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.

Development and validation of a method for phenobarbital in serum: anticonvulsant pharmacotherapy monitoring

The therapeutic drug monitoring (TDM) is an important strategy for the effectiveness and safety of long-term pharmacotherapy, such as the use of phenobarbital as an anticonvulsant drug in epilepsy. In this sense, HLPC has been presented as a technique for the measurement of phenobarbital in serum. However, the ideal conditions for carrying out the method must be established for each laboratory reality. An analytical method using HPLC was developed and validated in order to identify and quantify Phenobarbital in blood. The chromatographic conditions were C-18 column (Shimpack XR-ODS 50L x 3.0), acetonitrile-water mobile phase (30:70, v v-1), 0.2 mL min-1 flow and reading wavelength of 210 nm. Linearity was established in the range of 2.5 to 80 µg mL-1, the linear correlation coefficient was 0.9981. The average of the coefficient of variation of the precision was 5.30%. The relative standard error of the accuracy was -2.17% and of the recovery coefficient was 97.83%. In all eleven patients, phenobarbital concentrations were below the therapeutic range. The tested method was selective, linear, precise, accurate and showed good recovery.(AU)

Experiencia de cambio de marcas comerciales de lamotrigina en una paciente ambulatoria del Hospital Vilardebó / Experience of changing commercial brands of lamotrigine in an outpatient of the Vilardebó Hospital

Se desarrolló una experiencia en una pacientede cambio entre dos marcas comerciales de lamotrigina: Lamictal (referencia) y Epilepax (test). Esto fue motivado por notificaciones sobre sospecha de falta de eficacia de una de las citadas presentaciones farmacéuticas utilizada en el Hospital Vilardebó. Se realizó la comparación de las curvas salivales de lamotrigina versus tiempo para las dos marcas, determinándose parámetros clínicos, farmacocinéticos y de seguridad. La experiencia de cambio entre las dos marcas en la paciente no evidenció diferencias en ninguno de los parámetros mencionados.

An experience was developed in a patient of change between two commercial brands of lamotrigine: Lamictal (reference) and Epilepax (test). This was motivated by notifications on suspicion of lack of efficacy of one of the aforementioned pharmaceutical presentations used in the Vilardebó Hospital. The comparison of salivary curves of lamotrigine versus time for the two brands was made, determining clinical, pharmacokinetic and safety parameters. The experience of change between the two brands in the patient did not show any differences in any of the mentioned parameters.

Notas de farmacología: estudios de disolución de medicamentos del sistema nervioso central / Pharmacology notes: drug dissolution studies of the central nervous system

El propósito de los estudios in vitro es comparar las características de liberación del principio activo contenido en una forma farmacéutica sólida oral mediante la cantidad, o porcentaje de la dosis, disuelta en función del tiempo en condiciones controladas y validadas. Se realizó una comparación de disolución in vitro de flunitrazepam (Rohypnol®, Somnidual® e Inervon®) y de lamotrigina (Lamictal® y Epilepax®). Para los perfiles de disolución de flunitrazepam, una de las marcas comerciales tuvo un perfil de disolución muy diferente a las otras dos marcas. Para el caso de lamotriginano existió diferencia para aquellos pH que se consideran fundamentales para la disolución del comprimido en el tracto gastrointestinal. Los resultados obtenidos de los estudios in vitro son simplemente orientadores, permiten tan solo guiar la puesta en marcha del ensayo de bioequivalencia entre el test evaluado in vitro y la referencia utilizada en el mismo ensayo. No obstante, estos resultados pueden constituirse en un elemento de apoyo a la presunción de bioinequivalencia como causa de un evento adverso (ineficacia o toxicidad) detectado en los programas de farmacovigilancia actualmente en marcha.

Stir bar-sorptive extraction, solid phase extraction and liquid-liquid extraction for levetiracetam determination in human plasma: comparing recovery rates / Extração sortiva em barra de agitação, extracção da fase sólida e de extracção líquido-líquido para a determinação de levetiracetam em plasma humano: comparando as taxas de recuperação

Levetiracetam (LEV), an antiepileptic drug (AED) with favorable pharmacokinetic profile, is increasingly being used in clinical practice, although information on its metabolism and disposition are still being generated. Therefore a simple, robust and fast liquid-liquid extraction (LLE) followed by high-performance liquid chromatography method is described that could be used for both pharmacokinetic and therapeutic drug monitoring (TDM) purposes. Moreover, recovery rates of LEV in plasma were compared among LLE, stir bar-sorptive extraction (SBSE), and solid-phase extraction (SPE). Solvent extraction with dichloromethane yielded a plasma residue free from usual interferences such as commonly co-prescribed AEDs, and recoveries around 90% (LLE), 60% (SPE) and 10% (SBSE). Separation was obtained using reverse phase Select B column with ultraviolet detection (235 nm). Mobile phase consisted of methanol:sodium acetate buffer 0.125 M pH 4.4 (20:80, v/v). The method was linear over a range of 2.8-220.0 µg mL^-1. The intra- and inter-assay precision and accuracy were studied at three concentrations; relative standard deviation was less than 10%. The limit of quantification was 2.8 µg mL^-1. This robust method was successfully applied to analyze plasma samples from patients with epilepsy and therefore might be used for pharmacokinetic and TDM purposes...

