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.     

Effects of cimetidine and poldine on nocturnal gastric secretion in duodenal ulcer.

Cimetidine inhibited nocturnal secretion of acid but only slightly inhibited the nocturnal secretion of pepsin in patients with duodenal ulcer. Administration of cimetidine (200 or 400 mg), together with an anticholinergic drug (poldine), augmented the inhibition of the nocturnal secretion of acid and of pepsin. The combination of an H2-receptor-blocking drug with an anticholinergic drug will have therapeutic application in the management of duodenal ulceration.     

Nocturnal gastric acid secretion in duodenal ulcer: inhibition by cimetidine

The inhibitory effect of cimetidine 200 mg, cimetidine 400 mg, cimetidine 200 mg + oxyphenonium bromide 10 mg and placebo was studied on nocturnal gastric acid secretion in 10 patients with duodenal ulcer. Each patient was studied over a period of four nights and trial medication was given in a randomized sequence. Cimetidine in both doses significantly inhibited the nocturnal gastric acid secretion. The drug reduced both the H+ concentration and gastric juice volume but the reduction of H+ concentration was more impressive. Mean percentage inhibition of nocturnal acid output with cimetidine 400 mg (89.6 +/- 2.868) was significantly higher than cimetidine 200 mg (80.3 +/- 4.085; p less than 0.01). Combination of cimetidine 200 mg and oxyphenonium bromide 10 mg was significantly better than cimetidine 200 mg alone (p less than 0.05) and this combination produced inhibition of gastric juice volume, H+ concentration and acid output comparable to cimetidine 400 mg.     

Total 24-hour gastric acid secretion in patients with duodenal ulcer. Comparison with normal subjects and effects of cimetidine and parietal cell vagotomy

The purposes of these studies were as follows: (a) to compare gastric acid secretion throughout an entire 24-h period in 8 patients with duodenal ulcer disease and in 7 normal subjects, and (b) to determine in duodenal ulcer patients to what extent total, 24-h acid secretion was reduced by oral cimetidine (n = 7) or parietal cell vagotomy (n = 7). Basal, interprandial, and nocturnal acid secretion were measured by gastric aspiration, whereas acid secretion in response to breakfast, lunch, and dinner was measured by in vivo intragastric titration. Total, 24-h acid secretion averaged 408.3 +/- 61.7 mmol in duodenal ulcer patients and 208.3 +/- 18.5 mmol in normal subjects (p less than 0.02). Acid secretion was higher in duodenal ulcer patients than in normal subjects during both day (p less than 0.01) and night (p less than 0.05). Cimetidine (400 mg twice daily) significantly (p less than 0.001) reduced total, 24-h acid secretion in duodenal ulcer patients to 235.3 +/- 58.6 mmol, a rate that was not significantly different from 24-h acid secretion in normal subjects. On the other hand, total, 24-h acid secretion averaged only 86.7 +/- 20.7 mmol after parietal cell vagotomy, a rate that was significantly lower than 24-h acid secretion in normal subjects (p less than 0.001) and in duodenal ulcer patients receiving cimetidine (p less than 0.05). These studies indicate that patients with duodenal ulcer disease secrete excessive amounts of gastric acid during the day and night and throughout an entire 24-h period. A twice-daily 400-mg dose of cimetidine reduces 24-h acid secretion in duodenal ulcer patients to nearly normal rates, whereas parietal cell vagotomy reduces acid secretion to well below normal rates.     

Inhibitory effect of cimetidine on gastric acid secretion vagally activated by physiological means in duodenal ulcer patients.

Vagal activation of gastric acid secretion by modified sham feeding in six patients with duodenal ulcer produced a peak acid response amounting to 52% of the peak acid output after pentagastrin stimulation (PAOpg). Cholinergic reflex stimulation of gastric acid secretion by fundic distension in another six patients with duodenal ulcer produced a peak acid response of 45% of PAOpg. Intravenous infusion of cimetidine in a dose of 100 mg/h markedly inhibited the acid sham feeding response by 90-100% and almost abolished the acid response to fundic distension. The results suggest that gastric acid secretion evoked by physiological vagal activation in man is profoundly inhibited by H2-receptor blocking agents.     

