Pharmacodynamic interactions between antiepileptic drugs: preclinical data based on isobolography

Czuczwar, Stanisław J.; Kaplanski, Jacek; Swiderska-Dziewit, Grazyna; Gergont, Aleksandra; Kroczka, Sławomir; Kaciński, Marek

doi:10.1517/17425250802677826

Cited by 34 publications

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“…Numerous studies in animal models and patient brain tissue have confirmed complex disease‐associated alterations affecting antiepileptic drug target sites . Respective alterations have been neglected in the past when determining the anticonvulsant and adverse effects of antiepileptic drug combination in a series of studies using acute seizure models . Stafstrom has emphasized this limitation in his comprehensive and critical review, stating that despite its elegant quantitative design, conclusions from isobolographic analysis data are limited due to the performance of these tests on naive rodents.…”

Section: Discussionmentioning

confidence: 99%

“…It is interesting to note that the slopes of the perampanel dose–response curves in the combination for desired anticonvulsant effects and for adverse motor effects differed. The fact that the ratio of the combination partners might have a major impact on the value of drug combinations has been emphasized previously with a focus on efficacy . For instance, the impact of a combination of stiripentol with carbamazepine even resulted in three different types of interaction with synergistic, additive, or antagonistic effects in the maximum electroshock seizure test depending on the drug ratio …”

Section: Discussionmentioning

confidence: 99%

“…Considering the numerous possibilities of combinations it is impossible to evaluate all relevant combinations in clinical studies. In the past, additive, synergistic, and antagonistic effects of antiepileptic drugs have been assessed in rodent models of acute seizures . However, these models do not reflect the complexity of disease‐associated target and network alterations that are likely to affect drug responses .…”

mentioning

confidence: 99%

“…In the past, additive, synergistic, and antagonistic effects of antiepileptic drugs have been assessed in rodent models of acute seizures. 3 However, these models do not reflect the complexity of disease-associated target and network alterations that are likely to affect drug responses. 4 The amygdala kindling model is an established chronic model of temporal lobe epilepsy, in which animals exhibit a variety of molecular, cellular, and network alterations reflecting those in patients.…”

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confidence: 99%

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Synergism of perampanel and zonisamide in the rat amygdala kindling model of temporal lobe epilepsy

et al. 2016

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SUMMARYObjective: Anticonvulsive monotherapy fails to be effective in one third of patients with epilepsy resulting in the need for polytherapy regimens. However, with the still limited knowledge, drug choices for polytherapy remain empirical. Here we report experimental data from a chronic epilepsy model for the combination of perampanel and zonisamide, which can render guidance for clinical studies and individual drug choices. Methods: The anticonvulsant effects of the combination of perampanel and zonisamide were evaluated in a rat amygdala kindling model. Furthermore, the potential for motor impairment was evaluated. The type of interaction was quantitatively assessed based on isobolographic analysis. Results: When administered alone, zonisamide dose-dependently increased the afterdischarge threshold in fully kindled rats. Moreover, data confirmed efficacy of perampanel to inhibit seizure initiation and progression with an impact on propagation of activity from the focus. Pronounced threshold increases were observed following administration of a constant zonisamide dosage combined with different doses of perampanel. Isobolographic analysis of drug responses, which is based on individual drug dose-effect data, revealed a synergistic interaction substantiating the high efficacy of the combination. Furthermore, rotarod data indicated that the combination has a favorable tolerability profile when zonisamide is coadministered with low doses of perampanel. Plasma concentration analysis argued against a pharmacokinetic interaction as a basis for the synergism. Significance: The findings clearly indicate a pronounced synergistic anticonvulsant effect for the combination of the noncompetitive a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist perampanel with zonisamide, which modulates voltage-sensitive sodium channels and T-type calcium currents. Consequently, polytherapy using these two antiepileptic drugs might be efficacious for clinical management of partial-onset seizures. The findings indicate that the impact of dose ratios on tolerability needs be taken into account. With regard to conclusions about the extent of the synergism and its implications further antiepileptic drug combinations need to be evaluated allowing direct comparison.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Synergism of perampanel and zonisamide in the rat amygdala kindling model of temporal lobe epilepsy

et al. 2016

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“…Thus, evaluation of drug-drug interaction is important in cancer chemotherapy. The quantitative assessment of drug combinations is necessary to the judgment of synergy in several areas, such as the combination therapy in the epilepsy, anti-HIV-1 infection, malaria, antibiotic therapy and cancer chemotherapy (3)(4)(5)(6)(7). Isobologram and combination index (CI) analyses are the two most popular methods for evaluating drug interactions (8).…”

