Healing process of duodenal ulcers induced by indomethacin plus histamine in rats

Healing of duodenal ulcers induced by indomethacin + histamine was investigated in rats. Animals were treated with indomethacin (5 mg/kg, s.c., once daily) and histamine (40 mg/kg, s.c., 3 times every 2.5 h after indomethacin treatment) for 2 days under fasting conditions, and they were fed normally thereafter. The duodenal ulcers so induced were confined to the proximal part of the duodenum and penetrated to the muscular mucosa with an incidence of over 80% when determined 32 h after the first injection of indomethacin (day 1). The ulcers became smaller and shallower within 7 days with granulation from the ulcer base, the mucosa grew in from the edges over the surface of granulation tissue, and they had healed almost completely after 15 days with epithelial regeneration from the edge of the ulcers. The healing of ulcers was significantly promoted by a 5-day treatment with an antacid (Al(OH)3) as well as antisecretory agents (omeprazole, cimetidine, propantheline bromide) and 16,16-dimethyl prostaglandin E2 at the dose which produced a potent inhibition of acid output and a marked increase in duodenal alkaline secretion. These results suggest that the duodenal ulcers induced in rats by indomethacin + histamine may provide a useful model for studying the healing process of duodenal ulcers and for the evaluation of the drugs with possible effects on ulcer healing.     

Effect of antisecretory agents and vagotomy on healing of “chronic” cysteamine-induced duodenal ulcers in rats

Penetrated cysteamine-induced duodenal ulcers in rats have a very prolonged course of healing. In this study, it was investigated how much the healing of these ulcers is accelerated by some treatments. The treatments included omeprazole, cimetidine, and truncal vagotomy. In addition, the effect of omeprazole and cimetidine on gastric acid secretion was investigated in chronic gastric fistula rats. After 25 days of treatment, significantly more rats in the treated groups had healed ulcers than in the control group. There was little further improvement up to 100 days of treatment, and the difference between treated and untreated groups decreased. The morphology of healing ulcers in treated and untreated rats was also compared. In controls, there was a simultaneous regeneration of mucosa and the submucosal Brunner's glands from the edges of the ulcer, the slow proliferation rate of the latter probably being decisive for the prolonged healing. In the treated rats, the mucosa first regenerated with formation of crypts and low villi and subsequently, the Brunner's glands were formed by proliferation from the bottom of the crypts.     

Significance of Helicobacter Pylori Infection in Human Peptic Ulcers

Abstract: Experimental studies have suggested that the continuous administration of 0.02% NH, solution, induced by Helicobacter pylori (H, Pylori), leads to a glandular atrophy of the gastric mucosa, and adversely affects healing of acetic acid ulcers in rats, because of the suppression of cell kinetics of the regenerative epithelial cells and connective tissues at ulcer margins. To visualize the distribution of H. pylori in human gastric mucosa, a phenol red dye spraying endoscopy was performed in 45 patients with gastric ulcers, and 43 patients with duodenal ulcers, who were medicated with a full dose of H₂-blocker until ulcer healing, and with half doses thereafter. In the H. pylori negative cases, 8 (88.9%) of 9 gastric ulcers healed within 3 months after medication, with no relapse discernible up to 6 months after healing of the preceding ulcer. The relapse rate was 25% up to 12 months after ulcer healing. In contrast, only 22 (66.1%) of 36 gastric ulcers healed within 3 months after medication in the H. pylori positive cases. The relapse rate was 12.5% up to 3 months, 30.4% UP to 6 months and 63.6% up to 12 months after ulcer healing. In addition, all 6 duodenal ulcers healed within 2 months after medication in the H. pylori negative cases, with no relapse discernible up to 12 months after healing of the preceding ulcer. In contrast, in the H. pylon positive cases, 20 (53.1%) of 37 duodenal ulcers healed within 2 months, and the relapse rate was 14.3%, 33.3%, and 66.7% up to 3, 6 and 12 months respectively after healing of the preceding ulcer. These data suggest that H. pylori is likely to interfer with ulcer healing, and promotes peptic ulcer relapse.     

