Synergism with GABAergic drugs in refractory epilepsy

Leach, John Paul; Brodie, M.J.

doi:10.1016/s0140-6736(94)93110-0

Cited by 44 publications

(17 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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)]. Low doses of LTG coadministered with VPA appear to produce a therapeutically desirable pharmacodynamic interaction in patients with typical absence seizures (35).…”

Section: Pharmacodynamic Interactionsmentioning

confidence: 52%

The Importance of Drug Interactions in Epilepsy Therapy

et al. 2002

View full text Add to dashboard Cite

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.

show abstract

Section: Pharmacodynamic Interactionsmentioning

confidence: 52%

The Importance of Drug Interactions in Epilepsy Therapy

et al. 2002

View full text Add to dashboard Cite

show abstract

“…To complicate matters, other studies have postulated that AEDs with similar mechanisms of action are more effective than two AEDs with different mechanisms [15]. Synergy between two GABAergic drugs, tiagabine and vigabatrin, has been demonstrated in brain slice experiments [16] as well as in a limited number of patients [17]. Although structurally and mechanistically similar, oxcarbazepine (OXC) added to CBZ has also been shown to be effective [18].…”

Section: Theoretical Considerationsmentioning

confidence: 99%

Rational Polytherapy with Antiepileptic Drugs

Lee

Dworetzky

2010

Pharmaceuticals

View full text Add to dashboard Cite

Approximately 30–40% of patients do not achieve seizure control with a single antiepileptic drug (AED). With the advent of multiple AEDs in the past 15 years, rational polytherapy, the goal of finding combinations of AEDs that have favorable characteristics, has become of greater importance. We review the theoretical considerations based on AED mechanism of action, animal models, human studies in this field, and the challenges in finding such optimal combinations. Several case scenarios are presented, illustrating examples of rational polytherapy.

show abstract

“…Reflecting the fact that the activation of the same (GABA-ergic) neurotransmitter system exerts synergy in seizure control in experimental model of epilepsy, it seems possible that the combinations of TGB with GBP may also be efficacious in patients with drug-resistant epilepsy, providing the most effective treatment regimen. Some existing clinical data indicate that coadministration of TGB with vigabatrin (VGB), two drugs exclusively influencing the GABA-ergic system, may considerably improve the control of seizure attacks (Leach and Brodie, 1994). The synergistic interaction observed between these AEDs was not casual because it was experimentally confirmed that lower doses of VGB coadministered with TGB significantly reduced GABA uptake from synaptic clefts (Leach et al, 1996), resulting in the increase of GABA in the whole mouse neocortex (Leach et al, 1997).…”

Section: Controlmentioning

confidence: 99%

Tiagabine Synergistically Interacts with Gabapentin in the Electroconvulsive Threshold Test in Mice

Łuszczki

Świąder

Parada-Turska

et al. 2003

Neuropsychopharmacol

View full text Add to dashboard Cite

Polytherapy, based on the rational combining of antiepileptic drugs (AEDs), is required for patients with drug-resistant epilepsy. In such cases, the combinations of AEDs usually offer a significant enhancement of their protective effects against seizures. There has appeared a hypothesis that combining two AEDs, influencing the same neurotransmitter system, results in the potentialization of their anticonvulsant effects. For corroborating this hypothesis, a pharmacological character of interaction between tiagabine (TGB) and gabapentin (GBP)Ftwo novel AEDs affecting the GABA-ergic system, in the maximal electroshock seizure threshold (MEST)-test in mice was evaluated. TGB at the dose of 4 mg/kg and GBP at 75 mg/kg significantly raised the electroconvulsive threshold. Further, using the isobolographic calculations, TGB was coadministered with GBP at three fixed-ratios (1 : 3, 1 : 1, and 3 : 1) of their respective protective drug doses. All examined combinations of TGB with GBP exerted supra-additive (synergistic) interactions against MEST-induced seizures in mice. The interaction index, describing the strength and magnitude of interaction, ranged between 0.25 and 0.50 indicating supraadditivity. Adverse (neurotoxic) effects were evaluated in the chimney (motor performance) and the step-through, light-dark passive avoidance (long-term memory) tests in mice. The examined combinations of TGB with GBP did not affect the motor coordination, except for the fixed-ratio of 1 : 1, at which significant impairment of motor performance was observed. Moreover, all combinations selectively impaired the acquisition of the task in the passive avoidance test, having no impact on consolidation and retrieval in the longterm memory test. The pain threshold test revealed that the observed disturbances in the passive avoidance testing resulted presumably from the antinociceptive activity of these AEDs in combinations. After lengthening the exposing time to the direct current stimulus in the passive avoidance test from 2 to 6 s, the acquisition of the task, in animals receiving the combinations of TGB and GBP was not impaired. Neither the plasma, nor brain concentrations of GBP were affected by TGB application, so pharmacokinetic events that might negatively influence the observed effects are not probable. Results of this study clearly indicate that the activation of the same neurotransmitter system (GABA-ergic) leads to a synergistic interaction. The pain threshold test is a very good paradigm for screening the antinociceptive properties of AEDs, which may disturb the long-term memory testing in animals. Combinations of TGB with GBP (very promising from a preclinical point of view) should be clinically verified for elaborating the most effective treatment regimen in patients with intractable seizures.

show abstract

Synergism with GABAergic drugs in refractory epilepsy

Cited by 44 publications

References 4 publications

The Importance of Drug Interactions in Epilepsy Therapy

The Importance of Drug Interactions in Epilepsy Therapy

Rational Polytherapy with Antiepileptic Drugs

Tiagabine Synergistically Interacts with Gabapentin in the Electroconvulsive Threshold Test in Mice

Contact Info

Product

Resources

About