Summary The antiepileptic effect of valproate sodium (VPA) versus that of placebo has been evaluated in a controlled clinical trial (double‐blind, crossover type). The concentration of VPA and that of other antiepileptic drugs in serum, as well as findings by EEG, were recorded in the course of the trial. When VPA was added to the conventional antiepileptic treatment, which preferably was maintained constant, the frequency of seizures was significantly reduced in 21 patients (60%); it remained unchanged in 7 (20%), and increased in 7 (20%). No correlation between a reduced frequency of seizures and the concentration of VPA in serum was observed. Nor was there any significant correlation between the clinical and the EEG ratings of the therapeutic effect. The adverse reaction most commonly encountered was fatigue associated with hypersalivation. Alopecia developed in 2 patients. When VPA was administered together with phenobarbital, the dose of the latter had to be reduced by approximately 30% if the serum concentration of phenobarbital was to be maintained at a constant level. When patients were treated with phenytoin, additional d o s e s of VPA brought about a decrease in the serum concentration of phenytoin even though doses remained unchanged. RÉSUMÉ On a øvalué l'action antiépileptique du sodium valproate (VPA) par rapport a Paction d'un placébo dans une étude contrôlée (en double‐aveugle). On a pris en considération les taux de VPA et ceux des autres drogues antiépileptiques et les données EEG. Si on ajoute du VPA à un traitement antépileptique de préférence inchingé il y a une réduction des crises, significative chez 21 sujets (60%) pas de modification chez 7 (20%), et une augmentation des crises chez 7 (20%). Il n'y avait pas de corrélation entre la diminution des crises et les taux sériques de VPA et entre les effets cliniques et les donndée EEG. Les effets fré‐quemment observés étaient une fatigabilityé et une hypersalivation; une alopécie est survenue chez deux patients. Si on administrait du VPA avec du phénobarbital, la dose de ce dernier devait être réduite d'environ 30% pour le garder dans des taux sériques constants. Si les patients étaient en traitement avec de la diphénylhydantoine l'addition de VPA deaterminait une diminution des taux de DPH. RESUMEN En un ensayo chínico controlado (tipo doble ciego crossover) se han valorado los efectos antiepilépticos del valproato sódico (di‐n‐propilacetato sódico, VPA) compareándolos con placebo. En el transcurso del ensayo se anotaron las concentraciones en suero de VPA y otros antiepilépticos a la vez que los hallazgos del EEG. Si el VPA se añadia al tratamiento anticonvulsive convencional, que se mantuvo constante, se re‐dujo significativamente la frecuencia de los ataques en 21 enfermos (60%), no se modificó en 7 (20%) y au‐mentó en 7 (20%). No se observó ninguna correlación entre la reducción de la frecuencia de los ataques y la concentración del VPA en suero. No se observó ninguna correlación significativa entre la valoración clínica y electroencefalog...

Clinical effects at three different serum levels of sodium valproate (VPA) were compared in a triple-blind, multiple crossover trial comprising 13 epileptic inpatients. Patients were selected regardless of seizure type, and all were in concomitant antiepileptic treatment, which was kept constant throughout the study. A significant relationship between the decrease in number of seizures and increasing VPA serum level was demonstrated. The relationship between VPA dose and serum level was curvilinear. Statistical evaluation of patients by seizure type in relation to clinical effect of VPA was only possible for secondary generalized seizures. Between phenytoin, phenobarbital, and carbamazepine and the different VPA serum levels no interactions could be demonstrated. Recorded side effects were always mild and transient. No obvious correlation between side effects and VPA serum level was established.

Summary A series of clinical‐pharmacological paramétérs implied in the compound valproate sodium (VPA) have been studied, e.g., the correlation between daily doses and attained serum concentrations of the drug during the steady state, the daily fluctuations in concentrations of VPA in serum, the half‐life of VPA after chronic treatment of patients, the degree of protein binding, and the ratio of VPA concentration in CSF to its concentration in serum. In addition, calculation of the half‐life of VPA after administration of a single dose to healthy volunteers has been attempted. In continuation of a controlled clinical trial where VPA was tested as an antiepileptic drug (Gram et al., 1977), the possibility of a correlation between the attained concentrations of VPA in serum and the clinical effects, including the adverse reactions, was evaluated. The half‐life was calculated to range between 8 and 10 hr, respectively, in patients whereas in healthy subjects it was found to be 8, 9, 10, 10, 11, and 15 hr. The ratio of VPA concentrations in CSF to concentrations in serum was détérmined. In patients, the protein binding was found to range from 84 to 95%. Notwithstanding that doses of VPA per kilogram of body weight were almost identical, its concentration in serum varied appreciably in the patients participating in the present trial. Any correlation between clinical effect, including the adverse reactions, and concentrations of VPA in serum was not demonstrable. In patients, the daily fluctuations in serum concentrations of VPA were pronounced throughout, although VPA was administered in four daily doses. Standardization of the time at which doses are given and blood samples drawn seems to be essential. RÉSUMÉ On a étudié pour le VPA, une série de paramètres clinico‐pharmacologiques, e.g., la corrélation entre les doses journaliéres et les concentrations sériques de la substance pendant le steady‐state, les variations journalières des taux sériques de VPA, la demi‐vie du VPA en traitement chronique, le degré de liaison avec les prolinés et le rapport de concentration VPA sérique et VPA dans le LCR. Par ailleurs on a essayé de cal‐culer la demi‐vie de VPA aprés une seule prise chez des sujets normaux volontaires. En continuation avec l'essai clinique contrôlé dans lequel le VPA était testé comme substance antiépileptique (Gram et al., 1977), on a évalué la possible corrélation entre les taux sériques de VPA et les effets cliniques, y compris les effets secondaires. Chez les patients, la demi‐vie était de 8 à 10 heures tandis qu'elle variait entre 8, 9, 10, 11, et 15 heures chez les volontaires normaux. Dans le Tableau 1, sont indiqués les rapports de VPA sériques et LCR. Chez les patients le degré de liaison protéique était entre 84 et 95%. Bien que les doses de VPA/kg de poids étaient presque identiques, les taux sériques de VPA étaient variables. RESUMEN Se ha estudiado una serie de parámetros clinicofarmacológicos implicados en el compuesto VPA, como por ejemplo: la correlación entre las dosis diarias y las concentr...