C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: effect on methotrexate-related toxicity in adult acute lymphoblastic leukaemia.

PubMed

Eissa, Deena Samir; Ahmed, Tamer Mohamed

2013-03-01

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism. Two polymorphisms, C677T and A1298C, were described leading to reduced enzyme activity. Methotrexate (MTX) is an antifolate agent of consolidation and maintenance therapy of acute lymphoblastic leukaemia (ALL). Despite its clinical success, MTX can be associated with serious toxicities resulting in treatment interruption or discontinuation, impacting disease outcome. There is evidence that MTX toxicity can be affected by polymorphisms in genes encoding for drug-metabolizing enzymes such as MTHFR. Therefore, we aimed to investigate the influence of MTHFR C677T and A1298C polymorphisms on the frequency of MTX-related toxicity, disease outcome and patients' survival. MTHFR polymorphisms were assessed in 50 adult patients with de novo ALL using real-time PCR. Patients were followed-up for the development of haematologic and/or nonhaematologic toxicity and assessment of clinical outcome. Frequency of C677T polymorphisms was 42% for TT, 24% for CT and 34% for CC; A1298C polymorphisms were 28, 6 and 66% for CC, AC and AA, respectively. MTX therapy was significantly associated with neutropaenia, hepatic and gastrointestinal toxicities, unfavourable response at day 14 of induction therapy, increased relapse and mortality rates and shorter survival in patients with 677 TT genotype than in those with CC and CT, whereas 1298 CC genotype patients had lower frequency of neutropaenia, hepatic toxicity and relapse than in those with AA and AC. Our study suggests MTHFR polymorphism as an attractive predictor of MTX-related toxicity in adult ALL, considering it a potential prognostic factor influencing disease outcome.

Influence of polymorphisms within the methotrexate pathway genes on the toxicity and efficacy of methotrexate in patients with juvenile idiopathic arthritis

PubMed Central

Yanagimachi, Masakatsu; Naruto, Takuya; Hara, Takuma; Kikuchi, Masako; Hara, Ryoki; Miyamae, Takako; Imagawa, Tomoyuki; Mori, Masaaki; Kaneko, Tetsuji; Morita, Satoshi; Goto, Hiroaki; Yokota, Shumpei

2011-01-01

AIMS We investigated whether several polymorphisms within the methotrexate (MTX) pathway genes were related to the toxicity and efficacy of MTX in 92 Japanese patients with articular-type juvenile idiopathic arthritis (JIA). METHODS Eight gene polymorphisms within the MTX pathway genes, namely, RFC, BCRP, MTHFR (two), FPGS, γ-glutamyl hydrolase (GGH; two) and ATIC, were genotyped using TaqMan assays. Liver dysfunction was defined as an increase in alanine transaminase to five times the normal upper limit. Non-responders to MTX were defined as patients refractory to MTX and were therefore treated with biologics. RESULTS The non-TT genotype at GGH T16C was associated with a high risk of liver dysfunction (P = 0.028, odds ratio = 6.90, 95% confidence interval 1.38–34.5), even after adjustment for the duration of MTX treatment. A longer interval from disease onset to treatment (8.5 and 21.3 months, P = 0.029) and rheumatoid factor positivity (P = 0.026, odds ratio = 2.87, 95% confidence interval 1.11–7.39) were associated with lower efficacy of MTX. CONCLUSIONS The non-TT genotype at GGH T16C was associated with a high risk of liver dysfunction, presumably because the C allele of GGH C16T may reduce the activity of GGH. The time interval before MTX treatment and rheumatoid factor positivity were associated with the efficacy of MTX treatment. The pharmacogenetics of the MTX pathway genes affects the toxicity and efficacy of MTX in Japanese JIA patients. PMID:21219404

Methotrexate pharmacogenetics in Uruguayan adults with hematological malignant diseases.

PubMed

Giletti, Andrea; Vital, Marcelo; Lorenzo, Mariana; Cardozo, Patricia; Borelli, Gabriel; Gabus, Raúl; Martínez, Lem; Díaz, Lilian; Assar, Rodrigo; Rodriguez, María Noel; Esperón, Patricia

2017-11-15

Individual variability is among the causes of toxicity and interruption of treatment in acute lymphoblastic leukemia (ALL) and severe non-Hodgkin lymphoma (NHL) patients under protocols including Methotrexate (MTX): 2,4-diamino-N10-methyl propyl-glutamic acid. 41 Uruguayan patients were recruited. Gene polymorphisms involved in MTX pathway were analyzed and their association with treatment toxicities and outcome was evaluated. Genotype distribution and allele frequency were determined for SLC19A1 G 80 A, MTHFR C 677 T and A 1298 C, TYMS 28bp copy number variation, SLCO1B1 T 521 C, DHFR C -1610 G/T, DHFR C -680 A, DHFR A -317 G and DHFR 19bp indel. Multivariate analysis showed that DHFR -1610 G/T (OR=0.107, p=0.018) and MTHFR 677 T alleles (OR=0.12, p=0.026) had a strong protective effect against hematologic toxicity, while DHFR -1610 CC genotype increased this toxicity (OR=9, p=0.045). No more associations were found. The associations found between gene polymorphisms and toxicities in this small cohort are encouraging for a more extensive research to gain a better dose individualization in adult ALL and NHL patients. Besides, genotype distribution showed to be different from other populations, reinforcing the idea that genotype data from other populations should not be extrapolated to ours. Copyright © 2017 Elsevier B.V. All rights reserved.

One-Carbon Metabolism and Breast Cancer Survival in a Population-Based Study

DTIC Science & Technology

2006-06-01

treatment strategy. BODY Task 1. To genotype polymorphisms in one-carbon-metabolizing genes on 1087 BC cases (Months 1- 24) Genotyping has...for treatment of the disease (e.g. 5-FU, methotrexate , etc.). We propose to utilize the resources of the Long Island Breast Cancer Study Project, a...promoter hypermethylation (presumably silencing) of the ER, PR, and BRCA1 genes . We will also examine whether functional polymorphisms in one- carbon

Role of Key TYMS Polymorphisms on Methotrexate Therapeutic Outcome in Portuguese Rheumatoid Arthritis Patients

PubMed Central

Lima, Aurea; Seabra, Vítor; Bernardes, Miguel; Azevedo, Rita; Sousa, Hugo; Medeiros, Rui

2014-01-01

Background Therapeutic outcome of rheumatoid arthritis (RA) patients treated with methotrexate (MTX) can be modulated by thymidylate synthase (TS) levels, which may be altered by genetic polymorphisms in TS gene (TYMS). This study aims to elucidate the influence of TYMS polymorphisms in MTX therapeutic outcome (regarding both clinical response and toxicity) in Portuguese RA patients. Methods Clinicopathological data from 233 Caucasian RA patients treated with MTX were collected, outcomes were defined and patients were genotyped for the following TYMS polymorphisms: 1) 28 base pairs (bp) variable number tandem repeat (rs34743033); 2) single nucleotide polymorphism C>G (rs2853542); and 3) 6 bp sequence deletion (1494del6, rs34489327). Chi-square and binary logistic regression analyses were performed, using genotype and haplotype-based approaches. Results Considering TYMS genotypes, 3R3R (p = 0.005, OR = 2.34), 3RC3RG (p = 0.016, OR = 3.52) and 6bp− carriers (p = 0.011, OR = 1.96) were associated with non-response to MTX. Multivariate analysis confirmed the increased risk for non-response to MTX in 6bp− carriers (p = 0.016, OR = 2.74). Data demonstrated that TYMS polymorphisms were in linkage disequilibrium (p<0.00001). Haplotype multivariate analysis revealed that haplotypes harboring both 3R and 6bp− alleles were associated with non-response to MTX. Regarding MTX-related toxicity, no statistically significant differences were observed in relation to TYMS genotypes and haplotypes. Conclusion Our study reveals that TYMS polymorphisms could be important to help predicting clinical response to MTX in RA patients. Despite the potential of these findings, translation into clinical practice needs larger studies to confirm these evidences. PMID:25279663

Impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on methotrexate-induced toxicities in acute lymphoblastic leukemia: a meta-analysis.

PubMed

Yang, Lin; Hu, Xin; Xu, Luhang

2012-10-01

The associations between methylenetetrahydrofolate reductase (MTHFR) polymorphism and methotrexate (MTX)-induced toxicities in patients with acute lymphoblastic leukemia (ALL) have been evaluated in various populations, with the results remained conflicting. Therefore, we conducted a meta-analysis by combining available data to derive a more precise estimation of the association. PubMed, Embase, and China National Knowledge Infrastructure were searched until 21 September 2011 to identify eligible studies. A total of 14 studies were included, with all studies investigating MTHFR C677T polymorphism while nine of them investigating MTHFR A1298C polymorphism only. Results suggested that MTHFR C677T polymorphism was associated with significantly increased risk of MTX-induced toxicity, specifically liver toxicity (TT/CT vs. CC: odds ratio (OR) = 1.70, 95 % confidence interval (CI) = 1.05-2.75), myelosuppression (TT vs. CT/CC: OR = 2.82, 95 %CI = 1.25-6.34), oral mucositis (TT/CT vs. CC: OR = 3.68, 95 %CI = 1.73-7.85), gastrointestinal toxicity (TT/CT vs. CC: OR = 2.36, 95 %CI = 1.36-4.11), and skin toxicity (T vs. C: OR = 2.26, 95 %CI = 1.07-4.74). MTHFR A1298C polymorphism was found to be associated with decreased risk of skin toxicity (CC/AC vs. AA: OR = 0.11, 95 %CI = 0.01-0.85). Genotyping of MTHFR polymorphism, C677T particularly, prior to treatment for ALL is likely to be useful with the aim of tailoring MTX therapy and thus reducing the MTX-related toxicities. However, further studies with larger data set and well-designed models are required to validate our findings.

The effect of RFC G80A polymorphism in Cretan children with acute lymphoblastic leukemia and its interaction with MTHFR C677T and A1298C polymorphisms.

PubMed

Karathanasis, N V; Stiakaki, E; Goulielmos, G Ν; Kalmanti, M

2014-08-01

The association between the risk of acute lymphoblastic leukemia (ALL) in children and enzymes involved in the folate metabolism has been under investigation lately. The reduced folate carrier gene (RFC) encodes reduced folate carrier, a protein that transports into the cell both folate and methotrexate, a commonly used chemotherapeutic drug, has been proved polymorphic at position 80 (G→A). The role of this polymorphism in childhood ALL and its interaction with other enzymes of the folate metabolic pathway, including MTHFR, has been examined in different populations with diverse results. In the present case-control study, 35 children with ALL and 48 healthy adult blood donors, all originating from the island of Crete (Greece), were screened for the presence of the RFC G80A polymorphism, using PCR/RFLP techniques. The effect on ALL risk and methotrexate-induced toxicities, along with the role of gene-gene interactions in our population, were examined. No significant association was observed between the RFC G80A genotypes and either the development of ALL or the presence of adverse events. However, a significant association was detected between the MTHFR A1298C/ RFC G80A genotype and a nonpredisposition for ALL (P = 0.035). This study suggests that gene-gene interactions in childhood ALL may be of prognostic value in our population. © 2013 John Wiley & Sons Ltd.

Influence of polymorphisms within the methotrexate pathway genes on the toxicity and efficacy of methotrexate in patients with juvenile idiopathic arthritis.

PubMed

Yanagimachi, Masakatsu; Naruto, Takuya; Hara, Takuma; Kikuchi, Masako; Hara, Ryoki; Miyamae, Takako; Imagawa, Tomoyuki; Mori, Masaaki; Kaneko, Tetsuji; Morita, Satoshi; Goto, Hiroaki; Yokota, Shumpei

2011-02-01

We investigated whether several polymorphisms within the methotrexate (MTX) pathway genes were related to the toxicity and efficacy of MTX in 92 Japanese patients with articular-type juvenile idiopathic arthritis (JIA). Eight gene polymorphisms within the MTX pathway genes, namely, RFC, BCRP, MTHFR (two), FPGS, γ-glutamyl hydrolase (GGH; two) and ATIC, were genotyped using TaqMan assays. Liver dysfunction was defined as an increase in alanine transaminase to five times the normal upper limit. Non-responders to MTX were defined as patients refractory to MTX and were therefore treated with biologics. The non-TT genotype at GGH T16C was associated with a high risk of liver dysfunction (P=0.028, odds ratio=6.90, 95% confidence interval 1.38-34.5), even after adjustment for the duration of MTX treatment. A longer interval from disease onset to treatment (8.5 and 21.3 months, P=0.029) and rheumatoid factor positivity (P=0.026, odds ratio=2.87, 95% confidence interval 1.11-7.39) were associated with lower efficacy of MTX. The non-TT genotype at GGH T16C was associated with a high risk of liver dysfunction, presumably because the C allele of GGH C16T may reduce the activity of GGH. The time interval before MTX treatment and rheumatoid factor positivity were associated with the efficacy of MTX treatment. The pharmacogenetics of the MTX pathway genes affects the toxicity and efficacy of MTX in Japanese JIA patients. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

[Association between the methylenetetrahydrofolate reductase gene polymorphisms and haplotype with toxicity response of high dose methotrexate chemotherapy].

PubMed

Liao, Qing-Chuan; Li, Xiao-Lei; Liu, Si-Ting; Zhang, Yong; Li, Tian-Yuan; Qiu, Jin-Chun

2012-07-01

To investigate the association between single nucleotide polymorphisms (SNP) and its haplotypes of methylenetetrahydrofolate reductase (MTHFR) gene with high dose methotrexate (HDMTX)-induced toxicity in children with acute lymphoblastic leukemia (ALL). HDMTX-treated children with ALL (1.2 to 14-years old) were selected from inpatient and followed for a retrospective study. The toxicity response of HDMTX chemotherapy was evaluated using WHO common toxicity criteria. Sixty-one patients with therapy-related toxicity and 36 patients without therapy-related toxicity were genotyped for 2 SNP (677C > T and 1298A > C) of the MTHFR gene by polymerase chain reaction-restriction fragment length polymorphism. Frequency of haplotypes and linkage disequilibrium of MTHFR gene were analyzed by SHEsis program. The distribution of MTHFR gene 677C > T polymorphism did not appeare different between groups with or without toxicity response (χ(2) = 4.609, P = 0.100), but the 1298A > C polymorphism was significantly different (χ(2) = 10.192, P = 0.006). Individuals who carried C allele (AC + CC genotype) had a decreased risk of toxicity response compared to AA genotype (OR = 0.245, 95%CI: 0.099 - 0.607, P = 0.002). 677C > T and 1298A > C polymorphisms showed strong linkage disequilibrium (D' = 0.895). The CC haplotype was significantly associated with decreased risk of toxicity response (OR = 0.338, 95%CI: 0.155 - 0.738, P = 0.005), while the TA haplotype was significantly associated with the increased risk of toxicity response (OR = 1.907, 95%CI: 1.045 - 3.482, P = 0.035). MTHFR gene 1298C allele and CC haplotype might serve as protective factors while TA haplotype as a risk factor for the susceptibility to toxicity response of HDMTX chemotherapy in children with ALL.

Influence of Folate-Related Gene Polymorphisms on High-Dose Methotrexate-Related Toxicity and Prognosis in Turkish Children with Acute Lymphoblastic Leukemia.

PubMed

Yazıcıoğlu, Burcu; Kaya, Zühre; Güntekin Ergun, Sezen; Perçin, Ferda; Koçak, Ülker; Yenicesu, İdil; Gürsel, Türkiz

2017-06-05

High-dose methotrexate (HD-MTX) is widely used in the consolidation phase of childhood acute lymphoblastic leukemia (ALL), but the roles that polymorphisms in folate-related genes (FRGs) play in HD-MTX toxicity and prognosis in children with ALL are not understood. The aims of this study were to investigate the frequencies of polymorphisms in the genes for thymidylate synthase (TS), methionine synthase reductase (MTRR), and methylene tetrahydrofolate reductase (MTHFR) in Turkish children with ALL and to assess associations between these polymorphisms and HD-MTX-related toxicity and leukemia prognosis in this patient group. FRG polymorphisms were assessed by real-time polymerase chain reaction. Survival status, MTX levels, and toxicity data were retrieved from 106 patients' charts. The allele frequencies for the FRG polymorphisms were as follows: TS 2R 41.0%, 3R 57.0%, and 4R 2.0%; MTRR 66A 42.4% and 66G 57.6%; MTHFR 677C 59.3% and 677T 40.7%; and MTHFR 1298A 58.1% and 1298C 41.9%. At the 48th hour of HD-MTX infusion, serum MTX was significantly higher in patients who had TS 2R/3R/4R variants as compared to those with wild-type TS (p<0.05). No significant differences were detected with respect to event-free survival or toxicity between wild-type and other FRG variants. The frequencies of FRG polymorphisms in Turkish children with ALL are similar to those reported in other Caucasian populations. This is the first published finding of the TS 3R/4R variant in the Turkish population. The results indicate that HD-MTX can be tolerated by leukemic children with some polymorphic variants of FRG; thus, it may prevent future risk of leukemic relapse.

Influence of genetic polymorphisms of FPGS, GGH, and MTHFR on serum methotrexate levels in Chinese children with acute lymphoblastic leukemia.

PubMed

Wang, Shu-mei; Sun, Lu-lu; Zeng, Wei-xin; Wu, Wan-shui; Zhang, Guo-liang

2014-08-01

To investigate the correlation between common genetic polymorphisms of folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), and methylenetetrahydrofolate reductase (MTHFR) and serum levels of methotrexate (MTX) in Chinese children with acute lymphoblastic leukemia (ALL). Ninety-one children with ALL who received high-dose MTX were recruited. The polymorphisms FPGS (rs1544105 G>A), GGH (rs3758149 C>T), and MTHFR (rs1801133 C>T) were genotyped through polymerase chain reaction-restriction fragment length polymorphism analysis. Serum MTX was measured by fluorescence polarization immunoassay. The association between targeted polymorphisms and MTX concentration-to-dose (C/D) ratios was assessed, and between targeted polymorphisms and the percent of MTX above the therapeutic threshold (40 µmol/L). The minor allele frequencies of rs1544105 G (34.1%), rs3758149 T (19.2%), and rs1801133 C (48.4%) observed in our population were significantly lower than those reported for European populations (64.2, 30.8, and 69.0%, respectively). The association between the GGH rs3758149 polymorphism and MTX C/D was gender-specific; in girls, the MTX C/D at 24 h of GGH rs3758149 CC carriers (12.09 μmol/L per g/m(2)) was significantly lower than that of CT or TT carriers (16.80 μmol/L per g/m(2)). The percent of serum MTX above the therapeutic threshold in GGH rs3758149 CC carriers (18.3%) was significantly lower than that of CT and TT carriers (38.7%). The MTX C/D ratios at 24 h and the percent of MTX >40 µmol/L for the A-T-T (three variant alleles) haplotype were significantly higher than those for other haplotypes combined (P < 0.05). These data indicate that FPGS rs1544105, GGH rs3758149, and MTHFR rs1801133 polymorphisms contribute to the variability of MTX pharmacokinetics, and their genotyping may be useful to reduce toxicities associated with MTX therapy.

Intraocular levels of methotrexate after oral low-dose treatment in chronic uveitis.

PubMed

Puchta, Joachim; Hattenbach, Lars-Olof; Baatz, Holger

2005-01-01

To determine the intraocular levels of methotrexate in low-dose treatment of noninfectious uveitis. One day after oral administration, the methotrexate level was measured in the aqueous humor and serum of a patient with noninfectious uveitis, who underwent cataract surgery. A fluorescence polarization immunoassay was used for determination. After oral administration, methotrexate was only measurable in aqueous humor but not in serum. In uveitis, orally administered low-dose methotrexate reaches detectable levels in aqueous humor, even in the absence of detectable levels in serum. Copyright (c) 2005 S. Karger AG, Basel.

Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate disposition

PubMed Central

Ramsey, Laura B.; Bruun, Gitte H.; Yang, Wenjian; Treviño, Lisa R.; Vattathil, Selina; Scheet, Paul; Cheng, Cheng; Rosner, Gary L.; Giacomini, Kathleen M.; Fan, Yiping; Sparreboom, Alex; Mikkelsen, Torben S.; Corydon, Thomas J.; Pui, Ching-Hon; Evans, William E.; Relling, Mary V.

2012-01-01

Methotrexate is used to treat autoimmune diseases and malignancies, including acute lymphoblastic leukemia (ALL). Inter-individual variation in clearance of methotrexate results in heterogeneous systemic exposure, clinical efficacy, and toxicity. In a genome-wide association study of children with ALL, we identified SLCO1B1 as harboring multiple common polymorphisms associated with methotrexate clearance. The extent of influence of rare versus common variants on pharmacogenomic phenotypes remains largely unexplored. We tested the hypothesis that rare variants in SLCO1B1 could affect methotrexate clearance and compared the influence of common versus rare variants in addition to clinical covariates on clearance. From deep resequencing of SLCO1B1 exons in 699 children, we identified 93 SNPs, 15 of which were non-synonymous (NS). Three of these NS SNPs were common, with a minor allele frequency (MAF) >5%, one had low frequency (MAF 1%–5%), and 11 were rare (MAF <1%). NS SNPs (common or rare) predicted to be functionally damaging were more likely to be found among patients with the lowest methotrexate clearance than patients with high clearance. We verified lower function in vitro of four SLCO1B1 haplotypes that were associated with reduced methotrexate clearance. In a multivariate stepwise regression analysis adjusting for other genetic and non-genetic covariates, SLCO1B1 variants accounted for 10.7% of the population variability in clearance. Of that variability, common NS variants accounted for the majority, but rare damaging NS variants constituted 17.8% of SLCO1B1's effects (1.9% of total variation) and had larger effect sizes than common NS variants. Our results show that rare variants are likely to have an important effect on pharmacogenetic phenotypes. PMID:22147369

Functional variants of gene encoding folate metabolizing enzyme and methotrexate-related toxicity in children with acute lymphoblastic leukemia.

PubMed

Kałużna, Ewelina; Strauss, Ewa; Zając-Spychała, Olga; Gowin, Ewelina; Świątek-Kościelna, Bogna; Nowak, Jerzy; Fichna, Marta; Mańkowski, Przemysław; Januszkiewicz-Lewandowska, Danuta

2015-12-15

Methotrexate (MTX) is commonly used agent in therapy of malignancies, including acute lymphoblastic leukemia (ALL). Based on the literature data it is known that MTX elimination and toxicity can be affected by polymorphisms in genes encoding enzymes involved in MTX metabolism. The aim of our study was to investigate the influence of C677T and A1298C polymorphisms in methylenetetrahydrofolate reductase (MTHFR) gene on MTX-induced toxicity during treatment of children with ALL. We also tried to answer the question whether simultaneous occurrence of these two polymorphisms has a clinical significance. MTHFR polymorphisms were assessed in 47 pediatric ALL patients, treated according to intensive chemotherapy for childhood ALL, ALL IC BFM 2009. Prolonged MTX elimination and higher incidence of toxicity were observed for patients with 677T-1298A haplotype. On the other hand, occurrence of 677C-1298A haplotype had protective effect on MTX clearance and toxicity, that was not observed in carriers of 677C-1298C haplotype. In patients with coexistence of studied variants 677CT/1298AC heterozygotes as well as in 677TT/1298AA homozygotes more frequently toxicity incidents were noted. The obtained results suggest that occurrence of 677T allele and coexistence of 677T and 1298C alleles may be associated with lower MTX clearance and elevated risk of adverse effects during MTX-treatment of pediatric ALL patients. Copyright © 2015 Elsevier B.V. All rights reserved.

Methylenetetrahydrofolate reductase (MTHFR) C677T and thymidylate synthase promoter (TSER) polymorphisms in Indonesian children with and without leukemia.

PubMed

Giovannetti, Elisa; Ugrasena, Dewa G; Supriyadi, Eddy; Vroling, Laura; Azzarello, Antonino; de Lange, Desiree; Peters, Godefridus J; Veerman, Anjo J P; Cloos, Jacqueline

2008-01-01

Genetic variations in the polymorphic tandem repeat sequence of the enhancer region of the thymidylate synthase promoter (TSER), as well as in methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, influence methotrexate sensitivity. We studied these polymorphisms in children with acute lymphoblastic leukaemia (ALL) and in subjects without malignancy in Indonesia and Holland. The frequencies of TT and CT genotypes were two-fold higher in Dutch children. The TSER 3R/3R repeat was three-fold more frequent in the Indonesian children, while the 2R/2R repeat was only 1% compared to 21% in the Dutch children. No differences of these polymorphisms were found between ALL cells and normal blood cells, indicating an ethnic rather than leukemic origin. These results may have implications for treatment of Indonesian children with ALL.

Influence of pre-hydration and pharmacogenetics on plasma methotrexate concentration and renal dysfunction following high-dose methotrexate therapy.

PubMed

Yanagimachi, Masakatsu; Goto, Hiroaki; Kaneko, Tetsuji; Naruto, Takuya; Sasaki, Koji; Takeuchi, Masanobu; Tanoshima, Reo; Kato, Hiromi; Yokosuka, Tomoko; Kajiwara, Ryosuke; Fujii, Hisaki; Tanaka, Fumiko; Goto, Shoko; Takahashi, Hiroyuki; Mori, Masaaki; Kai, Sumio; Yokota, Shumpei

2013-12-01

High-dose methotrexate therapy (HD-MTX) has been well established for the treatment of childhood acute lymphoblastic leukemia (ALL). The aims of this study were to investigate whether clinical and pharmacogenetic factors influence plasma MTX concentration and renal dysfunction in patients treated with HD-MTX. In a total of 127 courses of HD-MTX in 51 patients with childhood ALL, influence of clinical and pharmacogenetic factors on plasma MTX concentration and HD-MTX-related renal dysfunction was evaluated. Clinical factors included age, gender, duration of HD-MTX continuous-infusion and duration of pre-hydration before HD-MTX. Pharmacogenetic factors included 5 gene polymorphisms within the MTX pathway genes, namely, SLC19A1, MTHFR, ABCC2 and ABCG2. Short duration of pre-hydration before HD-MTX is the most important risk factor for prolonged high MTX concentration (p < 0.001, OR 6.40, 95 % CI 2.39-17.16) and renal dysfunction (p = 0.013, OR 3.15, 95 % CI 1.27-7.80). The T allele at MTHFR C677T was the risk factor for prolonged high MTX concentration (p = 0.009, OR 5.54, 95 % CI 1.54-19.85), but not for renal dysfunction. We found the influence of MTHFR C677T polymorphism on prolonged high MTX concentration. We reconfirmed the importance of adequate pre-hydration before HD-MTX to prevent prolonged high MTX concentration and MTX-related renal dysfunction.

