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Advances in Promoting Wakefulness in Narcolepsy

Advances in Promoting Wakefulness in Narcolepsy. Michael Thorpy M.D. Montefiore Medical Center and the Albert Einstein College of Medicine Bronx, New York. NESS, Boston, March 27, 2010. Narcolepsy Treatment Goals. Reduce excessive sleepiness Control cataplexy

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Advances in Promoting Wakefulness in Narcolepsy

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  1. Advances in Promoting Wakefulness in Narcolepsy Michael Thorpy M.D. Montefiore Medical Center and the Albert Einstein College of Medicine Bronx, New York NESS, Boston, March 27, 2010

  2. Narcolepsy Treatment Goals • Reduce excessive sleepiness • Control cataplexy • Other associated REM-related symptoms (sleep paralysis, hypnagogic and hypnopompic hallucinations) • Improve nighttime sleep • Reduce psychosocial problems Krahn LE et al. (2001), Mayo Clin Proc 76(2):185-194; Black J (2001), Central Nervous System News Special Edition 25-29; U.S. Xyrem Multicenter Study Group (2002), Sleep 25(1):42-49

  3. Narcolepsy: Management Approaches • Excessive daytime sleepiness • Structured nocturnal sleep • Naps: scheduled and prn • Stimulants or wake-promoting agents • Sodium Oxybate • Cataplexy • Antidepressants (TCA, SSRI, NERI) • Sodium oxybate Parkes D (1994), Sleep 17(suppl):S93-S96; Mitler MM et al. (1994), Sleep 17(4):352-371; Daly DD, Yoss RE (1976), Narcolepsy. In: Handbook of Clinical Neurology Vol. 15, Vinken PJ, Bruyn GW, eds. New York: Elsevier Publishing, pp836-852; Bassetti C, Aldrich MS (1996), Neurol Clin 14(3):545-571; Mamelak M et al. (1986), Sleep 9(1 pt 2):285-289

  4. Narcolepsy: Management Approaches (Cont.) • Sleep fragmentation • Sleep hygiene • Hypnotics • Sodium oxybate • Sleep disorders • Hypnagogic Hallucinations – TCA’s, sodium oxybate • Nightmares – TCA’s, sodium oxybate • Sleep Paralysis – TCA’s, sodium oxybate • Periodic Limb Movements – Dopamine agonists • REM Sleep Behavior Disorder – Clonazepam, melatonin Parkes D (1994), Sleep 17(suppl):S93-S96; Mitler MM et al. (1994), Sleep 17(4):352-371; Daly DD, Yoss RE (1976), Narcolepsy. In: Handbook of Clinical Neurology Vol. 15, Vinken PJ, Bruyn GW, eds. New York: Elsevier Publishing, pp836-852; Bassetti C, Aldrich MS (1996), Neurol Clin 14(3):545-571; Mamelak M et al. (1986), Sleep 9(1 pt 2):285-289

  5. Narcolepsy: Management Approaches (Cont.) • General • Personal and family counseling • Support – • Narcolepsy Network • State funded support programs • Sleep hygiene • Naps

  6. Treatment of Excessive Sleepiness • Daytime Sleepiness • Stimulants • Methylphenidate • Dextroamphetamine • Methamphetamine • Modafinil/ Armodafinil • Sodium Oxybate

  7. Stimulants and Wake-Promoting Medications Drug Formulations Schedule Dose T1/2 (Hours) Dextroamphetamine Tablets, SR C-II 5-60 mg/day 12 Methamphetamine (Desoxyn) Tablets C-II 5-60 mg/day 4-5 Amphetamine sulfate/saccharate/aspartate (Adderall) Capsules, XR C-II 5-60 mg/day 10-13 Methylphenidate Tablets, SR, LA C-II 5-60 mg/day 3-5 Modafinil Tablets C-IV 200-400 mg/day 15 Armodafinil Tablets C-IV 150-250 mg/day 15 Physicians’ Desk Reference (2005), Montvale, N.J.: Medical Economics Company; Nishino S, Mignot E (2005), Wake-promoting medications: basic mechanisms and pharmacology. In: Principles and Practice of Sleep Medicine, Kryger MH et al., eds. Philadelphia: Elsevier