Section: Introductionmentioning

confidence: 99%

A traditional Chinese medicine formulation consisting of Rhizoma Corydalis and Rhizoma Curcumae exerts synergistic anti-tumor activity

Wang¹

2009

Oncol Rep

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Abstract. Synergy analysis of anticancer agents is an important approach to determining the ratio and/or dose of drugs for clinical combination therapy. However, this method is rarely used to evaluate the composition of traditional Chinese medicine formulation. 'Yanhusuo San' (YHSS), which consists of yanhusuo (Rhizoma Corydalis) and Ezhu (Rhizoma Curcumae), has been an archaic Chinese medicine prescription since the Song dynasty (960-1279 AD). We previously demonstrated that either yanhusuo or ezhu has strong anticancer effect. Herein, we sought to determine the possible synergic effect between these two Chinese herbs. We measured the IC 50 of each herb extract and both extracts at different ratios of doses by MTT assay. Isobologram and combination index (CI) analyses were used to evaluate the synergistic effect of yanhusuo and ezhu in different fixed ratios. Our results indicated that a combination of two herbal extracts exhibits the strongest anticancer cell proliferation effect at the ratio of 3:2 (ezhu to yanhusuo; referred to as E3Y2). Using Boyden Chamber assay, flow cytometry, and fluorescence microscopy analysis, we found that E3Y2 could markedly reduce the cell invasion ability and induce cytochrome c release rather than single use, but E3Y2 could not influence the cell cycle distribution. When the levels of ERK1/2, p-ERK1/2 and p-Rb were determined by Western blot analysis, we found that the E3Y2 significantly suppresses the level of p-ERK. Thus, our studies provide a plausible molecular basis of the synergistic anti-tumor effect of ezhu and yanhusuo.

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What Are the Arguments For and Against Rational Therapy for Epilepsy?

Barker‐Haliski

Sills

White

2014

Issues in Clinical Epileptology: A View From the Bench

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Although more than a dozen new anti-seizure drugs (ASDs) have entered the market since 1993, a substantial proportion of patients (~30 %) remain refractory to current treatments. Thus, a concerted effort to identify and develop new therapies that will help these patients continues. Until this effort succeeds, it is reasonable to re-assess the use of currently available therapies and to consider how these therapies might be utilized in a more efficacious manner. This applies to the selection of monotherapies in newly-diagnosed epilepsy, but perhaps, more importantly, to the choice of combination treatments in otherwise drug-refractory epilepsy. Rational polytherapy is a concept that is predicated on the combination of drugs with complementary mechanisms of action (MoAs) that work synergistically to maximize efficacy and minimize the potential for adverse events. Furthermore, rational polytherapy requires a detailed understanding of the MoA subclasses amongst available ASDs and an appreciation of the empirical evidence that supports the use of specific combinations. The majority of ASDs can be loosely categorized into those that target neurotransmission and network hyperexcitability, modulate intrinsic neuronal properties through ion channels, or possess broad-spectrum efficacy as a result of multiple mechanisms. Within each of these categories, there are discrete pharmacological profiles that differentiate individual ASDs. This chapter will consider how knowledge of MoA can help guide therapy in a rational manner, both in the selection of monotherapies for specific seizure types and syndromes, but also in the choice of drug combinations for patients whose epilepsy is not optimally controlled with a single ASD.

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Pharmacodynamic interactions between antiepileptic drugs: preclinical data based on isobolography

Cited by 34 publications

References 29 publications

Synergism of perampanel and zonisamide in the rat amygdala kindling model of temporal lobe epilepsy

Synergism of perampanel and zonisamide in the rat amygdala kindling model of temporal lobe epilepsy

A traditional Chinese medicine formulation consisting of Rhizoma Corydalis and Rhizoma Curcumae exerts synergistic anti-tumor activity

What Are the Arguments For and Against Rational Therapy for Epilepsy?

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