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Biomedical subjects

R Whelpton

Publications and source records attributed to R Whelpton.

52 records · Page 3Linked to original sources
PubMed1979

Pharmacokinetics of closely related benzodiazepines.

1 It is commonplace for drugs to vary by only minor chemical differences. This is particularly so for those seven benzodiazepines discussed in this paper which are related both as precursors and as metabolites. However, minor chemical differences may cause major differences in physicochemical and pharmacodynamic properties. 2 Although the physicochemical differences are difficult to relate to effect, the influence of structure on absorption, distribution and elimination is of considerable importance in governing duration of effect, as shown by studies in monkeys and in man. This in turn dictates the suitability of a particular drug as a day or night sedative, as an anticonvulsant, or as an anxiolytic. 3 Structure affects the relative potency of the compounds as anticonvulsants, anxiolytics or sedatives so that judicious choice of a particular compound for a particular patient and condition will lead to improved therapy. It is fallacious to consider all benzodiazepines as similar.

Anti-Anxiety Agents↗
PubMed1979

Kinetics of fluphenazine after fluphenazine dihydrochloride, enanthate and decanoate administration to man.

1 Fluphenazine (1,2-ethanol 14C) was administered to seven human subjects as the dihydrochloride and as the enanthate and decanoate esters. 2 The subjects had previously been treated with fluphenazine injections for at least 6 months. 3 Fluphenazine was separated from its radioactive metabolites by selective solvent extraction. Plasma concentrations were measured for up to 21 days after dosing. 4 The preparations showed differences in peak concentrations, times of the peaks and half-times of the elimination phase. The longest half-times occurred with the decanoate and the shortest with the dihydrochloride. 5 It is postulated that the differences in kinetics relate principally to the release of the compound from the site of injection. 6 There was no evidence for presence of the esters in plasma, urine or faeces.

Adult↗
PubMed1977

Changes in reaction time and drug plasma concentrations after nitrazepam and glutethimide.

1 The effects of nitrazepam, glutethimide and placebo were assessed in a double-blind cross-over study with five healthy human subjects, using reaction time, and relating changes to drug concentrations in the plasma. 2 After glutethimide in all five subjects, and after nitrazepam in four subjects, larger doses led to higher concentrations in plasma and to greater changes in reaction time; one subject displayed the higher nitrazepam concentrations and the greater effect following the smaller dose. 3 The relationship between change in reaction time and concentration appeared to be mainly a within-subject dose-effect relationship, with the peak concentration in plasma as the 'dose' and the area under the reaction time curve as the effect.

Adult↗
PubMed1977

Behavioural and pharmacokinetic studies in the monkey (Macaca mulatta) with diazepam, nordiazepam and related 1,4-benzodiazepines.

1. Behavioural activity (delayed differentiation and spatial delayed alternation) and pharmacokinetics of diazepam and its metabolites, N-desmethyldiazepam (nordiazepam), 3-hydroxydiazepam (temazepam) and 3-hydroxy-N-desmethyldiazepam (oxazepam), and of dipotassium clorazepate (clorazepate), were studied in the monkey (Macaca mulatta). Diazepam and its metabolites (1.8 and 3.0 mg/kg) and clorazepate (2.6 and 4.3 mg/kg) were given by intraperitoneal injection. 2. Hydroxylation of diazepam (temazepam and oxazepam) led to a loss of, or a considerable reduction in, behavioural activity, whereas activity was preserved, though modified, by demethylation (nordiazepam). It was not possible to establish change in behaviour at specific time intervals after clorazepate, but combined performance data revealed an effect. 3. The maximum mean plasma concentrations of diazepam, temazepam, oxazepam and clorazepate were observed at 0.5 h, and the maximum mean plasma concentration of nordiazepam was observed at 1 hour. Plasma concentrations of nordiazepam were the highest and decreased monoexponentially. Plasma concenqrations of the other drugs declined rapidly at first but more slowly later, and these data were analysed as biexponential models. In the analysis for metabolites, nordiazepam reached measurable levels after the injection of diazepam and clorazepate. 4. It is suggested that differences in the effects of closely related benzodiazepines may not be due solely to their plasma pharmacokinetic properties, but may arise from differences in their intrinsic activity.

Animals↗
PubMed1976

Methods for study of fluphenazine kinetics in man.

