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)

The wood frog (Rana sylvatica) is a terrestrial hibernator that can accumulate urea as an osmoprotectant in autumn and winter. This study tested the hypothesis that elevated urea can also function as a cryoprotectant in this freeze-tolerant species. Performance characteristics (threshold stimulus voltage, maximal isometric twitch and tetanic contraction forces, and (1/2) fatigue time) of isolated gastrocnemius muscles were measured before and after experimental freezing at -1.5 degrees C for 18 h, followed by thawing. Frozen/thawed muscles exhibited reduced function relative to baseline (prefreeze) levels; however, muscles preincubated in a saline solution containing urea (80 mmol l(-1)) performed substantially better in some tests than muscles incubated without urea. Concentrations of urea in these treated muscles, approximately 65 mmol l(-1), were within the physiological range in winter R. sylvatica. Reducing tissue urea levels to approximately 33 mmol l(-1) resulted in a similar pattern of response, although the differences between urea-incubated and saline-incubated muscles were not statistically significant. Tests of cryoprotective efficacy were also performed on gastrocnemius muscles from R. pipiens, a closely related, but freeze-intolerant species that hibernates aquatically and thus has little need to accumulate urea. Urea-treated muscles from this species performed no better than muscles incubated in saline, attesting that freeze tolerance cannot be conferred simply by augmenting cryoprotectant levels. Overall, these results bolster an earlier report that urea accumulated in response to low moisture availability can serve a cryoprotective role in freeze-tolerant ectotherms.
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PMID:Urea loading enhances postfreeze performance of frog skeletal muscle. 1808 69

Now peptides achieve distinct advantages over protein in biological application because of its quick and easy absorption, low power, and high activity. Some bioactive peptides had been developed to be used in the management of exercise-related disorders. In this study, we investigated whether the decapeptide CMS001 (Pro-Thr-Thr-Lys-Thr-Tyr-Phe-Pro-His-Phe) isolated from pig spleen had anti-fatigue effects. Male Balb/c mice were administered CMS001 (20 microg/(kgd)(-1) or 5 microg/(kgd)(-1) for 30 d, intraperitoneal injections) and tested in an exhaustive swim time task. In order to examine the mechanisms of CMS001 anti-fatigue effects, we analyzed liver glycogen stores, blood urea nitrogen (BUN) levels, lactic acid levels, ultrastructural integrity, and levels of both a free radical metabolite and an anti-oxidant enzyme. CMS001 treatment prolonged exhaustive swim time, increased liver glycogen levels, reduced BUN levels, and decreased accumulation of lactic acid in the blood, relative to mice injected with only saline. Examination of the ultrastructure of mitochondria and sarcoplasmic reticulum in skeletal and cardiac muscle of CMS001-treated and control mice revealed that CMS001 can reduce the damage to cardiac and skeletal muscle caused by an exhaustive swim challenge, such that the structure of most tissue specimens were normal in the peptide-treated group. Furthermore the free radical analysis after acute exercise indicated that CMS001 treatment decreased malondialdehyde (MDA) and increased superoxide dismutase (SOD) levels. The present findings indicate that the spleen-derived peptide CMS001 has anti-fatigue effects in mice, and further suggest that the mechanism may involve reduction of tissue damaging free radicals in muscle tissues.
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PMID:The decapeptide CMS001 enhances swimming endurance in mice. 1844 Jun 69

Sorafenib (BAY 43-9006) is a novel oral bis-aryl urea compound originally developed as an inhibitor to RAF kinase for its anti-proliferative property. It also inhibits receptor tyrosine kinases of multiple pro-angiogenic factors such as VEGFR-2/3, Flt-3/ and PDGFR-beta. The combination of both its anti-proliferative and anti-angiogenic properties makes sorafenib an attractive agent in cancer treatment. Phase I studies demonstrated that sorafenib was well tolerated, and the recommended phase II dose was 400 mg twice daily continuously. Common toxicities included skin toxicity (rash and hand-foot syndrome), gastrointestinal toxicities (nausea and diarrhea) and fatigue. Anti-tumor activities were observed in multiple tumors types including renal cell carcinoma and hepatocellular carcinoma. Randomized phase III studies in these tumor types are ongoing, and results are eagerly waited.
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PMID:Sorafenib (BAY 43-9006): review of clinical development. 1866 47

