The potential use of daridorexant in eating disorders: beyond the treatment of insomnia?

International Clinical Psychopharmacology, Journal Year: 2024, Volume and Issue: unknown

Published: May 9, 2024

A strong interplay exists between sleep and dietary habits, disturbances have been repeatedly documented in individuals with eating disorders (EDs). The orexin system - implicated regulation, energy homeostasis, food reward may represent a mechanist link alterations disordered behaviors. Daridorexant is dual receptor antagonist (DORA) recently approved for the treatment of insomnia, demonstrated efficacy tolerability. Owing to its action on neurons, compound represents an intriguing option addressing both sleep-related core symptoms EDs. By inhibiting motor hyperactivity, daridorexant reduce excessive physical exercise anorexia nervosa (AN) restricting type. Additionally, exert anti-binge effects, suggesting broad applicability binge ED, bulimia nervosa, binge/purging AN. In this framework, emerges as promising therapeutic option, offering multifaceted approach improving circadian rhythms, balance, overall quality life diverse ED subtypes.

Language: Английский

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Orexin Receptor Antagonists for the Prevention and Treatment of Alzheimer’s Disease and Associated Sleep Disorders

Drugs, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 4, 2024

Orexins/hypocretins are neuropeptides produced by the hypothalamic neurons, binding two G-protein coupled receptors (orexin 1 and orexin 2 receptors) playing a critical role in regulating arousal, wakefulness, various physiological functions. Given high prevalence of sleep disturbances Alzheimer's disease (AD) their reported involvement AD pathophysiology, system is hypothesized to contribute pathogenesis. Specifically, recent evidence suggests that orexin's influence may extend beyond regulation, potentially affecting amyloid-β tau pathologies. Dual receptor antagonists (DORAs), namely suvorexant, lemborexant, daridorexant, demonstrated efficacy treating chronic insomnia disorder across diverse clinical populations. Considering stabilizing effects on parameters emerging possible neuroprotective role, these agents represent promising strategy for management. This leading article reviews potential use AD, particularly focusing effect modulating disease-associated outcomes. Overall, studies support DORAs enhance quality patients with comorbid circadian sleep-wake rhythm disorders. Preliminary results also suggest compounds might pathology, progression. Conversely, research selective currently limited. Further investigation needed explore antagonism not only as symptomatic treatment disturbances, but its broader implications modifying neurodegeneration, emphasizing mechanisms action long-term

Language: Английский

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Novel Compounds as Orexin Receptor Agonists for Treating Sleep Disorders, Namely, Narcolepsy and Hypersomnia

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(8), P. 1178 - 1179

Published: July 3, 2024

Provided herein are novel compounds as orexin receptor agonists, pharmaceutical compositions, use of such in treating sleep disorders, namely, narcolepsy and hypersomnia, processes for preparing compounds.

Language: Английский

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Effects of Approved Pharmacological Interventions for Insomnia on Mood Disorders: A Systematic Review.

PubMed, Journal Year: 2024, Volume and Issue: 21(5), P. 385 - 402

Published: Oct. 1, 2024

Insomnia can be a contributing factor, comorbid disorder, or transdiagnostic element to several mental disorders, including mood disorders (MDs). A recent meta-analysis has already shown the effectiveness of cognitive behavioral treatment (CBT) for insomnia that is with MDs. This work aimed systematically review data on pharmacological in context MDS. In agreement current guidelines, interventions include gamma-aminobutyric acid (GABA)A receptor agonists such as short-medium acting benzodiazepines and benzodiazepine - Z-drugs, melatonergic receptors agonists, specifically melatonin 2 mg Prolonged Release (PR) ramelteon, dual orexin antagonists (DORA) daridorexant, lemborexant, suvorexant. systematic search was carried out PUBMED database, according PRISMA Guidelines. Thirty-three papers, 15 gabaergic 14 4 DORA, were selected. Available suggests symptoms specific options improve both conditions. Specifically, eszopiclone PR have demonstrated promising outcomes. Moreover, daridorexant suvorexant, belonging DORA class, efficacy treating symptoms. To summarize, literature would suggest targeting could potentially regulate sleep system and, such,

Language: Английский

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The Orexinergic System: Neurobiology and Clinical Implications

Annals of Indian Psychiatry, Journal Year: 2024, Volume and Issue: 8(2), P. 89 - 92

