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)

Five children, ages 2.5 to 12 years (mean 6.2 years), with acute lymphoblastic leukemia or non-Hodgkin's lymphoma were given 22 courses of high-dose methotrexate (HD-MTX) therapy (6-8 g/m2/24 h). No serious clinical complications were encountered, but stomatitis occurred after three (14%) of the courses. First-phase elimination half-lives (t1/2(alpha)) of MTX and 7-hydroxy-methotrexate (7-OH-MTX) after 21 infusions were 2.7 +/- 0.4 h and 6.5 +/- 1.8 h (mean +/- SD). In one course (4.5%) there was delayed systemic MTX elimination, with first-phase elimination half-lives (t1/2(alpha] for MTX and 7-OH-MTX of 4.2 and 9.9 h, respectively, and second-phase elimination half-lives (t1/2(beta)) of 43 and 58 h. Significant decreases in white blood cell count, increases in serum creatinine, and increases in alanine aminotransferase and/or aspartate aminotransferase during the first 2-6 days were present in five (23%), three (14%), and six (27%) of the courses, respectively. The regimen was tolerated well by the children.
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PMID:High-dose methotrexate therapy (6-8 g/m2) in childhood malignancies: clinical tolerability and pharmacokinetics. 315 11

Methotrexate-loaded glutaraldehyde-treated canine carrier erythrocytes were used to deliver a 1.6-mg/kg dosage of drug. About 90% of the drug-loaded cells disappeared from circulation within 1 h. Approximately 11 mg of drug reached the liver, and a substantial portion of the methotrexate entered the enterohepatic bile salt circulation. Biochemical tests of liver function, such as alkaline phosphatase and serum glutamine pyruvate transaminase, indicated mild hepatocellular necrosis which was attributed to the action of methotrexate on the hepatocytes. Bilirubin levels were unchanged during and following drug treatment. The plasma half-life of the drug was extended 2.4-fold in the first 24 h following injection.
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PMID:Hepatic pharmacokinetics of glutaraldehyde-treated methotrexate-loaded carrier erythrocytes in dogs. 641 45

Methotrexate (MTX) has become an important drug in the treatment of rheumatoid arthritis (RA). The American College of Rheumatology convened a committee to assess the risks of development of clinically significant liver disease (CSLD) during MTX treatment, to evaluate the risk and role of surveillance liver biopsies, and to provide recommendations about monitoring patients for liver toxicity. The committee recommends obtaining liver blood tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, albumin, bilirubin), hepatitis B and C serologic studies, and other standard tests including complete blood cell count and serum creatinine tests prior to starting treatment with MTX. A pretreatment liver biopsy should be considered only for patients with a history of prior excessive alcohol consumption, persistently abnormal baseline AST values, or chronic hepatitis B or C infection. At intervals of every 4-8 weeks the AST, ALT, and albumin levels should be monitored. Routine surveillance liver biopsies are not recommended for RA patients receiving traditional doses of MTX. However, a biopsy should be performed if a patient develops persistent abnormalities on liver blood tests. These are defined as elevations (above the upper limit of laboratory normal) in the AST in 5 of 9 determinations within a given 12-month interval (6 of 12 if tests are performed monthly) or a decrease in serum albumin below the normal range. The recommendations for monitoring and selection of patients for liver biopsy identify patients at potential risk for CSLD, and thus significantly reduce the number or patients who would be exposed to this procedure. Close monitoring is essential to reduce the risk of unrecognized serious liver disease. These recommendations should be revised as necessary to reflect new and compelling information.
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PMID:Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology. 798 33

Methotrexate is widely used as a therapeutic agent in different diseases. This therapy is connected with various side effects, including liver toxicity. We have developed a mouse model to demonstrate the toxic effects of methotrexate: mice were given 50 mg/kg acetaminophen, which itself has no effect on the liver. If, additionally, methotrexate is applied, there is an increase in the death rate, as well as in glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) activities. If methotrexate is administered in conjunction with either nicotinamide or methionine, the rise in the death rate and in GOT and GPT activities associated with methotrexate application is markedly reduced. On the basis of these results, it can be concluded that methotrexate therapy should be combined with either nicotinamide or methionine, respectively.
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PMID:Nicotinamide and methionine reduce the liver toxic effect of methotrexate. 1046 59

