Comparison of cimetidine and tripotassium dicitrato bismuthate in healing and relapse of duodenal ulcers

A comparison between cimetidine and tripotassium dicitrato bismuthate liquid (TDB) in the treatment of endoscopically diagnosed duodenal ulcer by single-blind randomized trial in 48 patients has shown 18 (75%) out of 24 patients receiving TDB and 13 (54%) out of 24 patients receiving cimetidine healed after 4 weeks' therapy. Symptomatic improvement within 1 month was seen in 19 patients on TDB and 18 patients on cimetidine, but did not only occur in patients whose ulcers healed. On follow-up, endoscopically proven relapse occurred within 1 year in 47% of patients whose ulcers had healed during treatment with TDB in comparison with 60% of those healing on cimetidine.     

Tripotassium dicitrate bismuthate and ranitidine in duodenal ulcer. Healing and influence on recurrence

One hundred patients were entered into a double-blind, double-dummy comparison of tripotassium dicitrate bismuthate (TDB) versus ranitidine, to evaluate short-term healing rates, and successfully healed patients were then entered into a follow-up phase to observe relapse rates. At 4 weeks 84% of patients treated with TDB and 68% of those treated with ranitidine had healed. At 8 weeks these figures had risen to 96% and 90%, respectively (p = NS). After a year's follow-up study 84% of patients healed initially with ranitidine had relapsed, whereas in the case of patients healed initially with TDB the relapse rate was 67% (p less than 0.05). The results confirm that in the short term, TDB is as effective as ranitidine, whereas the significantly better protection against relapse offered by TDB compared with ranitidine underlines the importance of restoring mucosal defence, an approach that to date has been somewhat overlooked.     

Double blind multicentre comparison of omeprazole 20 mg once daily versus ranitidine 150 mg twice daily in the treatment of cimetidine or ranitidine resistant duodenal ulcers.

The purpose of the present study was to compare omeprazole 20 mg once daily and ranitidine 150 mg twice daily in healing duodenal ulcers unhealed by previous treatment with cimetidine greater than or equal to 0.8 g or ranitidine greater than or equal to 0.3 g daily for at least six weeks. In a double blind multicentre trial, 151 patients were randomly assigned to either omeprazole or ranitidine. Clinical assessments and endoscopies were carried out at two and four weeks. Patients characteristics were similar in both groups. Statistical analysis (chi 2 test) did not show any significant difference in healing rate (p greater than 0.20) irrespective of the method of calculation. On an 'intent-to-treat' analysis (n = 151), healing was: omeprazole 46.6%, ranitidine 43.3% at day 15 and omeprazole 70.7%, ranitidine 68.4% at day 29; and among the patients who completed treatment, healing was: omeprazole 48.3%, ranitidine 46.3% at day 15 (n = 125; 95% confidence interval of the difference--17 to 21) and omeprazole 79.6%, ranitidine 75.4% at day 29 (n = 115; 95% confidence interval of the difference--13 to 21). After a further four weeks treatment with omeprazole, healing occurred in 16/20 (80%) who still had active disease at day 29. Patients on omeprazole and on ranitidine experienced similar decrease in day time and night time epigastric pain and in heartburn. Multivariate analysis (logistic regression) did not indicate any influence on age, sex, smoking and alcohol habits, previous drug administered, duodenitis and duodenal erosions on the healing rate. In this model, healing rate was not significantly influenced by previous treatment duration (p = 0.09 at day 15 and p greater than 0.2 at day 29) but was significantly influenced by ulcer size (p = 0.04 at day 15 and p = 0.02 at day 29). Forty one patients complained of adverse events: 19 on omeprazole (four trial withdrawals), 22 on ranitidine (three trial withdrawals).     

Medium-dose antacids versus cimetidine in the short-term treatment of duodenal ulcer

Seventy-eight patients with endoscopically proven duodenal ulcer were randomly allocated to be treated with a medium dose of liquid aluminum-magnesium antacid (75 ml in five daily doses) or cimetidine (400 mg twice daily) for 4 weeks in a prospective double-blind, double-dummy study. Healing rates at completion of trial were 66.7% in the cimetidine-treated group and 71.8% in the antacid group (p, ns). Both treatments were equally effective in relieving ulcer symptoms. Among the patient variables considered, only cigarette smoking was found to have a significant negative effect on ulcer healing. These results indicate that medium doses of antacids are as effective as cimetidine in the short-term treatment of duodenal ulcer.     

