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Sleep Tracks

Sleep Tracks, also called as SleepTracks Sleep Optimization program, is created by a former insomnia sufferer Yan Muckle. This is a comprehensive program developed in 2007 to provide people with an alternative treatment for sleep disorders, particularly insomnia. Basically, Sleep Tracks program contains an educational part and audio sessions which have undergone a few changes and improvements based on the recommendations and feedbacks of both sleep experts and real users. Sleep Tracks contains 3 critical steps for restored sleep, which are brainwave reboot, confidence reboot, and habit reboot. Sleep Tracks is not suitable for those with medical conditions especially epileptics, those wearing pace makers, pregnant woman, and those who are prone to seizures due to noise pulses in the audios that may stimulate the brainwaves. More here...

Sleeptracks Sleep Optimization Program Insomnia Buster Overview


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Sleep Disorders A Common Problem Among Kidney Patients

Summary In this article, the author provides readers with information about an often-encountered, but little-discussed complication of dialysis, insomnia. Topics include the adequacy of dialysis and its impact on the sleep habits of patients restless leg syndrome (RLS) and the role of peripheral neuropathy in its development the use of Sinemet to treat RLS using conventional sleep aids, including Ambien the use of muscle relaxants, or benzodiazepines, for milder forms of RLS psychological sleep disturbances and adjunctive therapies, including Qigong, biofeedback, and meditation. The author encourages readers to become more self-aware and to participate as an active member of their own health care team. The article includes a short list of references and organizations that may provide additional information about sleep disorders and their therapy.

Management Of Insomnia

Adequate sleep improves the quality of daytime wakefulness, and hypnotics should be used judiciously to avoid its impairment. A number of pharmacological agents are available for the treatment of insomnia. The perfect hypnotic would allow sleep to occur with normal sleep architecture rather than produce a pharmacologically altered sleep pattern. It would not cause next-day effects, either of rebound anxiety or of continued sedation. It would not interact with other medications. It could be used chronically without causing dependence or rebound insomnia on discontinuation. Regular moderate exercise meets these criteria but often is not effective by itself, and many patients may not be able to exercise. However, even small amounts of exercise often are effective in promoting sleep. Controversy in the management of insomnia revolves around two issues pharmacological versus nonpharmacological treatment and the use of short-acting versus long-acting hypnotics. The side effects of hypnotic...

Insomnia Accompanying Major Psychiatric Illnesses

Insomnia caused by major psychiatric illnesses often responds to specific pharmacological treatment for that illness. In major depressive episodes with insomnia, for example, the selective serotonin reuptake inhibitors, which may cause insomnia as a side effect, usually will result in improved sleep because they treat the depressive syndrome. In patients whose depression is responding to the serotonin reuptake inhibitor but who have persistent insomnia as a side effect of the medication, judicious use of evening trazodone may improve sleep, as well as augment the antidepressant effect of the reuptake inhibitor. However, the patient should be monitored for pri-apism, orthostatic hypotension, and arrhythmias. Adequate control of anxiety in patients with anxiety disorders often produces adequate resolution of the accompanying insomnia. Sedative use in the anxiety disorders is decreasing because of a growing appreciation of the effectiveness of other agents, such as adrenergic receptor...

Insomnia Accompanying Other Medical Illnesses

For long-term insomnia owing to other medical illnesses, adequate treatment of the underlying disorder, such as congestive heart failure, asthma, or COPD, may resolve the insomnia. Adequate pain management in conditions of chronic pain, including terminal cancer pain, will treat both the pain and the insomnia and may make hypnotics unnecessary. Many patients simply manage their sleep poorly. Adequate attention to sleep hygiene, including reduced caffeine intake, avoidance of alcohol, adequate exercise, and regular sleep and wake times, often will reduce the insomnia. CONDITIONED (LEARNED) INSOMNIA In patients without major psychiatric or medical illness and in whom attention to sleep hygiene is ineffective, attention should be directed to conditioned (learned) insomnia. These patients have associated the bedroom with activities consistent with wakefulness rather than sleep. In such patients, the bed should be used only for sex and sleep. All other activities associated with waking,...

Fatal familial insomnia FFI

Hypersomnia or insomnia are well known to occur in CJD, and were reported by Heidenhain in one of his original cases. Nevertheless, a new disease was later described, in which the insomnia was very severe.44 These patients also had autonomic symptoms such as hypertension, tachycardia, hyperhydrosis and hyperthermia. Dysarthria, dysphagia, ataxia and myoclonus developed later. Because of the predominance of the sleep abnormalities, this variant of prion disease was termed fatal familial insomnia. The pathological features include severe destruction of the thalamic nuclei with astrogliosis, but without spongiform changes or amyloid deposits.

Treating Sleep Disorders in Patients With Fibromyalgia

Summary This journal article for health professionals reviews current knowledge about sleep disorders in patients with fibromyalgia and the treatment strategies currently used. Sleep disturbance may be central to the fibromyalgia syndrome. Many patients have difficulty in falling and staying asleep and awaken unrefreshed with intensified morning aching. Alpha-delta sleep, in which internally triggered arousal results in delta sleep deprivation, appears responsible. Moreover, such triggers may also lead to depressed and anxious mood, fatigue, morning stiffness, and musculoskeletal pain, which, in turn, contribute to the nonrestorative sleep cycle. Success in improving sleep is greatest when general approaches and specific sleep interventions are combined. Psychotherapy, behavioral therapy, and exercise may lead to better sleep habits and symptomatic relief. Tricyclic agents improve sleep and overall functioning. Benzodiazepines administered with nonsteroidal anti-inflammatory drugs may...

Longterm Insomnia

Nonpharmacological treatments (see above) are important for all patients with long-term insomnia. Side effects of hypnotic agents may limit their usefulness for insomnia management. Long-term hypnotic use leads to a decrease in effectiveness and may produce rebound insomnia on discontinuance. Almost all hypnotics change sleep architecture while the significance of these findings is not clear, there is an emerging consensus that slow-wave sleep is particularly important for physical restorative processes. REM sleep may also aid in the consolidation of learning. The consensus is that hypnotics should not be given to patients with sleep apnea, especially of the obstructive type, because these agents decrease upper airway muscle tone while also decreasing the arousal response to hypoxia. These individuals benefit from all-night sleep studies to guide treatment. INSOMNIA IN OLDER PATIENTS The elderly, like the very young, tend to sleep in a polyphasic (multiple sleep episodes per day)...

Sleep Disorders

Sleep disturbances are common among patients with a variety of pain disorders (Moldofsky 2001) patients may report difficulty falling asleep, frequent awakenings and disrupted sleep, decreased total sleep time, and daytime fatigue. The etiology is likely to be multifactorial, including disruptions due to pain itself, comorbid psychiatric disturbances, effects of pain medications, lack of aerobic exercise, and behavioral conditioning due to protracted reclining and daytime napping (Cohen et al. 2000). Protracted sleep deprivation can increase pain severity (Moldofsky and Scarisbrick 1976) and can predispose patients to additional medical complications, e.g., impaired immune functioning, weight gain, and insulin resistance diabetes (Irwin et al. 1996, Knutson et al. 2007). Interventions can include (a) patient education and training in the development of appropriate sleep hygiene techniques (b) use of long-acting analgesics to reduce sleep-interfering effects of pain (c) prudent use of...


In vivo research on animals has shown that melatonin overcomes cardiac injury after arterial occlusion followed by reperfusion. It appears that melatonin is more powerful than other antioxidants tested, in terms of ameliorating hypoxia and reoxygenation damage.114 Intraperitoneal doses of 150 xg kg were found to be most effective.115 Humans dosed with 3 mg oral melatonin showed dramatic increase in plasma melatonin concentrations, at 1830 848 pg mL, compared with 14 11 pg mL before ingestion, with maximal levels at 75 minutes after ingestion. This shows that in humans melatonin attenuates the reflex sympathetic increases that occur in response to orthostatic stress.116

Moderators Of The Depressionimmune Link

Insomnia is one of the most common complaints of depressed subjects, but its role in moderating and or mediating immune alterations in depression has been relatively unexplored. However, with evidence that subjective insomnia correlates with NK activity in depression (Cover & Irwin, 1994), the hypothesis emerged that disordered sleep may be a distinct factor accounting for some of the observed immune alterations found in depression. Consequently, a series of studies have now been conducted to test more carefully the role of sleep in the modulation of multiple aspects of the immune system and to determine the moderating effects of sleep disturbance on immune measures in depressed subjects. First, observations regarding subjective complaints of insomnia and immunity were extended by assessment of disordered sleep by EEG (Irwin et al., 1992b). Many aspects or parameters of sleep are assessed during all-night EEG studies, thus the initial approach was to...

Pharmacological Properties

Although Parkinson's disease (PD) is classified as a movement disorder, it should also be considered as a neuro-behavioral'' disorder. The diagnosis of PD is based on the presence of clinical criteria having to do purely with movements and the absence of exclusionary or atypical features, laboratory tests being of little or no value. Nevertheless, the most devastating aspects of PD are more often behavioral. Other nonmotor problems, such as sympathetic dysfunction and sleep disorders have only attracted clinical and research attention in the last few years. For perspective two studies, one a large retrospective review in Australia, and the other, a county wide prospective study with formal testing in Norway, both concluded that by the time of death, 80 of PD patients are demented. In addition, at any point in time, somewhere between 30 and 50 are depressed 40 suffer from anxiety 40 with apathy 30 of drug treated patients with visual hallucinations 5-10 of drug treated patients with...

