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Background: We previously showed that Toll-like receptor-9 (TLR-9) ligands ameliorate experimental colitis. In this study, we evaluated the effect of TLR-9 ligands on the generation of proinflammatory cytokines by human colonic mucosa., Materials and Methods: Colonoscopic biopsies were obtained from patients with active ulcerative colitis (UC) and from normal subjects. The tissue was organ cultured for 24 hours in the presence or absence of different types of immunostimulatory (ISS) (CpG)-oligonucleotides (ODNs). Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels in the medium were determined by enzyme-linked immunosorbent assay., Results: In active UC, hTNF-alpha and hIL-lbeta generation by inflamed colonic mucosa is 7- and 3-fold higher, respectively, than their generation by normal mucosa. Class B CpG ODNs inhibited colonic TNF-alpha and IL-1beta generation by 50%, whereas class A or C ODNs had a partial or no effect, respectively. A novel class of ODNs that is based on multiple TCG repeats was as effective as class B ODNs. This inhibition resulted from the transcriptional suppression of IL-1beta that occurred within the first 2 hours after ISS-ODN incubation. The addition of chloroquine abolished the inhibitory effects of ISS-ODNs on colonic TNF-alpha and IL-1beta generation., Conclusions: Only certain classes of ISS-ODNs inhibit the enhanced TNF-alpha and IL-1beta generated ex vivo by inflamed colonic mucosa of patients with UC. The effect of ISS-ODNs is mediated by triggering of TLR-9. These results suggest a potential therapeutic value for ISS-ODNs in UC.

Reactive oxygen-derived species and redox-active metals are implicated in mediation of the pathogenesis of gastric mucosal damage and ulceration. Therefore, common strategies of intervention employ metal chelators, antioxidative enzymes, and low-molecular-weight antioxidants (LMWA). The aim of the present study was to elaborate the mechanism(s) responsible for the protection provided by nitroxide radicals in the experimental model of gastric ulceration. Fasted male rats were treated ig with 1 ml 96% ethanol, with or without ig pretreatment with nitroxide or hydroxylamine. In several experiments, rats were injected ip or iv with iron(III) or iron(II) prior to ethanol administration. Rats were sacrificed 10 min after ethanol administration, the stomach was removed, washed and lesion area measured. Pretreatment with iron(III) complexed to nitrilotriacetate or citrate, aggravated the extent of the gastric injury. Conversely, iron(II) inhibited the formation of lesions. The nitroxides were rapidly reduced to their respective hydroxylamines and demonstrated antiulcerative activity for rats treated with iron. However, injecting the hydroxylamine resulted in a similar tissue distribution of nitroxide/hydroxylamnine but did not provide protection. The results show that: (a) the nitroxide radicals, rather than their respective non-radical reduced form, are the active species responsible for protection; (b) nitroxides protect by dismutating O2*- and possibly indirectly increasing the NO level; (c) unlike classical LMWA which are reducing agents, nitroxides inhibit gastric damage by acting as mild oxidants, oxidizing reduced metals and pre-empting the Fenton reaction; and (d) the nitroxides act catalytically as recycling antioxidants.

Background: Sulphydryl compounds and nitric oxide are essential in maintaining gastric mucosal integrity., Aims: To characterise the gastric damage induced by a sulphydryl blocker, to evaluate the role of nitric oxide in its pathogenesis, and to reveal its possible prevention by scavenging of free radicals., Methods: Gastritis was induced in rats by addition of iodoacetamide (0.1%) to the drinking water, with and without daily intragastric administration of TEMPOL. After death, the stomach was resected, washed, lesion area assessed, and mucosal inflammatory mediators, myeloperoxidase and nitric oxide synthase activities were determined., Results: Administration of iodoacetamide induced gastric mucosal erosions present for up to two weeks. Myeloperoxidase activity was increased for up to seven days and nitric oxide synthase activity was significantly decreased for up to 14 days. Treatment for seven days with the free radical scavenger, TEMPOL, decreased by 68% the damage induced by iodoacetamide., Conclusions: Gastric damage induced by iodoacetamide, a sulphydryl alkylator, accompanied by inhibition of nitric oxide synthase activity shows the important contribution of sulphydryl compounds and nitric oxide to the maintenance of gastric mucosal integrity. Nitric oxide donation and scavenging of free radicals may be a novel approach to prevent gastric damage.

