Clinical Significance of Animal Seizure Models and Mechanism of Action Studies of Potential Antiepileptic Drugs

Abstract

Summary: More than 50 million persons worldwide suffer from epilepsy, many of whom are refractory to treatment with standard antiepileptic drugs (AEDs Although epilepsy affects more than 50 million persons worldwide (l), the development of new pharmacologic interventions has lagged behind that of many other therapeutic categories. Until recently, physicians have had available a relatively limited armamentarium of antiepileptic drugs (AEDs) to treat patients with seizure disorders. This group of "standard" AEDs includes phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), barbiturates such as phenobarbital (PB) and primidone (PRM), certain benzodiazepines (BZDs), and ethosuximide (ESM). Most of these agents have a limited spectrum of antiepileptic activity, and all have certain negative properties that limit their utility and complicate patient management. At least 25% of epilepsy patients remain refractory to these AEDs ( 2 ) . Seirecently been discovered. FBM appears to be active at the strychnine-insensitive glycine binding site of the NMDA receptor. TPM is active on the kainate/AMPA subtype of glutamate receptor and at a potentially novel site on the GABAA receptor. For several reasons, availability of a single AED with multiple mechanisms of action may be preferred over availability of multiple AEDs with single mechanisms of action. These reasons include ease of titration, lack of drugdrug interactions, and reduced potential for pharmacodynamic tolerance. Key Words: Anticonvulsants-Drug screening -Neurotransmitters -Phenytoin -Ethosuximide-Topiramate-Valproate-Benzodiazepines-Barbitu-zure control in many more patients is achieved only at the expense of various types and severities of AEDrelated adverse effects. The need for new AEDs with improved clinical profiles is therefore quite clear.Fortunately, the present decade has been marked by a number of advances in AED development. Since 1990, several novel AEDs have been commercialized in one or more countries and are in the process of evaluation for worldwide registrations. These include vigabatrin (VGB), lamotrigine (LTG), gabapentin (GBP), tiagabine (TGB), felbamate (FBM), and topiramate (TPM). This report briefly discusses the preclinical models supporting the clinical evaluation of these AEDs, reviews the presently proposed mechanisms of old and new AEDs, somewhat more closely examines the recently emerging mechanistic profile of the clinically promising new AED TPM, and offers some observations about the significance of mechanism findings from the scientific and the clinical perspective.

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.…”

Choosing the Correct Antiepileptic Drugs: From Animal Studies to the Clinic

“…The maximal electroshock (MES) test, the subcutaneous pentylenetetrazol (scPTZ) test, and the electrical kindling model are the most commonly used models to evaluate potential new AEDs [33][34][35][36][37]. In the MES test an electric current of fixed intensity and duration is applied via ear-clips or corneal electrodes resulting in tonic extension of the hindlimbs.…”

“…The MES and scPTZ tests have markedly different pharmacological profiles [33]. The MES test identifies agents with activity against generalized tonic-clonic seizures while the scPTZ identifies compounds that are effective against absences and myoclonic seizures [38].…”

Tiagabine Synergistically Interacts with Gabapentin in the Electroconvulsive Threshold Test in Mice

“…Nevertheless, it has been shown that TGB is active in MES-test only at doses two-to three-fold higher than those producing motor impairment (more than 40 mg/kg; i.p.) (White, 1997). GBP at the dose of approximately 10 mg/kg; i.p., reduces MES-induced convulsions in rats, although the drug was reported to be completely inactive in mice (for a review, see Rogawski and Porter, 1990).…”