Carbamazepine (Tegretol) as an anticonvulsant. A controlled double-blind comparison with diphenylhydantoin (Dilantin).

A large double blind crossover study of carbamazepine (CBZ) in comparison to diphenylhydantoin (DPH) is underway, and the results are presented for the first 20 patients to complete the protocol. The importance of preparatory steps is outlined-beginning with the gathering of preliminary kinetic data about half-life and peak-time in epileptic patients. A detailed pilot study was performed with open administration of the agents and hospitalization during the crossover. Detailed blood level monitoring and dose-equivalence calculations lead to the design of blind crossover protocol from the pilot study. Of the 20 patients reported on at this point, 12 had fewer seizures on CBZ, but 4 of these preferred DPH because of the CBZ side effects. Of the 8 having fewer seizures on DPH, 3 preferred CBZ - leading to a final disposition of 11 on CBZ and 9 on DPH. Mean serum levels were 34.1 mug/ml for DPH and 10.6 mug/ml for CBZ. The patients having fewer seizures on DPH had higher serum DPH levels than those doing better on CBZ, but the opposite was found for the CBZ levels. The implications of this difference are discussed. Over all, DPH and CBZ are effective anticonvulsants of the same general magnitude, but individual patient responses to effects and side-effects will influence their usefulness in any given case.

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.

Pharmacokinetics of carbamazepine in normal man.

The bioavailability of commercial carbamazepine talbets with and without meals was compared to a propylene glycol solution respect to extent of absorption in 6 normal humans after a dose of 6 MG/KG. The presence of dose-dependent kinetics within a clinically sigificant range was also investigated. Serum and urine samples were assayed by gal-liquid chromatography (GLC). Carbamazepine is rapidly absorbed from the propylene glycol solution. Eight per cent of the dose was absorbed from the commercial tablet, resulting in therapeutic serum concentrations(30 to 6 mcg/ni). The data were consitent with disolution rate-limited absorption. Mean half-lives ranged from 31 to 35 hr. No dose-dependent kinetics were observed following administration of does of 3. 6. or 9 mg/kg. The fraction of dose abosrbed, the fraction excredted unchanged in urine, the time of maxium serum concentration, and absorption and elimination half-lives appear to be independent of dose. The time course of side effects could not be correlated with serum carbamazepine levels, suggesting that metabolities contributed to side effects.

Seizures and adaptive abilities. A case of identical twins.

The effects of seizures on performance were investigated in a pair of identical twins who were concordant for incidence of epilepsy, but who had highly contrasting histories of seizure frequency. An evaluation of abilities focused on intelligence, academic achievement, neuropsychologic functions, and emotional and social adjustments. While both twins showed some disabilities, the twin with the larger number of seizures was less able in every area examined. The results suggest that the greater seizure frequency is related to the lesser abilities.

Methysergide in the treatment of narcolepsy.

Five patients with narcolepsy (four with the allied symptom of cataplexy) were treated with the serotonin antagonist methysergide. All patients had as good control of their sleep attacks while on methysergide therapy as on a control period of dextroamphetamine therapy. The cataplexy was less well controlled by methysergide than by dextroamphetamine, but improved when compared to a period without medication. Two patients developed severe calf claudication while on methysergide.

Prophylactic effects of phenytoin, phenobarbital, and carbamazepine examined in kindling cat preparations.

Prophylactic effects of phenobarbital, phenytoin (diphenylhydantoin), and carbamazepine were examined in amygdaloid kindling preparations in cats. Daily electrical stimulation was delivered at the time of peak plasma levels. Comparative examination of the chronological pattern of the clinical seizure development, after discharge growth, and formation of distant independent spike foci was made between periods of kindling with chronic drug administration and of rekindling without drugs. Both phenobarbital and carbamazepine were effective, but phenytoin was totally ineffective. Prophylactic action of phenobarbital and carbamazepine was mainly through the suppression of the development of motor seizures manifestations in the former and the same with the development of sustained after discharge in the latter. The kindling preparation appears to possess many desirable features as an ideal model of human epilepsy for the purpose of assessment and recruitment of potential antiepileptic drugs and development of a rational pharmacotherapeutic approach for the management and prevention of seizure disorder.

