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)

Abnormalities in the regulation of the hypothalamo-pituitary-adrenal (HPA) axis are a well recognised feature of endogenous depression. The mechanism underlying this phenomenon remains obscure although there is strong evidence suggesting excessive CRH activity at the level of the hypothalamus. We propose a novel hypothesis in which we suggest that the aetiological antecent to CRH hyperactivity is cytokine activation in the brain. It is now well established both that interleukins -1 and -6 are produced in a number of central loci and that cytokines are potent stimulators of the HPA axis. Hence, we suggest that activation of IL-1 and IL-6 by specific mechanisms (such as neurotropic viral infection) in combination with the consequent CRH-41 stimulation, may (via their known biological effects) underly many of the features found in major depression and other related disorders, particularly where chronic fatigue is a prominent part of the symptom complex. This theory has considerable heuristic value and suggests a number of experimental stratagems which may employed in order to confirm or reject it.
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PMID:Hypothesis: cytokines may be activated to cause depressive illness and chronic fatigue syndrome. 160 97

To evaluate the hematologic effects of recombinant human interleukin-6 (rhIL-6, Escherichia coli, SDZ ILS 969, IL-6), and determine its toxicity profile, we performed a phase I trial of IL-6 in 22 patients with various myelodysplastic syndromes (MDS), platelet counts < 100,000/microL, and < 5% bone marrow (BM) blasts. Patients received one of four doses of IL-6 (1.0, 2.5, 3.75, and 5.0 micrograms/kg/d) as a subcutaneous injection on day 1, followed by a 7-day wash-out period, and then 28 days of IL-6 therapy. Dose-limiting toxicities of fatigue, fever, and elevated alkaline phosphatase were seen at 5.0 micrograms/kg/d; the maximum tolerated dose was 3.75 micrograms/kg/d. All patients experienced at least grade II fever and all had an increase in acute phase proteins. Eight patients (36%) experienced at least a transient improvement in platelet counts; three fulfilled the criteria for response, whereas five others had clinically significant increases that failed to meet response criteria. Various IL-6-related toxicities prevented more than three patients from receiving maintenance therapy. Two of the three patients who received maintenance IL-6 therapy had a persistent increase in platelet counts, during 3 and 12 months of IL-6 therapy, respectively. Laboratory studies indicated that IL-6 increased the frequency of higher ploidy megakaryocytes but did not significantly increase the number of assayable megakaryocytic progenitor cells, suggesting that IL-6 acts as a maturational agent rather than a megakaryocyte colony-stimulating factor. Although IL-6 therapy can promote thrombopoiesis in some MDS patients, its limited activity and significant therapy-related toxicity preclude its use as a single agent in this patient population. Further studies, combining low doses of IL-6 with other hematopoietic growth factors, are underway.
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PMID:A phase I trial of recombinant human interleukin-6 in patients with myelodysplastic syndromes and thrombocytopenia. 753 15

