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MTX
Kinds of MTX Terms modified by MTX Selected AbstractsLipophilic methotrexate conjugates with glucose-lipoamino acid moieties: Synthesis and in vitro antitumor activityDRUG DEVELOPMENT RESEARCH, Issue 3 2001Rosario Pignatello Abstract To obtain methotrexate (MTX) derivatives with a balanced hydrolipophilic character, we synthesized a series of conjugates in which the drug was linked to lipoamino acid (LAA)-glucose residues (LAAG-MTX). These conjugates displayed increased solubility in polar media compared with the corresponding LAA-MTX conjugates previously described. In vitro biological testing of LAAG-MTX indicated that the introduction of the sugar moiety decreased the biological activity of these MTX conjugates. The tetradecyl derivative 6b, however, was effective in inhibiting the dihydrofolate reductase activity in vitro and showed an inhibitory effect on human lymphoblastoid cell growth. Drug Dev. Res. 52:454,461, 2001. © 2001 Wiley-Liss, Inc. [source] Determination of dissociation constants of folic acid, methotrexate, and other photolabile pteridines by pressure-assisted capillary electrophoresisELECTROPHORESIS, Issue 17 2006Zoltán Szakács Abstract Pressure-assisted CE (PACE) was applied to determine the previously inaccessible complete set of pK values for folic acid and eight related multiprotic compounds. PACE allowed the determination of all acidity macroconstants at low (,0.1,mM) concentration without interferences of selfassociation or photodegradation throughout the pH range. The accuracy of the constants was verified by NMR-pH, UV-pH, and potentiometric titrations and the data could be converted into physiological ionic strength. It was shown that even three overlapping pK values can be determined by CE with good precision (<0.06) and accuracy if an appropriately low sample throughput is used. Experimental aspects of PACE for the quantitation of acid,base properties are analyzed. The site-specific basicity data obtained for folic acid and methotrexate (MTX) reveal that apparently slight constitutional differences between folic acid and MTX carry highly different proton-binding propensities at analogous moieties, especially at the pteridine N1,locus, providing straightforward explanation for the distinctive binding to dihydrofolate reductase at the molecular level. [source] Determination of the chiral and achiral related substances of methotrexate by cyclodextrin-modified micellar electrokinetic chromatographyELECTROPHORESIS, Issue 16 2004Roberto Gotti Abstract A cyclodextrin-modified micellar electrokinetic chromatographic (CD-MEKC) method for the determination of the most important potential impurities of methotrexate (MTX): 2,4-diamino-6-(hydroxymethyl)pteridine, aminopterine hydrate, 4-[N -(2-amino-4-hydroxy-6-pteridinylmethyl)- N -methylamino] benzoic acid, 4-[N -(2,4-diamino-6-pteridinylmethyl)- N -methylamino] benzoic acid, and the distomer D -MTX is presented. The MEKC separation of these compounds was optimized by applying a step-by-step approach. The addition of ,-CD to a conventional MEKC system, based on sodium dodecyl sulfate (SDS) as surfactant, showed to be essential for the enantioresolution of racemic MTX as well as for the separation of the achiral impurities. To achieve high-resolution factor between the peaks adjacent to the main component (L -MTX), as required in the analysis of related impurities, the separation conditions were stressed; in particular, the addition of methanol to the CD-MEKC system resulted in a very effective choice. Under the optimized final conditions (100 mM SDS and 45 mM ,-CD in a mixture of 50 mM borate buffer, pH 9.30-methanol (75:25 v/v)), the method was validated showing a general adequate accuracy (93,106% recovery) in the determination of L -MTX related substances at the impurity level of 0.12% w/w with a relative standard deviation (RSD)% lower than 8% (n = 4). The method was successfully applied to the analysis of pharmaceuticals (tablets and injections) which showed to contain the distomer D -MTX as major impurity and aminopterine hydrate as a further related substance in the commercial tablets. [source] Sustained and stable hematopoietic donor-recipient mixed chimerism after unrelated cord blood transplantation for adult patients with severe aplastic anemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2005P. Mao Abstract:, We evaluated the engraftment of donor cells from unrelated cord blood into adult patients with severe aplastic anemia (SAA) and the outcome of allo-CBSCT (cord blood stem cell transplantation). Nine patients were conditioned with decreased dosage of immunosuppressive agents of CTX (60 mg/kg) and ALG (120 mg/kg). The prophylaxis of GVHD consisted of standard CsA and MTX. Patients have a media age of 25.3 yr (range: 15,37), and a median weight of 57.2 kg (range: 52.5,60) at the time of transplantation. Cord blood searches were all conducted at Guangzhou Cord Blood Bank. The engraftment state of the donor cells into recipients was confirmed by microsatellite DNA fingerprinting and fluorescent quantitative PCR analysis. Engrafted evidence has been found in seven patients involved by biomolecular analyses showing donor-recipient mixed chimerism post-transplant which was stable and persistent. After a median follow up of 32.2 months (range: 4,69), seven patients were alive and disease free. This study shows that durable donor-recipient stable mixed chimerism can be achieved by unrelated CBSCT in patients with SAA. Umbilical cord blood could be employed as a source of hematopoietic stem cell for adult transplantation. [source] Disseminated necrotizing leukoencephalopathy following low-dose oral methotrexateEUROPEAN JOURNAL OF NEUROLOGY, Issue 3 2007S. Raghavendra Leukoencephalopathy is a recognized complication with intrathecal or intravenous methotrexate (MTX). We report a 59-year-old lady who developed MTX leukoencephalopathy with long-term low-dose oral MTX. She developed posterior leukoencephalopathy (PLE) that initially was reversible on discontinuation of oral MTX. Four months later, she developed disseminated necrotizing leukoencephalopathy (DNL), and was left with devastating neurological deficits. The sequential conventional magnetic resonance imaging (MRI), diffusion weighted imaging (DWI), MR perfusion (MRP) and MR spectroscopic (MRS) changes are highlighted in this report. MRP and MRS showed more wide spread abnormalities than DWI. Stereotactic biopsy from the lesion revealed demyelination with macrophagic infiltration, pericapillary lymphomononucear aggregation, fibrinoid changes in the capillaries and neovascularization. Of