Estudio del índice nivel/dosis de la fenitoína en pacientes epilépticos voluntarios de Mérida / Study of the level/dose index of phenytoin in volunteer epileptic patients from Mérida

INTRODUCCIÓN La fenitoína es usada con mucha frecuencia en nuestro medio, por lo que se requiere hacer estudios de monitorización terapéutica, que contribuya a minimizar los efectos adversos y optimizar la terapia farmacológica. En ese contexto, nuestro objetivo ha sido determinar el índice nivel/dosis de la fenitoína en pacientes epilépticos voluntarios de Mérida. MÉTODOS Se realizó un estudio descriptivo, observacional y por reclutamiento consecutivo concurrente, conformado por 30 pacientes voluntarios con diagnóstico de epilepsia. Las muestras de suero se obtuvieron en niveles mínimos de pacientes que estaban en tratamiento con fenitoína durante 1 mes. Los niveles del fármaco se cuantificaron por el método de Inmunoensayo de enzima donante clonada en el equipo Indiko Thermo Scientific. RESULTADOS El índice nivel/dosis fue de 1,4 y 1,6, la concentración plasmática de 4,8mg/l y 8,0mg/l, la capacidad metabólica de 388,4 y 462,9mg/día, respectivamente en mujeres y hombres. Mientras que el nivel de la concentración plasmática en el estado estacionario fue de 6,5mg/l y 5,5mg/l, la dosis de carga máxima de 237,3mg y de 395,6mg, respectivamente en mujeres y hombres con epilepsia de la ciudad de Mérida. CONCLUSIONES Nuestros resultados sugieren que se debe individualizar la dosis en base al índice nivel/dosis de cada paciente, ya que no se puede extrapolar para todos los pacientes con epilepsia, debido a diversos factores como al fenotipo metabólico y al uso de fármacos inductores e inhibidores enzimáticos.

INTRODUCTION Phenytoin is used very frequently in our environment, so it is necessary to do studies of therapeutic monitoring, which helps to minimize adverse drug reaction and optimize pharmacological therapy. In this context, our objective was to determine the level/dose index of phenytoin in volunteer epileptic patients from Mérida. METHODS A descriptive, observational and consecutive concurrent recruitment study was carried out, consisting of 30 volunteer patients with a diagnosis of epilepsy. The serum samples were obtained in minimum levels from patients who were in treatment with phenytoin for 1 month. The levels of the drug were quantified by the method of donor enzyme immunoassay cloned in the Indiko Thermo Scientific equipment. RESULTS The level/dose index was 1,4 and 1,6, the plasma concentration of 4,8mg/l and 8,0mg/l, the metabolic capacity of 388,4 and 462,9mg/day, respectively in women and men. While the level of plasma concentration at steady state was 6,5mg/l and 5,5mg/l, the maximum loading dose of 237,3mg and 395,6mg, respectively in women and men with epilepsy of the city of Mérida. CONCLUSIONS Our results suggest that the dose should be individualized based on the level/dose index of each patient, since it can not be extrapolated for all patients with epilepsy, due to various factors such as the metabolic phenotype and the use of enzyme-inducing drugs and inhibitors.

Differences between the Measured and Calculated Free Serum Phenytoin Concentrations in Epileptic Patients

PURPOSE: The pharmacokinetics of phenytoin is complicated by genetic and environmental differences. It is, therefore, important to monitor the serum concentrations in patients who receive phenytoin. Because most of the phenytoin in serum is bound to proteins, the level of serum albumin influences the amount of free phenytoin. MATERIALS AND METHODS: We compared the measured and calculated free phenytoin levels in epileptic patients who were taking phenytoin monotherapy, using the Sheiner-Tozer equation. A total of 49 patients (30 men and 19 women; age range, 15 - 87 years) were included in the study and their trough serum phenytoin and albumin concentrations were analyzed. RESULTS: The linear correlation between free and total phenytoin concentrations was moderate (r = 0.822, p or = 20%) than observed in the normoalbuminemic (> or = 3.5 g/dL) group. CONCLUSION: In hypoalbuminemic patients, the measurement of free phenytoin level is necessary to properly evaluate the phenytoin level than that calculated from total phenytoin level.

Therapeutic drug monitoring of antiepileptic drugs.

