Discovery of Antiepileptic Drugs

Abstract

Since 1993, the Anticonvulsant Drug Development Program has contributed to the successful development of nine clinically effective drugs for the symptomatic treatment of epilepsy. These include felbamate (1993), gabapentin (1994), lamotrigine (1994), fosphenytoin (1996), topiramate (1996), tiagabine (1997), levetiracetam (1999), zonisamide (2000), and oxcarbazepine (2000). Despite the apparent success of the current discovery process, a significant need persists for more efficacious and less toxic antiepileptic drugs (AEDs). This is particularly true for patients whose seizures remain refractory to the currently available AEDs. This chapter will review the current process for AED discovery employed by the Anticonvulsant Drug Development Program at the University of Utah and other laboratories working toward the common goal of discovering better therapeutic options for patients living with epilepsy. It will discuss some of the inherent advantages and limitations of the primary animal models employed, while offering insight into potential future directions as we seek to better understand the pathophysiology underlying acquired epilepsy, therapy resistance, and epileptogenesis.

Bioassay-guided evaluation of central nervous system effects of citronellal in rodents

“…MES test is the most frequently used as an animal model for identification of anticonvulsant activity of drugs for the "grand mal" (Oliveira et al, 2001;Smith et al, 2007). All the currently available antiepileptic drugs (AEDs), which are clinically effective in the treatment of generalized tonic-clonic convulsions, such as phenobarbital, lamotrigine and carbamazepine, are effective in the MES test (Löscher, 1998).…”

“…PTZ was used to induce clonic convulsions (Smith et al, 2007). Mice were divided into five groups (n=8, per group).…”

Anticonvulsant evaluation of Rauvolfia ligustrina Willd. ex Roem. & Schult., Apocynaceae, in rodents

“…It produces clonic and tonic convulsions when administrated parenterally (Smith et al, 2007). PTZ may cause convulsions by inhibiting chloride ion channels associated with GABAA receptors (Löscher & Schmidt, 2006).…”

“…In contrast, MES test is the most frequently used as an animal model for identification of anticonvulsant activity of drugs for the "grand mal" (Oliveira et al, 2001;Smith et al, 2007). All the currently available AEDs, wich are clinically effective in the treatment of generalized tonicclonic convulsions (PHE), phenobarbital, lamotrigine and carbamazepine are effective in the MES test (Löscher, 1998).…”

“…The detailed method has been previously described (Smith et al, 2007). Animals were divided into five groups (n = 10), the first group served as control and received Tween 80 (0.2%) with one drop of cremophor, while the second group was treated with diazepam (DZP, 2 mg/kg i.p.).…”