Gastroenterol Clin Biol. 1989 Jun;13(6-7):585-90.
[Relation of the kinetics of the antisecretory effect and kinetics of blood concentration in man. Comparing cimetidine and ranitidine]

[Article in French]

Raoul JL, Trouvin JH, Farinotti R, Lewin MJ, Bonfils S.

Inserm U10, Hopital Bichat, Paris.

The time course of antisecretory effects of ranitidine and cimetidine and their relationship to plasma concentration were studied in 4 healthy volunteers. Placebo, cimetidine (266 mg) or ranitidine (100 mg) were infused during one hour preceding the 90 minute assessment of food-stimulated gastric acid secretion (intragastric titration); cimetidine and ranitidine blood levels and gastric acid outputs were measured at 15 min intervals. For each test a significant (p less than or equal to 0.01) correlation was found between concentration and effect. The half-life effect of ranitidine (t1/2 E) was significantly (p less than or equal to 0.05) greater than t1/2 E of cimetidine whereas their plasma half-lives (t1/2) were similar. The ratio t1/2 E/t1/2 was significantly (p less than or equal to 0.05) lower with cimetidine than with ranitidine. Explanations for this discrepancy are analyzed according to various hypotheses. The determination of t1/2 E seems to be a good approach to the duration of action of H2-antagonists. Our results show that the ratio t1/2 E/t1/2 and the t1/2 E might be important pharmacokinetic parameters to compare various H2-receptor antagonists.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2753306&dopt=Abstract ranitidine






Regul Pept. 1989 May;25(2):235-46.
Omeprazole and ranitidine, antisecretagogues with different modes of action, are equally effective in causing hyperplasia of enterochromaffin-like cells in rat stomach.

Ryberg B, Bishop AE, Bloom SR, Carlsson E, Hakanson R, Larsson H, Mattsson H, Polak JM, Sundler F.

AB Hassle, Dept. of Biolopgy, Molndal, Sweden.

Female rats were treated for 28 days with high doses of the gastric acid secretion inhibitors omeprazole and ranitidine. Omeprazole, which is long-acting, was given orally once daily. Ranitidine, which is short-acting, was given by continuous infusion (via osmotic minipumps, implanted subcutaneously). The aim was to produce a similar degree of acid inhibition with the two drugs. The inhibition of acid secretion over the day and night was more pronounced in the omeprazole-treated rats (maximal inhibition 100%, minimum 85%) than in those receiving ranitidine (mean 70%). In both groups, there was a great increase in plasma gastrin, somewhat greater after omeprazole than after ranitidine. The gastrin concentration in the antrum was almost doubled by both treatments and there was a moderate increase in the number of antral gastrin cells in the omeprazole-treated rats. The number of enterochromaffin-like (ECL) cells (per visual field) increased in the oxyntic mucosa to the same extent (greater than 100%) in the ranitidine- and omeprazole-treated rats. Apart from the gastrin cells in the antrum and the ECL cells in the corpus no other gastric endocrine cell type seemed to respond to treatments with antisecretagogues. We conclude that, regardless of the type of antisecretagogue used, effective and long-term suppression of gastric acid secretion results in sustained hypergastrinemia and increased number of ECL cells. Conceivably therefore, the ECL cell hyperplasia reflects the trophic effect of gastrin.

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J Chromatogr. 1989 May 5;490(1):175-85.
Simultaneous determination of ranitidine and its metabolites in human plasma and urine by high-performance liquid chromatography.

Prueksaritanont T, Sittichai N, Prueksaritanont S, Vongsaroj R.

Drug Analysis Division, Department of Medical Sciences, Yod-se, Bangkok.

A sensitive high-performance liquid chromatographic method was developed for the simultaneous determination of ranitidine and its metabolites, ranitidine N-oxide, ranitidine S-oxide and desmethylranitidine, in human plasma and urine. For the plasma analysis, 1-ml plasma samples spiked with phenylpyramidol as the internal standard were extracted at basic pH with acetonitrile-ethyl acetate (3:2, v/v). After evaporation and reconstitution, the samples were chromatographed on a cation-exchange column, with a mobile phase of 0.1 M sodium acetate buffer (pH 5)-acetonitrile-tetrahydrofuran (56.5:36:7.5, v/v) and ultraviolet detection at 320 nm. The extraction recoveries were 99.8, 30.4, 74.2 and 80.2% and the detection limits were 5, 15, 10 and 4 ng/ml for ranitidine, ranitidine N-oxide, ranitidine S-oxide and desmethylranitidine, respectively. For the urine analysis, a simple deproteinization with an equal volume of acetonitrile was satisfactory for sample preparation. The applicability of this method for the pharmacokinetic study of ranitidine following oral administration was demonstrated.

