New visions in the pharmacology of anticonvulsion

Abstract

Seizures are resistant to treatment with currently available anticonvulsant drugs in about 1 out of 3 patients with epilepsy. Thus, there is a need for new, more effective anticonvulsant drugs for intractable epilepsy. Furthermore, because of the inadequacy of the currently available anticonvulsant armamentarium with respect to safety, newly developed drugs should be less toxic than existing drugs. Previous and current strategies for development of novel anticonvulsants with improved efficacy or safety are critically discussed in this review. `Old drugs' (or `first generation' drugs), which were developed and introduced between 1910 and 1970, are compared with new anticonvulsants both in terms of clinical efficacy and safety and in terms of mechanisms of action. The new drugs are referred to as `second generation' drugs, i.e. anticonvulsants which have been introduced into clinical practice in recent years, or `third generation' drugs, i.e. compounds in the pipeline of development. In spite of some 30 years of `modern' neuroscientific epilepsy research, most novel, clinically effective second generation anticonvulsants have been found by screening (i.e. serendipity) or structural variation of known drugs and not by rational strategies based on knowledge of processes involved in generation of seizures or in development of epilepsy. An exception are only the GABA(γ-aminobutyrate)-mimetic drugs vigabatrin and tiagabine and, to some extent, gabapentin, which have been developed by a rational strategy, i.e. the `GABA hypothesis' of epilepsy. The fact that preclinical seizure models used for identification and development of novel drugs have been originally validated by old drugs, i.e. conventional anticonvulsants, may explain that several of the new drugs possess mechanisms which do not differ from those of the standard drugs. This may also explain that none of the new drugs seems to offer any marked advantage towards the old, first generation drugs with respect to the ultimate goal of drug treatment of epilepsy, i.e. complete control of seizures, although some of the second generation drugs may have benefits in terms of side effects and tolerability. It is to be hoped that the various novel currently used or planned strategies for drug development produce more effective and safe anticonvulsants than previous strategies. This goal can only be achieved by strengthening our understanding of the fundamental pathophysiology of seizure expression and epileptogenesis as theoretical substrates for new pharmacological strategies, and by devising and refining laboratory models for studying new agents obtained by such strategies.

Introduction

Epilepsy is one of the most common diseases of the brain, affecting at least 50 million persons worldwide (Scheuer and Pedley, 1990). Epilepsy is a chronic and often progressive disorder characterized by the periodic and unpredictable occurrence of epileptic seizures which are caused by an abnormal discharge of cerebral neurons. Many different types of seizures can be identified on the basis of their clinical phenomena. These clinical characteristics, along with their electroencephalographic (EEG) features, can be used to categorize seizures (Commission, 1981). Seizures are fundamentally divided into two major groups: partial and generalized. Partial (focal, local) seizures are those in which clinical or electrographic evidence exists to suggest that the attacks have a localized onset in the brain, usually in a portion of one hemisphere, while generalized seizures are those in which evidence for a localized onset is lacking. Partial seizures are further subdivided into simple partial, complex partial, and partial seizures evolving to secondarily generalized seizures, while generalized seizures are categorized into absence (nonconvulsive), myoclonic, clonic, tonic, tonic–clonic and atonic seizures. In addition to classifying the seizures that occur in patients with epilepsy, patients are classified into appropriate types of epilepsy or epileptic syndromes characterized by different seizure types, etiologies, ages of onset and EEG features (Commission, 1989). More than 40 distinct epileptic syndromes have been identified, making epilepsy a remarkably diverse collection of disorders. The first major division of epilepsy are localization-related (focal, local, partial) epilepsies, which account for roughly 60% of all epilepsies, and generalized epilepsies, which account for approximately 40% of all epilepsies. An epilepsy or epileptic syndrome is either idiopathic, which is virtually synonymous with genetic epilepsy, or symptomatic, i.e. due to structural lesion or major identifiable metabolic derangements. Both type of seizure and epilepsy determine the choice and prognosis of therapy. For instance, the most common and most difficult-to-treat type of seizures in adult patients are complex partial seizures, while primary generalized tonic–clonic (`grand mal') seizures respond in most patients to treatment with anticonvulsants. For many of the seizure types and epilepsy syndromes we have little information about their pathophysiological basis. Yet our insight into how partial seizures, generalized tonic–clonic seizures and generalized absence seizures arise is substantial, which is fortunate since these constitute around 90% of seizures (Lothman, 1996).

In the absence of a specific etiological understanding in any of the epilepsies or epileptic syndromes, approaches to drug therapy of epilepsy must necessarily be directed at the control of symptoms, i.e. the suppression of seizures. In fact, all currently available drugs are anticonvulsant (antiseizure) rather than antiepileptic. The latter term should only be used for drugs which prevent or treat epilepsy and not solely its symptoms (see Section 4). The goal of therapy with an anticonvulsant drug is to keep the patient free of seizures without interfering with normal brain function. The selection of an anticonvulsant drug is based primarily on its efficacy for specific types of seizures and epilepsy (Mattson, 1995). For instance, valproic acid is usually the drug of choice for the generalized idiopathic epilepsies, while carbamazepine and phenytoin show the best balance of seizure control with relatively few adverse effects for the treatment of partial epilepsy (Mattson, 1995). In most patients with epilepsy the prognosis for seizure control is very good. However, a significant proportion of individuals with epilepsy suffer from intractable, i.e. pharmacoresistant epilepsy despite early treatment and an optimum daily dosage of an adequate anticonvulsant drug (Dam, 1986; Dreifuss, 1992; Leppik, 1992; Forsgren, 1995; Sillanpää, 1995). Thus, there is a clear need for new drugs or new strategies of therapeutic management. Although surgical treatment of epilepsy may be an alternative if anticonvulsant drugs fail, surgery for epilepsy might not be needed if we knew more about ways to prevent medical intractability or if we had more effective and less toxic anticonvulsant drugs (Theodore, 1992).

In addition to the need for new drugs for epileptic patients whose seizures are resistant to available anticonvulsants, new drugs with benefits in terms of side effects and tolerability are needed even if they do not demonstrate greater efficacy than established anticonvulsants (Richens, 1991; Schmidt and Krämer, 1994). Furthermore, in view of the fact that the therapeutic effectiveness of the older anticonvulsant drugs has usually been limited by their narrow therapeutic ratio, i.e. the ratio of toxic dose against the effective dose, it is hoped that an improved therapeutic ratio may be seen with some of the novel compounds currently being developed.