Beck Depression Inventory

Ideation is helpful in assessing suicidality in chronic pain patients. The BDI is predictive of many aspects of patient functioning.26 Comparing the BDI to another measure of depression, the CES-D, Geisser et al.27 found that both the BDI and the CES-D discriminated significantly between chronic pain patients who were depressed versus those who were not. One of the criticisms of the use of an instrument such as the BDI is that some of the physical vegetative items such as sleeplessness, which can be endorsed because of pain, can artificially elevate BDI scores for pain patients. Geisser et al.27 found, however, that removal of these somatic items did not improve its accuracy.

Alterations in Physiological Function Circardian Rhythms Sleep Pain Perception and Appetite

As part of circadian effects, there are normal 24-h fluctuations in neuroendocrine secretion, especially cortisol, growth hormone, TSH, and melatonin, as already noted above. These hormonal systems are often disrupted in depression thought to be due to heightened arousal. With shorter daylight hours, some individuals who experience the aforementioned have recurring autumn and winter depression (seasonal affective disorder, SAD) thought to be related to phase delay in the sleep-wake cycle (186, 188). Sleep is often disturbed in depression. Imaging studies using 18(F) 2-fluoro-2-deoxy-D-glucose PET have noted changes in oxygen utilization consistent with abnormal arousal in depressed patients associated with increased glucose utilization in ventromedial prefrontal cortex (189) and blunted response in anterior paralimbic regions during REM sleep (190). Hyper-aroused patients demonstrate loss of delta sleep, loss of sleep continuity, and increased core body temperature during sleep....

Pharmacogenetics Moving From Research To The Clinic

With a few exceptions, the current level of knowledge of efficacy pharmacogenetics in psychiatry is still in the exploratory stage, with as yet no robust results for genes predicting efficacy. However, some findings are replicating in independent sample sets and promising leads are developing, for example the serotonin gene promoter gene and SSRI response, dopamine D3 receptor gene and risk of anti-psychotic induced tardive dyskinesia. Many of these are presented within the following chapters of this book. Understanding of the impact of allelic variance on pharmacokinetic parameters can perhaps be considered to represent our current, most advanced state of pharmacogenetic knowledge. An example of this was recently seen in the approval of atomoxetine (Strattera Eli Lilly), approved by the FDA in November 2002 for attention-defeceit hyperreactive disorder. This drug is metabolised by CYP2D6 with the ratio (PM EM) for an area under the curve (AUC) of 10. Lilly conducted a post-facto...

Lesley R Brown and David A Harris

The prion disorders include Creutzfeldt-Jakob disease (CJD), kuru, Gerstmann-Straussler syndrome, and fatal familial insomnia in man, as well as scrapie and bovine spongiform encephalopathy (mad cow disease) in animals. In man, these diseases are characterized clinically by dementia and motor dysfunction and neuropathologically by neuronal loss, spongiosis, and amyloid deposition. Infectious, inherited, and sporadic forms of prion diseases have been described. Prion diseases are of now of enormous concern from a public health standpoint because of an epidemic of bovine spongiform encephalopathy in Britain and other European countries and recent evidence that this disease has already been transmitted to human beings by consumption of contaminated beef (1,2).

Attentiondeficithyperactivity Disorder

ADHD, usually first evident in childhood, is characterized by excessive motor activity, difficulty in sustaining attention, and impulsiveness. A variety of stimulant drugs have been utilized in the treatment of ADHD, and they are particularly indicated in moderate-to-severe cases. Methylphenidate is effective in children with ADHD and is the most common intervention treatment may start with a dose of 5 mg in the morning and at lunch, increasing gradually over a period of weeks depending on the response as judged by parents, teachers, and the clinician. The total daily dose generally should not exceed 60 mg. Methylphenidate has a short duration of action thus, most children require 2-3 doses day, with the timing individualized for effect. Methylphenidate, dextroamphetamine, and amphetamine probably have similar efficacy in ADHD. pemoline appears to be less effective, although like sustained release preparations of methylphenidate (ritalin sr, concerta, metadate) and amphetamine...

HT2CRMediated Effects on Sleep and Entrainable Rhythms

At a global level of behavioral organization, the changes in regulation of ingestive behavior, metabolism, and circadian entrainment give rise to observable phenotypic differences in sleep architecture (Frank et al. 2002). Over the entire day, constitutive 5-HT2CR Y mice show less non-REM sleep (particularly during the active phase) and increased waking bouts (again, most prominent during the active phase) compared with wild-type littermates. Constitutive 5-HT2CR mutant mice also showed a greater homeostatic drive to sleep after 6 h of sleep deprivation. By EEG studies, no phenotypic differences in spectral power density were observed during REM sleep, non-REM sleep, or wakefulness.

Posttraumatic stress disorder

As well as genetic heterogeneity, incomplete penetrance, pleiotropy, and interaction multiple genes complicate genetic studies of PTSD and its treatment. One strategy to get around these problems is to perform genetic analysis of traits associated with PTSD, rather than PTSD itself, an approach that has yielded promising results for other diseases with complex genetics. Hypothalamic-pituitary-adrenal axis dysfunction, physiologic markers of increased arousal, and increased acoustic startle response are PTSD-associated traits accessible to genetic analysis. However, the power of these traits to distinguish PTSD from non-PTSD patients need to be determined before they can be employed in genetic studies. Only a few association studies have been reported. Comings et al. (1996) reported that the A1 allele of the dopamine D2 receptor gene (DRD2) was significantly more common among PTSD patients as compared to veteran controls. Differences in rates of substance abuse, which appear also be...

Synthesis And Metabolism

A close relative of 5-HT, melatonin (5-methoxy-N-acetyltryptamine), is formed by sequential N-acetylation and O-methylation (Figure 11-1). Melatonin is the principal indoleamine in the pineal gland, where it may be said to constitute a pigment of the imagination. External factors including environmental light control melatonin synthesis. Melatonin induces pigment lightening in skin cells and suppresses ovarian functions it also serves a role in regulating biological rhythms and shows promise in the treatment of jet lag and other sleep disturbances.

Nitric Oxide And Global Ischemia

Increased cerebral NO concentration on reperfusion in a four-vessel occlusion rat model after 30 min of global ischemia and 15 min of reperfusion (134). It was demonstrated that hypothermia suppresses the elevation in intrajugular NO after cerebral ischemia-reperfusion (135). Exogenous melatonin administration prevented the increases in cerebral cortical and cerebellar NO production (nitrite nitrate levels and cGMP) after transient bilateral carotid artery occlusion reperfusion in adult Mongolian gerbils (136).

Potential Consequences of Drug Drug Interactions

A final point to consider is that some drugs may affect the disposition of chemicals in foods and beverages through P450 interactions. For instance, the drug disulfiram (Antabuse) inhibits P450 2E1. This would affect ethanol oxidation by P450 2E1, although the more serious effect is on aldehyde dehydrogenase (Guengerich et al, 1991). The P450 1A2 inhibitor furafylline blocks caffeine iV'-demethylation to the point where severe insomnia is associated with drinking coffee (Sesardic et al, 1990 Kunze and Trager, 1993).

Selective Serotonin Reuptake Inhibitors

Of all three groups of antidepressants, the SSRI group (see Table 5.2) has the poorest profile for pain relief (APS, 2006). When compared with placebo, these medications did not have any significant advantage for pain relief. Given the lack of efficacy for pain relief in these medications and the profile of side effects, sexual dysfunction, anxiety, sleep disorder, and headache, the SSRIs are not medications that should be given unless there is a specific indication for use. The recommended use for this group of medications is for patients who have concurrent depression, anxiety, or insomnia (APS, 2008).

Serotonin Transporter And Antidepressant Anxiolytic Response

Shortened response delay in l l subjects at week 1 and 2 compared to l s and s s no difference in placebo group Higher rate of insomnia and agitation in s s subjects compared to l s and l l Finally, Mundo et al. (2001) found that 63 bipolar patients with a history of antidepressant-induced mania had the s allele compared to 29 in bipolar subjects who had been exposed to antidepressants, but did not develop mania. A role of the 5HTTLPR in rapid cycling, though not in antidepressant-induced mania, was supported in an independent cohort of patients with bipolar affective disorder, further supporting the notion that the low-activity s allele of the 5HTTLPR contributes to a pattern of affective instability (Rousseva et al. 2003). The role of allelic variation of 5HTT function in the development of adverse effects of SSRI treatment in patients with major depression was investigated by Perlis and coworkers (2003). A higher rate of fluoxetine-induced insomnia and agitation was found in s s...

Dose versus Treatment Chronicity

Mood and cognitive changes generally resolve within 2 to 3 weeks following the discontinuation of therapy (Meyers & Valentine, 1995). However, in some patients neurotoxic side-effects persist for months and years off treatment (Meyers, Scheibel, & Forman, 1991). For example, we evaluated a 54 year old male patient who was diagnosed with CML and treated with 12MIU IFN-a daily for 5 years. At the time of neuropsychological assessment he had been off of all treatment for 3 years and in complete cytogenetic remission. The patient had a Ph.D. in mathematics, was a professor at a university, and owned and operated a computer services business. He was diagnosed with CML one year after starting his business, which was rapidly expanding. His initial symptoms related to IFN-a therapy consisted of fatigue, difficulty concentrating, and difficulty retaining complex technical information. Memory loss extended to difficulty recalling names of associates and business contacts, necessitating...