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Anesth Analg. 1989 Nov;69(5):611-3.
Intravenous ranitidine antagonizes intense atracurium-induced neuromuscular blockade in rats.

Law SC, Ramzan IM, Brandom BW, Cook DR.

Department of Anesthesiology, University of Pittsburgh School of Medicine, Pennsylvania.

The neuromuscular action of ranitidine, an H2-receptor antagonist, was investigated by determining its effect on atracurium-induced neuromuscular blockade in urethane-anesthetized and mechanically ventilated male Sprague-Dawley rats. An intravenous bolus and an infusion of atracurium were administered to produce a stable 93 +/- 5% (n = 11) neuromuscular blockade as judged by tibialis anterior muscle twitch response. Ranitidine administered as a 1, 5, or 10 mg/kg normal body weight IV bolus during continuous atracurium infusion produced marked antagonism of neuromuscular paralysis. The percentage of antagonism (25 +/- 9%; n = 4; 53 +/- 19%, n = 4; and 79 +/- 9%, n = 3, respectively) was linearly related to the dose of ranitidine (r = 0.86, P less than 0.05). These results suggest that IV ranitidine has a significant anticholinesterase action against atracurium-induced neuromuscular blockade.

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Psychopharmacology (Berl). 1990;102(1):106-11.
Effects of antihistaminics on naloxone-induced withdrawal in morphine-dependent mice.

Leza JC, Lizasoain I, Lorenzo P.

Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid, Spain.

Some histamine H1 (tripelennamine, diphenhydramine and cyclizine) and H2 (ranitidine and cimetidine) antagonists (1 and 10 mg/kg) were administered to morphine-dependent mice to evaluate the changes on naloxone-induced abstinence syndrome. When antihistaminics were administered 30 min before naloxone (1 mg/kg) on day 4 of morphine addiction, the two doses of three H1 antagonists and the higher dose of ranitidine inhibited shaking behavior. Furthermore, the two doses of tripelennamine and the higher dose of diphenhydramine, cyclizine and cimetidine enhanced jumping behavior. When antihistaminics were administered chronically (during the 4 days of morphine addiction), tripelennamine, cyclizine and ranitidine (all at 10 mg/kg) inhibited shaking behavior. The three H1 antihistaminics used enhanced the number of jumps per mouse whereas ranitidine decreased this response. No significant changes were found in the rest of the withdrawal symptoms after the antihistaminics were administered. The participation of serotonergic and catecholaminergic mechanisms is discussed.

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Basic Res Cardiol. 1990 Sep-Oct;85(5):519-30.
H2-receptor antagonism is not pro-arrhythmic in a chronic canine model.

Uprichard AC, Harron DW.

Department of Therapeutics and Pharmacology, Queen's University of Belfast, Northern Ireland.

Seven to 28 days after coronary artery ligation, programmed electrical stimulation was performed in conscious dogs. Groups of 6 previously inducible dogs in which no arrhythmia could presently be achieved were randomly allocated to receive quinidine, cimetidine, ranitidine or placebo. Results were assessed for the drugs' ability to induce ventricular tachycardia or fibrillation, and compared with placebo using Fisher's Exact Test. In the placebo group 4/6 dogs remained unchanged, one developed an arrhythmia, and one died. With quinidine, 3/6 dogs developed an arrhythmia (0.5 mg/kg, 4.0 mg/kg, 4.0 mg/kg) and three died (4 mg/kg, 8 mg/kg, 16 mg/kg) (p less than 0.05 compared with placebo). With cimetidine, 4/6 dogs remained unchanged, one developed an arrhythmia after 4 mg/kg, and one died after 0.5 mg/kg. After ranitidine 3/6 dogs remained unchanged and three died (1.0 mg/kg, 4.0 mg/kg, 16.0 mg/kg). PR, QTc, QRS, refractory periods, and mean systolic pressure remained unchanged after placebo, cimetidine, and ranitidine, but QTc increased (p less than 0.05) and mean systolic pressure fell (p less than 0.01) after quinidine. Heart rate did not change following placebo, but increased (p less than 0.05) after each of the three drug treatments. These results fail to show a significant arrhythmogenic effect of cimetidine or ranitidine in a model validated by the significant pro-arrhythmic effects of quinidine. The cause of death in all cases was ventricular fibrillation.

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J Pharm Biomed Anal. 1989;7(6):747-53.
Determination of ranitidine in plasma by high-performance liquid chromatography.

Rahman A, Hoffman NE, Rustum AM.

Chemistry Department, Marquette University, Milwaukee, WI 53233.

