piperidines and roxatidine-acetate

The aim of the review is to evaluate the putative clinical interactions between alcohol metabolism and the administration of H2-receptor antagonists. Places of the first-pass metabolism of ethanol in the body have been investigated as well. According to the in vitro experimental results the H2-receptor antagonists can inhibit the ethanol metabolism which may have clinical relevance. When low doses of alcohol (below 0.3 g/kg) are given per os, the administration of H2-receptor antagonists results in an increase in the blood ethanol concentrations. Since that challenged increase never exceeds the level of 0.3/1000 blood alcohol concentration, it has hardly any clinical or medico-legal significance.

Topics: Cimetidine; Clinical Medicine; Drug Interactions; Ethanol; Famotidine; Gastric Mucosa; Histamine H2 Antagonists; Humans; Liver; Nizatidine; Piperidines; Ranitidine

Gastro-oesophageal reflux disease (GORD) is a very common disorder of upper gastro-intestinal motility, differing widely in severity and prognosis. Medical therapy of GORD has involved antacids, alginates, prokinetic agents and antisecretory compounds, primarily H2 receptor antagonists and proton pump inhibitors. Knowledge of the pharmacokinetics of these compounds is important, to optimise the therapeutic benefit in each patient. GORD patients are often elderly and pharmacokinetics are move variable in this group. Furthermore, they often suffer from other diseases needing medical therapy and may need a combination of drugs to heal reflux oesophagitis and relieve reflux symptoms. The ideal therapy for GORD will have linear pharmacokinetics, a relatively long plasma half-life (t1/2), a duration of action allowing once daily administration, and a stable effect independent of interactions with food, antacids and other drugs. Over-the-counter antacids and alginates are widely used, buy may affect absorption of H2 receptor antagonists like cimetidine and ranitidine. Aluminium-containing antacids may, over time, cause toxicity in patients with renal insufficiency. In the treatment of GORD, cisapride presents important advantages over earlier prokinetic compounds, with a longer plasma t1/2, low penetration of the blood-brain barrier and fewer adverse effects. The group of H2 receptor antagonists is still the most frequently use therapy for GORD. Linear pharmacokinetics make dose adjustments easy and safe. In individual patients, suppression of gastric secretion is related to the area under the plasma concentration-time curve (AUC), but there is wide interindividual variation in the effect of the same oral dose. Only with frequent administration and high doses will acid suppression approximate that of proton pump inhibitors. Tolerance, with loss of effect over time, however, is most pronounced in this situation. H2 receptor antagonists seem well suited for on-demand treatment of reflux symptoms, due to the rapid onset of effect and a decrease likelihood of the development of tolerance. Effervescent formulations provide more rapid absorption and almost immediate clinical effect. Cimetidine, however, causes interference with the metabolism of several other drugs in common use. In elderly patients elimination is delayed and in patients with renal insufficiency, dose reductions of all H2 receptor antagonists are recommended. The most effective medical therapy for any

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Antacids; Benzimidazoles; Cimetidine; Cisapride; Domperidone; Famotidine; Gastroesophageal Reflux; Histamine H2 Antagonists; Humans; Lansoprazole; Metoclopramide; Nizatidine; Omeprazole; Pantoprazole; Piperidines; Proton Pump Inhibitors; Ranitidine; Sucralfate; Sulfoxides

Roxatidine acetate is a histamine H2-receptor antagonist which, after almost complete oral absorption (greater than 95%), is rapidly converted to its active metabolite, roxatidine, by esterases in the small intestine, plasma and liver. Roxatidine is a potent inhibitor of basal and stimulated gastric acid secretion in animals and humans and, like most other H2-receptor antagonists, has no anti-androgenic effects and does not interfere with the hepatic metabolism of other drugs. Large-scale trials have shown that roxatidine acetate 150mg per day is as effective as standard doses of cimetidine and ranitidine in the treatment of patients with duodenal or gastric ulcer, and that roxatidine acetate 75mg in the evening is likely to become a 'standard' regimen for the prevention of peptic ulcer recurrence. Preliminary data also suggest that roxatidine acetate may be useful in the treatment of reflux oesophagitis and stomal ulcer, and in the prevention of pulmonary acid aspiration. Roxatidine acetate is an H2-receptor antagonist which has been well tolerated in clinical trials. However, broader experience is required before definitive statements about tolerability relative to other H2-receptor antagonists can be made, and before the role of roxatidine acetate in the treatment of reflux oesophagitis and stomal ulcer, and the prophylaxis of acid aspiration pneumonitis, can be clearly defined.

Topics: Animals; Drug Evaluation; Histamine H2 Antagonists; Humans; Peptic Ulcer; Piperidines

The first H2-receptor antagonist, cimetidine, has been succeeded by ranitidine, and more recently nizatidine and famotidine. Others will doubtless follow. The pharmacodynamic differences between cimetidine and ranitidine, in terms of potency, are not obviously translated into therapeutic differences. Some studies have shown that the increased potency of standard doses of ranitidine affords an advantage, in terms of ulcer healing and relapse, over cimetidine. The therapeutic effects of these drugs can be predicted from their pharmacodynamic profiles and in the doses recommended differences between the newest agents and ranitidine would not be expected. It is, thus, difficult to define a specific clinical role for the newer drugs on the grounds of efficacy. Their importance may relate to the provision of encouragement for future drug development.

Topics: Animals; Famotidine; Histamine H2 Antagonists; Humans; Nizatidine; Peptic Ulcer; Piperidines; Thiazoles

This article reviews the published and unpublished results of pharmacokinetic studies with roxatidine acetate in healthy volunteers of different ethnic origins, patients with various degrees of renal impairment, patients on maintenance hemodialysis, lactating women, and elderly patients. In addition, it reports on the findings of interaction studies with food and other drugs. The pharmacokinetic characteristics of roxatidine were found to be nearly identical for different doses, formulations, and ethnic groups. The decrease in relative total clearance (oral clearance) in patients with renal impairment and in the elderly can be explained almost completely by their level of renal function. As expected from the pharmacokinetic characteristics in healthy volunteers, only a small amount of roxatidine is removed by hemodialysis. Dose reduction is recommended in patients with renal impairment, but dose supplementation after hemodialysis is not necessary. Only a negligible fraction of the dose administered is excreted with breast milk. No pharmacokinetic interactions were found with theophylline, warfarin, propranolol, diazepam, and desmethyldiazepam, antipyrine or antacids. Food did not interfere with the absorption or disposition of roxatidine.

Topics: Aged; Aged, 80 and over; Drug Interactions; Female; Histamine H2 Antagonists; Humans; Lactation; Piperidines; Pregnancy; Renal Dialysis

There was no significant difference between the concentration-dependent inhibitory effects produced by roxatidine acetate, roxatidine and ranitidine on adenylate cyclase derived from isolated and enriched guinea-pig parietal cells. All the compounds shifted the concentration-response curve of histamine to the right and transformation of this data to Schild-plots produced straight lines with slopes greater than 1 but not significantly different from each other. The pA2 values characterising the potencies were roxatidine acetate 6.85 +/- 0.86, roxatidine 7.14 +/- 0.04, and ranitidine 6.92 +/- 0.01. Histamine-stimulated acid production from isolated guinea-pig parietal cells, measured by the 14C-aminopyrine accumulation technique, was similarly affected by the 3 compounds. Schild-plot slopes of roxatidine acetate and ranitidine were not significantly different from unity and pA2 values were similar to those of the adenylate cyclase inhibition, roxatidine acetate 7.15 +/- 0.09, roxatidine 7.03 +/- 0.02, and ranitidine 6.83 +/- 0.10. In conclusion, roxatidine acetate and its major metabolite roxatidine behave like competitive antagonists with potencies similar to ranitidine on H2-receptors on the guinea-pig parietal cell.

Topics: Histamine H2 Antagonists; Humans; Piperidines; Ranitidine; Receptors, Histamine H2

In this paper the effects of chronic renal failure on the pharmacokinetics of H2-antagonists are reviewed and the results obtained with roxatidine presented. In normal renal function renal clearance is around 60-80% of total plasma clearance of all H2-antagonists. Consequently, prolongation of serum half-life, mainly due to a decrease in urinary excretion, is noted in patients with decreasing glomerular filtration rate. In chronic renal failure, a dose reduction is therefore necessary with all H2-antagonists, including roxatidine. It appears that neither haemodialysis nor peritoneal dialysis substantially influences the pharmacokinetics of these drugs. Therefore, the same dosage schedule as in uraemia may be applied in patients with dialysis. Finally, in the elderly the dosage of all H2-antagonists should be adapted to the expected decrease in renal function.

Topics: Anti-Ulcer Agents; Cimetidine; Famotidine; Histamine H2 Antagonists; Humans; Kidney Failure, Chronic; Piperidines; Ranitidine; Renal Dialysis; Thiazoles

Pharmacodynamic studies revealed that 150 mg of roxatidine acetate were optimal in suppressing gastric acid secretion, and that a single bedtime dose of 150 mg was more effective than a dose of 75 mg twice daily in terms of inhibiting nocturnal acid secretion. When administered orally as a capsule containing a granule formulation, the drug displayed modified-release properties, which led to a sustained suppression of gastric acid secretion. Clinical trials revealed that roxatidine acetate, 75 mg twice daily and 150 mg at night, was highly effective in healing duodenal and gastric ulcers and in reducing ulcer pain, over 4, 6, and 8 weeks of therapy. A steady reduction in diameter was observed in those ulcers not completely healed during therapy. The single bedtime dose regimen, while producing the same degree of healing as the divided daily dose during controlled clinical trials, may be of greater value in therapeutic use owing to improved patient compliance. In all efficacy criteria (cure, reduction in ulcer size, and pain relief) there was no significant difference between roxatidine acetate in a total daily dose of 150 mg, ranitidine in a total daily dose of 300 mg, and cimetidine in a total daily dose of 800 mg. Prevention of gastric and duodenal ulcer relapse was achieved by roxatidine acetate, 75 mg at night for 6 months, in about 70% of patients, as determined in open, pilot studies--a rate comparable to those reported for cimetidine and ranitidine. Roxatidine acetate shares with ranitidine an improved safety profile when compared with cimetidine. Human pharmacology studies and short-term and long-term clinical trials have all shown that roxatidine acetate is an exceptionally well tolerated compound, without the antiandrogenic activity and interference with hepatic drug metabolism which have characterized cimetidine treatment. A reason for the improved safety profile of roxatidine acetate may be its greater potency than cimetidine (six times less potent) and ranitidine (half as potent), so that lower doses of roxatidine acetate, representing a lower chemical load, are therapeutically effective. The novel structure of roxatidine acetate probably also underlies the improved safety of the compound.

Topics: Cimetidine; Clinical Trials as Topic; Duodenal Ulcer; Gastric Acid; Histamine H2 Antagonists; Humans; Piperidines; Ranitidine; Stomach Ulcer

Possible mechanisms of drug interactions with H2-antagonists are outlined. The mode of action of roxatidine acetate on hepatic microsomal enzymes is contrasted with those of cimetidine and ranitidine, and their differing structure-activity relationships are discussed. In the light of the mechanisms of drug interactions with H2-antagonists, clinical studies with roxatidine acetate are contrasted with published interaction data of cimetidine and ranitidine. The therapeutic consequences of these data are considered.

Topics: Anti-Ulcer Agents; Cimetidine; Drug Interactions; Histamine H2 Antagonists; Humans; Peptic Ulcer; Piperidines; Ranitidine; Structure-Activity Relationship

This study aimed to evaluate the bioequivalence between a generic roxatidine acetate hydrochloride (RAH) sustained-release capsule and brand-named formulation (ALTAT) under fasting and fed conditions. An open-label, single-center, randomized 2-period crossover study with a 5-day washout period was conducted. A single oral dose of 75-mg generic RAH sustained-release capsule (test drug) or a commercial capsule (reference drug) was given to healthy volunteers under fasting (n = 36) and fed conditions (n = 36). Blood samples were collected at baseline and during the 24 hours after dosing. The concentrations of roxatidine acetate (ROX) and bioactive metabolite roxatidine in plasma were detected using a validated high-performance liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were analyzed with noncompartmental methods. As prodrug, RAH was dehydrochloric acid to ROX in body and further rapidly converted to roxatidine. Such a rapid metabolism resulted in ROX that was hardly detected in plasma. Active metabolism roxatidine was therefore used to evaluate the pharmacokinetic process. The major pharmacokinetic parameters of roxatidine including peak plasma concentration, area under the plasma concentration-time curve from time 0 to time t, and area under the plasma concentration-time curve from time 0 to infinity were similar between the 2 preparations under fasting and fed conditions. The generic RAH sustained-release capsule is bioequivalent to the reference drug under fasting and fed conditions in healthy Chinese subjects.

Topics: Area Under Curve; Capsules; China; Cross-Over Studies; Delayed-Action Preparations; Drugs, Generic; Healthy Volunteers; Humans; Piperidines; Tablets; Therapeutic Equivalency

The ideal medication for the treatment of acid-related diseases, e.g., peptic ulcers, stress-related gastric bleeding, functional dyspepsia, and gastroesophageal reflux disease, should have a rapid onset of action to promote hemostasis and relieve the symptoms. The aim of our study was to investigate the inhibitory effects on gastric acid secretion of a single oral administration of a proton pump inhibitor, omeprazole 20 mg, and an H(2)-receptor antagonist, roxatidine 75 mg.. Ten Helicobacter pylori-negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 6 h after single oral administration of omeprazole 20 mg and roxatidine 75 mg. Each administration was separated by a 7-d washout period.. During the 6-h study period, the average pH after administration of roxatidine was higher than that after administration of omeprazole (median: 4.45 vs. 2.65; P=0.0367). Also during the 6-h study period, a longer duration of maintenance at pH above 2, 5, and 6 was observed after administration of roxatidine 75 mg than after administration of omeprazole 20 mg (median: 90.6% vs. 55.2%, P=0.0284; 43.7% vs. 10.6%, P=0.0125; 40.3% vs. 3.3%, P=0.0125; respectively).. In Helicobacter pylori-negative healthy male subjects, oral administration of roxatidine 75 mg increased the intragastric pH more rapidly than that of omeprazole 20 mg.

Topics: Adult; Cross-Over Studies; Gastric Acid; Gastric Acidity Determination; Histamine H2 Antagonists; Humans; Hydrogen-Ion Concentration; Male; Omeprazole; Piperidines; Proton Pump Inhibitors; Young Adult

Clinical studies were conducted to investigate the pharmacokinetics of roxatidine acetate hydrochloride capsules (ALTAT(®) CAPSULES) in children. In a single-dose pharmacokinetic (PK) study in pediatric patients aged between 6 and 14 years with acid-related diseases, 37.5 mg or 75 mg roxatidine capsules were given orally, and blood samples were collected to determine the plasma roxatidine concentrations. Meanwhile, a single-dose PK study in healthy adult volunteers was newly conducted; subjects were given 37.5 mg, 75 mg or 150 mg roxatidine capsules. Differences were present between the PK parameters in pediatric patients and those in healthy adult volunteers. However, the CL/F and Vd/F adjusted by body surface area (BSA) or body weight (BW) were comparable. A close correlation of the C(max) and AUC(0-∞) to the dose per unit BSA (mg/m(2)) or BW (mg/kg) was also shown. In the multiple-dose study in pediatric patients, no roxatidine accumulation in plasma was observed, as was the case with a previous study in adults. These data show that the PK profile of roxatidine in pediatric patients is similar to the profile in healthy adult volunteers when adjusted by BSA or BW.

Topics: Administration, Oral; Adolescent; Adult; Age Factors; Anti-Ulcer Agents; Area Under Curve; Body Surface Area; Body Weight; Capsules; Child; Drug Dosage Calculations; Female; Histamine H2 Antagonists; Humans; Japan; Male; Metabolic Clearance Rate; Models, Biological; Piperidines; Reproducibility of Results

Recent preanesthetic fasting practice allows patients to take clear fluids up to 2 h before surgery without taking any antacid for the prophylaxis of aspiration pneumonia; this practice is defined as oral rehydration therapy (ORT). It has been reported that with ORT the gastric volume may be significantly lower than that with a standard fasting regimen, although in a standard fasting regimen without preanesthetic antacid, gastric pH and volume values could be critical for causing aspiration pneumonia. In this study we compared gastric fluid status in patients with ORT and those with a standard fasting regimen; patients in both groups received a preanesthetic H(2) antagonist. One hundred and four patients were randomly assigned to either the ORT or standard fasting group, and all were given roxatidine 75 mg 2 h before surgery. After the induction of anesthesia, the gastric contents were collected via a gastric tube to measure gastric volume and pH. Neither gastric volume nor pH differed between the groups (ORT 9.6 ± 8.2 ml and 5.6 ± 1.7, respectively, vs. standard fasting 8.5 ± 6.8 ml and 5.5 ± 1.7, respectively). These data suggest that ORT may not reduce gastric volume in patients receiving a preanesthetic H(2) antagonist.

