An inverse agonist of the histamine H(3) receptor improves wakefulness in narcolepsy: studies in orexin-/- mice and patients

Neurobiol Dis. 2008 Apr;30(1):74-83. doi: 10.1016/j.nbd.2007.12.003. Epub 2007 Dec 27.


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.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzhydryl Compounds / therapeutic use
  • Central Nervous System Stimulants / therapeutic use
  • Disease Models, Animal
  • Female
  • Histamine Agonists / therapeutic use*
  • Humans
  • Intracellular Signaling Peptides and Proteins / deficiency*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Modafinil
  • Narcolepsy / drug therapy*
  • Narcolepsy / genetics
  • Narcolepsy / physiopathology
  • Neuropeptides / deficiency*
  • Orexins
  • Piperidines / therapeutic use*
  • Polysomnography
  • Prospective Studies
  • Reaction Time / drug effects
  • Severity of Illness Index
  • Single-Blind Method
  • Sleep Stages / drug effects
  • Wakefulness / drug effects*


  • Benzhydryl Compounds
  • Central Nervous System Stimulants
  • Histamine Agonists
  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Orexins
  • Piperidines
  • pitolisant
  • Modafinil