Comparison of low-dose antacids,cimetidine, and placebo on 24-hour intragastric acidity in healthy volunteers

Low-dose aluminium (Al) antacids are effective in promoting ulcer healing and symptomatic relief in peptic ulcer patients, although the effect on intragastric acidity is very weak. In this randomized, double-blind study, 24-hr intragastric acidity was compared in 11 healthy volunteers, treated with a low-dose Al antacid regimen (1 tablet four times a day), cimetidine (800 mg at bedtime) and placebo, using the double-dummy technique. Standardized meals were given at 8am, noon, and 5pm. Medication was given 1 hr after meals and at bedtime. Intragastric acidity was recorded with a nasogastric monocrystant antimony pH catheter, connected to an ambulatory digital data recorder. No significant difference in intragastric acidity was observed between antacid and placebo treatment. Treatment with cimetidine reduced circadian and nocturnal (but not diurnal) intragastric acidity significantly, as compared to both placebo and antacid treatment. The results support the hypothesis that Al antacids promote peptic ulcer healing by other mechanisms than acid neutralization.     

Comparison of the effects of ranitidine, cimetidine and placebo on the 24 hour intragastric acidity and nocturnal acid secretion in patients with duodenal ulcer.

Twenty-four hour intragastric acidity and nocturnal acid secretion were measured in 10 males with duodenal ulcer in four separate 24 hour studies, during which the subjects ate normal meals, had unrestricted physical activity, and consumed their customary quantities of tobacco. The medication consisted of either placebo, cimetidine 200 mg tds and 400 mg at night, or ranitidine 150 mg bd, or 200 mg bd. Ranitidine 150 mg bd decreased mean 24 hour hydrogen ion activity from 41.8 mmol/l to 13.1 mmol/l (-69%, P less than 0.001) and nocturnal acid output from 6.1 mmol/h to 0.6 mmol/h (-90%, P less than 0.01). This degree of inhibition was significantly greater than that due to cimetidine (P less than 0.001 for 24 hours acidity, less than 0.05 for night time acid output). Plasma concentrations of ranitidine were greater than the IC50 for more than eight hours after the 150 mg dose. Ranitidine 200 mg conferred no additional advantage. Ranitidine 150 mg bd should be tested in therapeutic trials.     

Effect of cimetidine on 24-hour intragastric acidity in normal subjects.

The effect of H2-receptor blockade on intragastric acidity was studied in nine normal males. The pH of their gastric contents was measured at hourly daytime and two hourly nighttime intervals for 48 hours. The subjects ate identical meals, drank identical volumes of fluid, and smoked the same number of cigarettes during the two study days. Their physical activity was unrestricted in a ward environment. Blood cimetidine and plasma gastrin were measured in serial blood samples. The nine subjects were treated in random sequence with cimetidine 0-8-1-0 g on one day and placebo capsules on the other. The drug was given in four divided doses: four subjects received it before, and five after, the three main meals. All took the fourth dose at bedtime. Replicate studies in an additional subject given placebo on both study days showed good reproducibility (r=0-80, P less than 0-01). Cimetidine therapy decreased intragastric acidity in all nine subjects. The decrease was similar in the two groups taking the drug before or after meals, mean 24 h intragastric hydrogen ion activity being lowered by 70 and 72% respectively. Nocturnal anacidity was recorded in only two of 45 samples. Administration of cimetidine before meals produced earlier and higher drug blood levels than post-prandial medication, but when it was taken after food the blood levels were highest at the time when the buffer capacity of the food was waning. Blood concentrations of cimetidine exceeded the secretory IC50 level for most of the time between doses. The results show that cimetidine 0-8-1-0 g/day in four divided doses produces a striking and consistent decrease of intragastric acidity. Although variation in the timing of the dose in relation to meals did not affect the decrease of acidity, the absorption data suggest that patients should take the drug after meals.     

Comparative study with ranitidine and cimetidine on gastric secretion in normal volunteers.

The inhibitory effect of ranitidine and cimetidine on pentagastrin stimulated volume, acid and pepsin secretion has been studied in eight healthy volunteers. Both compounds inhibit all measured components of gastric secretion in a dose dependent manner. On a molar basis ranitidine is on average 11.14 times for volume, 13.04 times for acid, and 9.74 times for pepsin secretion more potent than cimetidine as measured by the ID50-values.     

