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T R Browne

Publications and source records attributed to T R Browne.

At least 73 records · Page 4Linked to original sources
PubMed1980

A mass spectrometric method for the determination of stable isotope labeled phenytoin suitable for pulse dosing studies.

A gas chromatographic mass spectrometric method has been developed for the determination in biological fluids of phenytoin (5,5-diphenylhydantoin), 5-(4-hydroxyphenyl)-5-phenylhydantoin (the major metabolite of phenytoin), and simultaneously, their stable isotope labeled analogs [5,5-diphenyl-2-13C-1,3-15N2-hydantoin and 5-(4-hydroxyphenyl)-5-phenyl-2-13C-1,3-15N2-hydantoin]. Quantification was achieved by an isotopic dilution technique: 5,5-di(pentadeuterophenyl)-hydantoin and 5-(4-hydroxy-3,5-dideuterophenyl)-5-phenyl-2-13C-1,3-15N2-hydantoin were used as internal standards. Molecular ion abundances of the permethylated derivatives were measured using a limited mass range repetitive scanning technique. The method is accurate, selective, reproducible and linear for analysis of 1.0 ml of serum and 0.5 ml of urine samples at the expected concentrations of drug (serum: 0.1-30.0 micrograms ml-1) and metabolite (serum: 0.1-10.0 micrograms ml-1; urine: 5.0-200.0 micrograms ml-1). The pharmacological equivalence of labeled and unlabeled phenytoin is demonstrated for a human volunteer. The results are discussed in the light of the further applications of the method, i.e. determination of the pharmacokinetics of a pulse dose of the labeled drug administered to patients who are taking a steady state dose of the unlabeled drug.

Animals↗
PubMed1978

Clonazepam.

Explore the source record for details and available documents.

Adult↗
PubMed1978

Drug therapy reviews: drug therapy of status epilepticus.

Drug treatment of status epilepticus is reviewed. Tonic-clonic, focal motor, complex partial and absence status epilepticus are discussed. In managing tonic-clonic status epilepticus one should: (1) maintain vital functions at all times, (2) identify and treat precipitating factors and (3) administer an intravenous loading dose of phenytoin sodium or phenobarbital sodium. Careful use of i.v. diazepam sometimes helps to achieve these objectives. Intravenous phenytoin sodium and phenobarbital sodium provide definitive, long-term control of tonic-clonic seizures but must be administered slowly and require time to reach peak brain concentrations. Intravenous diazepam appears to enter and exit from the brain rapidly and may control seizures while therapeutic brain concentrations of long-acting drugs are being achieved. Phenytoin, phenobarbital and diazepam should not be administered intramuscularly in treating status epilepticus. Treatment of focal motor and complex partial status epilepticus is similar to that of tonic-clonic status epilepticus, but i.v. diazepam is required less frequently and loading doses of phenytoin and phenobarbital sometimes can be given more slowly. Status epilepticus of the absence type is managed with i.v. acetazolamide sodium or diazepam. Paraldehyde, muscle relaxants, general anesthesia and lidocaine may be tried when conventional therapies fail.

Anesthesia, General↗
PubMed1978

Drug therapy reviews: clinical pharmacology of antiepileptic drugs.

The absorption, distribution, biotransformation, excretion and clinical pharmacokinetics of antiepileptic drugs are reviewed. Six guidelines for the therapeutic use of these drugs are given: (1) when therapy with an antiepileptic drug is initiated or when dosage is raised or lowered, the new steady-state drug serum concentration and the full effect of the dosage change will not occur for five elimination half-lives; (2) a loading dose is usually necessary to immediately achieve a steady-state serum drug concentration equal to the usual maintenance steady-state serum drug concentration; (3) the choice of dosage intervals for antiepileptic drugs is determined in part by the range of fluctuation in drug concentration between doses that is acceptable; (4) addition of a drug to an existing antiepileptic regimen may raise or lower the serum concentration of prior drugs by inhibition or induction of their metabolism; (5) if possible, make only one change at a time in an antiepileptic drug regimen; and (6) antiepileptic drugs should not be given by the i.m. route in emergency situations.

Absorption↗
PubMed1976

Clonazepam. A review of a new anticonvulsant drug.

Clonazepam is a new benzodiazepine anticonvulsant recently approved by the Food and Drug Administration for the treatment of typical absence, infantile myoclonic, atypical absence, myoclonic, and akinetic seizures. It is rapidly absorbed by the oral route and appears to pass quickly from blood to brain. Preliminary results indicate a biological half-life of 22 to 32 hours and a therapeutic serum concentration of 5 to 50 ng/ml. Many studies report tolerance to the anticonvulsant effects with chronic administration. Major side effects of the drug are drowsiness, ataxia, and behavior changes. They tend to be dose related, occur early in the course of therapy, and may subside with chronic administration. Accordingly, the dosage is begun at a low level and increased slowly.

Adult↗
PubMed1976

Hemangioblastoma of the spinal cord. Review and report of five cases.

