Gastroenterol Jpn. 1990 Aug;25(4):425-31.
The effects of histamine on the concentrations of immunoreactive thyrotropin-releasing hormone in the stomach and hypothalamus in rats.

Nakada K, Mitsuma T, Furusawa A, Maeda Y, Morise K.

Fourth Department of Internal Medicine, Aichi Medical University, Japan.

The effects of histamine and its related compounds on the concentrations of immunoreactive thyrotropin-releasing hormone (ir-TRH) in the stomach, gastric juice and hypothalamus in rats were studied. Histamine, ranitidine or ethanolamine was injected intraperitoneally, and the rats were decapitated at various times after the injection. Ir-TRH concentrations in the stomach, gastric juice and hypothalamus were measured by a radioimmunoassay. Ir-TRH concentrations in the stomach decreased significantly after histamine injection and increased significantly after ranitidine injection in a dose-dependent manner, but did not change with ethanolamine. Ir-TRH concentrations in the gastric juice increased in a dose-dependent manner, peaking at 30 min after histamine injection, and its effect was blocked with ranitidine. Ir-TRH concentrations in the hypothalamus elevated significantly after histamine injection and reduced significantly after ranitidine injection, but did not change with ethanolamine. The effects of histamine on ir-TRH concentrations in the stomach and hypothalamus were significantly blocked with ranitidine, but not with ethanolamine. These findings suggest that histamine stimulates ir-TRH release from the stomach and inhibits ir-TRH release from the hypothalamus, and that these effects of histamine on ir-TRH release are mediated via an H2-receptor.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2120101&dopt=Abstract ranitidine






J Immunol. 1990 Dec 15;145(12):4365-70.
Role of histamine in natural killer cell-mediated resistance against tumor cells.

Hellstrand K, Asea A, Hermodsson S.

Department of Clinical Virology, University of Goteborg, Sweden.

The formation of lung metastases by i.v.-injected B16 melanoma (F1 and F10 strain) cells in Swiss albino, C57BL/6, and BALB/c mice was reduced by a single dose of histamine given 24 h before tumor cell inoculation. The antimetastatic effect of histamine was specifically mediated by histamine H2-receptors (H2R): it was blocked by the H2R antagonist ranitidine and mimicked by dimaprit, a specific H2R agonist but not by an H2R-inactive structural analog of this compound, nor-dimaprit, or the H1R agonist 2-thiazolyl-ethylamide. A single dose of any of the H2R antagonists ranitidine, tiotidine, famotidine, or cimetidine drastically augmented metastasis. Effects of H2R-interactive compounds on B16 metastasis required intact NK cells, as judged by the inability of histamine or ranitidine to affect B16 metastasis after NK cell depletion in vivo using antibodies to asialo-GM1. NK-cell-mediated lysis of YAC-1 lymphoma cells in vivo was enhanced by histamine and reduced by ranitidine within 4 h after inoculation of tumor cells. The antimetastatic effect of IL-2 was potentiated by histamine; in some experiments, combined treatment with a low dose of IL-2 (6000 U/kg) and histamine completely eliminated metastasis, whereas concomitant treatment with ranitidine abrogated antimetastatic effects of IL-2; animals treated with ranitidine and IL-2 displayed the same level of enhanced metastasis as those treated with ranitidine alone. The presented data are suggestive of an earlier unrecognized role for histamine in NK cell-mediated resistance against metastatic tumor cells.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2147942&dopt=Abstract ranitidine






Res Exp Med (Berl). 1990;190(5):345-56.
Effect of histamine H2-receptor antagonist, ranitidine on renal brush border and basolateral membranes.

Gill M, Sanyal SN, Sareen ML.

Department of Zoology, Panjab University, Chandigarh, India.

The antiulcerogenic drug ranitidine, given orally to mice, brought about reductions of kidney-bound hydrolytic enzymes at three different dose levels, viz. 10 mg, 100 mg, and 1000 mg/kg body weight, and for three different time points (single administration for 2 h and 24 h, and daily administration for 15 days). The activities of Na+, K(+)-ATPase, Ca2(+)-ATPase, and Mg2(+)-ATPase (marker enzymes of basolateral membranes) were reduced, and these reductions were significant at higher doses and after a 24-h single treatment or 15 days' daily treatment. Maltase, alkaline phosphatase, and leucine aminopeptidase (marker enzymes of brush border membrane [BBM]) activities were significantly inhibited after ranitidine treatment. Kinetic analysis of BBM-associated enzymes indicated that ranitidine decreased the maximum of apparent initial enzyme velocity (Vmax) of maltase, alkaline phosphatase, and leucine aminopeptidase. The substrate affinity constant (Km) was decreased in the case of alkaline phosphatase and maltase, while it was not altered in the case of leucine aminopeptidase. In vitro addition of ranitidine to renal BBM also produced significant inhibition of these enzymes, the inhibition constants (Ki) for maltase, alkaline phosphatase, and leucine aminopeptidase being 7.5, 15.5, and 3.5 mM, respectively. Membrane-bound lipid estimation showed a significant increase in phospholipids, triglycerides, and free fatty acids. Cholesterol, however, was decreased in both renal basolateral and brush border membranes.

