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)

AIDS-related gastrointestinal disease is common, presenting a challenge to all nutritional support clinicians. Patients frequently suffer from weight loss, diarrhea, malabsorption, and cachexia. Many factors complicate the course of AIDS-related gastrointestinal disease, including decreased food intake (resulting from fatigue and malaise), increased metabolic demand and nutritional requirements, and identifiable gastrointestinal pathology. Gastrointestinal pathology is well-documented, and in approximately 50% of persons with AIDS-related gastrointestinal disease, a causative agent can be identified. In general, treatment of AIDS-related gastrointestinal disease is not always curative. Much of the chronic gastrointestinal dysfunction is caused by recurring opportunistic pathogens that are resistant to chemotherapy. Often, patient care and long-term management can focus only on fluid and electrolyte balance, nutritional support, and symptom control. Even clinically stable patients have been diagnosed as chronically malnourished and, for reasons that remain unclear, are prone to rapid nutritional deterioration during disease exacerbations. Published reports of nutritional assessment and intervention in persons with AIDS are now appearing in the literature. However, the eventual mortality associated with AIDS still results in a hesitancy on the part of many clinicians to prescribe aggressive nutritional support, especially parenteral nutrition. Who to treat and at what stage of illness becomes the question. As new agents, such as AZT, are prescribed on a more frequent basis for persons with AIDS, the use of nutritional support as adjunctive therapy early in the course of disease becomes an issue. Although improving nutrition has not been shown to reverse any of the cellular immunodeficiency caused by HIV infection, quality of life may be improved. In specific cases, nutritional support, whether through diet counseling, food programs, or intervention with enteral or parenteral nutrition, appears to improve strength and endurance, thus enhancing quality of life.
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PMID:Gastrointestinal manifestations of the acquired immunodeficiency syndrome. 249 50

Zidovudine-induced myopathy is characterized by reversible muscle weakness, wasting, myalgia, fatigue, and elevated creatine kinase (CK). Some zidovudine-treated patients with normal muscle strength experience excessive fatigue, myalgia, or transient mild CK elevations that improve when zidovudine is stopped. To determine the cause of these symptoms, we studied 13 physically fit, HIV-infected men who developed fatigue, myalgia, and reduced endurance, while taking zidovudine for a mean period of 20 months (2-39 months), with neurological evaluation and muscle biopsy processed for enzyme histochemistry and electron microscopy (EM). All subjects had normal muscle strength. In 6 of the 13 patients, muscle biopsies were normal by enzyme histochemistry. EM, however, demonstrated proliferation of normal or abnormal mitochondria, and increased amounts of lipid, glycogen, and lipofuscin. Electromyographic (EMG) studies (5/5) and serum CK (6/6) were normal. The other 7 individuals had signs of moderate to severe mitochondrial abnormalities shown by both light microscopy and EM, characterized by severe destruction, vacuolization, and rare paracrystalline inclusions. Most had elevated CK (4 out of 7) and normal EMG (5 out of 7). The severity of morphological abnormalities did not correlate with duration of HIV infection, zidovudine therapy, or zidovudine dosage. We conclude that in zidovudine-treated patients, symptoms of fatigue, myalgia, reduced endurance, and exercise intolerance represent early signs of zidovudine-induced mitochondriotoxicity, which causes an energy shortage within the muscle fibers even when muscle strength is still normal. Zidovudine, a DNA chain terminator, results in overt myopathy when a critical threshold of molecular, histological, and biochemical dysfunction of mitochondria is crossed, which seems to vary between individuals.
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PMID:Early features of zidovudine-associated myopathy: histopathological findings and clinical correlations. 757 71

