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Biomedical subjects

R L McIsaac

Publications and source records attributed to R L McIsaac.

At least 19 recordsLinked to original sources
PubMed2002

Determination of the time of onset of action of ranitidine and famotidine on intra-gastric acidity.

BACKGROUND: No standard methods exist for determining the onset of action of gastric antisecretory agents in human subjects. METHODS: Intragastric pH was measured when placebo, ranitidine 150 mg, ranitidine 75 mg or famotidine 10 mg were administered 30 min after the end of a meal. RESULTS: When the onset of action was defined as the earliest time that mean gastric pH with active treatment was statistically significantly higher (P < 0.05) than the corresponding placebo value, the onsets of action of ranitidine 75 mg and 150 mg were 55 min, and of famotidine 10 mg, 90 min. When onset was defined in terms of a particular decrease in gastric acid concentration for the group as a whole or for individual subjects, there was an important variation in the relative times of onset of ranitidine 75 mg and famotidine 10 mg. CONCLUSIONS: When administered after a meal, the onset of action of ranitidine and famotidine on gastric pH can be determined for individual subjects as well as for the group as a whole. When onset was determined for the group using statistical significance, which does not depend on arbitrary cut-off points, ranitidine 75 mg had an earlier onset of action than did famotidine 10 mg.

Adolescent↗
PubMed1991

Ranitidine in the treatment of duodenal ulcer disease: relationship between antisecretory effect and ulcer healing rate.

The relationship between drug-induced suppression of intragastric acidity and the rate of duodenal ulcer healing was examined using data for a single drug, ranitidine, from 156 clinical trials involving 16,362 patients together with data on acid suppression from 37 studies of intragastric acidity in 630 subjects. In these studies ranitidine was given in doses ranging from 150 mg to 1200 mg per day administered in 9 different dosage regimens. The overall percentage of patients whose duodenal ulcers healed at 2 and 4 weeks on the different regimens was highly correlated with the percentage suppression of 24-hour intragastric acidity induced by different regimens. Thus the therapeutic benefit of a given ranitidine dosage regimen in healing duodenal ulcers relates directly to its antisecretory effect.

Drug Administration Schedule↗
PubMed1991

The evolution of peptic ulcer therapy. A role for temporal control of drug delivery.

The treatment of acid peptic disease has involved a series of attempts to control gastric acid secretion in order to heal and to prevent recurrence of duodenal ulcers. Early treatment attempted to heal by neutralizing gastric acid with diet modification, the Sippy diet, and Doll's milk drip. Just before the turn of the century, surgeons began performing gastric resections. In 1943, Dr. Lester Dragstedt performed the first truncal vagotomy to limit cholinergic stimulation of gastric acid secretion. This led to surgery that combined gastric resections with vagotomy. In 1970, the first parietal cell vagotomy was performed. This microsurgical technique limited vagal initiation of acid secretion while minimizing the impact on other gastrointestinal functions. By the 1960s, pharmacological intervention included antacids to neutralize acid and anticholinergics to reduce the amount of acid produced. These treatments varied in their effectiveness, and some of them caused significant side effects. In 1976, treatment of acid peptic disease began a new phase with the introduction of the first H2 receptor antagonist, cimetidine. Ranitidine, the second H2 receptor antagonist, produced greater acid suppression in the morning and at night with bid dosing than cimetidine with quid dosing. The knowledge that there is a circadian pattern in acid production, with higher levels between 10 PM and 2 AM, resulted in the development and use of a single evening dose of ranitidine. Ongoing research continues to investigate the effects of dose timing and the influence of more potent acid-suppressing agents. Finally, the issue of maintenance therapy and gastric acid secretion was addressed. The clinical advantage that ranitidine has over cimetidine in the prevention of ulcer recurrence can be attributed to its control of nocturnal acid suppression.

Gastric Acid↗
PubMed1990

The timing of the evening meal affects the pattern of 24-hour intragastric acidity.

The object of the study was to examine the effect of varying the time of the evening meal on the pattern of 24-h intragastric acidity. Ten healthy subjects were studied; they ate regular meals throughout the day, but between 17.00 and 21.35 hours were separated into three groups. On three different days each group was fed the same dinner at either 17.15, 19.15, or 21.15 hours (early, standard or late). Variation in the evening meal's time caused significant changes in the pattern of acidity in the afternoon and evening, but did not affect 24-h intragastric acidity or nocturnal acidity. Integrated afternoon acidity (14.00 hours to dinner) was 69, 169 and 324 mmol.h/L when the subjects ate early, standard and late meals, respectively; evening acidity (dinner to midnight) was 235, 43 and 1 mmol.h/L with the three meals, respectively. The results suggest that, to control intragastric acidity, when the evening meal is eaten early (17.15 hours) dosing with an H2-antagonist should be after that meal, when eaten at the standard time (19.15 hours) dosing should be at bedtime, but when dinner is late (21.15 hours) the optimal regimen may involve dosing after lunch and also at bedtime.

