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Biomedical subjects

A J Wilensky

Publications and source records attributed to A J Wilensky.

14 recordsLinked to original sources
PubMed1992

Long-term treatment with gabapentin for partial epilepsy.

Gabapentin was studied as an open-label 'add-on' antiepileptic drug in 35 patients with partial seizures. Follow-up at 6 months, 12 months, 18 months, and 24 months is reported. There was a trend toward improvement in simple (SPS) and complex partial seizures with it reaching significance for SPS at 12 and 24 months and for the weighted combination of seizures at 3 months. Five of nine patients were subsequently successfully converted to gabapentin monotherapy. Of those five, one is now seizure free and three are significantly improved since baseline. One remains with unchanged seizure frequency compared to baseline, but is experiencing less toxicity than at that time. This long-term observation suggests that the short-term effect demonstrated in blinded studies continues and that indeed some patients with refractory epilepsy can be maintained on gabapentin alone. Based on these findings, double-blind monotherapy trials of this drug are presently being conducted.

Acetates↗
PubMed1979

Single-dose pharmacokinetics and anticonvulsant efficacy of primidone in mice.

The pharmacokinetics and efficacy of the anticonvulsant primidone (PRM) and its active metabolites, phenobarbital (PB) and phenylethylmalonamide (PEMA), were studied after single-dose administration in mice. The half-life of PB is twice that of PRM and PEMA. The plasma/brain ratios provide evidence of poor penetration of PRM into brain. The results support our findings of negligible or absent PRM concentrations in the brains of patients on primidone therapy who were undergoing surgery for intractable epilepsy. The anticonvulsant properties of PRM, PB, and PEMA against maximal electroshock in mice were also studied with the use of the metabolic inhibitor SKF 525A. The half-life, potency, peak anticonvulsant effect, and effective dose curves of these compounds indicate that the anticonvulsant effect of short-term oral PRM administration in mice is from derived PB.

Animals↗
PubMed1979

Clinical pharmacology of mephenytoin and ethotoin.

Effective prescribing of anticonvulsants requires foreknowledge of baseline pharmacokinetic data. Little such information is available about the hydantoins other than phenytoin, although one of them, mephenytoin, is widely used. Useful pharmacokinetic data should be derived from patients already exposed to anticonvulsants to reflect the induction of hepatic oxidative enzymes. Single-dose studies of mephenytoin (Mesantoin) and ethotoin (Peganone) were performed in adult inpatients on stable regimens of other anticonvulsants. Five patients received mephenytoin, 7 mg per kilogram of body weight. Serial blood sampling was performed rigorously. The time to peak concentration (Tmax) for mephenytoin was 1 hour, with a half-life (T 1/2) of 7 hours; the T 1/2 of its metabolite, 5-ethyl-5-phenylhydantion, was 96 hours. Ethotoin administration was 25 mg per kilogram in 5 patients. Ethotoin Tmax was 2 hours, with a T 1/2 of 5 hours. Saliva accurately represented the unbound fraction for all three agents. Mean salivary levels (as percentage of total levels) were 61% for mephenytoin, 73% for its metabolite, and 54% for ethotoin. The implications for therapy are that following mephenytoin administration, the metabolite 5-ethyl-5-phenylhydantoin will provide anticonvulsant effectiveness, with its long half-life producing stable blood levels on simple dose schedules. Ethotoin, in contrast, has a short half-life and would require divided daily doses to achieve a steady state. This, rather than pharmacological ineffectiveness, limits its usefulness.

Biotransformation↗
PubMed1979

Valproic acid-phenytoin interaction.

The interaction between valproic acid (VPA) and phenytoin (DPH) was examined during therapeutic monitoring in an epileptic outpatient population. Gas-liquid chromatographic methods were used to measure DPH and VPA concentrations. (1) In 12 patients on stable DPH regimens, the mean DPH level declined from 19.7 to 15.3 microgram/ml when VPA was added (p less than 0.001). (2) In 20 patients receiving DPH and VPA, the median free fraction was 15.8%, compared to 9.1% free DPH in 40 patients receiving DPH only or DPH and phenobarbital (p less than 0.001). (3) Addition of VPA to a stable DPH regimen may result in a transient increased risk of DPH toxicity, followed by restabilization at the original free DPH level.

Adult↗
PubMed1979

Evaluation of clorazepate (Tranxene) as an anticonvulsant--a pilot study.

