Omeprazole and cimetidine in the treatment of ulcers of the body of the stomach: a double blind comparative trial. Danish Omeprazole Study Group.

OBJECTIVE--To see whether omeprazole was superior to cimetidine in healing ulcers of the body of the stomach. DESIGN--Double blind randomised parallel group study of omeprazole versus cimetidine for six weeks with assessment of healing at end of every second week. SETTING--Outpatient referrals in 11 centres in Denmark. PATIENTS--One hundred sixty one patients who satisfied the following criteria: age 18-79; one or more ulcers of body of stomach (that is, at or above the angulus) seen endoscopically within four days before study treatment; no H2 receptor antagonists taken within previous two weeks; no history of gastric surgery and no complications needing surgery; no concurrent treatment or disease that might confound assessment; oral contraception or an intrauterine device being used by women of childbearing age. INTERVENTIONS--Omeprazole 30 mg daily (one capsule in the morning) or cimetidine 1 g daily (one 200 mg tablet thrice daily, two tablets at bedtime) for six weeks. Inactive capsules and tablets provided so that all patients took same number of capsules and tablets daily. Compliance monitored by pill counts. END POINT--Endoscopic evidence of accelerated healing of type I gastric ulcers after four weeks of omeprazole. MEASUREMENTS AND MAIN RESULTS--Pain recorded on diary cards and patients assessed after two, four, and six weeks of treatment for clinical state and by endoscopy and biopsy and repeat laboratory tests. Twenty eight patients withdrawn during trial for violations of protocol. At two weeks healing rates were identical in the two treatment groups (omeprazole 41% (30/73 patients); cimetidine 41% (30/73]. At four weeks cumulative healing rates were 77% (53/69 patients) in the omeprazole treatment group and 58% (41/71) in the cimetidine treatment group (95% confidence interval of difference between groups 4% to 34%). By six weeks the cumulative healing rates in the two treatment groups differed by only 6% (60/68 patients (88%) given omeprazole; 53/65 (82%) given cimetidine). Log rank analysis with ulcer size used as covariable showed a significant difference in healing times in favour of omeprazole. There was no difference in the occurrence of pain relief between the two treatment groups. No serious clinical or biochemical side effects of treatment were noted. CONCLUSIONS--Omeprazole 30 mg daily accelerates healing of ulcers in the body of the stomach as compared with cimetidine 1 g daily. This effect is more pronounced in ulcers greater than 12 mm diameter.     

Controlled comparison of cimetidine and carbenoxolone sodium in gastric ulcer.

Fifty-four outpatients with endoscopically diagnosed benign gastric ulcer were allocated at random to treatment with either cimetidine 800 mg daily for six weeks or carbenoxolone sodium 300 mg daily for one week then 150 mg daily for five weeks. Ulcers were reassessed by endoscopy at the end of the trial. The endoscopist was unaware of the treatment and did not take part in the clinical care of the patients. Twenty-one of the 27 patients (78%) given cimetidine and 14 of the 27 (52%) given carbenoxolone had healed ulcers. Symptomatic response occurred earlier with cimetidine but was not significantly better. Unwanted effects were more common in the carbenoxolone group: 12 patients developed hypokalaemia, four of whom needed oral potassium supplements. The results suggest that histamine H2-receptor blockade is at least as effective as carbenoxolone sodium for benign gastric ulcer and produces fewer side effects.     

Cimetidine in patients with gastric ulcer: a multicentre controlled trial.

Forty-five adult outpatients with endoscopically confirmed gastric ulceration completed a double-blind trial of either cimetidine (1 g/day) or placebo. After six weeks 18 of the 23 patients receiving cimetidine showed complete ulcer healing compared with only six of the 22 patients receiving placebo. The cimetidine group also had fewer days with pain than the placebo group but the difference was not statistically significant. Cimetidine therefore seems to promote healing of gastric ulcers without severe side effects, although its effect on pain is less pronounced than in patients with duodenal ulcers.     

A new ulcer model, "unhealed gastric ulcers", induced by chronic treatment with indomethacin in rats with acetic acid ulcers.