Molecularly imprinted solid-phase extraction combined with electrochemical oxidation fluorimetry for the determination of methotrexate in human serum and urine

NASA Astrophysics Data System (ADS)

Chen, Suming; Zhang, Zhujun

2008-06-01

The method of synthesis and evaluation of molecularly imprinted polymers was reported. As a selective solid-phase extraction sorbent, the polymers were coupled with electrochemical fluorimetry detection for the efficient determination of methotrexate in serum and urine. Methotrexate was preconcentrated in the molecularly imprinted solid-phase extraction microcolumn packed with molecularly imprinted polymers, and then eluted. The eluate was detected by fluorescence spectrophotometer after electrochemical oxidation. The conditions of preconcentration, elution, electrochemical oxidation and determination were carefully studied. Under the selected experimental conditions, the calibration graph of the fluorescence intensity versus methotrexate concentration was linear from 4 × 10 -9 g mL -1 to 5 × 10 -7 g mL -1, and the detection limit was 8.2 × 10 -10 g mL -1 (3 σ). The relative standard deviation was 3.92% ( n = 7) for 1 × 10 -7 g mL -1 methotrexate. The experiments showed that the selectivity and sensitivity of fluorimetry could be greatly improved by the proposed method. This method has been successfully applied to the determination of methotrexate. At the same time, the binding characteristics of the polymers to the methotrexate were evaluated by batch and dynamic methods.

Prediction of Methotrexate Clinical Response in Portuguese Rheumatoid Arthritis Patients: Implication of MTHFR rs1801133 and ATIC rs4673993 Polymorphisms

PubMed Central

Lima, Aurea; Monteiro, Joaquim; Bernardes, Miguel; Sousa, Hugo; Azevedo, Rita; Seabra, Vitor; Medeiros, Rui

2014-01-01

Objective. Methotrexate (MTX), the most used drug in rheumatoid arthritis (RA) treatment, showing variability in clinical response, is often associated with genetic polymorphisms. This study aimed to elucidate the role of methylenetetrahydrofolate reductase (MTHFR) C677T and aminoimidazole carboxamide adenosine ribonucleotide transformylase (ATIC) T675C polymorphisms and clinicopathological variables in clinical response to MTX in Portuguese RA patients. Methods. Study included 233 RA patients treated with MTX for at least six months. MTHFR C677T and ATIC T675C polymorphisms were genotyped and clinicopathological variables were collected. Statistical analyses were performed and binary logistic regression method adjusted to possible confounding variables. Results. Multivariate analyses demonstrated that MTHFR 677TT (OR = 4.63; P = 0.013) and ATIC 675T carriers (OR = 5.16; P = 0.013) were associated with over 4-fold increased risk for nonresponse. For clinicopathological variables, noncurrent smokers (OR = 7.98; P = 0.001), patients positive to anti-cyclic citrullinated peptide (OR = 3.53; P = 0.004) and antinuclear antibodies (OR = 2.28; P = 0.045), with higher health assessment questionnaire score (OR = 2.42; P = 0.007), and nonsteroidal anti-inflammatory drug users (OR = 2.77; P = 0.018) were also associated with nonresponse. Contrarily, subcutaneous administration route (OR = 0.11; P < 0.001) was associated with response. Conclusion. Our study suggests that MTHFR C677T and ATIC T675C genotyping combined with clinicopathological data may help to identify patients whom will not benefit from MTX treatment and, therefore, assist clinicians in personalizing RA treatment. PMID:24967362

Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial.

PubMed

Busard, C I; Menting, S P; van Bezooijen, J S; van den Reek, J M; Hutten, B A; Prens, E P; de Jong, E M; van Doorn, M B; Spuls, P I

2017-02-02

The introduction of anti-tumor necrosis factor medications has revolutionized the treatment of psoriasis with achievement of treatment goals (Psoriasis Area and Severity Index score 75, remission) that are not usually met with conventional systemics. Nevertheless, some patients continue to experience persistent disease activity or treatment failure over time. Strategies to optimize treatment outcomes include the use of concomitant methotrexate, which has demonstrated beneficial effects on pharmacokinetics and treatment efficacy in psoriasis and other inflammatory diseases. This is an investigator-initiated, multicenter randomized controlled trial (RCT) designed to compare the combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis. The primary outcome is adalimumab drug survival at week 49. Other outcomes include improvement in disease severity and quality of life, tolerability, and safety. Moreover, anti-adalimumab antibodies and adalimumab serum concentrations will be measured and correlations between genotypes and clinical outcomes will be assessed. Patient recruitment started in March 2014. Up to now, 36 patients have been randomized. Many more patients have been (pre)screened. A total of 93 patients is desired to meet an adequate sample size. In our experience, the main limitation for recruitment is prior adalimumab therapy and intolerability or toxicity for methotrexate in the past. OPTIMAP is the first RCT to examine combination therapy with adalimumab and methotrexate in a psoriasis population. With data derived from this study we expect to provide valuable clinical data on long-term treatment outcomes. These data will be supported by assessment of the impact of concomitant methotrexate on adalimumab pharmacokinetics. Furthermore, the influence of several single nucleotide polymorphisms on adalimumab response will be analyzed in order to support the development of a more personalized approach for this targeted therapy. NTR4499 . Registered on 7 April 2014.

Association between SLC19A1 Gene Polymorphism and High Dose Methotrexate Toxicity in Childhood Acute Lymphoblastic Leukaemia and Non Hodgkin Malignant Lymphoma: Introducing a Haplotype based Approach

PubMed Central

Kotnik, Barbara Faganel; Jazbec, Janez; Grabar, Petra Bohanec; Rodriguez-Antona, Cristina

2017-01-01

Abstract Background We investigated the clinical relevance of SLC 19A1 genetic variability for high dose methotrexate (HD-MTX) related toxicities in children and adolescents with acute lymphoblastic leukaemia (ALL) and non Hodgkin malignant lymphoma (NHML). Patients and methods Eighty-eight children and adolescents with ALL/NHML were investigated for the influence of SLC 19A1 single nucleotide polymorphisms (SNPs) and haplotypes on HD-MTX induced toxicities. Results Patients with rs2838958 TT genotype had higher probability for mucositis development as compared to carriers of at least one rs2838958 C allele (OR 0.226 (0.071–0.725), p < 0.009). Haplotype TGTTCCG (H4) statistically significantly reduced the risk for the occurrence of adverse events during treatment with HD-MTX (OR 0.143 (0.023–0.852), p = 0.030). Conclusions SLC 19A1 SNP and haplotype analysis could provide additional information in a personalized HD-MTX therapy for children with ALL/NHML in order to achieve better treatment outcome. However further studies are needed to validate the results. PMID:29333125

Analytical interference in the therapeutic drug monitoring of methotrexate.

PubMed

Oudart, Jean-Baptiste; Marquet, Benjamin; Feliu, Catherine; Gozalo, Claire; Djerada, Zoubir; Millart, Hervé

2016-06-01

High-dose of methotrexate chemotherapy is used in the treatment of some tumors. It presents several side effects that required therapeutic drug monitoring, which is commonly performed on 24, 48 and 72h after the beginning of the methotrexate infusion. Treatment of overexposure to methotrexate is based on injection of carboxypeptidase G2, which specifically degrades methotrexate into inactive metabolite: DAMPA. FPIA immunoassay on TDx automated analyzer (Abbott™) was used for therapeutic drug monitoring of methotrexate. This immunoassay presented a significant cross-reactivity between methotrexate and DAMPA, which widely overestimate the residual concentration compared to the gold standard HPLC/MS. TDx automated analyzer was substituted by a new immunoassay on Architect automated analyzer (Abbott™). However, this immunoassay has the same cross-reactivity, which needs to be careful when monitoring methotrexate after an injection of carboxypeptidase G2. In order to determine the most suitable assay for the therapeutic drug monitoring of methotrexate, the knowledge of injection of carboxypeptidase G2 remains essential.

Urinary coproporphyrin I/(I + III) ratio as a surrogate for MRP2 or other transporter activities involved in methotrexate clearance.

PubMed

Benz-de Bretagne, Isabelle; Zahr, Noël; Le Gouge, Amélie; Hulot, Jean-Sébastien; Houillier, Caroline; Hoang-Xuan, Khe; Gyan, Emmanuel; Lissandre, Séverine; Choquet, Sylvain; Le Guellec, Chantal

2014-08-01

The urinary coproporphyrin I/(I + III) ratio may be a surrogate for MRP2 activity. We conducted a prospective study in patients receiving methotrexate (MTX) to examine the relationship between this ratio and the pharmacokinetics of a MRP2 substrate. Three urine samples were collected from 81 patients for UCP I/(I + III) ratio determination: one before (P1), one at the end of MTX infusion (P2), and one on the day of hospital discharge (P3). Three polymorphisms of ABCC2 were analysed and their relationships with basal UCP I/(I + III) ratio values assessed. All associated drugs were recorded and a drug interaction score (DIS) was assigned. Population pharmacokinetic analysis was conducted to assess whether MTX clearance (MTXCL) was associated with the basal UCP I/(I + III) ratio, its variation during MTX infusion, the DIS or other common covariates. The basal UCP I/(I + III) ratio was not associated with ABCC2 polymorphisms and did not differ according to the DIS. Significant changes in the ratio were observed over time, with an increase between P1 and P2 and a decrease at P3 (P < 0.001). No association was found between basal UCP I/(I + III) ratio and MTXCL. The final model indicates that MTXCL was dependent on the change in the ratio between P1 and P3, DIS and creatinine clearance. The basal UCP I/(I + III) ratio is not predictive of MTXCL. However, it is sensitive to the presence of MTX, so it is plausible that it reflects a function modified in response to the drug. © 2014 The British Pharmacological Society.

Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cronstein, B.N.; Eberle, M.A.; Levin, R.I.

1991-03-15

Although commonly used to control a variety of inflammatory diseases, the mechanism of action of a low dose of methotrexate remains a mystery. Methotrexate accumulates intracellularly where it may interfere with purine metabolism. Therefore, the authors determined whether a 48-hr pretreatment with methotrexate affected adenosine release from ({sup 14}C)adenine-labeled human fibroblasts and umbilical vein endothelial cells. Methotrexate significantly increased adenosine release by fibroblasts. The effect of methotrexate on adenosine release was not due to cytotoxicity since cells treated with maximal concentrations of methotrexate took up ({sup 14}C)adenine and released {sup 14}C-labeled purine (a measure of cell injury) in a mannermore » identical to control cells. Methotrexate treatment of fibroblasts dramatically inhibited adherence to fibroblasts by both unstimulated neutrophils and stimulated neutrophils. One hypothesis that explains the effect of methotrexate on adenosine release is that, by inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, methotrexate induces the accumulation of AICAR, the nucleoside precursor of which has previously been shown to cause adenosine release from ischemic cardiac tissue. The observation that the antiinflammatory actions of methotrexate are due to the capacity of methotrexate to induce adenosine release may form the basis for the development of an additional class of antiinflammatory drugs.« less

Reduction in Serum Uric Acid May Be Related to Methotrexate Efficacy in Early Rheumatoid Arthritis: Data from the Canadian Early Arthritis Cohort (CATCH)

PubMed Central

Lee, Jason J.; Bykerk, Vivian P.; Dresser, George K.; Boire, Gilles; Haraoui, Boulos; Hitchon, Carol; Thorne, Carter; Tin, Diane; Jamal, Shahin; Keystone, Edward C.; Pope, Janet E.

2016-01-01

OBJECTIVES The mechanism of action of methotrexate in rheumatoid arthritis (RA) is complex. It may increase adenosine levels by blocking its conversion to uric acid (UA). This study was done to determine if methotrexate lowers UA in early RA (ERA). METHODS Data were obtained from Canadian Early Arthritis Cohort, an incident ERA cohort. All ERA patients with serial UA measurements were included, comparing those with methotrexate use vs. no methotrexate exposure (controls). Analyses were exploratory. Patients with concomitant gout or taking UA-lowering therapies were excluded. RESULTS In total, 49 of the 2,524 ERA patients were identified with data available for both pre-methotrexate UA levels and post-methotrexate UA levels (300 µmol/L and 273 µmol/L, respectively; P = 0.035). The control group not taking methotrexate had a mean baseline UA level of 280 µmol/L and a follow-up level of 282 µmol/L (P = 0.448); mean change in UA with methotrexate was −26.8 µmol/L vs. 2.3 µmol/L in the no methotrexate group (P = 0.042). Methotrexate users with a decrease in UA had a disease activity score of 2.37 for 28 joints when compared with the controls (3.26) at 18 months (P = 0.042). Methotrexate users with decreased UA had a lower swollen joint count (SJC) of 0.9 at 18 months, whereas methotrexate users without lowering of UA had an SJC of 4.5 (P = 0.035). Other analyses were not significant. CONCLUSIONS Methotrexate response is associated with lowering of serum UA in ERA compared to nonusers. This may be due to changes in adenosine levels. Methotrexate response is associated with lower UA and fewer swollen joints compared to nonresponders. PMID:27081318

Toxic corneal epitheliopathy after intravitreal methotrexate and its treatment with oral folic acid.

PubMed

Gorovoy, Ian; Prechanond, Tidarat; Abia, Maravillas; Afshar, Armin R; Stewart, Jay M

2013-08-01

To determine whether oral folic acid can ameliorate an iatrogenic, visually significant corneal epitheliopathy, which commonly occurs with intravitreal injections of methotrexate for the treatment of intraocular lymphoma. We report 2 cases of visually significant corneal epitheliopathy occurring after intravitreal injections of methotrexate for intraocular lymphoma. The first patient did not receive any treatment for the corneal disease, and the second patient with bilateral intraocular lymphoma received 1 mg of oral folic acid daily, a commonly used dosage for patients on systemic methotrexate. In the first patient without treatment, there was a complete regression of the corneal epithelial disease only when the frequency of intravitreal methotrexate was reduced from weekly to monthly as per a commonly used dosage regimen for methotrexate. In the second patient, the corneal disease improved 80% within 1 week of initiating oral folic acid for her eye already experiencing severe epitheliopathy during her weekly dosing regimen of methotrexate and also had significantly decreased epithelial disease in her second eye that started weekly intravitreal methotrexate several weeks after beginning oral folic acid. Currently, oral folic acid supplements are recommended for patients using systemic methotrexate to minimize drug toxicity. We suggest a similar use in patients undergoing intravitreal methotrexate injections to decrease toxic effects on the corneal epithelium.

Population Pharmacokinetics of Intravenous Methotrexate in Patients with Hematological Malignancies: Utilization of Routine Clinical Monitoring Parameters.

PubMed

Nader, Ahmed; Zahran, Noran; Alshammaa, Aya; Altaweel, Heba; Kassem, Nancy; Wilby, Kyle John

2017-04-01

Clinical response to methotrexate in cancer is variable and depends on several factors including serum drug exposure. This study aimed to develop a population pharmacokinetic model describing methotrexate disposition in cancer patients using retrospective chart review data available from routine clinical practice. A retrospective review of medical records was conducted for cancer patients in Qatar. Relevant data (methotrexate dosing/concentrations from multiple occasions, patient history, and laboratory values) were extracted and analyzed using NONMEM VII ® . A population pharmacokinetic model was developed and used to estimate inter-individual and inter-occasion variability terms on methotrexate pharmacokinetic parameters, as well as patient factors affecting methotrexate pharmacokinetics. Methotrexate disposition was described by a two-compartment model with clearance (CL) of 15.7 L/h and central volume of distribution (V c ) of 79.2 L. Patient weight and hematocrit levels were significant covariates on methotrexate V c and CL, respectively. Methotrexate CL changed by 50 % with changes in hematocrit levels from 23 to 50 %. Inter-occasion variability in methotrexate CL was estimated for patients administered the drug on multiple occasions (48 and 31 % for 2nd and 3rd visits, respectively). Therapeutic drug monitoring data collected during routine clinical practice can provide a useful tool for understanding factors affecting methotrexate pharmacokinetics. Patient weight and hematocrit levels may play a clinically important role in determining methotrexate serum exposure and dosing requirements. Future prospective studies are needed to validate results of the developed model and evaluate its usefulness to predict methotrexate exposure and optimize dosing regimens.

Genetic Polymorphisms Associated to Folate Transport as Predictors of Increased Risk for Acute Lymphoblastic Leukemia in Mexican Children.

PubMed

Zaruma-Torres, Fausto; Lares-Asseff, Ismael; Lima, Aurea; Reyes-Espinoza, Aarón; Loera-Castañeda, Verónica; Sosa-Macías, Martha; Galaviz-Hernández, Carlos; Arias-Peláez, María C; Reyes-López, Miguel A; Quiñones, Luis A

2016-01-01

Acute lymphoblastic leukemia (ALL) is a frequent neoplasia occurring in children. The most commonly used drug for the treatment of ALL is methotrexate (MTX), an anti-folate agent. Previous studies suggest that folate transporters play a role in ALL prognosis and that genetic polymorphism of genes encoding folate transporters may increase the risk of ALL. Therefore, the main goal of this study was to determine the associations among six genetic polymorphisms in four genes related with the folate transporter pathway to determine a relationship with the occurrence of ALL in Mexican children. A case-control study was performed in 73 ALL children and 133 healthy children from Northern and Northwestern Mexico. COL18A1 (rs2274808), SLC19A1 (rs2838956), ABCB1 (rs1045642 and rs1128503), and ABCC5 (rs9838667 and rs3792585). Polymorphisms were assayed through qPCR. Our results showed an increased ALL risk in children carrying CT genotype (OR = 2.55, CI 95% 1.11-5.83, p = 0.0001) and TT genotype (OR = 21.05, CI 95% 5.62-78.87, p < 0.0001) of COL18A1 rs2274808; in SLC19A1 rs2838956 AG carriers (OR = 44.69, CI 95% 10.42-191.63, p = 0.0001); in ABCB1 rs1045642 TT carriers (OR = 13.76, CI 95% 5.94-31.88, p = 0.0001); in ABCC5 rs9838667 AC carriers (OR = 2.61, CI 95% 1.05-6.48, p < 0.05); and in ABCC5 rs3792585 CC carriers (OR = 9.99, CI 95% 3.19-31.28, p = 0.004). Moreover, several combinations of genetic polymorphisms were found to be significantly associated with a risk for ALL. Finally, two combinations of ABCC5 polymorphisms resulted in protection from this neoplasia. In conclusion, certain genetic polymorphisms related to the folate transport pathway, particularly COL18A1 rs2274808, SLC19A1 rs2838956, ABCB1 rs1045642, and ABCC5 rs3792585, were associated with an increased risk for ALL in Mexican children.

SLCO1B1 Polymorphisms are Associated With Drug Intolerance in Childhood Leukemia Maintenance Therapy.

PubMed

Eldem, İrem; Yavuz, Duygu; Cumaoğullari, Özge; İleri, Talia; Ünal İnce, Elif; Ertem, Mehmet; Doğanay Erdoğan, Beyza; Bindak, Recep; Özdağ, Hilal; Şatiroğlu-Tufan, N Lale; Uysal, L Zümrüt

2018-04-20

Therapy discontinuations and toxicities occur because of significant interindividual variations in 6-mercaptopurine (6-MP) and methotrexate (MTX) response during maintenance therapy of childhood acute lymphoblastic leukemia (ALL). 6-MP/MTX intolerance in some of the patients cannot be explained by thiopurine S-methyl transferase (TPMT) gene variants. In this study, we aimed to investigate candidate pharmacogenetic determinants of 6-MP and MTX intolerance in Turkish ALL children. In total, 48 children with ALL who had completed or were receiving maintenance therapy according to Children's Oncology Group (COG) protocols were enrolled. Fifteen single-nucleotide polymorphisms in 8 candidate genes that were related to drug toxicity or had a role in the 6-MP/MTX metabolism (TPMT, ITPA, MTHFR, IMPDH2, PACSIN2, SLCO1B1, ABCC4, and PYGL) were genotyped by competitive allele-specific PCR (KASP). Drug doses during maintenance therapy were modified according to the protocol. The median drug dose intensity was 50% (28% to 92%) for 6-MP and 58% (27% to 99%) for MTX in the first year of maintenance therapy, which were lower than that scheduled in all patients. Among the analyzed polymorphisms, variant alleles in SLCO1B1 rs4149056 and rs11045879 were found to be associated with lower 6-MP/MTX tolerance. SLCO1B1 rs4149056 and rs11045879 polymorphisms may be important genetic markers to individualize 6-MP/MTX doses.

Methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms and therapy-related toxicity in children treated for acute lymphoblastic leukemia and non-Hodgkin lymphoma.

PubMed

Kantar, Mehmet; Kosova, Buket; Cetingul, Nazan; Gumus, Sevinc; Toroslu, Ertug; Zafer, Nur; Topcuoglu, Nejat; Aksoylar, Serap; Cinar, Mehtap; Tetik, Asli; Eroglu, Zuhal

2009-06-01

This study aimed to investigate the association of the methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms with serum drug levels and toxicities after high-dose methotrexate (MTX) infusion. The study included 37 children with acute lymphoblastic leukemia or non-Hodgkin lymphoma. Serum MTX levels and toxicities of bone marrow, liver and kidney were analysed. Genotype analysis of the C677T and A1298C gene polymorphisms from genomic DNA of the subjects was performed by real-time PCR. Subjects with MTHFR polymorphism for C677T (CT, TT) had significantly higher MTX levels at 24 h (p = 0.009), and these genotypes did not seem to cause toxicity. Subjects with MTHFR polymorphism for A1298C (AC, CC) had significantly higher MTX levels at 48 h (p = 0.02), and had more grade III/IV anemia (p = 0.02), thrombocytopenia (p = 0.0001), elevated AST levels (p = 0.04) and frequent febrile neutropenic episodes (p = 0.004). The present study suggests that A1298C gene, but not C677T polymorphism is associated with MTX-related toxicity.

DNA variants in DHFR gene and response to treatment in children with childhood B ALL: revisited in AIEOP-BFM protocol.

PubMed

Ceppi, Francesco; Gagné, Vincent; Douyon, Laurance; Quintin, Camille J; Colombini, Antonella; Parasole, Rosanna; Buldini, Barbara; Basso, Giuseppe; Conter, Valentino; Cazzaniga, Giovanni; Krajinovic, Maja

2018-01-01

We have previously reported an association of dihydrofolate reductase promoter polymorphisms with reduced event-free survival in childhood acute lymphoblastic leukemia (ALL) patients treated with Dana Farber Cancer Institute protocol. Here, we assessed whether these associations are applicable to other protocol, based on different methotrexate doses. Genotypes for six tag polymorphisms and resulting haplotypes were analyzed for an association with ALL outcome. The association was found with the polymorphisms A-680C, A-317G and C-35T in high-risk group patients. Carriers of haplotype *1 had a remarkably higher risk of events compared with noncarriers and a lower probability of event-free survival (21.4 vs 81.3%). The role of DHFR variants in predicting the outcome of childhood ALL extends beyond single-treatment protocol and can be useful biomarker in personalizing treatment.

Delimiting Allelic Imbalance of TYMS by Allele-Specific Analysis.

PubMed

Balboa-Beltrán, Emilia; Cruz, Raquel; Carracedo, Angel; Barros, Francisco

2015-07-01

Allelic imbalance of thymidylate synthase (TYMS) is attributed to polymorphisms in the 5'- and 3'-untranslated region (UTR). These polymorphisms have been related to the risk of suffering different cancers, for example leukemia, breast or gastric cancer, and response to different drugs, among which are methotrexate glutamates, stavudine, and specifically 5-fluorouracil (5-FU), as TYMS is its direct target. A vast literature has been published in relation to 5-FU, even suggesting the sole use of these polymorphisms to effectively manage 5-FU dosage. Estimates of the extent to which these polymorphisms influence in TYMS expression have in the past been based on functional analysis by luciferase assays and quantification of TYMS mRNA, but both these studies, as the association studies with cancer risk or with toxicity or response to 5-FU, are very contradictory. Regarding functional assays, the artificial genetic environment created in luciferase assay and the problems derived from quantitative polymerase chain reactions (qPCRs), for example the use of a reference gene, may have distorted the results. To avoid these sources of interference, we have analyzed the allelic imbalance of TYMS by allelic-specific analysis in peripheral blood mononuclear cells (PBMCs) from patients.Allelic imbalance in PBMCs, taken from 40 patients with suspected myeloproliferative haematological diseases, was determined by fluorescent fragment analysis (for the 3'-UTR polymorphism), Sanger sequencing and allelic-specific qPCR in multiplex (for the 5'-UTR polymorphisms).For neither the 3'- nor the 5'-UTR polymorphisms did the observed allelic imbalance exceed 1.5 fold. None of the TYMS polymorphisms is statistically associated with allelic imbalance.The results acquired allow us to deny the previously established assertion of an influence of 2 to 4 fold of the rs45445694 and rs2853542 polymorphisms in the expression of TYMS and narrow its allelic imbalance to 1.5 fold, in our population. These data circumscribe the influence of these polymorphisms in the clinical outcome of 5-FU and question their use for establishing 5-FU dosage, above all when additional genetic factors are not considered.

Interaction of dihydrofolate reductase with methotrexate: Ensemble and single-molecule kinetics

NASA Astrophysics Data System (ADS)

Rajagopalan, P. T. Ravi; Zhang, Zhiquan; McCourt, Lynn; Dwyer, Mary; Benkovic, Stephen J.; Hammes, Gordon G.

2002-10-01

The thermodynamics and kinetics of the interaction of dihydrofolate reductase (DHFR) with methotrexate have been studied by using fluorescence, stopped-flow, and single-molecule methods. DHFR was modified to permit the covalent addition of a fluorescent molecule, Alexa 488, and a biotin at the N terminus of the molecule. The fluorescent molecule was placed on a protein loop that closes over methotrexate when binding occurs, thus causing a quenching of the fluorescence. The biotin was used to attach the enzyme in an active form to a glass surface for single-molecule studies. The equilibrium dissociation constant for the binding of methotrexate to the enzyme is 9.5 nM. The stopped-flow studies revealed that methotrexate binds to two different conformations of the enzyme, and the association and dissociation rate constants were determined. The single-molecule investigation revealed a conformational change in the enzyme-methotrexate complex that was not observed in the stopped-flow studies. The ensemble averaged rate constants for this conformation change in both directions is about 2-4 s1 and is attributed to the opening and closing of the enzyme loop over the bound methotrexate. Thus the mechanism of methotrexate binding to DHFR involves multiple steps and protein conformational changes.

Methotrexate Elimination When Coadministered With Levetiracetam.

PubMed

Reeves, David; DiDominick, Sarah; Finn, Suzanne; Kim, Hyeon Jin; Shake, Amanda

2016-12-01

Delayed elimination of methotrexate was previously reported in 2 patients receiving concomitant levetiracetam. To explore the potential interaction between methotrexate and levetiracetam in patients receiving high-dose methotrexate. This retrospective study reviewed the records of 81 adults receiving 280 cycles of methotrexate to determine the effects of levetiracetam on methotrexate elimination. Institutional review board approval was obtained. Levetiracetam was administered in 33 (12%) cycles of methotrexate. Patients receiving levetiracetam had significantly lower 24-hour methotrexate concentrations compared with those not receiving levetiracetam (2.91 vs 7.37 µmol/L, P = 0.005). Despite this difference, concentrations at 48 and 72 hours were similar between groups. Times to nontoxic methotrexate concentration (<0.1 µmol/L) were the same regardless of the presence of levetiracetam. The frequency of delayed elimination at 24, 48, and 72 hours was similar in both groups as was the frequency of delayed elimination at any time point. Cox regression demonstrated that levetiracetam was not a significant predictor of time to nontoxic methotrexate concentration (P = 0.796; HR = 1.058; 95% CI = 0.692-1.617), and logistic regression demonstrated that levetiracetam was not a significant predictor of delayed elimination at any time point. Levetiracetam use was similar between groups when comparing patients experiencing delayed elimination at any time point with those without delayed elimination (13% vs 10%, respectively, P = 0.527). This study does not support the previous reports of a significant interaction between levetiracetam and methotrexate. A clinically significant interaction is unlikely in those without additional risk factors for delayed elimination. © The Author(s) 2016.

