A resurging boom in new drugs for epilepsy and brain disorders

References

• Banerjee PN, Filippi D, Hauser WA. The descriptive epidemiology of epilepsy—a review. Epilepsy Res. 2009;85(1):31–45.
   PubMed Web of Science ®Google Scholar
• Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the international league against epilepsy: position paper of the ILAE commission for classification and terminology. Epilepsia. 2017;58(4):522–530.
   PubMed Web of Science ®Google Scholar
• Younus I, Reddy DS. Epigenetic interventions for epileptogenesis: a new frontier for curing epilepsy. Pharmacol Ther. 2017;177:108–122.
   PubMed Web of Science ®Google Scholar
• Reddy DS. Neurosteroids: endogenous role in the human brain and therapeutic potentials. Prog Brain Res. 2010;186:113.
   PubMed Web of Science ®Google Scholar
• Kaminski RM, Livingood MR, Rogawski MA. Allopregnanolone analogs that positively modulate GABAA receptors protect against partial seizures induced by 6‐Hz electrical stimulation in mice. Epilepsia. 2004;45(7):864–867.
   PubMed Web of Science ®Google Scholar
• Reddy DS, Rogawski MA. Neurosteroids – endogenous regulators of seizure susceptibility and role in the treatment of epilepsy. In: Noebels JL, Avoli M, Rogawski MA, et al., editor. Jasper’s basic mechanisms of the epilepsies. 4th ed. Oxford:Oxford University Press; 2012. p.984–1002.
   Google Scholar
• Rogawski MA, Loya CM, Reddy K, et al. Neuroactive steroids for the treatment of status epilepticus. Epilepsia. 2013;54:93–98.
   PubMed Web of Science ®Google Scholar
• Reddy DS. Role of anticonvulsant and antiepileptogenic neurosteroids in the pathophysiology and treatment of epilepsy. Front Endocrinol (Lausanne). 2011;2(38):1–11.
   PubMedGoogle Scholar
• Timby E, Balgård M, Nyberg S, et al. Pharmacokinetic and behavioral effects of allopregnanolone in healthy women. Psychopharmacology. 2006;186(3):414.
   PubMed Web of Science ®Google Scholar
• Kanes S, Rosenthal E, Vaitkevicius H, et al. 547-SSE-201 for super-refractory status epilepticus: response and relationship to underlying patient characteristics (S14. 003). Neurology. 2016;86(16Suppl):S14–003.
   Google Scholar
• Reddy DS, Woodward R. Ganaxolone: a prospective overview. Drugs Future. 2004;29:227–242.
   Web of Science ®Google Scholar
• Gasior M, Ungard JT, Beekman M, et al. Acute and chronic effects of the synthetic neuroactive steroid, ganaxolone, against the convulsive and lethal effects of pentylenetetrazol in seizure-kindled mice: comparison with diazepam and valproate. Neuropharmacology. 2000;39(7):1184–1196.
   PubMed Web of Science ®Google Scholar
• Reddy DS, Rogawski MA. Ganaxolone suppression of behavioral and electrographic seizures in the mouse amygdala kindling model. Epilepsy Res. 2010;89(2):254–260.
   PubMed Web of Science ®Google Scholar
• Lappalainen J, Tsai J, Amerine W, et al. Double-blind, randomized, placebo-controlled phase 3 trial to determine the efficacy and safety of ganaxolone as adjunctive therapy for adults with drug-resistant focal-onset seizures (P5. 237). Neurology. 2017;88(16Supplement):P5–237.
   Google Scholar
• Reddy DS. Neurosteroids for the potential protection of humans against organophosphate toxicity. Ann N Y Acad Sci. 2016;1378:25–32.
   PubMed Web of Science ®Google Scholar
• Reddy SD, Younus I, Clossen BL, et al. Antiseizure activity of midazolam in mice lacking δ-subunit extrasynaptic GABAA receptors. Jpet. 2015;353(3):517–528.
   PubMed Web of Science ®Google Scholar
• Bialer M, Johannessen SI, Levy RH, et al. Progress report on new antiepileptic drugs: a summary of the thirteenth Eilat conference on new antiepileptic drugs and devices (EILAT XIII). Epilepsia. 2017;58(2):181–221.
