piperidines and Narcolepsy

Topics: Adolescent; Adult; Cataplexy; Child; Drug Inverse Agonism; Histamine Agonists; Humans; Narcolepsy; Piperidines; Pyrazoles

Narcolepsy is a chronic sleep disorder characterized by a pentad of excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations, and disturbed nocturnal sleep. Treatment of narcolepsy remains challenging and current therapy is strictly symptomatically based.. The present manuscript is based on an extensive Internet and PubMed search from 1990 to 2020. It is focused on the clinical and pharmacological properties of pitolisant in the treatment of narcolepsy.. Currently there is no cure for narcolepsy. Although efforts have been made, current treatments do not always allow to obtain an optimal control of symptoms. Pitolisant is an antagonist/inverse agonist of the histamine H3 autoreceptor. Its mechanism of action is novel and distinctive compared to the other available therapies for narcolepsy. Clinical trials suggest that pitolisant administered at a dose of ≤36 mg/day is an effective treatment option for narcolepsy, reducing EDS and cataplexy. Pitolisant is available as oral tablets and offers a convenient once-daily regimen. Pitolisant is generally well tolerated and showed minimal abuse potential in animals and humans. Long-term studies comparing the effectiveness and tolerability of pitolisant with active drugs (e.g. modafinil, sodium oxybate) are needed.

Topics: Animals; Cataplexy; Humans; Modafinil; Narcolepsy; Piperidines; Sleep; Sodium Oxybate; Treatment Outcome

Topics: Clinical Trials as Topic; Histamine Agonists; Histamine Antagonists; Humans; Hypothalamus; Narcolepsy; Piperidines; Receptors, Histamine H3

Excessive daytime sleepiness is considered as the prominent symptom in narcolepsy and Obstructive Sleep Apnea (OSA). Pitolisant is a novel selective histamine H3 receptor antagonist approved for improving excessive daytime sleepiness. The meta-analysis is conducted to assess the efficacy and safety of pitolisant versus placebo for excessive daytime sleepiness in narcolepsy and OSA. PubMed, Embase and Cochrane Library databases were searched from earliest date to November 2020 for randomized controlled trials (RCTs). The primary outcomes were mean changes in Epworth Sleepiness Scale (ESS), mean sleep latency, European quality-of-life questionnaire (EQ-5D), and risk ratio of treatment-emergent adverse events (TEAEs). We pooled 678 patients from four RCTs and found pitolisant significantly decreased ESS by mean difference (MD) of - 2.86 points (95% CI: -3.75 to -1.96), increased mean sleep latency by MD of 3.14 min (95% CI: 2.18-4.11), and increased EQ-5D by MD of 3.32 points (95% CI: 0.26-6.39) compared with placebo. The risk ratio of TEAE was 1.37 (95% CI: 1.08-1.74). Insomnia was the only TEAE significantly associated with pitolisant treatment. In conclusion, pitolisant showed great efficacy and controllable security versus placebo for excessive daytime sleepiness in narcolepsy and OSA. Compared with narcolepsy, patients with OSA were deemed to benefit more from pitolisant especially in terms of improving mobility and quality of life of patients without continuous positive airway pressure therapy.

Topics: Disorders of Excessive Somnolence; Histamine Antagonists; Humans; Narcolepsy; Piperidines; Placebo Effect; Quality of Life; Randomized Controlled Trials as Topic; Sleep Apnea, Obstructive

Narcolepsy is a rare, chronic, and disabling central nervous system hypersomnia; two forms can be recognized: narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). Its etiology is still largely unknown, but studies have reported a strong association between NT1 and HLA, as well as a pathogenic association with the deficiency of cerebrospinal hypocretin-1. Thus, the most reliable pathogenic hypothesis is an autoimmune process destroying hypothalamic hypocretin-producing cells. A definitive cure for narcolepsy is not available to date, and although the research in the field is highly promising, up to now, current treatments have aimed to reduce the symptoms by means of different pharmacological approaches. Moreover, overall narcolepsy symptoms management can also benefit from non-pharmacological approaches such as cognitive behavioral therapies (CBTs) and psychosocial interventions to improve the patients' quality of life in both adult and pediatric-affected individuals as well as the well-being of their families. In this review, we summarize the available therapeutic options for narcolepsy, including the pharmacological, behavioral, and psychosocial interventions.

Topics: Behavior Therapy; Carbamates; Counseling; Humans; Modafinil; Narcolepsy; Phenylalanine; Piperidines; Wakefulness-Promoting Agents

Topics: Animals; Cataplexy; Drug Inverse Agonism; Histamine Agonists; Histamine H3 Antagonists; Humans; Narcolepsy; Piperidines; Receptors, Histamine H3

Topics: Animals; Cataplexy; Clinical Trials, Phase III as Topic; Humans; Narcolepsy; Piperidines

Narcolepsy is the most common cause of excessive daytime sleepiness (EDS) following obstructive sleep apnea. Its treatment aims to reduce EDS and cataplexy, improve nighttime sleep disturbance, sleep paralysis and sleep-related hallucinations. Pitolisant (a histamine H3 receptor antagonist) and solriamfetol (a norepinephrine reuptake inhibitor) have recently been approved effective for narcolepsy in the United States and the European Union. Pitolisant has proved to be effective for both EDS and cataplexy. Besides being effective on EDS, solriamfetol seems to have advantages in abuse potential and withdrawal syndrome. As potential treatments for EDS and cataplexy associated with narcolepsy, several new drugs are being developed and tested. These new drugs include new hydroxybutyrate preparations (controlled release sodium hydroxybutyrate FT218, low sodium hydroxybutyrate JZP-258), selective norepinephrine reuptake inhibitor (AXS-12), and modafinil combined with astroglial junction protein inhibitor (THN102). This paper reviews the recently approved drugs and potential treatments for narcolepsy.

Topics: Carbamates; Cataplexy; Drug Development; Humans; Narcolepsy; Phenylalanine; Piperidines

Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness and rapid eye movement sleep dysregulation, manifesting as cataplexy and sleep paralysis, as well as hypnagogic and hypnopompic hallucinations. Disease onset may occur at any age, although adolescents and young adults are mainly affected. Currently, the diagnosis delay ranges from 8 to 10 years and drug therapy may only attenuate symptoms. Pitolisant is a first-in-class new drug currently authorized by the European Medicines Agency to treat narcolepsy with or without cataplexy in adults and with an expanded evaluation for the treatment of neurologic diseases such as Parkinson's disease and epilepsy. This article reviews the pharmacokinetic and pharmacodynamic profile of pitolisant, highlighting its effectiveness and safety in patients with narcolepsy. We performed a systematic review of the literature using PubMed, Embase, and Google Scholar. We report on the efficacy and safety data of pitolisant in narcoleptic patients regarding cataplexy episodes and subjective and objective daytime sleepiness. The development program of pitolisant was characterized by eight Phase II/III studies. One proof-of-concept study followed by two pivotal studies, three randomized controlled trials, and two open studies were evaluated. Our review confirmed the effectiveness of pitolisant in treating major clinically relevant narcolepsy symptoms, including cataplexy, as compared to placebo. In addition, pitolisant revealed a safe profile when compared with placebo and active comparators. Headache, insomnia, and nausea were the prominent side effects. Further long-term randomized controlled trials comparing the efficacy of pitolisant with active comparators (ie, modafinil and sodium oxybate) may clarify its real place in therapy and its possible use as a first-line agent on the basis of its safety and tolerability.