Fluphenazine and its principal metabolites, fluphenazine sulphoxide, and 7-hydroxyfluphenazine were identified and quantified in human plasma, urine and faeces following intramuscular and oral administration of 14C-fluphenazine dihydrochloride. The presence of a conjugate fraction was also noted. Unmetabolized fluphenazine was selectively extracted into n-heptane. The metabolites were separated by solvent extraction into toluene. Conjugates were hydrolysed back to fluphenazine, fluphenazne sulphoxide and 7-hydroxyfluphenazine. Fluphenazine and fluphenazine conjugates were also measured in the urine of patients receiving long term non-radioactive fluphenazine decanoate therapy. The urinary excretion rate of the conjugate fraction was systematically related to the plasma concentration, regardless of urine flow rate or pH, providing a convenient method for the assessment of fluphenazine kinetics by urinary excretion studies not involving administration of labelled drug.

Administration, Oral↗
PubMedDate not supplied

Animal model for investigation of fluphenazine kinetics after administration of long-acting esters.

A model was developed for studying fluphenazine availability and disposition. Rats were given doses of radioactively labelled esters of fluphenazine by intramuscular injection. Radioactivity excreted in urine, faeces, and expired air was assessed for fluphenazine esters, fluphenazine, and CO2 content. Levels of fluphenazine and its esters were measured in plasma, brain, and muscle (injected and non-injected samples). The data mimicked those obtained in other studies involving the same material given to human subjects, and posed new questions concerning the factors controlling fluphenazine availability when given as 'long-acting' intramuscular injections.

Animals↗
PubMedDate not supplied

Liquid chromatographic determination of hyoscine (scopolamine) in urine using solid phase extraction.

A sensitive method for the determination of hyoscine (scopolamine) in urine is described. After concentration and "clean-up" on C18 and CN solid phase extraction columns, hyoscine was quantified by high performance liquid chromatography with coulometric detection (oxidation at +0.9 V). The limit of detection was 5 ng per sample and the precision for 5 mL samples containing 2 ng/mL was 12.3%. The method was applied to urine samples collected from 12 volunteers wearing Scopoderm TTS patches. The mean excretion rate of unmetabolized hyoscine was 0.45 micrograms/h and 87% of the total hyoscine was present as conjugates. Apohyoscine (aposcopolamine) was identified as a urinary metabolite. The significance of this with regard to hyoscine assays is discussed.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

Determination of paracetamol (acetaminophen) in blood and plasma using high performance liquid chromatography with dual electrode coulometric quantification in the redox mode.

A simple, but sensitive, micro-assay for paracetamol in blood and plasma is described. Samples were prepared by precipitation with trichloroacetic assay solution and the drug quantified by reversed phase liquid chromatography with dual electrode electrochemical detection in the redox mode (oxidation at +0.25 V followed by reduction at -0.15 V). The limit of detection was 0.1 mg/L for a 10 microL sample of blood or plasma, the coefficient of variation at this concentration being 11.4%. The method was applied to a study of gastric emptying in patients before and after cardiac surgery.

Acetaminophen↗
PubMedDate not supplied

Micro-extraction techniques in analytical toxicology: short review.

This paper discusses new developments in plasma micro-extraction techniques in the context of established micro-extraction and protein precipitation methodology. Simple liquid-liquid solvent extraction (LLE) of plasma with direct GC or HPLC analysis of the resulting extract has been used for many years. Butyl acetate and methyl t-butyl ether (MTBE) give efficient extraction of many drugs and metabolites from small volumes of plasma or whole blood at an appropriate pH, and form the upper layer, thus simplifying extract removal. Butyl acetate does not interfere with NPD, ECD or MS in GC, whilst MTBE has a relatively low UV cutoff (220 nm). Thus, HPLC eluents that use a high proportion of an organic component allow MTBE extracts to be analysed directly. 'Salting-out' and extractive derivatization using acetic anhydride or phenylboronic acid can be used with appropriate analytes. As regards protein precipitation, an important consideration is lowering the pH, although this is not feasible with acid-labile analytes. More recent developments include sold-phase micro-extraction (SPME) and liquid-phase micro-extraction (LPME). This latter technique especially may prove invaluable as analytes that cannot easily be extracted with LLE can be isolated simply at low cost with a minimum of apparatus.

Chemical Precipitation↗