pyrimidinones has been researched along with oxmetidine* in 10 studies
1 review(s) available for pyrimidinones and oxmetidine
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Antihistamines.
Topics: Animals; Astemizole; Benzhydryl Compounds; Benzimidazoles; Child; Child, Preschool; Cimetidine; Drug Synergism; Guanidines; Guinea Pigs; Histamine; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Imidazoles; Infant; Infant, Newborn; Kinetics; Pyrimidinones; Ranitidine; Terfenadine | 1986 |
9 other study(ies) available for pyrimidinones and oxmetidine
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Toxicity of H2-receptor antagonists to isolated rat hepatocytes: structure-activity relationships.
Oxmetidine is a potent and specific antagonist of the histamine H2-receptor. Oxmetidine is also cytotoxic to isolated rat hepatocytes through inhibition of mitochondrial oxidative phosphorylation. The purpose of this investigation was to test a variety of H2-receptor antagonists that are structural analogs of oxmetidine in an attempt to identify a critical structural component or a physicochemical property of the molecule which may be responsible for cytotoxicity. Six histamine receptor H2-antagonists were tested. The minimum drug concentrations that caused 100% cell death (leakage of intracellular lactate dehydrogenase and loss of intracellular potassium) ranged from 0.87 to 22.50 mM for the analogs tested. At toxic concentrations, two of the least potent analogs, SK&F 92909 and SK&F 9205A both caused a rapid decrease in hepatocyte O2 consumption and ATP content which occurred before any evidence of cell injury. The potency of these molecules as cytotoxicants to isolated hepatocytes did not correlate with their potency as histamine H2-receptor antagonists whereas there was a significant correlation between increasing potency and increasing octanol/water partition coefficients. These data suggest that lipid solubility may be a key factor in the cytotoxicity of this class of drugs to isolated rat hepatocytes. Topics: Animals; Dose-Response Relationship, Drug; Histamine H2 Antagonists; Imidazoles; L-Lactate Dehydrogenase; Liver; Male; Metiamide; Pyrimidinones; Rats; Rats, Inbred Strains; Structure-Activity Relationship | 1988 |
Gastric ECL-cell hyperplasia and carcinoids in rodents following chronic administration of H2-antagonists SK&F 93479 and oxmetidine and omeprazole.
The histamine H2-receptor antagonist SK&F 93479 induced gastric neuroendocrine (carcinoid) ECL-cell tumor formation in 6/34 male and 8/37 female rats treated for 22-24 months at 1,000 mg/kg/day po. Focal ECL-cell hyperplasia was present in 21/34 males and 15/37 females, with local infiltration through the muscularis mucosae in half these cases. No focal hyperplasias or carcinoids were present after 200 mg/kg/day po treatment. Investigative studies showed evidence for marked and sustained hypergastrinemia increasing on chronic dosing which was capable of restoring gastric acid secretion and pH to near control values. Using morphometric analysis of immunoperoxidase anti-chromogranin A stained sections, a dose-related and time-dependent neuroendocrine ECL-cell hyperplasia was correlated with the sustained elevated hypergastrinemia. A 21-month mouse oncogenicity study showed no focal neuroendocrine cell hyperplasia or carcinoid tumor induction, but a diffuse neuroendocrine cell hyperplasia and an increase in multifocal glandular hyperplasia of the oxyntic mucosa was observed in mice treated with 1,000 mg/kg SK&F 93479 po. The morphological changes observed in both rat and mouse were considered to be secondary to the hypergastrinemia resulting from the pharmacological suppression of gastric acid secretion by SK&F 93479. These changes were also observed to a more marked degree following omeprazole treatment and were only slight following oxmetidine treatment in the rat. Topics: Animals; Carcinogens; Carcinoid Tumor; Enterochromaffin Cells; Female; Gastric Acid; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Hydrogen-Ion Concentration; Hyperplasia; Imidazoles; Male; Mice; Omeprazole; Pyrimidinones; Rats; Stomach Neoplasms | 1988 |
[Inhibition of microsomal enzyme activity of the liver by various H2 receptor antagonists].
