Allan S. Troupin

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 MMPl 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.

Pharmacokinetics of carbamazepine in normal man

The bioavailability of commercial carbamazepine tablets with and without meals was compared to a propylene glycol solution with 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 significant range was also investigated. Serum and urine samples were assayed by gas‐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 (3 to 6 mcg/ml). The data were consistent with dissolution rate‐limited absorption. Mean half‐lives ranged from 31 to 35 hr. No dose‐dependent kinetics were observed following administration of doses of 3, 6, or 9 mg/kg. The fraction of dose absorbed, the fraction excreted unchanged in urine, the time of maximum 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 metabolites contributed to side effects.

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.

Effects of repeated administrations of a comprehensive neuropsychological battery among chronic epileptics.

Effects of repeated administrations of the neuropsychological battery originated by Halstead and developed by Reitan were assessed by administration of the battery on four occasions at 6− to 12-month intervals to 17 epileptics with stable neurological dysfunction. Changes in drug regimen complicated interpretation to some degree, but it appeared that: a) the majority of the neuropsychological measures did not demonstrate significant practice effects; and b) there were statistically and clinically significant practice effects on some of Halsteads most sensitive measures (Category Test, Tactual Performance Test—Localization. Impairment Index). In addition, the question was raised as to whether or not the Wechsler Adult Intelligence Scale may be more effected by the administration of anticonvulsants than are many of the other neuropsychological procedures. Caution was urged in interpretation when the battery is used on a repeated basis.

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.

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.

Carbamazepine and the electroencephalogram of epileptics: a double blind study in comparison to phenytoin.

In double blind crossover 4 month trials, carbamazepine was compared to phenytoin as sole treatment for 45 patients with uncontrolled partial and generalized epilepsy. EEGs performed at the end of these trials revealed that while using carbamazepine the patients manifested a significant overall increase in diffuse slow waves and an increase in generalized epileptiform discharges without significant accompanying changes in seizure incidence Also, during the carbamazepine trial generalized epileptiform discharges activated by hyperventilation were more frequent in patients with a higher seizure incidence compared to subjects with a lower seizure incidence or patients taking phenytoin. No significant focal EEG changes occurred.

Acute anticonvulsant effects of diphenylhydantoin, phenobarbital, and carbamazepine: a combined electroclinical and serum level study in amygdaloid kindled cats and baboons.

This preliminary study utilizing the kindling model of established epilepsy has provided information about the most effective routes of administration for diphenylhydantoin, phenobarbital, and carbamazepine in baboons and cats. The time of peak plasma levels for these drugs has been demonstrated in these animals so that experimental protocols can be designed to deliver the agents at appropriate times prior to the kindling stimulation. In addition, dose‐effectiveness data is presented for these species. In 1 baboon, phenobarbital was also seen to suppress photosensitive seizures. The potential usefulness of the kindling model in anticonvulsant research is suggested.

Sulthiame: Evaluation as an Anticonvulsant

A double‐blind crossover study showed that sulthiame as sole anticonvulsant was preferable to diphenylhydantoin in only 4 of 21 patients, and other patients had more seizures or unbearable toxicity on sulthiame. When the concentration of diphenylhydantoin in serum was increased and other anticonvulsants withdrawn, seizures were better controlled and side effects often diminished. Although the few patients benefited by sulthiame alone felt more alert, neuropsychologic tests showed that organic communications and intellectual processing deficits were accentuated. Hyperpnea could be troublesome. Previous favorable reports on sulthiame may have been due to the increase it causes in serum diphenylhydantoin when the two drugs are given together.