Upload
neal-terry
View
222
Download
0
Embed Size (px)
Citation preview
Use of the New Antiepileptic Agents
Anthony Murro, M.D.
Research Support
• I currently received support for research involving biravacetam from UCB
New Antiepileptic Agents
• Lacosamide (Vimpat)
• Rufinamide (Banzel)
• Vigabatrin (Sabril)
• Clobazam (Onfi)
• Ezogabine (Potiga)
Lacosamide• Adjunctive therapy in the treatment of
partial-onset seizures• Functionalized amino acid
Lacosamide - Mechanism• Lacosamide facilitates slow inactivation of
voltage gated sodium ion channels
Lacosamide - Slow inactivation
• Membrane depolarization occurs
• A relatively slower & more sustained ion channel conformation occurs at a intra-membrane channel site
• This conformation blocks sodium ion flow
• Lacosamide enhances slow inactivation
• (Goldin, 2011)
Sodium Ion Channel Fast Inactivation
• Voltage gated sodium ion channel conformation occurs post-depolarization
• An intracellular protein segment (inactivating particle) binds to a docking site & blocks sodium ion flow
• Carbamazepine, felbamate, lamotrigine, phenytoin, oxcarbazepine, topiramate enhance fast inactivation
• (Goldin, 2011)
Slow inactivationIntra-membrane sites S5 & S6 block ion
channel
Fast Inactivation
Intracellular loop between domains III & IV blocks ion channel
CRMP-2 Binding• Lacosamide also binds to a collapsin
response mediator protein-2 (CRMP-2)
CRMP-2 Binding• This protein performs important roles that
include cytoskeletal, vesicle, and synaptic functions in the developing brain.
• The significance of this binding is an area of current research (Hensley et al., 2011)
Lacosamide Dosing
• Adult: 50 mg twice daily; may be increased at weekly intervals by 100 mg/day
• Maintenance dose: 200-400 mg/day
Lacosamide Metabolism
• Linear kinetics 100-800 mg/d dose
• Metabolism (CYP2C19) by de-methylation to form O-desmethyl-lacosamide (inactive)
• No significant induction/inhibition or P450 mediated interaction
(Chu et al, 2010)
Lacosamide Effectiveness• Multi-center randomized prospective
controlled trials
• > 400 patients per trial
• Age 16 years and older
• Adjunctive therapy with 1-3 anti-epileptic medications
Lacosamide Median Sz ReductionGroup Ben-Menachem Halasz
Placebo 10% 20.5%
200 mg/d 26% 35.3%
400 mg/d 39% 36.4%
600 mg/d 40% ---
(Ben-Menachem et al, 2007, Halasz et al, 2009)
Lacosamide Effectiveness
• Dose of 600 mg/day not more effective but did have increased side effect risk
• Events leading to discontinuation: Dizziness, nausea, ataxia, vomiting, nystagmus
• (Ben-Menachem et al, 2007)
Effect of Sodium Channel Blocker
Retrospective analysis suggests:
• Lacosamide will reduce seizure frequency even when combined with a fast sodium channel blocker (Sake et al., 2010, Stephen et al., 2011)
Effect of Sodium Channel Blocker
Retrospective analysis suggests:
• Lacosamide with a sodium channel blocker (e.g. phenytoin) will lead to less seizure reduction & increased side effects
• Caution: Post-hoc analysis, small samples, multiple comparisons, and potential confounding factors.
(Sake et al., 2010, Stephen et al., 2011)
Lacosamide Pooled Analysis
Median Seizure Reduction
Sodium Channel Blocker
Group Present Absent
Placebo 18.9% 28%
200 mg/d 33.3% 38%
400 mg/d 39% 62.5%
600 mg/d 42.7% 79%
Lacosamide Case Reports• Intravenous lacosamide has been used to
treat status epilepticus & seizure clusters. Bolus of 200 mg IV at rate of 60 mg/min (Höfler et al., 2011)
• Lacosamide has been used in primary generalized epilepsy (Afra et al., 2012)
• A single report described worsening of seizures in Lennox Gastaut syndrome with lacosamide (Cuzzola et al., 2010)
Lacosamide SummaryPositive
• No significant drug interactions
• Common side effects are dose dependent & easily managed with dose reduction
• Infrequent need for serum drug levels
• Low protein binding
Negative
• High cost
Role of Lacosamide
• The favorable profile makes lacosamide a likely early choice for adjuvant drug therapy of partial seizures
• Future research might confirm effectiveness for primary generalized epilepsy & status epilepticus.
