Current Pharmaceutical Design - Volume 17, Issue 15, 2011

Sleep disorders are increasingly recognized as a serious medical problem in the general population as well as to an individual's well being [1]. Moreover, excessive daytime sleepiness (EDS) continues to be an important public health concern. EDS related to sleep disorders is present in about 10% of adults. Complaints such as non-restorative sleep, insomnia, and EDS are obtained from at least 50% of subjects in general population-based epidemiological surveys [2,3,4]. Medications available for treatment of various sleep disorders and their consequent impact on the quality of life represents an important aspect of public health expenses [5-7]. On the other hand, pharmacological advances for sleep disorders treatment represent exciting discoveries and may ultimately change the course of how we treat sleep-related disorders. Insomnia is the most common sleep disorder with a prevalence of 10-15% in the United States adult population [2,3]. Currently approved pharmacologic treatments for insomnia include benzodiazepine receptor agonists, non-benzodiazepine receptor agonists, and melatonin receptor agonist. In addition, unapproved medications are commonly prescribed including sedating antidepressants, antipsychotics, antihistamines, and herbal supplements. Many unapproved and approved hypnotics are associated with significant side-effect profile including cognitive and psychosocial impairment, anterograde amnesia, rebound insomnia, development of tolerance, addiction, and even death by overdose. It is not surprising that new pharmacological compounds are vigorously being investigated. In addition, Major Depressive Disorder is a common psychiatric disorder co-existing with insomnia [8-9], and the investigation of melatonin agonists such as agomelatine has demonstrated interactions between circadian rhythm disorders, sleep, mood, and important clinical benefits with this new type of drug. Evidence from research has demonstrated that the neuropeptide hypocretin (orexin) is critical in arousal and stabilization of wakefulness. This discovery has paved the way for new and exciting research on pharmacological modulation of the hypocretin system in an effort to find new treatment modalities for insomnia. In addition, there is evidence that hypocretin is involved in energy homeostasis and reward behavior beyond its pivotal role in sleep/wake regulation [10,11]. Obstructive Sleep Apnea (OSA) is the most common sleep-related breathing disorder, affecting 5-10% of the adult population. It is increasingly being recognized as an important public health problem leading to driving and industrial accidents [12,13]. The gold-standard treatment for OSA with nasal CPAP is associated with variable compliance rates and therefore less than optimal treatment success. Usage of pharmacological agents to treat OSA has been in question for a long time, however in the recent past, studies have accumulated and results are just coming in. Research on sleep is focused on finding new compounds to treat EDS: from histamine (H3) receptor antagonist and inverse agonist, to GABA-β agonists, to sodium oxybate. Discovery of new compounds that are successful in treating EDS will benefit disorders that cause excessive sleepiness including narcolepsy with cataplexy, obstructive sleep apnea, and shift-work. Treatment of sleep-related problems in children is a dilemma for the pediatrician and sleep specialist. As of recent, investigation on dopamine agonists has been performed in children with Restless Leg Syndrome (RLS), a syndrome that has a prevalence of approximately 2%. Moreover, the frequency of attention deficit/hyperactivity syndrome (ADHD), depression, and anxiety is higher in children with RLS compared to the general population. The discussion of various pharmacological treatment approaches will be much appreciated in the pediatric community, as will the discussion on various compounds used in ADHD treatment and their impact on sleep, as sleep problems are both part of the symptoms themselves, as well as complications of treatment [14,15]. Similar to a double-edged sword, pharmacologic therapy has its risks and benefits which can be seen in individuals with chronic opioid use. The use of opioid medications has increased by approximately 600% in the last 10 years with a corresponding rise in pain management, greater attention paid to the treatment of pain syndromes, and higher percentage of prescriptions for opioid medications by general practitioners. This has led to an increase in the prevalence and types of breathing disorders during sleep including central sleep apnea, which are often not well recognized or understood, and is a challenge to treat [16]. This issue of Current Pharmaceutical Design focuses on advances in pharmacological treatment of the major sleep-related disorders. Current research, advances in pharmacologic therapy, as well as prospective pharmacological compounds for the treatment of sleep-related disorders will be discussed.

Obstructive sleep apnea (OSA) is a growing public health hazard fueled by the obesity epidemic and an aging population. Untreated sleep apnea can result in significant consequences both in the short-term and long-term. We need to educate the public to recognize the symptoms of sleep apnea and to publicize that effective treatments are available. Positive airway pressure therapy remains the gold standard currently in treating OSA. Alternative treatments include an oral appliance or surgical options. This paper discusses the pharmacologic treatment of sleep apnea: goals include medications to address the ventilatory control of breathing, treat co-morbid diseases, treat associated health problems/complaints, address special issues, such as anesthetic precautions, and propose future targets.

After the discovery and characterization of the H3R and H4R receptors, they have become widely anticipated as potential therapeutic agents in the treatment of sleep disorders. In preliminary studies, histamine H3 receptor (H3R) antagonists and inverse agonists have demonstrated promise in the treatment of sleep disorders associated with excessive daytime sleepiness. This review article summarizes the current research in this area and characteristics of H3R and H3R antagonists and inverse agonists in development.