  8. Alerting Agents Mechanism • Sympathomimetic: enhance neurotransmission of dopamine, norepinephrine, serotonin • Caffeine: adenosine receptor antagonist • Modafinil: specific mechanism remains unclear

  9. Considerations for Use of Stimulants and Wake-Promoting Agents • Drug-drug interactions: CYP 450 • Adverse effects: anxiety/nervousness,restlessness, insomnia, headache, tremor, dyskinesia, tachycardia, hypertension, psychosis • Abuse potential • Tolerance

  10. Caffeine Medial Prefrontal Cortex Regions (BA 10) Activated by Caffeine vs. Placebo During Verbal Working Memory Adapted from Koppelstaetter et al. (2008)

  11. Rx Clock Time Adapted from Killgore et al. (2008)

  12. Sites of Action of Amphetamines Amphetamine Dopamine reuptake transporter MAO Vesicular Monoamine transporter Dopamine Dopamine receptors + Courtesy of Thomas Scammell, MD.

  13. High-dose Stimulants • 58 patients who were taking high-dose stimulants for narcolepsy or idiopathic hypersomnia were compared with 58 control patients. • High dose stimulants were >120mg/day. • The prevalence of psychosis, psychiatric hospitalizations, tachyarrhythmias, polysubstance abuse, anorexia and weight loss were significantly increased in the stimulant group. Auger et al. Risks of high dose stimulants in the treatment of disorders of excessive somnolence. A case control study. Sleep 2005;28:667-672

  14. Pharmacotherapy: Sleepiness • Modafinil • 150 - 500 mg/day • Moderate efficacy, long half life • Best side effect profile • Schedule IV, most expensive • Methylphenidate • 5 - 100 mg/day • Short half life formulation, variable dosing • Used alone or in combination • Sympathomimetic effects, mood alterations

  15. Modafinil: Sites of Action • Chemically unrelated to CNS stimulants • Inhibits the dopamine transporter (DAT) • Contrary to amphetamine, may not induce release of dopamine • Activates wake-promoting neurons • Inhibits norepinephrine transporter in the VLPO • Contrary to amphetamine, may not induce release of norepinephrine • Enhanced norepinephrine inhibits sleep promoting VLPO neurons • Stimulates hypocretin release • Stimulates histamine release from the TMN VLPO = Ventrolateral preoptic area

  16. Neurotransmitter Method of action Site of Action Dopamine Inhibition of dopamine reuptake transporter Multiple arousal systems Norepinephrine (NE) Inhibition of the NE reuptake transporter VLPO Hypocretin Stimulation Lateral hypothalamus Histamine Stimulation Tuberomamillary nucleus Modafinil: Sites of Action VLPO = Ventrolateral preoptic area

  17. MAO Norepinephrine Norepinephrine reuptake transporter Sleep-promoting neurons (GABA; VLPO) 2 Norepinephrine receptors Dopamine reuptake transporter Modafinil - Wake-promoting neurons MAO Dopamine receptors Dopamine + Proposed Sites of Action of Modafinil

  18. GABA (ventrolateral Preoptic area) Norepinephrine Histamine Dopamine Serotonin Acetylcholine Alerting Agents Stabilize Wakefulness Modafinil Amphetamines GABA – + Sleep Wake – – Norepinephrine Serotonin Modafinil

  19. Pharmacokinetic Properties of Modafinil • Pharmacokinetics Linear, Independent of dose • Peak Plasma Concentration 2 - 4 hrs, Tmax delayed (~ 1 hr) by food • Plasma Protein Binding: Moderate (~60%) • Elimination Half-life 15 hrs • Metabolism: Metabolized by liver (~90%) • Urinary Excretion: < 10% of unchanged drug, All metabolites

  20. Disorder Measures Modafinil 200mg Modafinil 400mg Baseline Change from baseline Baseline Change from baseline OSA I study ESS MSLT - - - - 14.2 7.4 -4.6 +1.2 OSA II study ESS MWT 13.1 -4.5 +1.6 13.6 -4.5 +1.5 SWD KSS MSLT PVT 7.3 2.1 12.5 -1.5 +1.7 -2.6 - - - - - - Narcolepsy I ESS MSLT MWT 17.9 2.9 5.8 -3.5 +1.8 +2.3 17.1 3.3 6.6 -4.1 +1.9 +2.3 Narcolepsy II ESS MSLT MWT 17.4 3.0 6.1 -4.4 +1.9 +2.1 18.0 2.7 5.9 -5.7 +2.4 +1.9 Modafinil

