Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 47-year-old woman visited a clinic with dyspnea which had continued for two months and was followed by general fatigue and fever. Antibiotics were not effective. Edematous erythema occurred on her face, elbows, knees and feet, and she entered our hospital. A skin biopsy revealed interface dermatitis with severe edema and mucinosis in dermis. Diffuse bilateral infiltration was observed in the chest X-ray, and laboratory findings showed increased LDH, GPT, GOT and CPK. No antinuclear factor was detected. Her respiratory condition rapidly worsened, and she died eight days after hospitalization in spite of corticosteroid pulse therapy. The autopsy revealed that the main cause of death was diffuse alveolar damage (DAD). Interstitial pneumonia related to dermatomyositis is not histologically uniform; the response to the therapy depends on its histological type. The patients with dermatomyositis who have poor prognosis are clinically characterized by acute onset with general symptoms and less pronounced muscle weakness; they generally show DAD in their lungs. We need to establish a simple method for distinguishing histological types of interstitial pneumonia and adequate therapy for each one.
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PMID:An autopsy case of dermatomyositis with rapidly progressive diffuse alveolar damage. 951 7

Deferiprone, also known as L1, is an orally active iron chelator that has been studied extensively in clinical trials. The sporadic occurrence of agranulocytosis in association with deferiprone and the highly variable frequency of other possible side effects such as arthralgia have created uncertainty about the true incidence of deferiprone-related complications. A multi-center, 1-year trial was initiated to determine the safety profile of deferiprone. Using the Apotex formulation of deferiprone, 187 patients with thalassemia who were unable or unwilling to use deferoxamine were enrolled in four centers; 162 patients completed one year of therapy. Agranulocytosis (ANC < 500/mm3) occurred in one patient after 15 weeks of treatment, was not accompanied by infection and resolved following treatment with G-CSF. Nine other subjects developed less severe neutropenia (ANC 500-1500/mm3) with the lowest absolute neutrophil count reaching 500-1250/mm3. The neutropenia in these patients developed after 1-50 weeks of therapy, frequently accompanied febrile illnesses, and occurred predominantly in non-splenectomized patients. Reasons other than neutropenia for discontinuing use of deferiprone included nausea (4), voluntary withdrawal (3), high ALT (2), platelet count < 100,000/mm3 (2), low but unconfirmed ANC (1), protocol violation (1) fatigue (1), and depression (1). Mean ALT levels rose within three months of therapy and stabilized thereafter. Arthralgia and nausea and/or vomiting occurred in 6% and 24% of subjects, respectively. In this multi-center trial with weekly monitoring of blood counts, the incidence of agranulocytosis was 0.58 per 100 patient-years, and the frequency of agranulocytosis after one year was 0.5%. These findings support the safety of this formulation of deferiprone, using the careful monitoring system employed in this trial.
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PMID:A multi-center safety trial of the oral iron chelator deferiprone. 966 43