• Future research might confirm greater benefit among patients not using sodium channel blockers
Rufinamide• Adjunctive therapy in the treatment of
generalized seizures of Lennox-Gastaut syndrome (LGS)
Rufinamide Mechanism• Rufinamide slows sodium ion channel
recovery from the inactivated state & limits repetitive neuronal firing
Rufinamide Dosing• Children: Initial: 10 mg/kg/day in 2 equally
divided doses; increase dose by ~10 mg/kg every other day to a target dose of 45 mg/kg/day or 3200 mg/day (whichever is lower) in 2 equally divided doses
• Adults: Initial: 400-800 mg/day in 2 equally divided doses; increase dose by 400-800 mg/day every other day to a maximum dose of 3200 mg/day in 2 equally divided doses.
Rufinamide Oral Absorption• Oral absorption increases with food due to
increased solubility (33% increase overall absorption & 50% increase in peak concentration).
• Keep relationship with meals constant.
Rufinamide Metabolism
• Carboxylesterase metabolism to inactive metabolite
• Rufinamide is a weak CYP3A4 inducer
• Non-linear drug kinetics
Rufinamide Drug Levels
• Drug levels correlate with effectiveness and frequency of adverse effects
• Mean plasma level causing a 50% decrease of seizure frequency was 30 mg/l; range in studies: 5-55 mg/l.
Rufinamide Drug Interactions
• Mild increased clearance of oral contraceptives (CYP3A4 induction)
• Phenobarbital, primidone, phenytoin, carbamazepine induce carboxyesterase & significantly increase rufinamide clearance
• Valproate significantly increases rufinamide levels by 60-70%
Rufinamide Lennox Gastaut Median Seizure Reduction
Group All Seizures Tonic-atonic
Placebo 11.7% -1.4%
45 mg/kg-d 32.7% 42.5%
(Glauser et al., 2007)
Rufinamide Partial Seizures Median Seizure Reduction
Group Seizure Reduction
Placebo -1.6%
Rufinamide* 20.4%
Dose: 1200-3200 mg/d (mean 2800 mg/d)
(Brodie et al, 2007)
Adverse Effects• Most common: Dizziness, fatigue,
somnolence, nausea, headache
• AED hypersensitivity syndrome (rash & fever) has occurred 1-4 weeks after therapy & more likely in children
• No significant effects on working memory, psychomotor speed, or attention
• (Wheles et al. 2010)
Rufinamide QT shortening
• > 20 msec reduction in QT can occur but in in study population had < 300 msec
• Rufinamide should not be given to those with familial short QT syndrome potassium channelopathy
• Do not administer in situations with reduced QT interval: digoxin, hpercalcemia, hyperkalemia, acidosis
Myoclonic-astatic epilepsy (Doose syndrome)
• Onset age 1-6 years of age
• Myoclonic, astatic, & myoclonic-astatic Sz
• Normal development prior to seizures
• Prognosis variable: spontaneous resolution in some; prolonged non-convulsive status epilepticus, cognitive impairments & evolution to Lennox-Gastaut in others
• EEG: 2-3 Hz generalized spike wave
• MRI normal
Myoclonic-astatic epilepsy & Rufinamide
• In a case series, rufinamide adjunctive therapy reduced seizure frequency by >75% in 6 of 7 cases
• Seizure reduction decreased for patients followed over longer time intervals of 6-18 months (von Stülpnagela et al. 2012)
Rufinamide SummaryPositive
• Most side effects are dose dependent & easily managed with dose reduction
• Infrequent need for serum drug levels
• Low protein binding
Negative
• Significant drug interactions are possible
• High cost
Role of Rufinamide
• Rufinamide has features similar to many of the approved drugs for Lennox-Gastaut (e.g. lamotrigine, topiramate).