  21. 200 mg qd 400 mg qd 400 mg split-dose MWT Sleep Latency: Split-Dose vs AM Dosing Regimens N=32 15 * † 10 Mean (+SEM) MWT change from baseline 5 0 Morning (9-11 AM) Afternoon (1-3 PM) Evening (5-7 PM) The % of patients able to sustain wakefulness was highest in the morning with the 400-mg single dose and in the evening with the split dose regimen *P<.001 vs 200 mg qd†P<.05 vs 400 mg qd Schwartz JRL, et al. Clin Neuropharmacol. 2003;26:252-257.

  22. 80 200 mg qd 70 400 mg qd 60 50 40 30 20 10 0 MWT Sleep Latency: Comparing Split-Dose Regimens N=24 ** 400 mg split-dose % of patients awake for 20 minutes 600 mg split-dose Morning (9-11 AM) Afternoon (1-3 PM) Evening (5-7 PM) *P<.05 vs 200 or 400 mg qd Schwartz JRL, et al. J Neurol Clin Neurosci. 2004; 27(2): 74-79.

  23. Armodafinil (Nuvigil) • R-(-)-modafinil • Longer acting isomer of modafinil • Half life approximately 3 x S-(-)-modafinil

  24. Disorder Measures Armodafinil 150mg Armodafinil 250mg Baseline Change from Baseline Baseline Change from baseline OSA I MWT 21.5 +1.7 23.3 +2.2 OSA II MWT 23.7 +2.3 - - SWD MSLT 2.3 +3.0 - - Narcolepsy MWT 12.1 +1.3 9.5 +2.6 Armodafinil

  25. Diagnosis Symptoms FDA approval Modafinil Doses studied Armodafinil Doses studied Obstructive Sleep Apnea EDS yes 200-400mg 150 – 250mg Shift Work Disorder EDS yes 200-400mg 150mg Narcolepsy EDS yes 200-400mg 150 – 250mg Depression Fatigue no 100-400mg N/A Multiple Sclerosis Fatigue no 200-400mg N/A Parkinson’s disease EDS no 100-400mg N/A Chronic fatigue syndrome Fatigue no 200-400mg N/A Traumatic Brain Injury Fatigue EDS no 100-400mg N/A Modafinil / armodafinil

  26. Adverse Effects Modafinil Armodafinil Headache 34% 17% Nausea 11% 7% Dizziness 5% 5% Nervousness 7% 1% Anxiety 5% 4% Insomnia 5% 5% Rhinitis 7% not reported Back pain 6% 6% Flu syndrome 4% 1% Hypertension 3% not reported Diarrhea 6% 4% Modafinil / Armodafinil

  27. Sodium Oxybate: Physiology • Endogenous metabolite of GABA • Affects the GHB and GABA-B receptors • Neuromodulator • GABA • Dopamine • Serotonin • Endogenous opioids • Evidence for role as neurotransmitter • Synthesized in neurons, stored in vesicles, released via depolarization into synaptic cleft, reuptake, specific receptors

  28. Sodium Oxybate: Pharmacokinetics Absorption Tmax = 0.5 h-1.25 h Dose proportionality Nonlinear kinetics Distribution <1% protein bound Metabolism Bioavailability ~25% (hepatic first-pass metabolism) Diffuse cellular metabolism End product CO2 + H2O No active metabolite Elimination Predominantly metabolized ~5% unchanged in urine T1/2 = 40-60 min Food Slows bioavailability (AUC 30% with full meal) AUC = area under the curve.