the two cases of PLE with oral MTX reported in literature, one reversed clinically and radiologically with the discontinuation of MTX. To the best of our knowledge, this is the first reported case of DNL following oral MTX in the world literature. [source] Disruption of transport activity in a D93H mutant thiamine transporter 1, from a Rogers Syndrome familyFEBS JOURNAL, Issue 22 2003Dana Baron Rogers syndrome is an autosomal recessive disorder resulting in megaloblastic anemia, diabetes mellitus, and sensorineural deafness. The gene associated with this disease encodes for thiamine transporter 1 (THTR1), a member of the SLC19 solute carrier family including THTR2 and the reduced folate carrier (RFC). Using transient transfections into NIH3T3 cells of a D93H mutant THTR1derived from a Rogers syndrome family, we determined the expression, post-translational modification, plasma membrane targeting and thiamine transport activity. We also explored the impact on methotrexate (MTX) transport activity of a homologous missense D88H mutation in the human RFC, a close homologue of THTR1. Western blot analysis revealed that the D93H mutant THTR1 was normally expressed and underwent a complete N -glycosylation. However, while this mutant THTR1 was targeted to the plasma membrane, it was completely devoid of thiamine transport activity. Consistently, introduction into MTX transport null cells of a homologous D88H mutation in the hRFC did not result in restoration of MTX transport activity, thereby suggesting that D88 is an essential residue for MTX transport activity. These results suggest that the D93H mutation does not interfere with transporter expression, glycosylation and plasma membrane targeting. However, the substitution of this negatively charged amino acid (Asp93) by a positively charged residue (His) in an extremely conserved region (the border of transmembrane domain 2/intracellular loop 2) in the SLC19 family, presumably inflicts deleterious structural alterations that abolish thiamine binding and/or translocation. Hence, this functional characterization of the D93H mutation provides a molecular basis for Rogers syndrome. [source] Characterization of a human alternatively spliced truncated reduced folate carrier increasing folate accumulation in parental leukemia cellsFEBS JOURNAL, Issue 3 2000Stavit Drori Human CEM-7A cells established by gradual deprivation of leucovorin from the growth medium, display 100-fold overexpression of methotrexate transport activity. We found that this was associated with 10-fold reduced folate carrier gene amplification and 50-fold overexpression of both the principal 3 kb reduced folate carrier transcript and, surprisingly, a novel truncated 2 kb reduced folate carrier mRNA poorly expressed in parental CEM cells. The molecular basis for the generation of this truncated reduced folate carrier transcript and its potential functional role in folate accumulation were studied. Reduced folate carrier genomic and cDNA sequencing revealed that the truncated transcript had an internal deletion of 987 nucleotides which was a result of an alternative splicing utilizing a cryptic acceptor splice site within exon 6. This deletion consisted of the 3,-most 480 nucleotides of the reduced folate carrier ORF and the following 507 nucleotides of the 3,-UTR. These resulted in a truncated reduced folate carrier protein, which lacks the C-terminal 160 amino acids, but instead contains 58 new C-terminal amino acids obtained from reading through the 3,-UTR. Consequently, a truncated reduced folate carrier protein is generated that lacks the 12th transmembrane domain and contains a new and much shorter C-terminus predicted to reside at the extracellular face. Western analysis with plasma-membrane fraction from CEM-7A cells revealed marked overexpression of both a broadly migrating , 65,90 kDa native reduced folate carrier and a , 40,45 kDa truncated reduced folate carrier, the core molecular masses of which were confirmed by in vitro translation. However, unlike the native reduced folate carrier, the truncated reduced folate carrier protein failed to bind the affinity labels NHS-[3H]MTX and NHS-[3H]folic acid. Stable transfection of the truncated reduced folate carrier cDNA into mouse L1210 leukemia cells: increased folate accumulation, decreased their leucovorin and folic acid growth requirements, and increased their sensitivity to methotrexate. This constitutes the first documentation of an expressed alternatively spliced truncated reduced folate carrier that, when coexpressed along with the native carrier, augments folate accumulation and consequently decreases the cellular folate growth requirement. The possible mechanisms by which the truncated reduced folate carrier may increase folate accumulation and/or metabolism in cells coexpressing the truncated and native reduced folate carrier are discussed. [source] Efficiency of combined methotrexate/chloroquine therapy in adjuvant-induced arthritisFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2005M.A.R.C.P. Silva Abstract The present study evaluates the effects of methotrexate (MTX) and chloroquine (CQ), and of combined MTX + CQ treatment, on the inflammatory response and on plasma and liver phosphatase and transaminase activities, employing an adjuvant-induced arthritis model in rats. Arthritis was induced by the intradermal injection of a suspension of Mycobacterium tuberculosis in mineral oil into the plantar surface of the hind paws. Development of the inflammatory response was assessed over a 21-day period. Animal groups received either: (i) MTX, administered i.p., weekly, in 0.15, 1.5, 3, 6 or 12 mg/kg doses; (ii) CQ, given intragastrically, in daily 25 or 50 mg/kg doses; or (iii) MTX + CQ, administered in two combinations (MTX1.5 mg/kg + CQ50 mg/kg, or MTX6 mg/kg + CQ50 mg/kg). At the end of the experimental period, the animals were anesthetized and killed, blood and liver samples were collected and prepared for measurement of acid and alkaline phosphatase (AP, ALP), and aspartate (AST) and alanine aminotransferase (ALT) activities. MTX at 6 and 12 mg/kg reduced the inflammatory response while CQ had no effect. MTX6 mg/kg + CQ50 mg/kg reduced the inflammatory response similar to MTX12 mg/kg, without affecting the bone marrow. Plasma AP and liver ALP activities were very elevated in the arthritic rats. While MTX treatment partially reduced both plasma AP and liver ALP activities at all doses used in the arthritic rats, CQ treatment reduced plasma AP, but increased liver AP activity. MTX + CQ treatment decreased plasma AP and liver ALP activities in the arthritic rats to control values. Plasma and liver AST