6-ketoprostaglandin-f1-alpha and Peptic-Ulcer

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

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 role of gastric acid in the development of gastroduodenal ulcers in prostaglandin-deficient conditions is unclear. In the current study, the effect of the proton pump inhibitor omeprazole on the formation of gastric ulcers was examined in a previously validated rabbit model of antibody-induced prostaglandin deficiency. Intragastric administration of 20 mg/kg omeprazole every 12 hours caused a profound suppression of gastric acidity (i.e., pH above 5 continuously). This same dose of omeprazole significantly reduced gastric ulcer formation induced by passive immunization with 6-keto-prostaglandin F1 alpha antibodies. It is concluded from these observations that gastric acid plays a critical role in the formation of gastric ulcers in rabbits with antibody-induced prostaglandin deficiency.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Antibodies; Cross Reactions; Gastric Acid; Gastric Fistula; Gastric Mucosa; Immunization, Passive; Omeprazole; Peptic Ulcer; Prostaglandins; Rabbits; Stomach

Gastroduodenal ulcer disease may result from the desynchronization of the circadian rhythms of gastric protective and destructive factors. The purpose of this study was to evaluate whether gastric tissue 6-keto prostaglandin F1 alpha (PGF1 alpha), a catabolic derivative of the putative protective factor prostacyclin, is produced in a circadian fashion in the rat model. Forty-eight male Sprague-Dawley rats were acclimatized in sound-attenuated, lightproof chambers for 3 weeks on a 12:12 hour light/dark entrainment schedule. After an 18-hour fast, six rats were killed at each of eight sampling times. The stomachs were exposed, removed, and assayed for total 6-keto PGF1 alpha content by radioimmunoassay. Cosinor analysis of the data showed significant (p = 0.0262) circadian rhythmicity in 6-keto PGF1 alpha content with an acrophase (peak time) value of 0503 HALO (hours after lights on) or in the middle of the lights-on inactive period for the rats. Hypothetically, the circadian rhythm in some gastric protective factors may render the gastric mucosa vulnerable to injury in a circadian fashion.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Circadian Rhythm; Fasting; Gastric Mucosa; Male; Peptic Ulcer; Radioimmunoassay; Rats; Rats, Inbred Strains

Circulating prostaglandin E2 antibodies were produced in 12 rabbits immunized with prostaglandin E2-thyroglobulin conjugate and ulcers occurred in 10, usually in the stomach and less often in the small intestine. Immunization of rabbits with both prostaglandin E2 and 6-keto prostaglandin F1 alpha significantly increased the number of gastric ulcers compared with rabbits immunized with prostaglandin E2 alone. Gastrointestinal ulceration in prostaglandin E2-immunized rabbits was not prevented by oral enprostil. Gastrointestinal ulcers occurred as early as 6 wk after beginning immunization and often perforated with resulting fatality. Neither prostaglandin E2 antibodies nor ulcers developed in rabbits immunized with thyroglobulin vehicle (controls). Passive immunization of unimmunized rabbits with prostaglandin E2-hyperimmune plasma led to acute gastric ulcers within 9 days, whereas passive transfer of nonimmune plasma did not produce ulcers. This latter finding suggests that prostaglandin E2 antibodies per se were responsible for ulcer formation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antibody Formation; Cross Reactions; Dinoprostone; Enprostil; Immunization; Immunization, Passive; Male; Peptic Ulcer; Prostaglandins E; Prostaglandins E, Synthetic; Rabbits

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

Rabbits immunized against prostaglandins develop antibodies to prostaglandins and peptic ulcer disease (duodenal and gastric ulcers). We have evaluated the hypothesis that idiopathic gastric or duodenal ulcer disease in humans may be associated with the spontaneous occurrence of serum antibodies directed against endogenous prostaglandins. We found that serum from 45 ulcer patients (34 duodenal, 11 gastric) had a low degree of binding of radiolabeled prostaglandin E2, prostaglandin F2 alpha, or 6-keto prostaglandin F1 alpha. The extent to which prostaglandins were bound to serum of ulcer patients was not statistically different from prostaglandin binding to serum from 25 normal subjects. Therefore, we conclude that spontaneous occurrence of circulating antibodies against endogenous prostaglandins is an unlikely cause of gastroduodenal ulceration in humans.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Antibodies; Dinoprost; Dinoprostone; Humans; Male; Middle Aged; Peptic Ulcer; Prostaglandins E; Prostaglandins F

It seems that the gastric antral mucosa either in normal, physiological circumstances, or in IND or STR induced gastric ulcer models, contains significantly more endogenous PG-I2 than that of gastric fundic mucosa, while the duodenal mucosa contains significantly lower endogenous PG-I2-level compared to the gastric antral or fundic level. Either in gastric or in duodenal ulceration the endogenous PG-I2 level basically decreased proportionally to the degree of ulceration - therefore it is tempting to speculate that the endogenous PG-I2 is most probably one of the natural protective substances in the gastrointestinal mucosa.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cysteamine; Epoprostenol; Female; Gastric Mucosa; Indomethacin; Peptic Ulcer; Prostaglandins; Rats; Rats, Inbred Strains; Stress, Physiological

The consistent occurrence of gastric and duodenal ulcers was observed in laboratory rabbits used for production of high-titer plasma antibody to 6-keto PGF1 alpha and PGE2. Perforations developed in 7 of 10 animals, usually just distal to the pyloroduodenal junction. The remaining rabbits showed gross and/or microscopic evidence of imperforate ulcers and erosions. These lesions appeared to be direct pathologic complications of an immune response directed against prostaglandins since animals immunized against met-enkephalin with similar methods had no ulcers.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antibody Formation; Dinoprostone; Male; Peptic Ulcer; Prostaglandins; Prostaglandins E; Rabbits