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The use of anti-ulcer medications, such as cimetidine, ranitidine, and omeprazole, is common in performance horses. The use of these drugs is regulated in performance horses, and as such a withdrawal time is necessary prior to competition to avoid a medication violation. To the authors' knowledge, there are no reports in the literature describing repeated oral administrations of these drugs in the horse to determine a regulatory threshold and related withdrawal time recommendations. Therefore, the objective of the current study was to describe the disposition and elimination pharmacokinetics of these anti-ulcer medications following oral administration to provide data upon which appropriate regulatory recommendations can be established. Nine exercised Thoroughbred horses were administered 20 mg/kg BID of cimetidine or 8 mg/kg BID of ranitidine, both for seven doses or 2.28 g of omeprazole SID for four doses. Blood samples were collected, serum drug concentrations were determined, and elimination pharmacokinetic parameters were calculated. The serum elimination half-life was 7.05 ± 1.02, 7.43 ± 0.851 and 3.94 ± 1.04 h for cimetidine, ranitidine, and omeprazole, respectively. Serum cimetidine and ranitidine concentrations were above the LOQ and omeprazole and omeprazole sulfide below the LOQ in all horses studied upon termination of sample collection., (© 2016 John Wiley & Sons Ltd.)

Aims: Voriconazole, a new triazole antifungal agent, is metabolized mainly by cytochrome P450s CYP2C19 and CYP2C9, and also by CYP3A4. The aim of this open-label, placebo-controlled, randomized, three-way crossover study was to determine the effects of cimetidine and ranitidine on the steady-state pharmacokinetics of voriconazole., Methods: Twelve healthy male subjects received oral voriconazole 200 mg twice daily plus cimetidine 400 mg twice daily, voriconazole 200 mg twice daily plus ranitidine 150 mg twice daily, and voriconazole 200 mg twice daily plus placebo twice daily. Treatment periods were separated by at least 7 days., Results: When cimetidine was administered with voriconazole, the maximum plasma voriconazole concentration (Cmax) and the area under the plasma concentration-time curve of voriconazole (AUCtau) was increased by 18.3%[90% confidence interval (CI) 6.0, 32.0] and 22.5% (90% CI 13.3, 32.5), respectively. Concomitant ranitidine had no significant effect on voriconazole Cmax or AUCtau. Time of Cmax (tmax) elimination half-life (t 1/2) or terminal phase rate constant (kel) for voriconazole were similar in all three treatment groups. Most adverse events were mild and transitory; two subjects were withdrawn due to adverse events., Conclusions: Coadministration of the histamine H2-receptor antagonists cimetidine or ranitidine does not affect the steady-state pharmacokinetics of voriconazole in a clinically relevant manner.

Background: A large proportion of patients in primary care are still being maintained on long-term acid suppression, without any attempts to identify Helicobacter pylori status and to treat those that test positive., Objectives: To assess the prevalence and economic and symptomatic benefits of H. pylori eradication in patients maintained on long-term H2 receptor antagonists (H2RA) in primary care., Patients and Methods: Patients on long-term (i.e. 6 months or longer) H2RA were identified from the computerised records of six practices in north England. Helicobacter pylori status was identified using serology and H. pylori positive patients were then offered standard 7-day proton pump based triple therapy, followed by a urea breath test (UBT) to confirm H. pylori eradication. Those who had a positive UBT were offered a second line course of H. pylori eradication therapy. Follow up period was 1 year. The main outcome measures were improvement in dyspepsia symptom scores, amount of H2RA being consumed, and economic benefits after H. pylori eradication., Results: One thousand and seven patients (1.5%) were identified on long-term H2RA, of whom 471 (46%) ultimately had their H. pylori serology assessed. Sixty-three (297) percent of the patients tested had a positive serology for H. pylori, the majority of whom (58%, 172) had prior evidence of peptic ulcer disease. The mean duration of therapy and mean time since endoscopy/barium studies was significantly longer in patients with peptic ulcer disease compared to their counterparts with nonulcer dyspepsia and gastro-oesophageal reflux disease, p =.0002 and.0001, respectively. After successful H. pylori eradication (which was possible in 84% of the patients), at the end of the 1-year study period, on an intention to treat basis 62% of the patients could either stop or significantly reduce dosage of their H2RA. There was also significant reduction in the mean dose of H2RA being consumed and severity of symptoms at the end of the study period (p <.00001)., Conclusion: Almost two-thirds of patients on long-term H2RA in primary care will have a positive serology for H. pylori; the majority of these will have peptic ulcer disease. In over 60% of cases H. pylori eradication led to significant improvement in symptom scores and reduction in dosage of H2RA being consumed. Cessation or reduction in long-term H2RA prescribing is cost effective.

This study assessed the duration of action of single doses of ranitidine (75 mg), cimetidine (200 mg), or placebo on intragastric acidity in healthy subjects. When dosed with placebo, mean daytime intragastric acidity (0-10 hr after dose) was 37.62 mmol/liter, decreasing to 17.21 mmol/liter (mean decrease 59%; P < 0.001 vs placebo) and 25.06 mmol/liter (mean decrease 35%; P < 0.001 vs placebo) when treated with ranitidine and cimetidine, respectively. Ranitidine inhibited intragastric acidity to a greater degree than cimetidine (P < 0.001). Mean nighttime (10-20 hr after-dose) intragastric acidity when dosed with placebo was 34.37 mmol/liter, decreasing to 29.06 mmol/liter (mean decrease 18%; P = 0.027 vs placebo) when dosed with ranitidine and remaining virtually unchanged at 33.85 mmol/liter (mean decrease 2%; NS vs. placebo) when dosed with cimetidine. Ranitidine inhibited acidity to a greater degree than cimetidine (P = 0.043). The inhibitory effect of ranitidine, 75 mg, on intragastric acidity can be detected from 0-15 hr after an oral dose. Cimetidine 200 mg has little inhibitory effect beyond 10 hr.

