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Biomedical subjects

M A Seymour

Publications and source records attributed to M A Seymour.

12 recordsLinked to original sources
PubMed2000

Validation of population pharmacokinetic parameters of phenytoin using the parallel Michaelis-Menten and first-order elimination model.

This study was conducted to assess whether the parallel Michaelis-Menten and first-order elimination (MM+FO) model fitted the data better than the Michaelis-Menten (MM) model, and to validate the MM+FO model and its parameter estimates. The models were fitted to 853 steady state dose: serum concentration pairs obtained in 332 adults with epilepsy using nonlinear mixed-effects modeling (NONMEM). The MM+FO model fitted the data better than the MM model. The validity of the pharmacokinetic models and the estimated population parameter values was tested using the naive prediction method. The estimation and validation of the pharmacokinetic parameters were undertaken in two separate patient groups (cross-validation) obtained by splitting the data set. Patients were randomly allocated to two equally matched groups (groups 1 and 2). The predictive performance was assessed using 770 paired predicted versus actual dose or measured serum concentrations. The population pharmacokinetic parameters estimated by NONMEM in group 1 were validated in group 2 and vice versa. When predicting steady state serum concentration, the MM+FO model was clearly superior to the MM model (mean bias of 0.91 and 8.13 mg/L, respectively).

Adolescent↗
PubMed1999

Optimization of phenytoin therapy in adults with epilepsy in the Western Cape, South Africa.

OBJECTIVE: To assess the extent to which adults with epilepsy were optimized and individualized on phenytoin monotherapy in the Western Cape, South Africa and to estimate the average optimized dose and serum phenytoin concentration, and the therapeutic range for this patient group. METHODS: Patients were considered to be optimized on phenytoin if they were seizure-free or the best compromise was achieved between seizure reduction and side-effects. RESULTS: 538 (233 black and 305 coloured) adult people with epilepsy were treated at nine epilepsy clinics as outpatients. Of these patients, 332 (226 male and 106 female, 149 black and 183 coloured) were included in the data analysis as they were considered to have reliable phenytoin levels. Phenytoin doses and steady-state serum concentrations were predicted using the Michaelis-Menten equation. Patients attended a clinical pharmacokinetic service for 7.7+/-5.3 (range 1-22) months. The average optimized dose was 305.8 (range 100-500) mg/day and the average optimized level was 62.7+/-23.9 (range 15-133) micromol/l. Most patients (61.9%) were optimized in the therapeutic range 40-79 micromol/l; 21.1% were optimized above and 17% below this range. In 1.6% of patients serum concentrations above 120 micromol/l were required. Dosage adjustments were made in 47.0% of patients, increased in 31.9% and reduced in 15.1%. CONCLUSION: These findings indicate that many patients (47%) attending outpatient clinics were not optimized on phenytoin therapy.

Adolescent↗
PubMed1999

Factors influencing the population pharmacokinetic parameters of phenytoin in adult epileptic patients in South Africa.

The influence of various covariates (including weight, race, smoking, gender, age, mild-to-moderate alcohol intake, and body surface area) on the population pharmacokinetic parameters of phenytoin in adult epileptic patients in South Africa was investigated. The parameters were the maximum metabolic rate (Vm) and the Michaelis-Menten (MM) constant (Km) of phenytoin. The study population comprised 332 black and colored epileptic patients (note: "black" refers to indigenous people of South Africa, who speak one of the Bantu languages as their native language; "colored" refers to people considered to be of mixed race, classified as such by the apartheid former government of South Africa). The influence of covariates on Vm and Km estimates was determined using nonlinear mixed-effects modeling (NONMEM). Parameter models describing the factors that could potentially influence Vm and Km were tested using the Michaelis-Menten parallel MM and first-order elimination models, to which 853 steady state dose-to-serum concentration pairs were fitted. The results indicated that body weight, smoking, race, and age (65 years or older), in descending order of importance, significantly influenced Vm (p < 0.05). Although a significant difference (p = 0.03) in Km was found between black and colored patients, incorporating the influence of race in Km in the final regression model did not improve the fit of the model to the data, which indicated that the variability in Km was accounted for by Vm. The scaling factors for smoking, colored patients and age (65 years or older) in Vm were 1.16, 1.10, and 0.88, respectively. These factors should be taken into account when adjusting phenytoin dose.