   PubMed Web of Science ®Google Scholar
• Hoffmann E, Wald J, Raines S, et al. The pharmacokinetics of SAGE-217 in Phase 1 SAD and MAD studies (P3. 008). Neurology. 2017;88(16Supplement):P3–008.
   Google Scholar
• Silverman RB. The 2011 EB hershberg award for important discoveries in medicinally active substances:(1 S, 3 S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a GABA aminotransferase inactivator and new treatment for drug addiction and infantile spasms. J Med Chem. 2012;55(2):567–575.
   PubMed Web of Science ®Google Scholar
• Doumlele K, Conway E, Hedlund J, et al. A case report on the efficacy of vigabatrin analogue (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115) in a patient with infantile spasms. Epilepsy Behavior Case Rep. 2016;6:67–69.
   PubMed Web of Science ®Google Scholar
• Briggs SW, Mowrey W, Hall CB, et al. CPP‐115, a vigabatrin analogue, decreases spasms in the multiple‐hit rat model of infantile spasms. Epilepsia. 2014;55(1):94–102.
   PubMed Web of Science ®Google Scholar
• Lee H, Doud EH, Wu R, et al. Mechanism of inactivation of γ-Aminobutyric Acid Aminotransferase by (1 S, 3 S)-3-Amino-4-difluoromethylene-1-cyclopentanoic Acid (CPP-115). J Am Chem Soc. 2015;137(7):2628–2640.
   PubMed Web of Science ®Google Scholar
• Miller SR. CPP-115: the next generation GABA-AT inhibitor. In: 2012 epilepsy pipeline update conference. 2012 Feb 2–4.
   Google Scholar
• Reddy DS, Golub VM. The pharmacological basis of cannabis therapy for epilepsy. Jpet. 2016;357(1):45–55.
   PubMed Web of Science ®Google Scholar
• Reddy DS. The utility of cannabidiol in the treatment of refractory epilepsy. Clin Pharmacol Ther. 2017;101(2):182–184.
   PubMed Web of Science ®Google Scholar
• Anderson CL, Evans VF, DeMarse TB, et al. Cannabidiol for the treatment of drug-resistant epilepsy in children: current state of research. J Pediatr Neurol. 2017 Jan 23. O’Connell BK, Gloss D, Devinsky O. Cannabinoids in treatment-resistant epilepsy: A review. Epilepsy Behav. 2017; 70(Pt B):341–348.
   PubMedGoogle Scholar
• Paolino MC, Ferretti A, Papetti L, et al. Cannabidiol as potential treatment in refractory pediatric epilepsy. Expert Rev Neurother. 2016;16(1):17–21.
   PubMed Web of Science ®Google Scholar
• Jones NA, Hill AJ, Smith I, et al. Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. Jpet. 2010;332(2):569–577.
   PubMed Web of Science ®Google Scholar
• Jones NA, Glyn SE, Akiyama S, et al. Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure. 2012;21(5):344–352.
   PubMed Web of Science ®Google Scholar
• Ibeas Bih C, Chen T, Nunn AV, et al. Molecular targets of cannabidiol in neurological disorders. Neurotherapeutics. 2015;12:699–730.
   PubMed Web of Science ®Google Scholar
• Bazelot M, Whalley B. Investigating the Involvement of GPR55 Signaling in the Antiepileptic Effects of Cannabidiol (P5. 244). Neurology. 2016;86(16Suppl):P5–244.
   Google Scholar
• Hawksworth G, McArdle K. Metabolism and pharmacokinetics of cannabinoids. London: Pharmaceutical Press; 2004.
   Google Scholar
• Geffrey AL, Pollack SF, Bruno PL, et al. Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56(8):1246–1251.
   PubMed Web of Science ®Google Scholar
• Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the dravet syndrome. Nejm. 2017;376(21):2011–2020.
   PubMed Web of Science ®Google Scholar
• Epilepsy: RC. Cannabidiol reduces seizure frequency in Dravet syndrome. Nat Rev Neurol. 2017;13(7):383.
   PubMedGoogle Scholar
• French J, Thiele E, Mazurkiewicz-Beldzinska M, et al. Cannabidiol (CBD) significantly reduces drop seizure frequency in Lennox-Gastaut syndrome (LGS): results of a multi-center, randomized, double-blind, placebo controlled trial (GWPCARE4)(S21. 001). Neurology. 2017;88(16Supplement):S21–S001.
