Investigational new drugs for focal epilepsy

Abstract

For more than 30 years, antiepileptic drug development has been based on specific assumptions regarding the neurobiology of epilepsy but all marketed drugs have not changed the proportion of drug refractory patients. It is, therefore, evident that new molecular targets need to be identified. Advances in neurobiology and molecular pharmacology are bringing into the epilepsy field new neurochemical functions such as those modulated by cannabinoid, serotonin, melatonin and galanin receptors. Among all the different compounds, the melatonin type 3 receptor agonist beprodone and cannabidiol are those at the more advanced stage of development. Interestingly, despite the structural analogies with tetrahydrocannabinol, the anticonvulsant activity of cannabidiol is not mediated by an interaction with cannabinoid receptors. Neurosteroids represent another remarkable class of drugs, and among them, ganaxolone is at the most advanced stage of development. Furthermore, for the first time, potential disease-modifying agents and techniques are entering the epilepsy market. Rapalogues such as everolimus and the antibiotic minocycline are currently under development for specific epileptic syndromes like tuberous sclerosis or Angelman syndrome. Finally, optogenetics, though still at an early stage of development, represents a futuristic therapeutic strategy for drug-refractory epilepsy.

Depression in epilepsy

“…Advances in the neurobiology and molecular pharmacology of the relationship between depression and epilepsy are bringing into the epilepsy field neurochemical pathways, such as serotonin and melatonin, traditionally investigated for mood disorders, and completely new biological targets such as galanin receptors [29]. Nalutozan is a selective 5HT1A agonist currently under investigation for both anxiety and epilepsy while beprodone is a melatonin type 3 receptor agonist under Phase IIb development in drug-refractory localisation-related epilepsies [29]. Galanin is one of the most inducible neuropeptides and its biosynthesis is increased 2 to 10-fold upon seizure activity in the brain.…”

Management of Adult Onset Seizures

“…Ganaxolone, an analogue of allopregnanolone, has shown benefit for focal epilepsy and infantile spasms in phase 2 trials. 5 It recently received orphan drug status in the treatment of epilepsy-associated syndrome because of sequence variations of the protocadherin 19 (PCDH19) gene. An intravenous form of allopregnanolone, SAGE-547, may be of benefit in super-refractory status epilepticus and is now entering phase 3 trials.…”

Melatonin as an Alternative to Sedation in Pediatric Electroencephalography: Need to Exercise Caution!

“…7 Few recent studies have highlighted significant anti-epileptic properties of melatonin. [8][9][10] Anti-epileptic property of melatonin was confirmed in pentylenetetrazole and electrically induced convulsions in mice where significant increase in seizure threshold after administration of melatonin was reported. 9 In such a case, melatonin can directly interfere with the EEG recording, thereby decreasing the yield of EEGs in detection of epileptiform discharges.…”

“…[8][9][10] Anti-epileptic property of melatonin was confirmed in pentylenetetrazole and electrically induced convulsions in mice where significant increase in seizure threshold after administration of melatonin was reported. 9 In such a case, melatonin can directly interfere with the EEG recording, thereby decreasing the yield of EEGs in detection of epileptiform discharges. If further studies substantiate the anti-epileptic properties of melatonin in children with epilepsy, use of melatonin as an alternative to sedation for pediatric EEGs would need to be investigated thoroughly in terms of its effect on reduction in epileptiform activities, thereby decreasing the yield of EEG.…”