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1دورية أكاديمية
المؤلفون: Alexander Treiber, Swen Seeland, Belal Haschimi, Aude Weigel, Jodi T. Williams, Jerome Gabillet
مصطلحات موضوعية: Biochemistry, Medicine, Genetics, Pharmacology, Ecology, Marine Biology, Cancer, Infectious Diseases, Virology, Computational Biology, Chemical Sciences not elsewhere classified, nivasorexant orexin metabolism metabolising enzymes excretion rat human
الوصف: Nivasorexant was the first orexin-1 selective receptor antagonist entering clinical development. Despite encouraging preclinical evidence in animal models, a proof-of-concept trial in binge-eating patients recently failed to demonstrate its clinical utility in this population. Across species, nivasorexant clearance was driven by metabolism along seven distinct pathways, five of which were hydroxylation reactions in various locations of the molecule. The exact sites of metabolism were identified by means of mass spectrometry, the use of deuterated analogues, and finally confirmed by chemical references. CYP3A4 was the main cytochrome P450 enzyme involved in nivasorexant metabolism in vitro and accounting for about 90% of turnover in liver microsomes. Minor roles were taken by CYP2C9 and CYP2C19 but individually did not exceed 3–7%. In the rat, nivasorexant was mostly excreted via the bile after extensive metabolism, while urinary excretion was negligible. Only traces of the parent drug were detected in urine, bile, or faeces. Nivasorexant was the first orexin-1 selective receptor antagonist entering clinical development. Despite encouraging preclinical evidence in animal models, a proof-of-concept trial in binge-eating patients recently failed to demonstrate its clinical utility in this population. Across species, nivasorexant clearance was driven by metabolism along seven distinct pathways, five of which were hydroxylation reactions in various locations of the molecule. The exact sites of metabolism were identified by means of mass spectrometry, the use of deuterated analogues, and finally confirmed by chemical references. CYP3A4 was the main cytochrome P450 enzyme involved in nivasorexant metabolism in vitro and accounting for about 90% of turnover in liver microsomes. Minor roles were taken by CYP2C9 and CYP2C19 but individually did not exceed 3–7%. In the rat, nivasorexant was mostly excreted via the bile after extensive metabolism, while urinary excretion was negligible. Only traces of the parent drug were ...
الإتاحة: https://doi.org/10.6084/m9.figshare.25324354.v1Test
https://figshare.com/articles/journal_contribution/The_metabolism_of_the_orexin-1_selective_receptor_antagonist_nivasorexant/25324354Test -
2مؤتمر
المؤلفون: Eugene Zubkov, Olga Abramova, Yana Zorkina, Aleksandra Ochneva, Valeria Ushakova, Anna Morozova, Olga Gurina, Alexander Majouga, Vladimir Chekhonin
مصطلحات موضوعية: Pharmacology, Basic Pharmacology, Clinical Pharmacology and Therapeutics, Clinical Pharmacy and Pharmacy Practice, Pharmaceutical Sciences, Pharmacogenomics, Toxicology (incl. Clinical Toxicology), Pharmacology and Pharmaceutical Sciences not elsewhere classified, stress, rats, antidepressants, melatonin, oxytocin, neuropeptide Y, orexin
الوصف: Objectives: In the current study, we compared the effects of a single intranasal administration of clomipramine with effects of four neuropeptides, melatonin, oxytocin, orexin, and neuropeptide Y, to compare them in an acute stress model. Methods: The anti-stress effect was evaluated in the sucrose preference and forced swimming tests. Serum corticosterone level in rats was measured to evaluate the stress response. Results: Neuropeptide Y reduced immobilization time in the Porsolt test and decreased corticosterone levels, but increased the anhedonia. Orexin had no positive effect on animal behavior, but decreased corticosterone levels. Oxytocin decreased immobilization time, maintained anhedonia at the level of control, but did not affect corticosterone levels. Melatonin demonstrated no positive effects in any of the tests. Conclusion: The intranasal administered neuropeptide Y could be a promising compound for the treatment of stress disorders.
