Duodenal Ulcer Recurrence Research Articles

Ulcer recurrence after treatment of Helicobacter pylori infections

Source Citation Graham DY, Lew GM, Klein PD, et al. Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer. A randomized, controlled study. Ann Intern Med. May

Helicobacter pylori and gastroduodenal disease.

Helicobacter pylori infection is now recognized as the primary cause of active chronic gastritis in humans. Most infected persons remain asymptomatic, but are at increased risk for the development of peptic ulcer disease and possibly gastric cancer. The pathogenesis of this infection is not well understood, but motility and urease activity are virulence factors in an animal model. The eradication of H. pylori infection is associated with resolution of gastritis and a decreased rate of duodenal ulcer recurrence.

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 > 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.

One week eradication regimen for Helicobacter pylori

Although Helicobacter pylori is both a frequent cause of gastritis and an important factor in duodenal ulcer recurrence, no treatment regimen exists that is completely safe and effective. We have studied a short eradication regimen of tripotassium dicitrato bismuthate 120 mg four times daily and amoxycillin 500 mg four times daily for seven days with metronidazole 400 mg five times daily for three days (days 5-7). 106 patients with peptic ulceration and non-ulcer dyspepsia, who were also infected with H pylori,were entered into the study. H pylori was successfully eradicated in 76/106 (72%) patients (median follow-up 9·3 months). The rate of eradication was higher among patients with metronidazole-sensitive H pylori (40/43, 93%). In 17/30 patients in whom eradication failed, pretreatment metronidazole-resistant strains were subsequently isolated. Side-effects were mild, the commonest (24/106, 24%) being taste disturbance with metronidazole. A one-week eradication regimen is a safe, effective, cheap, and well-tolerated treatment for metronidazole-sensitive H pylori.

Maintenance therapy with sucralfate in duodenal ulcer: Genuine prevention or accelerated healing of ulcer recurrence?

We sought to compare the efficacy of sucralfate to placebo for the prevention of duodenal ulcer recurrence and to determine that the efficacy of sucralfate was due to a true reduction in ulcer prevalence and not due to secondary effects such as analgesic activity or accelerated healing. This was a double-blind, randomized, placebo-controlled, parallel groups, multicenter clinical study with 254 patients. All patients had a past history of at least two duodenal ulcers with at least one ulcer diagnosed by endoscopic examination 3 months or less before the start of the study. Complete ulcer healing without erosions was required to enter the study. Sucralfate or placebo were dosed as a 1-g tablet twice a day for 4 months, or until ulcer recurrence. Endoscopic examinations once a month and when symptoms developed determined the presence or absence of duodenal ulcers. If a patient developed an ulcer between monthly scheduled visits, the patient was dosed with a 1-g sucralfate tablet twice a day until the next scheduled visit. Statistical analyses of the results determined the efficacy of sucralfate compared with placebo for preventing duodenal ulcer recurrence. Comparisons of therapeutic agents for preventing duodenal ulcers have usually been made by testing for statistical differences in the cumulative rates for all ulcers developed during a follow-up period, regardless of the time of detection. Statistical experts at the United States Food and Drug Administration (FDA) and on the FDA Advisory Panel expressed doubts about clinical study results based on this type of analysis. They suggested three possible mechanisms for reducing the number of observed ulcers: (a) analgesic effects, (b) accelerated healing, and (c) true ulcer prevention. Traditional ulcer analysis could miss recurring ulcers due to an analgesic effect or accelerated healing. Point-prevalence analysis could miss recurring ulcers due to accelerated healing between endoscopic examinations. Maximum ulcer analyses, a novel statistical method, eliminated analgesic effects by regularly scheduled endoscopies and accelerated healing of recurring ulcers by frequent endoscopies and an open-label phase. Maximum ulcer analysis reflects true ulcer recurrence and prevention. Sucralfate was significantly superior to placebo in reducing ulcer prevalence by all analyses. Significance (p <0.05) was found at months 3 and 4 for all analyses. All months were significant in the traditional analysis, months 2–4 in point-prevalence analysis, and months 3–4 in the maximal ulcer prevalence analysis. Sucralfate was shown to be effective for the prevention of duodenal ulcer recurrence by a true reduction in new ulcer development.