• Future research might confirm the beneficial effect of rufinamide for treatment of myoclonic-astatic epilepsy.
Vigabatrin• Adjunctive treatment for infantile spasms and
adult refractory complex partial seizure
Vigabatrin Mechanism
• Irreversible & competitive binding to GABA transaminase (Chu-Shore et al., 2010)
Vigabatrin Mechanism
• Possibly also might stimulate GABA release
• Brain GABA increases by 40% at 2 hours post-dose
• (Chu-Shore et al., 2010)
Vigabatrin
• Linear dose relationship
• Reduces phenytoin level by 20%
• Dosage adjustment for decreased renal clearance
• (Chu-Shore et al., 2010)
Vigabatrin Dosing Complex Partial Seizures
• Adults: Initial: 500 mg twice daily; increase daily dose by 500 mg at weekly intervals based on response and tolerability. Recommended dose: 3 g/day
• Children: Oral: Initial: 40 mg/kg/day divided twice daily; maintenance dosages based on patient weight
Vigabatrin Dosing Infantile Spasm
• Initial dosing: 50 mg/kg/day divided twice daily; may titrate upwards by 25-50 mg/kg/day every 3 days to a maximum of 150 mg/kg/day
Vigabatrin Effectiveness Complex Partial Seizures
(Dean et al., 1999)
Vigabatrin Effectiveness Complex Partial Seizures
(French et al., 1996)
Vigabatrin Treats Infantile SpasmsTuberous Sclerosis Responds Best
Group % Spasm Free day 14Vigabatrin low dose 11%Vigabatrin high dose 36%• Tuberous sclerosis 52%• Cryptogenic 27%• Symptomatic 10%Low: 18-36 mg/kg-d; High: 100-148 mg/kg-d(Elterman et al., 2001)
Hormonal Therapy Better Early Response For Non-Tuberous
Sclerosis CasesPercent Spasm Free
Group 2 wks* 12-14 months
Hormonal 73% 75%
Vigabatrin 54% 76%
• Significant difference (Lux et al., 2005)
Tuberous sclerosis cases were excluded
Better Cognitive Outcome: Hormonal Treatment Cryptogenic Cases
Outcome at 12-14 months Following Treatment
Symptomatic Vineland Adaptive Behavior Scale
Hormonal 70.8
Vigabatrin 75.9
Cryptogenic* Vineland Adaptive Behavior Scale
Hormonal 88.2**
Vigabatrin 78.9**• Significant difference (Lux et al., 2005)
Tuberous sclerosis cases were excluded
Better Cognitive Outcome: Hormonal Treatment Cryptogenic Cases
Outcome at 4 years Following Treatment
Symptomatic Vineland Adaptive Behavior Scale
Hormonal 45
Vigabatrin 50
Cryptogenic* Vineland Adaptive Behavior Scale
Hormonal 96
Vigabatrin 63
* Significant difference (Darke et al., 2005)
Tuberous sclerosis cases were excluded
Vigabatrin Effectively Treats Tuberous Sclerosis
Practice Parameter: Medical Treatment of Infantile Spasms:
“Overall cessation of spasms was seen in 41 of 45 (91%) of children treated with vigabatrin, with a 100% response rate seen in five studies.”
(Mackay et al. 2004)
Vigabatrin Visual Adverse Effects
• Bilateral irreversible concentric peripheral field defects occur in 30-50% of cases
• Most with defects were treated for at least 6 months; often stable after 2 years
• Defects often asymptomatic but might impair driving (Chu-Shore et al., 2010)
Vigabatrin Visual Adverse Effects
• Adults: visual testing done at baseline & each 6 months
• Infants: visual testing done at baseline & test each 3 months for 18 months, then each 6 months (sedate for electroretinogram)
(Chu-Shore et al., 2010)
Vigabatrin Visual Effects• Common approach is treatment for a
duration under 3 months; consider discontinuation after 6 months, if seizures are effectively controlled (Kossoff EH, 2010).