The -174G/C Interleukin-6 Gene Promoter Polymorphism as a Genetic Marker of Differences in Therapeutic Response to Methotrexate and Leflunomide in Rheumatoid Arthritis.

PubMed

Ruiz-Padilla, A J; Gamez-Nava, J I; Saldaña-Cruz, A M; Murillo-Vazquez, J D; Vazquez-Villegas, M L; Zavaleta-Muñiz, S A; Martín-Márquez, B T; Ponce-Guarneros, J M; Rodriguez Jimenez, N A; Flores-Chavez, A; Sandoval-Garcia, F; Vasquez-Jimenez, J C; Cardona-Muñoz, E G; Totsuka-Sutto, S E; Gonzalez-Lopez, L

2016-01-01

Objective . To evaluate the association of -174G/C IL-6 polymorphism with failure in therapeutic response to methotrexate (MTX) or leflunomide (LEF). This prospective, observational cohort included 96 Mexican-Mestizo patients with moderate or severe rheumatoid arthritis (RA), initiating MTX or LEF, genotyped for IL-6 -174G/C polymorphism by PCR-RFLP. Therapeutic response was strictly defined: only if patients achieved remission or low disease activity (DAS-28 < 3.2). Results . Patients with MTX or LEF had significant decrement in DAS-28 ( p < 0.001); nevertheless, only 14% and 12.5% achieved DAS-28 < 3.2 at 3 and 6 months. After 6 months with any of these drugs the -174G/G genotype carriers (56%) had higher risk of therapeutic failure compared with GC (RR: 1.19, 95% CI: 1.07-1.56). By analyzing each drug separately, after 6 months with LEF, GG genotype confers higher risk of therapeutic failure than GC (RR = 1.56; 95% CI = 1.05-2.3; p = 0.003), or CC (RR = 1.83; 95% CI = 1.07-3.14; p = 0.001). This risk was also observed in the dominant model (RR = 1.33; 95% CI = 1.03-1.72; p = 0.02). Instead, in patients receiving MTX no genotype was predictor of therapeutic failure. We concluded that IL-6 -174G/G genotype confers higher risk of failure in therapeutic response to LEF in Mexicans and if confirmed in other populations this can be used as promissory genetic marker to differentiate risk of therapeutic failure to LEF.

Association of the TYMS 3G/3G genotype with poor response and GGH 354GG genotype with the bone marrow toxicity of the methotrexate in RA patients.

PubMed

Jekic, Biljana; Lukovic, Ljiljana; Bunjevacki, Vera; Milic, Vera; Novakovic, Ivana; Damnjanovic, Tatjana; Milasin, Jelena; Popovic, Branka; Maksimovic, Nela; Damjanov, Nemanja; Radunovic, Goran; Kovacevic, Ljiljana; Krajinovic, Maja

2013-03-01

Gamma-glutamyl hydrolase (GGH), cyclin D1 (CCND1) and thymidylate synthase (TS) genes encode enzymes that are involved in methotrexate (MTX) action. In a group of 184 RA patients treated with MTX, we have investigated whether selected polymorphisms in these genes modulate MTX efficacy and/or have impact on adverse drug effects (ADEs). The efficacy of the MTX therapy has been estimated using the disease activity score in 28 joints (DAS28-ESR) based on EULAR criteria and relative DAS28 values (rDAS28). All adverse drug events were recorded. Patients were genotyped for selected polymorphisms of the GGH (-354 G > T and 452 C > T), CCND1 (870 A > G) and TYMS (variable number of tandem repeats, VNTR, and G to C substitution of triple repeat, 3R allele) gene. Association studies have been performed between obtained genotypes and the efficacy and toxicity of MTX. According to the EULAR response criteria, 146 RA patients (79.3 %) were classified as responders (good/moderate response) and 38 (20.7 %) as non-responders (poor response). Higher frequency of the TYMS 3 G/3 G genotype has been found among non-responders as compared to individuals with remaining genotypes (p = 0.02). ADEs were recorded in 53 patients. Among those patients eight experienced bone marrow toxicity, all of them carried GGH -354GG genotype (p = 0.003). No other significant association were observed. The 3 G/3 G genotype of the TYMS gene may indicate predisposition of poor response to MTX and GG genotype of GGH -354 T > G polymorphism may have high predictive value for myelosuppression in RA patients.

Yellow fever vaccine used in a psoriatic arthritis patient treated with methotrexate: a case report.

PubMed

Stuhec, Matej

2014-01-01

The yellow fever vaccines on the market are contraindicated for immunocompromised and elderly patients. A case of yellow fever vaccine used in a 27-year-old Slovenian male with psoriatic arthritis during treatment with methotrexate is described. We demonstrate a positive case, since there were no adverse effects in concurrent administration of yellow fever vaccine and methotrexate. This patient did not show severe adverse reactions and did not contract yellow fever despite potential exposure. More research is needed on possible adverse effects of concurrent administration of yellow fever vaccine and methotrexate to determine the potential of this method for more frequent use.

Local Methotrexate Injection as the First-line Treatment for Cesarean Scar Pregnancy: Review of the Literature.

PubMed

Cheung, Vincent Y T

2015-01-01

The objective of this study was to determine the outcome of using ultrasound-guided local methotrexate injection as the first-line treatment of cesarean scar pregnancy (CSP). A literature review was performed on all eligible reports using this modality as the first-line treatment of CSP. Relevant publications were obtained from the PubMed electronic database from inception to December 2014. Ninety-six cases from 95 women reported in 17 articles were reviewed. The success rate was 73.9% after a single local methotrexate injection. An accumulated success rate of 88.5% could be achieved after additional local or intramuscular methotrexate administration. Eleven cases (11.5%) failed methotrexate treatment and required surgical interventions. Except for women with serum human chorionic gonadotropin levels higher than 100 000 IU/L, ultrasound-guided local methotrexate injection could be considered as a first-line treatment modality for CSP. Copyright © 2015 AAGL. Published by Elsevier Inc. All rights reserved.

Targeting TNF-α and NF-κB Activation by Bee Venom: Role in Suppressing Adjuvant Induced Arthritis and Methotrexate Hepatotoxicity in Rats

PubMed Central

Darwish, Samar F.; El-Bakly, Wesam M.; Arafa, Hossam M.; El-Demerdash, Ebtehal

2013-01-01

Low dose methotrexate is the cornerstone for the treatment of rheumatoid arthritis. One of its major drawbacks is hepatotoxicity, resulting in poor compliance of therapy. Dissatisfied arthritis patients are likely to seek the option of complementary and alternative medicine such as bee venom. The combination of natural products with modern medicine poses the possibility of potential interaction between the two groups and needs investigation. The present study was aimed to investigate the modulatory effect of bee venom acupuncture on efficacy, toxicity, and pharmacokinetics and tissue disposition of methotrexate. Complete Freund's adjuvant induced arthritic rats were treated for 3 weeks with methotrexate and/or bee venom. Arthritic score, ankle diameter, paw volume and tissue expression of NF-κB and TNF-α were determined to assess anti-arthritic effects, while anti-nociceptive effects were assessed by gait score and thermal hyperalgesia. Methotrexate toxicity was assessed by measuring serum TNF-α, liver enzymes and expression of NF-κB in liver. Combination therapy of bee venom with methotrexate significantly improved arthritic parameters and analgesic effect as compared to methotrexate alone. Bee venom ameliorated serum TNF-α and liver enzymes elevations as well as over expression of NF-κB in liver induced by methotrexate. Histological examination supported the results. And for the first time bee venom acupuncture was approved to increase methotrexate bioavailability with a significant decrease in its elimination. Conclusion: bee venom potentiates the anti-arthritic effects of methotrexate, possibly by increasing its bioavailability. Also, it provides a potent anti-nociceptive effect. Furthermore, bee venom protects against methotrexate induced hepatotoxicity mostly due to its inhibitory effect on TNF-α and NF-κB. PMID:24278124

Evaluation of Novel Agents Which Target Neovasculature of Breast Tumors

DTIC Science & Technology

2005-04-01

chemotherapeutic agents including cyclophosphamide, methotrexate, anthracycline, cytarabine , paclitaxel, and corticosteroids (28). To determine whether the...cyclophosphamide, methotrexate, anthracycline, cytarabine , paclitaxel, and corticosteroids (28). Sasaki et al reported that the level of Bcl-2 in cancer cells

C677T (RS1801133 ) MTHFR gene polymorphism frequency in a colombian population.

PubMed

Romero-Sánchez, Consuelo; Gómez-Gutierrez, Alberto; Gómez, Piedad Elena; Casas-Gomez, Maria Consuelo; Briceño, Ignacio

2015-01-01

Abnormal levels of the enzyme methylenetetrahydrofolate reductase (MTHFR) are associated with an increased risk of both cardiovascular and cerebrovascular disease and higher concentrations of homocysteine. Abnormal levels are also related to birth defects, pregnancy complications, cancer and toxicity to methotrexate (MTX). Polymorphisms of MTHFR affect the activity of the enzyme. Genetic associations have been related to treatment efficacy. To establish the frequency of the C> T polymorphism at nucleotide 677 of the MTHFR gene in a group of Colombian individuals. Data from pharmacogenetic microarrays that include MTX sensibility-associated polymorphisms were retrospectively collected (Pathway Genomics(®)). The frequency of the C> T MTHFR rs1801133 marker polymorphism was analyzed. Microarray data from 68 men and 84 women were analyzed. Comparisons of genotype C/C vs. C/T and T/T were statistically significantly different (p= 0.00, p= 0.026, respectively), as were C/T and T / T (p= 0.0001). Results for the C/C and C/T genotypes in a Colombian population are similar to other previously studied groups of healthy subjects. Subjects from our population might be at risk of developing diseases associated with MTHFR polymorphisms and might present toxicity and adverse effects if treated with MTX, which suggests the need to evaluate therapeutic alternatives based on individual pharmacogenetic studies.

Dialysis of the rectum for sampling drug concentrations in the luminal extracellular fluid of the gut: technique and precision.

PubMed

Egan, L J; Sandborn, W J; Mays, D C; Tremaine, W J; Lipsky, J J

1998-07-01

It is useful to measure the luminal concentration of drugs which act in the gut. Dialysis of the rectum has not previously been used or validated for this purpose. To determine the precision of rectal dialysis for measuring rectal drug concentrations. To establish the duration of dialysis required to approach equilibrium, the rate of methotrexate diffusion into dialysis bags was first determined in vitro. The precision of rectal dialysis for sampling the methotrexate concentration of colonic lumen extracellular fluid was determined in seven subjects who underwent two consecutive dialysis procedures. Subjects treated with subcutaneous methotrexate for refractory inflammatory bowel disease were studied. Methotrexate crossed the dialysis membrane by a first-order process, and after a 2 h in vitro dialysis, equilibration was 74 +/- 2% (mean +/- s.d.) complete. Rectal dialysis was well tolerated by all subjects. The mean +/- s.e. methotrexate concentration of 3.6 +/- 1.1 nmol/L in the first dialysate was not significantly different from 3.6 +/- 0.9 nmol/L in the second dialysate. P = 0.99 (paired two-tailed t-test). Similar precision was obtained for an endogenous molecule, potassium, secreted by the rectal mucosa. Dialysis of the rectum is a well tolerated and precise technique for sampling the colonic lumen extracellular fluid for quantitative analyses of exogenous and endogenous substances.

Efficacy of Glucarpidase (Carboxypeptidase G2) in Patients with Acute Kidney Injury After High-Dose Methotrexate Therapy

PubMed Central

Widemann, Brigitte C.; Schwartz, Stefan; Jayaprakash, Nalini; Christensen, Robbin; Pui, Ching-Hon; Chauhan, Nikhil; Daugherty, Claire; King, Thomas R.; Rush, Janet E.; Howard, Scott C.

2013-01-01

STUDY OBJECTIVE As the incidence rate of renal impairment is 2–10% for patients treatment with high-dose methotrexate , and renal impairment develops in 0–12.4% of patients treated for osteosarcoma, we sought to evaluate the efficacy of glucarpidase, a recently approved drug that rapidly hydrolyzes methotrexate to inactive metabolites, which allows for nonrenal clearance in patients with delayed renal methotrexate elimination. DESIGN Pooled analysis of efficacy data from four multicenter, single-arm, compassionate-use clinical trials using protocols from 1993–2007. PATIENTS Of 476 patients with renal toxicity and delayed methotrexate elimination who were treated with intravenous glucarpidase for rescue after high-dose methotrexate, 169 patients had at least one preglucarpidase (baseline) plasma methotrexate concentration greater than 1 µmol/L and one postglucarpidase methotrexate concentration measurement by high-performance liquid chromatography and were included in the efficacy analysis; renal recovery was assessed in 436 patients who had at least one recorded preglucarpidase and postglucarpidase serum creatinine concentration measurement. MEASUREMENTS AND MAIN RESULTS Efficacy was defined as rapid and sustained clinically important reduction (RSCIR) in plasma methotrexate concentration, with a concentration of 1 µmol/L or lower at all postglucarpidase determinations. Median age of efficacy-evaluable patients was 20 years (range 5 wks–84 yrs). Osteosarcoma (36%), non-Hodgkin’s lymphoma (27%), and acute lymphoblastic leukemia (20%) were the most frequent underlying diagnoses. Median preglucarpidase serum methotrexate was 11.7 µmol/L. At the first (median 15 min) through the last (median 40 hrs) postglucarpidase measurement, plasma methotrexate concentrations demonstrated consistent 99% median reduction. RSCIR was achieved by 83 (59%) of 140 patients. Sixty-four percent of patients with renal impairment greater than or equal to Common Terminology Criteria for Adverse Events grade 2 recovered to grade 0 or 1 at a median of 12.5 days after glucarpidase administration. CONCLUSION Glucarpidase caused a clinically important 99% or greater sustained reduction of serum methotrexate levels and provided noninvasive rescue from methotrexate toxicity in renally impaired patients. PMID:24132809

Improvement in work place and household productivity for patients with early rheumatoid arthritis treated with adalimumab plus methotrexate: work outcomes and their correlations with clinical and radiographic measures from a randomized controlled trial companion study.

PubMed

van Vollenhoven, Ronald F; Cifaldi, Mary A; Ray, Saurabh; Chen, Naijun; Weisman, Michael H

2010-02-01

To evaluate household and work place outcomes for patients with rheumatoid arthritis (RA) who were homemakers or employed workers, respectively, and who were treated with adalimumab plus methotrexate versus methotrexate monotherapy. We also determined baseline predictors of household and work place outcomes. Data were from a health economic companion study to PREMIER, a 2-year, randomized controlled trial of methotrexate-naive patients with early RA (<3 years) who received treatment with adalimumab plus methotrexate, adalimumab, or methotrexate. Absenteeism (number of days missed or unfit to work), presenteeism (self-judgment of the effects of RA on job or household performance), and employment status were collected from self-reports at baseline and varying time points during the study. Household and work place outcomes were generally similar for homemakers and employed workers. Over 2 years, patients who received combination therapy missed approximately half as many days as patients who received methotrexate (17.4 versus 36.9 days for employed workers; 7.9 versus 18.6 days for homemakers). Presenteeism was lower (reflecting better productivity) for combination therapy than methotrexate monotherapy. The likelihood of gaining/retaining employment over 2 years was greater for combination therapy than methotrexate monotherapy (odds ratio 1.530, 95% confidence interval 1.038-2.255; P = 0.0318). Baseline radiographic progression was an independent predictor for retaining/gaining employment at 2 years. Compared with methotrexate monotherapy, combination therapy was associated with more positive work outcomes: less absenteeism, less presenteeism, and greater likelihood of gaining/retaining employment. Radiographic progression at baseline was predictive of the ability to retain or gain employment.

Methotrexate consolidation treatment according to pharmacogenetics of MTHFR ameliorates event-free survival in childhood acute lymphoblastic leukaemia.

PubMed

Salazar, J; Altés, A; del Río, E; Estella, J; Rives, S; Tasso, M; Navajas, A; Molina, J; Villa, M; Vivanco, J L; Torrent, M; Baiget, M; Badell, I

2012-10-01

Recent advances in treatment for childhood acute lymphoblastic leukaemia (ALL) have significantly increased outcome. High-dose methotrexate (MTX) is the most commonly used regimen during the consolidation period, but the optimal dose remains to be defined. We investigated the usefulness of the MTHFR genotype to increase the MTX dosage in the consolidation phase in 141 childhood ALL patients enrolled in the ALL/SHOP-2005 protocol. We also investigated the pharmacogenetic role of polymorphisms in genes involved in MTX metabolism on therapy-related toxicity and survival. Patients with a favourable MTHFR genotype (normal enzymatic activity) treated with MTX doses of 5 g m⁻² had a significantly lower risk of suffering an event than patients with an unfavourable MTHFR genotype (reduced enzymatic activity) that were treated with the classical MTX dose of 3 g m⁻² (P=0.012). Our results indicate that analysis of the MTHFR genotype is a useful tool to optimise MTX therapy in childhood patients with ALL.

Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients.

PubMed

Taylor, John C; Bongartz, Tim; Massey, Jonathan; Mifsud, Borbala; Spiliopoulou, Athina; Scott, Ian C; Wang, Jianmei; Morgan, Michael; Plant, Darren; Colombo, Marco; Orchard, Peter; Twigg, Sarah; McInnes, Iain B; Porter, Duncan; Freeston, Jane E; Nam, Jackie L; Cordell, Heather J; Isaacs, John D; Strathdee, Jenna L; Arnett, Donna; de Hair, Maria J H; Tak, Paul P; Aslibekyan, Stella; van Vollenhoven, Ronald F; Padyukov, Leonid; Bridges, S Louis; Pitzalis, Costantino; Cope, Andrew P; Verstappen, Suzanne M M; Emery, Paul; Barnes, Michael R; Agakov, Felix; McKeigue, Paul; Mushiroda, Taisei; Kubo, Michiaki; Weinshilboum, Richard; Barton, Anne; Morgan, Ann W; Barrett, Jennifer H

2018-05-25

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10 -7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.

Hypoxia-induced resistance to doxorubicin and methotrexate in human melanoma cell lines in vitro.

PubMed

Sanna, K; Rofstad, E K

1994-07-15

Rodent cell lines can develop resistance to doxorubicin and methotrexate during hypoxic stress. This has so far not been observed in human tumor cell lines. The purpose of our communication is to show that doxorubicin and methotrexate resistance can also develop in human melanoma cells during exposure to hypoxia. Four cell lines (BEX-c, COX-c, SAX-c, WIX-c) have been studied. Cells were exposed to hypoxia (O2 concentration < 10 ppm) for 24 hr prior to reoxygenation. Doxorubicin and methotrexate cell survival curves were determined immediately after as well as 18 and 42 hr after reoxygenation. The 4 cell lines were relatively sensitive to doxorubicin without hypoxia pre-treatment, and all developed resistance during exposure to hypoxia. Hypoxic stress also induced methotrexate resistance in BEX-c and SAX-c but not in COX-c and WIX-c. BEX-c and SAX-c were sensitive to methotrexate without hypoxia pre-treatment, whereas COX-c and WIX-c were resistant initially. Hypoxia-induced drug resistance was present immediately after reoxygenation and tended to decrease with time but remained statistically significant even 42 hr after reoxygenation.

Nonassociation of homocysteine gene polymorphisms with treatment outcome in South Indian Tamil Rheumatoid Arthritis patients.

PubMed

Muralidharan, Niveditha; Gulati, Reena; Misra, Durga Prasanna; Negi, Vir S

2018-02-01

The aim of the study was to look for any association of MTR 2756A>G and MTRR 66A>G gene polymorphisms with clinical phenotype, methotrexate (MTX) treatment response, and MTX-induced adverse events in South Indian Tamil patients with rheumatoid arthritis (RA). A total of 335 patients with RA were investigated. MTR 2756A>G gene polymorphism was analyzed by PCR-RFLP, and MTRR 66A>G SNP was analyzed by TaqMan 5' nuclease assay. The allele frequencies were compared with HapMap groups. MTR 2756G allele was found to be associated with risk of developing RA. The allele frequencies of MTR 2756A>G and MTRR 66A>G SNPs in controls differed significantly when compared with HapMap groups. Neither of the SNPs influenced the MTX treatment outcome and adverse effects. Neither of the SNPs seems to be associated with MTX treatment outcome and adverse events in South Indian Tamil patients with RA.

Fractional model for pharmacokinetics of high dose methotrexate in children with acute lymphoblastic leukaemia

NASA Astrophysics Data System (ADS)

Popović, Jovan K.; Spasić, Dragan T.; Tošić, Jela; Kolarović, Jovanka L.; Malti, Rachid; Mitić, Igor M.; Pilipović, Stevan; Atanacković, Teodor M.

2015-05-01

The aim of this study is to promote a model based on the fractional differential calculus related to the pharmacokinetic individualization of high dose methotrexate treatment in children with acute lymphoblastic leukaemia, especially in high risk patients. We applied two-compartment fractional model on 8 selected cases with the largest number (4-19) of measured concentrations, among 43 pediatric patients received 24-h methotrexate 2-5 g/m2 infusions. The plasma concentrations were determined by fluorescence polarization immunoassay. Our mathematical procedure, designed by combining Post's and Newton's method, was coded in Mathematica 8.0 and performed on Fujicu Celsius M470-2 PC. Experimental data show that most of the measured values of methotrexate were in decreasing order. However, in certain treatments local maximums were detected. On the other hand, integer order compartmental models do not give values which fit well with the observed data. By the use of our model, we obtained better results, since it gives more accurate behavior of the transmission, as well as the local maximums which were recognized in methotrexate monitoring. It follows from our method that an additional test with a small methotrexate dose can be suggested for the fractional system parameter identification and the prediction of a possible pattern with a full dose in the case of high risk patients. A special feature of the fractional model is that it can also recognize and better fit an observed non-monotonic behavior. A new parameter determination procedure can be successfully used.

Pharmacogenomics of Methotrexate Membrane Transport Pathway: Can Clinical Response to Methotrexate in Rheumatoid Arthritis Be Predicted?

PubMed Central

Lima, Aurea; Bernardes, Miguel; Azevedo, Rita; Medeiros, Rui; Seabra, Vitor

2015-01-01

Background: Methotrexate (MTX) is widely used for rheumatoid arthritis (RA) treatment. Single nucleotide polymorphisms (SNPs) could be used as predictors of patients’ therapeutic outcome variability. Therefore, this study aims to evaluate the influence of SNPs in genes encoding for MTX membrane transport proteins in order to predict clinical response to MTX. Methods: Clinicopathological data from 233 RA patients treated with MTX were collected, clinical response defined, and patients genotyped for 23 SNPs. Genotype and haplotype analyses were performed using multivariate methods and a genetic risk index (GRI) for non-response was created. Results: Increased risk for non-response was associated to SLC22A11 rs11231809 T carriers; ABCC1 rs246240 G carriers; ABCC1 rs3784864 G carriers; CGG haplotype for ABCC1 rs35592, rs2074087 and rs3784864; and CGG haplotype for ABCC1 rs35592, rs246240 and rs3784864. GRI demonstrated that patients with Index 3 were 16-fold more likely to be non-responders than those with Index 1. Conclusions: This study revealed that SLC22A11 and ABCC1 may be important to identify those patients who will not benefit from MTX treatment, highlighting the relevance in translating these results to clinical practice. However, further validation by independent studies is needed to develop the field of personalized medicine to predict clinical response to MTX treatment. PMID:26086825

Pharmacogenomics of Methotrexate Membrane Transport Pathway: Can Clinical Response to Methotrexate in Rheumatoid Arthritis Be Predicted?

PubMed

Lima, Aurea; Bernardes, Miguel; Azevedo, Rita; Medeiros, Rui; Seabra, Vítor

2015-06-16

Methotrexate (MTX) is widely used for rheumatoid arthritis (RA) treatment. Single nucleotide polymorphisms (SNPs) could be used as predictors of patients' therapeutic outcome variability. Therefore, this study aims to evaluate the influence of SNPs in genes encoding for MTX membrane transport proteins in order to predict clinical response to MTX. Clinicopathological data from 233 RA patients treated with MTX were collected, clinical response defined, and patients genotyped for 23 SNPs. Genotype and haplotype analyses were performed using multivariate methods and a genetic risk index (GRI) for non-response was created. Increased risk for non-response was associated to SLC22A11 rs11231809 T carriers; ABCC1 rs246240 G carriers; ABCC1 rs3784864 G carriers; CGG haplotype for ABCC1 rs35592, rs2074087 and rs3784864; and CGG haplotype for ABCC1 rs35592, rs246240 and rs3784864. GRI demonstrated that patients with Index 3 were 16-fold more likely to be non-responders than those with Index 1. This study revealed that SLC22A11 and ABCC1 may be important to identify those patients who will not benefit from MTX treatment, highlighting the relevance in translating these results to clinical practice. However, further validation by independent studies is needed to develop the field of personalized medicine to predict clinical response to MTX treatment.

Use of calcium folinate in the management of accidental methotrexate ingestion in two dogs.

PubMed

Lewis, Daniel H; Barfield, Dominic M; Humm, Karen R; Goggs, Robert A

2010-12-15

2 English Pointers were suspected of having consumed toxic doses of methotrexate, a dihydrofolate reductase inhibitor frequently used in human and veterinary chemotherapeutic protocols. Potentially toxic plasma concentrations of methotrexate were detected in both dogs. Results of physical examination, a CBC, blood gas analysis, and serum biochemical analysis were predominantly unremarkable, although 1 dog had mild hyponatremia (1372 mmol/L; reference range, 140 to 153 mmol/L) and mild hypocalcemia (1.03 mmol of ionized calcium/L; reference range, 1.13 to 1.33 mmol of ionized calcium/L). Point-of-care determination of plasma methotrexate concentrations was not available; thus, palliative care was provided. Emesis was induced in both dogs by SC administration of apomorphine, and 3 doses of a suspension of activated charcoal with sorbitol were administered orally over a 6-hour period. Fluid diuresis was initiated in both dogs by administration of a compound sodium lactate solution, and N-acetylcysteine was administered IV to both dogs as a hepatoprotectant. A solution of calcium folinate (also known as leucovorin) was administered IV to both dogs to mitigate the effects of ingested methotrexate. No adverse effects associated with calcium folinate administration were identified, and no clinical or pathological evidence of methotrexate intoxication was detected. IV administration of calcium folinate appeared to prevent the pathological sequelae of methotrexate intoxication without adverse effects. Administration of calcium folinate is recommended for the treatment of dogs with suspected or confirmed methotrexate overdose.

