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Biomedical subjects

J Boutagy

Publications and source records attributed to J Boutagy.

At least 19 recordsLinked to original sources
PubMed1994

Daunorubicin pharmacokinetics and the correlation with P-glycoprotein and response in patients with acute leukaemia.

The aim of this study was to examine the relationship between the pharmacokinetics of daunorubicin (DNR), overexpression of P-glycoprotein (Pgp) and treatment response in acute leukaemia. Twenty-seven patients with acute leukaemia received DNR as part of induction therapy. The plasma and cellular levels of DNR and its metabolite daunorubicinol (DOL) were determined using high-performance liquid chromatography. There were no significant differences between patients who went into complete remission (12/23) compared with those who did not respond for the following pharmacokinetic parameters: DNR and DOL plasma AUC (area under the curve) and DNR plasma half-life and clearance. There was a significant difference in the cellular DNR and DOL AUC between responders and non-responders (P < 0.02). Seven patients were Pgp positive and 18 Pgp negative. There was no correlation between patient response and the presence of Pgp (P > 0.1), nor was there any correlation between the cellular concentration of DNR or DOL and Pgp (P > 0.3). To our knowledge this is the first report examining the relationship between DNR pharmacokinetics, patient response and Pgp expression. Our data indicated that acute leukaemia patients responding to chemotherapy had higher cellular DNR and DOL than non-responders; also, overexpression of Pgp appeared not to be the sole explanation for the lower cellular DNR levels as expected from in vitro studies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Comparative and combined efficacy of doxazosin and enalapril in hypertensive patients.

Twenty patients with essential hypertension were randomised to a 7-week period of dose titration with doxazosin, 1-8mg/day or enalapril, 5-20mg/day. In a further 7-week period the dosage level reached with the initial drug was halved, and titration with the second agent was carried out. Blood pressure responses at the end of each treatment period were assessed by clinic measurements made 24 hours post-dose. In the first treatment period, enalapril (mean dose 19mg/day) reduced serum free ACE activity by 40% and had a greater effect than doxazosin (mean dose 5.2mg/day) on clinic supine blood pressure (systolic and diastolic). In the second period, the addition of enalapril to doxazosin was associated with a significant fall in clinic standing blood pressure (systolic and diastolic), despite the doxazosin dose reduction and consequent decrease in median plasma doxazosin concentration (from 10.6 to 5.2ng/ml). Alternatively, when doxazosin was added to enalapril, free ACE activity remained 40% decreased despite enalapril dose reduction, and blood pressure was not further affected. Plasma renin activity was increased by enalapril. No changes were observed in plasma aldosterone or lipid concentrations with either drug. The combination of doxazosin and enalapril was well tolerated and lowered blood pressure overall. Judged by clinic measurements 24 hours post-dose, most of the antihypertensive effect was attributable to the enalapril component. However, ambulatory blood pressure monitoring 0-12 hours post-dose in a subset of patients suggested a contribution of doxazosin earlier in the dose interval.

Acetylcholinesterase↗
PubMed1993

Determination of dexfenfluramine and nordexfenfluramine in urine by high-performance liquid chromatography using ultraviolet detection.

A method to determine the concentration of dexfenfluramine and its active metabolite nordexfenfluramine in human urine from healthy volunteers is described utilising a high-performance liquid chromatographic procedure with liquid-liquid extraction and ultraviolet detection. Analytes are measured after extraction of alkalinised urine with diethyl ether and subsequent back extraction with 0.5 M H2SO4 and with chromatography performed on a reversed-phase C18 column, using a mobile phase of acetonitrile-50 mM K2HPO4 (25:75, v/v) (flow-rate 1.3 ml/min) and ultraviolet detection at 210 nm. The sensitivity of the technique (10 ng/ml) is appropriate to measure both parent drug and metabolite in urine in humans for up to 5 days after a single 30-mg dose. The method is selective, reproducible (within- and between-day coefficient of variation ranged from 4.2 to 15%) and accurate (bias less than 8%) and thus suitable for dexfenfluramine pharmacokinetic investigations.

Chromatography, High Pressure Liquid↗
PubMed1991

Simplified procedure for the determination of sotalol in plasma by high-performance liquid chromatography.