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Toxicol Appl Pharmacol. 1990 Mar 1;102(3):430-42.
Excretion of high concentrations of cimetidine and ranitidine into rat milk and their effects on milk composition and mammary gland nucleic acid content.

Dostal LA, Weaver RP, Schwetz BA.

National Institute of Environmental Health Sciences, National Toxicology Program, Research Triangle Park, North Carolina 27709.

The excretion of cimetidine and ranitidine into rat milk following single or multiple oral doses and the subsequent effects on their suckling pups and on milk composition and milk synthesis were investigated. Following a single dose of [3H]cimetidine, peak milk cimetidine concentrations were maintained from 1 until 4 hr, while plasma concentrations peaked at 10% of the milk level at 30 min and then declined. Multiple doses of cimetidine (18 or 180 mg/kg/day) on Days 13-16 of lactation led to milk cimetidine concentrations of 17 and 113 micrograms/ml. The milk/plasma ratios far exceeded the theoretical milk/plasma ratio of 2.0. Ranitidine concentrations in rat milk following ranitidine treatment (4.5 or 45 mg/kg/day) were also greater (6.8-15 times) than in plasma, but only slightly greater than the predicted ratio of 5.0. There were no changes in liver weight or in hepatic aminopyrine N-demethylase activity in the cimetidine- or ranitidine-treated dams or their pups. Cimetidine treatment had no effect on milk lipid, solid, or protein content, but at 180 mg/kg/day, caused a significant increase in milk lactose. The RNA/DNA ratio in the mammary gland was significantly increased by cimetidine, suggesting increased milk synthesis. Ranitidine had no effect on milk composition or on mammary gland RNA, DNA, or RNA/DNA. Therefore, high concentrations of cimetidine and ranitidine were excreted into rat milk, but no deleterious effects on the suckling pups, or the composition of the milk, or on the milk synthetic activity were observed.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1690458&dopt=Abstract ranitidine






APMIS. 1990 Apr;98(4):305-12.
The influence of a histamine2-receptor antagonist on the healing of an experimentally induced gastric mucosal lesion.

Park PO, Alumets J, Arvidsson S, Grimelius L, Haglund U.

Department of Surgery, University of Lund, Malmo General Hospital, Sweden.

The effect of an H2-receptor antagonist (ranitidine) on the healing of gastric mucosal lesions was studied. Mucosal lesions were induced by a standardized thermo-mechanical technique. The healing process was assessed by macro- and light microscopical examination. It was further evaluated by measurements of the tissue contents of hydroxyproline, a chemical compound reflecting collagen, and of DNA and RNA, reflecting cell frequency and protein synthesis respectively, in the gastric wall from both injured and wound-free areas. The healing process was more rapid in ranitidine-treated animals than in controls. After four weeks, however, the lesion in nine out of ten animals had healed in the ranitidine-treated group and seven of nine rats in the control group. At that time the amounts of hydroxyproline, DNA and RNA did not differ between the two groups. These findings may be taken as an indication that the tissue components of the healed lesions were similar in ranitidine-treated rats and in the saline controls, i.e. the different speeds of the healing process did not seem to influence the components of the scar tissue.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1693852&dopt=Abstract ranitidine






Am J Hosp Pharm. 1990 Sep;47(9):2043-6.
Stability of ranitidine in intravenous admixtures stored frozen, refrigerated, and at room temperature.

Stewart JT, Warren FW, Johnson SM, Galante LJ.

Department of Medicinal Chemistry, College of Pharmacy, University of Georgia, Athens 30602.

The stability of ranitidine in concentrations of 0.5, 1.0, and 2.0 mg/mL in admixtures with commonly used i.v. fluids was studied. The admixture vehicles were 0.9% sodium chloride, 5% dextrose, 10% dextrose, 5% dextrose and 0.45% sodium chloride, and 5% dextrose with lactated Ringer's (DLR) injections in polyvinyl chloride bags. Three bags were prepared for each test solution and stored under each of the following conditions: seven days at room temperature (23 +/- 1 degrees C) in normal laboratory lighting, 30 days at 4 degrees C, and 60 days at -20 degrees C followed by either seven days at room temperature (in light) or 14 days at 4 degrees C. Ranitidine content was determined by high-performance liquid chromatography at several intervals. Color, clarity, and pH were also examined. Ranitidine concentrations remained greater than or equal to 90% of initial concentrations under all storage conditions except in the frozen DLR admixtures. Drug loss in the DLR admixtures was greatest at the lower ranitidine concentrations. The only visual changes were yellow color in the thawed DLR admixtures and those containing ranitidine 2.0 mg/mL in 5% dextrose and 0.45% sodium chloride. Slight increases in the pH of some admixtures were noted. Ranitidine is stable for seven days at room temperature and 30 days at 4 degrees C at all concentrations and in all vehicles studied. At the studied concentrations, the drug is stable in admixtures frozen for 60 days and stored for seven days at room temperature or 14 days refrigerated, except in DLR admixtures; these admixtures should not be stored frozen.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2220860&dopt=Abstract ranitidine






Int J Clin Pharmacol Res. 1990;10(3):179-82.
Ranitidine in children with peptic ulcer and patients with pancreatic cystic fibrosis.