Effects of bombesin on gastrin and gastric acid secretion in patients with duodenal ulcer

The effect of bombesin, a possible neurotransmitter of gastrin release, upon gastrin and gastric acid secretion was investigated in 25 patients with duodenal ulcer and in 16 normal subjects. In patients with duodenal ulcer bombesin (10 ng/kg/min) produced an increase in plasma gastrin output (median 22·4 (range 7·5-75·8) pmol/l/min) similar to that obtained in normal subjects (median 24·4 (range 5·8-56·5) pmol/l/min), whereas gastrin stimulated by a meal was significantly higher in the group of patients with duodenal ulcer (median 20·7 (range 9·2-42·9) vs 16·2 (range 3·4-22·2) p<0·05). Peak acid output induced by bombesin was significantly higher in patients with duodenal ulcer than in normal subjects (median 24·4 (range 9·0-63·8) vs 14·0 (range 3·0-24·8) mmol/h, p<0·05) despite identical gastrin outputs. The ratio (%) obtained by dividing the acid secretory response to bombesin by the response to pentagastrin, however, was similar in both normal subjects and patients with duodenal ulcer (median 55 (range 20-116) vs 58 (range 31-95) respectively). The difference between the gastrin response to food and bombesin could be explained by the fact that bombesin releases gastrin directly, whereas a protein meal involves several mechanisms (neural, peptidergic, paracrine, endocrine), either stimulatory or inhibitory. The above results indicate that a higher concentration in antral and/or duodenal gastrin is unlikely to be present in patients with duodenal ulcer. An increased parietal cell mass could explain the higher gastric acid response after bombesin infusion in our group of patients with duodenal ulcer.     

Effect of smoking on gastric acid secretion in patients with duodenal ulcer

The effect of smoking on gastric secretion was studied in 15 consecutive patients with duodenal ulcer--six normosecretors (basal acid output less than or equal to 3 mEq/h), and nine hypersecretors (basal acid output greater than 3 mEq/h). The volume, acid output, acid concentration, and pH of the gastric juice measured before, during and after 1 h of smoking did not show any significant difference in these patients taken as a single group, or when the normosecretors and hypersecretors were analysed as separate groups (P greater than 0.05 for each parameter in each group). The higher acid output before and during smoking in hypersecretors than in normosecretors was due to the higher acid concentration in the gastric juice (P less than 0.01). Study of the pH curves of the gastric juice after acute smoking showed that hypersecretors had a lower pH for a longer duration compared with normosecretors. This could make the hypersecretors with a history of chronic smoking more prone to developing duodenal ulcer.     

Effects of parenteral secretincholecystokinin and of duodenal acid perfusion on gastric secretion in duodenal ulcer patients

The effect of parenteral secretin-cholecystokinin and duodenal acid perfusion on brothstimulated gastric acid secretion was studied in 11 duodenal ulcer patients. Statistically significant inhibition occurred in both experimental conditions. The effect of secretincholecystokinin was more marked than the effect of duodenal acid perfusion. A poorly responsive subgroup of patients appeared to be responsible for the diminished inhibitory effect of duodenal acid perfusion. In this poorly responsive group there was a diminished duodenal volume response as well as diminished duodenal acid clearing. We conclude that there may exist a diminished release of gastrointestinal hormones such as secretin and cholecystokinin in certain duodenal ulcer patients.Presented in part at the meeting of the American College of Physicians, Pittsburgh, Pennsylvania, June 1972; and published in abstract in Gastroenterology 62:729, 1972, and in Clinical Research 24:565A, 1976.     

24-hour intragastric acidity and nocturnal acid secretion in patients with duodenal ulcer during oral administration of cimetidine and atropine.

Cimetidine markedly inhibits gastric acid secretion, but from the therapeutic point of view it is important to know whether concurrent treatment with an anticholinergic increases its effect. This possibility has been investigated by measuring the 24 h intragastric acidity and nocturnal output of acid in four duodenal ulcer patients, each receiving on separate occasions cimetidine 1 g/day and placebo, atropine 2-4 mg/day and placebo, cimetidine and atropine, or two placebos. Cimetidine alone decreased mean hourly hydrogen ion activity by 63% of control values, decreased mean hourly hydrogen ion concentration (total acid) by 41%, inhibited nocturnal acid secretion by 83% and resulted in half the nocturnal samples being anacidic. Atropine alone had no effect when compared with control and combined treatment with both drugs was not superior to cimetidine alone. Atropine did not affect the absorption or urinary excretion of cimetidine. Fasting serum gastrin concentrations were not changed by any of the treatments. At the doses studied, the combination of cimetidine with an anticholinergic appears to offer no advantages over treatment with the H2-antagonist alone. Cimetidine is the only potent anti-secretory drug that does not cause acute side-effects and this important advantage would be lost if it were given with a maximal dose of an anticholinergic.     