Patients on long-term zidovudine (AZT) therapy experience muscle fatigue and weakness attributed to AZT-induced mitochondrial toxicity in skeletal muscle. To determine if the clinico-pathological abnormalities in these patients correspond to abnormal muscle energy metabolism, we used 31P in vivo magnetic resonance spectroscopy to follow phosphorylated metabolites during exercise. We studied 19 normal volunteers, 6 HIV-positive patients never treated with AZT, and 9 HIV-positive patients who had been treated with AZT for a mean period of 33 mo (range 12-48 mo) and had muscle biopsy-proven AZT-myopathy with abnormal mitochondria. Changes in phosphocreatine, ATP, and intracellular pH in the gastrocnemius muscle were followed during a graded steady state exercise protocol, and the recovery of phosphocreatine was followed on cessation of exercise. We found that graded steady state exercise produced a greater depletion of muscle phosphocreatine levels in the AZT-treated patients, compared to either HIV-positive patients who were not treated with AZT or normal controls. No differences in the effects of steady state exercise on muscle phosphocreatine levels were observed between the control group and the HIV-positive patients who had not been treated with AZT. The results suggest that the effect of AZT on muscle energy metabolism is significant, and similar to the effect observed in patients with known mitochondrial myopathies. Using a well-known model for control of mitochondrial metabolism, the observed differences in steady state phosphocreatine levels during exercise suggest that AZT treatment decreases the maximal work output and the maximal rate of muscle ATP synthesis.
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PMID:Metabolic abnormalities in skeletal muscle of patients receiving zidovudine therapy observed by 31P in vivo magnetic resonance spectroscopy. 761 82

Zidovudine is known to be responsible for a mitochondrial myopathy with ragged-red fibres and mitochondrial DNA depletion in muscle. Lactic acidosis alone or associated with hepatic abnormalities has also been reported. A single report mentioned the concomitant occurrence of muscular and hepatic disturbances and lactic acidosis in a patient receiving zidovudine, but muscle and liver tissues were not studied. A 57-year-old man with AIDS, who had been treated with zidovudine for 3 years, developed fatigue and weight loss. Serum creatine kinase and hepatic enzyme levels were high. Lactic acidosis was present. Liver biopsy showed diffuse macrovacuolar and microvacuolar steatosis. After withdrawal of zidovudine, creatine kinase, aspartate aminotransferase, and alanine aminotransferase levels normalised within 5 days, and lactacidaemia decreased. Acidosis persisted. The patient became confused and febrile and died 8 days after detection of high blood lactic acid. A muscle sample obtained at autopsy showed mitochondrial abnormalities with ragged-red fibres and lipid droplet accumulation. Southern blot analysis showed depletion of mitochondrial DNA, affecting skeletal muscle and liver tissue. No depletion was found in myocardium and kidney. This case emphasises that zidovudine treatment can induce mitochondrial multisystem disease, as revealed in our case by myopathy, liver steatosis and lactic acidosis.
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PMID:Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. 1070 83

Zidovudine (AZT) and didanosine (ddI), two drugs used in the treatment of AIDS, are also known to cause mitochondrial abnormalities. We investigated the physiological relevance of the mitochondrial defects by measuring in situ skeletal muscle performance and cytochrome c oxidase (CYTOX) enzyme activity in heart muscle, red highoxidative (RG) and white low-oxidative (WG) portions of the gastrocnemius muscle of control (n = 17), AZT-(n = 14), or ddI-treated (n = 11) rats for 28 days. We also evaluated the hypothesis that AZT treatment could alter the expression of the mitochondrial transcription factor A (mtTFA), a key molecule involved in mitochondrial DNA (mtDNA) replication and transcription. AZT had a pronounced effect on blood pressure and skeletal muscle performance, which were significantly decreased during contractile activity at 2 and 5 Hz, compared with control. A significant decrease in CYTOX activity in heart and RG, but not WG muscles, was also evident. In the heart, this was accompanied by an apparent compensatory increase in mtTFA mRNA level that could not be attributed to enhanced transcriptional activation mediated by nuclear respiratory factor 1 (NRF-1). In contrast with AZT, no effect of ddI was found on the extent of fatigue or muscle enzyme activity. These results indicate that AZT induces mitochondrial defects primarily in muscles with the highest oxidative capacities (heart and RG). The long-term effects of AZT on mitochondrial biogenesis have the potential to reduce muscle performance, but the effects on performance in this short-term study were likely due to an inability of the AZT-treated animals to maintain blood pressure during contractile activity.
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PMID:Zidovudine (AZT) induced alterations in mitochondrial biogenesis in rat striated muscles. 1053 63