Scorza A, Conti-Nibali S, Sferlazzas C, Saitta G, Tedeschi A.

Polyclinic, University of Messina, Italy.

This article describes experience of the use of ranitidine in children with peptic ulcer and patients with pancreatic cystic fibrosis. Ranitidine proved to be efficacious and well tolerated, the percentage of healing being 89.4%. Ranitidine was also used in subjects with gastritis from Campylobacter pylori, obtaining rapid regression of subjective symptoms. Administration of ranitidine to cystic fibrosis patients improved the efficacy of the pancreatic extract, with consequent enhancement of digestive compensation.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2228343&dopt=Abstract ranitidine






Am J Gastroenterol. 1990 Nov;85(11):1458-62.
Effect of omeprazole and high doses of ranitidine on gastric acidity and gastroesophageal reflux in patients with moderate-severe esophagitis.

Fiorucci S, Santucci L, Morelli A.

Department of Internal Medicine, Perugia University, Italy.

Thirty to fifty percent of patients with reflux esophagitis fail to heal after treatment with conventional doses of H2-receptor antagonists, whereas omeprazole administration induces more than 90% healing. To investigate the effect of omeprazole and higher-than-presently-recommended doses of H2-blockers, we evaluated gastric acidity and gastroesophageal reflux in 17 patients with severe-moderate esophagitis before and after treatment with 300 mg ranitidine twice daily or 20 mg omeprazole once daily. Three pH-metric studies were performed, in a cross-over design, before and after 8 days of treatment with omeprazole or ranitidine. Both drugs significantly reduced intragastric acidity (p less than 0.001) during both night and day hours. Median hourly 24-h intragastric pH was 1.8 in the basal study, 2.9 after ranitidine, and 3.4 after omeprazole. Intragastric acidity fell from 84.0 mmol/L in the basal study to 14.2 mmol/L (79% inhibition) with ranitidine and 9.3 mmol/L (84% inhibition) with omeprazole. Patients with esophagitis were significantly more exposed to acid than healthy subjects, in both the supine and upright position (p less than 0.01). The time with esophageal pH less than 4 dropped from 23.9% in the basal study to 8.5% with ranitidine and to 7.2% with omeprazole (p less than 0.001). Both drugs significantly reduced esophageal exposure to acid in both the supine and upright positions (p less than 0.001), whereas neither had any effect on esophageal acid clearance.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2239873&dopt=Abstract ranitidine






J Pharmacol Exp Ther. 1990 Dec;255(3):1177-82.
Ontogeny of fetal renal organic cation excretion: a study with cimetidine and ranitidine during the latter half of gestation in the pregnant ewe.

Czuba MA, Morgan DJ, Ching MS, Mihaly GW, Hardy KJ, Smallwood RA.

Department of Surgery, University of Melbourne, Austin Hospital, Victoria, Australia.

The organic cation cimetidine undergoes renal tubular secretion in the near-term ovine fetus. We investigated the ontogeny of renal tubular secretion of organic cations in the fetus from 80 days of gestation (term = 145). Sixteen sheep were administered both cimetidine and ranitidine in random order by a combination of bolus and i.v. infusion to achieve steady-state plasma concentrations of 1000 to 2000 ng/ml. A further two sheep received cimetidine only. Steady-state plasma concentrations were reached within 2 to 3 hr. Creatinine was used as a marker of glomerular filtration rate. Maternal renal clearance of cimetidine (0.51 +/- 0.18 l/min) and ranitidine (0.54 +/- 0.14 l/min) were not correlated with the period of gestation. Cimetidine/creatinine and ranitidine/creatinine renal clearance ratios were higher than unity being 5.48 +/- 1.91 and 5.65 +/- 1.18, respectively. Fetal creatinine renal clearance increased exponentially with gestational age (r2 = 0.577, P less than .001). Fetal renal clearance of both cimetidine and ranitidine also increased exponentially with gestational age, this trend being more clear-cut for cimetidine (r2 = 0.582, P less than .001) than for ranitidine (r2 = 0.254, P = .046). The rates of increase for cimetidine and ranitidine were similar to that for creatinine (P greater than .05). At 80 days, cimetidine/creatinine and ranitidine/creatinine renal clearance ratios (3.0 and 4.4, respectively) were higher than unity and did not increase further during the remainder of gestation. Therefore, the ovine fetus possesses an efficient tubular secretory pathway for organic cations by 80 days of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)