Prospects of epileptogenesis prevention.

Epilepsy is a common neurologic disease, affecting about 1-2% of the population. In around 30% of patients with epilepsy, their seizures are not satisfactorily controlled and drug-resistant epilepsy constitutes a real therapeutic challenge. Consequently, there are efforts aimed at the inhibition of epileptogenesis, a process of converting a normal into an epileptic brain. Data on this problem have been mainly obtained in post-status epilepticus rodent models in which spontaneous seizure activity and behavioral disturbances develop over time. Among antiepileptic drugs, diazepam at high dose of 20mg/kg given during status epilepticus, significantly inhibited the development of spontaneous seizures and also, a strong neuroprotective effect was evident. Also gabapentin and valproate (over a period of 40 days) proved effective in the inhibition of spontaneous seizure activity and reduction of behavioral deficit. However, there are also data that valproate (over 28 days) significantly improved the behavioral performance without affecting the occurrence of spontaneous seizures. A number of antiepileptic drugs, carbamazepine, lamotrigine, levetiracetam, phenobarbital, and topiramate were completely ineffective. Among non-antiepileptic drugs, some promise show rapamycin, losartan and combinations of anti-inflammatory drugs, targeting different inflammatory pathways. Inhibition of epileptogenesis may become a valuable therapeutic approach provided that there are reliable markers of this process. Actually, such markers begin to emerge.

Safety considerations for patients with epilepsy taking antiepileptic drugs alongside caffeine or other methylxanthine derivatives.

INTRODUCTION: Antiepileptic drugs (AEDs) are widely used for the treatment of epilepsy. However, ∼ 30% of patients do not remain seizure free. It is possible that methylxanthine derivatives (e.g., caffeine and theophylline) may partially account for this outcome. AREAS COVERED: Data on the convulsive activity of methylxanthines are reviewed. The negative impact of caffeine and theophylline (or aminophylline) on the protective activity of classic and newer AEDs is also considered. Case report studies indicate that ingestion of caffeine may increase seizure frequency, which returns to baseline when the consumption of coffee or caffeine-rich drinks is terminated. However, the existing data also provide clinical evidence that caffeine may not be a trigger for precipitation of seizure activity and this discrepancy is evaluated. EXPERT OPINION: Experimental data indicate that caffeine and aminophylline both significantly reduce the anticonvulsant activity of a number of AEDs. Clinical data are controversial. Patients with epilepsy should be advised not to take methylxanthine-containing medications. Caffeine consumption, especially accidental and in huge quantities, should be avoided in patients with epilepsy.

Novel approaches to anticonvulsant drug discovery.

INTRODUCTION: The history of epilepsy dates back to 2000 BC. Yet, it was not until 1912 that the activity of the first antiepileptic, phenobarbital was discovered by accident. After this discovery, the next antiepileptic drugs to be discovered (phenytoin and primidone) were based on the phenobarbital's structure. Then, in 1960, carbamazepine was developed empirically, while in 1962, valproate demonstrated anticonvulsant activity against experimental seizures. The next antiepileptic drugs synthesized were either modifications of the existing drugs (such as oxcarbazepine and pregabalin) or completely novel chemical structures (lacosamide, perampanel and retigabine). AREAS COVERED: The present paper briefly refers to the history of epilepsy and development of antiepileptic drugs. Further, the paper provides a discussion on the antiepileptogenic effects of antiepileptic drugs in terms of the constant percentage of epileptic patients with refractory seizures. The authors also review the likely factors involved in the false refractoriness (such as through the use of caffeine-containing beverages and smoking). Finally, the authors consider future directions in the search of novel antiepileptic drugs. EXPERT OPINION: In spite of the considerable number of newer antiepileptic drugs, the number of drug-resistant epileptic patients remains unchanged. This may be rather an indication of the suitability of the currently available discovery procedures for effective antiepileptic drugs in the whole population of epileptic patients. The authors, however, believe that it is likely that models of mimic chronic epilepsy will help bridge the gaps and aid in the discovery of novel antiepileptic drugs - ones that can effectively modify the course of the disease.