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)

Caffeine is the most widely consumed central-nervous-system stimulant. Three main mechanisms of action of caffeine on the central nervous system have been described. Mobilization of intracellular calcium and inhibition of specific phosphodiesterases only occur at high non-physiological concentrations of caffeine. The only likely mechanism of action of the methylxanthine is the antagonism at the level of adenosine receptors. Caffeine increases energy metabolism throughout the brain but decreases at the same time cerebral blood flow, inducing a relative brain hypoperfusion. Caffeine activates noradrenaline neurons and seems to affect the local release of dopamine. Many of the alerting effects of caffeine may be related to the action of the methylxanthine on serotonin neurons. The methylxanthine induces dose-response increases in locomotor activity in animals. Its psychostimulant action on man is, however, often subtle and not very easy to detect. The effects of caffeine on learning, memory, performance and coordination are rather related to the methylxanthine action on arousal, vigilance and fatigue. Caffeine exerts obvious effects on anxiety and sleep which vary according to individual sensitivity to the methylxanthine. However, children in general do not appear more sensitive to methylxanthine effects than adults. The central nervous system does not seem to develop a great tolerance to the effects of caffeine although dependence and withdrawal symptoms are reported.
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PMID:Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. 135 51

Muscular fatigue is manifested by a decline in force- or power-generating capacity and may be prominent in both submaximal and maximal contractions. Disturbances in muscle electrolytes play an important role in the development of muscular fatigue. Intense muscular contraction is accompanied by an increased muscle water content, distributed in both intracellular and extracellular spaces. This water influx will modify ionic changes in both compartments. Changes in muscle intracellular electrolyte concentrations with intense contraction may be summarised as including decreases in potassium (6 to 20%) and in creatine phosphate (up to 70 to 100%) and increases in lactate (more than 10-fold), sodium (2-fold) and small, variable increases in chloride. The net result of these intracellular ionic concentration changes with exercise will be a reduction in the intracellular strong ion difference, with a consequent marked rise in intracellular hydrogen ion concentration. This intracellular acidosis has been linked with fatigue via impairment of regulatory and contractile protein function, calcium regulation and metabolism. Potassium efflux from the contracting muscle cell dramatically decreases the intracellular to extracellular potassium ratio, leading to depolarisation of sarcolemmal and t-tubular membranes. Surprisingly little research has investigated the effects of intense exercise training on electrolyte regulation and fatigue.
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PMID:The roles of ionic processes in muscular fatigue during intense exercise. 137 45

The adequate treatment of a disease syndrome is dependent upon a clear definition of the symptomatic, pathological, physiological and prognostic targets against which therapy is to be deployed. The syndromes of ischaemic heart disease, including angina pectoris, are complex in origin, pathology, pathophysiology and natural history, and a complete clinical profile is difficult, if not impossible, to achieve in individual patients. The prime goals of pharmacotherapy in ischaemic heart disease are easy to define, but difficult to accomplish in practice. Relief of pain, breathlessness and fatigue are the prime clinical targets for pharmacotherapy. In view of their sinister significance, the electrophysiological indications of myocardial ischaemia, whether symptomatic or silent, are also crucial targets towards which therapy must be directed. Ischaemic heart disease is accompanied by a wide variety of regional and global abnormalities of myocardial contractile function associated with widespread reflex stimulation of the peripheral vascular system and neuroendocrine systems. Primarily, drug therapy must be directed at correction of these pathophysiological components of the syndrome. Longer term but no less essential goals in the treatment of ischaemic heart disease are the prevention of the clinical sequelae of the syndrome and its progression. A natural sequel of coronary artery obstructive disease is successive thrombotic events and loss of myocardium. Calcium antagonists, by preventing the increase in myocardial cytosolic calcium during acute ischaemic episodes, defer cell necrosis; in this respect, they are unique among currently available antianginal drugs. With regard to progression, the prime pathological cause of ischaemic heart disease is coronary atheroma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Therapeutic targets in ischaemic heart disease. 137 82

