Therapeutic drug monitoring of valproic acid in patients with monotherapy at steady state

The role of therapeutic drug monitoring [TDM] in patient care has grown rapidly since its introduction three decades ago. The aim of present study was to evaluate the possible relationship between serum levels and the clinical response of valproic acid [VPA]. In the present study we evaluated a homogeneous group of adult patients receiving VPA monotherapy. A total of 18 epileptic patients who fulfilled inclusion and exclusion criteria were entered this prospective study. Steady state trough plasma concentration was determined by fluorescence polarization immunoassay [FPIA]. The correlation between therapeutic response and VPA serum concentration was evaluated. Mean VPA dose and mean total VPA plasma concentrations were 8.35 +/- 1.49 mg/kg/day and 50.40 +/- 4.18 micro g/ml respectively. Mean VPA clearance was 8.84 +/- 4.43 [ml/kg/h]. Plasma levels within the therapeutic range were found in 33% of epileptic patients. Plasma levels were below the therapeutic range in 67% of study population. Of patients 75% and 17% with sub-therapeutic levels achieved complete control and partial control respectively. Poor correlation was found between the plasma concentration of VPA and its therapeutic effects. Therefore, this study showed that TDM of VPA will be useful only when individuals are non-responsive to treatment or vulnerable to adverse reactions with standard doses

Epilepsia Mioclónica Juvenil (Síndrome de Janz) / Juvenile Myoclonic Epilepsy

Las convulsiones mioclónicas representan uno de los tipos de epilepsia, que aunque poco frecuentes, son importantes en la infancia. La epilepsia mioclónica juvenil es un síndrome epiléptico generalizado que ocurre en el 2.7 a 11 por ciento de todos los síndromes convulsivos en pediatría; puede tener un inicio tan temprano comolos ocho años y tan tardío como 24 y 40 años. Se caracteriza por sacudidas mioclónicas al despertar, ausencias típicas y crisis tónico-clónicas generalizadas, exploración neurológica normal y anomalías típicas en el electroencefalograma; la caída recordada y la conciencia es conservada durante el ataque. Los factores desencadenantes pueden ser detectados en el 93 por ciento de los pacientes y deben ser evitados. El fármaco de elección es el ácido valproico; este permite controlar las crisis en el 64 a 90 por ciento de los casos. En ocasiones se utiliza la terapia multidroga, principalmente cuando la respuesta clínica al ácido valproico como monoterapia no es la adecuada. El riesgo de recidivas, al interrumpir la farmacoterapia es de 75 a 100 por ciento

Terapêutica em epilepsia / Therapeutics in epilepsy

Esta revisão sumária sobre terapêutica em epilepsia aborda questões tais como quando começar o tratamento, qual a droga antiepilética (DAE) indicada para os diversos tipos de crise, quando retirar a DAE, sua posologia, frequência de tomadas, efeitos colaterais e idução/inibição enzimática da DAE, monitorização do tratamento e epilepsia refratária. Várias dessas questões são dependentes do conhecimento de farmacocinética e farmacodinâmica, fatos que também são considerados.

Estudio preliminar de la hepatotoxicidad del anticonvulsionante DL-4-hidroxi, 4-etil, 4-fenil butiramida (HEPB) y sus homólogos inferiores HEPP y HEPA / Preliminary study of the hepatotoxicity of the anticonvulsant DL-4-hydroxy, 4-ethyl, 4-phenyl butyramide (HEPB) and its inferior homologues HEPA and HEPP

