Search PubMed⌕ Search

Biomedical subjects

T R Browne

Publications and source records attributed to T R Browne.

At least 55 records · Page 3Linked to original sources
PubMed1988

Phenobarbital does not alter phenytoin steady-state serum concentration or pharmacokinetics.

Phenytoin pharmacokinetics and biotransformation were studied with stable isotope tracer techniques in six patients before and after addition of phenobarbital. No significant (p less than 0.05) changes in phenytoin serum concentration, clearance, elimination half-life, volume of distribution, or clearance via production of p-hydroxyphenyl-phenylhydantoin or phenytoin dihydrodiol occurred after addition of phenobarbital. Thus, frequent phenytoin serum concentration determinations or a change in phenytoin dosing rate are probably not necessary after adding phenobarbital.

Adult↗
PubMed1988

Carbamazepine increases phenytoin serum concentration and reduces phenytoin clearance.

Addition of carbamazepine to phenytoin monotherapy resulted in the following significant (p less than 0.05) changes: (1) increased mean phenytoin serum concentration; (2) decreased phenytoin clearance, due to decreased production of phenytoin dihydrodiol and p-hydroxyphenyl-phenylhydantoin; (3) increased phenytoin elimination half-life; and (4) increased drug-related toxicity. Close monitoring is required after addition of carbamazepine to phenytoin.

Adult↗
PubMed1987

Estimation of the elimination half-life of a drug at any serum concentration when the Km and Vmax of the drug are known: calculations and validation with phenytoin.

A method of estimating the elimination half-life of a drug at any selected serum concentration when the Km and Vmax of that drug are known is described. The method was validated in six patients by determining their Km and Vmax values for phenytoin, using data obtained at two serum concentrations and then using the Km and Vmax values to predict the elimination half-life of phenytoin at a third serum concentration. The predicted elimination half-lives at the third serum concentration did not differ significantly (t = 1.16, P = .30) from observed elimination half-lives determined with stable isotope tracer techniques.

Half-Life↗
PubMed1987

Determination of the in vivo Km and Vmax of a drug with tracer studies.

A method is described for determining the in vivo Km and Vmax values for a drug, utilizing a variant of the Michaelis-Menten equation and the elimination-rate constants of tracer doses of the drug administered at two different serum concentration values. The new method is the most accurate yet devised; unlike older methods, it is dependent on assumptions that generally are true and can be validated empirically. Application of the method is demonstrated by a study of phenytoin in humans.

Humans↗
PubMed1987

Vigabatrin for refractory complex partial seizures: multicenter single-blind study with long-term follow-up.

The irreversible GABA transaminase inhibitor vigabatrin (VGB) was given in a single-blind fashion to 89 patients with complex partial seizures (CPS) refractory to conventional drugs. The median number of CPS per month decreased from 11.0 to 5.0 after addition of VGB, and 51% of patients had a 50% or greater decrease in CPS frequency (p less than 0.001). Side effects (principally drowsiness, ataxia, and headache) occurred mainly during the initiation of therapy and decreased during therapy. After 12 weeks on VGB, side effects significantly interfered with functioning in only 13% of patients, and the efficacy:toxicity ratio warranted continued administration in 74% of patients. Coadministration of VGB resulted in a mean decrease of 20% in phenytoin serum concentration (p less than 0.001). Sixty-six patients with a favorable response to VGB during the single-blind study have been followed for a median of 16.7 months on VGB. No serious systemic or neurologic toxicity has been detected, and most patients have retained their initial favorable CPS control.

Aminocaproates↗
PubMed1985

Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures.

We conducted a 10-center, double-blind trial to compare the efficacy and toxicity of four antiepileptic drugs in the treatment of partial and secondarily generalized tonic-clonic seizures in 622 adults. Patients were randomly assigned to treatment with carbamazepine, phenobarbital, phenytoin, or primidone and were followed for two years or until the drug failed to control seizures or caused unacceptable side effects. Overall treatment success was highest with carbamazepine or phenytoin, intermediate with phenobarbital, and lowest with primidone (P less than 0.002). Differences in failure rates of the drugs were explained primarily by the fact that primidone caused more intolerable acute toxic effects, such as nausea, vomiting, dizziness, and sedation. Decreased libido and impotence were more common in patients given primidone. Phenytoin caused more dysmorphic effects and hypersensitivity. Control of tonic-clonic seizures did not differ significantly with the various drugs. Carbamazepine provided complete control of partial seizures more often than primidone or phenobarbital (P less than 0.03). Overall, carbamazepine and phenytoin are recommended drugs of first choice for single-drug therapy of adults with partial or generalized tonic-clonic seizures or with both.