Levetiracetam, fármaco antiepiléptico com perfil farmacocinético favorável, tem sido cada vez mais utilizado na prática clínica, embora informações sobre seu metabolismo e disposição cinética ainda estejam sendo geradas. Um método simples, robusto e rápido de extração líquido-líquido seguido por análise por cromatografia líquida de alta eficiência é aqui descrito para servir tanto a investigações farmacocinéticas quanto à monitorização terapêutica. Além disso, as taxas de recuperação do levetiracetam em plasma foram comparadas entre a extração líquido-líquido, a extração sortiva em barra de agitação e a extração em fase sólida. Extração com o solvente diclorometano resultou em plasma livre de interferentes, tais como fármacos antiepilépticos co-prescritos, e apresentou taxas de recuperação em torno de 90% (extração líquido-líquido), 60% (extração em fase sólida) e 10% (extração sortiva em barra de agitação). A separação foi obtida utilizando-se coluna de fase reversa Select B e detecção ultravioleta (235 nm). A fase móvel foi composta por metanol:tampão acetato de sódio 0,125 M pH 4,4 (20:80, v/v). O método mostrou-se linear para o intervalo de 2,8 a 220,0 µg mL^-1. Precisão intra- e interdias e a exatidão foram avaliadas em três concentrações; o desvio padrão relativo foi inferior a 10%. O limite de quantificação foi 2.8 µg mL^-1. Este método foi aplicado para análise de amostras de plasma de pacientes com epilepsia e, desta forma, pode ser utilizado satisfatoriamente tanto para fins de farmacocinética quanto de monitorização terapêutica...

The Anticonvulsant Effect of Eupatorium Birmanicum DC Leave Extract Alone and in Combination with Phenytoin Against MES Seizure in Albino Mice.

To evaluate the anticonvulsant activity of aqueous extract of Eupatorium birmanicum DC leave (EB) alone and in combination with phenytoin against MES seizure in albino mice. Method: Aqueous extract of EB was prepared using Soxhlet apparatus. The anticonvulsant effect of the extract was tested on prescreened albino mice at 3 doses (200, 400 & 800 mg/kg). After 1 hr of oral administration of EB the animals were subjected to MES seizures by convulsiometer with a current of 45 mA for 0.2 sec via transauricular electrodes and the duration of the THLE was recorded. Sub-anticonvulsant dose of phenytoin was also determined and the effect of its combination with the most effective dose of EB tested. Results: EB aqueous extract exhibited significant anticonvulsant activity in the MES model at doses 400 mg/ kg (p<0.01) & 800 mg/kg (p<0.001). This reduction in the duration of THLE at 800mg/kg of EB was further reduced significantly (p<0.001) when combined with subanticonvulsant doses of phenytoin (10mg/kg). Conclusion: The aqueous extract of E. birmanicum leaves showed significant anticonvulsant activity in MES seizure model in albino mice and it significantly increased the anticonvulsant effect of phenytoin in the same animal model.

The influence of estazolam on human neurobehavioral function / 法医学杂志

OBJECTIVE@#To study the relation between human blood estazolam concentration and neurobehavioral function.@*METHODS@#The neurobehavioral ability of 10 volunteers were measured with computer-administered neurobehavioral evaluation system-chinese3 (NES-C3) and SMART EquiTest system.@*RESULTS@#The neurobehavioral ability and balance function declined 1 h later after dosing estazolam. The neurobehavioral ability index and balance function declined to the lowest level 3 h later after dosing estazolam. The neurobehavioral ability recovered partly 6 h later after dosing estazolam, and neurobehavioral ability recovered completely 10 h later.@*CONCLUSION@#Driving ability was impaired when estazolam concentration in blood is 20 ng/mL, and the neurobehavioral ability declined when estazolam concentration is 40 ng/mL in blood. The influence to human in absorption process is greater than the metabolic process with the same estazolam concentration.