Rats with portal hypertension and experimental liver disease may exhibit increased susceptibility of the gastric mucosa to damage by noxious agents, and increased bacterial translocation through the bowel wall. The aim of this study was to determine mucosal gastric and colonic generation of vasoactive substances, because they may contribute to the altered mucosal function. Rats with partial vein ligation (n = 7), complete bile duct ligation (n = 6) and sham-operated rats (n = 10) were studied. Three weeks following surgery rats were anesthetized, splenic pulp pressure was measured, stomachs and colons were removed and mucosa was extracted for determination of prostaglandin E2, thromboxane B2, leukotriene B4, leukotriene C4 and endothelin-1 by radioimmunoassay (ng/g) and platelet activating factor activity (pg/10 mg) by platelet aggregation. Pulp pressure was > 13 mmHg in partial vein ligated rats and bile duct ligated rats and 6 mmHg in sham-operated rats. No macroscopic or microscopic lesions were seen any of the removed tissues. Gastric mucosal prostaglandin E2 and thromboxane B2 generation were decreased by 35% and 7%, respectively, in bile duct ligated rats (bile duct ligated versus sham-operated, p < 0.05 for prostaglandin E2 and thromboxane B2). Gastric leukotriene B4 and C4 generation, platelet activating factor activity and endothelin-1 content did not differ significantly among the three groups. A different pattern of changes was observed in the colon. Colonic leukotriene B4 generation and endothelin-1 content were increased in bile duct ligated rats by 105% and 210%, respectively (bile duct ligated versus sham-operated, p < 0.05 for leukotriene B4 and endothelin-1). The decreased gastric mucosal prostaglandin E2 generation of bile duct ligated rats may render the gut mucosa of these animals relatively ischemic and vulnerable to damage by noxious agents. The increased colonic leukotriene B4 generation and the increased endothelin-1 content of the colonic mucosa of bile duct ligated rats may promote inflammatory and ischemic changes in the colonic mucosa and may enable bacterial translocation.

Systemic administration of capsaicin aggravates ethanol-induced injury of rat gastric mucosa. We evaluated the effect of subcutaneous administration of capsaicin on the gastric mucosa and on inflammatory mediators in saline- and ethanol-treated rats. Functional ablation of primary afferent C-fibers by capsaicin (total 100 mg/kg subcutaneous) tripled ethanol-induced damage. Pretreatment with ketotifen, a mast cell stabilizer (1 mg/kg) protected rat gastric mucosa from the amplified injury induced by capsaicin and ethanol. Tempol, a selective nontoxic cell-permeable nitroxide, completely prevented the amplified gastric ulceration induced by capsaicin and ethanol. This was accompanied by a significant decrease in leukotriene B4 and C4 generation. It is therefore suggested that mast cells and free radicals contribute to the amplified injury observed in rats pretreated with capsaicin and ethanol and that the pharmacological modulation of mast cell release and scavenging of free radicals may be of therapeutic efficacy in the prevention of gastric injury.

Nitric oxide, the product of nitric oxide synthase in inflammatory cells, may have a role in tissue injury through its oxidative metabolism. Nitric oxide may have a role in the pathogenesis of duodenal ulcer and may be one of the mechanisms responsible for the association between gastric infection with Helicobacter pylori and peptic disease. In this study, calcium independent nitric oxide synthase activity was detected in human gastric mucosa suggesting expression of the inducible isoform. In 17 duodenal ulcer patients gastric antral and fundic nitric oxide synthase activity was found to be two and 1.5-fold respectively higher than its activity in the antrum and fundus of 14 normal subjects (p < 0.05). H pylori was detected in the antrum of 15 of 17 duodenal ulcer patients and only in 7 of 14 of the control subjects. Antral nitric oxide synthase activity in H pylori positive duodenal ulcer patients was twofold higher than in H pylori positive normal subjects (p < 0.05). In duodenal ulcer patients antral and fundic nitric oxide synthase activity resumed normal values after induction of ulcer healing with ranitidine. Eradication of H pylori did not further affect gastric nitric oxide synthase activity. These findings suggest that in duodenal ulcer patients stimulated gastric mucosal nitric oxide synthase activity, though independent of the H pylori state, may contribute to the pathogenesis of the disease.