   Google Scholar
• Hill AJ, Mercier MS, Hill TD, et al. Cannabidivarin is anticonvulsant in mouse and rat. Brit J Pharmacol. 2012;167(8):1629–1642.
   PubMed Web of Science ®Google Scholar
• Hill TD, Cascio MG, Romano B, et al. Cannabidivarin‐rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor‐independent mechanism. Br J Pharmacol. 2013;170(3):679–692.
   PubMed Web of Science ®Google Scholar
• Amada N, Yamasaki Y, Williams CM, et al. Cannabidivarin (CBDV) suppresses pentylenetetrazole (PTZ)-induced increases in epilepsy-related gene expression. Peer J. 2013;1:e214.
   PubMed Web of Science ®Google Scholar
• Morano A, Cifelli P, Nencini P, et al. Cannabis in epilepsy: from clinical practice to basic research focusing on the possible role of cannabidivarin. Epilepsia Open. 2016;1(3–4):145–151.
   PubMedGoogle Scholar
• Kaila K, Price TJ, Payne JA, et al. Cation-chloride cotransporters in neuronal development, plasticity and disease. Nat Rev Neurosci. 2014;15(10):637–654.
   PubMed Web of Science ®Google Scholar
• Töllner K, Brandt C, Römermann K, et al. The organic anion transport inhibitor probenecid increases brain concentrations of the NKCC1 inhibitor bumetanide. Eur J Pharmacol. 2015;746:167–173.
   PubMed Web of Science ®Google Scholar
• Erker T, Brandt C, Töllner K, et al. The bumetanide prodrug BUM5, but not bumetanide, potentiates the antiseizure effect of phenobarbital in adult epileptic mice. Epilepsia. 2016;57(5):698–705.
   PubMed Web of Science ®Google Scholar
• Ben‐Ari Y. Blocking seizures with the diuretic bumetanide: promises and pitfalls. Epilepsia. 2012;53(2):394–396.
   PubMed Web of Science ®Google Scholar
• Löscher W, Puskarjov M, Kaila K. Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments. Neuropharmacology. 2013;69:62–74.
   PubMed Web of Science ®Google Scholar
• Puskarjov M, Kahle KT, Ruusuvuori E, et al. Pharmacotherapeutic targeting of cation‐chloride cotransporters in neonatal seizures. Epilepsia. 2014;55(6):806–818.
   PubMed Web of Science ®Google Scholar
• Jullien V, Pressler RM, Boylan G, et al. Pilot evaluation of the population pharmacokinetics of bumetanide in term newborn infants with seizures. J Clin Pharmacol. 2016;56(3):284–290.
   PubMed Web of Science ®Google Scholar
• Allegaert K, Lahav A, Van Den Anker JN. Erratum to: a mechanism to explain ototoxicity in neonates exposed to bumetanide: lessons to help improve future product development in neonates. Pediatric Drugs. 2016;18(6):475.
   PubMed Web of Science ®Google Scholar
• Ben-Ari Y, Damier P, Lemonnier E. Failure of the nemo trial: bumetanide is a promising agent to treat many brain disorders but not newborn seizures. Front Cell Neurosci. 2016;10:90. doi:10.3389/fncel.2016.00090.
   PubMed Web of Science ®Google Scholar
• Lykke K, Töllner K, Feit PW, et al. The search for NKCC1-selective drugs for the treatment of epilepsy: structure–function relationship of bumetanide and various bumetanide derivatives in inhibiting the human cation-chloride cotransporter NKCC1A. Epilepsy Behav. 2016;59:42–49.
   PubMed Web of Science ®Google Scholar
• Curatolo P, Moavero R. mTOR inhibitors as a new therapeutic option for epilepsy. Expert Rev Neurother. 2013;13(6):627–638.
   PubMed Web of Science ®Google Scholar
• Galanopoulou AS, Gorter JA, Cepeda C. Finding a better drug for epilepsy: the mTOR pathway as an antiepileptogenic target. Epilepsia. 2012;53(7):1119–1130.
   PubMed Web of Science ®Google Scholar
• Zeng LH, Xu L, Gutmann DH, et al. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol. 2008;63(4):444–453.
   PubMed Web of Science ®Google Scholar
• Zhang B, Wong M. Pentylenetetrazole‐induced seizures cause acute, but not chronic, mTOR pathway activation in rat. Epilepsia. 2012;53(3):506–511.
