New antiepileptic drugs: Comparative studies of efficacy and cognition

Over the past 10 years, the Food and Drug Administration has approved eight prophylactic antiepileptic drugs (AEDs). Although the goal of universal seizure control without side effects has not been reached, the tolerability of medications has improved. This paper reviews the AEDs introduced since 1993 and tries to objectively present comparative data obtained in double-blind studies.     

New antiepileptic drugs

Finding a niche for each antiepileptic drug has become challenging as more new agents are approved. In this article, the most recent information regarding these drugs is reported, with emphasis on the agents approved in the past 10 years. The evidence clearly shows that, despite limited Food and Drug Administration indications, all drugs are useful in monotherapy, and many have broader spectrums of action. Adverse effects can also help distinguish between agents. Familiarity with this latest information will help clinicians make the best choice for each of their patients with epilepsy.     

癫痫治疗药物选择新动向

近年来,尽管有许多新的癫痫治疗方法陆续问世,但迄今为止,癫痫的药物治疗仍然是预防和治疗癫痫的主要方法。尤其近年围绕抗癫痫药物的选择和研制,一些新的观点开始进入临床实践,了解这些新观念有助于改善癫痫治疗前景。 一、抗癫痫药物治疗的困境 自人类发现溴化剂可治疗癫痫以来,业已研制近20种不同作用机制的抗癫痫药物,其中18种已批准用于临床。这些抗癫痫药物的临床应用使癫痫发作从一种不可治疗性疾病成为一种可治疗性疾病,通过这些已研制出的药物,有可能使60%以上患者的癫痫发作得到满意控制,相当一部分患者可以停药且终生不再发作,显示出癫痫可控的良好前景。     

New antiepileptic drugs and women

Since 1990, sixteen new antiepileptic drugs (AEDs) have been introduced. Most of these new AEDs have only been insufficiently studied with respect to women-specific aspects such as endogenous sex hormones, hormonal contraception, pregnancy, breastfeeding, or menopause. This is of concern because it has been shown for some of the new AEDs that these factors may have a clinically significant impact on their pharmacokinetics and seizure control. Also, new AEDs may affect hormone homeostasis and pass over into breast milk. The best studied of the new AEDs are lamotrigine, levetiracetam and oxcarbazepine. Although gabapentin and pregabalin are even more frequently used (due to their therapeutic effects in nonepileptic conditions), our understanding of these two drugs in relation to women's issues is surprisingly poor. Little to nothing is known about zonisamide, retigabine/ezogabine, lacosamide, perampanel and the other new AEDs. Nevertheless, many small studies and case series have been published on new AEDs and women-specific aspects. This review gives an overview on what is known today.     

New antiepileptic drugs: Prospects for the future

Considerable advances have been made in the understanding of the pathophysiology of epilepsy, which has led to the development of a large number of unique antiepileptic drugs affecting a broader array of pharmacological targets than traditional anticonvulsants. In this paper we discuss seven anticonvulsants that are either recently released, or are being actively investigated in the United States. A review of their pharmacological properties and clinical efficacy is presented.     

New antiepileptic drugs in pediatric epilepsy

New antiepileptic drugs (AEDs), introduced since 1993, provide more diverse options in the treatment of epilepsy. Despite the equivalent efficacy and better tolerability of these drugs, more than 25% of patients remain refractory to treatment. Moreover, the issues for pediatric patients are different from those for adults, and have not been addressed in the development and application of the new AEDs. Recently published evidence-based treatment guidelines have helped physicians to choose the most reasonable AED, although they cannot fully endorse new AEDs because of the lack of well-designed, randomized controlled trials. We review the mechanisms of action, pharmacokinetic properties, adverse reactions, efficacy, and tolerability of eight new AEDs (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, vigabatrin, and zonisamide), focusing on currently available treatment guidelines and expert opinions regarding pediatric epilepsy.     

New antiepileptic drugs and non-pharmacological treatments

Many new drugs and therapies can now be offered to patients with epilepsy. The problem is that we do not know just how much better these new and more expensive therapies are compared with the old ones, nor do we know the full range of side-effects. This review focuses on the major clinical studies that have been published in the past year with emphasis on information as to tolerability and efficacy, especially when there is some information comparing different drugs or therapies. The topics include vigabatrin, lamotrigine, gabapentin, felbamate, topiramate, tiagabine, oxcarbazepine, levetiracetam, vagus nerve stimulation and the ketogenic diet. It is encouraging that some of the newly published double-blinded placebo-controlled studies now include children and the elderly, patient groups that have previously been neglected.     

New horizons in the development of antiepileptic drugs

Significant advances have been made in the treatment of epilepsy over the past decades. However, despite the development of various novel antiepileptic drugs, about one third of patients with epilepsy is resistant to current pharmacotherapies. Even in patients in whom pharmacotherapy is efficacious, current antiepileptic drugs do not seem to affect the progression or underlying natural history of epilepsy. Furthermore, there is currently no drug available which prevents the development of epilepsy, e.g. after head trauma. Thus, there are at least three important goals for the future. (1) Better understanding of processes leading to epilepsy, thus allowing to create therapies aimed at the prevention of epilepsy in patients at risk; (2) improved understanding of biological mechanisms of pharmacoresistance, allowing to develop drugs for reversal or prevention of resistance; and (3) development of disease-modifying therapies, inhibiting the progression of epilepsy. The ultimate goal would be a drug combining these three properties, thus resulting in a complete cure for epilepsy. In this review, the current status of antiepileptic therapies is critically assessed, and innovative approaches for future therapies are highlighted.     

