Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reactive oxygen species increase during exhaustive contraction of skeletal muscle, but characterization of the specific species involved and their rates of production during nonexhaustive muscle contraction have not been investigated. We hypothesized that the production rate of hydroxyl radical (.OH) increases in contracting muscle and that this rate is attenuated by pretreatment with deferoxamine (Def) or dimethylthiourea (DMTU). We measured the rate of production of .OH before, during, and after 5 min of intermittent static contraction of the triceps surae muscles in cats (n = 6) using the formation of p-, m-, and o-tyrosines by hydroxylation of phenylalanine. L-Phenylalanine (30 mg/kg i.v.) was administered to each animal 3 min before contraction. Blood samples were collected from the popliteal vein 1 min before contraction; 1, 3, and 4.5 min during contraction; and 1 min after contraction. During and after contraction, the cumulative production rates of p-, m-, and o-tyrosines were elevated by 42.84 +/- 5.41, 0.25 +/- 0.04, and 0.21 +/- 0.03 nmol.min-1.g-1, respectively, compared with noncontracting triceps surae muscles. Pretreatment with Def (10 mg/kg i.v.; n = 5) or DMTU (10 mg/kg i.v.; n = 4) decreased the cumulative rates of production of p-, m-, and o-tyrosines during and after contraction. Additionally, the rate of tyrosine production increased in proportion to the percentage of maximal tension developed by the triceps surae muscles. These results directly demonstrate that .OH is produced in vivo in the skeletal muscle of cats during intermittent static contraction and that production can occur before the onset of fatigue.
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PMID:Production of hydroxyl radicals in contracting skeletal muscle of cats. 888 54

Effects of a serotonin re-uptake inhibitor and oral amino acid supplementations on physical and mental performance as well as neuroendocrine variables were investigated. 10 male subjects cycled in four trials until exhaustion. Participants ingested a placebo in trial (T) I, 20 mg paroxetine in T II, 21 g branched-chain amino acids (BCAA) in T III and 20g tyrosine (TYR) in T IV. Heart rate, capillary lactate, plasma insulin, free fatty acids, glucose, serotonin and beta-endorphin did not differ in trials. Plasma ammonia increments during exercise were higher in T III. Plasma BCAA in T III and plasma TYR in T IV were increased after 30 min of exercise according to the supplemented substances. In contrast to all other trials, the ratio of plasma free TRP/BCAA did not increase in T III. Plasma TYR/BCAA was augmented in T IV and decreased in T III after 30 min of exercise, whereas it did not change in T I and II. Plasma prolactin (PRL), growth hormone, cortisol, adrenocorticotropic hormone, norepinephrine and epinephrine increased during all trials. Plasma PRL increments were higher in T IV. Exhaustion was reached earlier in T II. No significant differences were found between other trials. Drive during psychometric testing subsequent to exercise was improved in T III and IV. The results indicate that fatigue during endurance exercise was increased by pharmacological augmentation of the brain serotonergic activity. However, a reduction of 5-HT synthesis via BCAA supplementation did not affect physical fatigue. TYR administration did not alter physical performance either although plasma PRL increments suggest that changes in the monoaminergic system were induced. Precaution is necessary before assuming an ergogenic value of amino acids.
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PMID:Influence of paroxetine, branched-chain amino acids and tyrosine on neuroendocrine system responses and fatigue in humans. 962 32

A number of peripheral indices of serotonergic function were examined in endurance-trained (ET) and sedentary males using the blood platelet as a model of the serotonergic neurone. The aim of the study was to investigate possible involvement and adaptation of the central serotonergic system in exercise-induced fatigue. The [3H] paroxetine-defined density of platelet serotonin transporters, platelet serotonin content and the plasma concentration of amino acids were determined in 10 ET and eight sedentary males. The mean (standard deviation) density of the serotonin transporter in the platelet membranes of the ET subjects was greater [1237 (182) fmol mg protein-1] than that of the sedentary subjects [910 (119) fmol mg protein-1; P = 0.013]. No difference (P = 0.51) could be seen between the median (range) platelet serotonin content of the ET subjects [0.98 (0.37-3.04) nmol platelet-10] and that of the sedentary subjects [0.82 (0.18-1.49) nmol platelet-10]. The platelet poor plasma concentrations of tryptophan and tyrosine were lower in the ET subjects (P = 0.028 and 0.015, respectively). The present study suggests that the platelet membrane of the ET subjects has a greater density of the serotonin transporter and that this is inversely related to the circulating concentration of the serotonin precursor, tryptophan. It remains to be resolved whether the increase in serotonin transporter density in the platelet membrane of ET subjects is reflected centrally and whether the ET platelet population may be sufficiently different from that of sedentary individuals to alter serotonin transporter density.
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PMID:Platelet serotonin transporter density and related parameters in endurance-trained and sedentary male subjects. 964 35