   PubMed Web of Science ®Google Scholar
• Russo E, Citraro R, Donato G, et al. mTOR inhibition modulates epileptogenesis, seizures and depressive behavior in a genetic rat model of absence epilepsy. Neuropharmacology. 2013;69:25–36.
   PubMed Web of Science ®Google Scholar
• Terashima A, Nakai M, Hashimoto T, et al. Single-channel activity of the Ca 2+-dependent K+ channel is modulated by FK506 and rapamycin. Brain Res. 1998;786(1):255–258.
   PubMed Web of Science ®Google Scholar
• Raab-Graham KF, Haddick PC, Jan YN, et al. Activity-and mTOR-dependent suppression of Kv1. 1 channel mRNA translation in dendrites. Science. 2006;314(5796):144–148.
   PubMed Web of Science ®Google Scholar
• Wang Y, Barbaro MF, Baraban SC. A role for the mTOR pathway in surface expression of AMPA receptors. Neurosci Lett. 2006;401(1):35–39.
   PubMed Web of Science ®Google Scholar
• Kirchner GI, Meier-Wiedenbach I, Manns MP. Clinical pharmacokinetics of everolimus. Clin Pharmacokinet. 2004;43(2):83–95.
   PubMed Web of Science ®Google Scholar
• French JA, Lawson JA, Yapici Z, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016;388(10056):2153–2163.
   PubMed Web of Science ®Google Scholar
• Klitgaard H, Matagne A, Nicolas JM, et al. Brivaracetam: rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment. Epilepsia. 2016;57(4):538–548.
   PubMed Web of Science ®Google Scholar
• Matagne A, Margineanu DG, Kenda B, et al. Anti‐convulsive and anti‐epileptic properties of brivaracetam (ucb 34714), a high‐affinity ligand for the synaptic vesicle protein, SV2A. Br J Pharmacol. 2008;154(8):1662–1671.
   PubMed Web of Science ®Google Scholar
• Leclercq K, Kaminski R. Anticonvulsant effects of brivaracetam in the 6 Hz fully-kindled mice. Epilepsia. 2015;56:53.
   Web of Science ®Google Scholar
• Gillard M, Fuks B, Leclercq K, et al. Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: relationship to anti-convulsant properties. Eur J Pharmacol. 2011;664(1):36–44.
   PubMed Web of Science ®Google Scholar
• Wood MD, Gillard M. Evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein. Epilepsia. 2017;58(2):255–262.
   PubMed Web of Science ®Google Scholar
• Rogawski MA. A new SV2A ligand for epilepsy. Cell. 2016;167(3):587.
   PubMed Web of Science ®Google Scholar
• Schoemaker R, Wade JR, Stockis A. Brivaracetam population pharmacokinetics and exposure‐response modeling in adult subjects with partial‐onset seizures. J Clin Pharmacol. 2016;56(12):1591–1602.
   PubMed Web of Science ®Google Scholar
• Stockis A, Sargentini-Maier ML, Brodie M. Brivaracetam and carbamazepine interaction study in adult patients with epilepsy. Epilepsia. 2015;56:210–211.
   Web of Science ®Google Scholar
• Klein P, Schiemann J, Sperling MR, et al. A randomized, double‐blind, placebo‐controlled, multicenter, parallel‐group study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with uncontrolled partial‐onset seizures. Epilepsia. 2015;56(12):1890–1898.
   PubMed Web of Science ®Google Scholar
• Quarato PP, Whitesides J, Johnson M, et al. Efficacy and safety of adjunctive brivaracetam for partial-onset (focal) seizures: pooled results from three fixed-dose, randomized, double-blind, placebo-controlled phase III studies (P2. 022). Neurology. 2016;86(16Supplement):P2–022.
   Google Scholar
• Large CH, Sokal DM, Nehlig A, et al. The spectrum of anticonvulsant efficacy of retigabine (ezogabine) in animal models: implications for clinical use. Epilepsia. 2012;53(3):425–436.
   PubMed Web of Science ®Google Scholar
• ILAE. Glaxosmithkline: Advance notification of trobalt (retigabine) discontinuation. [cited 2017 Jul 11]. Available from: http://www.ilae.org/Visitors/News/documents/GSK_Retigabine_market_withdrawal.pdf
   Google Scholar
• Roeloffs R, Wickenden AD, Crean C, et al. In vivo profile of ICA-27243 [N-(6-chloro-pyridin-3-yl)-3, 4-difluoro-benzamide], a potent and selective KCNQ2/Q3 (Kv7. 2/Kv7. 3) activator in rodent anticonvulsant models. Jpet. 2008;326(3):818–828.