Medical treatment of duodenal ulcer: Acid inhibition or Helicobacter pylori eradication?

To ascertain whether acid inhibition or Helicobacter pylori (HP) colonization is the decisive factor in the healing of duodenal ulcer, we treated 54 patients with famotidine and carried out long-term follow-up. Helicobacter pylori colonization was found in 70.4% of patients before treatment. There were no differences in the pre-treatment characteristics between patients with HP positive or HP negative ulcers. The 4-week and 8-week healing rates after famotidine treatment were 72.5% and 82.4% respectively. No difference in HP colonization was found between patients with ulcer healed and those with ulcer not healed (78.4% vs 64.3% at 4th week and 77.3% vs 71.4% at 8th week, P greater than 0.05). In patients with ulcer healed at 4th week, the intragastric pH was raised significantly and the antral acute inflammation was less severe than those with ulcer not healed. Ulcer recurrence was found in 76.9% of patients within 1 year, but there was no difference in ulcer recurrence between the patients with positive or negative HP colonization at the time of ulcer healing. Our results suggest that duodenal ulcer healing and recurrence are closely related to acid inhibition rather than to HP colonization.

Nizatidine matches ranitidine in the prevention of duodenal ulcer recurrence

Nizatidine matches ranitidine in the prevention of duodenal ulcer recurrence

The evolution of peptic ulcer therapy. A role for temporal control of drug delivery.

The treatment of acid peptic disease has involved a series of attempts to control gastric acid secretion in order to heal and to prevent recurrence of duodenal ulcers. Early treatment attempted to heal by neutralizing gastric acid with diet modification, the Sippy diet, and Doll's milk drip. Just before the turn of the century, surgeons began performing gastric resections. In 1943, Dr. Lester Dragstedt performed the first truncal vagotomy to limit cholinergic stimulation of gastric acid secretion. This led to surgery that combined gastric resections with vagotomy. In 1970, the first parietal cell vagotomy was performed. This microsurgical technique limited vagal initiation of acid secretion while minimizing the impact on other gastrointestinal functions. By the 1960s, pharmacological intervention included antacids to neutralize acid and anticholinergics to reduce the amount of acid produced. These treatments varied in their effectiveness, and some of them caused significant side effects. In 1976, treatment of acid peptic disease began a new phase with the introduction of the first H2 receptor antagonist, cimetidine. Ranitidine, the second H2 receptor antagonist, produced greater acid suppression in the morning and at night with bid dosing than cimetidine with quid dosing. The knowledge that there is a circadian pattern in acid production, with higher levels between 10 PM and 2 AM, resulted in the development and use of a single evening dose of ranitidine. Ongoing research continues to investigate the effects of dose timing and the influence of more potent acid-suppressing agents. Finally, the issue of maintenance therapy and gastric acid secretion was addressed. The clinical advantage that ranitidine has over cimetidine in the prevention of ulcer recurrence can be attributed to its control of nocturnal acid suppression.

Impaired neutralizing capacity of duodenal mucosa following luminal acidification in recurrent duodenal ulcer.

To investigate the role of the mucus-bicarbonate barrier in the prevention of duodenal ulcer recurrence, duodenal mucosal neutralizing capacity and mucosal prostaglandin (PG) synthesis were examined in 5 normal controls (NC) and 12 duodenal ulcer (DU) patients. DU patients were divided into non-recurrent (NR,7) and recurrent (R,5) groups based on endoscopic follow-up study. The recovery time (RT) was significantly longer and the mucosal PGE2 synthesis was significantly lower in R than in NC and NR groups. There was a proportional correlation between mucosal PG synthesis and RT in DU These results indicate that impaired neutralizing capacity caused by reduced endogenous PG synthesis in duodenal mucosa may contribute to recurrence of DU.