Topics: Animals; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Design; Humans; Narcolepsy; Piperidines; Randomized Controlled Trials as Topic

Randomized controlled trials (RCTs) that compared the safety and efficacy of medical treatments for narcolepsy were analyzed using network meta-analysis.. The RCTs in narcolepsy were searched. Network meta-analysis compared efficacy and safety of multiple treatments, multi-arm studies, and multi-criteria treatment decisions, based on a random model that assumed heterogeneity between studies, with corrections for multi-arm studies.. Fourteen RCTs, three drug treatments, and six doses were identified: sodium oxybate (6 and 9 g/d), modafinil (between 200 and 400 mg/d), and pitolisant (up to 20 and up to 40 mg/d). Significant heterogeneity (>50%) between studies was found in 12/14 studies for almost all endpoints, but between-design consistency was present. For ESS and MWT, sodium oxybate 9 g/d, modafinil, and pitolisant up to 40 mg/d had similar efficacy. Pitolisant 40 mg/d and sodium oxybate 9 g/d in two nightly doses had similar efficacy in reducing cataplexy. A good safety profile characterized by a TEAE incidence risk ratio (IRR) <1.5 was found for all the compared treatments, except for sodium oxybate 9 g/d. Although no significant difference was found, Pitolisant 40 mg was shown with the best P scores for the benefit/risk (BR) ratio.. Modafinil (200-400 mg/d), sodium oxybate 9 g/d, and pitolisant up to 40 mg/d had similar efficacy in reducing excessive day time sleepiness. Only sodium oxybate 9 g/d and pitolisant up to 40 mg/d were shown with a comparable beneficial effect on cataplexy. Overall, Pitolisant was found with the best P score on the BR ratio.. PROSPERO 2017 CRD42017054686. Efficacy, safety, and benefit-risk comparison of alternative treatments in narcolepsy: a network multiple comparisons of treatment meta-analysis. http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017054686.

Topics: Adult; Cataplexy; Humans; Modafinil; Narcolepsy; Network Meta-Analysis; Odds Ratio; Piperidines; Risk Assessment; Sleepiness; Sodium Oxybate

Narcolepsy is an orphan neurological disease and presents with sleep-wake, motoric, neuropsychiatric and metabolic symptoms. Narcolepsy with cataplexy is most commonly caused by an immune-mediated process including genetic and environmental factors, resulting in the selective loss of hypocretin-producing neurons. Narcolepsy has a major impact on workableness and quality of life. Areas covered: This review provides an overview of the temporal available treatment options for narcolepsy (type 1 and 2) in adults, including authorization status by regulatory agencies. First- and second-line options are discussed as well as combination therapies. In addition, treatment options for frequent coexisting co-morbidities and different phenotypes of narcolepsy are presented. Finally, this review considers potential future management strategies. Non-pharmacological approaches are important in the management of narcolepsy but will not be covered in this review. Expert opinion: Concise evaluation of symptoms and type of narcolepsy, coexisting co-morbidities and patients´ distinct needs is mandatory in order to identify a suitable, individual pharmacological treatment. First-line options include Modafinil/Armodafinil (for excessive daytime sleepiness, EDS), Sodium Oxybate (for EDS and/with cataplexy), Pitolisant (for EDS and cataplexy) and Venlafaxine (for cataplexy (off-label) and co-morbid depression). New symptomatic and causal treatment most probably will be completed by hypocretin-replacement and immune-modifying strategies.

Topics: Adult; Benzhydryl Compounds; Cataplexy; Drug Therapy, Combination; Humans; Modafinil; Narcolepsy; Neuropeptides; Off-Label Use; Orexins; Piperidines; Quality of Life; Sleep; Sodium Oxybate; Venlafaxine Hydrochloride; Wakefulness-Promoting Agents

Since March 2016, a new treatment option for adult patients with narcolepsy – with or without cataplexy – has been granted marketing authorization in Europe. Pitolisant (Wakix®) is an inverse agonst at the histamine-3 (H3) receptor. In clinical studies, tests for measurement of wakefulness and attention, pitolisant showed significantly better results in comparison with placebo and similar results in comparison with modafinil. Pitolisant is well tolerated. Postmarketing analyses have to collect data about the long-term safety of pitolisant when used in a real-life setting.

Topics: Administration, Oral; Adult; Arousal; Attention; Contraindications; Dose-Response Relationship, Drug; Female; Histamine H3 Antagonists; Humans; Male; Narcolepsy; Piperidines; Randomized Controlled Trials as Topic

Pitolisant (Wakix™) is an inverse agonist of the histamine H3 receptor that is being developed by Bioproject. Oral pitolisant is approved in the EU for the treatment of narcolepsy with or without cataplexy in adults. Pitolisant has received a Temporary Authorization of Use in France for this indication in case of treatment failure, intolerance or contraindication to currently available treatment. Pitolisant has orphan drug designation in the EU and the USA. In the pivotal HARMONY I trial, pitolisant significantly decreased excessive daytime sleepiness versus placebo in adults with narcolepsy with or without cataplexy (primary endpoint). Pitolisant also significantly decreased cataplexy rate versus placebo in these patients. This article summarizes the milestones in the development of pitolisant leading to this first approval for narcolepsy.

Topics: Administration, Oral; Adolescent; Adrenergic Neurons; Adult; Animals; Child; Clinical Trials as Topic; Histamine Agonists; Humans; Mice; Narcolepsy; Piperidines; Receptors, Histamine H3

Narcolepsy is a disorder of the central nervous system, the main symptoms of which are excessive daytime sleepiness (EDS) and cataplexy (an abrupt and reversible decrease in or loss of muscle tone, affecting the limbs or trunk or both, elicited by emotional stimuli). Narcolepsy has an adverse impact on people's quality of life. Together with stimulant drugs (used to control EDS), antidepressants are usually recommended to counteract cataplexy. In addition, some antidepressants are also reported to improve EDS.. To evaluate the effects of antidepressant drugs on EDS, cataplexy, quality of life, and their side effects in people with narcolepsy.. We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2007), MEDLINE (1966 to 2007), EMBASE (1980 to 2007), PsycINFO (1872 to 2007), and CINAHL (1981 to 2007). Bibliographies of identified articles were reviewed to find additional references. Unpublished randomised trials were searched for by consulting governmental and non-governmental clinical trial registers, disease-specific websites, investigators and experts in the field, pharmaceutical companies/manufacturers.. Parallel or cross-over randomised or quasi-randomised controlled trials testing the treatment of narcolepsy with any type of antidepressant drug versus no treatment, placebo, or another antidepressant drug.. Two review authors independently assessed trial quality and extracted data.. Three cross-over and two parallel trials were included with a total of 246 participants. The methodological quality of all studies was unclear. As the trials tested different comparisons, or had a different design or dealt with different outcome measures, meta-analysis was not performed. In one cross-over trial (10 participants) femoxetine had no significant effect in eliminating or reducing EDS but significantly reduced cataplexy. Mild and transient side effects were reported in the femoxetine treatment period by two participants. In a second cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy. In a third cross-over trial the authors inappropriately treated the trial design as a parallel study and no conclusions can be reached in favour of either drug. Two more trials with parallel design tested ritanserin versus placebo without finding differences of effectiveness in reducing EDS or cataplexy.. There was no good quality evidence that antidepressants are effective for narcolepsy or improve quality of life. Despite the clinical consensus recommending antidepressants for cataplexy there is scarce evidence that antidepressants have a positive effect on this symptom. There is a clear need for well-designed randomised controlled trials to assess the effect of antidepressants on narcolepsy.