Restless Legs Syndrome Detection and Management in Primary Care

Summary Restless legs syndrome (RLS) is a neurologic movement disorder that is often associated with a sleep complaint. This article explores the role of the primary care physician in the diagnosis and management of RLS. Patients with RLS have an irresistible urge to move their legs, usually due to disagreeable sensations that are worse during periods of inactivity and often interfere with sleep. The authors estimate that between 2 and 15 percent of the population may experience symptoms of RLS. Primary RLS likely has a genetic origin. Secondary causes of RLS include iron deficiency, neurologic lesions, pregnancy, and uremia (urea in the blood). RLS also may occur secondarily to certain medications. The diagnosis of RLS is based primarily on the patient's history. A list of questions to assess the likelihood of RLS is included in the article. Drug therapy includes dopaminergic agents, opioids, benzodiazepines, and anticonvulsants. The primary care physician can incorporate sleep and...

Nonprescription Hypnotic Drugs

As part of the ongoing systematic review of over-the-counter (OTC) drug products, the FDA has ruled that diphenhydramine is the only ingredient that is recognized as generally safe and effective for use in nonprescription sleep aids. Despite the prominent sedative side effects encountered during the use of antihistamines previously included in OTC sleep aids (e.g., doxylamine and pyrilamine), these agents have been eliminated as ingredients in the OTC nighttime sleep aids marketed in the U.S. With an elimination t 2 of about 9 hours, diphenhydramine at nighttime is associated with prominent residual daytime sleepiness.

Characterization Of Depressive And Anxiety Disorders

Clinical depression must be distinguished from normal grief, sadness, disappointment, and the dysphoria or demoralization often associated with medical illness. The condition is underdiagnosed and frequently undertreated. Major depression is characterized by feelings of intense sadness and despair, mental slowing and loss of concentration, pessimistic worry, lack of pleasure, self-deprecation, and variable agitation or hostility. Physical changes also occur, particularly in severe depression, including insomnia or hypersomnia altered eating patterns, with anorexia and weight loss or sometimes overeating decreased energy and libido and disruption of the normal circadian and ultradian rhythms of activity, body temperature, and many endocrine functions. As many as 10-15 of individuals with severe clinical depression, and up to 25 of those with bipolar disorder, display suicidal behavior at some time. Depressed patients usually respond to antidepressant drugs, or, in severe or...

Jimo Borjigin Xing Sun and Michael M Wang

Circadian rhythms are found in virtually all organisms and are tightly coupled to environmental lighting conditions. These rhythms dictate our daily sleep schedule and hormonal fluctuations (1) and even influence our susceptibility to disease such as heart attacks (2), strokes (3), and seizures (4). One of the best studied circadian rhythms is the activity of the pineal gland, an organ situated deep within the brain. The pineal exhibits dramatic diurnal fluctuations in secretion of the hormone mela-tonin, which is best known for its soporific effects in humans. Melatonin is the only vertebrate hormone that is known to universally link environmental light information to the body's physiological responses, including clock resetting, seasonal reproduction, and sleep (5). To understand the molecular basis of the circadian regulation of the pineal gland, we identified a set of genes expressed exclusively in the nighttime pineal. One of these genes, the pineal night-specific ATPase (PINA)...

Causes and Treatment of Behavioral Changes

Summary This article describes Alzheimer's disease as an increasingly common management concern for primary care physicians. Although little can be done for the primary symptoms of the dementing process, the secondary behavioral complications of this illness may be amenable to behavioral or pharmacologic manipulation. Agitation may be responsive to environmental or psychosocial intervention. Treatment with low doses of antidepressants can improve depressive symptoms. Mild anxiety is best treated with emotional support from the family and caregiver. Benzodiazepines can be used with caution. Insomnia can be reduced by encouraging a routine that prevents daytime napping and keeping the patient busy during the day. Pharmacotherapy for disturbed sleep often causes more harm than good and should be avoided if possible. 3 references. (AA-M).

Sympathomimetics Stimulants

Although the literature is limited by number of subjects, duration, and trial design, there is some evidence to support the use of methylphenidate (5-15 mg two to four times daily), donepezil (5-10 mg daily), and modafinil (200-400 mg daily) for the pharmacologic management of opioid-induced sedation and fatigue (Larijani et al. 2004, Reissig and Rybarczyk 2005). Potential adverse effects can include overstimulation (e.g., anxiety, insomnia, and even paranoia), appetite suppression, exacerbation of motor abnormalities (e.g., tics, dyskinetic movements), and confusion. Contraindications for stimulant use include glaucoma, poorly controlled hypertension, arrhythmias, and cardiovascular disorders, anorexia, seizure disorders, and hyperthyroidism. Methylphenidate is a schedule II medication under federal regulatory control caution is advised in patients with current or preexisting substance use disorders, especially prior stimulant abuse (e.g., cocaine).

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Hop (Humulus lupulus) is a flowering vine that grows in Europe, Western Asia, and North America, and is reported to have anxiolytic sedative effects (figure 6.8) (Kowalchik and Hylton 1987). It is an ingredient of beer, but is also consumed as a tea. The female flowers are placed in a pillow to treat insomnia by their fragrance. It has not been well studied, but the responsible agent is believed to be 2-methyl-3-butene-2-ol, because it produces sedation when injected intraperitoneally in mice (Hansel et al. 1980). In humans, one study found no CNS depressant effects when administered orally (Hansel and Wagener 1967). However, the effects produced by inhalation (thus avoiding digestion and absorption issues), have not been studied.

Practical Considerations in Managing Alzheimers Disease

Summary This article presents a panel discussion on the role of the physician in the treatment of Alzheimer's, including handling the patient's response to the diagnosis, managing behavioral aspects of the illness, treatment of depression and other emotional symptoms, treatment of other medical conditions, and helping patients live with cognitive impairment. The panelists also considered such drug therapy as THA, Hydergine neuroleptics for agitation, and benzodiazepines for sleep disorders.

Pharmacological Treatments

Recently, the focus of much of the research on pharmacotherapy has switched its focus from symptoms to disease progression. The range of drugs that have, in most cases, been tested in 6-OHDA models is too wide to be reviewed here, but includes (in alphabetical order) antioxidants, anti-inflammatory agents, calcium channel antagonists, creatine, DA agonists, glutamate antagonists, free radical scavengers, iron chelators, melatonin, MAO-B inhibitors, nitric oxide synthase inhibitors, and polyphenols see reviews 130,131 .

Psychiatry and Psychopharmacology

Beginning with the 1860s, and completely independently from the developments summarized above, a number of drugs were introduced for the treatment of mentally ill patients (see Table 1). In this early phase of psychiatric pharmacotherapy, drugs were used to achieve three main effects sedation, deep sleep, and convulsions. Morphine, potassium bromide, chloral hydrate, atropine, hyoscyamine, and scopolamine were used, alone or in combination, for the control of agitated, aggressive patients, thereby reducing the need for physical restraint. Morphine was isolated from opium (which had been used for centuries to control frenzy) by Friedrich Wilhelm Adam Serturner in 1804 but its widespread use in

Copper And Neurodegenerative Diseases

Some very interesting recent findings have linked copper to various devastating neurological conditions and a common theme that emerges is the possibility of Cu-induced free-radical production leading to neuronal damage. Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurones, leads to progressive muscular weakness, atrophy, and death. An autosomal dominant form of ALS is caused by mutations in Cu Zn superoxide dismutase (SOD). It appears that the disease results from a gain of function of Cu Zn SOD, associated with abnormal forms of the protein in which copper is bound in a manner that allows the generation of reactive oxygen species (155). Alzheimer's disease is a progressive neurodegenerative disease characterized by amyloid plaques and neuronal cell loss. A major constituent of the plaques is the amyloid-P protein (APP). APP is a copper-binding molecule and can reduce Cu(II) to Cu(I) (156) it may be involved in copper transport in neurones, so...

Role of Pharmacotherapy

The severity of daytime sleepiness can be quantified subjectively, using the Epworth Sleepiness Scale, a scale rating the probability of dozing in eight more or less soporific daily situations (Johns 1994), and objectively, using the Multiple Sleep Latency Test, a test measuring the tendency to fall asleep in a quiet situation, repeated five times throughout the day (Littner et al. 2005). According to a recent study that reviewed the diagnoses of 1,243 patients referred to a Japanese outpatient clinic for complaint of excessive daytime sleepiness, the most frequent diagnosis (34.7 ) was obstructive sleep apnea syndrome (not a disorder of hypersomnia of central origin), followed by idiopathic hypersomnia (10.9 ), narcolepsy (8.8 ), behaviorally induced insufficient sleep syndrome (7.1 ), circadian rhythm sleep disorders (6.1 ) (not a disorder of hypersomnia of central origin), and hypersomnia not due to substance or known physiological condition (4.3 ) (Komoda et al. 2008). Hypersomnia...

Diagnostic Categories

There are four main diagnostic categories of Sleep Disorders, according to presumed etiology (DSM-IV, APA 2000). These are (a) Sleep Disorder related to another mental disorder (usually depression or anxiety) (b) Sleep Disorder due to a general medical condition, (c) Substance-induced Sleep Disorder, and (d) Primary Sleep Disorders, in which none of the above etiologies can be identified. Primary sleep disorders are therefore presumed to arise from endogenous abnormalities in sleep wake generating or timing mechanisms or conditioning factors. The specific type of sleep complaint may vary over time with difficulty in falling asleep at one time and difficulty in staying asleep at other times. Maladaptive sleep habits may set in with erratic sleep schedules these perpetuate the disorder patients to complain about decreased attention, energy, and concentration and increased feelings of fatigue and malaise. Many sufferers have previous history of increasing sleep difficulties culminating...