Topics: Adult; Aged; Aged, 80 and over; Anesthesia, General; Fasting; Female; Fluid Therapy; Gastric Acidity Determination; Histamine H2 Antagonists; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Piperidines; Pneumonia, Aspiration; Preoperative Care; Stomach; Young Adult

Proton pump inhibitors have been reported to be more useful than histamine-2 receptor antagonists for the prevention of bleeding after endoscopic submucosal dissection (ESD) for superficial gastric neoplasia. The aim of this study was to assess the effects of the proton pump inhibitor lansoprazole and the histamine-2 receptor antagonist roxatidine for the prevention of bleeding and the promotion of ulcer healing after ESD and to compare the cost-effectiveness of these two drugs.. The study subjects were 129 patients who underwent ESD for superficial gastric neoplasia. The patients were randomly assigned to the lansoprazole group (L group) or the roxatidine group (R group). Either drug was administered intravenously from the morning of the ESD day to the day after the ESD, followed by oral treatment for an additional 8 weeks. A second-look endoscopy was performed on the day after the ESD, and a repeat endoscopy was performed at 8 weeks after the ESD. The incidence of bleeding and the ulcer-healing rate at 8 weeks after the ESD were analyzed, as well as the total cost of treatment with these antisecretory agents.. Three patients in each group were excluded from the analysis, leaving 62 patients in L group and 61 in R group. Two of the 62 patients (3.2%) in L group and three of the 61 patients (4.9%) in R group showed bleeding after ESD ; there was no significant difference between the two groups (P = 0.68). The ulcer-healing rate was 93.5% (58/62) in L group and 93.4% (57/61) in R group (P = 1). The total cost of treatment with the antisecretory agent from the day of the ESD to day 56 after the ESD was Yen 13,212 for lansoprazole and Yen 5,841 for roxatidine.. Roxatidine appears to have high cost-effectiveness in the prevention of bleeding and in the promotion of ulcer healing after ESD for superficial gastric neoplasia.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Aged; Aged, 80 and over; Anti-Ulcer Agents; Cost-Benefit Analysis; Dissection; Female; Gastric Mucosa; Gastrointestinal Hemorrhage; Gastroscopy; Humans; Lansoprazole; Male; Middle Aged; Pilot Projects; Piperidines; Postoperative Complications; Prospective Studies; Stomach Neoplasms; Stomach Ulcer; Treatment Outcome

The H(2) receptor antagonist roxatidine is routinely used as an oral pre-anesthetic medication in surgical patients at night and 2 h before surgery. In the present study, we have compared the effects of roxatidine, rabeprazole and lansoprazole given singly at night as an alternative to the standard double roxatidine medication.. 120 adult patients undergoing urological surgery were randomly assigned to three groups: roxatidine, rabeprazole and lansoprazole (n = 40 each). Following induction of anesthesia, gastric fluid was obtained by aspiration using a syringe to measure pH and volume of gastric contents.. Gastric volume (14.1 +/- 1.9 mL) in the lansoprazole group was significantly larger than that in roxatidine (8.6 +/- 1.7 mL) and rabeprazole (7.5 +/- 1.1 mL) groups (P < 0.05). Gastric pH in lansoprazole group (4.10 +/- 0.38) was also significantly lower than that in the roxatidine group (5.41 +/- 0.31, P < 0.05). The numbers of patients with critical factors for acid aspiration pneumonia (gastric pH < 2.5 or volume > 25 mL) in the lansoprazole group was significantly higher than in the roxatidine group (P < 0.05). Gastric pH and volume in all groups were constant even in the afternoon.. Single rabeprazole (but not lansoperazole) medication may be a suitable alternative to standard roxatidine for prophylaxis of acid aspiration pneumonia.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Administration, Oral; Aged; Drug Administration Schedule; Female; Gastric Acidity Determination; Histamine H2 Antagonists; Humans; Lansoprazole; Male; Middle Aged; Piperidines; Pneumonia, Aspiration; Preanesthetic Medication; Proton Pump Inhibitors; Rabeprazole; Respiratory Aspiration; Risk Factors; Treatment Outcome; Urologic Surgical Procedures

Aspiration of acid to the airway causes airway inflammation, and acid stress to the airway caused by gastroesophageal reflux disease (GERD) has been known as a potential mechanism of deteriorated asthma symptoms. However, the efficacy of the acid suppressive drugs, H(2)-receptor blockers (H(2) blocker) and proton pump inhibitors, on asthma symptoms and pulmonary functions remains controversial. We therefore designed the randomized prospective study to determine the efficacy of an H(2) blocker (roxatidine, 150 mg/day) and a proton pump inhibitor (lansoprazole, 30 mg/day) on asthma symptoms of 30 asthmatic patients with GERD. These patients were divided in the two groups (15 patients for each group) and treated with either roxatidine or lansoprazole. The diagnosis of GERD was established by the method of Los Angeles classification including mucosal minimum change of Grade M and questionnaire for the diagnosis of reflux disease (QUEST) score. The efficacy of acid suppressive drugs was evaluated by peak expiratory flow (PEF), asthma control questionnaire (ACQ) that evaluates the improvement of asthma symptoms, and forced expiratory volume in 1 second (FEV(1.0)). Lansoprazole, but not roxatidine, significantly improved PEF and ACQ scores (p < 0.05) with the improved QUEST scores. However, these acid suppressive drugs did not change the pulmonary function of FEV(1.0) in asthmatic patients. In conclusion, treatment with a proton pump inhibitor, lansoprazole, appears to be useful in improvement of asthma symptoms in asthmatic patients with GERD.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Administration, Oral; Adult; Aged; Asthma; Drug Evaluation; Female; Forced Expiratory Volume; Gastroesophageal Reflux; Humans; Lansoprazole; Male; Middle Aged; Omeprazole; Peak Expiratory Flow Rate; Piperidines; Prospective Studies; Proton Pump Inhibitors; Surveys and Questionnaires

The sensitivity of the urea breath test (UBT) has been reported to be influenced by the administration of omeprazole, lansoprazole and ranitidine. However, it is unclear whether other H2 receptor antagonists (H2RA), except ranitidine, and rebamipide, a mucosal protective agent, affect UBT sensitivity. The aim of this study is to clarify the effects of lansoprazole, famotidine, roxatidine and rebamipide administration on UBT sensitivity.. Subjects comprised 30 volunteers with Helicobacter pylori infection. All subjects were examined by the 13C-UBT on four occasions: (i) without medication (control); (ii) after the administration of 30 mg lansoprazole (u.i.d) for 14 days; (iii) after the administration of 100 mg rebamipide (t.i.d) for 14 days; and (iv) after the administration of 20 mg famotidine or 75 mg roxatidine (b.i.d) for 14 days. In the H2RA study, individuals were randomized into two groups of 15 subjects and were administered either famotidine or roxatidine.. Five of the 30 cases administered lansoprazole and one of the 15 cases given roxatidine gave a false-negative UBT result. No negative UBT results were observed in patients administered famotidine or rebamipide.. Patients showing negative UBT results during the administration of proton pump inhibitors and H2RA should be re-examined after the cessation of these drugs to confirm the true negativity of H. pylori infection.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Alanine; Anti-Ulcer Agents; Breath Tests; False Negative Reactions; Famotidine; Female; Helicobacter Infections; Helicobacter pylori; Humans; Lansoprazole; Male; Omeprazole; Piperidines; Predictive Value of Tests; Quinolones; Urea

Roxatidine acetate hydrochloride capsule is slowly absorbed from the gastrointestinal tract, and its acid suppressive effect on the stomach is long-lasting compared with other H2-blockers. The reduction of gastric juice in perioperative period is considered advantageous for patients not only because it decreases the risk for aspiration pneumonia but also because it reduces the risk of bronchial spasm induced by gastroesophageal reflux of acidic gastric content. The effects of single oral administration of roxatidine acetate hydrochloride 150 mg at night before the operation on the volume and pH of gastric juice were investigated during anesthesia using two types of anesthetic agents (isoflurane and propofol) in 93 patients of three age groups (group Y: age 20-40, group M: age 41-64, group O: age 65 <). The effect of roxatidine on reduction of gastric juice was found at the time of anesthetic induction and 2 hours after the induction in any age group with either anesthetic agent. The serum concentration of roxatidine at the time of induction was much higher in group O. The value of residual concentration of roxatidine 20 hours after oral intake was estimated from the intraoperative measurements of serum concentration. The results suggest that single administration at night before the operation is sufficient for the oldest group, but an additive dose is recommended for the younger groups.

Topics: Adult; Age Factors; Aged; Anesthesia, General; Bronchial Spasm; Delayed-Action Preparations; Depression, Chemical; Female; Gastric Acid; Histamine H2 Antagonists; Humans; Intraoperative Complications; Male; Middle Aged; Piperidines; Pneumonia, Aspiration; Preanesthetic Medication

This study was conducted using roxatidine acetate or Mylanta combined with metronidazole and amoxicillin to evaluate the role of acid and Helicobacter pylori in the natural course of the duodenal ulcer. Eighty-three patients with H. pylori positive duodenal ulcers were randomly allocated into one of four treatment groups. Group A: roxatidine 75 mg hs for 8 weeks; Group B: the same as group A + metronidazole 250 mg and amoxicillin 250 mg qid for 1 week on the 3rd week; Group C: Mylanta (combined hydroxide of magnesium and aluminum) 20 ml qid for 8 weeks; Group D: the same as group C + metronidazole 250 mg and amoxicillin 250 mg qid for 1 week on the 3rd week. Repeated endoscopies were performed on the 8th week post the initial treatment and the sixth and 12th month post the termination of treatment, or, at the earliest recurrence of symptoms. Eradication of H. pylori was considered to be successful if the culture, histology and CLO test all showed negative. The ulcer healing rates of Groups A, B, C and D were 95%, 100%, 61% and 86%, respectively, with a significant difference between A and C. The eradication rates of groups B and D were 81% and 62%, respectively, without any significant difference. The 12 months cumulative ulcer recurrence rates were 72%, 15%, 80% and 22%, respectively, with a significant difference between each paired groups with and without antibiotics. In conclusions, roxatidine is effective in the healing of duodenal ulcer. One-week roxatidine-based triple therapy is powerful in the eradication of H. pylori. Potent acid suppression is sufficient to heal the duodenal ulcer. Eradication of H. pylori can potentiate ulcer healing under insufficient acid suppression. A causal role for H. pylori in recurrent duodenal ulcer is strongly supported by a much lower recurrence of ulcer in H. pylori free patients.

Topics: Adolescent; Adult; Aged; Aluminum Hydroxide; Drug Combinations; Duodenal Ulcer; Female; Gastric Acid; Helicobacter pylori; Humans; Magnesium Hydroxide; Male; Middle Aged; Piperidines; Prospective Studies; Recurrence; Simethicone

To assess the usefulness of early evening administration of roxatidine 150 mg as an alternative to the traditional bedtime regimen.. Twenty-four patients with healed duodenal ulcer were dosed according to a balanced incomplete-block design, with two of the following regimens: placebo, roxatidine 150 mg at 07.30 h (early evening) or roxatidine 150 mg at 22.00 h (bedtime). Twenty-four-hour intragastric pH-metry was started at 18.00 h on the first day of dosing. Median pH was determined for the 24-h period, and for the following time intervals: 20.00-00.00 h, 00.00-08.00 h and 08.00-18.00 h. Percentage time in the 24-h period with pH greater than 4.0 was also calculated.. The two roxatidine regimens proved significantly superior to the placebo, decreasing 24-h acidity for all the time intervals, except the 20.00-00.00 h period, when mean intragastric pH with the early evening regimen (4.5 +/- 1.1) proved significantly higher than after placebo (2.2 +/- 1.0) or when roxatidine was taken at bedtime (2.4 +/- 1.1).. Early evening administration of roxatidine may afford satisfactory control of 24-h acidity, offering a useful alternative to conventional bedtime administration.

Topics: Administration, Oral; Adult; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Duodenal Ulcer; Female; Gastric Acid; Histamine H2 Antagonists; Humans; Male; Middle Aged; Piperidines

There is much experimental work on the occurrence of tolerance to the antisecretory effect of H2-receptor antagonists in healthy subjects, while data on its development in patients with duodenal ulcer are poor and conflicting. Moreover, this phenomenon has not been studied previously with 24 h gastric pH-metry in patients with active duodenal ulcer. For these reasons, we carried out a prospective pharmacodynamic investigation in 48 patients with endoscopically proven duodenal ulcer using the well-established once daily dosing schedule of H2 blockers. They were studied by means of 24 h continuous endoluminal pH-metry which was performed before, on d1 and d28 after receiving an oral bedtime dose (2200 hours) of either roxatidine 150 mg or ranitidine 300 mg, given in randomized and single-blind fashion. Eight patients did not complete the study for various reasons and 82% of ulcers healed after 4 weeks of therapy. Gastric pH was higher (P < 0.001) on d1 and d28 than basal values during all time periods, but the evening, with both H2 blockers. There was no significant difference between pH values of d1 and d28 in any time interval with both roxatidine and ranitidine. There was also no difference in pharmacodynamic data between the two active treatments. We conclude that tolerance does not develop after 1 month's treatment with a bedtime dose of H2 antagonist in patients with active duodenal ulcer and therefore data gathered on this phenomenon in healthy subjects are not applicable to ulcer patients.

Topics: Adult; Analysis of Variance; Drug Tolerance; Duodenal Ulcer; Female; Gastric Acidity Determination; Histamine H2 Antagonists; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Piperidines; Prospective Studies; Ranitidine; Single-Blind Method

The effect of preoperative oral fluid intake on the volume and pH of gastric fluid was examined in 45 elective surgical patients ranged in ages from 18 to 70 years. Two hours preoperatively they all received oral roxatidine 75 mg with 10 ml water, immediately followed by 150 ml oral water or 150 ml refreshing drink or no fluid as control. Just after the induction of anesthesia, a Salem-sump tube was put down to the stomach to collect gastric fluid in each patient. The volume and pH of gastric fluid taken were 10.9 +/- 7.9 ml, 16.3 +/- 2.3 in control group, 8.0 +/- 6.0 ml, 6.2 +/- 2.4 in the water group and 6.3 +/- 6.0 ml, 7.1 +/- 1.7 in the refreshing drink group. As there were no significant differences in gastric pH values in the three groups, the highest value was found in the refreshing drink group. No significant difference in VAS of hungry and thirsty feeling was found among the three groups. We conclude that preoperative oral water or refreshing drink with roxatidine 75 mg 2 hours before the start of anesthesia may not increase the risk of aspiration during the induction of anesthesia.

Topics: Adolescent; Adult; Aged; Drinking; Elective Surgical Procedures; Female; Gastric Juice; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Piperidines; Preoperative Care; Risk Factors; Time Factors

In this randomized single-blind cross-over study the gastroduodenal damaging effect of indometacin 75 mg bid alone and in combination with roxatidine acetate (CAS 78628-28-1, Roxit) 75 mg nocte or 75 mg bid was evaluated in 12 healthy male volunteers. Prior to the start of the three therapeutic periods subjects underwent endoscopic examination to exclude gastroduodenal mucosa lesions. On days 7 and 14 of therapy 2 h after the application of the last indometacin dose subjects underwent endoscopy again. The 7- and 14-days administration of indometacin 75 mg bid, indometacin 75 mg bid plus roxatidine 75 mg nocte and indometacin 75 mg bid plus roxatidine 75 mg bid led to gastroduodenal mucosa lesion scores of 1.67 +/- 0.40 and 2.00 +/- 0.35, 1.33 +/- 0.28 and 1.50 +/- 0.29, 0.42 +/- 0.23 and 1.00 +/- 0.33 (mean +/- SEM), respectively. These differences were statistically significant when comparing indometacin 75 mg bid versus indometacin 75 mg bid plus roxatidine 75 mg bid (p < 0.004 and < 0.008, respectively). This study shows that roxatidine acetate represents an effective alternative in the prophylaxis of NSAID-induced gastroduodenal mucosa lesions.

Topics: Adult; Cross-Over Studies; Histamine H2 Antagonists; Humans; Indomethacin; Male; Peptic Ulcer; Piperidines; Single-Blind Method

This study reports preliminary results of a controlled, multicenter trial on the quality of ulcer healing induced by lansoprazole (LPZ) or roxatidine (R) in gastric ulcer (GU) or duodenal ulcer (DU) patients. Group A received LPZ 30 mg q.d. and group B received R 75 mg b.i.d. All drugs were given for 8 weeks in GU and for 6 weeks in DU. Endoscopy and gastric biopsy were performed to detect Helicobacter pylori before and on completion of treatment. The healing rates of groups A and B were 100 and 69.2%, respectively, in GU and 100 and 70.0%, respectively, in DU. This difference (p < 0.01) was significant between the two groups in GU. There was no significant difference between the two groups in the S2 stage shift rate in GU and DU. The H. pylori clearance rates of groups A and B were 33.3 and 20.0%, respectively, in GU and 62.5 and 33.3%, respectively, in DU. The differences in treatment response (healing rates and S2 shift rates) between the LPZ group and the R group may be related to the differences in suppression of acid secretion and in bactericidal effects on H. pylori.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Aged; Aged, 80 and over; Anti-Ulcer Agents; Duodenal Ulcer; Female; Helicobacter pylori; Humans; Lansoprazole; Male; Middle Aged; Omeprazole; Peptic Ulcer; Piperidines; Proton Pump Inhibitors; Stomach Ulcer

To compare the efficacy and tolerability of early evening (19.00-21.00 hours) vs. bedtime (22.00-00.00 hours) oral administration of roxatidine 150 mg in the short-term treatment of active duodenal ulcer.. The trial was randomized, double-blind and double-dummy, with parallel groups. A total of 276 patients were recruited and randomly assigned either to roxatidine in the early evening (n = 139) or roxatidine at bedtime (n = 137).. After 4 weeks, 78% of patients receiving roxatidine in the early evening and 74% of those treated at bedtime had achieved complete healing, as determined by per-protocol analysis. With intention-to-treat analysis the healing rates were 70.5% and 70.8%, respectively. After 8 weeks the healing rates in the early evening and bedtime treatment groups were 92% and 95% (per-protocol analysis) and 78% and 84% (intention-to-treat analysis). Both treatments proved effective in reducing the frequency and severity of daytime and nocturnal epigastric pain, as well as other ulcer-related symptoms.. This study confirmed the healing and analgesic properties of roxatidine in duodenal ulcer disease. Early evening or bedtime dosing with roxatidine 150 mg resulted in similar 4- to 8-week rates of duodenal ulcer healing.