Objective: To characterize the change of pH in the abomasal lumen throughout a 24-hour period, to determine whether pH of the abomasal body differs from pH of the pyloric antrum, and to determine whether oral administration of cimetidine and ranitidine alters pH of the abomasal lumen in milk-fed calves., Animals: 5 male dairy calves (4 Holsteins-Friesian, 1 Ayrshire), 5 to 15 days old., Procedure: Cannulas were surgically positioned in the abomasal body and pyloric antrum of each calf. Calves received the following treatments in a randomized crossover design: milk replacer (60 ml/kg of body weight, q 12 h [untreated control calves]), milk replacer and cimetidine (50 or 100 mg/kg, q 8 h), or milk replacer and ranitidine (10 or 50 mg/kg, q 8 h). The pH of the abomasal body and pyloric antrum was measured for 24 hours, using miniature glass pH electrodes., Results: Suckling of milk replacer immediately increased abomasal luminal pH from 1.4 to 6.0, followed by a gradual decrease to preprandial values by 6 hours. Preprandial and postprandial pH values were not significantly different between the abomasal body and pyloric antrum, indicating lack of pH compartmentalization in the abomasum of milk-fed calves. Administration of cimetidine and ranitidine caused a significant dose-dependent increase in mean 24-hour abomasal luminal pH., Conclusions and Clinical Relevance: Abomasal acid secretion in milk-fed calves is mediated in part by histamine type-2 receptors. Cimetidine and ranitidine may be efficacious in the treatment of abomasal ulcers in milk-fed calves.

Background: Because of their tolerance and safety, low doses of H2-receptor antagonists are now increasingly used in some countries for self-care medication of gastro-oesophageal reflux symptoms., Aim: The purpose of this randomized, double-blind, placebo-controlled, five-way crossover study was to determine and to compare the effects of low doses of ranitidine and cimetidine both on gastric pH and on oesophageal acid exposure., Methods: Gastric and oesophageal pH were simultaneously monitored in 20 healthy subjects using two glass pH electrodes, after placebo and single doses of ranitidine 75 mg and cimetidine 200 mg (effervescent and tablet forms), for 4 h before and after a meal., Results: During the fasting period, median gastric pH rose significantly with both drugs, but more rapidly with the effervescent forms; the oesophageal acid exposure was significantly decreased by all drug regimens. After the meal, although there was no significant difference in gastric pH values, oesophageal acid exposure was significantly decreased in comparison with placebo with both forms of ranitidine (P < 0.05), and also for ranitidine tablets in comparison with cimetidine tablets (P < 0.05)., Conclusions: Low doses of ranitidine and cimetidine increase gastric pH, with a more pronounced effect for ranitidine. Effervescent formulations of both drugs induce a slightly more rapid initial increase in pH than tablets. Ranitidine demonstrates a more prolonged effect than cimetidine and decreases oesophageal acid exposure monitored after a meal ingested 4 h after the drug intake.

Aim: To compare the effects of ranitidine 75 mg with those of either cimetidine 200 mg or placebo given on demand for relief of typical symptoms of gastro-oesophageal reflux disease during a 15-day period., Methods: A total of 1336 patients (aged > or = 18 years) with heartburn episodes were recruited and randomly assigned to a ranitidine 75 mg, cimetidine 200 mg or placebo group. Depending on the occurrence or persistence of heartburn, treatment was administered as required up to three times daily, with at least 2 h between drug doses. Antacids were allowed as rescue medication if symptoms persisted for at least 2 h after the third medication on any given day. The primary end-point was defined as the proportion of patients with relief of at least 75% of heartburn episodes during the study period (i.e. relief occurring within 2 h after drug ingestion and lasting for at least 5 h)., Results: Analysis was performed in an intention-to-treat population comprising 504 subjects in the ranitidine group, 515 in the cimetidine group and 270 in the placebo group. Primary end-point success rates were 41, 38 and 28%, respectively, for the three groups (P < 0.001 for ranitidine vs. placebo, P = 0.274 for ranitidine vs. cimetidine). Ranitidine 75 mg was significantly more effective than placebo in providing overall heartburn relief (P < 0.001). The differences between the ranitidine and cimetidine groups were not significant, except for a greater reduction in heartburn frequency in the ranitidine group at the end of the study period (P < 0.05). Drug dose was lower and less rescue medication was used in the ranitidine group than the placebo group. The three treatment groups did not differ in terms of tolerability., Conclusion: On-demand ranitidine 75 mg or cimetidine 200 mg are safe and effective treatment for reflux-related symptoms.

Background: Erosive oesophagitis refractory to high dose histamine H2 receptor antagonists (definition: failure to heal fully after > or = 3 months' treatment with cimetidine 3.2 g or ranitidine 0.9 g) responds well to omeprazole 40 mg daily but frequently relapses when the patients are put back on maintenance H2 receptor antagonists at medium or even high dose (e.g. cimetidine 1.6 g and 3.2 g, respectively)., Aim: To investigate the efficacy of maintenance omeprazole 20 mg daily in refractory erosive oesophagitis., Patients & Methods: In this open, sequential study, patients with H2 receptor antagonist-refractory oesophagitis were healed on omeprazole 40 mg daily and then put on maintenance H2 receptor antagonists (cimetidine 1.6 g or 3.2 g). Relapses were re-treated with omeprazole 40 mg; upon rehealing, patients were put on maintenance omeprazole 20 mg daily for up to 4.5 years., Results: Healing on omeprazole occurred in 38 out of 39 patients (97%) at 12 weeks. Only six of the 38 patients (16%) relapsed (asymptomatic in half) during subsequent maintenance treatment, whereas all had relapsed earlier on high dose H2 receptor antagonists., Conclusion: Within the limits of interpretation of an open study, omeprazole 20 mg daily seems effective in maintaining prolonged remission in this group of patients with H2 receptor antagonist-refractory oesophagitis.

Ranitidine 150 mg twice daily (BID) is an approved therapeutic approach for relieving the symptoms of gastroesophageal reflux disease. Ranitidine 150 mg four times daily (QID) and cimetidine 800 mg BID are indicated for endoscopically diagnosed erosive esophagitis. This 12-week, randomized, multicenter trial involving 696 patients compared ranitidine 150 mg BID and ranitidine 150 mg QID with cimetidine 800 mg BID in healing erosive esophagitis. Healing rates, as determined by endoscopy, at 4, 8, and 12 weeks were comparable with ranitidine 150 mg BID (38%, 56%, and 71%, respectively) and cimetidine 800 mg BID (37%, 52%, and 68%, respectively), as were reductions in heartburn frequency and antacid consumption. However, ranitidine 150 mg QID produced significantly higher healing rates (49%, 67%, and 77%, respectively) and greater reductions in heartburn frequency and antacid consumption than cimetidine 800 mg BID. All treatment regimens were well tolerated. Thus ranitidine 150 mg BID is as effective as cimetidine 800 mg BID, and ranitidine 150 mg QID is more effective than cimetidine 800 mg BID in healing erosive esophagitis and reducing heartburn frequency and antacid consumption.