Patients treated with nucleoside analogue reverse transcriptase inhibitors (NRTIs) develop a varying degree of myopathy or neuropathy after long-term therapy. Zidovudine (AZT) causes myopathy; zalcitabine (ddC), didanosine (ddl) and lamuvidine (3TC) cause neuropathy; stavudine (d4T) and fialuridine (FIAU) cause neuropathy or myopathy and lactic acidosis. The tissue distribution of phosphorylases responsible for phosphorylation of NRTIs relates to their selective tissue toxicity. The myopathy is characterized by muscle wasting, myalgia, fatigue, weakness and elevation of CK. The neuropathy is painful, sensory and axonal. In vitro, NRTIs inhibit the gamma-DNA polymerase, responsible for replication of mtDNA, and cause mtDNA dysfunction. In vivo, patients treated with AZT, the best studied NRTI, develop a mitochondrial myopathy with mtDNA depletion, deficiency of COX (complex IV), intracellular fat accumulation, high lactate production and marked phosphocreatine depletion, as determined with in vivo MRS spectroscopy, due to impaired oxidative phosphorylation. Animals or cultured cells treated with NRTIs develop neuropathy, myopathy, or cell destruction with similar changes in the mitochondria. There is evidence that the NRTI-related neuropathy is also due to mitochondrial toxicity. The NRTIs (AZT, ddC, ddl, d4T, 3TC) contain azido groups that compete with natural thymidine triphosphate as substrates of DNA pol-gamma and terminate mtDNA synthesis. In contrast, FIAU that contains 3'-OH groups serves as an alternate substrate for thymidine triphosphate with DNA pol-gamma and is incorporated into the DNA causing permanent mtDNA dysfunction. The NRTI-induced mitochondrial dysfunction has an influence on the clinical application of these agents, especially at high doses and when combined. They have produced in humans a new category of acquired mitochondrial toxins that cause clinical manifestations resembling the genetic mitochondrial disorders.
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PMID:Peripheral neuropathy and antiretroviral drugs. 1129 2

3TC can raise T4 counts and lower HIV levels, and its use may increase the effectiveness of AZT. Studies show that HIV levels decrease by more than 90 percent in people taking the 2 drugs in combination. Side effects are manageable, and few participants drop out of the studies. Another study showed that 3TC also lowered the amount of hepatitis B virus in the blood to a level where it could not be detected. Side effects include headache, nausea, fatigue, diarrhea, neuropathy, and lowered levels of both red and white blood cells. HIV cells can mutate and resist the effects of 3TC within a few weeks of beginning treatment. The manufacturer, Glaxo Wellcome, has a patient assistance program and an expanded access program for the drug.
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PMID:AZT and 3TC. 1136 95

It is critical to take HIV medications, particularly protease inhibitors, exactly as prescribed to reduce the risks of developing resistance. The Food and Drug Administration (FDA) recently approved a new drug, Combivir, a combination of 3TC (lamivudine) and AZT in one tablet. Combivir works by interfering with the HIV life cycle to prevent it from replicating, and is taken twice a day with or without food. Patients with low body mass, hepatitis, or liver or kidney disease should not take Combivir. Blood counts need to be monitored regularly when taking this drug. Potential side effects include headache, nausea, fatigue, diarrhea, nasal congestion, or flu-like symptoms. A phone number is provided for more information on Combivir.
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PMID:What you need to know about Combivir. 1136 67

A Glaxo-Wellcome study of anti-HIV-drug-naive patients taking amprenavir at 1200 mg and abacavir at 300 mg twice daily reveals viral load drops to below 500 copies. Another study involving abacavir at 300 mg, amprenavir at 1200 mg, AZT at 300 mg, and 3TC at 150 mg, all taken twice daily was conducted with recently infected patients and chronically infected patients. Viral load drops and rises in CD4+ cell counts were reported in both groups after 20 weeks. A rash associated with abacavir tends to occur in about 5 percent of the patients tested. Fatigue, nausea, vomiting, and fever are also possible side effects.
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PMID:New drugs: amprenavir and abacavir. 1136 35

Information on dosage, cost, side effects, and interactions is provided for each of the seven nucleoside analog drugs available currently: Retrovir (AZT, ZDV), Videx (ddI), Hivid (ddC), Zerit (d4T), Epivir (3TC), Combivir (AZT/3TC), and Ziagen (abacavir sulfate). Most nucleoside analogs (with the exception of ddI) do not have food restrictions, but do have potential side effects such as nausea and fatigue. An activist, a doctor, and the drug's manufacturer offer comments. Contact information is provided.
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PMID:What they say about nucleoside drugs. 1136 20


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