Topics: Administration, Oral; Adolescent; Adult; Aged; Anti-Ulcer Agents; Double-Blind Method; Duodenal Ulcer; Female; Follow-Up Studies; Humans; Male; Middle Aged; Piperidines; Time Factors; Treatment Outcome

Roxatidine acetate is a novel H2-receptor antagonist and several studies have shown that it is effective in healing duodenal ulcers. We evaluated the efficacy of roxatidine in a non-western society with particular different features and its healing of duodenal ulcers was compared in Thailand with that of ranitidine.. The design was controlled, randomized, double-blind, and multicenter. The study recruited a total of 215 patients who were endoscoped at the start of the trial and then randomized to receive a single capsule of roxatidine acetate, 150 mg, or an identical capsule containing ranitidine, 300 mg, both to be taken at night. Patients were evaluated at 1, 2, and 4 weeks, including endoscopy at the last session, as well as at 6 weeks with repeat endoscopy if the ulcer had not healed.. Both drugs relieved pain rapidly, usually within a week, and at repeat endoscopy at 4 weeks most ulcers (78%) were healed, 77.0 and 79.5 per cent in ranitidine and roxatidine, and in those patients in whom healing was not completed the healing rate had risen appreciably to 89.8 and 93.8 per cent respectively at 6 weeks. Small ulcers tended to heal quicker than larger ones, but smoking and alcohol intake had no negative effects on the results.. The study was valid proof that roxatidine, in a single evening dose of 150 mg, was found to be both safe and effective in the rapid healing of duodenal ulcers when compared with 300 mg ranitidine.

Topics: Adult; Aged; Aged, 80 and over; Double-Blind Method; Drug Administration Schedule; Duodenal Ulcer; Female; Histamine H2 Antagonists; Humans; Male; Middle Aged; Pain Measurement; Piperidines; Ranitidine; Risk Factors; Thailand; Treatment Outcome

For prophylaxis of gastroduodenal lesions induced by non-steroidal antirheumatic drugs (NSAID) acid-lowering as well as mucosa protective substances are used. Direct comparison of both therapeutic regimens are lacking. In randomized parallel studies the gastroduodenal tolerability of 100 mg diclofenac daily in slow-release form was evaluated in the presence and absence of 150 mg roxatidine (CAS 78273-80-0) daily as well as in the presence of 75 mg bid roxatidine or 200 micrograms bid misoprostol (CAS 59122-46-2). The drugs were taken over a period of 14 days. Endoscopic controls were performed at entry, as well as after 14 days of treatment. A quantitative damaging score was used. Study A: Both treatment groups (n = 20) had at entry comparable mucosal damages: placebo/diclofenac: 0.9 +/- 0.1 (+/- SEM), roxatidine/diclofenac: 0.9 +/- 0.1; after 14 days of treatment the score increased in the diclofenac/placebo group to 7.6 +/- 1.9 and, in the corresponding diclofenac/roxatidine group, only to 2.1 +/- 0.9. The difference between the two treatment groups after 14 days was significant (p < 0.05). Study B: Both treatment groups (n = 24) had comparable mucosal damages at entry: diclofenac/roxatidine: 0.9 +/- 0.1, diclofenac/misoprostol: 0.8 +/- 0.1. Following 14 days treatment with 100 mg diclofenac daily the damaging score in both group rose to comparable levels: roxatidine group 2.1 +/- 0.7 and misoprostol group 2.0 +/- 0.4 (n.s.). The data suggest that for prophylaxis of NSAID-induced gastroduodenal lesions substances with different mechanism of action can be used. The findings underline the complex way by which NSAID can damage the mucosa of the upper gastrointestinal tract.

Topics: Adult; Anti-Ulcer Agents; Delayed-Action Preparations; Diclofenac; Gastric Acid; Gastroscopy; Histamine H2 Antagonists; Humans; Misoprostol; Piperidines; Stomach Ulcer

Topics: Anti-Ulcer Agents; Bismuth; Drug Therapy, Combination; Helicobacter Infections; Helicobacter pylori; Histamine H2 Antagonists; Humans; Omeprazole; Organometallic Compounds; Piperidines; Roxithromycin

Topics: Adolescent; Adult; Aged; Cimetidine; Female; Histamine H2 Antagonists; Humans; Male; Middle Aged; Peptic Ulcer; Piperidines

Some histamine-H2-receptor antagonists block gastric first-pass metabolism of ethanol and lead to increased blood alcohol concentrations after ingestion of a low dose (0.15 and 0.3 g/kg) of alcohol. To investigate whether the histamine-H2-receptor antagonist roxatidine acetate has a similar effect, we administered a low dose (0.3 g/kg) of ethanol to eleven volunteers before and after seven days treatment with roxatidine acetate (150 mg once daily). No effect of the drug on mean peak serum alcohol concentrations or on areas under the serum alcohol curves was found. In vitro, roxatidine acetate and its active metabolite roxatidine had almost no effect on guinea-pig gastric alcohol dehydrogenase activity. We conclude that roxatidine acetate does not block gastric first-pass metabolism of ethanol and can be considered as a safe histamine-H2-receptor antagonist in individuals who do not refrain from alcohol consumption under treatment for gastric or duodenal ulcer disease.

Topics: Adult; Alcohol Dehydrogenase; Alcohol Drinking; Animals; Cimetidine; Ethanol; Female; Guinea Pigs; Histamine H2 Antagonists; Humans; Liver; Male; Metabolic Clearance Rate; Piperidines; Stomach

A double blind randomised trial, comparing a new H2-receptor antagonist, Roxatidine acetate, with Cimetidine was carried out in 47 patients of uncomplicated, endoscopically proven duodenal ulcer. Twenty seven patients were treated with Roxatidine 75 mg twice daily and 20 patients were treated with Cimetidine 200 mg 3 times a day and 400 mg at bed time for 4 weeks. At the end of 4 weeks, total pain relief was obtained in 74% and 70% patients receiving Roxatidine and Cimetidine respectively. Complete endoscopic healing at the end of 4 weeks was observed in 92.3% patients receiving Roxatidine and 85% patients receiving Cimetidine. These differences were statistically not significant. No significant side effects were observed in either group. We conclude that Roxatidine acetate is comparable to cimetidine in relieving pain and endoscopic healing of duodenal ulcer and has an excellent safety profile.

Topics: Cimetidine; Double-Blind Method; Duodenal Ulcer; Female; Histamine H2 Antagonists; Humans; Male; Piperidines

In a multicenter, placebo-controlled, comparative trial with 196 general practitioners and internists 730 18 to 70 year-old patients with endoscopic evidence of a duodenal ulcer were enrolled. Each group of 365 patients received 150 mg Roxatidine acetate once daily, either late in the evening (bedtime administration, between 10.00 p.m. and 11.00 p.m.) or early in the evening (after dinner, between 6.00 p.m. and 7.00 p.m.). The endoscopic control revealed that the ulcers healed after four weeks of treatment in 74% (bedtime administration) and 77% (administration early in the evening), respectively. There was no significant difference ascertained between both groups. At the last visit, epigastric pain was removed during the day in 86% and during the night in 90% in both groups.

Topics: Adolescent; Adult; Aged; Drug Administration Schedule; Duodenal Ulcer; Duodenoscopy; Female; Histamine H2 Antagonists; Humans; Intestinal Mucosa; Male; Middle Aged; Piperidines

The haemodynamic effects of roxatidine were investigated in 12 patients with congestive heart failure (New York Heart Association class II) in a placebo-controlled, double-blind, randomized, cross-over study. Impedance and mechanocardiography were determined following successive 7-day treatment periods with placebo and roxatidine 150 mg once daily. Comparison with placebo values showed roxatidine to significantly increase the preejection period (109.7 +/- 2.7 ms versus 117.3 +/- 2.7 ms, 1.5 h after administration). Heart rate and blood pressure remained the same. In contrast to other, newer H2-receptor antagonists, which decrease stroke volume and/or cardiac output, roxatidine did not reduce these parameters but increased the preejection period and the ratio of the preejection period to the left ventricular ejection time, indicating a slight negative influence on cardiac performance.

Topics: Blood Pressure; Cardiac Output; Coronary Disease; Double-Blind Method; Electrocardiography; Heart Failure; Heart Rate; Hemodynamics; Histamine H2 Antagonists; Humans; Middle Aged; Piperidines; Stroke Volume

This multicenter randomized, double-blind, 4-wk study compared the new H2-receptor antagonistic roxatidine (R) to placebo (P) for treatment of endoscopically diagnosed active duodenal ulcer disease. Subjects were evaluated after 2 and 4 wk of treatment. Those whose ulcer was unhealed at 2 wk received 2 more weeks of treatment before final evaluation. Ulcer healing (endoscopically determined) with roxatidine was more effective than placebo at both wk 0-2 (R = 33.9%, P = 21.9%, p = 0.018) and wk 2-4 (R = 68.2%, P = 29.7%, p less than 0.001), with an overall 4-wk effectiveness of 78.9% compared to 44.8% (p less than 0.001). At the end of treatment, average maximum ulcer diameter diminished 83% in R and 50% in P (p less than 0.001). Roxatidine was also more effective than placebo in decreasing abdominal pain (p less than 0.001), decreasing the number of antacid tablets taken for pain relief (p less than 0.001), improving dyspeptic symptoms (p less than 0.001), and permitting return to a normal routine for subjects with previous illness-imposed restrictions on work and/or other daily activities. The profile of laboratory values and adverse experiences demonstrated roxatidine to be safe and well-tolerated. The efficacy of roxatidine as evaluated by the healing rate of duodenal ulcer and reduction in abdominal pain emphasize its value as an addition to the family of H2-receptor antagonists.

Topics: Abdominal Pain; Adult; Aged; Double-Blind Method; Drug Administration Schedule; Duodenal Ulcer; Female; Histamine H2 Antagonists; Humans; Logistic Models; Male; Middle Aged; Piperidines; Severity of Illness Index

Topics: Biological Availability; Drug Interactions; Histamine H2 Antagonists; Humans; Male; Piperidines; Sucralfate

Roxatidine acetate is a new histamine H2-antagonist of about twice the potency of ranitidine on a weight-for-weight basis. Two hundred and thirty-two patients participated in a double-blind randomized trial of duodenal ulcer healing comparing 300 mg ranitidine nocte with 150 mg roxatidine nocte. Endoscopy was repeated fortnightly to 4 weeks in each of four participating centres. Usual exclusion criteria applied but NSAID users were allowed. There were no important demographic differences between treatment recipients. Three analyses were used: protocol (dropouts and violators not included), intention-to-treat I (dropouts considered failures), and intention-to-treat II (dropouts considered failures, but violators outcome included). Healing rates differed markedly (but not significantly) with each analysis. After 2 weeks of treatment ulcers had healed in 51% versus 45% using the intention to treat I analysis with roxatidine and ranitidine, respectively; by the protocol analysis the healing proportions were 60% and 55%. These differences between treatments were not significant. After 4 weeks of treatment healing rates ranged from 71% to 83% on roxatidine and between 69% and 84% on ranitidine depending on the analysis. Differential healing proportions of smokers and non-smokers were non-significant (83% vs. 79%). Both drugs were well tolerated and adverse events were similar with each agent. Roxatidine should prove as effective as ranitidine for acute duodenal ulcer treatment.

Topics: Adult; Aged; Duodenal Ulcer; Female; Histamine H2 Antagonists; Humans; Male; Middle Aged; Piperidines; Ranitidine

The effects of single intravenous administration of roxatidine acetate hydrochloride 75 mg on the volume and pH of gastric juice were investigated in 43 patients undergoing elective surgery under general anesthesia. The drug was given 1 hour before anesthesia. The percentages of patients with gastric pH above 2.5 and gastric juice volume under 25 ml were 95.3% and 97.7% at the time of induction of anesthesia and at the time of extubation, respectively. As for overall assessment on gastric secretion, 93.0% was judged as very effective. In 2 cases, pricking sensations were observed at the time of injection, but these symptoms disappeared without any treatment within a few minutes. No other adverse reactions nor abnormal laboratory test findings were observed. In conclusion, roxatidine acetate hydrochloride administered intravenously 1 hour prior to anesthesia is thought to be useful to prevent acid aspiration pneumonitis.

Topics: Adult; Female; Histamine H2 Antagonists; Humans; Male; Middle Aged; Piperidines; Pneumonia, Aspiration; Preanesthetic Medication

Inhibitory effects of roxatidine acetate upon human gastric secretion have been shown to be dose-related after oral administration. In order to correlate this effect with drug pharmacokinetics, blood concentration of the active metabolite, roxatidine, was assessed in 10 healthy volunteers, each receiving in random order 75, 150, 300, 600 mg of roxatidine acetate and placebo. Blood was drawn for roxatidine measurement at T 0 (time of drug intake) T 75, 90, 120, 150, 210, 240 and 300 min. Meal-induced gastric secretion was studied by intragastric titration (IGT) at 15 min intervals, from T 150 to T 240. Mean peak of blood concentration occurred at T 150 with significant correlation with the administered dosage. Gastric secretion inhibition over the 90 min of IGT correlated with peak concentration exclusively for the subpopulation with peak occurrence at T 150. Beyond the peak, decrease in roxatidine concentrations was slow, as expected from a known 6-h half-life. However, overall results showed that mean blood concentration was correlated with gastric secretion inhibition from T 180 on. The last IGT sample also correlated with the peak. Interpretation of these results would be different whether roxatidine concentration variations are appreciated as exhibiting a significant decrease or not. Infusion studies of roxatidine would be a valuable technique for further analysis and comparison of blood-concentration/efficacy relationships as compared with other H2-antagonists.

Topics: Adult; Cimetidine; Double-Blind Method; Gastric Juice; Histamine H2 Antagonists; Humans; Male; Piperidines; Random Allocation; Ranitidine

We examined the effects of the combined use of H2-receptor antagonist (roxatidine) and muscarinic receptor antagonist (pirenzepine) by oral administration on gastric juice and acid secretion in humans. The volume, pH level, and acidity of gastric juice were determined in the sample collected at 9:00 AM 10 hr after either the oral administration of 150 mg of roxatidine or the combined administration of 150 mg of roxatidine and 50 mg of pirenzepine. Significant decrease in volume and acidity and increase in pH were observed in both roxatidine group and combined group compared with control placebo group, but significant difference were not observed in gastric pH and acidity between roxatidine group and combined group. The volume of gastric juice was decreased significantly by the combined administration in comparison with the sole administration of roxatidine. Consequently, the combined oral administration of the two agents was considered to be more effective than the sole administration of roxatidine for clinical cases which require stronger suppression of gastric secretion at the night.

Topics: Adult; Depression, Chemical; Drug Synergism; Gastric Acid; Gastric Juice; Gastric Mucosa; Histamine H2 Antagonists; Humans; Male; Piperidines; Pirenzepine

The effect of pretreatment for 7 days with either roxatidine acetate 75 mg twice daily or cimetidine 200 mg four times daily on the kinetics of antipyrine (AP), trimethadione (TMO) and indocyanine green (ICG) was studied in seven healthy, male, nonsmoking subjects. After pretreatment with cimetidine, the plasma clearances (CL) of AP and TMO were significantly lower and the elimination half-life (t1/2) of AP was significantly increased. The volumes of distribution (V) of AP and TMO were not affected. After roxatidine acetate, the pharmacokinetics of AP and TMO were unchanged. The cumulative renal excretion (% dose) and formation clearance of 3-hydroxymethyl-3-nor-antipyrine (NORA) were lowered by cimetidine treatment, but not following the administration of roxatidine acetate. ICG clearance was not changed significantly by either pretreatment. The results of this study show that roxatidine acetate does not impair the metabolism of three model substrates used to assess hepatic drug clearance.

Topics: Adult; Antipyrine; Cimetidine; Half-Life; Histamine H2 Antagonists; Humans; Indocyanine Green; Liver; Male; Pharmaceutical Preparations; Piperidines; Trimethadione

The effects of a new H2-receptor antagonist, roxatidine acetate, have been investigated in both clinical and pharmacodynamic trials in Europe and the United States. A series of four double-blind randomized studies are reviewed, reporting the effects of different dose regimens of roxatidine acetate compared with ranitidine and placebo in healthy volunteers using continuous intragastric pH monitoring. These pharmacodynamic studies clearly demonstrate that roxatidine acetate is an effective gastric antisecretory agent, which is up to twice as potent as ranitidine. The results of several clinical studies of roxatidine acetate in patients with gastric as well as duodenal ulcer conducted in Europe, Japan, and the United States are also reviewed. These studies show that roxatidine acetate is comparable to other potent H2-receptor antagonists in terms of cumulative healing rates, pain relief, and safety. Overall, the pharmacodynamic and clinical data indicate that the efficacy of roxatidine acetate 75 mg twice-daily (b.i.d.) does not differ significantly from ranitidine 150 mg b.i.d. Roxatidine acetate is equally effective in the treatment of peptic disease including gastric ulcer, duodenal ulcer, and reflux esophagitis.

Topics: Cimetidine; Clinical Trials as Topic; Double-Blind Method; Drug Administration Schedule; Histamine H2 Antagonists; Humans; Peptic Ulcer; Piperidines; Random Allocation; Ranitidine

The effects of roxatidine acetate hydrochloride and cimetidine during multiple dosing on the pharmacokinetics of theophylline was studied in nine healthy volunteers, five smokers and four non-smokers, in comparison with placebo treatment. Cimetidine reduced the terminal elimination rate constant and the total body clearance of theophylline from 0.119 to 0.101 h-1 (p less than 0.05) and from 31.2 to 26.5 ml/min (p less than 0.05), respectively, in comparison with those of placebo. There was no significant change in the volume of distribution (16.3 l for placebo and 15.5 l for cimetidine) and the renal clearance (4.5 ml/min for placebo and 3.9 ml/min for cimetidine). Roxatidine acetate hydrochloride did not significantly influence theophylline disposition in comparison with placebo treatment. The interaction of cimetidine on theophylline disposition was observed in both smokers and non-smokers, but the degree was greater in smokers.

