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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibromyalgia is usually treated by rheumatologists but since co-morbid depression and anxiety are frequent, psychiatrists are likely to be confronted with patients suffering from the syndrome. The symptoms associated with fibromyalgia vary from patient to patient but there is one common symptom-they ache all over. In addition to pain, patients report headaches, poor sleep, fatigue, depressed mood and irregular bowel habits, which are also all symptoms of depression. For a formal diagnosis of fibromyalgia, the American College of Rheumatology (ACR) criteria require the patient to have widespread pain for at least 3 months together with tenderness at 11 or more of 18 specific tender points.Treatment of fibromyalgia requires a comprehensive approach involving education, aerobic exercise and cognitive behavioural therapy in addition to pharmacotherapy. The most effective drugs available for the treatment for fibromyalgia, the serotonin noradrenaline reuptake inhibitors, milnacipran and duloxetine and the anti-epileptic, pregabalin, are well known to psychiatrists. Thus the psychiatrist is well placed to initiate treatment in these patients.
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PMID:The psychiatrist confronted with a fibromyalgia patient. 1947 4

Fibromyalgia is a syndrome of widespread chronic pain associated with sleep disorders, depressed mood, cognitive impairment and fatigue. Its etiology and pharmacopathology are poorly understood but it is thought to result from a dysfunction of central pain processing mechanisms leading to generalised pain sensitisation. Pain perception is the result of a bidirectional process of ascending and descending pathways. Nociceptive input from peripheral afferent neurons is sent via the dorsal horn of the spinal cord to the higher brain centres involved in pain perception. Some descending inhibitory projections to the spinal cord attenuate the nociceptive effects. Numerous neurotransmitters including serotonin, dopamine, noradrenaline and substance P are involved in these processes. In other neuronal pathways in the brain, the same neurotransmitters are involved in mood control, sleep regulation and cognitive function providing a neurochemical substrate for the wide range of symptoms seen in fibromyalgia. Attenuation of neuronal hyperactivity through ligands acting at the alpha2-delta subunits of voltage-dependent calcium channels and increased inhibitory activity of the descending pathways by inhibition of serotonin and noradrenaline reuptake are two mechanisms that are currently exploited by new medication for the treatment of fibromyalgia.
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PMID:Fibromyalgia--pathways and neurotransmitters. 1947 6

Fibromyalgia is a pain syndrome which is not due to tissue damage or inflammation and is thus fundamentally different from rheumatic disorders and many other pain conditions. In addition to widespread pain it is associated with a range of other symptoms such as sleep disturbance, fatigue, cognitive disturbance, stiffness and depressive symptoms. A number of multidisciplinary therapeutic programmes involving education, exercise and cognitive therapy have been shown to be effective in bringing relief. The various medications that are currently being developed for the treatment of fibromyalgia are based on different mechanistic approaches. In particular, serotonin noradrenaline reuptake inhibitors (SNRI) such as duloxetine and milnacipran and alpha2-delta receptor ligands such as pregabalin have been shown, in a variety of placebo-controlled studies, to bring significant relief from pain and other symptoms. The complex symptomatology of fibromyalgia will, however, continue to require a multidisciplinary approach including education and exercise in addition to drug therapy to achieve the most efficient management of fibromyalgia.
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PMID:Fibromyalgia: a complex syndrome requiring a multidisciplinary approach. 1947 7