Development and validation of LC-MS/MS assay for the simultaneous determination of methotrexate, 6-mercaptopurine and its active metabolite 6-thioguanine in plasma of children with acute lymphoblastic leukemia: Correlation with genetic polymorphism.

PubMed

Al-Ghobashy, Medhat A; Hassan, Said A; Abdelaziz, Doaa H; Elhosseiny, Noha M; Sabry, Nirmeen A; Attia, Ahmed S; El-Sayed, Manal H

2016-12-01

Individualized therapy is a recent approach aiming to specify dosage regimen for each patient according to its genetic state. Cancer chemotherapy requires continuous monitoring of the plasma concentration levels of active forms of cytotoxic drugs and subsequent dose adjustment. In order to attain optimum therapeutic efficacy, correlation to pharmacogenetics data is crucial. In this study, a specific, accurate and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) has been developed for determination of methotrexate (MTX), 6-mercaptopurine (MP) and its metabolite 6-thioguanine nucleotide (TG) in human plasma. Based on the basic character of the studied compounds, solid phase extraction using a strong cation exchanger was found the optimum approach to achieve good extraction recovery. Chromatographic separation was carried out using RP-HPLC and isocratic elution by acetonitrile: 0.1% aqueous formic acid (85:15v/v) with a flow rate of 0.8mL/min at 40°C. The detection was performed by tandem mass spectrometry in MRM mode via electrospray ionization source in positive ionization mode. Analysis was carried out within 1.0min over a concentration range of 6.25-200.00ng/mL for the studied analytes. Validation was carried out according to FDA guidelines for bioanalytical method validation and satisfactory results were obtained. The applicability of the assay for the monitoring of the MTX, MP and TG and subsequent application to personalized therapy was demonstrated in a clinical study on children with acute lymphoblastic leukemia (ALL). Results confirmed the need for implementation of reliable analysis tools for therapeutic dose adjustment. Copyright © 2016 Elsevier B.V. All rights reserved.

C677T (RS1801133 ) MTHFR gene polymorphism frequency in a colombian population

PubMed Central

Gómez-Gutierrez, Alberto; Gómez, Piedad Elena; Casas-Gomez, Maria Consuelo; Briceño, Ignacio

2015-01-01

Introduction: Abnormal levels of the enzyme methylenetetrahydrofolate reductase (MTHFR) are associated with an increased risk of both cardiovascular and cerebrovascular disease and higher concentrations of homocysteine. Abnormal levels are also related to birth defects, pregnancy complications, cancer and toxicity to methotrexate (MTX). Polymorphisms of MTHFR affect the activity of the enzyme. Genetic associations have been related to treatment efficacy. Objective: To establish the frequency of the C> T polymorphism at nucleotide 677 of the MTHFR gene in a group of Colombian individuals. Methods: Data from pharmacogenetic microarrays that include MTX sensibility-associated polymorphisms were retrospectively collected (Pathway Genomics®). The frequency of the C> T MTHFR rs1801133 marker polymorphism was analyzed. Results: Microarray data from 68 men and 84 women were analyzed. Comparisons of genotype C/C vs. C/T and T/T were statistically significantly different (p= 0.00, p= 0.026, respectively), as were C/T and T / T (p= 0.0001). Conclusions: Results for the C/C and C/T genotypes in a Colombian population are similar to other previously studied groups of healthy subjects. Subjects from our population might be at risk of developing diseases associated with MTHFR polymorphisms and might present toxicity and adverse effects if treated with MTX, which suggests the need to evaluate therapeutic alternatives based on individual pharmacogenetic studies. PMID:26309343

Comparison of enteral and parenteral methods of urine alkalinization in patients receiving high-dose methotrexate.

PubMed

Rouch, Jamie A; Burton, Bradley; Dabb, Alix; Brown, Vicky; Seung, Amy H; Kinsman, Katharine; Holdhoff, Matthias

2017-01-01

Purpose Hyperhydration and urinary alkalinization is implemented with all high-dose (HD)-methotrexate infusions to promote excretion and prevent precipitation of methotrexate in the renal tubules. Our institution utilized enteral alkalinizing agents (sodium bicarbonate tablets and sodium citrate/citric acid solution) to alkalinize the urine of patients receiving HD-methotrexate during a parenteral sodium bicarbonate and sodium acetate shortage. The purpose of this study is to establish the safety and efficacy of the enteral route for urine alkalinization. Methods A single-center, retrospective, cohort study was conducted comparing cycles of HD-methotrexate using enteral alkalinizing agents to parenteral sodium bicarbonate. The primary objective was to compare the time, in hours, from administration of first inpatient administered dose of alkalinizing agent to time of achieving goal urine pH. Secondary objectives evaluated total dose of sodium bicarbonate required to achieve goal urine pH, time from start of urine alkalinizing agent until time of achieving methotrexate level safe for discharge, and toxicities associated with methotrexate and the alkalinizing agents. Results A total of 118 patients were included in this study, equally divided into two cohorts based on parenteral versus enteral routes of administration. No statistical difference was determined between the two cohorts regarding time to goal urine pH (6.5 h versus 7.9 h, P = 0.051) or regarding time to methotrexate level deemed safe for discharge (63.5 h versus 62.5 h, p = 0.835). There were no significant differences in methotrexate-induced toxicities. Conclusion Our study found enteral routes of urine alkalinization to be a viable alternative to the traditional parenteral sodium bicarbonate, especially during parenteral sodium bicarbonate and acetate shortages.

Methotrexate Reduces DNA Integrity in Sperm From Men With Inflammatory Bowel Disease.

PubMed

Ley, Dana; Jones, Jeffrey; Parrish, John; Salih, Sana; Caldera, Freddy; Tirado, Edna; Leader, Benjamin; Saha, Sumona

2018-06-01

There are few data on the effects of methotrexate on reproductive capacity in men with inflammatory bowel diseases (IBDs). We performed a case-control study to determine the effects of methotrexate on sperm quality and genetic integrity. We compared sperm samples from 7 men with IBD who had been exposed to methotrexate for at least 3 months with sperm samples collected from 1912 age-matched men at fertility centers (controls) where sperm parameters would be expected to be worse than those of the general population. Sperm were evaluated by basic semen analysis and advanced sperm integrity testing. In samples from men with IBD, all basic semen analysis parameters were within normal limits. However, these samples had reduced sperm integrity, based on significant increases in levels of DNA fragmentation and damage from oxidative stress compared with controls. Our findings indicate that methotrexate can reduce DNA integrity in sperm and cause damage via oxidative stress. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

More severe toxicity of genetic polymorphisms on MTHFR activity in osteosarcoma patients treated with high-dose methotrexate

PubMed Central

Xie, Lu; Guo, Wei; Yang, Yi; Ji, Tao; Xu, Jie

2018-01-01

5,10-Methylenetrahydrofolate reductase (MTHFR), a key enzyme for folate metabolism, catalyses the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is located at the end of the short arm (1p36.3). Two common non-synonymous variants, the C677T (Ala222Val) and A1298C (Glu429Ala), were mainly described with decreased enzymatic activity and an alteration of intracellular folate distribution. Osteosarcomas are currently treated with high dose of methotrexate (MTX). The decreased enzyme activity of MTHFR theoretically could increase the drug action of MTX and at the same time increase toxic and side effect. Germline variants of C677T and A1298C were studied in 59 osteosarcoma patients, with whom the A1298C is detected with particularly low rate of mutant genotype (N = 1, 0.8%) and could not proceed with statistical calculations. 15 patients were wild type of C677T (CC, 25.4%), 20 were heterozygous mutant genotype (CT, 33.9%) and 24 were homozygous mutant genotype (TT, 40.7%). Patients harboring the TT/CT genotype had the same progression-free survival and tumor necrosis rate in comparison with patients having the CC genotype (P = 0.349 and P = 0.465 respectively). And the C677T polymorphisms had no significant correlation with MTX initial plasma concentration (P = 0.867; r = 0.024) and delayed elimination (P = 0.305; r = −0.136). However patients with mutant genotype of C677T were associated with higher degree of liver toxicity (P = 0.043) and fever reaction of MTX (P = 0.050) while G3/G4 hematologic toxicity were more likely to be noticed with TT than CT/CC (P = 0.095). The study suggests that genetic polymorphism of MTHFR C677T in the MTX metabolic pathway seems to be associated with the trend for more side effects statistically, but has no obvious effect on histologic response and survival. PMID:29545912

Poor early response to methotrexate portends inadequate long-term outcomes in patients with moderate-to-severe psoriasis: Evidence from 2 phase 3 clinical trials.

PubMed

Gordon, Kenneth B; Betts, Keith A; Sundaram, Murali; Signorovitch, James E; Li, Junlong; Xie, Meng; Wu, Eric Q; Okun, Martin M

2017-12-01

Most methotrexate-treated psoriasis patients do not achieve a long-term PASI75 (75% reduction from baseline Psoriasis Area and Severity Index score) response. Indications of nonresponse can be apparent after only 4 weeks of treatment. To develop a prediction rule to identify patients unlikely to respond adequately to methotrexate. Patient-level data from CHAMPION (NCT00235820, N = 110) was used to construct a prediction model for week 16 PASI75 by using patient baseline characteristics and week 4 PASI25. A prediction rule was determined on the basis of the sensitivity and specificity and validated in terms of week 16 PASI75 response in an independent validation sample from trial M10-255 (NCT00679731, N = 163). PASI25 achievement at week 4 (odds ratio = 8.917) was highly predictive of response with methotrexate at week 16. Patients with a predicted response probability <30% were recommended to discontinue methotrexate. The rates of week 16 PASI75 response were 65.8% and 21.1% (P < .001) for patients recommended to continue and discontinue methotrexate, respectively. The CHAMPION trial excluded patients previously treated with biologics, and the M10-255 trial had no restrictions. A prediction rule was developed and validated to identify patients unlikely to respond adequately to methotrexate. The rule indicates that 4 weeks of methotrexate might be sufficient to predict long-term response with limited safety risk. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Methotrexate polyglutamates as a marker of patient compliance and clinical response in psoriasis: a single-centre prospective study.

PubMed

Woolf, R T; West, S L; Arenas-Hernandez, M; Hare, N; Peters van Ton, A M; Lewis, C M; Marinaki, A M; Barker, J N W N; Smith, C H

2012-07-01

Methotrexate is activated by the sequential addition of glutamic acid residues to form methotrexate polyglutamates (MTXPG(1-5)). MTXPG(1-5) inhibit enzymes of the folate-purine-pyrimidine pathways, and longer-chain MTXPG(3-5) species are more active. To determine the pattern of erythrocyte MTXPG(1-5) in patients initiated on oral methotrexate for psoriasis, and to investigate the potential utility of MTXPGs as markers of compliance and/or clinical response. This was a single-centre, prospective study of 55 adult patients with chronic plaque psoriasis initiated on weekly oral methotrexate. Erythrocyte MTXPG(1-5) concentrations were measured (at weeks 4, 8, 12, 24 and 52) using high-performance liquid chromatography. Methotrexate responders achieved ≥ 50% improvement in Psoriasis Area and Severity Index or physician's global score of 'clear'/'nearly clear' at 24 weeks. MTXPG levels were measured in 14-33 patients at each time point. All MTXPG(1-5) species were detected at week 4 of therapy. Steady state for long-chain MTXPG(3-5) and total MTXPG(1-5) was achieved by week 24. MTXPG(3) emerged as the predominant MTXPG species (from week 12 onwards) and reflected overall polyglutamate status (correlating strongly with MTXPG(2-5) , MTXPG(3-5) and MTXPG(4-5) ; R = 0·76-0·95, P < 1·55 × 10(-5)). Age, renal function and sex were not significant determinants of MTXPG(3) concentration. No significant association was identified between MTXPG and adverse events or responder status. This is the first study to demonstrate the prospective accumulation of MTXPG(1-5) in patients with psoriasis. The detection of MTXPGs early in therapy and the establishment of a steady state with continuous treatment may offer measuring of MTXPG as a test to monitor patient compliance with therapy. Larger studies are required to determine the role of MTXPG as a potential biomarker of clinical response. © 2012 The Authors. BJD © 2012 British Association of Dermatologists.

Methotrexate Polyglutamate Monitoring in Patients With Crohn's Disease.

PubMed

Fischer, Monika; Siva, Shivi; Cook, Gwendolyn K; Jones, David R; Fadda, Hala M

2017-05-01

Methotrexate is an efficacious immunosuppressant for induction and maintenance of remission in Crohn's disease. The goal of this pilot study was to determine whether total or individual methotrexate glutamate levels (MTXGlu n ) in red blood cells correlate with disease activity and adverse events in Crohn's disease. A cross-sectional study was undertaken with 12 patients on a stable dose of 25 mg weekly methotrexate (oral or subcutaneous). Clinical disease activity was assessed by the Harvey-Bradshaw Index (HBI), and biologic disease activity was measured by inflammatory markers. Concentrations of individual MTXGlu n levels were measured in red blood cells (RBCs) using high-performance liquid chromatography-mass spectrometry. No association was observed between RBC individual (MTXGlu n ) or total methotrexate glutamate concentrations and clinical disease activity (HBI score) or inflammatory markers or adverse events. Although Crohn's disease patients in remission appeared to generally have higher RBC total longer-chain methotrexate polyglutamate (MTXGlu 3+4+5 ) concentrations compared with those with active disease, a definitive association between RBC MTXGlu 3+4+5 levels and clinical disease activity could not be established. Larger longitudinal studies in patients with diverse disease activity are needed to establish the value of MTXGlu n levels as indicators of treatment efficacy and clinical outcome. © 2016, The American College of Clinical Pharmacology.

Diagnostic performance of transient elastography for detection of methotrexate-induced liver injury using Roenigk classification in Asian patients with psoriasis: a retrospective study.

PubMed

Rongngern, Pasinee; Chularojanamontri, Leena; Wongpraparut, Chanisada; Silpa-Archa, Narumol; Chotiyaputta, Watcharasak; Pongpaibul, Ananya; Charatcharoenwitthaya, Phunchai

2017-07-01

Liver biopsy, the gold standard for monitoring methotrexate-induced liver fibrosis in psoriasis patients, has potential morbidity and mortality. Transient elastography (TE) has been widely used as an alternative non-invasive method. Currently, psoriasis-specific data of TE comparing to Roenigk histopathology is lacking. This retrospective study assessed the diagnostic performance of TE in the detection of methotrexate-induced liver injury and liver fibrosis in Asian psoriasis patients. Risk factors that associated with liver injury by TE and histopathology were also determined. Psoriasis patients who had received methotrexate and undergone both TE and liver biopsy (gold standard) examinations between 2005 and 2016 were enrolled. Ten of 41 patients developed methotrexate-induced liver injury (Roenigk grade ≥3a) and two of them had significant liver fibrosis (Metavir fibrosis stage ≥2). Area under the receiver operating characteristic curve (AUROC = 0.78) indicated that TE was capable of identifying patients with and without liver injury. Using a cut-off TE value of 7.1 kilopascal (kPa), this ultrasound-based elastography yielded 50% sensitivity and 83.9% specificity for detecting methotrexate-induced liver injury and had 50% sensitivity and 76.9% specificity for identifying significant liver fibrosis. A total cumulative dosage of methotrexate, age, gender, metabolic syndrome, and metabolic components were not significantly associated with TE values ≥7.1 kPa and Roenigk grade ≥3a. Thus, using clinical context, laboratory information, and a cut-off TE value of 7.1, TE is an attractable non-invasive tool for identify psoriasis patients who have a low probability of methotrexate-induced liver injury and significant liver fibrosis. Liver biopsy can be reserved for selected patients.

Genetic polymorphisms of enzyme proteins and transporters related to methotrexate response and pharmacokinetics in a Japanese population.

PubMed

Hashiguchi, Masayuki; Shimizu, Mikiko; Hakamata, Jun; Tsuru, Tomomi; Tanaka, Takanori; Suzaki, Midori; Miyawaki, Kumika; Chiyoda, Takeshi; Takeuchi, Osamu; Hiratsuka, Jiro; Irie, Shin; Maruyama, Junya; Mochizuki, Mayumi

2016-01-01

Methotrexate (MTX) is currently the anchor drug widely used worldwide in the treatment of rheumatoid arthritis (RA). However, the therapeutic response to MTX has been shown to vary widely among individuals, genders and ethnic groups. The reason for this has been not clarified but it is considered to be partially due to several mechanisms in the cellular pathway of MTX including single-nucleotide polymorphisms (SNPs). The purpose of this study was to investigate the allelic frequencies in different ethnic and/or population groups in the 10 polymorphisms of enzyme proteins and transporters related to the MTX response and pharmacokinetics including MTHFR, TYMS, RFC1, FPGS, GGH, ABCB1, ABCC2 and ABCG2 in unrelated healthy Japanese adults and patients with RA. Ten polymorphisms, methylenetetrahydrofolate reductase (MTHFR) 1298, thymidylate synthase (TYMS) 3'-UTR, reduced folate carrier 1 (RFC1) 80 and-43, folypolyglutamyl synthase (FPGS) 1994, γ-glutamyl hydrolase (GGH) 452 and-401, the ABC transporters (ABCB1 3435, ABCC2 IVS23 + 56, ABCG2 914) of enzyme proteins and transporters related to MTX response and pharmacokinetics in 299 unrelated healthy Japanese adults and 159 Japanese patients with RA were investigated to clarify their contributions to individual variations in response and safety to MTX and establish personalized MTX therapy. SNPs were evaluated using real-time polymerase chain reaction (PCR). Comparison of allelic frequencies in our study with other ethnic/population groups of healthy adults and RA patients showed significant differences in 10 polymorphisms among healthy adults and 7 among RA patients. Allelic frequencies of MTHFR 1298 C, FPGS 1994A and ABCB1 3435 T were lower in Japanese than in Caucasian populations and those of ABCC2 IVS23 + 56 C and ABCG2 914A were higher in Japanese than in Caucasian/European populations in both healthy adults and RA patients. Allelic frequencies of MTHFR 1298 C, GGH-401 T, ABCB1 3435 T, and ABCG2 914A were higher in healthy Japanese adults than in an African population, and those of RFC1 80A, RFC1-43C and ABCC2 IVS23 + 56 C in healthy Japanese adults were lower than in Africans. However, no significant differences were seen in the distribution of allelic frequencies between healthy Japanese adults and RA patients. The variations in allelic frequencies in different ethnic and/or population groups in healthy adults and RA patients may contribute to individual variations in MTX response and toxicity.

Evaluation of the concomitant use of methotrexate and curcumin on Freund's complete adjuvant-induced arthritis and hematological indices in rats.

PubMed

Banji, David; Pinnapureddy, Jyothi; Banji, Otilia J F; Kumar, A Ranjith; Reddy, K Narsi

2011-09-01

To evaluate the concomitant administration of methotrexate and curcumin for antiarthiritic activity in rats. Arthritis was induced in rats following a single subplantar injection of Freund's complete adjuvant (0.1 ml). Rats were divided into six groups of six animals each. Group I and II were control injected with saline and Freund's complete adjuvant (0.1 ml), respectively. Group III arthritic rats were treated with curcumin (100 mg/kg, i.p.) on alternate days. Group IV received methotrexate (MTX) (2 mg/kg, i.p.) once in a week. Group-V and VI were treated with MTX (1 mg/kg, i.p.) once in a week and after 30 min received curcumin (30 mg/kg and 100 mg/kg, thrice a week, i.p.) from 10(th) to 45(th) days, respectively. Body weight and the paw volume was measured on 9(th), 16(th), 23(rd), 30(th), 37(th), and 45(th) days. Determination of complete blood cell counts, hemoglobin concentration, hematocrit, mean corpuscular volume, and mean corpuscular hemoglobin concentration was determined on the 46(th) day. An improvement in body weight and a significant (P < 0.05) reduction in arthritis was observed with the combination treatment as compared to the positive control. A significant improvement in the hematological profile was also observed in rats treated with curcumin and methotrexate. The study showed a significant anti-arthritic action and protection from hematological toxicity with the combination treatment of methotrexate and curcumin.

Development and validation of a rapid reverse-phase HPLC method for the determination of methotrexate from nanostructured liquid crystalline systems.

PubMed

Zuben, E S Von; Oliveira, A G; Chorilli, M; Scarpa, M V

2018-03-05

A reversed-phase liquid chromatography (RP-LC) method was successfully developed and validated for the determination of methotrexate in nanostructured liquid crystalline systems composed by polyether functional siloxane and silicone polyether copolymer. The LC method was performed on RP C18-ODS column, Agilent Zorbax® (4.6 x 250 mm, 5 μm), maintained at room temperature, with a mobile phase constituted by a mixture of 50 mM ammonium acetate buffer (pH 6.0) and methanol (77:23,v/v) with a flow rate of 1.0 mL/min, using ultraviolet detection at 313 nm. The parameters used in the validation process were linearity, specificity, intra and inter-day precision, accuracy, robustness. The quantitation and detection limits yielded good results. The calibration plot assumed linear behavior from 5.0-150.0 μg. mL-1 (r2 = 0.9999). The methotrexate was subjected to oxidation, acid, base and neutral degradation, photolysis and heat as stress conditions. There were no interfering peaks at or near the retention time of methotrexate. The nanostructured liquid crystalline systems did not interfere with the analysis and the recovery was quantitative. The intra and inter-day assay relative standard deviation were less than 0.20 %. The method developed proved to be simple, sensitive, accurate, precise, reproducible and therefore adequate for routine analysis of methotrexate in nanostructured liquid crystalline systems.

Poor knowledge of methotrexate associated with older age and limited English-language proficiency in a diverse rheumatoid arthritis cohort

PubMed Central

2013-01-01

Introduction Our objective was to determine rheumatoid arthritis (RA) patients’ understanding of methotrexate and assess whether knowledge varies by age, education, English language proficiency, or other disease-related factors. Methods Adults with RA (n = 135) who were enrollees of an observational cohort completed a structured telephone interview in their preferred language between August 2007 and July 2009. All subjects who reported taking methotrexate were asked 11 questions about the medication in addition to demographics, education level, and language proficiency. Primary outcome was a total score below the 50th percentile (considered inadequate methotrexate knowledge). Bivariable and multivariable logistic regressions were performed. Covariates included demographics, language proficiency, education, and disease characteristics. Results Of 135 subjects, 83% were female, with a mean age of 55 ± 14 years. The majority spoke English (64%), followed by 22% Spanish and 14% Cantonese or Mandarin. Limited English language proficiency (LEP) was reported in 42%. Mean methotrexate knowledge score was 5.4 ± 2.6 (range, 0 to 10); 73 (54%) had a score lower than 5 (of 10). Age older than 55, less than high school education, LEP, better function, and biologic use were independently associated with poor knowledge. Conclusions In a diverse RA cohort, overall methotrexate knowledge was poor. Older age and limited proficiency in English were significant correlates of poor knowledge. Identification of language barriers and improved clinician-patient communication around methotrexate dosing and side effects may lead to improved safety and enhanced benefits of this commonly used RA medication. PMID:24432366

Chemotherapy administration directly into the fourth ventricle in a nonhuman primate model.

PubMed

Sandberg, David I; Peet, M Melissa; Johnson, Mark D; Cole, Phaedra; Koru-Sengul, Tulay; Luqman, Ali W

2012-05-01

The authors hypothesized that chemotherapy infusions directly into the fourth ventricle might potentially play a role in treating malignant fourth ventricular tumors. The study tested the safety and pharmacokinetics of short- and long-term infusions of methotrexate into the fourth ventricle in a new nonhuman primate model. Six rhesus monkeys underwent posterior fossa craniectomy and catheter insertion into the fourth ventricle. In Group I (3 animals), catheters were externalized, and lumbar drain catheters were placed simultaneously to assess CSF distribution after short-term methotrexate infusions. In 2 animals, methotrexate (0.5 mg) was infused into the fourth ventricle daily for 5 days. Serial CSF and serum methotrexate levels were measured. The third animal had a postoperative neurological deficit, and the experiment was aborted prior to methotrexate administration. In Group II (3 animals), catheters were connected to a subcutaneously placed port for subsequent long-term methotrexate infusions. In 2 animals, 4 cycles of intraventricular methotrexate, each consisting of 4 daily infusions (0.5 mg), were administered over 8 weeks. The third animal received 3 cycles, and then the experiment was terminated due to self-inflicted wound breakdown. All animals underwent detailed neurological evaluations, MRI, and postmortem histological analysis. No neurological deficits were noted after intraventricular methotrexate infusions. Magnetic resonance images demonstrated catheter placement within the fourth ventricle and no signal changes in the brainstem or cerebellum. Histologically, two Group I animals, one of which did not receive methotrexate, had several small focal areas of brainstem injury. Two Group II animals had a small (≤ 1-mm) focus of axonal degeneration in the midbrain. Intraventricular and meningeal inflammation was noted in 4 animals after methotrexate infusions (one from Group I and all three from Group II). In all Group II animals, inflammation extended minimally into brainstem parenchyma. Serum methotrexate levels were undetectable or negligible in both groups, ranging from 0.00 to 0.06 μmol/L. In Group I, the mean peak methotrexate level in fourth ventricle CSF exceeded that in the lumbar CSF by greater than 10-fold. Statistically significant differences between fourth ventricle and lumbar AUC (area under the concentration-time curve) were detected at peaks (p = 0.04) but not at troughs (p = 0.50) or at all time collection points (p = 0.12). In Group II, peak fourth ventricle CSF methotrexate levels ranged from 84.62 to 167.89 μmol/L (mean 115.53 ± 15.95 μmol/L [SD]). Trough levels ranged from 0.06 to 0.55 μmol/L (mean 0.22 ± 0.13 μmol/L). Methotrexate can be infused into the fourth ventricle in nonhuman primates without clinical or radiographic evidence of injury. Observed inflammatory and other histological changes had no clinical correlate. This approach may have pharmacokinetic advantages over current treatment paradigms. Further experiments are warranted to determine if fourth ventricular chemotherapy infusions may benefit patients with malignant fourth ventricular tumors.