الإتاحة: https://doi.org/10.3389/fphar.2022.1033186.s001Test
https://figshare.com/articles/presentation/Presentation1_Intranasal_neuropeptide_Y_is_most_effective_in_some_aspects_of_acute_stress_compared_to_melatonin_oxytocin_and_orexin_pdf/21664577Test -
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المؤلفون: Hye Ji J. Kim, Samuel A. Dickie, Robert B. Laprairie
المصدر: Psychopharmacology. 240:15-25
مصطلحات موضوعية: Male, Pharmacology, Orexins, Estradiol, Orexin Receptors, Animals, Female, Estrous Cycle, Peptides, Progesterone
الوصف: Rationale The female menstrual or estrous cycle and its associated fluctuations in circulating estradiol (E2), progesterone, and other gonadal hormones alter orexin or hypocretin peptide production and receptor activity. Depending on the estrous cycle phase, the transcription of prepro-orexin mRNA, post-translational modification of orexin peptide, and abundance of orexin receptors change in a brain region-specific manner. The most dramatic changes occur in the hypothalamus, which is considered the starting point of the hypothalamic-pituitary–gonadal axis as well as the hub of orexin-producing neurons. Thus, hypothalamus-regulated behaviors, including arousal, feeding, reward processing, and the stress response depend on coordinated efforts between E2, progesterone, and the orexin system. Given the rise of orexin therapeutics for various neuropsychiatric conditions including insomnia and affective disorders, it is important to delineate the behavioral outcomes of this drug class in both sexes, as well as within different time points of the female reproductive cycle. Objectives Summarize how the menstrual or estrous cycle affects orexin system functionality in animal models in order to predict how orexin pharmacotherapies exert varying degrees of behavioral effects across the dynamic hormonal milieu.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bcc65aac9c825002990632265f8857e3Test
https://doi.org/10.1007/s00213-022-06296-1Test -
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المصدر: European Journal of Clinical Pharmacology. 78:1749-1761
مصطلحات موضوعية: Lipopolysaccharides, Pharmacology, Orexins, Pyrrolidines, Imidazoles, General Medicine, Receptors, GABA-A, Antidepressive Agents, Benzodiazepines, Double-Blind Method, Sleep Initiation and Maintenance Disorders, Humans, Hypnotics and Sedatives, Orexin Receptor Antagonists, Pharmacology (medical)
الوصف: The involvement of the orexin system in the physiopathology of insomnia has been rapidly increasing in understanding. In this sense, daridorexant was the third orexin receptor antagonist approved by the FDA in January 2022. This review aims to summarize the chemistry, pharmacodynamics, pharmacokinetics, efficacy, safety, and tolerability profile of daridorexant for the treatment of insomnia disorder.We performed a review of daridorexant for the treatment of insomnia disorder. The search was carried out in Medline via PubMed, Embase, and clinical trials, up to March 2022.Daridorexant 25 and 50 mg had more significant improvement for the wake after sleep onset (WASO), latency to persistent sleep (LPS), and subjective total sleep time (sTST) than placebo. In addition, daridorexant 50 mg was better for Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) than placebo. The most common adverse events were nasopharyngitis and headache.Daridorexant was efficacious and safe. Studies that evaluate the long-term safety and compare daridorexant with benzodiazepines, benzodiazepine receptor agonists, sedative antidepressants, and other orexin receptor antagonists are required.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ed7d9878012b615d27144d6e8fcc7749Test
https://doi.org/10.1007/s00228-022-03381-4Test -
5
المؤلفون: Soghra Borneh Deli, Samira Iman Bonab, Roghaieh Khakpay, Fatemeh Khakpai, Mohammadali Hosseinpour Feyzi
المصدر: Psychopharmacology. 239:3171-3184
مصطلحات موضوعية: Male, Pharmacology, Benzoxazoles, Orexins, Basolateral Nuclear Complex, Cannabinoids, Pain, Rats, Receptor, Cannabinoid, CB1, Orexin Receptors, Formaldehyde, Animals, Urea, Dimethyl Sulfoxide, RNA, Messenger, Naphthyridines, Rats, Wistar, Endocannabinoids, Pain Measurement
الوصف: The amygdala has emerged as the main brain center for the emotional affective dimension of pain and pain modulation. In the amygdala, orexin and cannabinoid receptors are expressed in relatively high concentrations. To investigate the possible interaction between the amygdala orexin and cannabinoid systems on the modulation of inflammatory pain, we conducted formalin, rotarod, and plethysmometer tests, as well as analyzing mRNA expression of orexin and cannabinoid receptors in male rats. The basolateral amygdala (BLA) was unilaterally implanted by a guide cannula. Our results showed that, compared to saline and DMSO/saline, intra-BLA microinjection of orexin-A (50 and 100 µM) decreased flinch response in the early phase, but not in the late phase of the formalin test. However, these injections had no significant effect on the mRNA expression level of BLA, orexin receptor type-1 (Orx