Whole cytosol isolated from human neutrophils was found to accelerate the Ca(2+)-dependent fusion of phospholipid vesicles with neutrophil plasma membranes as measured by several fluorescence resonance energy transfer lipid dilution assays or by the fate of an encapsulated aqueous soluble fluorophore. The Ca2+ (threshold of 2-10 microM) and protein concentration dependencies for fusion mediated by purified human neutrophil annexin I (lipocortin I), recombinant annexin I and des(1-9)annexin I showed behavior similar to that of whole cytosol. A monoclonal antibody against the N-terminal region of annexin I strongly inhibited the action of isolated annexins as well as whole cytosol, indicating that annexin I is the major activity of this type in whole neutrophil cytosol and that it functions even in this complex mixture of proteins. Residual Ca(2+)-dependent fusion activity in the absence of cytosol or annexin I was not inhibited by several antibodies against annexin I, implicating an as yet unknown protein. Kinetic analysis of liposomal fusion showed that annexin I, as in the case of synexin, accelerates aggregation of vesicles but not the actual fusion event per se. The disposition of annexin I in liposomal aggregates was studied by monitoring binding of the protein with a pyrene-phospholipid and by simultaneously monitoring vesicular aggregation by turbidity. An antibody to the N-terminus of annexin I inhibited vesicular aggregation but not binding, suggesting that initial binding of annexin I is similar to that of annexin V. A relatively small proportion of the bound annexin was involved in intervesicular linkage, and no exchange of bound annexin to subsequently added vesicles was observed. The lack of extensive contact between lipids of aggregated vesicles was supported by a lack of energy transfer between phospholipid probes on separate aggregating vesicles. Covalent linkage of maleimidyl or photoaffinity phospholipid derivatives with annexin I in vesicular aggregates did not allow complete disaggregation of vesicles by EDTA, suggesting that monomers of annexin I can contact two membranes simultaneously at the point of intervesicular linkage. These data are discussed in terms of possible models for the structure of this site.
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PMID:Annexin I-mediated vesicular aggregation: mechanism and role in human neutrophils. 138 75

Experimental therapies for McArdle's disease have been directed toward increasing substrate availability to exercising muscle. Such therapies to date have proven largely unsuccessful. These include administration of isoproterenol to increase blood flow, glucagon treatment to elevate serum glucose and increased dietary fat intake. Each of these therapies also results in greater levels of unesterified fatty acids in blood. More recently, a high protein diet is suggested to provide increased amounts of amino acids which would be available as fuel sources. We hypothesize that the absence of myophosphorylase in McArdle's disease creates an imbalance between the enzymes of the redox systems that control the generation, propagation and inactivation of free radicals. This occurs because muscle cells are forced to rely more heavily on fatty acid oxidation. The resulting free radical damage to cellular components disrupts metabolic control and increases the permeability of membranes. Elevated levels of Ca2+ in the sarcoplasm activate proteases, phospholipases and other catabolic enzymes initiating muscle fatigue and cramping. Lipid peroxidation is a consequence of normal muscle activity and may occur unchecked in individuals with McArdle's disease. Continued muscle activity in the absence of a favorable nutritional environment may promote the progression of the disease by increasing susceptibility to oxidative stress.
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PMID:The role of lipid peroxidation in McArdle's disease: applications for treatment of other myopathies. 146 Nov 77

The calcium antagonist, diltiazem is effective in the treatment of patients with various types of angina pectoris, as well as with essential and renovascular arterial hypertension. Sustained-release diltiazem in dose of 180 mg once daily is effective as sustained-release diltiazem in dose of 90 mg twice daily. Besides, in patients with stable angina pectoris and essential arterial hypertension the monotherapy with sustained-release diltiazem in dose of 180 mg is similarly effective as beta blockers and thiazide diuretics. However, monotherapy with sustained-release diltiazem is at least effective as monotherapy with sustained-release verapamil. Comparative clinical investigations showed that diltiazem is more effective than propranolol in decreasing ischemic attacks, whereas the risk of bradycardia is smaller. On the other hand, nifedipine (dihydropyridine calcium antagonist) is more effective than diltiazem in lowering ischemic electrocardiographic changes, incidence of attacks and improving working capability. The efficacy of diltiazem, nifedipine and verapamil is similar in the treatment of patients with spastic angina pectoris, whereas the least effective is propranolol. As far as the arterial hypertension is concerned, clinical investigations showed that the efficacy of diltiazem and nifedipine is similar. Side effects are relatively rare (1.8-9.6% patients) and depend on the dose (nausea, fatigue, dizziness, headache and itching).
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PMID:[Pharmacology--new therapy. Calcium channel blockers: new aspects of therapeutic use of diltiazem]. 146 75