The pathogenesis of gastric mucosal injury is still poorly understood. Recent reports implicate redox active metals and reactive oxygen species as mediators of gastric damage induced by ethanol or non-steroidal anti-inflammatory drugs. Attempts were made therefore to prevent gastric injury using chelators and the antioxidant enzymes catalase and superoxide dismutase. These attempts, at best, would only detoxify extracellular reactive species, such as those produced by activated circulating granulocytes and macrophages. This study utilises another strategy by pre-emption of both intra and extracellular reactive species using radical-radical annihilation reactions and by detoxifying redox active transition metals. Nitroxide, stable free radicals were shown to enter mucous cells, protect against the ethanol induced damage, and prevent gastric lesions induced by aspirin, indomethacin, 25% NaCl, or 0.6 N HCl. These findings confirm that gastric mucosal damage from the above agents is mediated by free radicals and, moreover, introduce a prototypical agent within a potential new class of gastric ulcer preventing drugs.

The interrelationship between somatostatin and its synthetic analog, sandostatin, with neuropeptides and inflammatory mediators, as well as their protection of gastric mucosal damage, were tested in rats. Rats were treated intragastrically with 1.0 ml of 96% ethanol with or without intravenous or intraperitoneal coadministration of somatostatin (1.0 microM/kg). Mucosal damage was also induced by the administration of either indomethacin (30 mg/kg subcutaneously) with or without intravenous sandostatin (10 micrograms/rat), given 30 min prior to damage induction. Somatostatin levels in ethanol-damaged gastric mucosa were significantly lower than in control rats. Substance P and vasoactive intestinal peptide (VIP) levels were significantly higher in the damaged mucosa in rats treated with ethanol, as was the mucosal generation of leukotriene B4 (LTB4) and cysteinyl-containing leukotrienes. The coadministration of somatostatin with ethanol significantly reduced gastric mucosal injury induced by ethanol alone. The protection of the mucosa was accompanied by reduction of mucosal substance P and VIP levels, as well as the generation of leukotrienes, an effect that was reversed by intraperitoneal or intravenous coadministration of somatostatin antagonist, cyclo-(7-aminoheptanoyl-PH-E-D-Trp-Lys-THR), 1.0 microM/100 g, with somatostatin (1.0 microM/kg) and ethanol. When given by itself somatostatin significantly reduced mucosal leukotriene generation compared with their generation in saline-treated rats. Sandostatin completely abolished gastric mucosal damage induced by indomethacin administration. In rats treated with somatostatin and indomethacin, this effect was accompanied by reduction of mucosal leukotriene generation. Administration of sandostatin to pylorus-ligated rats significantly reduced gastric acid output.(ABSTRACT TRUNCATED AT 250 WORDS)

We have reviewed the effects of nonsteroidal antiinflammatory drugs (NSAIDs) on the gastroduodenal mucosa and then, by means of meta-analysis, have evaluated the results of therapeutical trials in the prevention of NSAID-induced gastroduodenal mucosal damage. We searched the literature through Medline (1980-1990) and through the references of relevant articles. Of 19 trials retrieved by these means, 11 proved eligible for meta-analysis on the basis of eight selection criteria defined a priori. The data included seven studies where the effect of preventive treatment during short-term use of NSAIDs was analyzed and four studies dealing with prevention of mucosal damage in subjects treated with NSAIDs for long periods. Results were expressed in terms of the percentage of patients developing severe mucosal damage or an ulcer during short- and long-term treatment with NSAIDs, respectively. The pooling of the results showed that, during short-term NSAID use, 37% of the subjects developed severe gastric mucosal damage as compared to 12% of subjects given some protective agent. The figures for the duodenum are 13% and 4%, respectively. Owing to the small number of studies on prevention of chronic NSAID-induced gastroduodenal damage, results were not pooled together; misoprostol was shown to be highly effective in reducing the prevalence of gastric ulcer, and ranitidine prevented the occurrence of duodenal but not gastric ulcer. Despite these positive results, there is no proof that protective agents should be recommended to the general population requiring NSAIDs therapy. Nor is there yet evidence that taking a protective agent will avoid the complications of NSAIDs, such as bleeding or perforation.