Neuropsychological effects of carbamazepine and phenytoin: a reanalysis.

We previously reported that carbamazepine had fewer adverse neuropsychological effects than phenytoin, but it is now clear that our patients had much higher phenytoin than carbamazepine serum levels. When persons with high initial phenytoin levels were excluded, the statistical significance of all neuropsychological differences between the drugs disappeared.

Psychotropic effects of carbamazepine in epilepsy: a double-blind comparison with phenytoin.

The "psychotropic" effects of carbamazepine were evaluated with phenytoin (Dilantin) as reference agent in a counterbalanced, crossover study. Forty adult epileptics were given a series of neuropsychologic tests and the MMPI after 4 months on each agent. Most abilities were much the same with either anticonvulsant, but there were fewer errors with carbamazepine on mental tasks requiring attention and problem solving, and some improvement in emotional status was suggested. The findings were consistent with patient reports of improvement in alertness and mental functioning. These results combine with the excellent anticonvulsant properties of carbamazepine to support its use as an anticonvulsant.

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.

Clorazepate and phenobarbital as antiepileptic drugs: a double-blind study.

The antiepileptic effect of clorazepate when given with phenytoin was compared, in a randomized double-blind crossover study, to the effect of the standard regimen of phenobarbital plus phenytoin in patients with partial seizures. Thirty of 42 subjects preferred the clorazepate-phenytoin regimen (p less than 0.01). The same number of subjects had fewer seizures while taking clorazepate as had fewer seizures while taking phenobarbital. However, subjects had significantly more toxicity, objective and subjective, on the phenobarbital-phenytoin regimen (p less than 0.01 in both cases). In some subjects, increased toxicity due to phenobarbital outweighed better seizure control, so that clorazepate was preferred. As an add-on antiepileptic drug, clorazepate is well tolerated, effective, and preferred by most patients to phenobarbital.

Dose-related adverse effects of anticonvulsants.

The serum concentration at which a given drug has full efficacy in delivering seizure control bears no predictable relationship to the concentration at which adverse effects will appear. In theory, the threshold for adverse effects should be considerably higher than that for efficacy. For each agent this obviously happens most of the time, or the anticonvulsant would not be on the market, but there are also patients in whom this relationship is reversed. The adverse effects of this class of drugs are discussed from three points of view: the adverse effect type, the kinetic factors that so frequently determine the presence of adverse effects, and the specific characteristics of each drug. Some less well recognized adverse effects syndromes that are not strictly dose related are considered. The importance of adverse effects in therapeutic monitoring is then addressed, and some strategies for maximising efficacy without the burden of long term functional impairment or distress are discussed. The usefulness of monotherapy is stressed with due attention to rational choice of second drugs, when necessary, based on mechanisms of antiepileptic action and adverse effects profiles. While most of these symptoms evolve gradually, there are times when acute, drastic, and even life threatening clinical overdose situations present themselves. Special attention is given to these scenarios, drawing on the drug profiles and clinical pharmacokinetics that define these events to propose methods of coping with the problems efficiently and effectively.

The Louisiana State University Comprehensive Epilepsy Program: procedures and outcomes.

The first comprehensive epilepsy surgery center in Louisiana was established in 1990 at the Louisiana State University Medical Center in New Orleans by the Departments of Neurology and Neurosurgery. The center performs a wide variety of diagnostic tests essential for the medical and surgical treatment of epilepsy including EEG and video monitoring, quantitative hippocampal MRI volumetry, ictal SPECT brain scanning, intracranial evoked potential and subdural stimulation functional mapping, neuropsychological evaluations, and intracarotid amobarbital (Wada) language and memory localization. Surgical interventions include (1) the placement of subdural strip and grid electrodes, depth electrodes, and foramen ovale electrodes, (2) temporal lobectomies, and (3) frontal, temporal, parietal, and occipital lobe resections. From August 1990 through October 1995 41 patients with medically intractable seizures underwent neurosurgical procedures for epilepsy. Thirty-five patients had resective surgery, while six had only intracranial monitoring by subdural or intracerebral electrodes. The surgical outcomes thus far compare favorably with those of other established centers in North America.