   PubMed Web of Science ®Google Scholar
• Aronica E, Zurolo E, Iyer A, et al. Upregulation of adenosine kinase in astrocytes in experimental and human temporal lobe epilepsy. Epilepsia. 2011;52(9):1645–1655.
   PubMed Web of Science ®Google Scholar
• Williams-Karnesky RL, Sandau US, Lusardi TA, et al. Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis. J Clin Invest. 2013;123(8):3552.
   PubMed Web of Science ®Google Scholar
• Boison D. The biochemistry and epigenetics of epilepsy: focus on adenosine and glycine. Front Mol Neurosci. 2016;9(26):1–17.
   Web of Science ®Google Scholar
• Pritchard EM, Boison D, Kaplan DL. Silk: a biocompatible and biodegradable biopolymer for therapeutic adenosine delivery. In: Adenosine (S. Masino and D. Boison, editors). New York (NY): Springer; 2013. p. 599–620.
   Google Scholar
• Stafstrom CE, Ockuly JC, Murphree L, et al. Anticonvulsant and antiepileptic actions of 2‐deoxy‐D‐glucose in epilepsy models. Ann Neurol. 2009;65(4):435–447.
   PubMed Web of Science ®Google Scholar
• Lian XY, Khan FA, Stringer JL. Fructose-1, 6-bisphosphate has anticonvulsant activity in models of acute seizures in adult rats. J Neurosci. 2007;27(44):12007–12011.
   PubMed Web of Science ®Google Scholar
• Clossen BL, Reddy DS. Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy. BBA-Molecular Basis of Disease. 2017;177:108–122.
   Google Scholar
• Gasior M, Yankura J, Hartman AL, et al. Anticonvulsant and proconvulsant actions of 2‐deoxy‐d‐glucose. Epilepsia. 2010;51(8):1385–1394.
   PubMed Web of Science ®Google Scholar
• Forte N, Medrihan L, Cappetti B, et al. 2‐Deoxy‐d‐glucose enhances tonic inhibition through the neurosteroid‐mediated activation of extrasynaptic GABAA receptors. Epilepsia. 2016;57(12):1987–2000.
   PubMed Web of Science ®Google Scholar
• Stein M, Lin H, Jeyamohan C, et al. Targeting tumor metabolism with 2‐deoxyglucose in patients with castrate‐resistant prostate cancer and advanced malignancies. Prostate. 2010;70(13):1388–1394.
   PubMed Web of Science ®Google Scholar
• Minor RK, Smith DL, Sossong AM, et al. Chronic ingestion of 2-deoxy-D-glucose induces cardiac vacuolization and increases mortality in rats. Toxicol Appl Pharmacol. 2010;243(3):332–339.
   PubMed Web of Science ®Google Scholar
• Ockuly JC, Gielissen JM, Levenick CV, et al. Behavioral, cognitive, and safety profile of 2-deoxy-2-glucose (2DG) in adult rats. Epilepsy Res. 2012;101(3):246–252.
   PubMed Web of Science ®Google Scholar
• Shekh‐Ahmad T, Hen N, Yagen B, et al. Stereoselective anticonvulsant and pharmacokinetic analysis of valnoctamide, a CNS‐active derivative of valproic acid with low teratogenic potential. Epilepsia. 2014;55(2):353–361.
   PubMed Web of Science ®Google Scholar
• Spampanato J, Dudek FE. Valnoctamide enhances phasic inhibition: a potential target mechanism for the treatment of benzodiazepine‐refractory status epilepticus. Epilepsia. 2014;55:9.
   PubMed Web of Science ®Google Scholar
• Shekh-Ahmad T, Mawasi H, McDonough JH, et al. The potential of sec-butylpropylacetamide (SPD) and valnoctamide and their individual stereoisomers in status epilepticus. Epilepsy Behav. 2015;49:298–302.
   PubMed Web of Science ®Google Scholar
• Bar‐Klein G, Swissa E, Kamintsky L, et al. sec‐Butyl‐propylacetamide (SPD) and two of its stereoisomers rapidly terminate paraoxon‐induced status epilepticus in rats. Epilepsia. 2014;55(12):1953–1958.