To elucidate the possible role of vasoactive intestinal peptide (VIP) in the pathogenesis of acute gastric mucosal damage, rats were treated intragastrically with 1.0 ml 96% ethanol with or without intravenous or intraperitoneal coadministration of VIP (1 nmol/liter to 1 mumol/liter/100 g). VIP was found to double the mean lesion area when compared with that induced by ethanol alone (P < 0.05), an effect that was prevented by VIP antagonist (1 mumol/liter/100 g). A substance P antagonist (1 mumol/liter/100 g) also reduced the extent of gastric damage induced by coadministration of VIP and ethanol. VIP antagonist or substance P antagonist significantly reduced ethanol-induced gastric mucosal damage. Gastric mucosal levels of LTB4, LTC4, VIP, and substance P were significantly increased in ethanol-treated rats as compared with saline-treated animals (P < 0.05). The augmentation of ethanol-induced damage by VIP was associated with increased gastric mucosal levels of LTB4. In VIP-treated rats, gastric mucosal levels of substance P were found to be significantly increased compared with control rats (P < 0.05). Administration of VIP to pyloric-ligated rats significantly increased gastric acid output and blood pepsinogen A levels as compared with saline treated rats (P < 0.05). Ketotifen, a mast cell stabilizer (100 micrograms/100 g), administered orally 30 min before damage induction by ethanol, with or without VIP, totally abolished the damage of the surface epithelium of the entire gastric mucosa and significantly reduced the mucosal levels of LTC4 and LTB4 (P < 0.05). It is suggested that VIP is involved in the pathogenesis of acute ethanol-induced gastric mucosal damage.(ABSTRACT TRUNCATED AT 250 WORDS)

The objective of the present study was to determine the efficacy of ketotifen (Zaditen), an effective antiasthmatic drug, in preventing indomethacin-induced gastroduodenal mucosal injury in a two-arm prospective, randomized, double-blind, controlled and open study. Thirty healthy volunteers with endoscopic normal-appearing mucosa were randomly treated, double-blindly, for 1 week with either placebo or ketotifen, 2 mg twice daily. On day 7 indomethacin, 50 mg three times daily, was added. Two subjects, one from each group, were withdrawn from the study owing to non-compliance. Ten additional subjects received ketotifen, 2 mg twice daily, 24 h before indomethacin administration, in an open manner. A second endoscopy was performed 24 h after indomethacin was initiated. Mucosal damage in the stomach and duodenum (hemorrhages, erosions, ulcers) was scored in accordance with Lanza et al. or counted numerically. Adverse reactions were documented. Ketotifen reduced indomethacin-induced gastric mucosal damage, reducing the mean gastric lesion score from 2.85 +/- 0.20 in the placebo-treated group to 1.86 +/- 0.36 and in the subjects pretreated with ketotifen for 7 days. Ketotifen protected (lesion score < or = 1) 6 of 14 subjects pretreated for 7 days, whereas none of the 14 placebo-treated subjects were protected. Ketotifen had no statistically significant protective effects in the duodenum. In the open study lesion scores of patients pretreated with ketotifen for 24 h were similar to those pretreated for 7 days. Ketotifen is effective in the reduction of indomethacin-induced acute gastric mucosal injury. Further studies are required to verify these data in a more relevant clinical setting.