  29. Sodium Oxybate OH NaO GABA O OH Na+ OH H2N -O O O GABA-B GHB receptor GABA-A Sodium Oxybate: Sites of Action

  30. Sodium Oxybate: CNS Pharmacology • Binds to GABAB receptor • Antagonism and deletion of GABAB in animal models inhibits sodium oxybate–induced sleep and some neuromodulation effects • Dual effect on noradrenergic locus coeruleus • Inhibition during administration of sodium oxybate • Potentiation following cessation of treatment

  31. Sodium Oxybate - Modafinil: 8-Week, Double Blind, Placebo-Controlled Trial  Treatment Arms Baseline Endpoint n=55 Placebo†(modafinil withdrawn) 200 to 600 mg/day n=63 Modafinil*(unchanged dosing) 200 to 600 mg/day 200 to 600 mg/day Modafinil (single blinded *) n=50 Sodium oxybate§ 200 to 600 mg/day 6.0 g 9.0 g n=54 ModafinilSodium oxybate 200 to 600 mg/day 200 to 600 mg/day 6.0 g 9.0 g N=222. SXB-22. *Placebo: sodium oxybate; †Placebos: modafinil + sodium oxybate; §Placebo: modafinil. Data on file, Orphan Medical. -4 0 4 8 Week

  32. Difference from placebo (modafinil withdrawn) P<0.001 Difference of the means (min) P<0.001 P=0.002 Placebo (modafinil withdrawn) Modafinil Sodium oxybate Modafinil + sodium oxybate Sodium Oxybate - Modafinil: 8-Week, Placebo-Controlled Trial MWT Sleep Latency N=230. SXB-22. MWT = Maintenance of Wakefulness Test. Data on file, Orphan Medical.

  33. Treatment Suggestions Main Symptom: • Severe or moderate daytime sleepiness: Modafinil • Moderate or mild sleepiness, and disturbed nocturnal sleep: Sodium oxybate • Severe sleepiness and severe cataplexy: Sodium oxybate and modafinil • Mild sleepiness and cataplexy: Sodium oxybate • Nocturnal sleep symptoms: Fragmented sleep, hypnagogic hallucinations and nightmares: Sodium oxybate

  34. Agents Under Development • Non-hypocretin-based therapies • Histaminergic H3 antagonist/inverse agonists • Novel monoaminergic reuptake inhibitors • Novel SWS enhancers • TRH analogues • Hypocretin-based Therapy • Hypocretin-1 • Hypocretin peptide agonist • Nonpeptide agonist • Hypocretin cell transplantation • Gene therapy • Immune-based therapies • Steroids • IVIg • Plasmapheresis

  35. C S F h i s t a m i n e l e v e l s ( p g / m l ) 2 0 0 4 0 0 6 0 0 8 0 0 0 1 0 0 0 ( A ) N e u r o l o g i c a l c o n t r o l s ( B 1 ) H c r t - / N / C / m e d - ** ( B 2 ) H c r t - / N / C / m e d + ( C ) H c r t + / N / C / m e d - ** ( D 1 ) H c r t - / N / w o C / m e d - ( D 2 ) H c r t - / N / w o C / m e d + ** ( E ) H c r t + / N / w o C / m e d - ** ( F 1 ) I H S / m e d - ( F 2 ) I H S / m e d + ( G ) O S A S Histamine in Sleep Disorders ** p<0.01 ANOVA with post-hoc, vs. N. Controls Kanbayashi T, Kodama T, Kondo H, Satoh S, Inoue Y, Chiba S, Shimizu T, Nishino S. CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome. Sleep. 2009 Feb 1;32(2):181-7.

  36. Histamine and Sleep • Histamine neurons project to practically all brain regions, including areas important for vigilance control, such as the hypothalamus, basal forebrain, thalamus, cortex, and brainstem structures. • Hcrtr 1 is enriched in the ventromedial hypothalamic nucleus, tenia tecta, hippocampal formation, dorsal raphe, and locus coeruleus (LC). • Hcrtr 2 is enriched in the paraventricular nucleus, cerebral cortex, nucleus accumbens, ventral tegmental area, substantia nigra, and histaminergic TMN. • TMN exclusively expresses Hcrtr 2. • Hypocretin potently excites TMN histaminergic neurons through Hcrtr 2. • Wake-promoting effects of hypocretins are totally abolished in histamine H1 receptor KO mice, • Therefore, the wake-promoting effects of hypocretin is dependent on the histaminergic neurotransmission 1 1. Barbier AJ, Bradbury MJ. Histaminergic control of sleep-wake cycles: recent therapeutic advances for sleep and wake disorders. CNS Neurol Disord Drug Targets 2007;6:31-43.