activities were unaltered in the arthritic rats, and were unaffected by treatment. However, plasma and liver ALT activities were significantly reduced in the arthritic rats. While MTX or CQ treatment did not alter plasma transaminase activity in the arthritic rats, after MTX + CQ treatment, plasma ALT activity returned to normal values. In conclusion, the present data suggest that MTX + CQ treatment provides more effective anti-inflammatory protection against adjuvant-induced arthritis than does MTX alone, reverting the alterations in enzyme activities induced by this inflammatory disease in rats. [source] Mechanisms of gene amplification and evidence of coamplification in drug-resistant human osteosarcoma cell linesGENES, CHROMOSOMES AND CANCER, Issue 4 2009Claudia M. Hattinger Gene amplification and copy number changes play a pivotal role in malignant transformation and progression of human tumor cells by mediating the activation of genes and oncogenes, which are involved in many different cellular processes including development of drug resistance. Since doxorubicin (DX) and methotrexate (MTX) are the two most important drugs for high-grade osteosarcoma (OS) treatment, the aim of this study was to identify genes gained or amplified in six DX- and eight MTX-resistant variants of the human OS cell lines U-2OS and Saos-2, and to get insights into the mechanisms underlying the amplification processes. Comparative genomic hybridization techniques identified amplification of MDR1 in all six DX-resistant and of DHFR in three MTX-resistant U-2OS variants. In addition, progressive gain of MLL was detected in the four U-2OS variants with higher resistance levels either to DX or MTX, whereas gain of MYC was found in all Saos-2 MTX-resistant variants and the U-2OS variant with the highest resistance level to DX. Fluorescent in situ hybridization revealed that MDR1 was amplified in U-2OS and Saos-2/DX-resistant variants manifested as homogeneously staining regions and double minutes, respectively. In U-2OS/MTX-resistant variants, DHFR was amplified in homogeneously staining regions, and was coamplified with MLL in relation to the increase of resistance to MTX. Gene amplification was associated with gene overexpression, whereas gene gain resulted in up-regulated gene expression. These results indicate that resistance to DX and MTX in human OS cell lines is a multigenic process involving gene copy number and expression changes. © 2008 Wiley-Liss, Inc. [source] Conjugation of methotrexate to immunoglobulins kills macrophages by Fc receptor mediated uptake?INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 3 2008X. WANG Summary The aim of this study was to conjugate methotrexate (MTX) with intravenous immunoglobulin (IVIG) and investigate whether the conjugate produce selective cytotoxicity on macrophages to provide a new strategy for the management of idiopathic thrombocytopenic purpura. MTX was bound to IVIG via human serum albumin as an intermediary. The binding activity of the Fc fragment of the conjugate was assayed by flow cytometry. The selective cytotoxicity of the conjugate was determined by trypan blue exclusion. After conjugating, the binding activity of the conjugate to Fc receptors did not diminish when compared with IVIG. In vitro, the conjugate showed significantly higher cytotoxicity to macrophages than Hela cells. The conjugate of IVIG and MTX showed potent and selective cytotoxicity to macrophages in vitro. [source] Methotrexate induction of human sulfotransferases in Hep G2 and Caco-2 cellsJOURNAL OF APPLIED TOXICOLOGY, Issue 5 2005Xinrong Chen Abstract Methotrexate (MTX) was the first antifolate drug developed for the treatment of cancer. It is also effective in treating inflammatory and autoimmune diseases. Sulfotransferases are phase II drug-metabolizing enzymes and their induction by hormones and endogenous molecules is relatively well known, although xenobiotic drug induction of sulfotransferases has not been well studied. In the present investigation, MTX is shown to be a xenobiotic inducer of human sulfotransferases in transformed human liver (Hep G2) and intestinal (Caco-2) cells. Following MTX treatment, various sulfotransferases were induced in both cell lines. Enzyme assay, Western blot and reverse-transcription polymerase chain reaction (RT-PCR) results demonstrated that protein and mRNA expressions of human simple phenol sulfotransferase (P-PST), human monoamine sulfotransferase (M-PST), human dehydroepiandrosterone sulfotransferase (DHEA-ST) and human estrogen sulfotransferase (EST) were induced in Hep G2 cells; M-PST and DHEA-ST were induced in Caco-2 cells. Inductions in both cell lines were dose dependent. Enzyme activity and Western blot results were in good agreement with RT-PCR results, suggesting that the induction is at the gene transcription level. Folic acid had a significantly lesser effect on sulfotransferases compared with MTX. Interestingly, the induction of different sulfotransferases by MTX was inhibited by high doses of folic acid at both protein and mRNA levels in Hep G2 cells. Methotrexate is the first antifolate and apoptosis-inducing drug to show induction of sulfotransferases in Hep G2 cells and Caco-2 cells. The inhibition by folic acid suggests a possible mechanism for MTX induction. Copyright © 2005 John Wiley & Sons, Ltd. [source] Methotrexate induced differentiation in colon cancer cells is primarily due to purine deprivationJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2006R. Singh Abstract The folate antagonist methotrexate (MTX) inhibits synthesis of tetrahydrofolate (THF), pyrimidines and purines, and induces differentiation in several cell types. At 1 µM, MTX reduced proliferation and induced differentiation in HT29 colon cancer cells; the latter effect was augmented (P,<,0.001) by thymidine (100 µM) but was reversed (P,<,0.001) by the purines, hypoxanthine (Hx; 100 µM) and adenosine (100 µM). In contrast 5-fluoro-uracil (5-FU), a specific thymidylate synthase (TS) inhibitor, had no effect on differentiation, suggesting that MTX-induced differentiation is not due to a reduction in thymidine but to the inhibition of purine biosynthesis. Inhibition of cyclic AMP (cAMP) by RpcAMP (25 µM) further enhanced (P,<,0.001) MTX induced differentiation, whereas the cAMP activator forskolin (10 µM) reversed (P,<,0.001) MTX induced differentiation. These observations implicate a central role of adenosine and cAMP in MTX induced differentiation. By combining Western blot analysis with liquid chromatography-mass spectrometry (LC-MS)and HPLC analyses we also reveal both the expression and activity of key enzymes (i.e. methionine synthase (MS), s-adenosylhomocysteinase, cystathionine ,-synthase and ornithine decarboxylase) regulating methyl cycle, transsulfuration and polyamine pathways in HT29 colon cancer cells. At 1 µM, MTX induced differentiation was associated with a marked reduction in the intracellular concentrations of adenosine and, consequently, S-adenosylmethionine (SAM), S-adenosylhomocysteine, polyamines and glutathione (GSH). Importantly, the marked reduction in methionine that accompanied MS inhibition following MTX treatment was non-limiting with respect to SAM synthesis. Collectively, these findings indicate that the effects of MTX on cellular differentiation and single carbon metabolism are primarily due to the intracellular depletion of purines. J. Cell. Biochem. © 2006 Wiley-Liss, Inc. [source] Combined local and systemic methotrexate treatment of viable ectopic pregnancy: Outcomes of 31 casesJOURNAL OF CLINICAL ULTRASOUND, Issue 9 2008Noam Smorgick MD Abstract Purpose. Medical treatment of viable unruptured ectopic pregnancies by systemic methotrexate (MTX) is controversial due to elevated failure rates. This study describes a combined local and systemic MTX administration and compares the outcomes between viable ectopics in different locations. Methods. This retrospective study evaluated 31 patients treated with combined local (sonographically guided) and systemic MTX for viable, unruptured ectopic pregnancies. Success was defined by pregnancy resolution without surgical intervention. Details on subsequent pregnancies were obtained via telephone questionnaires. Results. The ectopic pregnancies were located in the fallopian tube (n = 23), cesarean section scar (n = 5), and intramural portion of the tube (interstitial pregnancy) (n = 3). ,-Human chorionic gonadotropin levels and gestational weeks were similar. The combined treatment was successful in 73.9%, 100%, and 66.7% of cases, respectively (p > 0.05). Details regarding reproductive outcomes were available for 28 women (90.3%). Eighteen of the 24 women attempting to conceive became pregnant, and 15 of these had at least one live birth. There were three subsequent tubal pregnancies, all in patients with previous tubal pregnancies. Conclusion. Combined MTX administration is effective and safe for treating viable cesarean scar pregnancies but is less successful for viable tubal or interstitial pregnancies. Reproductive outcomes following the combined MTX treatment are comparable to other treatment modalities for ectopic pregnancy. © 2008 Wiley Periodicals, Inc. J Clin Ultrasound, 2008 [source] Methotrexate loaded poly(l -lactic acid) microspheres for intra-articular delivery of methotrexate to the jointJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2004Linda S. Liang Abstract A controlled release delivery system that localizes methotrexate (MTX) in the synovial joint is needed to treat inflammation in rheumatoid arthritis (RA). The purpose of this work was to develop and characterize MTX loaded poly(l -lactic acid) (PLLA) microspheres and evaluate in vivo tolerability and MTX plasma concentrations following intra-articular injection into healthy rabbits. MTX loaded PLLA (2 kg/mole) microspheres were prepared using the solvent evaporation method and characterized in terms of size, molecular weight, thermal properties, and release rates into phosphate buffered saline (PBS) (pH 7.4) at 37°C. Biocompatibility was evaluated by observing the swelling of the joints of the rabbits and histological analysis following the injection of the microspheres. MTX concentrations in the plasma and urine samples of rabbits were evaluated by high-performance liquid chromatography (HPLC). MTX loaded microspheres showed a rapid burst phase followed by a slow release phase. MTX loaded and control microspheres were biocompatible and plasma concentrations of MTX were tenfold higher in rabbits injected intra-articularly with free MTX than MTX microspheres. MTX microspheres may retain the drug in the joint by reducing clearance from the joint into the blood. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93: 943,956, 2004 [source] Application of pharmacokinetic,pharmacodynamic modeling to predict the kinetic and dynamic effects of anti-methotrexate antibodies in miceJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2003Evelyn D. Lobo Abstract We have shown that intravenous (iv) administration of anti-methotrexate (MTX) antibodies (AMAb) reduces the systemic exposure of intraperitoneal (ip) MTX therapy, and we have proposed that AMAb effects on MTX systemic exposure would allow a reduction in MTX-induced systemic toxicity (i.e., producing a desirable antagonistic effect). However, many literature reports have shown that anti-toxin antibodies occasionally demonstrate unexpected agonist-like activity, increasing the extent of toxicity induced by their ligand. In this report, we have utilized a pharmacokinetic,pharmacodynamic (PKPD) model to predict the potential of AMAb to increase or decrease the magnitude of MTX-induced body weight loss in mice. Simulations predicted that both anti-MTX immunoglobulin G (AMI) and anti-MTX Fab fragments (AMF) would lead to increases or decreases in MTX toxicity, with effects dependent on the dosing protocol used. Based on the computer simulations, two protocols were selected for in vivo evaluation of predicted agonistic or antagonistic effects. Murine monoclonal AMI and AMF were produced, purified, and characterized. Agonistic effects were tested after 24-h infusion of ip MTX (10 mg/kg) and iv administration of an equimolar dose of AMI. Antagonistic effects were tested after 72-h infusion of ip MTX (5 mg/kg) and iv infusion of an equimolar dose of AMF. Consistent with model predictions of agonist-like activity, the 24-h AMI protocol led to significantly increased animal mortality (all animals died, p,<,0.005) and mean nadir weight loss (p,<,0.005). Also consistent with the predictions of the PKPD model, the 72-h AMF protocol significantly decreased animal mortality and mean nadir body weight loss (p,<,0.01). Thus, these studies demonstrate that agonistic and antagonistic effects of anti-toxin antibodies may be predicted through the use of an integrated PKPD model. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1665,1676, 2003 [source] Methotrexate in psoriasis: 26 years' experience with low-dose long-term treatmentJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 5 2000U-F. Haustein Abstract Objective,To evaluate the efficacy, safety and side-effects of methotrexate (MTX) in psoriasis. Design,A 26-year retrospective study. Setting,Department of Dermatology, Leipzig University, Leipzig, Germany. Patients,One hundred and fifty-seven patients with extensive plaque psoriasis, erythrodermic, pustular and arthropathic forms, were treated with low-dose methotrexate (15,20 mg maximum weekly dosage [Weinstein schedule]), the majority for long-term periods. The mean cumulative dose was 3394 mg, the mean duration 237 weeks. Results,The effect of MTX treatment was good in 76%, moderate in 18% and poor in 6% of subjects; 61% experienced side-effects, most frequently due to liver function abnormalities, bone marrow suppression, nausea, gastric complaints and hair loss. In 20% of cases the subjects were forced to discontinue therapy; 9% refused therapy due to physical and psychological discomfort, 2% wanted to become pregnant, 16% were lost to follow-up, 6% died from multimorbidity and old age. Three subjects (2%) developed cancer of the lung, breast or cervix uteri, possibly in relation to long-term MTX treatment. Altogether there were no deaths or life-threatening side-effects attributable to MTX treatment, and no cases of progressive liver cirrhosis apart from two extensive skin necroses due to overdosage (misunderstanding, suicidal attempt) that were treated successfully with citrovorum factor. Conclusion,Low-dose MTX (<15,20 mg/week) is an effective therapy for extensive and severe forms of psoriasis if patients are selected carefully and monitored regularly, particularly with respect to liver and bone marrow toxicity. This helps to reduce severe side-effects even during long-term treatment. Drug interactions must be avoided. MTX therapy according to the guidelines is relatively safe and still has a place in the systemic treatment of psoriasis with 40 years of experience and an acceptable safety record. [source] Efficacy of methotrexate in Crohn's disease and ulcerative colitis patients unresponsive or intolerant to azathioprine,/mercaptopurineALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2009M. WAHED Summary Background, Despite the wide use of azathioprine/mercaptopurine (AZA/MP) therapy in the management of both Crohn's disease (CD) and ulcerative colitis (UC), approximately 20% of patients cannot tolerate the drugs and 30% do not respond. Aim, To examine the efficacy and safety profile of methotrexate (MTX) in patients with CD or UC who are either intolerant or non-responsive to AZA/MP. Methods, A total of 131 patients with IBD treated with MTX were identified. Retrospective data were obtained by case note review. Clinical response (defined as steroid withdrawal, normalization of previously raised CRP or physician's clinical assessment of improvement) was assessed at 6 months. Results, Clinical response in Crohn's disease occurred in 18 of 29 patients (62%) refractory to AZA/MP and 42 of 70 patients (60%) intolerant to AZA/MP, with no difference between the groups (P = 1.0). In UC, clinical response was seen in 7 of 9 (78%) patients refractory to AZA/MP and 15 of 23 (65%) intolerant to thiopurines. MTX was well tolerated in a majority of individuals. Conclusions, Methotrexate appears effective in both CD and UC patients who fail to respond to or are intolerant to AZA/MP therapy. [source] Infliximab and other immunomodulating drugs in patients with inflammatory bowel disease and the risk of serious bacterial infectionsALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2009S. SCHNEEWEISS Summary Background, There remain concerns about the safety of infliximab therapy in patients with inflammatory bowel disease (IBD). Aim, To assess the association between the initiation of infliximab and other immunomodulating drugs and the risk of serious bacterial infection in the treatment of IBD. Methods, We assembled a cohort study of patients with IBD, including Crohn's disease (CD) and ulcerative colitis (UC). All patients initiating an immunomodulating drug between January 2001 and April 2006 were identified in British Columbia from linked health care utilization databases. Exposure of interest was initiation of infliximab or corticosteroids compared with initiation of other immunosuppressive agents, including azathioprine, mercaptopurine (MP) and methotrexate (MTX). Outcome of interest was serious bacterial infections requiring hospitalization, including Clostridium difficile. Results, Among 10 662 IBD patients, the incidence rate of bacteriaemia ranged from 3.8 per 1000 person-years (95% confidence interval 2.1,6.2) for other immunosuppressive agents to 7.4 (3.3,19.3) for infliximab with slightly higher rate for serious bacterial infections resulting in an adjusted relative risk 1.4 (0.47,4.24). Clostridium difficile infections occurred in 0/1000 (0,5.4) among 521 infliximab initiations and 14/1000 (10.6,18.2) for corticosteroids. Corticosteroid initiation tripled the risk of C. difficile infections (RR = 3.4; 1.9,6.1) compared with other immunosuppressant agents. This corticosteroid effect was neither dose-dependent nor duration-dependent. Bacteriaemia and other serious bacterial infections were not increased by corticosteroids or infliximab (5 events). Conclusions, In a population-based cohort of patients with IBD, we found no meaningful association between infliximab and serious bacterial infections, although some subgroups had few events. Corticosteroid initiation increased the risk for C. difficile infections in these patients. [source] Methotrexate-related leukoencephalopathy without radiation therapy: Distribution of brain lesions and pathological heterogeneity on two autopsy casesNEUROPATHOLOGY, Issue 2 2009Jun Matsubayashi This report concerns two rare autopsy cases of methotrexate (MTX)-related leukoencephalopathy without radiation therapy. In the first case, there were widespread necrotic foci with prominent spheroids, that is, disseminated necrotizing leukoencephalopathy (DNL), mainly in the cerebral white matter. In contrast, in the second case, there were widespread demyelinated foci without significant axonal changes, which we would like to name disseminated demyelinating leukoencephalopathy (DDL), mainly in the cerebral white matter. We emphasize that the pathology of pure MTX-related leukoencephalopathy is not uniform, and may show at least two kinds of histologic change. Furthermore, both cases did not develop significant vascular changes, which are usually induced by radiation therapy. The distribution of the lesions in two cases was examined by large specimens, including hemisphere specimens. The distribution of the lesions in the brain of our cases was also different. In the first case, the DNL lesions were predominantly distributed in the frontal and temporal lobes. In the second case, the DDL lesions were prominently localized in the occipital lobe. To our knowledge, this