Topics: Adult; Aminophylline; Cimetidine; Half-Life; Humans; Infusions, Intravenous; Male; Piperidines; Smoking; Theophylline

Pharmacodynamic studies revealed that 150 mg of roxatidine acetate were optimal in suppressing gastric acid secretion, and that a single bedtime dose of 150 mg was more effective than a dose of 75 mg twice daily in terms of inhibiting nocturnal acid secretion. When administered orally as a capsule containing a granule formulation, the drug displayed modified-release properties, which led to a sustained suppression of gastric acid secretion. Clinical trials revealed that roxatidine acetate, 75 mg twice daily and 150 mg at night, was highly effective in healing duodenal and gastric ulcers and in reducing ulcer pain, over 4, 6, and 8 weeks of therapy. A steady reduction in diameter was observed in those ulcers not completely healed during therapy. The single bedtime dose regimen, while producing the same degree of healing as the divided daily dose during controlled clinical trials, may be of greater value in therapeutic use owing to improved patient compliance. In all efficacy criteria (cure, reduction in ulcer size, and pain relief) there was no significant difference between roxatidine acetate in a total daily dose of 150 mg, ranitidine in a total daily dose of 300 mg, and cimetidine in a total daily dose of 800 mg. Prevention of gastric and duodenal ulcer relapse was achieved by roxatidine acetate, 75 mg at night for 6 months, in about 70% of patients, as determined in open, pilot studies--a rate comparable to those reported for cimetidine and ranitidine. Roxatidine acetate shares with ranitidine an improved safety profile when compared with cimetidine. Human pharmacology studies and short-term and long-term clinical trials have all shown that roxatidine acetate is an exceptionally well tolerated compound, without the antiandrogenic activity and interference with hepatic drug metabolism which have characterized cimetidine treatment. A reason for the improved safety profile of roxatidine acetate may be its greater potency than cimetidine (six times less potent) and ranitidine (half as potent), so that lower doses of roxatidine acetate, representing a lower chemical load, are therapeutically effective. The novel structure of roxatidine acetate probably also underlies the improved safety of the compound.

Topics: Cimetidine; Clinical Trials as Topic; Duodenal Ulcer; Gastric Acid; Histamine H2 Antagonists; Humans; Piperidines; Ranitidine; Stomach Ulcer

In 10 healthy male volunteers a dose-response study was carried out with roxatidine acetate, 75, 150, 300, and 600 mg, and placebo on food-stimulated gastric acid secretion (intragastric titration (IGT]. The design of the study, with drug intake 150 min before starting IGT, enabled stable inhibition over the 90-min observation period of the test. Cumulative secretory results showed a dose-related acid secretion inhibition (67% for 75 mg; 87.6% for 150 mg; 98.8% for 300 mg; 99.6% for 600 mg). The results were statistically significantly different from placebo and from each other, except for 300 mg versus 600 mg. With a Lineweaver-Burk plot, the ED50 was 41 mg and r = 0.98. Peak concentrations of roxatidine were observed either at T 150 or T 180. Significant correlation (r = 0.7; p less than 0.001) was obtained for the percentage inhibition with 75 mg and 150 mg together versus peak concentrations. Antisecretory potency with the IGT model applied to normal subjects appears to be of the same order for roxatidine acetate and for ranitidine.

Topics: Adult; Dose-Response Relationship, Drug; Food; Gastric Acid; Histamine H2 Antagonists; Humans; Male; Piperidines

Unlike other methods for assessing intragastric pH or total acid output, the reproducibility of ambulatory pH-monitoring is excellent but is critically dependent on the electrode system and the recording device. In three double-blind randomized studies in normal volunteers the effects of different dosage regimens of roxatidine acetate were compared with placebo and ranitidine. Roxatidine acetate, 75 mg twice daily, raised median 24-h gastric pH from 1.6 to 3.2 and median nocturnal pH from 1.5 to 3.0 Roxatidine acetate, 150 mg at bedtime, raised median 24-h pH to 2.4 and nocturnal pH to 5.9. Roxatidine acetate, 150 mg at bedtime, was as effective as ranitidine, 300 mg at night, in raising median nocturnal pH. However, when drugs were taken after the evening meal, 150 mg roxatidine acetate was less potent than 300 mg ranitidine or 300 mg roxatidine acetate.

Topics: Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gastric Acidity Determination; Histamine H2 Antagonists; Humans; Hydrogen-Ion Concentration; Male; Monitoring, Physiologic; Piperidines; Random Allocation; Ranitidine

In a series of double-blind randomized studies in normal volunteers using continuous intragastric pH monitoring, the effects of different dosage regimens of roxatidine, a new H2-receptor antagonist, were compared with placebo and ranitidine. Roxatidine acetate, 75 mg twice daily, decreased median 24 h gastric acidity from pH 1.6 to 3.2 and median nocturnal acidity from 1.5 to 3.0. Roxatidine acetate, 150 mg at bedtime, raised median 24 pH of the same 17 subjects to 2.4 and nocturnal pH to 5.9. In another series of experiments, 150 mg roxatidine acetate at bedtime was as effective as ranitidine 300 mg nocte raising median nocturnal pH (14 volunteers) from 1.4 to 6.65 compared to 6.7, respectively. However, when drugs were taken after the evening meal (post cenam nocte, pcn) roxatidine acetate 150 mg was less potent than ranitidine 300 mg with median night-time pH rising from 1.3 to 3.2 and 4.0, respectively, in 28 volunteers. Roxatidine acetate 300 mg pcn raised the pH to 4.9 suggesting that roxatidine is 1-2 times as potent as ranitidine, on a milligram-for-milligram basis.

Topics: Adolescent; Adult; Double-Blind Method; Gastric Acid; Histamine H2 Antagonists; Humans; Middle Aged; Piperidines; Ranitidine; Reference Values

Capsular contracture is an important complication after silicone mammary implant surgery. Fibroblasts and macrophages play critical roles in the pathogenesis of capsular contracture, making these two cell types therapeutic targets. It has been reported that inhibiting histamine receptors results attenuates fibrosis, but the role of roxatidine (a histamine receptor 2 inhibitor) in preventing fibrosis caused by breast implant materials remains unknown. The aim of the present study was to assess the hypothesis that roxatidine might have a prophylactic effect in capsular contracture induced by implant material. Inflammation induced by breast implant materials was mimicked by co‑culturing macrophages or fibroblasts with these materials in vitro. Capsular contracture was modeled in mice by planting breast implant materials in a subcutaneous pocket. Roxatidine was added in the culture medium or administered to mice bearing breast implant materials. By co‑culturing macrophages or fibroblasts with common breast implant materials (micro‑textured or smooth breast implants), the present study demonstrated that macrophages respond to these materials by producing pro‑inflammatory cytokines, a process that was abolished by addition of roxatidine to the culture medium. Although fibroblasts did not respond to implant surface materials in the same way as macrophages, the conditioned media of macrophages induced proliferation of fibroblasts. Mechanistically, administration of roxatidine inhibited activation of NF‑κB and p38/mitogen‑activated protein kinase (MAPK) signaling in macrophages. Furthermore, treatment with roxatidine in implant‑bearing mice reduced serum concentrations of transforming growth factor‑β and the abundance of fibroblasts around the implant. The present study concluded that roxatidine plays an important role in preventing fibrosis by inhibiting activation of NF‑κB and p38/MAPK signaling in macrophages.

Topics: Animals; Breast Implants; Female; Fibroblasts; Fibrosis; Humans; Macrophages; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinases; Piperidines; RAW 264.7 Cells; Surface Properties

Degradation of extracellular matrix such as type II collagen and aggrecan induced by proinflammatory cytokines has been considered as an important hallmark of Osteoarthritis (OA). Roxatidine is a licensed specific competitive H (2) -receptor antagonist used for the treatment of gastric and duodenal ulcers. The pharmacological function of roxatidine on Osteoarthritis (OA) remains unknown. In the current study, we report that roxatidine attenuated TNF-α- induced degradation of type II collagen by suppressing the expression of MMP-3 and MMP-13 in human chondrosarcoma cell line SW1353 cells. In addition, roxatidine ameliorated TNF-α- induced reduction of aggrecan by inhibiting the expression of ADAMTS-4 and ADAMTS-5. Notably, results indicate that roxatidine ameliorated TNF-α- induced the phosphorylations of IKK, IκBα, and NF-κB p65 as well as nuclear translocation of NF-κB p65 and the transcriptional activity of NF-κB, suggesting that roxatidine abolished the activation of NF-κB signaling pathway. Our findings implicate that roxatidine might be considered as an anti-osteoarthritic agent.

Topics: ADAMTS Proteins; Cell Line, Tumor; Collagen Type II; Extracellular Matrix; Humans; Matrix Metalloproteinase 13; Matrix Metalloproteinase 3; Nitric Oxide; Nitric Oxide Synthase Type II; Piperidines; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Topics: Animals; Caspase 1; Cell Line; Cytokines; Deoxyribonucleases, Type II Site-Specific; Enzyme Activation; Histamine H2 Antagonists; Humans; Hypersensitivity; Inflammation Mediators; Male; Mast Cells; Mice; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Piperidines

Premedication with a combination of histamine H₁ receptor (H₁R) and H₂ receptor (H₂R) antagonists has been suggested as a prophylactic principle, for instance, in anaesthesia and surgery. Aiming at pharmacological hybrids combining H₁R and H₂R antagonistic activity, a series of cyanoguanidines 14-35 was synthesized by linking mepyramine-type H₁R antagonist substructures with roxatidine-, tiotidine-, or ranitidine-type H₂R antagonist moieties. N-desmethylmepyramine was connected via a poly-methylene spacer to a cyanoguanidine group as the "urea equivalent" of the H₂R antagonist moiety. The title compounds were screened for histamine antagonistic activity at the isolated ileum (H₁R) and the isolated spontaneously beating right atrium (H₂R) of the guinea pig. The results indicate that, depending on the nature of the H₂R antagonist partial structure, the highest H₁R antagonist potency resided in roxatidine-type compounds with spacers of six methylene groups in length (compound 21), and tiotidine-type compounds irrespective of the alkyl chain length (compounds 28, 32, 33), N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-N″-[2-[N-[2-[N-(4-methoxybenzyl)-N-(pyridyl)-amino] ethyl]-N-methylamino]ethyl] guanidine (25, pKB values: 8.05 (H₁R, ileum) and 7.73 (H₂R, atrium) and the homologue with the mepyramine moiety connected by a six-membered chain to the tiotidine-like partial structure (compound 32, pKB values: 8.61 (H₁R) and 6.61 (H₂R) were among the most potent hybrid compounds. With respect to the development of a potential pharmacotherapeutic agent, structural optimization seems possible through selection of other H₁R and H₂R pharmacophoric moieties with mutually affinity-enhancing properties.

Topics: Animals; Cimetidine; Guanidines; Guinea Pigs; Histamine H1 Antagonists; Histamine H2 Antagonists; Magnetic Resonance Spectroscopy; Male; Molecular Structure; Piperidines; Pyrilamine

Compared with the aggressive factors, little attention has been paid to the mucosal defensive factors in ulcer therapy, and the role of the H2-receptor antagonists in gastric mucosal protection has not been well characterized. In the present study, the effects of different types of H2-receptor antagonists (famotidine and roxatidine) on rat gastric mucus cells were investigated using both biochemical and histological methods. Each drug (famotidine, 3 mg/kg; roxatidine, 100 mg/kg) was orally administered to rats by gavage once daily for 7 days. The biosynthesis and tissue content of mucin were compared in the gastric mucosa treated with each drug. Using anti-mucin monoclonal antibodies, the mucin content and immunohistochemical localization were also compared. Both the biosynthesis and the accumulation of gastric mucin were significantly decreased in the famotidine-treated rats, but not in the roxatidine. Both the content and the immunoreactivity of surface mucus cell-derived mucin were reduced by famotidine, while they were maintained in roxatidine-treated rat stomachs. There was no difference between the groups in the content and immunoreactivity of mucous neck cell-derived mucin. H2-receptor antagonists should be classified in relation to gastric surface mucus cell function, raising the possibility of more effective ulcer therapy.

Topics: Animals; Anti-Ulcer Agents; Famotidine; Gastric Mucins; Gastric Mucosa; Histamine H2 Antagonists; Male; Mucus; Piperidines; Rats; Rats, Wistar

To evaluate the anti-ovulatory activity of H(2) receptor blockers (ranitidine, famotidine and roxatidine) in albino rabbits considering the role of histamine in ovulation.. The drugs were orally administered once daily for three days to adult female rabbits weighing between 1.3-2.0 kg (four groups of three animals). The control group received the 1% weight/volume gum acacia suspension. Thirty minutes after the administration of the last dose, a freshly prepared 0.4 % solution of cupric acetate was administered to each animal intravenously via the marginal ear vein (4 mg/kg body weight) to induce ovulation. To assess ovulation, laparotomy was carried out 48 h after cupric acetate injection. The ovaries were exposed, bleeding points on each ovary were counted, and the ovaries and uteri were subjected to histopathological evaluation.. Based on the number of bleeding points (ovulation sites) observed on the ovary, H(2) blockers showed varying degrees of anti-ovulatory activity. Roxatidine exerted the most pronounced activity. Histopathological observations of uterus and ovary confirmed the aforementioned observations.. H(2) receptor blockers appeared to inhibit the cupric acetate-induced ovulation in albino rabbits. Our results seem to confirm the role of histamine in ovulation reported by other authors.

Topics: Administration, Oral; Animals; Contraceptive Agents; Dose-Response Relationship, Drug; Famotidine; Female; Histamine H2 Antagonists; Histamine Release; Ovulation; Piperidines; Rabbits; Random Allocation; Ranitidine

Topics: Carcinoma; Chemotherapy, Adjuvant; Drug Eruptions; Histamine H2 Antagonists; Humans; Lymph Node Excision; Lymphatic Metastasis; Male; Middle Aged; Piperidines; Psoriasis; Radiodermatitis; Radiotherapy, Adjuvant; Tongue Neoplasms

Roxatidine is a novel, specific, competitive H(2) -receptor antagonist that is used to treat gastric and duodenal ulcers, and which is known to suppress the growth of several tumors by reducing vascular endothelial growth factor (VEGF) expression. Nevertheless, it remains unclear whether roxatidine has anti-inflammatory effects. In this study, we the authors investigated the anti-inflammatory effect of roxatidine in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. It was found that roxatidine dose-dependently inhibited the productions of prostaglandin E(2) (PGE(2)), nitric oxide (NO), and histamine, and the protein and mRNA expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and histidine decarboxylase (HDC). In addition, roxatidine reduced the productions and expressions of VEGF-1 and pro-inflammatory cytokines, including those of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Electrophoretic mobility shift assays (EMSA) and reporter gene assays revealed that treatment with roxatidine attenuated the LPS-induced DNA-binding and transcriptional activity of nuclear factor kappa B (NF-κB). In addition, it was found that pretreatment with roxatidine significantly inhibited the nuclear translocations of the p65 and p50 subunits of NF-κB, and these inhibitions were not found to be associated with decreases in the phosphorylation or degradation of inhibitory kappa B-α (IκBα). Furthermore, roxatidine suppressed the phosphorylation of p38 MAP kinase, but not of IκB kinase-α/β (IKKα/β), c-Jun NH(2) -terminal kinase (JNK), or extracellular signal-regulated kinase (ERK). Taken together, these results indicate that the anti-inflammatory properties of roxatidine in LPS-treated RAW 264.7 macrophages are mediated by the inhibition of NF-κB transcriptional activity and the p38 MAP kinase pathway.

Topics: Animals; Cell Line; Electrophoretic Mobility Shift Assay; Histamine H2 Antagonists; Humans; Inflammation; Lipopolysaccharides; Macrophages; Mice; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Piperidines; Reverse Transcriptase Polymerase Chain Reaction

NMR chemical shift changes of the cyclomaltoheptaose (β-cyclodextrin, β-CD) cavity protons as well as roxatidine acetate hydrochloride aromatic ring protons revealed the formation of a RAH-β-CD inclusion complex. Detailed FTIR and NMR spectroscopic ((1)H NMR, COSY, NOESY, ROESY) studies have been done. The stoichiometry of the complex was determined to be 1:1, and the overall binding constant was also determined by Scott's method. The NOESY spectrum confirmed the selective penetration of the aromatic ring of RAH into the β-CD cavity in comparison to that of the piperidine ring. The mode of penetration of the guest into the CD cavity and structure of the complex has been established.

Topics: beta-Cyclodextrins; Magnetic Resonance Spectroscopy; Molecular Structure; Piperidines; Spectroscopy, Fourier Transform Infrared

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most significant causative factors of gastroduodenal ulcers. Recent reports have demonstrated that NSAIDs can also frequently induce ulceration and erosions of the small intestine. The aim of this study was to examine whether or not roxatidine (an H(2) receptor antagonist), which is known to increase gastric mucus in addition to inhibiting gastric acid, might suppress indomethacin-induced small intestinal mucosal injury, through an increase in mucus in rats.. Rats were given two p.o. doses of roxatidine, famotidine or cimetidine before and after the s.c. indomethacin injection. The injured area of the small intestine was analyzed. To examine effects of drugs on small intestinal mucus, rats were also given two p.o. doses of roxatidine, famotidine or cimetidine, and the ratio of the periodic acid Schiff (PAS)-positive area to the area of the mucosa in the small intestine was analyzed. In addition, we evaluated the involvement of nitric oxide (NO) and prostaglandins (PG) in the effect of roxatidine on small intestinal mucus.. Roxatidine significantly ameliorated indomethacin-induced small intestinal injury and increased the PAS-stained areas in the small intestinal mucosa, while cimetidine and famotidine had no significant effect. Pretreatment with N-nitro-L-arginine methyl ester but not with indomethacin, suppressed the effect of roxatidine on small intestinal mucus, suggesting that the effect is mediated by endogenous NO but not by PG.. Roxatidine suppressed indomethacin-induced small intestinal injury in rats. One possible mechanism is an increase of small intestinal mucus, mediated by NO.

