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)

1. Raising the intracellular [Ca2+] for 10 s at 23 degrees C abolished depolarization-induced force responses in mechanically skinned muscle fibres of toad and rat (half-maximal effect at 10 and 23 microM, respectively), without affecting the ability of caffeine or low [Mg2+] to open the ryanodine receptor (RyR)/Ca2+ release channels. Thus, excitation-contraction coupling was lost, even though the Ca2+ release channels were still functional. Coupling could not be restored in the duration of an experiment (up to 1 h). 2. The Ca(2+)-dependent uncoupling had a Q10 > 3.5, and was three times slower at pH 5.8 than at pH 7.1. Sr2+ caused similar uncoupling at twenty times higher concentration, but Mg2+, even at 10 mM, was ineffective. Uncoupling was not noticeably affected by removal of ATP or application of protein kinase or phosphatase inhibitors. 3. Confocal laser scanning microscopy showed that the transverse tubular system was sealed in its entirety in mechanically skinned fibres and that its integrity was maintained in uncoupled fibres. Electron microscopy revealed distorted or severed triad junctions and Z-line aberrations in uncoupled fibres. 4. Only when uncoupling was induced at a relatively slow rate (e.g. over 60 s with 2.5 microM Ca2+) could it be prevented by the protease inhibitor leupeptin (1 mM). Immunostaining of Western blots showed no evidence of proteolysis of the RyR, the alpha 1-subunit of dihydropyridine receptor (DHPR) or triadin in uncoupled fibres. 5. Fibres which, whilst intact, were stimulated repeatedly by potassium depolarization with simultaneous application of 30 mM caffeine showed reduced responsiveness after skinning to depolarization but not to caffeine. Rapid release of endogenous Ca2+, or raised [Ca2+] under conditions which minimized the loss of endogenous diffusible myoplasmic molecules from the skinned fibre, caused complete uncoupling. Taken together, these results suggest that Ca(2+)-dependent uncoupling can also occur in intact fibres. 6. This Ca(2+)-dependent loss of depolarization-induced Ca2+ release may play an important feedback role in muscle by stopping Ca2+ release in localized areas where it is excessive and may be responsible for long-lasting muscle fatigue after severe exercise, as well as contributing to muscle weakness in various dystrophies.
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PMID:Raised intracellular [Ca2+] abolishes excitation-contraction coupling in skeletal muscle fibres of rat and toad. 884 31

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) which shows good inhibitory activity against HIV-1. Reduced susceptibility to efavirenz has been reported with HIV-1 variants containing single and multiple mutations to the reverse transcriptase enzyme. In vitro and in vivo data suggest that the resistance profile of efavirenz overlaps with that of the NNRTIs nevirapine and delavirdine. Clinically significant drug interactions have been reported with efavirenz and indinavir and saquinavir. An increase in dosage of indinavir from 800 to 1000 mg 3 times daily is recommended during coadministration with efavirenz. Use of efavirenz in combination with saquinavir as the sole protease inhibitor is not recommended. Once-daily efavirenz in combination with zidovudine plus lamivudine or indinavir or nelfinavir increased CD4+ cell counts and reduced HIV RNA plasma levels to below quantifiable levels (< 400 copies/ml) in HIV-infected patients. A sustained reduction in viral load was maintained for at least 72 weeks in 1 study. Nervous system symptoms (including headache, dizziness, insomnia and fatigue) and dermatological effects (including maculopapular rash) appear to be the most common adverse events reported with efavirenz-containing antiretroviral regimens.
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PMID:Efavirenz. 987 93

Indinavir is a protease inhibitor used in the treatment of patients with HIV infection. Combination antiretroviral therapy with indinavir plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) is associated with greater reductions in viral load, greater increases in CD4+ cell counts, and reduced morbidity and mortality when compared with 2 NRTIs alone. In the landmark clinical trial ACTG 320, the rate of progression to AIDS or death (primary end-point) among zidovudine-experienced patients treated with indinavir, zidovudine and lamivudine was approximately half that of patients who received only zidovudine plus lamivudine (6 vs 11%; p < 0.001). The durability of an indinavir-containing regimen was demonstrated in Merck protocol 035, an ongoing trial in which a significant proportion of patients had sustained viral suppression for up to 3 years. Merck protocol 039, also an ongoing trial, showed a greater effect on surrogate markers of HIV disease progression with indinavir-based triple therapy than with zidovudine plus lamivudine or indinavir monotherapy in patients with advanced disease (median baseline CD4+ count 15 cells/microL). Numerous additional clinical trials have established the beneficial antiviral and immunological effects of indinavir in both antiretroviral-naive and -experienced patients with HIV infection. Indinavir is associated with various drug class-related adverse events, including gastrointestinal disturbances (e.g. nausea, diarrhoea), headache and asthenia/fatigue. A lipodystrophy syndrome has been commonly reported with indinavir and other protease inhibitors combined with NRTIs, but it has also been reported in many protease inhibitor-naive patients, and a definitive causal link has not been established between the syndrome and protease inhibitors. Nephrolithiasis may develop in about 9% of patients receiving indinavir but does not appear to be associated with other protease inhibitors; <0.5% of patients receiving indinavir discontinue the drug because of nephrolithiasis, which may be the extreme end of a continuum of crystal-related renal syndromes. Additional renal problems (e.g. nephropathy) have been reported in small numbers of patients receiving indinavir. In summary, indinavir is a protease inhibitor with well documented efficacy when used as part of combined therapy in patients with HIV infection. Both US and UK treatment guidelines continue to recommend protease inhibitor-based regimens including indinavir as a first-line option. Indinavir is being studied as a twice daily and once daily regimen with a low dosage of ritonavir as a way to alleviate tolerability, drug interaction and patient compliance/adherence issues. Indinavir-containing triple therapy has demonstrated positive effects not only on surrogate markers of disease progression, but also on clinical end-points of mortality and morbidity in patients with HIV disease. Protease inhibitors are a significant advance in the care of patients with HIV infection, and, in an era of evidence-based medicine, indinavir represents an important component of antiretroviral treatment strategies.
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PMID:Indinavir: a review of its use in the management of HIV infection. 1065 94