To elucidate the possible role of substance P in the pathogenesis of acute gastric mucosal damage, rats were treated intragastrically with 1.0 mL 96% ethanol, 0.6N HCl, or 25% NaCl, with or without IP coadministration of substance P, senktide, or septide (1 mumol/L per 100 g). All three peptides were found to double the mean lesion area when compared with that induced by ethanol, whereas substance P antagonist (1 mumol/L per 100 g) prevented the expansion of damage extent. The increased damage was associated with increased gastric mucosal levels of platelet activating factor, leukotriene B4, and leukotriene C4. Substance P antagonists also reduced by half the extent of the gastric damage induced by ethanol when administered by itself. WEB 2086 (platelet-activating factor antagonist; Boehringer Ingelheim KG, Germany), hydroxyzine (H1 blocker), and cimetidine (H2 blocker) reduced lesion area by 50%, but only in rats treated with both substance P and ethanol. Ketotifen (mast-cell stabilizer) (100 micrograms/100 g), administered orally 30 minutes before damage induction, totally abolished the extent of the damage induced by either ethanol or the coadministration of ethanol and peptides in the surface epithelium of the entire mucosa. The protective effect of ketotifen was accompanied by significant reduction in mucosal generation of platelet-activating factor, leukotriene C4, and leukotriene B4. Similar mucosal protection was afforded by ketotifen against damage induced by 0.6N HCl, 25% NaCl, or indomethacin. Therefore, it is suggested that substance P is involved in the pathogenesis of acute ethanol-induced gastric mucosal damage. The effective mucosal protection provided by ketotifen indicates the important role of mast cells and their mediators in the pathogenesis of acute gastric mucosal damage and may have therapeutic implications.

We determined endogenous gastric prostaglandin synthesis and its correlation with the prevention of duodenal ulcer relapse by misoprostol and ranitidine. Sixty-one patients with recent endoscopically healed duodenal ulcer were randomly allocated in a double-blind fashion for one year of treatment with misoprostol 400 micrograms nocte, ranitidine 150 mg nocte or placebo. Patients were followed every two months. Endoscopy was repeated at six and 12 months or beforehand, if relapse was suspected. Antral and fundic biopsies, 3-4 from each region, were obtained at each endoscopy for determination of prostaglandin synthesis. During the one year of treatment, 11 out of the 12 placebo treated patients flared up, as opposed to 10 out of 25 and four out of 24 misoprostol and ranitidine treated patients, respectively. The difference between all treatment groups was significant (P less than 0.0001). In all subjects who flared up, pretrial endogenous antral and fundic prostaglandin E2 synthesis were not different from their respective synthesis in those who did not relapse.

Platelet-activating factor (PAF), leukotriene B4 (LTB4), and leukotriene C4 (LTC4) generation by gastroduodenal mucosa was assessed in duodenal ulcer patients and in normal subjects, to elucidate their possible role in the pathogenesis of peptic ulcer disease. Endoscopic fundic, antral, and duodenal biopsy specimens were obtained from 35 duodenal ulcer patients on the day the diagnosis was established and from 42 normal controls. In duodenal ulcer patients PAF generation, determined by platelet aggregation, was two- to three-fold higher than its respective generation by normal subjects. LTB4 and LTC4 synthesis by cultured antral and duodenal mucosa obtained from duodenal ulcer patients was twofold higher than their synthesis by normal subjects. Fundic LTB4 and LTC4 generation was similar in ulcer patients and controls. In 11 patients PAF, LTB4, and LTC4 generation was also assessed after 4 weeks of treatment resulting in ulcer healing and found to be significantly reduced when compared with their synthesis when the ulcer was active. These results thus suggest that PAF, LTB4, and LTC4 may have a role in the pathogenesis of duodenal ulcer, and therefore their modulation may have therapeutic benefits.

The effects of misoprostol 200 micrograms q.i.d. and cimetidine 300 mg q.i.d. on gastric cell turnover were investigated in duodenal ulcer patients before and after four weeks of therapy. Endoscopic biopsies were incubated with 3H-thymidine. Glandular column length (number of cells per column) and the number of labelled cells per column were determined by autoradiography. There were no significant treatment effects on column length of the gastric pits of either the antrum or fundus. However, misoprostol and cimetidine had opposing effects on cell turnover. Misoprostol significantly decreased the number of labelled cells in antral (P less than 0.01) and fundic (P less than 0.001) gastric pits. However, cimetidine significantly increased (P less than 0.01) the number of labelled cells in antral and fundic columns. The increased gastric cell turnover caused by cimetidine may contribute to its activity in peptic ulcer disease. The decreased cell turnover induced by misoprostol does not appear to be a mechanism responsible for its well-established cytoprotective activity.