Choosing the correct antiepileptic drugs: from animal studies to the clinic

Epilepsy is a chronic condition caused by an imbalance of normal excitatory and inhibitory forces in the brain. Antiepileptic drug therapy is directed primarily toward reducing excitability through blockage of voltage-gated Na(+) or Ca(2+) channels, or increasing inhibition through enhancement of gamma-aminobutyric acid currents. Prior to clinical studies, putative antiepileptic drugs are screened in animals (usually rodents). Maximal electrical shock, pentylenetetrazol, and kindling are typically used as nonmechanistic screens for antiseizure properties, and the rotorod test assesses acute toxicity. Whereas antiseizure drug screening has been successful in bringing drugs to the market and improving our understanding of the pathophysiology of seizures, it merits emphasis that the vast majority of drug screening occurs in mature male rodents and involves models of seizures, not epilepsy. Effective drugs in acute seizures may not be effective in chronic models of epilepsy. Seizure type, clinical and electroencephalographic phenotype, syndrome, and etiology are often quite different in children with epilepsy than in adults. Despite these age-related unique features, drugs used in children are generally the same as those in adults. As awareness of the unique features of seizures during development increases, more drug screening in the immature animal will likely occur.     

New Horizons in the development of antiepileptic drugs: Innovative strategies

The past decades have brought many advances to the treatment of epilepsy. However, despite the continued development and release of new antiepileptic drugs, many patients have seizures that do not respond to drug therapy or have related side effects that preclude continued use. Even in patients in whom pharmacotherapy is efficacious, current antiepileptic drugs do not seem to affect the progression or the underlying natural history of epilepsy. Furthermore, there is currently no drug available which prevents the development of epilepsy, e.g. after head trauma or stroke. Thus, there are at least four important goals for the future: (1) development of better antiepileptic ("anti-ictal") drugs with higher efficacy and tolerability to stop seizures compared to current medications; (2) better understanding of processes leading to epilepsy, thus allowing to create therapies aimed at the prevention of epilepsy in patients at risk; (3) development of disease-modifying therapies, interfering with progression of epilepsy, and (4) improved understanding of neurobiological mechanisms of pharmacoresistance, allowing to develop drugs for reversal or prevention of drug resistance. The third Workshop on New Horizons in the Development of Antiepileptic Drugs explored these four goals for improved epilepsy therapy, with a focus on innovative strategies in the search for better anti-ictal drugs, for novel drugs for prevention of epilepsy or its progression, and for drugs overcoming drug resistance in epilepsy. In this conference review, the current status of antiepileptic therapies under development is critically assessed, and innovative approaches for future therapies are highlighted.     

Interactions between antiepileptic drugs,and between antiepileptic drugs and other drugs

Interactions between antiepileptic drugs, or between antiepileptic drugs and other drugs, can be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions involve changes in absorption, distribution or elimination, whereas pharmacodynamic interactions involve synergism and antagonism at the site of action. Most clinically important interactions of antiepileptic drugs result from induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital and primidone are strong inducers of cytochrome P450 and glucuronizing enzymes (as well as P‐glycoprotein) and can reduce the efficacy of co‐administered medications such as oral anticoagulants, calcium antagonists, steroids, antimicrobial and antineoplastic drugs through this mechanism. Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate (at doses ≥200 mg/day) and perampanel (at doses ≥8 mg/day) have weaker inducing properties, and a lower propensity to cause interactions mediated by enzyme induction. Unlike enzyme induction, enzyme inhibition results in decreased metabolic clearance of the affected drug, the serum concentration of which may increase leading to toxic effects. Examples of important interactions mediated by enzyme inhibition include the increase in the serum concentration of phenobarbital and lamotrigine caused by valproic acid. There are also interactions whereby other drugs induce or inhibit the metabolism of antiepileptic drugs, examples being the increase in serum carbamazepine concentration by erythromycin, and the decrease in serum lamotrigine concentration by oestrogen‐containing contraceptives. Pharmacodynamic interactions between antiepileptic drugs may also be clinically important. These interactions can have potentially beneficial effects, such as the therapeutic synergism of valproic acid combined with lamotrigine, or adverse effects, such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of sodium channel blocking antiepileptic drugs.     

Currently available antiepileptic drugs

Many new antiepileptic drugs (AEDs) have become available over the past 15 years. At the same time, the emphasis on treating patients with epilepsy has grown from stopping seizures to avoiding side effects and maximizing quality of life. This review summarizes currently available AEDs, and presents general treatment principles and guidelines for AED selection. Unfortunately, despite the increased treatment options of today, seizure freedom without side effects remains unattainable for too many patients with epilepsy. Consequently, there remains a significant need for further development of new therapies.     

P-glycoprotein-mediated efflux of antiepileptic drugs: preliminary studies in mdr1a knockout mice

Evidence suggests that the efflux transporter P-glycoprotein (P-gp) may play a facilitatory role in refractory epilepsy by limiting the brain access of antiepileptic drugs (AEDs). We have conducted a preliminary pharmacokinetic study of seven commonly used AEDs in mdr1a knockout mice, devoid of P-gp at the blood-brain barrier. A parallel group of matched wild-type mice served as controls. AEDs were administered by subcutaneous injection and serum and brain drug concentrations determined at 30, 60, and 240min post-dosing. The brain-serum concentration ratio for topiramate was higher in mdr1a(-/-) mice than in wild-type controls at all time points investigated. No consistent effects were observed with any other AED investigated. These findings suggest that topiramate may be a substrate for P-gp-mediated transport. Further studies employing a range of model systems are required to substantiate this observation and to address the potential role of drug transporters in refractory epilepsy.