Topics: Animals; Anti-Ulcer Agents; Cimetidine; Disease Models, Animal; Famotidine; Histamine H2 Antagonists; Indomethacin; Intestinal Mucosa; Intestine, Small; Male; Mucus; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Peptic Ulcer; Piperidines; Prostaglandins; Rats; Rats, Sprague-Dawley

Roxatidine is an H(2) receptor blocker frequently used in the treatment of peptic ulcers. H(2) receptor blockers are reported to show antifertility activity. To examine the mechanism of antifertility, estrogenic and antiestrogenic activity was studied using an in vitro rat and rabbit uterine receptor binding assay and in vivo using the uterotrophic assay in immature Wistar rats. The results revealed that roxatidine showed mild receptor binding affinity to both rat and rabbit uterine receptors when compared to estradiol. Interstingly, in vivo roxatidine increases the wet uterine weight of immature Wistar rats significantly (P<0.001) when compared to a control group. The increase in uterine weight within the roxatidine treated group was somewhat similar to that of the estradiol treated group. Histopathological results and the structure of the roxatidine support that H(2) receptor blocker roxatidine is an estrogenic compound.

Topics: Animals; Estrogens; Female; Histamine H2 Antagonists; Organ Size; Ovariectomy; Piperidines; Rabbits; Rats; Rats, Wistar; Uterus

We have synthesized a number of phenoxypropylamines from N-{3-[3-(1-piperidinylmethyl)phenoxy]propyl}chloroacetamide (3). All the products have been characterized by elemental analysis, (1)H-NMR and MS. The biological activity effects of the title compounds were examined. From the biological activity results, we found that two of themshowed significant gastric acid antisecretory activity.

Topics: Amines; Animals; Anti-Ulcer Agents; Gastric Acid; Guinea Pigs; Histamine H2 Antagonists; Humans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Structure; Piperidines

A sensitive and specific method using a one-step liquid-liquid extraction (LLE) with ethyl acetate followed by high-performance liquid chromatography (HPLC) coupled with positive ion electrospray ionization tandem mass spectrometry (ESI-MS/MS) detection was developed and validated for the determination of roxatidine in human plasma using famotidine as an internal standard (IS). Data acquisition was carried out in multiple reaction monitoring (MRM) mode, by monitoring the transitions m/z 307.3-->107.1 for roxatidine and m/z 338.4-->189.1 for famotidine. Chromatographic separation was performed on a reverse phase Hydrosphere C(18) column at 0.2 mL min(-1) using a mixture of methanol-ammonium formate buffer as mobile phase (20:80, v/v; adjusted to pH 3.9 with formic acid). The achieved lower limit of quantification (LLOQ) was 1.0 ng mL(-1) and the standard calibration curve for roxatidine was linear (r(2)=0.998) over the studied range (1-1000 ng mL(-1)) with acceptable accuracy and precision. Roxatidine was found to be stable in human plasma samples under short-, long-term storage and processing conditions. The developed method was validated and successfully applied to the bioequivalence study of roxatidine administrated as a single oral dose (75 mg as roxatidine acetate hydrochloride) to healthy female Korean volunteers.

Topics: Drug Stability; Humans; Piperidines; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Therapeutic Equivalency

A rapid and sensitive liquid chromatography/mass spectrometry (LC/MS) method was developed and validated for the determination of roxatidine in human plasma. Roxatidine was extracted by single liquid-liquid extraction with tert-butyl methyl ether, and the chromatographic separation was performed on a C8 column. The total analytical run time was relatively short (5 min), and the limit of assay quantification was 2 ng/mL using 0.1 mL of human plasma. Roxatidine and the internal standard, propranolol, were monitored in selected ion monitoring (SIM) mode at m/z 307.3 and 260.3, respectively. The standard curve was linear over a concentration range from 2-500 ng/mL, and the correlation coefficients were >0.999. The mean intra- and inter-day assay accuracy ranged from 103.4-108.8% and 102.3-110.0%, respectively, and the mean intra- and inter-day precision was between 3.3-8.8% and 5.3-6.2%, respectively. The developed assay method was successfully applied to a pharmacokinetic study in human volunteers after oral administration of roxatidine acetate hydrochloride at a dose of 75 mg.

Topics: Administration, Oral; Adult; Anti-Ulcer Agents; Blood Chemical Analysis; Chromatography, High Pressure Liquid; Humans; Male; Metabolic Clearance Rate; Microchemistry; Piperidines; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization

Previous reports suggest that complete tolerance to H2 receptor antagonists (H2RAs) in patients with regular H2RA medication may be due to hypergastrinemia-increased histamine synthesis or upregulation of H2 receptors. As proton pump inhibitors (PPIs) have been reported to induce hypergastrinemia (similar to H2RAs), patients receiving long-term medication with PPIs may show tolerance to preanesthetic H2RA. Therefore, we studied the efficacy of an H2RA, roxatidine, in patients receiving long-term PPI medication.. Effects of H2RA in 15 surgical patients receiving a regular PPI for more than 4 weeks (PPI+H2RA group) were compared with those in 30 patients not receiving regular PPIs or H2RAs (None+H2RA group and None+None group, n = 15 each). Oral roxatidine was given to both PPI+H2RA and None+H2RA group patients as an anesthetic premedication, while it was not given to None+None group patients. Gastric volume and pH were measured after induction of anesthesia.. Gastric pH and volume (ml) in the PPI+H2RA group (5.79 +/- 1.61 and 9.1 +/- 16.7, respectively) were both similar to those in the None+H2RA group (5.54 +/- 2.20 and 9.7 +/- 10.8, respectively) but were significantly higher (gastric pH) and lower (volume) than in the None+None group (2.29 +/- 1.84 and 29.3 +/- 22.8, respectively, P < 0.01).. These data suggest that long-term PPI medication may not induce a tolerance to H2RAs.

Topics: Drug Tolerance; Female; Gastric Acid; Gastric Acidity Determination; Histamine H2 Antagonists; Humans; Male; Middle Aged; Piperidines; Pneumonia, Aspiration; Proton Pump Inhibitors; Time Factors

H(2) antagonist premedication is common in surgical patients to control gastric pH and volume. However, several reports suggest that long-term medication may produce tolerance. Therefore, we studied the efficacy of a preanesthetic H(2) antagonist (oral roxatidine) in patients on regular H(2) antagonist therapy.. Forty-eight patients undergoing elective surgery were studied and grouped according to medication: those on no medication (control group) and those receiving H(2)-antagonists for less than two weeks (< or =2 w group), between two and four weeks (2-4 w group) and for longer than four weeks (> or =4 w group; n =12 each). All patients were given oral roxatidine as anesthetic premedication. Gastric volume and pH were measured after induction of anesthesia. Arterial blood was simultaneously collected for measurement of plasma gastrin levels using an enzyme-linked immunosorbent assay. We observed a significant decrease and increase in, respectively, gastric pH and volume (mL) in the < or =2 w group [6.50 +/- 0.43 (NS) and 11.6 +/- 10.3 (NS)], 2-4 w group [4.77 +/- 2.11 (P < 0.01) and 14.1 +/- 10.8 (P < 0.05)], > or =4 w group [2.32 +/- 1.46 (P < 0.01) and 22.2 +/- 14.2 (P < 0.01)] compared to patients in the control group (6.35 +/- 1.32 and 4.9 +/- 4.7). Plasma gastrin levels were decreased with increasing time on medication with a significant difference (46%) observed after two weeks' treatment. In addition, there was a significant correlation between gastric pH and plasma gastrin levels (r = 0.43, P < 0.01).. These data suggest that regular H(2) antagonist treatment for longer than two weeks may produce tolerance to pre-anesthetic H(2) antagonist administration.

Topics: Aged; Anesthesia; Bile; Drug Tolerance; Enzyme-Linked Immunosorbent Assay; Female; Gastric Acid; Gastric Acidity Determination; Gastrins; Histamine H2 Antagonists; Histamine Release; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Piperidines; Preanesthetic Medication; Stomach

Topics: Amino Acids; Chemistry, Pharmaceutical; Drug Stability; Histamine H2 Antagonists; Parenteral Nutrition; Piperidines; Solutions

Topics: Dermatitis, Exfoliative; Drug Eruptions; Histamine H2 Antagonists; Humans; Male; Middle Aged; Piperidines

We previously reported that H2-antagonist medication given for longer than 4 wk may produce complete tolerance to preanesthetic H2 antagonist therapy. In this study, we evaluated the efficacy of preanesthetic proton pump inhibitor (PPI; oral rabeprazol) use in patients receiving regular H2-antagonist (oral famotidine) therapy for more than 4 wk. Forty-eight patients with assumed complete tolerance to H2 antagonists undergoing elective surgery were recruited and randomly assigned to receive either a preanesthetic PPI (rabeprazol 20 mg; n = 24) or H2-antagonist (H2 group; roxatidine 75 mg; n = 24) at 9:00 pm on the day before surgery and 2 h before the induction of anesthesia. Volume of gastric contents and pH values were measured after the induction of anesthesia. Gastric pH value in the PPI group (5.38 +/- 2.42) was significantly higher than in the H2 group (3.27 +/- 1.98; P < 0.01). Gastric volume in the PPI group (8.6 +/- 1.5 mL) was significantly smaller than in the H2 group (15.4 +/- 2.8 mL; P < 0.05; cf. PPI). Fourteen patients in the H2 group were at risk of acid aspiration pneumonia (gastric pH <2.5 or volume >25 mL), whereas only four patients in the PPI group (P < 0.05) were at risk. These data suggest that in patients receiving H2-antagonist therapy for longer than 4 wk, prophylaxis for acid aspiration pneumonia should include preanesthetic PPI medication.. We previously reported that more than 4 wk of administration of H2-antagonists may produce a full tolerance to preanesthetic H2-antagonists. The present study suggests that a proton pump inhibitor may be effective for prophylaxis of acid aspiration pneumonia in patients showing the full tolerance to H2 antagonists.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Aged; Anti-Ulcer Agents; Benzimidazoles; Drug Tolerance; Famotidine; Female; Gastric Acidity Determination; Gastrins; Histamine H2 Antagonists; Humans; Male; Middle Aged; Omeprazole; Piperidines; Pneumonia, Aspiration; Preanesthetic Medication; Proton Pump Inhibitors; Rabeprazole

The present study examined the effect of histamine H2-receptor antagonists and exogenous histamine on growth of malignant melanoma implant in mice. Drugs were administered to B16BL6 malignant-melanoma-implanted syngeneic mice, and the tumor volume was measured throughout the experiments. Cell proliferation was assessed by MTT assay and mRNA expression was determined by RT-PCR. Both roxatidine and cimetidine significantly suppressed growth of B16BL6 implant compared with vehicle. On the other hand, systemically administered histamine significantly stimulated growth of B16BL6 implants. In addition, the histamine-stimulated B16BL6 implant growth was markedly suppressed by co-administration of cimetidine in a dose-dependent manner. H2-receptor antagonists, however, failed to affect in vitro proliferation of B16BL6 cells. H2-receptor mRNA was detected in B16BL6 implants but not in the cell line. These results indicated that both endogenous and exogenous histamine have ability to stimulate growth of malignant melanoma implants via H2 receptors expressed in host cells.

Topics: Administration, Oral; Animals; Cell Line, Tumor; Cell Proliferation; Cimetidine; Dose-Response Relationship, Drug; Gene Expression; Histamine; Histamine Agents; Histamine H2 Antagonists; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Piperidines; Receptors, Histamine H2; RNA, Messenger

A NMR spectroscopic study of mixtures of varying ratios of roxatidine acetate hydrochloride (RAH) and beta-cyclodextrin (beta-CD) in D2O revealed the formation of a 1:1 inclusion compound. The aromatic ring of RAH selectively penetrates the beta-CD cavity in preference to the piperidine ring.

Topics: Anti-Ulcer Agents; beta-Cyclodextrins; Cyclodextrins; Deuterium Oxide; Excipients; Magnetic Resonance Spectroscopy; Piperidines

Cimetidine is known to suppress the growth of several tumors, including gastrointestinal cancer, in humans and animals. Nonetheless, whether other histamine H(2)-receptor antagonists exert such tumor suppressive effects remains unclear. The effect of roxatidine acetate hydrochloride (roxatidine), an H(2)-receptor antagonist, on the growth of colon cancer implanted in mice was examined and compared with that of cimetidine. Drugs were orally delivered for 26 - 29 days beginning before or after implantation of syngeneic colon cancer (Colon 38) in C57BL/6 mice. Tumor volume was determined throughout and histochemical analysis was also performed. Tumor tissue and serum vascular endothelial growth factor (VEGF) levels were measured. In vitro cell growth was assessed by the MTT assay. Both roxatidine and cimetidine significantly suppressed the growth of Colon 38 tumor implants. Histologic analysis revealed that such antagonists markedly increased necrotic areas and decreased the density of microvessels in tumor tissue. Both H(2)-receptor antagonists suppressed VEGF levels in tumor tissue and significantly decreased serum VEGF levels in Colon 38-bearing mice. Such drugs, however, failed to suppress in vitro growth of the cell line. In conclusion, both roxatidine and cimetidine were found to exert suppressive effects on the growth of colon cancer implants in mice by inhibiting angiogenesis via reducing VEGF expression.

Topics: Angiogenesis Inhibitors; Animals; Cell Line, Tumor; Cimetidine; Colonic Neoplasms; Male; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Piperidines; Xenograft Model Antitumor Assays

Therapy for the relief of symptoms of functional dyspepsia is unpredictable.. To identify which patients may benefit from antisecretory therapy.. Twenty-seven patients with functional dyspepsia were selected to receive H2-receptor antagonist (H2RA) treatment for 4 weeks. Serum pepsinogen A, pepsinogen C and gastrin were measured, and Helicobacter pylori status was determined. Symptoms were assessed at baseline and after H2RA treatment.. Fourteen patients were identified as H2RA responders and the remaining patients were non-responders. No differences were found between responders and non-responders with regard to serum pepsinogen A, pepsinogen C, gastrin and H. pylori status. However, the pepsinogen A/C ratio was significantly higher in responders than in non-responders. Ten of the 13 functional dyspepsia patients (77%) with a high value of the pepsinogen A/C ratio (> or = 4.5) achieved symptom resolution by H2RA, compared with only one of the eight patients (13%) with a low value of the pepsinogen A/C ratio (< or = 3.0).. The serum pepsinogen A/C ratio seems to identify those functional dyspepsia patients for whom acid control provides benefit. This ratio may be a practical tool for the management of functional dyspepsia patients.

Topics: Adult; Aged; Anti-Ulcer Agents; Biomarkers; Dyspepsia; Female; Gastrins; Helicobacter pylori; Histamine H2 Antagonists; Humans; Male; Middle Aged; Patient Selection; Pepsinogen A; Pepsinogen C; Piperidines; Treatment Outcome

Patients with liver disease are prone to develop peptic ulceration and often receive H(2)-receptor antagonists. Therefore, it is important to clarify whether the pharmacokinetics of H(2)-receptor antagonists is affected by hepatic function. However, pharmacokinetics of a new H(2)-receptor antagonist, roxatidine acetate, in chronic liver disease has not been well known. In this study, we analyzed the pharmacokinetics of roxatidine in patients with liver disease.. Blood samples were obtained from 11 patients with chronic hepatitis, 11 patients with cirrhosis and six healthy subjects. Under fasting conditions, 75 mg of roxatidine acetate was administered orally, and plasma roxatidine levels were determined sequentially from 3 to 12 h. Relationships between pharmacokinetic variables and each parameter related to hepatic functions were also investigated.. There was no difference in the pharmacokinetic variables and serum levels of roxatidine between chronic hepatitis and healthy controls. In contrast, in cirrhosis, serum roxatidine levels were significantly higher than those in chronic hepatitis and normal control. Half-life, the area under the plasma concentration-time curve and clearance in cirrhosis were also significantly longer, bigger and smaller than those in chronic hepatitis and healthy controls, respectively. The half-life became longer and the clearance became smaller in parallel with the progression of liver disease. Serum levels of hyaluronate and gamma-glutamyl transpeptidase showed a good correlation with half-life, clearance and elimination rate. A good correlation between creatinine clearance and elimination rate was found.. Pharmacokinetics of roxatidine acetate is affected by hepatic function, and the dosage of roxatidine acetate for patients with liver disease, especially cirrhosis, should be modified.

Topics: Administration, Oral; Adult; Aged; Area Under Curve; Chronic Disease; Creatinine; Half-Life; Hepatitis C, Chronic; Histamine H2 Antagonists; Humans; Liver Cirrhosis; Liver Function Tests; Metabolic Clearance Rate; Middle Aged; Peptic Ulcer; Piperidines

Roxatidine acetate hydrochloride (ROX, 2-acetoxy-N-[3-[m-(1-piperidinylmethyl)phenoxy]propyl]acetamide hydrochloride, CAS 78273-80-0), a histamine 2 (H2)-receptor antagonist, has been clinically applied for the treatment of gastritis, gastric and duodenal ulcers. There is no report on the identification of the metabolic enzyme of M-1 (2-hydroxy-N-[3-[m-(1-piperidinylmethyl)phenoxy]propyl]acetamide), the pharmacologically active metabolite, in humans. In this study, the Cytochrome P450 (CYP or P450) enzymes which participate in the metabolism of ROX were identified using human liver microsomes and S9 fractions. M-1 was converted to M-4 (3-[m-(1-piperidinyl-methyl)phenoxy]propylamine) by the enzyme reaction with the S9 but not with microsomes. M-4 was further metabolized to M-5 (3-[m-(1-piperidinylmethyl)phenoxy]propanol) by microsomes. The metabolism was inhibited by coumarin and anti-CYP2A1 serum. (3-[m-(1-piperidinylmethyl)-phenoxy]propionic acid) and M-3 (m-(1-piperidinylmethyl) phenol) formation from M-5 were inhibited by quinidine and anti-CYP2D6 serum. Moreover, M-5 was converted to M-2 and M-3 by cDNA-expressed CYP2D6. In conclusion, this study shows that microsomal enzymes do not participate in the clearance of the active metabolite M-1, CYP2A6 primarily catalyzes M-5 formation from M-4, and CYP2D6 primarily catalyzes M-2 and M-3 formation from M-5 in humans.

