An inverse agonist of the histamine H(3) receptor improves wakefulness in narcolepsy: studies in orexin-/- mice and patients.
Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy, direct onsets of rapid eye movement (REM) sleep from wakefulness (DREMs) and deficiency of orexins, neuropeptides that promote wakefulness largely via activation of histamine (HA) pathways. The hypothesis that the orexin defect can be circumvented by enhancing HA release was explored in narcoleptic mice and patients using tiprolisant, an inverse H(3)-receptor agonist. In narcoleptic orexin(-/-) mice, tiprolisant enhanced HA and noradrenaline neuronal activity, promoted wakefulness and decreased abnormal DREMs, all effects being amplified by co-administration of modafinil, a currently-prescribed wake-promoting drug. In a pilot single-blind trial on 22 patients receiving a placebo followed by tiprolisant, both for 1 week, the Epworth Sleepiness Scale (ESS) score was reduced from a baseline value of 17.6 by 1.0 with the placebo (p>0.05) and 5.9 with tiprolisant (p<0.001). Excessive daytime sleep, unaffected under placebo, was nearly suppressed on the last days of tiprolisant dosing. H(3)-receptor inverse agonists could constitute a novel effective treatment of EDS, particularly when associated with modafinil.
Lin
Jian-Sheng
JS
INSERM-U628, 69373-Lyon, France; Faculté de Médecine, Université Claude Bernard, 69373-Lyon, France. lin@univ-lyon1.fr
Dauvilliers
Yves
Y
Arnulf
Isabelle
I
Bastuji
Hélène
H
Anaclet
Christelle
C
Parmentier
Régis
R
Kocher
Laurence
L
Yanagisawa
Masashi
M
Lehert
Philippe
P
Ligneau
Xavier
X
Perrin
David
D
Robert
Philippe
P
Roux
Michel
M
Lecomte
Jeanne-Marie
JM
Schwartz
Jean-Charles
JC
D000818:Animals; D001559:Benzhydryl Compounds / Q000627:therapeutic use; D000697:Central Nervous System Stimulants / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D017442:Histamine Agonists / Q000627:therapeutic use*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077408:Modafinil; D009290:Narcolepsy / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D009479:Neuropeptides / Q000172:deficiency*; D000068797:Orexins; D010880:Piperidines / Q000627:therapeutic use*; D017286:Polysomnography; D011446:Prospective Studies; D011930:Reaction Time / Q000187:drug effects; D012720:Severity of Illness Index; D016037:Single-Blind Method; D012894:Sleep Stages / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects*
D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D017442:Histamine Agonists; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D010880:Piperidines; C516975:pitolisant; D000077408:Modafinil