Topics: Antidepressive Agents; Cataplexy; Clomipramine; Fluvoxamine; Humans; Narcolepsy; Piperidines; Randomized Controlled Trials as Topic

Narcolepsy is a disorder of the central nervous system, the main symptoms of which are excessive daytime sleepiness (EDS) and cataplexy (an abrupt and reversible decrease in or loss of muscle tone, affecting the limbs and/or trunk, elicited by emotional stimuli). Narcolepsy has an adverse impact on people's quality of life. Together with stimulant drugs (used to control EDS), antidepressants are usually recommended to counteract cataplexy. In addition, some antidepressants are also reported to improve EDS.. To evaluate the effects of antidepressant drugs on EDS, cataplexy, quality of life, and their side effects in people with narcolepsy.. We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2003), MEDLINE (1966 to 2003), EMBASE (1980 to 2003), PsycINFO (1872 to 2003), and CINAHL (1981 to 2003). Bibliographies of identified articles were reviewed to find additional references. Unpublished randomised trials were searched for by consulting governmental and non-governmental clinical trial registers, disease-specific websites, investigators and experts in the field, pharmaceutical companies/manufacturers.. Parallel or cross-over randomised or quasi-randomised controlled trials testing the treatment of narcolepsy with any type of antidepressant drug versus no treatment, placebo, or another antidepressant drug.. Two reviewers independently selected trials for inclusion and extracted data. Outcomes were: (a) elimination of EDS; (b) mean reduction of EDS; (c) elimination of cataplexy; (d) 50% or greater reduction in cataplexy frequency; (e) mean reduction of cataplexy; (f) mean improvement in quality of life; (g) adverse events; (h) withdrawal from treatment.. Two cross-over trials were included. The methodological quality of both studies was unclear and so the influence of common biases was impossible to define. As the trials tested two different comparisons (one femoxetine versus placebo, the other fluvoxamine versus clomipramine) meta-analysis was not performed. In the first trial (10 participants) femoxetine had no significant effect in eliminating or reducing EDS; a significant reduction of cataplexy was in favour of femoxetine. Mild and transient side effects were reported in the femoxetine treatment period by two participants. In the second trial the authors inappropriately treated the trial design as a parallel study and no conclusions can be reached in favour of either drug.. There was no good quality evidence that antidepressants are effective for narcolepsy or improve quality of life. Despite the clinical consensus recommending antidepressants for cataplexy there is scarce evidence that antidepressants have a positive effect on this symptom. There is a clear need for well-designed randomised controlled trials to assess the effect of antidepressants on narcolepsy.

Topics: Antidepressive Agents; Cataplexy; Clomipramine; Fluvoxamine; Humans; Narcolepsy; Piperidines; Randomized Controlled Trials as Topic

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).. The objective of this study was to evaluate the clinical impact of pitolisant for the reduction in excessive daytime sleepiness or cataplexy in adults with narcolepsy.. This post hoc analysis incorporated data from two 7-week or 8-week randomized placebo-controlled trials (HARMONY 1, HARMONY CTP). Study medication was individually titrated, with a maximum possible pitolisant dose of 35.6 mg/day. Efficacy was assessed using the Epworth Sleepiness Scale (ESS) and weekly rate of cataplexy (HARMONY CTP only). Cohen's d was derived from the least-squares mean difference between treatment groups (pitolisant vs placebo), and NNTs were calculated from response rates. Treatment response was defined for excessive daytime sleepiness in two ways: (a) reduction in ESS score ≥ 3 or final ESS score ≤ 10 and (b) final ESS score ≤ 10. Treatment response was defined for cataplexy as a ≥ 25%, ≥ 50%, or ≥ 75% reduction in weekly rate of cataplexy.. The analysis population included 61 patients in HARMONY 1 (pitolisant, n = 31; placebo, n = 30) and 105 patients in HARMONY CTP (pitolisant, n = 54; placebo, n = 51). For pitolisant vs placebo, Cohen's d effect size values were 0.61 (HARMONY 1) and 0.86 (HARMONY CTP) based on changes in ESS scores, and 0.86 (HARMONY CTP) based on changes in weekly rate of cataplexy. NNTs for pitolisant were 3-5 for the treatment of excessive daytime sleepiness and 3-4 for the treatment of cataplexy.. The results of this analysis demonstrate the robust efficacy of pitolisant for the reduction in both excessive daytime sleepiness and cataplexy. These large effect sizes and low NNTs provide further evidence supporting the strength of the clinical response to pitolisant in the treatment of adults with narcolepsy.. ClinicalTrials.gov identifiers: NCT01067222 (February 2010), NCT01800045 (February 2013).

Topics: Adolescent; Adult; Aged; Cataplexy; Disorders of Excessive Somnolence; Double-Blind Method; Female; Humans; Male; Middle Aged; Narcolepsy; Piperidines; Treatment Outcome; Young Adult

Pitolisant is approved in the USA and Europe for the treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy.. Analyses evaluated the time to onset of clinical response during treatment with pitolisant.. Data were obtained from two randomized, double-blind, 7-week or 8-week, placebo-controlled studies (HARMONY 1, HARMONY CTP). Study medication was individually titrated to a maximum dose of pitolisant 35.6 mg/day and then remained stable. Efficacy assessments included the Epworth Sleepiness Scale and weekly rate of cataplexy (calculated from patient diaries). Onset of clinical response was defined as the first timepoint at which there was statistical separation between pitolisant and placebo.. The analysis included 61 patients in HARMONY 1 (pitolisant, n = 31; placebo, n = 30) and 105 patients in HARMONY CTP (pitolisant, n = 54; placebo, n = 51). Onset of clinical response began at week 2 (HARMONY 1) or week 3 (HARMONY CTP) for the mean change in Epworth Sleepiness Scale score, and week 2 (HARMONY CTP) or week 5 (HARMONY 1) for the mean change in weekly rate of cataplexy, with further improvements observed in pitolisant-treated patients through the end of treatment. The percentage of treatment responders was significantly greater with pitolisant vs placebo beginning at week 3 for excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score reduction ≥ 3) and week 2 for cataplexy (defined as a ≥ 50% reduction in weekly rate of cataplexy [HARMONY CTP]).. Onset of clinical response for excessive daytime sleepiness and/or cataplexy was generally observed within the first 2-3 weeks of pitolisant treatment in patients with narcolepsy. CLINICALTRIALS.. NCT01067222 (February 2010), NCT01800045 (February 2013).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cataplexy; Circadian Rhythm; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Narcolepsy; Piperidines; Time Factors; Treatment Outcome; Young Adult

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.. 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 213.6 mg (supratherapeutic dose), phentermine HCl 60 mg, and placebo. The primary endpoint was maximum effect (Emax) on the 100-point Drug Liking ("at this moment") visual analog scale.. In 38 study completers (73.7% male; 65.8% white; mean age, 33.3 years), mean Drug Liking Emax was significantly greater for phentermine versus pitolisant 35.6 mg (mean difference, 21.4; p < 0.0001) and pitolisant 213.6 mg (mean difference, 19.7; p < 0.0001). Drug Liking Emax was similar for pitolisant (both doses) and placebo. Similarly, for key secondary measures of Overall Drug Liking and willingness to Take Drug Again, mean Emax scores were significantly greater for phentermine versus pitolisant (both doses) and similar for pitolisant (both doses) versus placebo. The incidence of adverse events was 82.1% after phentermine HCl 60 mg, 72.5% after pitolisant 213.6 mg, 47.5% after pitolisant 35.6 mg, and 48.8% after placebo administration.. In this study, pitolisant demonstrated significantly lower potential for abuse compared with phentermine and an overall profile similar to placebo; this suggests a low risk of abuse for pitolisant.. ClinicalTrials.gov NCT03152123. Determination of the abuse potential of pitolisant in healthy, nondependent recreational stimulant users. https://clinicaltrials.gov/ct2/show/NCT03152123.