Metabolic and inflammatory responses and changes in fatigue were studied in groups of patients undergoing either laparoscopic (n = 14) or open (n = 10) elective cholecystectomy. The mean(s.e.m.) cortisol concentration was significantly (P < 0.001) increased from 342(80) and 424(91) nmol l-1 before operation to 895(46) and 966(53) nmol l-1 after surgery in patients undergoing laparoscopic and open cholecystectomy respectively. There was no difference in cortisol response between the groups. Glucose concentration was increased (P < 0.02) at the end of surgery from mean(s.e.m.) preoperative levels of 5.54(0.15) and 6.16(0.15) mmol l-1 to postoperative values of 7.46(0.29) and 8.46(0.86) mmol l-1 for the laparoscopic and open procedures respectively. The mean glucose concentration during the initial 12 h after surgery was significantly greater (P < 0.02) following open than laparoscopic cholecystectomy. The mean(s.e.m.) albumin concentration fell significantly (P < 0.01) during surgery by an equivalent extent from 38.9(0.77) and 38.5(1.10)g l-1 to 35.2(0.79) and 34.6(0.97) g l-1. The mean (95 per cent confidence interval) interleukin (IL)6 concentration peaked 4 h after surgery at 57.2 (44.6-73.4) pg ml-1 following laparoscopic and 99.3 (72.8-135.4) pg ml-1 after open cholecystectomy. Mean (95 per cent confidence interval) C-reactive protein (CRP) levels at 24 h were 17.0 (12.7-21.2) and 49.0 (25.3-93.6) mg l-1 and at 48 h 28.0 (21.4-35.4) and 70.0 (36.4-133.6) mg l-1 following laparoscopic and open operations. The differences in IL-6 and CRP level between the groups were significant (P < 0.01). Mean(s.e.m.) fatigue scores were significantly (P < 0.05) increased from preoperative values of 2.4(0.24) and 2.6(0.44) to 5.5(0.56) and 6.8(0.51) at 24 h after laparoscopic and open operations. At 48 h the mean(s.e.m.) fatigue score (5.6(0.57)) remained significantly (P < 0.05) raised only after open cholecystectomy. Hand grip strength was significantly (P < 0.05) reduced only after the open procedure, to a mean(s.e.m.) of 88(6) per cent of the preoperative value. These results demonstrate that aspects of the metabolic and acute-phase responses are attenuated following laparoscopic cholecystectomy, consistent with a reduction in tissue trauma.
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PMID:Metabolic and inflammatory responses after open or laparoscopic cholecystectomy. 831 88

In the literature the separation between RS and RLS is confusing and makes it difficult to plan an appropriate preventive action or to develop new therapeutic approaches. We suggest that the generalized damage and encephalopathy seen in both RS and RLS may be due to a wide variety of causative agents that contribute to a common derangement, principally involving mitochondrial oxidative pathway. Fasting status and infections increase the catabolism and the subsequent flux of metabolites from peripheral tissues to the liver (FA and amino acids); cytokines (TNF, IL-1, and IL-6), in particular, mediate this effect during infection and experimental endotoxemia. Some drugs and other toxic compounds induce functional and morphological liver mitochondrial derangement. Oxidative metabolism is impaired, with subsequent stimulation of alternative pathways of oxidation, following production of unusual toxic acyl CoAs and dicarboxylic acids. Toxic compounds accumulate in the liver, deranging its functions and causing energy depletion, and are also released in the circulation from which they reach other tissues, including the brain. Neurons and astrocytes in the brain may be affected differently: Neurons suffer from the lack of energy and the effect of toxic compounds arriving from the bloodstream, and astrocytes may be directly affected by the beta-oxidation derangement. Very important may be genetic predisposition, which, by making the patient more sensitive to a particular causative agent, may facilitate the onset of RS and RLS. The therapeutic approach is, presently, mainly symptomatic, directed as it is to counteracting each alteration shown, depending by the clinical gravity. Other pharmacological approaches are only studied experimentally, like carnitine supplementation and PGE2 administration, or theoretically envisaged, like monoclonal antibody therapy directed at LPS or at pro-inflammatory cytokines or treatment with interferon-alpha.
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PMID:Reye's and Reye-like syndromes, drug-related diseases? (causative agents, etiology, pathogenesis, and therapeutic approaches). 852 53

The role of elevations of serum cytokines in psoriasis is a provocative issue. We report two patients with psoriasis who had episodes of fever, arthritis, and general fatigue. Their symptoms seemed to be associated with increases in serum levels of interleukin (IL)-6, which paralleled the severity of clinical symptoms as well as elevated serum titers of C-reactive protein (CRP) and platelet counts. Since IL-6 is a multipotential cytokine with B-cell activating, T-cell activating, and thrombocytopoietic functions, the symptoms and abnormal laboratory findings in these patients may have been related to their increased serum levels of IL-6. Monitoring the serum level of this cytokine may thus be useful in evaluating the clinical status of patients with psoriatic arthritis.
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PMID:Increased serum level of interleukin-6 in patients with psoriatic arthritis and thrombocytosis. 858 48

