Extemporaneously prepared controlled release formulations for accelerating the early phase development of drug candidates.

Extemporaneous drug preparations, which are compounded by a pharmacist at a clinical site, are commonly used in early clinical studies to evaluate the performance of drug candidates. However, the types of formulations compounded have been limited to relatively simple preparations such as solutions, suspensions and active ingredients filled into capsules. This article describes the preparation of advanced formulations, specifically extemporaneously prepared matrix tablets and osmotic capsules, which can be used to evaluate the feasibility of controlled release for exploratory new drug candidates or new formulations of existing drugs with a differentiated medical advantage.

Displacement of serotonin and dopamine transporters by venlafaxine extended release capsule at steady state: a [123I]2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane single photon emission computed tomography imaging study.

Both positron emission tomography and single photon emission computed tomography (SPECT) studies suggest that saturation of serotonin transporters (SERT) is present during treatment with therapeutic doses of selective serotonin reuptake inhibitors (SSRIs). Selective serotonin reuptake inhibitors also appear to increase the availability of dopamine transporters (DAT). The current study measured SERT occupancy and modulation of DAT by the serotonin/norepinephrine reuptake inhibitor (SNRI) venlafaxine using [123I]2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane SPECT.

Pharmacogenetics affects dosing, efficacy, and toxicity of cytochrome P450-metabolized drugs.

Drug-metabolizing enzyme activity is one of many factors affecting patient response to medications. The objective of this review is to highlight the potential for genetic variability in cytochrome P450 enzyme activity that can lead to interperson differences in response to drugs. Awareness and application of this knowledge will improve drug use in clinical practice and provide the physician with further appreciation that standard drug dosing may not be appropriate in all patients.

Flumazenil reduces midazolam-induced cognitive impairment without altering pharmacokinetics.

Objectives: Intravenous midazolam is used as an in vivo biomarker of hepatic cytochrome P450 (CYP) 3A activity. Midazolam is a central nervous system depressant and can produce cognitive impairment. The purpose of this study was 2-fold: (1) to determine whether administration of intravenous flumazenil given before intravenous midazolam minimizes cognitive impairment and (2) to determine whether flumazenil pretreatment has an effect on midazolam pharmacokinetics during hepatic CYP3A phenotyping.

Single plasma concentrations of 1'-hydroxymidazolam or the ratio of 1'-hydroxymidazolam:midazolam do not predict midazolam clearance in healthy subjects.

The 30-minute ratio of 1'-hydroxymidazolam:midazolam plasma concentrations has been used as a measure of midazolam clearance in liver transplant patients. This study determined if a single concentration of 1'-hydroxymidazolam or the ratio of 1'-hydroxymidazolam:midazolam could be used to predict midazolam clearance in healthy subjects. Plasma midazolam and 1'-hydroxymidazolam concentrations from three previous studies were used for analyses.