Flow cytometric analysis of cell proliferation kinetics during duodenal ulcer healing

Cell proliferation in the gastroduodenal mucosa of patients with duodenal ulcers was evaluated using flow cytometry. Forty patients with duodenal ulcers and 12 normal subjects were investigated. Biopsy samples were obtained during endoscopic examination and subjected to DNA analysis by flow cytometry. Thirty patients with duodenal ulcers were healed within 3 months with H₂ blockers (tractable or responsive ulcers), whereas 10 patients did not respond to treatment (intractable ulcers). The percentage of cells at the DNA-synthetic phase, an index of cell proliferation, was constant in the adjacent duodenal mucosa 2cm from ulcer margin and antral mucosa during duodenal ulcer healing. The index at the margin of tractable ulcers was elevated during the active stage (12.9 ± 1.3), peaked during the healing stage (15.4 ± 2.8) and returned to the same level at the scarring stage (10.9 ± 2.0) as normal controls (10.3 ± 1.7). However, the index was not elevated in intractable ulcers (10.3 ± 1.7 in the healing stage) and was smaller than in tractable ulcers. These data indicate that augmented mucosal cell proliferation at the ulcer margin plays an important role in duodenal ulcer healing and intractable ulcers are characterized by an abnormal failure to accelerate DNA synthesis to achieve ulcer repair.     

Healing of duodenal ulcers is not impaired by indomethacin or rofecoxib,the selective COX-2 inhibitor,in rats

BACKGROUND/AIM: Studies have demonstrated an important role for endogenous PG and NO in the healing of chronic gastric ulcers. We investigated the effects of COX and NOS inhibitors on the healing of duodenal ulcers, in comparison with gastric ulcers, in rats. METHODS: Gastric and duodenal ulcers were induced by serosal application of acetic acid (0.1 ml of 100% acetic acid) for 60 and 20 s, respectively. Indomethacin (a nonselective COX inhibitor) or rofecoxib (a selective COX-2 inhibitor) was given p.o. once daily for 14 days from 3 days after ulcer induction, while N(G)-nitro-L-arginine methyl ester (L-NAME: a nonselective NOS inhibitor) or aminoguanidine (a relatively selective iNOS inhibitor) was given s.c. twice daily during this period. RESULTS: Both gastric and duodenal ulcers induced by acetic acid healed spontaneously within 17 days to a minimal size. Daily administration of indomethacin or rofecoxib significantly delayed the healing of gastric but not duodenal ulcers. In contrast, the healing of both gastric and duodenal ulcers was delayed by repeated administration of either L-NAME or aminoguanidine. Ulceration markedly increased the PGE(2) content of the ulcerated mucosa in both the stomach and duodenum, and the increased PG biosynthetic response was inhibited by either indomethacin or rofecoxib in both tissues. The expression of both COX-2 and iNOS mRNAs was upregulated in the ulcerated mucosa of the stomach and duodenum. CONCLUSION: These results suggest that COX-2/PG is actively involved in the healing of gastric but not duodenal ulcers, although the mRNA for COX-2 is expressed in the duodenal mucosa after ulceration, as potently as in the gastric mucosa. In contrast, NO produced by both cNOS and iNOS plays a role in the healing of both gastric and duodenal ulcers.     

Mucosal Tag of the Duodenum: —Report of a Case—

Abstract: We studied a 66-year-old female who had a dull epigastric pain. An upper gastrointestinal (GI) series revealed a cordlike protrusion in the duodenal region, and a gastroendoscopic examination was performed and revealed a mucosal tag (MT) about 3 cm in length in the duodenal bulb. The MT was resected endoscopically and was found to be lined by normal duodenal mucosa and to have developed hyperplasia of the Brunner's glands. This MT was considered to be a congenitally-developed, hamartomatous hyperplasia of the duodenal mucosa, and of the Brunner's glands in particular.     

