At the present time there are several

At the present time, there are several clinical trial studies being conducted with a variety of indications for pitolisant. Various studies in different phases assess different aspects of pitolisant efficacy and safety in narcoleptic patients (Szakacs et al., 2017) (NCT01800045, NCT02611687, NCT03433131, NCT01399606, NCT01789398, and NCT01067235). Five phase III trials have also been completed for efficacy assessment of pitolisant in the treatment of EDS in different conditions including Parkinson's disease (NCT01066442 and NCT01036139), narcolepsy (NCT01067222 and NCT01638403) (Dauvilliers et al., 2013), and obstructive sleep x gal synthesis (OSA) (NCT02739568, NCT01072968, and NCT01071876). Moreover, two completed phase II clinical trial studies aiming at determining the minimum effective dose of pitolisant have been conducted in patients with Parkinson's disease (NCT00642928) and OSA (NCT01620554) experiencing EDS. Furthermore, a phase II study has assessed the cognitive-enhancing effect of pitolisant in subjects with schizophrenia in a randomized, double blind, and placebo-controlled study (NCT00690274). However, there is a controversy on the potential therapeutic application of pitolisant in schizophrenia according to other reports (Burban et al., 2010; Ligneau, Landais, et al., 2007). The pharmacokinetic profile of pitolisant has been studied in two phase I trials using healthy CYP2D6 genotyped individuals (NCT02929342) and subjects with renal dysfunction (NCT01619033). In addition, the addictive properties of pitolisant have also been evaluated in a randomized, double-blind, active-and placebo-controlled study in healthy, non-dependent recreational stimulant users (NCT03152123). Although several clinical trials are currently underway, no results have yet been publicized from the all above mentioned clinical trial studies. Betahistine (N-methyl-2-(2-pyridyl)ethylamine) is a well-known dual H1 receptor agonist/H3 receptor antagonist with structural resemblance to histamine. Though it has been approved long before the discovery of H3R to treat disorders of vestibular function as Menières-Disease, the evidence for this indication is not clear until today (Casani, Navari, Guidetti, & Lacour, 2018). Recently, a meta-analysis by the Cochrane collaboration including studies from 1967 to 2012 assessed the benefit of betahistine in treatment of patients suffering from idiopathic and secondary vertigo. Among 11 studies including 606 patients in total, the reduction of symptoms was higher in the group receiving betahistine than placebo while not showing more adverse events (Murdin, Hussain, & Schilder, 2016). Despite low evidence due to high statistical heterogeneity of the studies, betahistine remains an attractive agent still being evaluated in several studies. Among them, a phase I study (program AM-125) from Auris Medical has been completed using the drug in a formulation for intranasal application resulting in significant increase of bioavailability, presumably enhancing effectiveness (AG, 2018) CEP-26401, known as Irdabisant (6- 4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl -2H-pyridazin-3-one]), is another H3R antagonist/inverse agonist (MW 313.39). CEP-26401 was first reported by Hudkins et al., 2011 (Hudkins et al., 2011), and is under development by Teva Pharmaceutical Industries. This candidate has excellent physicochemical properties that make it ideal from a drug-likeness (Table 2) and pharmacokinetic perspective (Hudkins, Raddatz, et al., 2011). The antagonistic effect of CEP-26401 in rat and human H3R expressing systems was investigated with results indicative of high affinity in radioligand binding assays (Raddatz et al., 2012).The pharmacokinetic, pharmacodynamic, and safety of CEP-26401 were evaluated in two randomized, double-blind, placebo-controlled studies in healthy subjects. The findings showed that this drug candidate has dose- and time-independent pharmacokinetics, being well tolerated after single and multiple oral administrations with a major elimination pathway via renal excretion (Spiegelstein et al., 2016).