Topiramato oral en status epiléptico refractario: revisión bibliográfica y experiencia local / Oral topiramate in refractory status epilepticus: bibliographic revision and local experience

Aim. To assess the efficiency of topiramate (TPM), an antiepileptic medication which possesses multiple mechanisms of action, a wide therapeutic spectrum and good pharmacokinetics in the management of status epilepticus (SE), especially in refractory. Several reports have shown that TPM presents different efficacy in the management of different types of refractory status epilepticus, both adults and children. Also present our experience with two patients with SE who responded early without TPM oral complications. Conclusions. TPM oral as drug associated, is an antiepileptic medication that has shown therapeuticefficacy in cases reports and observational studies the management SE of different types and nature. This efficacy has not been contrasted with randomized controlled trials and prospective studies, therefore, future studies with larger numbers of patients are needed to confirm published reports.

Avaliação eletrofisiológica in vitro de drogas antiepilépticas em fatias hipocampais humanas provenientes de pacientes portadores de epilepsia do lobo temporal refratária ao tratamento medicamentoso / In vitro electrophysiological assessment of antiepileptic drugs in human hippocampal slices originating from patients with refractory temporal lobe epilepsy

The absence of a satisfactory response to antiepileptic drug (AED) therapy, is an unresolved problem in a significant number of epileptic patients. Mechanisms of intractability are not well understood but may include a combination of poor penetration of AED across a functionally altered blood-brain barrier owing to increased expression of multiple drug resistance transporters. Therefore, the aim of this work was to assess the in vitro efficacy of antiepileptic drugs through human hippocampal slices originating from patients with refractory temporal lobe epilepsy submitted to corticoamygdalohippocampectomy. Slices was prepared from a 1 cm3 block of the hippocampus body 30 min after resection. Briefly, hippocampal slices of 400 µM thickness was cut coronally. Extracellular field potentials was recorded from the st. Granulosum of the dentate gyrus. The antiepileptic drugs added in the bath were Carbamazepine, Topiramate and Phenytoin. The phenytoin was effective reducing the hyperexcitability (polispikes) in 60% of the experiments (n = 5). On the other hand, the carbamazepine promoted a decrease in evoked epileptiform activity in 37,5% of the cases (n = 8). The application of topiramate in the bath reduced in 30% the number of polispikes (n = 10). Our results showed that the phenytoin application resulted in a significant reduction in neuronal excitability, however, the carbamazepine and topiramate were not able to control of the hiperexcitability, suggesting that local neuronal alterations, as well changes in blood brain barrier, could be responsible for such behaviors.

Study on the anticonvusant activity of thymoquinone, the major constituent of Nigella Sativa L.seeds, through intracerebroventricular injection

Thymoquinone, the major constituent of Nigella sativa seeds, is a biologically active compound, which possesses several pharmacological effects. The aim of the present study was to evaluate the anticonvulsant effect of thymoquinone through intracerebroventricular [i.c.v.] injection. The anticonvulsant effects of thymoquinone, the major constituent of Nigella sativa seeds, were investigated using pentylenetetrazole [PTZ]-induced seizure model. In PTZ-induced epileptic seizures, the i.c.v. injection of thymoquinone [200 and 400 mol] prolonged the onset and reduced the duration of tonic-clonic seizures. The protective effect of thymoquinone against lethality was 45% and 50% in the mentioned doses, respectively. In this study, flumazenil [1 nmol, i.c.v.] reversed the anticonvulsant activity of thymoquinone. Also, pretreatment with naloxone [10 mol, i.c.v.] antagonized the prolongation of tonic-clonic seizure latency, as well as reduction in seizure duration both induced by thymoquinone [200 mol, i.c.v.]. These results indicate that thymoquinone may possess anticonvulsant activity probably through an opioid receptor-mediated increase in GABAergic tone

Avances recientes en el manejo farmacológico de la epilepsia / Recent advances in the pharmacologic management of epilepsy

Numerosos estudios y ensayos clínicos de nuevos fármacos antiepilépticos (FAE) se han desarrollado para el control y manejo de epilepsias refractarias. En la última década se han incorporado nuevos antiepilépticos, cuyos estudios actuales están orientados a demostrar su eficacia y menores efectos secundarios comparados con los “FAE clásicos”, utilizándolos como monoterapia en el control de epilepsias de reciente diagnóstico. Diferentes mecanismos de acción han sido investigados en los nuevos FAE, pero el mecanismo fisiopatológico exacto de cada uno de ellos aún no está totalmente definido. Ninguno de los FAE ha demostrado una eficacia superior a la de los “clásicos” en el control de las crisis parciales y/o generalizadas, con la excepción de algunos estudios que apoyarían una mayor eficacia de Lamotrigina sobre Carbamazepina y de Oxcarbazepina sobre Fenitoína. Mientras que otros nuevos fármacos, como la Vigabatrina, han mostrado una eficacia inferior a la Carbamazepina. Es ampliamente aceptado que estos nuevos fármacos presentan una mejor tolerabilidad y menores efectos adversos. Revisaremos en detalle los nuevos FAE aprobados por FDA, sus mecanismos de acción, farmacocinética, indicaciones principales y efectos colaterales.