A simple, specific and rapid reversed-phase high-performance liquid chromatographic (HPLC) procedure for sotalol determination is described requiring small plasma volumes. The high recovery of sotalol from plasma and the high precision of measurement obviate the need for an internal standard. Plasma samples (300 microliters) were deproteinised with 50 microliters of 70% (w/w) perchloric acid in disposable glass tubes. After vortex-mixing and centrifugation, 30 microliters of 4 M K2HPO4 were added followed by gentle shaking. A 20-microliters aliquot was then injected (by autosampler) for HPLC analysis. Chromatography was performed on a glass-lined 250 mm x 4 mm 5-micron C18 steel column. The mobile phase was 6% (v/v) acetonitrile in 0.08 M KH2PO4 buffer (pH 4.6). The flow-rate was 0.8 ml/min. Detection was by fluorescence with excitation and emission wavelengths at 235 and 310 nm, respectively. The retention time for sotalol was 7.1 min. Calibration was linear from 0.16 to 10 micrograms/ml in plasma (r greater than 0.999 for detector response to sotalol). The minimum concentration for quantitation was 0.08 micrograms/ml [within assay coefficient of variation (C.V.) less than 5%]. Recovery was near quantitative (greater than 98%) and replicate (intra-assay precision was less than 5% C.V.). Analysis of samples (n = 10) at concentrations of 0.42 and 4.2 micrograms/ml gave mean values of 0.44 and 4.3 micrograms/ml, respectively. The inter-assay C.V. values were 4.5 and 2.2%, respectively. Other clinically used antiarrhythmic drugs did not interfere. This assay can be performed using other commercial C18 analytical columns by suitable adjustment of mobile phase flow-rate and acetonitrile composition.

Chromatography, High Pressure Liquid↗
PubMed1990

The pharmokinetics of isradipine in hypertensive subjects.

In conjunction with a multicentre clinical trial of the calcium antagonist isradipine in hypertension, pharmacokinetic and pharmacodynamic studies were conducted in 9 subjects. An initial dose of 5 mg (capsule formulation) of isradipine was given orally. The mean Cmax, tmax and AUC(0-8) were 6.0 ng.ml-1, 1.5 h and 15.1 h.ng.ml-1 respectively. Seven subjects repeated the study at steady state after 10 week's dose titration with isradipine. Cmax, tmax and AUC(0-8) were 3.7 ng.ml-1, 1.2 h and 12.2 h.ng.ml-1 respectively indicating that the drug does not accumulate over time. Control of blood pressure paralleled plasma isradipine concentrations which suggested that the drug should be given at least twice daily. Pharmacokinetic studies performed in conjunction with clinical trials can provide valuable information about the patterns of drug response.

Adult↗
PubMed1990

Timing of blood pressure measurements in determining anomalies in duration of effect of an antihypertensive drug: assessment of isradipine.

Analysis of an antihypertensive drug trial, which involved measurements of blood pressure (BP) during visits to the clinic at a set time of day, showed that the initial dosage titration procedure had been inadequate in some patients. Plasma drug concentration-time curves and corresponding BP values suggested that control of BP was closely related to plasma drug concentration and that the duration of drug effect was shorter than the dosage interval of 12 h. This interpretation was supported by measurements of BP and drug concentrations taken at steady state, before and 2 h after taking the drug. Measurements of ambulatory BP revealed that some patients whose doses had been titrated at peak plasma drug concentrations had high BP at the time of trough plasma drug concentrations, whereas some of those titrated at trough times were hypotensive at peak times. Adjustment of antihypertensive therapy should entail observations of BP at times coincident with both peak and trough concentrations of the drug concerned, and can be facilitated by ambulatory BP monitoring.

Adult↗
PubMed1989

The metabolism of glyburide in subjects of known debrisoquin phenotype.