Commonly used conventional antiepileptic drugs for pharmacotherapy in epilepsy are phenytoin, carbamazepine and valproic acid. These drugs have complex pharmacokinetic properties leading to fluctuation in their plasma level at given same therapeutic dose. The present study was done to monitor their plasma levels. A prospective observational study was conducted at National Public Health Laboratory. After taking detail history, blood samples were taken from epileptic patients of all age groups and both gender who were on usual therapeutic dose of one or two combined antiepileptic drugs. Plasma level of these drugs were analyzed by using Fluorescence Polarization Immuno Assay (FPIA) technique. Out of total 417 testing, 81 were tested for phenytoin , 241 for carbamazepine and 95 for valproic acid. Their levels were further analyzed to find therapeutic, subtherapeutic and toxic levels. Out of total 81 blood samples tested for phenytoin, 38.8% had plasma drug at therapeutic level, 38.8% at subtherapeutic level and 28.4% had toxic level. Carbamazepine was tested in 241 samples and 79.3% cases had at therapeutic drug level, 15.8% had subtherapeutic drug level and 4.9% had toxic level. Out of 95 samples tested for valproic acid, 62% had therapeutic level and 20% had subtherapeutic and 18% had toxic level of drug. Therapeutic drug monitoring of phenytoin showed wide fluctuation in its plasma level. Its toxic and subtherapeutic levels were quite high. It is suggested that the dose of phenytoin should be adjusted after regular plasma level monitoring only. Monitoring of carbamazepine and valproic acid were also helpful when their toxicity and efficacy are doubtful.

Drug and substance abuse in refractory epilepsy

Drugs and substances abuse in patients with refractor epilepsy were investigated in this study which includes 924 patients with intractable epilepsy were studied for serum levels of antiepileptic drugs and for drugs and substances abuse. Positive results for abuse were detected in 246 patients [26.62%], 56.5% of them were in the age group 20 - 30 years. Males outnumbered females with a sex ratio 1.46: 1. Cannabis was the first abused drug as it was detected in 29.27% followed by opiates in 21.95%, alcohol in 17.88%, benzodiazepine in 16.26%, tricylic in 8.54%, barbiturates in 6.1%. So, a screening test for drugs and substances abuse must be done in cases with resistant epilepsy even if patients deny the use of them

Relación entre niveles de carbamazepina en saliva y plasma: Estudio piloto / Saliva and plasma levels of carbamazepine have a poor correlation: a pilot study

Abstract: Carbamazepine is one of the most commonly used anticonvulsants for the treatment of epilepsy and its plasma concentrations must be monitored periodically to obtain a useful and safe clinical effect. There is not a good relationship between the dose of the carbamazepine and their effects in humans, but the effects of this drug have been well correlated with its plasma levels. Aim: To measure the correlation between plasma and saliva levels of carbamazepine in children with epilepsy. Material and Methods: Saliva and plasma levels of carbamazepine were measured by using instrumental planar chromatography in 11 epileptic children aged 8 to 15 years treated with the drug for at least six months. Results: The mean saliva/plasma ratio was 0.18±0.05 and the mean of carbamazepine concentration in saliva, expressed as a percentage of concentrations in plasma, was 17.97±5.40. There was a poor linear correlation (r =0.37) between the concentrations of carbamazepine in both fluids. Conclusions: In this group of epileptic children the correlation between saliva and plasma carbamazepine levels was weak.

A reverse phase high performance liquid chromatography method for simultaneous estimation of melatonin, carbamazepine epoxide and carbamazepine simultaneously in serum.

Monitoring of plasma antiepileptic drugs is useful for better clinical management in epileptic patients, particularly in children. Carbamazepine (CBZ) is one of the commonly prescribed anticonvulsants. The active metabolite of carbamazepine-carbamazepine-10-11 epoxide (CBZ-Epo) also exhibits anticonvulsant effect. The pineal hormone, melatonin exerts an anticonvulsant effect in experimental seizure models and recently has also been used in cases of childhood epilepsy. To facilitate the simultaneous plasma estimation of carbamazepine, carbamazepine epoxide, and melatonin, a new HPLC method was developed. Waters millennium 2010 chromatography manager with a 515 HPLC pump and Waters 24879 dual absorbance UV detector was used. A 25 microlitre of sample and standards were injected, and chromatographic separation was achieved by Merck C18 reverse phase column particle size 5 micro, 250 mm x 4 mm. It was quantitated at UV light 210 nm. The retention times of melatonin, CBZ-Epo, and CBZ were 6.3 min, 7.5 min, and 13.9 min respectively. The Mobile Phase used was water: acetonitrile (70:30), pH 3.0 adjusted with orthophosphoric acid at the flow rate of 1 ml/min. The limits of detection of melatonin, carbamazepine epoxide, and carbamazepine were 800, 500, and 1300 pg respectively.