En este trabajo los efectos hepatotóxicos del anticonvulsionantes 4-hidroxi,, 4-etil, 4-fenil butiramida (HEPB) y sus homólogos HEPA y HEPP fueron evaluados y comparados con los efectos del valproato de sodio y del fenobarbital en cultivos de hepatocitos de larga sobrevivencia. Los hepatocitos se sembraron sobre una monocapa alimentadora de células 3T3 letalmente tratadas con mitomicina C y fueron expuestos por una o dos semanas a los anticonvulsionantes (50-500 mg/ml). Se seterminó en el medio de cultivo la liberación de las enzimas citoplásticas transaminasa glutámico oxalacética (GOT). Transaminasa glutámico pirúvica (GPT) y deshidrogenasa láctica (LDH), se determinó también el contenido de triclicéridos (TG) mediante tinción con rojo oleoso O. HEPB produjo gotas intracitoplásmicas de lípidos, ensanchamiento de los espacios intercelulares y retracción de las células. HEPA y HEPP produjeron efectos similares pero en menor grado. El valproato de sodio causó retracción de las células, ensanchamiento de los espacios intracelulares y también vacuolización de las células. Después de una exposición de una semana el valproato de sodio produjo la liberación más alta de TGO, TGP y LDH. Los cultivos tratados con los otros anticonvulsionantes mostraron poca diferencia con los cultivos control. Después de dos semanas de exposición los efectos fueron menores. El mayor contenido de TG lo produjo el HEPB, mientras que el valpoatro de sodio produjo una disminución en el contenido de TG. Nuestros resultados muestran que el rango de toxicidad de los anticonvulsionantes probados es valproato de sodio >HEPB>HEPA>HEPP>fenobarbital

Pharmacokinetic comparison of two valproic acid formulations: a plain and a controlled release enteric-coated tablets

We investigated the single- and multiple dose pharmacokinetics of a new controlled-release formulation (Orfil retard enteric coated tablet) of valproic acid in comparison with those of the plain tablet as a reference. Twelve healthy volunteers were given each formulation of 300 mg in the single-dose study. In the steady-state multiple-dose study, twelve epileptic patients received 1200 mg/day of the reference drug (300 mg 9 AM, 300 mg 3 PM, 600 mg 9 PM) and the test formulation (600 mg 9 AM, 600 mg 9 PM) with at least one week interval in cross-over manner. The AUC values of the test controlled release formulation were 91.7% (95% confidence interval: 78.4-100.4%) of the reference drug in the single-dose study and 98.2% (95% confidence interval: 86.2%-109.9%) in the steady-state study. The AUC's of the two formulations were not significantly different by ANOVA test. The Cmax and Tmax values of the test formulation were significantly different from the values of the reference in single-(Tmax: 158.4%, Cmax: 52.5% of the reference) and multiple-dose study (Tmax: 153.5% of the reference). The MRT values of the test formulation were also significantly greater (129.4% of the reference) in the single-dose study. Regarding the controlled-release characteristics of the test formulation, fluctuation index and percentage fluctuation of the twice a day dosage regimen of the test formulation were comparable with those of the thrice a day dosage regimen of the conventional tablet. Area deviation was even smaller in the test regimen of the controlled release formulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Valproate sodium in epilepsy. A clinical trial including monitoring of drug levels.

Sodium valproate was used as monotherapy in 90 cases with epilepsy who had at least one fit per week, irrespective of the type of seizures. The effect of the drug was evaluated on the basis of change in seizure frequency. Serum valproic acid levels were estimated by homogenous enzyme immunoassay. All the patients with absence (5/5) and myoclonic (3/3) seizures and 80% (42/53) of cases with generalized tonic-clonic seizures, became seizure free. Six of ten patients with only tonic seizures became seizure free. An average daily dose of 19.6 mg/kg provided a mean valproic acid level of 81.4 micrograms/ml in all seizure free patients. No correlation could be established between valproate dose and serum levels. Mild transient side effects were noted. No haematologic abnormality or hepatotoxicity was observed. Valproate sodium effectively controlled seizures in a majority of patients with partial seizures. Serum level monitoring helps to establish an optimal dose to keep the patient seizure free. No correlation could be established between side effects and serum levels.

Normorregulaçäo do humor e valpromida / Normoregulation of humor and valpromide

Normorregulaçäo do humor é uma propriedade farmacológica descrita inicialmente para o lítio. Atualmente ele é também observada para a carbamazepina e para a avalpromida, que é apresentada neste trabalho, mais detalhadamente

Farmacocinesia de los medicamentos antiepilepticos / Antiepileptic drugs pharmacocinesia

Se hace una revisión de la literatura sobre la farmacología de los medicamentos anticomiciales. Se discute los aspectos más importantes de la farmacocinesia de las drogas a la luz de su importancia clínica. se examina algunos medicamentos por separado. Finalmete se presentan algunas recomendaciones sobre la suspensión de la medicación