The healing of experimental gastric ulcers induced in rats is consistently delayed upon chronic treatment with indomethacin. This study was designed to examine both the fate of such delayed ulcers and the effects of various antiulcer drugs on the delayed ulcers. Four-week treatment with indomethacin significantly delayed the healing of acetic acid ulcers. Such ulcers remained unhealed for up to 12 weeks after cessation of indomethacin treatment, and were thus designated as "unhealed ulcers". Two-week administration of sucralfate, cimetidine or omeprazole significantly reduced the ulcerated area, yet aluminum hydroxide had little or no effect. Four-week administration of sucralfate also extensively reduced the size of the "unhealed ulcers", yet aluminum hydroxide, cimetidine and omeprazole had an insignificant effect on "unhealed ulcers". In the 2 and 4 week sucralfate-treated group, the pH of the gastric contents was 4.0 vs. 1.7 and 4.5 vs. 2.1 in the control groups, respectively. Gastric acid secretion was extensively inhibited by cimetidine and omeprazole. It is concluded that prolonged indomethacin treatment results in the development of "unhealed ulcers" and that only sucralfate has a beneficial effect on such ulcers, irrespective of the length of the treatment.     

Therapeutic effect of cimetidine in patients undergoing haemodialysis.

Blood concentrations of cimetidine were measured and the therapeutic effect of the drug assessed patients undergoing maintenance haemodialysis. Thirteen patients were given a single oral 200-mg dose of cimetidine a mean of 2.7 hours before the start of dialysis. Dialysing for 6--12-6 m2 hours led to a mean fall of 71% in blood cimetidine concentration during haemodialysis. Nine patients with various upper gastrointestinal lesions diagnosed endoscopically were treated for up to six weeks with a reduced cimetidine dose of 200 mg 12-hourly; two patients received two courses of treatment. Repeat endoscopy after treatment disclosed satisfactory healing, and the drug did not accumulate. This lower dose regimen is recommended for patients receiving dialysis who develop upper gastrointestinal lesions for which a histamine H2-receptor antagonist is indicated.     

Prophylactic effect of cimetidine in duodenal ulcer disease.

Fifty-seven symptom-free patients with duodenal ulcer entered a double-blind trial to assess the prophylactic effect of cimetidine. Patients were randomly allocated to receive cimetidine 400 mg twice daily (29 patients) or placebo (28 patients). The trial was designed to imitate daily clinical practice, so duodenal ulcer disease was diagnosed by means of x-ray examination. Three patients from each group withdrew from the trial. All remaining patients continued to receive treatment for 12 months or until symptoms recurred. Three out of 26 patients suffered relapses during cimetidine treatment, compared with 20 out of 25 receiving placebo. No side effects were attributable to cimetidine. Long-term cimetidine treatment had no curative effect as relapses occurred soon after treatment was stopped. The estimated chance (cumulative remission rate +/- 2 SE) of remaining symptom-free 13 weeks after one year''s cimetidine treatment had been completed was 47 +/- 21%. Maintenance treatment with cimetidine is a suitable alternative to elective in surgery in patients with duodenal ulcer subjects frequent relapses. Further study is needed to establish the optimal duration and safety of prolonged cimetidine treatment.     

Long-term cimetidine does not alter serum prolactin.

The effect of repeated cimetidine ingestion on serum prolactin values was studied prospectively in 17 men with proven duodenal ulcers. These patients received 400 mg of cimetidine twice daily for 12 weeks but showed no alteration in their mean serum prolactin levels. Cimetidine-induced hyperprolactinaemia is not the explanation for the development of gynaecomastia in men exposed to this drug.     

Is there a place in the United Kingdom for intensive antacid treatment for chronic peptic ulceration?

Sixty nine patients with chronic duodenal or juxtapyloric ulceration were studied in a prospective double blind randomised trial to compare the efficacy of antacid and placebo at high (30 ml seven times daily) and low (10 ml as required) doses. After four weeks ulcers had healed in 12 out of 18 patients (67%) receiving "low dose" antacid compared with in six out of 17 patients (35%) receiving low dose placebo; ulcers had also healed in six out of 19 patients (32%) receiving "high dose" antacid compared with in two out of 15 patients (13%) receiving high dose placebo. Overall, the effect of antacid was superior to that of placebo in healing ulcers (p less than 0.05) and the effect of low dose treatment was superior to that of high dose treatment (p less than 0.01). There were no significant differences between antacid and placebo at eight weeks. Antacid was better than placebo in relieving pain, but the difference was not significant. Poor compliance and high incidence of diarrhoea made high dose antacid an impractical treatment. Low dose antacid was associated with a significantly better rate of healing than high dose antacid and was far better tolerated. This low dosage of antacid should be considered to be an active treatment in trials of ulcer healing.     