Increased expression of epidermal growth factor receptor during gastric ulcer healing in rats.

Expression of epidermal growth factor receptor (EGFR) was studied immunohistochemically in rat gastric mucosa during healing of acetic acid-induced ulcers. In normal control gastric oxyntic mucosa, EGFR was expressed in proliferative zone cells and in some parietal cells. In mucosa of the ulcer margin, at 3, 7, and 16 days after ulcer induction, there was a 75-fold increase (over controls) in the number of cells expressing EGFR. Seventy percent of ulcers healed by the 16th day, and all were healed by the 25th day. The mucosal scar that replaced the ulcer was composed of dilated glands lined with poorly or aberrantly differentiated cells showing persistence of increased EGFR expression. An increased EGFR expression indicates an important role of EGF in ulcer healing and scar formation.     

Role of epidermal growth factor in healing of chronic gastroduodenal ulcers in rats

The healing of acetic acid-induced gastric and duodenal ulcers was examined together with biochemical indices of growth in gastric and duodenal mucosa in rats with intact or removed salivary glands after treatment with epidermal growth factor (EGF) or somatostatin, or both. After the extirpation of salivary glands, the healing rate of gastric and duodenal ulcerations was delayed and gastric content of immunoreactive EGF was reduced. This was accompanied by a significant decrease in the contents of deoxyribonucleic acid and ribonucleic acid in the gastric and duodenal mucosa. Repeated administration of EGF either subcutaneously or orally accelerated the healing of gastroduodenal ulcers in rats with intact salivary glands and completely reversed the delay in ulcer healing in sialoadenectomized animals. These effects were also accompanied by a significant increase in the growth parameters of gastric and duodenal mucosa. Administration of somatostatin, which prevented the growth-promoting action of subcutaneous EGF, resulted in a significant decrease in the EGF-stimulated healing of gastric and duodenal ulcerations in both intact and sialoadenectomized rats. Our findings suggest that cell proliferation is an important factor in healing of gastric and duodenal ulcerations and that EGF plays an important role in ulcer healing due to its mitogenic action.     

Histological maturity of healed duodenal ulcers and ulcer recurrence after treatment with colloidal bismuth subcitrate or cimetidine

The relationship between histological maturity of healed duodenal ulcers and ulcer recurrence after 6 weeks of treatment with colloidal bismuth subcitrate or cimetidine was investigated. There was no significant difference in healing rates between colloidal bismuth subcitrate- and cimetidine-treated patients (85.7% and 71.8%, respectively; P greater than 0.05). Histologically, the regenerating mucosa of healed ulcers was divided into three categories--good, fair, and poor--according to pattern. Sixty percent of healed colloidal bismuth subcitrate-treated and 30.9% of healed cimetidine-treated ulcers had a good pattern; the difference was statistically significant (P = 0.027). The difference in recurrence rates between healed colloidal bismuth subcitrate-treated and healed cimetidine-treated patients was statistically significant at 3 months (3.45% and 20%, respectively; P = 0.044). All recurrent ulcers in both groups had fair or poor patterns of regenerating mucosa. It was concluded that the greater histological maturity of the regenerating mucosa may contribute to the lower recurrence rate in colloidal bismuth subcitrate-treated patients than in cimetidine-treated patients.     

Cytoprotective doses of arbacet with minimal antisecretory properties are not effective in duodenal ulcer healing

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 g 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.     

Successful endoscopic removal of a duodenal adenoma occurring in Brunner's gland hyperplasia

A case of duodenal neoplasm in the second portion of the duodenum is presented. Endoscopically, the lesion was characterized by a broad‐based, submucosal tumor‐like protrusion with a shallow central depression. The lesion was successfully removed by endoscopic mucosal resection. Histological examination of the resected specimen revealed the lesion to be composed of Brunner's gland hyperplasia in the submucosal layer and adenomatous glands in the mucosa. Our case suggests that neoplastic transformation possibly occurs in Brunner's gland hyperplasia.     