Published: April 1, 2024

Orexins, also known as hypocretins, are neuropeptides that play a crucial role in regulating various physiological processes, including sleep–wake cycles, energy homeostasis, and arousal. Orexins selectively produced by group of neurons located the dorsolateral part hypothalamus.[1] In 1998, two independent research groups exploring novel signaling molecules discovered orexin their receptors. The peptides were named orexin-A B Sakurai et al.,[1] with belief they played promoting feeding (the term "orexin" derived from Greek word "orexis," meaning appetite). At same time, Sutcliffe de Lecea[2] designated hypocretin-1 2 due to production hypothalamus certain similarities incretin family peptides. As years passed, further showed have main effect arousal sleep system, while having minor effects on appetite. disease, which there is loss orexin-producing called narcolepsy. This one most common causes daytime sleepiness. discovery prompted interest development antagonists approach promote treat insomnia.[3] We know now these diverse functions, regulation cycle,[4] control homeostasis,[5] modulation neuroendocrine activities,[6] impact glucose metabolism,[7] (Tsuneki al., 2010), involvement stress-adaptive responses,[8] influence reward-seeking behavior drug addiction.[9] exert binding specific G-protein-coupled receptors (GPCRs), namely receptor type 1 (OX1R, Hcrtr-1) (OX2R, or Hcrtr-2). These activate distinct downstream pathways hence contribute array functions.[10] OREXINS AND OREXIN RECEPTORS situated region hypothalamus. forms – A B, comprising 33 28 amino acids, respectively, sharing 64% similarity acid sequences. bind GPCRs OX1 OX2 equal affinity for both B. contrast, tenfold higher compared orexin-B.[11] OREXINERGIC SYSTEM ITS NEURAL CONNECTIONS Studies shown expressing confined minute area within central nervous system. Specifically, predominantly perifornical lateral hypothalamus, particularly at tuberal level where median eminence observable. involved range behavioral homeostatic regulatory systems. presence orexin-expressing this location has generated hypotheses regarding significance.[12,13] INPUTS TO NEURONS Hypothalamus: Orexin receive projections ventrolateral preoptic nucleus (VLPO), control, suprachiasmatic nucleus, houses master circadian clock[14] Basal Forebrain: Connections basal forebrain neuron activity[15] Amygdala: amygdala, emotion memory, projects neurons[16] Brainstem: inputs brainstem, essential autonomic motor functions.[17] OUTPUTS FROM VLPO: project back VLPO, influencing control[18] Tuberomammillary (TMN): TMN contributing regulation[19] Locus coeruleus (LC): send LC pons, impacting control[20] Arcuate (ARC): ARC control[21] Ventral tegmental (VTA): midbrain VTA, relevant motivation reward.[22] Distribution pons medulla fibers distributed through raphe nuclei reticular formation medulla. areas control.[23] Autonomic structures network. Its targets include rostral hypothalamic paraventricular nucleus. sympathetic parasympathetic control.[24] Receptor expression Different express (OX1R OX2R) varying extents. For example, TMN, mostly OX2R, OX1R, respectively.[25] To summarize, function regulators, integrating signals brain regions modulate functions such sleep, feeding, motivation, control. complicated network shows widespread processes. SLEEP system wakefulness, absence leads narcolepsy-like symptoms rodents. Human narcoleptics lack neurons. Central administration induces wakefulness alleviates narcoleptic mice cerebral cortex implicated arousal, dorsal They stimulate cholinergic serotonergic raphe, cortical activation wakefulness.[26] Certain regions, LC, laterodorsal pedunculopontine exclusively OX1R mRNA. vital REM maintenance, dense innervation, leading neuronal excitation. Conversely, expresses only OX2R mRNA important maintaining excitatory, form synapses histaminergic induced relies an intact system.[27] been used aids, several reasons support use context. high genetic conservation among mammals, means more translatable target. drugs mechanism action, fewer serious side no gait, balance, coordination. addition, being significant than supports rationale using antagonists.[28] Numerous studies demonstrated instrumental sustaining wakefulness. Intraventricular injections orexins lengthen awake time. integrate inputs, metabolic signals, convey them neuromodulators, thereby overall transition.[29] context insomnia, single (SORAs) dual (DORAs) under investigation. DORAs, block utility nonrapid eye movement rapid (REM) sleep. increase duration decrease latency studies, appear beneficial insomnia cases comorbidities schizophrenia Parkinson's disease.[30] DEMENTIA Emerging begun unveil potential connection between dysfunction dementia, Alzheimer's disease (AD). AD, degenerate early process. degeneration disrupts delicate balance disturbances rhythms quality. Poor quality, turn, associated increased risk cognitive decline dementia progression. Moreover, modulating neurotransmitter systems memory cognition, acetylcholine, dopamine, glutamate. Dysfunction could impair synaptic plasticity, deficits learning processes characteristic dementia. Interestingly, some suggest levels may be altered individuals even before clinical manifest, indicating biomarkers neurodegeneration.[31] Understanding intricate interplay pathology holds promise developing therapeutic strategies. Targeting offer avenues improving enhancing function, ultimately mitigating progression Further into precise mechanisms underlying orexin's effective interventions combat devastating condition.[32] ALCOHOL DEPENDENCE Increasing evidence suggests alcohol dependence addiction. Alcohol consumption can disrupt pathways, dysregulation reward processing. Chronic exposure potentially withdrawal tolerance.[33] reinforcing alcohol. indicate VTA accumbens. enhances rewarding properties promotes alcohol-seeking behavior. Furthermore, stress responses, closely linked dependence. Stress-induced drive craving relapse history disorder.[34] EATING DISORDERS suggested link compulsive eating binge disorder (BED). proposal based showing adapts significantly abuse, hypothesis chronic palatable foods similarly activity, causing disrupted patterns. worsens BED, creating cycle uncontrollable food consumption. There translational implication pharmacotherapies targeting signaling, currently undergoing trials substance disorders, might useful managing disorders.[35] DRUGS - CLINICAL ASPECTS Over past decade, system's anatomical connections sleep/wake circuits had implications patients physicians, treating insomnia. promising target its regulation, addiction mechanisms, stress/emotion Drug exacerbate feedback loop involving production.[2] Recent DORAs SORAs spurred numerous innovative treatments, aiming long-term efficacy other hypnotic drugs. positive total time without affecting non-REM However, foolproof data SORAs' safety still limited, systematic comparisons scarce.[36] Despite many remain preclinical study stage long periods often exceeding 4–5 years. One example molecule SB-334867 (a SORA OX1R), exhibited results epilepsy treatment.[37] primarily rather successfully progressing viable candidate. idea pharmacological blockade seizures anxiety disorders flouted, but successful candidate not yet realized. Similarly, evaluated treatment cluster headaches migraine. Dysfunctional orexinergic observed etiology conditions, lower episodic migraineurs headache patients. this, contributed generating conjectures offering established options.[38] CONCLUSIONS especially shift workers those tone. elderly patients, avoiding seen traditional medications. effectiveness limited pain. Beyond addressing abuse reducing cravings aiding withdrawal. agonists benefit narcolepsy While challenges exist small-molecule agonists, allosteric modulators enhance signaling. Ongoing animals humans provides insights neurobiology. coming years, information expected effectiveness, safety, benefits compounds different antagonists, present avenue management targeted patient populations, comorbid conditions.