Long-term low-dose antacid versus cimetidine therapy in the treatment of duodenal ulcer recurrence

The effect of cimetidine (400 mg at night) and of low-dose antacid (400 mg of aluminum hydroxide plus 400 mg of magnesium hydroxide four times a day) given alone or in combination was assessed in a double-blind double-dummy endoscopic trial on prevention of duodenal ulcer (DU). Seventy-five outpatients with healed DU were followed up clinically for 1 year and were checked endoscopically after 6 and 12 months of therapy or in case of symptomatic relapse. After 6 and 12 months, 25% and 41%, respectively, of patients treated with cimetidine alone experienced a relapse, compared with 42% and 54% of those treated with antacid alone and 25% and 43% of patients treated with the combination therapy. The differences are not statistically significant. No relevant side effects were observed in patients of any group. It is concluded that long-term prophylactic treatment of DU with low-dose antacid is as safe and effective as cimetidine treatment, whereas a combination of the two drugs does not achieve a therapeutic gain.     

Effects of cimetidine on the healing and recurrence of duodenal ulcers and gastric ulcers

The effects of cimetidine on the healing and recurrence of duodenal ulcers and gastric ulcers were compared. The extent of the acid secreting areas was examined by the endoscopic Congo red methylene blue test. Using the extent of acid secreting areas gastric ulcers were classified into ulcers with and without extensive acid secreting areas. Duodenal ulcers were all associated with extensive acid secreting areas. The gastric acid outputs in the basal state and after maximal stimulation with gastrin were highest in duodenal ulcers, and lowest in gastric ulcers without extensive acid secreting areas. Cimetidine treatment significantly promoted the healing of duodenal ulcers and gastric ulcers with extensive acid secreting areas when compared with placebo, but not of the gastric ulcers without extensive acid secreting areas. Cimetidine also significantly diminished the recurrence of duodenal ulcers, but not gastric ulcers with and without extensive acid secreting areas. These findings indicate that in Japan cimetidine promotes the healing of duodenal and gastric ulcers associated with high gastric acid production and prevents recurrence of duodenal ulcers, but has little or no influence on the healing and recurrence of gastric ulcers associated with low acid secretion.     

Efficacy of ranitidine and cimetidine in the treatment of gastric or duodenal ulcer resistant to an initial treatment with cimetidine. Multicenter controlled therapeutic trial

In a controlled clinical trial conducted in 28 centers, 354 ambulatory patients with a cimetidine-resistant duodenal or gastric ulcer (at least six weeks of treatment at a dose of 1 g/day) confirmed by endoscopy were allocated at random to either ranitidine or cimetidine treatment: 166 patients received cimetidine (1.6 g/day in 4 oral doses), and 188, ranitidine (0.3 g/day in 2 oral doses). The two groups differed significantly with regard to sex and history of gastrointestinal hemorrhage but not with regard to age, weight, history of peptic disease, history of perforated ulcer, duodenal/gastric ulcer ratio, number of smokers and alcohol consumers. The criterion of effectiveness was endoscopic healing of the ulcer after six weeks of treatment; in case of doubt, vital staining with methyl blue was performed. A significant difference was observed between the results of the two treatments in the duodenal group (p less than 0.05) but not in the gastric group, the healing rates being respectively 71 p. 100 and 65 p. 100 with ranitidine, and 59 p. 100 and 44 p. 100 with cimetidine. Twelve patients developed side-effects with a highly significant difference between the two groups: 11 patients under cimetidine and one patient under ranitidine (p less than 0.001). These results show the effectiveness of ranitidine as a complementary treatment in cimetidine-resistant peptic ulcers of duodenal location.     

Interaction of tripotassium dicitrato bismuthate with macrophages in the rat and in vitro

Tripotassium dicitrato bismuthate (TDB), De-Nol, heals peptic ulcers with an efficacy similar to the H2 antagonists. Tripotassium dicitrato bismuthate may also be effective in decreasing relapse rates. Its mode of action is unknown, but it was recently observed that TDB rapidly increased the number of macrophages in experimental ulcers. This might accelerate reparative processes, accounting for the drug's action. Using more sophisticated techniques we could not demonstrate any macrophage influx in response to single, or multiple, doses of TDB. Electron micrographs did demonstrate that monocytes, the precursors of macrophages, could internalize TDB. This process occurred rapidly in the presence of plasma where an avid TDB-protein interaction was observed. It has been suggested that such an interaction upon the ulcer may form a protective layer allowing mucosal regeneration to occur unhindered beneath. We believe our electron micrographs support this theory.     