Topics: Adult; Cataplexy; Cross-Over Studies; Double-Blind Method; Female; Histamine Agonists; Humans; Male; Narcolepsy; Piperidines

This multicenter, open-label, single-dose study of pitolisant 17.8 mg enrolled patients aged 6 through 17 years with a diagnosis of narcolepsy. Blood samples were collected at prespecified time points for analysis of pharmacokinetic parameters, including maximum serum concentration (C. Of the 25 enrolled patients, 24 were included in the pharmacokinetic analysis. Pitolisant C. After single-dose administration, the exposure parameters of pitolisant were significantly greater in the younger compared with older pediatric patients with narcolepsy. Pitolisant doses up to 17.8 mg/d (in children with body weight <40 kg) or 35.6 mg/d are appropriate for further evaluation in pediatric patients.. EudraCT Number: 2013-001505-93.

Topics: Adolescent; Adult; Age Factors; Child; Female; Humans; Male; Narcolepsy; Piperidines

SUVN-G3031 is a novel, potent, and selective histamine-3 receptor (H. A single ascending dose (SAD) and a multiple ascending dose (MAD) study for 14 days was conducted in healthy young adults using a randomized, double-blind study design. The effect of food, gender, and age on SUVN-G3031 pharmacokinetics (6 mg as a single dose) was evaluated using an open-label, two-period, randomized, crossover design in fed and fasted states. Pharmacokinetics and safety assessments were conducted throughout the study.. Single doses of SUVN-G3031 up to 20 mg and multiple doses up to 6 mg once daily were found to be safe and well tolerated in healthy young adults. The most frequently reported adverse events were abnormal dreams, dyssomnia, and hot flushes. SUVN-G3031 exposure was dose proportional across the tested doses. Steady state was achieved on day 6 after once-daily dosing. Renal excretion (~ 60%) of unchanged SUVN-G3031 was the major route of elimination. Food, gender, and age did not have any clinically meaningful effect on SUVN-G3031 exposure.. SUVN-G3031 was found to be safe and well tolerated in healthy human subjects without any effect of age, gender, and food on the pharmacokinetics and safety profile. Clinical Trials Registration (https://clinicaltrials.gov): NCT04072380 and NCT02342041.

Topics: Administration, Oral; Adult; Cross-Over Studies; Double-Blind Method; Drug Inverse Agonism; Female; Healthy Volunteers; Histamine; Humans; Male; Middle Aged; Morpholines; Narcolepsy; Piperidines

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.. 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). Patients were eligible if they were aged 18 years or older, diagnosed with narcolepsy with cataplexy according to version two of the International Classification of Sleep Disorders criteria, experienced at least three cataplexies per week, and had excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score ≥12). We used a computer-generated sequence via an interactive web response system to randomly assign patients to receive either pitolisant or placebo once per day (1:1 ratio). Randomisation was done in blocks of four. Participants and investigators were masked to treatment allocation. Treatment lasted for 7 weeks: 3 weeks of flexible dosing decided by investigators according to efficacy and tolerance (5 mg, 10 mg, or 20 mg oral pitolisant), followed by 4 weeks of stable dosing (5 mg, 10 mg, 20 mg, or 40 mg). The primary endpoint was the change in the average number of cataplexy attacks per week as recorded in patient diaries (weekly cataplexy rate [WCR]) between the 2 weeks of baseline and the 4 weeks of stable dosing period. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01800045.. The trial was done between April 19, 2013, and Jan 28, 2015. We screened 117 patients, 106 of whom were randomly assigned to treatment (54 to pitolisant and 52 to placebo) and, after dropout, 54 patients from the pitolisant group and 51 from the placebo group were included in the intention-to-treat analysis. The WCR during the stable dosing period compared with baseline was decreased by 75% (WCR. Pitolisant was well tolerated and efficacious in reducing cataplexy. If confirmed in long-term studies, pitolisant might constitute a useful first-line therapy for cataplexy in patients with narcolepsy, for whom there are currently few therapeutic options.. Bioprojet, France.

Topics: Adolescent; Adult; Aged; Cataplexy; Databases, Bibliographic; Double-Blind Method; Female; Follow-Up Studies; Histamine H3 Antagonists; Humans; Male; Middle Aged; Narcolepsy; Piperidines; Retrospective Studies; Severity of Illness Index; Treatment Outcome; Young Adult

To validate the Sustained Attention to Response Task (SART) as a treatment effect measure in narcolepsy, and to compare the SART with the Maintenance of Wakefulness Test (MWT) and the Epworth Sleepiness Scale (ESS).. Validation of treatment effect measurements within a randomized controlled trial (RCT).. Ninety-five patients with narcolepsy with or without cataplexy.. The RCT comprised a double-blind, parallel-group, multicenter trial comparing the effects of 8-w treatments with pitolisant (BF2.649), modafinil, or placebo (NCT01067222). MWT, ESS, and SART were administered at baseline and after an 8-w treatment period. The severity of excessive daytime sleepiness and cataplexy was also assessed using the Clinical Global Impression scale (CGI-C).. The SART, MWT, and ESS all had good reliability, obtained for the SART and MWT using two to three sessions in 1 day. The ability to distinguish responders from nonresponders, classified using the CGI-C score, was high for all measures, with a high performance for the SART (r = 0.61) and the ESS (r = 0.54).. The Sustained Attention to Response Task is a valid and easy-to-administer measure to assess treatment effects in narcolepsy, enhanced by combining it with the Epworth Sleepiness Scale.

Topics: Adult; Attention; Benzhydryl Compounds; Cataplexy; Double-Blind Method; Female; Humans; Male; Modafinil; Narcolepsy; Piperidines; Reproducibility of Results; Sleep Stages; Time Factors; Treatment Outcome; Wakefulness

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 BF2.649), a selective histamine H3 receptor inverse agonist that activates these neurons, in patients with narcolepsy.. For this double-blind, randomised, parallel-group controlled trial, we recruited patients with narcolepsy from 32 sleep disorder centres in five European countries. Patients were eligible if they were aged 18 years or older, had not taken psychostimulants for at least 14 days, and had EDS (defined as an Epworth Sleepiness Scale [ESS] score of at least 14). Using a computer-generated randomisation sequence, we randomly allocated patients to receive pitolisant, modafinil, or placebo (1:1:1). Treatment lasted 8 weeks: 3 weeks of flexible dosing according to investigator's judgment (10 mg, 20 mg, or 40 mg a day of pitolisant; 100 mg, 200 mg or 400 mg a day of modafinil) followed by 5 weeks of stable dosing. Patients took four tablets a day in a double-dummy design to ensure masking. For the primary analysis, assessed in the intention-to-treat population, we assessed the superiority of pitolisant versus placebo, and the non-inferiority of pitolisant versus modafinil. This trial is registered with ClinicalTrials.gov, number NCT01067222.. Between May 26, 2009, and June 30, 2010, we screened 110 patients, 95 of whom were eligible and randomly assigned to treatment: 30 to placebo, 32 to pitolisant, and 33 to modafinil. Over the 8-week treatment period, mean ESS score reductions were -3·4 (SD 4·2) in the placebo group, -5·8 (6·2) in the pitolisant group, and -6·9 (6·2) in the modafinil group. Our primary analysis of between-group differences in mean ESS score at endpoint (adjusted for baseline) showed pitolisant to be superior to placebo (difference -3·0, 95% CI -5·6 to -0·4; p=0·024), but not non-inferior to modafinil (difference 0·12, 95% CI -2·5 to 2·7; p=0·250). We recorded 22 adverse events with pitolisant, 26 with modafinil, and ten with placebo. Six severe adverse events were treatment-related: one with pitolisant (abdominal discomfort) and five with modafinil (abdominal pain, abnormal behaviour, amphetamine-like withdrawal symptoms, lymphoadenopathy, and inner ear disorders).. Pitolisant at doses up to 40 mg was efficacious on EDS compared with placebo and well tolerated compared with modafinil. If these findings are substantiated in further studies, pitolisant could offer a new treatment option for patients with narcolepsy.. Bioprojet, France.

