Patrick N. Friel

Zonisamide in epilepsy: a pilot study.

Summary: We compared zonisamide monotherapy (12 weeks) to carbamazepine monotherapy (12 Weeks) after phenytoin baseline monotherapy (8 weeks) in an open crossover pilot study of eight adults with uncontrolled partial seizures. Zonisamide had definite antiepilepitic activity in five subjects. In two of these, response to zonisamide was superior to that to either phenytoin or carbamazepine. A third subject became seizure free on zonisamide, but had to be withdrawn after 18 days because of mild stevens‐Johnson syndrome. The other three subjects were withdrawn from the study because of drug toxicity, manifested mainly by impaired higher mental function and increased seizures. The best response to zonisamide was at doses approximating 6 mg/kg/day, with plasma levels of 20–30 mg/L. Plasma levels of > 30 mg/L usually were associated with toxicity. the pharmacokinetics of zonisamide are complex and nonlinear, with steady‐state plasma levels being approximately three times higher than those predicted from a singledose study.

Pharmacokinetics of anticonvulsants in pregnancy: Alterations in plasma protein binding

Anticonvulsant levels decline as pregnancy progresses, even in the face of constant and, in some cases, increased dosages of medications. It has been suggested that this decline is responsible for the increase in seizure frequency seen in approximately one-third of the women with epilepsy who become pregnant. Changes in plasma protein binding may explain the declines in anticonvulsant concentrations during pregnancy. A prospective cohort study was designed to test this hypothesis. Carbamazepine, phenytoin and phenobarbital were studied. The mean total concentrations of all 3 drugs declined as pregnancy progressed, rising in the postpartum period. Free concentrations also declined, but did so significantly only for phenobarbital. The free fraction for all anticonvulsants studied rose significantly throughout pregnancy. Protein binding is significantly altered during pregnancy for all 3 drugs studied and appears to account for much of the decline in anticonvulsant concentrations seen in this condition. It is suggested that free rather than total drug concentrations be monitored in pregnant women with epilepsy.

Effects of polytherapy with phenytoin, carbamazepine, and stiripentol on formation of 4‐ene‐valproate, a hepatotoxic metabolite of valproic acid

The incidence of valproic acid hepatotoxicity has been reported to increase in patients who are receiving polytherapy. A minor valproic acid metabolite, 2‐propyl‐4‐pentenoic acid (4‐ene‐VPA), formed by a cytochrome P450‐mediated reaction, has been shown to be a potent inducer of microvesicular steatosis in rats. This study tested the hypothesis that formation of 4‐ene‐VPA would be increased in patients taking valproic acid with carbamazepine or with phenytoin but decreased with coadministration of an inhibitor of cytochrome P450 (the antiepileptic drug stiripentol in 300 to 1200 mg daily doses) in healthy subjects. Blood and urine samples in the studies were collected during a dosing interval at steady state. Valproic acid was assayed in plasma by capillary gas chromatography; valproic acid and 15 metabolites were measured in urine by gas chromatography/mass spectrometry. The formation clearance (CLf) of 4‐ene‐VPA was increased twofold in the valproic acid‐carbamazepine and valproic acid‐phenytoin groups. In the valproic acid/stiripentol studies, the CLf of 4‐ene‐VPA decreased by 32% in the 1200 mg/day stiripentol study. Similar findings were obtained at 600 and 300 mg/day stiripentol. These findings provide evidence supporting a role for cytochrome P450 in the formation of the hepatotoxic metabolite, 4‐ene‐VPA, in humans. The increased formation of 4‐ene‐VPA associated with carbamazepine and phenytoin is striking in relation to the epidemiologic finding of increased incidence of valproic acid–related hepatotoxicity during polytherapy with P450 inducers.

Carbamazepine--a double-blind comparison with phenytoin.

In a double-blind crossover study, carbamazepine and phenytoin were compared as single anticonvulsants in 47 patients with focal and major generalized seizures. Each drug provided superior seizure control in about half the patients, but significantly fewer patients had objective side effects while taking carbamazepine. Neuropsychologic testing showed improved performance in cognitive function and emotional status of patients while on carbamazepine. No hematotoxic complications arose, but vigilant follow-up is advised. Mean serum level of carbamazepine was 9.3 μg per milliliter with a suggested therapeutic range of 8 to 12 μg per milliliter, reached by eventual doses of 16 to 20 mg per kilogram. Carbamazepine offers an independent choice of improved seizure control with a possibility of fewer side effects.

Anticonvulsant level in saliva, serum, and cerebrospinal fluid.

