Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In principle, target inactivation analysis provides a means of determining the molecular weights (Mr) and states of aggregation of proteins in native environments where they are functionally active. We applied this irradiation technique to the rat liver microsomal membrane proteins: cytochrome b5, epoxide hydrolase, flavin-containing monooxygenase, NADH-ferricyanide reductase, NADPH-cytochrome P-450 reductase, and seven different forms of cytochrome P-450. Catalytic activities, spectral analysis of prosthetic groups, and sodium dodecyl sulfate-polyacrylamide electrophoresis/peroxidase-coupled immunoblotting were used to estimate apparent Mr values in rat liver microsomal membranes. Except in one case (cytochrome P-450PCN-E), the estimated Mr corresponded most closely to that of a monomer. Purified cytochrome P-450PB-B, NADPH-cytochrome P-450 reductase and epoxide hydrolase were also subjected to target inactivation analysis, and the results also suggested monomeric structures for all three proteins under these conditions. However, previous hydrodynamic and gel-exclusion results clearly indicate that all three of these proteins are oligomeric under these conditions. The discrepancy between target inactivation Mr estimates and hydrodynamic results is attributed to a lack of energy transfer between monomeric units. Thus, while P-450PCN-E may be oligomeric in microsomal membranes, target inactivation analysis does not appear to give conclusive results regarding the states of aggregation of these microsomal proteins.
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PMID:Target inactivation analysis applied to determination of molecular weights of rat liver proteins in the purified state and in microsomal membranes. 311 94

Caffeine ingestion prior to prolonged exercise delays fatigue. However, the mechanisms involved are very unclear. Caffeine is associated with elevated plasma epinephrine but the metabolic impact of this is uncertain. Glycogen sparing occurs in active muscle, at least in the first few minutes, but studies have generally failed to demonstrate enhanced fat metabolism. The demethylation of caffeine by the hepatic cytochrome P-450 oxygenases begins within minutes and dimethylxanthines (especially paraxanthine) are generated. These compounds appear in the plasma within an hour of caffeine ingestion and may have effects on tissues that have been attributed to caffeine and/or epinephrine. While the most widely supported theory is that caffeine and other methylxanthines are adenosine receptor antagonists, this action alone cannot explain all of the observed responses. Nevertheless, habituation to and withdrawal from caffeine are associated with up and down regulation of adenosine receptors. One study demonstrated marked differences in the effects of caffeine on the plasma concentrations of epinephrine and dimethylxanthines between caffeine users and nonusers. Caffeine is clearly a very active drug that has many effects on humans including increasing exercise endurance. This can be associated with muscle glycogen sparing and elevated plasma epinephrine, but the underlying mechanisms are unknown.
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PMID:Caffeine and exercise: metabolism and performance. 808 18

We studied the effect of 3 weeks treatment with the selective serotonin reuptake inhibitor (SSRI), fluvoxamine, on hormonal and psychological responses to buspirone, a 5-HT1A receptor partial agonist which also binds to dopamine receptors, in normal male volunteers. Eleven subjects received buspirone, 30 mg, and placebo before, and in week 3 of fluvoxamine treatment (mean dose 127 mg/day). Placebo and buspirone were given in a balanced order, double-blind. Buspirone significantly elevated plasma prolactin (PRL) and growth hormone (GH) concentrations but had no significant effect on cortisol (CORT) or temperature. Significant psychological effects of lightheadedness, tiredness and difficulty thinking occurred. Fluvoxamine treatment resulted in a nearly 3-fold increase in plasma buspirone with a similar enhancement of the PRL response. In contrast the GH and psychological responses were blunted. The increased buspirone concentrations are likely to be due to inhibition of first pass liver metabolism by fluvoxamine acting on the cytochrome P-450 system. The PRL response is probably mediated by antagonism of pituitary dopamine-D2 receptors and its enhancement by fluvoxamine treatment may be a pharmacokinetic effect. The blunting of GH and psychological responses suggest that 5-HT1A receptor function is reduced by chronic fluvoxamine treatment.
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PMID:The effect of chronic fluvoxamine on hormonal and psychological responses to buspirone in normal volunteers. 894 9