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.     

Effect of cimetidine on augmented gastric blood flow in duodenal ulcer patients.

Blood flow in the human stomach was measured during operation with a 85Krypton washout method which made simultaneous determinations of total blood flow and intramural flow distribution possible. The antrum and the corpus of the stomach could be investigated separately. Eleven patients with duodenal ulcer disease were studied during pentagastrin infusion and after the addition of cimetidine, 3 mg/kg bw, to evaluate the effect of the drug on augmented gastric blood flow. Eight recordings were made over the corpus of the stomach and three recordings over the antrum. Cimetidine caused a 66 +/- 5% decrease (mean +/- SE; range 56-86) in acid secretion and a 62 +/- 5% decrease (range 44-91) in the corpus mucosal blood flow within 15 minutes. Changes were only seen in the acid secreting part of the stomach while the antral circulation remained unaltered. It is concluded that the decrease in pentagastrin induced vasodilatation in the stomach seen after giving cimetidine was secondary to an inhibition of acid secretion.     

Effect of an antacid containing calcium on gastric acid secretion, in patients with duodenal ulcer

In eight fasting men with duodenal ulcer disease, oral administration of therapeutic dose of 49,5 mEq of neutralizing potency of either sodium bicarbonate or a preparation of calcium hidroxogluconaluminate did not produce significant increase in gastric acid secretion above basal levels for 90 minutes. This data support the conclusion that this specific antacid-containing calcium preparation does not stimulate the gastric secretion of acid.     

Effect of cimetidine on pentagastrin-stimulated gastric secretion before and after proximal gastric vagotomy for duodenal ulcer.

Nine patients with duodenal ulcer were studied before and 2--3 months after proximal gastric vagotomy (PGV). Infustion or cimetidine, 1.2 mg.kg-1h-1, reduced mean gastric acid output, in response to infusion of 1.5 microgram.kg-1h-1 of pentagastrin, by, on an average, 79.4% before and 79.1% after vagotomy. The corresponding values for pepsin output were 66.5% before and 77.0% after the operation. The values were not statistically different. Thus, in terms of per cent inhibition, cimetidine was similarly effective before and after PGV. No correlation was found between per cent reduction of acic output by vagotomy and by cimetidine. The effect of the drug was added to that of the vagotomy. Patients with relapse ulcer after vagotomy are therefore interesting candidates for cimetidine treatment.     

Interaction of calcium and gastrin on gastric acid secretion in duodenal ulcer patients

A dose response study of the effect on gastric acid secretion of synthetic human gastrin-17 in doses of 50,200, and 500 ng/kg/h was performed in eight healthy volunteers and in eight patients with duodenal ulcer. The study was repeated on a separate day during intravenous infusion of calcium gluconate (0.1 mmol Ca2+/kg/h). In healthy subjects the acid response to the combined infusion of synthetic human gastrin and calcium did not significantly exceed the response to synthetic human gastrin alone, in contrast with patients with duodenal ulcer in whom the combined infusion did significantly improve acid output compared with infusion of synthetic human gastrin alone. The dose of synthetic human gastrin required for half maximal acid response (D50) was reduced in both groups but significantly more in patients with duodenal ulcer. No difference in serum gastrin concentrations or in serum calcium concentrations were found. It is hypothesised that extracellular calcium plays a role in gastrin stimulated acid secretion in man and that patients with duodenal ulcer are more sensitive to this calcium dependent mechanism than non-duodenal ulcer subjects.     

Effect of doxepin on basal gastric acid and salivary secretion in patients with duodenal ulcer

We compared the effect of 50- or 100-mg doses of oral doxepin or a placebo on basal gastric acid secretion, salivary flow, and pulse rate in seven asymptomatic patients with chronic duodenal ulcer disease. Acid secretion and salivary flow were measured for four 1-hour periods beginning at 3.5, 5.5, 7.5, and 9.5 hours after medication, with plasma sampling for measurement of doxepin at the midpoint of each collection period. Compared to placebo, the 50- and 100-mg doses of doxepin reduced mean basal acid output by 46% and 37%, respectively. There was no significant difference in the effect of the 50- or 100-mg dose on acid secretion even though mean plasma concentrations of doxepin were higher with the 100-mg than with the 50-mg dose (p less than 0.01). Salivary flow was reduced by 62% and 84% with the 50- and 100-mg doses, respectively, whereas doxepin had no effect on mean pulse rate.