Effect of ranitidine on meal-induced gastric pepsin and acid secretion and the influence of adding ethanol to the meal.

The effect of ranitidine on meal-stimulated pepsin and acid secretion 3-4 h after administration of the drug was compared in 10 healthy volunteers. The results showed an insignificant reduction of pepsin output, whereas acid output was reduced 78.5%, demonstrating the difference in response of the chief and parietal cells to an H2-receptor antagonist. Adding ethanol to the meal did not reduce the acid-inhibiting effect of ranitidine.

Augmented postprandial gastric acid secretion due to exposure to ranitidine in healthy subjects.

In 10 healthy volunteers gastric acid output in response to a meal was significantly increased 60-64 h after cessation of 4 weeks of ranitidine treatment as compared with the response before treatment. Four to 6 weeks after discontinuation of treatment the acid secretory response to the meal had returned to values not significantly different from those seen before treatment. There was no change in pepsin output owing to ranitidine treatment.

Gastric secretion in response to a meal 12-13 h after ranitidine.

In a recent study we demonstrated a marked inhibition of basal gastric acid secretion 12-14 h after oral administration of 150 mg ranitidine. This study investigates the effect of ranitidine on meal-evoked secretion, time interval between drug administration and measurements remaining the same as in a former study. Under the present conditions 150 mg ranitidine had no effect on acid secretion and enhanced pepsin secretion. The results indicate that the effect of the H2-receptor antagonist is surmountable by meal stimulation. The concentrations of ranitidine in basal gastric juice was approximately the same as in blood. The gastric excretion of ranitidine did not increase by meal stimulation and was approximately 0.5% of the excretion in urine.

Kinetics of the inhibition of food-stimulated secretion by ranitidine in dogs.

Five Labrador retrievers provided with one vagally innervated and one denervated pouch were given graded doses of food composed of liver, heart and bonemeal to make dose/response curves of food-stimulated gastric secretion. A constant ranitidine infusion resulted in a decreased inhibition of acid output as the physiological stimulation increased both in the innervated and in the denervated pouch. The pepsin output behaved quite differently. The increased physiological stimulation did not increase the pepsin output. There was no inhibition by ranitidine in the innervated pouch and a constant inhibition by ranitidine in the denervated pouch. The results indicated a component of competitive interaction between meal-stimulated acid secretion and the H2-receptor antagonist, which is similar to the interaction between H2-receptor antagonist and histamine.

Simulated meal test. A new method for estimation of parietal and non-parietal secretion in response to food.

In ten healthy volunteers gastric secretion was stimulated by a simulated meal, in which the cephalic phase was activated by modified sham feeding and the gastric phase by repeated instillations and withdrawals of a meat soup. The gastric aspirates were analyzed for acid and pepsin and the outputs quantitated by the recovery of an unabsorbable marker (polyethylene glycol). Instillation of liquid meal without sham feeding produced 58% and 65% of pentagastrin-stimulated secretion of acid and pepsin, respectively. Concomitant sham feeding increased the stimulation further, so that the outputs evoked by the combined stimulus (simulated meal test) were similar to that achieved by the pentagastrin test. The coefficient of variation of duplicate tests was 4.5% for acid and 5.4% for pepsin output. The technique is suitable for measuring both parietal and non-parietal secretion in response to food.

Prolonged influence of a meal on the effect of ranitidine.

Ten healthy volunteers received 150 mg ranitidine or placebo. Eight hours after drug administration they were served a standard meal or continued fasting. Four hours later the gastric acid and pepsin secretion and gastrin and ranitidine levels in blood were recorded for a further 2 h. At the time when secretion was measured, the meal neither stimulated acid or pepsin secretion nor altered the circulating plasma levels of ranitidine or gastrin. In spite of that, the meal significantly reduced the acid-inhibitory effect of ranitidine from 63% to 39% (p less than 0.01). Pepsin secretion was not affected by the meal or the administration of ranitidine. The results indicate that a meal may decrease the acid-inhibitory effect of the H2-receptor antagonist longer than it stimulates acid secretion.

Treatment of gastric ulcer with ranitidine.

