vet.auth.gr

The present study examines the pharmacodynamic interaction between the H(2)-receptor antagonist ranitidine and the prokinetic agent cisapride on the isolated rabbit intestine. Ranitidine produced a concentration-dependent contractile effect on the duodenal, ileal and ascending colon preparations, with EC(50)values of 1.35 x 10(-4)M for the duodenum, 1.2 x 10(-4)M for the ileum and 1.15 x 10(-4)M for the ascending colon. The effect of cisapride on the ranitidine contractile effect was dependent on the cisapride concentration used. Thus, cisapride, at concentrations from 10(-10)up to 5 x 10(-7)for the duodenum and the ascending colon and up to 10(-6)M for the ileum, potentiated the contractile responses of the preparations to ranitidine. However, at higher concentrations cisapride produced a non-competitive inhibition of the intestinal contractile responses to ranitidine with IC(50)values of 4.2 x 10(-5)M for the duodenum, 1.65 x 10(-5)M for the ileum and 3.2 x 10(-6)M for the ascending colon. These data show that cisapride may modify the contractile responses of the isolated rabbit intestine to ranitidine, having a potentiating effect up to a certain concentration and an antagonistic one at higher concentrations. In conclusion, co-administration of the above drugs may lead to enhanced or reduced intestinal motility. Copyright 2001 Academic Press.

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Crit Care Med. 2001 Apr;29(4):759-64.
Pharmacokinetics and pharmacodynamics of ranitidine in critically ill children.

Lugo RA, Harrison AM, Cash J, Sweeley J, Vernon DD.

Department of Pharmacy Practice, the University of Utah College of Pharmacy, Salt Lake City, UT, USA.

OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of ranitidine in critically ill children and to design a dosage regimen that achieves a gastric pH > or =4. DESIGN: Prospective, open-label, pharmacokinetic-pharmacodynamic study. SETTING: Pediatric intensive care unit in a tertiary care children's hospital. PATIENTS: Mechanically ventilated, critically ill children > or =10 kg who required intravenous ranitidine for stress ulcer prophylaxis. INTERVENTIONS: Ranitidine pharmacokinetics were determined after a single intravenous dose. Gastric pH was monitored hourly via nasogastric pH probe. After the last blood sample, patients received an intravenous bolus of ranitidine (0.5 mg/kg) followed by a continuous infusion (0.1 mg x kg(-1) x hr(-1)). The infusion was increased incrementally (0.05 mg x kg(-1) x hr(-1)) until reaching gastric pH > or =4 for > or =75% of a 24-hr period, after which steady-state plasma concentrations were measured. Plasma concentrations were analyzed by high-pressure liquid chromatography. MEASUREMENTS AND MAIN RESULTS: Twenty-three children (ranging in age from 1.4 to 17.1 yrs) were studied. Pharmacokinetic variables included a clearance of 511.7 +/- 219.7 mL x kg(-1) x hr(-1), volume of distribution of 1.53 +/- 0.99 L/kg, and half-life of 3.01 +/- 1.35 hrs. After the single intravenous dose (1.52 +/- 0.47 mg/kg), gastric pH increased from 1.6 +/- 1.0 to 5.1 +/- 1.1 (p <.001), which was associated with a plasma concentration of 373 +/- 257 ng/mL. Based on the pharmacokinetic variables, the dose of intravenous ranitidine required to target 373 ng/mL as the average steady-state concentration is 1.5 mg/kg administered every 8 hrs. During the continuous infusion, the mean s




Crit Care Med. 1999 Jan;27(1):90-4.
Effect of omeprazole, lansoprazole, and ranitidine on the DNA synthesis of mononuclear cells.

Peddicord TE, Olsen KM, Collier DS.

Department of Pharmacy Practice, University of Nebraska Medical Center, Omaha 68198-6045, USA.

OBJECTIVE: To examine and compare the effects of omeprazole, lansoprazole, and ranitidine on the DNA synthesis of peripheral blood mononuclear cells. DESIGN: Ex vivo laboratory study. SETTING: Clinical research laboratory of an academic medical center. SUBJECTS: Healthy volunteers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Venous blood was collected from normal subjects and peripheral blood mononuclear cells (PBMCs) were isolated using centrifugation techniques over a Ficoll-Hypaque density gradient. PBMCs were added to 12-well culture plates in four groups of media: a) control; b) control plus lansoprazole (25 microg/mL); c) control plus omeprazole (0.35 microg/mL); and d) control plus ranitidine (50 microg/mL). PBMCs were exposed to the drug for 96 hrs, with addition of phytohemagglutinin (2.5 microg/ mL) for the last 48 hrs, and 3H-thymidine (1 microCi) during the final 6 hrs. PBMCs were filtered onto glass-fiber filter paper and the radioactivity was determined by scintillation counting. Since radioactivity is measured only in those cells undergoing DNA synthesis or cell division, results are expressed as quantification of 3H-thymidine uptake. Median disintegrations per min (DPM)/number of PBMCs per well+/-SEM are reported: control 68.3+/-37.8; ranitidine 38.4 +/-94.2; lansoprazole 14.6+/-84.4; and omeprazole 15.1+/-48.9. There was a significant difference between lansoprazole vs. ranitidine (p< .01), and omeprazole vs. ranitidine (p< .05), and no significant difference between lansoprazole and omeprazole. CONCLUSIONS: This is the first study to compare the potential immunomodulating effects of these commonly used agents. Ranitidine caused increased DNA synthesis in PBMCs when compared with lansoprazole and ome




