First-line epilepsy treatment with valproate
40 years of clinical experience--and promising result in tumor busting
An "exceptional drug" was how Prof. Philippe Evrard, chief of pediatric neurology and metabolic diseases at the Hôpital Robert-Debré, France, described the drug valproate. Speaking at a symposium on Valproate in the Modern Therapeutic Arsenal in Pediatric Neurology organized by Abbott Laboratories in November 2004, Evrard shared with members of the Child Neurology Society, Philippines the 40-year clinical experience on the use of valproate and promising new areas for the use of the drug.
At present, valproate is widely used in the treatment of epilepsy in Western Europe. In fact, valproate is considered the first-line drug in a broad range of epileptic syndromes in patients three years and above. Evrard said that valproate is "the first of the modern treatments for epilepsy, which is unsurpassed in many aspects."
However, Evrard pointed out some exceptions. Valproate is considered a second-line drug in status epilepticus and is "strictly forbidden" in metabolic diseases such as mitochondrial diseases and ammonium problems (cycle of urea). It is also not automatically the first-line drug for children under three years.
Status epilepticus
Evrard said that determining exactly when an epileptic fit becomes status epilepticus is a "very difficult point to delineate, but the transition point could be very short." "The neurochemical transition point is when NMDA excitatotoxicity starts," he said. "There is GABAergic system failure, which is a crucial errant in the decompensation of status epilepticus." He then recommended that treatment of epileptic fits be started early to avoid status epilepticus.
Evrard said that the first line of defense in first-aid situations is a combination of lorazepam given intrarectally or by IV, and fosphenytoin administered intramuscularly. The ease and rapidity of administration of both drugs help reduce the risk of decompensation in status epilepticus. When lorazepam and fosphenytoin are not available, diazepam and phenytoin may be given intravenously.
When status epilepticus starts to decompensate, the combination of diazepam and phenytoin, which is ideally lorazepam and fosphenytoin, will no longer have any effect. Close EEG monitoring is recommended. As for the use of a second-line drug, Evrard said that "at the very top" of the list is intravenous valproate.
Migraines
Valproate has also been used in migraines. Although not officially approved in Western Europe for this indication, valproate, Evrard said, is very largely used to treat children with migraines under the responsibility of the attending physicians and the pharmacists.
Said Evrard: "With valproate, [migraine] is said to be a 'channel' disease and also GABA-dependent. So there are two possible main targets--one is in the stimulation of the GABAergic system to stop the spreading neural depression; the other possibility is the inhibition of abnormal channel errors."
Tumor busting
In recent years, studies are showing promising results in the use of valproate in the inhibition of tumor growth and metastasis and in the induction of tumor differentiation.
Evrard said that this property was discovered in the course of studying the risk of developing neural-tube defects among the children of pregnant mothers taking valproate. Like other antiepileptics, valproate carries with it a low but definite risk for this complication.
Based on available data, valproate holds the biggest promise in two particular areas--an adjuvant role in chemoprevention and control of residual minimal diseases of the tumors.
Practical concerns
Evrard advised physicians not to be overly cautious with the administration and titration of valproate. He said: "I am more and more surprised that new epileptologists recommend going slowly with medication. In my opinion, [they] sometimes go too far, and I see reluctance in them."
He added: "If you are not careful, a patient can have status epilepticus…because you didn't give enough. This is why I never hesitate to give a good dose if there is a risk of relapse of status epilepticus." If a child is in the hospital and develops intoxication, the dose can be titrated and the child detoxified.
If it is not too urgent and the physician decides to treat the patient on an outpatient basis, a dose of 10 mg/kg/day for three days, then 20 mg/kg/day for the next three days, and then 30mg/kg/day can be given. "I do not go beyond that very often," said Evrard.
Precautionary measures in using valproate include measuring baseline prothrombin and transaminases levels. These should be checked again sometime during the first six months to ensure that there will not be any metabolic problems. Evrard recommended testing for carnitine in long-term epilepsy treatment because valproate could provoke a carnitine deficiency without much consequence.
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