The synthetic polynucleotide polyadenylic-polyuridylic acid (polyA:polyU) has shown antitumor activity in murine studies and human breast cancer. PolyA:polyU was evaluated in 25 cancer patients receiving weekly intravenous doses between 3 and 600 mg/m2. PolyA:polyU was well tolerated up to 600 mg/m2, with no doselimiting toxicity (all < grade 3). Side effects included mild elevation in temperature, fatigue, and mild hyperglycemia. No changes outside of the normal range in hematocrit, WBC count, platelet count, total bilirubin, or alkaline phosphatase were observed. Of 25 patients, 18 completed at least one cycle of 6 weeks, and 5 completed two cycles (median 6 weeks). Four patients had stable disease over 11-13 weeks of treatment, and no clinical responses were observed. At 24 h after the first treatment, there were no significant increases in biologic response (beta 2-microglobulin and neopterin in serum, or 2',5'-oligoadenylate synthetase in peripheral blood mononuclear cells). A small increase in beta 2-microglobulin was observed 24 h after the week 3 treatment (1.1-fold, p < 0.01). By the third week of treatment, 2-5A synthetase levels decreased slightly (to 80% of baseline, p < 0.01). No changes in cytokines IL-6, IL-12, tumor necrosis factor (TNF), or IL-2 receptor in serum were detected after 24 h of treatment. Thus, at these doses, polyA:polyU had no marked modulation on biologic responses in vivo, although this preparation significantly induced 2-5A synthetase in peripheral blood mononuclear cells in vitro. PolyA:polyU was well tolerated. An MTD was not reached but was greater than 600 mg/m2 on this weekly schedule.
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PMID:Phase I/IB study of polyadenylic-polyuridylic acid in patients with advanced malignancies: clinical and biologic effects. 887 34

The cytokines tumor necrosis factor-alpha (TNF alpha), interleukin-1 (IL-1), and IL-6 are secreted at inflammatory sites in tandem and play a crucial role in the inflammatory and wound-healing processes. All three cytokines are potent activators of the hypothalamic-pituitary-adrenal axis, through which they restrain inflammation, whereas IL-6 itself plays a role in the termination of inflammation as well. To test the hypothesis that endogenous glucocorticoids exert a negative tonic effect on the secretion of these cytokines, we studied 17 patients with Cushing's disease and 2 patients with primary adrenal Cushing's syndrome before and after surgery. Plasma TNF alpha, IL-1 beta and IL-6 were measured before surgery, while the patients were hypercortisolemic; on postoperative day 4 or 5, when they were hypocortisolemic; and on postoperative day 9 or 10, when they were receiving glucocorticoid replacement. During severe hypocortisolism, on postoperative day 4 or 5, plasma IL-6 levels rose significantly, compared to the preoperative values (P < 0.001). During the same interval, TNF alpha and IL-1 beta also rose, albeit to a lesser extent. Over the same interval, patients with severe hypocortisolism experienced temperature elevation, fatigue, somnolence, flu-like symptoms, and anorexia, symptoms that have been traditionally attributed to glucocorticoid deficiency; these were also experienced by subjects that received recombinant human IL-6. There was no postoperative increase in any of the cytokines studied in the patients who were not hypocortisolemic after surgery and who also lacked the corresponding symptomatology. Plasma IL-6 concentrations decreased significantly, albeit not to normal levels, in the hypocortisolemic group of patients on postoperative day 9 or 10, when they were receiving glucocorticoid replacement. We conclude that the peripheral levels of IL-6 and to a lesser extent, those of TNF alpha and IL-1 beta are tonically inhibited by basal levels of glucocorticoids. The increased IL-6 production that occurs when cortisol levels fall might explain the symptomatology of acute glucocorticoid deficiency.
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PMID:Acute glucocorticoid deficiency is associated with plasma elevations of interleukin-6: does the latter participate in the symptomatology of the steroid withdrawal syndrome and adrenal insufficiency? 896 68