Adolescent↗
PubMed1983

Clinical and EEG estimates of absence seizure frequency.

Absence seizure frequency was estimated in 20 patients (5 to 15 years old) before and after treatment with ethosuximide. Estimates were obtained from mothers' histories, observations by nurses, intensive observation by trained observers, physical and neurological examinations, routine EEG, and 12-hour telemetered EEG. Both before treatment (high seizure frequency) and after treatment (low frequency), telemetered EEG was the most reliable method of estimation, and intensive observation was the next best method. After treatment, the mothers' and nurses' estimates of seizure frequency were significantly less than the telemetered EEG estimates. The neurological examination and routine EEG were sufficient to diagnose absence attacks in all 20 patients and to determine if the attacks were completely controlled by therapy in all but two patients.

Adolescent↗
PubMed1983

Methsuximide for complex partial seizures: efficacy, toxicity, clinical pharmacology, and drug interactions.

Methsuximide (MSM; Celontin) was administered for 8 weeks to 26 patients with complex partial seizures (CPS) refractory to phenytoin and carbamazepine and phenobarbital or primidone. A 50% or greater reduction in CPS frequency was obtained in eight patients. MSM therapy was continued chronically in these eight patients, and five continued to have a 50% or greater reduction in CPS frequency after 3 to 34 months of follow-up. Drowsiness, gastrointestinal disturbance, hiccups, irritability, and headache were the common side effects of MSM. No serious toxicity occurred. N-desmethylmethsuximide was the principal substance detected in plasma and had the following pharmacokinetic values: accumulation half-life, 49.7 hours; time to steady state, 10.4 days; elimination half-life, 72.2 hours; therapeutic range of plasma concentration, 10 to 30 mg per liter. Plasma concentrations of phenytoin and phenobarbital derived from primidone rose significantly (p less than 0.05) after addition of MSM.

Adult↗
PubMed1982

Simultaneous determination of phenobarbital and p-hydroxyphenobarbital and their stable isotope labeled analogs by gas chromatography mass spectrometry.

A method suitable for pulse dosing studies is described for the quantitation by gas chromatography mass spectrometry of phenobarbital (5-ethyl-5-phenylbarbituric acid), p-hydroxyphenobarbital (5-ethyl-5(4-hydroxyphenyl)barbituric acid) and, simultaneously, their (13C15N2)-labeled analogs in serum and urine. Differently labeled analogs are used as internal standards (5-ethyl-5(2,3,4,5-tetradeuterophenyl)-2-(13C)barbituric acid for quantitation of phenobarbital, and 5-ethyl-5(4-hydroxy-3,5-dideuterophenyl)2-(13C)-1,3-(15N2)barbituric acid for p-hydroxyphenobarbital). In the procedure, the chemical work-up of the samples (1.0 ml for serum, 0.5 ml for urine) is based on an extractive methylation technique for the generation of the permethylated derivatives. The mass spectrometric measurement technique consists of repetitive scanning over a preselected mass region of the permethylated derivatives of the analytes as they elute from the gas chromatograph. The method is evaluated for serum concentrations ranging from 0.1-30.0 micrograms ml-1 for phenobarbital and 0.1-10.0 micrograms ml-1 for p-hydroxyphenobarbital, and for urine concentrations of both phenobarbital and p-hydroxyphenobarbital of 1.0-50.0 micrograms ml-1. Application of the method to determination of the pharmacological equivalence of phenobarbital and (13C15N2)-labeled phenobarbital in man is also demonstrated.

Carbon Isotopes↗
PubMed1982

Pharmacokinetic equivalence of stable-isotope-labeled and unlabeled drugs. Phenobarbital in man.

Stable isotope labeling of drugs has been used in human metabolism studies because it eliminates the risk of radiation exposure accompanying use of radioactive tracers. The labeled drug can be measured by gas-chromatographic mass spectrometry (GCMS). However, if reliable pharmacokinetic data are to be obtained, one has to be certain the rate of metabolism of labeled and unlabeled drug is the same, i.e., there is no kinetic isotope effect. To evaluate this for phenobarbital (PB), three humans were infused with a 1:1 mixture of phenobarbital and 1,3-15N2-2-13C-PB. Serum was collected at regular intervals. Concentrations of labeled and unlabeled phenobarbital were determined by GCMS. Within each subject, there was no trend for concentrations of labeled phenobarbital to be higher or lower than concentrations of unlabeled phenobarbital (P greater than 0.90 for all three subjects). There was no difference in the zero time intercepts, distribution and elimination time constants and half-lives, volumes of distribution and central compartment, or clearance of the two forms of phenobarbital. Thus, no isotope effect was found. Published data on other labeled drugs and the likelihood of encountering an isotope effect based on type of isotope and its location in the molecule are discussed.

