Pharmacological Inhibition of Lipid Import and Transport Proteins in Ovarian Cancer.

Ovarian cancer (OC) is the most lethal gynecological malignancy with a 5-year survival rate of 49%. This is caused by late diagnosis when cells have already metastasized into the peritoneal cavity and to the omentum. OC progression is dependent on the availability of high-energy lipids/fatty acids (FA) provided by endogenous de novo biosynthesis and/or through import from the microenvironment.

The Pharmacological or Genetic Blockade of Endogenous Fatty Acid Synthesis Does Not Increase the Uptake of Exogenous Lipids in Ovarian Cancer Cells.

Ovarian cancer(OC) is a serious threat to women worldwide. Peritoneal dissemination, ascites and omental metastasis are typical features for disease progression, which occurs in a micro-environment that is rich in high-energy lipids. OC cells require high amounts of lipids for survival and growth.

Disposition and biotransformation of the antipsychotic agent olanzapine in humans.

Disposition and biotransformation of the new antipsychotic agent olanzapine (OLZ) were studied in six male healthy volunteers after a single oral dose of 12.5 mg containing 100 microCi of [14C]OLZ. Biological fluids were analyzed for total radioactivity, the parent compound (GC/MS), and metabolites (electrospray LC/MS and LC/MS/MS).

The effects of renal and hepatic disease on the pharmacokinetics, renal tolerance, and risk-benefit profile of fluoxetine.

Renal and hepatic diseases have a significant impact on the plasma concentration profiles and the dose requirements for almost all drugs. This paper reviews the effect of these diseases and their associated physiological derangements on the pharmacokinetics of fluoxetine and norfluoxetine. Metabolic studies of fluoxetine in man show that more than 70% of the radiolabelled compound is excreted in the urine.

Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction.

Clinical reports of concurrent use of fluoxetine and tricyclic antidepressant agents suggest that tricyclic concentrations increase upon coadministration with fluoxetine. This study was conducted to confirm the clinical reports, to quantify the degree of change in tricyclic kinetics, and to establish the mechanism of interaction. Twelve male subjects were given 50 mg desipramine (six subjects) or 50 mg imipramine (six subjects) on three occasions: alone, after a 60 mg dose of fluoxetine, and after eight daily 60 mg doses of fluoxetine.

Fluoxetine disposition and elimination in cirrhosis.

Fluoxetine is a specific and potent inhibitor of presynaptic serotonin reuptake and has been shown to be a clinically effective antidepressant. Elimination of the drug depends primarily on hepatic metabolism, with formation of a pharmacologically active demethylated product, norfluoxetine. The present study assesses for the first time the effect of chronic liver disease on these processes.

The effect of fluoxetine on the pharmacokinetics and psychomotor responses of diazepam.

To determine the effect of fluoxetine on diazepam's pharmacokinetic and psychomotor responses, single oral doses of 10 mg diazepam were administered to six normal subjects on three occasions, either alone or in combination with 60 mg fluoxetine. Diazepam was given alone, after a single dose of fluoxetine, and after eight daily doses of fluoxetine. Psychometric data showed that fluoxetine had no significant effect on the psychomotor responses to diazepam.

Pressor responses to tyramine and norepinephrine after subchronic administration of fluoxetine to man.

The effects of subchronic, oral administration of fluoxetine (60 mg daily for 45 days) were studied in three healthy male volunteers. The pressor responses to intravenous bolus tyramine injections or norepinephrine infusions were assessed during the one-week placebo period, periodically after daily fluoxetine dosing, and then for 11 days post-fluoxetine dosing. The dose-pressor responses, determined from the incremental elevation of systolic blood pressure, were unchanged in each of the three dosing intervals.

Early clinical evaluation in man: the buck stops here.

The development of new drugs as potential therapeutic agents involves multi-discipline 'team' research. The clinician has to deal with scientific and ethical issues and keep in mind the axiom 'Primum no nocere--Above all, do no harm.' The clinical pharmacologist has to address the pharmacologic actions of a potential new drug and if any antidotes are available.

Effect of fluoxetine on psychomotor performance, physiologic response, and kinetics of ethanol.

The effects of fluoxetine, a specific serotonin reuptake inhibitor, on the psychomotor performance, physiologic response, and kinetic disposition of ethanol were examined. Fluoxetine (30 or 60 mg) with ethanol (45 ml absolute alcohol per 70 kg body weight) did not alter the plasma or blood concentrations of fluoxetine or ethanol, respectively, when compared with levels after either drug alone. There was no significant effect on standing or recumbent blood pressure or heart rate after single or multiple doses of fluoxetine alone or in the combination.

Single-dose and steady-state pharmacokinetics of tomoxetine in normal subjects.

A pharmacokinetic profile of tomoxetine, a selective norepinephrine uptake inhibitor, was developed in human volunteers following single and multiple oral administrations. Following the administration of a single 90-mg oral dose of tomoxetine to four normal volunteers, the plasma half-life was 4.3 +/- 0.

Fluoxetine: clinical pharmacology and physiologic disposition.

Fluoxetine (30 mg), administered for 7 days to normal volunteers, produced a 66% inhibition of tritiated serotonin uptake into platelets. Plasma concentrations of fluoxetine correlated positively with inhibition of serotonin uptake. Fluoxetine is well absorbed after oral administration in both the fed and fasted states and demonstrates dose proportionality.

Clinical pharmacology of tomoxetine, a potential antidepressant.

Tomoxetine (LY139603) selectively inhibits norepinephrine uptake in animals and has activity in animal models of depression. Tomoxetine was administered in single oral doses up to 90 mg to healthy normal volunteers. In addition, normal human subjects received either 20 or 40 mg of tomoxetine b.

Fluoxetine kinetics and protein binding in normal and impaired renal function.

The effect of decreased renal function on the disposition and elimination of the nontricyclic antidepressant fluoxetine was examined in 25 adult male subjects after a single 40-mg oral dose. Blood samples for the measurement of fluoxetine and its active metabolite norfluoxetine were drawn 13 times in the first 48 hr after dosing and thrice weekly thereafter for 4 wk. All urine was collected in daily aliquots for 4 wk and was assayed for fluoxetine and norfluoxetine concentrations.

Pharmacological activity of the basic fraction of marihuana whole smoke condensate alone and in combination with delta-9-tetrahydrocannabinol in mice.

This basic fraction (BF) of marihuana whole smoke condensate was subjected to pharmacological testing in males, Swiss-Webster mice. In a general pharmacological activity screen looking at behavioral, neurologic, and autonomic parameters, BF, at iv doses of 5, 10, and 20 mg/kg, caused impairment of visual placing, increase in tail pinch response, decrease in tail elevation, and induction of piloerection. These effects, although statistically significant, were slight and not consistently dose dependent.

Determination of fluoxetine and norfluoxetine in plasma by gas chromatography with electron-capture detection.

This gas-chromatographic method for assay of fluoxetine and norfluoxetine in human plasma involves extraction of the drugs and use of a 63Ni electron-capture detector. The linear range of detection is 25 to 800 micrograms/L for each drug. Overall precision (CV) in the concentration range of 10 to 100 micrograms/L for both drugs was approximately 10%.

Physiologic disposition of pergolide.

Pergolide, a synthetic ergoline, is a potent long-acting dopaminergic drug effective in Parkinson's disease and amenorrhea-galactorrhea. After 138 micrograms 14C-pergolide orally to healthy subjects, radioactivity was present in plasma and red blood cells. Salivary radioactivity was one third to one tenth that in plasma.