Adolescent↗
PubMed1998

The use of stable carbon isotope analysis to detect the abuse of testosterone in cattle.

The use of stable carbon isotope analysis to detect the administration of anabolic steroids to cattle was investigated. Samples were extracted by solid-phase extraction on C18 cartridges. Stable isotope ratios (13C:12C) were measured by gas chromatography-isotope ratio mass spectrometry (GC-IRMS) of the underivatised extracts. A programmed temperature vaporiser (PTV) injector was installed in the GC-IRMS system, which conferred a number of advantages. First, it allowed large volumes of sample to be injected whilst the injector liner was cool. The solvent was subsequently vented to the atmosphere prior to transfer of the sample to the GC column. Thus a significantly greater amount of sample could be presented for analysis, thereby increasing the sensitivity. Second, by this means virtually all the solvent could be removed prior to analysis. This eliminates solvent peak tailing, which can be a major problem in GC-IRMS. Finally, the PTV allowed the use of higher initial GC oven temperatures, which in turn facilitated the analysis of underivatised steroids by reducing the GC run time and improving the chromatographic peak shape. The carbon isotope composition of 5 beta-androstane-3 alpha,17 alpha-diol, the major metabolite of testosterone found in bovine bile, was measured in bile samples from untreated cattle and from cattle injected intramuscularly with testosterone or a mixture of testosterone esters. There was considerable inter-animal variation in the values obtained and there was no significant difference between samples from treated and untreated animals. However, when the isotopic composition of the metabolite was normalised with respect to that of an endogenous reference compound (cholesterol) in the same sample, the difference between treated and untreated animals become statistically significant.

Anabolic Agents↗
PubMed1998

Study of the metabolism of testosterone, nandrolone and estradiol in cattle.

The current metabolism study was undertaken to identify key analytes in urine, plasma and bile following testosterone, nandrolone and estradiol administrations to cull cows, heifers and steers. This information will be used to develop confirmatory analysis procedures. In the present study, mixtures (1:1) of testosterone, nandrolone or estradiol and their deuterium labelled analogues were administered to cull cows, heifers and steers. Two analogues of deuterium labelled testosterone were synthesised and administered, to facilitate identification of metabolites. Following administration, urine, plasma and bile samples were collected and subjected to solid phase extraction. The extracts were derivatised and analysed by GC-MS. The major analytes derived from the administered steroids were identified on the basis of the twin ion peaks produced for their non-labelled and deuterium labelled analogues and their stereochemistries determined by comparison of retention times with appropriate reference standards. Using suitable internal markers, excretion profiles for the major analytes in urine and plasma have been determined and levels in isolated bile samples estimated. This work is on-going, and this paper is a summary of some of the studies completed to date.

Animals↗
PubMed1998

Residues and metabolism of 19-nortestosterone laurate in steers.

The illegal use of 19-nortestosterone (19NT; 4-estren-17 beta-ol-3-one; nandrolone) and its esters in livestock, for growth promotion purposes, has been widely reported in the European Union. The target residues for surveillance of abuse in bovine urine and bile samples are 17 alpha- and 17 beta-19NT, although this choice of target residues is not based on in vivo radiotracer biotransformation data. In this study, four steers were administered [3H2]- and [2H3] 17 beta-19NT laurate (2 mg kg-1 body mass) by intramuscular injection and blood, urine, faeces and bile samples were taken for 30 d until slaughter, after which tissues were sampled for total residue analysis. Total plasma radiolabelled residues reached a maximum of 56.3 +/- 15.9 pmol ml-1 at 36 h and were still appreciable (13.3 +/- 1.6 pmol ml-1) 30 d after treatment. Throughout the study period, total residue concentrations in bile (about 2-16 nmol ml-1), urine and faeces (0.5-3 nmol ml-1 or g-1) were higher than in other tissues sampled at slaughter. At slaughter there was evidence of residue accumulation in pigmented eye tissue (33.1 +/- 6.1 pmol g-1) and in white (13.4 +/- 3.4 pmol g-1) and black hair (28.9 +/- 8.9 pmol g-1). Evaluation of radio-HPLC profiles of urine and bile extracts generally indicated that 19NT and 19NT laurate residues were present in relatively small amounts among a complex mixture of metabolites. GC-MS analysis of glucuronidase-hydrolysed bile extracts indicated that the major metabolites were 5 beta-estrane-3 alpha, 17 alpha-diol, 5 alpha-estrane-3 beta, 17 alpha-diol. 5 alpha-estran-3 alpha-ol-17-one (norandrosterone) and estra-1,3,5(10)-triene-3,17 alpha-diol (17 alpha-estradiol).

