The Problem of Intractability: The Continuing Need for New Medical Therapies in Epilepsy

Abstract

Summary: Treatment of epilepsy, one of the most common neurologic disorders, has evolved from "institutional" polytherapy to "dogmatic" monotherapy, and, most recently, to "rational" polypharmacy. The introduction of bromides for the treatment of epilepsy was followed first by phenobarbital and then by phenytoin as therapeutic options. Although attempts to combine medications were legion, none was supported by studies that demonstrated the benefit of such combinations. The issue of adverse effects became a principal argument in favor of monotherapy. Monotherapy, using newly developed drugs, avoided problems due to drug interactions but was ineffective in 20-30% of patients. A greater understanding of basic disease mechanisms and developments in molecular biology have led to an increased number of effective drugs for the estimated 6 1 2 % of patients with epilepsy whose condition is intractable. Clinical research continues to build on the work of basic scientists in attempting to develop treatments based on a desire to move beyond the palliative and to affect the causative mechanisms of the disease. Novel medical approaches now under exploration include the use of drugs with complementary mechanisms of action, stimulation of various components of the nervous system, biochemical manipulations, focal intracerebral drug perfusion, and gene therapy.

Pharmacodynamic Analysis of the Interaction between Tiagabine and Midazolam with an Allosteric Model That Incorporates Signal Transduction

“…It is possible to observe synergism between two drugs that modulate the function of one and the same neurotransmitter. A generally held principle is that two drugs sharing the same mechanism of action are not likely to interact synergistically (3)(4)(5). This is true when drugs exert their action through the same binding site, but in other cases, a synergistic interaction may occur.…”

“…Important issues in the development of rational combination therapy are (a) identification of drug combinations that provide the largest degree of synergism with regard to the desired therapeutic effect, and (b) determination of the optimal dose ratio of such drugs. In theory, the largest degree of synergism is to be expected when two drugs with specific and differing mechanisms of action are combined (3)(4)(5). The combined response to two AEDs also depends on the concentrations of both drugs in the combination.…”

The adenosine kinase hypothesis of epileptogenesis

“…Thus, to date no effective prophylaxis or true pharmacotherapeutic cure is available. In addition, the progression of epileptogenesis to chronic epilepsy often leads to pharmacoresistance and intractable seizures, which afflict up to 30% of all patients with epilepsy in particular those with temporal lobe epilepsy (TLE), the most prevalent form of refractory symptomatic epilepsy (Engel, 2001;Jallon, 1997). These patients are often severely disabled by their condition, have an unsatisfactory quality of life, and are at increased risk of sudden unexpected death.…”

Suppression of Neuronal Hyperexcitability and Associated Delayed Neuronal Death by Adenoviral Expression of GABACReceptors

“…An alternative to receptor modulation is changing the number or type of GABA receptors, with consequent suppression of hyperexcitability. In epilepsy, in which relatively few hyperexcitable neurons are responsible for the initiation of seizures, overexpression of GABA receptors restricted to those few neurons might enhance inhibition with fewer side effects than conventional systemic pharmacotherapy (Jallon, 1997;Loscher, 1998).…”