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)

A formalin-inactivated aluminium hydroxide adsorbed hepatitis A vaccine was evaluated in a dose-response study on 195 healthy male adults (age range: 18-31 years) in two French hospitals (Lyon, Rouen). Four doses (20, 40, 80, 160 RIA antigen units) were administered intramuscularly (i.m.) in two injections over a 6-month period. At the time of the first vaccine injection, 32 subjects (16.4%) were found positive (> 20 mIU ml-1) for HAV antibody (total Ig RIA HAVAB assay, Abbott Laboratories) and were excluded from the analysis of immunogenicity criteria. Fourteen days after the first vaccine injection, 78.1% (95% confidence interval (CI): 62-90) of seronegative subjects who received the 160 RIA antigen unit dose seroconverted with a geometric mean titre (GMT) of 43 mIU ml-1 (95% CI: 33-56). Seroconversion was 100% (95% CI: 91-100) at 1 month with a GMT of 95 mIU ml-1 (95% CI: 79-112). Statistical analysis revealed a significant dose-related effect (p < 0.0001) on GMT by multivariate regression analysis of the results after the first injection. Biological safety was evaluated and alanine aminotransferase and aspartate aminotransferase levels were similar prior to and 14 days after the first injection in the four groups. Reactions after injection were similar in the four dosage groups: 6.2% of subjects reported immediate reactions after first vaccination (feeling sick, spontaneous pain, headache), 8.9% reported local reactions at the site of injection (spontaneous pain, haematoma, local adenopathy) and 13.5% reported general reactions ('flu-like' syndrome, gastrointestinal tract disorders, fatigue, headache).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Good immunogenicity of GBM strain inactivated hepatitis A vaccine in healthy male adults. 762 20

The use of herbal and other "natural" health products by healthy and ill people is more common than is appreciated by many health care providers. Since most of these substances are not categorized as medicines, they are exempt from U.S. Government approval processes, and are essentially uncontrolled. In this article we describe a patient who developed painless jaundice, fatigue, and pruritus after taking chaparral tablets, 160 mg/day, for approximately 2 months. Serial liver biopsies and serum chemistries documented severe cholestasis and hepatocellular injury, i.e., a severe cholangiolitic hepatitis. Serum enzyme levels were markedly elevated: alk. phos. to four-fold, alanine aminotransferase and aspartate aminotransferase to 25-fold, total bilirubin to 30-fold, and gamma-glutamyl transpeptidase to 35-fold. Endoscopic retrograde cholangiopancreatography showed smooth, but severely narrowed biliary ducts without sclerosing cholangitis, distal obstruction, tumor, or stenosis. The diagnosis remained in doubt until the publication of two cases of chaparral hepatotoxicity. Because of the similarity of our patient's illness to those cases we concluded that chaparral was almost certainly the cause. Chaparral, also known as creosote or greasewood, is used by some practitioners to treat a diverse group of ailments including ethanol withdrawal. This report should heighten the awareness by primary care physicians and gastroenterologists that any chaparral herbal preparation is a potential hepatotoxin that can lead to serious illness.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cholestatic hepatitis after ingestion of chaparral leaf: confirmation by endoscopic retrograde cholangiopancreatography and liver biopsy. 780 38

A study of the clinical profile of 59 patients who presented with hepatitis A virus infection showed that dark urine, fatigue, gastrointestinal complaints, and fever were the most common presenting symptoms. The most frequent physical findings were hepatomegaly and jaundice. The mean presenting laboratory tests included total bilirubin of 5 mg/dL, alkaline phosphatase of 269 units/L, and serum aspartate aminotransferase and alanine aminotransferase levels of 1442 mIU/mL and 1952 mIU/mL, respectively. Atypical manifestations included relapse, cholestasis, rash, and arthralgia. Two patients presented with hepatitis A and concomitant type I autoimmune chronic hepatitis, and both required immunosuppressive therapy. Five patients who presented with hepatitis A were pregnant, and during follow-up, none of their infants developed elevated serum transaminase values or had detectable IgM anti-HAV antibody. All 59 patients experienced complete clinical and biochemical recovery within 6 months after onset of illness.
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PMID:Clinical manifestations of hepatitis A: recent experience in a community teaching hospital. 787 41