• An experimental animal study found that taurine prevented the visual adverse effect (Firas et al, 2009)
Vigabatrin White Matter Changes
• Lesions were asymptomatic & reversible
• Age: 9 months - 18 years (median 5.4 yrs)
• 8 of 23 (34%) subjects were affected
• T2/DWI scans show lesions in basal ganglia, thalamus, brainstem, & dentate nucleus (Pearl et al., 2009)
Vigabatrin White Matter Changes
Feature With Lesions Without Lesions
Number 8 subjects 15 subjects
Age 11 months 5 years
Duration 3 months 12 months
Dose 170 mg/kg-d 87 mg/kg-d
(Pearl et al., 2009)
Vigabatrin White Matter Changes
Vigabatrin Summary
Positive• High effectiveness for infantile spasms• Few significant drug interactions; exception is
phenytoin• Infrequent need for serum drug levels• Low protein bindingNegative• Irreversible visual field defects• White matter lesions • High cost
Role of Vigabatrin
• Vigabatrin is likely to be among the last choices for adjuvant treatment of partial seizures
• Vigabatrin is a good 1st choice for infantile spasms from tuberous sclerosis (TS)
• Hormonal therapy might provide more effective early control for non-TS cases & better cognitive outcome for cryptogenic infantile spasms
ClobazamAdjunctive treatment of seizures associated
with Lennox-Gastaut syndrome
Clobazam Mechanism• Allosteric activation of GABAa receptor
Clobazam Mechanism• Allosteric activation of GABAa receptor
• Up-regulation GABA transporters 1 to 3 (GAT1 to GAT3)
• Clobazam has decreased affinity for GABAa subunits that mediate sedative effects
Clobazam Dosing• ≤30 kg: Initial: 5 mg once daily for ≥1
week, then increase to 5 mg twice daily for ≥1 week, then increase to 10 mg twice daily thereafter
• >30 kg: Initial: 5 mg twice daily for ≥1 week, then increase to 10 mg twice daily for ≥1 week, then increase to 20 mg twice daily thereafter
Clobazam DosingCYP2C19 poor metabolizers:
• ≤30 kg: Initial: 5 mg once daily for ≥2 weeks, then increase to 5 mg twice daily; after ≥1 week may increase to 10 mg twice daily
• >30 kg: Initial: 5 mg once daily for ≥1 week, then increase to 5 mg twice daily for ≥1 week, then increase to 10 mg twice daily; after ≥1 week may increase to 20 mg twice daily
Clobazam Metabolism• Hepatic via CYP3A4 and to a lesser extent via
CYP2C19 and 2B6
• N-demethylation to active metabolite [N-desmethyl] with ~20% activity of clobazam.
• CYP2C19 primarily mediates subsequent hydroxylation of the N-desmethyl metabolite.
• Carbamazepine reduces clobazam level, & clobazam decreases valproate (Riss et al, 2008)
• Many other potential drug interactions
Clobazam• Placebo controlled trial in 238 cases
(age 2-60 years) with Lennox-Gastaut syndrome (Ng YT et al, 2011)
• Treatment groups: placebo, 0.25 mg/kg-d, 0.5 mg/kg-d, 1.0 mg/kg-d.
• Weekly seizure rate reduction showed a dose response effect
• Side effects: somnolence, pyrexia, respiratory infections, lethargy, behavioral problems.
Clobazam Treatment Response
Group Drop Attack Reduction
Placebo 12.1%
0.25 mg/kg-d (max 10 mg/d) 41.2%
0.5 mg/kg-d (max 20 mg/d)49.4%
1.0 mg/kg-d (max 40 mg/d)68.3%
(Ng YT et al, 2011)
Clobazam Side Effects
• Somnolence
• Fever
• Lethargy
• Drooling
• Constipation
Clobazam Other Studies• Retrospective studies involving refractory
partial seizures reported an early improvement in seizure reduction.
• Many could not tolerate the drug due to somnolence.