Adult↗
PubMed1988

A comparison of two ranitidine intravenous infusion regimens in critically ill patients.

The effect of two ranitidine intravenous infusion regimens on intragastric pH was studied in 134 critically ill patients admitted to 15 intensive care units. Intragastric pH was determined hourly for 30 hours. Those patients whose intragastric acidity fell below pH 4.0 for 3 or more of the first 6 hours were considered 'at risk' of developing stress-related gastric lesions and randomized to receive a 50 mg bolus of ranitidine together with a continuous intravenous infusion of either 0.125 or 0.25 mg kg-1 h-1 ranitidine for 24 hours. The maximal elevation in intragastric pH was achieved within 12 hours. The median intragastric pH for the last 20 hours of the infusion period was 5.9 for the higher dose group and 5.6 for the lower dose group. The increase in intragastric pH achieved by the two dosage regimens did not differ significantly throughout the 24 hour period. Patients having two or more of five major risk factors (head injury, major trauma, sepsis, respiratory failure/insufficiency and major surgery) had better overall control of intragastric pH on the higher dose of ranitidine than those receiving the lower dose. The majority of intensive care patients are likely to receive satisfactory treatment with the lower dosage regimen that was tested (0.125 mg kg-1 h-1). Those with multiple risk factors may, however, require treatment with higher doses of ranitidine (0.25 mg kg-1 h-1).

Adolescent↗
PubMed1987

Ranitidine and cimetidine in the healing of duodenal ulcer: meta-analysis of comparative clinical trials.

All available ranitidine and cimetidine comparative trials in acute duodenal ulcer disease were examined: of the 44 trials, 36 favoured ranitidine, and there was an overall difference in ulcer healing of 7%. Further stratification enabled examination of trials with common attributes: the most frequent endoscopic assessment was at 4 weeks to compare ranitidine 150 mg twice daily with cimetidine 1 g day-1 or 400 mg b.d. Twenty of these trials had sufficient data to permit pooling. Ranitidine was favoured in 18/20 trials and in three the differences achieved statistical significance. Results of the trials were combined using meta-analysis to calculate differences in ulcer healing. Most studies had sample sizes that were insufficient to detect clinically-important differences; the power to detect a 20% difference was less than 80% in 15/20 trials, and for a 10% difference was less than 80% in all but one trial. Fifteen trials compared ranitidine 150 mg b.d. with cimetidine 1 g day-1: healing after 4 weeks therapy was overall 6% greater for ranitidine. This was statistically significant (P less than 0.05) and the combined total number of patients had a power of 83% to detect this difference. In five trials the dose of cimetidine used was 400 mg b.d.: the 12% difference in healing in favour of ranitidine 150 mg b.d. was statistically significant, and the combined trials had a power of 95% to detect this difference. Ranitidine 150 mg twice daily heals significantly more duodenal ulcers after 4 weeks of therapy than either cimetidine 400 mg b.d. or cimetidine 1 g day-1.

Cimetidine↗
PubMed1986

Acute treatment of duodenal ulcer: a multicentre study to compare ranitidine 150 mg twice daily with ranitidine 300 mg once at night.

A randomised double blind clinical trial was undertaken in the UK and Ireland to compare ranitidine 300 mg given as a single bed time tablet with ranitidine 150 mg twice daily in the acute treatment of duodenal ulcers. Of the 594 patients with endoscopically diagnosed duodenal ulcer entered into the trial, 424 patients had complete endoscopic findings on which healing rates at four weeks were determined. By this time 156 of 201 (78%) patients healed with ranitidine 300 mg nocte compared with 186 of 223 (83%) receiving ranitidine 150 mg twice daily (p = 0.28). After eight weeks of treatment 97% of the patients in each group were healed. The healing rates for smokers and non-smokers did not differ significantly at either four or eight weeks. Each regimen was equally effective in reducing day and night-time pain. Adverse events were reported in 23 patients overall; 12 were withdrawn from the trial. Minor abnormalities in liver function tests were noted in three patients. The trial confirmed that a single dose of ranitidine 300 mg given at night is a safe, effective alternative treatment to ranitidine 150 mg bd for the acute treatment of duodenal ulcer.

Clinical Trials as Topic↗
PubMed1984

An assessment of ciclazindol in stimulating thermo-genesis in human volunteers: a detailed metabolic study.

