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.

Enteral nutrition and phenytoin administration in head trauma patients

Seizure is common after head trauma and neurosurgery. Phenytoin is the most common anti-convulsant drug used in epileptic patients and for prevention of seizure in patients with head trauma and stroke. This drug has unique pharmacokinetic and pharmacodynamic characteristics. Phenytoin administration along with enteral nutrition in ICU patients may be accompanied by decreased phenytoin absorption and inadequate therapeutic concentration. The present study was performed to assess the effect of enteral nutrition on the pharmacokinetic therapeutic parameters of phenytoin given to our patients. In a clinical trial, the study group was divided into two groups of 15 patients each. After obtaining steady-state phenytion serum concentration, two blood samples were obtained from each patient on 2 consecutive days and then analyzed. The mean was assessed on the basis of serum albumin level of the patient. Clearance and maximum metabolic capacity were also calculated. Serum phenytoin level was below the therapeutic range [10- 20 mg/l] in 70% of patients in group 1 and was higher than the therapeutic range in 70% of patients in group 2 who received oral phenytoin [by dissolving in water] 2h after enteral nutrition. Mean phenytion concentration was 6.3 +/- 4mg/l and 24.7 +/- 9.4mg/l in group 1 and group 2, respectively. We found oral phenytoin administration with enteral nutrition [gavage solutions] to result in a significant decrease in absorption and blood concentration of phenytoin. We recommend administration of phenytoin with water only. In addition, monitoring of phenytoin serum concentration is necessary for assessment of therapeutic concentration and prevention of side effects

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.

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.

Fluctuating phenytoin levels in a patient with epidermolysis bullosa dystrophica

Epidermolysis bullosa dystrophica being a genetically determined disorder, and when other factors that could cause fluctuations in the serum phenytoin levels are being eliminated, it is likely that the wide fluctuations of phenytoin in the blood could be a pharmacogenetic variation. The only course of action left in such patients could be to monitor the drug frequently and ensure that the levels are within the therapeutic margin

Seguridad de la lactancia en hijos de mujeres que reciben fenitoina / Safety of breast feeding in children of women with intake phenytoin

Antecedentes. La fenitoína (DFH) está indicada durante el embarazo para controlar las crisis convulsivas. Además del riesgo teratogénico que implica su administración en esta etapa, se excreta en leche materna y sus efectos en el lactante preocupan al médico y a la madre. Objetivo: medir la excreción de DFH a través de la leche materna en mujeres durante diferentes etapas de posparto y determinar si varia su eliminación por los cambios fisiológicos que sufre la madre en este periodo. Material y métodos: se midió la concentración de DFH en plasma y leche de 20 mujeres en los 5, 15, 30, 45 y 60 del posparto. La obtención de las muestras se realizó en la predosis y antes de lactar y a las 2, 3, 4, 5 y 8 horas posdosis. La concentración de DFH se determinó por la técnica de Inmunoanálisis Enzimático. Resultados: la concentración máxima en plasma fué de 10.2 ñ 5.8 µg/mL a las 4 horas posdosis y de 2.71 ñ 1.94 µg/mL en leche durante el primer día, sin presentar diferencias estadísticamente significativas con los demás días de estudio. El índice de excreción de leche fue de .034 a .129. El cálculo de las dosis que recibirá un recién nacido que consume cada tres horas un promedio de 50 mL de leche varió de 0.022 a .190 mg/Kg/día de DFH, dosis inferior a la recomendada en lactantes con crisis convulsivas. Los valores del área de bajo la curva en plasma y la vida media de eliminación fueron mayores en los días 45 y 60 (p<.05), lo opuesto se observó en le volumen de distribución y depuración , encontrandose los valores más altos durante los primeros días de estudio. De acuerdo a nuestros resultados no se justifica suspender la lactancia materna en hijos de mujeres que esten recibiendo DFH para el control de sus crisis convulsivas, ya que la lactancia materna en este tipo de pacientes es segura durante toda esta etapa del posparto

Determination of phenobarbital, phenytoin and carbamazepine in human serum: comparison of fluorescence polarization immunoassay with high performance liquid chromatography

