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Biomedical subjects

M L Powell

Publications and source records attributed to M L Powell.

47 records · Page 3Linked to original sources
PubMedDate not supplied

Quantitative determination of CGS 18102A, a new anxiolytic, in human plasma using capillary gas chromatography/mass spectrometry.

CGS 18102A is a novel hexahydrobenzopyranopyridine that has a mixed pharmacological profile of 5-HT-1A agonist and 5-HT-2 antagonist properties. Based upon these mechanisms, the compound is predicted to have anxiolytic efficacy with possible efficacy in depression. Preclinical studies in the rat have shown the drug to be well absorbed and extensively metabolized. Because of the anticipated low plasma levels in humans a gas chromatography/mass spectrometry (GC/MS) analytical method has been developed and validated to determine plasma concentrations of CGS 18102A in early clinical studies. The method utilizes CGS 18416A as the internal standard. Samples (1 mL) were extracted with pentane:ethyl acetate (75:25, v:v). Extracts were then concentrated and analysed directly by GC/MS. Separation was accomplished on a methylsilicone capillary column (30 m x 0.32 mm i.d.). GC/MS was carried out under positive ion ammonia CI conditions, with selected ion monitoring of the [M + H]+ ions (m/z = 262 and 248) for CGS 18102A and CGS 18416A, respectively. The method was successively applied to the analysis of clinical samples from an ascending multidose safety and tolerability study conducted in six normal healthy male volunteers.

Adolescent↗
PubMedDate not supplied

An automated method for the determination of a new potential antiepileptic agent (CGP 33101) in human plasma using high performance liquid chromatography.

An automated analytical method utilizing laboratory robotics has been developed and validated for quantifying concentrations of a new antiepileptic drug candidate (CGP 33101) in human plasma. The robotic system aliquots the biological sample, adds the internal standard (CGP 23901) and pH 12 buffer, extracts the compounds from the basified matrix into an organic phase (methyl-t-butyl ether:dichloromethane, 2:1) and concentrates the extracts for reversed-phase, high performance liquid chromatographic (HPLC) analysis. The robotic system is directly interfaced with the HPLC system. Separation is achieved on a Hypersil 3 microns C18 column (4.6 x 50 mm) with ultraviolet detection of the analytes at 230 nm. Specificity was demonstrated by the lack of interfering peaks at the retention times for both the drug and internal standard. Recovery and reproducibility assessments indicated good accuracy (overall mean relative recovery of 102.7%) and precision (coefficient of variation of 4.4 to 7.7%) for CGP 33101 over the concentration range of 50-4000 ng/mL. The limit of quantification (LOQ) is 50 ng/mL. The method has been successfully applied to a clinical study in which normal volunteers received single oral doses of 400-1200 mg of this new drug candidate.

Anticonvulsants↗
PubMedDate not supplied

A quantitative analytical method for the determination of a new thromboxane synthetase inhibitor (CGS 22652) in human plasma using high performance liquid chromatography.

A quantitative analytical method for the determination of a new thromboxane synthetase inhibitor (CGS 22652) in human plasma has been developed using high performance liquid chromatography (HPLC). The drug and internal standard (CGS 23298) were extracted with methylene chloride at pH 4.8. Separations were achieved by reversed phase chromatography using a mobile phase consisting of acetonitrile: 0.01M citrate/phosphate buffer (pH 3.5): methanol:tetrahydrofuran (45:45:9:1, v/v/v/v), on a 5 microns C18 column at a flow rate of 1.0 mL/min. Plasma standard curves were linear from 50 to 2000 ng/mL, with recovery of the drug being greater than 94% at all concentrations. The method was validated over a concentration range of 50 to 2000 ng/mL, with a limit of quantification of 50 ng/mL. The method was successfully applied to the analysis of clinical samples from a single-dose safety and tolerability study conducted in healthy male volunteers.

Caprylates↗
PubMedDate not supplied

A quantitative analytical method for the determination of a new anxiolytic (CGS 19480A) in human plasma using high performance liquid chromatography.

A sensitive and specific analytical method has been developed for the determination of a new anxiolytic (CGS 19480A) in human plasma using high performance liquid chromatography (HPLC). The drug and internal standard (CGS 18102A), were extracted with hexane at pH 7. Separations were achieved by reversed phase chromatography on a Nucleosil 5 C18 column at a flow rate of 1.0 mL/min. The mobile phase consisted of acetonitrile: 0.01 M phosphate buffer (pH 7): methanol (51:35:14, v:v:v), where the final pH of the mobile phase was adjusted to 4.0 using 85% phosphoric acid. Plasma standard curves were linear from 5.0 to 500 ng/ml, with recovery of the drug being greater than 95% at all concentrations. The method was validated over a concentration range of 5.0 to 500 ng/mL with a limit of quantification of 5.0 ng/mL. The method was successfully applied to the analysis of clinical samples from a single-dose safety and tolerability study conducted in six healthy male volunteers.

Anti-Anxiety Agents↗
PubMedDate not supplied

Multiple-dose albuterol kinetics.

Albuterol, a beta-adrenergic agonist bronchodilator, was studied in 12 healthy male volunteers to evaluate the steady-state pharmacokinetics following oral administration of 4-mg tablets, given every six hours for five days. The kinetics of albuterol were best described by a two-compartment open model with first-order absorption kinetics. Steady-state plasma levels were predictable from the kinetic data and were reached by the third day of dosing (ninth and tenth dose). Small accumulation ratios of approximately two were seen based on area under the plasma concentration-time curve and maximal and minimal concentration data. The elimination phase half-life was determined to be 6.5 hours, which is similar to the values reported following single-dose administration.

Adolescent↗
PubMedDate not supplied

Evidence for an arene oxide-NIH shift pathway in the metabolic conversion of propranolol to 4'-hydroxypropranolol in the rat and in man.

To determine whether the 4'-hydroxylation of propranolol occurs by an arene oxide-NIH shift process, 4'-deuteropropranolol, prepared from 4'-iodopropranolol, was subjected to in vitro metabolic experiments in the rat liver 9000 g supernatant fraction and to in vivo metabolic experiments in man. Deuterium retention in the resulting 4'-hydroxypropranolol, determined by mass spectrometry after gas- or high-pressure liquid-chromatographic separation, was 73--75%. The results are interpreted to indicate that 4'-hydroxylation of propranolol proceeds by way of an arene oxide-NIH shift process in these two metabolic systems.

Animals↗