"Almorexant"

Investigation of the effect of the dual orexin receptor antagonist almorexant on ophthalmological, spermatogenic, and hormonal variables in healthy male subjects. The aim of this single-center, double-blind study was to investigate the effect of a 4-week once daily administration of 200 mg almorexant on tear film break-up time, spermatogenesis, hormone levels, and pancreatic elastase in stool in healthy male subjects. Almorexant 200 mg or matching placebo was administered in the evening for 4 weeks once daily to 56 healthy male subjects. Changes in ophthalmological variables, sperm composition, hormone levels, and pancreatic elastase levels in stool were evaluated periodically up to 8 weeks after discontinuation of drug administration. Blood samples for pharmacokinetic measurements were taken

Acute cognitive effects of the hypocretin receptor antagonist almorexant relative to zolpidem and placebo: a randomized clinical trial. Hypnotic medications can adversely affect behavior during unanticipated awakenings during the night. Animals treated with the hypocretin (Hcrt) receptor antagonist almorexant (ALM) have less acute cognitive impairment compared to the GABAA receptor modulator

In vitro, in vivo and ex vivo demonstration of the antitumoral role of hypocretin-1/orexin-A and almorexant in pancreatic ductal adenocarcinoma Pancreatic ductal adenocarcinoma (PDAC) is still the poorest prognostic tumor of the digestive system. We investigated the antitumoral role of orexin-A and almorexant in PDAC. We analyzed the orexin receptor type 1 (OX1R) expression by immunohistochemistry in human normal pancreas, PDAC and its precursor dysplastic intraepithelial lesions. We used PDAC-derived cell lines and fresh tissue slices to study the apoptotic role of hypocretin-1/orexin-A and almorexant and . We analyzed the hypocretin-1/orexin-A and almorexant effect on tumor growth in mice xenografted with PDAC cell lines expressing, or not, OX1R. Ninety-six percent of PDAC expressed

Efficacy and safety of almorexant in adult chronic insomnia: a randomized placebo-controlled trial with an active reference. The orally active dual OXR and OXR antagonist, almorexant, targets the orexin system for the treatment of primary insomnia. This clinical trial assessed the effect of almorexant on sleep maintenance and other sleep endpoints, and its safety and tolerability in adults . Prospective, randomized, double-blind, placebo-controlled, active referenced trial in male and female adults aged 18-64 years with chronic, primary insomnia. Patients were randomized 1:1:1:1 to receive placebo, almorexant 100 mg, almorexant 200 mg, or zolpidem 10 mg (active reference) for 16 days. Primary efficacy assessments were objective (polysomnography-measured) and subjective (patient-recorded) wake

Dual Orexin Receptor Antagonist, Almorexant, in Elderly Patients With Primary Insomnia: A Randomized, Controlled Study. Sleep laboratory study to determine the dose-related efficacy and safety of almorexant in elderly patients with primary chronic insomnia. Patients aged ≥65 years with primary insomnia were enrolled into a prospective, randomized, double-blind, placebo-controlled, multicenter dose-finding study with a five-period, five-way Latin square cross-over design. Patients were randomized to one of 10 unique sequences of two-night treatment with oral almorexant 25, 50, 100, or 200 mg capsules, or matching placebo. The primary efficacy endpoint was polysomnography (PSG)-determined mean wake time after sleep onset (WASO). Secondary and exploratory efficacy endpoints were also

Dual orexin receptor antagonist, almorexant, in elderly patients with primary insomnia: a randomized, controlled study.

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems. The dual hypocretin receptor (HcrtR) antagonist almorexant (ALM) may promote sleep through selective disfacilitation of wake-promoting systems, whereas benzodiazepine receptor agonists (BzRAs) such as zolpidem (ZOL) induce sleep through general inhibition of neural activity. Previous studies

Pharmacokinetic Interactions Between the Orexin Receptor Antagonist Almorexant and the CYP3A4 Inhibitors Ketoconazole and Diltiazem. Almorexant, a tetrahydroisoquinoline orexin receptor antagonist and first representative of a new class of compounds for the treatment of insomnia, is a substrate of the cytochrome P450 3A4 isoenzyme (CYP3A4). Two randomized two-way crossover studies were performed in healthy subjects investigating the pharmacokinetic interaction between almorexant and the CYP3A4 inhibitors ketoconazole and diltiazem. When administered as a single dose of 100 mg almorexant during steady state of ketoconazole (400 mg once daily for 14 days) or diltiazem treatment (300 mg once daily for 11 days), the exposure to almorexant was 10.5- and 3.5-fold, respectively, greater when compared

