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

This paper summarizes the current knowledge concerning the biosynthesis of neurosteroids in the human brain, the enzymes mediating these reactions, their localization, and the putative effects of neurosteroids. The presence of the steroidogenic enzymes cytochrome P450(SCC), aromatase, 5alpha-reductase, 3alpha-hydroxysteroid dehydrogenase, and 17beta-hydroxysteroid dehydrogenase in the human brain has now been firmly established by molecular biological and biochemical studies. Their presence in the cerebral cortex and in the subcortical white matter indicates that various cell types, either neurons or glial cells, are involved in the biosynthesis of neuroactive steroids in the brain. The following functions are attributed to specific neurosteroids: modulation of GABA(A), N-methyl-d-aspartate (NMDA), nicotinic, muscarinic, serotonin (5-HT(3)), kainate, glycine and sigma receptors, neuroprotection and induction of neurite outgrowth, dendritic spines, and synaptogenesis. We still do not know whether and how the steroidogenic enzymes are involved in the pathophysiology of the nervous system. The first clinical investigations in humans produced evidence for an involvement of neuroactive steroids in conditions such as fatigue during pregnancy, premenstrual syndrome, postpartum depression, catamenial epilepsy, and depressive disorders. Further and improved knowledge of the biochemical pathways of neurosteroidogenesis and their actions on the brain may enable new perspectives in the understanding of the physiology of the human brain as well as in the pharmacological treatment of its disturbances.
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PMID:Neurosteroid biosynthesis in the human brain and its clinical implications. 1499 41

Aprepitant (Emend) is the first commercially available drug from a new class of agents, the neurokinin NK(1) receptor antagonists. Oral aprepitant, in combination with other agents, is indicated for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with highly emetogenic chemotherapy in adults. In three randomised, double-blind, placebo-controlled trials comparing aprepitant (125 mg day 1, 80mg once daily on days 2 and 3 or 2-5) plus standard therapy (intravenous ondansetron and oral dexamethasone) with standard therapy plus placebo, overall complete responses (primary endpoint, defined as no emesis and no rescue therapy) were seen in significantly more patients in the aprepitant arms (63-73% versus 43-52%, p < 0.01 for all comparisons). Complete responses and complete protection during the acute and delayed phase, and overall complete protection were also observed in significantly more patients in the aprepitant arms. The difference between treatment groups was more marked in the overall and delayed phases than in the acute phase. The antiemetic efficacy of aprepitant plus standard therapy in the prevention of CINV was maintained for up to six cycles of chemotherapy. Where assessed, more patients in the aprepitant plus standard therapy arms than the standard therapy plus placebo arms reported no impact of CINV on daily life, as assessed by the Functional Living Index-Emesis. Aprepitant is generally well tolerated. The most common adverse events in randomised trials were asthenia or fatigue. Other adverse events experienced by aprepitant recipients include anorexia, constipation, diarrhoea, nausea (after day 5 of the study) and hiccups. In addition to being a substrate for cytochrome P450 (CYP) 3A4, aprepitant is also a moderate inhibitor and inducer of this isoenzyme as well as an inducer of CYP2C9. Thus, aprepitant has the potential to interact with other agents metabolised by hepatic CYP isoenzymes. In one trial, there was a higher incidence of serious infection or febrile neutropenia in the aprepitant plus standard therapy arm than the standard therapy plus placebo arm; this was attributed to a pharmacokinetic interaction between aprepitant and dexamethasone. In subsequent trials, a modified dexamethasone regimen was used. In conclusion, when added to standard therapy (a serotonin 5-HT(3) receptor antagonist and a corticosteroid), aprepitant is effective and generally well tolerated in the prevention of CINV associated with highly emetogenic chemotherapy in adults. Despite marked advances in the prevention of CINV, standard therapy does not protect all patients. The addition of aprepitant to standard therapy provides an advance in the prevention of both acute and delayed CINV in adults with cancer.
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PMID:Aprepitant: a review of its use in the prevention of chemotherapy-induced nausea and vomiting. 1502 55

