Stupor Following Administration of Valproic Acid to Patients Receiving Other Antiepileptic Drugs

Sackellares, J. Chris; Lee, Soo Ik; Dreifuss, Fritz E.

doi:10.1111/j.1528-1157.1979.tb04853.x

Cited by 117 publications

(50 citation statements)

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“…It should be noted that this interaction can have highly variable outcomes in different patients, and this is partly dependent upon the concentration of PB. Furthermore, in some patients, stupor or coma (VPA-induced encephalopathy) may occur with this combination and can occur without a significant elevation of the plasma concentrations of PB; the mechanism of this interaction is currently unclear (69)(70)(71).…”

Section: Phenobarbitone Coadministered With Valproatementioning

confidence: 99%

The Importance of Drug Interactions in Epilepsy Therapy

et al. 2002

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Summary: Long-term antiepileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to control seizures effectively, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. The fact that over-the-counter drugs and nutritional supplements are increasingly being self-administered by patients also must be considered. Therefore the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and on drug discontinuation. Although pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine (LTG) and valproic acid (VPA); these drugs exhibit synergistic efficacy when coadministered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions, and enzyme-inducing drugs such as phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) will readily enhance the metabolism of other AEDs [e.g., LTG, topiramate (TPM), and tiagabine (TGB)].The enzyme-inducing AEDs also enhance the metabolism of many other drugs (e.g., oral contraceptives, antidepressants, and warfarin) so that therapeutic efficacy of coadministered drugs is lost unless the dosage is increased. VPA inhibits the metabolism of PB and LTG, resulting in an elevation in the plasma concentrations of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of CBZ by VPA results in an elevation of the metabolite CBZepoxide, which also increases the risk of toxicity. Other examples include the inhibition of PHT and CBZ metabolism by cimetidine and CBZ metabolism by erythromycin. In recent years, a more rational approach has been taken with regard to metabolic drug interactions because of our enhanced understanding of the cytochrome P450 system that is responsible for the metabolism of many drugs, including AEDs. The review briefly discusses the mechanisms of drug interactions and then proceeds to highlight some of the more clinically relevant drug interactions between AEDs and between AEDs and non-AEDs. Understanding the fundamental principles that contribute to a drug interaction may help the physician to better anticipate a drug interaction and allow a graded and planned therapeutic response and, therefore, help to enhance the management of patients with epilepsy who may require treatment with polytherapy regimens.

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Section: Phenobarbitone Coadministered With Valproatementioning

confidence: 99%

The Importance of Drug Interactions in Epilepsy Therapy

et al. 2002

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“…In some patients with this condition, hepatocellular damage, highly elevated serum ammonia and liver enzyme levels, and microvesicular steatosis are seen on liver biopsy. Fatal hepatic failure is more common when VPA is used by children younger than 2 years than it is in older children and adults and also when used in polytherapy than in monotherapy (1,2). Patients with urea cycle defects or carnitine deficiency also are at high risk to develop VPA-related hyperammonemic encephalopathy (VHE) with hepatic failure.…”

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confidence: 99%

“…It can occur immediately after large loading doses of VPA or more insidiously over time, often in a level-or dose-related fashion (2,4). VHE is more common when VPA is used adjunctively with phenobarbital (PB), phenytoin (PHT), or carbamazepine (CBZ) than when used in monotherapy (5,6).…”

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Serum and CSF Glutamine Levels in Valproate‐related Hyperammonemic Encephalopathy

et al. 2002

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Summary:Purpose: To investigate ammonia and glutamine levels in valproate (VPA)-related hyperammonemic encephalopathy (VHE).Methods: We reviewed the medical records and EEG recordings of seven adults diagnosed with VHE.Results: Venous ammonia levels were elevated in five (71%) of the seven patients. Elevated serum or cerebrospinal fluid (CSF) glutamine levels were found in four (80%) of five cases tested, including two who had normal ammonia levels. Initial behavioral signs included violent outbursts in three patients, paranoid ideation severe enough to require restraint in two cases, and milder abnormalities in two instances. The severity of encephalopathy was not related to any particular serum VPA level. In four patients serum VPA levels did not exceed 100 g/ml, and in one case, VHE developed after taking only one 250-mg dose. Symptoms eventually cleared after reducing the dose of, or discontinuing, VPA. Liver-function tests were normal. Each of six patients tested had EEG findings that supported the diagnosis of VHE and excluded nonconvulsive status epilepticus. The rate of normalization of one patient's serum glutamine level and the EEGs of two cases correlated better with the timing of their delayed clinical recovery than did the more rapid rate of decline of the serum ammonia levels. Conclusions: Serum or CSF glutamine levels are initially elevated in a majority of patients with suspected VHE, sometimes in the absence of hyperammonemia. Glutamine levels may be useful adjunctive laboratory tests for the diagnosis of VHE.

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“…O Manual Diagnóstico e Estatístico dos Transtornos Mentais (DSM) III abandonou inteiramente o termo e a Classificação Internacional de Doenças (CID) 9 o classifica em dois locais: como estupor psicogênico (298.8) junto à psicose histérica ou como sintoma genérico (780.0), junto com o coma; mas nenhum critério de identificação é fornecido. Essas dificuldades de definição se refletem na ampla variedade de estados clínicos descritos como associados ao estupor: esquizofrenia e mania (Kraepelin, 1919), depressão (Baillarger, 1843;Hoch, 1921), histeria (Neustatter, 1942;Gómez, 1980), estresse emocional agudo (Weitbrecht, 1968;Garmany, 1955), estado confusional agudo (Hoenig et al, 1959), estados induzidos por drogas (Bloom et al, 1976;Jong, 1956;Mavrojannis, 1903;Sackellares, 1979), enxaquecas (Lee Ch. et al, 1977), dano cerebral difuso, demência (Joyston-Bechal, 1966), parkinsonismo (Von Economo, 1931), psicoses cicloides (Leonhard, 1979).…”

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2011

Rev. latinoam. psicopatol. fundam.

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Stupor Following Administration of Valproic Acid to Patients Receiving Other Antiepileptic Drugs

Cited by 117 publications

References 8 publications

The Importance of Drug Interactions in Epilepsy Therapy

The Importance of Drug Interactions in Epilepsy Therapy

Serum and CSF Glutamine Levels in Valproate‐related Hyperammonemic Encephalopathy

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