Topics: Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Inhibitors; Histamine H2 Antagonists; Humans; In Vitro Techniques; Isoenzymes; Kinetics; Lymphatic System; Microsomes, Liver; Piperidines; Spectrophotometry, Ultraviolet; Subcellular Fractions

Topics: Adult; Arm; Diagnosis, Differential; Drug Eruptions; Erythema Multiforme; Female; Histamine H2 Antagonists; Humans; Neck; Piperidines

Many clinicians have believed that H2-blockers and proton pump inhibitors ameliorate gastric ulcers via their antacid function. We examined the effects of these antacids on granulocytes. Gastric ulcer patients were administered an H2-blocker or proton pump inhibitor for a week and the number of granulocytes and the superoxide production were examined. To determine the trafficking of granulocytes, mice were exposed to restraint stress for 24 hr. The H2-blocker decreased the number of granulocytes, while the proton pump inhibitor suppressed their superoxide production in humans and mice. The major function of H2-blockers and proton pump inhibitors in curing gastric ulcers seems to be their suppressive effects on granulocytes. In this case, stress accelerates the trafficking of granulocytes from the bone marrow to the gastric mucosa. If we demonstrate a role for granulocytes in gastric ulcer formation, an gap in the acid-pepsin theory and the Helicobacter pylori theory is filled in.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Animals; Anti-Ulcer Agents; Depression, Chemical; Granulocytes; Histamine H2 Antagonists; Humans; Lansoprazole; Leukocyte Count; Luminescent Measurements; Mice; Middle Aged; Omeprazole; Piperidines; Proton Pump Inhibitors; Stomach Ulcer; Stress, Physiological; Superoxides

Although the involvement of nitric oxide (NO) in an increasing gastric mucus metabolism has been reported, information on whether or not its activation is limited to the specific mucus-producing cells is lacking. In this paper, we report the effect of the exogenous NO-donor, isosorbide dinitrate (ISDN), and second-generation histamine H2 receptor antagonist roxatidine (2-acetoxy-N-(3-[m-(1-piperidinylmethyl)phenoxy]propyl)acetamide hydrochloride) which is demonstrated to accelerate the mucin metabolism mediated by endogenous NO, on the mucin biosynthesis in distinct sites and layers of the rat gastric mucosa using an organ culture technique. Radiolabeled mucin was obtained from the tissue of full-thickness and the deep corpus layer, and the antrum of the rat stomach incubated for 5 hr with [3H]glucosamine(GlcN) in vitro. With the addition of ISDN to the culture medium, 3H-labeled mucin in the full-thickness corpus mucosa increased to 124-145% of the control (p<0.05), but not in the antrum. This stimulation of the mucin synthesis disappeared by the removal treatment of the surface mucous cell layer which has immunoreactivity of neuronal NO synthase. Similarly, roxatidine stimulated the mucin biosynthesis in the full-thickness corpus mucosa, but not in the gland mucous cell layer. These results suggest that the stimulation of the mucin biosynthesis mediated by NO is restricted to the surface mucous cells of the rat gastric oxyntic mucosa.

Topics: Animals; Culture Techniques; Gastric Mucosa; Glucosamine; Histamine H2 Antagonists; Immunoenzyme Techniques; Isosorbide Dinitrate; Male; Mucins; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Piperidines; Rats; Rats, Wistar

To evaluate in vitro inhibitory effects of four types of histamine H2-receptor antagonist (H2-receptor antagonists), famotidine, roxatidine, cimetidine and ranitidine, on platelet function, we examined aggregating potency and P-selectin levels with agonist-induced aggregation. Ranitidine and cimetidine inhibited, in concentration of 0.35 mM, the secondary aggregation induced by 5 microM adenosine diphosphate (ADP), the aggregation induced by 1 microg/mL collagen and 3 microM arachidonic acid. All of H2-receptor antagonists inhibited, in concentration of 1.4 mM, the aggregation induced by ADP, collagen and arachidonic acid. Ranitidine and cimetidine reduced markedly, in same concentration, P-selectin levels after induction of aggregation by 5 microm ADP, 1 microg/mL collagen and 3 microM arachidonic acid. When classified by the strength of inhibitory action, ranitidine and cimetidine were strong, followed by famotidine and roxatidine. It is considered that inhibitory effects of H2-receptor antagonists on platelet function are weaker than those of acetylsalicylic acid (ASA), since ASA inhibited platelet aggregation in concentration of 100 microM. No relationship was observed between inhibitory effects of H2-receptor antagonists on platelet aggregation induced by above agonists and the presence or absence of imidazole ring in the chemical structure.

Topics: Adenosine Diphosphate; Adult; Arachidonic Acid; Aspirin; Blood Platelets; Cimetidine; Collagen; Famotidine; Female; Heterocyclic Compounds, 1-Ring; Histamine H2 Antagonists; Humans; In Vitro Techniques; Male; Middle Aged; P-Selectin; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Ranitidine; Structure-Activity Relationship

We found that roxatidine stimulates mucus secretion and synthesis by cultured rabbit gastric mucosal cells. In this study, we examined the roles of the extracellular Ca++ and calmodulin in these effects of roxatidine. Reduction of the extracellular Ca++ concentration decreased the roxatidine-induced increases in mucus secretion and synthesis by gastric mucosal cells. Roxatidine concentration-dependently promoted Ca++ influx and caused an increases in intracellular Ca++. After the addition of roxatidine, the increases in the secretion and synthesis reflected those in Ca++ influx and intracellular Ca++ concentration and then disappeared as Ca++ influx and intracellular Ca++ concentration returned to the control level. The roxatidine-stimulated Ca++ influx and intracellular Ca++ mobilization were abolished by reduction of the extracellular Ca++ concentration. Nifedipine and diltiazem inhibited both the effects of roxatidine, but even at 10 microM, the inhibition was partial. Furthermore, W-7 (a calmodulin antagonist) completely abolished the effects of roxatidine on mucus secretion and synthesis without causing a reduction of the stimulated Ca++ influx. Taken together, these results suggest that roxatidine promotes Ca++ influx through both voltage-sensitive Ca++ channels and other Ca++ entry gates and the subsequent intracellular Ca++ mobilization, leading to potentiation of mucus secretion and synthesis by rabbit gastric mucosal cells. In addition, Ca(++)-activated calmodulin may play a pivotal role in these stimulatory effects of roxatidine.

Topics: Animals; Calcium; Calmodulin; Cells, Cultured; Diltiazem; Gastric Mucosa; Histamine H2 Antagonists; Male; Mucus; Nifedipine; Piperidines; Rabbits; Sulfonamides

IT-066 (3-amino-4-[4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis-2- butenylamino]-3-cyclobutene-1,2-dione hydrochloride), an H2-receptor antagonist, shows highly potent, time-dependent, and irreversible antagonism at H2-receptors. We identified the structurally important parts of IT-066 involved in its interaction with the H2-receptor, and explored its unique mode of action by investigating the H2-receptor blocking action of IT-066 and related compounds in guinea pig isolated atria. IT-066 is structurally divided into three different parts: a tertiary amine and hydrophobic group, a connecting carbon chain, and a polar group. Though the replacement of its pyridine ring with a benzene ring maintained the mode of the H2-receptor blocking action of IT-066, the oxidation of the piperidine ring completely attenuated this blocking action. By replacing the connecting carbon chain of IT-066, cis-2-butene, with butane, trans-2-butene, or 2-butyne, the irreversible antagonism disappeared and the potency was reduced. On the other hand, BMY25368, whose connecting carbon chain is trimethylene, showed irreversible antagonism comparable to that of IT-066. Hydrolysis of the polar group of IT-066 completely attenuated the H2-receptor blocking activity. Among the compounds tested, only the compound that had 3,4-diamino-3-cyclobutene-1,2-dione as a polar group showed time-dependent and insurmountable H2-receptor blocking action. These data suggest the importance of the following structural features of IT-066: the piperidine ring of IT-066 and -NH2 in its polar group are essential for the interaction with the H2-receptor; and the 3,4-diamino-3-cyclobutene-1,2-dione group and the connecting carbon chain of IT-066 are crucial for determining the irreversibility of H2-receptor blocking action, though the connecting carbon chain is replaceable with another chain with appropriate length and configuration.

Topics: Animals; Guinea Pigs; Heart Atria; Heart Rate; Histamine; Histamine H2 Antagonists; In Vitro Techniques; Male; Molecular Structure; Piperidines; Pyridines; Structure-Activity Relationship; Triazoles

In an attempt to develop new types of anti-ulcer agents, a series of N-(phenoxypropyl)acetamide derivatives with a thioether moiety and their sulfur-oxidized analogues were synthesized and evaluated for histamine H2-receptor antagonistic activity, Ca antagonistic activity and gastric anti-secretory activity in the lumen-perfuseed rat. Selected compounds were also tested for gastroprotective activity, which was expected to be based on Ca antagonistic activity. Structure-activity relationships are discussed. As a thioether moiety, -CH2-S(O)p-CH2-Ar (Ar; phenyl or furyl) was found to be optimal for the above activities. Especially, N-[3-[(3-(piperidinomethyl) phenoxy]propyl]acetamide with a benzyl sulfinyl, benzylsulfonyl, furfurylsulfinyl or furfurylsulfonyl group showed potent gastroprotective activity upon oral administration in a rat model. These compounds are candidates for novel anti-ulcer drugs with gastric anti-secretory and gastroprotective activities. 2-Furfurylsulfinyl-N-[3-[(piperidinomethyl)phenoxy]propyl]ac etamide was the most potent among the compounds tested and was given the code designation FRG-8701.

Topics: Acetamides; Administration, Oral; Animals; Anti-Ulcer Agents; Benzothiazoles; Calcium Channel Blockers; Gastric Acid; Histamine H2 Antagonists; Male; Perfusion; Piperidines; Rats; Rats, Wistar; Stomach; Structure-Activity Relationship; Sulfides; Thiazoles

A series of hybrid compounds combining the pharmacophores of both pheniramine-type histamine H1 receptor antagonists and roxatidine-type H2 receptor antagonists have been synthesized and tested for histamine antagonism at the isolated ileum (H1) and the spontaneously beating right atrium (H2) of the guinea pig. The 'polar group' of the H2 antagonist moiety (cyanoguanidine, nitroethenediamine or urea) and the side chain amino group of the H1 antagonist portion have been linked by a polymethylene spacer or by a piperazine system. The incorporation of a flexible spacer (2-7 methylene groups) resulted in H1 antagonists achieving up to 2.4 times the activity of pheniramine. Depending on the nature of the polar group the highest H2 antagonist potency resides in compounds with spacers ?2 methylene groups. Nitroethenediamine 24c with a seven-membered chain and a chlorpheniramine substructure proved to be approximately equipotent with pheniramine at the H1 and with ranitidine at the H2 receptor (pKB values 7.82 and 7.1, respectively).

Topics: Animals; Dose-Response Relationship, Drug; Guinea Pigs; Heart Atria; Histamine H1 Antagonists; Histamine H2 Antagonists; Ileum; In Vitro Techniques; Male; Pheniramine; Piperidines; Structure-Activity Relationship

From the marketed drug product Roxane(R) 75 mg C/MR capsules (roxatidine controlled/modified-release capsules), an in vitro/in vivo comparison was performed to demonstrate a 1:1 correlation between in vitro and in vivo dissolution, and, furthermore, to ensure bioequivalence of the roxatidine controlled/modified-release (C/MR) capsules exhibiting dissolution profiles within the defined acceptance criteria. This 1:1 in vitro/in vivo comparison was calculated using a model independent numerical deconvolution method. The high degree of correlation is extremely rare, nevertheless it allows to omit the testing of clinical side batches for the setting of acceptance criteria for the in vitro dissolution of roxatidine controlled/modified-release (C/MR) capsules. The 1:1 in vitro/in vivo correlation can be explained by the biopharmaceutical characteristics of the drug substance as well as the drug product, that is, pH-independent high solubility of the drug substance as well as dissolution which is independent of pH and agitation. These facts lead to a controlled/modified-release formulation. Therefore, it is important to keep in mind that in most cases in which a pH-dependent solubility/dissolution as well as permeability characteristics can be found, a 1:1 in vitro/in vivo correlation could not be expected.

Topics: Administration, Oral; Biological Availability; Chemistry, Pharmaceutical; Cross-Over Studies; Delayed-Action Preparations; Histamine H2 Antagonists; Humans; Piperidines

In an attempt to improve the low oral absorbability of previously reported dual histamine H2 and gastrin receptor antagonists, compounds of a different type were synthesized and evaluated for biological activity. These new compounds bear a histamine H2 receptor antagonist (H2A) pharmacophore moiety attached to a gastrin receptor antagonist (GA) pharmacophore moiety in a reversed manner, namely the head-to-head manner, different from the previously reported head-to-tail manner. These new hybrid compounds were classified into three types: type I, the regular amide type bearing a roxatidine moiety; type II, the reversed amide type bearing a roxatidine moiety; and type III, hybrid compounds bearing a famotidine moiety directly connected to a GA moiety without a spacer. Among them, only (R)-1-[3-(N'-(4-[2-(N-aminosulfonylamidino)ethylthiomethyl] thiazol-2-yl) guanidinomethyl)phenyl]-3- (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl) ure a (42), belonging to type III, showed a weak but distinct histamine H2 receptor-antagonistic activity as well as a modest gastrin receptor-antagonistic activity. Of most importance was the finding that this compound showed a weak but clearly improved in vivo oral antigastric acid secretory activity as a result of the structural changes, including the decreased molecular weight.

Topics: Animals; Anti-Ulcer Agents; Benzodiazepines; Drug Design; Famotidine; Gastric Acid; Histamine H2 Antagonists; Molecular Weight; Piperidines; Rats; Receptors, Cholecystokinin

Topics: Aged; Allopurinol; Anemia; Captopril; Drug Interactions; Drug Resistance; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Piperidines; Recombinant Proteins

In order to study structure-activity relationships of the previously reported dual histamine H2 and gastrin receptor antagonists and also to improve their low oral absorbability, we tried two chemical modifications. One tried to decrease the high hydrophobicity of the parent hybrid compounds to an appropriate level by incorporating a hydrophilic group into the molecule and the other by replacing the more hydrophobic groups with less hydrophobic ones. The former compounds (type I) involved hybrid compounds with a hydroxyl group at a position of a spacer, a piperidine moiety of H2A, or a phenyl ring at the C5 of the benzodiazepine skeleton as well as those with a free carboxyl group in the piperidine moiety of H2A. The latter (type II) involved hybrid compounds with the C5-phenyl group replaced with either a methyl group or hydrogen atom. Among them, only a type I compound, ([2-[3-(3-piperidin-1-ylmethylphenoxy)propylcarbamoyl] ethylcarbamoyl]methyl)carbamic acid 3-[3-[5-(3-hydroxyphenyl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiaz epin-3-yl]ureido]benzyl ester (18), showed potent dual histamine H2 and gastrin receptor antagonistic activity, whereas others resulted in a significant decrease of histamine H2 receptor antagonistic activity. The in vivo gastric acid antisecretory activity of 18 evaluated by Schild's rat method, however, did not suggest any notable improvement in oral absorbability.

Topics: Animals; Benzodiazepines; Chemical Phenomena; Chemistry, Physical; Gastric Acid; Gastrins; Guinea Pigs; Histamine H2 Antagonists; In Vitro Techniques; Mice; Piperidines; Rats; Receptors, Cholecystokinin; Solubility; Structure-Activity Relationship

We have studied the effect of the newly synthesized agent MX1, a salt of the active metabolite of the H2-blocker roxatidine with a complex of bismuth and citric acid (N-[3-(3-(1-piperidinylmethyl)phenoxy)propyl]-hydroxyacetamide+ ++ -2-hydroxypropane-1,2,3-tricarboxilate-bismuth(3+) complex), against restraint stress ulcers in rats (24 h immobilization). The effects of MX1 (12.5, 50, 125, 184 and 250 mg kg-1) were compared with the effects of equimolar doses of roxatidine (6.5, 25, 70, 100 and 140 mg kg-1) and bismuth subcitrate (6.5, 25, 70, 100 and 140 mg kg-1). The results show that MX1-pre-treatment, at all the doses used, significantly reduces the mean number and size of ulcers. Even at the lowest dose the number of ulcers was reduced by 64.3% and the size of the ulcer by 55.9%. Roxatidine (25, 70, 100 and 140 mg kg-1) dose-dependently reduces ulcer size and number by 24.6, 55.6, 85.3 and 89.0% and by (+7.2), 14.3, 57.1 and 67.9%, respectively. Bismuth subcitrate significantly reduces ulcer size and number only at the highest dose employed (-28.5 and -44.8%, respectively). The morphometric results have been confirmed histomorphologically. The results suggest that MX1 has a gastroprotective effect against stress-induced ulcers which is similar to that of the parent compound and more pronounced than that of bismuth subcitrate.