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

Six amino acids are metabolized in resting muscle. They are leucine, isoleucine, valine, asparagine, aspartate, and glutamate. These amino acids provide the amino groups and probably the ammonia required for synthesis of glutamine and alanine, which are released in excessive amounts in the postabsorptive state and during ingestion of a protein-containing meal. Only leucine and part of the isolecine molecule can be oxidized in muscle as they are converted to acetyl-CoA. The other carbon skeletons are used solely for de novo synthesis of TCA-cycle intermediates and glutamine. The carbon atoms of the released alanine originate primarily from glycolysis of blood glucose and from muscle glycogen (about half each in resting conditions). After consumption of a protein-containing meal, BCAA and glutamate are taken up by muscle and their carbon skeletons are used for de novo synthesis of glutamine. About half of the glutamine released from muscle originates from glutamate taken up from the blood, both after overnight starvation, after prolonged starvation, and after consumption of a mixed meal. Glutamine produced by muscle is an important fuel and regulator of DNA and RNA synthesis in mucosal cells and immune system cells, and fulfils several other important functions in human metabolism. The alanine aminotransferase reaction functions to establish and maintain high concentrations of TCA-cycle intermediates in muscle during the first 10 min of exercise. The increase in concentration of TCA-cycle intermediates probably is needed to increase the flux of the TCA-cycle and meet the increased energy demand of exercise. A gradual increase in leucine oxidation subsequently leads to a carbon drain on the TCA-cycle in glycogen-depleted muscles, and may thus reduce the maximal flux in the TCA-cycle and lead to fatigue. Deamination of amino acids and glutamine synthesis present alternative anaplerotic mechanisms in glycogen-depleted muscles, but only allow exercise at 40-50% of Wmax. One-leg exercise leads to the net breakdown of muscle protein. The liberated amino acids are used for synthesis of TCA-cycle intermediates and glutamine. Today, the importance of this process in endurance exercise in the field (running or cycling) in athletes who ingest carbohydrates is not clear. It is proposed that the maximal flux in the TCA-cycle is reduced in glycogen-depleted muscles due to insufficient TCA-cycle anaplerosis, and that this presents a limitation for the maximal rate of fatty acid oxidation. Interactions between the amino acid pool and the TCA-cycle are suggested to play a central role in the energy metabolism of the exercising muscle.
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PMID:Muscle amino acid metabolism at rest and during exercise: role in human physiology and metabolism. 969 93

Muscle proteins turn over slowly and there are minimal diurnal changes in the size of the muscle protein pool in response to feeding and fasting. Nitrogen balance and tracer studies indicate that protein oxidation and net protein breakdown (degradation--synthesis) is not increased during dynamic exercise at intensities of < or = 70% VO2max. An imbalance between muscle protein synthesis and degradation does exist during one leg knee extensor exercise and during two legged cycling in patients with glycogen phosphorylase deficiency. In these latter cases amino acids liberated from the protein pool are used for synthesis of TCA-cycle intermediates and glutamine. Six amino acids are metabolized in resting muscle: leucine, isoleucine, valine, asparagine, aspartate and glutamate. Only leucine and part of the isoleucine molecule can be converted to acetylCoA and oxidized. The carbon skeleton of the other amino acids is used for synthesis of TCA-cycle intermediates and glutamine. The six amino acids provide the amino groups and the ammonia for synthesis of glutamine and alanine, which are released by muscle in excessive amounts. About half of the glutamine release from muscle originates from glutamate taken up from the blood. Glutamine produced by muscle is an important fuel and regulator of DNA and RNA synthesis in mucosal cells and immune system cells and fulfils several other important functions in human metabolism. The alanine aminotransferase reaction functions to establish and maintain high concentrations of TCA-cycle intermediates and a high TCA cycle flux in the first minutes of exercise. A gradual increase in leucine oxidation subsequently leads to a carbon drain on the TCA-cycle in glycogen depleted muscles and may thus reduce the maximal flux in the TCA-cycle and lead to fatigue. Deamination of amino acids and glutamine synthesis present alternative anaplerotic mechanisms in glycogen depleted muscles but only allow exercise at 40-50% of Wmax. It is proposed that the maximal flux in the TCA-cycle is reduced in glycogen depleted muscles due to insufficient TCA-cycle anaplerosis and that this presents a limitation for the maximal rate of fatty acid oxidation. Interactions between the amino acid pool and the TCA-cycle thus seem to play a central role in the energy metabolism of the exercising muscle.
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PMID:Protein and amino acid metabolism in human muscle. 978 36