  37. Histamine Receptor Subtypes • There are four histamine receptor subtypes, (H1R-H4R) • All G protein coupled receptors (GPCRs). Greater than 50% of the most successful pharmaceutical treatments are drugs that act via GPCRs pathways. • H1R blockers have sedative effects are anti-allergy. • H2R based drugs are anti-ulcer drugs. • H3R antagonists activate histaminergic neurons, increasing histamine, and producing wakefulness. • H4R is expressed in hematopoietic cells suggesting a strong role in inflammatory and immunomodulatory processes.

  38. Histaminergic H3R Antagonists • H3R, presynaptic autoreceptor of histamine neurons. • Histamine inhibits its own synthesis and release by a negative feedback process and that these actions are mediated by H3 receptors. • Stimulation of H3R causes sedation, antagonism causes wakefulness. • H3R is densely located centrally in the hippocampus, amygdala, nucleus accumbens, globus pallidus, hypothalamus striatum, substantia nigra, and the cerebral cortex. • Peripherally, H3R are also located in the GI tract, airways and cardiovascular system. • H3R antagonists are being studied for sleep wake disorders, ADHD, epilepsy, cognitive impairment, schizophrenia, obesity, and neuropathic pain.

  39. Histamine 3 receptor (H3R) antagonists • Effective in canines on sleepiness and cataplexy • Promotes wakefulness in mice with ablation of hypocretin neurons (ataxin-3) • H3R antagonists thioperamide, carboperamide, and ciproxifan have been tested in rats, mice and cats. • Increase in wakefulness without rebound hypersomnolence or increasing locomotor activity. • APD916 is currently in Phase 1 trials for narcolepsy by Arena Pharmaceuticals 1. Barbier AJ, Bradbury MJ. Histaminergic control of sleep-wake cycles: recent therapeutic advances for sleep and wake disorders. CNS Neurol Disord Drug Targets 2007;6:31-43.

  40. Histaminergic H3R Inverse Agonists- Tiprolisant • Tiprolisant or BF2.649 is the first H3 inverse agonist that passed clinical Phase II trials in the treatment of EDS in narcolepsy. • In a pilot study single blinded with 22 patients, receiving a placebo followed by tiprolisant for one week, the ESS was reduced from baseline of 17.6, by 5.9 with tiprolisant compared to 1.0 for placebo. • Effect similar to modafinil. • Tiprolisant has been granted orphan drug status by the European Medicine Agency for the therapeutic treatment of narcolepsy. • Multiple other compounds in development: Conessine , JNJ-637940 , GSK 189254 Lin JS, Dauvilliers Y, Arnulf I, et al. An inverse agonist of the histamine H(3) receptor improves wakefulness in narcolepsy: studies in orexin-/- mice and patients. Neurobiol Dis 2008;30:74-83.

  41. Hypocretin • Intracerebroventricular hypocretin replacement, intranasal hypocretin administration, hypocretin cell transplantation, hypocretin gene therapy, and hypocretin stem cell transplantation are being studied for narcolepsy. • Hypocretin-1 low permeability to the blood-brain barrier. • Hypocretin-2 does not cross the blood-brain barrier. • Hypocretin-1 more stable in the blood and CSF than hypocretin-2. • Hypocretin-1 binds with two to three times the affinity to HCTR-1 than hypocretin-2

  42. Systemic and ICV Hypocretin-1 • Intra-cerebro-ventricular (ICV) hypocretin-1 can suppress cataplexy and improve sleep in narcoleptic mice and canines. • Not effective in hcrt2 mutated dogs. • Systemic administration of hypocretin-1 in canines with narcolepsy produces increases in activity levels, wake times, reduces sleep fragmentation, and has a dose dependent reduction in cataplexy. • Small peptide hypocretin analogues might be an alternative. • Intranasal hypocretin administration holds promise.

  43. Intranasal Hypocretin-1 • Intranasal hypocretin bypasses the blood brain barrier with the added benefits of onset of action within minutes and fewer peripheral side effects. • Intranasal delivery works through the olfactory and trigeminal nerves. • The mechanism of action is extracellular so there is no dependence on receptors or axonal transport for drug delivery. • Csf fluid levels are detectable after intranasal delivery of hypocretin. • Intranasal hypocretin concentrations were highest in the hypothalamus and the trigeminal nerve. Hanson LR , Taheri M, Kamsheh L, et al. Intranasal administration of hypocretin 1 (orexin A) bypasses the blood-brain barrier and target the brain: a new strategy for the treatment of narcolepsy. . Drug Deliv Tech 2004;4:1-10. Born J, Lange T, Kern W, et al.. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci 2002;5:514-6.