Language: Английский

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Orexants, Orexin Receptor Antagonists: Novel Therapeutic Agents for Insomnia Disorder

International Neuropsychiatric Disease Journal, Journal Year: 2024, Volume and Issue: 21(6), P. 92 - 108

Published: Dec. 2, 2024

Insomnia is when a person feels difficulty falling asleep or staying asleep, often associated with complications, such as fatigue, sleepiness, etc. may cause disruptions in daytime physical and mental abilities. Orexins hypocretins are the neuropeptides secreted from lateral hypothalamus play major role sleep-wake cycle through complex interplay between wake-promoting sleep-promoting neuronal systems. Orexin receptor antagonists (Orexants) new treatment options for insomnia disorder, narcolepsy, other sleep disturbances. There two classes of Orexants, namely those that bind selectively to specific orexin selective (SORA), others both receptors dual (DORA). The first DORA was almorexant but restricted use three approved DORAs, suvorexant, lemborexant, daridorexant were by FDA, several DORAs SORAs under various stages discovery clinical investigation. Among labeled limitations, currently Orexants contraindicated people narcolepsy controlled substances owing their misuse liability. present review discussed cycle, phases orexins, summarized pharmacology type potential advantages limitations pharmacotherapy disorder.

Language: Английский

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Long-term physiological impact of PTSD on Yazidi women in Northern Iraq refugee camps

Journal of Taibah University Medical Sciences, Journal Year: 2024, Volume and Issue: 19(6), P. 1117 - 1118

Published: Dec. 1, 2024

Language: Английский

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