Studies examining GABAB receptor agonists have reported effects on sleep including decreased sleep onset latency (SOL), increased sleep consolidation and increases in slow wave sleep (SWS). γ-hydroxybutyrate (GHB) is proposed to act as a GABAB receptor agonist; however, the mechanism of action of GHB is controversial. In addition, the GABAB receptor agonist, baclofen, has also been proposed to exert similar effects on sleep. The aim of this paper is to provide a review of the human clinical studies of sodium oxybate and baclofen regarding sleep and the treatment of sleep disorders including narcolepsy and insomnia, as well as other disorders involving disrupted sleep such as fibromyalgia.

Restless legs syndrome (RLS), formally identified and described by Ekbom in the 1940s, is a common clinical disorder, characterized by an overwhelming urge to move the legs, often accompanied by uncomfortable and unpleasant sensations. This impulse can also be present in the upper limbs or other parts of the body. Well recognized in the adult population, the symptoms associated with this condition have commonly been reported to originate in childhood. However, identifying prospectively children suffering from RLS is still a challenging issue. Iron deficiency has been recognized as a feature frequently associated with RLS. Some authors also make a connection with the deficiency, RLS and other common problems encountered in children, such as attention deficit disorder with hyperactivity (ADHD). Linkage to different chromosomal loci has been achieved in recent genetic studies of large kindred, as well as identification of specific genes. Therapeutic considerations in children range from providing sound sleep hygiene to intervening pharmacologically. In that regard, use of iron supplements, dopaminergic stimulation, anticonvulsants, opiates, and benzodiazepines will be assessed along with newer options, such as rotigotine and gabapentin enacarbil. Considerations specific to childhood do apply, as no pharmacological therapy for restless legs syndrome have been approved by the Federal Drug Administration (FDA) in individuals of the pediatric age group.

Opioid medications are increasingly used to treat chronic pain. Opioid-associated respiratory depression, and their potential to cause nocturnal apneas, is increasingly recognized as a major contributor to nocturnal hypoxemia and sleep-disordered breathing. Given the widespread use of opioids, understanding their mechanism of action and their potential to cause adverse effects particularly during sleep is critical. This article reviews the salient features of the physiologic control of respiration and sleep, and the role opioids play in altering that regulation. Additionally, we summarize the evidence regarding the association between opioid use and sleep-disordered breathing and explore treatment modalities for opioid-associated nocturnal respiratory depression and apneas.

There is growing research focusing on the sleep problems of children with attention-deficit/hyperactivity disorder (ADHD) in recent years. High incidence of sleep disorders in children with ADHD may be associated with a substantial impact on their quality of life and exacerbation of ADHD symptoms. The core symptoms of ADHD can be effectively treated by various medications, including methylphenidate (MPH), amphetamine, pemoline, and the newly FDA-approved extended-release α2 adrenergic agonists. However, most of them are known to affect patients' sleep because of their pharmacological actions on dopaminergic and/or noradrenergic release in the central nervous system. Previous studies have found increased incidence of insomnia and sleep disturbances in ADHD children treated with CNS (central nervous system) stimulants. In contrast, recent prospective, double-blind, placebo-controlled trials concluded that MPH, by objective polysomnographic or actigraphic measurements, did not cause significant sleep problems in children or adolescents with ADHD. Given the fact that sleep quality and core symptoms of ADHD are highly correlated, it is imperative that we understand the effects of ADHD medications on sleep while prescribing either CNS stimulants or non-CNS stimulants. Here we will concisely review the pharmacological treatments of ADHD, and provide the relevant data discussing their short- and long-term effects on sleep.

The master biological clock situated in the suprachiasmatic nuclei of the anterior hypothalamus plays a vital role in orchestrating the circadian rhythms of multiple biological processes. Increasing evidence points to a role of the biological clock in the development of depression. In seasonal depression and in bipolar disorders it seems likely that the circadian system plays a vital role in the genesis of the disorder. For major unipolar depressive disorder (MDD) available data suggest a primary involvement of the circadian system but further and larger studies are necessary to conclude. Melatonin and melatonin agonists have chronobiotic effects, which mean that they can readjust the circadian system. Seasonal affective disorders and mood disturbances caused by circadian malfunction are theoretically treatable by manipulating the circadian system using chronobiotic drugs, chronotherapy or bright light therapy. In MDD, melatonin alone has no antidepressant action but novel melatoninergic compounds demonstrate antidepressant properties. Of these, the most advanced is the novel melatonin agonist agomelatine, which combines joint MT1 and MT2 agonism with 5-HT2C receptor antagonism. Adding a chronobiotic effect to the inhibition of 5-HT2C receptors may explain the rapid impact of agomelatine on depression, since studies showed that agomelatine had an early impact on sleep quality and alertness at awakening. Further studies are necessary in order to better characterize the effect of agomelatine and other novel melatoninergic drugs on the circadian system of MDD patients. In summary, antidepressants with intrinsic chronobiotic properties offer a novel approach to treatment of depression.

