Valproate-Ethosuximide Combination Therapy for Refractory Absence Seizures

Rowan, Alison; Meijer, J. W. A.; Beer-Pawlikowski, Nina de; Geest, Peter van der; Meinardi, H.

doi:10.1001/archneur.1983.04050120047006

Cited by 145 publications

(46 citation statements)

References 13 publications

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“…Anticonvulsants are often combined to achieve greater seizure control. Interestingly, ethosuximide and VA can be combined to achieve greater seizure control than either drug alone, and this combination is currently used in clinical practice (Rowan et al, 1983;Bourgeois, 1988). This result is consistent with our data suggesting that these two drugs act differently and form an effective combination.…”

Section: General Models For the Mechanism Of Action Of Va In Lifespanmentioning

confidence: 99%

Valproic acid extends Caenorhabditis elegans lifespan

et al. 2008

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SummaryAging is an important biological phenomenon and a major contributor to human disease and disability, but no drugs have been demonstrated to delay human aging. Caenorhabditis elegans is a valuable model for studies of animal aging, and the analysis of drugs that extend the lifespan of this animal can elucidate mechanisms of aging and might lead to treatments for age-related disease. By testing drugs that are Food and Drug Administration approved for human use, we discovered that the mood stabilizer and anticonvulsant valproic acid (VA) extended C. elegans lifespan. VA also delayed age-related declines of body movement, indicating that VA delays aging. Valproic acid is a small carboxylic acid that is the most frequently prescribed anticonvulsant drug in humans. A structure-activity analysis demonstrated that the related compound valpromide also extends lifespan. Valproic acid treatment may modulate the insulin/IGF-1 growth factor signaling pathway, because VA promoted dauer larvae formation and DAF-16 nuclear localization. To investigate the mechanism of action of VA in delaying aging, we analyzed the effects of combining VA with other compounds that extend the lifespan of C. elegans . Combined treatment of animals with VA and the heterocyclic anticonvulsant trimethadione caused a lifespan extension that was significantly greater than treatment with either of these drugs alone. These data suggest that the mechanism of action of VA is distinct from that of trimethadione, and demonstrate that lifespan-extending drugs can be combined to produce additive effects.

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Section: General Models For the Mechanism Of Action Of Va In Lifespanmentioning

confidence: 99%

Valproic acid extends Caenorhabditis elegans lifespan

et al. 2008

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“…Animal studies have provided useful evidence of pharmacodynamic interactions involving AEDs (18)(19)(20)(21)(22), and results from in vitro studies are promising (23), although there is still little evidence of the applicability of such interactions in humans (24). However, anecdotal evidence and clinical experience has shown that some combinations of AEDs are more effective in controlling seizures than either drug used alone, and such combinations will be used despite a lack of scientific evidence to explain the favourable drug interaction; examples of these AED combinations include VPA and ethosuximide (ESM) (25), clonazepam (CZP) plus VPA (26), and CBZ plus VPA (27,28). Similar enhancement in clinical efficacy has been reported for combinations that include the newer AEDs [for example, TGB plus VGB (29), VGB plus LTG (30), LTG plus TPM (31), and VPA plus LTG (32)(33)(34)].…”

Section: Pharmacodynamic Interactionsmentioning

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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“…Regarding combinations of AEDs, the following question arises: Do patients respond better to the combination of two drugs given after each failed as monotherapy? Some studies have addressed this question, investigating combinations of CBZ with valproate [49], PHT with CBZ [50], lamotrigine with valproate [51], valproate with ethosuximide [52] and vigabatrin with CBZ [53]. These studies indicate that patients who have failed to respond to these drugs as a monotherapy may respond to combinations.…”

Section: Combined Aedsmentioning

confidence: 99%

Evidence for Efficacy of Combination of Antiepileptic Drugs in Treatment of Epilepsy

2015

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Epilepsy is the tendency to have recurrent, unprovoked seizures. Although 70% of epileptic seizures can be controlled with monotherapy (treatment by single antiepileptic drug), a combination of two or more anti-epileptic drugs (AEDs) may be required to improve efficacy (seizure control) and tolerability. Polytherapy (treatment with two or more AEDs) can affect efficacies and side effects in additive, supra-additive (synergistic) or infra-additive fashion. The effect is considered supraadditive when the efficacy of the combination is greater than the sum of the individual drug efficacies, while it is considered infra-additive when the efficacy of the combination is less than the sum of the individual drug efficacies. Here, we have reviewed the available studies and evidences for the application of polytherapy in humans and animal models, to understand which combination of AEDs act as a synergistic polytherapy for epilepsy. We have searched the bibliographic databases MEDLINE and PubMed for studies conducted from 1950 to 2013 and have concluded that, although promising results from the experimental point of view support the combinations of topiramate separately with lamotrigine, gabapentin and felbamate, the most reliable evidence supports the use of valproate and lamotrigine, as this combination generates encouraging results in animal models. Though effectiveness of this combination is supported by human data, there is the possibility of increased side effects. The new drugs are all effective as add-on therapy; there is some evidence that at present, in clinical practice, levetiracetam and topiramate may be the most effective add-on therapies in partial and some generalized epilepsies.

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Valproate-Ethosuximide Combination Therapy for Refractory Absence Seizures

Cited by 145 publications

References 13 publications

Valproic acid extends Caenorhabditis elegans lifespan

Valproic acid extends Caenorhabditis elegans lifespan

The Importance of Drug Interactions in Epilepsy Therapy

Evidence for Efficacy of Combination of Antiepileptic Drugs in Treatment of Epilepsy

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