Comparison of cimetidine and ranitidine on 24-hour intragastric acidity and serum gastrin profile in patients with esophagitis

Twenty-four-hour intragastric pH and serum gastrin profiles were monitored in six male asymptomatic patients who previously were found to have esophagitis on endoscopy and biopsy. They received cimetidine 300 mg qid (C), ranitidine 150 mg bid (R), or placebo (P) for one week each, utilizing the Latin-square design. The mean BAO was 0.4 +/- 0.2 mmol/hr, and the pentagastrin-stimulated MAO was 21.2 +/- 3.2 mmol/hr. In the P-treated patients, the pH fluctuated between 1.8 and 3.5 and over 90% of the readings were less than pH 4. As compared to P, both C and R significantly suppressed H+ after breakfast, overnight, and over the 24-hr period. The mean pH after lunch was significantly higher in R than in P, but not in C. Over the 24-hr period, a higher percentage of the readings were above pH 4.0 in R as compared to C. During the night, 50% of the pH readings were above pH 4.0 in C and R, whereas in P 50% of the pH readings were less than pH 2.0. The integrated gastrin responses after each meal were similar in C and R and were greater than in P. The biphasic response of the ratio of H+ and gastrin (H+/G) following each meal was suppressed by both H2-receptor antagonists, with numerically lower values obtained in R than in C. This study suggests that ranitidine 150 mg bid is superior to cimetidine 300 mg qid in suppressing the 24-hr intragastric acidity.     

Continuous 24-hour intragastric pH monitoring in the evaluation of the effect of a nightly dose of famotidine, ranitidine and placebo on gastric acidity of patients with duodenal ulcer

In 11 duodenal ulcer patients, the antisecretory effects of bedtime famotidine 40 mg were compared to those obtained with ranitidine 300 mg and placebo by means of continuous 24-hour intragastric pH monitoring. The 24-hour areas under the curve of pH profiles of the two H2 blockers were significantly different from those related to placebo (p approximately 0 for ranitidine and p = 0.00001 for famotidine), but not from each other (p = 0.51). Onset and duration of the famotidine action, however, were respectively earlier and longer lasting (12 vs. about 9 h) than those of ranitidine. Famotidine was also significantly superior (p approximately 0) to ranitidine in keeping intragastric pH at high values (especially those comprised between 6 and 8 pH units), although theoretically equipotent doses of the two H2 antagonists were used.     

Effect of cimetidine, ranitidine, famotidine and omeprazole on hepatocyte proliferation in vitro

Recently reports have indicated that both cimetidine and ranitidine delay cell proliferation in rats following 70% partial hepatectomy and result in an increased mortality following this procedure. The present study was designed to determine whether three H2 blocking agents (cimetidine, ranitidine, famotidine) and a new, powerful antisecretory drug (omeprazole) specifically influence hepatocyte proliferation in primary culture. Hepatocytes were isolated from livers of normal male rats by the standard collagenase perfusion technique. Hepatic DNA synthesis and percent of labelled nuclei were determined after 48 h incubation. Hepatocytes in culture were incubated with the H2 blocking agents and omeprazole or with different concentrations of serum obtained from sham-operated or 70% hepatectomized rats treated or not with the same agents. Rats were injected intraperitoneally at 8:00 a.m. on two consecutive days. In hepatectomized rats, the first dose was injected at 8:00 a.m. immediately after surgery, the second, 24 h later. The serum of sham-operated or 70% hepatectomized rats that did not receive drugs served as control. No changes in DNA synthesis, percentage of labelled nuclei and transaminase were detected when the agents were added to the hepatocytes in culture at concentrations within the effective pharmacological dosage and 30 times higher. Similarly, no changes in these parameters were obtained when different concentrations of serum obtained from sham-operated rats treated with H2 blocking agents or omeprazole were added to the basal culture medium. However, a significant inhibition of DNA synthesis and of percentage of labelled nuclei was observed when hepatocytes were incubated in the presence of serum from 70% hepatectomized rats that had been treated with cimetidine or with ranitidine. The serum of 70% hepatectomized rats treated with famotidine and omeprazole had no effect on hepatocyte proliferation in vitro. No effect on transaminase was found in these conditions.     

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).     

Double blind comparison between cimetidine and gefarnate in cases of duodenal ulcer.

Thirty outpatients suffering from duodenal ulcer of recent onset were given cimetidine 1 g/day or gefarnate 250 mg/day for 6 weeks in a double blind trial, randomly balances between the groups. Endoscopic assessment was carried out at 4 and 6 weeks; patients healed after 4 weeks were withdrawn from the trial. In all parameters considered, cimetidine showed a highly significant difference. The healing rate at 4--6 weeks was 67--93% after cimetidine treatment and 27--53% after gefarnate treatment. The effect of cimetidine on the disappearance of symptoms, mainly the nocturnal ulcer pain, and on antacid consumption was greater than that after medication wity gefarnate. After 4--6 weeks of a full dose cimetidine regimen, both basal and pentagastrin stimulated gastric acid secretion were reduced and peptone meal stimulated serum gastrin increased; the basal gastrinaemia remained unchanged.     