A high-performance liquid chromatographic method has been developed for the determination of ranitidine in plasma. Ranitidine was extracted with acetonitrile by adding it to the plasma and then salting it out with potassium carbonate. The chromatographic column was 5-microns ODS silica, the mobile phase being acetonitrile-7 mM triethylammonium ion in phosphoric acid (pH 3.00) (30:70, v/v). The ranitidine peak was monitored at a wavelength of 315 nm, the retention time for ranitidine being 4.6 min. A limit of detection of 3 ng ml-1 was obtained for a 100-microliters injection of ranitidine. The method was found to be reproducible with a relative standard deviation (RSD) between 0.8-5.3% (n = 5) over the concentration range 25-80 ng ml-1 in plasma. The ranitidine concentration was determined in 18 different patients' plasmas. Ranitidine and its metabolites ranitidine S-oxide, ranitidine N-oxide and desmethyl-ranitidine, were also studied for chromatographic resolution from each other. It was shown that a group of common drugs did not interfere with ranitidine determination.

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Am J Hosp Pharm. 1989 Feb;46(2):304-7.
Concentration uniformity of extemporaneously prepared ranitidine suspension.

Karnes HT, Harris SR, Garnett WR, March C.

Department of Pharmacy and Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond 23298.

The concentration uniformity of an extemporaneously prepared ranitidine suspension was studied. To prepare the ranitidine suspension, 36 150-mg tablets were pulverized and suspended in 180 mL of distilled water. This mixture was diluted with simple syrup to a total volume of 360 mL, resulting in a final ranitidine concentration of 150 mg/10 mL. Samples from each of three bottles that had been filled with 60 mL of the suspension were assayed for ranitidine content by high-performance liquid chromatography. The sedimentation of suspended ranitidine tablet particles was studied by visual observation of the setting process in 10-mL samples from the same batch. The overall mean concentrations (in milligrams per milliliter) of ranitidine were 14.53, 15.25, 13.92, 12.67, and 12.72 at 0, 3, 7, 14, and 21 days, respectively. Compared with baseline, the difference in the ranitidine concentration was not significant over days 0-7. The ranitidine concentration was significantly reduced during the following time intervals: days 0-14, days 0-21, and days 7-21. In the settling experiments, the mean time (+/- S.D.) for sediment to first appear on the test tube bottom was 14.67 +/- 5.35 seconds. Approximately 40-50% (mean level = 3.2 mm) of the total sedimentation level (mean level = 7.3 mm) was observed one minute after shaking. The uniformity of ranitidine suspensions compounded according to procedures described in this report possibly could be improved with sonication. The ranitidine suspension should be well shaken, the dosage should be measured immediately after shaking, and the suspension should be used within seven days of compounding.

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Can J Vet Res. 1989 Apr;53(2):231-8.
The protective effects of sucralfate and ranitidine in foals experimentally intoxicated with phenylbutazone.

Geor RJ, Petrie L, Papich MG, Rousseaux C.

Department of Veterinary Internal Medicine, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon.

The effects of sucralfate and ranitidine on the gastrointestinal manifestations of phenylbutazone (PBZ) toxicity in horse foals were determined by complete blood count, serum chemistry profile, and gross and histological necropsy examinations. Twenty-eight, three to four month old Belgian-cross foals were randomly assigned to one of four groups. Phenylbutazone was administered at a dosage of 10 mg/kg of bodyweight (BW) per day, intravenously (IV), in equally divided doses to three of the groups. In addition to PBZ, ranitidine was administered at 2 mg/kg BW, IV, twice daily, to one group of seven foals (PBZ/ranitidine group), and sucralfate was administered at 4 g, orally, twice daily to another group of seven foals (PBZ/sucralfate group). A fourth group received normal saline IV and corn syrup orally, twice daily, as placebos (control group). Treatments were administered for ten days. Clinical signs included oral ulceration (in all PBZ-treated foals) and diarrhea (5/7 and 2/7 foals from the PBZ and PBZ/ranitidine groups, respectively). A reduction in total protein and albumin was greatest in the PBZ group and least in the PBZ/ranitidine and PBZ/sucralfate groups when compared to the control group. The PBZ group lost weight during the treatment period. At necropsy, the PBZ group had the greatest area of oral ulceration compared to the other treatment groups. All foals treated with PBZ had gastric ulcers; however, the PBZ group had the most severe gastric epithelial necrosis compared to the other three treatment groups. Duodenal villous atrophy, epithelial necrosis and mucosal inflammation, and a reduction in epithelial mitotic figures were seen in all PBZ-treated foals.(ABSTRACT TRU