Drug Chem Toxicol. 1989 Mar;12(1):49-59.
Disposition kinetics of cimetidine and ranitidine in endotoxin pretreated rats.

Kaka JS, Tanira MO, al-Khamis KI.

Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Saudi Arabia.

Cimetidine and ranitidine are used in patients with life-threatening gram-negative infections, endotoxemia and acute stress erosions. Disposition kinetics of cimetidine and ranitidine in endotoxin pretreated rats was investigated. The H2-antagonists were administered intravenously 24 h after endotoxin (10 mg/kg) pretreatment. This endotoxin dosage resulted in 50% mortality in rats. Blood samples (0.25 ml) were collected at different timed intervals. No significant differences were observed in plasma clearance, half-life and volume of distribution between endotoxin pretreated and control rats. Cimetidine is eliminated extensively by the renal route in animals and man with metabolism being a minor process. Ranitidine is metabolized to a large extent (70%) in rats, while in humans this represents a minor process. No significant changes in cimetidine and ranitidine disposition parameters in endotoxin pretreated rats were observed. These results suggest that cimetidine and ranitidine may be used in normal dosages in endotoxemia patients since their pharmacokinetic parameters would not be affected under these circumstances.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2714208&dopt=Abstract ranitidine






Hum Toxicol. 1989 Jan;8(1):23-32.
An evaluation of the safety of ranitidine during seven years daily oral administration to beagle dogs.

Spurling NW, Selway SA, Poynter D.

Division of Pathology and Toxicology, Glaxo Group Research Limited, Ware, Hertfordshire, UK.

1. Ranitidine hydrochloride was administered orally to Beagles at doses equivalent to 50 mg once daily, or 5 mg twice daily, of ranitidine base/kg for more than 7 years. 2. Apart from looseness of faeces, seen mainly after doses of 50 mg/kg and only rarely after the first year of such treatment, there were no adverse clinical effects. There were no deaths related to treatment. 3. Periodic gastroscopy revealed nothing abnormal. 4. Peak plasma levels of ranitidine occurred within 2 h of dosing; levels were proportional to the doses administered. 5. There were no major differences in fasting plasma gastrin levels between treated and untreated dogs; the expected increase occurred in response to the provision of food and, predictably, this was greater following a dose of ranitidine. 6. A normal histamine-induced gastric secretory response was demonstrated. 7. Necropsy revealed no lesions of toxicological significance. Macroscopically the stomachs appeared normal but microscopic examination showed some gastritis in both treated and control dogs. No changes in enterochromaffin-like (ECL) cells were detected. Electron microscopy showed unimpaired secretory activity of parietal cells. 8. Thus, after more than 7 years administration to beagle dogs of doses in excess of the normal daily therapeutic dose, the stomachs showed no changes attributable to treatment and their secretory capacity was unimpaired.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2714806&dopt=Abstract ranitidine






Arch Gerontol Geriatr. 1989 Mar;8(2):139-50.
Pharmacokinetics of ranitidine in geriatric patients with multiple diseases.

Platt D, Bauer M, Eicher H.

Institute of Gerontology, University of Erlangen-Nuremberg, FRG.

Ranitidine pharmacokinetics was measured after intravenous administration of 50 mg of the drug in 18 geriatric patients suffering from multiple diseases. Elimination half-life was prolonged (3.05 +/- 0.58 h) and total clearance was reduced (282 +/- 97 ml/min) as compared to the results of studies on normal younger persons by other investigators. In comparison to other studies on healthy elderlies, the pharmacokinetic parameters of ranitidine were only slightly different. Statistical analyses showed correlations of pharmacokinetic parameters of ranitidine with creatinine clearance, serum creatinine, uric acid concentration and alkaline phosphatase activity. These results disclose that reduced creatinine clearance or serum creatinine concentration in the upper normal range, for example, might serve as indicators for a possible dose reduction of ranitidine to prevent unnecessary overmedication in elderly patients.

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Drugs Exp Clin Res. 1989;15(5):235-8.
Validity of high-dose ranitidine treatment (300 mg b.i.d.) in clinical practice: an open study in 68 consecutive cases of severe peptic disease.

Ghidini O, Adamo S.

Division of Medicine, Bussolengo Hospital, Verona, Italy.

Ranitidine, at doses of 300 mg b.i.d., brings about a pronounced inhibition of both daytime and nocturnal acid secretion. The aim of the present open study, conducted in 68 patients with peptic lesions of the upper gastrointestinal tract, was to assess whether or not ranitidine at 300 mg b.i.d. for 4 weeks was capable of healing these lesions, which had failed to respond to treatment with H2-antagonists at standard doses, even when administered over fairly lengthy periods (greater than 8 weeks). The results obtained show that the 300 mg b.i.d. regimen yields a marked gain in terms of healing of lesions and relief of symptoms (achieved in roughly 80% of cases), accompanied by excellent tolerance. It is concluded that a double dose of ranitidine is clinically justified in particular cases.