20 year old man 2 years treated for the seropositive rheumatoid arthritis was admitted for fever accompanied with jaundice, anemia and leukopenia. The underlying disease has been compensated already for long period of time, before his admission only Prednisone (in the dose of 5 mg daily) and Methotrexate (15 mg once a week) was given. His physical examination of admission was without any significant abnormalities, out of the routine laboratory examination the value of leukocytes count was 2.1 x 10(9)/L, erythrocytes 3.7 x 10(12)/L, hemoglobin 95 g/l, hematocrit 0.29, platelets 156 x 10(9)/L. Since admission to hospital the hepatic enzymes ALT, AST, GMT, ALP were about ten times elevated comparing to normal values, the coagulation examination has shown the decrease of Quick test to 55%. With respect to the permanent leukopenia the bone marrow aspiration was taken with the finding of the increase number the RES elements (18.4%) with the signs of hemophagocytosis. The phagocytic reticulum absorbs blood elements erythrocytes, normoblasts, granulocytes, platelets. According to the literature experience we started the combination of the immunosuppressive treatment consisting of corticosteroids and Cyclosporine. Already the day following the application of the high dose of corticosteroids the fever subsided, icterus went away gradually with the normalization of the liver tests. After 20 days of hospitalisation the patient was discharged in good shape. Now, after 4 months the is stabilized on the follow-up treatment of Prednisone a Cyclosporine.
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PMID:[Secondary hemophagocytic syndrome in a systemic disease]. 1095 9

We retrospectively analyzed the factors that affect serum cyclosporine (CsA) concentrations up to day 14 after allogeneic hematopoietic stem cell transplantation (HSCT). In all, 103 transplant recipients who received MTX and CsA for acute GVHD prophylaxis were analyzed. No significant relationships between serum CsA concentrations and gender, age, serum creatinine levels, AST/ALT levels, or antibiotic/fluconazole administration were found by comparing median CsA concentrations or by using longitudinal or regression multivariate analyses. However, the mean of the median serum CsA concentration in patients (n=54) receiving the regimen containing cyclophosphamide (CY) (149.7 ng/ml; 95% confidence interval (CI): 132.1-167.4) was significantly (P<0.0001) lower than that in patients (n=49) receiving the non-CY regimen (217.3 ng/ml; 95% CI: 198.9-235.6). Longitudinal analysis and regression multivariate analysis showed that only administration of CY had a significant effect on the serum CsA concentration. Our results suggest that administration of CY during conditioning can reduce the effects on serum CsA concentrations during the 2 weeks following HSCT. The mechanism of this effect is not clear, but it may be due to the autoinduction of CY.
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PMID:Effect of cyclophosphamide on serum cyclosporine levels at the conditioning of hematopoietic stem cell transplantation. 1462 75

Dendrimers based on melamine can reduce the organ toxicity of solubilized cancer drugs administered by intraperitoneal injection. Methotrexate and 6-mercaptopurine, both FDA approved anticancer drugs, are known hepatotoxins. The solubility of these molecules can be increased by mixing them with a dendrimer based on melamine. C3H mice were administered subchronic doses of methotrexate or 6-mercaptopurine with and without a solubilizing dendrimer. Forty-eight hours after dosing, the mice were sacrificed and serum was collected for biochemical analyses. The levels of alanine transaminase, ALT, were used to probe liver damage. When the drugs are encapsulated by the dendrimer, a significant reduction in hepatotoxicity is observed: ALT levels from the rescued groups (drug + dendrimer) were 27% (methotrexate) and 36% (6-mercaptopurine) lower than those of animals treated with the drug alone.
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PMID:Reduction of drug toxicity using dendrimers based on melamine. 1602 11