Serotonin As A Neurotransmitter

In the stomach, most of the current interest on serotonin is focused on its role in the brain. It is biosynthesized from the amino acid tryptophan 4.40 by hydroxylation 4.41 and decarboxylation. The principle metabolic route involves the monoamine oxidase system, MAO-A. Serotonin is converted via the aldehyde, to 5-hydroxyindolylacetic acid. Another pathway involves N-acetylation and O-methylation. A product of this pathway, melatonin 4.43, is involved in the regulation of various time-related processes in the body. The other major deactivation mechanism for serotonin is that of pre-synaptic re-uptake.

Ligand Modulation Of Oligomers Detected By Biochemical And Biophysical Methodologies

Similarly, investigations using BRET have revealed differences in the effects of ligand on oligomerization. Agonist-induced BRET was observed for homo-oligomerization of the P2-ARs (11) and TRH receptors (71) as well as hetero-oligomerization between the adenosine Ai and P2Yi receptors (50). In contrast, agonist-induced decreases in the BRET signal between CCKA (72) and neuropeptide Y Y4 receptor (80) homo-oligomers were interpreted as indicative of receptor dissociation. However, many studies have demonstrated no change in BRET signals in the presence of agonists (74,76,79,91). This may suggest that the oligomerization state of the receptor is not affected by ligand and is consequently unrelated to the activation state of the receptor. Detection of changes in BRET between melatonin MT2 receptors following the binding of agonists and antagonists supports the idea that changes in resonance energy transfer efficiencies following ligand binding result from conformational changes that...

Cardiovascular health

There is evidence that a number of nutraceuticals are beneficial in the prevention or symptom reduction of CHD, including black and green tea and their flavonoids, soy protein and isoflavones, essential fatty acids, flax lignans, coenzyme Q10, lycopene, policosanol and Pycogenol, melatonin, resveratrol, grape seed proanthocyanidin extract (GSPE), lutein, carnitine, and dehydroepiandrosterone (DHEA). The aim of this chapter is to determine what effects these nutraceuticals have on the cardiovascular system and what evidence there is to support their use,

An Interdisciplinary Approach To Characterize The Oligomerization Interface Of Rhodopsinlike Gpcrs

Based on the principle that residues involved in a common function tend to mutate together, we recently searched for lipid-exposed correlated mutations within multiple sequence alignments of rhodopsin-like GPCRs for which homodimerization had been experimentally demonstrated. Specifically, calculations were performed for the following GPCRs adenosine 1 receptors angiotensin II type 1 receptors a1b-adrenoreceptors p1-ARs p2-ARs B2Rs cannabinoid 1 receptors CCR2s, CCR5s, and CXCR4s D1, D2, D3 dopamine receptors H1, H2 , and H4 histamine receptors 5-HT1B and 5-HT1D serotonin receptors leukotriene B4-1 receptors luteinizing hormone receptors m2 and m3 muscarinic acetylcholine receptors MT1 and MT2 melatonin receptors neuropeptide Y type 1, type 2, and type 5 receptors 5-, p-, and K-opioid receptors SST2A, SST5, SST3, and SST1 receptors thyrotropin-releasing hormone receptors and V2 vasopressin receptors (3,40,52-55). Several receptors were excluded from analysis, including rhodopsin-like...

Painful Polyneuropathies

The persistent pain associated with PHN is variable in nature and can be characterized as any of the following (1) burning background pain with fluctuating severity (2) sudden, sharp shooting pain and (3) mechanical or thermal allodynia (pain produced by non-noxious stimulus). As a result of this severe, often debilitating pain, a patient's quality of life is often adversely affected. In addition to interfering with activities of daily living, PHN may lead to fatigue, insomnia, anxiety, and depression. Because of the severity and complexity of the disease, treatment is initiated at the onset of the rash and may be necessary months to years later.

Assessment and Diagnostic Evaluation of Patients with Neuropathic Pain

Mechanism or mechanisms are often difficult to diagnose and a distinction between noci-ceptive and neuropathic types of pain is sometimes challenging because conditions such as diabetes mellitus, cancer, and other neurological diseases can produce mixed pain pictures. It is important, of course, that the clinical assessment of a patient with suspected neuropathic pain focus on ruling out treatable conditions (e.g., spinal cord compression, neoplasm), confirming the diagnosis of neuropathic pain, and identifying clinical features (e.g., insomnia, autonomic neuropathy) that might help individualize treatment. Crucial to any pain assessment is the clinician's acknowledgment that the patient is experiencing pain and that the pain is real. This validation of the patient's pain is critical in developing rapport with the patient and establishing a meaningful therapeutic relationship. Without this, any further steps in the care of the pain patient are unproductive, if not meaningless.

Performance Deficits By Nicotinic Drugs

Attention deficit hyperactivity disorder (ADHD) is among the most prevalent of childhood and adolescent disorders, accounting for up to 50 of clinic visits in these populations. The predominant characteristics of ADHD, inattention and dis-tractibility, are also among the symptoms associated with prenatal and early postnatal exposure to a variety of toxicants, as well as with a wide variety of neurologic and psychiatric disorders including AD, Parkinson's disease, Huntington's disease, Tourettes syndrome, and schizophrenia. The primary therapeutic agents utilized for ADHD and other disorders where distractibility and inattention are prominent features include methylphenidate, dextroamphetamine, mixed amphetamine isomers, and pemoline. While the efficacy of these agents has been demonstrated, they are also associated with a wide variety of adverse effects including insomnia, decreased

Assess the pain severity and disability

The impact of pain on the patient's function and quality of life should be assessed, by asking the patient what activity they enjoy and document how much of that activity they can do. This serves as a useful guide for initial assessment and follow-up progress over time. Additionally, assessment of the patient's sleep quality, work capabilities, and self-care skills all contribute to the understanding of disability.

Non Rapid Eye Movement Sleep

Subdivided into stages of increasing depth of sleep leading to REM sleep (NREM 1,2, and 3 4). About 80 of sleep is NREM sleep. In the rat, it is identified by the presence of high-voltage slow cortical waves interrupted by low-voltage fast electroencephalographic activity, whereas slow-wave sleep distinguishes as continuous high-amplitude slow frontal and occipital waves combined with a reduced electromyogram.

Cytochromes p450 in the metabolism of xenobiotics

Aromatic hydrocarbon, as well as of globular molecules such as the anticonvulsant phenobarbitone. Naturally, no single enzyme can accommodate in its substrate-binding site such a diversity of substrates, and consequently it is not surprising that cytochrome P450 is not a single enzyme, but a superfamily comprising a number of enzymes, each with different, albeit overlapping, substrate specificity.89 The cyto-chrome P450 superfamily is divided into a number of families, which in turn are subdivided into subfamilies, each of which may consist of one or more enzymes (isoforms). Classification of cytochrome P450 enzymes within families and subfamilies is carried out strictly on the basis of primary sequence homology, with no consideration of their substrate specificity. Cytochrome P450 enzymes belonging to the same family share at least a 40 structural homology whereas homology between enzymes within a subfamily is at least 55 . For example, CYP3A4 enzyme denotes a cytochrome P450 protein...

Other Neuropathologies

In addition to AD, other neuropathologies and neurological disorders of DS are also believed to result partly from ROS-induced cellular damage and enhanced apoptosis caused by elevated levels of SOD1 and ROS. Elroy-Stein and Groner (1988) observed that rat PC12 cells overexpressing the human SOD1 gene have altered neurotransmitter (serotonin and catecholamine) uptake resulting from an impaired chromaffin granule transport mechanism. This impairment appears to be caused by lipid peroxidation of the membrane due to oxidative stress. These data are similar to some of the neurophysiological abnormalities seen in patients with DS, e.g., the reduction in neurotransmitter content in the nerve terminals of DS brains (Yates et al., 1983) and the defective membrane K+ permeability of cultured neurons from individuals with DS (Scott et al., 1983). In addition, Schickler et al. (1989) found that serotonin levels are reduced in blood platelets of SOD1 transgenic mice, which is similar to the...

Perospirone Definition

Perospirone is a benzisothiazole derivative that belongs to the class of second-generation (atypical) antipsychotic drugs and is indicated for the treatment of schizophrenia. It has high-affinity antagonist activity at 5-HT2A and D2 receptors. It also displays partial 5-HT1A agonist properties and some affinity for D1, ( -adrenergic and H1 receptors, but has no appreciable affinity for muscarinic receptors. It has at least four active metabolites, but all of them have lower affinity for D2 and 5-HT2A receptors than the parent drug. It can induce extrapyramidal motor side effects and insomnia, but it displays low toxicity.

A NNRTIs in Current Clinical

Efavirenz (Fig. 3) is a benzoxazinone with exceptionally potent antiviral activity against HIV-1 (EC50 < 1 nM). Efavirenz has a serum half-life similar to nevirapine and crosses the blood-brain barrier, but is less orally available ( 40 ). The drug has a high degree of protein binding (> 99 ). Efavirenz also seems to produce more pronounced side effects than either nevirapine or delavirdine. The most serious are a range of CNS symptoms including insomnia, confusion, and abnormal dreams and hallucinations, which may lead to patient-initiated discontinuation of therapy. Efavirenz may induce the CYP3A family of cytochrome P450 enzymes, thereby affecting its own metabolism and that of other drugs.