Antiepileptic TDM pattern at a tertiary care hospital in India.

Therapeutic drug monitoring, a comparatively new investigational procedure in clinical pharmacology, is considered very beneficial to epilepsy patients though it increase the health care cost. Aim of this study was to determine the pattern of use of antiepileptic drug level monitoring over the last 7 years in our tertiary care centre and to critically comment on its utility. Retrospective data audit of archived data from 1998 to 2004 and age, sex, estimated levels of phenytoin, carbamazepine and phenobarbitone by HPLC were noted down, tabulated and compared. Chi square test was used for analysis. Three thousand five jundred thirty four blood samples of patients requesting for 4213 estimations of phenytoin, phenobarbitone or carbamazepine were received. Among the obtained samples, 44.0% (1058) were of children, 68.0% (2402) were of males, 0.6% (22) patients were getting 3 and 18.0% (635) getting 2, antiepileptic medications. 13.0% (546) samples showed level in the toxic range and 39.0% (1653) in lower range. There was increasing demand observed for estimation of antiepileptic drugs, over the 7 years. The number of abnormal values of phenytoin, phenobarbitone and carbamazepine did not show any significant difference over the years. The pattern was similar to that observed in other countries.

Disminución de ácido fólico y alteraciones cognitivas en pacientes con epilepsia tratados con fenitoína o carbamazepina, estudio piloto / Decrease of folic acid and cognitive alterations in patients with epilepsy treated with phenytoin or cartnabazepine, pilot study

Introduction. Phenytoin and carbamazepine were the antiepileptic drugs most frequently used in Mexico and throughout the world. Epileptic patients who take these drugs have a variety of collateral effects including the decrease of Mates plas-matic level. Low serie folie acid concentration has been associated with a decline in cognitive functions. The administration of a combined treatment with folie acid could ameliorate these difficulties. Objective.To describe the effect of the folie acid in the cognitive function in epileptic patients who take phenytoin and carbamazepine. Methods. We chose patient who have epilepsy and that are being treated with phenytoin, carbamazepine or both and formed two groups. The study group was treated with a daily dose of 5 mg of folie acid and the control group was administered placebo for a period of six months, with nine patients in each group of same age, sex, education level, epilepsy's evolution, frequency of seizures, EEG abnormalities and antiepileptic drugs plasma levels. We registered data at the beginning (basal) and at the end of the study. Results.Measurements of basal folie acid plasma levels in both groups were under the referential value. The neuropsychological assessment at the beginning (Mini-Barcelona test) showed a deficit in the verbal memory skills in both groups. After six months of treatment with folie acid (study group), the folie acid plasma level was 12.2 mg/mL (p < 0.01) higher than the basal value. Verbal memory test has improved with respect to the basal value (p < 0.05). The numbers of seizures and the plasma levels of the antiepileptic drugs remained unchanged. On the other hand, the group treated with placebo did not improve. Conclusion.Treatment with folie acid is safe and without side effects, it improved the cognitive function in patients with epilepsy treated with phenytoin and carbamazepine.

Introducción. La difenilhidantoína (DFH) y la carbamazepina (CBZ) son los antiepilépticos más empleados en México y en el mundo, los pacientes con epilepsia que emplean estos fármacos presentan una disminución en las concentraciones séricas de ácido fólico, una de las causas que pueden contribuir a un deterioro cognitivo, por lo que la terapia sustitutiva con ácido fólico pudiera mejorar estas alteraciones. Objetivo. Describir el efecto de la disminución del ácido fólico en la cognición de pacientes con epilepsia tratados con difenilhidantoína y carbamazepina. Material y métodos. Incluimos pacientes tratados con carbamazepina, fenitoína o ambos, con epilepsia. Formamos dos grupos: Un grupo experimental recibió ácido fólico 5 mg/día y otro grupo control recibió placebo durante seis meses, nueve pacientes en cada grupo; pareados en la edad, sexo, escolaridad, tiempo de evolución, námero de crisis, alteraciones EEG, niveles séricos de anticonvulsivos, realizamos estudios neuropsicológicos al inicio (básales) y al final del estudio a ambos grupos. Resultados. Las básales del ácido fólico en ambos grupos estuvieron por debajo del valor de referencias. En las pruebas neuropsicológicas (básales) (prueba de Mini-Barcelona) se halló un déficit en el área de la memoria verbal en ambos grupos. Después de seis meses de tratamiento con ácido fólico (grupo experimental) los niveles de ácido fólico alcanzaron 12.2 ng/mL (p < 0.01) con respecto a su basal; las pruebas de memoria verbal mejoraron con respecto a su basal (p < 0.05); el námero de crisis y los niveles séricos de los anticonvulsivos no se modificaron. El grupo con placebo no presentó ninguna mejoría. Conclusiones. El tratamiento coadyuvante con ácido fólico es seguro, libre de efectos adversos y mejoró las alteraciones cognitivas (memoria verbal) de estos pacientes.