Bismuth subsalicylate in the treatment of H2 blocker resistant duodenal ulcers: role of Helicobacter pylori.

Fifty nine patients with Helicobacter pylori positive duodenal ulcers that failed to heal after a six week course of treatment with H2 blockers were randomly assigned to one of the following three regimens: (i) bismuth subsalicylate, 600 mg three times daily (n = 19), (ii) ranitidine, 300 mg at night (n = 20), (iii) bismuth subsalicylate plus ranitidine (n = 20). Cumulative ulcer healing rates after four and eight weeks respectively were as follows: bismuth subsalicylate 74% (14/19) and 95% (18/19), ranitidine 40% (8/20) and 65% (13/20), bismuth subsalicylate plus ranitidine 80% (16/20) and 95% (19/20). Bismuth subsalicylate treatment was better than ranitidine at both four and at eight weeks (p less than 0.05). The clearance rates for H pylori after four weeks were: bismuth subsubsalicylate 58%, ranitidine 0%, bismuth subsalicylate plus ranitidine 55%. After stopping bismuth therapy bacterial recrudescence frequently occurred. After bismuth treatment 86% (19/22) of ulcers had healed if H pylori had been cleared, whereas only 65% (11/17) had healed if H pylori persisted (NS). This study shows that bismuth subsalicylate is more effective in the treatment of resistant duodenal ulcers than standard dose ranitidine. It may be that suppression of H pylori by bismuth subsalicylate promotes ulcer healing.     

Pirenzepine and cimetidine in the treatment of duodenal ulcer

The efficacy of pirenzepin--of anticholinergic effect--and the H2-receptor blocking cimetidine has been studied in duodenal ulcer with random, double blind fashion. Recurrence examinations were carried out 6 and 12 months following the treatment. 50 patients were given pirenzepin and 50 cimetidine. The average age of the patients was 44.5 and 43.8 years respectively. Of them 60 (24 + 36) were men and 40 (26 + 14) women. At the start, 6 weeks following the start 6 and 12 months after the finishing of the treatment gastroscopy was performed. In the course of the six-week-long treatment 38 (76%) of the pirenzepin taking patients and 36 (72%) of the cimetidine taking patients recovered. No significant difference was found between the efficacy of the both treatments. In the respect of the half and one year recurrence, no significant difference was observed between the two patient groups. Ten of the patients taking pirenzepin and 4 of those taking cimetidine complained of side effects. Dryness of mouth, visual disturbance in the former group and constipation in the latter one. On the basis of the examinations both secretion inhibitors were found equally suitable for the therapy of duodenal ulcer.     

Refractory duodenal ulcers (nonhealing duodenal ulcers with standard doses of antisecretory medication)

To evaluate possible differences between patients with refractory duodenal ulcers and those with duodenal ulcers that respond to standard doses of antisecretory medications, we determined basal acid outputs by nasogastric suction and daily smoking histories in 75 patients with endoscopically documented active duodenal ulcers. Patients were treated for at least eight weeks with standard doses of antisecretory medications and endoscopic healing or nonhealing was documented. Fifty-five patients that had complete healing of their duodenal ulcers had a mean basal acid output of 6.6 +/- 5.3 meq/hr, and 18/55 had daily cigarette smoking histories, whereas 20 patients that had nonhealing duodenal ulcers had a mean basal acid output of 20.0 +/- 9.6 meq/hr, and 8/20 had daily cigarette smoking histories. There were no significant differences between the two groups with regard to age, duodenal ulcer size, or cigarette smoking history. However, there were significant differences in male-female ratio (P less than 0.02) and in mean basal acid output (P less than 0.001), and all patients with nonhealing duodenal ulcers had basal acid outputs of greater than 10.0 meq/hr. Patients with nonhealing duodenal ulcers were treated with increased doses of ranitidine, mean 675 mg/day (range 600-1200 mg/day), and all had complete healing endoscopically documented. These results indicate that patients treated with standard doses of antisecretory medications with nonhealing duodenal ulcers have increased basal acid outputs of greater than 10.0 meq/hr, and the duodenal ulcers heal with increased doses of antisecretory medication.     

Predictors of duodenal ulcer healing during treatment with cimetidine.