Study Objective: To evaluate the possibility of a drug interaction with zidovudine and histamine2-receptor antagonists in individuals infected with the human immunodeficiency virus., Design: Randomized crossover study., Setting: University-affiliated research center., Patients: Six HIV-infected individuals., Interventions: The subjects received 7-day regimens of zidovudine 600 mg/day alone, zidovudine with cimetidine 1200 mg/day, and zidovudine with ranitidine 300 mg/day., Measurements and Main Results: The renal clearance of zidovudine when given alone was 0.41 L/kg/hour, and was reduced to 0.18 L/kg/hour (p = 0.002) when given with cimetidine. In the presence of cimetidine the urinary excretion of zidovudine decreased from 89.5 to 53.7 microM (p = 0.01), the urinary ratio of metabolite to parent increased from 5.16 to 9.96 (p = 0.0001), and the fraction of zidovudine converted to metabolite increased from 0.86 to 0.92 (p = 0.0025)., Conclusion: Cimetidine presumably inhibits the renal clearance of zidovudine by competing for tubular secretion. Based on the observation that neither cimetidine nor ranitidine had a significant effect on serum concentrations of zidovudine or zidovudine glucuronide, a change in the dosage of zidovudine is not warranted.

Twenty parturients in labour received emergency obstetric anesthesia were randomly divided into two equal groups. Group "R" received 150 mg oral ranitidine tablet on admission, followed by 50 mg infusion in 250 ml dextrose 5% over 30 minutes prior to anesthetic induction. Group "Ce" received 400 mg cimetidine oral tablet and 100 mg infusion in 250 ml dextrose 5% over 30 minutes. Ten parturients were considered as control. Ranitidine significantly reduced the maternal gastric volume with marked alkalinization of gastric pH. No significant changes were detected in the height, frequency or amplitude of uterine contraction or neonatal assessment.

This paper is a meta-analysis of 30 published, double-blind clinical trials comparing omeprazole with ranitidine or cimetidine for the treatment of duodenal ulcer, gastric ulcer and reflux oesophagitis. These studies compare the recommended doses of omeprazole with those for ranitidine and cimetidine, and the confidence intervals for the therapeutic gain show that the findings are highly reliable. The difference in healing rates favoured omeprazole over ranitidine in patients with duodenal ulcer after 2 weeks of treatment (15.2 percentage units; P < 0.001), and after 4 weeks of treatment in patients with gastric ulcer (9.9 percentage units; P = 0.005), or reflux oesophagitis (23 percentage units; P < 0.001). Similarly, omeprazole gave a 20.6 percentage units higher average healing rate than cimetidine in patients with duodenal ulcer after 2 weeks of treatment (P < 0.0001). Significantly more patients treated with omeprazole were free of symptoms at their first follow-up visit than patients treated with ranitidine or cimetidine.

Study Objective: To evaluate the influence of cimetidine, ranitidine, famotidine, and placebo on cardiac performance as determined by echocardiography., Design: Randomized, four-way crossover trial., Setting: Echocardiography laboratory at a university hospital., Participants: Twelve healthy volunteers., Interventions: Volunteers received oral treatment with placebo, cimetidine 800 mg, ranitidine 300 mg, or famotidine 40 mg once/day for 7 days., Measurements and Main Results: On the seventh day of each study phase, 2 hours after administration of the final dose, each subject underwent cardiac echocardiography and Doppler flow studies. No significant differences were detected in ejection fraction, peak flow velocity, or percentage fractional shortening among the treatment phases. A large degree of variability in ejection fraction was observed, with some subjects experiencing marked decreases., Conclusion: The histamine-2 (H2)-receptor antagonists had no effect on the hemodynamic variables as determined by echocardiography. The variability in the hemodynamic response may in part explain the conflicting results reported in the literature. It also raises the question as to whether certain individuals are more sensitive to the potential cardiac effects of H2-receptor antagonists.

Aims: To compare the effects on intragastric acidity of a single evening dose of either standard or effervescent formulations of ranitidine (300 mg) or cimetidine (800 mg)., Methods: Twelve healthy subjects were studied, using a four-period randomized cross-over design and an ambulatory intragastric pH monitoring technique. The subjects received a standard evening meal at 17.00 hours and one of the H2-receptor antagonist formulations was given at 23.00 hours., Results: Both effervescent formulations caused a transient rapid increase in intragastric pH, reaching a maximum at about 3 min after ingestion. After both effervescent formulations a significantly higher pH was measured during the first 45 min after ingestion (P < 0.05), compared to the regular formulations. The onset of action of the H2-receptor antagonists was similar for both formulations of ranitidine and the effervescent cimetidine, but tended to be slower for the regular cimetidine (P = 0.06). Nocturnal intragastric pH was significantly increased by all four formulations, but more effectively so by the two ranitidine formulations. The duration of action (taken as time with pH > 4) of both ranitidine formulations was longer than that of both cimetidine formulations (P < 0.002)., Conclusions: A single evening dose of 300 mg ranitidine produces a stronger decrease of nocturnal gastric acid secretion than 800 mg cimetidine. The effervescent formulations of both drugs offer the advantage of a rapid decrease (within minutes) of intragastric acidity, with preservation of the sustained systemic effect.

