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:2.6.1.1 (aspartate aminotransferase)
21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The occurrence of overall toxicity was analyzed for 43 patients with osteosarcoma who received 349 high-dosage courses of methotrexate (HD-MTX) with citrovorum factor (Leukovorin) "rescue" (CF). The dosages of HD-MTX ranged from 50 to 350 mg/kg. Overall toxicity was assessed on the basis of five manifestations of toxicity: stomatitis, dermatitis, myelosuppression, liver dysfunction, and kidney function abnormalities. The great majority (91.4%) of the infusions were well tolerated, but 8.6% were associated with moderate or severe toxicity. Stomatitis and serum glutamic-oxaloacetic transaminase (SGOT) changes were the most frequent postinfusion findings. Three patients died from causes related to MTX toxicity. Dose, age, sex, and number of prior infusions were investigated by logistic regression analysis for prognostic effect on frequency of moderate to severe overall toxicity. Age and number of prior infusions had significant (P less than 0.06) effects on overall toxicity. Patients older than 15 years with greater than 10 prior infusions constituted the "high risk" group with a risk of moderate to severe toxicity 6.3 times that of the younger patients with fewer than 10 infusions.
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PMID:Evaluation of overall toxicity of high-dosage methotrexate regimens. 31 42

Ursodiol is a hydrophilic, non-hepatotoxic bile salt indicated for the medical treatment of cholesterol gallstones. This pilot study explored the use of prophylactic ursodiol in an attempt to decrease the incidence and severity of veno-occlusive disease (VOD) of the liver following allogeneic bone marrow transplantation (BMT). Between February 1991 and January 1992, 22 consecutive patients undergoing BMT for hematologic malignancies received the BU(4)/CY(2) preparative regimen and CSA/MTX for GVHD prophylaxis. Ursodiol, 600-900 mg daily by mouth was begun at least 1 day prior to beginning the preparative regimen. Results for this pilot group were compared to a control group of 28 consecutive patients transplanted between June 1989 and January 1991 with the same regimen without ursodiol. There were no significant differences in disease or clinical status between the groups pretransplant. However, mean baseline AST levels were significantly higher in the ursodiol group, 28.0 U/l vs 18.1 U/l in the control group (p = 0.001). The median maximum bilirubin observed post-transplant was 2.35 mg/dl (range 0.9-45) in the ursodiol group, and 5.05 mg/dl (range 0.7-29.4) in controls. The incidence of VOD was 2/22 (9.1%) in the ursodiol group and 18/28 (64.3%) in controls (p = 0.0001). Death due to VOD occurred in 1/22 patients (4.5%) in the ursodiol group and in 6/28 (21.4%) controls (p = 0.12). Our data suggest that ursodiol may decrease the incidence of VOD in allogeneic BMT patients.
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PMID:Pilot trial of prophylactic ursodiol to decrease the incidence of veno-occlusive disease of the liver in allogeneic bone marrow transplant patients. 142 93

Methotrexate (MTX) accumulates in erythrocytes (ery) during weekly MTX administration, and the ery-MTX concentration reaches a steady state after 4-6 weeks. In order to study MTX accumulation and metabolism to polyglutamate derivatives in different age populations of red blood cells, we took erythrocytes from 12 children with ALL who were receiving maintenance treatment with MTX and 6-MP and separated them according to age on a discontinuous Percoll gradient. When the erythrocytes of these children were separated according to specific gravity a normal distribution was obtained. Age fractionation was confirmed by the exponential decline of the erythrocyte aspartate aminotransferase (ery-ASAT) and by the reticulocyte counts. The ery-MTX declined with increasing red blood cell age in an exponential manner no different from the decline of the ery-ASAT. The youngest population of red blood cells contained 2.3-5.9 (mean 3.8) times more MTX than the oldest population. By linear regression analysis the t1/2 of the ery-MTX was 19-79 days (mean 37 days). The ery-MTX t1/2 seemed to be directly related to the amount of MTX which had been metabolized to MTX-glu3-5. The decline of the ery-MTX was predominantly due to selective disappearance of MTX-glu1+2, whereas MTX-glu3-5 changed to a much lesser extent with advancing red blood cell age. The present investigation showed that steady-state ery-MTX concentration was determined by (1) the amount of MTX added to the circulation by the reticulocytes, (2) the in vivo loss predominantly of MTX with low numbers of glutamyl derivatives from erythrocytes, and (3) the loss of MTX from destroyed red blood cells. The observed in vivo disappearance of MTX from erythrocytes offers a possible explanation of the observation that the ery-MTX steady state was reached after 4-6 weeks of unaltered weekly MTX treatment.
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PMID:In vivo decline of methotrexate and methotrexate polyglutamates in age-fractionated erythrocytes. 245 Jun 91

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 (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 (MTX) has become one of the most widely prescribed second-line agents world-wide for rheumatoid arthritis (RA). Studies have established efficacy in populations which have failed other second-line agents. Although MTX must be considered as a potential hepatotoxin, studies have shown that liver histologic changes can be predicted by monitoring of serum albumin and AST at four to eight week intervals. MTX pulmonary toxicity appears to be more common than liver disease. It most often presents with a subacute course with dry cough and dyspnea with or without fever. Clinicians must be aware of this presentation and withhold the drug when these symptoms appear. MTX may also cause mild renal impairment when used with NSAIDs. This effect has been observed with higher mean weekly doses in the 15 to 20 mg range, but not with a starting dose of 7.5 mg. Although MTX may exhibit a variety of effects in in vitro systems its mechanism of action in patients with RA has not yet been determined.
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PMID:Methotrexate update. 899 67

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

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

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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