Attenuation of benzodiazepine-induced passive avoidance deficit by post-training administration of muscimol: interaction with the cholinergic neuronal system

We examined the involvement of GABAergic neuronal systems in benzodiazepine-induced passive avoidance deficit. Chlordiazepoxide impaired the passive avoidance response dose dependently when it was given prior to training. Post-training administration of muscimol improved the performance of chlordiazepoxide-pretreated mice. The effects of muscimol were antagonized completely by the GABAA antagonist, bicuculline, and the muscarinic acetylcholine receptor antagonist, scopolamine, but not by the benzodiazepine receptor antagonist, flumazenil, when the latter was administered immediately after training. It appears from these results that the GABAergic neuronal system plays an important role in the benzodiazepine-induced passive avoidance deficit by interacting with the cholinergic neuronal system.     

Alteration of cytochrome P-450 by prolonged administration of imipramine and/or lithium to rats

Summary The aim of this study was to investigate imipramine-induced alterations of cytochrome P-450 and to determine whether prolonged concomitant administration of imipramine and lithium results in a pharmacokinetic interaction.Male Wistar rats received imipramine (10 mg/kg i. p.) at 12 h intervals or lithium chloride (100 mg/kg in drinking water) or they were treated with the combination of these drugs for 2 weeks. The long term treatment with imipramine produced a very complex alteration of cytochrome P-450: imipramine increased the level of the cytochrome, but it decreased the rate of its own aromatic hydroxylation in position 2. The rate of N-demethylation in the side chain was not changed. Consequently, in the case of both hydroxylation and demethylation, calculated molecular activities were decreased to 48% and 70% respectively. This differential change in activities corresponded well to the observed decrease of absorption in difference spectra (type I) produced in microsomes by imipramine. Carbamazepine-induced type I difference spectra were also decreased by imipramine pretreatment, but to a lesser extent. In contrast, hexobarbital type I binding was increased by imipramine treatment while type II difference spectra produced by metyrapone were not affected. The preliminary SDS-PAGE analysis of cytochrome P-450 isoenzymes of control and imipramine treated rats showed that the investigated antidepressant markedly intensified a protein band at 50.11 kD while bands at 51.28 kD, 56.20 kD and 56.88 kD were less intensive. These results indicate that the alteration of cytochrome P-450 by imipramine treatment is not only of quantitative but also of qualitative character. Lithium alone given to rats affected neither the concentration of cytochrome P-450 in microsomal protein nor the rate of imipramine metabolism in vitro. Lithium given jointly with imipramine reduced imipramine-induced elevation of cytochrome P-450. This, however, did not cause any change in the rate of imipramine metabolism in vitro and accordingly in imipramine pharmacokinetics in vivo. The concentration of lithium in the blood plasma tended to increase by concurrent administration of imipramine.Send offprint requests to K. J. Netter at the above address     

Modulation of carbohydrate metabolism in the selected tissues of marine prawn, Penaeus indicus (H. Milne Edwards), under phosphamidon-induced stress

Changes in carbohydrate metabolism were studied in midgut gland, muscle, and gill tissues of marine prawn Penaeus indicus exposed to a sublethal concentration (0.3 ppm) of phosphamidon. A significant decrease in glycogen and pyruvate and an increase in lactate content were observed in all phosphamidon-exposed prawn tissues after 96 hr. An increase in phosphorylase a and aldolase activity levels suggested the increased formation of triose sugars during phosphamidon toxicity. LDH activity was considerably decreased and an increment in lactate content was observed which indicates reduced mobilization of pyruvate into the citric acid cycle. Glucose-6-phosphate dehydrogenase activity was considerably increased, suggesting the enhanced oxidation of glucose in the hexose monophosphate shunt pathway. Krebs cycle enzymes such as NAD-isocitrate dehydrogenase, succinate dehydrogenase, and malate dehydrogenase were found to be decreased, suggesting the impairment in mitochondrial oxidative metabolism due to the acute toxic impact of phosphamidon. Cytochrome-c oxidase and Mg2+ ATPase activity levels were also decreased considerably, suggesting impaired energy synthesis and breakdown during phosphamidon toxicity, as a result of reduced oxidation of glucose aerobically. The increase in acid and alkaline phosphatase activities indicates the enhanced breakdown of phosphate to release energy in view of inhibiton or impairment in the ATPase system during phosphamidon-induced stress. These results suggest that phosphamidon has a profound effect on the oxidative metabolism of prawn which results in the triggering of compensatory metabolic pathways for survivability.     

