In vitro assays and biomarkers for drug-induced phospholipidosis.

Drug-induced phospholipidosis is the cytoplasmic accumulation of phospholipids as a result of xenobiotic exposure. This accumulation results in a unique histological effect in cells noted as electron-dense lamellar inclusions or whorls in the cytoplasm when observed with transmission electron microscopy. Electron microscopy has been the widely accepted standard for classification of the phospholipidosis effect.

Effect of age on the pharmacokinetics of duloxetine in women.

Aims: The effect of age on duloxetine pharmacokinetics was evaluated in healthy volunteers and in patients with urinary incontinence.

Methods: Twenty-four healthy subjects (12 women 65-77 years, and 12 women 32-50 years) were given a single 40-mg oral dose of duloxetine in Study 1. Plasma concentration-time data were analysed by noncompartmental pharmacokinetic methods.

Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers.

Background And Objectives: Duloxetine, a potent dual reuptake inhibitor of serotonin and norepinephrine currently undergoing clinical investigation for treatment of depression and stress urinary incontinence, has the potential to act as both a substrate and an inhibitor of cytochrome P4502D6 (CYP2D6). Our objectives were to determine the effect of duloxetine on the pharmacokinetics of desipramine, a tricyclic antidepressant metabolized by CYP2D6 (study 1), and the effect of paroxetine, a potent CYP2D6 inhibitor, on duloxetine pharmacokinetics (study 2).

Methods: Subjects were healthy men and women between 21 and 63 years old.

Divergent effects of raloxifene HCI on the pharmacokinetics and pharmacodynamics of warfarin.

Purpose: Evista (raloxifene HCl) is a nonsteroidal selective estrogen receptor modulator that displays estrogen agonist effects on bone and lipid metabolism but estrogen antagonist effects on the breast and endometrium. The potential for drug-drug interaction between raloxifene and warfarin was assessed in 15 healthy postmenopausal women.

Methods: Single doses of warfarin (20 mg) were administered prior to and during 2 weeks of dosing with raloxifene 120 mg/day.

Confidence interval criteria for assessment of dose proportionality.

Purpose: The aim of this work was a pragmatic, statistically sound and clinically relevant approach to dose-proportionality analyses that is compatible with common study designs.

Methods: Statistical estimation is used to derive a (1-alpha)% confidence interval (CI) for the ratio of dose-normalized, geometric mean values (Rdnm) of a pharmacokinetic variable (PK). An acceptance interval for Rdnm defining the clinically relevant, dose-proportional region is established a priori.

Pharmacokinetics and safety of duloxetine, a dual-serotonin and norepinephrine reuptake inhibitor.

The pharmacokinetics and safety of duloxetine were evaluated in a single-blind, placebo-controlled, escalating multiple-dose study in 12 healthy male subjects. In the treatment group (n = 8), duloxetine was administered orally at a starting dose of 20 mg twice daily (bid) and escalated at weekly intervals to 30 mg bid, then to 40 mg bid. The observed plasma concentration-time data at all three dose levels were adequately described by a one-compartment model with a first-order absorption rate constant.

Olanzapine. Pharmacokinetic and pharmacodynamic profile.

Multicentre trials in patients with schizophrenia confirm that olanzapine is a novel antipsychotic agent with broad efficacy, eliciting a response in both the positive and negative symptoms of schizophrenia. Compared with traditional antipsychotic agents, olanzapine causes a lower incidence of extrapyramidal symptoms and minimal perturbation of prolactin levels. Generally, olanzapine is well tolerated.

Effects of food on the pharmacokinetics of sparfloxacin.

Sparfloxacin, a fluoroquinolone with a broad antimicrobial spectrum and long elimination half-life, is indicated for the treatment of community-acquired pneumonia and acute bacterial exacerbations of chronic bronchitis in adult patients. The present study was undertaken to determine the effects of skim milk and a high-fat breakfast without milk on the single-dose pharmacokinetic characteristics of this antibiotic. The pharmacokinetics of a single 200-mg dose of sparfloxacin were assessed in a 3-way crossover study that included 23 healthy male volunteers who had fasted, had ingested 240 mL of skim milk, or had consumed a standard high-fat breakfast.

Lack of effect of olanzapine on the pharmacokinetics of a single aminophylline dose in healthy men.

Study Objective: To test whether olanzapine, an atypical antipsychotic, is an inhibitor of cytochrome P450 (CYP) 1A2 activity, we conducted a drug interaction study with theophylline, a known CYP1A2 substrate.

Design: Two-way, randomized, crossover study.

Setting: Clinical research laboratory.

Why rate of absorption inferences in single dose bioequivalence studies are often inappropriate.

Purpose: Peak drug concentration (Cmax) measures the extremity of drug exposure and is a secondary indicator of the extent of absorption after area under the concentration time curve (AUC). Cmax serves as the indicator of absorption rate in bioequivalence (BE) studies in the US (1). The use of Cmax, not the time to Cmax (Tmax), as the metric to assess absorption rate causes erratic inferences in BE studies, and incorrect conclusions for some.

Olanzapine: interaction study with imipramine.

Olanzapine is an "atypical" antipsychotic agent with a high affinity for serotonin 5HT2A/C, 5HT3, 5HT6, and dopamine D1, D2, D3, D4 receptors. Depressed patients with psychotic disorders frequently require treatment with concomitant antipsychotic and antidepressant medications. Imipramine pharmacokinetics serve as a marker for hepatic CYP2D6, CYP1A2, CYP3A activity.