Topics: Adult; Benzhydryl Compounds; Double-Blind Method; Female; Histamine Agonists; Humans; Male; Middle Aged; Modafinil; Narcolepsy; Piperidines; Placebos; Severity of Illness Index; Treatment Outcome; Wakefulness-Promoting Agents; Young Adult

Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy, direct onsets of rapid eye movement (REM) sleep from wakefulness (DREMs) and deficiency of orexins, neuropeptides that promote wakefulness largely via activation of histamine (HA) pathways. The hypothesis that the orexin defect can be circumvented by enhancing HA release was explored in narcoleptic mice and patients using tiprolisant, an inverse H(3)-receptor agonist. In narcoleptic orexin(-/-) mice, tiprolisant enhanced HA and noradrenaline neuronal activity, promoted wakefulness and decreased abnormal DREMs, all effects being amplified by co-administration of modafinil, a currently-prescribed wake-promoting drug. In a pilot single-blind trial on 22 patients receiving a placebo followed by tiprolisant, both for 1 week, the Epworth Sleepiness Scale (ESS) score was reduced from a baseline value of 17.6 by 1.0 with the placebo (p>0.05) and 5.9 with tiprolisant (p<0.001). Excessive daytime sleep, unaffected under placebo, was nearly suppressed on the last days of tiprolisant dosing. H(3)-receptor inverse agonists could constitute a novel effective treatment of EDS, particularly when associated with modafinil.

Topics: Animals; Benzhydryl Compounds; Central Nervous System Stimulants; Disease Models, Animal; Female; Histamine Agonists; Humans; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Modafinil; Narcolepsy; Neuropeptides; Orexins; Piperidines; Polysomnography; Prospective Studies; Reaction Time; Severity of Illness Index; Single-Blind Method; Sleep Stages; Wakefulness

In a double-blind placebo-controlled trial, ritanserin (a 5-HT2 receptor blocker) 5 mg/day or placebo was added to the usual medication in 28 patients with narcolepsy during 4 wk. The effect was assessed by means of polysomnography, daily and weekly subjective evaluations, and Multiple sleep latency tests (MSLT). During the night ritanserin increased the amount of nonrapid eye movement slow wave sleep and reduced wakefulness after sleep onset. It improved the feeling of being refreshed in the morning after awakening and reduced subjective daytime sleepiness. The drug did not significantly influence sleep latency in the MSLT.

Topics: Adolescent; Adult; Animals; Circadian Rhythm; Double-Blind Method; Histamine H2 Antagonists; Humans; Middle Aged; Narcolepsy; Piperidines; Placebos; Ritanserin; Sleep

A survey was conducted on 10 polysomnographic studies on the pharmacologic treatment of the sleepiness of narcolepsy. Three studies employed the MSLT and 7 employed the MWT as their polygraphic measure of sleep tendency. Statistically and clinically significant therapeutic changes were apparent for pemoline, modafinil, dextroamphetamine and methylphenidate. Codeine, ritanserin and protriptyline did show statistically significant effects. The common feature among the drugs that did produce clinically significant improvements seems to be facilitatory action on central catecholaminergic transmission. Within this group of drugs, only methylphenidate and dextroamphetamine brought MWT sleep latencies to approximately 70% of normal levels.

Topics: Adult; Arousal; Benzhydryl Compounds; Central Nervous System Stimulants; Codeine; Dextroamphetamine; Female; Humans; Male; Methylphenidate; Modafinil; Narcolepsy; Pemoline; Piperidines; Protriptyline; Reaction Time; Ritanserin; Sleep Stages; Sodium Oxybate; Viloxazine; Wakefulness

A randomized, double-blind cross-over trial was carried out in 10 patients with narcolepsy to evaluate the effect of 600 mg femoxetine versus placebo. In comparison to placebo, femoxetine treatment resulted in a significant decrease in both the number and severity score of cataplectic attacks per day. There were also significantly fewer attacks of sleep paralysis, whilst the effects on nightmare and hypnogenic hallucinations were minor. The frequency of sleep attacks decreased slightly during femoxetine treatment, but the overall estimated sleep time during the day and excessive daytime sleepiness remained un-affected. An ambulatory sleep recording for 48 h one week after the start of the femoxetine and placebo period showed that femoxetine treatment resulted in a significant decrease in the total time spent in REM sleep. The side-effects of femoxetine were restricted to transient nausea in 2 patients. It is concluded that femoxetine or other selective serotonin reuptake inhibitors may be a useful alternative for narcoleptic patients who experience troublesome side-effects with tricyclic antidepressants.

Topics: Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Middle Aged; Narcolepsy; Nausea; Piperidines; Sleep Stages

First symptoms of narcolepsy mostly present during childhood. Pharmacological management options in children are limited, also due to approval status. Pitolisant is an inverse histamine 3 receptor agonist and has been approved for the treatment of adult narcolepsy with or without cataplexy by EMA and FDA. Clinical experience indicates for a beneficial use also in children and adolescents. Our goal was to evaluate the effects and tolerability of pitolisant in narcolepsy children/adolescents in a real-world setting.. This multicentre retrospective observational study included 55 patients with narcolepsy from three international narcolepsy centers (Germany, France and Italy) who were treated with pitolisant. Patients were eligible if they were at least 6 years old and diagnosed with narcolepsy type 1 or 2. Demographic and clinical characteristics, questionnaires, sleep medicine and laboratory data were collected.. 55 children/adolescents (25 girls, 45.45%, 30 boys, 54.55%) aged 6-18 years, with narcolepsy (type 1 = 92.7%, type 2 = 7.3%), were treated with pitolisant. The mean pitolisant dose was 34.1 mg/d. Treatment was effective for excessive daytime sleepiness (EDS) and cataplexy: the pediatric Epworth Sleepiness Scale (ESS) score decreased from 19 to 13.5 (p < 0.001) and the weekly cataplexy frequency improved from 7.9 at baseline to 5.2 (p < 0.001). Treatment with pitolisant was well tolerated. Side effects were mild and mostly short-term. Insomnia was reported most frequently (5.5%).. First real-world results suggest that pitolisant treatment is effective in improving EDS and cataplexy in children with narcolepsy, and also is well tolerated.

Topics: Adolescent; Adult; Amines; Cataplexy; Child; Disorders of Excessive Somnolence; Female; Histamine Agonists; Humans; Male; Narcolepsy; Piperidines; Retrospective Studies

Modafinil is a common treatment for excessive daytime sleepiness (EDS) in narcolepsy. The long-term use of modafinil can lead to tolerance with the loss of efficacy and the continuous increase of its dose. Pharmacological strategies to deal with the tolerance to modafinil are lacking. We investigated the efficacy and safety of pitolisant-supported bridging during drug holidays in patients with tolerance to modafinil.. Narcolepsy patients on monotherapy with modafinil who developed symptoms of tolerance were eligible. The following alternating therapy regimen was established: Monday to Friday patients continued on modafinil whereas Saturday and Sunday they switched to pitolisant to "bridge" the EDS symptoms. Patients were assessed at baseline and after three months with the Epworth Sleepiness Scale (ESS) and the Ullanlinna Narcolepsy Scale (UNS). Health-related quality of life (HrQol) was evaluated by EuroQol5D. Adverse events were documented in the patients' diaries.. 41 patients aged 30.9 ± 5.6 years were included. After three months of the alternating therapy regimen, the symptoms of tolerance decreased and the modafinil dose could be reduced by 41% (p < 0.01) resulting in better safety. The EDS improved on ESS (baseline: 18.2 ± 4.2, follow-up: 12.6 ± 4.0, p < 0.0001) and UNS (baseline: 25.8 ± 7.9, follow-up: 18.9 ± 5.9, p < 0.0001). The HrQol increased significantly.. Patients with tolerance to modafinil could benefit from pitolisant-supported bridging during drug holidays. This alternating pharmacological strategy proved to be safe and helped to reduce EDS and to decrease the modafinil dose. Further randomized controlled studies are required to evaluate the different strategies to deal with the tolerance to modafinil.. Clinical Trials.gov Identifier NCT05321355.