Duloxetine (Cymbalta(R)) is a potent serotonin and noradrenaline (norepinephrine) reuptake inhibitor (SNRI) in the CNS. It is indicated for the treatment of generalized anxiety disorder (GAD) as well as other indications. In patients with GAD of at least moderate severity, oral duloxetine 60-120 mg once daily was effective with regard to improvement from baseline in assessments of anxiety and functional impairment, and numerous other clinical endpoints. Longer-term duloxetine 60-120 mg once daily also demonstrated efficacy in preventing or delaying relapse in responders among patients with GAD. In addition, duloxetine was generally well tolerated, with most adverse events being of mild to moderate severity in patients with GAD in short- and longer-term trials. Additional comparative and pharmacoeconomic studies are required to position duloxetine among other selective serotonin reuptake inhibitors and SNRIs. However, available clinical data, and current treatment guidelines, indicate that duloxetine is an effective first-line treatment option for the management of GAD. Duloxetine is a potent and selective inhibitor of serotonin and noradrenaline transporters, and a weak inhibitor of dopamine transporters. It has a low affinity for neuronal receptors, such as alpha(1)- and alpha(2)-adrenergic, dopamine D(2), histamine H(1), muscarinic, opioid and serotonin receptors, as well as ion channel binding sites and other neurotransmitter transporters, such as choline and GABA transporters. It does not inhibit monoamine oxidase types A or B. The pharmacokinetics of duloxetine in healthy volunteers were dose proportional over the range of 40-120 mg once daily. Steady state was typically reached by day 3 of administration. Duloxetine may be administered without regard to food or time of day. Duloxetine is highly protein bound and is widely distributed throughout tissues. It is rapidly and extensively metabolized in the liver by cytochrome P450 (CYP) 1A2 and 2D6, and its numerous metabolites, which are inactive, are mainly excreted in the urine. The mean elimination half-life of duloxetine is approximately 12 hours. Duloxetine is a substrate for CYP1A2 and CYP2D6 and a moderate inhibitor of CYP2D6. Concomitant use of duloxetine and potent CYP1A2 inhibitors should be avoided and duloxetine should be used with caution in patients receiving drugs that are extensively metabolized by CYP2D6, particularly those with a narrow therapeutic index. Duloxetine was effective in the short-term treatment of patients with primary GAD of at least moderate severity. In four randomized, double-blind, placebo-controlled, multicentre, phase III trials, duloxetine 60-120 mg once daily for 9 or 10 weeks was significantly more effective than placebo with regard to the primary endpoint of mean change in Hamilton Anxiety Rating Scale (HAM-A) total score from baseline to study endpoint. In addition, all other endpoints were generally improved from baseline to a greater extent with duloxetine 60-120 mg once daily than with placebo. Duloxetine also improved patient role functioning (assessed using Sheehan Disability Scale global impairment functioning scores), health-related quality of life and patient well-being compared with placebo. Duloxetine was effective in patients with GAD who were aged >/=65 years. Pooled results of data from the two short-term efficacy trials that also included an active comparator arm showed that the mean change in HAM-A scores with duloxetine relative to placebo were of the same magnitude as those with venlafaxine extended release versus placebo. Duloxetine 60-120 mg once daily was also more effective than placebo in preventing or delaying relapse in responders to duloxetine in a longer-term study. In this study, patients with GAD received duloxetine during a 26-week, open-label, acute treatment phase and responders were then randomized to continue on duloxetine or receive placebo during a 26-week, double-blind, continuation phase. Time to relapse was significantly longer in duloxetine recipients than in placebo recipients. In addition, significantly fewer duloxetine recipients than placebo recipients relapsed during the double-blind phase of the trial and more duloxetine recipients achieved remission. Short- (9-10 weeks) and longer-term (52 weeks) treatment with duloxetine 60-120 mg once daily was generally well tolerated in patients with GAD, with the majority of adverse events being of mild to moderate severity. Nausea, dry mouth, headache, constipation, dizziness and fatigue were among the most common treatment-emergent adverse events. The adverse event profile of duloxetine did not differ with dose or treatment duration. Significantly more patients receiving short-term duloxetine than placebo discontinued treatment because of an adverse event, with nausea being the only event that resulted in significantly more treatment discontinuations in duloxetine recipients than in placebo recipients. Serious adverse events were uncommon with both short- and longer-term duloxetine treatment. Two episodes of attempted suicide and one episode of completed suicide occurred in duloxetine recipients during the 24-week open-label phase of a longer-term trial. No deaths or suicides were reported in any of the short-term trials. Discontinuation-emergent adverse events, most commonly nausea and dizziness, occurred in up to one-third of duloxetine recipients in the short-term trials.
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PMID:Duloxetine: a review of its use in the treatment of generalized anxiety disorder. 1948 Apr 70