Ten normal subjects of known debrisoquin phenotype (six extensive (EM) and four poor (PM) metabolizers) were given of 5 mg glyburide (glibenclamide) suspension orally. Plasma glyburide and urinary cis-3-hydroxy-(30H) and trans-4-hydroxyglyburide (40H) were measured by a sensitive HPLC assay. No unchanged glyburide was detected in urine but both metabolites were identified in urine in all subjects. There were no significant differences in any respect with regard to glyburide metabolism or pharmacokinetics between EM and PM of debrisoquin. Estimated mean elimination half-life of glyburide was 3.3 +/- 1.1 hours for EM and 2.5 +/- 0.4 hours for PM. In one subject (EM), with reduced excretion of 30H, glyburide was detected in plasma at 24 and 30 hours and the apparent elimination half-life was 9.3 hours. There was no significant difference for total metabolite recovery between EM and PM. Eight of the subjects (six EM and two PM) had previously taken part in a study of tolbutamide metabolism, and a comparison of metabolic clearances by hydroxylation for the two sulfonylurea drugs showed no significant correlation. Glyburide is therefore unlikely to be metabolized by the enzymes that metabolize either debrisoquin or tolbutamide.

Adult↗
PubMed1988

Comparison of methylprednisolone (1 g i.v.) with prednisolone (1 g orally) in rheumatoid arthritis: a pharmacokinetic and clinical study.

Methylprednisolone pulse therapy is often used in patients with severe rheumatoid arthritis (RA). To compare clinical and pharmacokinetic variables of methylprednisolone and oral prednisolone in patients with RA, a controlled crossover study was carried out. Pharmacokinetic variables for methylprednisolone were Vd of 69.9 l, t1/2 of 2.96 h, total plasma clearance of 17.5 l/h. Pharmacokinetic variables for prednisolone were Vd of 47.5 l, t1/2 of 3.08 h and total plasma clearance of 11.3 l/h. During the elimination phase, a secondary rise in methylprednisolone concentration occurred which may be related to enterohepatic circulation. Clinical response to both prednisolone and methylprednisolone was short-lived with neither lasting more than 6 weeks.

Arthritis, Rheumatoid↗
PubMed1987

Lack of relationship between tolbutamide metabolism and debrisoquine oxidation phenotype.

The oxidative metabolism of tolbutamide was studied in 13 healthy subjects of known debrisoquine phenotype. Three were poor (PM) and ten were extensive (EM) metabolisers of debrisoquine. The mean values for total plasma clearance, elimination half-life, and metabolic clearance were 0.26 ml.min-1.kg-1, 3.4 h, and 0.17 ml.min-1. kg-1 in PM subjects and 0.22 ml.min-1.kg-1, 4.3 h and 0.15 ml.min-1.kg-1 in EM subjects. Total urinary recovery (% of dose) and ratio of hydroxy- to carboxytolbutamide were 69.4% and 0.219 respectively in PM subjects and 70.9% and 0.226 in EM subjects. There were no statistically significant differences between EM and PM metabolisers for any of these parameters. In addition there was no correlation between the debrisoquine metabolic ratio and tolbutamide urinary metabolite recovery or plasma clearance. These data indicate that hydroxylation of debrisoquine and tolbutamide are not catalyzed by the same enzyme. The ratio of hydroxy- to carboxytolbutamide in our subjects, and in other recent studies, suggests that some previous publications were inaccurate and their conclusions about the genetic control of tolbutamide metabolism were incorrect.

Adult↗
PubMed1986

Debrisoquine oxidation in an Australian population.

The standard laboratory method for determination of debrisoquine phenotype has been modified and shortened with no loss of sensitivity. Debrisoquine metabolic ratios (MR) at 4 and 8 h showed excellent correlation indicating that collection time can also be shortened. Same day phenotyping is therefore possible. One hundred normal, Caucasian Australian subjects were phenotyped (46 males, 54 females) and 6% were poor metabolisers (PM) of debrisoquine. Fifty of the original subjects were also acetylation phenotyped and 34% were fast and 66% slow acetylators. One PM of debrisoquine was a fast acetylator of sulphadimidine and four PM were slow acetylators. This was a non-significant association.

Acetylation↗
PubMed1986

The effect of glucose on acetylation status.

