Serum thromboxane profile suggested surreptitious NSAID use in many of the non-H. pylori and apparently non-NSAID patients.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Female; Gastrins; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Peptic Ulcer; Prospective Studies; Singapore; Thromboxane B2

The PG content were determined in 62 cases with peptic ulcer and erosive gastritis before and after the treatment of Chinese herbal drugs. The value of PGE2,PGF1 alpha, 6-keto-PGF1 alpha and TXB2 were 96.25 +/- 28.51, 14.24 +/- 13.26, 10.72 +/- 9.14 and 16.51 +/- 12.24 pg/mg respectively before the treatment and were 121.42 +/- 30.02, 18.59 +/- 18.40, 18.79 +/- 12.61, 8.29 +/- 6.27 pg/mg respectively after the treatment. 6-keto-PGF1 alpha was significantly increased (P < 0.01), TXB2 was decreased (P < 0.01), but there were no significant changes in PGE2 and PGF1 alpha. Experimental study also showed that Chinese Herbal drugs played an important role in protecting indomethacine induced ulcer rats.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Animals; Dinoprostone; Drugs, Chinese Herbal; Female; Gastric Mucosa; Gastritis; Humans; Male; Middle Aged; Peptic Ulcer; Rats; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Chronic Disease; Female; Gastric Juice; Gastric Mucosa; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Male; Peptic Ulcer; Prostaglandins; Thromboxane B2

The endogenous mucosal PG levels (PGE2, PGF2 alpha, PGI2, TXB2) of the gastric stump were investigated from biopsy materials, after partial gastrectomy made for ulcer disease. The mucosa of the stomach remnant were found to contain mainly PGE2 and PGI2. The PG contents of the mucosa of gastric stump were not influenced by the type of resection. Mucosal PG concentrations on the greater curvature were not dependent on the patients' age, the indication of the gastrectomy, the duration of postoperative interval, or the sex of the patient. There was no relation between the secretion capacity of the resected stomach and the mucosal PG contents of the greater curvature. After Billroth I and II gastrectomy procedures equivalently fair correlations have been established between the mucosal levels of PGE2 and PGF2 alpha, PGE2 and TXB2, PGF2 alpha and TXB2, PGI2 and TXB2 on the greater curvature, respectively. After both types of gastrectomy the mean PGI2 mucosal concentration of the greater curvature was significantly lower than those of the gastroenteroanastomosis and lesser curvature below the cardia, which in turn did not differ from each other. Biliary reflux does not cause characteristic alterations of the mucosal PG levels on the greater curvature. No definite relation between the histological findings of the mucosa and the PG concentrations was observed, which suggests a secondary role of the endogenous PGs in the pathogenesis of light microscopic mucosal alterations of the resected stomach.

Topics: Adult; Aged; Dinoprost; Dinoprostone; Epoprostenol; Female; Gastrectomy; Gastric Mucosa; Humans; Male; Middle Aged; Peptic Ulcer; Prostaglandins; Thromboxane B2; Time Factors

In this study we present evidence to suggest that gastroduodenal mucosal defects may occur in gastric fistula dogs actively immunized with PGE2-thyroglobulin conjugate. One of four PGE2-immunized dogs developed a chronic pyloroduodenal ulcer with penetration into the pancreas and the other three had endoscopic evidence of gastric and/or duodenal erosions. In contrast, no gastroduodenal mucosal defects were seen in control dogs immunized with thyroglobulin alone. Occurrence of gastroduodenal ulcers or erosions was temporally related to formation of specific antibody to PGE2 suggesting that PGE2 antibody may be responsible for lesion formation. An increase in gastric acid secretion was not observed in PGE2-immunized dogs. Thus, it is likely that mucosal defects occur as a result of an impairment of PGE2-mediated mucosal defense mechanisms. Since gastroduodenal lesions can be visualized by endoscopy, the dog may prove to be useful in studying the role of endogenous PG in ulcer diseases.

Topics: Animals; Antibody Specificity; Autoantibodies; Dinoprostone; Dogs; Gastric Juice; Gastric Mucosa; Gastroscopy; Immunization; Intestinal Mucosa; Pentagastrin; Peptic Ulcer; Prostaglandins; Prostaglandins E; Thromboxane B2

The protective effect of sucralfate against gastric and intestinal mucosal damage was studied in rats. Sucralfate (125 mg) significantly reduced gastric mucosal lesion formation induced by s.c. administration of indomethacin (30 mg/kg) or intragastric administration of aspirin (100 mg/kg), HCl (0.6 N), NaOH (0.2 N) or sodium taurocholate (30 mM). Furthermore, when given in three doses of 125 mg each, sucralfate significantly decreased the development of small intestinal lesions induced by indomethacin in the re-fed rat. Gastric mucosal cyclooxygenase activity in sucralfate-treated rats expressed as prostaglandin E2 formation--388 +/- 140 (ng/g wet weight; mean +/- SE)--was significantly higher (P less than 0.01) than its activity in the control--264 +/- 62 (ng/g wet weight). Sucralfate also slightly, but significantly, decreased indomethacin-induced gastric mucosal cyclooxygenase inhibition. Intestinal mucosal cyclooxygenase activity was not affected by sucralfate. The results suggest that gastric and intestinal mucosal damage induced by various ulcerogens is significantly reduced by sucralfate. Sucralfate-induced stimulation of endogenous gastric mucosal prostanoid formation may in part explain its effective protective properties.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dinoprostone; Gastric Mucosa; Indomethacin; Intestinal Mucosa; Male; Peptic Ulcer; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Prostaglandins E; Rats; Sucralfate; Thromboxane B2

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Peptic Ulcer; Rats; Thromboxane B2; Thromboxanes

Topics: Adult; Dyspepsia; Ethanol; Gastric Juice; Gastric Mucosa; Humans; Male; Middle Aged; Peptic Ulcer; Thromboxane B2; Thromboxanes