A four-way crossover pilot study was conducted to compare the pharmacodynamic response of intermittent famotidine (20 mg every 12 hr) to continuous infusions of cimetidine (1200 mg/24 hr), ranitidine (150 mg/24 hr), and famotidine (40 mg/24 hr) in six normal male volunteers. Intragastric pH was monitored continuously for 24 hours. Comparisons included percent time during the 24-hour period that gastric pH was greater than pH 4.0, and pH 5.0, and also for the steady-state period of each regimen (12-24 hr). Although no statistically significant difference was observed for any of these comparisons, a clinically relevant trend was observed. In crossover experiments, famotidine intermittent infusions provided gastric pH readings above 4.0 and 5.0 for a longer duration than any of the continuous infusion regimens. Famotidine intermittent infusion regimens (20 mg every 12 hr) are at least equivalent to continuous infusions of cimetidine, ranitidine, and famotidine. Based on these findings, comparative studies in an appropriate critical care population would be beneficial, but any such studies must use a crossover design because of the even higher degree of intersubject variance in pH control. For this reason, the normal volunteer crossover model used here may provide important comparative information for the various regimens used in suppression of gastric acidity.

1. The effects of in vivo administration of H2 blockers, cimetidine and ranitidine (0.6 mmol/kg body weight/day, for 5 days), on several P450 isozymes, the P450IID (CYP2D) subfamily, and their monooxygenase activities in rat liver microsomes were investigated. 2. In vivo administration of cimetidine and ranitidine decreased the contents of P450 isozymes and the activities of P450-linked monooxygenase systems; i.e., benzphetamine N-demethylase, aminopyrine N-demethylase, 7-ethoxycoumarin O-deethylase, debrisoquine 4-hydroxylase and bufuralol 1'-hydroxylase. 3. The inhibitory effect on the enzymatic activities of the P450IID (CYP2D)-linked monooxygenase systems was studied by Western blot analysis with serum containing anti-CYP2D6 IgG, i.e., LKM1 autoantibody. The amount of P450IID (CYP2D) in liver microsomes decreased more remarkably in the group administered ranitidine or cimetidine in vivo than in controls. 4. The effects of cimetidine and ranitidine on the activities of the P450IID (CYP2D)-linked monooxygenase systems were investigated in vitro. The activities of debrisoquine 4-hydroxylase and bufuralol 1'-hydroxylase were inhibited in vitro by cimetidine or ranitidine at a higher concentration than that on in vivo administration of either H2 blocker. 5. The kinetic parameters for cimetidine or ranitidine as to the activities of debrisoquine 4-hydroxylase and bufuralol 1'-hydroxylase in liver microsomes were determined by means of Lineweaver-Burk plots. 6. The suppressive effects of cimetidine and ranitidine on the activities of P450IID (CYP2D)-linked monooxygenase systems in vivo were found to be due to a decrease of the content of the P450IID (CYP2D) protein.

Objective: To identify risk factors for adverse drug reactions (ADRs) in patients receiving intravenous histamine2-receptor antagonists (H2-RAs)., Design: The study hypothesis was evaluated by performing a logistic regression procedure with a backward elimination of the explanatory variables associated with ADRs., Main Outcome Measures: ADRs temporally associated with the use of intravenous H2-RAs served as the dependent variable. Background information about the patients and drug use evaluation criteria in three general areas were entered into the regression analysis., Setting: Hospitals were selected from the southeastern US, based on their willingness to participate and their characteristics. Participating hospitals exhibited a variety of sizes and ownership arrangements., Patients: 1200 adult patients who were receiving intravenous H2-RAs., Results: Seven percent of patients experienced a presumed ADR (PADR) to intravenous H2-RAs. The only risk factor for ranitidine was for patients who did not have their dosage corrected for renal function ("overdose"); these patients were twice as likely to experience a PADR compared with patients who received the correct dosage as determined by their renal function. Two risk factors for cimetidine were identified: (1) patients taking cimetidine with another medication known to cause a drug interaction; and (2) patient age. No risk factors were identified for famotidine., Conclusions: The two risk factors for ADRs identified in this study are preventable. Healthcare providers should strive to prevent ADRs by adjusting patients' dosages based on their renal function and by monitoring patients receiving cimetidine with another medication known to interact with cimetidine.

Parenteral control of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome is increasingly required; however, existing methods of determining the required dose are cumbersome and not applicable in all centers. A previous study suggested that the required parenteral dose of histamine H2-receptor antagonists correlated with the previous oral dose. In the present study, in 31 patients with Zollinger-Ellison syndrome we evaluated the hypothesis that an effective parenteral histamine H2-receptor antagonist dose could be predicted from the previous oral dose. Twenty-three patients were taking oral ranitidine (mean 1.3 g/day), six patients famotidine (152 mg/day), and two patients cimetidine (1.8 g/day). Each patient was treated with a continuous intravenous infusion of the equivalent dose of ranitidine (mean dose 1 mg/kg/hr with 35% requiring 0.5 mg/kg/hr, 49% 1 mg/kg/hr, 3% 1.5 mg/kg/hr, 10% 2 mg/kg/hr, and 3% 2.5 mg/kg/hr. This dose of ranitidine acutely controlled acid secretion (< 10 meq/hr) in all patients. To evaluate long-term efficacy and safety, 20 patients were maintained on this dose through the peri- and postoperative periods. Mean duration was 7.1 days with 25% treated 3-5 days, 40% 6-8 days, 30% 8-10 days, and 5% > 10 days. The predicted dose continued to control acid secretion in 95% of patients with one patient requiring one dose adjustment. No biochemical, clinical, or hematological toxicity was seen, although ranitidine was stopped in one patient because of skin rash. These results demonstrate that the parenteral dose of ranitidine required to control acid secretion in patients with Zollinger-Ellison syndrome can be predicted from the oral dose.(ABSTRACT TRUNCATED AT 250 WORDS)

The drug experiences of 1200 patients receiving i.v. histamine H2-receptor antagonists were studied. Forty hospitals in five southeastern states participated in a drug-use evaluation (DUE). In addition to supplying background information, a pharmacist at each hospital used a standardized form to perform a concurrent review of 30 consecutive adult patients who had been started on i.v. cimetidine, ranitidine, or famotidine. In addition to the patient's age and the prescriber's medical specialty, specific DUE criteria included the reason given in the medical record for use; dosage regimen and adjustments made on the basis of the patient's renal function; other GI drugs taken concurrently; pharmacist intervention; simultaneous use of oral medications; occurrence of adverse events; H2-antagonist use with specified drug products known to affect serum drug concentrations of one or both medications; and use of gastric pH monitoring. Therapy with i.v. H2 antagonists was usually started by internal medicine specialists or surgeons, and most of the evaluated patients received such therapy for prevention of stress-related mucosal damage. According to estimated creatinine clearance, 34% of patients were in need of dosage adjustments, but such adjustments were made in only 49% of these. Forty percent of patients began therapy while taking at least one medication orally, and almost one fourth of patients were receiving an additional drug for the treatment of an acid-peptic or related indication. The occurrence of adverse events was similar for the three H2 antagonists studied. The findings identify several problematic areas in the way H2 antagonists are used in clinical practice.

