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Biomedical subjects

E M Hawes

Publications and source records attributed to E M Hawes.

108 records · Page 6Linked to original sources
PubMed1983

Radioimmunoassay for prochlorperazine in human plasma.

A new sensitive, specific, and rapid radioimmunoassay procedure for the determination of plasma concentrations of the antiemetic drug prochlorperazine is described. The assay enables the quantitation of 31 pg of the drug in 200 microliters of plasma with a coefficient of variation of approximately 2%. Except for N-desmethylprochlorperazine, the antiserum did not cross-react with the available metabolites tested. Also there was no cross-reactivity with the tricyclic antidepressants and antianxiety agents commonly co-administered with the drug. The method is suitable for single-dose pharmacokinetic and bioavailability studies. It should be adequate for the therapeutic monitoring of the drug in patients.

Animals↗
PubMed1983

Kinetics of oral trifluoperazine disposition in man.

The disposition of trifluoperazine (TFP) was studied in five healthy volunteers following oral administration of a 5 mg tablet. Using a very sensitive GC-MS technique plasma TFP concentrations were measured up until 24 h following drug ingestion. Peak plasma concentrations varied widely (range 0.53-3.09 ng ml-1) and were reached 2.8 +/- 0.5 h following ingestion of the TFP tablet. The apparent terminal elimination half-life of TFP was 12.5 +/- 1.4 h. The area under the plasma concentration-time curve differed widely between subjects (range: 5.9-17.6 ng ml-1 h) suggesting large individual differences in the extent of presystemic TFP elimination.

Administration, Oral↗
PubMed1983

Identification of new secondary metabolites of methoxyphenamine in man.

Metabolites of methoxyphenamine were examined in the urine of three healthy human volunteers. The metabolites were separated by g.l.c. and identified by comparison of their chromatographic and mass-spectrometric behaviours with those of authentic synthetic compounds. 5-Hydroxy-2-methoxy-N-methylamphetamine, a metabolite previously identified by indirect methods, was conclusively identified by comparison with the now-available authentic synthetic material. In addition, three new metabolites of methoxyphenamine were identified--5-hydroxy-2-methoxyamphetamine, 2-methoxyphenylacetone and 5-hydroxy-2-methoxyphenylacetone.

Chromatography, Gas↗
PubMed1982

High-performance liquid chromatographic assay of indomethacin and its application in pharmacokinetics in healthy volunteers.

A new sensitive high-performance liquid chromatographic method for indomethacin from plasma on a reversed-phase column (C18) has been developed. The method involves precipitation of plasma with perchloric acid followed by diethyl ether extraction. The assay is quantitative down to 0.25 microgram ml-1 from a 200-microliters aliquot of plasma with a detection limit of 0.1 microgram ml-1 and a recovery of approximately 90%. The method was applied to single-dose studies with volunteers under various dietary restrictions. The results of these studies indicated that intrasubject variability within these regimens may be as important a factor as the intersubject variability already documented for this drug. These results have important implications in the determination of bioavailability and pharmacokinetic parameters of this drug.

Chromatography, High Pressure Liquid↗
PubMed1982

Gas chromatographic--mass spectrometric procedure for the quantitation of chlorpromazine in plasma and its comparison with a new high-performance liquid chromatographic assay with electrochemical detection.

A gas chromatographic--mass spectrometric assay using selected ion monitoring is compared with a high-performance liquid chromatographic assay using an electrochemical detector for single-dose studies of the psychotherapeutic phenothiazine drug chlorpromazine. Measurements were made after extraction of chlorpromazine and the internal standard, prochlorperazine, from basified plasma with an isopropanol--pentane solvent mixture. Following evaporation of the organic solvents the residue was reconstituted in a small volume of methanol and subjected to gas chromatographic--mass spectrometric selected ion detection. The residual sample was then evaporated and made up in a larger volume of acetonitrile and analyzed by high-performance liquid chromatography using an electrochemical detector. These specific methods display excellent correlation for plasma concentration determinations in the range of 0.25-10 ng ml-1 and will allow for the study of the pharmacokinetics of chlorpromazine following single low doses of the drug.

Chlorpromazine↗
PubMed1982

A gas chromatographic mass spectrometric assay for plasma trifluoperazine concentrations following single doses.