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J Pharmacol Exp Ther. 1988 Aug;246(2):493-9.
Inhibition of acid secretion in guinea pigs by tricyclic antidepressants: comparison with ranitidine and omeprazole.

Batzri S, Brugada O, Harmon JW, Rich NM.

Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland.

The antisecretory properties of imipramine on gastric secretion in guinea pig in comparison with other antisecretory agents was determined. In awake guinea pigs s.c. infusion of histamine (30 micrograms/kg/hr) increased acid and fluid secretion by 3- to 4-fold. When acid output peaked, a bolus administration of the tricyclic anti-depressant imipramine inhibited acid and fluid secretion. Imipramine and other agents, such as ranitidine and omeprazole, inhibited gastric secretion in a dose-dependent fashion. The most potent was the H2-antagonist ranitidine (IC50, 0.2-0.3 mumol/kg), followed by the gastric H-K-adenosine triphosphatase inhibitor, omeprazole (IC50, 0.5-0.6 mumol/kg). Imipramine (IC50 1-2 mumol/kg) was the least potent of the inhibitors. Both ranitidine and omeprazole could abolish acid secretion, but maximal inhibition with imipramine was 60% of initial. Promethazine (25 mumol/kg), an H1 antagonist, and atropine (12 mumol/kg), a muscarinic antagonist, inhibited gastric secretion by 40 to 50%. Imipramine and atropine also inhibited basal acid secretion. In dispersed gastric cells comparison between imipramine and omeprazole showed that imipramine was about 5-fold more potent than omeprazole in blocking histamine or dibutyryl cyclic AMP stimulation of aminopyrine accumulation. Imipramine probably acts as a protonophore by increasing the rate of proton-gradient dissipation rather than by interfering with the hydrogen-pump system because, in gastric membranes, imipramine was 20-fold less potent than omeprazole in inhibiting the gastric H-K-adenosine triphosphatase activity. These results suggest that imipramine administered s.c. in guinea pigs is a potent antisecretory drug. Its action may be d




Ann Surg. 1988 Mar;207(3):274-82.
Metabolic intervention in surgical patients. An assessment of the effect of somatostatin, ranitidine, naloxone, diclophenac, dipyridamole, or salbutamol infusion on energy and protein kinetics in surgical patients using stable and radioisotopes.

Shaw JH, Wolfe RR.

University Department of Surgery, Auckland Hospital, New Zealand.

We have assessed the effect of a variety of forms of metabolic intervention on both energy and protein metabolism in 44 severely ill surgical patients. The patients were studied either in the basal state or while receiving total parenteral nutrition (TPN), and the metabolic effects were assessed using the primed-constant infusion of a combination of stable isotopes and radioisotopes. Somatostatin infusion, either in the basal state or in the TPN, did not change glucose kinetics, but there was a significant decrease in the rate of net protein catabolism (NPC). In the basal studies the rate of NPC decreased from 3.4 +/- 0.7 g/kg/d to 2.9 +/- 0.7 g/kg/d (p less than 0.002), while in the TPN patients the corresponding values were 1.48 +/- 0.61 g/kg/d and 1.10 +/- 0.50 g/kg/d, respectively (p less than 0.005). Histamine type 2 blockade with ranitidine did not significantly alter glucose kinetics, but in both the TPN patients and in the basal state ranitidine was associated with a significant decrease in the rate of NPC. In the basal state rate of NPC was 2.44 +/- 0.53 g/kg/d and during ranitidine infusion the value was 2.08 +/- 0.42 g/kg/d (p less than 0.04). Naloxone infusion did not alter glucose kinetics, but there was a significant decrease in the rate of NPC from a basal value of 2.6 +/- 0.6 g/kg/d to 2.3 +/- 0.5 g/kg/d (p less than 0.04). The infusion of the prostaglandin antagonists diclofenac or dipyridamole resulted in increases in the plasma insulin level, and as a result glucose turnover decreased in both groups. In the diclofenac group the rate of glucose turnover decreased from 14.4 +/- 1.7 mumol/kg/min to 12.6 +/- 1.3




Biopharm Drug Dispos. 1989 Jan-Feb;10(1):35-41.
Effect of bupropion on cimetidine and ranitidine absorption in rats.

Tanira MO, Kaka JS, al-Khamis KI.

Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Cimetidine and ranitidine absorption were studied in rats, alone or in combination with concurrent but separate bupropion oral administration. Blood samples were collected before and 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.5, and 6.0 h after dosing. In ranitidine-treated rats, an extra blood sample at 8 h was collected. Assays of cimetidine and ranitidine were carried out using a HPLC method. Mean cimetidine plasma concentrations on concurrent bupropion administration at 0.25 and 0.5 h were approximately 2 and 1.5 times compared to the control. Similarly, mean ranitidine plasma concentrations with bupropion combination at 0.25 and 0.5 h were significantly different and approximately 2 and 3 times higher. Time of maximum concentration for cimetidine and ranitidine on combination were reduced to almost half of the control value. However, only the time of maximum concentration for cimetidine showed statistically significant difference. No significant differences were observed between AUCs, maximum concentrations, and half-lives of cimetidine and ranitidine compared to their respective controls. The results suggest that concurrent bupropion administration may affect the rate but not the extent of absorption of cimetidine and ranitidine.

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Arzneimittelforschung. 1988 Mar;38(3):366-72.
Antisecretory and antiulcer activities of a potent new histamine H2-receptor antagonist with an intermediate duration of action.

Borella L, Russell J, Rimele TJ, Grimes D, Failli A, Mir GN.

Department of Pharmacology, Ayerst Laboratories Research, Inc., Princeton, NJ.

The antisecretory activities of 4-(dimethylamino)- N-[2-[3-[3-(1-piperidinyl)methyl]phenoxy]propyl]amino]- 1,2,5-thiadiazol-4-yl]amino]ethyl]-butanamide, S-oxide (AY-29,315) and ranitidine were determined in the rat, dog and monkey. In conscious, chronically cannulated rats, AY-29,315 was 10 and 208 times more potent than ranitidine as an inhibitor of spontaneous gastric acid secretion by the p.o. and i.v. routes, respectively. Tolerance did not develop in the conscious rat with either compound when administered for 8 consecutive days at doses equivalent to 4 times their antisecretory ED50. In lumen-perfused, anesthetized rats, AY-29,315 i.v. was 44 times more potent than ranitidine as an inhibitor of dimaprit-induced acid secretion. In the gastric fistula dog, AY-29,315 was 7.5 times more potent than ranitidine as an inhibitor of dimaprit-induced secretion by the i.v. route but 3 times less potent by the oral route. In the monkey, against dimaprit, AY-29,315 was 3 and 12 times more potent than ranitidine by the oral and i.v. routes, respectively. p.o./i.v. ratios indicate that, relative to ranitidine, the bioavailability of AY-29,315 by the oral route was low, particularly in the dog. In the dog, at 4 times the oral ED50 dose, the antisecretory effect of ranitidine lasted 190 +/- 3 min, while that of AY-29,315 lasted more than 9 h. AY-29,315 was 8 times more potent than ranitidine as an inhibitor of acetylsalicylic acid-induced ulcers in the rat.(ABSTRACT TRUNCATED AT 250 WORDS)

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Clin Pharmacol Ther. 1988 Oct;44(4):442-52.
Pharmacokinetic interactions between NSAIDs (indomethacin or sulindac) and H2-receptor antagonists (cimetidine or ranitidine) in human volunteers.

Delhotal-Landes B, Flouvat B, Liote F, Abel L, Meyer P, Vinceneux P, Carbon C.

Department of Clinical Pharmacology, Ambroise Pare Hospital, University of Paris V, Boulogne-Billancourt, France.

The reciprocal effects on pharmacokinetic parameters after a single oral dose of the nonsteroidal antiinflammatory drugs (NSAIDs) indomethacin and sulindac and repeated oral doses of the H2-receptor antagonists cimetidine and ranitidine were determined in two groups of nine healthy subjects each (indomethacin and sulindac groups). Administration of NSAIDs increased the AUC and decreased the oral clearance and apparent volume of distribution of the H2-receptor antagonists without modifying their t1/2. Urinary data and observed modifications in ranitidine and cimetidine metabolites seem to justify a greater increase of H2-receptor antagonist bioavailability with indomethacin (p less than 0.05) than with sulindac (NS). The administration of ranitidine significantly reduced the sulindac volume of distribution without modifying its clearance, which caused an increase in the maximum concentration and a decrease in the t1/2 (p less than 0.05). The effects of cimetidine on the two NSAIDs were more intense than the effect of ranitidine: the decrease in sulindac volume of distribution (p less than 0.02) was accompanied by a significant reduction in sulindac clearance (p less than 0.05). AUC and urinary amounts of sulindac's sulfone metabolite were decreased. These results show that NSAIDs increased the bioavailability of H2-receptor antagonists, and that the latter drugs decrease the volume of distribution of NSAIDs. Furthermore, cimetidine modifies the oxidation metabolism of sulindac.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2901930&dopt=Abstract ranitidine