The effect of H2-receptor antagonists on alcohol absorption appears to vary, depending on testing conditions and subject population. In this crossover study of cimetidine (400 mg b.i.d.) and ranitidine (150 mg b.i.d.), we evaluate alcohol pharmacokinetics in 10 subjects after ingestion of moderate doses (0.5 g/kg) of ethanol under four challenge conditions: (a) a single dose of placebo prior to alcohol ingestion in the morning, (b) a single dose of H2-antagonist prior to alcohol ingestion in the morning, (c) 14-day chronic dosing with H2-antagonist prior to alcohol ingestion in the evening, and (d) 28-day chronic dosing with H2-antagonist prior to alcohol ingestion in the morning. No significant increases were observed for alcohol in the area under the curve (AUC) or Cmax. Significant decreases in AUC (16 and 13%) were observed following administration of single- and multiple-dose cimetidine, and a significant decrease in Cmax (14%) was observed following a single dose of ranitidine--all given prior to alcohol ingestion in the morning. These results do not support any clinically meaningful effect of H2-antagonists on alcohol absorption following ingestion of a moderate dose of ethanol.

A modern approach to the evaluation of combined effects of two active drugs, A and B, in clinical trials is described, based on modern understanding of actions and interactions of drugs which act at distinct molecular sites. It rests on a comparison of observed combined effects with calculated effects of independent action of A plus B--greater than independent effects are considered as a potentiated response. It is illustrated by reanalysis of single-dose and time-course studies of the antisecretory action of pirenzepine and H2-receptor antagonists (cimetidine, ranitidine). Briefly, peptone-stimulated acid output was measured in 15 min periods over 3 h after the injection of drugs in three trials, one with five duodenal ulcer patients, two of them with 8 healthy volunteers each. The doses of pirenzepine and H2-blockers were fixed in each trial. The results were either expressed by the total acid output (single-dose analysis) or by the acid secretion over 15 min as time course. The results with the drug combination show greater reduction in acid secretion in all three trials with respect to independent effects. The time-course studies more clearly showed greater reduction in acid output than the analysis of total acid output, not the least with respect to p-values of differences between observed combined effects and calculated independent effects. They were obtained by the chi-square (chi 2) goodness-of-fit test, recently applied for the evaluation of dose-response curves.(ABSTRACT TRUNCATED AT 250 WORDS)

A double-blind multinational comparison of ranitidine 300 mg post evening meal (pem), ranitidine 300 mg nocte and cimetidine 800 mg nocte has been carried out in 1677 patients with endoscopically verified duodenal ulcer disease. Fifty-three percent of ulers healed by two weeks during treatment with ranitidine 300 mg pem and 88% by four weeks, while the results for ranitidine 300 mg nocte were 50% and 86%, respectively, and 44% and 84% for cimetidine. The difference between ranitidine 300 mg pem and cimetidine was significant at two weeks (P = 0.002, Mantel-Haenszel chi-squared test). The relative efficacy of the treatments was not dependent upon gender, smoking habit, alcohol intake, or ulcer frequency. However, the overall differences in healing between patients with small and large ulcers and patients with single and multiple ulcers were significantly different at weeks 2 and 4 (P < 0.001). Significantly more patients treated with ranitidine (60%) had complete relief of epigastric pain than those treated with cimetidine (54%) (P < 0.05). A meta-analysis of the four double-blind comparisons of ranitidine 300 mg pem (N = 841) and 300 mg nocte (N = 849), including the present study, failed to show the benefits of pem dosing, predicted from pharmacological studies.

It has been demonstrated, that the H2-receptor antagonists: cimetidine and ranitidine-administered in doses of the same order of magnitude as reported for the inhibition of rat gastric secretion and development of the experimentally induced gastric and duodenal ulcer-are capable of increasing significantly the parotid secretion evoked by the cholinergic stimulant bethanechol. The salivary carbonic anhydrase activity was also elevated after combined treatment of bethanechol(+)-cimetidine. The similar action of the two H2-antagonists appears to suggest that their effect on salivation is connected probably with the cholinergic activity and it is concluded that the combination of bethanechol with these blockers may improve the esophageal clearance, an action that may be beneficial in the treatment of the gastroesophageal reflux disease.

The effects of concurrent administration of either cimetidine 800 mg once daily or ranitidine 300 mg once daily on the single-dose pharmacokinetics of ritanserin 10 mg were investigated in an open, randomized three-way cross-over, controlled investigation in 9 healthy volunteers. Concurrent administration of cimetidine had no significant effect on the area under the plasma concentration-time curve of ritanserin compared with control experiments. The maximum plasma concentration of ritanserin was decreased significantly (105.0 +/- 9.2 versus 125.0 +/- 13.8 ng/mL; P = .0039), whereas time to reach maximal concentration (tmax) of ritanserin was only slightly but not significantly increased, if the subjects were pretreated with cimetidine. After concurrent ingestion of ranitidine, only a trend to a decrease in the maximum plasma concentration of ritanserin was observed. Time to achieve the maximum plasma concentration, terminal half-life of elimination, and the total area under the plasma concentration-time curve of ritanserin were not altered in comparison with control experiments. The results of the study show that concurrent treatment with cimetidine 800 mg once daily or ranitidine 300 mg once daily has no apparent effect on the systemically available amount of ritanserin after a single oral dose of 10 mg. Both H2-antagonists cause a significant (cimetidine) or borderline significant (ranitidine) decrease of the maximum plasma concentration of ritanserin and a slight but not significant increase in tmax (cimetidine). These effects are of minor clinical importance and seem most likely be due to a decrease of the rate of absorption of ritanserin during concurrent administration of cimetidine/ranitidine.