High dose methotrexate (HDMTX) with folinic acid rescue is widely used to treat osteosarcoma, which predominantly afflicts children; the study investigated HDMTX pharmacokinetics (pk) in adult subjects in neoadjuvant/adjuvant settings. Twenty five patients with advanced osteosarcoma (11 females--14 males, median age 26.0 years) were treated by 12 g/m2 HDMTX 4 hour iv infusion (64 total courses, range 1-7 courses). Pk was determined by non-compartmental analysis and population pk modeling. Median (range) bioavailability pk parameters were: C(max) (maximum MTX concentration) 1149.5 microM (692-2,200), AUC(tot) (total area under curve) 6,955.1 micromol*h/l (3,477-12,681). C(max)>1,000 microM gave increased histological responses (p < 0.05). Six covariates (height-weight-hemoglobin-AST-ALT-creatinine) were found to influence MTX volume of distribution (V) and elimination rate constant (K(el)). Toxicity was mild: only two reversible G4 events were observed, related to AUC(tot) >12,000 micromol*h/l (p < 0.001). HDMTX pk and interpatient variability in adults are comparable to those in children. No correlation between C(max)/AUC(tot) and subject age/sex was found, even in the population pk model. The excretion mechanism is not affected by sex/age differences. HDMTX can safely be administered to adults: as in younger patients, a good clinical response can be predicted by C(max), while severe toxicity depends on highest AUC(tot) values.
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PMID:High dose methotrexate in adult patients with osteosarcoma: clinical and pharmacokinetic results. 1612 May 50

We conducted a clinical study of MTX-HOPE (day 1, methotrexate 20 mg per os (po); day 2, hydrocortisone 100 mg intravenous (iv), vincristine 1 mg iv; day 3,4 sobuzoxane 400 mg po; etoposide 25 mg po, repeating every 2 or 3 weeks) in 14 relapsed or refractory patients with non-Hodgkin's lymphoma. Ten responders were obtained 5 CR and 5 PR), and heavily treated patients were included in the responders. The median duration of over all survival which was estimated with Kaplan-Meier curve was 11.1 months (range, 2-18+ months), and the median duration of response was 6.9 months (range, 0.8+ -16.4+ months). Out of the 14 patients,eleven were treated with this regimen in an outpatient setting. Grade 4 neutropenia and thrombocytopenia were observed in 4 and 2 patients,and grade 3 GPT-elevation and stomatitis in two and one, respectively. This newly developed MTX-HOPE therapy may be a promising treatment option for such patients as are intolerable for high-dose chemotherapies with PBSC rescue or wish for outpatient therapy.
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PMID:[MTX-HOPE (methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide) as a low-dose salvage chemotherapy for recurrent or refractory non-Hodgkin's lymphoma]. 1756 51

Methotrexate (MTX) is used to treat a variety of chronic inflammatory and neoplastic diseases. However, it can induce hepatotoxicity such as microvesicular steatosis and necrosis. To explore the mechanisms of MTX-induced hepatic steatosis, we used microarray analysis to profile the gene expression patterns of mouse liver after MTX treatment. MTX was administered orally as a single dose of 10mg/kg (low dose) or 100 mg/kg (high dose) to ICR mice, and the livers were obtained 6 h, 24 h, and 72 h after treatment. Serum alanine aminotransferase, aspartate aminotransferase and triacylglycerol levels were not significantly altered in the experimental animals. Signs of steatosis were observed at 24 h after administration of high dose of MTX. From microarray data analysis, 908 genes were selected as MTX-responsive genes (P<0.05, two-way ANOVA; cutoff > or =1.5-fold). Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis revealed that the predominant biological processes associated with these genes are response to unfolded proteins, phosphate metabolism, and cellular lipid metabolism. Functional categorization of these genes identified 28 genes involved in lipid metabolism that was interconnected with the biological pathways of biosynthesis, catabolism, and transport of lipids and fatty acids. Taken together, these data provide a better understanding of the molecular mechanisms of MTX-induced steatogenic hepatotoxicity, and useful information for predicting hepatotoxicity through pattern recognition.
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PMID:Gene expression profiles of murine fatty liver induced by the administration of methotrexate. 1850 57


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