Derived from the aerial parts of the plant, St. John's wort generally is used for depression, seasonal affective disorder, and anxiety. Products currently are standardized based on hypericin content, although the hyperforin and bioflavonoid contents are also believed responsible for activity. St. John's wort is metabolized primarily by the liver. Some studies comparing St. John's wort to standard antidepressants suggest that it may be as effective as imipramine or selective serotonin reuptake inhibitors (SSRIs) to treat mild to moderate depression. Results from another clinical trial indicate that the effectiveness of St. John's wort is comparable to paroxetine, an SSRI, in the treatment of moderate to severe depression and is well tolerated. But a meta-analysis shows that data are inconsistent. Studies also show possible efficacy in the management of anxiety and premenstrual syndrome, although additional research is necessary. St. John's wort can interact with many medications owing to induction of cytochrome P-450 3A4 and other mechanisms. Significant interactions include decreased efficacy of antiretrovirals, cyclosporine, tacrolimus, antiepileptics, irinotecan, and other chemotherapeutic agents. Serotonin syndrome may occur when St. John's wort is combined with sympathomimetics, antidepressants, or triptans. Frequently reported adverse events include nausea, headache, constipation, dizziness, confusion, fatigue, and dry mouth. St. John's wort should be used under medical supervision.
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PMID:About the cover: St. John's wort. 1673 73

Ixabepilone is a novel microtubule-stabilizing agent with clinical efficacy in advanced breast cancer, including patients whose disease has progressed on prior anthracyclines and taxanes. The safety profile of single-agent ixabepilone and combination ixabepilone plus capecitabine therapy is reviewed, outlining the steps to effectively manage and prevent common adverse events. Ixabepilone is generally well tolerated, and importantly, its toxicity profile does not overlap with that of capecitabine. Peripheral sensory neuropathy and neutropenia are the most common toxicities associated with ixabepilone; both can be effectively managed by monitoring patients and then, depending on severity, instituting a treatment delay until recovery and reducing the ixabepilone dose for subsequent treatment cycles. Ixabepilone dose reductions are recommended for most grade 3 events, excluding transient fatigue, arthralgia, and myalgia, whereas treatment discontinuation is recommended for persistent grade 3 neuropathy or any grade 4 nonhematological toxicity. Because ixabepilone exposure is greater in patients with hepatic impairment and those receiving concomitant strong cytochrome P-450 CYP3A4 inhibitors, dose adjustments and restrictions are recommended according to the degree of hepatic impairment, whether ixabepilone is administered alone or in combination with capecitabine, and whether a strong CYP3A4 inhibitor is being coadministered. Patients should be premedicated with oral H(1) and H(2) antihistamines to prevent hypersensitivity reactions. Unlike taxanes, corticosteroid premedication is not required unless a hypersensitivity reaction occurred during a previous cycle or during treatment with another Cremophor-containing agent. By effectively managing adverse events and taking steps to minimize them, clinicians can ensure that patients derive the maximum benefit from ixabepilone therapy.
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PMID:Proactive management of adverse events maintains the clinical benefit of ixabepilone. 1941 15

Peripheral T-cell lymphoma is a heterogenous non-Hodgkin Lymphoma with historically poor outcomes. Currently, response rates remain poor with traditional chemotherapy and many of those responding to initial therapy will relapse. Belinostat (Beleodaq, Spectrum Pharmaceuticals) is a histone deacetylase inhibitor (HDACi) approved for use in relapsed or refractory peripheral T-cell lymphoma (PTCL). Belinostat is metabolized hepatically through cytochrome P-450 enzymes 3A4, 2C9, and 2A6; however, no empiric dosage adjustments of belinostat are recommended during concurrent use of inhibitors or inducers of these enzymes. Belinostat's efficacy has been evaluated in a clinical trial showing an overall response rate (ORR) of 25.8% and a median duration of response of 8.4 months. Belinostat is generally well tolerated, with the most common adverse reactions (>25%) being nausea, vomiting, fatigue, pyrexia, and anemia in patients with relapsed or refractory PTCL. Belinostat is a safe and effective treatment option for relapsed and refractory peripheral T-cell lymphoma, with many future applications currently being investigated.
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PMID:Belinostat for the treatment of relapsed or refractory peripheral T-cell lymphoma. 2692 Oct 86