Antiepileptic drug discovery: lessons from the past and future challenges

Historically, most antiepileptic drugs (AEDs) have been discovered either by serendipity, or the screening of compounds using acute seizure models. However, an increasing understanding of the molecular mechanisms underlying epileptogenesis has led to more rational approaches to drug discovery, which have focused on either enhancing inhibitory γ -amino butyric acid (GABA)-ergic, or antagonizing excitatory glutamatergic, neurotransmission. Unfortunately, AEDs generated using such strategies have poor efficacy and safety profiles, as they interfere with normal cell processes, while ignoring the complex underlying pathophysiology of epilepsy. Recently, however, the use of new epilepsy models has led to the discovery of levetiracetam, an AED with a truly unique mechanism of action, devoid of anticonvulsant activity in normal animals, but with potent seizure suppression in genetic and kindled chronic epilepsy models, and an unusually high safety margin. The recent identification of brivaracetam and seletracetam, which optimize this unique mechanism of action, may further improve the medical management of epilepsy. The experience with levetiracetam, brivaracetam and seletracetam reveals that new experimental epilepsy models can detect AEDs possessing a unique mechanism of action and thereby target the future challenge of providing clinicians novel additions to the current armamentarium of AEDs.     

Antiepileptic Drug Therapy: General Treatment Principles and Application for Special Patient Populations

Summary: Over the past 10 years, the goal of treating epilepsy has evolved from attaining complete control of seizures, regardless of medication-related side effects or psychosocial problems, to enabling the patient to lead a lifestyle consistent with his or her capabilities. The recent introduction of new medications has brought hope to patients who have previously been unable to function optimally because of refractory seizures or side effects. A rational approach to selecting antiepileptic drug (AED) therapy for a particular patient would require a detailed understanding of the underlying cause(s) of seizures in that patient. Unfortunately, this is often not possible. Furthermore, currently available AEDs have been tested on the basis of seizure type rather than etiology. Nevertheless, an individualized empirical approach based on an open dialog with the patient and perseverance is often successful. There have also been significant advances in the understanding of seizures at the cellular level, notably in the role of γ-aminobutyric acid. Medical, social, and psychosocial issues relevant to particular patient populations (such as women of childbearing age and elderly patients) also must be considered when treatment plans are formulated. The recent addition of new AEDs, with unique mechanisms of action and favorable pharmacokinetic and tolerability profiles, has greatly widened the range of therapeutic options for patients.     

Epilepsy Care: Image of the Future

Summary: A number of factors have contributed to improvements in the care of epilepsy during the past decade, including the International League Against Epilepsy classifications, therapeutic antiepileptic drug (AED) monitoring and the concept of monotherapy, new AEDs with novel mechanisms of action, and new insights into etiology that suggest novel therapies. Pharmacologically "clean" AEDs acting on a single known mechanism will be an important element in the future care of patients with epilepsy. Augmentation of GABAergic inhibition is being successfully exploited by AEDs, and there remains much room for further pharmacologic innovation. The potential role of AEDs acting specifically on the GAT-1 or GAT-4 sub-group of γ-aminobutyric acid transporters is a topic of current research. Specifically acting AEDs designed to have a single and known mode of action will permit true monotherapy, one AED with one target as opposed to one AED with several targets, and may open the way to rational polytherapy, i.e., designed use of one AED per mechanism in epilepsies with multifactorial causation. New research demonstrating a possible autoimmune basis for some forms of epilepsy illustrates the potential for novel nonpharmacologic approaches, and the role of prevention must also be emphasized. The image of the future is an optimistic one.     

Development of new antiepileptic drugs: challenges, incentives, and recent advances

Despite the introduction of many second-generation antiepileptic drugs (AEDs) in the past 15 years, a third of patients with epilepsy remain refractory to available treatments, and newer and more effective therapies are needed. Although our understanding of the mechanisms of drug resistance is fragmented, novel AED targets have been identified, and models of refractory epilepsy have been developed that can help to select candidate compounds for development. There are more than 20 compounds with potential antiepileptic activity in various stages of clinical development, and for many of these promising clinical trial results are already available. Several incentives justify further investment into the discovery of newer and more effective AEDs. Moreover, developments in clinical trial methodology enable easier completion of proof-of-concept studies, earlier definition of the therapeutic potential of candidate compounds, and more efficient completion of trials for various epilepsy indications.     

An Introduction to Antiepileptic Drugs

Summary:  In recent years, the number of commercially available antiepileptic drugs (AEDs) has increased steadily. Although this may complicate management choices, it also offers welcome new options to individualize treatment more effectively. Because each of the available AEDs differs from others in many clinically relevant properties, opportunities to tailor drug treatment to the characteristics of the individual patient have never been greater. Properties that are especially important in drug selection in patients with epilepsy include spectrum of efficacy in different seizure types, adverse effects profile, pharmacokinetic properties, susceptibility to cause or be a target of clinically important drug–drug interactions, ease of use, and cost. Other factors that need to be considered in tailoring drug choice include availability of user-friendly pediatric formulations, and potentially favorable effects on co-morbid conditions. In fact, a number of AEDs are efficacious and widely prescribed in additional indications, particularly psychiatric disorders, migraine prophylaxis, and neuropathic pain. Recently, advances have been made in understanding the mechanisms of actions of AEDs at the molecular level. While a fully mechanistic approach to the clinical use of these agents is not yet feasible, knowledge of mechanisms of action offers useful clues in predicting their efficacy profile and spectrum of potential adverse effects.     