Recent advances in neurobiology have aided our understanding of attention-deficit hyperactivity disorder (ADHD). The higher-order association cortices in the temporal and parietal lobes and prefrontal cortex (PFC) interconnect to mediate aspects of attention. The parietal association cortices are important for orienting attentional resources in time/space, while the temporal association cortices analyse visual features critical for identifying objects/places. These posterior cortices are engaged by the salience of a stimulus (its physical characteristics such as movement and colour). Conversely, the PFC is critical for regulating attention based on relevance (i.e. its meaning). The PFC is important for screening distractions, sustaining attention and shifting/dividing attention in a task-appropriate manner. The PFC is critical for regulating behaviour/emotion, especially for inhibiting inappropriate emotions, impulses and habits. The PFC is needed for allocating/planning to achieve goals and organizing behaviour/thought. These regulatory abilities are often referred to as executive functions. In humans, the right hemisphere of the PFC is important for regulating distractions, inappropriate behaviour and emotional responses. Imaging studies of patients with ADHD indicate that these regions are underactive with weakened connections to other parts of the brain. The PFC regulates attention and behaviour through networks of interconnected pyramidal cells. These networks excite each other to store goals/rules to guide actions and are highly dependent on their neurochemical environment, as small changes in the catecholamines noradrenaline (NA) or dopamine (DA) can have marked effects on PFC function. NA and DA are released in the PFC according to our arousal state; too little (during fatigue or boredom) or too much (during stress) impairs PFC function. Optimal amounts are released when we are alert/interested. The beneficial effects of NA occur at postsynaptic alpha(2A)-receptors on the dendritic spines of PFC pyramidal cells. Stimulation of these receptors initiates a series of chemical events inside the cell. These chemical signals lead to the closing of special ion channels, thus strengthening the connectivity of network inputs to the cell. Conversely, the beneficial effects of moderate amounts of DA occur at D(1) receptors, which act by weakening irrelevant inputs to the cells on another set of spines. Genetic linkage studies of ADHD suggest that these catecholamine pathways may be altered in some families with ADHD, e.g. alterations in the enzyme that synthesizes NA (DA beta-hydroxylase) are associated with weakened PFC abilities. Pharmacological studies in animals indicate catecholamine actions in the PFC are highly relevant to ADHD. Blocking NA alpha(2A)-receptors in the PFC with yohimbine produces a profile similar to ADHD: locomotor hyperactivity, impulsivity and poor working memory. Conversely, drugs that enhance alpha(2)-receptor stimulation improve PFC function. Guanfacine directly stimulates postsynaptic alpha(2A)-receptors in the PFC and improves functioning, while methylphenidate and atomoxetine increase endogenous NA and DA levels and indirectly improve PFC function via alpha(2A)- and D(1) receptor actions. Methylphenidate and atomoxetine have more potent actions in the PFC than in subcortical structures, which may explain why proper administration of stimulant medications does not lead to abuse. Further understanding of the neurobiology of attention and impulse control will allow us to better tailor treatments for specific patient needs.
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PMID:Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction. 1962 76

Although originally developed for the treatment of hypertension, alpha(2)-agonists have been used to treat Tourette's syndrome, attention-deficit hyperactivity disorder (ADHD), developmental disorders and substance abuse for nearly three decades. Based on studies of clonidine, alpha(2)-agonists were presumed to reduce arousal by decreasing the firing of noradrenaline neurons in locus ceruleus. Accumulated preclinical evidence indicates that guanfacine has features in common with clonidine, in addition to other pharmacological effects. Clonidine binds to the three subtypes of alpha(2)-receptors, A, B and C, whereas guanfacine binds more selectively to alpha(2A)-receptors, which appears to enhance prefrontal function. Several reports on the use of the alpha(2)-agonists show improvements in children with ADHD and improvements in hyperactivity, impulsiveness and inattention in children with tic disorders and pervasive developmental disorders. Both clonidine and guanfacine are associated with sedation, fatigue and somnolence. Reductions in heart rate and blood pressure are modest and rarely lead to discontinuation of treatment across these trials.
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PMID:Alpha-2 adrenergic agonists in children with inattention, hyperactivity and impulsiveness. 1962 77

Fibromyalgia (FM) conceptualized by the American College of Rheumatology is characterized by long-lasting chronic widespread pain and stiffness of the fibro-muscular system associated with various unidentified symptoms. Since most of the patients are female and the onset and clinical course of FM involves various kinds of bio-psychosocial stress factors, it is very important to consider the psychosomatic background of the patient. The symptom of FM is not readily improved with conventional analgesic drugs, antirheumatic agents or various kinds of physiotherapy, however current guidelines recommend tricyclic antidepressants, SSRIs and SNRIs as first-line therapies to treat the multiple symptom of the FM. It is considered that antidepressants may operate the functional impairment of descending (efferent) analgesic system, in which serotonin and noradrenaline take an important role. Among 199 certified physicians of the Japanese Society of Psychosomatic Medicine, the largest number of respondents selected SSRI, SNRI and other antidepressants as first-line drugs. Because the psychological and physical exhaustion due to an irregular life style, physical strain, and accumulated fatigue may be the key stress factors for the organization of symptoms, psychosomatic approach and guidance should be conducted to enable patients to reduce stress in daily life. For the problems of personality and psychological stress, counseling and advanced psychotherapy such as cognitive behavioral therapy (CBT) should be also conducted.
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PMID:[Treatment of myalgia]. 1976 13

