Administration of oxathridine, a first-in-class histamine-3 receptor partial agonist in healthy male volunteers: Central nervous system depression and pseudo-hallucinations.

Aims: To characterise the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of oxathridine, a first-in-class histamine-3 receptor partialagonist, in healthy male volunteers.

Methods: A randomised, double-blind, placebo-controlled study including the NeuroCart, consisting of a battery of drug sensitive neurophysiological tests, was performed. Oxathridine was administered orally as an aqueous solution.

Bioavailability and cardiovascular effects of adrenaline administered by Anapen 500 μg auto-injector in healthy volunteers.

Aims: Anaphylaxis guidelines recommend intramuscular adrenaline, commonly 300 μg administered using an auto-injector device. However, overweight/obese patients may require a higher adrenaline dose for adequate cardiovascular (CV) response. This study evaluated the pharmacokinetics (PK) and pharmacodynamic (PD) CV profiles after a single 500 μg adrenaline injection via Anapen auto-injector in healthy normal weight males and otherwise healthy, overweight or obese females.

Clinical Impact of Pitolisant on Excessive Daytime Sleepiness and Cataplexy in Adults With Narcolepsy: An Analysis of Randomized Placebo-Controlled Trials.

Background: Pitolisant, a selective histamine 3 receptor antagonist/inverse agonist, is indicated for the treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy. The efficacy and safety of pitolisant have been demonstrated in randomized placebo-controlled trials. When evaluating the results of randomized placebo-controlled trials, the clinical impact of a treatment can be assessed using effect size metrics that include Cohen's d (the standardized mean difference of an effect) and number needed to treat (NNT; number of patients that need to be treated to achieve a specific outcome for one person).

Pitolisant, a wake-promoting agent devoid of psychostimulant properties: Preclinical comparison with amphetamine, modafinil, and solriamfetol.

Several therapeutic options are currently available to treat excessive daytime sleepiness (EDS) in patients suffering from narcolepsy or obstructive sleep apnea. However, there are no comparisons between the various wake-promoting agents in terms of mechanism of action, efficacy, or safety. The goal of this study was to compare amphetamine, modafinil, solriamfetol, and pitolisant at their known primary pharmacological targets, histamine H3 receptors (H3R), dopamine, norepinephrine, and serotonin transporters, and in various in vivo preclinical models in relation to neurochemistry, locomotion, behavioral sensitization, and food intake.

Efficacy of pitolisant in patients with high burden of narcolepsy symptoms: pooled analysis of short-term, placebo-controlled studies.

Study Objective: To evaluate the efficacy of pitolisant, a histamine 3 (H)-receptor antagonist/inverse agonist, in adult patients with high burden of narcolepsy symptoms.

Methods: Data were pooled from two randomized, placebo-controlled, 7- or 8-week studies of pitolisant (titrated to a potential maximum dose of 35.6 mg/day) in adults with narcolepsy.

Pitolisant for Residual Excessive Daytime Sleepiness in OSA Patients Adhering to CPAP: A Randomized Trial.

Background: Excessive daytime sleepiness (EDS) in individuals with OSA syndrome persisting despite good adherence to CPAP is a disabling condition. Pitolisant is a selective histamine H3-receptor antagonist with wake-promoting effects.

Research Question: Is pitolisant effective and safe for reducing daytime sleepiness in individuals with moderate to severe OSA adhering to CPAP treatment but experiencing residual EDS?

Study Design And Methods: In a multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was titrated individually at up to 20 mg/day and taken over 12 weeks.

Exploring occupancy of the histamine H receptor by pitolisant in humans using PET.

Background And Purpose: BF2.649 (pitolisant, Wakix®) is a novel histamine H receptor inverse agonist/antagonist recently approved for the treatment of narcolepsy disorder. The objective of the study was to investigate in vivo occupancy of H receptors by BF2.

Pharmacokinetics of pitolisant in children and adolescents with narcolepsy.

Objective: To evaluate the pharmacokinetic profile and tolerability of pitolisant, a selective histamine 3 (H)-receptor antagonist/inverse agonist, in children and adolescents with narcolepsy.

Methods: This multicenter, open-label, single-dose study of pitolisant 17.8 mg enrolled patients aged 6 through 17 years with a diagnosis of narcolepsy.

Pitolisant for Daytime Sleepiness in Patients with Obstructive Sleep Apnea Who Refuse Continuous Positive Airway Pressure Treatment. A Randomized Trial.

Excessive daytime sleepiness is a common disabling symptom in obstructive sleep apnea syndrome. To evaluate the efficacy and safety of pitolisant, a selective histamine H3 receptor antagonist with wake-promoting effects, for the treatment of daytime sleepiness in patients with moderate to severe obstructive sleep apnea refusing continuous positive airway pressure treatment. In an international, multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was individually titrated at up to 20 mg/d over 12 weeks.

Evaluation of the abuse potential of pitolisant, a selective H3-receptor antagonist/inverse agonist, for the treatment of adult patients with narcolepsy with or without cataplexy.

