UMLS:C0015672 - FACTA Search

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

Much interest has focused on the role of glutamate-mediated excitotoxicity in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). We therefore conducted a phase I study of high-dose dextromethorphan (DM) in ALS. DM is a selective, noncompetitive antagonist of the N-methyl-D-aspartate subtype of the glutamate receptor. Thirteen patients were given DM in an escalating dose fashion, to a target of 10 mg/kg/day or the maximum tolerable dose, and then maintained on this dose for up to 6 months. Total daily doses ranged from 4.8 to 10 mg/kg (median, 7 mg/kg). Side effects were dose limiting in most patients. The most common side effects were light-headedness, slurred speech, and fatigue. Detailed pharmacokinetic and neuropsychology studies were performed. This study demonstrates the feasibility of long-term administration of high-dose DM in ALS, as well as in other conditions associated with glutamate excitotoxicity.
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PMID:High-dose dextromethorphan in amyotrophic lateral sclerosis: phase I safety and pharmacokinetic studies. 799 81

The purpose of this study was to examine the effect of glutamate-arginine salt (AGs) or placebo (P1) on ammonemia during and after 1 hour exercise on sporting event bicycle under ergonomic device at 80% VO2max in 3 healthy male volunteers (age 18-25 years). Subjects were tested in three sessions, at rest after AGs and during exercise with placebo (Pl) or AGs. The subjects were given 20 g of AGs or Pl orally and 30 min later, exercised at 75-80% VO2max for 30 min. Blood samples were taken at 0, +30, +60, +90, +120 min after AGs and analyzed for ammonemia. Our results show a highly significant increase in plasma ammonia concentration during exercise. The magnitude of this increase was diminished when subjects were given AGs before the exercise session, suggesting that AGs may help reduce physiologic fatigue.
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PMID:Effects of an ingested glutamate arginine salt on ammonemia during and after long lasting cycling. 800 36

Topiramate is a recently licensed and marketed antiepileptic drug in the UK for use as add-on therapy for refractory partial epilepsy. It has multiple modes of action involving voltage-dependent sodium channels, GABA receptors and glutamate receptors. Topiramate has very favourable pharmacokinetics as it is primarily excreted unchanged. Its metabolism is, however, increased by enzyme inducers, and it can inhibit the metabolism of phenytoin in some patients. Its efficacy as adjunctive treatment in refractory partial epilepsy in adults appears good, over 40% of patients have a 50% or greater reduction in seizure frequency when topiramate is added to their regime with up to 7% becoming seizure free. The main adverse events are ataxia, impaired concentration, confusion, dizziness, fatigue, parasthesia, somnolence and "thinking abnormal'. Most of these occurred during rapid titration. During long-term treatment, weight loss also occurred and nephrolithiasis occurred in 1.5% of patients receiving topiramate. Topiramate is a useful and well-tolerated addition to our treatment of refractory epilepsy, but it should be titrated slowly in order to avoid adverse events.
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PMID:Topiramate: a new antiepileptic drug for refractory epilepsy. 890 21

This review considers four experimental models for studying the dynamics of ammonia and amino acid metabolism in skeletal muscle: the rat hindlimb, the isolated dog gastrocnemius, the leg extensor for humans, and the traditional approach of humans performing two-legged exercise. The rat hindlimb is well suited for studying intense exercise with fast-twitch white fibers, but it is poorly suited for studying prolonged exercise because of rapid fatigue of major portions of the muscle and the restrictions of taking multiple blood samples. The traditional human model is limited because of the inability to quantify accurately the active muscle mass and to determine the true blood flow to the entire active tissue. Despite species differences and the various limitations of the paradigms, there are numerous consistencies in the literature. For example, human muscle and the canine gastrocnemius demonstrate similar magnitudes of efflux of ammonia, glutamine, and alanine (when indexed for the active mass) during prolonged exercise. Muscle has a large ammonia producing capacity during either intense or prolonged exercise. In prolonged exercise this is accompanied by similar productions of alanine and glutamine as well as a large uptake of glutamate. Despite the latter, the intramuscular glutamate concentration rapidly declines by more than 50% and remains constant throughout the exercise period. The leg extensor model and the canine gastrocnemius offer the greatest opportunities to quantify these responses during prolonged exercise.
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PMID:Ammonia and amino acid metabolism in skeletal muscle: human, rodent and canine models. 947 42

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with evidence of both anterior horn cell and corticospinal tract degeneration. The incidence of ALS is 1 to 2.5 cases per 100,000 population and the disease occurs primarily in adult life. The etiology of sporadic ALS remains unknown, although 5 to 10% of cases are familial. The diagnosis of ALS requires the presence of both upper and lower motor neuron findings and progressive motor dysfunction. Several theories regarding the pathogenesis of ALS have emerged including glutamate excitotoxicity, free radical oxidative stress, neurofilament accumulation, and autoimmunity. Clinical trials involving antiglutamate agents, antioxidants, immunosuppressants, and growth factors have shown no substantial benefit in slowing progression, with death usually occurring 2 to 5 years following the onset of symptoms. The management of ALS patients requires a multidisciplinary team that can provide the numerous medical and physical interventions necessary to treat weakness and fatigue, bulbar dysfunction, spasticity and pain, depression, and respiratory failure.
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PMID:Amyotrophic lateral sclerosis. 956 65