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2212e8c221f35261d5c148466982f00fTest
https://doi.org/10.1007/s00213-022-06199-1Test -
6دورية أكاديمية
مصطلحات موضوعية: medicine, pharmacology, orexin, dopamine, self-stimulation, self-deprivation, overeating, sulpiride, rats
الوصف: The orexin A receptors are preferably involved in emotional eating compared with orexin B (OX2R TCS-OX2-29) and D2 dopamine receptors. Because emotional eating is significantly related to clinical eating disorders, like bulimia and binge eating disorder, it seems promising to use drugs of the orexin system to treat and prevent the issue
العلاقة: Role of orexin peptide system in emotional overeating induced by brain reward stimulation in fed rats / A.A. Lebedev [et al.] // Research Results in Pharmacology. - 2020. - Vol.6, №1.-P. 81-91. - Doi:10.3897/rrpharmacology.6.52180.; http://dspace.bsu.edu.ru/handle/123456789/46562Test
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المؤلفون: Clemens, Muehlan, Sander, Brooks, Cedric, Vaillant, Michael, Meinel, Gabriël E, Jacobs, Rob G, Zuiker, Jasper, Dingemanse
المساهمون: Anesthesiology
المصدر: Clinical Pharmacology and Therapeutics, 111(6), 1334-1342. Wiley-Blackwell
مصطلحات موضوعية: Male, Pharmacology, Automobile Driving, Cross-Over Studies, Pyrrolidines, Double-Blind Method, Imidazoles, Humans, Female, Orexin Receptor Antagonists, Pharmacology (medical), Psychomotor Performance
الوصف: Use of hypnotics is often associated with next-morning residual effects and a higher risk of motor vehicle accidents. Measuring next-morning effects on driving performance is therefore advised by regulatory agencies. Here, we examined driving performance following administration of daridorexant, a new dual orexin receptor antagonist developed to treat insomnia. Sixty healthy male and female subjects (50–79 years of age) were randomized in a placebo- and active-controlled, four-way cross-over study. Each subject received evening administration of daridorexant 50 and 100 mg, zopiclone 7.5 mg, and placebo, in separate treatment phases of 4 days. Simulated driving performance was assessed after initial (day 2) and repeated dosing (day 5), 9 hours postdose. Standard deviation of the lateral position (SDLP) was the main outcome. On both days, with zopiclone, SDLP increased significantly compared with placebo, which confirmed sensitivity of the simulator. With daridorexant, on day 2, the placebo-corrected mean (97.5% confidence interval) SDLP increased by 2.19 cm (0.46–3.93) and 4.43 cm (2.72–6.15) for 50 and 100 mg, respectively. On day 5, SDLP values for both daridorexant doses were significantly below the prespecified threshold of impairment (2.6 cm) and statistically not different from placebo. Daridorexant showed a lower self-rated driving quality and higher effort compared to placebo on day 2 but not on day 5. In non-insomnia subjects, daridorexant impaired simulated driving after initial but not after repeated dosing. Subjects should be cautioned about driving until they know how daridorexant affects them.
وصف الملف: application/pdf
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::308009fca90d1f05472c607fee53708fTest
https://pure.eur.nl/en/publications/0ad54f4f-38df-4fb8-955e-229cd04c45f3Test -
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المؤلفون: Ishani Landry, Nancy Hall, Jagadeesh Aluri, Gleb Filippov, Beatrice Setnik, Satish Dayal, Larisa Reyderman, Margaret Moline
المصدر: Journal of Psychopharmacology. 36:745-755
مصطلحات موضوعية: Adult, Male, Pharmacology, Psychiatry and Mental health, Cross-Over Studies, Pyrimidines, Ethanol, Pyridines, Humans, Female, Orexin Receptor Antagonists, Pharmacology (medical)
الوصف: Background: Lemborexant is a dual orexin receptor antagonist approved to treat insomnia in adults in several countries including the USA, Canada, and Japan. Aims: This study was conducted to investigate effects of lemborexant and alcohol coadministration on postural stability, cognitive performance, and the pharmacokinetics, safety, and tolerability of lemborexant. Methods: This was a Phase 1, double-blind, placebo-controlled, four-period crossover study in 32 healthy adults. Individuals were randomized into one of four treatment sequences to receive single doses of placebo, lemborexant 10 mg (LEM10), alcohol (males, 0.7 g/kg; females, 0.6 g/kg), and LEM10 plus alcohol, each separated by a 14-day washout. Postural stability (body sway) was measured by ataxiameter and a cognitive performance assessment battery evaluated four domains of attention and memory. Results: Pharmacodynamic outcomes were analyzed for the 18 participants who completed all four treatments. Change from baseline in body sway showed no significant differences between lemborexant plus alcohol versus alcohol alone. Compared with alcohol alone, coadministration of lemborexant with alcohol showed additive negative effects on cognitive performance domains, corresponding approximately with peak plasma lemborexant concentrations (median = 1.5 h). Cognitive performance was also impaired with lemborexant alone at 0.5 and 2 h in this experimental paradigm with morning dosing. Alcohol increased plasma lemborexant exposure by 70% based on area under the curve to 72 h, and increased peak plasma lemborexant concentrations by 35%. The most commonly reported treatment–emergent adverse event was somnolence. Conclusion: Coadministration of lemborexant with alcohol showed additive negative effects on cognitive measures, but not on postural stability, compared with alcohol alone. Lemborexant exposure was increased with alcohol. Lemborexant alone or with alcohol was well tolerated. Patients are advised not to consume alcohol with lemborexant.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::af988ba1fff485a84bf557e019b83748Test