Excessive daytime sleepiness (EDS) and fatigue are frequent symptoms in the general population and the chief complaint of the majority of patients at Sleep Disorders Centers. There is evidence that the inflammatory cytokines tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta), and IL-6 are involved in physiological sleep regulation and that their administration to humans is associated with sleepiness and fatigue. To explore whether plasma levels of TNF alpha, IL-1beta, and IL-6 are elevated in patients with EDS, we measured morning plasma levels of TNF alpha, IL-1beta, and IL-6 in 12 sleep apneics, 11 narcoleptics, 8 idiopathic hypersomniacs, and 10 normal controls. TNF alpha was significantly elevated in sleep apneics and narcoleptics compared to that in normal controls (P < 0.001 and P = 0.001, respectively). Plasma IL-1beta concentrations were not different between sleep disorder patients and controls, whereas IL-6 was markedly and significantly elevated in sleep apneics compared to that in normal controls (P = 0.028). The primary factor influencing TNF alpha values was the degree of nocturnal sleep disturbance, whereas the primary determinant for IL-6 levels was the body mass index. Our findings suggest that TNF alpha and IL-6 might play a significant role in mediating sleepiness and fatigue in disorders of EDS in humans.
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PMID:Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. 914 8

Various interferon-alpha (IFN-alpha) preparations, either as individual subtypes or natural mixtures, induce or inhibit expression of several other cytokines, as well as cytokine receptors and chemokines. The cytokines and receptors reportedly affected by IFN-alpha include interleukin-1 (IL-1), IL-2, IL-6, IL-8, IL-1 receptor, IL-1 receptor antagonist, tumor necrosis factor, tumor necrosis factor receptor, and IFN-gamma, all of which may amplify the effects of IFN-alpha treatment. The mechanism by which IFN-alpha induces expression of these cytokines is not clear. Some of the therapeutic and toxic effects associated with IFN-alpha therapy may be caused by the induction or inhibition of other cytokines and their respective cellular effects. Side effects including fever, anorexia, and fatigue can be caused by one or more of the cytokines induced by IFN-alpha. The response of different cell types, normal or malignant, to cytokines can vary. Such variation in cell type-specific responses may contribute to the diverse array of physiologic effects associated with IFN-alpha therapy. Further research is required to systematically uncover how other cytokines, receptors, or cellular factors contribute to the therapeutic and toxic effects of IFN-alpha.
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PMID:The effects of interferon-alpha on the production and action of other cytokines. 948 37

The present phase II study was undertaken to assess antitumoral activity, safety and tolerability of recombinant human interleukin-6 (rh IL-6) in patients with advanced renal cell cancer. Rh IL-6 was administered as a daily subcutaneous injection at a fixed dose of 150 micrograms/day for a maximum of 42 consecutive days. 12 patients with metastatic renal cell cancer without previous immunotherapy were enrolled and were evaluated for response. No objective clinical responses were observed in the trial. Toxicity was moderate and reversible and mainly comprised fever, influenza-like symptoms, fatigue and moderate hepatotoxicity. Anaemia, leucocytosis, thrombocytosis and induction of an acute phase response were observed in most patients. In conclusion, prolonged subcutaneous administration of rh IL-6 on an outpatient basis is safe and feasible. However, rh IL-6 exhibited no antitumoral activity in patients with metastastic renal cell cancer. Profound regulatory effects on haematopoiesis and inflammatory response of rh IL-6 were observed.
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PMID:Lack of efficacy of recombinant human interleukin-6 in patients with advanced renal cell cancer: results of a phase II study. 971 86


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