Enoxacin is a quinolone antibacterial agent currently being developed for oral and intravenous treatment of bacterial infections. Ten healthy subjects received a single 400-mg intravenous dose of enoxacin alone, with 300 mg (four times daily) oral cimetidine and with 150 mg (twice daily) oral ranitidine. Serial blood and urine samples were collected over a 48-hour period. Plasma and urine enoxacin concentrations were determined using a validated high-performance liquid chromatographic method. Mean enoxacin plasma concentrations were higher after administration of enoxacin with cimetidine than those measured after enoxacin alone or enoxacin with ranitidine. Cimetidine coadministration reduced enoxacin renal clearance by 26% and systemic clearance by 20%, and resulted in a 30% increase in elimination half-life. In contrast, concurrent ranitidine therapy did not significantly alter the pharmacokinetics of intravenous enoxacin.

Terfenadine is a widely prescribed non-sedating antihistamine which undergoes rapid and almost complete first pass biotransformation to an active carboxylic acid metabolite. It is unusual to find unmetabolised terfenadine in the plasma of patients taking the drug. Terfenadine in vitro is a potent blocker of the myocardial potassium channel. Overdose, hepatic compromise and the coadministration of ketoconazole and erythromycin result in the accumulation of terfenadine, which is thought to be responsible of QT prolongation and Torsades de Pointes ventricular arrhythmia in susceptible individuals. Cimetidine and ranitidine are two popular H2 antagonists which are often taken with terfenadine. The effects of cimetidine and ranitidine on terfenadine metabolism were studied in two cohorts of 6 normal volunteers given the recommended dose of terfenadine (60 mg every 12 h) for 1 week prior to initiation of cimetidine 600 mg every 12 h or ranitidine 150 mg every 12 h. Pharmacokinetic profiles and morning pre-dose electrocardiograms were obtained whilst the patients were on terfenadine alone and after the addition of cimetidine or rantidine. One of the subjects in each cohort had a detectable plasma level of parent compound after 1 week of terfenadine therapy alone; it did not accumulate further after addition of the H2 antagonist. The pharmacokinetics of the carboxylic acid metabolite of terfenadine (Cmax, tmax, AUC) were not significantly changed after co-administration of either H2 antagonist. None of the remaining 5 subjects in either cohort demonstrated accumulation of unmetabolised terfenadine after addition of the respective H2 antagonist and electrocardiographic QT intervals and T-U morphology in them was not changed during the course of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

This paper has studied the effect of i.v. cimetidine and ranitidine, given 1 h prior to anesthesia, on gastric volume and pH in three homogeneous groups undergoing emergency surgery. Group I (10 patients) received placebo, group II (20 patients) cimetidine 400 mg in saline solution, and group III (20 patients) ranitidine 150 mg in saline. Standardised premedication was administered and anesthesia induced. Immediately after tracheal intubation the stomach contents were aspirated and analysed for volume and pH. There were no significant differences in gastric volume among the three groups. However, treated patients had significantly elevated pH as compared with the control group and the number of patients at risk (pH < 2.5 and volume > 25 ml) was significantly smaller at 20% and 15%, respectively, than in the control group (40%). It is concluded that cimetidine 400 mg, and ranitidine 150 mg i. v., given about 70 min. prior to induction of anesthesia may decrease the risk of the acid aspiration syndrome in emergency operations.

In a prospective, randomized, single-blind, single-center, controlled study, we compared the effectiveness of single doses of cimetidine 800 mg, ranitidine 300 mg, and famotidine-40 mg given either as evening or morning doses for duodenal ulcer healing. One hundred eighty-six male patients with endoscopically confirmed duodenal ulcer were treated for 6 wk, and ulcer healing was endoscopically evaluated. The duodenal ulcer healing rate for each of the three H2-receptor antagonists was always less after morning administration than was achieved with the respective evening regimen: 59% versus 86% for cimetidine, 83% versus 94% for ranitidine, and 93% versus 97% for famotidine, but the difference was statistically significant for cimetidine only. This study confirms the importance of nocturnal therapy for duodenal ulcer healing. The importance is obscured when H2-receptor antagonists with higher potency and long duration of action are used.

Gastric emptying was measured using applied potential tomography (APT) after crossover administration of 800 mg cimetidine and 300 mg ranitidine orally. Ten volunteers were studied, each on two occasions. Two hours after taking ranitidine or cimetidine, the volunteer was given a liquid and gastric emptying was measured over 60 min. There was a small but statistically significant delay in gastric emptying following ranitidine compared with cimetidine (P less than 0.04). The median (range) time to 50% emptying (t50) was 24 (15-60) min after ranitidine compared with 22 (15-46) min after cimetidine.

Recently the term H2 receptor antagonist-resistant (H2RA-resistant) ulcer has been used increasingly commonly, instead of the conventional term of intractable ulcer, to designate an ulcer which does not respond to treatment with an H2 receptor antagonist (H2RA). However, many authors report that an H2RA resistant ulcer can be cured by increasing the dosage of H2RA, or using another H2RA. In this study, the absorption and bioavailability of oral doses of each of three H2RAs, which are possible factors in these effects, were studied in healthy volunteers. The results showed that there was a great difference in bioavailability between cimetidine (80%), famotidine (39%) and ranitidine (50%). The lower bioavailability of famotidine and ranitidine may be partially explained by the following facts: 35.8% to 57.8% of orally administered famotidine is decomposed in gastric acid (pH 1) before absorption; and about 50% of ranitidine is metabolized in the liver before distribution (first-pass effect). Thus famotidine and ranitidine should be carefully administered to patients with slow gastric emptying and hepatic dysfunction, respectively. In general practice, many patients may not respond well to treatments because of their poor absorption, or extensive metabolism. In such cases, further effectiveness and safety could be expected if another H2RA, appropriately tailored to patients' conditions, were chosen. On the basis of these findings, it would seem premature to conclude that H2RA-resistant ulcer exists.

Histamine-2 receptor antagonists have been available for fifteen years for the treatment of peptic ulcer disease and related disorders. While very safe, clinicians need to know correct dosing guidelines, drug interactions, and side effect profiles. Long-term therapy should be reserved for patients at high risk of recurrence.