The chemistry, pharmacology, pharmacokinetics, clinical use, adverse effects, drug interactions, and dosage of felbamate are discussed. Felbamate (2-phenyl-1,3-propanediol dicarbamate) is chemically unrelated to any of the other currently marketed antiepileptic drugs (AEDs). It appears that felbamate, like phenobarbital and valproic acid, decreases the frequency of seizures by decreasing seizure spread and increasing seizure threshold. Oral felbamate is at least 90% absorbed, and peak concentrations are reached in one to six hours. The half-life is a little less than one day. A therapeutic range of plasma concentrations has not been determined. Felbamate has been used effectively as monotherapy and adjunctive therapy in patients with partial seizures with or without secondary generalization and as adjunctive therapy in children with partial or generalized seizures associated with Lennox-Gastaut syndrome. Felbamate may also be safe and effective in patients with generalized, absence, atypical absence, juvenile myoclonic, infantile, and gelastic seizures. The most frequently reported adverse effects of felbamate include nausea, anorexia, vomiting, headache, fatigue, somnolence, insomnia, and increased serum aspartate aminotransferase levels. The frequency of adverse effects is greater in patients receiving other AEDs in addition to felbamate. Felbamate affects the pharmacokinetics of phenytoin, carbamazepine, valproic acid, and methsuximide; other AEDs also affect the pharmacokinetics of felbamate. The dosage of felbamate should begin at 400 mg orally three times daily and then increase by 600 mg/day every two weeks to up to 3600 mg/day. If the patient is receiving other AEDs concurrently, their dosage should be decreased as the dosage of felbamate is increased. If the goal is to switch to felbamate, the dosage should be increased weekly as the dosages of other AEDs are reduced. Felbamate offers a safe and effective alternative to other AEDs in the treatment of partial and secondarily generalized seizures; partial and generalized seizures associated with Lennox-Gastaut syndrome; and atypical absence seizures, gelastic seizures, and other difficult to control seizures.
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PMID:Felbamate: a new antiepileptic drug. 794 90

The investigations of enzyme activity such as aspartate aminotransferase (AST, KE 2.6.1.1.) and alanine aminotransferase (ALT, KE 2.6.1.2) playing an important role in proteins metabolism were carried out in cell fraction of rat liver, myocardial and skeleton muscle after the influence of ionizing radiation (6 Gy) and the maximum physical loading. It was shown that physical loading furthered the increase of ALT-activity in all cell fractions except liver cytosol. And it was noted a strongly pronounced tendency of AST-activity to lowering, except muscle cell fractions. ALT-activity level in irradiated animals showed phase changes dependent on the term of observation and the kind of investigated tissues. The primary lowering of AST-activity in cell fractions of the investigated tissues is a conformity to natural laws of the gamma-irradiation influence on AST in most cases. It was shown that the physical tiredness made worse penetrated radiation action on the investigated enzymes.
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PMID:[Activity of alanine- and aspartate-aminotransferases in organs of albino rats subjected to whole body gamma-irradiation and physical exercise]. 795 96

Primary sclerosing cholangitis is a cholestatic disease of the liver characterized by progressive fibrotic inflammation and obliteration of the extra- and/or intrahepatic bile ducts. There is no effective therapy. We, therefore, studied the safety and efficacy of ursodeoxycholic acid in patients with primary sclerosing cholangitis with or without additional ulcerative colitis. In a 1-year ursodeoxycholic acid treatment period, which preceded the controlled study period, ursodeoxycholic acid was well tolerated in 22 of 24 patients with ulcerative colitis and in all three patients without ulcerative colitis. In two patients with ulcerative colitis the dose of 750 mg ursodeoxycholic acid/day led to diarrhea, but following reduction of the dose to 500 and 250 mg/day ursodeoxycholic acid was well tolerated. After 1 year of ursodeoxycholic acid treatment, 20 patients were randomly assigned to receive either ursodeoxycholic acid 750 mg/day or placebo. All of them finished a double-blind, placebo-controlled study period. During ursodeoxycholic acid treatment, the liver enzymes improved markedly. The difference in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma-glutamyltransferase between the placebo and ursodeoxycholic acid group was significant (p < 0.05). Following ursodeoxycholic acid treatment, pruritus and fatigue improved in half of the patients but the difference between the placebo and ursodeoxycholic acid group was not significant. According to the ethical guidelines, after 3 months of placebo treatment, the controlled study had to be discontinued because of a more than twofold increase of serum transaminases in 8/10 patients on placebo. After the end of the controlled study, all patients were continuously treated with ursodeoxycholic acid for up to 4 years.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of ursodeoxycholic acid on liver and bile duct disease in primary sclerosing cholangitis. A 3-year pilot study with a placebo-controlled study period. 820 Dec 24

