Description
Pitolisant hydrochloride,
a first-in-class inverse agonist of the histamine H3
receptor, was approved in the EU for the treatment of excessive
daytime sleepiness (EDS) in adults with narcolepsy with or
without cataplexy. The drug, which was developed by
Bioprojet and has orphan drug designation in the EU and
US, enhances wakefulness by increasing histaminergic neuron
activity. With once daily oral administration in the morning,
patients taking pitolisant exhibited significantly reduced EDS
versus placebo but not versus modafinil. Plasma levels of the
drug are reduced at the end of the day such that its waking
effect is minimized at night (plasma t1/2 10-12 h). Several
articles have been published detailing the discovery of
pitolisant.
in vivo
pitolisant hcl was an oral bioavailable agonist. in mice, after oral and i.v. administrations of pitolisant hcl, the ratio of plasma areas under the curve was 84%. bf2.649 enhanced tele-methylhistamine levels in mouse brain, an index of histaminergic neuron activity in a dose dependent manner with an ed50 value of 1.6 mg/kg p.o. the response persisted after repeated administrations for 17 days [1]. treatment with 20-, 40-, or 60-mg doses of pitolisant showed a statistically significant suppressive effect (standardized photosensitive response [spr] reduction as measured with paired t-tests) in 9/14 (64%) patients of whom 6/14 (43%) showed abolition of the response to intermittent photic stimulation (ips) [3]. bf2.649 showed significant inhibitory activity in several mouse models of schizophrenia [4].
References
[1] ligneau x, perrin d, landais l, camelin jc, calmels tp, et al, bf2. 649 [1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine, hydrochloride], a nonimidazole inverse agonist/antagonist at the human histamine h3 receptor: preclinical pharmacology. j pharmacol exp ther.2007 jan;320(1):365-75.
[2] t a esbenshade, k e browman, r s bitner, m strakhova, m d cowart, j d brioni the histamine h3 receptor: an attractive target for the treatment of cognitive disorders. br j pharmacol. 2008 jul; 154(6): 1166–1181.
[3] kasteleijn-nolst trenité d, parain d, genton p, masnou p, schwartz jc, hirsch e. efficacy of the histamine 3 receptor (h3r) antagonist pitolisant (formerly known as tiprolisant; bf2.649) in epilepsy: dose-dependent effects in the human photosensitivity model. epilepsy behav.2013 jul;28(1):66-70.
[4] ligneau x, landais l, perrin d, piriou j, uguen m, denis e, robert p, parmentier r, anaclet c, lin js, burban a, arrang jm,schwartz jc. brain histamine and schizophrenia: potential therapeutic applications of h3-receptor inverse agonists studied with bf2.649. biochem pharmacol. 2007 apr 15;73(8):1215-24. a