Desmethyldiazepam--providing the long-term anticonvulsant effect when diazepam is given orally--is conveniently administered as clorazepate (Tranxene). In this study, clorazepate was compared to phenobarbital as a secondary anticonvulsant in eight ambulatory, adult outpatients. Stable doses of phenytoin were maintained throughout. Drowsiness was present in all on phenobarbital, but there were no clorazepate-related side effects. Seizure control did not differ for each treatment. Addition of common side effects of phenytoin and phenobarbital limited the attained serum levels of each when used together. Clorazepate doses in the 0.56-mg-per-kilogram range gave desmethyldiazepam levels in the 1.0-microgram-per-milliliter range. Induction of metabolism was suggested by falling desmethyldiazepam levels despite increasing doses. Clorazepate is an effective, nontoxic secondary anticonvulsant.

Adolescent↗
PubMed1979

A methods comparison: clonazepam by gas chromatography-electron capture and gas chromatography-mass spectroscopy.

Clonazepam is an antiepileptic drug for which a number of analytical procedures have been presented, none of which have been subjected to comparison studies. We present two gas chromatographic (GC) methods involving distinct forms of detection for determining plasma or serum drug levels. Both methods involve simple extractions, common GC conditions, and routine data reduction. Both employ nitrazepam as an internal standard, require 1 ml of sample, and have a detection limit of 1 ng/ml. The two methods, GC-electron capture and GC-mass spectroscopy, are precise and accurate. Correlation of the two methods paired sample analysis gave a regression equation of y = 0.988x - 0.14 (n = 30, r = 0.971, p less than 0.001). We suggest that either method is a reasonable alternative for the clinical laboratory with the proper instrumentation.

Benzodiazepinones↗
PubMed1978

Clorazepate kinetics in treated epileptics.

Clorazepate is decarboxylated to form desmethyldiazepam and is a convenient way of administering it. Its kinetics were investigated in epileptic patients after single oral and multiple oral doses. Peak serum concentrations of demethyldiazepam occurred in 0.5 to 1 hr. There appeared to be a brief lag before rapid absorption. Because of the rapid absorption with resulting high serum levels, daily doses should be divided. Serum concentration/time curves were best fitted by the two-compartment open model. The apparent t1/2 of the distribution phase was 1.28 +/- 0.44 hr and the t1/2 of the disposition phase was 40.8 +/- 9.96 hr. Serum concentrations rose after meals. Whole body apparent volume of distribution (VB/F) was 1.63 +/- 0.24 L/kg. Total plasma clearance was 34.4 +/- 7.2 ml/min, which is greater than clearance levels for desmethyldiazepam in normals and reflects the greater hepatic metabolism which occurs in treated epileptics. The discrepancy illustrates the hazards of extrapolating data collected in normals to patients with multiple drug exposures.

Adult↗
PubMedDate not supplied

Neuropsychological abilities before and after 5 years of stable antiepileptic drug therapy.

Detailed neuropsychological evaluations were conducted on 198 adults with epilepsy before and after a 5-year study period. Of these, three groups of 11 persons each were formed in which the patients did not change their medication: (a) phenytoin (PHT) monotherapy; (b) PHT and other drug(s); (c) drug regimens exclusive of PHT. The typical patient had few seizures during the study period. Examination of data from 20 neuropsychological and intellectual variables obtained at the beginning and end of the 5-year study period revealed few statistically significant changes in mental abilities and no losses. Thus, we were unable to find evidence for insidious cognitive losses with PHT and other drugs over time with normal therapeutic serum levels and in the absence of active seizure disorders.

Adult↗
PubMedDate not supplied

Effect of valproate dose on formation of hepatotoxic metabolites.

Valproate (VPA) therapy has been associated with a rare but fatal hepatotoxicity. 4-ene-VPA and 2(E),4-diene-VPA, unsaturated metabolites of VPA, are hepatotoxins several times more potent than VPA. In a previous study, a dose-dependent excretion of hepatotoxic metabolites was noted in patients receiving VPA. Our study was designed to evaluate the effect of dose on VPA metabolism under controlled conditions. Nineteen healthy volunteers sequentially received three different daily doses of VPA (250, 500, and 1,000 mg). Each dose was given twice daily for 4 days. Urine was collected for one dosage interval (12 h) at steady state for each dose and assayed for 15 VPA metabolites by gas chromatography/mass spectrometry (GCMS). Blood samples were also obtained from eight of the subjects, and VPA was assayed by GCMS. No effect of dose was noted on total plasma clearance. There was a significant dose-dependent decrease in intrinsic hepatic clearance. The intrinsic formation clearance (Clf) of the 4-ene-VPA pathway showed a statistically significant dose-dependent increase (0.22, 0.33, 0.40 ml/h/kg). The corresponding percentage of dose recovered as 4-ene-VPA and its sequential metabolites showed significant dose-dependent increases (0.15, 0.27, 0.62%). The role of VPA dose in the pathogenesis of hepatotoxicity may be more important than was previously believed.

Adult↗