Neue Behandlungsansätze in der Narkolepsie

Zusammnefassung

In Deutschland sind nur wenige Medikamente zur Behandlung der Narkolepsie zugelassen. Da die Medikamente meist nur auf eines der Kernsymptome der Narkolepsie wirken (Tagesschläfrigkeit bzw. Kataplexie) und für die Behandlung der fakultativen Symptome wie Schlaflähmungen, Halluzinationen nicht gut untersucht sind, sind die Behandlungsoptionen erheblich eingeschränkt. Medikamente mit neuen pharmakologischen Ansatzpunkten könnten – sofern sie zugelassen werden – das Behandlungsspektrum erweitern und damit die Lebensqualität der Patienten erheblich verbessern. Zu den neuen Präparaten gehören ein inverser Histamin-3 Rezeptor Agonist, ein Präparat mit indirekter noradrenerger- und dopaminerger Wirkung und möglicherweise bald ein synthetisierter Hypocretin-2 Rezeptor Agonist. Einige der neuen Präparate wirken auf beide Kernsymptome der Narkolepsie. Die derzeitige Datenlage für immunsuppressive Therapien ist noch begrenzt, könnte aber bei Einsatz kurz nach Beginn der ersten Symptome erfolgversprechend sein.

Abstract

Only a few drugs are approved for the treatment of narcolepsy in Germany. Since these medications are effective mainly in the treatment of one or the other of the 2 core symptoms of narcolepsy, (namely excessive daytime sleepiness and cataplexy), and the treatment of facultative symptoms, such as sleep paralysis and hallucinations, have not been well studied, therapy options are rather restricted. Medications with new pharmacological profiles – if they receive approval – can broaden the treatment option and thus the quality of life of patients. The new medications comprise an inverse histamine-3 receptor agonist, a drug with indirect noradrenergic and dopaminergic effect and possibly in the near future a synthesized hypocretin-2 receptor agonist. Some of the new medications are effective against both of the narcoleptic core symptoms. Current findings on immunosuppressive therapies are still limited, but might be promising if given shortly after onset of the first symptoms of this disorder.

Schlüsselwörter

Narkolepsie - Stimulanzien - Antikataplektika - Hypocretin - immunsuppressive Therapie

Key words

narcolepsy - stimulants - anticataplectic medication - hypocretin - immunosuppressive therapy