Maintenance of the red blood cell volume is a fundamental aspect of ensuring oxygen supply to the tissue. Recombinant human erythropoietin (rHuEPO) was approved for marketing in Japan in 1990 for the treatment of anemia in patients on dialysis. Recombinant human erythropoietin caused a significant increase in hemoglobin (Hb) levels in patients on dialysis. However, not all have a good response to rHuEPO therapy; the causes of rHuEPO failure include iron deficiency, infection, uremia, and interaction of some drugs. Juzen-taiho-to (TJ-48), a mixture of extracts from 10 medicinal herbs, has been used traditionally to treat patients with anemia, anorexia, or fatigue. To clarify the effect of TJ-48 on erythropoietin-resistant anemia, we studied the effect of TJ-48 in patients on hemodialysis with erythropoietin-resistant anemia. We divided 42 end-stage renal disease patients on hemodialysis with erythropoietin-resistant anemia (Hb<10.0 g/dL with rHuEPO 9000 U/wk or 15 U/kg/wk treatment) into 2 groups as follows: a TJ-48-treated group (TJ-48 group, 7.5 g/d, n=22) and a TJ-48 nontreated (control group, n=20). At the beginning of this study, there was no significant difference between the groups in age, sex, serum creatinine, blood urea nitrogen, serum iron, and ferritin. After 12 weeks of treatment, the Hb level had significantly increased from 8.4 +/- 1.1 to 9.5 +/- 1.3 g/dL (P=0.0272) in the TJ-48 group. C-reactive protein (CRP) had significantly decreased from 1.4 +/- 1.7 to 0.6 +/- 0.8 mg/dL (P=0.0438). There was a significant negative correlation between Hb and CRP in the TJ-48 group (r(2)=0.121, P=0.0066). In contrast, in the control group, Hb and CRP showed no significant changes throughout this study. Nor was there a significant correlation between Hb and CRP in the control group. In conclusion, TJ-48 was effective in improving erythropoietin-resistant anemia in end-stage renal disease patients. This effect was, at least in part, due to the anti-inflammatory effect of TJ-48 in patients on hemodialysis.
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PMID:Orally administrated Juzen-taiho-to/TJ-48 ameliorates erythropoietin (rHuEPO)-resistant anemia in patients on hemodialysis. 1883 71

20(R)-ginsenoside Rg3 (20(R)-Rg3) has shown multiple pharmacological activities and been considered as one of the most promising approaches for fatigue treatment. However, 20(R)-Rg3 has a low bioavailability after oral administration in human due to the first-pass effect. Recently, nasal route has gained increasing interest as it can avoid first-pass effect for its lower enzymatic activity compared with the gastrointestinal tract and liver. In order to provide an animal experimental evidence of 20(R)-Rg3 intranasal administrated preparation, the anti-fatigue effect of 20(R)-Rg3 after intranasal administration was investigated. Two weeks after 20(R)-ginsenoside Rg3 was administrated intranasally to mice at three different doses, the anti-fatigue effect of 20(R)-Rg3 was evaluated by the weight-loaded swimming test and biochemical parameters related to fatigue, such as serum urea nitrogen (SUN), lactic dehydrogenase (LDH), superoxide dismutase (SOD), malondialdehyde (MDA), blood lactic acid (LA) and hepatic glycogen. The results showed that compared with the negative control group, the intermediate-dose and the high-dose groups significantly prolonged the weight-loaded swimming time (p<0.05; p<0.01), and also increased the hepatic glycogen levels (p<0.05); SUN levels were decreased considerably in three 20(R)-Rg3-treated groups (p<0.01). In addition, the low-dose group obviously decreased the content of blood LA (p<0.05). However, the levels of LDH, SOD and MDA did not show a significant change. Our results predicted a benefit of 20(R)-Rg3 as an anti-fatigue treatment by intranasal administration. The mechanism was related to the increase of the storage of hepatic glycogen, and the decrease of the accumulation of metabolite such as lactic acid and serum urea nitrogen.
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PMID:The anti-fatigue effect of 20(R)-ginsenoside Rg3 in mice by intranasally administration. 1898 67