Intrinsic Severity as a Determinant of Antiepileptic Drug Refractoriness

For the most part, resistance to medications in epilepsy is independent of the choice of antiepileptic drug. This simple clinical observation constrains the possible biological mechanisms for drug refractory epilepsy by imposing a requirement to explain resistance for a diverse set of chemical structures that act on an even more varied group of molecular targets. To date, research on antiepileptic drug refractoriness has been guided by the “drug transporter overexpression” and the “reduced drug-target sensitivity” hypotheses. These concepts posit that drug refractoriness is a condition separate from the underlying epilepsy. Inadequacies in both hypotheses mandate a fresh approach to the problem. In this article, we propose a novel approach that considers epilepsy pharmacoresistance in terms of intrinsic disease severity. We suggest that neurobiological factors that confer increased disease severity lead to drug intractability. The occurrence of frequent seizures at disease onset is an important factor that signals increased severity.At the molecular level, marketed antiepileptic drugs (AEDs) reduce the incidence of seizures by effects on 1) voltage-gated sodium channels; 2) components of the GABA system including GABA_A receptors, the GAT-1 GABA transporter and GABA transaminase; and 3) voltage-gated calcium channels (1). Recently, several additional molecular targets have been defined, including α₂δ, SV2A and Kv7/KCNQ/M potassium channels (2). Different AEDs acting on the same target may affect the target in biophysically distinct ways, and some AEDs act on more than one of the molecular targets. It is safe to say that no marketed AED acts in an identical fashion to any other, with the possible exception of carbamazepine and oxcarbazepine that may have very similar modes of action. There is no simple, universally accepted definition of drug refractory epilepsy (3). Operationally, however, we consider drug-resistant epilepsy to be epilepsy in which uncontrolled seizures persist despite state-of-the-art medical management. A neurobiological understanding of drug resistance in epilepsy requires an explanation of the failure to obtain seizure control despite the availability of nearly 25 different AEDs, each of which has distinct physical-chemical properties and modes of action.     

Efficacy and safety of adjunctive zonisamide therapy for refractory partial seizures

An approach to the selection of appropriate antiepileptic drugs (AEDs) for inclusion in polytherapy is to take into account both the efficacy of a drug and also its mechanism of action and pharmacokinetic profile. The AED zonisamide is licensed in Europe and the USA for use as adjunctive therapy in adult patients with partial onset epilepsy. Four pivotal clinical studies in patients with refractory partial seizures demonstrated that zonisamide as an add-on was most effective at doses of >or=300 mg/day, with responder rates (>or=50% reduction from baseline in seizure frequency) ranging from 28 to 47% for all seizures. In addition, zonisamide has a unique combination of multiple mechanisms of action that are potentially complementary with concomitant AEDs. Zonisamide has no clinically relevant effects on the pharmacokinetics of other commonly used AEDs, however, co-administration with cytochrome P450 3A4 (CYP3A4) inducers or inhibitors may change zonisamide's pharmacokinetic profile. Zonisamide is well tolerated with the majority of adverse events being mild-to-moderate and generally manageable. The tolerability of zonisamide has also been shown to improve with slower drug titration and duration of drug treatment. These characteristics suggest that zonisamide may be suitable as a key adjunct in rational polytherapy.     

Clinical Significance of Animal Seizure Models and Mechanism of Action Studies of Potential Antiepileptic Drugs

Summary: More than 50 million persons worldwide suffer from epilepsy, many of whom are refractory to treatment with standard antiepileptic drugs (AEDs). Fortunately, new AEDs commercialized since 1990 are improving the clinical outlook for many patients. Our growing understanding of anticonvulsant mechanisms and the relevance of preclinical animal studies to clinical antiepileptic activity have already contributed to the design of several new AEDs and should be increasingly beneficial to further efforts at drug development. Mechanisms have been identified for older AEDs [phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), barbiturates, benzodiazepines (BZDs), ethosuximide (ESM)] and newer AEDs [vigabatrin (VGB), lamotrigine (LTG), gabapentin (GBP) tiagabine (TGB), felbamate (FBM), topiramate (TPM)]. Several novel anticonvulsant mechanisms have recently been discovered. FBM appears to be active at the strychnine-insensitive glycine binding site of the NMDA receptor. TPM is active on the kainate/AMPA subtype of glu-tamate receptor and at a potentially novel site on the GABA_A receptor. For several reasons, availability of a single AED with multiple mechanisms of action may be preferred over availability of multiple AEDs with single mechanisms of action. These reasons include ease of titration, lack of drug-drug interactions, and reduced potential for pharmacodynamic tolerance.     

Role of Vigabatrin and Lamotrigine in Treatment of Childhood Epileptic Syndromes

Summary: Purpose: Vigabatrin (VGB) and lamotrigine (LTG) are two new antiepileptic drugs (AEDs) with different mechanisms of action for treatment of refractory epilepsies. Previous reports have indicated efficacy of both drugs in a number of epileptic syndromes.
Methods: We compared these new AEDs drugs to determine their respective efficacy against different types of epileptic syndrome and to develop a rational approach to their use. We reviewed the charts of 105 children, with partial and generalized epilepsies.
Results: VGB was to be significantly more effective in children with partial epilepsies, and LTG was more effective in those with generalized epilepsies.
Conclusions: VGB and LTG have different therapeutic profiles. Combination treatment with the two drugs may represent rational polytherapy for patients with epilepsy resistant to treatment with either drug alone or as add-on to other AED treatment.