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Biomedical subjects

J Lund

Publications and source records attributed to J Lund.

At least 181 records · Page 10Linked to original sources
PubMed1983

Hepatic elimination of femoxetine in pig.

Hepatic elimination of femoxetine was studied in seven anaesthetized 40 kg pigs by means of constant rate infusions of 3-41 mg/min. (8.6-118 mumol/min.) into the portal vein. The elimination followed saturation kinetics (Michaëlis-Menten constants: Vmax 12 mg . min.-1 . kg-1 liver; Km 1.3 mg . 1-1 blood) and was characterised by high hepatic extraction, due to metabolism. The hepatic output of the active metabolite, nor-femoxetine, was very low, indicating that other metabolic pathways than demethylation were more important in the pig. The high hepatic elimination in the pig corresponds to the high first pass effect, earlier found in man, and it depends upon the infusion rate as well as the total dose.

Animals↗
PubMed1983

Hepatic elimination of femoxetine in pig during intravenous infusion.

Hepatic elimination of femoxetine was studied in six anaesthetized pigs during intravenous administration. Femoxetine was given into a jugular vein as a constant infusion of 0.4-7.2 mg/min. in five pigs and as a bolus injection of 383 mg in one pig. The hepatic extraction was high (92-98%) corresponding to earlier findings of 91-99% when femoxetine was infused into the portal vein in pig or given orally to man. The urinary excretion was low, less than 5% of the dose, and the estimated extrahepatic metabolism was not significantly different from zero.

Animals↗
PubMed1983

Biovailability and pharmacokinetics of femoxetine.

The availability of trans-(+)-3-[(4-methoxy-phenoxy)methyl]-1-methyl-4-phenylpiperidine (femoxetine, HCl; 500 mg) from an enteric coated tablet and from a water solution, respectively, have been compared in a single dose, cross-over study using six healthy volunteers. The tablet gave a longer lag time and a slower absorption rate than the solution. The mean availability of the tablet was 71% (range 12-150%), relative to the availability of the solution in five of the subjects. During a multiple dose study, where the same six volunteers took 400-600 mg (as tablets) per day for a week, no change in the kinetic parameters was observed and no discrepancy between the parameters obtained in the single dose study and the ones from the multiple dose study was seen within each subject. A high first pass effect is presumed to be the main reason for the relatively great inter-individual variations. The formation and elimination rate of an active metabolite, norfemoxetine, were very similar in three of the four subjects for whom the rates could be calculated.

Adult↗
PubMed1982

Differential effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on nuclear RNA polymerase activity in the rat liver and thymus.

AN increase in RNA polymerase B activity in hepatic cell nuclei was observed after a single intravenous injection 1 microgram/rat of TCDD. The enzyme activity was about above the control value at 1 hr after injection and then declined rapidly. A secondary increase was evident at 24 hr. Prior to the secondary increase in RNA polymerase B activity, there was an increase in RNA polymerase A activity which was about 125% above the control value. The initial increase in RNA polymerase B activity was sensitive to both alpha-amanitin and actinomycin D injected min before TCDD administration. In the thymus, an increase in RNA polymerase B activity was observed 4 hr after injection (25% above control value) but thereafter it declined and at 24 hr it was about 30% below the control value. RNA polymerase A activity was inhibited as early as 1 hr after injection but had returned to the control value at 4 hr and then paralleled RNA polymerase B activity. Thus, TCDD stimulated RNA synthesis in the rat liver but the drug inhibited RNA synthesis in the rat thymus. Since these effects were detected as early as 1 hr after TCDD administration it is proposed that TCDD action requires transcriptional response and that this response may represent a primary site of TCDD action in the cell. The cellular entities or mechanisms which TCDD uses to alter transcription in the cell nucleus remain to be determined.

Animals↗
PubMed1982

High-affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin in cell nuclei from rat liver.

The intranuclear binding of radioactive 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rat liver has been studied both in vivo and in vitro. Following the intravenous administration of [1,6-3H]TCDD, a maximum uptake by cell nuclei could be observed at 2 h after injection with a concurrent decrease in the cytosolic uptake. Using linear sucrose density gradient centrifugation, dextran-coated charcoal adsorption assay, DEAE-Sepharose ion-exchange chromatography, competition, enzymatic and saturation studies, a high-affinity binding protein for TCDD in liver cell nuclei could be demonstrated both in vivo and after an exchange in vitro of intravenously administered unlabelled 2,3,7,8- tetrachlorodibenzofuran (TCDBF) for [3H]TCDD. Sucrose density gradient analysis showed a size of 4-5 S for both the cytosolic and nuclear TCDD binding entity. The specific binding of [3H]TCDD to nuclear components was heat labile and saturable and had an equilibrium dissociation constant of 1.05 nM. Based on a differential susceptibility to specific hydrolases, i.e. DNAase, RNAase, trypsin and pronase, the binding entity appears to be a 4-5 S salt-extractable protein.

Animals↗
PubMed1982

Paroxetine: pharmacokinetics and cardiovascular effects after oral and intravenous single doses in man.

Paroxetine kinetics and cardiovascular effects were studied in 4 healthy male subjects after single oral doses of 45 mg and after slow intravenous infusion of 23-28 mg. The plasma concentration/time curves could be described by a two-compartment open model, but the estimates of the model parameters were relatively inaccurate after the oral test. Plasma half-lives were longer after oral (19.8 hrs. S.D. 1.3 hrs) than after intravenous test (12.3 hrs. S.D. 3.8 hrs). Different methods of calculation of the systemic availability resulted in different values, most probably due to dose dependent kinetics. This is possibly related to saturated elimination kinetics during the first pass metabolism. Systolic time interval measurements showed that paroxetine causes a shortening of the electromechanical systole (QS2 corrected for heart rate) indicating a positive inotropic effect of the compound. Paroxetine also caused a reduction in heart rate and a moderate rise in systolic and diastolic blood pressure. After the intravenous dose some subjects experienced nausea and one subject a quite pronounced anxiety.

