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Biomedical subjects

G M Shenfield

Publications and source records attributed to G M Shenfield.

At least 19 recordsLinked to original sources
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↗
PubMed1991

A screening test for slow metabolisers of tolbutamide.

1. Six subjects participated in a detailed pharmacokinetic study of tolbutamide (pilot study). Using parameters based on these data, sixty-three non-diabetic volunteers underwent a simple screening test designed to identify slow metabolisers of tolbutamide. 2. The screening test was an estimate of tolbutamide plasma elimination half-life from plasma concentrations at 8 and 24 h after 500 mg tolbutamide orally, and urinary recovery of the hydroxy- and carboxytolbutamide metabolites over the 4-8 h post-dose period. 3. The mean tolbutamide half-life for 61 of the screened subjects was 7.5 +/- 1.5 h (range 5.2-12.2 h). Two subjects had half-lives of 21.6 and 16.1 h. Their urinary metabolite recoveries were within the range of those in the screening test but lower than those in the pilot study. 4. The subject with the 21.6 h half-life was restudied with intensive serial sampling for 72 h post-dose. She was confirmed as a 'slow' metaboliser of tolbutamide since her terminal half-life was 25.9 h but plasma Cmax and tmax were within the range of those in the detailed study. This subject's 24 h urinary recoveries of both hydroxytolbutamide and carboxytolbutamide were clearly different from the mean values for the pilot study subjects implicating hydroxylation of tolbutamide as the metabolic defect. 5. The two point plasma half-life is therefore a discriminatory screening test but a 4-8 h urinary recovery is not. 6. A partial family study did not provide conclusive evidence of the inheritance of slow tolbutamide metabolism but the screening test should allow simple identification of slow metabolisers for further study.

Adolescent↗
PubMed1991

Clinical pharmacokinetics of contraceptive steroids. An update.

The present article should be read in conjunction with the original review published in the Journal in 1983. There is no new information of major significance about the pharmacokinetics of levonorgestrel, norethisterone (norethindrone) or ethinylestradiol, although it has been shown that the concentrations of these hormones secreted in breast milk are small and mothers taking combined oral contraceptive steroids may breast-feed safely. Both levonorgestrel and ethinylestradiol can be successfully administered from appropriate vaginal formulations, but no clear advantages over oral administration have been demonstrated. Several new progestogens have been investigated. Desogestrel is a prodrug for its active metabolite 3-keto-desogestrel, gestodene is itself an active progestogen and norgestimate is a prodrug acting by conversion to norgestrel and its metabolites. All 3 compounds have good bioavailability with wide intersubject variation. The newer progestogens, like norethisterone and levonorgestrel, are bound to sex hormone binding globulin (SHBG). This causes their plasma concentrations to increase with time, since SHBG is induced by ethinylestradiol even in doses of 30 micrograms daily. The binding capacity and affinity of SHBG do not increase in direct proportion to its concentration. Further drug interactions with oral contraceptive steroids have been described. Contraceptive steroids may inhibit hepatic microsomal enzyme metabolism and increase the plasma concentration and effect of some tricyclic antidepressants, the hydroxylated benzodiazepines, some beta-blocking drugs, methylxanthines, prednisolone and cyclosporin. There are no significant effects on vitamins. Oral contraceptive steroids induce glucuronidation and hence decrease plasma concentrations of some benzodiazepines, clofibric acid, paracetamol (acetaminophen) and possibly morphine. The plasma concentration of ethinylestradiol may be increased by competitive sulphation with paracetamol. Plasma concentrations of contraceptive steroids are decreased by griseofulvin, which induces their hepatic metabolism. The role of other antibiotics remains controversial but there is probably a group of susceptible women who have lower plasma contraceptive hormone concentrations and experience breakthrough bleeding or pregnancy when given broad spectrum antibiotics. This may relate to interruption of the enterohepatic recirculation of ethinylestradiol. Anticonvulsants, other than valproic acid, all induce contraceptive steroid metabolism and therefore lower plasma hormone concentrations, thus reducing contraceptive effectiveness.

Contraceptives, Oral, Hormonal↗
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

A screening test for detecting sulfonylureas in plasma.

Hypoglycemia induced by surreptitious sulfonylurea ingestion can be difficult to distinguish from an insulin-secreting tumor. We describe a technique for detecting most of the common sulfonylurea drugs in plasma. After preliminary acidification, and extraction in ether, the residue is reconstituted and injected onto a Versapack high-performance liquid chromatography column. Detection is at 230 nm. This procedure gives good separation of chlorpropamide, glibenclamide, gliclazide, glipizide, and tolbutamide. Results are semiquantitative but the sensitivity of the assay is sufficient to detect and identify clinically active concentrations of all five drugs. It is a rapid and reliable screening test. Four representative case histories are reported in which the screen proved to be of diagnostic value.

Aged↗
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↗
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↗
PubMed1985

Combination therapy with ranitidine and pirenzepine for control of intragastric pH in the critically ill.

In a prospective study of pH control for stress ulcer prophylaxis, intermittent iv infusion of the anticholinergic drug pirenzepine maintained the intragastric pH above 4 in only one of 17 ICU patients, while similar administration of the H2-receptor antagonist ranitidine was successful in seven of 32 patients. This difference was not statistically significant. Of 15 patients in whom a maximum dose of 600 mg/day of ranitidine or 90 mg/day of pirenzepine failed to maintain pH, combination therapy was successful in 11, a significant (p less than .01) improvement. We conclude that neither ranitidine nor pirenzepine provides adequate control of pH for stress ulcer prophylaxis when used alone. If used together they are the most effective combination so far described for parenteral control of gastric pH in the critically ill. Regular monitoring of gastric pH is nevertheless essential to allow detection of therapeutic failures.

Adolescent↗
PubMed1985

Randomized, prospective trial of cimetidine and ranitidine for control of intragastric pH in the critically ill.

Forty-eight critically ill patients in an intensive care unit were enrolled in a prospective study of stress ulcer prophylaxis. The H2-receptor antagonists cimetidine and ranitidine were used, patients being randomized on hospital number. Response was assessed by measuring gastric pH every 2 hours. The drugs were administered by intravenous infusion, and up to three dosage increments fo each of the drugs were titrated against the pH of the aspirated gastric juice. If one drug, in maximum dose, failed to maintain the pH above 4, the other drug was administered at maximum dose. If both drugs failed to achieve control of gastric pH, antacids were administered in an endeavor to ensure patient safety. Cimetidine was successful in maintaining the intragastric pH above 4, for the duration of the intensive care admission, in five of 28 patients. Ranitidine was successful in 10 of 20 patients. The difference between these two groups was statistically significant (p = 0.04). In patients in whom cimetidine therapy failed, ranitidine provided adequate control of pH in four of 13. Cimetidine controlled one of six patients who had failed to improve with ranitidine therapy. Plasma concentrations of both drugs were well above established acid inhibitory concentrations. However, even with much lower plasma concentrations of ranitidine, similar amounts of both drugs were present in the gastric juice, suggesting a possible explanation for the greater efficacy of ranitidine. We conclude that, although ranitidine is more effective than cimetidine, neither of these drugs is adequate for stress ulcer prophylaxis. If they ae used for this purpose in the critically ill patient, regular monitoring of gastric pH is essential to allow detection of therapeutic failures.

Cimetidine↗