Purpose: We performed a randomized controlled trial to compare the efficacy of seven forms of maintenance treatment of duodenal ulcer, including a mealtime regimen of antacids., Patients and Methods: We randomized 785 patients with healed duodenal ulcer to receive: (1) no treatment; (2) mealtime antacids with an acid-neutralizing capacity of 80 mmol/day; (3) an antidepressant, trimipramine 25 mg; (4) an anticholinergic, pirenzepine 50 mg; (5) cimetidine 200 mg; (6) cimetidine 400 mg; (7) ranitidine 150 mg; or (8) sucralfate 1 g twice a day. Symptomatology and side effects were assessed every 2 months and endoscopy was performed every 4 months up to 1 year., Results: The patients were comparable in the majority of clinical characteristics before entry. The cumulative percentages of patients with relapse of ulcers at 12 months by life-table analysis were 61% with no treatment, 38% with mealtime antacids, 60% with trimipramine, 52% with pirenzepine, 46% with cimetidine 200 mg, 44% with cimetidine 400 mg, 30% with ranitidine 150 mg, and 40% with sucralfate. Cimetidine 400 mg, antacids, ranitidine 150 mg, and sucralfate were significantly better than no treatment and the other forms of treatment. Ranitidine was significantly better than antacids, cimetidine, and sucralfate in preventing endoscopically documented duodenal ulcer relapse by multiple comparison at 12 months, but not by life-table analysis nor when symptomatic relapses were compared. No significant difference was detected among antacids, cimetidine, and sucralfate. No major side effects occurred with the seven forms of treatment, but those receiving antacids had the highest incidence of minor adverse events (26%)., Conclusion: This study suggests that mealtime antacids are as effective as H2-receptor antagonists and sucralfate in the maintenance treatment of duodenal ulcer disease, but have to be taken three times a day and had the highest incidence of reported minor adverse events. The relapse rate was lower with ranitidine than with cimetidine, sucralfate, and antacids, but the difference was small and may not be clinically important.

Ranitidine may be used at doses of up to 300 mg twice daily in the healing of duodenal ulcers, and this study investigated the potential for a pharmacokinetic or pharmacodynamic interaction between nifedipine 10 mg three times daily and ranitidine 300 mg twice daily compared with cimetidine 800 mg daily and placebo in a randomised crossover study in 18 healthy male subjects. Twelve blood samples were taken on the fifth day in each treatment period and assayed for nifedipine by h.p.l.c. Pulse, blood pressure and ECG recordings were also taken. Cimetidine, but not ranitidine, produced significant changes in the pharmacokinetics of nifedipine at steady state. Mean +/- s.d. values of AUC were 105 +/- 40 micrograms l-1 for placebo treatment, 111 +/- 45 micrograms l-1 h for ranitidine and 211 +/- 64 micrograms l-1 h for cimetidine (P less than 0.001), and Cmax values were 33 +/- 14, 39 +/- 27 and 76 +/- 40 micrograms l-1 (P less than 0.001), respectively. Neither ranitidine nor cimetidine produced statistically significant changes in the pharmacological response to nifedipine.

Plasma alcohol concentration following oral ingestion of 0.3 g/kg of alcohol (ethyl alcohol), one hour after an evening meal, was measured in four groups of 12 healthy subjects. Each group had a control study and a repeat study after 7 days dosing with either placebo or an H2-receptor antagonist (300 mg ranitidine nocte, 800 mg cimetidine nocte, or 40 mg famotidine nocte). There was no significant difference between the control and post-dosing studies in the integrated 4-h plasma alcohol concentration, peak plasma alcohol concentration, or time to reach peak alcohol concentration. This study shows that post-prandial alcohol absorption after 0.3 g/kg of alcohol is not affected by ranitidine, cimetidine or famotidine.

Twenty-five patients with bleeding peptic ulcers were randomized to receive either ranitidine 50 mg 8 hourly i.v. (control group) or a continuous nasogastric antacid infusion at the rate of 0.5 ml/min along with an i.v. injection of cimetidine 100 mg/h (treatment group). Twelve patients were included in the control group and 13 in the treatment group. The mean gastric pH on therapy was significantly higher in the treatment group (7.88 +/- 0.37) than in the control group (5.00 +/- 0.55) (p less than 0.001), and the gastric pH was noted to be greater than 7 on 95% of the occasions in the treatment group and on 8.6% of the occasions in the control group. An overall control of bleeding was achieved in 92.3% of the patients in the treatment group and 50% of the patients in the control group (p less than .05). Thus, the failure of therapy was significantly more common in the control group than in the treatment group (p less than 0.05), and more patients of the control group had to undergo emergency surgery than that in the treatment group. None of the patients in the treatment group, but 16.6% of the patients in the control group, died during the study period in the hospital stay. We conclude that in patients with bleeding peptic ulcer an intensive medical therapy comprising hourly injections of cimetidine (or presumably of other H2 blockers) and continuous nasogastric antacid infusion can achieve sustained achlorhydria, better control of bleeding, and reduce the need for emergency surgery.

The effects of intramuscular administration of multiple doses of cimetidine and ranitidine on basal gastric pH, free and total acid content from young adult pigs were studied. Cimetidine (4.5 mg kg-1, four times a day, intramuscularly, for three days) significantly (P less than 0.05) raised the basal gastric pH above 3.5 with a simultaneous reduction in free acid content at two, three and 26 hours after the administration of the eighth dose. Ranitidine (0.75 mg kg-1, four times a day, intramuscularly, for three days) significantly (P less than 0.05) raised the basal gastric pH above 3.5 with a concomitant reduction in free acid content at three and 38 hours after the administration of the eight dose. Neither cimetidine nor ranitidine had any significant effects on total acid content. These results confirm that the pig is a basal acid secretor and that the pharmacodynamics and pharmacokinetics of cimetidine and ranitidine in pigs might be different from those in humans.