Helicobacter pylori and Zollinger-Ellison syndrome

Helicobacter pylori (previously Campylobacter pylori) is almost invariably associated with chronic duodenal ulcer disease. The relationship between H. pylori infection and duodenal ulcer in Zollinger-Ellison syndrome is unknown. We investigated the frequency of H. pylori infection in Zollinger-Ellison syndrome and also what effect H. pylori infection had on gastric function in patients with Zollinger-Ellison syndrome. H. pylori infection was diagnosed based on a specific serologic (ELISA) assay based on high-molecular-weight cell-associated proteins of H. pylori. We studied 20 patients with Zollinger-Ellison syndrome; 15 men and 5 women ranging in age from 24 to 71 years, median age 51. Six Zollinger-Ellison syndrome patients had H. pylori infection compared to 100 consecutive patients with chronic recurrent duodenal ulcer disease (P less than 0.05). Pretreatment basal acid output in Zollinger-Ellison syndrome patients ranged from 7.9 to 95.0 mmol/hr, median 35.2. Pentagastrin-stimulated maximal acid output ranged from 8.5 to 132 mmol/hr; median 52.7. Acid secretion was lower in the H. pylori-infected patients than the uninfected patients (BAO 24.5 +/- 6.5 vs 45.4 +/- 6.6, and MAO 44.3 +/- 11.8 vs 67.9 +/- 10.7, for H. pylori infected vs uninfected patients, respectively). The difference in BAO was statistically significant (P less than 0.05). The present results indicate that H. pylori is not a major contributing factor in duodenal ulcer associated with Zollinger-Ellison syndrome. The association of a reduced BAO with H. pylori suggests that these findings may be related.

Treatment of Duodenal Ulcer with Sucralfate

Sucralfate attains a healing rate of about 79% for duodenal ulcer in 4 weeks, which is similar to the effects of cimetidine and ranitidine. Whereas cigarette smoking significantly affects duodenal ulcer healing by acid-reducing agents, the healing rates of smokers and non-smokers treated with sucralfate or colloidal bismuth are indistinguishable, suggesting an inherent advantage through the cytoprotective mechanisms of these agents. The 12-month relapse curves for duodenal ulcers initially healed with sucralfate and colloidal bismuth subcitrate closely overlap each other and are significantly lower than the curves for the histamine H2-receptor antagonists. These findings cannot be accounted for by clearance of Helicobacter pylori, on which sucralfate has little effect. Preliminary evidence suggests that the use of acid-reducing agents results in up-regulation of the parietal cells and may help to explain the differences in relapse rates. Sucralfate is superior to placebo and comparable to H2 antagonists in the prevention of duodenal ulcer recurrence.

The Site of Recurrent Duodenal Ulcer

The aim of this retrospective study was to determine the site of recurrent duodenal ulcer in relation to the site of the index ulcer. One hundred and thirty-five patients who had recurrent duodenal ulcer after documented healing of an index ulcer were studied. The recurrent ulcer was more likely to occur in the anterior bulb if the index ulcer was anterior (35 of 58 = 60%) than if the index ulcer was not anterior (29 of 77 = 38%, p less than 0.01). However, the likelihood of a recurrent ulcer on the posterior wall of the bulb was not significantly different whether the index ulcer was posterior (11 of 36 = 31%) or not (22 of 99 = 22%, p less than 0.24). Three of 20 patients (15%) who initially presented with bleeding bled again with their recurrent ulcers, compared with eight of 115 patients (7%) who first presented with dyspepsia only (p = 0.39). Thirteen patients were assessed independently by two endoscopists to determine ulcer site. Their assessments concurred for 12 (92%).

Oxygen-Derived Free Radicals and the Prevention of Duodenal Ulcer Relapse: A New Approach