Influence of cimetidine on pharmacokinetics of propranolol.

Whole-blood propranolol concentrations were estimated for 12 hours after a single 80 mg oral dose was given in six patients taking cimetidine and two weeks after they had stopped the drug. Mean blood propranolol concentrations were higher throughout the sampling period when the patients were taking cimetidine than when they were not, and the difference was statistically significant between one and four hours (p less than 0.05). The mean relative bioavailability of propranolol, measured as the area under the concentration time curve, was significantly higher when the patients were taking cimetidine (p less than 0.025). The mean increase in bioavailability was 136.5 +/- 57.6%, and the results were consistent in each subject. It is concluded from these results that cimetidine reduces the hepatic first-pass extraction of propranolol.     

Cimetidine and gastric cancer: preliminary report from post-marketing surveillance study.

Widespread publicity has been given to te possibility that cimetidine treatment might cause gastric cancer. Preliminary data are given from a post-marketing surveillance study in four centres. A total of 9940 patients taking the drug entered study and 9504 were observed for at least a year. Seventy-four cases of gastric cancer were identified in those taking cimetidine, but 23 of these were diagnosed before the use of the drug and 29 others with advanced malignancy had received cimetidine within the previous six months only. Ten of the remaining 22 had gastric cancer diagnosed within a year of starting treatment, and 12 after more than a year; only four of the total group had histologically "early" cancer. The occurrence of gastric cancer a long time after starting cimetidine treatment cannot be explained in every case, but it is noteworthy that in control group (which is not directly comparable) gastric cancer was observed in eight patients. The hypothesis that cimetidine treatment predisposes to gastric cancer cannot be excluded by our findings: in our view, however, they do not support such an association.     

Comparison of the results of the treatment with pirenzepine combined with cimetidine and sucralfate of stomach ulcer resistant to cimetidine

Increased inhibition of gastric acid release through simultaneous blockade of H2-receptors and muscarine-receptors or administration of gastroprotective agent is theoretically justified in patients with peptic ulcer unresponsive to cimetidine. The study involved 70 patients with peptic ulcer previously treated with cimetidine in daily dose 1000 mg for 6 weeks without an effect. Patients were divided into two groups: group 1 treated with cimetidine plus pirenzepine, and group 2 given sucralfate in daily dose 4.0 g. Pirenzepine to patients of group 1 was given in a single dose of 50 mg before bedtime. Both groups were comparable in age, sex, disease onset, smoking, gastric acid secretion, and ulcer size. Healing was evaluated with endoscopic technique following 2 and weeks of therapy. Ulceration healed up within 2 weeks in 40% of patients treated with cimetidine combined with pirenzepine and in 31.4% patients treated with sucralfate. After 4 weeks, healing of ulceration was 71.4% and 68.6%, respectively. Large ulcers (over 1 cm in diameter) and previous partial gastrectomy did not affect healing rate. The obtained results suggest that administered therapies enable recovery in over 2/3 of patients with peptic ulcer unresponsive to a 6-week therapy with cimetidine alone.     

Endoscopic injection of adrenaline for actively bleeding ulcers: a randomised trial

A prospective randomised trial was performed to assess the efficacy of endoscopic injection of adrenaline for actively bleeding ulcers. Emergency endoscopy in 961 patients admitted for upper gastrointestinal haemorrhage identified 68 patients with actively bleeding ulcers. These 68 patients were randomised to receive either endoscopic injection of adrenaline or no endoscopic treatment. After endoscopy both groups were managed in an identical manner, and strict criteria for emergency operation were adhered to in both groups. Bleeding was initially controlled in all 34 patients assigned to the treatment group. Significantly fewer patients in the treatment group than in the control group needed emergency operations (five v 14, respectively). In addition, in the treatment group the median transfusion requirement was significantly less (three v five units of blood) and the median hospital stay shorter (six v eight days). No complications were observed with the injection of adrenaline, and the rate of healing of ulcers in those attending for endoscopy six weeks after discharge was similar in both groups (81% (17 out of 21 patients) in the treatment group v 79% (11 out of 14) in the control group).Injection of adrenaline is effective in stopping bleeding from actively bleeding ulcers.     