The balance between descending controls, both excitatory and inhibitory, can be altered in various pain states. There is good evidence for a prominent alpha(2)-adrenoceptor-mediated inhibitory system and 5-HT(3) (and likely also 5-HT(2)) serotonin receptor-mediated excitatory controls originating from brainstem and midbrain areas. The ability of cortical controls to influence spinal function allows for top-down processing through these monoamines. The links between pain and the comorbidities of sleep problems, anxiety, and depression may be due to the dual roles of noradrenaline and of 5-HT in these functions and also in pain. These controls appear, in the cases of peripheral neuropathy, spinal injury, and cancer-induced bone pain to be driven by altered peripheral and spinal neuronal processes; in opioid-induced hyperalgesia, however, the same changes occur without any pathophysiological peripheral process. Thus, in generalized pain states in which fatigue, mood changes, and diffuse pain occur, such as fibromyalgia and irritable bowel syndrome, one could suggest an abnormal engagement of descending facilitations with or without reduced inhibitions but with central origins. This would be an endogenous central malfunction of top-down processing, with the altered monoamine systems underlying the observed symptoms. A number of analgesic drugs can either interact with or have their actions modulated by these descending systems, reinforcing their importance in the establishment of pain but also in its control.
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PMID:Preclinical and early clinical investigations related to monoaminergic pain modulation. 1978 74

We examined the effect of intensity during prolonged exercise (PE) on left (LV) and right ventricular (RV) function. Subjects included 18 individuals (mean +/- SE: age = 28.1 +/- 1.1 yr, maximal aerobic power = 55.1 +/- 1.6 ml . kg(-1) . min(-1)), who performed 150 min of exercise at 60 and 80% maximal aerobic power on two separate occasions. Transthoracic echocardiography assessed systolic and diastolic performance, and blood sampling assessed hydration status and noradrenaline levels before (pre), during (15 and 150 min), and 60 min following (post) PE. beta-Adrenergic sensitivity pre- and post-PE was assessed by dobutamine stress. High-intensity PE (15 vs. 150 min) induced reductions in LV ejection fraction (69.3 +/- 1.3 vs. 63.5 +/- 1.3%, P = 0.000), LV strain (-23.5 +/- 0.6 vs. -22.3 +/- 0.6%, P = 0.034), and RV strain (-26.3 +/- 0.6 vs. -23.0 +/- 0.6%, P < 0.01). Both exercise intensities induced diastolic reductions (pre vs. post) in the ratio of septal early wave of annular tissue velocities to late/atrial wave of annular tissue velocities (2.15 +/- 0.15 vs. 1.62 +/- 0.09; 2.21 +/- 0.15 vs. 1.48 +/- 0.10), ratio of lateral early wave of annular tissue velocities to late/atrial wave of annular tissue velocities (3.84 +/- 0.42 vs. 2.49 +/- 0.20; 3.56 +/- 0.32 vs. 2.08 +/- 0.18), ratio of early to late LV strain rate (2.42, +/- 0.16 vs. 1.97 +/- 0.13; 2.30 +/- 0.15 vs. 1.81 +/- 0.11), and ratio of early to late RV strain rate (2.03 +/- 0.17 vs. 1.51 +/- 0.09; 2.16 +/- 0.16 vs. 1.44 +/- 0.11) (P < 0.001). Evidence of beta-adrenergic sensitivity was supported by a decreased strain, strain rate, ejection fraction, and systolic pressure-volume ratio response to dobutamine (P < 0.05) with elevated noradrenaline (P < 0.01). PE-induced reductions in LV and RV systolic function were related to exercise intensity and beta-adrenergic desensitization. The clinical significance of exercise-induced cardiac fatigue warrants further research.
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PMID:Impaired left and right ventricular function following prolonged exercise in young athletes: influence of exercise intensity and responses to dobutamine stress. 1989 22

Fibromyalgia is a chronic pain disorder characterized by widespread pain, stiffness, insomnia, fatigue and distress. Several randomized controlled trials (RCTs) have shown moderate effectiveness of pharmacological therapies for fibromyalgia pain. Evidence from these trials suggests that pharmacological therapy can not only improve pain but also fatigue, function and well-being in patients with fibromyalgia. Duloxetine and milnacipran, two highly selective serotonin-norepinephrine (noradrenaline) reuptake inhibitors, and the alpha(2)delta agonist pregabalin have been approved by the US FDA for the treatment of fibromyalgia symptoms. In general, about half of all treated patients seem to experience a 30% reduction of symptoms, suggesting that many patients with fibromyalgia will require additional therapies. Thus, other forms of treatment, including exercise, cognitive behavioural therapies and self-management strategies, may be necessary to achieve satisfactory treatment outcomes. Despite promising results of pilot trials, RCTs with dopamine receptor agonists and sodium channel antagonists have so far been disappointing for patients with fibromyalgia. However, new pharmacological approaches for the treatment of fibromyalgia pain and insomnia using sodium oxybate appear to be promising.
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PMID:Pharmacological treatment of fibromyalgia syndrome: new developments. 2003 Apr 22


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