Diagnostic decision. The measurement of anticonvulsant agent levels.

Monitoring levels of antiepileptic drugs is useful in formulating a therapeutic plan but not in making a diagnosis. Differences in assay methods are not important. Differences in therapeutic ranges do not reflect procedural differences but merely the source that is quoted. Therapeutic ranges are not absolute criteria for therapy, but guides to a clinical balance between dose and side effects. Because therapeutic ranges reflect trough (early morning) serum levels, clinical determinations should be done at this time. Serum drug determinations should be used to establish the successful drug level for a patient; assess compliance; identify the relative contributions of each drug to efficacy and to side effects in complex programs; identify bioavailability problems; and characterize idiosyncrasies in the rate of drug metabolism.

Clinical pharmacology of anti-epileptic drugs: a summary of current information.

This compendium represents what we believe to be the most current and reliable pharmacological data on anticonvulsant drugs. The information presented is derived from determinations of the drugs in plasma or serum by gas--liquid chromatography in studies of the efficacy of anti-epileptic agents. We present information on the limitations of therapeutic concentration ranges, half-lives, active and inactive metabolites, and structure/activity relationships of anticonvulsant drugs. This report provides answers to many of the questions clinicians direct to anticonvulsant-monitoring laboratories. Information on other pharmacoloical variables supplements this review in the interest of the clinical investigator.

Lingual myoclonus. Case report and review.

Myoclonus of the tongue is described for the first time as an isolated phenomenon and is related to the palatal-branchial myoclonus syndrome. Literature on the subject is reviewed. In the case which is presented the lingual myoclonus is seen to disappear, which is not the characteristic behavior of the palatal myoclonus syndrome. Since myoclonus of the tongue or palate is felt to represent a release of the primitive mechanism for integration of oral-pharyngeal movement from suprasegmental modulation, a sequence of events is proposed to explain the clinical findings on the basis of a discreet brain stem contusion at the upper medullary level.

A new centrifugal filtration device for free drug separation.

A new centrifugal membrane filtration device (Syva Corporation) has been evaluated to determine its capabilities for separation of free phenytoin for analysis. The device is a test tube-size cylinder with two compartments separated by the membrane. In serum samples from 70 patients at the Hospital of the University of Pennsylvania, free phenytoin was prepared by the new device and by equilibrium dialysis. Levels were assayed by gas chromatography and enzyme immunoassay with good agreement at all phenytoin levels. Although pH has a significant effect on the binding of some drugs to serum proteins, phenytoin binding increased to only a small extent as pH was increased from 7.0 to 7.8 (85-88.5% bound). Centrifugal filtration with this device is a reliable, fast, and easy way to prepare free drug from serum and does not include the dilution artifact inherent in equilibrium dialysis.

Paradoxical intoxication--a complication of anticonvulsant administration.

A new syndrome, paradoxical intoxication, has been defined in which high levels of hydantoins, and in one instance carbamazepine, produced an increase in seizures with little or no evidence of intoxication; a decrease in these levels produced an improvement in seizure control. This syndrome occurs often but not exclusively in those people who are less astute in assessing their neurologic status and therefore may experience unexpectedly higher blood levels of their anticonvulsants. Instances have been documented with serum levels above 40 mugm/ml for phenytoin or mephenytoin alone, or above 50 mugm/ml of combined hydantoins phenytoin and mephenytoin, and when the level is in the range of 20 mugm/ml and above for carbamazepine. Possible mechanisms underlying the syndrome are reviewed. Appropriate therapy is a reduction of the dose of the drug in question.