We examined the effects of L-ornithine administration on physical fatigue. In a double-blind, placebo-controlled, 2-way crossover study, 17 healthy volunteers were randomized to L-ornithine (2000 mg/d for 7 days and 6000 mg/d for 1 day as L-ornithine hydrochloride) or placebo for 8 days. The fatigue-inducing physical task consisted of workload trials on a cycle ergometer at fixed workloads for 2 hours on 2 occasions. We found that oral L-ornithine administration promoted lipid metabolism and activated the urea cycle from serum triacylglycerol, ketone bodies, free fatty acids, and blood ammonia level changing. L-ornithine significantly attenuated the subjective feeling of fatigue (measured by visual analog scale at postrecovery) compared with postload (P < .01). Moreover, in female subjects, the subjective feeling of fatigue was significantly lower compared with the placebo group (P < .05). In the physical performance test in female subjects, the decrease in mean speed for 10 seconds maximum pedaling from 0.5- to 3.5-hour trials in the group receiving L-ornithine was smaller than that in the group receiving placebo (P < .05). These results suggest that L-ornithine has an antifatigue effect by increasing the efficiency of energy consumption and promoting the excretion of ammonia. L-ornithine is a free amino acid and is not rich in meats or fish, so it is difficult to obtain amounts of L-ornithine from ordinary meals that would be sufficient to promote the antifatigue effect. We recommend L-ornithine intake as a nutritional supplement in cases of physical fatigue.
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PMID:L-ornithine supplementation attenuates physical fatigue in healthy volunteers by modulating lipid and amino acid metabolism. 1908 82