This study investigated whether or not oxygen-derived free radicals are implicated in the mechanism of recurrence of duodenal ulceration. To this end, allopurinol (50 mg qds)--a hydroxyl scavenger and an inhibitor of xanthine oxidase which forms superoxide radicals--and dimethyl sulphoxide (DMSO, 500 mg qds)--a hydroxyl scavenger--were given orally. Three hundred and two consecutive patients with previous symptomatic, endoscopy-proven duodenal ulceration which had been shown endoscopically to have healed and who were smokers and social drinkers, were randomized to receive for one year either placebo, cimetidine 400 mg at bedtime, allopurinol, or DMSO. In two hundred and twenty patients evaluable for efficacy, the cumulative relapse at one year was: placebo 65%, cimetidine 30%, allopurinol 12% and DMSO 13%. Cimetidine was significantly effective (p less than 0.01); however, allopurinol and DMSO were equally efficacious and superior to cimetidine (p less than 0.05). In patients who relapsed, the ulcer recurrence tended to occur early on placebo and to be evenly distributed over the year on active therapy. In all the groups, the relative frequency of symptomatic to silent relapses was similar in the first and second halves of the year and was comparable among the groups. The results suggest that oxygen-derived free radicals are directly implicated in the mechanism of duodenal ulcer relapse and that removing the radicals reduces recurrence of this ulceration.

In vivo cell kinetics studies of the duodenum during and after healing of cysteamine‐induced duodenal ulcer in rats using bromodeoxyuridine incorporation

The present study investigated the defect of duodenal defence responsible for the tendency of recurrence of duodenal ulcer. Male Wistar rats were treated with cysteamine-HCl subcutaneously to induce duodenal ulcer, and bromodeoxyuridine (BrdU) was given intraperitoneally 1 h before laparotomy. Serial tissue sections and immunocytochemical staining of BrdU were done to study the cell kinetics during and after healing. Deep ulcers developed in the proximal part of the duodenum 24 h after cysteamine injection, and the ulcer was replaced by scar tissue 1 week later. BrdU-labelling index of normal duodenal mucosa in control rats was 30-34%. On the peripheral part of the regenerative mucosa, BrdU-labelling index increased from 1.5% to 26-27%, 1-4 weeks after injection and remained at this level thereafter. On the central part, except the most central area, the labelling index remained at 0% until 3 weeks, and was 15% 6 weeks after cysteamine treatment. It never achieved the level seen in control normal mucosa. The labelling rate of fibrous cells in scar tissue decreased from 28% to nearly 0% 1-4 weeks after the injection. It is concluded that both the ulcer scar and the regenerative mucosa do not achieve a mature state in the initial scarred stage; they need more time to reach a relatively mature condition. Moreover, the regenerative mucosa will be the weak, easily damaged part of the duodenum.

Clinical Review of Histamine2 Receptor Antagonists

Histamine2 receptor antagonists are beneficial in treating gastric and duodenal ulcers, gastroesophageal reflux, and hypersecretory states. Histamine2 receptor antagonists are helpful for the prevention of stress ulceration and recurrence of gastric and duodenal ulcer. Four histamine2 blockers are approved for clinical use: cimetidine, famotidine, ranitidine, and nizatidine. This review compares these agents in three areas: efficacy, adverse drug reactions, and drug interactions. Although limited published data exist for famotidine and nizatidine, both are as effective as the better-studied ranitidine and cimetidine when administered appropriately. Subtle differences exist among the four agents in the areas of drug interactions and adverse effects. Individual practitioners may decide if these differences are important enough to affect drug choice.

Acyclovir in the prevention of duodenal ulcer recurrence.

This study tests the hypothesis that reactivation of a latent herpes simplex virus infection may be a cause of recurrent duodenal ulceration. Patients with recently healed duodenal ulcer were entered into a double blind, randomised study of maintenance treatment with the antiviral drug acyclovir (400 mg bid) versus placebo, to determine if suppression of herpes virus infection would influence the natural history of the ulcer disease. One hundred and fifteen patients entered the trial and 76 patients completed it according to the protocol. Endoscopy was performed when ulcer symptoms recurred and at the end of the 25 week trial period. In the acyclovir group the cumulated relapse rate was 63% compared with 56% in the placebo group (NS). This result suggests that reactivation of herpes simplex virus is not a cause of recurrent duodenal ulcer.