   PubMed Web of Science ®Google Scholar
• White HS, Alex AB, Pollock A, et al. A new derivative of valproic acid amide possesses a broad‐spectrum antiseizure profile and unique activity against status epilepticus and organophosphate neuronal damage. Epilepsia. 2012;53(1):134–146.
   PubMed Web of Science ®Google Scholar
• Mawasi H, Shekh-Ahmad T, Finnell RH, et al. Pharmacodynamic and pharmacokinetic analysis of CNS-active constitutional isomers of valnoctamide and sec-butylpropylacetamide—amide derivatives of valproic acid. Epilepsy Behav. 2015;46:728.
   Web of Science ®Google Scholar
• Mawasi H, Bibi D, Shekh-Ahmad T, et al. Pharmacokinetic–pharmacodynamic correlation and brain penetration of sec-butylpropylacetamide, a new CNS drug possessing unique activity against status epilepticus. Mol Pharm. 2016;13(7):2492–2496.
   PubMed Web of Science ®Google Scholar
• Robertson CR, Scholl EA, Pruess TH, et al. Engineering galanin analogues that discriminate between GalR1 and GalR2 receptor subtypes and exhibit anticonvulsant activity following systemic delivery. J Med Chem. 2010;53(4):1871–1875.
   PubMed Web of Science ®Google Scholar
• Mazarati A, Lu X, Kilk K, et al. Galanin type 2 receptors regulate neuronal survival, susceptibility to seizures and seizure‐induced neurogenesis in the dentate gyrus. Eur J Neurosci. 2004;19(12):3235–3244.
   PubMed Web of Science ®Google Scholar
• Mazarati A, Lu X. Regulation of limbic status epilepticus by hippocampal galanin type 1 and type 2 receptors. Neuropeptides. 2005;39(3):277–280.
   PubMed Web of Science ®Google Scholar
• Metcalf CS, Klein BD, McDougle DR, et al. Preclinical evaluation of intravenous NAX 810‐2, a novel GalR2‐preferring analog, for anticonvulsant efficacy and pharmacokinetics. Epilepsia. 2017;58(2):239–246.
   PubMed Web of Science ®Google Scholar
• Damar U, Gersner R, Johnstone JT, et al. Huperzine A as a neuroprotective and antiepileptic drug: a review of preclinical research. Expert Rev Neurother. 2016;16(6):671–680.
   PubMed Web of Science ®Google Scholar
• Gersner R, Ekstein D, Dhamne SC, et al. Huperzine A prophylaxis against pentylenetetrazole-induced seizures in rats is associated with increased cortical inhibition. Epilepsy Res. 2015;117:97–103.
   PubMed Web of Science ®Google Scholar
• Tang XC, Han YF. Pharmacological profile of huperzine A, a novel acetylcholinesterase inhibitor from Chinese herb. CNS Drug Rev. 1999;5(3):281–300.
   Google Scholar
• Chu D, Liu W, Li Y, et al. Pharmacokinetics of huperzine A in dogs following single intravenous and oral administrations. Planta Med. 2006;72(06):552–555.
   PubMedGoogle Scholar
• Ceulemans B, Schoonjans A, Marchau F, et al. PP07. 2–2774: five-yearfollow-up of Fenfluramine as add-on treatment in Dravet syndrome. Eur J Paediatric Neurol. 2015;19:S56.
   PubMedGoogle Scholar
• Zhang Y, Kecskés A, Copmans D, et al. Pharmacological characterization of an antisense knockdown zebrafish model of Dravet syndrome: inhibition of epileptic seizures by the serotonin agonist fenfluramine. PloS One. 2015;10(5):e0125898.
   PubMed Web of Science ®Google Scholar
• Sourbron J, Smolders I, De Witte P, et al. Pharmacological analysis of the anti-epileptic mechanisms of fenfluramine in scn1a mutant zebrafish. Front Pharmacol. 2017;8(1910):1–12.
   PubMed Web of Science ®Google Scholar
• Schoonjans AS, Marchau F, Paelinck B, et al. Cardiovascular safety of long-term, low-dose fenfluramine use in Dravet syndrome; where are we now? Eur J Pediatr Neurol. 2017;21:e32–e23.