Physician knowledge and attitudes about health insurance after the introduction of capitated health care plans

A two-part closed-end survey similar to a survey done in 1980 was given to 25 family physicians at an academic family medical center to assess physician knowledge about five insurance programs covering most of the patients seeking care in the center, and to assess physician attitudes about the capitated insurance plan with which the clinic was affiliated. Results did not differ significantly from those obtained in a similar survey four years earlier at the same center. Physicians correctly identified benefits offered by insurance programs only about one half of the time and many did not ascertain patient insurance coverage at all. Physicians considered the most important advantages of capitated health care to be the patient protection from fees for services obtained, the coverage for health care maintenance, and the potential for controlling health care costs. Physician-perceived disadvantages included difficulties controlling costs generated by other specialists, dealing with after-the-fact authorization requests, controlling access to services, and obtaining information about costs within the capitated system.     

Electrophysiologic effects of betaxolol on conduction properties of the antegrade and retrograde pathway in patients with typical atrioventricular node reentry tachycardia following intravenous and oral administration

The electrophysiologic effects of the beta-1 selective beta adrenergic blocking drug Betaxolol were investigated after intravenous (0.15 mg/kg body weight) and oral (20 mg/day) administration in 11 patients with atrioventricular-nodal reentrant tachycardia. Betaxolol significantly (p less than 0.01) prolonged cycle length, sinus node recovery time, AH-interval, as well as the antegrade functional refractory period of the slow and fast AV-nodal pathway. The effective refractory period of the fast AV-nodal pathway was also markedly increased (p less than 0.05). In only six patients could the effective refractory period of the slow AV-nodal pathway be determined; in the other patients, it was shorter than the effective refractory period of the atrium. The effective refractory period of the atrium and the ventricle was not significantly altered by Betaxolol. Intravenous administration of Betaxolol suppressed induction of tachycardia in eight patients, whereas after oral Betaxolol, tachycardia was not inducible in ten patients. Betaxolol prevented induction of tachycardia in two patients by prolonging antegrade conduction over the slow AV-nodal pathway. The retrograde fast AV-nodal pathway was blocked in eight patients. Presumably the increased effectiveness of oral Betaxolol can be attributed to higher Betaxolol plasma concentrations, reached after oral treatment (58 +/- 38 ng/ml), as compared to intravenous administration (40 +/- 40 ng/ml). There were no false positive results after intravenous testing of Betaxolol.     

Evidence for a maternal yolk factor associated with increased tolerance and resistance of feral white sucker (Catostomus commersoni) to waterborne copper

White suckers, collected from lakes containing elevated levels of copper (12 micrograms liter-1) and zinc (250 micrograms liter-1), were evaluated for reproductive performance, growth and survival of the larvae, and tolerance of the larvae to waterborne copper. Fertilization success was not impaired in white suckers from contaminated sites; metal-exposed males performed better than control males in fertilization trials with control eggs. Larvae hatched from eggs collected at contaminated sites and fertilized in clean water were smaller, developed at a slightly increased rate, and exhibited poorer growth and survival than larvae from control sites. Larvae showed significant changes in resistance and tolerance to copper with age. During the period of endogenous nutrition, larvae from eggs taken at contaminated sites showed increased resistance and tolerance to waterborne copper relative to controls. The effect was not seen in larvae at first feeding, at ages older than 4 days after the onset of feeding (25 days posthatch) or in larvae hatched from control eggs fertilized with sperm from males taken at contaminated sites. This study provides evidence for a maternal yolk factor associated with increased tolerance and resistance of larvae to copper.