Effect of nimodipine, a dihydropyridine calcium channel antagonist on the pharmacokinetics of carbamazepine in rhesus monkeys.

Calcium channel antagonists have been shown to have an anticonvulsant activity in a variety of seizure models and also to potentiate the anticonvulsant activity of other standard antiepileptic drugs like carbamazepine, phenytoin and valporoate. A pharmacokinetic interaction may be involved in such potentiation. This cross over single dose study was carried out to find out if there was a pharmacokinetic interaction between carbamazepine, a commonly used antiepileptic drug and nimodipine, a dihydropyridine calcium channel antagonist in rhesus moneys. Carbamazepine 46 mg/kg and nimodipine 9.6 mg/kg was administered through a nasogastric tube and blood samples were collected at 0.5, 1, 2, 3, 6, 9, 12, 24, 48, 72 and 96 hours after drug administration and were assayed for carbamazepine. Nimodipine caused a significant increase in peak plasma concentration (C(max)) of carbamazepine and a decrease in plasma absorption half life (t1/2 alpha). There was no significant change in other pharmacokinetic parameters between the two groups. The results of the study suggest that concurrent administration of carbamazepine and nimodipine may cause a significant rise in carbamazepine concentration as may contribute to a potentiation of anticonvulsant effect of carbamazepine and an increase in the incidence of adverse effects warranting that nimodipine should be prescribed cautiously in epileptic patients receiving carbamazepine and it might be very appropriate to do therapeutic drug monitoring of carbamazepine in such patients.

Simultaneous determination of some anticonvulsants in some pharmaceutical preparations and in serum by high-performance liquid chromatography

The separation and determination of some anticonvnlsant drugs were done in some pharmaceutical preparations and in serum by high-performance liquid chromatography reverse phase. The chromatographic condition were: mobile phase Acetonitril - Methanol - 0.06 M Potassium phosphate 25: 15: 60 W/W pH 4.0, column of octadecyle 5 mico [250 mm x 46 mm] Nucleosil with guard column. The extraction method was based on pharmacopia procedures for pharmaceutical preparations, and the technique used solid / liquid [SEP] for serum. This method permits the Simultaneous determination of all these compounds in pharmaceutical forms for different companies and in serum. Our method is simple and sensitive, based on qualitative and quantitative studies, the Coefficient regression was 0.9998 and Coefficient of variation was between 0.46% - l.t7% and the limit of detection was between 0.9%. Consequently our results showed a very good correlation and they were useful for quality control in the drug industries, the poisoning control centers and in medical laboratories

Association of drug levels & pharmacokinetics of carbamazepine with seizure control.