Topics: Benzhydryl Compounds; Disorders of Excessive Somnolence; Humans; Modafinil; Narcolepsy; Piperidines; Quality of Life

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).. 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.. 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.. 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.

Topics: Cross-Sectional Studies; Disorders of Excessive Somnolence; Humans; Narcolepsy; Piperidines

Type 1 narcolepsy is a disabling disease that requires continuous treatment, which is not always effective. Pitolisant is a new drug with a different mechanism of action that offers a new treatment option. The objective of the study was to analyse the effectiveness and safety of pitolisant in patients with type 1 narcolepsy that did not respond to or tolerate previous standard treatments.. Real-life multicentre descriptive observational study that included patients diagnosed with type 1 narcolepsy who did not respond to or tolerate previous treatments and started treatment with pitolisant. The study evaluated three different moments: the start of treatment, the stabilization of treatment with pitolisant and the three months after.. In 32 patients included (mean age, 44 years; 37.5% women) the mean of the Epworth Sleepiness Scale was reduced from 17.1 to 13.5; 47.8% of the patients improved from their cataplexy; 65% of the patients improved their clinical global impression at the physician's and at the patient's discretion and the mean number of medications consumed was reduced from 2.0 to 1.4. The most frequent adverse effect was insomnia in 43.8% of patients. Of the 32 patients, 23 continued with the treatment during the 3-month follow-up period.. In patients with type I narcolepsy who do not respond to or do not tolerate the available treatments, pitolisant can improve their clinical situation and reduce their medication consumption. Studies with a higher level of evidence are needed to confirm these results.. Estudio WAKE de vida real en pacientes con narcolepsia con cataplejía tratados con pitolisant no respondedores a tratamientos previos.. Introducción. La narcolepsia de tipo 1 es una enfermedad incapacitante que requiere tratamiento continuo, que no siempre es eficaz. El pitolisant es un nuevo fármaco con un mecanismo de acción diferente que ofrece una nueva opción de tratamiento. El objetivo del estudio fue analizar la efectividad y la seguridad del pitolisant en pacientes con narcolepsia de tipo 1 que no hubieran respondido o tolerado previamente los tratamientos habituales. Pacientes y métodos. Estudio observacional descriptivo multicéntrico de vida real que incluyó a pacientes diagnosticados de narcolepsia de tipo 1 no respondedores a tratamientos previos que iniciaron tratamiento con pitolisant. El estudio evaluó tres momentos: el inicio del tratamiento, la estabilización del tratamiento con pitolisant y los tres meses posteriores. Resultados. En 32 pacientes incluidos (media de edad, 44 años; 37,5% de mujeres), la media de la escala de somnolencia de Epworth se redujo de 17,1 a 13,5; un 47,8% de los pacientes mejoró subjetivamente de su cataplejía; un 65% de los pacientes mejoró su impresión clínica global a criterio médico y a criterio del paciente; y se redujo la media de medicamentos consumidos de 2,0 a 1,4. El efecto adverso más frecuente fue el insomnio, en un 43,8% de los pacientes. De los 32 pacientes, 23 mantuvieron el tratamiento durante los tres meses de seguimiento. Conclusiones. En pacientes con narcolepsia de tipo 1 que no responden a o no toleran los tratamientos disponibles, el pitolisant puede mejorar su situación clínica y reducir su consumo de medicamentos. Son necesarios estudios de mayor nivel de evidencia para confirmar estos resultados.

Topics: Adult; Cataplexy; Female; Humans; Male; Narcolepsy; Piperidines; Sleep Initiation and Maintenance Disorders

Samelisant (SUVN-G3031) is a potent and selective histamine H3 receptor (H3R) inverse agonist with good brain penetration and oral bioavailability.. Pharmacological and neurochemical characterisation to support the utility of Samelisant (SUVN-G3031) in the treatment of sleep-related disorders like narcolepsy.. Samelisant (SUVN-G3031) was tested in rat brain microdialysis studies for evaluation of modulation in histamine, dopamine and norepinephrine. Sleep EEG studies were carried out in orexin knockout mice to study the effects of Samelisant (SUVN-G3031) on the sleep-wake cycle and cataplexy.. Pre-clinical studies of Samelisant (SUVN-G3031) provide a strong support for utility in the treatment of sleep-related disorders related to EDS and is currently being evaluated in a phase 2 proof of concept study in the USA for the treatment of narcolepsy with and without cataplexy.

Topics: Animals; Electroencephalography; Histamine; Histamine Agonists; Humans; Male; Methylhistamines; Mice; Mice, Inbred C57BL; Mice, Knockout; Morpholines; Narcolepsy; Orexins; Piperidines; Rats; Rats, Wistar; Sleep; Wakefulness

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. Analyses included three independent patient subgroups: Epworth Sleepiness Scale (ESS) baseline score ≥16, Maintenance of Wakefulness Test (MWT) sleep latency ≤8 min, and ≥15 cataplexy attacks per week.. The analysis populations included 118 patients for ESS (pitolisant, n = 60; placebo, n = 58), 105 for MWT (pitolisant, n = 59; placebo, n = 46), and 31 for cataplexy (pitolisant, n = 20; placebo, n = 11). On the ESS, least-squares mean change from baseline was significantly greater for pitolisant (-6.1) compared with placebo (-2.3; P < 0.001). Significantly more pitolisant-treated patients were classified as treatment responders: ESS score reduction ≥3, 69.0% in the pitolisant group versus 35.1% in the placebo group (P = 0.001); final ESS score ≤10, 36.2% versus 10.5%, respectively (P = 0.005). On the MWT, mean sleep latency increased from 3.5 min to 10.4 min with pitolisant and from 3.4 min to 6.8 min with placebo (P = 0.017). Least-squares mean change in the weekly rate of cataplexy was significantly greater for pitolisant (-14.5; baseline, 23.9; final, 9.4) compared with placebo (-0.1; baseline, 23.1; final, 23.0; P = 0.004). Headache was the most common adverse event with pitolisant.. Pitolisant, at once-daily doses up to 35.6 mg, was efficacious for reducing excessive daytime sleepiness and cataplexy in patients with severe narcolepsy symptom burden.

Topics: Adult; Cataplexy; Humans; Narcolepsy; Piperidines; Treatment Outcome; Wakefulness

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. Results confirmed that the primary pharmacological effect of amphetamine, modafinil, and solriamfetol was to increase central dopamine neurotransmission, in part by inhibiting its transporter. Furthermore, solriamfetol increased levels of extracellular dopamine in the nucleus accumbens, and decreased the 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA ratio in the striatum, as reported for modafinil and amphetamine. All these compounds produced hyperlocomotion, behavioral sensitization, and hypophagia, which are common features of psychostimulants and of compounds with abuse potential. In contrast, pitolisant, a selective and potent H3R antagonist/inverse agonist that promotes wakefulness, had no effect on striatal dopamine, locomotion, or food intake. In addition, pitolisant, devoid of behavioral sensitization by itself, attenuated the hyperlocomotion induced by either modafinil or solriamfetol. Therefore, pitolisant presents biochemical, neurochemical, and behavioral profiles different from those of amphetamine and other psychostimulants such as modafinil or solriamfetol. In conclusion, pitolisant is a differentiated therapeutic option, when compared with psychostimulants, for the treatment of EDS, as this agent does not show any amphetamine-like properties within in vivo preclinical models.