Pinch skin grafting or porcine dermis in venous ulcers: a randomised clinical trial.

Chronic venous ulcers are common, and even with effective compression or elevation large ulcers may take months to heal. Pinch skin grafting may allow healing from epithelial islands throughout the surface area of the ulcer, and a prospective randomised trial was therefore conducted comparing this treatment with porcine dermis dressings. Most patients were treated as outpatients, 25 ulcers being randomised to treatment with pinch skin grafts and 28 to treatment with porcine dermis. Though the groups were well matched, the mean healing rate in the first week was 15 cm2 for pinch skin grafts compared with 3.5 cm2 with porcine dermis (p less than 0.02). By life table analysis 64% of ulcers treated by pinch grafts were healed at six weeks and 74% by 12 weeks compared with 29% and 46% of ulcers, respectively, treated with porcine dermis dressings (chi2 = 4.1; p less than 0.05). All ulcers that failed to heal within 12 weeks included an area posterior to the medial malleolus, where local compression may have been inadequate. Pinch skin grafting improves the rate of healing in large venous ulcers and is a simple technique that may be performed as an outpatient procedure under local anaesthesia.     

Highly selective vagotomy and duodenal ulcers that fail to respond to H2 receptor antagonists

A study was conducted to see whether patients with duodenal ulcers that failed to heal in response to H₂ receptor antagonists had a higher incidence of recurrent ulceration after highly selective vagotomy than patients whose ulcers healed with these drugs. Between 1977 and 1983, 157 patients had a highly selective vagotomy for uncomplicated duodenal ulcer; in 57 patients the ulcer had failed to heal despite treatment with H₂ receptor antagonists (refractory group), 19 patients had developed recurrent ulceration while receiving maintenance treatment, 67 patients had remained healed while taking H₂ receptor antagonists but suffered frequent relapses when treatment was stopped, and 14 patients had not been given these drugs before operation. The overall incidence of recurrent ulceration was 6% after two years and 11% after five years of follow up. In the refractory group, however, the incidence of recurrent ulceration was 18% at two years and 34% after five years, whereas the incidence of recurrence was only 1.5% at two years and 3% after five years in patients whose ulcers had healed with H₂ receptor antagonists. Resistance to H₂ receptor antagonists was not related to preoperative basal or peak acid output but was related to cigarette smoking. Factors associated with recurrent ulceration after highly selective vagotomy were basal acid outputs before and after operation, cigarette smoking, and the surgeon who performed the operation.Duodenal ulcers that fail to respond to H₂ receptor antagonists represent a more severe ulcer diathesis, for which highly selective vagotomy is less effective.     

Treatment of diabetic neuropathy by decompression of the posterior tibial nerve

A series of 58 operations on 36 patients were performed for decompression of the posterior tibial nerve for the treatment of diabetic neuropathy. Preoperative symptoms included lack of sensation, pain, or both. Eleven of the 36 patients had neurotrophic ulcers, which were treated simultaneously. The operation was found to be effective for relief of pain in 24 of the 28 patients with that complaint (86 percent). Restoration of sensation was less consistent with improvement noted in 18 of the 36 patients (50 percent). The follow-up period ranged from 12 to 84 months (mean, 32 months) and five patients had some degree of recurrent symptoms. No patient has developed a new ulcer after nerve decompression. Wound complications were minimal (12 percent), even though ulcers were treated simultaneously. No patient required surgical treatment for the decompression incision, although one did require hospital admission for treatment of a wound infection. In general, the procedure seemed to be a worthwhile treatment, which should be considered ill selected diabetics with symptomatic neuropathy.     

Randomised controlled trial of short term treatment to eradicate Helicobacter pylori in patients with duodenal ulcer.