  44. Hypocretin Gene Therapy • Aimed at stimulating the production of hypocretin. • Ectopic transgenic expression of hypocretin in mice prevents cataplexy even with hypocretin neuron ablation. • Hypocretin gene therapy with viral vectors are a potential future treatment for narcolepsy-cataplexy. Mieda M, Willie JT, Hara J, et al. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc Natl Acad Sci U S A 2004;101:4649-54.

  45. Hypocretin Cell Transplantation • Normal subjects have approximately 70,000 hypocretin neurons and in narcolepsy-cataplexy, 85-95% of hypocretin neurons are lost. • A minimum of 10% of hypocretin producing cells need to be replaced for a therapeutic effect. • Transplantation is limited by graft survival and immune reactions. • Transplantation of neonatal rat hypothalami into the brainstem of adult rats produced poor graft survival. • Donor supply may be a problem if the survival of grafts is improved. • The barrier of graft survivability, graft reactions, and cost barriers could be reduced if genetically engineered cells or employing stem cell techniques were used instead.

  46. Thyrotrophin-releasing Hormone Agonists • TRH is a small peptide of 3 amino acids • TRH receptor-1 is found predominantly in the hypothalamus. • TRH receptor-2 is more widespread and in the reticular nucleus of the thalamus. • TRH in high dose stimulates wakefulness and anticataplectic in the narcoleptic canine • TRH is excitatory on neurons and enhances dopamine and adrenergic transmission. • May promote wakefulness by direct effect on thalamocortical pathways Nishino S, Arrigoni J, Shelton J, et al. Effects of thyrotropin-releasing hormone and its analogs on daytime sleepiness and cataplexy in canine narcolepsy. J Neurosci 1997;17:6401-8

  47. Thyrotrophin-releasing hormone agonists • Three compounds had a significant impact on cataplexy, whereas only two of the three had benefit in excessive sleepiness. • Oral CG-3703 at two weeks was shown to reduced cataplexy and excessive sleepiness in a dose dependent manner. • The effective dose in producing wakefulness was similar to a reasonable dose of D-amphetamine. • The action CG-3703 is due to enhancement of dopaminergic effects. • TRH-degrading enzyme inhibitor, metallopeptidase, may be promising. Nishino S, Arrigoni J, Shelton J, et al. Effects of thyrotropin-releasing hormone and its analogs on daytime sleepiness and cataplexy in canine narcolepsy. J Neurosci 1997;17:6401-8

  48. Immune-based Therapies • Steroids: • Ineffective in 1 human and 1 canine case • Plasmapheresis • Little data available • More invasive than IVIg • IVIg • Effective in two studies • May need to be used early (<1 year of onset) • No placebo controlled trials • Generally safe but can cause life threatening side effects.

  49. Intravenous Immunoglobulin (IVIg) • One case study 10 year old (Lecendreaux et al.) • Sleepiness and cataplexy improved. • 4 case studies (Dauvilliers et al.) • Cataplexy improved. • 4 cases (Zuberi et al.) • Sleepiness improved more than cataplexy. Lecendreux M, Maret S, Bassetti C, Mouren MC, Tafti M. Clinical efficacy of high-dose intravenous immunoglobulins near the onset of narcolepsy in a 10-year-old boy. J Sleep Res. 2003 Dec;12(4):347-8. Yves Dauvilliers MD, Bertrand Carlander MD, François Rivier MD, PhD, Jacques Touchon MD, Mehdi Tafti, PhD. Successful management of cataplexy with intravenous immunoglobulins at narcolepsy onset Ann Neurol. 2004 Dec;56(6):905-8. Zuberi SM, Mignot E, Ling L, McArthur I. Variable response to intravenous immunoglobulin therapy in childhood narcolepsy. J Sleep Res., 2004;13(suppl1) 828.

  50. Future Directions • Other potential targets for reducing EDS will likely involve: • Developing novel neuropeptides • Targeting: • proteins such as circadian clock proteins, • specific ion channels such as prokineticin or neuropeptide S.

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