Topics: 3,4-Dihydroxyphenylacetic Acid; Adrenergic Uptake Inhibitors; Amphetamine; Animals; Carbamates; Corpus Striatum; Disorders of Excessive Somnolence; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Drug Evaluation, Preclinical; Drug Inverse Agonism; Feeding Behavior; Histamine Antagonists; Locomotion; Mice; Modafinil; Narcolepsy; Neostriatum; Norepinephrine Plasma Membrane Transport Proteins; Nucleus Accumbens; Phenylalanine; Piperidines; Receptors, Histamine H3; Sleep Apnea, Obstructive; Wakefulness-Promoting Agents

The cost-effectiveness of available pharmacological treatments for narcolepsy is largely unknown. Available pharmacological treatments are associated with tolerability, abuse, and adherence issues. Pitolisant is the first inverse agonist of the histamine H3 receptor to be prescribed for the treatment of narcolepsy with and without cataplexy. Studies suggest that pitolisant is both as effective as previously introduced drugs and is associated with fewer adverse effects. The objective in this study was to estimate the cost-effectiveness of pitolisant as monotherapy, and pitolisant as an adjunctive treatment to modafinil, compared with standard treatment.. Calculations were performed using a Markov model with a 50-year time horizon. Healthcare utilization and quality-adjusted life years (QALYs) for each treatment alternative were calculated assuming no treatment effect on survival. Probabilistic sensitivity analyses were performed for treatment effectiveness and healthcare cost parameters.. The cost per additional quality-adjusted life year was estimated at SEK 356 337 (10 SEK ≈ 1 Euro) for pitolisant monotherapy, and at SEK 491 128 for pitolisant as an adjunctive treatment, as compared to standard treatment. The cost-effectiveness measure was demonstrated to be particularly sensitive to the assumptions made concerning indirect effects on total healthcare utilization and the pitolisant treatment cost.. The incremental cost-effectiveness ratios were below the unofficial willingness-to-pay threshold at SEK 500 000. The estimated costs per additional QALY obtained here are likely to overestimate the true cost-effectiveness ratio since significant potential indirect effects-pertaining both to labor-market and household-related productivity-of treatment are not taken into account.

Topics: Cost-Benefit Analysis; Drug Utilization; Histamine Agents; Humans; Narcolepsy; Piperidines; Quality-Adjusted Life Years; Treatment Outcome

Topics: Aged; Female; Humans; Narcolepsy; Parkinson Disease; Piperidines

SUVN-G3031 is a potent and selective inverse agonist of Histmine-3 (H

Topics: Animals; Dogs; Drug Interactions; Hepatocytes; Histamine; Humans; Microsomes, Liver; Morpholines; Narcolepsy; Pharmaceutical Preparations; Piperidines

To asses the long-term safety and efficacy of pitolisant, an histamine H3-receptor antagonist, on narcolepsy.. 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. Concomitant stimulants and anti-cataplectic agents were allowed. The primary endpoint was safety; secondary endpoints included ESS, cataplexy, and other diary parameters.. Patients (n = 102, 75 with cataplexy) received pitolisant, for the first time in 73 of them. Sixty-eight patients (51 with cataplexy) completed the 12-month treatment. Common treatment-emergent adverse events were headache (11.8% of patients), insomnia (8.8%), weight gain (7.8%), anxiety (6.9%), depressive symptoms (4.9%), and nausea (4.9%). Seven patients had a serious adverse effect, unrelated to pitolisant except for a possibly related miscarriage. One-third of patients stopped pitolisant, mostly (19.6%) for insufficient benefit. ESS score decreased by 4.6 ± 0.6. Two-thirds of patients completing the treatment were responders (ESS ≤ 10 or ESS decrease ≥ 3), and one third had normalized ESS (≤10). Complete and partial cataplexy, hallucinations, sleep paralysis, and sleep attacks were reduced by 76%, 65%, 54%, 63%, and 27%, respectively. Pitolisant as monotherapy (43% of patients) was better tolerated and more efficacious on ESS than on add-on, but efficacy was maintained in this last case.. Long-term safety and efficacy of pitolisant on daytime sleepiness, cataplexy, hallucinations, and sleep paralysis is confirmed.

Topics: Adult; Anxiety; Central Nervous System Stimulants; Depression; Female; Headache; Histamine H3 Antagonists; Humans; Male; Narcolepsy; Piperidines; Sleep Initiation and Maintenance Disorders; Treatment Outcome

The lateral hypothalamus contains neurons producing orexins that promote wakefulness and suppress REM sleep as well as neurons producing melanin-concentrating hormone (MCH) that likely promote REM sleep. Narcolepsy with cataplexy is caused by selective loss of the orexin neurons, and the MCH neurons appear unaffected. As the orexin and MCH systems exert opposing effects on REM sleep, we hypothesized that imbalance in this REM sleep-regulating system due to activity in the MCH neurons may contribute to the striking REM sleep dysfunction characteristic of narcolepsy. To test this hypothesis, we chemogenetically activated the MCH neurons and pharmacologically blocked MCH signaling in a murine model of narcolepsy and studied the effects on sleep-wake behavior and cataplexy. To chemoactivate MCH neurons, we injected an adeno-associated viral vector containing the hM3Dq stimulatory DREADD into the lateral hypothalamus of orexin null mice that also express Cre recombinase in the MCH neurons (MCH-Cre::OX-KO mice) and into control MCH-Cre mice with normal orexin expression. In both lines of mice, activation of MCH neurons by clozapine-N-oxide (CNO) increased rapid eye movement (REM) sleep without altering other states. In mice lacking orexins, activation of the MCH neurons also increased abnormal intrusions of REM sleep manifest as cataplexy and short latency transitions into REM sleep (SLREM). Conversely, a MCH receptor 1 antagonist, SNAP 94847, almost completely eliminated SLREM and cataplexy in OX-KO mice. These findings affirm that MCH neurons promote REM sleep under normal circumstances, and their activity in mice lacking orexins likely triggers abnormal intrusions of REM sleep into non-REM sleep and wake, resulting in the SLREM and cataplexy characteristic of narcolepsy.

Topics: Animals; Female; Hypothalamic Hormones; Male; Melanins; Mice; Mice, Knockout; Narcolepsy; Neurons; Piperidines; Pituitary Hormones; Sleep, REM

On 31 March 2016, the European Commission issued a decision for a marketing authorisation valid throughout the European Union (EU) for pitolisant (Wakix) for the treatment of narcolepsy with or without cataplexy in adults. Pitolisant is an antagonist/inverse agonist of the human histamine H3 receptor. The dose should be selected using an up-titration scheme depending on individual patient response and tolerance and should not exceed 36 mg/day. The main evidence of efficacy of pitolisant was based on two Phase III clinical trials. The improvement on excessive daytime sleepiness was shown against placebo in the Harmony I study (-3.33 points; 95% confidence interval (CI) [-5.83; -0.83]; p = 0.024) and in Harmony CTP (-3.41 points; 95% CI [-4.95; -1.87]; p < 0.0001). The daily cataplexy rate in Harmony I improved against placebo with a rate ratio (rR) of 0.38 whilst in the Harmony CTP the ratio of improvement on weekly cataplexy rate against placebo was 0.512. The most commonly reported adverse reactions were headache, insomnia and nausea. This article summarizes the scientific review leading to approval of pitolisant in the EU. The assessment report and product information are available on the European Medicines Agency website (http://www.ema.europa.eu).