The effects of the amino acid tyrosine on cognitive task performance were studied on a group of 21 cadets during a demanding military combat training course. In addition, the effects on mood, blood pressure and the norepinephrine metabolite MHPG were determined. Ten subjects received five daily doses of a protein-rich drink containing 2 g tyrosine, and 11 subjects received a carbohydrate rich drink with the same amount of calories (255 kcal). Assessments were made both immediately prior to the combat course and on the 6th day of the course. The group supplied with the tyrosine-rich drink performed better on a memory and a tracking task than the group supplied with the carbohydrate-rich drink. In addition, the supplementation of tyrosine decreased systolic blood pressure. No effects on mood were found. These findings suggest that supplementation with tyrosine may, under operational circumstances characterized by psychosocial and physical stress, reduce the effects of stress and fatigue on cognitive task performance.
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PMID:Tyrosine improves cognitive performance and reduces blood pressure in cadets after one week of a combat training course. 1023 Jul 11

Sodium vanadate inhibits protein tyrosine phosphatases, including in skeletal muscle. Vanadate increases contractile force of airway, vascular and gastrointestinal smooth muscle. The present study tested the hypothesis that vanadate augments skeletal muscle contractility. Rat diaphragm muscle strips (n=26 from 12 animals) were studied in vitro at 37 degrees C. Muscles contracted isometrically while stimulated supramaximally with one of two protocols: 30 min of continuous 0.1 Hz stimulation, or 5 min of intermittent 20 Hz stimulation (duty cycle 0.33). Vanadate (500 microM)-treated muscle strips were compared with untreated muscle. Vanadate did not affect force or isometric twitch kinetics of otherwise quiescent muscle. During prolonged 0.1 Hz stimulation, force of control muscles declined by 17 +/- 4% over 30 min, whereas muscles incubated with vanadate maintained force virtually unchanged. Force over time was significantly greater with than without vanadate (P = 0.03), with values being significantly different during the last 10 min of the 30 min stimulation period. In the absence of vanadate force declined at a rate of approximately 0.6% per min, whereas with vanadate the rate of force decline was less than 0.1% per min (P < 0.02). During intermittent 20 Hz stimulation, the degree of force decline was not affected by vanadate at any time over a course of 5 min. Isometric contractile kinetics were not altered by vanadate during either 0.1 or 20 Hz stimulation. These data suggest that vanadate ameliorates low- but not higher-frequency fatigue in diaphragm, suggesting a role for protein tyrosine phosphorylation in the regulation of muscle fatigue resistance.
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PMID:Attenuation of rat diaphragm low-frequency fatigue by vanadate in vitro. 1056 40

The effect of catecholamine depletion, achieved by per-oral administration of 5250 mg alpha-methyl-para-tyrosine (AMPT) given in the 29 h prior to [11C]raclopride positron emission tomography (PET) was studied on measures of dopamine (DA) release, mood, and attention. Neostriatal DA levels in vivo were estimated by comparing the neostriatal DA D(2) receptor binding potential (D(2)RBP) before and after catecholamine depletion using PET and the radiotracer [11C]raclopride. Six healthy subjects completed the protocol. The AMPT treatment increased D(2)RBP significantly by 13.3+/-5.9% (average+/-standard deviation) and decreased plasma levels of the DA metabolite homovanillic acid (HVA) by 62+/-17%, and levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) by 66+/-5%. Catecholamine depletion resulted in decreased happiness, euphoria, energy, talkativeness, vigor, and attentiveness, and in increased sleepiness, fatigue, sedation, and eye blink rate (EBR). These changes were not correlated with the D(2)RBP increments. The results of this study are overall consistent with previous findings by our group using the same methodology in a different cohort of six healthy subjects.
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PMID:Effects of catecholamine depletion on D2 receptor binding, mood, and attentiveness in humans: a replication study. 1247 64

Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are adverse prognostic features in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDSs). VEGF is a soluble circulating angiogenic molecule that stimulates signaling via receptor tyrosine kinases (RTKs), including VEGF receptor 2 (VEGFR-2). AML blasts may express VEGFR-2, c-kit, and FLT3. SU5416 is a small molecule RTK inhibitor (RTKI) of VEGFR-2, c-kit, and both wild-type and mutant FLT3. A multicenter phase 2 study of SU5416 was conducted in patients with refractory AML or MDS. For a median of 9 weeks (range, 1-55 weeks), 55 patients (33 AML: 10 [30%] primary refractory, 23 [70%] relapsed; 22 MDS: 15 [68%] relapsed) received 145 mg/m2 SU5416 twice weekly intravenously. Grade 3 or 4 drug-related toxicities included headaches (14%), infusion-related reactions (11%), dyspnea (14%), fatigue (7%), thrombotic episodes (7%), bone pain (5%), and gastrointestinal disturbance (4%). There were 11 patients (20%) who did not complete 4 weeks of therapy (10 progressive disease, 1 adverse event); 3 patients (5%) who achieved partial responses; and 1 (2%) who achieved hematologic improvement. Single agent SU5416 had biologic and modest clinical activity in refractory AML/MDS. Overall median survival was 12 weeks in AML patients (range, 4-41 weeks) and not reached in MDS patients. Most observed toxicities were attributable to drug formulation (polyoxyl 35 castor oil or hyperosmolarity of the SU5416 preparation). Studies of other RTKI and/or other antiangiogenic approaches, with correlative studies to examine biologic effects, may be warranted in patients with AML/MDS.
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PMID:SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. 1264 63