Preclinical schedule dependency suggests that prolonged maintenance of low plasma levels of topotecan, a specific inhibitor of the nuclear enzyme topoisomerase I, results in optimal antitumor activity. The pharmacokinetics and pharmacodynamics of topotecan, administered as single agent in second-line therapy as a continuous low-dose infusion for 21 days, were evaluated in nine patients with small cell lung cancer (SCLC). Topotecan was administered i.v. as a 21 day continuous infusion every 28 days via an ambulatory pump. Dosages ranged from 0.4 to 0.6 mg/m2/day. Plasma levels of topotecan, the sum of topotecan, and its hydroxy acid congener and the N-desmethyl metabolite were determined at 1, 7, 14 and 21 days during infusion, using a validated high-performance liquid chromatography method with fluorescence detection. Myelosuppression was the most important toxicity. All patients experienced anemia, being severe (grade 3/4) in 55% of all courses. Other adverse effects were relatively mild and reversible, and included nausea, vomiting, diarrhea and fatigue. Three patients achieved a partial response. Mean steady-state concentrations of topotecan (C(ss)) in the first course were 0.46+/-0.17 and 0.47+/-0.19 ng/ml after doses of 0.4 and 0.5 mg/m2/day, respectively. Steady-state levels of the total of topotecan and hydroxy acid (C(ss,tot)) were 1.28+/-0.25 (range 0.93-1.58) and 1.57+/-0.19 (range 1.43-1.70) ng/ml at doses of 0.4 and 0.5 mg/m2/day, respectively. The percentage of the administered topotecan dose excreted in the urine within 24 h was 40+/-14 and 1.2+/-1.0% for total topotecan and N-desmethyltopotecan, respectively. During the second course, C(ss,tot) was significantly higher (p=0.032, paired t-test), which suggests altered topotecan disposition. A sigmoidal relationship was found between C(ss,tot) and the percent decrease in platelets (r=0.76, p=0.018). We conclude that topotecan administered as a 21 day continuous low-dose infusion has activity as single-agent, second-line therapy in patients with SCLC. There was considerable interpatient and intrapatient variability in systemic exposure to topotecan. Differences in organ function might contribute to this variation. Serum aspartate aminotransferase and albumin levels were predictive of topotecan pharmacokinetics.
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PMID:Continuous infusion of low-dose topotecan: pharmacokinetics and pharmacodynamics during a phase II study in patients with small cell lung cancer. 966 May 38

Oxygen free radicals have been implicated in exercise-induced cell and tissue injury, indicating an oxidative stress. Fatigue accompanied by a number of physiological and metabolic changes is in indication of overtraining. This study aimed to examine the influence of a continuous 24-h intermittent speed driving (1 h driving/1 h stop), on the response of hormones, antioxidative factors, lipid, and enzyme levels. Seven race car drivers of national level were examined before, during, and immediately after the trial of speed driving on a test designed to check endurance to stress. The parameters measured were: testosterone (Tes), cortisol (Cor), IgM, IgA, cholesterol, HDL, billirubin, ceruloplasmin, urea, uric acid, creatine kinase, and transaminases. Stress hormone Cor declined significantly (p < 0.05), while Tes did not change significantly. Fatigue enzyme, aspartate transaminase (GOT) increased significantly (p < 0.05), while alanine transaminase (GPT) did not change and urea declined. Muscle enzyme, creatine kinase (CK) increased to sixfold (p < 0.01). IgA, IgM and lipids did not change. The primary antioxidant ceruloplasmin increased significantly (p < 0.001), while antioxidants uric acid and glucose remained unchanged. Among the factors measured, ceruloplasmin, cortisol, urea, GOT, and CK seem to give a picture of the organism's alertness and defence capabilities in conditions of stress and fatigue.
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PMID:Stress hormonal factors, fatigue, and antioxidant responses to prolonged speed driving. 967 60