   Google Scholar
• Caccia S, Ballabio M, De Ponte P. Pharmacokinetics of fenfluramine enantiomers in man. Eur J Drug Metab Pharmacokinet. 1979;4(3):129–132.
   PubMedGoogle Scholar
• Chen Y, Huang J, Paskavitz J, et al. Evaluation of drug-drug interactions between VX-765 and common anti-epileptic medications in subjects with treatment-resistant partial-onset epilepsy (P02. 216). Neurology. 2013;80(7Supplement):P02–216.
   Google Scholar
• Gilbert DL, Franko BV, Ward JW, et al. Toxicologic studies of fenfluramine. Toxicol Appl Pharmacol. 1971;19(4):705–711.
   PubMed Web of Science ®Google Scholar
• Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine–phentermine. Nejm. 1997;337(9):581–588.
   PubMed Web of Science ®Google Scholar
• Slassi M, Dove P, Climie S, et al. FV-082: a safer orally active broad-spectrum antiepileptic drug candidate. Epilepsy Behav. 2015;46:57–58.
   Google Scholar
• Wang DD, Englot DJ, Garcia PA, et al. Minocycline-and tetracycline-class antibiotics are protective against partial seizures in vivo. Epilepsy Behav. 2012;24(3):314–318.
   PubMed Web of Science ®Google Scholar
• Nasr SM, Moghimi A, Mohammad-Zadeh M, et al. The effect of minocycline on seizures induced by amygdala kindling in rats. Seizure. 2013 Oct 31;22(8):670–674.
   PubMed Web of Science ®Google Scholar
• Abraham J, Fox PD, Condello C, et al. Minocycline attenuates microglia activation and blocks the long-term epileptogenic effects of early-life seizures. Neurobiol Dis. 2012;46(2):425–430.
   PubMed Web of Science ®Google Scholar
• Lang N, Rothkegel H, Terney D, et al. Minocycline exerts acute inhibitory effects on cerebral cortex excitability in humans. Epilepsy Res. 2013;107(3):302–305.
   PubMed Web of Science ®Google Scholar
• Grieco JC, Ciarlone SL, Gieron-Korthals M, et al. An open-label pilot trial of minocycline in children as a treatment for Angelman syndrome. BMC Neurol. 2014;14(1):232.
   PubMed Web of Science ®Google Scholar
• Ruiz-Antorán B, López AS, Cazorla R, et al. Randomized clinical trial, placebo compared to evaluate the efficacy and safety of minocycline In Angelman syndrome (A-Manece study). Clin Ther. 2015;37(8):e154.
   Web of Science ®Google Scholar
• Bialer M, Johannessen SI, Levy RH, et al. Progress report on new antiepileptic drugs: a summary of the Eleventh Eilat Conference (EILAT XI). Epilepsy Res. 2013;103(1):2–30.
   PubMed Web of Science ®Google Scholar
• Lee SJ. YKP3089 novel neurotherapeutic. 2012 epilepsy pipeline update. San Francisco (CA) 2012 Feb 2-4. [cited 2017 Jul 12]. Available from: https://www.epilepsy.com/sites/core/files/atoms/files/6-6_S_James_Lee.pdf
   Google Scholar
• Krauss G, French J, Kamin M, et al. Seizure freedom with YKP3089 as adjunctive therapy for refractory partial-onset seizures in double-blind placebo-controlled trials (P2. 019). Neurology. 2016;86(16Supplement):P2–019.
   Google Scholar
• Rickels K, Mathew S, Banov MD, et al. Effects of PRX-00023, a novel, selective serotonin 1A receptor agonist on measures of anxiety and depression in generalized anxiety disorder: results of a double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2008;28(2):235–239.
   PubMed Web of Science ®Google Scholar
• Stefulj J, Bordukalo-Niksic T, Hecimovic H, et al. Epilepsy and serotonin (5HT): variations of 5HT-related genes in temporal lobe epilepsy. Neurosci Lett. 2010;478(1):29–31.
   PubMed Web of Science ®Google Scholar
• Bagdy G, Kecskemeti V, Riba P, et al. Serotonin and epilepsy. J Neurochem. 2007;100(4):857–873.
