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Biomedical subjects

T R Browne

Publications and source records attributed to T R Browne.

At least 37 records · Page 2Linked to original sources
PubMed1991

Test performance characteristics of the serum phenytoin concentration (SPC): the relationship between SPC and patient response. The Veterans Administration Epilepsy Cooperative Study Group.

A retrospective analysis of Veterans Administration (VA) Cooperative Study No. 118 was conducted to examine the relationship between serum phenytoin concentration (SPC) and various measures of patient response in 111 patients on monotherapy, mostly after 12 months of treatment. Using patient response rating scales specifically developed and validated for the VA study, we plotted SPC vs overall composite score as well as vs each of the three component ratings of neurotoxicity, systemic toxicity, and seizure type and frequency. No statistically significant association was noted between SPC and any of the response measures. We also calculated test performance characteristics for using SPC and a therapeutic range of 10-22 micrograms/ml to categorize patient status with regard to overall response, toxicity, and seizure frequency. Test sensitivities (0.13-0.53), specificities (0.62-0.81), and positive predictive values (0.08-0.44) were much lower than desirable. This results in a large proportion of false-positive and false-negative errors associated with the use of SPC as a test. Our retrospective evaluation suggests that the range of SPC values in successfully treated patients is quite broad; the value of the commonly accepted SPC therapeutic range in predicting various measures of patient response is quite limited; and patient response, therefore, should be the ultimate end point in monitoring patients on phenytoin. Prospective studies of the relationship between SPC and response should be conducted.

Double-Blind Method↗
PubMed1991

Multicenter long-term safety and efficacy study of vigabatrin for refractory complex partial seizures: an update.

We followed 66 patients with refractory complex partial seizures and a favorable initial response to vigabatrin for 5 to 72 (median, 43) months. Thirty-seven patients discontinued vigabatrin for the following reasons: benefit-to-risk evaluation, 8; seizure breakthrough, 6; adverse events, 6; seizure breakthrough and adverse events, 5; moved or lost, 4; no longer eligible for study, 2; non-drug-related death, 2; narcotic abuse, 1; and patient request, three. There were no clinically significant abnormalities in laboratory studies including SMA 12, complete blood count, ECG, EEG, and visual evoked response testing, and no toxicity other than reversible, dose-dependent side effects. Based on this and other long-term data, clinical trials of vigabatrin have resumed in the United States and Canada.

Aminocaproates↗
PubMed1991

New pharmacokinetic methods for the study of antiepileptic medications of the 1990s.

New methods that will be useful in the study of the pharmacokinetics of both new and established antiepileptic drugs include stable-isotope tracer techniques for studies of absorption, elimination, and drug interactions; the microperfusion technique and the staggered stable-isotope administration technique for the study of distribution; and the correction of trough drug serum concentration values to mean serum concentration values. New pharmacokinetic methods for a study of drugs with new and unique properties include a double stable-isotope technique to deal with the unique pharmacokinetic properties of prodrugs and techniques for describing the biologic half-life of drugs that have a high affinity for active sites.

Absorption↗
PubMed1990

Simultaneous separation and determination (in serum) of phenytoin and carbamazepine and their deuterated analogues by high-performance liquid chromatography--ultraviolet detection for tracer studies.

The use of stable isotope-labeled tracer compounds is the safest and most effective method to perform many steady state pharmacokinetic and drug interaction studies. We describe a method by which the heavily deuterated 2H10 analogues of carbamazepine (2H10 CBZ) and phenytoin (2H10 PHT) can be chromatographically separated by high-performance liquid chromatography from unlabeled CBZ and PHT. All compounds are quantitated against an internal standard (IS) (10,11-dihydrocarbamazepine) and measured using conventional UV detection rather than mass spectrometry. Baseline resolution of extracted serum containing 2H10 CBZ, CBZ, 2H10 PHT, PHT and IS is achieved on a heated (55 degrees C) 25 cm x 4.6 mm BioAnalytical Systems Phase II 5 microns ODS column with an isocratic mobile phase consisting of water-acetonitrile-tetrahydrofuran (80:16:4, v/v/v) at 1.2 ml/min. Eluting compounds were monitored at a UV wavelength of 214 nm. Calculated resolution of 2H10 CBZ from CBZ and of 2H10 PHT from PHT were 1.3. Serum standard curves were linear (R greater than or equal to 0.999) over a range of 0.5-14 micrograms/ml for 2H10 CBZ, 0.5-20 micrograms/ml for CBZ, 0.5-20 micrograms/ml for 2H10 PHT, and 0.5-30 micrograms/ml for PHT. Within-day percent relative standard deviations (precision) were less than 6% in all cases.