Objectives: To evaluate the human abuse potential of pitolisant, a selective histamine 3 (H3)-receptor antagonist/inverse agonist recently approved by the US Food and Drug Administration for the treatment of excessive daytime sleepiness in adult patients with narcolepsy.

Methods: Nondependent, recreational stimulant users able to distinguish phentermine HCl 60 mg from placebo in a drug discrimination test were randomized in a four-period, double-blind, crossover design to receive single doses of pitolisant 35.6 mg (therapeutic dose), pitolisant 213.

Long-term use of pitolisant to treat patients with narcolepsy: Harmony III Study.

Study Objectives: To asses the long-term safety and efficacy of pitolisant, an histamine H3-receptor antagonist, on narcolepsy.

Methods: This open-label, single-arm, pragmatic study, recruited adult patients with narcolepsy and Epworth Sleepiness Scale (ESS) score ≥12. After a titration period, patients were treated for up to 1 year with oral pitolisant once-a-day at up to 40 mg.

Occupancy of dopamine D and D receptors by a novel D3 partial agonist BP1.4979: a [C]-(+)-PHNO PET study in humans.

There has been considerable interest in the development of dopamine D3 receptor (DRD) partial agonists and antagonists for the treatment of substance use disorders. Pre-clinical evidence overwhelmingly supports the use of these drugs, but translation to humans has remained elusive due to the lack of selective compounds that are suitable for use in humans. Although it has been established for full antagonists, little in vivo occupancy data are available with DRD partial agonists.

Bioavailability and Cardiovascular Effects of Adrenaline Administered by Anapen Autoinjector in Healthy Volunteers.

Background: The administration of adrenaline is a life-saving intervention for anaphylactic reactions. However, it has been questioned whether the needle length of the autoinjectors is sufficient to achieve genuine intramuscular delivery and optimal bioavailability.

Objective: To assess the adequacy of Anapen, which has a relatively short needle length (10.

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

Background And Purpose: We evaluated the concordance of results from two sets of nonclinical cardiovascular safety studies on pitolisant.

Experimental Approach: Nonclinical studies envisaged both in the International Conference on Harmonization (ICH) S7B guideline and Comprehensive in vitro Pro-arrhythmia Assay (CiPA) initiative were undertaken. The CiPA initiative included in vitro ion channels, stem cell-derived human ventricular myocytes, and in silico modelling to simulate human ventricular electrophysiology.

Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial.

Background: Histaminergic neurons are crucial to maintain wakefulness, but their role in cataplexy is unknown. We assessed the safety and efficacy of pitolisant, a histamine H3 receptor inverse agonist, for treatment of cataplexy in patients with narcolepsy.

Methods: For this randomised, double-blind, placebo-controlled trial we recruited patients with narcolepsy from 16 sleep centres in nine countries (Bulgaria, Czech Republic, Hungary, Macedonia, Poland, Russia, Serbia, Turkey, and Ukraine).

Synthesis and evaluation of a 2-benzothiazolylphenylmethyl ether class of histamine H4 receptor antagonists.

Synthesis and biological evaluation of a new class of histamine H receptor ligands, distinct from the previously reported chemotypes, are described. A virtual screening of our corporate compound collection identified a hit with an undesired dual H3R/H4R activity. Chemical exploration led to the discovery of a more potent and selective 2-benzothiazolylphenylmethyl ether lead compound.

Discovery of nanomolar ligands with novel scaffolds for the histamine H4 receptor by virtual screening.

The involvement of histamine H4 receptor (H4R) in immune cells chemotaxis and mediator release makes it an attractive target for the treatment of inflammation disorders. A decade of medicinal chemistry efforts has led to several promising ligands, although the chemical structures described so far possesses a singular limited diversity. We report here the discovery of novel structures, belonging to completely different scaffolds.

Exploratory Phase II Trial to Evaluate the Safety and the Antiepileptic Effect of Pitolisant (BF2.649) in Refractory Partial Seizures, Given as Adjunctive Treatment During 3 Months.

Background: Pitolisant (BF2.649) is a nonimidazole histamine 3 receptor antagonist. In previous animal studies, it has been shown that pitolisant might be helpful in chronic seizure treatment of both partial and generalized epilepsies.

Improving selectivity of dopamine D3 receptor ligands.

The seminal human dopamine D3 receptor (hD3R) ligand BP 897 has shown interesting properties during clinical trials. However, its lack of selectivity towards human adrenergic receptor impedes further development. Two approaches were followed to increase hD3R selectivity.

Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial.

Background: Narcolepsy is characterised by excessive daytime sleepiness (EDS) and cataplexy. Histamine neurons are crucial to maintain wakefulness. We assessed the safety and efficacy of pitolisant (previously called BF2.

Determination of the binding mode and interacting amino-acids for dibasic H3 receptor antagonists.

Due to its involvement in major CNS functions, the histamine H3 receptor (H3R) is the subject of intensive medicinal chemistry investigation, supported by the range of modern drug discovery tools, such as receptor modeling and ligand docking. Although the receptor models described to date share a majority of common traits, they display discrete alternatives in amino-acid conformation, rendering ligand binding modes quite different. Such variations impede structure-based drug design in the H3R field.