Six amino acids are metabolized in resting muscle. They are leucine, isoleucine, valine, asparagine, aspartate, and glutamate. These amino acids provide the amino groups and probably the ammonia required for synthesis of glutamine and alanine, which are released in excessive amounts in the postabsorptive state and during ingestion of a protein-containing meal. Only leucine and part of the isolecine molecule can be oxidized in muscle as they are converted to acetyl-CoA. The other carbon skeletons are used solely for de novo synthesis of TCA-cycle intermediates and glutamine. The carbon atoms of the released alanine originate primarily from glycolysis of blood glucose and from muscle glycogen (about half each in resting conditions). After consumption of a protein-containing meal, BCAA and glutamate are taken up by muscle and their carbon skeletons are used for de novo synthesis of glutamine. About half of the glutamine released from muscle originates from glutamate taken up from the blood, both after overnight starvation, after prolonged starvation, and after consumption of a mixed meal. Glutamine produced by muscle is an important fuel and regulator of DNA and RNA synthesis in mucosal cells and immune system cells, and fulfils several other important functions in human metabolism. The alanine aminotransferase reaction functions to establish and maintain high concentrations of TCA-cycle intermediates in muscle during the first 10 min of exercise. The increase in concentration of TCA-cycle intermediates probably is needed to increase the flux of the TCA-cycle and meet the increased energy demand of exercise. A gradual increase in leucine oxidation subsequently leads to a carbon drain on the TCA-cycle in glycogen-depleted muscles, and may thus reduce the maximal flux in the TCA-cycle and lead to fatigue. Deamination of amino acids and glutamine synthesis present alternative anaplerotic mechanisms in glycogen-depleted muscles, but only allow exercise at 40-50% of Wmax. One-leg exercise leads to the net breakdown of muscle protein. The liberated amino acids are used for synthesis of TCA-cycle intermediates and glutamine. Today, the importance of this process in endurance exercise in the field (running or cycling) in athletes who ingest carbohydrates is not clear. It is proposed that the maximal flux in the TCA-cycle is reduced in glycogen-depleted muscles due to insufficient TCA-cycle anaplerosis, and that this presents a limitation for the maximal rate of fatty acid oxidation. Interactions between the amino acid pool and the TCA-cycle are suggested to play a central role in the energy metabolism of the exercising muscle.
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PMID:Muscle amino acid metabolism at rest and during exercise: role in human physiology and metabolism. 969 93

In addition to the regulation of neuronal survival and differentiation, neurotrophins may play a role in synapse development and plasticity. Application of brain-derived neurotrophic factor (BDNF) promotes long-term potentiation (LTP) in CA1 synapses of neonatal hippocampus, which otherwise exhibit only short-term potentiation. This is attributable, at least in part, to an attenuation of the synaptic fatigue induced by high-frequency stimulation (HFS). However, the prevention of synaptic fatigue by BDNF could be mediated by an attenuation of synaptic vesicle depletion from presynaptic terminals and/or a reduction of the desensitization of postsynaptic receptors. Here we provide evidence supporting a presynaptic effect of BDNF. The effect of BDNF on synaptic fatigue depended on the stimulation frequency, not on the stimulus duration nor on the number of stimulation pulses. BDNF was only effective when the synapses were stimulated at frequencies >50 Hz. Treatment with BDNF also potentiated paired-pulse facilitation (PPF), a parameter reflecting changes in the properties of presynaptic terminals. This effect of BDNF was restricted only to PPF elicited with interpulse intervals </=20 msec. Changes in the extracellular calcium concentration altered the magnitude of the BDNF effect on PPF and synaptic responses to HFS, suggesting that BDNF regulates neurotransmitter release. When the desensitization of glutamate receptors was blocked by cyclothiazide or aniracetam, the BDNF potentiation of the synaptic responses to HFS was unaltered. Taken together, these results suggest that BDNF acts presynaptically. When two pathways in the same slice were monitored simultaneously, BDNF treatment potentiated the tetanized pathway without affecting the synaptic efficacy of the untetanized pathway. The selective potentiation of high-frequency transmission by BDNF appears to contribute directly to the effect of BDNF on LTP rather than indirectly by inducing the release of additional diffusible factors. The preferential potentiation of highly active synapses by BDNF may have implications in the Hebbian mechanism of synaptic plasticity.
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PMID:Presynaptic modulation of synaptic transmission and plasticity by brain-derived neurotrophic factor in the developing hippocampus. 971 54

