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    • The more important effect of pitolisant is related

    2021-10-15

    The more important effect of pitolisant is related to its wake-promoting and arousal activities as a result of enhanced T16Ainh - A01 release in animal models (Ligneau, Perrin, et al., 2007). Moreover, its potential in the treatment of severe excessive daytime sleepiness (EDS) in narcoleptic teenagers refractory to therapeutic agents (e.g. modafinil and methylphenidate) was evaluated and the findings indicate its capability to significantly diminish sleepiness after the administration of a single dose (Inocente et al., 2012). In another study by Leu-Semenescu et al., the pitolisant efficacy in patients with symptomathic idiopathic hypersomnia refractory to current stimulants was assessed showing increased activity of the histaminergic neurons in such patients (Leu-Semenescu, Nittur, Golmard, & Arnulf, 2014). Moreover, preclinical investigations show useful effects of pitolisant on EDS in orexin-/- mice and narcoleptic patients (Lin et al., 2008). Pitolisant has also been shown to improve consolidation processes in mouse fear memory (C. Brabant, Charlier, & Tirelli, 2013). Furthermore, the application of pitolisant for sleep-deficits in Prader-Willi syndrome has been demonstrated in mouse-models and described as off-label use, though this has not been investigated in interventional clinical trials yet (Balzani, Pace, Falappa, & Tucci, 2017; Falappa et al., 2018; Ghergan et al., 2017; Pace et al., 2018; Pullen, Picione, Tan, Johnston, & Stark, 2018; Pullen, Picione, Tan, Johnston, & Stark, 2019). A suppressive effect of pitolisant on epileptiform discharges in photosensitive patients with epilepsy was observed following the administration of a single dose, suggesting effectiveness in the treatment of both partial and generalized chronic seizures (Kasteleijn-Nolst Trenité et al., 2013). Further, a phase II study showed some benefit with pitolisant as adjunctive for patients suffering from epilepsy (Collart Dutilleul et al., 2016). Additional indication of pitolisant has been prompted for disorders as Guilles de la Tourette syndrome and autism that often are comorbidities with epileptic disorders (Hartmann, Martino, & Murphy, 2016). In another study, the effect of pitolisant on side-effects associated with olanzapine at the initial period of administration in mice was monitored, and the results indicated a reduction in olanzapine-induced sedation and depression-like symptoms (Dudek et al., 2016). Recently, the anti-obesity activity of pitolisant has been evaluated in terms of controlling body weight in obese mice. The results of this investigation supported its effectiveness in lowering plasma glucose and triglyceride levels by improving glucose tolerance and lipid profile (Kotanska, Kuder, Szczepanska, Sapa, & Kiec-Kononowicz, 2018). From a toxicity point of view, a non-clinical cardiovascular safety assessment was conducted for pitolisant and the results revealed lack of QT-liability and proarrhythmic risk according to International Conference on Harmonization (ICH) guidelines (Ligneau et al., 2017). The abuse liability of pitolisant was also tested in different in vivo rodent models and the outcome of the studies showed no addictive potential (Christian Brabant, Charlier, Navacerrada, Alleva, & Tirelli, 2016; Uguen et al., 2013). 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 apnea (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.