Topics: Animals; Antacids; Anti-Ulcer Agents; Drug Combinations; Gastric Mucosa; Histamine H2 Antagonists; Male; Organometallic Compounds; Peptic Ulcer; Piperidines; Rats; Rats, Wistar; Restraint, Physical

1. The structural requirements of the histamine H2-receptor antagonist, roxatidine (2-acetoxy-N-(3-[m-(1-piperidinylmethyl)phenoxy]-propyl)acetamide hydrochloride), for the stimulant effect on mucin biosynthesis and their relation to histamine H2-receptor antagonism were identified by considering the structural analogues of this drug using an organ culture system of the rat stomach and competition studies with [125I]iodoaminopotentidine ([125I]-APT) binding to membranes of the guinea pig striatum. 2. [3H]Glucosamine incorporation into mucin during 5 h incubation period was stimulated by roxatidine and its structural analogues A (2-hydroxy-N-(3-[m-(1-piperidinylmethyl)phenoxy]-propyl)acetamide) and B (N-(3-[m-(1-piperidinylmethyl)phenoxy]-propyl)acetamide). This effect was seen in mucosal cultures of the corpus, but not antrum, region. 3. Structural analogues, in which the length of the flexible chain between the benzene ring and the amide structure differs from that of roxatidine, failed to activate mucin synthesis. No significant change in mucus synthesis occurred with the addition of analogues in which the piperidine ring attached to the benzene ring via a methylene bridge was changed. 4. Specific [125I]-APT binding to the histamine H2 receptor of guinea pig brain membranes was inhibited by roxatidine and all structural analogues used in this study, except F (N-(3-[m-(N, N-dimethyl-aminomethyl)phenoxy]-propyl)acetamide). 5. Ranitidine at 10(-4) M did not suppress the roxatidine-induced increase in [3H]glucosamine incorporation into mucin. 6. Roxatidine-induced stimulation of [3H]glucosamine incorporation into mucin was completely blocked by the addition of either NG-nitro-L-arginine (10(-5) M) or 2-(4-carboxyphenyl)-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide sodium salt (10(-5) M). The inhibitory action of NG-nitro-L-arginine was totally reversed by L-arginine (5 x 10(-3) M). 7. These results suggest that the cardinal chemical features of roxatidine for the activation of mucin biosynthesis in the corpus region of the rat stomach are the appropriate length of the flexible chain between the amide structure and the aromatic ring system bearing the methylpiperidinyl group at the meta position. The activity of roxatidine and its analogues to stimulate mucin synthesis is not related to their histamine H2 receptor antagonistic activity. Roxatidine-induced activation of mucin biosynthesis in the corpus tissue is mediated by nitric oxide.

Topics: Animals; Benzoates; Enzyme Inhibitors; Free Radical Scavengers; Gastric Mucosa; Histamine H2 Antagonists; Imidazoles; Male; Mucins; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Piperidines; Ranitidine; Rats; Rats, Wistar; Receptors, Histamine H2

Gastric mucosal cell migration and proliferation are crucial events in the repair of gastric mucosal erosions. This study was designed to test the hypothesis that the H2 blockers roxatidine and ranitidine might stimulate migration and proliferation of gastric mucous cells derived from a human well-differentiated gastric adenocarcinoma cell line (MKN 28 cells) in vitro, in conditions independent of systemic factors and of acid inhibition. Confluent monolayers of MKN 28 cells were wounded with a razor blade and were then incubated with roxatidine or ranitidine. The number of cells migrating to the damaged area was determined 24 hr later. Cell proliferation was assessed by means of [3H] thymidine uptake and cell counts after incubation with roxatidine or ranitidine. Neither H2 antagonist significantly stimulated cell migration. On the other hand, cell proliferation was dose-dependently and significantly enhanced by incubation with roxatidine and ranitidine. Exogenous administration of TGF-alpha significantly stimulated MKN 28 cell division. However, incubation with roxatidine or ranitidine did not increase the steady-state mRNA expression of TGF-alpha or EGFR as assessed by northern blot analysis. Based on these in vitro findings, we postulate that the ulcer healing effect of these H2 antagonists in vivo might be due in part to stimulation of gastric mucosal cell proliferation.

Topics: Adenocarcinoma; Blotting, Northern; Cell Division; Cell Movement; Dose-Response Relationship, Drug; ErbB Receptors; Gastric Mucosa; Histamine H2 Antagonists; Humans; Piperidines; Ranitidine; RNA, Messenger; RNA, Neoplasm; Stimulation, Chemical; Stomach Neoplasms; Time Factors; Transforming Growth Factor alpha; Tumor Cells, Cultured

MX1 (N-[3-(3-(1-piperidinylmethyl)phenoxy)propyl]-hydroxyacetamide+ ++ 2-hydroxypropane-1,2,3-tricarboxylate bismuth (3+) complex) is a novel salt of the active metabolite of H2-antagonist roxatidine with a complex of bismuth with citric acid. In a model of ethanol-induced ulcers in male Wistar rats, both roxatidine and the bismuth salt reduced the number and the total length of lesions. Comparison of roxatidine and MX1 at equimolar doses of 160 mumol kg-1 showed a more potent cytoprotective effect of MX1. The potency of anti-secretory and antiacidic effects of MX1 was more than twice that of roxatidine on histamine-stimulated secretion in female Wistar pylorus-ligated rats. Microbiological tests with the reference bismuth preparation De-Nol showed prominent anti-Helicobacter properties of MX1 in-vitro. Both test compounds had similar range of MICs to Helicobacter pylori, from 4 to 64 microgram bismuth mL-1. The cytoprotective, antisecretory, anti-acidic and anti-Helicobacter properties of the new agent MX1 warrant further more extensive pharmacological and clinical trials.

Topics: Animals; Anti-Ulcer Agents; Ethanol; Female; Gastric Mucosa; Helicobacter pylori; Histamine; Male; Microbial Sensitivity Tests; Organometallic Compounds; Piperidines; Rats; Rats, Wistar; Stomach Ulcer; Tricarboxylic Acids

A total of 3409 patients with gastro-oesophageal reflux disease were treated with roxatidine acetate. 60.7% of the patients received a daily dose of 2 x 75 mg roxatidine acetate, and the median duration of treatment was 5 weeks. Symptoms improved in about 90% of patients. For 1687 patients, endoscopic findings were available at the beginning and end of the treatment period. The overall endoscopic healing rate was 65.3%, and, depending on the initial finding (if), decreased from 92.9% (if: Savary-Miller stage I) to 67.5% (if: stage II), 40.7% (if: stage III), and to 22.5% (if: stage IV). Twenty-one patients experienced adverse events during the course of treatment, which, however, were either only minor or not related to the use of roxatidine acetate.

Topics: Anti-Ulcer Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Esophagoscopy; Female; Gastroesophageal Reflux; Humans; Male; Middle Aged; Piperidines

Topics: Aged; Aged, 80 and over; Anti-Ulcer Agents; Drug Eruptions; Female; Histamine H2 Antagonists; Humans; Lichenoid Eruptions; Piperidines; Ranitidine; Stomach Ulcer

The effects of IGN-2098 on the healing process of acetic acid-induced gastric ulcer was investigated in comparison with the other histamine H2-receptor antagonists, famotidine and roxatidine acetate HCl, in rats. Ulcer was induced by the injection of acetic acid solution (20%, 0.05 ml). From the 4th day to 17th day after the ulcer induction, drugs were orally administered twice a day. On the 18th day after the ulcer induction, rats were sacrificed to measure the ulcer index macroscopically and to take pictures of the stomachs. Judging from the photographs, the prominence of ulcer the edge was graded into 4 classes, which showed a significant correlation with the histological amount of connective tissue at the ulcer edge. All drugs accelerated the healing of the ulcer, and the effect of IGN-2098 was the most remarkable. In addition, IGN-2098-treatment exhibited more marked inhibition against the prominence of the ulcer edge as compared with the control group. Based on these results, it is concluded that IGN-2098 may be a useful drug for the clinical treatment of ulcer and that the healing acceleration by IGN-2098 without prominence of the ulcer edge may induce no relapse of the ulcer after healing.

Topics: Acetates; Acetic Acid; Animals; Anti-Ulcer Agents; Famotidine; Histamine H2 Antagonists; Male; Piperidines; Pyrimidinones; Rats; Rats, Sprague-Dawley; Stomach Ulcer

1. Roxatidine acetate, a new histamine H2-receptor antagonist, was administered in the evening (75 mg p.o.) to eight patients with renal insufficiency (CLCR 8-17 ml min-1) for 12 days and plasma drug concentrations were measured. 2. Ambulatory intragastric pH was monitored following the last dose and values were compared with those on day 1 when all patients received a placebo. 3. The terminal elimination half-life (mean +/- s.d.) of roxatidine was 10.8 +/- 2.4 h and its oral clearance was 178 +/- 43 ml min-1. 4. During roxatidine treatment gastrin levels increased slightly (median 189 vs 289 ng l-1) and the hyperparathyroid status of the patients was almost normalized (parathyroid hormone levels: median 199 vs 132 ng l-1). 5. The mean latency to a gastric pH of at least 4 was 4.3 +/- 1.4 h. The duration of action (intragastric pH > 4) was 10.6 +/- 3.9 h. 6. As in a pilot study with six patients (CLCR < or = 17 ml min-1) the recommended dosage regimen (75 mg 48 h-1) was unable to maintain gastric pH > 4 for more than 6 h, daily nocturnal intake of 75 mg roxatidine acetate appears appropriate to elevate gastric pH > 4 for a sufficient period of time.

Topics: Adult; Drug Administration Schedule; Female; Gastric Acid; Gastric Acidity Determination; Gastrins; Histamine H2 Antagonists; Humans; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Piperidines

The effects of roxatidine acetate hydrochloride (Rox) on the pharmacokinetics of theophylline were compared to those of cimetidine in rats in vivo, Cimetidine or Rox was maintained at a steady state level using continuous infusion, then theophylline was injected into the rats as a bolus (7.5 mg/kg). Cimetidine showed competitive inhibition of theophylline elimination in vivo, with an inhibition constant (Ki) of 28.5 microM. Cimetidine significantly decreased the total body clearance and extended the plasma half-life of theophylline, but did not change its volume of distribution. In contrast, Rox did not significantly influence the pharmacokinetics of theophylline in rats. The in vivo animal model used in the present study for investigating the mechanism of the drug interaction showed good agreement with the results obtained in clinical and in vitro studies.

Topics: Animals; Bronchodilator Agents; Chromatography, High Pressure Liquid; Cimetidine; Drug Interactions; Half-Life; Histamine H2 Antagonists; Male; Piperidines; Rats; Rats, Wistar; Spectrophotometry, Ultraviolet; Theophylline

We examined the effects of the known antisecretory and mucosal protective drug, roxatidine, on the secretion and synthesis of mucus by cultured rabbit gastric mucosal cells. The amounts of secreted and synthesized mucus were determined by the [3H] glucosamine labelling method. Exposure of the cells to roxatidine for 8 hr caused increases in the secretion and synthesis of mucus in a dose-related manner. The increase in mucus synthesis was maximally induced 4 hr after the addition of roxatidine, while mucus secretion was maximally enhanced a further 4 hr later. However, other H2 antagonists such as cimetidine, rantidine and famotidine failed to stimulate the secretion and synthesis of gastric mucus. In addition, neither indomethacin nor NG-nitro-L-arginine methyl ester affected the roxatidine-induced increases in mucus secretion and synthesis. We conclude that roxatidine directly acts on gastric mucosal cells, inducing increases in both the secretion and synthesis of mucus, and that an unknown regulatory pathway might be involved in these stimulatory actions of roxatidine.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arginine; Cells, Cultured; Dinoprostone; Enzyme Inhibitors; Gastric Mucosa; Histamine H2 Antagonists; Indomethacin; Male; Mucus; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Piperidines; Rabbits

The action of H1 and H2 blockers on the spontaneous and evoked contractile activity of gastric fundus smooth muscles as well as the effects of H2 antagonists on the release of acetylcholine (ACh) from gastric myenteric neurons were studied. The experiments were performed on smooth muscle strips (25 x 3 mm) cut out in circular direction from guinea pig fundus region. In concentrations of 1 x 10(-7) M to 1 x 10(-4) M, the H1 blockers diphenhydramine (DPH), mepyramine (MEP) and dimethpyrindene (DMPD), but not the H2 blockers ranitidine (RAN), cimetidine (CIM) and roxatidine (ROX), increased in a concentration-dependent manner the smooth muscle tone, the maximum contractions being about 50% of the contractile effects of 1 x 10(-5) M ACH and 5 x 10(-5) M histamine (HA). The concentration-dependent contractions of the stomach fundus strips in response to electrical field stimulation (EFS) were enhanced by RAN, CIM and ROX (but not by MEP and DPH), all in concentrations of 1 x 10(-7) M to 1 x 10(-4) M. EFS increased the resting [3H]-ACh release by 67.8%, the S2/S1 ratio being 0.85 +/- 0.04. ROX in a concentration of 1 x 10(-5) M significantly increased (by 16.1%) the EFS-induced release with a S2/S1 ratio of 1.22 +/- 0.04. The ROX effect on the [3H]-ACh release was reduced or even abolished by 1 x 10(-6) M tetrodotoxin (TTX) and 1 x 10(-6) M scopolamine or in Ca(2+)-free medium, while 1 x 10(-6) M hexamethonium did not change it. It might be concluded that H2 blockers have no direct myogenic effect and do not interfere with muscarinic receptors in guinea pig stomach fundus. The H2 antagonists enhance the EFS-evoked contractions of the gastric smooth muscle most probably by increasing the release of ACH.

Topics: Acetylcholine; Animals; Cimetidine; Dose-Response Relationship, Drug; Guinea Pigs; Histamine; Histamine H1 Antagonists; Histamine H2 Antagonists; Muscle, Smooth; Piperidines; Ranitidine; Stomach

In about 50% of patients with liver cirrhosis, upper digestive bleeding is not due to oesaphageal varices rupture, but to a group of peculiar mucosal lesions usually referred as "congestive gastropathy" and "hepatogenic ulcer". The pathogenesis of such mucosal damage is still unclear: an important causative role is commonly thought to be played by portal hypertension, but the role of peptical pathway and of the mucosal barrier impairment must not be underscored as well. Aim of this study was to evaluate the effect of roxatidine in the long-term treatment of mucosal damage in 19 patients with liver cirrhosis. Patients showed a good tolerance and no side effects. The improvement of endoscopic pattern after a three months period of roxatidine therapy was statistically significant; moreover there was no occurrence of digestive bleeding. In conclusion, H2 antagonist may be considered as the drug of choice for the treatment of mucosal damage in patients with liver cirrhosis, for both its safety and effectiveness.

Topics: Adult; Aged; Duodenal Diseases; Female; Gastric Mucosa; Histamine H2 Antagonists; Humans; Intestinal Mucosa; Liver Cirrhosis; Male; Middle Aged; Piperidines; Stomach Diseases

It has been reported that time to peptic ulcer healing is shorter with proton pump inhibitors (PPI) than with H2-receptor antagonists (H2-RA). This study was designed to examine the difference in the healing process between gastric ulcers treated with PPI and those treated with H2-RA.. The healing of deep gastric ulcers treated with PPI (n = 11) or H2-RA (n = 13) was evaluated with endoscopic ultrasonography (EUS). Every 2 weeks during treatment EUS variables such as the width and the depth of the ulcer crater, the thickness and size of the low echoic area of the ulcer base, and the distance of the disrupted muscularis propria were measured. The contraction rates of EUS variables, the ratios of the contraction rate of the depth to that of the width of the ulcer crater (D/W ratio) and the contraction rate of the distance of the disrupted muscularis propria layer to that of the width of the ulcer crater (Dm/W ratio) were calculated.. Only at week 2 were the D/W ratio and Dm/W ratio significantly higher in the group receiving PPI (D/W ratio, 1.79 +/- 0.701; Dm/W ratio, 0.938 +/- 0.207) than in the group receiving H2-RA (D/W ratio, 1.10 +/- 0.559; Dm/W ratio, 0.641 +/- 0.166).. This study demonstrated that PPI therapy is associated with more rapid and stronger healing than obtained with H2-RA during the early treatment period.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Aged; Anti-Ulcer Agents; Famotidine; Female; Gastroscopy; Histamine H2 Antagonists; Humans; Lansoprazole; Male; Middle Aged; Nizatidine; Omeprazole; Piperidines; Proton Pump Inhibitors; Stomach Ulcer; Ultrasonography, Interventional; Wound Healing

Effects of various histamine H2-receptor antagonists (H2-RA) on gastrointestinal motility and gastric emptying were investigated. Ranitidine, nizatidine and cimetidine dose dependently induced contractions over the entire gastrointestinal tract, and the order of their effects was ranitidine > nizatidine > cimetidine. Roxatidine or famotidine had no effects on motility of the gastrointestinal tract. Ranitidine and nizatidine also induced contractions during the postprandial period and facilitated gastric emptying, while cimetidine, roxatidine or famotidine did not influence gastric emptying. Since acid reduction is thought to be the most important element of the treatment of peptic ulcer and reflux esophagitis, it was inferred that administration of a H2-RA selected with consideration of its property of facilitating gastrointestinal motility is effective in the treatment of patients with abnormal gastrointestinal motility.