https://doi.org/10.1177/02698811221080459Test -
9
المؤلفون: Rüdiger Kornberger, Benjamin Berger, Jasper Dingemanse
المصدر: European Neuropsychopharmacology. 51:90-104
مصطلحات موضوعية: Pyrrolidines, Visual analogue scale, Citalopram, Pharmacology, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Pharmacokinetics, mental disorders, Humans, Medicine, Single-Blind Method, Pharmacology (medical), Biological Psychiatry, business.industry, Imidazoles, Antagonist, Healthy Volunteers, Orexin receptor, 030227 psychiatry, Psychiatry and Mental health, Neurology, Tolerability, Pharmacodynamics, Orexin Receptor Antagonists, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug, Blood sampling
الوصف: Daridorexant (ACT-541468) is a new dual orexin receptor antagonist being evaluated for the treatment of insomnia, which is a common comorbidity of depression and anxiety. Therefore, daridorexant is likely to be administered concomitantly with agents (e.g., citalopram) used to treat these disorders. In this single-centre, single-blind, randomized, placebo-controlled, sequential design Phase 1 study with the inclusion of two double-blind crossover parts, the pharmacokinetic (PK; blood sampling at regular intervals) and pharmacodynamic (PD; battery of objective and subjective PD tests performed at regular intervals) interactions between daridorexant (50 mg) and citalopram (20 mg, single dose and at steady state) as well as the safety/tolerability in healthy subjects were investigated. There were no relevant effects of citalopram (single dose/steady state) on daridorexant exposure and vice versa. PD variables measured after morning administration of daridorexant alone showed effects consistent with a sleep-promoting compound. Only co-administration of daridorexant with citalopram at steady state led to relevant changes in objective (unstable tracking) and subjective (visual analogue scale alertness and Karolinska Sleepiness Scale) PD endpoints compared to daridorexant alone. No serious or severe adverse events were reported, while no clinically relevant treatment-emergent effects on ECG parameters, clinical laboratory, or vital signs were observed. In conclusion, the co-administration of daridorexant and citalopram lead to only minor changes in PK parameters, while performance of PD assessments following co-administration were mainly driven by the expected central nervous system effects of daridorexant. Doses up to 50 mg daridorexant can be safely co-administered with citalopram.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fd9f9245670717330f545cd9619d54e6Test
https://doi.org/10.1016/j.euroneuro.2021.05.005Test -
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المؤلفون: Mirunalini Ravichandran, Subhiksha Subramanian
المصدر: Fundamental & Clinical Pharmacology. 36:72-80
مصطلحات موضوعية: Pharmacology, Nervous system, Orexins, Drug discovery, Neuropeptides, digestive, oral, and skin physiology, Optogenetics, Biology, Orexin receptor, Receptors, G-Protein-Coupled, medicine.anatomical_structure, nervous system, Orexin Receptors, Sleep Initiation and Maintenance Disorders, mental disorders, medicine, Drug approval, Humans, Pharmacology (medical), Receptor, Neuroscience, hormones, hormone substitutes, and hormone antagonists, G protein-coupled receptor
الوصف: Over the years, elucidating targets from the neural circuits that can be used to treat disorders pertaining to the nervous system and extending their scope to other systems has always proved interesting to researchers. The role of various peptides and neurotransmitters have been elucidated and are being developed as therapeutic targets. Out of these, orexins are neuropeptides produced in the hypothalamus that stimulate a specific type of G-Protein coupled receptors (GPCR) called orexin receptors and bring about various physiological and pathological roles. Orexin receptors are of interest not only because of their wide applications such as insomnia, obesity, inflammatory disorders, etc. but also because of their contribution to promising aspects of drug discovery such as optogenetics and their tremendous growth from the stage of being orphans to orexins. This review will discuss in detail the structure of orexin receptors, their physiological role and various applications in disease states adding a note on agonists and antagonists and finally summarizing the recent drug approvals in the field.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3940a00d6a047f0695b9a1c4ed9a95caTest
https://doi.org/10.1111/fcp.12723Test