Twenty four hour intragastric acidity and plasma gastrin concentration in healthy volunteers taking nizatidine 150 mg, nizatidine 300 mg, ranitidine 300 mg, or placebo at 21:00 h.

Nine healthy volunteers were studied on the seventh day of dosing at 21:00 h with nizatidine 150 mg (N 150), nizatidine 300 mg (N 300), ranitidine 300 mg (R 300), or placebo, given in a predetermined random order. The double-blind 24 hour studies, using the Royal Free Hospital standard protocol, simultaneously measured intragastric acidity and plasma gastrin concentration. Compared with placebo, subjects responded to dosing with each H2-antagonist by a significant decrease of 24 hour intragastric acidity (N 150-45%; N 300-49% R 300-56%; p less than 0.01) and a significant rise of plasma gastrin concentration (N 150 + 20%; N 300 + 27%; R 300 + 58%; p less than 0.01). All three drug regimens caused similar significant decreases of nocturnal acidity (N 150-72%; N 300-79%; R 300-85%; p less than 0.01) and increases of nocturnal plasma gastrin concentration (N 150 + 41%; N300 + 52%; R 300 + 80%; p less than 0.01). Dosing with ranitidine 300 mg at 21:00 h also caused a simultaneous significant decrease of morning acidity (-32%; p less than 0.05) with a significant increase of plasma gastrin concentration (+36%; p less than 0.05), but the antisecretory effects of nizatidine 150 or 300 mg at 21:00 h were only observed during the night, with no effect during the morning. No drug regimen had any effect on acidity or plasma gastrin in the afternoon or early evening.     

The effects of famotidine, 40 mg at night, on 24-hour intragastric acidity and plasma gastrin concentration in healthy subjects

The effects of 40 mg oral famotidine at 2115 h on 24-h intragastric acidity and plasma gastrin concentration were measured in a double-blind placebo-controlled study in 10 healthy subjects. The subjects were studied on the 7th day of treatment with either famotidine or placebo. Famotidine, 40 mg at night, caused a pulse of decreased intragastric acidity during the night, with a longer-lasting elevation of plasma gastrin concentration. However, in the latter part of the day there was complete recovery from the antisecretory effects of the drug, with normal intragastric acidity and normal concentrations of plasma gastrin.     

Effect of bedtime ranitidine on overnight gastric acid output and intragastric pH: dose/response study and comparison with cimetidine.

A dose/response study has been carried out in seven patients with endoscopically proven duodenal ulcers in symptomatic remission, measuring intragastric pH and gastric acid output overnight after a bedtime dose of ranitidine (75 mg, 150 mg, and 300 mg); and the results have been compared with placebo and with bedtime cimetidine 400 mg. The currently recommended ranitidine maintenance dose (150 mg) was the optimum because it was significantly more effective than ranitidine 75 mg in terms of intragastric pH but not of acid output, and there was no difference from 300 mg in terms of either measurement. It was also significantly more effective than the currently recommended cimetidine maintenance dose (400 mg) in terms of inhibiting overnight acid output (92% vs 80% inhibition, p less than 0.05), and of maintaining intragastric pH above 5 (100% vs 17% of the overnight period, p less than 0.001).     

Double blind controlled comparison of aspirin, allopurinol and placebo in the management of arthralgia during pyrazinamide administration.

Chinese patients with arthralgia during treatment with an antituberculosis regimen containing pyrazinamide were allocated at random to 3 anti-arthralgia treatment series in a controlled double-blind study. One series (18 patients) received soluble aspirin 2.4 g daily, the second (23 patients) allopurinol 200 mg daily, and the third (19 patients) placebo only, for 8 weeks. The response was assessed both by independent assessors and by the patients themselves using a diary card. The serum uric acid concentration was measured before and during anti-arthralgia treatment. The joints most commonly affected were the shoulders, the knees and the fingers, and symptoms and signs were in general neither severe nor protracted. For most of the patients in all 3 series the joint symptoms and signs improved during the 8 weeks, but a higher proportion of patients in the aspirin and placebo series than in the allopurinol series experienced improvement, this being most rapid in the aspirin series. Only in the aspirin series was the mean serum uric acid concentration lower during treatment than before it, and this effect was related to the dose in mg per kg. It is concluded that the arthralgia was often self-limiting, that aspirin had a small beneficial effect, that allopurinol, in the dosage studied, may have had a slightly deleterious effect, but that it would be worth studying larger dosages of allopurinol because the dosage studied did not affect the serum uric acid concentration.     