Characterization and analyses of multidrug resistance-associated protein 1 (MRP1/ABCC1) polymorphisms in Chinese population

PubMed Central

Yin, Ji-Ye; Huang, Qiong; Yang, Youyun; Zhang, Jian-Ting; Zhong, Mei-Zuo; Zhou, Hong-Hao; Liu, Zhao-Qian

2009-01-01

Multidrug resistance (MDR) is one of the major obstacles for successful cancer chemotherapy. Over-expression of ATP-binding cassette (ABC) transporters such as MRP1/ABCC1 has been suggested to cause MDR. In this study, we explored the distribution frequencies of four common single nucleotide polymorphisms (SNPs) of MRP1/ABCC1 in a mainland Chinese population and investigated whether these SNPs affect the expression and function of the MRP1/ABCC1. We found that the allelic frequencies of Cys43Ser (128G>C), Thr73Ile (218C>T), Arg723Gln (2168G>A) and Arg1058Gln (3173G>A) in mainland Chinese were 0.5%, 1.4%, 5.8% and 0.5%, respectively. These four SNPs were recreated by site-directed mutagenesis and tested for their effect on MRP1/ABCC1 expression and MDR function in HEK293 and CHO-K1 cells lines. We found that none of these mutations had any effect on MRP1/ABCC1 expression and trafficking, but that Arg723Gln mutation significantly reduced MRP1/ABCC1-mediated resistance to daunorubicin, doxorubicin, etoposide, vinblastine and vincristine. The Cys43Ser mutation did not affect all tested drugs resistance. On the other hand, the Thr73Ile mutation reduced resistance to methotrexate and etoposide while the Arg1058Gln mutation increased the response of two anthracycline drugs and etoposide in HEK293 and CHO-K1 cells as well as vinblastine and methotrexate in CHO-K1 cells. We conclude that the allelic frequency of the Arg723Gln mutation is relatively higher than other SNPs in mainland Chinese population and therefore this mutation significantly reduces MRP1/ABCC1 activity in MDR. PMID:19214144

Thiopurine methyltransferase polymorphisms and mercaptopurine tolerance in Turkish children with acute lymphoblastic leukemia.

PubMed

Albayrak, Meryem; Konyssova, Uljan; Kaya, Zuhre; Gursel, Turkiz; Guntekin, Sezen; Percin, E Ferda; Kocak, Ulker

2011-11-01

Thiopurine methyltransferase (TPMT) enzyme is involved in the metabolism of 6-mercaptopurine (6-MP), a key component of acute lymphoblastic leukemia (ALL) treatment protocols in children. The aims of this study were to investigate the frequency of common genetic polymorphisms associated with low TPMT activity and correlations of polymorphic variants with 6-MP tolerance in a group of Turkish children with ALL. Genotyping for G238C, A719G, and G460A mutations were performed by using NanoChip Technology. Adverse reactions during the first 6 months of maintenance therapy with oral 6-MP and methotrexate were retrospectively analyzed from patient's files. Five (8.6%) of 58 children with ALL had a polymorphic TPMT allele: 4 (3.4%) were heterozygous for TPMT*3A (G460A and A719G), and one (0.9%) was heterozygous for TPMT*3C (A719G). No cases with TPMT*3B (G460A) or TPMT*2 (G238C) variants were identified. Children with TPMT*3A and *3C had significantly lower leukocyte and neutrophil counts and percentage of target 6-MP dosage, and longer periods with ≥grade 2 infections, ≥grade 2 liver toxicity, and chemotherapy interruptions than the children with wild-type TPMT during the first 24 weeks of maintenance therapy. The frequency and distribution of common TPMT polymorphisms in Turkish children with ALL is similar to other Caucasian populations. Polymorphic variants were associated with excessive 6-MP toxicity supporting the suggestion that TPMT genotyping should be performed before institution of 6-MP therapy.

Evaluation of incidence and risk factors for high-dose methotrexate-induced nephrotoxicity.

PubMed

Wiczer, Tracy; Dotson, Emily; Tuten, Amy; Phillips, Gary; Maddocks, Kami

2016-06-01

High-dose methotrexate (doses ≥1 g/m(2)) is a key component of several chemotherapy regimens used to treat patients with leukemia or lymphoma. Despite appropriate precautions with hydration, urine alkalinization, and leucovorin, nephrotoxicity remains a risk which can lead to significant morbidity and mortality. Current reports of risk factors for nephrotoxicity focus on patients with nephrotoxicity with a lack of comparison to those without toxicity. This study aimed to describe the incidence of high-dose methotrexate-induced nephrotoxicity at our institution and determined risk factors for high-dose methotrexate-induced nephrotoxicity by examining characteristics of patients with and without nephrotoxicity. This was a retrospective, single-center, chart review. Adult patients with a diagnosis of leukemia or lymphoma who received high-dose methotrexate were included. Serum creatinine values were used to evaluate nephrotoxicity according to Common Terminology Criteria for Adverse Events criteria v4.03. Data related to the following proposed risk factors were collected: age, sex, body mass index, methotrexate dose, number of high-dose methotrexate exposures, leucovorin administration route, baseline renal function, albumin, hydration status, Clostridium difficile infection, urine pH, and concomitant interacting and nephrotoxic medications. The primary endpoint was evaluated with exact binomial methods and risk factors were identified using multivariable random-effects logistic regression. Final analyses included 140 patients with 432 high-dose methotrexate exposures. There were no differences in baseline demographical characteristics. Fifty-four patients (38.6%) experienced nephrotoxicity of any grade: 27.9% with grade 1, 5.7% with grade 2, 3.6% grade 3, 0% with grade 4, and 1.4% with grade 5 toxicity. More patients in the toxicity group received doses of methotrexate ≥3 g/m(2) (58.3% versus 57.2%, p < 0.001), had an albumin level <3 g/dL (31.9% versus 15.9%, p = 0.04), and received an interacting medication during high-dose methotrexate clearance (44.4% versus 24.7%, p = 0.003). Male gender (OR 2.3, 95% CI: 1.27-4.18, p = 0.006), albumin (OR 0.44, 95% CI: 0.26-0.75, p = 0.002), number of drug interactions (OR 1.60, 95% CI: 1.15-2.21, p = 0.005), and use of furosemide (OR 2.56, 95% CI 1.46-4.48, p = 0.001) were all independent risk factors for the development of nephrotoxicity. Nephrotoxicity is a possible complication of therapy with high-dose methotrexate with most instances comprising grade 1-2 toxicity. Male gender, low albumin, and administration of interacting drugs or furosemide during high-dose methotrexate clearance may predispose patients to nephrotoxicity. © The Author(s) 2015.

Methotrexate

MedlinePlus

... You are here: Home / Vasculitis Treatments / Methotrexate (MTX) Methotrexate (MTX) Methotrexate (MTX) is used to treat forms ... your primary care provider. Frequently Asked Questions Regarding Methotrexate How does MTX work? MTX works by dampening ...

Study of stability of methotrexate in acidic solution spectrofluorimetric determination of methotrexate in pharmaceutical preparations through acid-catalyzed degradation reaction.

PubMed

Sabry, Suzy M; Abdel-Hady, M; Elsayed, M; Fahmy, Osama T; Maher, Hadir M

2003-07-14

Study of the degradation reaction of methotrexate (MTX) in acidic solution was carried out. Optimization of the experimental parameters of MTX acid hydrolysis was investigated. Spectrofluorimetric method for determination of MTX through measurement of its acid-degradation product, 4-amino-4-deoxy-10-methylpteroic acid (AMP), was developed. Stability of the standard solution of MTX prepared in sulfuric acid was discussed in the view of accelerated stability analysis. Two other comparative spectroflourimetric methods based on measuring the fluorescence intensities from either a condensation reaction with acetylacetone-formaldehyde (Hantzsch reaction) or a reaction with fluorescamine were also described. Beer's law validation, accuracy, precision, limits of detection, limits of quantification, and other aspects of analytical merit are presented in the text. The proposed methods were successfully applied for the analysis of MTX in pure drug and tablets dosage form. The sensitivity of the developed methods was favorable, so it was possible to be adopted for determination of MTX in plasma samples for routine use in high-dose MTX therapy.

Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: abridged Cochrane systematic review and network meta-analysis

PubMed Central

Barnabe, Cheryl; Tomlinson, George; Marshall, Deborah; Devoe, Dan; Bombardier, Claire

2016-01-01

Objective To compare methotrexate based disease modifying antirheumatic drug (DMARD) treatments for rheumatoid arthritis in patients naive to or with an inadequate response to methotrexate. Design Systematic review and Bayesian random effects network meta-analysis of trials assessing methotrexate used alone or in combination with other conventional synthetic DMARDs, biologic drugs, or tofacitinib in adult patients with rheumatoid arthritis. Data sources Trials were identified from Medline, Embase, and Central databases from inception to 19 January 2016; abstracts from two major rheumatology meetings from 2009 to 2015; two trial registers; and hand searches of Cochrane reviews. Study selection criteria Randomized or quasi-randomized trials that compared methotrexate with any other DMARD or combination of DMARDs and contributed to the network of evidence between the treatments of interest. Main outcomes American College of Rheumatology (ACR) 50 response (major clinical improvement), radiographic progression, and withdrawals due to adverse events. A comparison between two treatments was considered statistically significant if its credible interval excluded the null effect, indicating >97.5% probability that one treatment was superior. Results 158 trials were included, with between 10 and 53 trials available for each outcome. In methotrexate naive patients, several treatments were statistically superior to oral methotrexate for ACR50 response: sulfasalazine and hydroxychloroquine (“triple therapy”), several biologics (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab), and tofacitinib. The estimated probability of ACR50 response was similar between these treatments (range 56-67%), compared with 41% with methotrexate. Methotrexate combined with adalimumab, etanercept, certolizumab, or infliximab was statistically superior to oral methotrexate for inhibiting radiographic progression, but the estimated mean change over one year with all treatments was less than the minimal clinically important difference of 5 units on the Sharp-van der Heijde scale. Triple therapy had statistically fewer withdrawals due to adverse events than methotrexate plus infliximab. After an inadequate response to methotrexate, several treatments were statistically superior to oral methotrexate for ACR50 response: triple therapy, methotrexate plus hydroxychloroquine, methotrexate plus leflunomide, methotrexate plus intramuscular gold, methotrexate plus most biologics, and methotrexate plus tofacitinib. The probability of response was 61% with triple therapy and ranged widely (27-70%) with other treatments. No treatment was statistically superior to oral methotrexate for inhibiting radiographic progression. Methotrexate plus abatacept had a statistically lower rate of withdrawals due to adverse events than several treatments. Conclusions Triple therapy (methotrexate plus sulfasalazine plus hydroxychloroquine) and most regimens combining biologic DMARDs with methotrexate were effective in controlling disease activity, and all were generally well tolerated in both methotrexate naive and methotrexate exposed patients. PMID:27102806

Studies of formation and efflux of methotrexate polyglutamates with cultured hepatic cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Galivan, J.; Balinska, M.

1983-01-01

Methotrexate polyglutamates are extensively synthesized when cultured hepatocytes and H35 hepatoma cells are exposed to micromolar concentrations of methotrexate. The predominant species found within the cell have from two to four additional gamma-linked glutamate residues. When either cell type containing a mixture of methotrexate and its polyglutamate derivatives is exposed to medium lacking methotrexate, there is a rapid release of methotrexate. This release has a T/sub 1/2/ of 2 to 4 min and is apparently complete within 30 to 60 min. Methotrexate polyglutamates leave the cells much more slowly and appear to do so by two mechanisms. Although cleavage tomore » methotrexate and subsequent efflux appears to be quantitatively the more important pathway, there is also a slow, finite loss of intact methotrexate polyglutamates from cells which exclude trypan blue. The T/sub 1/2/ for the loss of methotrexate polyglutamates by both cell types, when placed in medium lacking methotrexate, is approximately 6 to 8 hr. These results suggest that the polyglutamate derivatives are forms of methotrexate which are as cytotoxic as methotrexate but which offer a potentially greater capacity for cellular destruction because they are retained longer in the tissue.« less

High-performance liquid chromatographic determination of methotrexate, 7-hydroxymethotrexate, 5-methyltetrahydrofolic acid and folinic acid in serum and cerebrospinal fluid.

PubMed

Belz, S; Frickel, C; Wolfrom, C; Nau, H; Henze, G

1994-11-04

A method for the simultaneous determination of the antifolates methotrexate and 7-hydroxymethotrexate as well as the folates 5-methyltetrahydrofolic acid and folinic acid (5-formyltetrahydrofolic acid) in serum and cerebrospinal fluid (CSF) is described. High-performance liquid chromatography with gradient elution and dual detection (ultraviolet absorption and fluorescence) was used to separate and quantitate the analytes. Serum samples containing high levels of the substances of interest and CSF samples were injected directly onto the HPLC column. For determination of low concentrations, serum samples were subjected to a solid-phase extraction method for clean-up and concentration purposes. The determination limits were 10 ng/ml for both antifolates, 100 ng/ml for folinic acid, and 0.1 ng/ml for the physiologically occurring methylated folate which is about 1/100 the serum concentration in healthy children. The suitability of the method for pharmacokinetic monitoring of high-dose methotrexate therapy combined with leucovorin rescue administered to children with acute lymphoblastic leukemia was demonstrated. Minimum values of the serum folate during treatment ranged from 0.2 to 3.1 ng/ml. Even those very low concentrations could be reliably measured.

Methotrexate-loaded porous polymeric adsorbents as oral sustained release formulations.

PubMed

Wang, Xiuyan; Yan, Husheng

2017-09-01

Methotrexate as a model drug with poor aqueous solubility was adsorbed into porous polymeric adsorbents, which was used as oral sustained release formulations. In vitro release assay in simulated gastrointestinal fluids showed that the methotrexate-loaded adsorbents showed distinct sustained release performance. The release rate increased with increase in pore size of the adsorbents. In vivo pharmacokinetic study showed that the maximal plasma methotrexate concentrations after oral administration of free methotrexate and methotrexate-loaded DA201-H (a commercial porous polymeric adsorbent) to rats occurred at 40min and 5h post-dose, respectively; and the plasma concentrations decreased to 22% after 5h for free methotrexate and 44% after 24h for methotrexate-loaded DA201-H, respectively. The load of methotrexate into the porous polymeric adsorbents not only resulted in obvious sustained release, but also enhanced the oral bioavailability of methotrexate. The areas under the curve, AUC 0-24 and AUC 0-inf , for methotrexate-loaded DA201-H increased 3.3 and 7.7 times, respectively, compared to those for free methotrexate. Copyright © 2017 Elsevier B.V. All rights reserved.

Does daily folic acid supplementation reduce methotrexate efficacy?

PubMed

Cline, A; Jorizzo, J L

2017-11-15

Methotrexate is a mainstay treatment for autoimmune and inflammatory conditions in the field of Dermatology. However, in some patients, its use is associated with significant side effects and toxicity. Folate supplementation with either folic acid or folinic acid often mitigates side effects and reduces the incidence of systemic toxicity related to methotrexate. Although the value of methotrexate is clear, debate remains about folate supplementation. There is little agreement about the proper dosing or frequency of folate supplementation as many believe that daily folate supplementation can reduce methotrexate efficacy. Although daily use of folic acid does not appear to affect methotrexate efficacy, dosing of folinic acid close to methotrexate administration may hinder methotrexate efficacy. Therefore, folic acid should be used daily with methotrexate to ameliorate side effects, whereas folinic acid should only be used for methotrexate toxicity.

Effect of infliximab on renal injury due to methotrexate in rat.

PubMed

Kirbas, Aynur; Cure, Medine Cumhur; Kalkan, Yildiray; Cure, Erkan; Tumkaya, Levent; Sahin, Osman Zikrullah; Yuce, Suleyman; Kizilkaya, Bayram; Pergel, Ahmet

2015-05-01

Methotrexate, an antagonist of folic acid used in the treatment of many cancers and inflammatory diseases, is associated with side effects that limit its usage. Infliximab has been reported to have a protective effect against nephrotoxicity induced by some drugs and ischemic reperfusion. We aimed to investigate whether infliximab has a protective effect against methotrexate-induced nephrotoxicity. We administered methotrexate at a dose of 20 mg/kg as a single intraperitoneal injection in 10 rats (methotrexate group). Another group of 10 rats received a single dose of infliximab, 7 mg/kg, intraperitoneally (infliximab group). The methotrexate and infliximab group received a similar single injection of infliximab 72 hours prior to methotrexate injection. After 72 hours a single dose of methotrexate, 20 mg/kg, was administered intraperitoneally. Five days after methotrexate injection, blood samples were collected and the kidney tissues were removed for biochemical and histological examination. The methotrexate group had significantly higher tissue levels of tumor necrosis factor-α (P = .008), interleukin-1β (P = .04), nitric oxide (P < .001), and adenosine deaminase (P < .001) than the methotrexate and infliximab group after the 5-day study. The methotrexate group also had significantly higher total histological scores (P < .001) and carbonic anhydrase-II activity (P < .001) when compared to the methotrexate and infliximab group. Infliximab has a strong protective effect against methotrexate-induced nephrotoxicity by suppressing cytokines release. It may decrease methotrexate-induced nephrotoxicity by regulating carbonic anhydrase-II enzyme activities and slowing down purine metabolism.

Infliximab plus methotrexate is superior to methotrexate alone in the treatment of psoriatic arthritis in methotrexate-naive patients: the RESPOND study

PubMed Central

Baranauskaite, Asta; Raffayová, Helena; Kungurov, NV; Kubanova, Anna; Venalis, Algirdas; Helmle, Laszlo; Srinivasan, Shankar; Nasonov, Evgeny; Vastesaeger, Nathan

2012-01-01

Objective To compare the efficacy and safety of treatment with infliximab plus methotrexate with methotrexate alone in methotrexate-naive patients with active psoriatic arthritis (PsA). Methods In this open-label study, patients 18 years and older with active PsA who were naive to methotrexate and not receiving disease-modifying therapy (N=115) were randomly assigned (1:1) to receive either infliximab (5 mg/kg) at weeks 0, 2, 6 and 14 plus methotrexate (15 mg/week); or methotrexate (15 mg/week) alone. The primary assessment was American College of Rheumatology (ACR) 20 response at week 16. Secondary outcome measures included psoriasis area and severity index (PASI), disease activity score in 28 joints (DAS28) and dactylitis and enthesitis assessments. Results At week 16, 86.3% of patients receiving infliximab plus methotrexate and 66.7% of those receiving methotrexate alone achieved an ACR20 response (p<0.02). Of patients whose baseline PASI was 2.5 or greater, 97.1% receiving infliximab plus methotrexate compared with 54.3% receiving methotrexate alone experienced a 75% or greater improvement in PASI (p<0.0001). Improvements in C-reactive protein levels, DAS28 response and remission rates, dactylitis, fatigue and morning stiffness duration were also significantly greater in the group receiving infliximab. In the infliximab plus methotrexate group, 46% (26/57) had treatment-related adverse events (AE) and two patients had serious AE, compared with 24% with AE (13/54) and no serious AE in the methotrexate-alone group. Conclusions Treatment with infliximab plus methotrexate in methotrexate-naive patients with active PsA demonstrated significantly greater ACR20 response rates and PASI75 improvement compared with methotrexate alone and was generally well tolerated. This trial is registered in the US National Institutes of Health clinicaltrials.gov database, identifier NCT00367237. PMID:21994233

Systematic review and network meta-analysis of the efficacy and safety of tumour necrosis factor inhibitor-methotrexate combination therapy versus triple therapy in rheumatoid arthritis.

PubMed

Fleischmann, Roy; Tongbram, Vanita; van Vollenhoven, Ronald; Tang, Derek H; Chung, James; Collier, David; Urs, Shilpa; Ndirangu, Kerigo; Wells, George; Pope, Janet

2017-01-01

Clinical trials have not consistently demonstrated differences between tumour necrosis factor inhibitor (TNFi) plus methotrexate and triple therapy (methotrexate plus hydroxychloroquine plus sulfasalazine) in rheumatoid arthritis (RA). The study objective was to estimate the efficacy, radiographic benefits, safety and patient-reported outcomes of TNFi-methotrexate versus triple therapy in patients with RA. A systematic review and network meta-analysis (NMA) of randomised controlled trials of TNFi-methotrexate or triple therapy as one of the treatment arms in patients with an inadequate response to or who were naive to methotrexate was conducted. American College of Rheumatology 70% response criteria (ACR70) at 6 months was the prespecified primary endpoint to evaluate depth of response. Data from direct and indirect comparisons between TNFi-methotrexate and triple therapy were pooled and quantitatively analysed using fixed-effects and random-effects Bayesian models. We analysed 33 studies in patients with inadequate response to methotrexate and 19 in patients naive to methotrexate. In inadequate responders, triple therapy was associated with lower odds of achieving ACR70 at 6 months compared with TNFi-methotrexate (OR 0.35, 95% credible interval (CrI) 0.19 to 0.64). Most secondary endpoints tended to favour TNFi-methotrexate in terms of OR direction; however, no clear increased likelihood of achieving these endpoints was observed for either therapy. The odds of infection were lower with triple therapy than with TNFi-methotrexate (OR 0.08, 95% CrI 0.00 to 0.57). There were no differences observed between the two regimens in patients naive to methotrexate. In this NMA, triple therapy was associated with 65% lower odds of achieving ACR70 at 6 months compared with TNFi-methotrexate in patients with inadequate response to methotrexate. Although secondary endpoints numerically favoured TNFi-methotrexate, no clear differences were observed. The odds of infection were greater with TNFi-methotrexate. No differences were observed for patients naive to methotrexate. These results may help inform care of patients who fail methotrexate first-line therapy.

Systematic review and network meta-analysis of the efficacy and safety of tumour necrosis factor inhibitor–methotrexate combination therapy versus triple therapy in rheumatoid arthritis

PubMed Central

Fleischmann, Roy; Tongbram, Vanita; van Vollenhoven, Ronald; Tang, Derek H; Chung, James; Collier, David; Urs, Shilpa; Ndirangu, Kerigo; Wells, George; Pope, Janet

2017-01-01

Objective Clinical trials have not consistently demonstrated differences between tumour necrosis factor inhibitor (TNFi) plus methotrexate and triple therapy (methotrexate plus hydroxychloroquine plus sulfasalazine) in rheumatoid arthritis (RA). The study objective was to estimate the efficacy, radiographic benefits, safety and patient-reported outcomes of TNFi–methotrexate versus triple therapy in patients with RA. Methods A systematic review and network meta-analysis (NMA) of randomised controlled trials of TNFi–methotrexate or triple therapy as one of the treatment arms in patients with an inadequate response to or who were naive to methotrexate was conducted. American College of Rheumatology 70% response criteria (ACR70) at 6 months was the prespecified primary endpoint to evaluate depth of response. Data from direct and indirect comparisons between TNFi–methotrexate and triple therapy were pooled and quantitatively analysed using fixed-effects and random-effects Bayesian models. Results We analysed 33 studies in patients with inadequate response to methotrexate and 19 in patients naive to methotrexate. In inadequate responders, triple therapy was associated with lower odds of achieving ACR70 at 6 months compared with TNFi–methotrexate (OR 0.35, 95% credible interval (CrI) 0.19 to 0.64). Most secondary endpoints tended to favour TNFi–methotrexate in terms of OR direction; however, no clear increased likelihood of achieving these endpoints was observed for either therapy. The odds of infection were lower with triple therapy than with TNFi−methotrexate (OR 0.08, 95% CrI 0.00 to 0.57). There were no differences observed between the two regimens in patients naive to methotrexate. Conclusions In this NMA, triple therapy was associated with 65% lower odds of achieving ACR70 at 6 months compared with TNFi–methotrexate in patients with inadequate response to methotrexate. Although secondary endpoints numerically favoured TNFi–methotrexate, no clear differences were observed. The odds of infection were greater with TNFi–methotrexate. No differences were observed for patients naive to methotrexate. These results may help inform care of patients who fail methotrexate first-line therapy. PMID:28123782

Characteristics of the accumulation of methotrexate polyglutamate derivatives in Ehrlich ascites tumor cells and isolated rat hepatocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fry, D.W.; Gewirtz, D.A.; Yalowich, J.C.

1983-01-01

The intracellular synthesis and retention of polygammaglutamyl derivatives of methotrexate and their interactions with H/sub 2/ folate reductase was evaluated. Methotrexate polyglutamates were detected within 15 minutes in hepatocytes exposed to 1 microM methotrexate, and continued to accumulate for at least 60 minutes producing a large transmembrane gradient. These derivatives appeared to be preferentially retained within the cell. In studies with the Ehrlich ascites tumor accumulation of methotrexate polyglutamates was increased over 5-fold by the addition of 5 mM L-glutamine or L-glutamate and exhibited a positive correlation with the extracellular concentration of methotrexate. When Ehrlich ascites tumor cells were exposedmore » to 10 microM methotrexate and 5 mM L-glutamine intracellular polyglutamates were detected within 10 minutes and their levels increased linearly over 4 hours. As these derivatives accumulated, there was a decline in intracellular methotrexate due at least in part to a replacement of methotrexate on H/sub 2/ folate reductase by polyglutamates and subsequent efflux of the previously bound methotrexate from the cell. When polyglutamate derivatives were in excess of the H/sub 2/ folate reductase binding capacity and extracellular methotrexate removed, methotrexate rapidly exited the cell whereas the majority of its metabolites were retained and eventually saturated the major portion of the enzyme. These studies indicate that (1) intracellular methotrexate is rapidly converted to polygammaglutamyl derivatives, (2) these metabolites effectively compete with methotrexate for binding sites on H/sub 2/ folate reductase, (3) these derivatives are retained within the cell more effectively than methotrexate, and (4) vincristine and probenecid may be potentially useful for selectively increasing methotrexate polyglutamates in tumor cells.« less

Methotrexate and Cytarabine-Loaded Nanocarriers for Multidrug Cancer Therapy. Spectroscopic Study.

PubMed

Pentak, Danuta; Kozik, Violetta; Bąk, Andrzej; Dybał, Paulina; Sochanik, Aleksander; Jampilek, Josef

2016-12-08

Determining the properties of nanoparticles obtained by novel methods and defining the scope of their application as drug carriers has important practical significance. This article presents the pioneering studies concerning high degree incorporation of cytarabine (AraC) and methotrexate (MTX) into liposome vesicles. The main focus of this study were cytarabine-methotrexate-dipalmitoylphosphatidylcholine (DPPC) interactions observed in the gel and fluid phases of DPPC bilayers. The proposed new method of use the Transmittance 2919/2850 ratio presented in our research is sensitive to subtle changes in conformational order resulting from rotations, kinks and bends of the lipid chains. The transition temperatures characterized by Fourier Transform Infrared Spectroscopy (FT-IR) were consistent with the results obtained by Differential Scanning Calorimetry (DSC). Transmission Electron Microscopy (TEM) was used in order to determine the size and shape of the liposomes obtained. The mutual interactions occurring between the drugs studied and the phospholipids were analyzed using the Nuclear Magnetic Resonance (NMR).

Effects of growth hormone plus a hyperproteic diet on methotrexate-induced injury in rat intestines.

PubMed

Ortega, M; Gomez-de-Segura, I A; Vázquez, I; López, J M; de Guevara, C L; De-Miguel, E

2001-01-01

The aim of this study was to determine whether growth hormone treatment reduces injury to the intestinal mucosa induced by methotrexate (MTX). Wistar rats with intestinal injury induced by methotrexate were treated with daily growth hormone, beginning 3 days before MTX treatment until 3 or 4 days after MTX administration. The rats were killed at 3 or 7 days post-MTX administration. The rats were fed with either a normoproteic diet or a hyperproteic diet. Body weight, mortality, bacterial translocation, intestinal morphometry, proliferation and apoptosis and blood somatostatin and IGF-1 were determined. Combined administration of growth hormone and a hyperproteic diet reduces MTX-induced mortality. This effect was accompanied by increased cell proliferation and decreased apoptosis within the crypt. Morphometric data showed complete recovery of the mucosa by day 7 post-MTX administration. These results indicate a synergistic protective action of growth hormone combined with a hyperproteic diet to MTX-induced injury.

