Third-generation antiepileptic drugs: mechanisms of action,pharmacokinetics and interactions

This review briefly summarizes the information on the molecular mechanisms of action, pharmacokinetic profiles and drug interactions of novel (third-generation) antiepileptic drugs, including brivaracetam, carabersat, carisbamate, DP-valproic acid, eslicarbazepine, fluorofelbamate, fosphenytoin, ganaxolone, lacosamide, losigamone, pregabalin, remacemide, retigabine, rufinamide, safinamide, seletracetam, soretolide, stiripentol, talampanel, and valrocemide. These novel antiepileptic drugs undergo intensive clinical investigations to assess their efficacy and usefulness in the treatment of patients with refractory epilepsy.     

Emerging drugs for epilepsy

Epilepsy affects ≤ 1% of the world's population. Antiepileptic drugs (AEDs) are the mainstay of treatment, although more than a third of patients are not rendered seizure free with existing medications. Uncontrolled epilepsy is associated with increased mortality and physical injuries, and a range of psychosocial morbidities, posing a substantial economic burden on individuals and society. Limitations of the present AEDs include suboptimal efficacy and their association with a host of adverse reactions. Continued efforts are being made in drug development to overcome these shortcomings employing a range of strategies, including modification of the structure of existing drugs, targeting novel molecular substrates and non-mechanism-based drug screening of compounds in traditional and newer animal models. This article reviews the need for new treatments and discusses some of the emerging compounds that have entered clinical development. The ultimate goal is to develop novel agents that can prevent the occurrence of seizures and the progression of epilepsy in at risk individuals.     

舒尼替尼可延长晚期胰腺神经内分泌肿瘤患者的生存期

一项在晚期胰腺神经内分泌肿瘤患者中进行的Ⅲ期临床试验结果表明,舒尼替尼（sunitinib;商品名：Sutent,索坦）可延长受试者的肿瘤无进展生存期。舒尼替尼是由辉瑞公司研发的新型多靶点抗肿瘤药物,可抑制血小板衍生因子受体（PDGFR）、血管内皮生长因子受体（VEGFR）以及多种酪氨酸激酶,     

Neurosteroid Agonist at GABAA Receptor Induces Persistent Neuroplasticity in VTA Dopamine Neurons

The main fast-acting inhibitory receptors in the mammalian brain are γ-aminobutyric acid type-A (GABA_A) receptors for which neurosteroids, a subclass of steroids synthesized de novo in the brain, constitute a group of endogenous ligands with the most potent positive modulatory actions known. Neurosteroids can act on all subtypes of GABA_A receptors, with a preference for δ-subunit-containing receptors that mediate extrasynaptic tonic inhibition. Pathological conditions characterized by emotional and motivational disturbances are often associated with perturbation in the levels of endogenous neurosteroids. We studied the effects of ganaxolone (GAN)—a synthetic analog of endogenous allopregnanolone that lacks activity on nuclear steroid receptors—on the mesolimbic dopamine (DA) system involved in emotions and motivation. A single dose of GAN in young mice induced a dose-dependent, long-lasting neuroplasticity of glutamate synapses of DA neurons ex vivo in the ventral tegmental area (VTA). Increased α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/N-methyl-D-aspartate ratio and rectification of AMPA receptor responses even at 6 days after GAN administration suggested persistent synaptic targeting of GluA2-lacking AMPA receptors. This glutamate neuroplasticity was not observed in GABA_A receptor δ-subunit-knockout (δ-KO) mice. GAN (500 nM) applied locally to VTA selectively increased tonic inhibition of GABA interneurons and triggered potentiation of DA neurons within 4 h in vitro. Place-conditioning experiments in adult wild-type C57BL/6J and δ-KO mice revealed aversive properties of repeated GAN administration that were dependent on the δ-subunits. Prolonged neuroadaptation to neurosteroids in the VTA might contribute to both the physiology and pathophysiology underlying processes and changes in motivation, mood, cognition, and drug addiction.     

Investigational small molecules in phase II clinical trials for the treatment of epilepsy

ABSTRACT

Introduction: Epilepsy is a neurological disorder that significantly impacts the quality of life of affected persons. Despite advances in research, nearly a third of patients have refractory or pharmacoresistant epilepsy. Even though numerous antiepileptic drugs (AEDs) have been approved over the past decade, there are no agents that halt the development of epilepsy. Thus, new and improved AEDs to prevent these conditions are necessary.

Areas covered: We highlight recent advances in new and innovative drugs for epilepsy disorders. We review three small molecule drugs in phase II clinical trials: Cannabidivarin, BGG492 (Selurampanel) and Ganaloxone.

Expert opinion: The full potential of Cannabidivarin will be realized by testing in other types of treatment-resistant seizures; if they are beneficial, larger phase III clinical trials would probably be undertaken in the same patient population. About BGG492, the challenge will be to find ‘superselective’ AMPAR antagonists targeting only calcium-permeable receptors, with specific mechanisms, that may be attractive partners for drugs in polytherapy. Moreover, there is anew interest surrounding Ganaloxone because of a new submicron formulation that improves its absorption and pharmacokinetic profile, but new studies are necessary before progressing. Further clinical innovations will define the future for these small molecule-type drugs in epilepsy therapeutics.     

