Interacción entre meropenem y ácido valproico: A propósito de dos casos pediátricos / Pharmacological interaction between meropenem and valproic acid: a report of two cases

The pharmacological interaction between meropenem and valproic acid is potentially serious, especially in critically ill patients, resulting in low plasmatic levels of the anticonvulsant. However, to our knowledge, this interaction between meropenem and reduced valproic acid plasma levels has not been reported in the pediatric chilean population. We present two clinical cases of chilean children, thus reporting that this interaction is present in our population, with an aim at educating physicians about the possibility of such interaction.

La interacción farmacológica entre meropenem y ácido valproico en pacientes críticos es potencialmente grave, reflejándose en una disminución del fármaco anticonvulsivante mayor a 70%. Se desconocen estrategias efectivas que la reviertan. Esta interacción no ha sido descrita en pacientes chilenos pediátricos. A través de la presentación de dos casos clínicos alertamos que la interacción puede suceder en nuestra población y educamos a los pediatras que indican meropenem sobre la posibilidad de este evento.

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

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.

effect of valproate monotherapy on hepatic and hemostatic functions in epileptic children: value of L-carnitine supplementation

The study included 15 epileptic children without previous hepatic or hemostatic defects [10 males and 5 females] aging 2 to 14 years selected from the outpatients attending the Pediatric Neurology Clinic of the Pediatric Department of Tanta University Hospital. We excluded patients receiving other medications which affect hepatic or platelet function, fifteen healthy children of matched age and sex served as controls. History, clinical examination and the following investigations were done for all of the cases: EEG, complete blood count, total serum proteins, albumin, bilirubin, ammonia, and alanine aminotransferase [ALT]. Hemostatic studies included bleeding time [BT], clotting time [CT], prothrombin time [PT], activated partial thromhopiastin time [PTT], serum fibrinogen, protein C, von Willebrand factor antigen, platelet count and platelet aggregation. All of the hepatic and hemostatic parameters were done before, and 9 weeks after commencement of antiepileptic therapy with valproate [VPA]. Serum valproate level was measured after establishment of therapy and showed a good complience to treatment. L-carnitine was measured before and after valproate therapy then oral L-carnitine was supplemented in a dose of 100 mg/kg/day for two weeks in all of the studied cases. The studied hepatic and hemostatic function parameters mentioned above were repeated again after L-carnitine supplementation. Valproate therapy was associated with a significant decrease in serum L-carnitine with impairment of hepatic functions [manifested by a significant increase in serum bilirubin, ammonia and ALT]. Following oral administration of L-carnitine there was a significant decrease in serum bilirubin and ALT, Hemostatic disturbances were also observed after valproate therapy in the studied cases [manifested by a significant increase in BT, CT, PT and PTT, with a significant decrease in serum fibrinogen, serum protein C, platelet count and platelet aggregation], VPA therapy or L-carnitine administration did not significantly affect Von Willebrand factor. Most of the studied hemostatic parameters improved significantly in response to oral L-carnitine. None of our studied cases showed life threatening or Reye-like hepatotoxicity. We conclude that within the usual therapeutic serum levels of VPA, it could be associated with L-carnitine deficiency and hepatic synthetic dysfunction as well as decreased number and function of platelets. Most of these abnormalities could be reversed by co-administration of L-carnitine. The latter might be recommended in epileptic children on VPA therapy particularly those with abnormal liver or platelet functions and those at risk for hepatotoxicity

Effect of sodium valproate on serum amylase in epileptics.

Thirty-eight patients of generalised tonic-clonic seizures of epileptics in the age group of 15-30 years were included in this study. Of these 20 were started sodium valproate afresh and 18 already taking it for more than one year prior to inclusion. Serum amylase and serum valproic acid levels were measured in all of them, initially and at every 3 months interval for 9 months. Though no clinical evidence was present, there was significant increase in serum amylase levels in both the groups which has no correlation with dose or serum valproic acid levels.

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.

Acido valpróico, cabelos cacheados e ganho de peso / Valproic acid, curly hair and weight gain

A literatura registra a ocorrência de ganho de peso em menos de 20% dos pacientes que recebem ácido valpróico e alteraçöes na textura de fâneros em até 9%. Relata-se o caso de uma paciente de 19 anos que desenvolveu ganho de 13 kg, perda parcial de cabelos seguida de transformaçäo deles de lisos e claros em cacheados e mais escuros, durante tratamento com 1000 mg de ácido valpróico ao dia, com nível sérico de 138,9 micron g/ml. Após diminuiçäo da dose para 500 mg ao dia, com nível sérico de 80,5 micron g/ml, ela perdeu 7 kg, porém näo recuperou a antiga textura dos cabelos. Devido ao completo controle de suas crises de ausência, mioclônicas e tônico-clônicas, jamais obtido com outra medicaçäo, a paciente escolheu manter tratamento com ácido valpróico