Failure rate of single dose methotrexate in managment of ectopic pregnancy.

PubMed

Sendy, Feras; AlShehri, Eman; AlAjmi, Amani; Bamanie, Elham; Appani, Surekha; Shams, Taghreed

2015-01-01

Background. One of the treatment modalities for ectopic pregnancy is methotrexate. The purpose of this study is to identify the failure rate of methotrexate in treating patients with ectopic pregnancy as well as the risk factors leading to treatment failure. Methods. A retrospective chart review of 225 patients who received methotrexate as a primary management option for ectopic pregnancy. Failure of single dose of methotrexate was defined as drop of BHCG level less than or equal to 14% in the seventh day after administration of methotrexate. Results. 225 patients had methotrexate. Most of the patients (151 (67%)) received methotrexate based on the following formula: f 50 mg X body surface area. Single dose of methotrexate was successful in 72% (162/225) of the patients. 28% (63/225) were labeled as failure of single dose of methotrexate because of suboptimal drop in BhCG. 63% (40/63) of failure received a second dose of methotrexate, and 37% (23/63) underwent surgical treatment. Among patient who received initial dose of methotrexate, 71% had moderate or severe pain, and 58% had ectopic mass size of more than 4 cm on ultrasound. Conclusion. Liberal use of medical treatment of ectopic pregnancy results in 71% success rate.

Delayed methotrexate elimination: Incidence, interaction with antacid drugs, and clinical consequences?

PubMed

Ranchon, Florence; Vantard, Nicolas; Henin, Emilie; Bachy, Emmanuel; Sarkozy, Clémentine; Karlin, Lionel; Bouafia-Sauvy, Fadhela; Gouraud, Aurore; Schwiertz, Verane; Bourbon, Estelle; Baudouin, Amandine; Caffin, Anne Gaelle; Vial, Thierry; Salles, Gilles; Rioufol, Catherine

2018-04-01

The aim of this retrospective cohort study was to investigate the incidence of delayed methotrexate elimination in patients treated with high-dose methotrexate (≥1 g/m 2 ) for haematological malignancy and to identify the impact of interacting drugs, especially proton-pump inhibitors (PPIs) and ranitidine. All patients treated with high-dose methotrexate over a 6 year period in the haematology department of the Lyon Sud University Hospital (Hospices Civils de Lyon, France) were included. Potential risk factors for delayed methotrexate elimination were tested in a generalized linear model by univariate analysis: patient age, gender, methotrexate dose, administration of PPI or ranitidine, and concomitant nephrotoxic drugs. A total of 412 cycles of methotrexate were administered to 179 patients. Proton-pump inhibitors were co-administered with methotrexate in 127 cycles and ranitidine in 192 cycles. Ninety-three cycles included no antacid drugs. A total of 918 plasma methotrexate assays were performed. Methotrexate concentrations were checked at 24 hours in 92% of cycles. Delayed methotrexate elimination was observed in 20.9% of cycles. A total of 63 cycles with delayed methotrexate elimination were only identified on plasma methotrexate measures at 72 hours: ie, plasma methotrexate was in the normal range at 24 and 48 hour post injection. Use of PPI/ranitidine or no antacid drugs did not increase risk of delayed elimination, with respectively delayed methotrexate elimination in 20.5%, 21.9%, and 19.4% of cycles (P = .89). Impaired baseline creatinine clearance showed significant association in univariate analysis. Fifteen patients showed grade 1 acute kidney injury, 1 grade 2, 2 grade 3, and none grade 4. For half of these cases, delayed methotrexate elimination was observed and the 2 grade 3 events appeared in patients treated with PPIs. This retrospective study suggests that there is no association between concomitant use of proton-pump inhibitors (pantoprazole and esomeprazole) or ranitidine and delayed methotrexate elimination. Copyright © 2017 John Wiley & Sons, Ltd.

An indirect comparison and cost per responder analysis of adalimumab, methotrexate and apremilast in the treatment of methotrexate-naïve patients with psoriatic arthritis.

PubMed

Betts, Keith A; Griffith, Jenny; Friedman, Alan; Zhou, Zheng-Yi; Signorovitch, James E; Ganguli, Arijit

2016-01-01

Apremilast was recently approved for the treatment of active psoriatic arthritis (PsA). However, no studies compare apremilast with methotrexate or biologic therapies, so its relative comparative efficacy remains unknown. This study compared the response rates and incremental costs per responder associated with methotrexate, apremilast, and biologics for the treatment of active PsA. A systematic literature review was performed to identify phase 3 randomized controlled clinical trials of approved biologics, methotrexate, and apremilast in the methotrexate-naïve PsA population. Using Bayesian methods, a network meta-analysis was conducted to indirectly compare rates of achieving a ≥20% improvement in American College of Rheumatology component scores (ACR20). The number needed to treat (NNT) and the incremental costs per ACR20 responder (2014 US$) relative to placebo were estimated for each of the therapies. Three trials (MIPA for methotrexate, PALACE-4 for apremilast, and ADEPT for adalimumab) met all inclusion criteria. The NNTs relative to placebo were 2.63 for adalimumab, 6.69 for apremilast, and 8.31 for methotrexate. Among methotrexate-naïve PsA patients, the 16 week incremental costs per ACR20 responder were $3622 for methotrexate, $26,316 for adalimumab, and $45,808 for apremilast. The incremental costs per ACR20 responder were $222,488 for apremilast vs. methotrexate. Among methotrexate-naive PsA patients, adalimumab was found to have the lowest NNT for one additional ACR20 response and methotrexate was found to have the lowest incremental costs per ACR20 responder. There was no statistical evidence of greater efficacy for apremilast vs. methotrexate. A head-to-head trial between apremilast and methotrexate is recommended to confirm this finding.

Underestimation of the efficacy, effectiveness, tolerability, and safety of weekly low-dose methotrexate in information presented to physicians and patients.

PubMed

Pincus, T; Furer, V; Sokka, T

2010-01-01

Ten specific examples of the underestimation of the efficacy, effectiveness and tolerability, and overestimation of adverse events of weekly, low-dose methotrexate, administered with folic acid, in treatment of rheumatic diseases are summarised. These examples include: 1) meta-analyses of clinical trials suggest that methotrexate has an efficacy similar to other disease-modifying anti-rheumatic drugs (DMARDs); 2) information in textbooks and websites may overstate adverse events and drug interactions associated with weekly low-dose methotrexate; 3) information presented to patients when filling a prescription for methotrexate understates 'side effects' of RA and overstates those of methotrexate; 4) an admonition to patients to refrain entirely from consumption of alcohol while taking methotrexate may be unnecessary; 5) frequent blood testing in patients who take methotrexate may be overused; 6) eligibility of only a small minority of patients for clinical trials to compare biologic agents and methotrexate; 7) Step-up design in most comparisons of biologic agents with methotrexate includes only patients who had experienced an incomplete response to methotrexate; 8) in parallel design trials, the efficacy of biologic agents is not substantially greater than that of methotrexate; 9) low, inflexible dosage schedules of methotrexate and requirement for withdrawal with minimal liver function abnormalities in many clinical trials may underestimate efficacy, effectiveness, tolerability and safety; 10) interpretation of clinical trial results may overstate the clinical significance of lower radiographic progression in patients treated with biologic agents versus patients treated with methotrexate. More accurate interpretation of information for physicians and other health professionals, as well as patients, concerning use of weekly low-dose methotrexate in contemporary care could improve care and outcomes for patients with RA and other rheumatic diseases.

Lumiracoxib does not affect methotrexate pharmacokinetics in rheumatoid arthritis patients.

PubMed

Hartmann, Stefan N; Rordorf, Christiane M; Milosavljev, Slavica; Branson, Janice M; Chales, Gérard H; Juvin, Robert R; Lafforgue, Pierre; Le Parc, Jean Marie; Tavernier, Christian G; Meyer, Olivier C

2004-10-01

Methotrexate and nonsteroidal antiinflammatory drugs are frequently coadministered in the treatment of rheumatoid arthritis (RA). To evaluate the effect of lumiracoxib, a novel cyclooxygenase-2 selective inhibitor, on methotrexate pharmacokinetics and short-term safety in patients with RA. This multicenter, randomized, double-blind, placebo-controlled crossover study enrolled 18 patients (mean age 49.1 y) with stable RA. Patients were randomized to receive methotrexate 7.5-15 mg orally once weekly plus either lumiracoxib 400 mg/day or placebo for 7 days. Patients then received the other treatment combination for an additional 7 days. Serial blood and urine were collected for 24 hours after the methotrexate dose on day 1 (methotrexate alone) and days 8 and 15 (combination treatment). Plasma methotrexate pharmacokinetics (AUC(0-t), maximum concentration [C(max)], time to C(max)) and methotrexate protein binding were similar for methotrexate alone (108.0 ng.h/mL, 26.7 ng/mL, 1.5 h, and 57.1%, respectively), methotrexate/lumiracoxib (110.2 ng.h/mL, 27.5 ng/mL, 1.0 h, and 53.7%, respectively), and methotrexate/placebo (101.8 ng.h/mL, 22.6 ng/mL, 1.0 h, and 57.0%, respectively). Similarly, no clinically significant difference was found in the urinary excretion of methotrexate. Mean exposure to the 7-OH metabolite was lower when methotrexate was given with lumiracoxib compared with placebo, shown by a reduction in AUC and C(max), although similar amounts of the metabolite were recovered in urine following both lumiracoxib and placebo. Coadministration of methotrexate and lumiracoxib was well tolerated. Lumiracoxib had no significant effect on the pharmacokinetics, protein binding, or urinary excretion of coadministered methotrexate in patients with RA.

Effect of ceftriaxone and cefepime on high-dose methotrexate clearance.

PubMed

Tran, Hieu X; Herrington, Jon D

2016-12-01

Numerous drug interactions with methotrexate have been identified, which can lead to serious life-threatening effects. Up to 90% of methotrexate is excreted unchanged in the urine with primary excretion dependent on organic anion transport in the renal proximal tubule. The two pathways responsible for methotrexate secretion are organic anion transport 1 and primarily organic anion transport 3. Penicillins undergo tubular secretion via organic anion transport, and cephalosporins are believed to also possess a similar risk when administered with methotrexate; however, there are no human studies observing this interaction with cephalosporins and methotrexate. Ceftriaxone undergoes biliary clearance and has low affinity for the same organic anion transports as methotrexate; therefore, ceftriaxone has a low potential to interact with methotrexate. Cefepime is primarily secreted by organic cation transport N2, and also has a low potential to interact with methotrexate. This case report describes the pharmacokinetic effect of concomitant beta-lactam therapy in a patient receiving high-dose methotrexate. © The Author(s) 2015.

Water channel in the binding site of a high affinity anti-methotrexate antibody.

PubMed

Gayda, Susan; Longenecker, Kenton L; Manoj, Sharmila; Judge, Russell A; Saldana, Sylvia C; Ruan, Qiaoqiao; Swift, Kerry M; Tetin, Sergey Y

2014-06-17

In the present study, we report the structure of the free and drug-bound Fab fragment of a high affinity anti-methotrexate antibody and perform a thermodynamic analysis of the binding process. The anti-methotrexate Fab fragment features a remarkably rigid tunnel-like binding site that extends into a water channel serving as a specialized route to move solvent out and into the site upon ligand binding and dissociation. This new finding in antibody structure-function relationships directly relates to the fast association (1 × 10⁷ M⁻¹ s⁻¹) and slow dissociation (4 × 10⁻⁵ s⁻¹) rates determined for mAb ADD056, resulting in a very strong binding with a K(D) ~ 3.6 pM at 20 °C. As follows from the X-ray data analysis, the methotrexate-antibody complex is stabilized by an extended network of hydrogen bonds and stacking interactions. The analysis also shows structural involvement of the CDR H3 in formation of the water channel revealing another important role of this hypervariable region. This suggests a new direction in natural affinity maturation and opens a new possibility in antibody engineering. Methotrexate is a widely used therapeutic agent for many malignant diseases and inflammatory disorders. Unfortunately, it may also interfere with central aspects of metabolism and thereby cause inevitable side effects. Therefore, methotrexate therapy requires careful monitoring of drug blood levels, which is traditionally done by immunoassays. An understanding of the structure-function properties of antibodies selected for drug monitoring substantiates the performance and robustness of such tests.

Failure Rate of Single Dose Methotrexate in Managment of Ectopic Pregnancy

PubMed Central

Sendy, Feras; AlShehri, Eman; AlAjmi, Amani; Bamanie, Elham; Appani, Surekha; Shams, Taghreed

2015-01-01

Background. One of the treatment modalities for ectopic pregnancy is methotrexate. The purpose of this study is to identify the failure rate of methotrexate in treating patients with ectopic pregnancy as well as the risk factors leading to treatment failure. Methods. A retrospective chart review of 225 patients who received methotrexate as a primary management option for ectopic pregnancy. Failure of single dose of methotrexate was defined as drop of BHCG level less than or equal to 14% in the seventh day after administration of methotrexate. Results. 225 patients had methotrexate. Most of the patients (151 (67%)) received methotrexate based on the following formula: f 50 mg X body surface area. Single dose of methotrexate was successful in 72% (162/225) of the patients. 28% (63/225) were labeled as failure of single dose of methotrexate because of suboptimal drop in BhCG. 63% (40/63) of failure received a second dose of methotrexate, and 37% (23/63) underwent surgical treatment. Among patient who received initial dose of methotrexate, 71% had moderate or severe pain, and 58% had ectopic mass size of more than 4 cm on ultrasound. Conclusion. Liberal use of medical treatment of ectopic pregnancy results in 71% success rate. PMID:25861275

Investigating methotrexate toxicity within a randomized double-blinded, placebo-controlled trial: Rationale and design of the Cardiovascular Inflammation Reduction Trial-Adverse Events (CIRT-AE) Study.

PubMed

Sparks, Jeffrey A; Barbhaiya, Medha; Karlson, Elizabeth W; Ritter, Susan Y; Raychaudhuri, Soumya; Corrigan, Cassandra C; Lu, Fengxin; Selhub, Jacob; Chasman, Daniel I; Paynter, Nina P; Ridker, Paul M; Solomon, Daniel H

2017-08-01

The role of low dose methotrexate (LDM) in potential serious toxicities remains unclear despite its common use. Prior observational studies investigating LDM toxicity compared LDM to other active drugs. Prior placebo-controlled clinical trials of LDM in inflammatory conditions were not large enough to investigate toxicity. The Cardiovascular Inflammation Reduction Trial (CIRT) is an ongoing NIH-funded, randomized, double-blind, placebo-controlled trial of LDM in the secondary prevention of cardiovascular disease. We describe here the rationale and design of the CIRT-Adverse Events (CIRT-AE) ancillary study which aims to investigate adverse events within CIRT. CIRT will randomize up to 7000 participants with cardiovascular disease and no systemic rheumatic disease to either LDM (target dose: 15-20mg/week) or placebo for an average follow-up period of 3-5 years; subjects in both treatment arms receive folic acid 1mg daily for 6 days each week. The primary endpoints of CIRT include recurrent cardio vascular events, incident diabetes, and all-cause mortality, and the ancillary CIRT-AE study has been designed to adjudicate other clinically important adverse events including hepatic, gastrointestinal, respiratory, hematologic, infectious, mucocutaneous, oncologic, renal, neurologic, and musculoskeletal outcomes. Methotrexate polyglutamate levels and genome-wide single nucleotide polymorphisms will be examined for association with adverse events. CIRT-AE will comprehensively evaluate potential LDM toxicities among subjects with cardiovascular disease within the context of a large, ongoing, double-blind, placebo-controlled trial. This information may lead to a personalized approach to monitoring LDM in clinical practice. Copyright © 2017 Elsevier Inc. All rights reserved.

Review of the bioanalytical methods for the determination of methotrexate and its metabolites in in vitro, preclinical and clinical studies: Case studies and perspectives.

PubMed

Patel, Harilal; Giri, Poonam; Ghoghari, Ashok; Delvadia, Prashant; Syed, Muzeeb; Srinivas, Nuggehally R

2017-01-01

Methotrexate is an old drug that has found use in several therapeutic areas, such as cancer to treat various malignancies, rheumatoid arthtritis and inflammatory bowel disease. Owing to its structural properties of possessing two carboxylic acid groups and having low native fluorescence, it has provided technical challenges for development of bioanalytical methods. Also, in vivo metabolism leading to circulatory metabolites such as 7-hydroxymethotrexate and 2,4-diamino N 10 -methylpteroic acid, as well as the formation of polyglutamate metabolites intracellularly have added further complexity for the assays in terms of the analytes that need to be quantified in addition to methotrexate. The present review is aimed at providing a concise tabular summary of chromatographic assays with respect to method nuances including assay/chromatographic conditions, key validation parameters and applicable remarks. Several case studies are reviewed under various subheadings to provide the challenges involved in the method development for methotrexate and metabolites. Finally, a discussion section is devoted to overall perspectives obtained from this review. Copyright © 2016 John Wiley & Sons, Ltd.

Methotrexate-induced nausea in the treatment of juvenile idiopathic arthritis.

PubMed

Falvey, Sonja; Shipman, Lauren; Ilowite, Norman; Beukelman, Timothy

2017-06-19

Methotrexate is the most commonly used disease modifying antirheumatic drug in the treatment of juvenile idiopathic arthritis and can be effective in controlling disease in many patients. A significant proportion of patients experience nausea and vomiting induced by methotrexate therapy, which can lead to decreased quality of life and discontinuation of treatment with methotrexate. Many strategies have been employed in attempts to reduce methotrexate-induced nausea, including folate supplementation, switching from oral to subcutaneous methotrexate, anti-emetic therapy, behavioral therapy, and others. Anticipatory nausea can be difficult to treat, making primary prevention of nausea with anti-emetics an attractive approach. Understanding the prevalence and impact of methotrexate-induced nausea, as well as potentially effective interventions, may help maximize the therapeutic benefits of methotrexate.

The role of HCG increment in the 48h prior to methotrexate treatment as a predictor for treatment success.

PubMed

Cohen, Aviad; Almog, Benny; Cohen, Yoni; Bibi, Guy; Rimon, Eli; Levin, Ishai

2017-04-01

To evaluate the role HCG change in the 48h prior to methotrexate treatment as a predictor for treatment success. Medical records of all women who were diagnosed with ectopic pregnancy between January 2001 and June 2013 were reviewed. Four hundred and nine patients received methotrexate due to ectopic pregnancy. The "single dose" methotrexate protocol with 50mg/m 2 was administered to patients with progressing ectopic pregnancy. HCG levels in days 1, 4 and 7 were used to evaluate methotrexate treatment success. The percentage of HCG change in the 48h prior to methotrexate treatment was compared between patients who were successfully treated and those who failed treatment with methotrexate. Single dose methotrexate was successful in 309 patients (75.4%, success group). The medians of HCG change in the 48h prior to methotrexate administration were significantly higher in the "failure group" (21% vs. 4%, p<0.01). In a logistic regression analysis, the of HCG percent increment prior to methotrexate administration was shown to be an independent predictor for treatment outcome. Receiver operator characteristic curve for HCG percent change was 0.751, at a cutoff value of HCG increment <12% the positive predictive value for treatment success reached 86%. Percentage of HCG increment in the 48h prior to methotrexate administration is an independent predictor for methotrexate treatment success. HCG increment <12% prior to methotrexate treatment is a good predictor for treatment success. Copyright © 2017 Elsevier B.V. All rights reserved.

Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial.

PubMed

Fleischmann, Roy; Mysler, Eduardo; Hall, Stephen; Kivitz, Alan J; Moots, Robert J; Luo, Zhen; DeMasi, Ryan; Soma, Koshika; Zhang, Richard; Takiya, Liza; Tatulych, Svitlana; Mojcik, Christopher; Krishnaswami, Sriram; Menon, Sujatha; Smolen, Josef S

2017-07-29

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. The Oral Rheumatoid Arthritis triaL (ORAL) Strategy aimed to assess the comparative efficacy of tofacitinib monotherapy, tofacitinib plus methotrexate, and adalimumab plus methotrexate for the treatment of rheumatoid arthritis in patients with a previous inadequate response to methotrexate. ORAL Strategy was a 1 year, double-blind, phase 3b/4, head-to-head, non-inferiority, randomised controlled trial in patients aged 18 years or older with active rheumatoid arthritis despite methotrexate therapy. Patients were randomly assigned (1:1:1) to receive oral tofacitinib (5 mg twice daily) monotherapy, oral tofacitinib (5 mg twice daily) plus methotrexate, or subcutaneous adalimumab (40 mg every other week) plus methotrexate at 194 centres in 25 countries. Eligible patients received live zoster vaccine at investigators' discretion. The primary endpoint was the proportion of patients who attained an American College of Rheumatology response of at least 50% (ACR50) at month 6 in the full analysis set (patients who were randomly assigned to a group and received at least one dose of the study treatment). Non-inferiority between groups was shown if the lower bound of the 98·34% CI of the difference between comparators was larger than -13·0%. This trial is registered with ClinicalTrials.gov, number NCT02187055. 1146 patients received treatment (384 had tofacitinib monotherapy; 376 had tofacitinib and methotrexate; and 386 had adalimumab and methotrexate). At 6 months, ACR50 response was attained in 147 (38%) of 384 patients with tofacitinib monotherapy, 173 (46%) of 376 patients with tofacitinib and methotrexate, and 169 (44%) of 386 patients with adalimumab and methotrexate. Non-inferiority was declared for tofacitinib and methotrexate versus adalimumab and methotrexate (difference 2% [98·34% CI -6 to 11]) but not for tofacitinib monotherapy versus either adalimumab and methotrexate (-6 [-14 to 3]) or tofacitinib and methotrexate (-8 [-16 to 1]). In total, 23 (6%) of 384 patients receiving tofacitinib monotherapy, 26 (7%) of 376 patients receiving tofacitinib plus methotrexate, and 36 (9%) of 386 patients receiving adalimumab plus methotrexate discontinued due to adverse events. Two (1%) of the 384 patients receiving tofacitinib monotherapy died. No new or unexpected safety issues were reported for either treatment in this study for up to 1 year. Tofacitinib and methotrexate combination therapy was non-inferior to adalimumab and methotrexate combination therapy in the treatment of rheumatoid arthritis in patients with an inadequate response to methotrexate in this trial. Tofacitinib monotherapy was not shown to be non-inferior to either combination. Pfizer Inc. Copyright © 2017 Elsevier Ltd. All rights reserved.

Development and validation of a fast RP-HPLC method for determination of methotrexate entrapment efficiency in polymeric nanocapsules.

PubMed

Sartori, Tatiane; Seigi Murakami, Fabio; Pinheiro Cruz, Ariane; Machado de Campos, Angela

2008-07-01

A rapid and effective isocratic chromatographic procedure is successfully developed to determinate methotrexate (MTX) entrapment efficiency (EE) in polymeric nanocapsules using reversed-phase high-performance liquid chromatography. The method employed a RP-C(18) Shimadzu Shim-pack CLC-ODS (150 mm x 4.6 mm, 5 microm) column with mobile phase constituted by a mixture of water-acetonitrile-tetrahydrofuran (65:30:5 v/v/v; pH 3.0) at a flow rate of 0.8 mL/min. The eluate is monitored with a UV detector set at 313 nm. The parameters used in the validation process are: linearity, specificity, precision, accuracy, and limit of quantitation (LOQ). The linearity is evaluated by a calibration curve in the concentration range of 10-50 microg/mL and presented a correlation coefficient of 0.9998. The polymers (PLA or PLA-PEG), oil, and surfactants used in the nanocapsule formulation did not interfere with analysis and the recovery was quantitative. The intra and inter-day assay relative standard deviation were less than 0.72%. Results are satisfactory, and the method proved to be adequate for the determination of methotrexate in nanocapsules formulations.

Accumulating Evidence for a Drug–Drug Interaction Between Methotrexate and Proton Pump Inhibitors

PubMed Central

Mackey, Ann Corken; Kluetz, Paul; Jappar, Dilara; Korvick, Joyce

2012-01-01

Background. A number of medications are known to interact with methotrexate through various mechanisms. The aim of this article is to apprise practitioners of a new labeling change based on the accumulating evidence for a possible drug–drug interaction between methotrexate (primarily at high doses) and proton pump inhibitors (PPIs). Methods. The U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database of spontaneous adverse event reports and the published literature were searched for cases reporting an interaction between methotrexate and PPIs. Results. A search of the AERS database and existing literature found several individual case reports of drug–drug interactions and three additional supportive studies that suggest potential underlying mechanisms for the interaction. Conclusion. There is evidence to suggest that concomitant use of methotrexate (primarily at high doses) with PPIs such as omeprazole, esomeprazole, and pantoprazole may decrease methotrexate clearance, leading to elevated serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. In several case reports, no methotrexate toxicity was found when a histamine H2 blocker was substituted for a PPI. Based on the reviewed data, the FDA updated the methotrexate label to include the possible drug–drug interaction between high-dose methotrexate and PPIs. Physicians should be alerted to this potential drug–drug interaction in patients receiving concomitant high-dose methotrexate and PPIs. PMID:22477728

Rechallenging With Intrathecal Methotrexate After Developing Subacute Neurotoxicity in Children With Hematologic Malignancies.

PubMed

Badke, Colleen; Fleming, Amy; Iqbal, Asneha; Khilji, Ohmed; Parhas, Sophia; Weinstein, Joanna; Morgan, Elaine; Hijiya, Nobuko

2016-04-01

Methotrexate is associated with neurologic side effects. It is recommended that patients who developed neurotoxicity be rechallenged with methotrexate, but little is known about the safety of this approach. We performed a chart review to identify patients who received high-dose or intrathecal (IT) methotrexate. Twenty-one of 298 patients (7%) experienced neurologic symptoms attributed to methotrexate treatment in the premaintenance phase. Seventeen of these patients were rechallenged with IT methotrexate and 13 (76%) had no further neurotoxic events. No patients rechallenged during maintenance (n = 9) experienced recurrence of neurotoxic events. It is safe to rechallenge with IT methotrexate in maintenance. © 2015 Wiley Periodicals, Inc.

[Munchhausen syndrome by proxy revealed by falsely toxic methotrexate levels].