Seven normal-weight young men lived for seven weeks in a metabolic unit on a diet (12 per cent protein, 30 per cent fat) equivalent in energy content to that calculated from a previous seven-day weighted intake. Three different doses of ciclazindol and a placebo were given for a week each on a Latin Square double-blind cross-over basis. At the end of each experimental week the subject occupied a whole-body indirect calorimeter at 26 degrees C for 36 h. Heart rate was monitored and a strict time-table of activity defined. Appetite and mood were assessed throughout the study period. Faecal and urinary energy excretion were used to define metabolisable energy intake. Multiple regression analysis showed a small but dose-dependent increase in energy output with the drug. This effect was present during the daytime when the subject was active and fed but not at night when he was lying still in bed. Heart rate rose significantly in both the day and night, and sleep was shortened. Appetite was suppressed; however, all but one subject maintained the diet. In conclusion, ciclazindol in man affects appetite, has a general arousal and a small thermogenic effect.

Adult↗
PubMed1983

Dose-response curve analysis of gastric secretory responses in the dog and man to impromidine: a new histamine-H2-receptor agonist.

The new histamine-H2-receptor agonist, impromidine, was assessed for its effect on gastric acid secretion using a dose-response format. Maximal acid output and ED50 were calculated for infusions of impromidine in the Heidenhain pouch dog (0.05-1.6 x 10(-8) mol/kg/hr) and in man (0.39-6.22 x 10(-8) mol/kg/hr). Analysis of the responses was carried out by nonlinear regression using the logistic function. This allowed the data to be analyzed without making assumptions about the steepness of the curve which in man was almost twice that found in the dog (1.8:1). The ED50 in the dog was 0.26 +/- 0.029 x 10(-8) mol/kg/hr. The control dose-responses could be inhibited in a competitive manner by histamine-H2-receptor antagonists. Analysis of the control curve and three curves in the presence of increasing doses of antagonist was carried out by fitting all the curves simultaneously to calculate an in vivo ID50. In the dog, the antagonist was tiotidine (0.05, 0.1 and 0.2 x 10(-6) mol/kg/hr) and the ID50 was 0.012 +/- 0.002 x 10(-6) mol/kg/hr. In man, cimetidine (1.05, 2.10 and 4.2 x 10(-6) mol/kg/hr) was used to inhibit secretion. The calculated ID50 was 0.63 +/- 0.085 x 10(-6) mol/kg/hr. Comparison of the effect of cimetidine and tiotidine against both impromidine and histamine showed that the ID50 was the same for both stimulants. Impromidine proved to be a potent stimulant of gastric acid secretion acting via the H2-receptor to produce readily definable dose-response curves in the dog and in man.

Adult↗
PubMed1982

Gastric acid secretion induced by impromidine in the dog and man: analysis of dose-response relationships.

The new histamine H2-receptor agonist, impromidine, was used to assess three models of dose-response curves in vivo. Vm and ED50 values were calculated for gastric acid output to infusions of impromidine in the dog with a Heidenhain pouch and in man. In two models Michaelis-Menten kinetics were assumed: the linear transformation using the Eadie-Hofstee plot and the non-linear hyperbola, but in the third method the logistic function allowed the data to be analysed without making assumptions about the steepness of the curves. In the dog all three models gave similar results both for calculated Vm and ED50. Curve steepness from the logistic function was found to be 0.98 +/- 0.023 - not different from that assumed for the hyperbola (where steepness = 1). The results in man were different: the Eadie-Hofstee plot did not produce a significantly linear fit while the logistic function produced the smallest standard errors. The logistic curve slope was almost twice that assumed for the hyperbola (1.8 : 1) and it seems, therefore, that impromidine-induced gastric acid secretion does not follow Michaelis-Menten kinetics in man and data should be analysed using methods which allow the calculation of curve steepness.

Animals↗
PubMed1981

Gastric mucosal blood flow and acid secretory changes in man with impromidine: a new specific histamine-H2-receptor agonist.

The effect of impromidine, a new histamine-H2-receptor agonist, on gastric mucosal blood flow (neutral red clearance) and acid secretion was studied in nine volunteers. Impromidine stimulated a dose-dependent increase in neutral red clearance and acid secretion. Simultaneous cimetidine in three doses caused a parallel shift to the right for both acid output and clearance with unchanged maxima compatible with simple surmountable antagonism. There were small cardiovascular changes: an increased heart rate with a decreased diastolic pressure during infusion of impromidine. These changes were antagonised by cimetidine.

Adult↗
PubMed1980

The effect of histamine and histamine antagonists on gastric acid secretion and mucosal blood flow in man.

Histamine has been investigated for its effect on gastric acid secretion and mucosal blood flow in man. Dose-response curves were constructed and analysed in the presence of H1- and H2-antagonists. Mepyramine had no effect on acid secretion or mucosal blood flow. Cimetidine reduced acid secretion but had no effect on blood flow. This suggests that the vasculature is less sensitive to cimetidine than the parietal cell.

Adult↗