Anabolic Agents↗
PubMed1998

Phenytoin auto-induction.

Information regarding phenytoin auto-induction is sparse and conflicting. However, confirmation of the presence or absence of auto-induction by phenytoin could have important implications in phenytoin therapy and research. This was an open, randomized, three-way crossover study in which each of the eighteen volunteers received three different formulations of phenytoin, which was allocated in a random order. The period effect between each crossover was determined to assess the effect of the previous exposure to phenytoin on the area under the concentration-time curve (AUC). The point estimate ratio of AUC(o-t) for the third dose relative to the first dose was 81.19% with 90% t-confidence limits of 74.37% to 88.00% and p = 0.3847. The point estimate ratio of AUC(o-infinity) for the third dose relative to the first dose was 76.25% with 90% t-confidence limits of 65.3% to 87.2% and p = 0.7169. These results suggest that the AUC (o-infinity) and AUC(o-t) measured after the third dose of phenytoin was statistically significantly smaller than those measured after the first dose. This decrease in AUC after the third dose of phenytoin is probably caused by enhanced elimination of the drug as a result of enzyme induction.

Adolescent↗
PubMed1998

Benefits of a clinical pharmacokinetic service in optimising phenytoin use in the western Cape.

OBJECTIVES: To study the benefits of a clinical pharmacokinetic service in optimising phenytoin use in the Western Cape. DESIGN: Assessment of the response to treatment was based on the number of seizures during the 3 months before entering the study (first baseline period), 3 months after entering the study (second baseline period) and 3 months before the termination of the study (test period). Patients kept a seizure diary throughout the study. The Michaelis-Menten model was used to calculate doses and predict steady-state serum concentrations. SETTING: Nine epilepsy clinics. SUBJECTS: One hundred and ninety-five (113 black and 82 coloured) compliant people with epilepsy receiving generic phenytoin monotherapy. OUTCOME MEASURES: Reduction in seizure frequency and adverse effects. RESULTS: A reduction in seizure frequency (64.8% compared with pre-optimisation) was experienced by 64.9% of patients. Mean seizure frequency was reduced from 3.39 to 1.18 per month. Reductions in seizure frequency of 100% and more than 50% were reported by 39.2% and 58.7% of patients, respectively. Adverse effects of phenytoin were reduced from 20.5% at the first visit to 3.2% at the last visit. CONCLUSION: The clinical pharmacokinetic dosing service for phenytoin applied in this study contributed significantly to the success of epilepsy management.

Ambulatory Care Facilities↗
PubMed1992

Anterior rectal wall hematoma: complication of transrectal ultrasound-guided biopsy of prostate.

Transrectal biopsy of the prostate, because of its directness and simplicity, is utilized by many practicing urologists to obtain prostatic tissue for histologic evaluation. Complications arising from this procedure are primarily of an infectious origin and less commonly of a vascular etiology. We report on the first known patient in whom a large hematoma of the anterior rectal wall with nearly total occlusion of the rectal lumen developed following a transrectal ultrasound-guided biopsy of the prostate. Guidelines to reduce the likelihood of vascular complications following biopsy of the prostate gland for patients consuming medications that may alter normal platelet function or interfere with the various clotting factors are described.

Aged↗
PubMed1981

Indomethacin or sulindac at night in rheumatoid arthritis.

The effects of indomethacin and sulindac in relieving troublesome morning stiffness and nighttime pain were tested in a double-blind cross-over trial. Thirteen of the 17 patients who completed the trial preferred indomethacin which was found to be superior to sulindac in all the parameters tested. Sulindac did, however, have some beneficial effect and can be used as an alternative to indomethacin when this drug cannot be used as the agent of first choice.

Adult↗