Adult↗
PubMed1982

Improved isocratic liquid-chromatographic simultaneous measurement of phenytoin, phenobarbital, primidone, carbamazepine, ethosuximide, and N-desmethylmethsuximide in serum.

We describe an improved "high-pressure" liquid-chromatographic assay for simultaneous determination in serum of the five major antiepileptic drugs (ethosuximide, primidone, phenobarbital, phenytoin, and carbamazepine) and N-desmethylmethsuximide (the compound that must be quantitated for therapeutic drug monitoring of the antiepileptic drug methsuximide). Serum protein is precipitated with an acetone solution containing 5-ethyl-5-(p-methylphenyl)barbituric acid as the internal standard. The centrifuged supernate is injected onto the chromatographic column. Drugs and internal standard are eluted at 30 degrees C with mobile phase containing acetonitrile/methanol/phosphate buffer (17/28/55 by vol) at a flow rate of 0.7 mL/min, monitored at 195 nm. Analysis time is about 20 min. Quantitation is by measurement of peak areas. Analytical and absolute recoveries varied from 95 to 104%. Within-day coefficients of variation ranged from 1.6 to 5.4%, between-day CVs from 0.0 to 3.4% in subtherapeutic, therapeutic, and toxic samples. Resolution of therapeutic concentrations of all six drugs was complete. As yet, we have found no drug or drug metabolite that interferes.

Carbamazepine↗
PubMed1981

A gas chromatographic/mass spectrometric method for the simultaneous quantitation of 5,5-diphenylhydantoin (phenytoin), its para-hydroxylated metabolite and their stable isotope labelled analogs.

A stable isotope dilution method for the quantitation by GC-MS of 5,5-diphenylhydantoin, its major metabolite (5-(4-hydroxyphenyl)-5-phenylhydantoin), and, simultaneously, their stable isotope labelled analogs (5,5-diphenyl-2-(13)C-1,3-(15)N2-hydantoin and 5-(4-hydroxyphenyl)-5-phenyl-2-(13)C-1,3-(15)N2-hydantoin) is discussed and evaluated. 5,5-di-(pentadeuterophenyl)hydantoin and 5-(4-hydroxy-3,5-dideuterophenyl)-5-phenyl-2-(13)C-1,3(15)N2-hydantoin are used as internal standards. The chemical work-up procedure of serum (1.0 ml) and urine (0.5 ml) involves acid hydrolysis, extraction at pH 7.4 and permethylation of drug and metabolite analogs by extractive methylation. The mass spectrometric technique consists of repetitive scanning over the molecular ion region of the permethylated derivatives of the phenytoin and para-hydroxy metabolite analogs as they elute from the gas chromatograph. Molecular ion abundances are measured. Reproducibility, selectivity and linearity of the method are discussed in the light of the planned applications.

Carbon Radioisotopes↗
PubMed1981

Kinetic equivalence of stable-isotope-labeled and unlabeled phenytoin.

Stable isotope labeling (SIL) of a drug results in a higher molecular weight than that of the unlabeled drug. SIL tracer doses can be quantitated separately from unlabeled drug by gas chromatography-mass spectrometry (GC-MS) without exposing the patient to radiation. The higher molecular weight of SIL drug could cause a higher energy of activation for (and slowing of) metabolic reactions ("isotope effect"). To evaluate possible isotope effect, three dogs and three men were infused with a mixture containing equal amounts of SIL (2-13C-1,3-15N2) and unlabeled phenytoin (PHT). Plasma and urine were collected at regular intervals. Concentrations of SIL and unlabeled PHT and HPPH (the major metabolite of PHT) were determined by GC-MS. Within each subject there was no trend for concentrations of SIL PHT or HPPH to be higher or lower than concentrations of their unlabeled analogs (greater than 0.20 to 0.90). There was no difference in the distribution and elimination half-lifes (t 1/2s), volume of distribution, volume of central compartment, or clearance of the two forms of PHT. Thus, no isotope effect was found.

Animals↗
PubMed1981

Seizure disorders.

Explore the source record for details and available documents.

Activities of Daily Living↗