"Mild irritants" have been shown to protect rat gastric mucosa from damage induced by noxious topical agents, supposedly by induction of mucosal prostaglandin (PG) biosynthesis. The protective effect of NaCl 5%, ethanol 20%, NaOH 0.075 N, HCl 0.35 N, salicylic acid 100 mg/kg and paracetamol 200 mg/kg was investigated in rats treated with an ulcerogenic dose (25 mg/kg) of indomethacin; mucosal PG synthesis was simultaneously determined. Significant protection was achieved only with NaCl 5%, salicylic acid and paracetamol. Salicylic acid and paracetamol significantly decreased acid secretion and enhanced PGE2 or 6-keto PGF1 alpha generation in control rats, while a small but significant change in the indomethacin-inhibited PG synthesis was observed after treatment with NaCl 5% or salicylic acid. We conclude that protection by "mild irritants" against indomethacin-induced mucosal damage may involve increased cytoprotective PG generation, as shown for paracetamol and salicylic acid, or partial blocking of indomethacin binding at the cyclooxygenase receptor site, as shown for NaCl 5% and salicylic acid.

Our recent identification of chondroitin sulphate E-containing mast cells (E-MC) in the human colonic mucosa is extended here to the human gastric mucosa by using a combination of both biochemical and immunochemical approaches. Most of the mast cells in human gastric biopsies, which were located mainly around small blood vessels in the submucosa, showed various degrees of degranulation and were granular when stained by monoclonal antibody against chondroitin sulphate proteoglycan. The human gastric mucosa biopsies incorporated (35S)-sulphate into proteoglycans. Cells in the tissues which were histamine-positive also incorporated (35S). The 35S proteoglycans, which were either left associated with the tissue or released into the medium, were found not to be heparin but chondroitin sulphate E. Incubation of the human gastric mucosa biopsies in the presence of anti-human IgE revealed significant enhancement in the release of both (35S)-chondroitin sulphate E proteoglycan and histamine.

Synthesis of prostaglandin E2 and 6-keto prostaglandin F1 alpha by cultured antral and fundic gastric mucosa obtained from 86 patients with active duodenal ulcer who were not receiving medication was 50% lower (p less than 0.01) than their respective synthesis by cultured gastric mucosa in normal subjects. Antral and fundic prostanoid synthesis in patients receiving chronic therapy with nonsteroidal antiinflammatory drugs was almost completely inhibited. The decreased synthesis of antral and fundic prostaglandin E2 and 6-keto prostaglandin F1 alpha in duodenal ulcer patients was not affected following ulcer healing achieved after 4 wk of therapy with placebo, arbacet, misoprostol, sucralfate, and pirenzepine. In contrast, following 4 wk of therapy with ranitidine, both antral and fundic prostaglandin E2 synthesis were significantly increased when compared with their respective synthesis before therapy. These results confirm that gastric prostanoid synthesis is decreased in patients with active duodenal ulcer and in subjects treated with nonsteroidal antiinflammatory drugs, suggesting that decreased endogenous prostanoid synthesis may contribute to the pathogenesis of mucosal damage. The induction of endogenous prostanoids by ranitidine may contribute to its therapeutic effect.

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.

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.

The efficacy of arbacet (a synthetic analog of prostaglandin E2) in definite cytoprotective but minimal antisecretory dose was evaluated in the treatment of duodenal ulcer. One hundred five patients with endoscopically proven duodenal ulcer were randomized in a double-blind manner to receive four times daily either arbacet 25 micrograms or placebo. Ulcer healing was assessed endoscopically after two and four weeks of treatment. The mean age, sex distribution, and tobacco and alcohol consumption were similar in the two treatment groups. The ulcers of 16 patients in both the placebo and the arbacet-treated group healed after 14 days of treatment. At the end of the study, healing of the ulcer was observed in 69.2% of the arbacet-treated patients and in 60.4% of patients in the placebo treated group. (Difference was not statistically significant). We conclude that cytoprotective doses of arbacet with minimal antisecretory properties are not effective in duodenal ulcer healing.