An assessment of rufinamide as an anti-epileptic in comparison with other drugs in clinical development

This article evaluates rufinamide, a new anti-epileptic drug (AED) in Phase III development. This review is done against the background of therapeutic challenges of epilepsy, old established AEDs, newly introduced AEDs and AEDs in clinical development. Pharmacological properties of 12 AEDs in clinical trials (Phases I - III) are compared: ADCI, AWD 131-138, DP-VPA, ganaxolone, levetiracetam, losigamone, pregabalin, remacemide hydrochloride, retigabine, rufinamide, soretolide and TV1901. One of these, levetiracetam has been approved in the USA and is waiting approval in other countries. The protective index of rufinamide, as shown in rodent models of epilepsy, is much higher than that of most common AEDs. Features which make it a desirable AED are: (i) a broad spectrum of anti-epileptic actions including both partial and symptomatic generalised epilepsy; (ii) a statistically significant reduction in seizure frequency in clinical trials; (iii) efficacy and safety shown in a broad range of age groups including children and the elderly; (iv) rapid oral absorption enabling quick titration to effective dose and (v) a benign adverse event profile. Most of the events did not lead to discontinuation in clinical trials. These features offer considerable advantages over the existing anti-epileptic drugs. It is one of the two drugs in development which have reached Phase III and is expected to be approved by the year 2001 - 2002.     

Place of neurosteroids in the treatment of status epilepticus

The treatment of refractory or super‐refractory status epilepticus (SE) currently relies on low‐evidence strategies, including general anesthetics to induce pharmacologic coma, ketogenic diet, immunosuppression, and other physical measures. Besides the formal uncertainty regarding efficacy, concerns have been about tolerability. In this situation, identification of alternative, higher evidence treatments is urgently needed. Allopregnanolone is an endogenous neurosteroid exerting a positive allosteric modulation on γ‐aminobutyric acid (GABA)_A receptors. In animal experiments it has been demonstrated that this neurosteroid displays relevant antiseizure properties in a variety of SE models, and that the tolerance to benzodiazepines, relying on receptor internalization, does not affect its action. An experimental clinical use in patients with SE older than 2 years was initated more than 5 years ago. Being a naturally occurring compound, no relevant adverse events are expected, and until now its safety profile appears reassuring. Preliminary results of a phase I/II trial seemed promising, but a recent well‐designed randomized, placebo‐controlled trial could not find any difference in terms of efficacy; tolerability seemed nevertheless good. Patients with refractory and super‐refractory SE still deserve further well‐designed studies to improve current treatment options.     

New anti-epileptic drugs

Epilepsy represents the most common serious neurological disorder, with a prevalence of 0.4 - 1%. Approximately 30% of patients are resistant to currently available drugs. New anti-epileptic drugs are needed to treat refractory epilepsy, improve upon current therapies, improve the prognosis of epilepsy and to prevent the epileptogenic process. Designing compounds with specific physiological targets would seem the most rational method of anti-epileptic drug development, but results from this approach have been disappointing; the widespread screening of compounds in animal models has been much more fruitful. Older methods of animal screening have used acute seizure models, which bear scant relationship to the human condition. More modern methods have included the development of animal models of chronic epilepsy; although more expensive, it is likely that these models will be more sensitive and more specific in determining anti-epileptic efficacy. In this review, we consider the possible physiological targets for anti-epileptic drugs, the animal models of epilepsy, problems with clinical trials and ten promising anti-epileptic drugs in development (AWD 131-138, DP16 (DP-VPA), ganaxolone, levetiracetam, losigamone, pregabalin, remacemide, retigabine, rufinamide and soretolide). Perhaps the most important advances will come about from the realisation that epilepsy is a symptom, not a disease. Preclinical testing should be used to determine the spectrum of epilepsies that a drug can treat, and to direct later clinical trials, which need to select patients based on carefully defined epilepsy syndromes and aetiologies. Not only will such an approach improve the sensitivity of clinical trials, but also will lead to a more rational basis on which to treat.     

A resurging boom in new drugs for epilepsy and brain disorders

Introduction: Epilepsy is one of the most common neurological diseases affecting approximately 50 million people worldwide. Despite many advances in epilepsy research, nearly a third of patients with epilepsy have refractory or pharmacoresistant epilepsy. Despite the approval of a dozen antiepileptic drugs (AEDs) over the past decade, there are no agents that halt the development of epilepsy. Thus, newer and better AEDs that can prevent refractory seizures and modify the disease are needed for curing epilepsy.

Areas covered: In this article, we highlight the recent advances and emerging trends in new and innovative drugs for epilepsy and seizure disorders. We review in detail top new drugs that are currently in clinical trials or agents that are under development and have novel mechanisms of action.

Expert commentary: Among the new agents under clinical investigation, the majority were originally developed for treating other neurological diseases (everolimus, fenfluramine, nalutozan, bumetanide, and valnoctamide); several have mechanisms of action similar to those of conventional AEDs (AP, ganaxolone, and YKP3089); and some new agents represent novel mechanisms of actions (huperzine-A, cannabidiol, tonabersat, and VX-765).