PubMed

Charfi, Rim; Trabelsi, Sameh; Salouage, Issam; Gaïes, Emna; Jebabli, Nadia; Lakhal, Mohamed; Klouz, Anis

2012-01-01

Methotrexate is an antifolate drug used intravenously at high-dose in acute lymphocytic leukemia (ALL). Therapeutic drug monitoring is required to identify patients at risk of developing toxicity and to control folinic acid rescue. We report a case of Münchausen syndrome by proxy revealed by high and persistent falsely toxic methotrexate plasmatic levels. A 12 year-old child was treated with chemotherapy including methotrexate every 70 days for an ALL. The last methotrexate plasmatic level was 0.15 μmol/L at the 72th hour of the infusion. Then, he was treated by oral rout low-dose methotrexate. Ten days after methotrexate infusion, the patient consulted for asthenia, vomiting and presented a mucositis. Methotrexate plasmatic level was 2323 μmol/L. Renal function was normal. All drugs' intake was stopped. Folinic acid rescue was instituted. Even though there was no clinical sign of toxicity, therapeutic drug monitoring showed persistent high methotrexate plasmatic levels. Investigations eliminated measurement errors and pharmacokinetic problems. A deliberate methotrexate addition in each child blood sample brought by the mother was highly suspected. We confirmed this hypothesis by measuring methotrexate plasmatic levels in three samples: one brought by the mother, the second brought by the child's doctor and the last collected in our laboratory. Methotrexate plasmatic levels were respectively over 10,000 μmol/L (first sample) and lower than 0.02 μmol/L (the two others). The diagnosis of Munchausen's syndrome by proxy revealed by falsely toxic methotrexate plasmatic levels was made and the mother was addressed to the psychiatric department.

Frequency of methotrexate intolerance in rheumatoid arthritis patients using methotrexate intolerance severity score (MISS questionnaire).

PubMed

Fatimah, Nibah; Salim, Babur; Nasim, Amjad; Hussain, Kamran; Gul, Harris; Niazi, Sarah

2016-05-01

The objective of the study was to determine the frequency of methotrexate intolerance in rheumatoid arthritis (RA) patients by applying the methotrexate intolerance severity score (MISS) questionnaire and to see the effect of dose and concomitant use of other disease-modifying antirheumatic drugs (DMARDS) on methotrexate (MTX) intolerance. For the descriptive study, non-probability sampling was carried out in the Female Rheumatology Department of Fauji Foundation Hospital (FFH), Rawalpindi, Pakistan. One hundred and fifty diagnosed cases of RA using oral MTX were selected. The MISS questionnaire embodies five elements: abdominal pain, nausea, vomiting, fatigue and behavioural symptoms. The amplitude of each element was ranked from 0 to 3 being no complaint (0 points), mild (1 point), moderate (2 points) and severe (3 points). A cut-off score of 6 and above ascertained intolerance by the physicians. A total of 33.3 % of the subjects exhibited MTX intolerance according to the MISS questionnaire. Out of which, the most recurring symptom of all was behavioural with a value of 44 % whereas vomiting was least noticeable with a figure of 11 %. About 6.6 % of the women with intolerance were consuming DMARDs in conjunction with MTX. Those using the highest weekly dose of MTX (20 mg) had supreme intolerance with prevalence in 46.2 % of the patients. The frequency of intolerance decreased with a decrease in weekly dose to a minimum of 20 % with 7.5 mg of MTX. MTX intolerance has moderate prevalence in RA patients and if left undetected, the compliance to use of MTX as a first-line therapy will decrease. Methotrexate intolerance is directly proportional to the dose of MTX taken. Also, there is no upstroke seen in intolerance with the use of other disease-modifying agents.

Time dependent inhibition of xanthine oxidase in irradiated solutions of folic acid, aminopterin and methotrexate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Robinson, K.; Pilot, T.F.; Meany, J.E.

1990-01-01

The xanthine oxidase catalyzed oxidation of hypoxanthine was followed by monitoring the formation of uric acid at 290 nm. Inhibition of xanthine oxidase occurs in aqueous solutions of folic acid methotrexate and aminopterin. These compounds are known to dissociate upon exposure to ultraviolet light resulting in the formation of their respective 6-formylpteridine derivatives. The relative rates of dissociation were monitored spectrophotometrically by determining the absorbance of their 2,4-dinitrophenylhydrazine derivatives at 500 nm. When aqueous solutions of folic acid, aminopterin and methotrexate were exposed to uv light, a direct correlation was observed between the concentrations of the 6-formylpteridine derivatives existing inmore » solution and the ability of these solutions to inhibit xanthine oxidase. The relative potency of the respective photolysis products were estimated.« less

Insights on methotrexate in psoriatic disease.

PubMed

Greb, Jacqueline E; Goldminz, Ari M; Gottlieb, Alice B

2016-11-01

The folic acid analogue methotrexate is used as an anti-neoplastic agent and treatment for inflammatory disorders including psoriasis, dermatomyositis, lupus erythematous, sarcoidosis, and systemic sclerosis. Despite the introduction of newer biologic agents, methotrexate remains a first-line systemic therapy for many patients with disorders of chronic inflammation. Here we briefly describe the current clinical evidence for methotrexate use in psoriatic disease, our current understanding of methotrexate's anti-inflammatory properties, and the future role of methotrexate in the treatment of immune mediated disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Cola beverage and delayed elimination of methotrexate

PubMed Central

Santucci, Raoul; Levêque, Dominique; Herbrecht, Raoul

2010-01-01

AIMS To report a case of severe delayed methotrexate elimination attributable to consumption of a cola beverage. METHODS To investigate unexplained low urinary pH in a lymphoma patient treated with high-dose methotrexate. RESULTS Unexpected urinary acidity, despite administration of large amounts of sodium bicarbonate, could be attributed to repeated consumption of a cola beverage. It resulted in a delayed elimination of methotrexate and acute renal failure. Discontinuation of cola drinks, increase in calcium folinate rescue and in sodium bicarbonate allowed satisfactory elimination of methotrexate on day 12 after infusion and recovery from renal impairment without other severe toxicity. No other cause of delay in methotrexate elimination could be identified. CONCLUSIONS Cola beverages have a low pH due to their phosphoric acid content that is excreted by renal route. We recommend patients receiving high dose methotrexate abstain from any cola drink within 24 h before and during methotrexate administration and until complete elimination of the drug. PMID:21545633

Mexican Childhood Acute Lymphoblastic Leukemia: A Pilot Study of the MDR1 and MTHFR Gene Polymorphisms and Their Associations with Clinical Outcomes.

PubMed

Ramírez-Pacheco, Arturo; Moreno-Guerrero, Selene; Alamillo, Ilse; Medina-Sanson, Aurora; Lopez, Briseida; Moreno-Galván, Monica

2016-10-01

Genetic polymorphisms in patients with acute lymphoblastic leukemia (ALL) may influence the toxicity of chemotherapeutic agents. Due to the importance of the transport P-glycoprotein and methylenetetrahydrofolate reductase in the metabolism of chemotherapeutic agents, we analyzed the MDR1 rs1045642 and MTHFR rs1801133 polymorphisms and their associations with clinical outcomes in Mexican childhood ALL patients. A total of 109 patients participated in this study. The clinical evaluation consisted of a physical examination and a laboratory test. Genotyping of MDR1 rs1045642 (3435 C>T) and MTHFR rs1801133 (677 C>T) was performed by polymerase chain reaction/restriction fragment length polymorphism. Statistical analyses were performed using SPSS 14.0. The odds ratios and 95% confidence intervals (CI) were estimated by logistic regression. Individuals who were CC homozygotes at MDR1 rs1045642 had lower risk of having methotrexate plasma concentrations >1 μM and leukopenia grade I (odds ratio [OR] = 0.30; 95% CI = 0.13-0.72 and OR = 0.32; 95% CI = 0.14-0.72, respectively). Patients who were CC homozygotes at MTHFR rs1801133 had a higher risk of developing mucositis (OR = 3.61; 95% CI = 1.42-9.14). MDR1 rs1045642 and MTHFR rs1801133 should be considered as diagnostic candidates for the identification of pediatric patients with a high risk of suffering adverse events during ALL treatment.

Methotrexate in the treatment of penile carcinoma.

PubMed

Sklaroff, R B; Yagoda, A

1980-01-15

Eight patients with epidermoid carcinoma of the penis received methotrexate, five with high-dose methotrexate, 250--1500 mg/m2 with citrovorum rescue Q 2--4 weeks, and three with low-dose methotrexate, 0.5--3.0 mg/kg weekly. Three (38%) patients achieved a complete or partial remission which persisted for 11, 3 and 2 months, respectively. Methotrexate appears to be an active agent in the treatment of advanced penile cancer.

Memantine Protects Rats Treated with Intrathecal Methotrexate from Developing Spatial Memory Deficits

PubMed Central

Cole, Peter D.; Vijayanathan, Veena; Ali, Nafeeza F.; Wagshul, Mark E.; Tanenbaum, Eric J.; Price, Jeremy; Dalal, Vidhi; Gulinello, Maria E.

2014-01-01

Purpose To test whether memantine can prevent methotrexate-induced cognitive deficits in a preclinical model. Experimental Design After noting that methotrexate exposure induces prolonged elevations of the glutamate analog homocysteic acid (HCA) within cerebrospinal fluid, we tested whether intrathecal injection of HCA would produce memory deficits similar to those observed after intrathecal methotrexate. We then tested whether memantine, an antagonist of the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors, could protect animals treated with clinically relevant doses of intrathecal methotrexate against developing memory deficits. Finally, we asked whether memantine affected this pathway beyond inhibiting the NMDA receptor by altering expression of the NMDA receptor or affecting concentrations of HCA or glutamate within the central nervous system. Results Four intrathecal doses of methotrexate induced deficits in spatial memory, persisting at least one month following the final injection. Intrathecal HCA was sufficient to reproduce this deficit. Concurrent administration of memantine during the period of methotrexate exposure was protective, decreasing the incidence of methotrexate-induced spatial memory deficits from 56% to 20% (P < 0.05). Memantine neither altered expression of NMDA receptors within the hippocampus nor blunted the methotrexate-induced increases in glutamate or HCA. Conclusions Excitotoxic glutamate analogs including HCA contribute to cognitive deficits observed after intrathecal methotrexate. Memantine, an NMDA receptor antagonist, reduces the incidence of cognitive deficits in rats treated with intrathecal methotrexate, and may therefore benefit patients with cancer receiving similar treatment. PMID:23833301

Concomitant use of low-dose methotrexate and NSAIDs and the risk of serious adverse events among patients with rheumatoid arthritis.

PubMed

Svanström, Henrik; Lund, Marie; Melbye, Mads; Pasternak, Björn

2018-05-24

Case reports and pharmacokinetic studies have suggested that concomitant use of low-dose methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with increased risk of methotrexate toxicity. This study aimed to investigate the risk of serious adverse events associated with concomitant use of low-dose methotrexate and NSAIDs, compared with use of methotrexate alone, among patients with rheumatoid arthritis. The study was conducted as a register-based cohort study in Denmark, 2004 to 2015, including episodes of concomitant use of methotrexate and NSAIDs (n = 21 536) and control episodes of use of methotrexate alone (n = 21 725). The primary outcome was the composite end point any serious adverse event, including liver toxicity, acute renal failure, and cytopenia. Secondary outcomes were the individual outcome components. Analyses were conducted using proportional-hazards regression, with adjustment using inverse-probability-of-treatment weighting based on propensity scores. During follow-up, 110 cases of the primary outcome occurred during concomitant use of methotrexate and NSAIDs (unadjusted incidence rate 12.1 per 1000 person-years) and 129 during control episodes (11.0 per 1000 person-years). Concomitant use of methotrexate and NSAIDs was associated with a significantly increased risk of any serious adverse event (weighted hazard ratio 1.40; 95% CI, 1.07-1.82). In secondary analyses, concomitant use of methotrexate and NSAIDs was associated with a significantly increased risk of acute renal failure and cytopenia. Concomitant use of low-dose methotrexate and NSAIDs was associated with a significantly increased risk of serious adverse events, expanding on the evidence base for current regulatory recommendations that advocate caution when low-dose methotrexate and NSAID are coprescribed. Copyright © 2018 John Wiley & Sons, Ltd.

Rheumatoid Arthritis Treatment After Methotrexate: The Durability of Triple Therapy Versus Etanercept.

PubMed

Peper, Shana M; Lew, Robert; Mikuls, Ted; Brophy, Mary; Rybin, Denis; Wu, Hongseng; O'Dell, James

2017-10-01

Although it is common for rheumatologists to initiate biologic agents after failure of methotrexate monotherapy in rheumatoid arthritis (RA), ample data support the initial use of combinations of conventional therapies in this clinical scenario. Our study explores the durability of triple therapy (methotrexate, sulfasalazine, and hydroxychloroquine) versus methotrexate-etanercept in RA. RA patients with suboptimal response to methotrexate (n = 353) were randomized to either triple therapy or methotrexate-etanercept therapy in a 48-week, double-blinded, noninferiority trial. Patients without clinical improvement at 24 weeks were switched to the alternative treatment. Of the total, 289 participated in followup. We report treatment durability, Disease Activity Score in 28 joints (DAS28), and other measures during an open-label extension for an additional period up to 72 weeks. Mean ± SD duration of open-label followup was 11 ± 6 months. The likelihood of continuing conventional therapy at 1 year was 78% for triple therapy versus 63% for methotrexate-etanercept, with most treatment changes occurring at the start of followup. More patients changed from methotrexate-etanercept to triple therapy than from triple therapy to methotrexate-etanercept (P = 0.005). DAS28 scores and other disease activity measures were not different for the 2 treatments and were stable during followup. In RA patients with suboptimal methotrexate response randomized to receive triple therapy or methotrexate-etanercept, the former was found to be significantly more durable. Given cost differences and similar outcomes, the variable durability demonstrated provides additional evidence supporting conventional combinations over biologic agent combinations as the first choice after methotrexate inadequate response. © 2017, American College of Rheumatology.

Cola beverage and delayed elimination of methotrexate.

PubMed

Santucci, Raoul; Levêque, Dominique; Herbrecht, Raoul

2010-11-01

To report a case of severe delayed methotrexate elimination attributable to consumption of a cola beverage. To investigate unexplained low urinary pH in a lymphoma patient treated with high-dose methotrexate. Unexpected urinary acidity, despite administration of large amounts of sodium bicarbonate, could be attributed to repeated consumption of a cola beverage. It resulted in a delayed elimination of methotrexate and acute renal failure. Discontinuation of cola drinks, increase in calcium folinate rescue and in sodium bicarbonate allowed satisfactory elimination of methotrexate on day 12 after infusion and recovery from renal impairment without other severe toxicity. No other cause of delay in methotrexate elimination could be identified. Cola beverages have a low pH due to their phosphoric acid content that is excreted by renal route. We recommend patients receiving high dose methotrexate abstain from any cola drink within 24 h before and during methotrexate administration and until complete elimination of the drug. © 2010 The Authors. British Journal of Clinical Pharmacology © 2010 The British Pharmacological Society.

Type I interferons modulate methotrexate resistance in gestational trophoblastic neoplasia.

PubMed

Elias, Kevin M; Harvey, Richard A; Hasselblatt, Kathleen T; Seckl, Michael J; Berkowitz, Ross S

2017-06-01

Resistance to methotrexate is a leading clinical problem in gestational trophoblastic neoplasia (GTN), but there are limited laboratory models for this condition. We created isogenic trophoblastic cell lines resistant to methotrexate and compared these to the parent cell lines using gene expression microarrays and qRT-PCR followed by mechanistic studies using recombinant cytokines, pathway inhibitors, and patient sera. Gene expression microarrays and focused analysis by qRT-PCR revealed methotrexate led to type I interferon upregulation, in particular interferon alpha 2 (IFNA2), and methotrexate resistance was associated with chronic low level increases in type I interferon expression. Recombinant IFNA2 imparted chemosensitive choriocarcinoma cells with partial resistance to methotrexate, while chemoresistant choriocarcinoma cells were uniquely sensitive to fludarabine, a STAT1 inhibitor. In pre-treatment patient sera, IFNA2 levels correlated with subsequent resistance to methotrexate chemotherapy. Methotrexate resistance is influenced by type I interferon signaling with prognostic and therapeutic implications for treating women with GTN. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The effects of a salicylate, ibuprofen, and naproxen on the disposition of methotrexate in patients with rheumatoid arthritis.

PubMed

Tracy, T S; Krohn, K; Jones, D R; Bradley, J D; Hall, S D; Brater, D C

1992-01-01

We have studied the pharmacokinetics of methotrexate in patients with rheumatoid arthritis concurrently treated with choline magnesium trisalicylate, ibuprofen, naproxen, or a non-NSAID analgesic (control treatment). The apparent systemic clearance of methotrexate was significantly reduced by all three treatments. Trisalicylate and ibuprofen both significantly reduced methotrexate renal clearance, but only the trisalicylate significantly displaced methotrexate from protein, increasing the fraction unbound by 28%. These data show that NSAIDs can affect the disposition of methotrexate, possibly increasing the potential for toxicity and necessitating dosage adjustments. However, large inter-subject variability precludes specific dosage recommendations.

The efficacy of methotrexate in the treatment of en coup de sabre (linear morphea subtype).

PubMed

Rattanakaemakorn, Ploysyne; Jorizzo, Joseph L

2018-03-01

En coup de sabre is a rare subtype of linear morphea, located on the forehead or frontoparietal scalp. Systemic treatment of localised morphea with methotrexate has been reported in a few clinical reports. However, there are no case series using methotrexate treatment for En coup de sabre. To evaluate the efficacy and tolerability of methotrexate in the treatment of en coup de sabre linear morphea subtype. A retrospective chart review was performed for paediatric and the adult patients with en coup de sabre evaluated in the Dermatology Clinic at Wake Forest University School of Medicine treated with methotrexate. There were 7 patients who met criteria for inclusion in the study. The mean age at the onset of disease was 11.8 years (ranging from 4 to 38 years). The mean duration of disease before receiving methotrexate therapy was 9.4 months (ranging from 3 to 24 months). Seven (100%) patients improved with methotrexate therapy, in an average of 2 months to disease inactivity, and 16 months to discontinuation of methotrexate. Methotrexate appeared to be an effective and safe therapy for en coup de sabre patients.

Methylenetetrahydrofolate reductase polymorphisms and therapy response in pediatric acute lymphoblastic leukemia.

PubMed

Aplenc, Richard; Thompson, Jennifer; Han, Peggy; La, Mei; Zhao, Huaqing; Lange, Beverly; Rebbeck, Timothy

2005-03-15

A significant portion of patients treated for pediatric acute lymphoblastic leukemia (ALL) relapse. We hypothesized that common polymorphisms with moderate effect sizes and large attributive risks could explain an important fraction of ALL relapses. Methylenetetrahydrofolate reductase (MTHFR) is central to folate metabolism and has two common functional polymorphisms (C677T and A1298G). Methotrexate (MTX), which interrupts folate metabolism, is a mainstay of pediatric ALL therapy. MTX inhibits the synthesis of dTMP needed for DNA replication by blocking the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate by MTHFR. We hypothesized that a deactivating MTHFR allele would increase ALL relapse risk by potentially increasing 5,10-methylenetetrahydrofolate and dTMP, enhancing DNA synthesis and thus opposing MTX. To test this hypothesis, we genotyped 520 patients on the Children's Cancer Study Group ALL study, CCG-1891. The MTHFR C677T variant allele was statistically significantly associated with relapse (chi2 = 4.38, P = 0.036). This association remained significant (hazard ratio = 1.82, P = 0.008), controlling for important covariates, and was more predictive of relapse than other predictors, including day 7 bone marrow response. The MTHFR C677T variant allele was not associated with an increased risk of toxicity or infection. The MTHFR A1298G polymorphism was not associated with altered risks of relapse, toxicity, or infection. Haplotype analysis showed six common haplotypes that did not provide additional information predictive for relapse. These data provide evidence that the MTHFR C677T polymorphism is a common genetic variant conferring a moderate relative risk and a high attributable risk for relapse in pediatric ALL patients.

Methotrexate induces high level of apoptosis in canine lymphoma/leukemia cell lines.

PubMed

Pawlak, Aleksandra; Kutkowska, Justyna; Obmińska-Mrukowicz, Bożena; Rapak, Andrzej

2017-10-01

Methotrexate is an antimetabolite used in the treatment of cancer and non-malignant diseases including rheumatoid arthritis, psoriasis and graft vs. host disease. Combination therapy with methotrexate was successful in the treatment of canine lymphoma, mammary tumor and invasive urinary bladder cancer. Lymphoma, the most common hematopoietic cancer in dogs, and leukemia are sensitive to chemotherapy, which is why methotrexate may be an important treatment option for these diseases. Although methotrexate is already used in veterinary oncology its effects on canine cancer cells has not been tested. The aim of the study was to evaluate for the first time methotrexate concentration-dependent cytotoxicity and its capability of inducing apoptosis in selected canine lymphoma/leukemia cell lines: CLBL-1, GL-1 and CL-1 as a first step before the in vitro development of new therapeutic options with the use of methotrexate. Methotrexate exhibited concentration-dependent inhibitory effect on proliferation of all the examined cell lines with different degree of apoptosis induction. The most methotrexate sensitive cells belonged to CL-1 cell line derived from T cell neoplasia and previously characterized by high resistance to the majority of anticancer drugs used in the therapy of lymphoma/leukemia in dogs. Canine lymphoma and leukemia cell lines are sensitive to methotrexate, and this drug may be useful in effective treatment of canine neoplasms and especially of T-type leukemia/lymphoma. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dermoscopic appearance of an amelanotic mucosal melanoma

PubMed Central

Blum, Andreas; Beck-Zoul, Ulrike; Held, Laura; Haase, Sylvie

2016-01-01

Background Hypomelanotic or amelanotic melanomas are challenging to identify, especially at mucosal sites. The dermoscopic clues to the diagnosis of mucosal melanomas have been reported to be structureless zones with the presence of blue, gray, or white colors. Case A female in her seventies noted a new lesion on the inside of her right labia that first appeared two months prior. Her past medical history was significant for rheumatoid arthritis requiring ongoing treatment with methotrexate for 20 years and adalimumab for 10 years. After no response to two weeks of local treatment for suspected herpes simplex infection, her gynecologist performed a skin biopsy. Based on the histopathological diagnosis of an amelanotic melanoma (Breslow thickness of 1.3 mm) the patient was referred to dermatology for further assessment. Polarized dermoscopy revealed a distinct asymmetric, sharply demarcated homogenous white papule (4 × 5 mm) as well as polymorphous vessels. Conclusion Dermoscopy may aid in the diagnosis of amelanotic mucosal melanomas. Our case revealed a structureless white area and polymorphous vessels. Additional clues to the diagnosis were the advanced age of the patient and the clinical presentation of a new lesion. PMID:27867742

Synergistic activity of curcumin with methotrexate in ameliorating Freund's Complete Adjuvant induced arthritis with reduced hepatotoxicity in experimental animals.

PubMed

Banji, David; Pinnapureddy, Jyothi; Banji, Otilia J F; Saidulu, A; Hayath, Md Sikinder

2011-10-01

Methotrexate is employed in low doses for the treatment of rheumatoid arthritis. One of the major drawbacks with methotrexate is hepatotoxicity resulting in poor compliance of therapy. Curcumin is an extensively used spice possessing both anti-arthritic and hepatoprotective potential. The present study was aimed at investigating the effect of curcumin (30 and 100 mg/kg) in combination with subtherapeutic dose of methotrexate (1 mg/kg) is salvaging hepatotoxicity, oxidative stress and producing synergistic anti-arthritic action with methotrexate. Wistar albino rats were induced with arthritis by subplantar injection of Freund's Complete Adjuvant and pronounced arthritis was seen after 9 days of injection. Groups of animals were treated with subtherapeutic dose of methotrexate followed half an hour later with 30 and 100mg/kg of curcumin from day 9 up to days 45 by intraperitoneal route. Methotrexate treatment in Freund's Complete Adjuvant induced arthritic animals produced elevation in the levels of aminotransferases, alkaline phosphatase, total and direct bilirubin. Enhanced oxidative stress in terms of measured lipid peroxides was observed in the methotrexate treated group. Curcumin significantly circumvented hepatotoxicity induced by methotrexate as evidenced by a change in biochemical markers possibly due to its strong anti-oxidant action. Hepatoprotective potential of curcumin was also confirmed from histological evaluation. Sub-therapeutic dose of methotrexate elicited substantial anti-arthritic action when used in combination with curcumin implying that the latter potentiated its action. Concomitant administration of curcumin with methotrexate was also found to minimize liver damage. Copyright © 2011 Elsevier B.V. All rights reserved.

Insights into the interaction of methotrexate and human serum albumin: A spectroscopic and molecular modeling approach.

PubMed

Cheng, Li-Yang; Fang, Min; Bai, Ai-Min; Ouyang, Yu; Hu, Yan-Jun

2017-08-01

In this study, fluorescence spectroscopy and molecular modeling approaches were employed to investigate the binding of methotrexate to human serum albumin (HSA) under physiological conditions. From the mechanism, it was demonstrated that fluorescence quenching of HSA by methotrexate results from the formation of a methotrexate/HSA complex. Binding parameters calculated using the Stern-Volmer method and the Scatchard method showed that methotrexate binds to HSA with binding affinities in the order 10 4  L·mol -1 . Thermodynamic parameter studies revealed that the binding reaction is spontaneous, and that hydrogen bonds and van der Waals interactions play a major role in the reaction. Site marker competitive displacement experiments and a molecular modeling approach demonstrated that methotrexate binds with appropriate affinity to site I (subdomain IIA) of HSA. Furthermore, we discuss some factors that influence methotrexate binding to HSA. Copyright © 2017 John Wiley & Sons, Ltd.

Sodium alginate inhibits methotrexate-induced gastrointestinal mucositis in rats.

PubMed

Yamamoto, Atsuki; Itoh, Tomokazu; Nasu, Reishi; Kajiwara, Eiji; Nishida, Ryuichi

2013-01-01

Gastrointestinal mucositis is one of the most prevalent side effects of chemotherapy. Methotrexate is a pro-oxidant compound that depletes dihydrofolate pools and is widely used in the treatment of leukemia and other malignancies. Through its effects on normal tissues with high rates of proliferation, methotrexate treatment leads to gastrointestinal mucositis. In rats, methotrexate-induced gastrointestinal mucositis is histologically characterized by crypt loss, callus fusion and atrophy, capillary dilatation, and infiltration of mixed inflammatory cells. The water-soluble dietary fiber sodium alginate (AL-Na) is derived from seaweed and has demonstrated muco-protective and hemostatic effects on upper gastrointestinal ulcers. In the present study, we evaluated the effects of AL-Na on methotrexate-induced small intestinal mucositis in rats. Animals were subcutaneously administered methotrexate at a dosage of 2.5 mg/kg once daily for 3 d. Rats were treated with single oral doses of AL-Na 30 min before and 6 h after methotrexate administration. On the 4th day, small intestines were removed and weighed. Subsequently, tissues were stained with hematoxylin-eosin and bromodeoxyuridine. AL-Na significantly prevented methotrexate-induced small intestinal mucositis. Moreover, AL-Na prevented decreases in red blood cell numbers, hemoglobin levels, and hematocrit levels. These results suggest the potential of AL-Na as a therapy for methotrexate-induced small intestinal mucositis.

PUVA and methotrexate therapy of psoriasis: how closely do dermatology departments follow treatment guidelines? Psoriasis Audit Workgroup of the British Association of Dermatologists.