Ranitidine in the treatment of non-steroidal anti-inflammatory drug associated gastric and duodenal ulcers.

In a multicentre study the effect of ranitidine on healing non-steroidal anti-inflammatory drug (NSAID) associated peptic ulcers was compared in a group of patients who had stopped NSAID treatment with another group who continued with NSAID treatment. A total of 190 patients with confirmed ulcers were randomised to continue or stop NSAID treatment. All patients in addition received ranitidine 150 mg twice daily. Patients were endoscopically monitored at four, eight, and 12 weeks. Gastric ulcers at eight weeks had healed in 63% of those taking NSAIDs compared with 95% of those who had stopped NSAID treatment. For duodenal ulcer the healing rates at eight weeks were 84% in the group continuing NSAIDs compared with 100% in those who stopped NSAIDs. The differences in healing rates were statistically significant for both gastric ulcer (p = 0.001) and for duodenal ulcer (p = 0.006). At 12 weeks, 79% of gastric ulcers and 92% of duodenal ulcers were healed in the group continuing with NSAIDs. All patients with gastric and duodenal ulcers who stopped taking NSAIDs were healed at 12 weeks. The study shows that ranitidine 150 mg twice daily effectively heals NSAID associated peptic ulcers. Healing is more successful when NSAID treatment stops but even if these drugs are continued, substantial healing rates are achievable.     

Roxatidine versus ranitidine in the treatment of duodenal ulcers: A randomized double-blind controlled multicentre study in Singapore

Roxatidine acetate, a new H₂ receptor antagonist, was compared with ranitidine in the treatment of duodenal ulcers in a double-blind multicentre study. Eighty-four patients with endoscopically proven duodenal ulcer were randomized to receive 150 mg roxatidine acetate or 300 mg ranitidine at bedtime. Repeat endoscopy was performed after 4 weeks (25–33 days) and if the ulcer had not healed, another endoscopy was performed after a further 4 weeks of treatment. Using per protocol analysis 73.6% of ulcers treated with roxatidine healed at 4 weeks compared to 72.2% of ulcers treated with ranitidine (P=NS). The healing rates at 8 weeks were 92% with roxatidine and 83.3% with ranitidine (P=NS). Using equivalence tests, the healing rate of roxatidine was found to be equivalent to that of ranitidine within a 20% region. Roxatidine users took significantly less antacids than ranitidine users (P < 0.05). There were no significant adverse effects due to roxatidine or ranitidine. Roxatidine is a safe effective drug in the treatment of duodenal ulcers with a healing rate comparable to that of ranitidine.     

Randomised study of the influence of non-steroidal anti-inflammatory drugs on the treatment of peptic ulcer in patients with rheumatic disease.

Sixty-seven patients with rheumatic disease, treated with non-steroidal anti-inflammatory drugs (NSAIDs), entered a controlled trial with a diagnosis of duodenal (n = 51), gastric (n = 14), or gastric and duodenal (n = 2) ulcers. The main objectives of the study were a comparison of ranitidine and sucralfate in ulcer treatment, and to observe the influence of continued NSAID administration during peptic ulcer therapy. Ulcers healed within nine weeks in 52 patients. The mean healing time was similar in 27 patients given ranitidine 150 mg bd (4.9 weeks) and 25 patients given sucralfate 1 g qid (4.6 weeks). In patients with unhealed ulcers after nine weeks of treatment, healing was obtained in seven after further therapy for 3-9 weeks. Of the 30 patients who continued NSAIDs during treatment with either ranitidine or sucralfate, 23 ulcers healed (mean healing time: 5.0 weeks). Of 32 patients in whom NSAIDs were stopped, ulcer healing was documented in 29 (mean healing time: 4.6 weeks). The difference in healing rates was not statistically significant (p greater than 0.10). The outcome of ulcer treatment did not differ in patients with rheumatoid arthritis and patients suffering from osteoarthritis. During a 12 month follow up 14 symptomatic ulcer recurrences were recorded.     