The inhibition of 7-ethoxycoumarin deethylase activity by four different H2-receptor antagonists was studied using rat liver microsomes. The compounds tested represent two classes of H2-antagonists, i. e. structures with (cimetidine and oxmetidine) and without (ranitidine and SKF 93479) an imidazole ring. The microsomes were prepared from untreated and phenobarbital-treated animals. It was found that all four compounds, even those without an imidazole ring, inhibited deethylase activity. The compounds inhibited in the following order: SKF 93479 (90%) greater than cimetidine (58%) = oxmetidine (58%) greater than ranitidine (23%). In microsomes from phenobarbital-induced animals, the inhibitory activity of oxmetidine was increased 5-fold. Only the inhibitory potency of cimetidine was increased by preincubation of the H2-antagonist with the microsomes prior to the addition of the substrate. Topics: 7-Alkoxycoumarin O-Dealkylase; Animals; Cimetidine; Culture Techniques; Histamine H2 Antagonists; Imidazoles; Male; Microsomes, Liver; Oxygenases; Pyrimidinones; Ranitidine; Rats; Rats, Inbred Strains; Structure-Activity Relationship | 1987 |
Effects of H2 receptor antagonists on the hepatotoxicity of various chemicals.
H2 receptor antagonist-hepatotoxicant interactions were evaluated in male Fischer-344 rats. The H2 receptor antagonists, cimetidine, ranitidine, oxmetidine, and 2-[2-(2-dimethyl-aminomethyl-5-furanylmethyl-thio)-ethylamino]-5-( 6-methyl- 3-picolyl)-4-pyrimidine trihydrohydrochloride (SK&F 93479) were administered (p.o.) at a dose of 0.143 mMoles/kg 30 minutes prior to hepatotoxicant treatment. Submaximal hepatotoxic doses (p.o.) of carbon tetrachloride (795 mg/kg), bromobenzene (748 mg/kg), chloroform (1,190 mg/kg), allyl alcohol (60 mg/kg), galactosamine (200 mg/kg, i.p.), and acetaminophen (1000 mg/kg) were employed. Hepatotoxicity was evaluated by determining serum alanine aminotransferase activity (ALT). Pretreatment with the H2 receptor antagonists did not significantly alter carbon tetrachloride or allyl alcohol hepatotoxicity. Bromobenzene and chloroform toxicities were unaffected by cimetidine, ranitidine, and oxmetidine pretreatment but were potentiated by SK&F 93479. Cimetidine and ranitidine decreased galactosamine mediated hepatotoxicity. Acetaminophen hepatotoxicity was markedly potentiated by ranitidine pretreatment but was unaltered by the other three H2 receptor antagonists. The mechanisms of hepatotoxicity potentiation or protection have not been determined, however, the lack of consistent H2 receptor antagonists effects indicates that it is unlikely that alterations in G.I. pH account for the effects observed. H2 receptor antagonist mediated changes in hepatotoxicant metabolism provide a more plausible mechanism of action, particularly in the cases of SK&F 93479 potentiation of bromobenzene and chloroform and ranitidine potentiation of acetaminophen hepatotoxicity. Topics: 1-Propanol; Acetaminophen; Animals; Bromobenzenes; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Chloroform; Cimetidine; Drug Antagonism; Drug Synergism; Histamine H2 Antagonists; Imidazoles; Liver; Male; Propanols; Pyrimidinones; Ranitidine; Rats; Rats, Inbred F344 | 1984 |
Inhibition of the histamine-stimulated adenylate cyclase activity of guinea pig gastric cells by the H2-receptor antagonists cimetidine, oxmetidine and SKF 93479.
The effect of cimetidine and two new histamine H2-receptor antagonists, oxmetidine and SKF 93479, on histamine-stimulated adenylate cyclase activity was studied in guinea pig gastric mucosal cells. Histamine stimulated the enzyme activity in concentration-dependent fashion. The concentration-response curve of histamine was progressively shifted to the right in the presence of increasing concentrations of each antagonist. The Schild plot gave a straight line for all three compounds, with a slope not significantly different from unity and this suggested a competitive antagonism. The calculated pA2 values were 8.45 +/- 0.20, 7.73 +/- 0.21 and 6.81 +/- 0.15 for SKF 93479, oxmetidine and cimetidine, respectively. These results are in accordance with the pharmacological potencies of the antagonists reported on isolated heart preparation and on gastric secretion in vivo. Therefore, the inhibition of histamine-sensitive adenylate cyclase of gastric cells may represent an additional tool for the in vitro evaluation of the H2-receptor antagonists. Topics: Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; Cimetidine; Gastric Mucosa; Guinea Pigs; Histamine Antagonists; Histamine H2 Antagonists; Imidazoles; In Vitro Techniques; Male; Pyrimidinones | 1984 |
Cardiac effects of the new H2-receptor antagonists.