A gas chromatography mass spectrometric assay using selected ion monitoring is described which permits the determination of trifluoperazine in plasma at concentrations ranging from 0.078 to 5.0 ng ml-1. It relies on the extraction of trifluoperazine and the internal standard, prochlorperazine or the tetradeuterated analogue of trifluoperazine, from basified plasma with a n-pentane/2-propanol solvent mixture. Following the evaporation of organic solvent, the residue is reconstituted in a small volume of methanol. Suitable aliquots were analysed by the combined technique of gas chromatography/electron impact mass spectrometry with a data system. The described procedure is specific and enables the quantitation of 78 pg ml-1 of the drug with a coefficient of variation less than 7%. The method has demonstrated sufficient sensitivity to permit pharmacokinetic and bioavailability studies after a single 5 mg oral dose.

Biological Availability↗
PubMed1982

A GLC-nitrogen phosphorous detector assay for trifluoperazine in plasma.

A GLC-nitrogen phosphorous detector (NPD) method for the quantitative determination of trifluoperazine in plasma is described. It depends on an organic extraction of trifluoperazine and the internal standard prochlorperazine from basified plasma. Following the extraction, the organic solvent is evaporated to dryness and the residue is reconstituted in a small volume of methyl alcohol. GLC analysis of aliquots of the methanolic solution using a NPD permitted the determination of 0.5 ng/ml of trifluoperazine in plasma. Standard curves for trifluoperazine over a concentration range of 0.5 to 15 ng/ml of plasma were linear with an overall variation coefficient of 5.3%. In isolated samples obtained from a normal healthy volunteer, application of this method to plasma concentration determinations after oral administration of a 5-mg trifluoperazine tablet, is demonstrated and compared with the concentrations obtained by GLC-mass spectrometry and radioimmunoassay procedures.

Chemical Phenomena↗
PubMed1981

Radioimmunoassay for trifluoperazine in human plasma.

1 A new sensitive and rapid radioimmunoassay procedure for the determination of the plasma concentrations of the neuroleptic drug trifluoperazine is described. 2 The antiserum developed for trifluoperazine cross-reacted with N-desmethyltrifluoperazine and 7-hydroxytrifluoperazine to the extent of 26 and 24% respectively but its cross-reactivity with commonly co-administered tricyclic antidepressants and antianxiety agents tested was negligible. 3 The assay, based on the above antiserum, enabled the quantitation of 50 pg of the drug in 200 microliters of plasma with a coefficient of variation of about 2% and therefore should be applicable for singly dose pharmacokinetic and bioavailability studies. It should be applicable to therapeutic monitoring of the drug in patients.

Animals↗
PubMed1977

2,3-Disubstituted 1,8-naphthyridines as potential diuretic agents. 2. 5,7-Dimethyl derivatives.

A variety of 2,3-disubstituted 5,7-dimethyl-1,8-naphthyridines was synthesized and tested in saline-loaded rats for their diuretic properties. The 2-amino-3-carbomethoxy and four 2-amino-3-N-alkylcarbamoyl compounds exhibited significant activity as measured by volume output; however, they were generally less potent than the corresponding 5,7-unsubstituted naphthyridines previously reported. Further screening without saline-loading indicated that the amides lacked kaliuretic properties; while, interestingly, the ester lacked an effect on either urine volume or sodium excretion.

Animals↗
PubMed1975

Molecular structure--activity relationship of hydrazides inhibiting glutamic acid decarboxylase, GABA-alpha-oxoglutarate aminotransferase, and monoamine oxidase activities in chick brain.

Several aryl and heteroaryl hydrazides were synthesized and evaluated for their inhibitory effects on glutamic acid decarboxylase (GAD), GABA-alpha-oxoglutarate aminotransferase (GABA-T), and monoamine oxidase (MAO) enzyme systems in chick brain 24 h after their intramuscular administration (0.75 mmol/kg). All compounds produced a reduction in GAD, GABA-T, and MAO activity. Structure-activity relationships indicated that the ring structure had a greater influence on the degree of GAD and GABA-T inhibition than did the N'-terminal group. In contrast, structural requirements for MAO inhibition were much more restrictive. The intramuscular administration of benzoic acid hydrazide to chicks 24 h prior to their being exposed to oxygen at high pressure provided significant protection against the onset of the hyperbaric oxygen-induced seizures.

Animals↗
PubMedDate not supplied

A bioequivalency study of two trifluoperazine tablet formulations using RIA and GC-MS.