Formulation Applications

Melanotan I is a tridecapeptide analog of a-MSH with melanotropic activity (Bhardwaj and Blanchard, 1996). It has been evaluated in clinical trials for its chemopreventative activity for sunlight-induced skin cancers (Bhardwaj and Blanchard, 1996). Melatonin I (pH 7.4) was formulated as a controlled release

Pharmacotherapy for Long Term Care Residents With Dementia Associated Behavioral Disturbance

Summary This journal article summarizes Federal guidelines for benzodiazepine and antipsychotic drug use in long-term care residents with dementia. The Nursing Home Reform Amendments of the Omnibus Budget Reconciliation Act of 1987 (OBRA 87) have resulted in close supervision of the use of unnecessary drugs for residents in Medicare and Medicaid certified nursing homes. They require documenting the behavioral indication for psychotropic drugs, monitoring their safety and efficacy, drug holidays, behavioral management instead of drugs when possible, and systematic dose reductions unless clinically contraindicated. Long-acting benzodiazepines generally are not recommended for use in older patients. Short-acting benzodiazepines may be used for anxiety, insomnia, and dementia-associated agitated states that represent a danger to the patient or others. Antipsychotics may be used for dementia with psychotic features, continuous crying or screaming that impairs functional status, and...

Local Administration of Selective and Nonselective 5HT2 Receptor Ligands to Laboratory Animals

Intraraphe or microiontophoretic administration of DOI inhibits the firing of sero-tonergic neurons in the DRN and reduces the extracellular concentration of 5-HT (Garratt et al. 1991). Notwithstanding the above, microinjection of DOI into the DRN results in the suppression of REM sleep (Table 20.3). Pretreatment with EMD 281014 or SB 243213 prevents the DOI-induced suppression of REM sleep, which indicates that it is mediated by the 5-HT2A and 5-HT2C receptors located in the DRN (Monti and Jantos 2006b). From a functional point of view, two types of GABA-ergic cells are found in the DRN GABA-ergic interneurons that project to 5-HT cells and contribute to the decrease of their activity during SWS and long-projection GABA-ergic interneurons that are responsible for REM sleep suppression (Ford et al. 1995). Activation of long-projection GABA-ergic interneurons by DOI would inhibit the activity of cholinergic cells in the LDT PPT nuclei and decrease REM sleep. Amici et al. (2004) locally...

Evidence for Oxidative Stress in Alzheimers Disease

Another indicator of oxidative stress in AD is glutamine synthetase, an enzyme which is highly sensitive to oxidative stress. Reduced activity of glutamine synthetase has been reported in the AD brain (Smith et al., 1991). Direct evidence of enhanced lipid peroxidation in the brains of AD patients has also been reported (Subbaro et al., 1990). More recent evidence comes in the form of antioxidant protection against the development of AD lesions (e.g. EUK8, melatonin and vitamin E) (Behl et al., 1992 Bruce et al., 1996 Pappolla et al., 1997) and the decreased levels of endogenous antioxidants in AD (reviewed by Shinobu and Beal, 1997).

Antioxidants In Neuroprotection In Vitro

Tective potential in vitro and in vivo. The most prominent lipophilic antioxidant is vitamin E which has not only a protective activity against Ap toxicity, but also against other oxidative challenges such as glutamate (33). On the other hand, it is known that vitamin E does not easily pass the blood-brain barrier, which makes it hard to enrich a powerful antioxidant in brain tissue in general (39). Therefore, the search for antioxidants with an increased permeability for endothelial tissues is very important and may lead to more effective antioxidant neuroprotection. Among the various other compounds that have been tested for an antioxidant activity against Ap toxicity or glutamate toxicity in vitro is also the pineal hormone melatonin, the 21-aminosteroids (lazaroids), and the prominent glucocorticoid and progesterone receptor antagonist RU 486 (mifepristone) (25,40,41). Rl, R2 H Rl, R2 H A second row of examples with neuroprotective activity consists of the group of indole...

Pharmacogenetics and Personalized Medicine

For example, rare variants of the human orexin-2 hypocretin-2 (OX2R) receptor, the ProlOSer and ProllThr variants (10), have been associated with mild sleep disorders (11). Evidence that these single-nucleotide polymorphisms (SNPs) have lower efficacy for orexin ligands in sleep disorder patients who carry the variants suggests that the receptors might be useful as reagents in drug development (11). This example suggests the potential for personalized medicine that considers identifying the best pharmacological agent for a given variant, however rare it may be. The more moderate changes in signaling, while not always associated with disease, may have significant effects on drug efficacy in a clinical setting (3). Similar phenomena are reviewed with respect to many GPCR systems.

Drug Treatments For Autism

Despite many trials to identify drugs that affect social interactions, no medication has been shown to unambiguously modify the core or associated symptoms in individuals with autism. Recent reviews describe drug treatment strategies for various associated symptoms commonly found in autism (Hollander et al., 2003). For instance, a-adrenergic agents, P- blockers and typical and atypical antipsychotic agents are prescribed to decrease aggressive behaviours. Selective serotonin reuptake inhibitors are used for treatment of the anxiety or for stereotypes and repetitive behaviours. Dopamine reuptake blocking agents, stimulants and a-adrenergic agents are used for hyperactive patients, and finally antidepressants, anticonvulsants and melatonin have shown some benefits for sleep disorders. However, none of these treatments can definitely improve the severe symptoms in autistic patients and it is some times necessary to try several of them before to observe a slight effect. Behavioural...

Neuroendocrine Alterations

Reduction of stage 4 non-REM, or deep sleep, which also leads to reduced pressure pain thresholds, increased aching and fatigue.46 FMS patients are frequently more painful and tender in the morning and experience significant morning stiffness, this is lessened after nights where they have had more restful sleep. Although a cause and effect relationship has not been established, this does appear to be an important factor in FMS.

Project Title Benzodiazepineinduced Gabaa Receptor Plasticity

Summary The GABA inhibitory synaptic system plays a major role in the central nervous system and is implicated in human neurological and psychiatric disorders such as epilepsy, stress, anxiety and panic disorders, sleep disorders, and drug dependence, especially to benzodiazepines and ethanol. The major postsynaptic GABA receptors involved in rapid inhibitory neurotransmission are the GABA A receptors (GABA). GABAR proteins are subject to regulation at the level of transcription, translation, assembly, cell targeting, and the functional level. Endogenous regulation includes modulation by phosphorylation, zinc ions, and neuroactive steroids. GABAR are the known target of numerous clinically relevant drugs, including anti-epileptic anti-anxiety, and sedative hypnotic aesthetic agents. These include the widely used benzodiazepines, barbiturates, and possibly alcohol. GABAR are widely accepted as the major candidate molecular target of general anesthetic action. Their predominant role in...

Project Title Chronic Benzodiazepines Behavior And Neurochemistry

Summary Benzodiazepine agonists continue to be the principal pharmacologic option available for the treatment of anxiety, panic disorders, and insomnia. Despite an overall record of efficacy and safety that is generally favorable, concerns regarding tolerance, dependence, withdrawal syndromes, and abuse of benzodiazepines remain issues of medical and public health importance. Also of concern is the usage of these agents by the elderly, who may have increased susceptibility to adverse CNS depressant effects. There is continuing need for basic mechanistic data on the causes and consequences of tolerance and withdrawal such data can form the basis for strategies to identify patients at highest risk, or to develop other pharmacologic interventions to minimize the risk of tolerance and dependence. We propose to continue and broaden our ongoing research program having this overall objective. The core of the model involves male CD-1 mice that receive continuous infusions of benzodiazepine...

Structures Compounds that Control Rhythms

Rhythms can be generated by exogenous sources or can be produced endogenously by a physiological clock.2-6 The daily light dark cycle is the best-known exogenous source that can set and regulate daily rhythms. This cycle is primarily conveyed to the nervous system by the retina. The site of the biological clock is the suprach-iasmatic nucleus of the hypothalamus6 and this nucleus receives input from the retina to synchronize the endogenous rhythms with the exogenous light dark cycle (Figure 12.2). Another site that contributes to timing mechanisms is the pineal gland. In mammals, this gland receives rhythmic neural information from the suprachiasmatic nucleus and produces a hormone, melatonin, in response. Melatonin (5-methoxy- -acetyltryptamine) can modulate the biological clock as well as provide a hormonal signal to other cells to produce coordinated rhythmic responses.7 Melatonin is currently used to reset circadian rhythms as a jet lag treatment and is used to induce sleep. It is...

Animal Experiments 1 Rhythms that Can be Measured

Besides analyzing the rhythmic nature of seizures, investigators can also examine other well-characterized rhythms and compare these rhythms to the seizure rhythm. Examples of other rhythms studied include locomotor activity (wheel running), body temperature, heart rate, feeding, and drinking. In the past, the easiest rhythms to measure were wheel running activity or feeding and drinking rhythms. However, with the advent of implantable transmitters (Table 12.1), generalized activity, body temperature, and heart rate can be measured in the same animal with relative ease. More difficult rhythms to determine include plasma levels of cortisol or melatonin, although some investigators have routinely measured these hormones with the use of indwelling venous catheters.

Is Depression Associated With Activation Of The Immune System

In his review of the immune changes that are observed in depressed patients, Irwin (this volume) points out that it is premature to throw the baby with the bath water. From the data available on lymphocyte functions, it is clear that depressed patients have a decreased number of lymphocytes, reduced mitogen-induced lymphocyte proliferation, and decreased NK cell activity. Some of these changes could be due to sleep disorders rather than to depression per se, and they might be associated with an increased sensitivity to certain viruses. Alternatively, a sleep disorder and or a viral infection may be integral parts of a depressive state. For example, sleep may be affected by immune response to a viral infection (Krueger and Majde, 1994). Molecular and cellular changes may underlie neurobehavioral changes resulting in a specific depressive state. A depressive state may be an integral sum of discernable and quantifiable behaviors out of tune with each other. This disharmony may be better...