• Literatur

• 1 Mayer G.. Narkolepsie. Nervenarzt 2014; 85: 26-34
• 2 Luca G, Haba-Rubio J, Dauvilliers Y et al. EUROPEAN NARCOLEPSY NETWORK ( EU – NN). Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study. J Sleep Res 2013; 22: 482-495
• 3 Morgenthaler TI, Kapur VK, Brown T et al. Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep 2007; 30: 1705-1711
• 4 Billiard M, Bassetti C, Dauvilliers Y et al. EFNS guidelines on management of narcolepsy. Eur J Neurol 2006; 13: 1035-1048
• 5 Vignatelli L, D’Allessandro R, Candelise L. Antidepressant drugs for narcolepsy. Cochrane Database of Systematic Reviews 2008; Issue 1. Art. No: CD00734
• 6 Parkes JD, Fenton GW. Levo(-) amphetamine and dextro(+) amphetamine in the treatment of narcolepsy. J Neurol Neurosurg Psychiatry 1973; 36: 1076-1081
• 7 Harris GC, Wimmer M, Aston-Jones G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature 2005; 437: 556-559
• 8 Guilleminault C. Amphetamines and narcolepsy: use of the Stanford database. Sleep 1993; 16: 199-201
• 9 Inocente C, Arnulf I, Bastuji H et al. Pitolisant, an inverse agonist of the histamine H3 receptor: an alternative stimulant for narcolepsy-cataplexy in teenagers with refractory sleepiness. Clin Neuropharmacol 2012; 35: 55-60
• 10 Bogan RK, Feldman N, Emsellem HA et al. Effect of oral JZP-110 (ADX-N05) treatment on wakefulness and sleepiness in adults with narcolepsy. Sleep Medicine 2015; 16: 1102-1108
• 11 Shindler J, Schachter M, Brincat S et al. Amphetamine, mazindol, and fencamfamin in narcolepsy. Br Med J (Clin Res Ed) 1985; 290: 1167-1170
• 12 Nittur N, Konofal E, Dauvilliers Y et al. Mazindol in narcolepsy and idiopathic and symptomatic hypersomnia refractory to stimulants: a long-term chart review. Sleep Med 2013; 14: 30-36
• 13 Bogan RK, Roth T, Schwartz J et al. Time to response with sodium oxybate for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy. J Clin Sleep Med 2015; 11: 427-432
• 14 Hasan S, Pradervand S, Ahnaou A et al. How to Keep the Brain Awake? The Complex Molecular Pharmacogenetics of Wake Promotion. Neuropsychopharmacology 2009; 34: 1625-1640
• 15 De Lecea L, Kilduff TS, Peyron C et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 1998; 95: 322-327
• 16 Sakurai T, Amemiya A, Ishii M et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998; 92: 573-585
• 17 Fujiki N, Yoshida Y, Ripley B et al. Effects of IV and ICV hypocretin-1 (orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin-ligand-deficient narcoleptic dog. Sleep 2003; 26: 953-959
• 18 John J, Wu MF, Siegel JM. Systemic administration of hypocretin-1 reduces cataplexy and normalizes sleep and waking durations in narcoleptic dogs. Sleep Res Online 2000; 3: 23-28
• 19 Deadwyler SA, Porrino L, Siegel JM et al. System and nasal delivery of orexin-A (hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci 2007; 27: 14239-14247
• 20 Baier PC, Hallschmid M, Seeck-Hirschner M et al. Effects of intranasal hypocretin-1 (orexin A) on sleep in narcolepsy with cataplexy. Sleep Med 2011; 12: 941-946
• 21 Stiasny-Kolster K, Doerr Y, Moller JC et al. Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for alpha-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 2005; 128 (Pt 1) 126-137
• 22 Weinhold SL, Seeck-Hirschner M, Nowaka A et al. The effect of intranasal orexin-A (hypocretin-1) on sleep, wakefulness and attention in narcolepsy with cataplexy. Behavioural Brain Research 2014; 2014 8-13
• 23 Nagahara T, Saitoh Kutsumura N. et al. Design and synthesis of non-peptide, selective orexin receptor 2 agonists. J Med Chem 2015;
• 24 Hasegawa E, Yanagisawa M, Sakurai T et al. Orexin neurons suppress narcolepsy via 2 distinct efferent pathways. J Clin Invest 2014; 124: 604-616
• 25 Juji T, Satake M, Honda Y et al. A antigens in Japanese patients with narcolepsy. All the patients were DR2 positive. Tissue Antigens 1984; 24: 316-319
• 26 Liblau RS, Vassalli A, Seifinejad A et al. Hypocretin (orexin) biology and the pathophysiology of narcolepsy with cataplexy. Lancet Neurol 2015; 14: 318-328
• 27 Hecht M, Lin L, Kushida CA et al. Report of a case of immunosuppression with prednisone in an 8-year old boy with an acute onset of hypocretin-deficiency narcolepsy. Sleep 2003; 26: 809-810
• 28 Lecendreux M, Maret S, Bassetti C et al. Clinical efficacy of high-dose intravenous immunoglobulins near the onset of narcolepsy in a 10-year-old boy. J Sleep Res 2003; 12: 347-348
• 29 Dauvilliers Y, Carlander B, Rivier F et al. Successful management of cataplexy with intravenous immunoglobulins at narcolepsy onset. Ann Neurol 2004; 56: 905-908
• 30 Dauvilliers Y, Abril B, Mas E et al. Normalization of hypocretin-1 in narcolepsy after intravenous immunoglobulin treatment. Neurology 2009; 73: 1333-1334
• 31 Valko PO, Khatami R, Baumann CR et al. No persistent effect of intravenous immunoglobulins in patients with narcolepsy with cataplexy. J Neurol 2008; 255: 1900-1903
• 32 Knudsen S, Biering-Sørensen B, Kornum BR et al. Early IVIg treatment has no effect on post-H1N1 narcolepsy phenotype or hypocretin deficiency. Neurology 2012; 79: 102-103
• 33 Fronczek R, Verschuuren J, Lammers GJ. Response to intravenous immunoglobulins and placebo in a patient with narcolepsy with cataplexy. J Neurol 2007; 254: 1607-1608
• 34 Donjacour CE, Lammers GJ. A remarkable effect of alemtuzumab in a patient suffering from narcolepsy with cataplexy. J Sleep Res 2012; 21: 479-480