Considerable evidence points towards a prominent role for central nervous system (CNS) mechanisms in the pathogenesis of chronic fatigue syndrome (CFS), a disorder characterized chiefly by persistent, often debilitating, fatigue. We wished to characterize circulating profiles of putative amino acid modulators of CNS 5-hydroxytryptamine (5-HT; serotoninergic) and dopaminergic function in CFS patients at rest, as well as during symptom-limited exercise and subsequent recovery. Groups of 12 CFS patients and 11 age- and sex-matched sedentary controls, with similar physical activity histories, underwent ramp-incremental exercise to the limit of tolerance. Plasma amino acid concentrations, oxygen uptake and ratings of perceived exertion were measured at rest, and during exercise and recovery. Peak oxygen uptake was significantly lower in the CFS patients compared with controls. Rating of perceived exertion in the patients was higher at all time points measured, including at rest, relative to controls. Levels of free tryptophan (free Trp), the rate-limiting 5-HT precursor, were significantly higher in CFS patients at exhaustion and during recovery, whereas concentrations of branched-chain amino acids (BCAA) and large neutral amino acids (LNAA) were lower in CFS patients at exhaustion, and for LNAA also during recovery. Consequently, the [free Trp]/[BCAA] and [free Trp]/[LNAA] ratios were significantly higher in CFS patients, except at rest. On the other hand, levels of tyrosine, the rate-limiting dopaminergic precursor, were significantly lower at all time points in the CFS patients. The significant differences observed in a number of key putative CNS 5-HT and dopaminergic modulators, coupled with the exacerbated perception of effort, provide further evidence for a potentially significant role for CNS mechanisms in the pathogenesis of CFS.
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PMID:Chronic fatigue syndrome: new evidence for a central fatigue disorder. 1270 66

CEP-2563 dihydrochloride (CEP-2563) is a soluble lysinyl-beta-alanyl ester of CEP-751, a potent inhibitor of the trk family of receptor tyrosine kinases and the platelet-derived growth factor (PDGF) receptor tyrosine kinase. CEP-2563 was developed because of the limited aqueous solubility of CEP-751. Preclinical models have demonstrated that both CEP-751 and CEP-2563 have antitumor activity in a variety of tumors. A Phase I clinical trial involving 18 patients was conducted to determine the toxicity profile, maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of CEP-2563 in patients with advanced solid tumors refractory to standard therapy. CEP-2563 was administered over 1 hour via a central venous catheter once daily for five consecutive days every three weeks. A rapid dose titration strategy with initial single patient cohorts and 100% dose escalations was used. With the appearance of drug-related toxicity, escalations were decreased to 50% or 25% and cohorts were expanded to 3 or 6 patients until establishment of the MTD. Dose escalation rapidly proceeded to 320 mg/m(2)/d. The dose limiting toxicities (DLTs) observed were grade 3 hypotension and grade 2 allergic reaction. Other toxicities included anemia, thrombocytopenia, anorexia, asthenia, diarrhea, fatigue, headache, nausea, vomiting, and rash. Pharmacokinetic analysis showed that CEP-2563 is reliably converted to CEP-751. This study demonstrated that single agent CEP-2563 therapy is feasible with acceptable toxicities. The recommended phase II dose is 256 mg/m(2)/d. Rapid dose escalation with single patient cohorts was a safe and efficient method of conducting this phase I trial.
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PMID:Phase I clinical trial of CEP-2563 dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solid tumors. 1529 15

The role of dopamine (DA) pathways in the pathophysiology of depressive disorder is poorly understood. However, because DA plays a key role in motivational behavior, it is important to study in a disorder characterized by anhedonia, lack of energy and psychomotor retardation. A recently developed dietary manipulation ('tyrosine (TYR) depletion') offers a novel method to assess the role of DA in major depression. We studied 15 euthymic women with a past history of recurrent depression, who received a 74 g amino-acid drink lacking TYR and phenylalanine (PHE) (TYR-free) and a balanced (BAL) amino acid drink on two separate occasions in a double-blind, random-order, crossover design. Plasma prolactin levels rose following the TYR-free drink relative to the balanced mixture, while performance on a spatial recognition memory task was impaired. However, relative to the BAL drink, the TYR-free drink did not lower objective or subjective measures of mood. We conclude that as in healthy volunteers, TYR depletion in euthymic subjects, with a past history of major depression, attenuated DA function, as reflected in increased plasma prolactin levels and decreased spatial memory performance. However ratings of depression were unaffected, suggesting that disruption of dopaminergic function by this manipulation does not induce a lowering of mood in individuals vulnerable to depression.
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PMID:Lack of effect of tyrosine depletion on mood in recovered depressed women. 1570 40


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