A simple high performance-liquid chromatography [HPLC] method for simultaneous determination of antiepileptic drugs i.e., carbamazepine, phenobaebital and phenytion in human serum is described. The procedure involves deproteinization of serum with acetonitrile containing phenacetin as an internal standard prior to injection onto the chromatograph. The drugs were eluted from a resolve 5 micro spherical c18 column with a mobile phase consisting of 0.01 m potassium dihydrogen phosphate: methanol [55:54%, v/v] adjusted to PH 6.0 with potassium hydroxide. The drugs and the internal standard were eluted at a flow rate of 1.5 ml per minute, and the optimum detector wavelength was 220 nm. The chromatography time was ten minutes and the resolution between the drugs and internal standard was excellent. Quantitation was achieved by the measurement of peak height ratios and the minimum detectable concentration was less than 0.1 mg/l. the calibration curve of the assay was linear over the range of 0.1-25 mg/l, 0.5-120mg/L and 0.1-80 mg/L for carbamazepine, Phenobarbital and phenytoin respectively respectively. The Abbott TDX FLXTM fluorescence polarization immunoassay [FPIA] has been evaluated and compared with the developed HPLC method for precision, calibration curve stability, specificity and accuracy. Using control samples in the subtherapeutic, therapeutic and toxic concentrations resulted in mean analytical recoveries which varied from 95.3 to 99.8% for HPLC and 96.8 to 101.2 for FPIA. Within run coefficient of variation was in the range of 1.66-4.47% for HPLC and 1.50-3.75% for FPIA. Between run precision ranged from 2.10-4.71% for HPLC and 1.21-4.28% for FPIA. Serum specimens from 270 patients taking carnamazepine, 191 patients taking Phenobarbital and 225 patients taking phenytion were analyzed by both methods, with good correlation. The HPLC method offered reproducibility and accuracy when compared with an established method for routine analysis of carbamazepine, Phenobarbital and phenytoin

Drogas anticonvulsivantes en suero y líquido cefalorraquideo de pacientes epilépticos: cuantificación por cromatografía líquida / Anticonvulsant drugs in serum and crebrospinal fluid of epileptical patients: liquid chromatography measurement

Se desarrolló un procedimiento de cromatografía líquida de alta presión para cuantificar simultáneamente varias drogas anticonvulsivantes en el suero y líquido cefalorraquídeo de 20 pacientes. Los coeficientes de correlación para las concentraciones en ambos líquidos decarbamazepina, fenobarbital y fenitoína fueron r=0,8588 (p<0,01), r=0,9721 (p<0,01) y r=0,9289 (p<0,01), respectivamente. Las concentraciones de cada droga en líquido cefalorraquídeo representaron porcentajes de la concentración en suero, comparables a los referidos en la literatura. Las concentraciones séricas de carbamazepina en los pacientes sin barbitúricos asociados fueron mayores que las de aquellos bajo politerapia con barbitúricos, independientemente de la dosis. La fenitoína y las concentraciones de fenobarbital en suero y líquido cefalorraquídeo. Estos resultados aqpoyan el uso de la monoterapia para tratar las epilepsias

Compliance monitoring in epileptic patients.

Poor patient compliance is one of the major causes of non responsiveness to antiepileptic drug therapy. Compliance is mostly assessed by self reporting, pill counting and plasma drug level estimation. However, none of them is fool proof. Subtherapeutic plasma drug levels can be due to poor compliance or need for higher dosage. Therefore, in the present study, 20 adult non responsive epileptic patients showing subtherapeutic plasma phenytoin levels inspite of receiving standard phenytoin therapy and history of good compliance were admitted in the clinical pharmacology ward and received supervised drug treatment for five days after which plasma phenytoin levels in 14 patients increased to therapeutic range. All except one (i.e. 9 out of 10) patients showing phenytoin levels < 5 ug/ml inspite of phenytoin dosage of > 300 mg/d and history of good compliance were found to be noncompliant. Hence adult patient receiving greater than or equal to 300 mg/day phenytion and showing phenytoin levels less than or equal to 5 ug/ml should be investigated for possible noncompliance before altering their dosage schedules.