BACKGROUND & OBJECTIVES: A sizeable number of epilepsy patients remain uncontrolled with carbamazepine (CBZ) monotherapy. While the therapeutic plasma concentration range of CBZ is only vaguely defined, pharmacokinetic differences in the disposition of CBZ among subjects could be responsible for the inadequate control of seizures in some. This study was aimed at associating serum CBZ levels with seizure control and elucidating any pharmacokinetic differences between patients with controlled and uncontrolled epilepsy. METHODS: The study was conducted in 16 controlled and 15 uncontrolled adult epileptic patients receiving CBZ monotherapy for the previous 3 or more months, without any dosage change. Blood samples were drawn from the patients before and 0.5, 1, 2, 3, 4, 8, 12 and 24 h after ingestion of their total daily dose of CBZ. Serum CBZ levels were measured by HPLC and the pharmacokinetic parameters were calculated. RESULTS: The uncontrolled epileptic patients were receiving a higher daily dose of CBZ (difference not significant). The trough and peak serum CBZ levels were relatively higher in the uncontrolled group, and at no time point were the drug levels lower in these patients compared to the controlled group. The absorption kinetics, volume of distribution and plasma half life of CBZ were similar in the two groups. Thus, non-attainment or non-maintenance of therapeutic CBZ level or other pharmacokinetic difference was not responsible for occurrence of seizures in the uncontrolled patients. A high percentage of patients with generalised tonic clonic seizures (73%) and simple partial seizures (SPS) with generalisation (66%) were controlled by CBZ, while SPS and complex partial seizures (CPS) were largely uncontrolled. INTERPRETATION & CONCLUSIONS: It appears that pharmacodynamic resistance of the seizure to CBZ rather than pharmacokinetic factors is responsible for lack of efficacy of CBZ in nonresponding epileptic patients.

Simultaneous Determination of six Antiepileptic Drugs in Plasma Samples by High-Performance Liquid Chromatography / Simultaneous Determination of six Antiepileptic Drugs in Plasma Samples by High-Performance Liquid Chromatography

Determinação Simultânea de Seis Antiepilépticos em Amostras de Plasma por Cromatografia a Líquido de Alta Eficiência. Um método simples, rápido e sensível foi proposto para a determinação simultânea de carbamazepina, fenitoína, fenobarbital, peimidona e seus principais metabólitos em amostras plasma por cromatografia a líquido de alta eficiência. Acetonitrila foi adicionada às aoatras de plasma para precipitar as proteínas. Após a centrifugação, 100µL do sobrenadante foram transferidos para um tubo de ensaio cônico e evaporado à secura com N2. O extrato foi reconstituído com 100µL de água e 10µL foram utilizados para análises cromatográficas. A separação dos fármacos foi realizada em coluna analítica C18 (25cm x 4,6 mm D.I.x 0,5 µm partícula) com a fase móvel tampão fosfato pH 4,8 - acetonitrila - metanol (55:25:20 v/v/v). A detecção foi realizada com detector ultravioleta a 210nm

Salivary antiepileptic drug levels in Thai children.

A total of 123 patients were enrolled in this study. 88 patients were enrolled in the first stage of the study, which was to evaluate the commercial salivary collecting devices: Orasure and Omnisol. 35 patients were enrolled in the second stage of the study and were asked to spit whole saliva samples for further analysis of AED levels. Serum AED levels and corresponding saliva AED levels were paired and analyzed for the correlation coefficients with the linear regression model. None of the commercial salivary collecting devices can provide the linear regression correlation between the serum AED level and saliva AED level in all three AEDs studied. The correlation coefficients of serum and whole saliva AED levels of phenobarbital, phenytoin, and carbamazepine were highly correlated (r-squared were 0.981, 0.976, and 0.888, respectively). Saliva samples can be used clinically to monitor the AEDs level in phenobarbital, phenytoin and carbamazepine. This would be another alternative method of therapeutic drug monitoring that can be done painlessly and is easier in children than the blood sampling method.

Anti-epileptic drug intake adherence: the value of the blood drug level measurement and the clinical approach

It was evaluated the patient antiepileptic drug (AED) intake adherence in a pilot cross-sectional study carried out at a neurologic out-patient clinic of a university hospital. Ninety-three AED blood concentration (phenobarbital, phenytoin, carbamazepine) were analyzed from 24 patients. The variability of the AED blood level was measured (in the steady state period by means of the variation coefficient) and compared with the self-reported antiepileptic medication non-adherence. AED blood level according to the range (therapeutic or not), and the seizure control. It was not observed any strong correlation between the higher value of variability and the other three parameters of no adherence. The highest correlation was with the blood drug level (therapeutic or not). The evaluation of blood drug measurement alone, except in cases of extreme low adherence and variability of drug intake, is not enough for the recognition of incorrect drug intake, but the clinical markers and the self-reported adherence have to be also considered for this sort of evaluation.

Effect of Septilin--a herbal preparation on pharmacokinetics of carbamazepine in rabbits.

