title: The effects of a novel histamine-3 receptor inverse agonist on essential tremor in comparison to stable levels of alcohol.
abstract: Essential tremor (ET) is a common movement disorder. Animal studies show that histaminergic modulation may affect the pathological processes involved in the generation of ET. Histamine-3 receptor inverse agonists (H3RIA) have demonstrated attenuating effects on ET in the harmaline rat model. In this double-blind, three-way cross-over, single-dose, double-dummy study the effects of 25 mg of a novel H3RIA (MK-0249) and a stable alcohol level (0.6 g L(-1)) were compared with placebo, in 18 patients with ET. Tremor was evaluated using laboratory tremorography, portable tremorography and a clinical rating scale. The Leeds Sleep Evaluation Questionnaire (LSEQ) and a choice reaction time (CRT) test were performed to evaluate potential effects on sleep and attention, respectively. A steady state of alcohol significantly diminished tremor as assessed by laboratory tremorography, portable tremorography and clinical ratings compared with placebo. A high single MK-0249 dose was not effective in reducing tremor, but caused significant effects on the LSEQ and the CRT test. These results suggest that treatment with a single dose of MK-0249 does not improve tremor in alcohol-responsive patients with ET, whereas stable levels of alcohol as a positive control reproduced the commonly reported tremor-diminishing effects of alcohol.
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands. rzoethout@chdr.nl
authors.forename: R W M
authors.initials: RW
authors.lastname: Zoethout
authors.forename: R
authors.initials: R
authors.lastname: Iannone
authors.forename: B R
authors.initials: BR
authors.lastname: Bloem
authors.forename: J
authors.initials: J
authors.lastname: Palcza
authors.forename: G
authors.initials: G
authors.lastname: Murphy
authors.forename: J
authors.initials: J
authors.lastname: Chodakewitz
authors.forename: A
authors.initials: A
authors.lastname: Buntinx
authors.forename: K
authors.initials: K
authors.lastname: Gottesdiener
authors.forename: S
authors.initials: S
authors.lastname: Marsilio
authors.forename: L
authors.initials: L
authors.lastname: Rosen
authors.forename: K
authors.initials: K
authors.lastname: van Dyck
authors.forename: E D
authors.initials: ED
authors.lastname: Louis
authors.forename: A F
authors.initials: AF
authors.lastname: Cohen
authors.forename: R C
authors.initials: RC
authors.lastname: Schoemaker
authors.forename: S
authors.initials: S
authors.lastname: Tokita
authors.forename: N
authors.initials: N
authors.lastname: Sato
authors.forename: K S
authors.initials: KS
authors.lastname: Koblan
authors.forename: R H
authors.initials: RH
authors.lastname: Hargreaves
authors.forename: Jj
authors.initials: J
authors.lastname: Renger
authors.forename: J M A
authors.initials: JM
authors.lastname: van Gerven
mesh_terms: D001288:Attention / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D020329:Essential Tremor / Q000188:drug therapy* / Q000378:metabolism; D000431:Ethanol / Q000378:metabolism*; D005260:Female; D017442:Histamine Agonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D052999:Quinazolinones / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011930:Reaction Time / Q000187:drug effects; D018100:Receptors, Histamine H3 / Q000378:metabolism
chemical_list: D017442:Histamine Agonists; C574738:MK-0249; D052999:Quinazolinones; D018100:Receptors, Histamine H3; D000431:Ethanol