Topics: Animals; Cimetidine; Dogs; Dose-Response Relationship, Drug; Famotidine; Gastric Emptying; Gastrointestinal Motility; Histamine H2 Antagonists; Nizatidine; Piperidines; Ranitidine

The histamine H2-receptor antagonistic activity and antisecretory effects of KU-1257 (N-ethyl-N'-[3-[3-(piperidinomethyl) phenoxy]propyl]urea, CAS 120958-90-9) were studied. The Ki values of KU-1257, roxatidine acetate, famotidine and cimetidine for the inhibition of [3H]-tiotidine binding to guinea-pig cerebral cortex were 0.040, 0.13, 0.016 and 0.40 mumol/l, respectively. The KB values of KU-1257, roxatidine acetate, famotidine and cimetidine for the antagonism against histamine-induced positive chronotropic response of isolated guinea-pig right atrium were 0.041, 0.14, 0.031 and 0.51 mumol/l, respectively. In pylorus-ligated rats, KU-1257, roxatidine acetate and famotidine inhibited gastric acid secretion with respective intraduodenal ID50 values of 12.3, 18.5 and 0.45 mg/kg. In dogs with Heidenhain pouch, the ID50 values of KU-1257 for the inhibition of acid output stimulated by histamine, tetragastrin and meat meal were 0.08, 0.39 and 0.15 mg/kg p.o., respectively. KU-1257 was 2-3 times more potent than roxatidine acetate regardless of secretagogues and twice less than famotidine in meat meal stimulation. These results indicate that KU-1257 is a potent and competitive histamine H2-receptor antagonist.

Topics: Animals; Cerebral Cortex; Cimetidine; Dogs; Famotidine; Food; Gastric Acid; Guinea Pigs; Heart Atria; Heart Rate; Histamine H2 Antagonists; In Vitro Techniques; Kinetics; Male; Phenylurea Compounds; Piperidines; Pylorus; Rats; Rats, Wistar; Tetragastrin

Healing-promoting actions of KU-1257 (N-ethyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]urea, CAS 120958-90-9) were investigated in chronic gastric and duodenal ulcer models induced by acetic acid in rats and the effects were compared with those of famotidine and roxatidine acetate by gross or histological evaluation. KU-1257 markedly promoted the well-balanced healing of gastric ulcer at oral doses of 10-50 mg/kg x 2/day, as evidenced by the reduction of ulcer, regeneration of mucosa and proliferation of connective tissue. KU-1257 caused an increase in gastric mucus secretion in the regenerated mucosa around the gastric ulcers. Famotidine and roxatidine acetate failed to promote the healing of gastric ulcers even at 100 mg/kg x 2/day p.o. KU-1257 also significantly accelerated the healing of acetic acid-induced duodenal ulcers as well as famotidine and roxatidine acetate. These results indicate that KU-1257 is characterized by a potent promoting action on the healing of chronic ulcers, suggesting that the increase in gastric mucus secretion might be associated with the antiulcer actions of KU-1257 in part.

Topics: Acetates; Animals; Anti-Ulcer Agents; Dose-Response Relationship, Drug; Duodenal Ulcer; Famotidine; Gastric Mucosa; Histamine H2 Antagonists; Intestinal Mucosa; Male; Phenylurea Compounds; Piperidines; Rats; Rats, Wistar; Stomach Ulcer

Omeprazole is an inhibitor of gastric H+,K(+)-ATPase. Although the major proton transport of osteoclast is mediated by a vacuolar-type H(+)-ATPase which is different from the gastric H+,K(+)-ATPase, in vitro studies have demonstrated that omeprazole inhibits bone resorption. In this study, the effect of omeprazole on bone resorption was evaluated in patients who had a history of gastric ulcer and were treated with maintenance doses of H2 blocker without any gastric complaints at the study time. H2-blocker administration was changed to omeprazole treatment in the study group and to no treatment in the control group. Urinary excretion of hydroxyproline and calcium decreased after omeprazole treatment in the study group. Serum intact PTH, alkaline phosphatase, osteocalcin, and tartrate-resistant acid phosphatase (TRAP) increased in this group. In the control group, there were not any changes in these parameters. The discrepancy between serum TRAP and urinary excretion of hydroxyproline and calcium in the study group was thought to be due to the suppression of bone resorption by omeprazole, which probably interfered the acidification at resorption lacunae and resulted in the inactivation of TRAP and other lysosomal enzymes. The results of our study suggest the possibility that the specific inhibitors of the osteoclastic proton pump (such as bafilomycins) will more effectively suppress bone resorption and be useful for the treatment of metabolic bone diseases with increased bone resorption.

Topics: Adolescent; Adult; Aged; Alkaline Phosphatase; Biomarkers; Body Weight; Bone Resorption; Calcium; Child; Cimetidine; Female; Histamine H2 Antagonists; Humans; Hydroxyproline; Male; Middle Aged; Omeprazole; Osteocalcin; Piperidines; Proton Pump Inhibitors; Stomach Ulcer

Effects of IGN-2098 (5,6-dimethyl-2-[4-[3-(1-piperidinomethyl)phenoxy]- (z)-2-butenylamino]-4(1H)-pyrimidone dihydrochloride, CAS 126869-04-3) a novel histamine H2-antagonist, on histamine-induced gastric acid secretion were investigated in Heidenhain pouch dogs in comparison with those of famotidine, roxatidine acetate HCl and cimetidine. Orally administered IGN-2098 (0.03-1.0 mg/kg), famotidine (0.01-0.3 mg/kg), roxatidine acetate HCl (0.1-1.0 mg/kg) and cimetidine (0.3-3.0 mg/kg) showed dose-dependent inhibition on histamine-induced gastric acid secretion, and ED50 values of IGN-2098, famotidine, roxatidine acetate HCl and cimetidine were 0.077, 0.024, 0.200 and 0.585 mg/kg, respectively. IGN-2098 was effective even at 6 h after administration and ED50 value was 0.315 mg/kg. IGN-2098 was effective also by intravenous route. The inhibitory effect of IGN-2098 on histamine-induced gastric secretion was not affected by the repeated administration of IGN-2098 (1 mg/kg b.i.d. for 14 days). These results show that IGN-2098 is a potent and long acting antisecretory agent and is a useful antisecretory drug for the treatment of peptic ulcer disease.

Topics: Administration, Oral; Animals; Cimetidine; Dogs; Dose-Response Relationship, Drug; Famotidine; Gastric Acid; Gastric Mucosa; Histamine; Histamine H2 Antagonists; Injections, Intravenous; Male; Piperidines; Pyrimidinones

A new compound, IGN-2098 [5,6-dimethyl-2-[4-<3-(1-piperidinomethyl) phenoxy>cis-butenylamino]-4-(1H)-pyrimidone.2HCl], was found to be a potential histamine H2-receptor antagonist in the guinea pig atrium. IGN-2098, given p.o., significantly and persistently (for more than 12 hr) inhibited the basal gastric secretion in pylorus-ligated rats. The agent also significantly inhibited the basal gastric secretion when given by the s.c.-, i.d.- or i.p.-route. Stimulated gastric secretion in fistula rats in response to histamine, carbachol or pentagastrin was also significantly inhibited with IGN-2098 given s.c. Pretreatment with IGN-2098 (p.o.) significantly protected the gastric mucosa against pylorus ligation-, water-immersion stress-, histamine-, indomethacin-, HCl.aspirin-, and HCl.ethanol-induced gastric lesions. In addition, the agent significantly protected the duodenal mucosa against mepirizole-induced ulcers. Based upon the ED50 values, the antisecretory effects on histamine, carbachol or pentagastrin-stimulated acid secretion were 6.0, 37.0 or 80 times more potent than roxatidine, respectively. As to the anti-lesion effects on HCl.aspirin-induced gastric lesions or mepirizole-induced duodenal ulcers, IGN-2098 was 8.1 or 14.8 times more potent than roxatidine, respectively. These results suggest that IGN-2098 will be a useful drug for the treatment of gastric and duodenal lesions in man.

Topics: Animals; Anti-Ulcer Agents; Dose-Response Relationship, Drug; Duodenal Ulcer; Gastric Juice; Histamine H2 Antagonists; Male; Piperidines; Pyrimidinones; Rats; Rats, Inbred Strains; Stomach Ulcer

We examined the effects of a new compound, N-[3-[3-(piperidinomethyl)phenoxy]-propyl]-2-(2-hydroxyethyl-1- thio)acetamido.2-(4-hydroxy benzoyl)benzoate (Z-300), on the histamine H2-receptor, gastric secretion in rats and dogs, and acute gastro-duodenal lesions or chronic gastric ulcers in rats. Roxatidine acetate hydrochloride (roxatidine), a known histamine H2-receptor antagonist, was used as a reference compound. The pA2 values for Z-300 and roxatidine for the isolated guinea pig atrium were 6.8 and 7.0, respectively. These agents at less than 10(-5) M did not affect the contraction of guinea pig ileum in response to carbachol. Z-300, administered either orally or parenterally, significantly inhibited the basal and histamine-stimulated gastric acid secretion in rats. Gastric acid secretion stimulated by histamine, pentagastrin or carbachol in Heidenhain pouch dogs was also significantly inhibited by the compound. The effect persisted for greater than 7 hr in the case of histamine-stimulation. Oral Z-300 significantly protected the gastric mucosa from water-immersion stress-, indomethacin-, aspirin- and HCl.ethanol-induced lesions and protected the duodenal mucosa against mepirizole- and cysteamine-induced ulcers. These effects on gastric secretion and lesion formation were, as a whole, stronger than those observed with roxatidine. Z-300, but not roxatidine, significantly accelerated the spontaneous healing of acetic acid ulcers induced in rats and prevented the delay in ulcer healing caused by indomethacin. The mechanism of action of Z-300 on acute lesions and chronic ulcers appears to be mostly related to its potent antisecretory and mucosal-protective activities.

Topics: Acetamides; Administration, Oral; Animals; Dogs; Duodenum; Female; Gastric Acid; Gastric Mucosa; Histamine H2 Antagonists; Male; Peptic Ulcer; Piperidines; Rats; Rats, Inbred Strains; Stomach; Stomach Ulcer

Cimetidine blunts the increase in cerebral blood flow (CBF) normally observed during hypoxia. It is important, therefore, to know whether other H2-blockers also affect the cerebral circulation adaptation to hypoxia. Cerebral blood flow was measured in 24 awake dogs after an intravenous injection of either saline (control) or one of three H2-blockers: 1 mg/kg ranitidine, 0.4 mg/kg famotidine, or 1 mg/kg roxatidine. These doses are equipotent blockers of H2-gastric receptors. Each dog was studied during normoxia and after 2 and 4 h of normocapnic hypoxia (FIO2, 0.10; FICO2, 0.035). During each set of experimental conditions, a bolus of either saline or one of the anti-H2 drugs was administered, and, 15 min later, radiolabeled microspheres (ruthenium 103, scandium 46, and cerium 141) were injected into the left atrium for measurement of regional CBF. After death by an overdose of thiopental, each dog's brain was excised and fixed in 10% formaldehyde; it was then weighed and dissected by region, with the radioactivity measured in each region using a gamma counter. During hypoxia, PaO2 ranged from 45 to 50 mm Hg, and pH, PaCO2, and hematocrit were within the normal limits. In the control group CBF increased 34% above normoxic baseline levels after 2 h and 31% after 4 h of hypoxia. Ranitidine (1 mg/kg) did not prevent the increase in CBF during hypoxia, but famotidine and roxatidine prevented it. When the dose of ranitidine was doubled (2 mg/kg), it too abolished the increase of CBF induced by hypoxia. In conclusion, H2-receptor blockers could interfere with the adaptation of CBF during hypoxia.

Topics: Animals; Cerebrovascular Circulation; Dogs; Famotidine; Hemodynamics; Histamine H2 Antagonists; Hypoxia; Injections, Intravenous; Microspheres; Piperidines; Pulmonary Gas Exchange; Ranitidine; Respiration

The effect of roxatidine acetate hydrochloride, administered 3 hours prior to induction of anesthesia, on pH and volume of gastric juice was investigated in preoperative patients. In fifty patients, who were scheduled to undergo elective surgery, 150 mg of roxatidine acetate hydrochloride was administered orally 3 hours before the induction of anesthesia. The volume and pH of gastric juice were measured immediately after the induction of anesthesia. In 46 patients out of fifty, pH of gastric juice was more than 2.5, and its volume was below 25 ml. In another 4 patients, pH of gastric juice was more than 2.5, or its volume below 25 ml. We conclude that, oral administration of 150 mg roxatidine 3 hours preoperatively could be effective for the prevention of an aspiration pneumonitis.

Topics: Administration, Oral; Adolescent; Adult; Aged; Female; Gastric Juice; Histamine H2 Antagonists; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Piperidines; Surgical Procedures, Operative

Topics: Animals; Dogs; Gastric Acid; Histamine H2 Antagonists; In Vitro Techniques; Parietal Cells, Gastric; Piperidines

Topics: Adult; Dose-Response Relationship, Drug; Duodenal Ulcer; Female; Gastric Acidity Determination; Histamine H2 Antagonists; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Monitoring, Physiologic; Piperidines

Topics: Histamine H2 Antagonists; Humans; Piperidines

An assay is described for the determination of roxatidine in human plasma, urine and milk by gas chromatography. Roxatidine is extracted from the basified matrix with dichloromethane and esterified with propionic anhydride prior to analysis of the extracts by capillary gas chromatography using a nitrogen-specific detector. Detection limits are 5 ng/ml for plasma and milk and 1 microgram/ml for urine, making the assay suitable for obtaining pharmacokinetic data from volunteer trials.

Topics: Chromatography, Gas; Female; Histamine H2 Antagonists; Humans; Indicators and Reagents; Milk, Human; Piperidines

Central nervous system side effects are occasionally associated with the administration of H2-receptor antagonists. There seems to be a direct correlation between the occurrence of side effects such as mental confusion and the drug concentration in the cerebrospinal fluid. In animal experiments the new H2-blocker roxatidine did not cross the blood-brain barrier. We therefore investigated the penetration of roxatidine into human cerebrospinal fluid (CSF). Nine healthy subjects scheduled for elective spinal anesthesia were premedicated with 150 mg roxatidine orally. Blood samples were taken at 30-min intervals for up to 6 h. A 2-ml CSF sample was taken from each patient at the time of spinal puncture. Small amounts of roxatidine were detectable in the CSF, the CSF to plasma ratio ranging from 0 to 0.89.

Topics: Animals; Blood-Brain Barrier; Female; Histamine H2 Antagonists; Humans; Male; Middle Aged; Piperidines; Time Factors

Roxatidine acetate is a specific and competitive H2-receptor antagonist, as shown in isolated rabbit gastric glands or guinea pig atria preparations. The antisecretory effect of roxatidine acetate is mediated by its main metabolite, roxatidine. In the rat, roxatidine acetate was equipotent after intraduodenal and intraperitoneal administration, indicating excellent bioavailability. Roxatidine acetate and roxatidine were equipotent in the rat after intravenous administration. In the Heidenhain-pouch dog stimulated by food ingestion or maximal histamine dosing, roxatidine acetate and roxatidine proved to be 3-6 times more potent than cimetidine in inhibiting gastric acid secretion. From in vitro experiments it can be concluded that roxatidine acetate and ranitidine are equipotent. Roxatidine acetate has no antiandrogenic effects and does not influence drug-metabolizing enzymes in the liver.

Topics: Animals; Anti-Ulcer Agents; Chemical Phenomena; Chemistry; Dogs; Endocrine Glands; Gastric Acid; Gastric Mucosa; Guinea Pigs; Histamine H2 Antagonists; Piperidines; Rabbits; Rats

Topics: Histamine H2 Antagonists; Molecular Conformation; Piperidines; X-Ray Diffraction

The metabolites were identified by gas chromatography-mass spectrometry (GC-MS). When an equimolar mixture of roxatidine acetate hydrochloride and its deuterated compound, labeled with ten deuterium atoms in the piperidine ring, was incubated with the 9000 X g supernatant (S-9) fraction of either rat or dog liver homogenate, the oxygenated metabolites of the piperidine ring such as the 3-hydroxypiperidine derivative (M1) and the 2-oxopiperidine derivative (M2) were isolated from rats but M2 was not isolated from dogs. These results suggested that the species differences in the metabolism of the piperidine ring in vitro are similar to that in vivo. The deuterium isotope effect (H/D) was 1.34 for M1 and 1.47 for M2 in rats, while the value for M1 in dogs was 1.69. On the other hand, the formation of these oxidative metabolites was inhibited by carbon monoxide in incubations using hepatic microsomes, suggesting that the reaction was catalyzed by cytochromes P-450.

Topics: Animals; Cytochrome P-450 Enzyme System; Dogs; Gas Chromatography-Mass Spectrometry; Histamine H2 Antagonists; In Vitro Techniques; Liver; Male; Microsomes, Liver; Piperidines; Rats; Species Specificity

The inhibitory effects of roxatidine acetate hydrochloride (ROX), a new H2-receptor antagonist, on the oxidative drug-metabolizing enzyme system in mouse hepatic microsomes and in man in vivo were compared with those of cimetidine (CIM). CIM markedly inhibited testosterone 6 beta-, 7 alpha- and 16 alpha-hydroxylase, aminopyrine N-demethylase and aniline hydroxylase activities in mouse hepatic microsomes with inhibition constants (Ki) of 0.2-3.49 mM. ROX exhibited much weaker inhibitory effects on each enzyme activity with 12 to 100-fold higher values of Ki than those of CIM. CIM gave type II difference spectra with dissociation constants (Ks) of 10.4 and 111 microM while ROX gave reverse type I difference spectra with Ks of 55.6 microM. The ratio of 6 beta-hydroxycortisol (6 beta-OHF) to 17-hydroxy corticosteroids (17-OHCS) in urine, used as an indicator of oxidative drug-metabolizing capacity in man, was decreased by 25-35% of the original level on 1-3 d after oral treatment with 800 mg/d of CIM. The ratio was not significantly changed during oral treatment with 150 mg/d of ROX. These results indicate that ROX exhibits a lower affinity for cytochrome P-450 and a lower inhibitory potency on the drug-metabolizing enzymes in hepatic microsomes than does CIM.

Topics: Aminopyrine N-Demethylase; Aniline Hydroxylase; Animals; Cimetidine; Cytochrome P-450 Enzyme Inhibitors; Histamine H2 Antagonists; Humans; Inactivation, Metabolic; Isoenzymes; Kinetics; Mice; Microsomes, Liver; Piperidines; Steroid 16-alpha-Hydroxylase