Assessment of the Abuse Liability of a Dual Orexin Receptor Antagonist: A Crossover Study of Almorexant and Zolpidem in Recreational Drug Users. Dual orexin receptor antagonists (DORAs) enable initiation and maintenance of sleep in patients with primary insomnia. Blockade of the orexin system has shown reduction of drug-seeking behavior in animal studies, supporting the role of orexin antagonism as a novel approach for treating substance abuse. Since hypnotics are traditionally associated with misuse, a lack of abuse liability of DORAs would offer significant benefits over current therapies for sleep disorders. In this randomized, crossover, proof-of-concept study, single oral doses of the DORA almorexant (200, 400, and 1,000 mg) were administered to healthy subjects with previous non-therapeutic

Entry-into-Humans Study with ACT-462206, a Novel Dual Orexin Receptor Antagonist, Comparing Its Pharmacodynamics with Almorexant. A double-blind, placebo- and active comparator-controlled, randomized, single-ascending-dose study was conducted to investigate the safety, pharmacokinetics, and pharmacodynamics of ACT-462206, a novel dual orexin receptor antagonist. Healthy male subjects received single oral doses of 5, 25, 100, 200, 400, 1,000, and 1,500 mg ACT-462206 (n = 6 per group) or placebo (n = 2 per group). In addition, subjects in the 400-mg group received a single oral dose of 400 mg almorexant (two-way crossover). ACT-462206 was generally well tolerated. Sleepiness, headache, and fatigue were the most frequently reported adverse events. The incidence of sleepiness appeared dose

Pharmacokinetic and pharmacodynamic interactions between almorexant, a dual orexin receptor antagonist, and desipramine. Almorexant is a dual orexin receptor antagonist (DORA) with sleep-enabling effects in humans. Insomnia is often associated with mental health problems, including depression. Hence, potential interactions with antidepressants deserve attention. Desipramine was selected as a model drug because it is mainly metabolized by CYP2D6, which is inhibited by almorexant in vitro. A single-center, randomized, placebo-controlled, two-way crossover study in 20 healthy male subjects was conducted to evaluate the pharmacokinetic and pharmacodynamic interactions between almorexant and desipramine. Almorexant 200mg or matching placebo (double-blind) was administered orally once daily

Formulation development for the orexin receptor antagonist almorexant: assessment in two clinical studies. Almorexant, a dual orexin receptor antagonist, was investigated for the treatment of insomnia. The following observations initiated further formulation development: the active pharmaceutical ingredient (API) was sticking to the apparatus used during tablet compression; almorexant has an absolute bioavailability of 11.2%; and almorexant modestly decreased the latency to persistent sleep by 10.4 minutes in patients. Two randomized crossover studies were performed to investigate the pharmacokinetics of several new formulations in healthy subjects. In study I, the old "sticky" tablet was compared to two new formulations developed to prevent sticking: a qualitatively similar tablet

Tolerability, pharmacokinetics, and pharmacodynamics of single-dose almorexant, an orexin receptor antagonist, in healthy elderly subjects. Sleep disorders are common in the elderly population. Orexin receptor antagonism has been proposed as a new sleep-enabling approach to treat insomnia. The tolerability, pharmacokinetics, and pharmacodynamics of ascending single doses of almorexant, a dual orexin receptor antagonist, were investigated in healthy elderly male and female subjects. In this double-blind, placebo- and active-controlled study, each dose (100, 200, and 400 mg) was investigated in a separate group of 12 subjects (almorexant, placebo, and zolpidem 10 mg in an 8:2:2 ratio). Morning doses of almorexant were well tolerated. As expected for sleep-enabling compounds, somnolence