Generalized Anxiety Disorder

Head-to-head comparisons between paroxetine and other medications in the treatment of GAD are sparse. One such study compared paroxetine 20-50 mg day with escitalopram 10-20 mg day (Bielski et al. 2005). Although there was no significant difference in efficacy between the two medications, as measured by the Ham-A, the authors noted considerably higher rates of adverse events, leading to withdrawal from the trial, in patients treated with paroxetine compared with those treated with escitalopram (22.6 vs. 6.6 ). Treatment-emergent side effects recorded more frequently with paroxetine therapy included insomnia, constipation, ejaculation disorder, anorgasmia, and decreased libido. Conversely, diarrhea and upper respiratory tract infection were more common with escitalopram than with paroxetine. One possible explanation for the divergence in dropout rates may be the seeming disparity in dose ranges between the two medications. Paroxetine was titrated to high-normal doses (between 30 and 50...

Do The Brain Action Of Cytokines And The Symptoms Of Depression Share Common Mechanisms

The analogy that has been drawn between brain effects of cytokines and symptoms of depression appears to be similar in its principle to the one that was proposed some time ago for CRH and depression. Like the macrophage theory of depression, the hypothesis of a causal role of CRH in the pathophysiology of depression has been built up on the convergence of two sets of data. At the experimental level, CRH infusion into the brain of laboratory rodents has been shown to induce depression-like signs, including sleep disorders, reduced appetite, decreased sexual behavior, and anxiety. At the clinical level, depressed patients are known to have an hyperactive HPA axis, as evidenced by higher levels of CRH in the cerebrospinal fluid, increased plasma Cortisol levels, and resistance to the dexamethasone suppression test. In line with the CRH hypothesis of depression, and as proposed by Miller et al in their chapter, proinflammatory cytokines would play a causal role in depression mainly...

Rhythms that Can be Measured

Virtually all of the rhythms that can be determined in animals can also be determined in humans. However, the methods for collecting these rhythms are quite different. General activity can be determined with the use of a wrist watch sized monitor (Ambulatory Monitoring, Inc., Ardsley, NY) (Table 12.1). Body temperature and heart rate can be assessed by placement of specific transceivers that relay the information to dedicated computers. Subjects can also have sequential blood samples collected for determination of hormonal rhythms, such as cortisol or melatonin.11

Immune Alterations In Depressed Patients

The increase of cytokines during depression may have an adaptive value as suggested by the data of Bauer, Hohagen, Gimmel, Bruns, Lis, Krieger, Ambach, Guthmann, Grunze, Fritsch-Montero, Weissbach, Ganter, Frommberger, Riemann, & Berger (1995). In patients with major depression, administration of endotoxin induced an increase of TNF and IL-6 plasma levels, as well as a higher expression of IL-l i mRNA in LPS-stimulated mononuclear blood cells. Interestingly, these cytokine changes were associated with an increase in body temperature, a transient suppression of REM sleep, and an improvement of depression, even though this improvement was only transient and usually followed by a relapse. Moreover, a correlation was observed between maximal plasma concentrations of IL-6 reached after endotoxin adminstra-tion and the decrease of Hamilton scores.

Synthesis Of Zolantidine

To classify HA responses, since these compounds share many activities but differ by several hundred-fold in their anti-H1 activity (Hill et al. 1997). The classical H1 antagonists have very good anti-allergic properties, and are also used widely as over-the-counter sleep aids.

Advantages And Limitations Of Biochemical And Biophysical Approaches

A potential limitation of BRET is the inability to clearly localize the receptor interaction. Imaging GPCR dimers through FRET microscopy has been performed (58,62). Furthermore, through the use of receptor-specific antibodies, dimers and oligomers could be monitored in native tissues. Imaging of BRET has been performed on Escherichia coli colonies (70) and in Chinese hamster ovary (CHO) cell extracts (95). Single-cell BRET was performed on the melatonin MT1R and MT2R expressed in HEK293 cells however, subcellular resolution was not observed (86). The development of BRET imaging to detect and localize GPCR dimers and oligomers within a single cell would represent a significant advance in this technology and allow the fate of dimers and oligomers to be monitored following agonist activation, signaling, and receptor trafficking to and from the cell surface. The development of alternative BRET donor and acceptor molecules that could be conjugated to receptor-specific antibodies would...

Modulation of Neurotransmission by Docosahexaenoic Acid

In addition, DHA modulates expression of genes for cytokines and their receptors, cell adhesion molecules, cytoskeleton proteins, and hormone receptors. The effect of DHA is sustained as long as DHA remains in the diet. Thus, DHA acts like a hormone to control the activity of key transcription factors, and modulates a variety of neural cell functions 44, 4850 . Collective evidence suggests that DHA modulates the expression of a number of genes with such broad functions as DNA binding, transcriptional regulation, transport, cell adhesion, cell proliferation, raft formation, membrane protrusions and membrane localization. These effects, in turn, may significantly modify cell function, development and or maturation. Collective evidence suggests that n-3 fatty acid-deficient diet through interactions with various neurotransmitter receptors produces symptoms of chronic locomotor hyperactivity, disturbance in melatonin rhythm, and striatal hyperdopaminergia. It is suggested that an n-3...

Role of 5HT2A and 5HT2C Receptors in the Regulation of the Behavioral State

Popa et al. (2005) investigated the role of the 5-HT2A receptor on non-rapid-eye-movement (NREM) sleep and W regulation using wild-type and knockout mice that do not express the 5-HT2A receptor. 5-HT2A receptor knockout mice showed a significant increase of W and a reduction of NREM sleep. Values of REM sleep were not significantly different from those found in the wild-type mice. Systemic administration of the selective 5-HT2A receptor antagonist MDL 100907 significantly augmented NREM sleep and decreased W and REM sleep in the wild-type mice only. Sleep has been characterized also in 5-HT2C receptor knockout mice (Frank et al. 2002). Mice lacking the 5-HT2C receptor had significantly less NREM sleep and greater amounts of W compared with the wild-type animals. In contrast, REM sleep values remained unchanged in the mutant mice. Since 5-HT2A and 5-HT2C receptors are positively coupled to PLC via G proteins and mobilize intracellular Ca2+, a reduction of W and an increase of NREM...

Historical Background And Classical Receptor Theory

What is considered a given today, namely that drugs interact with specific binding sites on the cell membrane called receptors, is an extremely important tenet of pharmacology. As stated by Rang 1 , it indeed was Pharmacology's big idea. The main reason it is such an important cornerstone of pharmacology is that it introduces order into the apparent chaos of physiology. For example, a simple molecule such as epinephrine mediates a myriad of physiological processes. A large subset of these, namely cardiac chronotropy, inot-ropy, lusitropy, vascular relaxation, lacrimal, pancreatic, and salivary gland secretion, bronchiole, uterine and urinary bladder muscle relaxation, decreased stomach motility, skeletal muscle tremor, and melatonin synthesis are mediated by a small subset of membrane-bound proteins, specifically p1- and p2-adrenoceptors. This immediately puts order in the collection of physiological processes in that it gives them a common place to start, namely the interaction of...

Agents Depleting Neurotransmitter Stores

Structure Guanethidine Oxide

Folk remedies prepared from species of Rauwolfia, a plant genus belonging to the Apocynaceae family, were reported as early as 1563. The root of the species Rauwolfia serpentina has been used for centuries as an antidote to stings and bites of insects, to reduce fever, as a stimulant to uterine contractions, for insomnia, and particularly for the treatment of insanity. Its use in hypertension was recorded in the Indian literature in 1918, but not until 1949 did hypotensive properties of Rauwolfia spp. appear in the Western literature.51 Rauwolfia preparations were introduced in psychiatry for the treatment of schizophrenia in the early 1950s, following confirmation of the folk remedy reports on their use in mentally deranged patients. By the end of the 1960s, however, the drug had been replaced by more efficacious neurotropic agents. Reserpine and its preparations remain useful in the control of mild essential hypertension.

Midazolam Log P 367 t12 2 h

Mt3 Receptores

Zolpidem (Ambien, an imidazopyridine) and eszopiclone (Lunesta, a cyclopyrrolone) are nonben-zodiazepines and have been introduced as short- and moderate-acting hypnotics, respectively. Zolpidem exhibits a high selectivity for the ai subunit of benzodiazepine-binding site on GABAA receptor complex, whereas es-zopiclone is a superagonist at BzRs with the subunit composition a1p2j2 and a1j2y3. Zolpidem has a rapid onset of action of 1.6 hours and good bioavailability (72 ), mainly because it is lipophilic and has no ionizable groups at physiological pH. Food can prolong the time to peak concentration without affecting the half-life probably for the same reason. It has short elimination half-life, because its aryl methyl groups is extensively a-hydroxylated to inactive metabolites by CYP3A4 followed by further oxidation by aldehyde dehydrogenase to the ionic car-boxylic acid. The metabolites are inactive, short-lived, and eliminated in the urine. Its half-life in the elderly or the...

Petra Kapkova Vildan Alptuzun Eberhard Heller Eva Kugelmann Gerd Folkers and Ulrike Holzgrabe

Several substances of peptidic and non-peptidic origin with anti-amyloid potencies were reported. Among the latter are endogenous compounds such as melatonin, rifampicin, benzofuran, and naphthylazo derivatives,810 classical antibiotics such as tetracycline and doxycycline,11 and cyclodextrins.12 Other researchers have patented several isoindoline13 and piperidine14 derivatives that inhibit amyloid protein aggregation and deposition.