Levels of four anticonvulsant drugs were measured simultaneously in saliva, spinal fluid, and dialyzed serum, i.e., free drug in serum. The level of diphenylhydantoin and possibly of carbamazepine was the same in the three body fluids. The level of phenobarbital was the same in spinal fluid and dialyzed serum, but was lower in saliva. The level of primidone was different in each body fluid. The technique is simple (flow of saliva stimulated when the subject chews candle wax or Teflon) and will be useful to determine the level of free diphenylhydantoin and carbamazepine, which is more closely related to intoxication or drug failure than is the total level of drug.

Effect of doxepin on seizure frequency in depressed epileptic patients

we performed a retrospective study of the effect of antidepressant treatment with doxepin on seizure frequency. From 47 patients treated with doxepin in 3 years, a confirmed seizure disorder and adequate follow-up (mean, 6.8 months) were available for 19 patients. Comparison of mean monthly seizure frequency during equal blocks of time before and during treatment with doxepin in doses of 5 to 400 mg/ day demonstrated improved seizure control in 15, no change in 2, and increased seizures in 2 patients. The reduction in seizure frequency may have been a result of a direct antiepileptic effect of doxepin, an indirect effect because of improved affective state, drug interactions, or some combination of these mechanisms.

Comparative pharmacokinetics of zonisamide (CI-912) in epileptic patients on carbamazepine or phenytoin monotherapy.

Zonisamide (CI-912) is an experimental antiepileptic drug. Since this drug is to be evaluated initially as an add-on medication, an investigation was conducted to study its kinetics in the presence of two standard antiepileptic drugs. Patients in two groups, one on maintenance phenytoin (PHT) monotherapy and the other on maintenance carbamazepine (CBZ) monotherapy, each received a single dose of four 100-mg capsules of zonisamide; and blood samples were obtained at periodic intervals. Plasma and red blood cell (RBC) concentrations of zonisamide were measured by high performance liquid chromatography. Plasma and RBC areas under the curve produced by single doses of zonisamide in patients receiving CBZ were significantly higher than those receiving PHT (p less than 0.05). Clearance values, although not statistically significantly different, were lower for the CBZ group; and consistent with this, plasma and RBC concentrations decreased more rapidly in the PHT group. The approximate values for t1/2 were 36.4 h in plasma and 54.2 h in RBC for patients treated with CBZ, and 27.1 h in plasma and 35.8 h in RBC for patients treated with PHT. The RBC/plasma ratio varied eightfold within a given curve. These findings suggest that the dosage of zonisamide in epileptic patients might need to be varied depending on the comedication.

Kinetics of phenobarbital in normal subjects and epileptic patients

SummaryThe kinetics of phenobarbital (PB) were evaluated in six normal subjects and six epileptic patients treated with phenytoin or carbamazepine. Each normal subject received three single doses of PB: PB-sodium 130 mg i.v. (IV), PB sodium 130 mg i.m. (IM), and PB acid 100 mg orally (PO), in random order at least one month apart. After IV PB distributive half-lives varied from 0.13 to 0.70 h, disposition half-lives were 75 to 126 h, steady state volume of distribution (Vss) was 0.54±0.03 l/kg, and clearance (CL) was 3.8±0.77 ml/h/kg. Absolute bioavailability of IM PB was 101±13%, of PO PB (corrected for dose) 100±11%. Peak serum PB concentrations were achieved from 2 to 8 h after IM administration, and from 0.5 to 4 h after PO administration. Epileptic patients exhibited similar PB kinetics: disposition half-lives were 77 to 128 h, Vss 0.61±0.05 l/kg, and Cl 3.9±0.76 ml/h/kg. Phenobarbital appears to represent an exception among antiepileptic drugs, in that pharmacokinetic data obtained in normals can reasonably be extrapolated to the epileptic population.

Quantitative assay for carbamazepine serum levels by gas-liquid chromatography

Abstract A gas-liquid Chromatographic method for determining carbamazepine serum levels from 0.5 to 10.0 μg/ml is presented. Carbamazepine was chromatographed directly; its absorption and decomposition were minimized by masking and neutralization of the column solid support and by use of a solvent of low dielectric constant. Acidic anticonvulsants were separated from carbamazepine by solvent partition, reextracted, and chromatographed separately as their N -methyl derivatives.

Serum prolactins in the diagnosis of epilepsy Sensitivity, specificity, and predictive value

Serum prolactin levels rise after generalized tonic-clonic and partial complex seizures, but not after pseudoepileptic seizures. The criteria for a significant elevation in serum prolactin vary with individual investigators. The prevalence of pseudoseizures in the population studied determines the predictive value of serum prolactin determinations. In populations where most patients have epilepsy, a rise in serum prolactin is highly predictive for true epilepsy, but no increase in serum prolactin is not predictive for pseudoseizures.