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. These medications have shorter durations of action than many traditional benzodiazepines and may be associated with less risk of tolerance and abuse. They have also been demonstrated to be helpful in cases in which insomnia is comorbid with depression or anxiety, leading to beneficial effects not only with sleep but also with mood and anxiety symptoms. Melatonin, a naturally-occurring substance intimately involved in the regulation of the circadian rhythm, has also been explored as a hypnotic. Little data to date support its use; however, there is evidence that ramelteon, a melatonin agonist, may be helpful for sleep initiation difficulties. Tri-cyclic antidepressants have long been used for insomnia, but use has been limited by unwanted anticholinergic side effects. Low-dose doxepin, at doses of 3 and 6mg, has been demonstrated to have the unique property among its class of being free of anticholinergic effects at those doses. In addition, it seems to have particular efficacy for sleep maintenance insomnia, exhibiting the most robust effects in the latter third of the night. The hypocretin/orexin system has been identified as a possible target. Almorexant, a hypocretin/orexin antagonist displayed evidence of efficacy during Phase III clinical trials but these trials were recently discontinued due to its side effect profile. Another hypocretin/orexin antagonist with a different mechanism of action, MK-4035, is presently in clinical trials. 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 GABAA (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.

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. The discovery of hypocretin and its effect upon the sleep-wake cycle has led to the development of a new class of pharmacologic agents that antagonize the physiologic effects of hypocretin (i.e. hypocretin antagonists). Further investigation of these agents may lead to novel therapies for insomnia without the side-effect profile of currently available hypnotics (e.g. impaired cognition, confusional arousals, and motor balance difficulties). 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.

Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma. There have been almost 200 clinical trials with bortezomib, both as a single agent and in combination with other drugs, for various cancers, as listed in the US National Cancer Institute database. However, bortezomib's mechanism of action remains elusive despite enormous progress in our knowledge of the cell biology of the ubiquitin-proteasome system (UPS) and bortezomibinduced signaling events in cancer cells. This review maps a rapidly growing and open body of research in both areas.

Until the 2000s Testosterone (T) Replacement Therapy (TRT) was not very satisfactory for male hypogonadic patients because the available T formulations were not able to reproduce the physiological pattern of T secretion in man. In fact, oral formulations (oral undecanoate T) showed very short half-life (<24 hours), requiring the administration of several daily doses, whereas the old injection products (T esters) were characterized by very long half-life (>7 days) because of their adipose tissue storage, requiring to be administered every 2-3 weeks but determining remarkable and quick fluctuations (in 2-3 weeks) of the testosteronemia with variations in a few days from over-physiological levels (> 2000 ng/dl) to very low levels (< 200 ng/dl). Nowadays, several compounds can attain the standards of suitability and effectiveness of TRT in hypogonadal men. Both transcutaneous (gel) T and long-acting injectable formulations are the most modern preparations that can satisfy the criteria of an ideal chronic replacement therapy. In fact, they keep the serum T levels in the physiological range imitating its circadian rhythm, leading to the development and/or the preservation of male sexual characteristics and, finally, positively influencing bone mass, skeletal muscle and adipose tissue distribution. In particular, the availability and use of long-acting injectable undecanoate T can really improve the patients' compliance as requested for a life-long treatment. However, definitive and conclusive evidence regarding the main end-points, such as the diminished recurrence of falls in elderly men, the decrease in fractures in osteoporotic subjects, the reduction in disabling conditions and the extension of life, have not been reached so far. Therefore, the aim of this review is to sum up the most important evidence that has been collected regarding TRT, highlighting in particular those concerning both transcutaneous and long-acting injectable T compounds.

Drugs for several diseases are still given without regard to the time of the day. Variation in dosing time is generally related with the effectiveness and toxicity of many drugs. On the other hand, several drugs affect the circadian clock. The knowledge of interactions between the circadian clock and drugs is valuable in clinical practice. The pharmacodynamics and pharmacokinetics of the medication influence the chronopharmacological phenomena and recent advances in it have made the traditional goal of pharmaceutics rather outdated. Enhanced progress in chronopharmacotherapy can be achieved if an identification of a rhythmic marker for selecting dosing time is done. However, technology involved in development of drug delivery systems (DDS) that match the circadian rhythm, and the unraveling of the relationship between circardian clock and pathology may be the hindrance in its prosperity for now. The Chronopharmaceutical Drug Delivery System (CDDS) has emerged during the last decade as a possible drug delivery system against several diseases, which may lead to the creation of a sub-disciple of pharmaceutics to be explored called ‘chronopharmaceutics’. The review addresses the approaches to this sub-discipline, call attention to potential disease-targets, identifies existing technologies, hurdles and future of chropharmaceuticals. Chronopharmaceuticals coupled with nanotechnology could be the future of DDS, and lead to safer and more efficient disease therapy in the future.

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. Erythropoietin (EPO), the principal hematopoietic hormone regulating erythropoiesis, exhibits diverse cellular effects in nonhematopoietic tissues. Due to its anti-apoptotic, anti-inflammatory, and anti-oxidant properties, as well as its angiogenic action, EPO plays a role in neuroprotection and cardioprotection. 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.