Carbamazepine↗
PubMed1990

Simultaneous determination of p-hydroxylated and dihydrodiol metabolites of phenytoin in urine by high-performance liquid chromatography.

Accurate urinary measurements of the two major metabolites of phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) and 5-(3,4-dihydroxy-cyclohexa-1,5-dienyl)-5-phenylhydantoin (dihydrodiol, DHD), are necessary for pharmacokinetic and drug-interaction studies of this commonly used antiepileptic drug. We describe a simple, rapid, acid hydrolysis, with liquid-liquid extraction and simultaneous isocratic reversed-phase high-performance liquid chromatography of p-HPPH and 5-(m-hydroxyphenyl)-5-phenylhydantoin (m-HPPH) (hydrolytic end product of DHD). p-HPPH and m-HPPH were quantitated against their separate respective internal standards of alphenal and tolylbarb. The mobile phase consisted of water-dioxane-tetrahydrofuran (80:15:5, v/v/v) at 2 ml/min and at 50 degrees C, with detection at 225 nm. Baseline separation was achieved by use of a 16 cm x 3.9 mm Nova-Pak C18 column and total analysis time of 12 min. p-HPPH and m-HPPH concentrations ranged from 10 to 200 and from 2 to 30 micrograms/ml, respectively, with between-day coefficients of variations of 3.3-4.5% and 2.2-5.1% for controls. All standard curves were linear with r values greater than 0.993. The DHD concentration was determined by multiplying m-HPPH concentrations by 2.3.

Chromatography, High Pressure Liquid↗
PubMed1990

New pharmacokinetic methods. II: Determination of the presence or absence of product inhibition in drugs with nonlinear pharmacokinetics.

We show that for drugs metabolized by one enzyme the slope of a plot of serum concentration (C) versus 1/clearance (CL) is linear with a value of 1/Vmax in the presence of substrate saturation and may be linear (rarely) or curved (usually) with a slope always greater than 1/Vmax in the presence of substrate saturation and product inhibition (competitive, noncompetitive, or uncompetitive) when the serum concentration of product varies with the serum concentration of substrate. Serum concentration, CL, and Vmax were determined for a group of six subjects receiving phenytoin monotherapy using three approaches. With each approach: 1) a plot C versus 1/CL was linear (r greater than or equal to 0.738, P less than .01); 2) the slope of this regression line did not differ significantly (P greater than .30) from 1/Vmax. We conclude: 1) our method is a simple and useful method for determination of mechanism of a drug's nonlinear pharmacokinetics (substrate saturation versus substrate saturation and product inhibition), 2) phenytoin has nonlinear pharmacokinetics due to substrate saturation only in man.

Humans↗
PubMed1990

New pharmacokinetic methods: I. Estimation of mean serum concentration from trough serum concentration.

An equation is derived to estimate mean steady state serum concentration (Css) from trough steady state serum concentration (Cmin) which can be used for drugs with either linear or nonlinear pharmacokinetic properties. In 15 subjects receiving phenytoin monotherapy, estimated Css did not differ significantly from measured Css, while Cmin differed significantly (P less than .0001) from measured Css and estimated Css. Clearance (CL) and elimination half-life (t1/2) values determined by stable isotope tracer methods or by standard equations and measured Css or estimated Css did not differ significantly, while CL and t1/2 values calculated with standard equations and Cmin differed significantly (P less than .02) from values obtained by any of the other three methods. We conclude: 1) Cmin values and CL and t1/2 values calculated with Cmin values may differ significantly from Css values and CL and t1/2 values calculated with Css; 2) accurate estimates of Css and of CL and t1/2 can be obtained using our procedure to correct a Cmin value to an estimated Css value.