3. Duodenal Ulcer Recurrence during Maintenance Treatment with Ranitidine

Three hundred and eighty-eight patients with duodenal ulcer disease received maintenance treatment with ranitidine for periods of time ranging from less than 1 year to more than 7 years. The product limit method was used to calculate the proportion of patients remaining free from symptomatic recurrence of ulcer. Intention-to-treat and efficacy analyses showed that for patients receiving ranitidine, 150mg/day, the cumulative remission rates were 95% at 1 year, 86-89% at 2 years, and 84-87% at 5 years, and for patients receiving ranitidine, 300 mg/day, the rates were 92-93% at 1 year, 88-90% at 3 years, and 82-90% at 5 years. An alternative method designed to analyse all patients, regardless of dose of ranitidine, showed that the remission rates were 94% at 1 year, 86% at 3 years, and 84% at 5 years. It is concluded that more than 80% of patients with duodenal ulcer disease remain free from symptomatic recurrence of ulcer during 5 years' maintenance treatment with ranitidine.

4. Risk Factors for Recurrence of Duodenal Ulcer during Maintenance Treatment with Ranitidine

During an analysis of the efficacy of long-term maintenance treatment with ranitidine in 388 patients with duodenal ulcer disease, the effect of risk factors for ulcer recurrence was assessed. The risk factors studied were age, gender, smoking habit, duration of ulcer disease, and acid secretory capacity. The survival curves of patients with and without the risk factor were compared by means of the logrank test, and multivariate analysis was carried out with the Cox proportional hazards model. Results show that none of the risk factors studied had a major effect on the rate of ulcer recurrence during maintenance treatment for periods up to 5 years. Males were shown to have a greater risk of recurrence than females (P<0.05), and young patients had a greater risk of recurrence than older patients (P<0.01). Smoking status (P>0.1), disease duration (P>0.1), and acid output (P>0.1) had no effect on the rate of ulcer recurrence.

Clinical Efficacy of Low Dose Antacids in the Treatment of Peptic Ulcer

Duodenal ulcer has generally been considered an acid-related disease. The original concept of therapy aimed to reduce acid secretion as much and for as long as possible. In several studies, a low dose antacid regimen has been reported to be superior to placebo and as effective as H2-receptor antagonists in the treatment of both duodenal and gastric ulcers. Similarly, a low dose antacid regimen has been shown to be as effective as H2-receptor antagonists in preventing duodenal ulcer recurrence.

Famotidine

Famotidine is a highly selective histamine H2-receptor antagonist. In healthy volunteers and patients with acid hypersecretory disease it is approximately 20 to 50 times more potent at inhibiting gastric acid secretion than cimetidine and 8 times more potent than ranitidine on a weight basis. As shown in placebo-controlled trials, famotidine is effective in healing both duodenal and gastric ulcers. Famotidine 20mg twice daily or 40mg at bedtime achieves healing rates and symptom relief similar or superior to those achieved by cimetidine 800mg daily or ranitidine 300mg daily in patients with peptic ulcer disease. Results of 1 placebo-controlled study suggest that famotidine prevents recurrence of duodenal ulcer, but comparative trials are needed to establish its relative efficacy in maintenance therapy. The few non-comparative trials conducted to date also suggest that famotidine 10 to 20mg twice daily may be effective in the treatment of gastritis and reflux gastro-oesophagitis. In comparative trials, famotidine was similar in efficacy to cimetidine in the treatment of upper gastrointestinal bleeding and to ranitidine in the prevention of pulmonary aspiration of acid. In patients with Zollinger-Ellison syndrome, the potency and long duration of action of famotidine may confer an advantage over other H2-receptor antagonists--in individualised doses (mean 0.33 g/day) famotidine successfully controlled acid secretion for up to 72 months in 1 study of such patients. Accumulated clinical evidence confirms that famotidine is very well tolerated and is free of the antiandrogenic effects infrequently reported with cimetidine. Moreover, famotidine is not associated with altered hepatic metabolism of drugs. Thus, famotidine is an effective, well-tolerated alternative to cimetidine and ranitidine. Famotidine is also promising as maintenance therapy for preventing recurrence of duodenal ulcer and as initial or maintenance treatment of gastric hypersecretory disorders, but further clinical experience, particularly in the long term, is needed to define the relative efficacy and tolerability of famotidine in these indications.