A series of new H2-receptor antagonists were tested for their effects on different isolated heart preparations. In the guinea-pig atria and papillary muscle the inhibitory effect on histamine H2-receptors was evaluated. In the perfused rabbit heart and in strips of human atria the effect of the H2-antagonists on the spontaneous or electrically-stimulated contractions was evaluated. In the first two preparations some main quantitative differences were pointed out, tiotidine and compound SKF 93479 being the most potent antagonists, cimetidine, metiamide and ranitidine the less effective. In the rabbit heart and in human atria results were quite different: cimetidine and ranitidine were virtually ineffective up to the maximum concentration tested (3 x 10(-3) M), oxmetidine and compound SKF 93479 had a negative inotropic and chronotropic effect starting from concentrations of 3 x 10(-6)-10(-5) M. On the basis of the behaviour of other compounds endowed with negative cardiac effects (propranolol, anaesthetic-like compounds, verapamil) and of that of compounds capable of counteracting the effect of oxmetidine (increased concentration of calcium ions and isoproterenol) it was hypothesized that oxmetidine may interfere in the transport of calcium ions. Our data emphasize the importance of the different structure of the H2-antagonists in determining non-specific effects absolutely independent of the primary action that is the H2-receptor blockade. Topics: Animals; Calcium Channel Blockers; Dose-Response Relationship, Drug; Female; Furans; Guinea Pigs; Heart; Heart Rate; Histamine H2 Antagonists; Humans; Imidazoles; In Vitro Techniques; Male; Myocardial Contraction; Papillary Muscles; Pyrimidinones; Rabbits; Ranitidine | 1983 |
Are there excitatory H2 receptors in guinea-pig ileum?
Topics: Animals; Dimaprit; Guinea Pigs; Histamine H2 Antagonists; Ileum; Imidazoles; Impromidine; In Vitro Techniques; Methylhistamines; Muscle Contraction; Muscle, Smooth; Pyrimidinones; Receptors, Histamine; Receptors, Histamine H2; Thiourea | 1983 |
Negative inotropic effect of some H2-receptor antagonists on the isolated human atria.
H2-Receptor antagonists were found to possess in various degrees a negative inotropic effect on human atria in vitro. This effect seemed to be independent of H2-receptor blockade and, at least in the case of oxmetidine, seemed to involve calcium ion transport and/or utilization. Topics: Calcium; Cimetidine; Depression, Chemical; Dose-Response Relationship, Drug; Heart Atria; Histamine H2 Antagonists; Humans; Imidazoles; Myocardial Contraction; Pyrimidinones; Verapamil | 1983 |
Further observations on the motor activity of some new histamine H2-receptor antagonists on the digestive system.
Some new H2-receptor antagonists were tested for their motor effects on the rat lower oesophageal sphincter, on the guinea pig ileum and on the guinea pig gall bladder. Two of these compounds, SKF93479 and DA4577, were found to be virtually inactive despite the fact that they are the most potent antagonists of the H2-receptors so far described. Ranitidine possessed a stimulatory effect on all the preparations examined and its mechanism of action was shown to involve the cholinergic system. Conversely oxmetidine exerted an inhibitory effect on the contractions produced by a variety of spasmogenic compounds. All of these observations, together with other data from our laboratory, seem to suggest that H2-receptors do not play an important role in the regulation of the motility of the digestive system. Moreover our data emphasize the fact that the motor effects of the H2-antagonists are connected with single molecules rather than with the entire class, and therefore represent side-effects of these compounds independent of the H2-receptor blockade. Topics: Acetylcholine; Animals; Ceruletide; Eledoisin; Esophagogastric Junction; Gallbladder; Gastrointestinal Motility; Guinea Pigs; Histamine H2 Antagonists; Ileum; Imidazoles; In Vitro Techniques; Pyrimidinones; Ranitidine; Rats | 1983 |