Sorafenib (Nexavar) is an orally active multikinase inhibitor that is approved in the EU for the treatment of hepatocellular carcinoma. Monotherapy with sorafenib prolongs overall survival and delays the time to progression in patients with advanced hepatocellular carcinoma who are not candidates for potentially curative treatment or transarterial chemoembolization. Sorafenib is generally well tolerated in patients with advanced hepatocellular carcinoma. Thus, sorafenib represents an important advance in the treatment of advanced hepatocellular carcinoma and is the new standard of care for this condition. The bi-aryl urea sorafenib is an oral multikinase inhibitor that inhibits cell surface tyrosine kinase receptors (e.g. vascular endothelial growth factor receptors and platelet-derived growth factor receptor-beta) and downstream intracellular serine/threonine kinases (e.g. Raf-1, wild-type B-Raf and mutant B-Raf); these kinases are involved in tumour cell proliferation and tumour angiogenesis. In vitro, dose-dependent inhibition of cell proliferation and induction of apoptosis was seen with sorafenib in human hepatocellular carcinoma cells lines. Sorafenib demonstrated dose-dependent antitumour activity in a murine xenograft model of human hepatocellular carcinoma. Steady-state plasma concentrations were reached within 7 days in patients with advanced, refractory solid tumours who received twice-daily oral sorafenib. Metabolism of sorafenib occurs primarily in the liver and is mediated via cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase 1A9. In advanced hepatocellular carcinoma, differences in sorafenib pharmacokinetics between Child-Pugh A and B patients were not considered clinically significant. Sorafenib may be associated with drug interactions. For example, sorafenib exposure was reduced by an average 37% with concomitant administration of the CYP3A4 inducer rifampicin (rifampin); sorafenib concentrations may also be decreased by other CYP3A4 inducers. Monotherapy with oral sorafenib 400 mg twice daily prolonged median overall survival and delayed the median time to progression in patients with advanced hepatocellular carcinoma, according to the results of two randomized, double-blind, placebo-controlled, multicentre, phase III trials (the SHARP trial and the Asia-Pacific trial). There was no significant difference between sorafenib and placebo recipients in the median time to symptomatic progression in either trial. The vast majority of patients included in these trials were Child-Pugh A. Combination therapy with sorafenib plus doxorubicin did not delay the median time to progression to a significant extent compared with doxorubicin alone in patients with advanced hepatocellular carcinoma, according to the results of a randomized, double-blind, phase II trial. However, the median durations of overall survival and progression-free survival were significantly longer in patients receiving sorafenib plus doxorubicin than in those receiving doxorubicin alone. Combination therapy with sorafenib plus tegafur/uracil or mitomycin also showed potential in advanced hepatocellular carcinoma, according to the results of noncomparative trials. Monotherapy with oral sorafenib was generally well tolerated in patients with advanced hepatocellular carcinoma, with a manageable adverse effect profile; diarrhoea and hand-foot skin reaction were consistently the most commonly occurring drug-related adverse events in clinical trials. In the SHARP trial, drug-related adverse events of any grade occurring in significantly more sorafenib than placebo recipients included diarrhoea, hand-foot skin reaction, anorexia, alopecia, weight loss, dry skin, abdominal pain, voice changes and 'other' dermatological events. A similar tolerability profile was seen in the Asia-Pacific trial. As expected given the addition of a chemotherapy agent, the adverse event profile in patients with advanced hepatocellular carcinoma who received combination therapy with sorafenib plus doxorubicin differed somewhat to that seen with sorafenib monotherapy in the SHARP trial. In patients receiving sorafenib plus doxorubicin, the most commonly occurring all-cause adverse events (all grades) included fatigue, neutropenia, diarrhoea, elevated bilirubin levels, abdominal pain, hand-foot skin reaction, left ventricular dysfunction, hypertension and febrile neutropenia.
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PMID:Sorafenib: a review of its use in advanced hepatocellular carcinoma. 1922 77

Adequacy of hemodialysis is frequently equated with Kt/V(urea) , the amount of urea clearance (K) multiplied by time (t) and divided by urea distribution volume (V). Several formulas have been developed to calculate Kt/V(urea) from the pre- and post-dialysis urea concentrations. In three-times-weekly hemodialysis, a single pool (spKt/V(urea)) value of 1.3 per treatment is commonly considered to indicate adequate therapy. Despite providing the recommended spKt/V(urea) of 1.3 per treatment, short dialysis with rapid ultrafiltration is associated with multiple intradialytic and interdialytic complications. Patients experience cramps, nausea, vomiting, headaches, fatigue, hypotensive episodes during dialysis, and hangover after dialysis; patients remain fluid overloaded with subsequent poor blood pressure control, left ventricular hypertrophy, diastolic dysfunction, and high cardiovascular mortality. According to Webster's dictionary, "optimal" means most desirable or satisfactory; "adequate" means sufficient for a specific requirement or barely sufficient or satisfactory. Optimal dialysis is the method of dialysis yielding results that cannot be further improved. New approaches, including hemeral quotidian or long nocturnal dialysis, provide opportunities to abandon the notion that adequate dialysis is "good enough" for our patients. Optimal dialysis should be our goal. Dialysis sessions should be long and frequent enough to provide excellent intra- and interdialytic tolerance of hemodialysis, normalization of serum calcium and phosphorus, blood pressure control, normal myocardial morphology and function, and hormonal balance, and to eliminate all, even subtle, uremic symptoms.
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PMID:We should strive for optimal hemodialysis: a criticism of the hemodialysis adequacy concept. 1937 36