Parvovirus B19 (B19), also known as "erythema infectiosum", is a disease that occurs in smaller outbreaks during late winter and early summer; and in Denmark an epidemic occurs every three years. The symptoms vary from fever, fatigue and the characteristic maculopapoulous erythema to asymptomatic cases in 50% of the infected patients. Two-thirds of the Danish population have been infected. The virus has a broad spectrum of clinical manifestations ranging from erythema nodosum in children, arthralgia/arthritis (especially in adults), aplastic crisis in patients with haemolytic anaemia, chronic anaemia in immunocompromised patients, to hydrops foetalis following acute infection during pregnancy. In two adult females aged 41 and 35 years with persisting fatigue, malaise, transitory swelling and arthralgia we found elevated ALT and alkaline phosphatase (pt. 1), despite no serological evidence of hepatitis, cytomegalovirus (CMV), or Epstein-Barrvirus and no story of alcohol consumption or recent travelling outside Denmark. Ongoing B19 infection was diagnosed by ELISA and confirmed by B19 DNA PCR in case 2 and IgG avidity and epitope-type specificity in case 1, who was B19 DNA negative in three different samples. The concentrations of alkaline phosphatase and ALT returned to normal as the antibody response shifted from acute B19 infection to IgG positivity. In conclusion we suggest that a serological test and/or B19 DNA for B19 infection is a relevant test to undertake when screening patients for viral hepatitis especially during B19 epidemics and in exposed individuals.
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PMID:[Parvovirus B19 as a cause of acute liver symptoms in adults]. 981 Feb 42

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

A 43-year-old man underwent living related-donor renal transplantation because of chronic renal failure in 1991. During the transplant period, both donor and recipient were seronegative for hepatitis B surface antigen (HBsAg). The donor was seropositive for antibody to hepatitis B surface antigen (anti-HBs) due to hepatitis B virus (HBV) vaccination. After transplantation, FK506 and methylprednisolone had been administered to the patient as immunosuppressants. In 1993, HBsAg appeared in his serum. His alanine aminotransferase level elevated gradually during 1995 and then in 1996, general fatigue, ascites and jaundice developed. At this time his serum was positive for hepatitis B e antibody, contained more than 100000 Meq/mL HBV-DNA and 100% precore mutant. Despite subsequent intensive therapy, liver dysfunction progressed and this patient died of hepatic failure 2 months following admission. At autopsy, the liver exhibited cholestasis, fibrosis extending from the portal tracts, mild inflammation and hepatocytes with a ground-glass appearance. In addition, HBsAg and hepatitis B core antigens had accumulated in the hepatocytes. Consequently, the final diagnosis was fibrosing cholestatic hepatitis (FCH) due to precore mutant HBV infection contracted after renal transplantation. It is unclear when and where the recipient liver became HBV infected. Nevertheless, after renal transplantation, while receiving immunosuppressive drugs, HBV appeared to have the potential to cause hepatic failure and FCH may have been a fatal complication for the recipient.
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PMID:Fibrosing cholestatic hepatitis after living related-donor renal transplantation. 987 Aug 1

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

Docetaxel has been reported to show promising anti-tumour activity in pancreatic ductal cancer (PC). This study was conducted to evaluate the activity and toxicity of moderate-dose (60 mg m(-2)) docetaxel in Japanese chemo-naive patients with measurable metastatic PC. The patients had a performance status of 0-2. They received docetaxel intravenously over a 1- to 2-h period without any premedication for hypersensitivity reactions. This treatment was repeated every 3-4 weeks with dose adjustments based on the toxic effects observed. Twenty-one patients were eligible and treated with docetaxel. The median number of courses was 2 (range, 1-4). None of the patients achieved an objective response; seven showed no change and 13 showed progressive disease. In one patient, the response was not assessable because of early death. The median survival time for all patients was 118 days. The main grade 3-4 toxicities by patient were leucocytopenia (67%) and neutropenia (86%). Other grade 3-4 toxicities included anaemia (10%), thrombocytopenia (5%), nausea/vomiting (29%), anorexia (29%), GOT/GPT increase (10%), alkaline phosphatase increase (14%), malaise/fatigue (33%) and alopecia (24%). In conclusion, docetaxel, administered on this schedule, did not show significant anti-tumour activity in patients with metastatic PC.
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PMID:Phase II study of docetaxel in patients with metastatic pancreatic cancer: a Japanese cooperative study. Cooperative Group of Docetaxel for Pancreatic Cancer in Japan. 1040 50


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