is the first report describing not only the pathological findings of MTX-related leukoencephalopathy without irradiation but also the precise distributions of the lesions. [source] Erythrocyte concentrations of metabolites or cumulative doses of 6-mercaptopurine and methotrexate do not predict liver changes in children treated for acute lymphoblastic leukemiaPEDIATRIC BLOOD & CANCER, Issue 7 2006Päivi Halonen MD Abstract Background During therapy consisting of 6MP and MTX, metabolites accumulate in the erythrocytes. The erythrocyte levels of metabolites reflect the intensity of therapy. Whether they are associated with hepatotoxicity manifested as histological liver changes is not known. We studied the association of the metabolites and cumulative doses of 6MP and MTX with histological liver disease. Methods Serial measurements of E-TGN, E-MTX, and ALT during maintenance therapy were performed and cumulative doses of 6MP and MTX were calculated as g/m2 in 16 children with ALL. Each subject underwent a percutaneous liver biopsy at the end of therapy to screen for histological liver disease. Results No differences in E-TGN, E-MTX, or cumulative doses of 6MP or MTX were detected in the children with ALL with liver fibrosis compared to those without fibrosis, or in the children with less liver fatty change compared to those with more fatty change. Serum median ALT levels correlated significantly positively with cumulative doses of 6MP during therapy (rS,=,0.527, P,=,0.036), but not with cumulative doses of MTX, or E-TGN, or E-MTX. Conclusions Erythrocyte levels of the metabolites or the cumulative doses of 6MP and MTX do not predict histological liver disease in children treated for ALL. © 2006 Wiley-Liss, Inc. [source] Influence of high-dose methotrexate therapy (HD-MTX) on glomerular and tubular kidney functionPEDIATRIC BLOOD & CANCER, Issue 6 2003Lutz Hempel MD Abstract Background The present investigation was intended to further clarify the mechanisms involved in renal dysfunction following high-dose methotrexate (HD-MTX) treatment. Patients and Methods Fifty eight predominately pediatric patients [39 male, 19 female; mean age 12.3 years (range 2.2,34.1)] suffering from acute lymphoblastic leukemia (ALL, n,=,28), Non Hodgkins lymphoma (NHL, n,=,13), osteosarcoma (n,=,8), malignant brain tumor (n,=,6), or an ALL relapse (n,=,3), were prospectively examined. In the course of 220 infusions of HD-MTX, glomerular and tubular renal function was determined by measuring proteinuria and glomerular filtration rate (GFR), as well as renal excretion of alpha-1-microglobulin (AMG) and N -acetyl-,- D -glucosaminidase (NAG). It was investigated whether there were differences in MTX toxicity in dependence on the administered dose (1, 5, or 12 g/m2 BSA), on the combination with other cytostatic agents (ifosfamide or cyclophosphamide), on the metabolism of MTX into 7-OH-MTX, and on pre-treatment with MTX. Results The administration of HD-MTX has no direct tubulotoxic effect. The disturbance in glomerular function was dose dependently and indicated by an increase in proteinuria as well as by a decrease in GFR; all changes were completely reversible and did not correlate to the metabolism of MTX to 7-OH-MTX. Increasing the number of MTX therapeutic cycles did not increase the nephrotoxicity of MTX. Conclusion MTX is not directly tubulotoxic. Its side effects on glomeruli are usually without clinical relevance. Med Pediatr Oncol 2003;40:348,354. © 2003 Wiley-Liss, Inc. [source] Effect of aged garlic extract against methotrexate-induced damage to the small intestine in ratsPHYTOTHERAPY RESEARCH, Issue 6 2006Mehmet Yüncü Abstract Methotrexate (MTX) chemotherapy is often accompanied by side effects such as gastrointestinal ulceration and diarrhea. The aim of this study was to examine histologically whether an aged garlic extract (AGE) had a protective effect on the small intestine of rats with MTX-induced damage. Forty male Wistar albino rats were randomized into experimental and control groups and divided into four groups of ten animals. To the first group, MTX was applied as a single dose (20 mg/kg) intraperitoneally. To the second group, in addition to MTX application, AGE (250 mg/kg) was administered orally every day at the same time by intragastric intubation until the rats were killed. To the third group, AGE only was given. The fourth group was the control. All animals were killed 4 days after the intraperitoneal injection of MTX for histopathologic analysis and tissue MDA levels. Before killing, intracardiac blood was obtained from each animal to perform biochemical analysis (plasma lactate level). MTX was found to lead to damage in the jejunal tissues and to increase the MDA and lactate levels in the plasma. Administration of the AGE decreased the severity of jejunal damage, but increased MDA and lactate levels caused by MTX treatment on the other hand. These results suggest that AGE may protect the small intestine of rats from MTX-induced damage. Thus this study substantiated the thought that the protective effect of AGE is derived from the manner in which it interacts with crypt cells. Copyright © 2006 John Wiley & Sons, Ltd. [source] Protection of the Peyer's patch-associated crypt and villus epithelium against methotrexate-induced damage is based on its distinct regulation of proliferationTHE JOURNAL OF PATHOLOGY, Issue 1 2002Ingrid B. Renes Abstract The crypt and villus epithelium associated with Peyer's patches (PPs) is largely spared from methotrexate (MTX)-induced damage, compared with the non-patch (NP) epithelium. To assess the mechanism(s) preventing damage to the PP epithelium after MTX treatment, epithelial proliferation, apoptosis, and cell functions were studied in a rat-MTX model. Small intestinal segments containing PPs were excised after MTX treatment. Epithelial proliferation and apoptosis were assessed by detection of incorporated BrdU and cleaved caspase-3, respectively. Epithelial functions were determined by the expression of cell type-specific gene products at mRNA and protein level. Before and after MTX treatment, the number of BrdU-positive cells was higher in PP crypts than in NP crypts. BrdU incorporation was diminished in NP crypts, while in PP crypts incorporation was hardly affected. In PP and NP crypts, similar and increased levels of cleaved caspase-3-positive cells were observed after MTX. The enterocyte markers, sucrase-isomaltase, sodium-glucose co-transporter 1, glucose transporters 2 and 5, and intestinal and liver fatty acid binding protein, were down-regulated after MTX in NP epithelium but not in PP epithelium. In contrast, expression of the goblet