Delayed gastric ulcer healing after extirpation of submandibular glands is sex-dependent

This study examines the effect of excision of the submandibular salivary glands, the main source of epidermal growth factor (EGF), and the role of gender on the healing of acetic acid-induced gastric ulcers in rats. In male rats excision of the submandibular glands delayed ulcer healing. At 15 and 25 days the unhealed ulcer areas were significantly larger in the sialoadenectomy group than in control animals, and fewer completely healed ulcers were seen in this group at 25 days. Ulcer healing in female rats was slower. At day 25 ulcers were healed in 12% of female rats with intact salivary glands, compared with 68% in males. Female rats also showed larger unhealed ulcer areas after sialoadenectomy than controls. We conclude that removal of the main source of EGF in the gastrointestinal tract is associated with a delay in healing of gastric ulcers. The significant difference in healing observed between female and male rats may be influenced by the known androgenic regulation of EGF production in the salivary glands.     

Histological maturity of healed duodenal ulcer and ulcer recurrence after treatment with omeprazole or cimetidine

Abstract We investigated the relationship between histological maturity of healed duodenal ulcer and ulcer recurrence after treatment with omeprazole or cimetidine for 4 weeks. The healing rates, 92.5 and 72.4% in omeprazole-treated and cimetidine-treated groups, respectively, showed no significant difference between groups ( P > 0.05). Histologically, the regenerating mucosa of healed ulcer was divided into three categories: good, fair and poor patterns. Of the healed cases, 22 (59.5%) of 37 omeprazole-treated and 12 (28.6%) of 42 cimetidine-treated ulcers achieved a good pattern, showing significant difference between groups ( P = 0.01). The recurrence rate at 3 months showed statistically significant difference ( P < 0.05) between two groups: 5.4% in omeprazole-treated and 23.8% in cimetidine-treated patients. During the period between 3 and 6 months after healing, the difference in recurrence rate between omeprazole-treated and cimetidine-treated groups was statistically not significant (12.5% and 25%, respectively, P > 0.05), though the cumulative recurrence rate at 6 months showed a significant difference between groups (17.6% vs 44.7%, P = 0.027). All the recurrent cases of both groups had a fair or poor pattern of regenerating mucosa. The difference in recurrence rate was statistically significant between the healed ulcers with a good pattern and that with a fair or poor patterns both at 3 months and between 3 and 6 months after healing ( P > 0.001 in each). We concluded that better histological maturity of regenerating mucosa may contribute to the lower early recurrence in omeprazole-treated cases than in cimetidine-treated cases.     

Gastric metaplasia of regenerating duodenal mucosa and deformity of duodenal bulb: A correlative study

The correlation between the presence and degree of gastric metaplasia of regenerating duodenal mucosa and the deformity of duodenal bulb was studied. Based on the endoscopically morphological patterns of bulb, the duodenal ulcers were divided into three types: type I, with a normal-shaped bulb; type II, with a mildly deformed bulb; and type III, with a markedly deformed bulb. A total of 159 patients with active duodenal ulcers were scheduled to be treated with H₂-receptor antagonists. Of these patients, 124 proved to have a healed duodenal ulcer 4 weeks after initial treatment upon follow-up endoscopic examinations. Two biopsies were taken from the centre of the ulcer scar when the ulcer was found to be healed for light microscopic study. Histologically, the degree of gastric metaplasia was divided into three grades: grades 0, 1 and 2. The results show that a healed duodenal ulcer with a normal-shaped bulb is not frequently accompanied by gastric metaplasia. However, a healed ulcer with a markedly deformed bulb has a high incidence and degree of gastric metaplasia, which may be easily colonized by Helicobacter pylori and thus develop an environment of easy recurrence. Therefore, a cycle of healing and recurrence may exist in patients with a duodenal ulcer and a markedly deformed bulb. Eradication of H. pylori may be the best way to break this cycle.     

