Combined Administration of Carbamazepine and Phenobarbital: Effect on Anticonvulsant Activity and Neurotoxicity

Bourgeois, Blaise F. D.; Wad, Nils

doi:10.1111/j.1528-1157.1988.tb03749.x

Cited by 36 publications

(24 citation statements)

References 23 publications

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“…In light of these facts, the synergistic 3-drug interaction of CBZ, PB and TPM should be compared with three 2-drug interactions between CBZ + TPM, PB + TPM and CBZ + PB. The isobolographic analysis of the 2-drug combination of CBZ with PB revealed that this combination produced additive interaction in the mouse MES model [32] . In the case of 2-drug combinations of CBZ with TPM and PB with TPM, experiments in vivo study revealed that TPM used at a sub-protective dose of 5 mg/ kg significantly potentiated the anticonvulsant action of CBZ and PB in the mouse MES model [33] .…”

Section: Discussionmentioning

confidence: 99%

Isobolographic Analysis of Interaction for Three-Drug Combination of Carbamazepine, Phenobarbital and Topiramate in the Mouse Maximal Electroshock-Induced Seizure Model

Łuszczki

2016

Pharmacology

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Background/Aims: To characterize the anticonvulsant effects of a combination of 3 antiepileptic drugs (AEDs; i.e. carbamazepine (CBZ), phenobarbital (PB) and topiramate (TPM)) at the fixed-ratio of 1:1:1 in the mouse maximal electroshock (MES)-induced seizure model. Methods: Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Type I isobolographic analysis for parallel dose-response relationship curves (DRRCs) was used to analyze the 3-drug combination. Results: In the mouse MES model, all the studied AEDs (i.e. CBZ, PB and TPM) administered singly had their DRRCs parallel to each other. With type I isobolography for parallel DRRCs, a combination of CBZ, PB and TPM at the fixed-ratio of 1:1:1 exerted supra-additive (synergistic) interaction in the mouse MES model. Conclusions: Synergistic interaction among CBZ, PB and TPM at the fixed-ratio of 1:1:1 against MES-induced seizures is worthy of consideration in further clinical settings. All detailed calculations required to perform type I isobolographic analysis for the 3-drug combination were presented.

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Section: Discussionmentioning

confidence: 99%

Isobolographic Analysis of Interaction for Three-Drug Combination of Carbamazepine, Phenobarbital and Topiramate in the Mouse Maximal Electroshock-Induced Seizure Model

Łuszczki

2016

Pharmacology

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“…However, pharmacodynamic interactions are more difficult to identify and measure than pharmacokinetic interactions and are often only concluded by default when a pharmacokinetic interaction has been ruled out. 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).…”

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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“…Pharmacodynamic interactions are difficult to prove and often are uncovered in the course of common clinical practice. However, some investigations performed using models of epilepsy seem to substantiate their existence [47][48][49][50][51][52]. Pharmacodynamic interactions usually enhance toxicity, but can either enhance or reduce efficacy.…”

Section: Hidden Interactionsmentioning

confidence: 95%

Drug interactions in epilepsy care: perspective on the newer generation antiepileptic drugs

Gidal¹,

Nemergut²,

French³

2002

Expert Review of Neurotherapeutics

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Pharmacokinetic interactions involving the antiepileptic drugs have long been considered to be an unavoidable component of epilepsy treatment. Many of the 'older' generation of antiepileptic drugs, including carbamazepine, phenytoin and phenobarbital, are recognized to cause hepatic induction of drug-metabolizing enzyme systems, such as the cytochrome P450 and UDP-gluculronyltransferase. Such interactions are not uncommonly implicated in resulting in clinically significant treatment complications. During the latter half of 1990s, a number of new antiepileptic drugs have become available to clinicians. Generally speaking, a common feature of these 'newer' generation medications are improved pharmacokinetic characteristics, including an improved drug interaction profile. The aim of this review is to summarize the data, both experimental and clinical, regarding pharmacokinetic interactions with the newer antiepileptic drugs.

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Combined Administration of Carbamazepine and Phenobarbital: Effect on Anticonvulsant Activity and Neurotoxicity

Cited by 36 publications

References 23 publications

Isobolographic Analysis of Interaction for Three-Drug Combination of Carbamazepine, Phenobarbital and Topiramate in the Mouse Maximal Electroshock-Induced Seizure Model

Isobolographic Analysis of Interaction for Three-Drug Combination of Carbamazepine, Phenobarbital and Topiramate in the Mouse Maximal Electroshock-Induced Seizure Model

The Importance of Drug Interactions in Epilepsy Therapy

Drug interactions in epilepsy care: perspective on the newer generation antiepileptic drugs

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