OBJECTIVE--To determine whether one week''s drug treatment is sufficient to eradicate Helicobacter pylori in patients with duodenal ulcer. DESIGN--Single blind, randomised controlled trial. SETTING--Specialised ulcer clinic in a teaching hospital. PATIENTS--155 patients with H pylori and a duodenal ulcer verified endoscopically which had either bled within the previous 24 hours or was causing dyspepsia. INTERVENTIONS--Patients were allocated randomly to receive either omeprazole for four weeks plus bismuth 120 mg, tetracycline 500 mg, and metronidazole 400 mg (all four times a day) for the first week (n = 78), or omeprazole alone for four weeks (n = 77). Further endoscopy was performed four weeks after cessation of all drugs. MAIN OUTCOME MEASURES--Presence or absence of H pylori (by urease testing, microscopy, and culture of antral biopsy specimens), duodenal ulcer, and side effects. RESULTS--Eradication of H pylori occurred in 70 (95%) patients taking the four drugs (95% confidence interval 86% to 97%) compared with three (4%) patients taking omeprazole alone (1% to 11%). Duodenal ulcers were found in four (5%) patients taking the four drugs (2% to 12%) and in 16 (22%) patients taking omeprazole alone (14% to 32%). Mild dizziness was the only reported side effect (six patients in each group) and did not affect compliance. CONCLUSIONS--A one week regimen of bismuth, tetracycline, and metronidazole is safe and effective in eradicating H pylori and reduces the number of duodenal ulcers four weeks after completing treatment.     

Recurrent breast cancer treated with the antioestrogen tamoxifen: correlation between hormonal changes and clinical course.

Forty-five post-menopausal women with recurrent breast cancer were treated with the antioestrogen, tamoxifen, 20 mg twice daily. Clinical assessment after 12 weeks indicated that 18 (40%) showed some remission. Gonadotrophins were suppressed within two weeks to relatively constant concentrations within the post-menopausal range, responses to luteinising hormone-releasing hormone (LH-RH) did not change, and androgen concentrations remained within the normal range in all patients. Oestradiol concentrations rose steadily only in women in whom treatment failed. Serum prolactin concentrations were raised in 18 out of the 44 (41%) patients in whom they were measured; 13 of these did not respond to treatment. Treatment did not change the average prolactin concentration when this was within the normal range, but it significantly reduced prolactin concentrations in hyperprolactinaemic patients--within two weeks (P less than 0-01) in those who responded well and by six weeks (P less than 0-05) in those who showed no remission. Among patients with normal prolactin values the release of prolactin after thyrotrophin-releasing hormone was significantly greater in those with no remission than in those who responded to tamoxifen. Responses in those with hyperprolactinaemia were reduced to about half the control values, and again this change occurred faster in those who were successfully treated. Patients therefore seem to have a better chance of responding to anti-oestrogen treatment if prolactin secretion is low.     

Effect of cimetidine on upper gastrointestinal bleeding after renal transplantation: a prospective study.

In 97 consecutive patients undergoing renal transplantation the incidence of upper gastrointestinal bleeding was registered over 180 days after allocation to treatment with either cimetidine or placebo. Bleeding episodes occurred in 12 patients, 11 of whom were receiving placebo and only one cimetidine (p less than 0.01). All bleeding episodes occurred during the first month after allotransplantation. Treatment with cimetidine did not lead to an increased incidence of rejection of the allograft. It is concluded that cimetidine is effective and safe in protecting against upper gastrointestinal bleeding after renal transplantation.     

Cimetidine for duodenal ulceration in patients undergoing haemodialysis.

Peptic ulcer is a common problem in advanced renal failure, but most drugs for ulcers are hazardous in this condition. In a small open study cimetidine was given to nine patients with acid hypersecretion and endoscopically diagnosed duodenal ulceration who were undergoing haemodialysis. The patients obtained good pain relief and suffered no serious side effects. Both basal and stimulated acid output fell considerably and the plasma gastrin response to food increased during treatment. Two patients with recurrent vomiting during haemodialysis had a striking response to cimetidine, which suggested that such vomiting may be acid-mediated in some patients. These preliminary results suggest that cimetidine may prove to be an advance in the management of peptic ulcer in uraemic patients.     

Recurrent oral ulceration treated with Mysteclin: a controlled study.

Twenty patients with recurrent oral ulceration participated in a placebo-controlled, double-blind trail of Mysteclin syrup (tetracycline hydrochloride and amphotericin) used as a mouthwash. Though a small, consistent improvement occurred with placebo, there was a significant reduction in mean pair scores and numbers of new ulcers recorded daily during the active-treatment periods, the effect lasting for at least four weeks after treatment was stopped. In contrast to topical steroid preparations, Mysteclin syrup is efficacious when begun at any stage of the disorder and is not associated with adverse systemic effects.