• Tolerance occurred; seizures re-occurred in subjects that had improved initially (Shimizu et al., 2003, da Silveira et al., 2006)
Clobazam SummaryPositive
• High level of effectiveness for a difficult to treat seizure disorder
• Common side effects are dose dependent & easily managed with dose reduction
• Parent compound & metabolite have long half life
Clobazam SummaryNegative
• High cost
• High protein binding
• Active metabolite & potentially significant drug interactions
Role of Clobazam• Clobazam is likely to be a useful drug for
adjuvant therapy of Lennox Gastaut
• Limiting factors are likely to be cost and occurrence of drug related side effects
• Research might confirm the benefit of this drug for refractory partial seizures.
Ezogabine (Retigabine)Adjuvant treatment of partial-onset seizures
Ezogabine
• Binds to KCNQ2/3 KCNQ3/5 potassium channels
Ezogabine• Ezogabine binds to KCNQ2/3 & KCNQ3/5
potassium channels at a hydrophobic pocket near channel gate
• This binding stabilizes the open KCNQ2/3 & KCNQ3/5 potassium channels
• This causes membrane hyperpolarization (Gunthorpe et al. 2012)
Ezogabine• At high concentrations: blocks sodium
voltage gated sodium & calcium channels and increases GABA synthesis (Czuczwar et al., 2010)
Autosomal Dominant Neonatal Epilepsy
• Loss of function mutation KCNQ2/3
• Focal or generalized tonic-clonic seizures on day 3; seizures remit by 1 month
• 10-15% develop epilepsy
• Therapy resistant epileptic encephalopathy might occur (Kurahashi et al., 2009)
Ezogabine Dosing
• Initial: 100 mg 3 times/day; may increase at weekly intervals in increments of ≤150 mg/day to a maintenance dose of 200-400 mg 3 times/day (maximum: 1200 mg/day)
Ezogabine Metabolism
• No P450 metabolism• Glucuronidation via UGT1A4, UGT1A1,
UGT1A3, and UGT1A9• Acetylation via NAT2 to an N-acetyl active
metabolite (NAMR) and other inactive metabolites (eg, N-glucuronides, N-glucoside)
• Linear drug kinetics (Weisenberg et al,, 2011)
Ezogabine Drug Interactions
• No effect on oral contraceptive clearance
• Lamotrigine decreases ezogabine clearance slightly; ezogabine increases lamotrigine clearance slightly
Ezogabine EffectivenessGroup Seizure Reduction
Placebo 13.1%
600 mg/d 23.4%
900 mg/d 29.3%
1200 mg/d 35.2%
(Porter et al., 2007)
Ezogabine EffectivenessGroup Seizure Reduction
Placebo 15.9%
600 mg/d 27.9%
900 mg/d 39.9%
(Brodie et al., 2010)
Ezogabine EffectivenessGroup Seizure Reduction
Placebo 17.5%
1200 mg/d 44.3%
(French et al., 2011)
Ezogabine Side Effectts
• Somnolence• Fatigue• Confusion• Dizziness• Headache• Dysarthria• Ataxia• Blurred vision
Ezogabine SummaryPositive
• Minimal drug interactions
• Common side effects are dose dependent & easily managed with dose reduction
• Infrequent need for serum drug levels
• Unique drug mechanism
Negative
• High cost
Ezogabine
Role of Ezogabine
• Ezogabine is likely to be a useful drug for adjuvant therapy for refractory partial seizures
• Limiting factors are likely to be cost and occurrence of drug related side effects
Cumulative SummaryLacosamide, & ezogabine are likely to be
considered early choices for adjuvant drug therapy of partial seizure because:
• Minimal drug interactions
• Novel mechanisms of action
• Relatively safe side effect profile.
Cumulative SummaryVigabatrin has a specialized role:• First choice therapy for infantile spasms
among those with tuberous sclerosis• Adjuvant therapy in otherwise refractory
infantile spasm cases.• ACTH may be a better choice in select
infantile cases. • Vigabatrin is likely to be among the later
choices for refractory partial seizures due to its risk of visual loss.
Cumulative SummaryRufinamide and clobazam have a
specialized role as adjuvant therapy for Lennox-Gastaut.
• Drug interactions are more complex with these medications.