Two sensitive analytical procedures, a radioimmunoassay (RIA) and a mass fragmentographic (GC-MS) method, were used to quantitate plasma trifluoperazine concentrations over 24 h in five healthy male volunteers following single 5 mg doses of two trifluoperazine tablet formulations (A and B) in a two-way cross-over design. Bioavailability in terms of area under the plasma concentration versus time curve to 24h or extrapolated to infinity, maximum plasma concentration and time to maximum plasma concentration using either RIA or GC-MS was not statistically significantly different from one formulation to the other. Also, there were no statistically significant differences between GC-MS and RIA values for AUC24(0) and Cmax for each of the two formulations examined. However, the mean AUC24(0) RIA/GC-MS ratios for formulations A and B were 3.1 and 3.4, respectively, while the mean Cmax RIA/GC-MS ratios were 1.7 and 2.1, respectively. These differences in AUC and Cmax are probably mainly due to the relative non-specificity of the RIA antiserum. Thus, where GC-MS is preferred for pharmacokinetic studies, both analytical procedures can be used for comparative single-dose bioequivalence studies of trifluoperazine. However, both the methods should be tested in patients in order to establish the suitability of one procedure over the other for the study of plasma level versus clinical response correlations.

Adult↗
PubMedDate not supplied

Cis-flupentixol metabolites in rat plasma and bile. The first proof of glutathione conjugation at the exocyclic double bond.

The plasma and biliary metabolites of cis-flupentixol (cis-FPT) were studied after ip administration to rats. Cis-FPT sulfoxide was found to be the major phase-I metabolite in plasma and bile. Five biliary metabolites were isolated by gradient elution HPLC and characterized by various spectroscopic methods: F1, 1'-S-glutathionyl-10,1'-dihydroFPT sulfoxide; F2, cis-FPT sulfoxide sulfate; F3, 8-O-(or 7-O) glucuronyl-cis-FPT; F4, cis-FPT sulfoxide; and F5, cis-FPT glucuronide. A novel non-enzymatic addition of glutathione (GSH) onto the exocyclic double bond was demonstrated to occur for the first time with not only flupentixol and certain of its metabolites, but also with other psychotropic drugs with a tricyclic nucleus and an exocyclic double bond. Specifically, these nonenzymatic additions of GSH were observed with cis-FPT, trans-FPT, cis-FPT sulfoxide, cis-, trans-dealkylFPT, cis-FPT N-oxide, cis-chlorprothixene, cis-thiothixene, and cyclobenzaprine. Among them, cis-FPT sulfoxide showed the most potent adduct formation activity, and the product was characterized to be identical with the in vivo metabolite F1 of cis-FPT.

Animals↗
PubMedDate not supplied

Identification of phase-I and phase-II metabolites of fluphenazine in rat bile. Intact glucuronide and sulfate conjugates.

In rat bile following ip administration of fluphenazine (FLU) dihydrochloride (20 mg/kg body weight), phase-I metabolites 7-hydroxyfluphenazine (7-HOFLU) and FLU sulfoxide (FLUSO), together with unmetabolized FLU, were isolated and identified by HPLC and fast atom bombardment spectrometry (FAB/MS) and also by comparison with authentic compounds. Two intact glucuronide conjugates of FLU were isolated and identified as phase-II metabolites: 7-hydroxyfluphenazine ring glucuronide (glucuronic acid linked to the aromatic hydroxyl group of 7-hydroxyfluphenazine), and FLU glucuronide (glucuronide linked to the aliphatic group of the side chain of FLU) by HPLC and FAB/MS in comparison with authentic compounds. Further confirmed by FAB/MS were several sulfate conjugates of FLU that were isolated and identified indirectly as phase-II sulfate metabolites: FLU sulfate, 7-hydroxyfluphenazine sulfate and/or 7-hydroxyfluphenazine ring sulfate, and FLU sulfoxide sulfate by HPLC and FAB/MS; their aglycones were identified after sulfatase hydrolysis as FLU, 7-HOFLU and FLUSO. A further phase-II metabolite, for which no authentic standard was available, was tentatively identified as a monoglucuronide of dihydroxy derivative of FLU. To our knowledge, this report provides the first direct evidence of the presence of intact phase-II metabolites of FLU in rat bile.

Animals↗