A two phase study was performed to identify factors that influence the healing rate of duodenal ulcer. The study included an initial clinical trial in 145 patients and a second trial in a further 61 patients. All patients were prescribed cimetidine at a daily dose of 800 mg for six weeks. The factors examined were age, sex, inpatient or outpatient treatment, duration of present ulcer pain, past history of duodenal ulcer, smoking, drinking, the length of time it took for symptoms to resolve after beginning treatment, and the characteristics of the ulcers themselves. Eighty four per cent of the duodenal ulcers healed after six weeks. Using univariate and multivariate analyses, it was found that three factors indicated a significant delaying effect on healing: (1) symptoms that persisted two weeks after treatment had begun; (2) heavy smoking (20 or more cigarettes daily); and (3) severe narrowing of the duodenal bulb. Patients with none of the three unfavourable factors (n = 90) had a healing rate of 95.6% compared with patients with one (n = 45) or two or more (n = 10) factors, whose healing rates were 75.6% and 20.0% respectively (p less than 0.001). The corresponding figures in a second study were 88.9%, 55.0%, and 0%, respectively (p less than 0.001). A prognostic score based on these three factors represents the severity of duodenal ulcers with regard to healing in patients treated with cimetidine.     

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.     

Famotidine versus cimetidine in the treatment of acute duodenal ulcer. Double-blind, randomized clinical trial comparing nocturnal administration of 40 mg famotidine to 800 mg cimetidine

The efficacy of famotidine, a potent new long-acting H2 receptor antagonist, was compared with cimetidine in 78 patients with endoscopically proven acute duodenal ulcers. Additional antacid self-medication was allowed if needed for relief of pain. Thirty-nine patients were allocated to each group, receiving a nocturnal oral dose of either 40 mg famotidine or 800 mg cimetidine. Patients were reassessed by endoscopy at 2, 4 and 6 weeks if ulcer healing had not occurred at the respective earlier control date. A diary was kept to record the duration and intensity of day and night pain and the amount of antacids ingested. After 2 and 4 weeks of treatment healing rates were not significantly different for either group (famotidine 31 and 95%, cimetidine 23 and 85%, respectively). Pain relief was rapid in both treatment groups with a tendency for better response of nighttime pain in famotidine-treated patients. Antacid consumption was not different in either group. Famotidine appears to be an effective treatment for acute duodenal ulcer. Compared to cimetidine, healing rates and relief of pain are not significantly different.     

Treatment of 'cimetidine-resistant' chronic duodenal ulcers with ranitidine or cimetidine: a randomised multicentre study.

Forty patients with endoscopically proven persistent duodenal ulcer who had been treated for six weeks with cimetidine (1 g/day) were randomly allocated to receive a further six weeks' treatment with cimetidine (1 g/day) or ranitidine (300 mg/day). Ulcers healed in 12 of 19 patients given cimetidine (63%) and in 13 of 21 given ranitidine (62%); two patients on cimetidine and two on ranitidine dropped out. In the unhealed ulcer group the ulcer size was reduced in most patients. There was no change in basal acid output, peak acid output, plasma gastrin and pepsinogen I levels after either treatment. Clinical data, gastric function tests, and endoscopic features did not predict ulcer healing. Both treatments were effective in the relief of pain: 72% of patients with unhealed ulcers were asymptomatic at the end of the trial.     

Relapse prevention of duodenal ulcers with trimipramine, cimetidine, or placebo. A double-blind comparison

In a double-blind study 83 patients with duodenal ulcers, initially healed after treatment with either 1 g cimetidine daily or 50 mg trimipramine daily, were allocated by randomization to maintenance treatment with either 400 mg cimetidine daily, 25 mg trimipramine daily, or placebo for 6 months. Monthly clinical interviews were carried out and endoscopy performed whenever the symptoms suggested ulcer relapse. After 6 months the treatment was discontinued, and the patients were observed similarly for another 6-month period. After 6 months of maintenance treatment 88% in the cimetidine group versus 55% in the trimipramine group and 53% in the placebo group remained in symptomatic remission, yielding a significant difference between the cimetidine-treated patients and the two other groups (P less than 0.05). After a further 6 months of drug-free follow-up study, the percentages were 48% versus 29% and 29% in the cimetidine, trimipramine, and placebo groups, respectively (P less than 0.05). Thus maintenance treatment with trimipramine proved no better than placebo in preventing relapses of duodenal ulcers. Second, maintenance treatment with 400 mg cimetidine daily did prevent ulcer relapse, and, third, maintenance treatment with cimetidine for 6 months did not alter the long-term course of the duodenal ulcer disease.