cell markers, Muc2 and trefoil factor 3, and the Paneth cell marker, lysozyme, was maintained after MTX in both PP and NP epithelium. In conclusion, as MTX-induced apoptosis was similar in PP and NP crypts, the protection of the PP epithelium seems to be based on differences in the regulation of epithelial proliferation. Enterocyte function in the PP epithelium was unaffected by MTX treatment. Goblet and Paneth cell function was maintained in both NP and PP epithelium. Copyright © 2002 John Wiley & Sons, Ltd. [source] Isolated Central Nervous System Posttransplant Lymphoproliferative Disorder Treated with High-Dose Intravenous MethotrexateAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2009L. B. Nabors Posttransplant lymphoproliferative disorder (PTLD) is an uncommon neoplastic complication of kidney transplantation, affecting about 1% of recipients. It is generally associated with Epstein,Barr virus (EBV) infection of B-lineage lymphocytes. Central nervous system (CNS) involvement is rare. There is little clinical experience with treatment of CNS PTLD due to the relative rarity of the disease other than reduction or withdrawal of immunosuppression, but it is usually fatal. We describe six patients with renal allografts and histologically proven isolated CNS PTLD. Tissue analysis from the biopsy specimens was positive for EBV material in five of the six patients. All six patients were treated with high-dose intravenous methotrexate (HD IV MTX). Methotrexate was initiated at 8 g/m2, with later adjustments for creatinine clearance. With MTX therapy, four patients have had a sustained complete response, and two had progressive disease and were referred for radiation therapy. This finding suggests a subgroup of patients may benefit from MTX but our case series is inadequate to describe overall efficacy. No unexpected toxicities were encountered in 37 courses of treatment. HD IV MTX chemotherapy should be considered as an alternative for treatment of CNS PTLD. [source] Effect of growth hormone on testicular dysfunction induced by methotrexate in ratsANDROLOGIA, Issue 2 2009H. Serati Nouri Summary Methotrexate (MTX) is a chemotherapeutic agent causing defective oogenesis and spermatogenesis. This study was performed to assess the role of human growth hormone (GH) on testis recovery after treatment with MTX. Forty male Wistar rats were selected and randomly divided into four groups (n = 10): control (vehicle), GH group (0.3 mg kg,1 GH for 28 days, IP), MTX group (MTX 1 mg kg,1 week,1 for 4 weeks, IP) and GH/MTX group (0.3 mg kg,1 GH for 28 day plus 1 mg kg,1 week,1 MTX for 4 weeks, IP). On days 14 and 28, five rats from each group were killed, testes of rats of all groups were removed, spermatozoa were collected from epididymis and then prepared for analysis. MTX caused significant increase in interstitial tissue and capsular thickness and decrease of testicular and body weight (P < 0.05). Moreover, it caused significant decline in seminiferous tubule diameter and epithelium thickness (P < 0.05). There was no obvious change in morphometrical parameters between MTX/GH and control groups. In MTX group, sperm parameters decreased significantly (P < 0.05). Administration of GH plus MTX reduced the effects of MTX on sperm parameters and testosterone concentration. These results suggested that GH had a protective effect on almost all destructive effects caused by MTX in rat testes and thus improved sperm parameters. [source] Long-term survival with favorable cognitive outcome after chemotherapy in primary central nervous system lymphomaANNALS OF NEUROLOGY, Issue 2 2010Annika Juergens MD Objective To evaluate long-term progression-free survival and overall survival, quality of life, and cognitive function in primary central nervous system lymphoma after systemic and intraventricular chemotherapy without radiotherapy. Methods A long-term follow-up was conducted on surviving primary central nervous system lymphoma patients having been enrolled in a pilot/phase II trial between September 1995 and December 2001. Initially, 65 patients (median age, 62 years) had been treated with systemic and intraventricular chemotherapy without radiotherapy. All living patients were contacted, and a neurological examination, comprehensive neuropsychological testing, quality-of-life assessment, and imaging were performed. Results Twenty-one of all 65 patients (32 %) and 17 of 30 patients 60 years or younger (57%), respectively, were still alive at median follow-up of 100 months (range, 77,149 months). Nineteen of 21 patients completed all investigations; 1 was lost to follow-up. In three patients, an exclusively extraneural relapse of a high-grade non-Hodgkin's lymphoma was diagnosed after 9, 31, and 40 months, respectively. All of them experienced complete remission to high dose. Neither late neurotoxicity nor compromise of quality of life was found in any of the patients examined. Interpretation Primary polychemotherapy based on high-dose methotrexate (MTX) and cytarabine (Ara-C) is highly efficient in treatment of primary central nervous system lymphoma. About half of patients 60 years or younger can obviously be cured with this regimen without long-term neurotoxic sequelae or quality-of-life compromise. ANN NEUROL 2010;67:182,189 [source] Synthesis and Biological Activities of 2,4-Diaminopteridine DerivativesARCHIV DER PHARMAZIE, Issue 5 2009Fei Ma Abstract Substituted 2,4-diaminopteridine derivatives 10a,10l were prepared in moderate to good yield. Their structures were confirmed by 1H-NMR and MS spectroscopy, as well as by elemental analysis. Their inhibitory properties against inducible nitric oxide synthase (iNOS) were evaluated in vitro. Biological tests indicated that compound 10a, 10d, 10e, 10h, 10i, and 10l showed potent inhibitory activities similar to that of methotrexate (MTX), while the activities of compound 10b, 10c, 10f, 10g, 10j, and 10k are stronger than MTX. Two compounds, i. e., 10b (IC50 = 18.85 ,M) and 10i (IC50 = 24.08 ,M) were further studied for their effect on septic shock in rats and immunologically liver injured mice (in vivo). The results demonstrated that 10b and 10i had the capacity to increase the blood pressure in septic shock and showed notable protective activities on immunological hepatic injury. [source] Similar effects of disease-modifying antirheumatic drugs, glucocorticoids, and biologic agents on radiographic progression in rheumatoid arthritis: Meta-analysis of 70 randomized placebo-controlled or drug-controlled studies, including 112 comparisonsARTHRITIS & RHEUMATISM, Issue 10 2010Niels Graudal Objective To define the differences in effects on joint destruction