Prostaglandins (PGs) are synthesised by gastric mucosa, and have been shown to inhibit gastric acid secretion and ulcer formation in man and experimental animals. Recently exogenous PGs, mainly of the E group, have been used for the treatment of peptic ulcer disease. We therefore searched for a drug that would stimulate endogenous gastric prostaglandin E(2) (PGE(2)) synthesis. Rabbit gastric mucosa slices were cultured for 22 hours at 77 degrees C. PGE(2), measured by radioimmunoassay, was found to be linearly secreted into the culture medium. PGE(2) accumulation in the medium during 22 hours of culture was 7.9+/-0.5 (SE) ng/mg tissue (N=20). Addition of papaverine (100 mu/ml), a cyclic nucleotide phosphodiesterase inhibitor, resulted in a significant increase (250% of control) in PGE(2) accumulation in the medium: 24.3+/-1.8 ng/mg tissue (N=25). Isobutylmethylxanthine (IBMX 100 mug/ml), another phosphodiesterase inhibitor, only slightly increased PGE(2) accumulation, while 8 bromo-cyclic AMP (1 mM) had no effect. Under these conditions IBMX increased by 20-fold mucosal cyclic AMP levels: 3.9+/-0.3 pmol/mg tissue (N=8) as compared with control levels: 0.2+/-0.03 pmol/mg tissue (N=8). Papaverine, however, did not alter mucosal cyclic AMP accumulation. These results indicate that papaverine stimulates PGE(2) production by cultured rabbit gastric mucosa and that this stimulation is not related to the inhibition of phosphodiesterase activity and accumulation of mucosal cyclic AMP. Papaverine induced stimulation of PGE(2) production should be further evaluated regarding its possible beneficial effects in protecting gastric mucosa and in reducing acid secretion in peptic ulcer patients.

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.

Somatostation has been postulated to have a paracrine modulating role in gastrin and gastric acid secretion. We applied the organ culture technique to examine somatostatin release by explants of human gastric mucosa taken from patients with active duodenal ulcer, from control subjects, and from patients with pernicious anemia. Somatostatin was found to be released at a constant rate by antral explants during 3 h of incubation. In active duodenal ulcer antral and fundic 2-h somatostatin release (18.7 +/- 2.6 pg/mg tissue (means + SE), n = 75; and 27 +/- 3 pg/mg tissue, n = 94, respectively) was significantly lower than release by control antral and fundic mucosa (83 +/- 17 pg/mg tissue, n = 39, and 72 +/- 16 pg/mg tissue, n = 42, respectively) (P less than 0.01). Somatostatin release by antral and fundic mucosa of patients with pernicious anemia was also significantly decreased (20 +/- 8 pg/mg tissue, n = 12, and 7.6 +/- 2 pg/mg tissue, n = 12, respectively) (P less than 0.05). These results imply possible impairments of the paracrine release of somatostatin in peptic ulcer disease and in pernicious anemia.

The effect of 1 week of treatment with indomethacin 150 mg/day on human gastric prostanoid synthesis was correlated with its effect on gastric and duodenal mucosa. Before and following 1 week of treatment, endoscopic appearance of the mucosa was evaluated and scored. Following 1 week of treatment with indomethacin, antral PGE2 and 6-keto-PGF1 alpha were significantly lower than in normal subjects, but similar in patients with significant or with no mucosal damage. Co-treatment with ranitidine 150 mg b.d. or with cimetidine 400 mg b.d. reduced the mean mucosal damage score but did not affect gastric prostanoid synthesis, which was similar irrespective of the presence or absence of mucosal damage. It is therefore suggested that there is no correlation between indomethacin-induced inhibition of gastric prostanoid synthesis and its induction of mucosal damage.