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Based on the unequivocal role of Ado in eliciting sleep, an obvious target for the development of new hypnotics would appear to be the Ai receptor agonists. However, while adenosine is a highly effective paracrine neuromodulator, its widespread distribution has confounded efforts in NCE discovery given the sedative effects of agonists in the CNS and the hypotensive actions of the purine nucleoside. Despite 30 years of research, the only Ado agonist approved for human use is Ado itself for the treatment of supraventricular tachycardia (see 6.33 Antiarrythmics) where the short halflife (10 s) of the natural agonist limits its side effect potential. Nonetheless, A1 receptor agonists like GR79236 are effective in reducing sleep apnea in rats.

The non-BZ based GABA o1 agonist replacements for traditional BZs represented a major step in the treatment of management of insomnia. Despite the properties of the 'Z-drugs' (zolpidem, zopiclone, and zaleplon), concerns for a residual/next-day effect, tolerance, and rebound insomnia still exist. These agents are also scheduled drugs and carry the stigma of 'sleeping pills.' The ideal hypnotic would be nonscheduled, nonabusable, rapidly inducing, and capable of maintaining sleep for 6-8 h without awakenings, preserving sleep architecture with a high safety margin. Preservation of sleep architecture is a characteristic that may enable drugs to provide a more recuperative sleep compared to those therapies that reduce the time that a patient spends in delta and REM stages. For the elderly patient population, where polypharmacy is typical, hypnotics must also work effectively in those settings with few side effects. There is increasing evidence that a combination of pharmacologic treatment and behavioral modifications (cognitive behavioral therapy) may produce clinically sustainable positive benefits. Circadian Rhythm Sleep Disorder

Advances in the biology and genetics of circadian clock rhythm have led a greater understanding of circadian sleep disorders but few drug targets have been identified. Therapeutic interventions such as melatonin treatment have demonstrated some utility but are not approved. Light therapy to reset circadian rhythms is still relatively empirical in its implementation. Breathing-Related Sleep Disorder

Sleep apnea is a relatively common clinical disorder, second only to asthma in prevalence among the chronic respiratory diseases, and can develop in children as well as adults. While CPAP and related mechanical devices can be effective in the management of moderate to severe sleep apnea, patient compliance can be a limiting factor in their effectiveness. Thus, the area of breathing-related sleep disorders would appear to be a logical target for one or more effective pharmacologic treatment approaches that would obviate the issue of patient compliance regarding mechanical treatment devices.

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