Effects of hepatic ischemia-reperfusion injury on the hepatic mixed function oxidase system in rats.

Hepatic ischemia induced in vivo by ligation of the left hepatic lobe of rats for up to 2 hr had no effect on cytochrome P-450, cytochrome c reductase, or lobe histology; however, cytochrome b5 increased with ischemia duration. Ethylmorphine demethylation decreased 35% after 2 hr of ischemia. Reperfusion of tissue previously made ischemic for up to 2 hr was associated with appreciable necrosis as well as decreases in cytochrome P-450, cytochrome b5, cytochrome c reductase, and ethylmorphine demethylation.

Pharmacokinetics of a novel butylated hydroxytoluene-thiazolidinone CNS antiischemic agent LY256548 in rats, mice, dogs, and monkeys.

Mice, rats, dogs, and monkeys were given a single 50 mg/kg oral dose of [14C]LY256548. Plasma levels of radioactivity and LY256548 were determined, as was the excretion of radioactivity. Peak plasma levels of LY256548 occurred prior to those of radioactivity in mice, dogs, and monkeys, but were coincident in rats.

Pharmacokinetics and disposition of the KS1/4 monoclonal antibody-desacetylvinblastine hydrazide conjugate LY203725 in rats and monkeys.

The plasma pharmacokinetics of the monoclonal antibody-vinca conjugate KS 1/4-desacetylvinblastine hydrazide (DAVLB-hyd; [3H]LY203725) have been evaluated in rats (17 mg/kg) and monkeys (15 mg/kg) after i.v. dosing.

Effect of different insulin regimens on plasma lipoprotein and apolipoprotein concentrations in patients with non-insulin-dependent diabetes mellitus.

The effect of insulin treatment with 2 different insulin regimens on the plasma concentrations of lipoproteins and apolipoproteins A1 and B was studied in 10 patients with non-insulin-dependent diabetes mellitus (NIDDM) and secondary failure to oral hypoglycaemic agents. The investigation was performed as a randomized crossover study with treatment periods of 8 weeks. Insulin was given either as mainly intermediate acting insulin before breakfast and dinner (2-dose insulin) or as regular insulin preprandially with intermediate acting insulin at bedtime (4-dose insulin).

Defence mechanisms and some notes on their relevance for the caring professions.

Freud's concept of defence mechanisms means a perceptual, emotional or cognitive distortion of the inner or outer reality. The opposite of defence mechanisms is coping mechanisms. The adaptiveness/maladaptiveness of defences are disputed.

Discovery and development of a novel class of nonsteroidal aromatase inhibitors.

Efforts to develop a novel class of nonsteroidal aromatase inhibitors began with the discovery that the infertility in male rats exposed to high levels of the agricultural fungicide, fenarimol (alpha-(2-chlorophenyl)-alpha-(4-chlorophenyl)-5-pyrimidine-methanol), was attributable to the inhibition of aromatase activity within the central nervous system during the critical neonatal period. Although fenarimol was not particularly potent in inhibiting rat ovarian microsome aromatase activity in vitro (50% inhibition (IC50) = 4.1 microM).

Inhibition of microsomal biotransformation by a series of nitrogen and oxygen heterocyclic histamine H2-antagonists.

A homologous series of potent, long-lasting thiazolo-pyrimidone-pyridine histamine H2-antagonists were examined for their inhibitory effects on rat hepatic ethylmorphine N-demethylation. Inhibitory potency increased in the order: 2-pyridinyl less than 3-pyridinyl less than 4-pyridinyl histamine H2-antagonist. Substitution ortho to the pyridine nitrogen decreased inhibitory potency.

Disposition of the aromatase inhibitor LY56110 and associated induction and inhibition studies in rats, dogs, and monkeys.

Compound LY56110 was well absorbed but slowly excreted in the rat, dog, and monkey. Oral administration of 5 mg/kg of [14C]LY56110 (5-bis(4-chlorophenyl)methylpyrimidine) to the rat, monkey, and dog resulted in a total excretion of 68, 65, and 30% of the radioactivity within 5 days, respectively. Very low urinary excretion was observed in the rat and dog (2%), with fecal excretion being the predominant mode of elimination in all three species.

Efficacy, tolerance and hormonal effects of a new oral angiotensin converting enzyme inhibitor, ramipril (HOE 498), in mild to moderate primary hypertension.

The immediate (0 to 24 hours) and long-term (4 weeks) hypotensive effects of a new long-acting angiotensin converting enzyme inhibitor, ramipril (HOE 498), as well as adverse effects and tolerance, were evaluated in 34 patients with primary hypertension. Further, effects on serum and urinary aldosterone and circulating angiotensin II concentrations were measured. After short- and long-term administration of 5 or 10 mg of ramipril, the mean blood pressure was significantly lowered compared with placebo.

