Acta pharmacologica et toxicologica最新文献

The metabolism of the 3,4-methylenedioxy derivatives of mandelic acid (1), phenylacetic acid (2), benzoic acid (3), 3-phenylpropionic acid (4) and cinnamic acid (5) was studied in rats. Following intragastric dosage (1 mmol/kg) the compounds and their metabolites were excreted in the urine within 24 hrs. Recoveries of roughly 85% were obtained. Except for compound (1) which was excreted to a large extent unchanged, glycine conjugates were the major urinary metabolites. Compound (2) formed 3,4-methylenedioxyphenylacetylglycine whereas compounds (3), (4) and (5) were converted to 3,4-methylenedioxybenzoylglycine. No evidence was found with any of the compounds for demethylenation and subsequent excretion of catecholic metabolites.

The oral absorption of pc V in different preparations, given at various times before and after a meal, was investigated in children with upper respiratory infections. The best absorption with respect to peak concentration was observed when potassium pc V (Calciopen) was given after at least two hours of fasting with no food intake within the following hour. Shorter periods of fasting (1, 1/2, 0 hrs) before drug intake resulted in significantly lower plasma concentrations. When drug intake was followed by a meal, the absorption was also decreased to some extent. When pc V was given in an oil suspension (Fenoxypen), or in a small volume (Roscopenin) together with a meal, the peak concentration was significantly lower than when pc V was given in an aqueous solution with a larger volume (Calciopen).

This study was performed in order to elucidate the mechanism behind the decreased responsiveness to beta-adrenergic stimulation occurring in uterine muscle after prolonged treatment with isoprenaline. Pretreatment of rats with isoprenaline, 20 nmol/kg, three times daily during four days, significantly decreased the myometrial relaxing effect of the beta-agonist. There was also a significant decrease of the beta-receptor binding capacity of the myometrial membranes measured by the (--)-(3H) DHA binding technique. In the animals pretreated with isoprenaline no significant increase of the adenylate cyclase activity could be observed after isoprenaline stimulation in vitro. The uterine cAMP level was diminished in the desensitized rats. The phosphodiesterase activity was increased. Thus both decreased production and increased degradation contribute to the lower level of uterine cAMP content. The activity of cAMP dependent protein kinase was also depressed. In this work, where low concentrations of isoprenaline have been administered in vivo, several biochemical parameters have been shown to contribute to the beta-adrenergic desensitization in myometrial tissue.

The effects of lofepramine on the isolated guinea pig atrial trabeculae were compared with those of desipramine. The preparations were taken from the same animal and mounted in the same tissue bath. All parameters were recorded in parallel. Lofepramine 10 microM was shown to exhibit minor changes in the transmembrane action potential duration only. The action potentials of the atrial trabeculae were prolonged, whereas they were shortened in the papillary muscles. Desipramine was about ten times more potent than lofepramine, but produced similar qualitative changes. Desipramine 10 microM and lofepramine 100 microM showed local anaesthetic properties: a decreased overshoot without a decreased resting potential, a decreased and rate-dependent Vmax, and a decrease in propagation velocity. After the addition of either drug in a lower concentration, a transient increase in force development and a concomitant increase in repolarization phase height (atrial trabeculum) or plateau length (papillary muscle) were recorded. The steady state effect on the force development was a decrease accompanied by a shortening of the action potential duration (papillary muscle). It is suggested that the action of lofepramine 100 microM and desipramine 10 microM on phase 0 of the action potential are produced by blockage of the fast sodium channel. The transient increase in developed force and the increase in repolarization phase height (atrial trabeculum) or plateau length (papillary muscle) could be caused by inhibition of the membrane re-uptake system for released noradrenaline. The steady state shortening and flattening of the plateau (papillary muscle) and the decrease in force development could be the cause of a block in the slow channel system.

The effect of furosemide 8 X 10(-4) mol/l an 8 X 10(-5) mol/l on parathyroid hormone stimulated adenylate cyclase was studied in renal tissue slices from guinea pigs. Furosemide caused a dose-dependent inhibition of the effect of parathyroid hormone on production of cyclic AMP, without having any significant effect on the basal cyclic AMP production. Furosemide in similar concentrations did not inhibit the stimulatory effect of thyrotrophin and fluoride in human thyroid homogenates suggesting that furosemide is not an universal inhibitor of adenylate cyclase and that the inhibition is not caused by a direct action of furosemide on the adenylate cyclase enzyme. Furosemide did not interfere with binding of cyclic AMP to cyclic AMP binding protein kinase from rabbit muscle. The results indicate that furosemide exerts an inhibitory influence either upon binding of parathyroid hormone to renal receptors or upon transmission of impulse from receptor to adenylate cyclase. The inhibitory influence of furosemide on parathyroid hormone action in kidney could explain the value of furosemide in the acute treatment of hypercalcaemia, but also suggest that chronic treatment with furosemide might interfere with normal calcium metabolism.

The role of intestinal flora in the decomposition and faecal excretion of methyl mercury was studied in mice treated with antibiotics. The antibiotics, neomycin sulfate and chloramphenicol, were given to mice in drinking water for six days before intraperitoneal administration of methyl mercuric chloride (MMC), and intestinal microorganisms were thereby reduced. Inorganic and organic mercury were determined separately for faeces, intestinal contents and organs. On the fourth day after the mercury administration, the percentage ratios of inorganic mercury to total mercury in the contents of the caecum and large intestine were less in the mice treated with antibiotics, at 37% and 39%, respectively, than in the control mice (66% and 65%, respectively). Administration of the antibiotics reduced the excretion of inorganic mercury in the faeces to 26% of that of control mice and also reduced the excretion of total mercury to 60%. Reduction of intestinal microorganisms by the antibiotics was assumed to have caused the reduced decomposition of methyl mercury in the caecal contents and the reduced excretion of total mercury in the faeces.

Zinc concentrations, determined with atomic absorption spectrophotometry, did not differ significantly in plasma from manic-depressive patients about to start lithium treatment and in patients having been in lithium treatment for six months or 1-2 years. Plasma zinc concentrations and zinc concentrations in liver, muscle, kidney, bone, and skin did not differ in control rats and rats given lithium with the food for four weeks.

Three different nitro compounds glyceryl mononitrate (GMN), glyceryl dinitrate (GDN) and ethylene glycol dinitrate (EGDN) were tested on histamine contracted bovine mesenteric artery. GDN and EGDN caused a dose-dependent relaxation which was accompanied by an increase in the endogenous cGMP level. The ED50-value for GDN and EGDN with regard to the relaxant action was 1.06 X 10(-6) M and 4.20 X 10(-8), respectively. GMN was almost completely ineffective as a relaxing agent and did not cause any significant change in cGMP. Regression analysis revealed a significant correlation between relaxation and increase in cGMP for both GDN and EGDN. The regression model for EGDN could be significantly improved by including the squared cGMP change, indicating a non-linear relationship. With regard to GDN a hyperbolic relationship between relaxation and cGMP increase was found. A slight improvement of the regression model was found for EGDN when the change in cAMP was included. For GMN and GDN no improvement of the regression model could be revealed by including the change of cAMP. It is suggested that the present data give further evidence for cGMP as a mediator of vascular smooth muscle relaxation induced by nitro compounds.