Rev Esp Quimioter. 1999 Mar;12(1):64-8.
Bacteriostatic and bactericidal activity of ranitidine bismuth citrate in Helicobacter pylori clinical isolates.

Alarcon T, Domingo D, Prieto N, Lopez-Brea M.

Servicio de Microbiologia, Hospital Universitario de la Princesa, Diego de Leon 62, 28006 Madrid.

Ranitidine bismuth citrate is a novel salt that seems to be useful in eradication of Helicobacter pylori from gastric mucosa when it is combined with antibiotics. The in vitro bacteriostatic (by MIC determination) and bactericidal (by killing curve) activity of ranitidine bismuth citrate was determined in this study. A total of 52 strains were cultured from gastric antral biopsy specimens taken at routine endoscopy and identified using standard methodology. MIC was determined by agar dilution using Mueller-Hinton agar supplemented with 7% horse blood. Killing curves were studied in 11 isolates. Ranitidine bismuth citrate at final concentrations of 1 mg/l and 8 mg/l were used. A starting inoculum of 10(4) to 10(6) CFU/ml was prepared in BHI with 10% fetal calf serum from a 48 h H. pylori broth culture. Viable colony counting was performed at 0, 2, 4, 6, 8 and 24 h. A control without the study drug was included in each experiment and treated identically. A reduction of 100 to 1,000 CFU/ml was considered bactericidal. The MIC50, MIC90 and range for ranitidine bismuth citrate was 1, 2 and 0.25-4 mg/l, respectively. At 1 mg/l it showed a bactericidal effect after 2 h in one strain, after 8 h in two and after 24 h in four strains, and four strains were not killed. At 8 mg/l it killed three strains in 2 h, one in 4 h, two in 6 h, one in 8 h and four strains in 24 h. Ranitidine bismuth citrate was active in vitro against the H. pylori clinical isolates tested (by MIC and killing curves).

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J Chromatogr B Biomed Sci Appl. 1997 May 23;693(1):228-32.
Simple and robust high-performance liquid chromatographic method for the determination of ranitidine in microvolumes of human serum.

Lopez-Calull C, Garcia-Capdevila L, Arroyo C, Bonal J.

Hospital Sta. Creu i St. Pau, Pharmacy Department, Pharmacokinetic Laboratory, Barcelona, Spain.

A simple robust high-performance liquid chromatographic method is described for the determination of ranitidine in microvolumes of human serum. The drug of interest was isolated using liquid-liquid extraction with dichloromethane and back-extraction with 0.1% phosphoric acid and separation was obtained using a reversed-phase column under isocratic conditions, with ultraviolet detection at 313 nm. Intra-day and inter-day coefficients of variation ranged from 1 to 6% and 3 to 10%, respectively. Accuracy of the assay was less than 10% at all concentrations. The limit of detection and the limit of quantitation were 2 and 7 ng/ml, respectively. The linearity was assessed in the range 10-1000 ng/ml. It was shown that a group of common drugs co-administered with ranitidine did not interfere with its determination. The applicability of this method for the pharmacokinetic study of ranitidine following i.v. infusion in patients was demonstrated using only 100 microl of serum. The ruggedness of the assay was demonstrated over a three-year period.

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J Chromatogr B Biomed Sci Appl. 1997 Jun 6;693(2):443-9.
Use of post-column fluorescence derivatization to develop a liquid chromatographic assay for ranitidine and its metabolites in biological fluids.

Vinas P, Campillo N, Lopez-Erroz C, Hernandez-Cordoba M.

Department of Analytical Chemistry, Faculty of Chemistry, University of Murcia, Spain.

Ranitidine and its main metabolites, ranitidine N-oxide and ranitidine S-oxide, were determined in plasma and urine after separation using reversed-phase liquid chromatography. The mobile phase consisted of an initial isocratic step with 7:93 (v/v) acetonitrile-7.5 mM phosphate buffer (pH 6) for 8 min, followed by a linear gradient up to a 25:75 (v/v) mixture over 1 min. Detection was carried out by a post-column fluorimetric derivatization based on the reaction of the drugs with sodium hypochlorite, giving rise to primary amines that reacted with o-phthalaldehyde and 2-mercaptoethanol to form highly fluorescent products. The calibration graphs, based on peak area, were linear in the range 0.1-4 microg/ml for all drugs. The detection limits were 30, 41 and 32 ng/ml (8.6, 12.5 and 9.1 pmol) for ranitidine S-oxide, ranitidine N-oxide and ranitidine, respectively. Chromatographic profiles obtained for plasma and urine samples showed no interference from endogenous compounds.