Effect of honey on carbamazepine kinetics in rabbits.

The study was undertaken to determine the effect of honey on carbamazepine kinetics in rabbits. The study was done on three occasions in each animal. Study 1 was carried out after single dose administration of carbamazepine (80 mg/kg, po), along with saline (2.34 ml/kg, po). After a wash out period of one week, the second study was carried out by co-administration of carbamazepine with honey (2.34ml/kg, po). After this, the animals continued to receive honey (2.34ml/kg, po), once daily, for 7 days. On the eighth day of honey treatment, the carbamazepine kinetics was studied again. Pharmacokinetic analysis revealed that single as well as multiple dose honey treatment showed a significant decrease in area under the plasma time concentration curve (AUC) when compared with saline treated control. A significant increase in the clearance (CL/F) rate of carbamazepine was observed only after multiple dose honey treatment. Both single and multiple dose honey treatment did not show any significant effect on other pharmacokinetic parameters like t1/2, Cmax, Tmax and Vd when compared with saline treated group. Data thus obtained suggested that honey decreases the bioavailability of carbamazepine.

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

Lamotrigina - novo adjuvante na terapia antiepiléptica / Lamotrigine - A novel comedication in the anticonvulsant therapy

A lamotrigina (LTG), derivado diclorofenílico da triazina-3,5-diamina, desenvolvido inicialmente como fármaco antifolato, em virtude de sua atividade anticonvulsivante tem sido proposto como adjuvante terapêutico no tratamento das epilepsias refratárias e naquelas não satisfatoriamente controladas por outros medicamentos. Aprovada pelo Food and Drug Administration, em 1994, é utilizada entre nós, na forma de comprimidos. Neste artigo de revisão são abordados os aspectos farmacológicos (esquema de dosagem, farmacocinética clínica, eficácia e farmacodinâmica), a importância de sua monitorização terapêutica bem como são apresentados os aspectos toxicológicos associados a seu uso terapêutico

Comparison of absorption rate and bioavailability of two brands of carbamazepine.

OBJECTIVE: To assess the bioavailability of carbamazepine from two brands of carbamazepine--Tegretol 200 and Zen-200. METHODS: A two-way randomised cross-over bioavailability of carbamazepine was carried out in twelve healthy male volunteers. Coded plasma samples were analysed for levels of carbamazepine by high performance liquid chromatography (HPLC) method. Tegretol 200 and Zen-200 were tested for in-vitro dissolution profiles. RESULTS: The mean Cmax, Tmax and t1/2a for Tegretol 200 were: 2.17 +/- 0.42 mcg/mL, 11.67 +/- 6.37 h and 2.72 +/- 1.87 h; for Zen-200 were 3.10 +/- 0.05 mcg/mL, 3.50 +/- 2.11 h and 0.76 +/- 0.76 h respectively. These values were statistically significant. However AUC (0-96 h) value of 150.16 +/- 27.13 mcg/ml.h after Zen-200 was not statistically significant as compared to 128.68 +/- 20.22 mcg/ml.h after Tegretol 200. The in-vitro dissolution profiles of the two formulations were dissimilar. The fluctuations in CBZ levels after Tegretol 200 was significantly less as compared to Zen-200. The absorption profile as judged by parameter 'A' was 50.44 +/- 10.95 for Tegretol 200 and 42.49 +/- 18.89 for Zen-200. CONCLUSION: Based on parameter 'A' and other pharmacokinetic parameters, the marketed generic carbamazepine product, Zen-200 is not bioequivalent to Tegretol 200.

A pilot study of topiramate in children with Lennox-Gastaut syndrome

We conducted an open, add-on study with topiramate (TPM) as adjunctive therapy in Lennox-Gastaut syndrome (LGS), to assess the long-term efficacy and safety and to evaluate quality of life (QL) measurements in the chronic use of TPM. We studied 19 patients (11 male; age ranging from 4 to 14 years) with uncontrolled seizures receiving 2-3 anti- epileptic drugs. Patients were followed up to 36 months of treatment. A questionnaire was used to query parents about QL. Seven patients completed the study at 36 months and seizure frequency was reduced = 75 per cent in 4, and < 50 per cent in patients. Two children became seizure free for more than 24 months. Most side effects were CNS related, with the most frequent being somnolence and anorexia. These were generally transient. One patient dropped-out due to powder in the urine. None of the patients required hospitalization. At 36 months, patients' alertness (2/7), interaction with environment (5/7), ability to perform daily activities (5/7), and verbal performance (6/7) improved on TPM. We conclude that TPM may be useful as adjunctive therapy in the treatment of LGS. The efficacy of TPM was maintained in long-term treatment in more than 40 per cent of patients, long term safety was confirmed and QL improve on TPM.