   PubMed Web of Science ®Google Scholar
• PRX-00023 Therapy in Localization-Related Epilepsy. National Institute of Neurological Disorders and Stroke (NINDS). [cited 2017 Jul 12]. Available from: https://www.ninds.nih.gov/Disorders/Clinical-Trials/PRX-00023-Therapy-Localization-Related-Epilepsy
   Google Scholar
• Iyer GR, John FR Jr, Oshana S, et al. Tolerability, pharmacokinetics, and neuroendocrine effects of PRX‐00023, a novel 5‐HT1A agonist, in healthy subjects. J Clin Pharmacol. 2007;47(7):817–824.
   PubMed Web of Science ®Google Scholar
• Blower P, White H, Elrod S. Tonabersat, a novel investigational anti-seizure drug, inhibits seizures in models of generalized epilepsy (P02. 209). Neurology. 2013;80(7 Supplement):P02–209.
   Google Scholar
• Maroso M, Balosso S, Ravizza T, et al. Interleukin-1β biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice. Neurotherapeutics. 2011;8(2):304–315.
   PubMed Web of Science ®Google Scholar
• Vezzani A, French J, Bartfai T, et al. The role of inflammation in epilepsy. Nat Rev Neurol. 2011;7(1):31–40.
   PubMed Web of Science ®Google Scholar
• Vezzani A, Friedman A, Dingledine RJ. The role of inflammation in epileptogenesis. Neuropharmacology. 2013;69:16–24.
   PubMed Web of Science ®Google Scholar
• Ravizza T, Lucas SM, Balosso S, et al. Inactivation of caspase‐1 in rodent brain: a novel anticonvulsive strategy. Epilepsia. 2006;47(7):1160–1168.
   PubMed Web of Science ®Google Scholar
• Noe FM, Polascheck N, Frigerio F, et al. Pharmacological blockade of IL-1β/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy. Neurobiol Dis. 2013;59:183–193.
   PubMed Web of Science ®Google Scholar
• Ravizza T, Noé F, Zardoni D, et al. Interleukin converting enzyme inhibition impairs kindling epileptogenesis in rats by blocking astrocytic IL-1β production. Neurobiol Dis. 2008;31(3):327–333.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Zheng Y. Effects and mechanisms of potent caspase-1 inhibitor VX765 treatment on collagen-induced arthritis in mice. Clin Exp Rheumatol. 2016;34(1):111–118.
   PubMed Web of Science ®Google Scholar
• Boxer MB, Quinn AM, Shen M, et al. A highly potent and selective caspase 1 inhibitor that utilizes a key 3‐cyanopropanoic acid moiety. ChemMedChem. 2010;5(5):730–738.
   PubMed Web of Science ®Google Scholar
• Wannamaker W, Davies R, Namchuk M, et al. (S)-1-((S)-2-{[1-(4-Amino-3-chloro-phenyl)-methanoyl]-amino}-3, 3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R, 3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765), an orally available selective interleukin (IL)-converting enzyme/caspase-1 inhibitor, exhibits potent anti-inflammatory activities by inhibiting the release of IL-1β and IL-18. Jpet. 2007;321:509–516.
   PubMed Web of Science ®Google Scholar
• Vertex announces completion of phase 2 study of VX-765 in people with epilepsy who did not respond to previous treatment. Vertex Pharmaceuticals Incorporated. May 20, 2011. Cambridge (MA). [cited 2017 Jul 13]. Available from: http://investors.vrtx.com/releasedetail.cfm?releaseid=555967
   Google Scholar
• Löscher W, Klitgaard H, Twyman RE, et al. New avenues for anti-epileptic drug discovery and development. Nat Reviews: Drug Discov. 2013;12(10):757.
   PubMed Web of Science ®Google Scholar
• Ma H, Harris S, Rahmani R, et al. Wide-field in vivo neocortical calcium dye imaging using a convection-enhanced loading technique combined with simultaneous multiwavelength imaging of voltage-sensitive dyes and hemodynamic signals. Neurophotonics. 2014;1(1):015003.
   PubMed Web of Science ®Google Scholar
• Zhao M, Alleva R, Ma H, et al. Optogenetic tools for modulating and probing the epileptic network. Epilepsy Res. 2015;116:15–26.
   PubMed Web of Science ®Google Scholar
• Kleen JK, Lowenstein DH. Progress in epilepsy: latest waves of discovery. JAMA Neurol. 2017;74(2):139–140.
   PubMed Web of Science ®Google Scholar