Disposition and biotransformation of quinpirole, a new D-2 dopamine agonist antihypertensive agent, in mice, rats, dogs, and monkeys.

The disposition and metabolism of quinpirole were studied in rats, mice, dogs, and monkeys. A single 2 mg/kg dose of 14C-quinpirole was administered orally to rats, mice, and monkeys. Dogs were given a single 0.

Disposition and metabolism of a new benzothiophene antiestrogen in rats, dogs and monkeys.

A new benzothiophene-derived antiestrogen (LY156758) when orally administered was well absorbed in rats and monkeys while approx. 20% was absorbed in dogs. In the rat the compound was subject to first-pass hepatic metabolism which led to low levels of parent drug in the systematic circulation together with a small amount as the glucuronide conjugate.

Metabolism of the antiarrhythmic agent, indecainide, in rats, dogs, and monkeys.

The biotransformation of indecainide, a potent new antiarrhythmic agent, has been studied in rats and dogs. Indecainide was excreted in the urine primarily as the unchanged compound. The major urinary metabolite was desisopropyl indecainide which accounted for approximately 5% of the urinary radioactivity in both species.

The pharmacokinetics of indecainide in mice, rats, dogs, and monkeys.

The pharmacokinetics of indecainide, a new antiarrhythmic agent, were studied in mice, rats, dogs, and monkeys. The drug was well absorbed in all species tested resulting in peak plasma levels of drug within 2 hr. The plasma half-life of indecainide after acute oral administration was 3-5 hr in rats, dogs, and monkeys but considerably shorter in mice.

Studies on cytochrome P-450-dependent lipid hydroperoxide reduction.

A reconstituted mixed-function oxidase system containing cytochrome P-450, cytochrome P-450 reductase, phosphatidylcholine, and NADPH catalyzed the reduction of 13-hydroperoxy-9,11-octadecadienoic acid to 13-hydroxy-9,11-octadecadienoic acid. Activity was stimulated by the addition of type I substrates, while carbon monoxide and oxygen inhibited the reaction. Perfluoro-n-hexane stimulated the reduction of lipid hydroperoxide to lipid alcohol in the reconstituted system but not by cytochrome P-450 alone.

Saturation of an alpha, beta-unsaturated ketone: a novel xenobiotic biotransformation in mammals.

Reduction of an alpha, beta-unsaturated ketone to the corresponding saturated ketone in a 2-benzylidene-3-ketocoumaran derivative has been investigated. Reductase activity resides in the cytosolic fraction of liver, lung and kidney. Rat and human blood also contain significant reductase activity.

Alpha, beta-ketoalkene reduction. A novel reduction pathway in mammalian tissues.

Reduction of an alpha, beta-unsaturated ketone to the corresponding saturated ketone in a 2-benzylidene-3-ketocoumaran derivative has been characterized with respect to subcellular and tissue distribution, species specificity, cofactor requirements, kinetic constants, and effects of inhibitors. In rats, the highest activity was found in the hepatic cytosolic (100,000g supernatant) fraction having an apparent substrate Km and Vmax of 5.6 microM and 1.

Determination of clofilium, a new antifibrillatory agent, in plasma by gas chromatography--mass spectrometry.

A sensitive and selective method for the assay of the new quaternary amine antifibrillatory agent clofilium is described. Plasma samples were extracted with dichloromethane (98.5 +/- 0.

Correlation between the disposition of [14C]clofilium and its cardiac electrophysiological effect.

The disposition of [14C]clofilium was studied in rats and dogs and related to the electrophysiological effects observed in isolated canine Purkinje fibers. Ten percent of the dose of [14C] clofilium administered to rats and dogs i.v.

Interactions of solvent with the heme region of methemoglobin and fluoro-methemoglobin.

It is now more than 20 years since Davidson and collaborators (1957, Biochim. Biophys, Acta. 26:370-373; J.

Proton nuclear magnetic resonance studies of hemoglobin M Milwaukee and their implications concerning the mechanism of cooperative oxygenation of hemoglobin.

Hemoglobin M Milwaukee (beta67E11 Val leads to Glu) is a naturally occurring valency hybrid containing two permanently oxidized hemes on the beta chains. In this mutant, the two abnormal beta chains cannot combine with ligands whereas the two alpha chains are normal and can combine with oxygen with a Hill coefficient varying from 1.1 to 1.

Intermolecular interactions of oxygenated sickle hemoglobin molecules in cells and cell-free solutions.

We have measured the intermolecular interactions of oxygenated sickle hemoglobin molecules in cells and in cell-free solutions, and have compared the results with similar data for liganded normal adult hemoglobin. The experiments involve the measurement of the spin-lattice relaxation time T1 of protons of solvent water molecules, as a function of an externally applied static magnetic field. From such data, one can derive a correlation time tauc, for each sample, which is a measure of the time taken for a hemoglobin molecule to randomize its orientation due to Brownian motion.