Forty-eight patients with endoscopically proven gastric ulcer were treated either with ranitidine tablets, 150 mg twice daily, or with placebo tablets under double-blind conditions. Three patients were for various reasons excluded from the study. After 6 weeks' treatment a second endoscopy was performed. The ulcer had healed in 22 (88%) of the 25 patients who had received ranitidine tablets and in 4 (20%) of the 20 patients who had received placebo tablets. The difference was statistically significant (p less than 0.002). The number of days and nights with pain attacks and the number of antacid tablets consumed were significantly (p less than 0.002) lower in the patient group treated with ranitidine. The 3 patients with non-healed ulcer after treatment with ranitidine had their ulcers healed after a further 6 weeks' treatment with ranitidine, and of the 16 patients with non-healed ulcer after treatment with placebo tablets, 13 had their ulcers healed after 6 weeks' open treatment with ranitidine, 150 mg twice daily. No serious side effects that could be ascribed to treatment occurred during the study.

Controlled clinical trial of duodenal ulcer healing with antacid tablets.

The effect of an antacid tablet regimen (total acid-neutralizing capacity, 280 mmol/day) and placebo was studied in 75 patients with duodenal ulcer in a double-blind 4-week trial. The ulcer healed in 30 out of 37 (81%) patients treated with antacids as compared with 9 out of 38 (24%) patients treated with placebo (p less than 0.001). Ulcer symptoms in the antacid- and the placebo-treated groups did not differ significantly until the last week of treatment (p less than 0.01). Both constipation and diarrhoea were slightly more common in antacid- than in placebo-treated patients (NS). Serum concentration of aluminium increased significantly (p = 0.01), whereas serum concentrations of calcium, phosphorus, magnesium, iron, and total iron-binding capacity did not change during treatment. No other side effects of antacids were recorded. Thirty-eight patients with unhealed ulcer after cessation of the antacid/placebo treatment were treated openly with 150 mg ranitidine twice daily. The ulcer healed in 31 out of 37 (83%) patients (one drop-out) after 4 weeks' treatment, and only one patient remained with unhealed ulcer after 6 weeks' ranitidine treatment. No side effects due to ranitidine were recorded.

Relationship between ranitidine plasma levels and reduction of postprandial intragastric acidity in healthy man.

Intragastric acidity was measured for 20 min before and 6 h 40 min after a steak meal by aspiration of small aliquots of the gastric content every 10 min in 11 healty volunteers. Administration of ranitidine hydrochloride (100 mg) at the beginning of the meal reduced postprandial acidity markedly throughout the test, but there was no correlation between the percentage reduction of acidity and the concentration of ranitidine in plasma. The effect of the drug lasted much longer than would be expected from the plasma values. The results suggest that ranitidine is cleared more rapidly from the blood than from the H2-receptors of the parietal cells, and the reduction of postprandial acidity by ranitidine cannot be deduced from the plasma values of the drug.

Reduction of postprandial gastric acidity and pepsin concentration by ranitidine and antacids in healthy volunteers.

Small aliquots of gastric content were withdrawn every tenth minute for 7 h in 11 healthy volunteers with a maximal gastric acid output of more than 20 mmol h-1. After 20 min a steak meal was given. Ranitidine hydrochloride 100 mg administered with the meal increased postprandial gastric pH and reduced acid concentration markedly throughout the test. Two tablets of antacids with a neutralizing capacity of approximately 20 mmol per tablet 1 and 3 h after the meal reduced gastric acidity significantly less than ranitidine and did not prevent an increase in acidity to control level during the interval between the two doses. In the control experiments 40% of the pH readings during the 4 postprandial hours were at or above the pre-prandial pH levels. Antacids and ranitidine increased this to 85% and 96% respectively. Antacids had no effect after the fourth postprandial hour, had very little effect when given in addition to ranitidine, but reduced the mean four hour postprandial pepsin concentration more than ranitidine.

Acetylsalicylic acid-induced gastrointestinal bleeding determined by a 51Cr method on a day-to-day basis.

The daily gastrointestinal blood loss caused by plain and microencapsulated acetylsalicylic acid (ASA) tablets was compared. Fourteen healthy, male volunteers participated in a double-blind, cross-over study, lasting 38 days. Before drug administration a median gastrointestinal bleeding of 0.9 ml/24 h was observed. During oral intake of 1.5 g ASA twice a day for 5 days, an increased faecal blood loss was seen in all volunteers. The increase was significant for both plain and microencapsulated ASA (p less than 0.01). Plain ASA tablets, however, caused a greater faecal blood loss than the microencapsulated tablets (p = 0.05), maximum median levels being 6.2 ml/24 h and 3.9 ml/24 h, respectively. An optimal design of radiochromium studies for determination of drug-induced gastrointestinal blood loss is discussed.

Treatment of duodenal ulcer with ranitidine, a new histamine H2-receptor antagonist.