Topics: Adolescent; Adult; Aged; Animals; Attention; Cataplexy; Clinical Trials, Phase III as Topic; Cognition; Drug Inverse Agonism; Humans; Middle Aged; Narcolepsy; Piperidines; Receptors, Histamine H3; Treatment Outcome; Wakefulness-Promoting Agents; Young Adult

▼Pitolisant (Wakix-Bioprojet Pharma) is a new treatment for adults with narcolepsy with or without cataplexy. It was licensed for use in the EU in March last year and has orphan drug status.

Topics: Adult; Contraindications; Disease Management; Histamine H3 Antagonists; Humans; Narcolepsy; Piperidines

Topics: Cataplexy; Humans; Narcolepsy; Piperidines

Topics: Benzhydryl Compounds; Female; Histamine Agonists; Humans; Male; Modafinil; Narcolepsy; Piperidines; Wakefulness-Promoting Agents

We report the anesthetic management of a narcoleptic patient performed using sevoflurane-remifentanil with bispectral index (BIS) monitoring. A 22-year-old man, who was diagnosed with narcolepsy at the age of 17, requested endoscopic sinus surgery, under general anesthesia, for chronic allergic rhinitis. On the morning of the day of operation, he took his daily dose of modafinil, used to control narcolepsy. Anesthesia was induced by 5% sevoflurane and maintained with sevoflurane and continuous infusion of remifentanil and 60% oxygen in conjunction with BIS monitoring. BIS values were between 47 and 58. Duration of surgery was 150 min. After surgery, the patient emerged from anesthesia within 10 min and was extubated. His recovery was uneventful. We found the use of BIS monitoring for titrating sevoflurane concentration in a narcoleptic patient is useful for preventing not only oversedation but also intraoperative awareness caused by the preoperative medication.

Topics: Anesthesia; Anesthetics, Inhalation; Anesthetics, Intravenous; Anti-Inflammatory Agents, Non-Steroidal; Benzhydryl Compounds; Central Nervous System Stimulants; Consciousness Monitors; Endoscopy; Flurbiprofen; Humans; Hypnotics and Sedatives; Male; Methyl Ethers; Modafinil; Narcolepsy; Pain, Postoperative; Piperidines; Remifentanil; Rhinitis, Allergic, Perennial; Sevoflurane; Sinusitis; Young Adult

The successful cloning and functional expression of the histamine H(3) receptor in the late 1990 s has greatly facilitated our efforts to identify small molecule, non-imidazole based compounds to permit the evaluation of H(3) antagonists in models of CNS disorders. High-throughput screening identified several series of lead compounds, including a series of imidazopyridines, which led to JNJ-6379490, a compound with high affinity for the human H(3) receptor. Analysis of structural features common to several series of non-imidazole H(3) receptor ligands resulted in a pharmacophore model. This model led to the design of JNJ-5207852, a diamine-based H(3) antagonist with good in vitro and in vivo efficacy but with an undesirable long half-life. However, further modifications of the template provided an understanding of the effect of structural modifications on pharmacokinetic properties, ultimately affording several additional series of compounds including JNJ-10181457, a compound with an improved pharmacokinetic profile. These compounds allowed in vivo pharmacological evaluation to show that H(3) antagonists promote wakefulness, but unlike modafinil and classical psychostimultants, they do not increase locomotor activity or produce any alteration of the EEG power spectral activity in rats. H(3) antagonists also increase extracellular acetylcholine and norepinephrine but not dopamine in rat frontal cortex and show efficacy in various models of learning-memory deficit. In addition, cFos immunoreactivity studies show H(3) antagonists activate neuronal cells in restricted rat brain regions in contrast to widespread activation after modafinil or amphetamine treatment. Therefore, H(3) antagonists are promising clinical candidates for the treatment of excessive day time sleepiness and/or cognitive disorders.

Topics: Animals; Cloning, Molecular; Cognition Disorders; Diamines; DNA, Complementary; Histamine Antagonists; Humans; Male; Morpholines; Narcolepsy; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3

Topics: Analgesia, Epidural; Anesthesia, Intravenous; Antiemetics; Benzhydryl Compounds; Chemical and Drug Induced Liver Injury; Clomipramine; Contraindications; Humans; Hypnotics and Sedatives; Intracellular Signaling Peptides and Proteins; Intraoperative Complications; Kidney Pelvis; Modafinil; Narcolepsy; Neuropeptides; Ondansetron; Orexins; Pain, Postoperative; Piperidines; Preanesthetic Medication; Propofol; Remifentanil; Ureteral Obstruction

Chronic excessive sleepiness impairs the daily life of patients suffering from narcolepsy. Antidepressants that enhance synaptic levels of noradrenaline and serotonin have been reported as having some therapeutic efficacy. For that reason, acetylcholinesterase inhibitors, which elevate acetylcholine levels, may have a protective function with respect to narcolepsy and cataplexy. The patient reported in this article received donepezil, 10 mg, for 3 consecutive months and showed an improvement of the Epworth Sleepiness Scale score from 20 up to 14.

Topics: Adult; Cataplexy; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Intracellular Signaling Peptides and Proteins; Narcolepsy; Neuropeptides; Orexins; Piperidines; Sleep, REM

Topics: Aged; Anesthesia, General; Anesthetics, Intravenous; Atracurium; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Humans; Intubation, Intratracheal; Male; Monitoring, Intraoperative; Myocardial Infarction; Narcolepsy; Neuromuscular Blocking Agents; Piperidines; Propofol; Remifentanil

To investigate the function of the muscarinic cholinergic receptor (mAchR) in narcolepsy and the effects of pharmacotherapy on mAchRs.. Muscarinic neural transmission serves as the main executive system in REM sleep. Studies in canine narcolepsy reported an increase in mAchRs in the pons.. The mAchRs of 11 drug naive/free patients with narcolepsy and 21 normal controls were investigated using PET with [11C]N-methyl-4-piperidylbenzilate ([11C]NMPB). Measurements were done in the pons, thalamus, striatum, and cerebral cortex. Seven of the 11 patients also underwent additional PET scans after the alleviation of symptoms by pharmacotherapy.. There were no differences in [11C]NMPB binding between the control and drug naive/free patients in all areas analyzed. At the time of on-medication PET scan, [11C]NMPB binding in the thalamus was decreased, but only to a small degree compared with that by anticholinergic drugs.. The present results do not support the notion that the mAchR is the main site of action of pharmacotherapy in the marked clinical improvement of human cataplexy.

Topics: Adult; Animals; Benzilates; Brain; Carbon Radioisotopes; Central Nervous System Agents; Dogs; Humans; Male; Narcolepsy; Organ Specificity; Parasympatholytics; Piperidines; Receptors, Muscarinic; Reference Values; Regression Analysis; Tomography, Emission-Computed

Topics: Amphetamine; Animals; Antidepressive Agents; Appetite Depressants; Bemegride; Caffeine; Cats; Central Nervous System Stimulants; Chlorphentermine; Desipramine; Electroencephalography; Ephedrine; Glycolates; Humans; Hydroxybutyrates; Imipramine; Mice; Narcolepsy; Pemoline; Phentermine; Piperidines; Rabbits; Rats; Sleep Wake Disorders; Strychnine; Sympathomimetics