The indolizidine alkaloid swainsonine, a potent inhibitor of Golgi alpha-mannosidase II, has been shown to reduce tumor cell metastasis, enhance cellular immune responses, and reduce solid tumor growth in mice. In our previous Phase I study, swainsonine administered by 5-day continuous infusion inhibited L-phytohemagglutinin-reactive N-linked oligosaccharide expression on peripheral blood lymphocytes. Significant toxicities included edema and elevated serum aspartate aminotransferase (AST). One patient with head and neck cancer had objective (>50%) tumor remission. Two patients showed symptomatic improvement. The objectives of this Phase IB trial were to examine the pharmacokinetics, toxicities, and biochemical effects of bi-weekly oral swainsonine at escalating dose levels (50-600 microgram/kg) in 16 patients with advanced malignancies and 2 HIV-positive patients unsuitable for conventional therapy. Eastern Cooperative Oncology Group performance status was </=2. The maximum tolerated dose was defined as 300 microgram/kg/day due primarily to serum AST abnormalities and dyspnea. Other adverse events present in >20% of patients included increase in serum AST (all patients), fatigue (n = 9), anorexia (n = 6), dyspnea (n = 6), and abdominal pain (n = 4). Inhibition of Golgi alpha-mannosidase II occurred in a dose-dependent manner. Examination of immunological parameters revealed a transient decrease in CD25(+) peripheral blood lymphocytes and, in seven of eight patients, an increase in CD4(+):CD8(+) ratios at 2 weeks. Serum drug levels peaked 3-4 h following a single oral dose in most patients and were proportional to dose at levels >/=150 microgram/kg. We conclude that oral swainsonine is tolerated by chronic intermittent administration at doses up to 150 microgram/kg/day. Adverse events considered drug related were similar to those observed in the infusional study but with fatigue and neurological effects also noted. Investigations of alternative dosing schedules with low starting doses are suggested for further clinical testing.
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PMID:Phase IB clinical trial of the oligosaccharide processing inhibitor swainsonine in patients with advanced malignancies. 981 86

AG331 (N6-[4-(morpholinosulfonyl)benzyl]-N6-methyl-2, 6-diaminobenz-[c,d]-indole glucuronate) is a lipophilic thymidylate synthase inhibitor with activity in solid tumor models. On the basis of preclinical data supporting regimens of frequent drug administration, we performed a Phase I trial of AG331 as a 5-day continuous infusion repeated every 3 weeks. Twenty-nine patients were entered at doses ranging from 25 to 1000 mg/m2/day. The major side effects were mild to moderate fatigue, nausea, vomiting, diarrhea, and fever. At doses >/=400 mg/m2, acute reversible elevation of bilirubin, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltranspeptidase was observed. All patients who received >/=600 mg/m2/day experienced elevated alanine aminotransferase. Elevated liver function tests were evident by day 3 of the infusion and had resolved by day 8 in the majority. This toxicity was dose limiting at 1000 mg/m2/day, at which dose two of two patients developed grade 4 reversible hyperbilirubinemia in addition to the enzyme elevations. Serum and urine samples were analyzed by a novel high-pressure liquid chromatography method for the determination of the pharmacokinetics of AG331. Over the 50-1000 mg/m2/day dose range, mean total clearance ranged from 11.6 to 30.0 liters/h/m2, and volume of distribution at steady state ranged from 279.5 to 758.7 liters/m2. These parameters were dose independent over the dose range tested. The harmonic mean terminal half-life of AG331 was 20.2 h. Less than 5% of an AG331 dose is eliminated unchanged in the urine. Both the administered dose and exposure to the drug were related to the changes in bilirubin and aminotransferase blood levels. Evidence for inhibition of thymidylate synthase was obtained at doses ranging from 100 to 1000 mg/m2 in seven patients; plasma deoxyuridine concentrations at end-infusion were 1.8-3.8-fold higher than pretreatment values. Because of the nature of toxicity on this schedule, more extensive Phase II evaluation is not recommended, although an AG331 dose of 800 mg/m2/day for 5 days is tolerable. Exploration of less frequent dose administration is under way.
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PMID:Phase I trial of the thymidylate synthase inhibitor AG331 as a 5-day continuous infusion. 981 17


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