This study explored associations between serum dehydroepiandrosterone sulfate (DHEAS), free and total testosterone levels, and HIV illness markers, including viral load, and the behavioral problems of fatigue and depressed mood. Subjects were 169 HIV-positive men evaluated at baseline, 6, and 12 months for levels of DHEAS, total and free testosterone, HIV RNA, CD4, HIV symptoms, opportunistic illnesses, fatigue, and depression. Men with AIDS (N = 105), compared with men with less advanced illness, had lower mean levels of DHEAS. Baseline DHEAS was positively correlated with CD4 count, HIV symptom severity, and was inversely correlated with HIV RNA. Baseline DHEAS below the laboratory reference range (96 microg/dl) was associated with history of opportunistic infections and malignancies (adjusted odds ratio [OR], 4.4; 95% confidence interval [CI], 1.9-10.4) and with incidence of these complications or death over 1 year (adjusted OR, 2.6; 95% CI, 1-7.2). Initiating protease inhibitor combination therapy was associated with an increase in DHEAS over 6 months. Free testosterone was inversely correlated with HIV RNA, but there were no other significant associations between testosterone and HIV illness markers. No hormone was related to fatigue or depression. This study confirms that low serum DHEAS is associated with HIV illness markers, including viral load, and carries negative prognostic value. Further, protease inhibitor therapy may result in increased circulating DHEAS.
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PMID:Dehydroepiandrosterone sulfate (DHEAS) and testosterone: relation to HIV illness stage and progression over one year. 1084 28

Agouron Pharmaceuticals is making their protease inhibitor, nelfinavir mesylate (Viracept), available in an expanded access program for people who are unable to use any of the three approved protease inhibitors due to intolerance, contraindication, or prior failure with those drugs. They must also have a CD4 count below 50. Viracept has already been studied in 500 patients, with the most frequent side effects being mild to moderate diarrhea, headache, and fatigue.
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PMID:New protease inhibitor available through expanded access. 1136 81

A combination of two protease inhibitors, saquinavir (Invirase) and ritonavir (Norvir), may produce a median drop in viral load of 99.9 percent. Several dosage variations were tested. The most common side effects of the combination regimen included tingling around the mouth, diarrhea, fatigue, and nausea. A low level of toxicity was found. This combination may be used for people who have failed other protease inhibitor therapy or have developed a resistance to nucleoside analogues.
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PMID:Saquinavir plus ritonavir reduce viral load by 99.9 percent. 1136 83

People who are using protease inhibitor therapies and are at risk for diabetes may develop hyperglycemia. All of the approved protease inhibitors have been implicated; however, discontinuation of the treatment has resolved the hyperglycemia. The role of protease inhibitors in hyperglycemia remains unclear, although the causes may include a patient's underlying risks and more frequent testing of a new drug. Frequent urination, thirst, and fatigue are among the symptoms that patients should report to their doctor and the Food and Drug Administration (FDA).
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PMID:Protease inhibitors and diabetes: a growing problem. 1136 47

A new study to be presented at the 12th World AIDS Conference demonstrates that IL-2 dramatically restores immune function in people with AIDS. The study group included patients with fewer than 200 CD4-cells and a history of severe AIDS-related complications including CMV retinitis, PCP, wasting syndrome, KS, and Cryptococcal meningitis. In the study, CD4 counts rose 96 percent when IL-2 was added to protease inhibitor therapy. The increases were sustained, and naive cells increased as well. Most common side effects included fever, fatigue, sinus congestion, and headache; most side effects stopped within 24 hours of completing the treatment cycle. The findings represent new hope for people whose immune systems are substantially compromised. Contact information is provided.
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PMID:New data on IL-2. 1136 33

The FDA has approved Agenerase (generic name amprenavir), a new protease inhibitor which costs about $6,500 per year. Eight 150mg gelatin capsules, twice a day, can be taken without food restrictions. Potential side effects include nausea, fatigue, and headache. About 20 percent of patients developed a rash, that was life-threatening in 1 percent. Early data indicate that the drug does not cause lipodystrophy. Drug interactions are possible with some antihistamines, sedatives, and anti-fungal agents. Website contact information is provided.
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PMID:New protease inhibitor. 1136 64

Use of the commonly prescribed protease inhibitor Crixivan appears to result in a bizarre adverse effect, despite its desirable effects on T-cell count and viral load. This adverse effect is more common in women than men, and includes the following symptoms: (1) limb wasting, (2) fat gain in the torso, (3) breast enlargement, (4) skin thinning, (4) vein enlargement, (5) irregular periods, (6) high blood pressure and high blood glucose, (6) fatigue, and (7) decreased sex drive. It is believed that 5 to 10 percent of patients taking Crixivan suffer from some of these symptoms, but the percentage would probably be much higher if the number of women alone were studied. Some physicians have been unsupportive about complaints of these symptoms, and have told their patients to exercise or that the changes may be due to aging. One suggestion for dealing with these symptoms is to get body composition measurements prior to starting a protease-containing regimen. Exercise continues to remain important, primarily to prevent wasting. However, dieting is not recommended since it does not reduce the fat deposits and it does contribute to wasting of the limbs. If the symptoms become intolerable, a change in regimen may be needed.
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PMID:The new body of AIDS: Crixivan bellies, legs, and humps. 1136 90


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