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Aliment Pharmacol Ther. 1997 Jun;11(3):511-4.
Comparison of ranitidine and lansoprazole in short-term low-dose triple therapy for Helicobacter pylori infection.

Kihira K, Satoh K, Saifuku K, Taniguchi Y, Takimoto T, Yamamoto H, Ido K, Yoshida Y, Kimura K.

Department of Gastroenterology, Jichi Medical School, Kawachi-gun, Japan.

AIM: To evaluate the efficacy and safety of two 1-week low-dose triple-therapy drug regimens involving antisecretory drugs for Helicobacter pylori infection. 99 patients with H. pylori infection were treated with either lansoprazole or ranitidine used together with clarithromycin and metronidazole. METHODS: The drug combination and administration periods in the proton pump inhibitor group were lansoprazole 30 mg o.m., clarithromycin 200 mg b.d. and metronidazole 250 mg b.d., all given for 7 days (LCM group). The ranitidine group received ranitidine 150 mg b.d., clarithromycin 200 mg b.d. and metronidazole 250 mg b.d. also for 7 days (RCM group). The presence or absence of H. pylori was determined from gastric biopsy specimens taken from both the antrum and the body, by smear, culture and tissue section (Giemsa stain). Cure was defined as failure to find evidence of H. pylori infection 4 weeks after antimicrobial therapy had ended. RESULTS: The cure of H. pylori infection was 88% in the LCM group (44 of 50; 95% confidence interval (CI) = 79-97%) and 92% in the RCM group (45 of 49; 95% CI = 84-99%). The incidence of adverse events was 16% and 18% for the two groups, respectively. CONCLUSIONS: No significant differences in cure rate and safety profiles were noted between the two regimens, suggesting that moderate acid inhibition using an H2-blocker is sufficient to achieve optimal H. pylori eradication.

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fhs.csu.mcmaster.ca

Published data and techniques for decision analysis were used to construct a model to estimate the cost effectiveness of nine alternative strategies for the management of patients diagnosed with uncomplicated duodenal ulcer. Two strategies of intermittent therapy with either ranitidine or omeprazole, one strategy of continuous maintenance treatment with ranitidine, and six strategies for ulcer healing and eradication of Helicobacter pylori infection were considered. Healing time curves were estimated by using published data, allowing for estimation of expected time for acute healing episodes. The expected number of weeks to heal per patient, in a one-year period, was estimated by combining healing time data with probability of ulcer recurrence. It was found that patients that underwent any of the six H pylori eradication regimens had fewer days with ulcer per year than those who underwent maintenance or intermittent ranitidine. Four eradication regimens had lower costs and better outcomes than ranitidine therapy. In comparing H pylori strategies, the two strategies of omeprazole plus one antibiotic (either amoxicillin or clarithromycin) are most costly than omeprazole plus two antibiotics (specifically amoxicillin and metronidazole or clarithromycin and metronidazole) and result in similar outcomes. Although omeprazole-based eradication regimens are more costly than ranitidine bismuth triple therapy, they are associated with fewer recurrences of ulcer and days of symptoms. A limitation of the analysis is that it did not incorporate issues of compliance and metronidazole resistance; however, the former concern may be less of an issue as H pylori regimens beco

glaxo.com

OBJECTIVE: The pharmacodynamics and pharmacokinetics of ranitidine were examined in subjects with varying degrees of renal function to determine the effect of this condition on acid-antisecretory activity. METHODS: Subjects with creatinine clearances (Ccr) ranging from 0 to 213 m1.min-1 received single 50-mg and 25-mg i.v. doses of ranitidine. This was followed by determination of serum and urine ranitidine concentrations, and continuous gastric pH monitoring for 24 h. RESULTS: Serum ranitidine concentrations were described by a two-compartment model linked to a sigmoidal Emax model describing gastric pH. Ranitidine renal clearance, ranging from 0 to 1003 m1.min-1, correlated with CPAH (r2 = 0.707), while non-renal clearance was unaltered. Steady-state volume of distribution decreased by half in severe renal impairment. No changes in the effective concentration at half-maximal response (EC50), maximal response (Emax), or basal response (E0) were observed. Thus, renal elimination of ranitidine declined in parallel with renal function, while sensitivity to the pharmacologic effect (gastric pH elevation) was unaltered. Ranitidine was cell tolerated in these renally impaired subjects. CONCLUSION: These data indicate that the current recommendation for renal impairment dose reduction (by two-thirds when Ccr < 50 m1-min-1) might result in under-treating moderately impaired patients, and suggests a less conservative dose reduction (by half when Ccr < 10 m1.min-1) to avoid therapeutic failure while remaining within the wide margin of safety for this drug.

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