Fatigue during prolonged exercise has traditionally been attributed to the occurrence of a "metabolic end point", where muscle glycogen concentrations are depleted, plasma glucose concentrations are reduced, and plasma free fatty acid levels are elevated. But there exists also a "central fatigue hypothesis" which is based on the increase in the concentration of brain serotonin (5-Hydroxytryptamine or 5-HT) during exercise. However, the physiological mechanisms for central fatigue are largely unexplored, therefore we designed several experiments where central serotonergic activity was manipulated. These animal and human experiments showed that although brain neurotransmission had significantly increased, the supplementation with L-TRP did not lead to premature fatigue. In human studies we used several reuptake inhibitors in order to modify brain activity during exercise. These results clearly showed that time trial performance could not be influenced, but that during prolonged exercise the brain activity can be influenced, as measured by the peripheral hormones.
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PMID:Exercise, fatigue, neurotransmission and the influence of the neuroendocrine axis. 1520 69

The purpose of the experiment was to examine whether selective serotonin (5-HT) re-uptake transporter blockade by paroxetine has any effect on perceived effort (RPE) during exercise or the time to reach volitional fatigue and on the prolactin and cortisol responses during prolonged exercise performed in a warm environment. Eight healthy males performed two cycle rides to exhaustion in a warm (32 degrees C) environment at 60% of maximum oxygen uptake. Paroxetine (20 mg) or placebo was administered 5 h before exercise trials in a randomised double blind fashion. Time to exhaustion was not significantly influenced by administration of paroxetine: median (range) time to exhaustion was 93.3 (76.2-175.0) min on the placebo trial and 92.5 (66.0-151.0) min on the paroxetine trial. Rectal temperature was higher at rest and throughout exercise on the paroxetine trial. The serum concentrations of prolactin and cortisol were determined throughout exercise as peripheral markers of central 5-HT activity. RPE increased over time but was not influenced by paroxetine administration. Prolactin and cortisol levels increased over time but paroxetine administration did not influence the hormone responses during exercise. In conclusion, acute administration of paroxetine failed to alter RPE, exercise capacity or the response of the determined peripheral hormone markers of central 5-HT activity during prolonged exercise in a warm environment.
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PMID:Paroxetine administration failed [corrected] to influence human exercise capacity, perceived effort or hormone responses during prolonged exercise in a warm environment. 1532 6

Fatigue is a common complaint in the community and medical care settings. Different studies show a high comorbidity between fatigue and depressive disorder. Furthermore, fatigue is an important somatic symptom of depressive disorder and one of the main depressive presentations in primary-care medicine. Fatigue shows a slow response to antidepressant treatment and psychotherapy. Improved work performance is strongly correlated to improvement in energy. However, the assessment and treatment of fatigue in depressive disorder remains understudied. Different definitions of fatigue in depressive disorder are applied in DSM-IV and ICD-10, and depression rating scales all show a different coverage of this core depressive symptom, thereby hampering scientific research. Serotonin, norepinephrine, dopamine and histamine mediate symptoms of fatigue in depressive disorder. Although few data address the effect of antidepressants or augmentation strategies on fatigue-related symptoms, there is a pharmacological rationale for using antidepressant monotherapies, such as venlafaxine, bupropion, sertraline, fluoxetine, or augmentation of first-line treatment with stimulants or modafinil.
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PMID:The many faces of fatigue in major depressive disorder. 1548 32

Activation of serotonin 5-HT(4) receptors has been proposed as treatment for irritable bowel syndrome, a common, complex and distressing gastrointestinal disorder. Abnormal intestinal motility and sensitivity in irritable bowel syndrome patients can result in diarrhea, constipation, abdominal pain, bloating, headache and fatigue; these and other symptoms can lead to exacerbation of psychological stress, which may in turn induce further physiological abnormalities and patient discomfort. The serotonin agonist tegaserod binds with high affinity to 5-HT(4) receptors and has demonstrated potent pharmacological effects on the mid- and distal gut. Tegaserod has been safely employed in clinical trials where it has demonstrated efficacy in normalizing intestinal function, thereby improving irritable bowel syndrome symptoms.
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PMID:Tegaserod: a serotonin 5-HT4 receptor agonist for treatment of constipation-predominant irritable bowel syndrome. 1564 12

