Almorexant (ACT-078573) is an orally active dual orexin receptor antagonist that is being developed by Actelion Ltd, in collaboration with GlaxoSmithKline plc, for the treatment of primary insomnia. Almorexant is a first-in-class compound that targets the orexin system, which plays a key role in wake promotion and stabilization, in addition to having other regulatory functions. Decreasing orexin activity was hypothesized to have a sleep-promoting effect. Preclinical studies and phase I clinical trials have demonstrated that almorexant decreases alertness and increases sleep in healthy rats, dogs and humans when administered during the active phase of the circadian cycle, at peak endogenous orexin tone. No significant toxicological or safety concerns have been identified in studies in animals and humans, including no evidence of cataplexy, a sudden postural muscle tone weakening that is triggered by emotional stimuli and is considered unique to narcolepsy. The reported efficacy and safety data for almorexant support the continued development of the compound. At the time of publication, phase III clinical trials were underway, but no results had been reported; Actelion and GlaxoSmithKline were also investigating almorexant for other orexin-related neurological disorders. The use of an orexin receptor antagonist for the treatment of sleep disorders appears to be an approach that may provide unique benefits.
"While the aforementioned studies provide some evidence that modafinil might be of potential use as an adjunctive therapy in some schizophrenia patients, the murky neurochemical mechanism of action of modafinil makes it difficult to ascertain whether any potential effects might be related to its actions on the orexin system. However, recently orexin receptor ligands such as almorexant has advanced to clinical trials , and thus the assessment of effects of such compounds in schizophrenia patients in future studies is warranted. "
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia affects approximately 1% of the world population, and the majority of pharmacologically based treatments for this disorder are ligands that interact with monoaminergic transmission. However, there is a wealth of evidence that various neuropeptides are often co-released with monoamine neurotransmitters, and that ligands acting at neuropeptide receptors modulate monoaminergic transmission as well as schizophrenia-related behaviors in preclinical animal models. Such neuropeptide systems include neurotensin, cholecystokinin, corticotropin releasing factor, neuropeptide Y, oxytocin, opioid peptides, tachykinins, thyrotropin-releasing hormone, and orexins. The purpose of this review will be to summarize the existing preclinical and clinical literature on the role of various neuropeptide systems as modulators of schizophrenia-related behaviors, and the potential of targeting these systems for the development of novel antipsychotic medications.
[Show abstract][Hide abstract] ABSTRACT: Insomnia is not only the most common sleep disorder in the population, it is a frequent complaint heard overall by primary care physicians and specialists alike. Given the high prevalence of this disorder, its tendency to persist, and the frequency with which patients complain of symptoms in practice, it is imperative to have an understanding of basic sleep-wake mechanisms and the evolving field of pharmacologic approaches to enhance sleep. Currently, pharmacologic approaches are among the most widely used therapies for insomnia. This article reviews sleep-wake mechanisms, the neuroanatomic targets for sleep and wake-promoting agents, and discusses currently used agents to promote sleep and investigational hypnotics.
The Medical clinics of North America 05/2010; 94(3):563-80. DOI:10.1016/j.mcna.2010.02.012 · 2.61 Impact Factor
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