The study was carried out in rabbits, to see the effects of Septilin, a herbal preparation on the single and multiple dose kinetics of carbamazepine. Single dose treatment of Septilin significantly decreased t 1/2a. t 1/2e. AUCo-alpha of carbamazepine. Steady state Cmax and AUC0-24 of carbamazepine were also reduced significantly in comparison to those of control rabbits after 7 days co-administration of Septilin. We conclude that Septilin decrease/hinder the absorption process of carbamazepine through an unknown mechanism.

Carbamazepine-induced sinus node dysfunction

Carbamazepine, a drug used for the treatment of epilepsy and neuralgias, may exert hazardous effects on the cardiac conduction system. We report such a case of symptomatic brady-arrhythmia occurring in a 43-years-old male while on therapy with carbamazepine. Additionally, a literature review is made of previous cases of carbamazepine-induced sinus mode, AV node and His-Purkinje conduction disturbances

Effect of pregnancy on the pharmacokinetics of lamotrigine in rabbits

The effect of pregnancy on the pharmacokinetic profile of orally administered doses of lamotrigine was investigated in the rabbit. Pregnant rabbits were given lamotrigine [20 mg/kg, p.o.] daily for one week starting on day 19 of gestation. Similarly, non-pregnant rabbits received the same oral doses of lamotrigine for the same period. Plasma lamotrigine levels were monitored over a 24 h period using a high-performance liquid chromatographic [HPLC] method. Administration of lamotrigine to pregnant rabbits resulted in a significant increase [p < 0.05] in the maximum plasma concentration C[max] and the mean area under the plasma concentration - time curve [AUC] and a significant decrease [p<0.05] in total body clearance [CL/F] and volume of distribution at steady state [V d[ss]/F] as compared to those obtained for lamotrigine given to non-pregnant rabbits. No significant changes were observed in the mean time to reach maximum concentration T[max] and the elimination half-lives t[1/2] of lamotrigine between pregnant and non-pregnant rabbits. Our data suggest that the plasma concentrations of lamotrigine tended to be higher in pregnant than in non-pregnant rabbits. These findings may emphasize the importance of monitoring the plasma concentrations of lamotrigine during pregnancy and dose adjustments made as needed

Monitorizaçäo terapêutica de anticonvulsivantes / Therapeutic monitoring of anticonvulsant drugs

Refere-se a monitorizaçao de níveis plasmáticos de fármacos como um instrumento valioso para assegurar uma terapia com o máximo de eficácia e o mínimo de efeitos tóxicos, de maneira individual, uma vez que os efeitos terapêuticos e tóxicos säo melhores relacionados à concentraçäo plasmática do que à dose administrada. Os métodos analíticos freqüentemente utilizados na determinaçäo e quantificaçäo dos anticonvulsivantes säo a cromatografia em fase gasosa (CG), a cromatografia líquida de alta eficiência (CLAE) e as técnicas de imunoensaio (IFP). Realizou-se a determinaçäo de primidona (PRD); fenobarbital (FNB); fenitoína (FNT); carbamazepina epóxido (CBZe) nas amostras de plasma liofilizado através de CG, CLAE e EFP e comparou-se os resultados obtidos pelos métodos utilizados a fim de verificar se há concordância entre os mesmos. A comparaçäo foi realizada frente aos resultados enviados pelo Health Control - Cardiff.

High doses of carbamazepine for refractory partial epilepsy

Forty-eight patients with partial seizures were analysed during treatment with 1200 mg/d or more of carabamazepine (CBZ). Thirty-three were on monotherapy and fifteen on polytherapy. The other drugs, were kept unchanged in the patients on polytherapy. The dose of CBZ was increased if no control was observed and the patient had no side effects. The doses used ranged between 1200 and 1900 mg/day 91200 mg/day, n=18; 1300 mg/day, n=l: 1400 mg/day, n=7: 1600 mg/day, n=9; 1700 mg/day, n=4; 1800 mg/day, n=8; 1900 mg/day, n=1). Anticonvulsant plasma levels were taken to confirm patient compliance. The average plasma level was 9.6 ug/mL. The period of follow up varied from 3 to 96 months (M=25,6). Seizure's control was observed in 7 (14.48 per cent) patients taking 1200 mg/day and in 2 (4.16 per cent patients taking 1400 mg/day of CBZ. Thirty-nine patients did not show any control (81.21 per cent). Ten patients (20.81 per cent) had signs of intoxication. When patients have no improvement with 1400 mg/day, it is difficult to obtain any control despite the use of higher doses of CBZ, which frequently expose the patient to signiflcant side effects.