Fatigue associated with cholestasis may impair health-related quality of life. The pathogenesis of this symptom is largely unknown, but it has been suggested that central serotoninergic neurotransmission may be implicated and that serotonin 1A receptor agonists may yield improvement. The aim of this study was to study the central serotoninergic system, specifically the serotonin (5-HT)(1A) receptor-mediated pathway of serotoninergic neurotransmission, in a bile duct resection rat model of cholestasis. Fatigue was assessed in the forced swim test in sham and bile duct-resected rats. The serotonin behavioral syndrome, which includes hyperlocomotion, was assessed in both groups of rats after escalating doses of the 5-HT(1A) receptor agonist 8-hydroxy(di-n-propylamine)tetralin (8-OH DPAT). 5-HT(1A) and 5-HT(2) receptor densities were explored in four brain regions using a receptor-binding assay. Extracellular 5-HT and 5-hydroxyindoleacetic acid were measured via in vivo brain dialysis. Bile duct-resected rats spent more time floating in the forced swim test, and 8-OH DPAT decreased floating time in cholestatic rats (P < .01). Dose-response curves created with 8-OH DPAT for the serotonin behavioral syndrome were similar in bile duct-resected and sham-operated rats. 5-HT(1A) and 5-HT(2) receptor densities in most brain regions and extracellular serotonin levels were similar in both groups of rats. In conclusion, 5-HT(1A) receptor agonist-induced amelioration of fatigue in cholestatic rats may be nonspecific and not linked to reversal of the pathophysiology of fatigue associated with cholestasis; however, these data do not exclude a potential role of the central serotoninergic system in the evolution of fatigue.
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PMID:Fatigue of cholestasis and the serotoninergic neurotransmitter system in the rat. 1572 42

BACKGROUND: The serotonergic system is associated with numerous brain functions, including the resetting of the mammalian circadian clock. The synthesis and metabolism of 5-HT in the brain increases in response to exercise and is correlated with high levels of blood-borne tryptophan (TRP). The present investigation was aimed at testing the existence of a daily rhythm of TRP and 5-HT in the blood of athletic horses. METHODS: Blood samples from 5 Thoroughbred mares were collected at 4-hour intervals for 48 hours (starting at 08:00 hours on day 1 and finishing at 4:00 on day 2) via an intravenous cannula inserted into the jugular vein. Tryptophan and serotonin concentrations were assessed by HPLC. Data analysis was conducted by one-way repeated measures analysis of variance (ANOVA) and by the single cosinor method. RESULTS: ANOVA showed a highly significant influence of time both on tryptophan and on serotonin, in all horses, on either day, with p values < 0.0001. Cosinor analysis identified the periodic parameters and their acrophases (expressed in hours) during the 2 days of monitoring. Both parameters studied showed evening acrophases. CONCLUSION: The results showed that serotonin and tryptophan blood levels undergo nycthemeral variation with typical evening acrophases. These results enhance the understanding of the athlete horse's chronoperformance and facilitate the establishment of training programs that take into account the nycthemeral pattern of aminoacids deeply involved in the onset of central fatigue.
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PMID:Central fatigue and nycthemeral change of serum tryptophan and serotonin in the athletic horse. 1586 Jan 31

Rizatriptan (MAXALT MK-0462) is a new 5-HT(1B/1D) receptor agonist for the acute treatment of migraine. The marketed 10 mg and 5 mg oral doses are rapidly and consistently effective in relieving headache pain with associated migraine symptoms, and in enabling patients to return to their normal activities of daily living. Rizatriptan 10 mg is more effective than rizatriptan 5 mg. Compared to oral sumatriptan, the established agent in this class, rizatriptan has a shorter Tmax and greater bioavailability. In comparative clinical trials, the probability of having pain relief sooner was higher for rizatriptan 10 mg than for sumatriptan 100 mg or 50 mg. Over the 2 h after dosing, rizatriptan 10 mg was also superior to sumatriptan 100 mg and 50 mg on a range of other outcome measures. Both doses of rizatriptan are well-tolerated. The most common side-effects are dizziness, drowsiness, and asthenia/fatigue, which are short-lasting and of mild or moderate severity. In summary, rizatriptan is an effective and well-tolerated acute treatment for migraine, which may offer some advantages over oral sumatriptan.
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PMID:Rizatriptan: a new 5-HT1B/1D receptor agonist for the treatment of migraine. 1599 22

There is growing evidence that 5-HT3 receptor blockade will benefit patients with fatigue. Further research is needed to determine the mechanism underlying this widespread clinically important symptom and therapies may be derived from targeting the 5-HT system.
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PMID:5-HT3 receptor antagonists ameliorate fatigue: so much potential, so little knowledge! 1600 90


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