ABSTRACT
Dazoxiben, an orally active specific inhibitor of thromboxane synthetase, was administered by mouth daily to dogs and rats for 6 months. Dogs showed no evidence of toxicity up to 300 mg day-1 kg-1, the highest dose level used. Rats showed no evidence of toxicity after 100 mg day-1 kg-1, but at 300 mg day-1 kg-1 there were slight increases in plasma calcium and urea concentrations and a moderate incidence of focal nephrosis; males showed a slightly increased platelet count. Studies in rats and rabbits at dose levels up to 400 mg day-1 kg-1, by mouth, revealed no adverse effects on male or female fertility, embryogenesis, parturition or postnatal development. As dazoxiben is well absorbed after oral administration, the generally negative outcome to these toxicity studies suggests that selective inhibitors of thromboxane synthesis may be largely free of adverse effects which might impede their therapeutic or prophylactic use in clinical medicine.
Subject(s)
Imidazoles/toxicity , Oxidoreductases/antagonists & inhibitors , Thromboxane-A Synthase/antagonists & inhibitors , Animals , Body Weight/drug effects , Chromatography, High Pressure Liquid , Dogs , Eating/drug effects , Imidazoles/blood , Male , Rabbits , Rats , Rats, Inbred StrainsSubject(s)
Computers , Information Systems , Teratogens , Toxicology/methods , Animals , Female , Mice , Pregnancy , RatsABSTRACT
Gentamicin was administered s.c. to rats once daily for 7 days at 5 mg kg-1. At the end of this period renal concentrations of gentamicin declined from day 1 to day 5 postdosing, but showed a second peak on day 8, after which they declined again through days 16 and 22. This second peak coincided with a peak of mitotic activity in the kidney, suggesting that this organ, while recovering from gentamicin-induced damage, passes through a temporary phase during which it has increased affinity for gentamicin.
Subject(s)
Gentamicins/metabolism , Kidney/metabolism , Animals , Female , Gentamicins/toxicity , Kidney/drug effects , Male , Rats , Rats, Inbred StrainsSubject(s)
Antifungal Agents , Candidiasis, Vulvovaginal/microbiology , Imidazoles/pharmacology , Animals , Antifungal Agents/metabolism , Antifungal Agents/toxicity , Carcinogens , Dogs , Female , Humans , Imidazoles/metabolism , Imidazoles/toxicity , Kinetics , Miconazole/pharmacology , Microbial Sensitivity Tests , Mutagens , Rabbits , RatsABSTRACT
Sodium, potassium, and chloride plasma levels were measured in 294 male and 286 female Sprague Dawley rats [Crl:COBS CD(SD)BR]. The rats were distributed between four groups according to age (65-125 days, 235-275 days, 353-482 days, and 665-775 days). The levels of all three ions were higher in males than in females: about 1% higher for sodium and chloride and about 7% higher for potassium. Potassium and chloride values decreased with increasing age in both sexes; potassium decreased 12% and chloride decreased 6%. Distributions were not perfectly Gaussian but the departures from normality were slight. It was concluded, therefore, that determinations based on parametric statistical tests on the data are unlikely to be seriously biased by the distribution.
Subject(s)
Chlorides/blood , Potassium/blood , Rats/blood , Sodium/blood , Age Factors , Animals , Animals, Laboratory , Female , Male , Sex FactorsSubject(s)
Liver/enzymology , Phospholipases/metabolism , Acylation , Adenosine Triphosphate , Animals , Calcium Chloride , Carbon Isotopes , Cell Fractionation , Cell Membrane/enzymology , Endoplasmic Reticulum/enzymology , Enzyme Activation , Hydrogen-Ion Concentration , Kinetics , Liver/cytology , Lysosomes/enzymology , Membranes/enzymology , Microsomes, Liver/enzymology , Mitochondria, Liver/enzymology , Oleic Acids , Phosphates , Phosphatidylethanolamines , Phospholipases/antagonists & inhibitors , Phosphorus Isotopes , Potassium Chloride , RatsSubject(s)
Cell Membrane/analysis , Endoplasmic Reticulum/analysis , Lipids/analysis , Liver/enzymology , Membranes/analysis , Microsomes, Liver/analysis , Mitochondria, Liver/analysis , Animals , Cell Membrane/enzymology , Centrifugation, Density Gradient , Cholesterol/analysis , Digitalis Glycosides , Endoplasmic Reticulum/enzymology , Fatty Acids/analysis , Liver/analysis , Liver/cytology , Membranes/enzymology , Microsomes, Liver/enzymology , Mitochondria, Liver/enzymology , Oxidoreductases , Phospholipids/analysis , Rats , Saponins , Sphingomyelins/analysis , Spirostans , Surface-Active AgentsSubject(s)
Endoplasmic Reticulum/metabolism , Glycerophosphates/metabolism , Microsomes, Liver/metabolism , Mitochondria, Liver/metabolism , Oleic Acids/metabolism , Phospholipids/biosynthesis , Animals , Autoradiography , Carbon Isotopes , Electron Transport Complex IV/metabolism , Endoplasmic Reticulum/enzymology , In Vitro Techniques , Liver/metabolism , Microsomes, Liver/enzymology , Mitochondria, Liver/enzymology , Monoamine Oxidase/metabolism , Oxidoreductases/metabolism , RatsSubject(s)
Mitochondria/analysis , Phospholipids/analysis , Yeasts/analysis , Adenosine Triphosphate/metabolism , Carbon Isotopes , Coenzyme A/metabolism , Mitochondria/metabolism , Oleic Acids/metabolism , Phosphatidylcholines/analysis , Phosphatidylethanolamines/analysis , Phosphatidylinositols/analysis , Phospholipases/analysisABSTRACT
Acyl-CoA: phospholipid acyl-transferase activity as well as phospholipase A activity were detected in inner and outer membrane preparations from rat liver mitochondria. Both enzyme systems have an optimum pH around 8 and act preferentially on phosphatidylethanolamine. While phospholipase A activity is much lower in the inner membrane than in the outer membrane of mitochondria the reverse is true for the incorporation of (14C)-oleic acid into endogenous phosphatidylethanolamine. These results bring an indirect evidence that the inner membrane per se possesses a phospholipase A activity.