Administration, Oral↗
PubMed1981

Effects of dioxane on RNA synthesis in the rat liver.

The effect of dioxane on transcription was investigated. On intravenous administration of the lower dose (10 mg/rat) both RNA polymerase A and B activities were initially depressed but recovered after 1 h. A secondary effect on RNA polymerase A was observed but the enzyme activity recovered at 24 h when it was about 35% above control values whereas RNA polymerase B activity had achieved control values. With a higher dose (100 mg/rat) the pattern was similar but the suppressive effects were more pronounced - RNA polymerase B activity never attained control values during the times studied whereas there was no increase in RNA polymerase A activity at 24 h.

Animals↗
PubMed1981

Prolongation of the Q-T interval (Romano-Ward syndrome): anaesthetic management.

The anaesthetic management is described of a patient with prolonged Q-T interval which had been complicated by ventricular fibrillation at induction of general anaesthesia for a previous operation. This complication was prevented by effective premedication with i.v. propranolol and block of the left stellate ganglion.

Adult↗
PubMed1981

Metabolism of femoxetine.

The metabolism of femoxetine, a serotonin uptake inhibitor, has been investigated in rats, dogs, monkeys, and human subjects using two 14C-femoxetine compounds with labelling in different positions. The metabolic pathways were oxidation (and glucuronidation) and demethylation, both reactions most probably taking place in the liver. Nearly all femoxetine was metabolised, and the same metabolites were found in urine from all four species. Only a small percentage of the radioactivity excreted in the urine was not identified. Rat and dog excreted more N-oxide than monkey and man, while most of the radioactivity (60-100%) in these two species was excreted as two hydroxy metabolites. The metabolic pattern in monkey and man was very similar. About 50% was excreted in these two species as one metabolite, formed by demethylation of a methoxy group. A demethylation of a N-CH3 group formed an active metabolite, norfemoxetine. The excretion of this metabolite in urine from man varied from 0 to 18% of the dose between individuals. Most of the radioactivity was excreted with the faeces in rat and dog, while monkey and man excreted most of the radioactivity in urine. This difference in excretion route might be explained by the difference in the metabolite pattern. No dose dependency was observed in any of the three animal species investigated.

Animals↗
PubMed1981

Radioreceptor assay for benzodiazepines in biological fluids using a new dry and stable receptor preparation.

A method for determination of benzodiazepines in human blood, plasma, saliva and urine has been developed. The method is based upon the competition between 3H-flunitrazepam and biologically active benzodiazepines in biological fluids for brain specific receptors, prepared in a stable, dry form and easy to handle. The pharmacological specificity for benzodiazepines of the dry stable receptor preparation is closely similar to that of fresh membrane-bound rat brain receptors. The method is specific for biologically active benzodiazepines; it is relatively rapid, sensitive and reproducible, and can be performed at room temperature.

Benzodiazepines↗
PubMed1979

Inhibition of 5-HT uptake into neurons and platelets in mice treated chronically with chlorimipramine and femoxetine.

A single treatment with 5-HT uptake inhibitors potentiates the hypermotility in mice produced by the MAO-inhibitor nialamide. The effect of nialamide on motility was studied in mice after 4 weeks of feeding with a normal diet and diets containing various concentrations of the 5-HT uptake inhibitors chlorimipramine and femoxetine. Chronic treatment with the two substances enhanced the motor effects of nialamide about equally, which indicates a preservation of the neuronal 5-HT uptake inhibition during such treatment. The effect of chlorimipramine and femoxetine was obtained at plasma levels equivalent to or lower than the steady-state plasma concentrations found in patients treated with two 5-HT uptake inhibitors. Determination of decreased blood 5-HT after the 4 weeks of treatment was used as an in vivo test for inhibition of 5-HT uptake into platelets. Femoxetine was a much weaker depletor of blood 5-HT than chlorimipramine. These results indicate that blockade of neuronal 5-HT uptake is obtained at lower doses of femoxetine than blockade of 5-HT uptake into platelets. In contrast, chlorimipramine presumably inhibits 5-HT uptake into neurons and platelets at about the same dose.

Animals↗
PubMed1979

Pharmacokinetics of femoxetine in man.

The pharmacokinetics of a structurally new 5HT-uptake inhibitor, femoxetine (FG 4963), with antidepressant properties have been investigated in man using a radioactive as well as a non-labelled substance. A two compartment open model gives a good description of the data, both after oral and intravenous administration. The substance was almost completely absorbed after an oral dose, but only 5-10% reached the systemic circulation due to extensive first pass metabolism. The metabolites had distribution and excretion rates similar to the parent compound. Only a small part (less than 2%) was excreted as femoxetine in the urine. The urinary excretion of the parent compound varied more than a 100-fold depending on the pH of the urine. The urine pH, however, did not influence the plasma concentration of femoxetine. Most of the substance (up to 80%) was eliminated by urinary excretion of metabolites, and only a small part of the radioactive dose was excreted in the faeces (up to 11%). The pharmacokinetic parameters were not found to be dose dependent in the range investigated, but it was not possible to decide whether the bioavailability was dependent on the dose. The variation between subjects was rather large, giving only a limited possibility for prediction of the plasma concentration from one subject to another.

Administration, Oral↗