Influence of mild and moderate liver impairment on the pharmacokinetics and metabolism of almorexant, a dual orexin receptor antagonist. This single-dose study aimed at investigating the effect of different degrees of hepatic impairment on the pharmacokinetics (PK), metabolism, and tolerability of almorexant, a first-in-class dual orexin receptor antagonist. Subjects with mild (Child-Pugh A, Group A, n=8) and moderate (Child-Pugh B, Group B, n=9) liver impairment and subjects with normal liver function (Group DA and DB, both n=9) received a dose of 100mg almorexant. PK parameters of almorexant and its four primary metabolites were determined. Almorexant exposure increased with severity of hepatic impairment. Geometric mean ratios (90% confidence interval) of AUC0-∞ were 2.8 (1.5-5.4), 7.2

Absence of pharmacokinetic and pharmacodynamic interactions between almorexant and warfarin in healthy subjects. Almorexant is the first representative of the new class of orexin receptor antagonists, which could become a new treatment option for insomnia. The present study investigated the potential interaction between almorexant and warfarin. In this open-label, two-way crossover, drug-drug interaction study, healthy male subjects received, in a randomized fashion, almorexant 200 mg once daily for 10 days and a single dose of 25 mg warfarin co-administered on day 5 (treatment A) and a single dose of 25 mg warfarin on day 1 (treatment B). Serial blood samples for warfarin pharmacokinetics and pharmacodynamics were drawn during both treatments. Of the 14 enrolled subjects, one withdrew due

Pharmacokinetic interactions of almorexant with midazolam and simvastatin, two CYP3A4 model substrates, in healthy male subjects. Pre-clinical experiments have shown that almorexant, a dual orexin receptor antagonist, is able to inhibit cytochrome P450 3A4 (CYP3A4). Therefore, a study was conducted to investigate the effects of multiple-dose almorexant on the pharmacokinetics of midazolam and simvastatin, two CYP3A4 model substrates. Fourteen healthy male subjects were enrolled in an open-label, randomized, two-way crossover study. Treatment period A consisted of a single oral dose of 2 mg midazolam on day 1 and 40 mg simvastatin on day 3. In treatment period B, subjects received 200 mg almorexant once daily for 9 days together with a single oral dose of midazolam on day 7 and simvastatin on day

Dual orexin receptor antagonism by almorexant does not potentiate impairing effects of alcohol in humans. The orexin system plays a pivotal role in the regulation of the sleep/wake state. Almorexant is a selective, orally available dual orexin receptor antagonist. This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between almorexant (200 mg p.o.) and alcohol (0.6 g/L i.v. ethanol clamp for 5 h) using various cognitive and psychomotor performance tests in healthy subjects (n=20; 10 males and 10 females) in a 4-way crossover study. No effect of almorexant on ethanol PK was observed. The effects of ethanol on the PK of almorexant were limited, its exposure (AUC) increased by 21%; the median difference in tmax was 1.2 h; t1/2 and Cmax of almorexant were

Orexin receptor antagonism: an ascending multiple-dose study with almorexant. The objectives of this study were to investigate the multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual orexin receptor antagonist almorexant. Healthy subjects received daily doses of almorexant (100, 200, 400 or 1000 mg) or placebo in the morning for four days followed by two days absorption was delayed and C(max) decreased. Almorexant at 400 and 1000 mg administered in the morning reduced vigilance, alertness, visuomotor coordination, and motor coordination assessed in a psychometric test battery. Polysomnography recordings following evening administration showed a trend towards shorter latency to sleep stages 3 and 4, and shorter latency to, and longer time in, rapid-eye-movement

Absolute oral bioavailability of almorexant, a dual orexin receptor antagonist, in healthy human subjects. The aim of this single-center, open-label study was to assess the absolute bioavailability of an oral (tablet) versus intravenous formulation of almorexant in healthy subjects. A pilot phase in 3 healthy male subjects, which preceded the main study, consisted of a single 30-min intravenous infusion of 10 mg almorexant. Its objectives were to ensure the tolerability of the intravenous formulation and to select the intravenous dose for the main study. The main study was a randomized, two-way crossover study in 20 healthy subjects (10 males and 10 females). Subjects received a single oral dose of 200 mg almorexant and a single 30-min intravenous infusion of 20 mg almorexant. All 23 subjects

. Phase II studies of dual orexin receptor antagonists (almorexant, lemborexant, and filorexant) have shown some improvement in sleep maintenance and sleep continuity. Piromelatine may improve sleep maintenance. Histamine receptor inverse agonists (APD-125, eplivanserin, and LY2624803) improve slow-wave sleep but, for various reasons, the drug companies withdrew their products.