Sleep disorders, treatment

Melatonin [73-31-4] C 2H N202 (31) has marked effects on circadian rhythm (11). Novel ligands for melatonin receptors such as (32) (12), C2yH2gN202, have affinities in the range of 10 Af, and have potential use as therapeutic agents in the treatment of the sleep disorders associated with jet lag. Such agents may also be usehil in the treatment of seasonal affective disorder (SAD), the depression associated with the winter months. Histamine (see Histamine and histamine antagonists), adenosine (see Nucleic acids), and neuropeptides such as corticotropin-like intermediate lobe peptide (CLIP) and vasoactive intestinal polypeptide (VIP) have also been reported to have sedative—hypnotic activities (7). 

Pharmacological Profiles of Anxiolytics and Sedative—Hypnotics. Historically, chemotherapy of anxiety and sleep disorders rehed on a wide variety of natural products such as opiates, alcohol, cannabis, and kawa pyrones. Use of various bromides and chloral derivatives ia these medical iadications enjoyed considerable popularity early ia the twentieth century. Upon the discovery of barbiturates, numerous synthetic compounds rapidly became available for the treatment of anxiety and insomnia. As of this writing barbiturates are ia use primarily as iajectable general anesthetics (qv) and as antiepileptics. These agents have been largely replaced as treatment for anxiety and sleep disorders. 

Esterification of the corresponding quinoline-4-carboxylic acid gave the ester 511 which upon reaction with pyrrolidine in THE gave the amide 512. Its phosphorylation and reaction with 513 in presence of KOBu afforded 514 which is useful in the treatment of anxiety, sleep disorders, panic states, convulsions, muscle disorders (95WOP9514020) and chronic neurodegen-erative diseases (97WOP9700074) (Scheme 87). 

The treatment of non-motor symptoms, such as psychological conditions, sleep disorders, and autonomic dysfunction, should include both pharmacologic and nonpharmacologic approaches. Patients should be given suggestions for maintaining ADLs, a positive self-image, family communication, and a safe environment. 

Evaluate the clinical outcomes of treatment by using the UPDRS. In addition, periodically ask patients to record the amount of on and off time they have with and without dyskinesias in a diary. There are a variety of scales that can be used to assess QOL, depression, anxiety, and sleep disorders. Patients with PD cannot be cured but treatment can delay the progression of symptoms and improve QOL. Delaying the patient s admission into a nursing home is a good outcome. 

Articulate the incidence and prevalence of sleep disorders, list the sequelae of undiagnosed or untreated sleep disorders, and appreciate the importance of successful treatment of sleep disorders. 

Educate patients about preventive behavior, appropriate lifestyle modifications, and drug therapy required for effective treatment and control of sleep disorders. 

Treatment goals vary between different sleep disorders but generally include restoration of normal sleep patterns, elimination of daytime sequelae, improvement in quality of life, and prevention of complications and adverse effects from therapy. 

Treatment of excessive daytime sleepiness in narcolepsy and other sleep disorders may require the use of sustained- and immediate-release stimulants to effectively promote wakefulness throughout the day and at key times that require alertness. 

Complicated processes govern wakefulness, sleep, and the transitions leading to sleep initiation and maintenance. Although the neurophysiology of sleep is complex, certain neurotransmitters promote sleep and wakefulness in different areas of the central nervous system (CNS). Serotonin is thought to control non-REM sleep, whereas cholinergic and adrenergic transmitters mediate REM sleep. Dopamine, norepinephrine, hypocretin, substance P, and histamine all play a role in wakefulness. Perturbations of various neurotransmitters are responsible for some sleep disorders and explain why various treatment modalities are beneficial. 

To determine the success of treatment, evaluate whether the treatment plan restored normal sleep patterns, reduced daytime sequelae, and improved quality of life without causing adverse effects. Schedule patients for follow-up within 3 weeks for insomnia and within 3 months for other sleep disorders. Perform a detailed clinical history to determine the patient s perception of treatment progress and symptoms along with medication effectiveness and side effects. 

A reduced endogenous melatonin production seems to be a prerequisite for effective exogenous melatonin treatment of sleep disorders. A recent metaanalysis of the effects of melatonin in sleep disturbances, including all age... 

Melatonin receptor agonists in the treatment of sleep disorders... 

FIGURE 72-1. Algorithm for treatment of dyssomnias. (BZDRA, benzodiazepine receptor agonist CPAP, continuous positive airway pressure.) (Adapted and reprinted with permission from Jermain DM, Sleep disorders. IntJann M, ed. Pharmacotherapy Self-Assessment Program, 2nd ed. Kansas City, MO, American College of Clinical Pharmacy, 1995 139-154.)... 

Compiled from US. Modafinil in Narcolepsy Multicenter Study Group and Standard of Practice Committee of the American Sleep Disorders Association. Pradice parameters for the use of stimulants in the treatment of narcolepsy. Seep 1994 17 348-351. 

Melatonin receptor agonists and their relevance for the treatment of sleep disorders and major depression have been previously reviewed in Ann. Rep. Med. Chem., volume 39 [29]. Since then, ramelteon has been approved, representing an important milestone for the proof of concept of this target, and has opened new possibilities for research. 

Subsequent to the extensive medicinal chemistry exploration of Orexin antagonism, its utility in the treatment of sleep disorders in man has been reported recently. This important milestone for the therapeutic validation of the target results from the 0X1 /OX2 receptor antagonist ACT-078573 (20) [57], SB-649868 has also been announced to be in phase II clinical development, but neither the structural formula nor the results have been reported to date [58,59]. Moreover, insomnia treatments based on orexin modulation may be addressed by not only receptor antagonism but by inhibition of pathways related to the genesis of the bioactive peptides Orexin A or B, e.g. inhibition of Orexin-converting enzyme [60]. 

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