Half-Life↗
PubMed1990

New pharmacokinetic methods. III. Two simple test for "deep pool effect".

If a portion of administered drug is distributed into a "deep" peripheral compartment, the drug's actual elimination half-life during the terminal exponential phase of elimination may be longer than determined by a single dose study or a tracer dose study ("deep pool effect"). Two simple methods of testing for "deep pool effect" applicable to drugs with either linear or nonlinear pharmacokinetic properties are described. The methods are illustrated with stable isotope labeled (13C15N2) tracer dose studies of phenytoin. No significant (P less than .05) "deep pool" effect was detected.

Carbon Radioisotopes↗
PubMed1990

The pharmacokinetics of agents used to treat status epilepticus.

A thorough understanding of the pharmacologic properties of lipid-soluble drugs is essential when using these agents to treat status epilepticus. In addition to physiologic factors, such as blood pressure and cerebral blood flow, pharmacokinetic principles, including half-life, distribution, elimination, and volume of distribution (with special regard to an agent's lipid-solubility rating), should be applied. These factors, in toto, will influence the choice of drug, its loading dose, and its therapeutic dose.

Anticonvulsants↗
PubMed1989

A multicentre study of vigabatrin for drug-resistant epilepsy.

1. Vigabatrin (GVG) was given in a single-blind fashion to 89 patients with complex partial seizures (CPS) refractory to conventional drugs. 2. The median number of CPS per month decreased from 11.0 to 5.0 after addition of GVG, and 51% of patients had a 50% or greater decrease in CPS frequency (P less than 0.001). 3. Side effects (principally drowsiness, ataxia, headache) occurred mainly during the initiation of therapy and decreased during therapy. After 12 weeks on GVG side effects significantly interfered with functioning in only 13% of patients, and the efficacy: toxicity ratio warranted continued administration in 74% of patients. 4. Co-administration of GVG resulted in a mean decrease of 20% in phenytoin serum concentration (P less than 0.001). 5. Sixty-six patients having a favourable response to GVG during the single-blind study have been followed for 6-54 (median 33) months on GVG. Only 17 patients have dropped out of long-term follow-up due to break through seizures and/or side effects. No serious systemic or neurological toxicity has been detected.

Adult↗
PubMed1989

Bioavailability of ACC-9653 (phenytoin prodrug).

The bioavailability of phenytoin from ACC-9653 versus intravenously administered sodium phenytoin was determined using a crossover design for intravenous and intramuscular administration of ACC-9653 to healthy volunteers. Absolute bioavailability of phenytoin derived from ACC-9653 in each subject was calculated as the ratio of the phenytoin area under the plasma concentration time curve for time 0 to infinity [AUC(0-inf)] after ACC-9653 divided by the phenytoin AUC(0-inf) after intravenous sodium phenytoin. The mean absolute bioavailability of ACC-9653 was 0.992 after intravenous administration and 1.012 after intramuscular administration. These data establish that the bioavailability of ACC-9653 is complete following intravenous or intramuscular administration in single-dose volunteer studies. The absolute bioavailability of phenytoin derived from ACC-9653 in subjects with therapeutic plasma phenytoin concentrations is being studied in patients given simultaneous infusions of stable isotope-labeled tracer doses of ACC-0653 and sodium phenytoin.

Biological Availability↗
PubMed1989

Time course of carbamazepine autoinduction. The VA Cooperative Study No.118 Group.

We sequentially determined carbamazepine clearance values in 17 patients at the end of weeks 1, 2, 4, 8, and 12 of monotherapy. There were no significant differences among these clearance values. In 11 of 17 patients, week 1 clearance accurately predicted week 12 carbamazepine serum concentration (within +/- 33%). Our data indicate that carbamazepine autoinduction was completed within the first 1 or 2 weeks of monotherapy. Serum concentration values obtained after 1 week of monotherapy, using our dosing regimen, can be used to predict directly the dosing rate needed to obtain a specific serum concentration in most patients.

Adult↗