It has long been appreciated that rates of ATP utilization and production need to be extremely closely balanced. To put it in molecular rather than molar terms, in human muscle engaged in a 15-min work protocol, approximately 3.3 x 10(20) ATP/g are used and resynthesized at approximately 100 times the resting cycling rates before fatigue, during which time only a 20-25% decrease in the ATP pool is sustained. Analysis of how such remarkable regulatory precision is achieved suggests that in resting muscle myosin behaves as a latent catalyst whose full catalytic potential 1) is realized with the arrival of an activator signal (Ca2+) and 2) is tempered with reaction products; such proactive control, initiated at ATP utilization, sets the required flux through ATP-producing pathways. For any given enzyme step in ATP-producing pathways, reaction velocity (v) becomes the independent parameter, with substrate concentration ([S], the dependent parameter) being adjusted accordingly. Because the dynamic range for muscles (change from resting to maximum ATP turnover rates) can exceed 100-fold, in many studies of working muscle the percent change in ATP turnover rate exceeds (sometimes by very large margins) the percent change in [S]. These observations are not easily explained by current metabolic regulation models but are consistent with pathway enzymes behaving as latent catalysts in resting muscle. In this view, the unmasking of such latent catalytic potential is the main explanation for how large changes in v can be achieved with modest (sometimes immeasurable) changes in [S].(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulating ATP turnover rates over broad dynamic work ranges in skeletal muscles. 828 52

A sixty nine-year-old woman was admitted to the hospital because of further examination of hypercalcemia. On July 1990, she complained of general fatigue and loss of appetite. She was pointed out to have hypercalcemia (15.1mg/dl), urolithiasis, and renal insufficiency. CT films of the chest showed swelling of the mediastinal lymphnodes and CT of the abdomen nephrocalcinosis. Ga-scintigraphy demonstrated an abnormal accumulation of gallium in the mediastinum. Levels of the parathyroid hormone was normal. Levels of the serum calcium (13.7mg/dl), angiotensin converting enzyme (30.4IU/L) and 1.25 (OH)2D (87PG/ml) were elevated. Giant cells were found in the biopsy specimen of the lung. A significant relationship between the serum calcium and creatinine were observed (r = 0.76, p < 0.02). Proximal fractional reabsorption of sodium showed to be suppressed (47.7%), and distal fractional reabsorption of sodium showed to be normal (88.4%). From these findings hypercalcemia and urolithiasis was suggested to result from sarcoidosis. The hypercalcemia and renal insufficiency improved with corticosteroid therapy.
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PMID:[A case of sarcoidosis with hypercalcemia, urolithiasis, nephrocalcinosis and renal insufficiency]. 148 16

We compared mdx and C57BL10 anterior tibial muscle force in situ (single pulse, multiple pulse, staircase, posttetanic potentiation, and fatiguing stimulation patterns) to define muscle strength, physiology, and fatigue resistance. The relatively hypertrophied mdx muscle showed: reduced strength (N/cm2), an increased twitch-tetanus ratio, and resistance to post-fatigue twitch slowing. These differences implicate altered mdx calcium regulation, and emphasize the importance of measuring both muscle function and morphology in mdx treatment trials.
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PMID:Twitch and tetanus in mdx mouse muscle. 150 27

We compared the safety of a new dihydropyridine calcium entry blocker, isradipine, with an equipotent dose of diltiazem in 174 mild hypertensives (diastolic blood pressure [DBP] 95 to 105 mm Hg). After appropriate washout and placebo periods, patients were randomly assigned to receive either 1.25 mg isradipine twice daily (Group I) or 40 mg diltiazem thrice daily (Group D). If DBP remained above 90 mm Hg, doses were increased to a maximum of 5 mg isradipine twice daily or 120 mg diltiazem thrice daily. Active therapy was given for a total of 12 weeks. Only 18 patients (nine from each group) did not complete the protocol. The patients were well-matched at baseline with a mean BP of 149/100 mm Hg for those who were randomized to isradipine and completed the protocol and 153/99 mm Hg for the diltiazem group. The responses to each drug were excellent with 72% of the isradipine patients and 73% of the diltiazem group having DBP less than 90 mm Hg at the completion of the study. Of the 156 patients who completed the protocol, only 18 patients (ten in Group I and eight in Group D) failed to respond. Both drugs were well-tolerated. No adverse reactions were reported by 68 percent of the patients in Group I and 65% of those in Group D. The most common side effect was headache (9.0% in Group I and 7.8% in Group D) followed by fatigue (5.2% in Group I and 3.9% in Group D). Age and race did not predict response to either agent but men responded slightly better to diltiazem than women. We conclude that isradipine and diltiazem are equally well tolerated and can be used successfully as a monotherapy to treat hypertension in a wide variety of patients.
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PMID:A comparison of the safety of therapeutically equivalent doses of isradipine and diltiazem for treatment of essential hypertension. 153 28


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