The steps taken to implement a therapeutic interchange program for i.v. histamine H2-receptor antagonists and to determine the potential cost savings are described. A literature review conducted by pharmacists at a 273-bed nonteaching community hospital showed that i.v. famotidine was as safe and effective as i.v. cimetidine or ranitidine and that it was feasible to add famotidine to total parenteral nutrition (TPN) solutions. Because of famotidine's cost advantage, it was proposed that i.v. famotidine be used in place of specific dosage regimens of i.v. ranitidine or cimetidine and in TPN solutions ordered for patients receiving concurrent H2-antagonist therapy. The approval of the hospital attorney and hospital gastroenterologists was secured, and a formal proposal was submitted. The pharmacy department distributed a memorandum describing the advantages of famotidine, conducted inservice education sessions, and sought the compliance of physicians by placing reminders on order forms and patient charts and by contacting physicians directly. The program was implemented in May 1989. During the first three months, only one physician insisted that patients receive i.v. ranitidine rather than famotidine. It was projected that the interchange of i.v. famotidine for cimetidine or ranitidine would result in a total savings of $37,565 during the first year due to reductions in the cost of drugs, supplies, and nursing labor. The acceptance of a therapeutic interchange program for H2 antagonists was excellent, and the projected savings are substantial.

The effects of two pharmacologically distinct histamine H2 receptor antagonists were studied in combination with ibuprofen (I) and diphenhydramine (D) in a porcine model of septic ARDS. Cimetidine (C) is reported as having direct oxygen radical scavenging abilities and is an inhibitor of cytochrome P-450, whereas ranitidine (R) acts solely by H2 receptor blockade. Four groups were studied: Group Ps (n = 8) received a continuous infusion of live Pseudomonas aeruginosa 5 x 10(8) CFU/ml at 0.3 ml/20kg/min, Group C (n = 6) received a control saline infusion, and the treatment groups received I (12.5 mg/kg) and D (10 mg/kg) in combination with either C (150 mg, CID, n = 6) or R (25 mg, RID, n = 5) given at 20 and 120 minutes after the onset of Ps. Pulmonary (PAP) and systemic (SAP) arterial pressures, cardiac index (CI), PaO2, thermal cardiogreen extravascular lung water (EVLW) and scintigraphically determined pulmonary albumin flux (slope index, SI) were measured. Ps infusion produced significant (p less than 0.05) cardiovascular collapse, hypoxemia and increased EVLW and SI. Both CID and RID temporarily reversed pulmonary arterial hypertension and maintained PaO2, EVLW, SAP and CI at control levels throughout the study, and significantly improved SI at 180 min. These results suggest that cimetidine and ranitidine act in this combination therapy primarily as H2 receptor antagonists.

Thirty adults with chronic obstructive airways disease, who were stabilised on theophylline and corticosteroids, took part in a single blind study of the effects of cimetidine and ranitidine on plasma theophylline concentrations. The patients were randomised to receive either 150 mg ranitidine b.d. or 400 mg cimetidine b.d. for one week and serial plasma theophylline measurements were made over a 12-hour period on two consecutive days before, during and after treatment with the H2-antagonist. There was a significant increase in plasma theophylline during treatment with cimetidine; two patients had levels greater than 20 mg.l-1. The average increase in the theophylline concentration due to cimetidine was 32%. There was no significant change in plasma theophylline during ranitidine administration. No adverse effect occurred in any patient during the study.

The effect on gastric emptying of 400 mg cimetidine and two doses of ranitidine (150 and 300 mg) given orally was evaluated in 45 patients with endoscopically proved duodenal ulcer and in 28 healthy controls. Gastric emptying of a radiolabeled solid phase meal was assessed. Cimetidine was confirmed not to have any significant influence on gastric emptying in duodenal ulcer patients or in healthy subjects. The significant delay in gastric emptying observed with ranitidine was dose dependent, and at the same time more pronounced in patients with duodenal ulcer than in healthy subjects. Early ulcer healing was unrelated to the changes in gastric emptying elicited by the tested drugs.

Ranitidine and cimetidine are competitive antagonists of histamine at H2-receptor sites in the gastric mucosa. Both drugs reduce output of basal and stimulated gastric acid and pepsin secretion in normal healthy subjects and duodenal ulcer patients. Pharmacodynamic and pharmacokinetic differences exist between the drugs, some of which are of clinical significance. Ranitidine is a 6-8 times more potent inhibitor of gastric secretions and also causes a greater reduction in intragastric acidity of nocturnal secretions after usual therapeutic doses. Absorption from the gastrointestinal tract of both drugs is good, with peak plasma concentration occurring approximately 90 minutes after oral administration. Systemic bioavailability is approximately 70% with cimetidine and 50% with ranitidine. Both drugs demonstrate biexponential elimination curves from the plasma after intravenous administration and a bimodal curve after oral administration which is probably the result of enterohepatic recirculation. The elimination half-lives of cimetidine and ranitidine are 1.7-2.1 hours and 2.1-3.1 hours, respectively, with apparent volumes of distribution approximating 50L and 75L, respectively. Both drugs are eliminated, largely unchanged, via the kidneys. Major differences between these agents are found in cimetidine's biological activity at sites other than the gastric H2-receptors. These include: antiandrogenic effects with the appearance of feminizing characteristics in men, especially with large doses, like those used to treat Zollinger-Ellison syndrome; interference with the hepatic P-450 mixed-function oxidase enzyme system, which results in drug interactions with warfarin, phenytoin, theophylline and other drugs; and central nervous system effects characterized by confusion, particularly in elderly patients and those with renal failure. Such side effects have not been directly related to ranitidine treatment and substitution of ranitidine for cimetidine has reportedly provided effective alternative treatment in patients intolerant to cimetidine.

The effect of concurrent ranitidine administration on the disposition of pethidine was investigated in eight healthy male volunteers (19-33 years). The subjects received 70 mg i.v. pethidine HCl doses before and during ranitidine treatment (150 mg p.o. twice daily). Ranitidine therapy was not associated with significant alterations in pethidine elimination rate constant, volume of distribution at steady state, total body clearance, and 24 h urinary excretion. No alteration in pethidine oxidation to norpethidine was noted, as suggested by nonsignificant changes in lag time to appearance of quantifiable norpethidine in serum, time to peak concentration, peak concentration, area under the curve from time 0.24 h, and 24 h urinary excretion. It would appear that, unlike cimetidine, ranitidine does not interact pharmacokinetically with pethidine. Further studies are necessary to evaluate the potential clinical advantages of ranitidine vs cimetidine therapy in patients also receiving pethidine.