Forty-nine healthy volunteers (47 male, 2 female) had their sulphadimidine acetylator status determined on a control day and on a second occasion when they were given an oral glucose load. They were classified as fast and slow acetylators using the standard urine method and as fast, slow and intermediate acetylators using calculated metabolic and total body clearances. Twenty-seven (55%) were slow acetylators and this proportion was not altered by glucose loading either with or before sulphadimidine ingestion. On the control day, five (10%) were fast and 17 (35%) were intermediate acetylators but these sub-groups were not clearly distinguishable from each other when glucose was given. The glucose load did not cause any individual to change from slow to fast categories. Two type 2 (insulin independent) diabetics also showed no difference in acetylator status when studied with widely different blood glucose concentrations. We conclude that glucose can induce minor increases in sulphadimidine clearance but is unlikely to alter phenotypic acetylation status. Previous observations of an increased incidence of fast acetylators in diabetics may therefore indicate a genetic marker.

Acetylation↗
PubMed1986

Measurement of circulating sodium-pump inhibitory activity in uraemia and essential hypertension.

By measuring in vitro the effect of deproteinized plasma on canine kidney Na+K+-ATPase activity, evidence was sought for the presence of a circulating inhibitor of the enzyme in 31 patients with end-stage renal failure, 10 patients treated with digoxin, and 22 patients with untreated essential hypertension. In the renal failure group, mean Na+K+-ATPase activity with plasma samples taken just before a regular haemodialysis was 88% of that obtained with plasma from a normotensive control group (P less than 0.001). In digoxin-treated patients, the result was 94% of that obtained in control subjects (P less than 0.005). There was no significant difference in mean Na+K+-ATPase activity with plasma, between the hypertensive and control groups, or between age- and sex-matched subsets of these groups. The hypertensive group did not differ significantly from the control group in plasma renin activity or erythrocyte Na+ concentration. It was concluded that a circulating digitalis-like sodium-pump inhibitor was readily detectable in volume-expanded renal failure, but not in normal-renin essential hypertension.

Adult↗
PubMed1986

Pharmacokinetics and effects of isoxicam on renal function in patients with renal insufficiency.

The pharmacokinetics of isoxicam, a new non-steroidal anti-inflammatory drug, were studied in 20 osteoarthritis patients with varying degrees of renal insufficiency. A wide variation in pharmacokinetic parameters was seen between individuals but there was no suggestion that renal function influenced pharmacokinetics. Steady state plasma isoxicam concentrations varied from 20 micrograms/ml to 130 micrograms/ml, while the plasma half-life varied from 23 hours to 58 hours. Despite a reduction in urinary prostaglandin E2 excretion, isoxicam administration did not alter renal function over a 4-week period.

Aged↗
PubMed1985

Interactions between ethanol and oral contraceptive steroids.

We investigated the effect of oral contraceptive steroids (OCSs) on plasma ethanol disposition and tolerance to ethanol. Fifty-four healthy women between 18 and 40 years old were classified as light (31) or moderate (23) drinkers. Each group was further subdivided into controls (no OCS; 10 light, seven moderate drinkers), 30 or 35 micrograms estrogen OCS (14 light, 11 moderate drinkers), and 50 micrograms estrogen OCS (seven light, five moderate drinkers). Four of the subjects were studied on a second occasion, thus acting as their own controls with and without OCS use. All women were studied between days 14 and 21 of their pill/menstrual cycle. Plasma ethanol concentrations and two simple tests of motor function were measured for 6 hours after ethanol, 0.9 gm/kg in orange juice drank over a 30-minute period. The groups were well matched for age and weight. There were no significant differences between any of the six subgroups in mean peak plasma ethanol concentration, mean time to peak, mean AUC, or mean rate of ethanol disappearance. This was also the case for the four women who acted as their own controls. Analyses between those receiving high and low progestogen OCSs and between smokers and nonsmokers showed no significant differences. There was acute deterioration in functional performance as measured by two motor function tests in all subjects, regardless of OCS use. Moderate drinkers were significantly less functionally impaired than light drinkers whether with or without OCS use, indicating acquired tolerance. The mean degree of impairment and mean recovery time for both tests were significantly less in the OCS groups than in the control groups. The same trend was seen in the four women who were their own controls. Our results suggest that OCS use may induce some form of "tolerance" to ethanol. However, because there is no evidence of any change in ethanol disposition even at high plasma ethanol concentrations (greater than 100 mg/dl), women taking OCSs should not attempt to drink more than usual.

Absorption↗