Regulation Of Retinal Pigment Epithelium Transport By Hormones And Agonists

RPE is unique in its regulation of ion transport by autocrine and exocrine factors. For example, growth factors, pyrimidines and changes in tonicity could trigger ATP release into the subretinal space. Apical ATP (or UTP) increases Ca2+ , and basolateral membrane Cl-conductance, while decreased apical membrane K+ conductance, a response that is blocked by the P2-purinoceptor blockers suramin and DIDS (138). Activation of P2Y(2) receptors in vivo directly stimulates rabbit RPE active transport as evidenced using the P2Y(2) receptor agonist, INS542 (139). Maminishkis et al. (140) have shown that P2Y(2) agonists (e.g., INS37217) increase Ca2+ , and stimulate RPE fluid transport in vitro, and retinal reattachment in rats, and therefore may be therapeutically useful for treating retinal disorders associated with fluid accumulation in the subretinal space. While RPE cells can release apical ATP, they also release ATP-hydrolyzing enzymes, and ADP has been detected in ARPE-19 media (141)....

Hypothalamic Pituitary Adrenal HPA Axis in Depression CRF

Neurotransmitters Concentration

As already noted, the inter-relatedness of catecholamine and serotonin systems in the brain with modulation of neuroendocrine function makes it difficult to address cause vs. effect as reflected in the above examples. An additional issue is that many of the observed abnormalities involve a circadian component, which, in other words, may only show differences at certain times of day, which leads to an interest in a pathophysiologic role of altered circadian regulation (104), particularly in terms of seasonal affective disorder (105). Melatonin secretion varies over the 24 h period in a circadian pattern related to light and darkness. Its secretion is partly under norepinephrine control and exogenous melatonin and or using light to shift the phase of endogenous melatonin may have a role in the treatment of circadian disorders under which seasonal affective disorder can be subsumed (105). It has also been suggested that blunted circadian variation in natural killer cell activity in...

Ghb Interpretation Issues And Postmortem Production

The most difficult aspect of GHB analysis is interpretation of the numbers that are generated. Helrich et al. (1964) correlated blood concentrations of GHB with state of consciousness in 16 adult human patients (Table 11.4). This study revealed that GHB blood concentrations as high as 99 mg mL-1 could be achieved with the patient still displaying an 'awake' state, the subject spontaneously coming in and out of consciousness characterized a light sleep state. Subjects in the medium sleep state were clearly asleep but were able to be roused. At the highest concentrations studied, GHB produced a deep sleep characterized by response to stimuli with a reflex movement only. It is clear from these data that blood concentrations of GHB display a large overlap across the four states of consciousness described. For example, a subject with a blood concentration of 250 mg mL-1 could be in a light, medium or deep sleep state. The smallest dose given, 50 mg kg-1, produced peak plasma concentrations...

Muscle Antispasmodics

Generally, antispasmodic agents are to be used for acute pain arising from muscle strain or injury (see Table 5-14). Baclofen might be indicated for more chronic pain arising from muscle spasticity (e.g., after stroke or severe spinal cord injury). The utility of these agents for long-term use is unclear. There may be abuse potential associated with carisoprodol and methocarbamol. Cariso-prodol is metabolized to meprobamate therefore, ongoing use might possibly lead to meprobamate dependence. Abrupt discontinuation of carisoprodol may produce mild withdrawal, including abdominal cramps, insomnia, nausea,

Perspectives For Pharmacogenetic Research Into Eating Disorders And Obesity

Sibutramine is a selective inhibitor of the presynaptical reuptake of serotonin and norepinephrine, leading to enhanced central serotonin and norepinephrine neurotransmission which is associated with decreased sensations of hunger and increased feeling of satiety besides, sibutramine leads to a slightly enhanced basal metabolic rate (Hansen et al., 1999). Sibutramine has the following side effects xerostomia, insomnia, obstipation and a mild increase of blood pressure and heart rate.

Caffeine and benzodiazepines

Benzodiazepines are widely used for the treatment of anxiety and insomnia as well as a variety of other disorders. In most countries they are available on medical prescription. Problems of dependence and abuse have been recognized for some time, although the dependence potential of these drugs remains a matter of contention.14 In addition to their anxiolytic and hypnotic effects, benzodiazepines produce sedation, muscle relaxation, and cognitive and psychomotor impairment.

Toxic Side Effects of As2O3

Instead, As2O3 induces leukocytosis in about 50 of patients.11,13,36 The leuko-cytosis can resolve in all cases without chemotherapy.87 The APL patients on As2O3 can also develop retinoic acid syndrome (RAS)-like symptoms such as fever, skin rash and edema, which can be readily relieved by steroid administra-tion.88 Other mild effects were reported in about 40-50 of relapsed patients, including fatigue, fever, edema, nausea, anorexia, diarrhea, emesis, headache, insomnia, cough, dyspnea, dermatitis, tachycardia, pain, hypokalemia, hypo-magnesemia and hyperglycemia. The most common (> 10 ) Grade 3 and 4 adverse events were abdominal pain, epistaxis, dyspnea, hypoxia, bone pain, thrombocytopenia, neutropenia, hypokalemia and hyperglycemia.11,36,89 In a clinical trial, prolonged QT intervals (the time intervals for the contraction of the ventricle from the beginning of the Q wave to the end of T wave a prolonged QT interval indicates cardiac toxicity) were observed in all patients...

Effects of Typical and Atypical Antipsychotics on Sleep in Schizophrenia Patients

Typical antipsychotic drugs including haloperidol, thiothixene, and flupentixol have been shown to reduce stage 2 sleep latency and to increase total sleep time and sleep efficiency. Stage 4 sleep and SWS remained unchanged, whereas REM latency was significantly increased (Taylor et al. 1991 Nofzinger et al. 1993 Wetter et al. 1996 Maixner et al. 1998). Olanzapine given to schizophrenia patients or healthy subjects reduced stage 2 sleep latency and wake time after sleep onset, whereas total sleep time and sleep efficiency were enhanced. Concerning sleep architecture, stage 1 sleep was decreased, whereas stage 2 and SWS were augmented. On the other hand, olanzapine tended to disrupt REM sleep as judged by the reduction of REM sleep duration and the increase of REM latency (Salin-Pascual et al. 1999 Sharpley et al. 2000 Muller et al. 2004). The limited information on risperidone tends to indicate that the compound improves sleep maintenance and increases SWS in schizophrenia patients...

Isbn 978 0 85369 659

Glucosamine 19 Chondroitin 20 Methylsulfonylmethane 21 Coenzyme Q10 22 Melatonin 23 Carnitine 24 Acetyl-L-carnitine 26 Octacosanol policosanol 27 S-Adenosyl methionine 28 Polyunsaturated fatty acids 29 n-3 Fatty acids from fish oils 30 7-Linolenic acid 31 Flaxseed a-linolenic acid 32 Conjugated linoleic acid 33 Flax lignans 34 Pycnogenol 35 Resveratrol 37 Octacosanol policosanol 136 Pycnogenol 138 Melatonin 140 Melatonin 183 Miscellaneous 188 References 188 n-3 Polyunsaturated fatty acids 212 Coenzyme Q10 214 Melatonin 215 Conjugated linoleic acid 218 Overall conclusions 220 References 220 Osteoporosis 231 Melatonin 233 L-Carnitine 235 Polyunsaturated fatty acids 237 Conjugated linoleic acid 239 Soy isoflavones 240 Conclusion 242 References 242 Soy isoflavones 293 Coenzyme Q10 294 Glucosamine 294 Melatonin 294

Tricyclic Antipsychotic Agents

Antipsychotic drugs share many pharmacological effects and therapeutic applications. Chlorpro-mazine and haloperidol are prototypic of the older, standard neuroleptic-type agents. Many antipsychotic drugs, especially chlorpromazine and other agents of low potency, have a prominent sedative effect. This is particularly conspicuous early in treatment, although some tolerance typically develops and can be of added value when very agitated psychotic patients are treated. Despite their sedative effects, neuroleptic drugs generally are not used to treat anxiety disorders or insomnia, largely because of their adverse autonomic and neurologic effects, which paradoxically can include severe anxiety and restlessness (akathisia). The risk of developing adverse extrapyramidal effects, including tardive dyskinesia, following long-term administration of neuroleptic drugs makes them less desirable than several alternative treatments for anxiety disorders (see Chapter 17).

Epinephrine and Norepinephrine

Between periods of rapid-eye movements (REM), which is associated with dreaming, and non-REM sleep. Changes in the release of norepinephrine, serotonin, and acetylcholine are observed during and between these sleep phases. During deep sleep, norepinephrine levels decline and serotonin levels rise, while REM sleep is thought to be induced by the release of norepinephrine and acetylcholine 7 .

Efficacy of 5HT2C Antagonists Alone and in Combination with SSRIs in Clinical Treatment of Depression

Several compounds that are clinically effective antidepressants are potent 5-HT2C antagonists (Millan 2006). Nefazodone, trazodone, and remeron all block 5-HT2C receptors however, their pharmacological profile also encompasses blockade of 5-HT2A receptors as well as histamine 1 and alpha 2 receptors (Hyttel 1982). Agomelatonine is a potent 5-HT2C antagonist that has been shown to be effective in treatment of major depression. However, this compound also activates melatonin receptors, which prevents concluding that the clinical effectiveness is merely due to blockade of 5-HT2C receptors (Goodwin et al. 2009). Depression is characterized by a high degree of comorbidity with closely related dysfunctions like anxiety and insomnia (van Mill et al. 2010). Although the efficacy of treatment of depression with selective 5-HT2C antagonists remains to be elucidated, it has been shown that blockade of 5-HT2C receptors alleviates anxiety and improves quality of sleep (Stahl et al. 2010)....

