New anti-epileptic drugs for the 21st century

Prior to 1993, there were only six major drugs available in the US for the treatment of patients with epilepsy. These included phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), primidone (PRIM), valproic acid/sodium valproate (VPA) and ethosuximide (ESX). Of these drugs, VPA has the broadest spectrum of activity and ESX the most limited. Despite these six agents, as well as several secondary drugs, it is estimated that over 30% of patients have inadequate seizure control, while others, whose disease is adequately controlled, suffer from bothersome adverse events (AEs). Since 1993, ten new drugs have entered the worldwide market (not all in the US). Those released include felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LVT), zonisamide (ZNS), clobazam (CLB) and vigabatrin (VGB). The purpose of this article is to review each of the above drugs, looking at efficacy, safety, tolerability and where they may play a role in the current treatment of epilepsy.     

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.     

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.     

Key challenges for toxicologists in the 21st century

The application of genomic technology to toxicology (toxicogenomics) has allowed the simultaneous identification of modified gene expression in response to a toxicant to be established for thousands of mammalian genes. This, together with the development of proteomics, metabonomics and our increasing understanding of individual human polymorphisms, will enable toxicologists in the next century to identify those individuals at particular risk from specific toxins, pesticides and pharmaceutical drugs. However, these new opportunities will prove fruitless unless toxicologists address some of the major issues that presently confront their discipline. If anything, the new technologies impose a greater demand on toxicologists to exercise expert judgement on the meaning of their data, and to apply 'common sense' when balancing risks and benefits.     

Improving medication reconciliation in the 21st century

Approximately 7000 deaths occur yearly in the United States as a result of medication errors, and 1.5 million people are harmed by adverse drug events at a cost of $3.5 billion per year. Computerized order entry has been shown to decrease the number of medication errors by 55% to 80 % in the hospital. This has led many to advocate the use of electronic medical records in both the inpatient and outpatient setting. However, there is little evidence at present that electronic medical records reduce adverse drug events in the outpatient setting. This may be largely due to the quality of medication lists in the medical record: Among complicated patients, complete agreement between the medication list and what the patient is actually taking occurs in only 5% of patients. Unless there is improved medication reconciliation, it will be difficult to realize the potential safety benefits of information technology. An accurate medication list requires a healthcare team dedicated to obtaining and maintaining this information.     

Conquering airways inflammation in the 21st century

This year's edition of the biennial meeting Conquering Airways Inflammation in the 21(st) Century was held September 11-13, 2000, in London. The meeting was devoted to understanding basic mechanisms of airway inflammation, the assessment of the therapeutic impact of existing treatments and the clinical potential of novel therapeutic targets, now and into the 21st century.