• Side effects might limit the use of these medications in some cases
Pharmacokinetic PropertiesDrug Tmax T1/2 %PB
Lacosamide 1-2 hr 13 hr <19%
Rufinamide 4-6 hr 6-10 hr 34%
Vigabatrin 2 hr 5-8 hr 0%
Clobazam 1-2 hr 10-30 hr 82-90%
Clobazam ** --- 36-46 hr ---
Ezogabine 1-2 hr 8-10 hr <80%
** desmethylclobazam active metabolite
(Chu et al, 2010)
References• Afra P, Adamolekun B. Lacosamide treatment of
juvenile myoclonic epilepsy. Seizure. 2012 Jan 24.
• Appleton RE, Peters ACB, Mumford JP, Shaw DE. Randomized,placebo-controlled study of vigabatrin as first-line treatment of infantile
• spasms. Epilepsia. 1999;40:1627–1633.• Ben-Menachem E, Biton V, Jatuzis D, Abou-
Khalil B, Doty P, Rudd GD. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia. 2007 Jul;48(7):1308-17.
References• Brodie M.J., W.E. Rosenfeld, B. Vazquez et al.
Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: A randomized placebo-controlled trial Epilepsia, 50 (2009), pp. 1899–1909
• Brodie MJ, Lerche H, Gil-Nagel A, Elger C, Hall S, Shin P, Nohria V, Mansbach H; RESTORE 2 Study Group. Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy. Neurology. 2010 Nov 16;75(20):1817-24.
• Chiron C, Dulac O, Beaumont D, Palacios L, Pajot N, Mumford J. Therapeutic trial of vigabatrin in refractory infantile spasms. J Child Neurol. 1991;6 Suppl 2:2S52–2S59.
References• Chiron C, Dulac O, Beaumont D, Palacios L, Pajot N,
Mumford J. Therapeutic trial of vigabatrin in refractory infantile spasms. J Child Neurol. 1991;6 Suppl 2:2S52–2S59.
• Chu-Shore CJ, Thiele EA. New drugs for pediatric epilepsy. Semin Pediatr Neurol. 2010 Dec;17(4):214-23.
• Cuzzola A, Ferlazzo E, Italiano D, Calabrò RS, Bramanti P, Genton P. Does lacosamide aggravate Lennox-Gastaut syndrome? Report on three consecutive cases. Epilepsy Behav. 2010 Dec;19(4):650-1
• Czuczwar P, Wojtak A, Cioczek-Czuczwar A et al. Retigabine: The newer potential antiepileptic drug Pharmacol Rep, 62 (2010), pp. 211–219
References• Darke K, Edwards SW, Hancock E, Johnson AL,
Kennedy CR, Lux AL, Newton RW, O'Callaghan FJ, Verity CM, Osborne JP; trial steering committee on behalf of participating investigators. Developmental and epilepsy outcomes at age 4 years in the UKISS trial comparing hormonal treatments to vigabatrin for infantile spasms: a multi-centre randomised trial.Arch Dis Child. 2010 May;95(5):382-6.
• da Silveira MRM , Montenegro MA, Franzon RC, Guerreiro CAM, Guerreiro MM. Effectiveness of clobazam as add-on therapy in children with refractory focal epilepsy. Arq Neuropsiquiatr 2006;64(3-B):705-710
• Dean C, Mosier M, Penry K. Dose-response study of vigabatrin as add-on therapy in patients with uncontrolled complex partial seizures. Epilepsia, 40 (1999), pp. 74–82
References• Elger C.E. , H. Stefan, A. Mann et al. A 24-week
multicenter, randomized, double-blind, parallel-group, dose-ranging study of Rufinamide in adults and adolescents with inadequately controlled partial seizures. Epilepsy Res, 88 (2010), pp. 255–263
• Elterman RD, Shields WD, Mansfield KA, et al; US Infantile Spasms Vigabatrin Study Group. Randomized trial of vigabatrin in patients with infantile spasms. Neurology. 2001;57:1416–1421.
• French JA, M. Mosier, S. Walker et al. A double-blind, placebo-controlled study of vigabatrin three g/day in patients with uncontrolled complex partial seizuresVigabatrin Protocol 024 Investigative Cohort Neurology, 46 (1996), pp. 54–61
References• French JA, Abou-Khalil BW, Leroy RF, Yacubian EM,
Shin P, Hall S, Mansbach H, Nohria V; RESTORE 1/Study 301 Investigators. Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy.
