Antiepileptic Drugs in Development: Prospects for the Near Future

Abstract

Among some 14 new antiepileptic drugs (AEDs), those most extensively tested in humans include felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OCBZ), vigabatrin (VGB), and zonisamide (ZNS). All are currently marketed in some but not all countries. Although no large, comparative studies on efficacy have been conducted, all of these new AEDs are effective in adult localization-related epilepsies, and some have activity in specific syndromes. Although these drugs all have some CNS side effects, especially when administered in combination with other AEDs, they also all have low toxicity profiles. The availability of AEDs with different mechanisms of action may facilitate rational polytherapy. FBM is not teratogenic in animals. Half-life of FBM in humans is 11-28 h. Daily FBM dosages are 15-45 mg/kg in children and 2,400-4,800 mg in adults. Side effects include insomnia and anorexia, with weight loss. FBM increases phenytoin (PHT) and valproate (VPA) concentrations, and FBM concentration may be affected by other drugs. It is available in the United States for treatment of Lennox-Gastaut syndrome and partial seizures in adults. GBP is very water soluble. Half-life of GBP in humans is 5-7 h and daily dosages range from 900 to 2,400 mg in adults. Few side effects have been observed. GBP is not metabolized by the liver and has no drug interactions. It is available in the United Kingdom and the United States. LTG has no teratogenicity in animal models. Half-life of LTG in humans depends on co-medication: with enzyme inducers it is 15-24 h, and with VPA it is approximately 60 h. LTG dosages are 100-600 mg/day in adults. LTG is available in Europe. OCBZ is rapidly metabolized to 10,11-dihydro-10-hydroxy-carbazepine (MHD), the active compound. Animal studies have shown similar efficacy but superior toxicity to carbamazepine (CBZ) in animal models. For MHD, half-life ranges from 10 to 15 h in patients. OCBZ dosages range from 300 to 1,800 mg/day. VGB is a potent, irreversible inhibitor of GABA transaminase which elevates GABA levels in the CNS. Daily dosages of 2,000-4,000 mg of VGB are needed in adults. Although intramyelinic edema has developed in rats and dogs, it has not yet presented in other mammals or humans. ZNS is a sulfonamide effective in animal models of epilepsy. Half-life of ZNS is 27-36 h. ZNS daily dosage is 400-600 mg. ZNS has been effective in some cases of Baltic myoclonic epilepsy.

Synthesis and Anticonvulsant Activity of Some 7-Alkoxy-2H-1,4-benzothiazin-3(4H)-ones and 7-Alkoxy-4H-[1,2,4]triazolo[4,3-d]benzo[b][1,4]thiazines

“…A series of 7-alkoxy-2H-1,4-benzothiazin-3(4H)-ones and a new series of 7-alkoxy-4H- [1,2,4] [1,4]thiazine 4k was the most active compound with ED 50 of 17.0 mg/kg, TD 50 of 243.9 mg/kg and PI of 14.3. Its neurotoxicity was lower than all other synthesized compounds and also markedly lower than that of the reference drug carbamazepine.…”

“…1) For epilepsy treatment, nearly 95% of today's clinically available drugs were approved before 1985 and provide satisfactory seizure control for only 60-70% of patients. These drugs, however, also cause notable adverse side effects such as drowsiness, ataxia, gastrointestinal disturbance, hepatotoxicity and megaloblastic anemia [2][3][4] and even life threatening conditions. 5) Research to find more effective and safer antiepileptic drugs is, therefore, imperative and challenging in medicinal chemistry.…”

“…1 to compounds pre. 2, we incorporated triazole with 7-alkoxyl-2H-benzo[b] [1,4]thiazin-3(4H)-ones at the third and fourth position of the latter and obtained 7-alkoxyl-4H- [1,2,4]triazolo [4,3- H-NMR spectroscopic data and microanalyses. The anticonvulsant activity was evaluated by maximal electroshock (MES) test; neurotoxicity was evaluated by rotarod test.…”

Choronic effects of Lamotrigine on liver function in adult male rats

“…It is effective in treating both partial and generalized seizure. LTG most probably exerts its antiepileptic activity by blocking the release of excitatory neurotransmitters, principally glutamate and aspartate in the central nervous system (1,2). At present it is one of the AEDS, which is frequently used in the medical world.…”

Lamotrigine Treatment During Amygdala‐Kindled Seizure Development Fails to Inhibit Seizures and Diminishes Subsequent Anticonvulsant Efficacy

“…Lamotrigine (LTG) is an anticonvulsant drug that has recently been developed as an augmentation treatment for generalized and partial seizure disorders in patients who do not respond adequately to the more well established drugs, such as carbamazepine (CBZ), valproate (VPA), and phenytoin (DPH) (1)(2)(3)(4)(5)(6)(7). LTG is also being investigated for its potential therapeutic benefits in affective disorders, where it shows promise against unipolar and bipolar (8)(9)(10)(11) depressive components of this illness.…”