Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive <i>in vitro</i> Pro‐arrhythmia Assay initiative studies

Ligneau, Xavier; Shah, Rajiv; Berrebi-Bertrand, Isabelle; Mirams, Gary R.; Robert, Philippe; Landais, Laurent; Maison‐Blanche, Pierre; Faivré, Jean-François; Lecomte, Jeanne‐Marie; Schwartz, Jean‐Charles

doi:10.1111/bph.14047

Cited by 14 publications

(8 citation statements)

References 53 publications

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“…These findings are in line with current Fig. 2 Significant post hoc comparisons between subgroups ("add-on group," "switched group," and "naive group" [3], but may also reflect the preference, in clinical practice, to prescribe pitolisant in patients with high cardiovascular burden, given its known negligible impact on the cardiovascular system [34]. Therefore, the high prevalence of cardiovascular comorbidities may be over-estimated in our sample.…”

Section: Discussionsupporting

confidence: 84%

Clinical characteristics of a large cohort of patients with narcolepsy candidate for pitolisant: a cross-sectional study from the Italian PASS Wakix® Cohort

et al. 2022

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Introduction Narcolepsy is a chronic and rare hypersomnia of central origin characterized by excessive daytime sleepiness and a complex array of symptoms as well as by several medical comorbidities. With growing pharmacological options, polytherapy may increase the possibility of a patient-centered management of narcolepsy symptoms. The aims of our study are to describe a large cohort of Italian patients with narcolepsy who were candidates for pitolisant treatment and to compare patients’ subgroups based on current drug prescription (drug-naïve patients in whom pitolisant was the first-choice treatment, switching to pitolisant from other monotherapy treatments, and adding on in polytherapy). Methods We conducted a cross-sectional survey based on Italian data from the inclusion visits of the Post Authorization Safety Study of pitolisant, a 5-year observational, multicenter, international study. Results One hundred ninety-one patients were enrolled (76.4% with narcolepsy type 1 and 23.6% with narcolepsy type 2). Most patients (63.4%) presented at least one comorbidity, mainly cardiovascular and psychiatric. Pitolisant was prescribed as an add-on treatment in 120/191 patients (62.8%), as switch from other therapies in 42/191 (22.0%), and as a first-line treatment in 29/191 (15.2%). Drug-naive patients presented more severe sleepiness, lower functional status, and a higher incidence of depressive symptoms. Conclusion Our study presents the picture of a large cohort of Italian patients with narcolepsy who were prescribed with pitolisant, suggesting that polytherapy is highly frequent to tailor a patient-centered approach.

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Section: Discussionsupporting

confidence: 84%

Clinical characteristics of a large cohort of patients with narcolepsy candidate for pitolisant: a cross-sectional study from the Italian PASS Wakix® Cohort

et al. 2022

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“…In particular, pitolisant is a potent histamine H3 receptor antagonist/inverse agonist that is approved for the treatment of narcolepsy in adults. It has also been reported to inhibit KCNH2, showing voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization 30 . From the inferred subnetworks, we also observed that KCNH2 indirectly interacts with BRAF via the AKT serine/threonine kinase 1.…”

Section: Discussionmentioning

confidence: 97%

Comprehensive network medicine-based drug repositioning via integration of therapeutic efficacy and side effects

et al. 2022

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Despite advances in modern medicine that led to improvements in cardiovascular outcomes, cardiovascular disease (CVD) remains the leading cause of mortality and morbidity globally. Thus, there is an urgent need for new approaches to improve CVD drug treatments. As the development time and cost of drug discovery to clinical application are excessive, alternate strategies for drug development are warranted. Among these are included computational approaches based on omics data for drug repositioning, which have attracted increasing attention. In this work, we developed an adjusted similarity measure implemented by the algorithm SAveRUNNER to reposition drugs for cardiovascular diseases while, at the same time, considering the side effects of drug candidates. We analyzed nine cardiovascular disorders and two side effects. We formulated both disease disorders and side effects as network modules in the human interactome, and considered those drug candidates that are proximal to disease modules but far from side-effects modules as ideal. Our method provides a list of drug candidates for cardiovascular diseases that are unlikely to produce common, adverse side-effects. This approach incorporating side effects is applicable to other diseases, as well.

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“…Some drugs used in the treatment of narcolepsy have shown promising results in patients with craniopharyngioma with EDS or secondary narcolepsy, such as modafinil ( 18 , 26 ), methylphenidate ( 18 ), dexamphetamine ( 29 ), and pitolisant ( 24 ). In particular, pitolisant, given its low cardiovascular risk profile, may be specifically indicated for CP patients, who have many metabolic comorbidities ( 69 ).…”

Section: Discussionmentioning

confidence: 99%

Sleep Disturbances in Pediatric Craniopharyngioma: A Systematic Review

et al. 2022

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Craniopharyngiomas are rare brain tumors of the sellar region and are the most common non-neuroepithelial intracerebral neoplasm in children. Despite a low-grade histologic classification, craniopharyngiomas can have a severe clinical course due to hypothalamic involvement. The hypothalamus plays a crucial role in regulating vital functions, and it is a critical component of the sleep-wake regulatory system. This systematic review aims to provide an overview of the current knowledge on sleep disorders in patients with craniopharyngioma to unravel their underlying mechanisms and identify possible therapeutic strategies. A comprehensive electronic literature search of the PubMed/MEDLINE and Scopus databases was conducted in accordance with the PRISMA® statement. Extensively published, peer-reviewed articles involving patients with childhood craniopharyngioma and focused on this specific topic were considered eligible for inclusion. Thirty-two articles were included; a high prevalence of excessive daytime sleepiness was reported in CP patients, with wide variability (25–100%) depending on the diagnostic method of detection (25–43% by subjective measures, 50–100% by objective investigations). In particular, secondary narcolepsy was reported in 14–35%, sleep-disordered breathing in 4–46%. Moreover, sleep-wake rhythm dysregulation has been notified, although no prevalence data are available. Possible mechanisms underlying these disorders are discussed, including hypothalamic injury, damage to the suprachiasmatic nucleus, low melatonin levels, hypocretin deficiency, and hypothalamic obesity. The diagnosis and management of sleep disorders and associated comorbidities are challenging. This review summarizes the pathophysiology of sleep disorders in childhood-onset CP and the main treatment options. Finally, a possible diagnostic algorithm in order to accurately identify and treat sleep disorders in these patients is proposed.

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Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro‐arrhythmia Assay initiative studies

Cited by 14 publications

References 53 publications

Clinical characteristics of a large cohort of patients with narcolepsy candidate for pitolisant: a cross-sectional study from the Italian PASS Wakix® Cohort

Clinical characteristics of a large cohort of patients with narcolepsy candidate for pitolisant: a cross-sectional study from the Italian PASS Wakix® Cohort

Comprehensive network medicine-based drug repositioning via integration of therapeutic efficacy and side effects

Sleep Disturbances in Pediatric Craniopharyngioma: A Systematic Review

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