Eighty-five cases of hemangioblastoma of the spinal cord are reviewed, including five new ones. While current views of the incidence, histology, and cytogenesis are presented, the main purpose of this article is to call attention to the identifying clinical and radiological characteristics of these spinal tumors. Median age at onset of symptoms was 30 years. The ratio of men to women was 1.1:1. Presenting symptoms were usually radicular pain or posterior column sensory loss or both. The lesions were most often single (79%), intramedullary (60%), and located in the cervical or thoracic spinal cord. There was associated syringomyelia in 67% of intramedullary cases and meningeal varicosities in 48% of all cases. Lindau disease and hemangioblastomas in other central nervous system locations were present in 33% of cases. The characteristic roentgenographic picture is a densely vascular tumor in association with a larger avascular syrinx and meningeal varicosities. Surgery is the only definitive treatment.

Adolescent↗
PubMed1975

Ethosuximide in the treatment of absence (peptit mal) seizures.

Thirty-seven patients with previously untreated absence seizures were treated with ethosuximide. Seizures were completely controlled in 7 patients (19 percent); 90 to 100 percent control was achieved in 18 patients (49 percent) and 50 to 100 percent control in 35 (95 percent). Plasma ethosuximide concentration increased with dose, but variability in the plasma concentration produced by a given ethosuximide dose made it impossible to predict a patient's plasma concentration from the dose. The therapeutic range of plasma ethosuximide concentration was 40 to 100 mug per milliliter. Patients with evidence of structural central nervous system abnormalities responded as well or better to the drug as patients without such evidence. Ethosuximide did not impair psychometric performance, but rather resulted in improved performance in 17 cases. The side effects of ethosuximide were minor, and rarely required withdrawal of the drug.

Adolescent↗
PubMedDate not supplied

Studies with stable isotopes I: Changes in phenytoin pharmacokinetics and biotransformation during monotherapy.

Six patients were given tracer doses of 13C15N2-phenytoin (PHT) before and four and 12 weeks after beginning monotherapy. The following significant (P less than .05) changes occurred during monotherapy: (1) Apparent (from tracer doses) PHT total clearance by linear method decreased; (2) apparent PHT elimination half-life increased; (3) apparent mean PHT serum concentration per unit dose increased; (4) apparent rate of excretion of p-hydroxyphenyl-phenylhydantoin (p-HPPH) decreased; (5) apparent rate of excretion of PHT dihydrodiol increased; and (6) apparent PHT total clearance and elimination half-life and apparent p-HPPH rate of excretion were dose dependent. Phenytoin apparent pharmacokinetic and biotransformation values undergo a typical series of changes after beginning monotherapy at typical dosing rates, because PHT's dose-dependent pharmacokinetics result in differing apparent values as the serum concentration rises to steady state. Stable isotope methods are particularly suitable for investigating such phenomena.

Adolescent↗
PubMedDate not supplied

Studies with stable isotopes II: Phenobarbital pharmacokinetics during monotherapy.

Six healthy adults receiving no other medications were given tracer doses of 90 mg of stable isotope-labeled phenobarbital (PB) intravenously before, and four weeks after, and 12 weeks after beginning therapy. Serum samples were collected for 96 hours after each injection, and the concentration of stable isotope-labeled PB in each sample was determined by gas chromatographic mass spectrometry. The volume of distribution, elimination half-life, and total clearance of PB did not differ significantly on any of the three occasions measured. Phenobarbital clearance did not correlate significantly with total PB serum concentration. Clearances determined from single-dose studies before beginning PB therapy accurately predicted steady-state PB serum concentrations. Therefore, it is not necessary to adjust PB dosage for time-dependent or dose-dependent changes in clearance during monotherapy. In addition, clearance or serum concentration determined at one dosing rate directly predicts serum concentration at another dosing rate.

Adult↗
PubMedDate not supplied

Studies with stable isotopes III: Pharmacokinetics of tracer doses of drug.

Stable isotope labeled tracer doses of phenytoin (PHT) and phenobarbital (PB) were given intravenously before and four and 12 weeks after beginning monotherapy in two groups of six patients. Phenytoin demonstrated nonlinear pharmacokinetics, while PB demonstrated linear pharmacokinetics. Each of the 36 sets of tracer dose serum concentration versus time data points appeared linear during the elimination phase on semilog plots, and each demonstrated a high degree of linearity using semilog regression analysis (r2 = .977-.999, P less than .001, for PHT; r2 = .791-.996, P less than .005, for PB). We conclude tracer doses administered at steady-state serum concentration will exhibit linear serum concentration versus time relationships on semilog plots regardless of whether the steady-state serum concentration is in the linear or the nonlinear portion of a drug's dose versus steady-state serum concentration relationship. The mechanism and implications of this conclusion are discussed.

Adolescent↗
PubMedDate not supplied

Staggered stable isotope administration technique for study of drug distribution.

By infusing intravenously a series of different stable isotope labeled forms of a drug at different times prior to performing a single collection of a body fluid via puncture (or tissue via biopsy), one can obtain the same information about a drug's distribution as would be obtained by infusing a single dose of drug and performing serial collections of fluid (or tissue). Application of this technique of "staggered stable isotope administration" is illustrated with a study of entry of phenobarbital into the cerebrospinal fluid of a dog. Advantages and disadvantages of this technique are discussed.

Animals↗