Dosagens séricas repetidas de anticonvulsivantes em pacientes epiléticas / Repetitive serum dosages of anticonvulsants in epileptic patients

Para avaliaçäo da aderência ao tratamento em epilépticas crônicas estudamos 38 pacientes através de 144 dosagens séricas repetidas de anticonbulsivantes a intervalos semanais. Todas as pacientes apresentavam crises supostamente de dificil controle, isto é, tiveram crises no mês anterior à última consulta. O nível sérico da droga antiepiléptica estava abaixo da faixa terapêutica em 34// das amostras analisadas. Houve ainda variaçöes semanais importantes do nível terapêutico para subterapêutico das drogas e vice-versa. Baseados nestes achados sugere-se que a estratégia de dosagens séricas repetidas possa diferenciar as pacientes resistentes à droga daquelas que näo fazem uso regular do medicamento

Cognitive functions, epileptic syndromes and antiepileptic drugs

Funçäo cognitiva de pacientes em monoterapia específica para sídrome epiléptica tem sido pouco avaliada. Estudamos: 7 pacientes com epilepsias localizadas sintomáticas (SEL) utilizando fenitoína, com 30 ñ 12 (média ñ desvio padräo) anos de idade; 8 com epilepsias generalizadas idiopáticas utilizando valproato de sódio, com 18 ñ 4 anos; 16 com SEL utilizando carbamazepina, com 28 ñ 11 anos; 35 controles sadios, com 27 ñ 11 anos. Todos tinham inteligência normal, educaçäo apropriada para a idade e vidas produtivas na sociedade. Dois dos pacientes utilizando carbamazepina e um valproato de sódio tinham menos de 5 crises parciais, de ausência ou mioclônicas ao mês. Os outros pacientes tinham crises controladas há mais de 6 meses. As concentraçöes séricas de carbamazepina, fenitoína e valproato tiveram performanece pior que controles em memória imediata; o grupo de carbamazepina foi pior que controles no teste de Stroop (p < 0.01) Os resultados indicam efeitos discretos das síndromes epilépticas, de fenitoína, carbamazepina e valproato de sódio na cogniçäo de pacientes com epilepsia eminentemente controlada e vida produtiva na comunidade. O déficit de pacientes com epilepsia crônica sob regimes politerapêuticos deve ser multifatorial. Estudos futuros devem controlar, em seu planejamento, fatores causais possíveis para que seus resultados sejam relevantes

Comparison of sodium valproate and phenytoin as single drug treatment in generalised and partial epilepsy.

Ninety four patients of generalised and partial epilepsy were randomly assigned to treatment with sodium valproate (49 cases) or phenytoin (45 cases). Serum levels were monitored. Cases were evaluated after 4, 12, 24 weeks of treatment. Both drugs were found to be equally effective in controlling generalised seizures. However, valproate is better in partial seizures. No correlation could be established. Side effects were minor with both the drugs.

Alguns efeitos adversos observados em pacientes epilépticos sujeitos a tratamento com fenobarbital ou fenobarbitar e fenitoína / Some adverse effects observed in patients epileptics in treatment with phenobarbital or phenobarbital and phenytoin

O fenobarbital e a fenitoína, reconhecidos como fármacos efetivos no tratamento da epilepsia, säo capazes de provocar efeitos adversos, algumas vezes graves, quer em funçäo da dose, quer em decorrência de concentraçäo plasmática, ou näo. Porém, em tratamento a longo prazo, pouco se sabe a respeito destes efeitos, razäo pela qual, procurou-se: estabelecer condiçöes para a verificaçäo das concentraçöes do fenobarbital e da fenitoína em amostras de plasma de pacientes epilépticos; verificar o comportamento bioquímico e hamtológico nas amostras de sangue destes pacientes; correlacionar níveis plasmáticos dos fármacos e efeitos adversos. Para isto, as amostras de sangue de pacientes submetidos a tratamento com fenobarbital, e com fenobarbital associado à fenitoína foram analizadas, por cromatografia em fase gasosa, para a determinaçäo dos níveis plasmáticos. Alguns parâmetros bioquímicos e hematológicos foram avaliados, os quais, na grande maioria, apresentaram-se alterados. Os resultados demonstraram que a dose, o tempo de exposiçäo e a concentraçäo plasmática influenciaram no efeito do fenobarbital e da fenitoína sobre alguns parâmetros bioquímicos e hematológicos, e que houve uma correlaçäo entre eles

Diálise de equilíbrio na determinaçäo de fenitoína näo ligada às proteínas plasmáticas / Equilibrium dialysis in the determination of phenytoin not bound to plasma proteins

A fraçäo livre de fenitoína no plasma de 59 pacientes, näo urêmicos, em tratamento com fenitoína associada ou näo a outros anticonvulsivantes foi determinada por espectrometria de cintilaçäo líquida após dialise de equilíbrio. Os resultados variaram numa faixa de 0,08 a 0,14 (8 a 14%). Foi verificada uma relaçäo inversa entre a concentraçäo plasmática da albumina e a da fenitoína näo ligada à proteína