in rheumatoid arthritis (RA) patients between therapy with single and combination disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, and biologic agents. Methods Randomized controlled trials in RA patients, investigating the effects of drug treatment on the percentage of the annual radiographic progression rate (PARPR) were included in a meta-analysis performed with the use of Review Manager 5.0 software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement protocol. Results Data from 70 trials (112 comparisons, 16 interventions) were summarized in 21 meta-analyses. Compared with placebo, the PARPR was 0.65% smaller in the single-DMARD group (P < 0.002) and 0.54% smaller in the glucocorticoid group (P < 0.00001). Compared with single-DMARD treatment, the PARPR was 0.62% smaller in the combination-DMARD group (P < 0.001) and 0.61% smaller in the biologic agent plus methotrexate (MTX) group (P < 0.00001). The effect of a combination of 2 DMARDs plus step-down glucocorticoids did not differ from the effect of a biologic agent plus MTX (percentage mean difference ,0.07% [95% confidence interval ,0.25, 0.11]) (P = 0.44). Conclusion Treatment with DMARDs, glucocorticoids, biologic agents, and combination agents significantly reduced radiographic progression at 1 year, with a relative effect of 48,84%. A direct comparison between the combination of a biologic agent plus MTX and the combination of 2 DMARDs plus initial glucocorticoids revealed no difference. Consequently, biologic agents should still be reserved for patients whose RA is resistant to DMARD therapy. Future trials of the effects of biologic agents on RA should compare such agents with combination treatments involving DMARDs and glucocorticoids. [source] Analysis of intracellular methotrexate polyglutamates in patients with juvenile idiopathic arthritis: Effect of route of administration on variability in intracellular methotrexate polyglutamate concentrationsARTHRITIS & RHEUMATISM, Issue 6 2010Mara L. Becker Objective Intracellular methotrexate (MTX) polyglutamates (MTXGlu) have been shown to be potentially useful biomarkers of clinical response in adult patients with rheumatoid arthritis. The present study was undertaken to measure intracellular MTXGlu concentrations in a cohort of patients with juvenile idiopathic arthritis (JIA) to determine the predictors of MTXGlu variability in these patients. Methods Blood samples were obtained from patients with JIA who were being treated with a stable dose of MTX for ,3 months. Clinical data were collected by chart review. Concentrations of MTXGlu1,7 in red blood cell lysates were quantitated using an innovative ion-pairing chromatography procedure, with detection by mass spectrometry. Results Patients with JIA from a single center (n = 99; mean ± SD age 117.8 ± 56.5 months, 69 female) were included in the analysis. The mean ± SD dose of MTX was 0.51 ± 0.25 mg/kg per week, with a median treatment duration of 18 months (interquartile range 3,156 months). MTX was administered subcutaneously in 66 patients (67%). Fifty-six patients (57%) had active arthritis at the time of the clinic visit. Total intracellular MTXGlu (MTXGluTOT) concentrations varied 40-fold, with a mean ± SD total concentration of 85.8 ± 48.4 nmoles/liter. Concentrations of each MTXGlu subtype (MTXGlu1,7) were measured individually and as a percentage of MTXGluTOT in each patient. MTXGlu3 was the most prominent subtype identified, comprising 42% of MTXGluTOT, and the interindividual variability in the concentration of MTXGlu3 was the most highly correlated with that of MTXGluTOT (r = 0.96). The route of MTX administration was significantly associated with MTXGlu1,5 subtypes; higher concentrations of MTXGlu1 + 2 were observed in patients receiving oral doses of MTX, whereas higher concentrations of MTXGlu3,5 were observed in patients receiving subcutaneous doses of MTX (P < 0.0001). Conclusion In this cohort of patients with JIA, the MTXGluTOT concentration varied 40-fold. Individual MTXGlu metabolites (MTXGlu1,7), which have, until now, not been previously reported in patients with JIA, were detected. The route of MTX administration contributed to the variability in concentrations of MTXGlu1,5. [source] Golimumab, a new human anti,tumor necrosis factor , antibody, administered intravenously in patients with active rheumatoid arthritis: Forty-eight,week efficacy and safety results of a phase III randomized, double-blind, placebo-controlled study ,ARTHRITIS & RHEUMATISM, Issue 4 2010Joel Kremer Objective To assess the efficacy and safety of intravenous administration of golimumab in patients with rheumatoid arthritis (RA). Methods Adult patients with RA in whom disease activity was persistent despite treatment with methotrexate (MTX) at a dosage of 15,25 mg/week for ,4 weeks were randomized to receive intravenous infusions of placebo plus MTX or intravenous infusions of golimumab at a dose of 2 mg/kg or 4 mg/kg, with or without MTX, every 12 weeks through week 48. Patients with <20% improvement in the swollen and tender joint counts could enter early escape and receive additional active treatment (week 16) or could have their dose regimen adjusted (week 24). The primary end point was the proportion of patients achieving a 50% response according to the American College of Rheumatology improvement criteria (ACR50) at week 14. Results The primary study end point was not met (at week 14, an ACR50 response was observed in 21% of the patients treated with golimumab plus MTX compared with 13% of the patients treated with placebo plus MTX [P = 0.051]). By week 24, significantly more patients treated with golimumab plus MTX had achieved an ACR50 response. Differences in the proportion of patients achieving an ACR50 response between the group receiving golimumab monotherapy and the group receiving placebo plus MTX were not significant at either week 14 (16% versus 13%) or week 24 (10% versus 9%). At week 48, the proportions of patients achieving ACR20 and ACR50 responses were highest among those who had received golimumab 4 mg/kg plus MTX (70% and 48%, respectively). Concomitant treatment with MTX was associated with a lower incidence of antibodies to golimumab. The most commonly reported adverse events through week 48 were infections (48% of patients treated with golimumab with or without MTX and 41% of patients receiving placebo plus MTX). Conclusion The primary end point was not met. However, intravenously administered golimumab plus MTX appears to have benefit in the longer-term reduction of RA signs/symptoms in MTX-resistant patients, with no unexpected safety concerns. [source] | |||||||||||||||||||||||||||||||