Fifty patients with endoscopically verified duodenal ulcer were treated with either 100 mg of ranitidine hydrochloride (corresponding to 89.4 mg of ranitidine base) or identical placebo tablets twice daily under double-blind conditions. One patient did not attend for the second endoscopy and was excluded. Endoscopic examination after 4 weeks of treatment showed that the ulcer had healed in 23 out of 25 patients (92%) treated with ranitidine and in 11 out of 24 patients (46%) treated with placebo (P < 0.01). The ranitidine-treated patients had significantly less ulcer symptoms during treatment. Antacid consumption was also less in the ranitidine than in the placebo-treated group, but the difference was not significant. After 4 weeks in the double-blind study 14 of the 15 patients with unhealed ulcer received open treatment with ranitidine for 4-6 weeks. The ulcer healed in all but one patient. No serious side effects of ranitidine were observed.

Serum levels and electrophysiological effects of N-acetlyprocainamide as compared with procainamide in the dog heart in situ.

The electrophysiological effects of procainamide and its major metabolite N-acetylprocainamide were tested and compared on the heart of the anaesthetized dog by means of His bundle electrography and programmed electrical stimulation. Both drugs exerted a negative chromotropic effect. They also increased intra-atrial and intraventricular conduction times; procainamide was, however, the more potent of the two drugs. In contrast to procainamide, N-caetylprocainamide did not increase His-Purkinje and atrioventricular nodal conduction times, and at the lowest dose employed, atrioventricular nodal conduction times were decreased during atrial pacing. Both drugs increased the functional and effective refractory period of the right atrium and ventricle. N-acetylprocainamide increased the functional refractory period of the atrioventricular node, but to a lesser extent than procainamide.

Maintenance therapy with a new retard tablet preparation of procainamide.

The procainamide plasma concentration was followed during maintenance therapy with a new procainamide retard tablet preparation in 23 hospitalized patients suffering from acute or chronic coronary heart disease with complicating ventricular arrhythmias. After initial individually adjusted treatment with Pronestyl every third hour, either orally or intramuscularly, for at least eight dose intervals, the retard tablets were given at 6 hour intervals for 2 to 12 days, or more. In 19 patients with no major fluctuations in their circulatory or renal state, adequate and relatively stable plasma procainamide concentration was obtained upon a constant dose of the retard preparation. On an average, the difference from minimum to maximum concentration was 55 per cent within the 6 hour dose intervals. In four patients with unstable circulation and/or renal function, procainamide therapy had to be disrupted in two because of severe side effects and toxic concentrations, and the dose was adjusted in the remaining two. It is concluded that the formulation of procainamide tablet preparations has simplified procainamide therapy within and outside hospital and improved our possibilities to perform short-and long-term studies on the risk/ benefit ratio of procainamide treatment in patients with severe ventricular arrhythmias.

Comparison of the acetylation of procainamide and sulfadimidine in man.

The acetylation of procainamide and sulfadimidine has been measured simultaneously in plasma and urine in 20 healthy human volunteers by a specific G.L.C. method, after single and multiple oral dral doses of procainamide retard tablets. A distinct bimodality (9 rapid and 11 slow acetylators) was apparent from the concentrations of procainamide and N-acetylprocainamide both in urine and plasma, which was in complete agreement with data about sulfadimidine acetylation. The influence of acetylator phenotype on the relative concentrations of procainamide and N-acetylprocainamide in plasma as cn 5 additional healthy subjects after a single oral dose of procainamide. The present results show that acetylator phenotype can now be determined using procainamide as the test substance, and for this purpose multiple doses offer hardly any advantage over a single dose of the drug. However, because the separation between rapid and slow acetylators is less pronounced for procainamide than for sulfadimidine, precise criteria must be established for the conditions of the test, and the influence of diseases, such as renal insufficiency, should be taken into consideration.

Effects of N-acetylprocainamide as compared with procainamide in isolated rat atria.

The actions of procainamide and its major metabolite N-acetylprocainamide were tested and compared on isolated rat atria. While procainamide exerted a negative chronotropic and iontropic effect, N-acetylprocainamide had the opposite effect. It is suggested that a N-acetylprocainamide-induced increase in myocardial work can counteract the negative inotropic action of procainamide and thus to some extent explain the variable results with the latter compound on myocardial performance reported from in vivo experiments. Procainamide increased the refractory period and reduced the excitability of isolated rat atria. N-acetylprocainamide, on the other hand, caused negligible effects on these parameters.