• Neurology. 2011 May 3;76(18):1555-63.• Firas Jammoul,, Qingping Wang, et al. Taurine
deficiency is a cause of vigabatrin-induced retinal phototoxicity. Ann Neurol. 2009 January ; 65(1): 98–107
• Glauser T, Kluger G, Sachdeo R et al. Rufinamide for generalized seizures associated with Lennox–Gastaut syndrome. Neurology, 70 (2008), pp. 1950–1958
References• Goldin AL. Mechanisms of sodium channel inactivation.
Curr Opin Neurobiol. 2003 Jun;13(3):284-90. • Gunthorpe MJ, Large CH, Sankar R, The mechanism of
action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy. Epilepsia, 1–13, 2012.
• Halász P, Kälviäinen R, Mazurkiewicz-Beldzińska M, Rosenow F, Doty P, Hebert D, Sullivan T; SP755 Study Group.l Adjunctive lacosamide for partial-onset seizures: Efficacy and safety results from a randomized controlled trial. Epilepsia. 2009 Mar;50(3):443-53
• Hensley K, Venkova K, Christov A, Gunning W, Park J. Collapsin response mediator protein-2: an emerging pathologic feature and therapeutic target for neurodisease indications. Mol Neurobiol. 2011 Jun;43(3):180-91
References• Höfler J, Unterberger I, Dobesberger J,
Kuchukhidze G, Walser G, Trinka E. Intravenous lacosamide in status epilepticus and seizure clusters. Epilepsia. 2011 Oct;52(10):e148-52.
• Kossoff EH, Infantile Spasms. The Neurologist 2010;16: 69–75.
• Kurahashi H, Wang JW, Ishii A et al. Deletions involving both KCNQ2 and CHRNA4 present with benign familial neonatal seizures. Neurology, 73 (2009), pp. 1214–1217
References• Lux AL, Edwards SW, et al. The United Kingdom
Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial The Lancet Neurology. Volume 4, Issue 11, November 2005, Pages 712–717.
• M. T. Mackay, S. K. Weiss, T. Adams-Webber, et al. Practice Parameter: Medical Treatment of Infantile Spasms : Report of the American Academy of Neurology and the Child Neurology Neurology Society . 2004;62;1668
• Ng YT, Conry JA, Drummond R, Stolle J, Weinberg MA; OV-1012 Study Investigators. Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome. Neurology. 2011 Oct 11;77(15):1473-81.
References• Pearl PL, Vezina LG et al.,Cerebral MRI abnormalities
associated with vigabatrin therapy. Epilepsia, 50(2):184–194, 2009.
• Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008 Aug;118(2):69-86.
• Sake JK, Hebert D, Isojärvi J, Doty P, De Backer M, Davies K, Eggert-Formella A, Zackheim J. A pooled analysis of lacosamide clinical trial data grouped by mechanism of action of concomitant antiepileptic drugs.
• Shimizu H, Kawasaki J, Yuasa S, Tarao Y, Kumagai S, Kanemoto K. Use of clobazam for the treatment of refractory complex partial seizures. Seizure. 2003 Jul;12(5):282-6.
References• Stephen LJ, Kelly K, Parker P, Brodie MJ. Adjunctive
lacosamide in clinical practice: sodium blockade with a difference? Epilepsy Behav. 2011 Nov;22(3):499-504 CNS Drugs. 2010 Dec;24(12):1055-68
• von Stülpnagel C. , Coppolab G. , P. Strianoc, A. Müllera, M. Staudta, d, G. Kluger. First long-term experience with the orphan drug rufinamide in children with myoclonic-astatic epilepsy (Doose syndrome) European Journal of Paediatric Neurology 2012 Jan 20
• Weisenberg JL, Wong M. Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures. Neuropsychiatr Dis Treat. 2011;7:409-14.
• Wheless JW, Vazquez B. Rufinamide: a novel broad-spectrum antiepileptic drug. Epilepsy Curr. 2010 Jan;10(1):1-6.