A higher rate of congenital anomalies has been found after prenatal exposure to some combinations of antiepileptic drugs than to the separate drugs. In an earlier study a rate of 58% congenital anomalies was found among infants exposed to carbamazepine plus phenobarbitone plus valproate. In this study an attempt was made to determine whether this specific combination of drugs has teratogenic activity due to metabolic interaction. The epidemiological data were analyzed further. The high rate of congenital anomalies after prenatal exposure to this combination could not be explained by the effects of one or two of these drugs only, nor by additional exposure to phenytoin. Assuming that metabolic interaction in the arene oxide pathway resulting in accumulation of epoxide intermediates of antiepileptic drugs could be responsible for teratogenesis, the ratio of carbamazepine to carbamazepine-10, 11-epoxide concentrations in serum was determined in adult patients with epilepsy who were treated with carbamazepine only and with different combinations of phenobarbitone, valproate, and/or phenytoin. For carbamazepine monotherapy the mean ratio was 8.19. For all combinations lower ratios were found, indicating accumulation of carbamazepine-10,11-epoxide. The combination of carbamazepine, phenobarbitone, valproate, and phenytoin showed the lowest ratio (1.94), followed by carbamazepine, valproate, and phenytoin and by carbamazepine, phenobarbitone, and valproate (2.81 and 3.18, respectively). These results give rise to the question of whether the combination of carbamazepine, phenobarbitone, valproate, and/or phenytoin has teratogenic activity by accumulation of carbamazepine-10,11-epoxide or other epoxide intermediates, and stress the need to take metabolic interactions into account when investigating the teratogenic activity of antiepileptic drugs.

A double-blind randomized crossover design trial of carbamazepine (CBZ) and oxcarbazepine (OCBZ) was performed with 48 in-patients with epilepsy. All were stabilized on polytherapy including CBZ and had at least two seizures per week. CBZ was replaced by the trial medication. Each trial period started with a titration, followed by a 12-week steady state. Concomitant medications were kept constant during the trial. The criteria for assessment were seizure fit frequency and severity; tolerability; hematology and blood chemistry; plasma levels of antiepileptic drugs; EEG; cardiovascular parameters; and treatment preference. The following differences regarding OCBZ were detected: 9% reduction of the total number of seizures, with a significant reduction of tonic-clonic (20%) and tonic (31%) seizures; increased alertness and concentration ability in five patients; an allergic skin reaction with CBZ that completely disappeared in two patients while receiving OCBZ; an increase of valproate and phenytoin plasma levels in a number of patients, probably caused by reduced enzyme induction; a slight but significant reduction of serum Na, not causing clinical symptoms; less seizures than in the CBZ period in 25 patients (52%); and a preference for OCBZ in 23 patients (48%). We consider OCBZ at least as effective as CBZ with a slightly better tolerability. In severe cases, the wider therapeutic window might improve seizure control.

Summary: In our clinic intermittent side effects–particularly diplopia, drowsiness, and headache–were often seen during the use of carbamazepine. It was remarkable that the complaints were not mentioned spontaneously but had to be asked for very specially in order to track them. They did not correlate with the serum concentrations determined in blood samples taken in the morning. In 43 patients suffering from intermittent side effects and using carbamazepine in combination with one or more anticonvulsants, blood samples were taken and analysed every 2 hr from 8 a.m. to 6 p.m. There appeared to be rather rapid resorption: Each patient showed a more or less prominent increase in the serum level 2 hr after carbamazepine intake. In the course of the afternoon, a maximum was often reached that was attended by side effects. The fluctuations were rather large: The average minimal serum concentration was 5.0 mg/liter, (SD ± 1.4 mg/liter), the average maximal concentration 10.0 mg/liter (SD ± 1.6 mg/liter). Fluctuation from the average was 68.5% (SD ± 21.2%). We also examined 19 patients on monotherapy of carbamazepine. In this group, fluctuations were less: The average minimal concentration was 5.5 mg/liter, (SD ± 1.0 mg/liter), the average maximal concentration 7.8 mg/liter (SD ± 1.6 mg/ liter). Fluctuation from the average was 34.5% (SD ± 10.9%). In both groups the drug was administered three times a day in equal doses at 8 a.m., 12.30 p.m., and 8 p.m. After changing the scheme of intake in such a way that the serum levels did not exceed 8 mg/liter, the side effects disappeared. As a rule, the 12.30 p.m. dose was diminished. None of the patients showed an increase of seizure frequency after this change. RÉSUMÉ Nous avons sou vent observé dans notre clinique, des effets secondaires àĽusage de la carbamazépine, principalement sous la forme de diplopie, de somnolence et de maux de tête, qui surviennent de façon intermittente. Ces effets ne sont ďailleurs pas mentionnés spontanément par les malades et doivent être recherchés. De plus ils ne sont pas en relation avec la concentration sérique déterminee par un prélèvement sanguin du matin. Chez 43 malades présentant de tels effets et utilisant la carbamazépine en combinaison avec un ou plusieurs autres anti‐convulsivants, nous avons effectués les dosages sur des prélèvements effectués toutes les 2 heures de 8 heures à 18 heures. II est apparu une assez grande rapidité de résorption, chaque patient montrant une augmentation plus ou moins importante du taux sérique de carbamazépine deux heures après la prise du médicament. Dans le courant de Ľaprès‐midi on observait souvent un maximum qui correspondait aux effets secondaires. Les fluctuations étaient assez importantes: la concentration moyenne minimum étant de 50 mg/litre (SD ± 1.4 mg/litre) et la concentration moyenne maximum de 10.0 mg/litre (SD ± 1.6 mg/litre). Les fluctuations par rapport à la moyenne étaient de 68.5% (SD ± 21.2%). Nous avons également examiné 19 patients en monothérapie avec la carbamazépine. Dans ce gro...

People suffering from epileptic seizures are often confronted with restrictions resulting from their attacks, such as exclusion from several professions and from some sports, not being allowed to drive a car, and prohibition of alcohol. Consultation of manuals to trace the literature studies on which this last prohibition was based was unsuccessful since there was no mention of the original research from which it appeared that alcohol was provocative of seizures. To be able to give a well-founded judgment on the influence of social alcohol intake on epilepsy, research was undertaken with epileptic patients who had never before or very sporadically used alcohol. During 16 weeks, twice a week, in a clinical setting, 1-3 glasses of an alcoholic beverage were consumed within a period of 2 h. The examination could be carried out double-blind since the drink that was chosen, vodka, is odorless and cannot be tasted when mixed with orangeade. We concluded the following. (a) No influence of social alcohol use on tonic-clonic convulsions or partial complex seizures is demonstrable. (b) Blood levels of carbamazepine, phenobarbital, and phenytoin are not influenced by alcohol intake. The valproic acid concentration is possibly slightly increased. However, this needs further examination before judgment can be made. (c) Both in frequency bands and in the amount of epileptic activity, no change is produced by alcohol use.

In a group of 65 epileptic outpatients the reliability of intake of prescribed medication was evaluated according to two criteria. The following results were obtained: the number of patients with no or irregular intake of antiepileptic drugs in the whole group was 28 %; the relationship between dose and observed plasma levels in patients reliable to intake could be verified; physicians were more often aware of unreliable intake by their patients than could be expected by chance.