Control of the intragastric pH value in infection and peritonitis by ranitidine versus cimetidine. A double-blind study

12 patients of an intensive care unit on respirator with peritonitis respectively septic complications were treated with 300 mg/die Ranitidine or 2000 mg Cimetidine/die administered via perfusor infusion under the conditions of a randomized double blind study. Both groups under investigation were comparable in respect to age, sex and grade of risk of stress induced bleedings. With ranitidine under the dosage mentioned above, a prophylactic sufficient control, yet not a complete control of intragastric pH-value was accomplished. With Cimetidine as monotherapy, however, even under the high dosage of 2000 mg/die, no successful control of the intragastric pH could be achieved. With 3 patients even the combinations of 2000 mg Cimetidine/die and 2 X 10 mg Pirenzepine/die did not prove sufficient. Especially for intensive care patients with a difficult to regulate intragastric pH (patients with peritonitis, sepsis) Ranitidine according to our findings is to prefer to Cimetidine for the prophylaxis of bleeding of gastroduodenal lesions.     

Double blind, placebo controlled trial of metronidazole in Crohn''s disease.

A double blind study compared the efficacy of metronidazole in two doses (20 mg/kg, 10 mg/kg) with placebo in patients with Crohn's disease. One hundred and five patients participated but only 56 completed the 16 week study -21 were withdrawn for deterioration of symptoms, 17 for adverse experiences, and 11 for protocol violation. Significant improvement in disease activity as measured by the Crohn's disease activity index (metronidazole 20 mg/kg, 97 units; metronidazole 10 mg/kg, 67 units; placebo -1 unit, p = 0.002) and serum orosomucoid (metronidazole 20 mg/kg/day, 49; 10 mg/kg/day, 38; placebo, -9, p = 0.001)) were detected. Changes in C reactive protein concentrations did not achieve significance when all three groups were considered but were significant when all metronidazole treated patients were grouped and compared with the placebo treated patients (0.8 v -0.9, p less than 0.05). Although patients receiving metronidazole 20 mg/kg/day had a greater improvement in disease activity than those receiving 10 mg/kg/day (difference 30 units (95% confidence intervals -27-87), the small sample size may have precluded the detection of statistical significance. Preliminary analysis suggests that metronidazole was more effective in patients with disease confined to the large intestine or affecting both small and large bowel than in those with small bowel disease only. There were no differences in remission rates between metronidazole and placebo treated patients. We conclude that metronidazole warrants further assessment in the treatment of patients with active Crohn's disease.     

Prevention of duodenal ulcer occurrence. Double-blind comparison of ranitidine and cimetidine

We compared ranitidine and cimetidine in maintenance therapy to prevent duodenal ulcer recurrence over a period of 24 months. Endoscopic examination at the end of 12 months showed that the ulcers of 26 of 31 patients (84%) on ranitidine in a dose of 150 mg remained healed and of 10 of 13 (77%) patients on cimetidine in a dose of 400 mg at night remained healed. Thirty-four patients continued in an open evaluation of ranitidine in a dose of 150 mg at night for a further 12-month period, and during this time there were four further recurrences. Life table estimates of duodenal ulcer recurrence during the 2-year period showed no significant difference between the two forms of treatment.     

Evaluation of pirenzepine on gastric acidity in healthy volunteers using ambulatory 24 hour intragastric pH-monitoring.

The effect of pirenzepine on 24 hour intragastric acidity was studied in 10 healthy volunteers using ambulatory 24 hour intragastric pH-monitoring in a double blind crossover study. Tests were performed on the seventh day of ingestion of either placebo, 75 mg pirenzepine or 150 mg pirenzepine per day. The drugs were given at two doses at 8.30 am and 8.30 pm. Mean nocturnal hydrogen ion activity during placebo treatment was 68 mmol/l +/- 9 SEM and was reduced by 75 mg (26%, p less than 0.01) and 150 mg of pirenzepine (36%, p less than 0.01), respectively. Mean diurnal hydrogen ion activity was 32 mmol/l +/- 6 SEM and was not significantly reduced (p greater than 0.1) by either dose of pirenzepine (4% and 12% respectively). Thus, the effect of pirenzepine on intragastric acidity is small, even with high doses of the drug, and becomes apparent only during the night.     

Effect of cimetidine and pirenzepine in combination on 24 hour intragastric acidity in subjects with previous duodenal ulceration.

Intragastric pH was monitored during 24 hours in eight volunteers with duodenal ulcer disease in remission, while on placebo, cimetidine 400 mg bd, pirenzepine 50 mg bd, cimetidine 400 mg bd + pirenzepine 50 mg bd, cimetidine 200 mg bd + pirenzepine 25 mg bd. The control of intragastric acidity during the 24 hour period by the combination of low dose cimetidine and pirenzepine was significantly better than with cimetidine, or pirenzepine alone in full dosage. This difference was most apparent after breakfast but was still present after lunch when cimetidine had no significant effect. Combination treatment is a logical approach when continuous control of intragastric acidity is needed, but a three times daily regimen will be necessary to cover the 24 hours.