Current pharmaceutical design
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Hypocretin neuropeptides have been shown to regulate transitions between wakefulness and sleep through stabilization of sleep promoting GABAergic and wake promoting cholinergic/monoaminergic neural pathways. Hypocretin also influences other physiologic processes such as metabolism, appetite, learning and memory, reward and addiction, and ventilatory drive. ⋯ However, antagonizing a system that regulates the sleep-wake cycle while also influencing non-sleep physiologic processes may create an entirely different but equally concerning side-effect profile such as transient loss of muscle tone (i.e. cataplexy) and a dampened respiratory drive. In this review, we will discuss the discovery of hypocretin and its receptors, hypocretin and the sleep-wake cycle, hypocretin antagonists in the treatment of insomnia, and other implicated functions of the hypocretin system.
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Sudden cardiac arrest is a leading cause of death worldwide with survival rates still remaining suboptimal. Unfortunately, most cardiac arrest patients, who achieve return of spontaneous circulation (ROSC), develop a multi-faceted post-cardiac arrest syndrome, including post-cardiac arrest brain injury, myocardial dysfunction, and systemic ischemia/reperfusion response. ⋯ In this regard, EPO represents a promising agent in the cardiac arrest setting, based on a therapeutic strategy that focuses on the post-resuscitation phase. This review aims to provide a comprehensive account of EPO's role in the treatment of each individual component of post-cardiac arrest syndrome.
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Insomnia is a highly prevalent condition, and due to ongoing demand from patients suffering with this condition, new pharmacological treatments are actively being sought. As our neurophysiological understanding of insomnia grows, so too do the available treatment options. A significant advance in the treatment of insomnia came with the development of the nonbenzodiazepine hypnotic medications, zolpidem, zaleplon and eszopiclone. ⋯ Serotonin antagonists and inverse agonists have been investigated; however, a recent trial with APD125 was discontinued due to lack of efficacy. Sodium oxybate has been used off-label for insomnia by some providers, although data supporting its use are limited. While the sleep-promoting effects of GABA(A) (nonbenzodiazepines and benzodiazepines) enhancement is well-established, newer research examining other mechanisms of action suggest that agents which modulate the histaminergic, serotonergic, melontonergic, and hypocretin/orexin and perhaps GABA-B systems show promise.
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The blood-brain barrier (BBB) protects the brain against endogenous and exogenous compounds and plays an important part in the maintenance of the microenvironment of the brain. In particular, the importance of brain-to-blood transport of brain-derived metabolites across the BBB has gained increasing attention as a potential mechanism in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease, which is characterized by the aberrant polymerization and accumulation of specific misfolded proteins, particularly β-amyloid (Aβ). There is growing evidence that the ABC transport protein P-glycoprotein (P-gp), a major component of the BBB, mediates the efflux of Aβ from the brain. In this review, we discuss the possible role of P-gp in Alzheimer's disease and other neurodegenerative disorders, and consider how a fuller understanding of this function might promote the development of more effective treatment strategies.
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There is a dramatic increase in the number of elderly persons on a worldwide scale with an increase in chronic comorbidities, especially type 2 diabetes (T2DM) and dementia. Although cognitive faculties commonly deteriorate in non-diabetic persons as they age, several studies have concluded that diabetes is uniquely associated with cognitive decline and is associated with a two-fold risk of Alzheimer's Disease (AD). Studies have also suggested that good glycemic has shown to improve cognitive status, however whether the use of specific anti-diabetic oral agents may play an additional role in controlling against cognitive deterioration is unknown. ⋯ The literature has suggested that the use of insulin sensitizers and statins is correlated with a lower rate of cognitive decline in older persons. In this paper, we will explore recent findings regarding diverse single nucleotide polymorphisms from GWAS on T2DM, AD and both. We will also shed light on future pathways, as the basis of improving drug and diagnostics development for a better integration of genetic studies for precise drug-development focusing on the role of genetic variation in maintaining metabolic control and cognitive performance.