Administration of Nonselective 5HT2 Receptor Ligands to

Idzikowski et al. (1986) characterized for the first time the effect of acute administration of ritanserin 10 mg on nocturnal sleep in healthy subjects. Administration of the 5-HT2A 2C receptor antagonist in the morning (8 00 am) significantly increased SWS (stages 3 and 4) and reduced stage 2 sleep. REM sleep was also suppressed when the compound was given in the evening (10 30 pm). Idzikowski et al. (1987) investigated also the effect of repeated morning administration of ritanserin 10 mg on sleep of healthy volunteers. After 2 weeks ritanserin treatment SWS remained increased. The increase of SWS was coupled with a reduction of stage 2 sleep. All other whole-night measures remained unchanged. During the comparison of 1, 3, 10, and 30 mg ritanserin, a clear dose-response relationship was observed for the 5-HT2 antagonist with greater doses inducing increased duration of SWS (Idzikowski et al. 1991). Ritanserin 10 mg discontinuation following daily administration for 8 weeks was not...

Benzodiazepines As Anxiolytic Agents

The treatment of anxiety and sleep disorders is dominated by the BZDs. These drugs induce sleep (act as hypnotics) in high doses and lead to sedation and reduced anxiety (anxiolytic) at lower doses. They function by an enhancement of the GABA-mediated inhibition of the CNS and act in an allosteric manner on the GABA receptor. The discovery of the

Aloe Vera- As A Treatment For Lung Cancer

The only clinical study on record on the antitumor activity of Aloe vera demonstrated that an aloe and melatonin combination might delay the onset of metastasis in patients with advanced-stage solid tumors, including breast cancer.164 Aloe is very safe when applied either orally and topically, and it also appears to be safe when injected in high doses. The FDA's approval of Aloe vera as a flavoring agent is a further indication of its safety.165 The benefits associated with the use of aloe may provide great impetus to the research community to design and implement further controlled studies on this important plant.

Proapoptotic Properties Of Antioxidants

Antioxidants such as melatonin and retinoic acid have oncostatic properties. They have been shown to suppress the growth of hormone-responsive breast cancer. Using the estrogen receptor-positive MCF-7 human breast tumor cell line, it has been shown that a sequential treatment regimen of melatonin followed by all-trans retinoic acid arrests breast tumor cell proliferation in vitro by enhancing apoptosis (Eck et al., 1998). Antioxidant vitamins in combination with direct-acting apoptotic agents (X-rays, chemo-therapeutic agents, and hyperthermia) or in combination with indirect-acting apoptotic agents (adenosine 3',5'-cyclic monophosphate, butyric acid, and interferon) produce a greater extent of apoptotic death in cancer cells in culture. In contrast to vitamin-induced apoptosis in cancer cells, normal cells never undergo apoptotic death after treatment with vitamins, not including retinoids (Cole and Prasad, 1997).

Melanophore Response to cAMP

A melanophore cell line was obtained from X laevis skin. Aggregation of melanosomes filled with melanin in the center of the cell and or their movement throughout the cytoplasm results in white-black color transformation of the cells. The distribution of the melanosomes is dependent upon intracellular levels of cAMP. In nature, activation of the MSH receptor on the cell surface couples the receptor to its G-protein leading to signal transduction and elevation in intracellular cAMP levels. This results in the dispersal of melanosomes producing a camouflaging pigment for the frog. Melatonin has the opposite effect of MSH in that it inhibits cAMP accumulation and causes melanosomes aggregation. The dispersal-aggregation of the melanosomes is related to the cAMP dependent phosphorylation-dephosphorylation of a protein associated with the melanosomes. Messenger systems other than cAMP, such as the phospholipase C pathway and PIP2 hydrolysis, can also cause dispersal of the...

Defect In Mitochondrial Oxidative

Other areas of the brain such as globus pallidus or cerebral cortex. Therefore, the specificity of mitochondrial impairment may play a role in the degeneration of nigrostriatal dopaminergic neurons. This view is supported by the fact that MPTP generating MPP+ destroys dopaminergic neurons in the substantia nigra (37). Mitochondrial respiratory complex I is also inhibited by 6-hydroxydopamine and the said effect is inhibited by desferoxamine (38). Moreover, 6-hydroxydopamine causes apoptosis and the said effect is prevented by melatonin (39).

Drug Treatment Of Psychoses

Neuroleptic agents are effective antipsychotics and are superior to sedatives (e.g., barbiturates and benzodiazepines), or alternatives (e.g., ECT, other medical or psychological therapies). The target symptoms for which antipsychotic agents are especially effective include agitation, com-bativeness, hostility, hallucinations, acute delusions, insomnia, anorexia, poor self-care, negativism, and sometimes withdrawal and seclusiveness. More variable or delayed are improvements in motivation and cognition, including insight, judgment, memory, orientation, and functional recovery. The most favorable prognosis is for patients with acute illnesses of brief duration who had functioned relatively well prior to the illness.

Systemic Administration of Selective and Nonselective 5HT2 Receptor Ligands to Laboratory Animals

Systemic administration of the 5-HT2A 2C receptor agonists DOI or (DOM) has been shown to reduce SWS and REM sleep and to augment W in the rat (Dugovic and Wauquier 1987 Dugovic et al. 1989 Monti et al. 1990). In addition, systemic or intrathalamic injection of DOI decreased the neocortical high-voltage spindle activity that occurs during relaxed W in the rat (J k l et al. 1995). The intraperitoneal (IP) and oral (p.o.) DRN dorsal raphe nucleus, LDT laterodorsal tegmental nucleus, W waking, SW slow wave sleep, REMS REM sleep, n.s. nonsignificant, increased, decreased DRN dorsal raphe nucleus, LDT laterodorsal tegmental nucleus, W waking, SW slow wave sleep, REMS REM sleep, n.s. nonsignificant, increased, decreased administration of the selective 5-HT2C receptor agonists RO 60-O175 ORG 35030 or RO-60-0332 ORG 35035 methyleth-ylamine induced also an increase of W and a reduction of REM sleep in the rat (Martin et al. 1998) (Table 20.3). Injection of the 5-HT2A 2C receptor antagonists...

Family 1 GPCRs

Angiotensin, bombesin, bradykinin, C5a anaphylatoxin, APJ-like, Fmet-leu-phe, interleukin-8, chemokine, CCK, endothelin, melanocortin, neuropeptide Y, neurotensin, opioid, somatostatin, tachykinin, thrombin, melatonin vasopressin, galanin, orexin, urotensin II, GnRH, TRH, GRH


Because depression is a treatable disorder, the practitioner should assess all chronic pain patients for this illness. While some patients may admit feelings of sadness, many patients deny or minimize the likelihood of being depressed. Thus, the practitioner should also screen the patient for symptoms characteristically found in depression, including anhedonia, fatigue, insomnia, appetite changes, and suicidal ideation. If a patient does admit to suicidal thoughts and impulses, the practitioner should contact psychiatric services and consider hospitalization to protect the patient.


Untoward effects of ephedrine include hypertension and insomnia. Tachyphylaxis may occur with repetitive dosing. Usual or higher-than-recommended doses may cause adverse cardiovascular effects in individuals with underlying cardiovascular disease. Herbal preparations containing ephedrine (ma huang, ephedra) are widely utilized these preparations vary in their content of ephedrine thus, their use may lead to inadvertent consumption of dangerously high doses of ephedrine and its isomers. Because of this, the FDA has banned the sale of dietary supplements containing ephedra in the U.S.


Insomnia BZ anxiolytics are recommended for short-term (< 1 month) relief of anxiety and insomnia and as an adjunct Speed of offset is determined by several factors of which the most important is the metabolic half-life of the drug. The first-generation BZs had half-lives of more than 24 h, with active metabolites with even slower clearance rates. While this was useful in conditions such as epilepsy, drug accumulation was an issue when they were used for anxiety and insomnia as it might cause sedation with a risk of fall hip fractures, especially in the elderly. To reduce this problem, lorazepam and alprazolam with a shorter half-life were developed. For hypnotic use, temazepam and triazolam were developed followed by the Z-drugs. All these have short half-lives with low risk of daytime sedation (Table 1).


The use of ma huang, still available over US borders, is highly relevant to the pain practitioner in the perioperative period. The possibility of hypertension causing myocardial ischemia or stroke needs to be considered. Further, ephedra or similar compounds readily available over the counter can potentially interact with general anesthetic agents, such as halothane, isoflurane, desflurane, or cardiac glycosides, like digitalis, to cause cardiac dysrhythmias. Patients taking ephedra for prolonged periods of time can also deplete their peripheral catecholamine stores. Therefore, under general anesthesia, these patients can potentially experience profound intraoperative hypotension which can be controlled with a direct vasoconstrictor (e.g., phenylephrine) instead of ephedrine. Finally, use of ephedra with phenelzine or other monoamine oxidase inhibitors may result in insomnia, headache, and tremulousness and concurrent use with the obstetric drug oxytocin has been resulted in...

Sirens Sleep Solution

Sirens Sleep Solution

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