Sleep Disorders and Medicine

Biography

Biography: Nava Zisapel

Abstract

Insomnia aff ects 30%-50% of the general population and even more so (63%) among patients with mild cognitive impairments (MCI). Alzheimer’s disease (AD) risk among insomnia patients is approximately 3 fold that of good sleepers. Furthermore, poor sleep quality is associated with faster cognitive decline and may be an early marker of cognitive decline in mid life. Improvement of sleep may be critically important for maintaining or enhancing cognitive function in patients with MCI or AD. Current hypnotic medications (benzodiazepines and benzodiazepines-like) are associated with cognitive and memory impairments, increased risk of falls, accidents and dependency. Melatonin receptors agonists are safe and eff ective drugs for primary insomnia and circadian rhythm sleep disorders and are potentially useful for cognition and sleep in. Piromelatine is a novel investigational MT1\\\\MT2 and 5HT1A\\\\D receptors agonist developed for primary and co-morbid insomnia. In Phase-I studies it demonstrated good oral bioavailability (Elimination half-life 2.8±1.4 hours), good safety & tolerability profi le across a wide dose range and provided the fi rst indication for benefi cial eff ects on sleep maintenance. In a Phase-II study in insomnia patients, piromelatine demonstrated signifi cant improvements in sleep maintenance based on objective assessments (polysomnography recorded wake aft er sleep onset, sleep effi ciency and total sleep time) and good safety profi le with no detrimental eff ects on next-day psychomotor performance and memory. Th e electroencephalographic (EEG) power spectral density (PSD) profi le of piromelatine indicated signifi cant reduction in beta power (p<0.05), a marker of cortical arousal and enhanced delta power (P<0.05), a marker of restorative sleep. In preclinical studies in rats, piromelatine enhanced memory performance, attenuated cellular loss and neuronal and cognitive impairment in intrahippocampal Aβ(1-42) injection-induced neurodegeneration and reversed memory, hippocampal BDNF, CREB and pCREB defi cits and hippocampal neurogenesis in chronic mild stress rats. Such unique eff ects suggest that piromelatine is a promising drug candidate in insomnia patients and particularly those with comorbid MCI or AD.