The Histological Maturity of Regenerating Mucosa of Healed Duodenal Ulcer and Ulcer Recurrence after Treatment with H2-Antagonist

We investigated the relationship between the histological maturity of regenerating mucosa of healed duodenal ulcer and ulcer recurrence, after treatment with an H2-antagonist. Duodenal ulcer patients were given H2-antagonists (either cimetidine or famotidine) for 4 wk of therapy. Fifty-two (77.6%) of the 67 patients were healed endoscopically. The histological state of the regenerating mucosa of healed duodenal ulcer was divided into three categories: good, fair, and poor patterns. Of the 52 healed patients, 15 achieved a good histological pattern. None of these 15 patients had a recurrence 3 months later. However, nine of the 37 patients with a fair or poor pattern of regenerating mucosa had a recurrence 3 months after healing (p = 0.034). We concluded that a duodenal ulcer should be treated until the regenerating mucosa of the healed ulcer reaches a good histological pattern, so as to prevent the recurrence of the ulcer.     

Oral tripotassium-dicitratobismuthate in gastric and duodenal ulceration

One hundred ambulant outpatients with active, endoscopically proven peptic ulceration entered a double-blind trial of either tripotassium-dicitratobismuthate or placebo. Thirty-four patients had gastric ulceration, 56 had duodenal ulceration, three had both gastric and duodenal ulcers, and two had stomal ulceration. Five patients with gastric ulceration were withdrawn from the trial. Three patients with both gastric and duodenal ulceration and two patients with stomal ulceration were excluded from statistical analysis. After 28 days of tripotassium-dicitratobismuthate 94% of gastric ulcer patients had significant endoscopic healing (P less than 0.01). Although 75% of duodenal ulcers healed after 28 days of tripotassium-dicitratobismuthate, this was not statistically significant because of a 60% rate of healing with placebo. Tripotassium-dicitratobismuthate produced a significantly quicker symptomatic response in duodenal ulcer patients (P less than 0.01). No serious side effects were recorded, and patient acceptability was high. It is concluded that tripotassium-dicitratobismuthate is an effective agent for promoting gastric ulcer healing and for symptomatic relief in duodenal ulceration.     

Comparison of relapse rates and of mucosal abnormalities after healing of duodenal ulceration and after one year's maintenance with cimetidine or sucralfate: a light and electron microscopy study.

Forty six patients with endoscopically diagnosed duodenal ulceration were randomly allocated to treatment with either sucralfate 1 g qds (n = 24) or cimetidine 200 mg tds and 400 mg nocte (n = 22). When the ulcers healed, a maintenance dose of sucralfate 1 g bd or cimetidine 400 mg nocte was given for one year (or until relapse if earlier). Biopsies of duodenal mucosa adjacent to ulcer sites for light and electron microscopy were obtained before and after healing and again after one year's maintenance if the ulcer remained healed. Duodenal biopsies were also taken from 20 age and sex matched controls. Rates of healing and relapse during maintenance did not differ between the two treatments, although relapses occurred earlier with cimetidine. In the three year post-maintenance follow up period 10/13 cimetidine patients relapsed compared with four of 11 sucralfate patients (p less than 0.05), the relapses occurring significantly earlier in the cimetidine treated patients (p less than 0.05). Mucosal biopsies from both treatment groups still showed considerable abnormalities after healing. During maintenance, however, the sucralfate scores fell significantly (p less than 0.02) to near control levels unlike the cimetidine scores which remained raised at pretreatment values. The histological and ultrastructural changes were not predictive of later relapse. These findings favour the use of sucralfate in preference to cimetidine for maintenance treatment in the prevention of relapse of healed duodenal ulcers.