The aim of this study was to investigate if enhanced peripheral ammonia production during exhaustive exercise increases ammonia detoxication in brain mediated by glutamine synthesis, and subsequently influences glutamate and gamma-aminobutyric acid (GABA) levels. This neurotransmitter production is related to the metabolism of glutamine. A group of rats was trained for 6 weeks by treadmill running (TR). They were compared to a group of untrained rats (UN). At the end of training, half of TR and UN rats were submitted to one session of treadmill running until exhaustion (288+/-12 min and 62+/-5 min in TR and UN group, respectively). At exhaustion, running and control rats were sacrificed in order to collect blood and to take samples of the following brain structures: cortex, striatum and cerebellum. Treadmill running until exhaustion induced an increase in blood ammonia by 140% without significant differences between TR and UN groups. Brain ammonia increased in both groups. However, TR group exhibited values 50% higher than those observed in UN group. Brain glutamine was increased at exhaustion in all groups of running rats by 30-75% of basal value whereas the glutamate only decreased in TR rats which were able to run for a longer time. In this group, the GABA level decreased in striatum. These data confirm that enhanced brain ammonia level during exercise stimulates glutamine synthesis as a mechanism of detoxication. After several hours of running, a reduction in brain glutamate levels was observed in all brain structures in trained rats but only in the striatum in untrained animals. The reduced availability of this GABA precursor decreases GABA levels only in the striatum of TR group by 45% of the resting value. These results suggest a relation between cerebral changes in neurotransmitters and excitatory amino acids, such as glutamate and GABA, and central fatigue.
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PMID:Effects of prolonged exercise on brain ammonia and amino acids. 972 Oct 55

Muscle proteins turn over slowly and there are minimal diurnal changes in the size of the muscle protein pool in response to feeding and fasting. Nitrogen balance and tracer studies indicate that protein oxidation and net protein breakdown (degradation--synthesis) is not increased during dynamic exercise at intensities of < or = 70% VO2max. An imbalance between muscle protein synthesis and degradation does exist during one leg knee extensor exercise and during two legged cycling in patients with glycogen phosphorylase deficiency. In these latter cases amino acids liberated from the protein pool are used for synthesis of TCA-cycle intermediates and glutamine. Six amino acids are metabolized in resting muscle: leucine, isoleucine, valine, asparagine, aspartate and glutamate. Only leucine and part of the isoleucine molecule can be converted to acetylCoA and oxidized. The carbon skeleton of the other amino acids is used for synthesis of TCA-cycle intermediates and glutamine. The six amino acids provide the amino groups and the ammonia for synthesis of glutamine and alanine, which are released by muscle in excessive amounts. About half of the glutamine release from muscle originates from glutamate taken up from the blood. Glutamine produced by muscle is an important fuel and regulator of DNA and RNA synthesis in mucosal cells and immune system cells and fulfils several other important functions in human metabolism. The alanine aminotransferase reaction functions to establish and maintain high concentrations of TCA-cycle intermediates and a high TCA cycle flux in the first minutes of exercise. A gradual increase in leucine oxidation subsequently leads to a carbon drain on the TCA-cycle in glycogen depleted muscles and may thus reduce the maximal flux in the TCA-cycle and lead to fatigue. Deamination of amino acids and glutamine synthesis present alternative anaplerotic mechanisms in glycogen depleted muscles but only allow exercise at 40-50% of Wmax. It is proposed that the maximal flux in the TCA-cycle is reduced in glycogen depleted muscles due to insufficient TCA-cycle anaplerosis and that this presents a limitation for the maximal rate of fatty acid oxidation. Interactions between the amino acid pool and the TCA-cycle thus seem to play a central role in the energy metabolism of the exercising muscle.
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PMID:Protein and amino acid metabolism in human muscle. 978 36

Adult motor neuron disease (amyotrophic lateral sclerosis [ALS]) is a neurodegenerative disorder characterized by loss of motor neurons in the cortex, brain stem, and spinal cord, manifested by upper and lower motor neuron signs and symptoms affecting bulbar, limb, and respiratory musculature. Clinically, the disease course is characterized by progressive weakness, atrophy, spasticity, dysarthria, dysphagia, and respiratory compromise, ultimately resulting in death or mechanical ventilation in the vast majority of patients. Patterns of presentation and pathological features of the disease, along with clinical and electrophysiologic criteria for diagnosis, are discussed in this review. Since 8% to 22% of patients survive more than 10 years without ventilator use, meticulous medical and rehabilitation management is extremely important to ensure optimal health and quality of life in these patients. Major issues in the care of individuals with ALS include weakness and spasticity, impairments in activities of daily living and mobility, communication deficits and dysphagia in those with bulbar involvement, respiratory compromise, fatigue and sleep disorders, pain, and psychosocial distress. Research in ALS changes rapidly, but is currently focused on potential etiologic factors such as glutamate excitotoxicity, role of oxidative stress, autoimmunity to calcium channels, and cytoskeletal abnormalities, as well as related treatment initiatives including glutamate modulators, neurotrophic factors, antioxidants, antiapoptotic factors, and gene therapy. Recently, mutations in the gene encoding Cu/Zn superoxide dismutase were identified in a subset of familial ALS patients. Riluzole, a glutamate antagonist and Na-channel blocker, became the only drug currently approved for treatment of ALS after studies showed a small positive effect on survival. Until a definitive treatment or cure for ALS is found, the multifaceted rehabilitation team approach remains the best hope for improving health and survival in this devastating illness.
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PMID:Evaluation and rehabilitation of patients with adult motor neuron disease. 1045 74

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