Chronic hemodialysis sessions, as developed in Seattle in the 1960s, were long procedures with minimal intra- and interdialytic symptoms. Financial and logistical pressures related to the overwhelming number of patients requiring hemodialysis created an incentive to shorten dialysis time to four, three, and even two hours per session in a thrice weekly schedule. This method spread rapidly, particularly in the United States, after the National Cooperative Dialysis Study suggested that time of dialysis is of minor importance as long as urea clearance multiplied by dialysis time and scaled to total body water (Kt/V(urea)) equals 0.95-1.0. This number was later increased to 1.3, but the assumption remained unchanged that hemodialysis time is of minimal importance as long as it is compensated by increased urea clearance. Patients accepted short dialysis as a godsend, believing that it would not be detrimental to their well-being and longevity. However, Kt/V(urea) measures only removal of low molecular weight substances and does not consider removal of larger molecules. Besides, it does not correlate with the other important function of hemodialysis, namely ultrafiltration. Whereas patients with substantial residual renal function may tolerate short dialysis sessions, the patients with little or no urine output tolerate short dialyses poorly because the ultrafiltration rate at the same interdialytic weight gain is inversely proportional to dialysis time. Rapid ultrafiltration is associated with cramps, nausea, vomiting, headache, fatigue, hypotensive episodes during dialysis, and hangover after dialysis; patients remain fluid overloaded with subsequent poor blood pressure control, left ventricular hypertrophy, diastolic dysfunction, and high cardiovascular mortality. Short, high-efficiency dialysis requires high blood flow, which increases demands on blood access. The classic wrist arteriovenous fistula, the access with the best longevity and lowest complication rates, provides "insufficient" blood flow and is replaced with an arteriovenous graft fistula or an intravenous catheter. Moreover, to achieve high blood flows, large diameter intravenous catheters are used; these fit veins "too tightly," so predispose the patient to central-vein thrombosis. Longer hemodialysis sessions (5-8 hrs, thrice weekly), as practiced in some centers, are associated with lower complication rates and better outcomes. Frequent dialyses (four or more sessions per week) provide better clinical results, but are associated with increased cost. It is my strong belief that a wide acceptance of longer, gentler dialysis sessions, even in a thrice weekly schedule, would improve overall hemodialysis results and decrease access complications, hospitalizations, and mortality, particularly in anuric patients.
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PMID:Fallacies of high-speed hemodialysis. 1937 49

Cooling the dialysate below 36.5 degrees C is an important factor that contributes to hemodynamic stability in patients during hemodialysis (HD). In this study, the effect of dialysate temperature on hemodynamic stability, patients' perception of dialysis discomfort and post dialysis fatigue were assessed in a group of patients on HD. A total of 50 patients, all of whom were on 3-times-per-week dialysis regimen, were studied. Patients were assessed during six dialysis sessions; in three sessions, the dialysate temperature was normal (37 degrees C) and in three other sessions, the dialysate temperature was low (35 degrees C). Specific scale questionnaires were used in each dialysis session, to evaluate the symptoms during the dialysis procedure as well as post-dialysis fatigue, and respective scores were noted. The results showed that usage of low dialysate temperature was associated with the following: higher post dialysis systolic blood pressure (P< 0.05) and lower post dialysis heart rate (P< 0.01), with similar ultrafiltration rates, better intra-dialysis symptoms score and post-dialysis fatigue scores (P< 0.001, and P < 0.001, respectively), shorter post-dialysis fatigue period (P< 0.001) as well as higher urea removal (P< 00001) and Kt/V (P< 0.0001). Patients' perceptions were measured by a questionnaire, which showed that 76% of them felt more energetic after dialysis with cool dialysate and requested to be always dialyzed with cool dialysate. Low temperature dialysate is particularly beneficial for highly symptomatic patients, improves tolerance to dialysis in hypotensive patients and helps increase ultrafiltration while maintaining hemodynamic stability during and after dialysis.
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PMID:Effect of dialysate temperature on hemodynamic stability among hemodialysis patients. 1958 99


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