The effect of sertraline on the pharmacokinetics of desipramine and imipramine.

Objective: To examine the pharmacokinetic interaction between the selective serotonin reuptake inhibitor sertraline and the tricyclic antidepressants desipramine or imipramine in 12 healthy male subjects.

Methods: Participants received a 50 mg single dose of either desipramine or imipramine under three conditions: alone, after a single 150 mg dose of sertraline, and after the eighth daily 150 mg dose of sertraline. Plasma samples were analyzed for desipramine or imipramine concentration by HPLC with electrochemical detection, and pharmacokinetics were determined with use of noncompartmental analysis of individual data.

Effect of dirithromycin on human CYP3A in vitro and on pharmacokinetics and pharmacodynamics of terfenadine in vivo.

Terfenadine is metabolized by the cytochrome P-450 3A subfamily of enzymes (CYP3A). Certain macrolide antibiotic agents inhibit CYP3A and, when coadministered with terfenadine, result in a drug interaction. The authors compared the abilities of dirithromycin (a new macrolide antibiotic agent), its major metabolite erythromycylamine, and the known CYP3A substrate terfenadine to inhibit CYP3A in vitro.

Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin.

Objective: The pharmacokinetics and glucodynamics of a new insulin analog, insulin lispro, and regular human insulin were compared and contrasted after subcutaneous administrations in femoral, deltoid, and abdominal injection sites.

Research Design And Methods: Single 0.2 U/kg doses of insulin lispro and regular insulin were administered to 12 healthy subjects in a six-way randomized crossover fashion.

Tmax: an unconfounded metric for rate of absorption in single dose bioequivalence studies.

Purpose: While peak drug concentration (Cmax) is recognized to be contaminated by the extent of absorption, it has long served as the indicator of change in absorption rate in bioequivalence studies. This concentration measure per se is a measure of extreme drug exposure, not absorption rate. This paper redirects attention to Tmax as the absorption rate variable.

Impact of the nutritional regimen on protein catabolism and nitrogen balance in patients with acute renal failure.

Background: Patients with acute renal failure are in substantial negative nitrogen balance as a result of their extremely high protein catabolic rates. We prospectively evaluated a series of patients with acute renal failure managed with continuous venovenous hemofiltration to determine which nutritional and nonnutritional variables might influence protein catabolism and nitrogen balance.

Methods: Forty consecutive patients (aged 52 +/- 20 years; mean +/- SD) were monitored for 357 treatment days (average treatment duration 8.

[Lys(B28), Pro(B29)]-human insulin: effect of injection time on postprandial glycemia.

Background: [Lys(B28), Pro(B29)]-human insulin (lispro) is an insulin analogue with a reduced capacity for self-association and faster absorption from subcutaneous injection sites. We hypothesized that administration of lispro closer to a meal would result in better glucose control than that achieved with regular insulin.

Methods: This trial used a randomized crossover design that consisted of a period of metabolic stabilization lasting 9 days followed by an evaluation period lasting 5 days.

Local and systemic phentolamine antagonism of norepinephrine-induced hand vein constriction.

The dorsal hand vein distention technique has been used to study the effects of alpha-adrenergic receptor antagonists on alpha-agonist-induced venoconstriction. Using this technique, we investigated the dose-effect relationships between different intravenous routes of phentolamine (an alpha-antagonist) administration on norepinephrine (an alpha-agonist)-induced hand vein constriction. Hand vein studies were done on healthy men; each man was studied on up to four occasions.

Gender differences in alcohol metabolism. Physiological responses to ethanol.

A gender difference in alcohol pharmacokinetics has been suggested to explain why women are more vulnerable to ethanol's toxic effects. The results of animal experiments suggest that females exhibit higher alcohol metabolic rates than males as a result of hormonal differences. Experimental results examining gender differences in human alcohol metabolism have been inconsistent; the diversity of experimental protocols and variety of pharmacokinetic parameters reported have made comparisons of these studies very difficult.

Comparative pharmacokinetics and glucodynamics of two human insulin mixtures. 70/30 and 50/50 insulin mixtures.

Objective: To compare and contrast the pharmacokinetics and glucodynamics of two insulin mixtures, one of 50% NPH human insulin and 50% Regular human insulin (50/50) and one of 70% NPH human insulin and 30% Regular human insulin (70/30), in healthy male volunteers after subcutaneous administrations of 0.3 U/kg.

Research Design And Methods: We administered single doses of 50/50 and 70/30 insulins to 18 volunteers in a randomized crossover fashion.

Column-switching high-performance liquid chromatographic method for the determination of a thymidylate synthase inhibitor, LY231514, an investigational agent for the treatment of solid tumors, in human plasma.

A reversed-phase, column-switching high-performance liquid chromatographic (HPLC) method is described for the determination of a new thymidylate synthase inhibitor in human plasma. The compound and an internal standard are extracted from plasma using a Certify II solid-phase cartridge. Extracts are evaporated to dryness and the residue is reconstituted with mobile phase buffer.

[Lys(B28), Pro(B29)]-human insulin. A rapidly absorbed analogue of human insulin.

[Lys(B28, Pro(B29)]-human insulin (LYSPRO) is an insulin analogue in which the natural amino acid sequence of the B-chain at positions 28 and 29 is inverted. These changes result in an insulin molecule with a greatly reduced capacity for self-association in solution. These clinical studies were designed to compare LYSPRO with human Regular insulin after subcutaneous injection in humans.