PubMed

Bilsland, D J; Rhodes, L E; Zaki, I; Wilkinson, S M; McKenna, K E; Handfield-Jones, S E; Williams, R E

1994-08-01

Following publication of treatment guidelines for patients with psoriasis, a six-centre audit was undertaken to assess current therapeutic practice for two second-line treatments, PUVA and methotrexate. The audit consisted of random sampling of casenotes by external auditors from a paired dermatology department, and assessment by questionnaire. One hundred and eight PUVA and 118 methotrexate casenotes were audited. The commonest indications for treatment were: (a) failure of tropical therapy--PUVA (mean 81% of casenotes), methotrexate (84%); (b) repeated hospital admissions--PUVA (16%), methotrexate (25%). For both PUVA and methotrexate, some aspects of treatment were well documented: PUVA--psoralen dosage (91%), response to PUVA (89%), cumulative lifetime UVA dosage (81%); methotrexate--pretreatment assessment of full blood count (91%), urea and electrolytes (85%), liver function tests (84%). For other aspects documentation was less complete: PUVA--no documentation of presence/absence of skin cancer history (66%), note of photoactive drugs (32%); methotrexate--concurrent medication (69%), history of presence/absence of liver disease (36%). Another aspect which was poorly documented in both PUVA and methotrexate notes was whether advice on contraception/fertility had been given. There was no indication in 29 of 32 casenotes of females of child-bearing age receiving PUVA, and 52 of 63 case notes of relevant patients on methotrexate. This project has demonstrated that formal, multicentre audit based on published guidelines is a practical proposition.

Biochemically and histopathologically comparative review of thiamine’s and thiamine pyrophosphate’s oxidative stress effects generated with methotrexate in rat liver

PubMed Central

Demiryilmaz, Ismail; Sener, Ebru; Cetin, Nihal; Altuner, Durdu; Suleyman, Bahadir; Albayrak, Fatih; Akcay, Fatih; Suleyman, Halis

2012-01-01

Summary Background Oxidative liver injury occurring with methotrexate restricts its use in the desired dose. Therefore, whether or not thiamine and thiamine pyrophosphate, whose antioxidant activity is known, have protective effects on oxidative liver injury generated with methotrexate was comparatively researched in rats using biochemical and histopathological approaches. Material/Methods Thiamine pyrophosphate+methotrexate, thiamine+methotrexate, and methotrexate were injected intraperitoneally in rats for 7 days. After this period, all animals’ livers were excised, killing them with high-dose anesthesia, and histopathologic and biochemical investigations were made. Result Biochemical results demonstrated a significant elevation in level of oxidant parameters such as MDA and MPO, and a reduction in antioxidant parameters such as GSH and SOD in the liver tissue of the methotrexate group. Also, the quantity of 8-OHdG/dG, a DNA injury product, was higher in the methotrexate group with high oxidant levels and low antioxidant levels, and the quantity of 8-OHdG/dG was in the thiamine pyrophosphate group with low oxidant levels and high antioxidant levels. In the thiamine and control groups, the 8-OHdG/dG rate was 1.48±0.35 pmol/L (P>0.05) and 0.55±0.1 pmol/L (P<0.0001). Thiamine pyrophosphate significantly decreased blood AST, ALT and LDH, but methotrexate and thiamine did not decrease the blood levels of AST, ALT and LDH. Histopathologically, although centrilobular necrosis, apoptotic bodies and inflammation were monitored in the methotrexate group, the findings in the thiamine pyrophosphate group were almost the same as in the control group. Conclusions Thiamine pyrophosphate was found to be effective in methotrexate hepatotoxicity, but thiamine was ineffective. PMID:23197226

Dexamethasone and High-Dose Methotrexate Improve Outcome for Children and Young Adults With High-Risk B-Acute Lymphoblastic Leukemia: A Report From Children’s Oncology Group Study AALL0232

PubMed Central

Devidas, Meenakshi; Chen, Si; Salzer, Wanda L.; Raetz, Elizabeth A.; Loh, Mignon L.; Mattano, Leonard A.; Cole, Catherine; Eicher, Alisa; Haugan, Maureen; Sorenson, Mark; Heerema, Nyla A.; Carroll, Andrew A.; Gastier-Foster, Julie M.; Borowitz, Michael J.; Wood, Brent L.; Willman, Cheryl L.; Winick, Naomi J.; Hunger, Stephen P.; Carroll, William L.

2016-01-01

Purpose Survival for children and young adults with high-risk B-acute lymphoblastic leukemia has improved significantly, but 20% to 25% of patients are not cured. Children’s Oncology Group study AALL0232 tested two interventions to improve survival. Patients and Methods Between January 2004 and January 2011, AALL0232 enrolled 3,154 participants 1 to 30 years old with newly diagnosed high-risk B-acute lymphoblastic leukemia. By using a 2 × 2 factorial design, 2,914 participants were randomly assigned to receive dexamethasone (14 days) versus prednisone (28 days) during induction and high-dose methotrexate versus Capizzi escalating-dose methotrexate plus pegaspargase during interim maintenance 1. Results Planned interim monitoring showed the superiority of the high-dose methotrexate regimens, which exceeded the predefined boundary and led to cessation of enrollment in January 2011. At that time, participants randomly assigned to high-dose methotrexate during interim maintenance 1 versus those randomly assigned to Capizzi methotrexate had a 5-year event-free survival (EFS) of 82% versus 75.4% (P = .006). Mature final data showed 5-year EFS rates of 79.6% for high-dose methotrexate and 75.2% for Capizzi methotrexate (P = .008). High-dose methotrexate decreased both marrow and CNS recurrences. Patients 1 to 9 years old who received dexamethasone and high-dose methotrexate had a superior outcome compared with those who received the other three regimens (5-year EFS, 91.2% v 83.2%, 80.8%, and 82.1%; P = .015). Older participants derived no benefit from dexamethasone during induction and experienced excess rates of osteonecrosis. Conclusion High-dose methotrexate is superior to Capizzi methotrexate for the treatment of high-risk B-acute lymphoblastic leukemia, with no increase in acute toxicity. Dexamethasone given during induction benefited younger children but provided no benefit and was associated with a higher risk of osteonecrosis among participants 10 years and older. PMID:27114587

Methotrexate and temozolomide versus methotrexate, procarbazine, vincristine, and cytarabine for primary CNS lymphoma in an elderly population: an intergroup ANOCEF-GOELAMS randomised phase 2 trial.

PubMed

Omuro, Antonio; Chinot, Olivier; Taillandier, Luc; Ghesquieres, Hervé; Soussain, Carole; Delwail, Vincent; Lamy, Thierry; Gressin, Rémy; Choquet, Sylvain; Soubeyran, Pierre; Huchet, Aymeri; Benouaich-Amiel, Alexandra; Lebouvier-Sadot, Sophie; Gyan, Emmanuel; Touitou, Valérie; Barrié, Maryline; del Rio, Monica Sierra; Gonzalez-Aguilar, Alberto; Houillier, Caroline; Delgadillo, Daniel; Lacomblez, Lucette; Tanguy, Marie Laure; Hoang-Xuan, Khê

2015-06-01

No standard chemotherapy regimen exists for primary CNS lymphoma, reflecting an absence of randomised studies. We prospectively tested two promising methotrexate-based regimens, one more intensive and a milder regimen, for primary CNS lymphoma in the elderly population, who account for most patients. In this open-label, randomised phase 2 trial, done in 13 French institutions, we enrolled immunocompetent patients who had neuroimaging and histologically confirmed newly diagnosed primary CNS lymphoma, were aged 60 years and older, and had a Karnofsky performance scale score of 40 or more. Participants were stratified by Karnofsky performance scale score (<60 vs ≥60) and treating institution and randomly assigned (1:1) to receive methotrexate (3·5 g/m(2)) with temozolomide (150 mg/m(2)) or methotrexate (3·5 g/m(2)), procarbazine (100 mg/m(2)), vincristine (1·4 mg/m(2)), and cytarabine (3 mg/m(2)). Neither regimen included radiotherapy; both included prophylactic G-CSF and corticosteroids. The primary endpoint was 1-year progression-free survival. Analysis was intent to treat, in a non-comparative phase 2 trial design. This study is registered with ClinicalTrials.gov, number NCT00503594. Between July 16, 2007, and March 25, 2010, 98 patients were enrolled, of whom 95 were randomly assigned and analysed; 48 to methotrexate with temozolomide and 47 to methotrexate, procarbazine, vincristine, and cytarabine. 1-year progression-free survival was 36% (95% CI 22-50) in the methotrexate, procarbazine, vincristine, and cytarabine group and 36% (22-50) in the methotrexate with temozolomide group; median progression-free survival was 9·5 months (95% CI 5·3-13·8) versus 6·1 months (3·8-11·9), respectively. Objective responses were noted in 82% (95% CI 68-92) of patients in the methotrexate, procarbazine, vincristine, and cytarabine group versus 71% (55-84) of patients in the methotrexate with temozolomide group. Median overall survival was 31 months (95% CI 12·2-35·8) in the methotrexate, procarbazine, vincristine, and cytarabine group and 14 months (8·1-28·4) in the methotrexate with temozolomide group. No differences were noted in toxic effects between the two groups. The most common grades 3 and 4 toxicities in both groups were liver dysfunction (21 [4%] in the the methotrexate and temozolomide group and 18 [38%] in the methotrexate, procarbazine, vincristine, and cytarabine group), lymphopenia (14 [29%] and 14 [30%]), and infection (six [13%] and seven [15%]). To date, 33 (69%) patients in the methotrexate and temozolomide group have died, versus 31 (55%) in the methotrexate, procarbazine, vincristine and cytarabine group. Quality-of-life evaluation (QLQ-C30 and BN20) showed improvements in most domains (p=0·01-0·0001) compared with baseline in both groups. Prospective neuropsychological testing showed no evidence of late neurotoxicity. In this study of two different methotrexate-based combination regimens in elderly patients, the efficacy endpoints tended to favour the methotrexate, procarbazine, vincristine, and cytarabine group. Both regimens were associated with similar, moderate toxicity, but quality of life improved with time, suggesting pursuing treatment in these poor prognosis patients is worthwhile. New alternatives are needed to improve response duration in this population. Schering-Plough/Merck and French Government. Copyright © 2015 Elsevier Ltd. All rights reserved.

High Methotrexate Triglutamate Level Is an Independent Predictor of Adverse Effects in Asian Indian Rheumatoid Arthritis Patients-A Preliminary Study.

PubMed

Sandhu, Amit; Dhir, Varun; Bhatnagar, Archana; Dhawan, Veena; Kaur, Jasbinder; Sood, Ankita; Naidu, Shankar; Ahmad, Shabeer; Varma, Neelam; Sharma, Aman; Sharma, Shefali

2017-04-01

It is unclear whether erythrocyte methotrexate polyglutamate levels (MTX-glun) are associated with response or adverse effects to methotrexate in rheumatoid arthritis. This preliminary study evaluated their utility in Asian Indian patients over 24 weeks. Rheumatoid arthritis patients were started on oral methotrexate at a dose of 15 mg/wk, which was escalated to 25 mg by 12 weeks and continued till 24 weeks. Erythrocyte (RBC) MTX-glu1 to MTX-glu5 levels (nmol/L RBC) were determined at 4, 8, 16, and 24 weeks by using reverse-phase high-performance liquid chromatography. Area under the concentration curve (AUC) of MTX-glu1-5, MTX-glu3-5, and MTX-glu3 levels was compared between groups with regards to response and adverse effects. This study included 117 patients with mean (SD) age of 42.7 (±11.9) years and disease duration of 2.0 (1.7) years. Mean (SD) RBC MTX-glu1-5 levels at 4, 8, 16, and 24 weeks were 93 (±29), 129 (±46), 143 (±49), and 159 (±65) nmol/L RBC; the highest individual polyglutamate was MTX-glu3 (40%). There was significant correlation between MTX-glu1-5 (r = 0.38, P < 0.001) and MTX-glu3 (r = 0.49, P < 0.001) with methotrexate dose. There was no significant difference of AUC MTX-glun between responders and nonresponders. However, AUC MTX-glu3 was significantly (P = 0.03) higher in patients with adverse effects. On logistic regression, AUC of MTX-glu3 [odds ratio = 1.004 (95% confidence interval 1.002-1.007)] and methotrexate dose at 24 weeks were independent predictors of adverse effects. In this preliminary study, higher levels of RBC MTX-glu3 were found to be the independent predictors for adverse effects in rheumatoid arthritis patients.

Delivery of Methotrexate and Characterization of Skin Treated by Fabricated PLGA Microneedles and Fractional Ablative Laser.

PubMed

Nguyen, Hiep X; Banga, Ajay K

2018-02-21

This study investigated in vitro transdermal delivery of methotrexate through dermatomed porcine ear and cadaver human skin treated with poly (D,L-lactide-co-glycolide) acid microneedles or fractional ablative laser. PLGA microneedles were fabricated and characterized using scanning electron microscopy and mechanical assessment techniques. The integrity of treated skin was evaluated by rheometer, transepidermal water loss, and skin electrical resistance measurements. Successful skin microporation was demonstrated by dye binding, histology, pore uniformity, confocal laser microscopy, and DermaScan studies. In vitro permeation experiment was performed on Franz diffusion cells to determine drug delivery into and across the skin. Both physical treatments resulted in a considerable decrease in skin resistance and an increase in transepidermal water loss value. The laser-created microchannels were significantly larger than those formed by microneedles (p < 0.05). An effective force of 41.04 ± 18.33 N was required to achieve 100% penetration efficiency of the microneedles. For both porcine ear and human skin, laser ablation provided a significantly higher methotrexate permeability into the receptor chamber and skin layers compared to microneedle poration and untreated skin (p < 0.05). Both fractional ablative laser and polymeric microneedles markedly enhanced in vitro transdermal delivery of methotrexate into and across skin. Graphical Abstract ᅟ.

The use of biochemical responses to assess ecotoxicological effects of Pharmaceutical and Personal Care Products (PPCPs) after injection in the mussel Elliptio complanata.

PubMed

Martín-Díaz, M Laura; Gagné, François; Blaise, Christian

2009-09-01

A biomarker approach was undertaken using the mussel Elliptio complanata to assess the ecotoxicological effects after injection of a range concentration (0-10mM) of three different PPCPs: carbamazepine, caffeine, methotrexate; and an effluent extract (C8) from St. Lawrence wastewaters treatment plant (Montreal, Canada). A battery of biomarkers, involving oxidative stress and genotoxicity responses: glutation-S-transferase (GST), ethoxyresorufin O-deethylase (EROD), dibenzylflourescein dealkylase (DBF), xanthine oxidoreductase (XOR) activities, lipid peroxidation (LPO) and DNA damage were determined in gonad and digestive gland tissues after 48 h of injection. Results showed an induction of the oxidative metabolism with increasing pharmaceutical concentration in those mussels injected with the PPCPs and the effluent extract. Phase I detoxification enzymes were significantly induced (p<0.05), concretely DBF activity was significantly induced after caffeine, carbamazipine and C8 injection; and EROD activity after C8 and methotrexate injection. Oxidative stress induction only lead to lipid peroxidation (p<0.05) in organisms injected with carbamazepine and caffeine and DNA damage in organisms injected with methotrexate (p<0.05). EROD and DBF enzymatic activities have been found to be suitable biomarkers to determine bioavailability of pharmaceuticals. LPO and DNA damage to determine possible associated adverse effects. Nevertheless, their validation in realistic exposure scenarios and under exposure conditions should be performed in future research.

Methotrexate use in allergic contact dermatitis: a retrospective study.

PubMed

Patel, Ashaki; Burns, Erin; Burkemper, Nicole M

2018-03-01

Methotrexate, a folate antimetabolite, is used to treat atopic dermatitis and psoriasis. Although methotrexate's therapeutic efficacy has been noted in the literature, there are few data on the efficacy of methotrexate treatment for allergic contact dermatitis. To evaluate the efficacy and tolerability of methotrexate in treating allergic contact dermatitis at a single institution, and also to assess methotrexate efficacy in patients with chronic, unavoidable allergen exposure. We performed a retrospective chart review of 32 patients diagnosed with allergic contact dermatitis by positive patch test reactions, and who received treatment with methotrexate from November 2010 to November 2014. Demographic and treatment-associated data were collected from electronic medical records. Ten patients were identified as allergen non-avoiders secondary to their occupation, and were subgrouped as such. Seventy-eight per cent (25/32) of patients showed either a partial or a complete response. Methotrexate had a comparable efficacy rate in the allergen non-avoiders subset, at 10 of 10. Of the 32 patients, 23% (5/22) had complete clearance of their dermatitis, and 1/10 of allergen non-avoiders had complete clearance of their dermatitis. Methotrexate is a well-tolerated and effective treatment for allergic contact dermatitis, and shows comparable efficacy to immunomodulatory agents such as cyclosporine and azathioprine, with robust efficacy despite persistent allergen exposure in patients with allergic contact dermatitis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chromatic response of polydiacetylene vesicle induced by the permeation of methotrexate.

PubMed

Shin, Min Jae; Kim, Ye Jin; Kim, Jong-Duk

2015-07-07

The noble vesicular system of polydiacetylene showed a red shift using two types of detecting systems. One of the systems involves the absorption of target materials from the outer side of the vesicle, and the other system involves the permeation through the vesicular layers from within the vesicle. The chromatic mixed vesicles of N-(2-aminoethyl)pentacosa-10,12-diynamide (AEPCDA) and dimethyldioctadecylammonium chloride (DODAC) were fabricated by sonication, followed by polymerization by UV irradiation. The stability of monomeric vesicles was observed to increase with the polymerization of the vesicles. Methotrexate was used as a target material. The polymerized mixed vesicles having a blue color were exposed to a concentration gradient of methotrexate, and a red shift was observed indicating the adsorption of methotrexate on the polydiacetylene bilayer. In order to check the chromatic change by the permeation of methotrexate, we separated the vesicle portion, which contained methotrexate inside the vesicle, and checked chromatic change during the permeation of methotrexate through the vesicle. The red shift apparently indicates the disturbance in the bilayer induced by the permeation of methotrexate. The maximum contrast of color appeared at the equal molar ratio of AEPCDA and DODAC, indicating that the formation of flexible and deformable vesicular layers is important for red shift. Therefore, it is hypothesized that the system can be applicable for the chromatic detection of the permeation of methotrexate through the polydiacetylene layer.

Review of dextromethorphan administration in 18 patients with subacute methotrexate central nervous system toxicity.

PubMed

Afshar, Maryam; Birnbaum, Daniel; Golden, Carla

2014-06-01

The pathogenesis of methotrexate central nervous system toxicity is multifactorial, but it is likely related to central nervous system folate homeostasis. The use of folinate rescue has been described to decrease toxicity in patients who had received intrathecal methotrexate. It has also been described in previous studies that there is an elevated level of homocysteine in plasma and cerebrospinal fluid of patients who had received intrathecal methotrexate. Homocysteine is an N-methyl-D-aspartate receptor agonist. The use of dextromethorphan, noncompetitive N-methyl-D-aspartate receptor receptor antagonist, has been used in the treatment of sudden onset of neurological dysfunction associated with methotrexate toxicity. It remains unclear whether the dextromethorphan impacted the speed of recovery, and its use remains controversial. This study reviews the use of dextromethorphan in the setting of subacute methotrexate central nervous system toxicity. Charts of 18 patients who had sudden onset of neurological impairments after receiving methotrexate and were treated with dextromethorphan were reviewed. The use of dextromethorphan in most of our patients resulted in symptomatic improvement. In this patient population, earlier administration of dextromethorphan resulted in faster improvement of impairments and led to prevention of recurrence of seizure activity induced by methotrexate central nervous system toxicity. Our study provides support for the use of dextromethorphan in patients with subacute methotrexate central nervous system toxicity. Copyright © 2014 Elsevier Inc. All rights reserved.

Ovarian reserve and subsequent ART outcomes following methotrexate therapy for ectopic pregnancy and pregnancy of unknown location

PubMed Central

Hill, Micah J.; Cooper, Janelle C.; Levy, Gary; Alford, Connie; Richter, Kevin S.; DeCherney, Alan H.; Katz, Charles; Levens, Eric D.; Wolff, Erin F.

2013-01-01

Objective It is unclear whether the stimulated state of the ovaries as part of ART results in an increased vulnerability to the effects of methotrexate. The objective of this study was to assess ovarian reserve following methotrexate treatment for ectopic pregnancy or pregnancy of unknown location after ART. Design Retrospective cohort study. Setting Large ART practice. Patients Methotrexate or surgery following ART. Interventions None. Main Outcome Measures Follicle stimulating hormone (FSH), antral follicle count (AFC), and oocyte yield were compared between subjects treated with methotrexate and surgery. Secondary outcomes were clinical pregnancy and live birth. Results There were 153 patients in the methotrexate group and 36 patients in the surgery group. Neither group demonstrated differences in ovarian reserve or oocyte yield comparing before and after treatment values. The change in ovarian reserve and oocyte yield after treatment were similar between the two groups. The number of doses of methotrexate was not correlated with changes in ovarian reserve, indicating no dose-dependent effect. Time between treatment and repeat ART was not correlated with outcomes. Live birth in subsequent cycles was similar in the two groups. Conclusions Ovarian reserve and subsequent ART cycle outcomes were reassuring following methotrexate and surgical management of ectopic pregnancy. An adverse impact of methotrexate was not detected in this large fertility cohort as has been previously described. PMID:24269042

Drug interactions may be important risk factors for methotrexate neurotoxicity, particularly in pediatric leukemia patients.

PubMed

Forster, Victoria J; van Delft, Frederik W; Baird, Susan F; Mair, Shona; Skinner, Roderick; Halsey, Christina

2016-11-01

Methotrexate administration is associated with frequent adverse neurological events during treatment for childhood acute lymphoblastic leukemia. Here, we present evidence to support the role of common drug interactions and low vitamin B 12 levels in potentiating methotrexate neurotoxicity. We review the published evidence and highlight key potential drug interactions as well as present clinical evidence of severe methotrexate neurotoxicity in conjunction with nitrous oxide anesthesia and measurements of vitamin B 12 levels among pediatric leukemia patients during therapy. We describe a very plausible mechanism for methotrexate neurotoxicity in pediatric leukemia patients involving reduction in methionine and consequential disruption of myelin production. We provide evidence that a number of commonly prescribed drugs in pediatric leukemia management interact with the same folate biosynthetic pathways and/or reduce functional vitamin B 12 levels and hence are likely to increase the toxicity of methotrexate in these patients. We also present a brief case study supporting out hypothesis that nitrous oxide contributes to methotrexate neurotoxicity and a nutritional study, showing that vitamin B 12 deficiency is common in pediatric leukemia patients. Use of nitrous oxide in pediatric leukemia patients at the same time as methotrexate use should be avoided especially as many suitable alternative anesthetic agents exist. Clinicians should consider monitoring levels of vitamin B 12 in patients suspected of having methotrexate-induced neurotoxic effects.

Mercaptopurine/Methotrexate Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia: Clinical Facts and Fiction

PubMed Central

Nielsen, Stine N.; Frandsen, Thomas L.; Nersting, Jacob

2014-01-01

The antileukemic mechanisms of 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy are poorly understood, but the benefits of several years of myelosuppressive maintenance therapy for acute lymphoblastic leukemia are well proven. Currently, there is no international consensus on drug dosing. Because of significant interindividual and intraindividual variations in drug disposition and pharmacodynamics, vigorous dose adjustments are needed to obtain a target degree of myelosuppression. As the normal white blood cell counts vary by patients’ ages and ethnicity, and also within age groups, identical white blood cell levels for 2 patients may not reflect the same treatment intensity. Measurements of intracellular levels of cytotoxic metabolites of 6MP and MTX can identify nonadherent patients, but therapeutic target levels remains to be established. A rise in serum aminotransferase levels during maintenance therapy is common and often related to high levels of methylated 6MP metabolites. However, except for episodes of hypoglycemia, serious liver dysfunction is rare, the risk of permanent liver damage is low, and aminotransferase levels usually normalize within a few weeks after discontinuation of therapy. 6MP and MTX dose increments should lead to either leukopenia or a rise in aminotransferases, and if neither is experienced, poor treatment adherence should be considered. The many genetic polymorphisms that determine 6MP and MTX disposition, efficacy, and toxicity have precluded implementation of pharmacogenomics into treatment, the sole exception being dramatic 6MP dose reductions in patients who are homozygous deficient for thiopurine methyltransferase, the enzyme that methylates 6MP and several of its metabolites. In conclusion, maintenance therapy is as important as the more intensive and toxic earlier treatment phases, and often more challenging. Ongoing research address the applicability of drug metabolite measurements for dose adjustments, extensive host genome profiling to understand diversity in treatment efficacy and toxicity, and alternative thiopurine dosing regimens to improve therapy for the individual patient. PMID:24936744

The effect of genotype on methotrexate polyglutamate variability in juvenile idiopathic arthritis and association with drug response.

PubMed

Becker, Mara L; Gaedigk, Roger; van Haandel, Leon; Thomas, Bradley; Lasky, Andrew; Hoeltzel, Mark; Dai, Hongying; Stobaugh, John; Leeder, J Steven

2011-01-01

The response to and toxicity of methotrexate (MTX) are unpredictable in patients with juvenile idiopathic arthritis (JIA). Intracellular polyglutamation of MTX, assessed by measuring concentrations of MTX polyglutamates (MTXGlu), has been demonstrated to be a promising predictor of drug response. Therefore, this study was aimed at investigating the genetic predictors of MTXGlu variability and associations between MTXGlu and drug response in JIA. The study was designed as a single-center cross-sectional analysis of patients with JIA who were receiving stable doses of MTX at a tertiary care children's hospital. After informed consent was obtained from the 104 patients with JIA, blood was withdrawn during routine MTX-screening laboratory testing. Clinical data were collected by chart review. Genotyping for 34 single-nucleotide polymorphisms (SNPs) in 18 genes within the MTX metabolic pathway was performed. An ion-pair chromatographic procedure with mass spectrometric detection was used to measure MTXGlu1-7. Analysis and genotyping of MTXGlu was completed in the 104 patients. K-means clustering resulted in 3 distinct patterns of MTX polyglutamation. Cluster 1 had low red blood cell (RBC) MTXGlu concentrations, cluster 2 had moderately high RBC MTXGlu1+2 concentrations, and cluster 3 had high concentrations of MTXGlu, specifically MTXGlu3-5. SNPs in the purine and pyrimidine synthesis pathways, as well as the adenosine pathway, were significantly associated with cluster subtype. The cluster with high concentrations of MTXGlu3-5 was associated with elevated liver enzyme levels on liver function tests (LFTs), and there were higher concentrations of MTXGlu3-5 in children who reported gastrointestinal side effects and had abnormal findings on LFTs. No association was noted between MTXGlu and active arthritis. MTXGlu remains a potentially useful tool for determining outcomes in patients with JIA being treated with MTX. The genetic predictors of MTXGlu variability may also contribute to a better understanding of the intracellular biotransformation of MTX in these patients. Copyright © 2011 by the American College of Rheumatology.

Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children

DOE Office of Scientific and Technical Information (OSTI.GOV)

Freeman, A.I.; Weinberg, V.; Brecher, M.L.

1983-03-03

The authors compared two regimens with respect to their ability to prolong disease-free survival in 506 children and adolescents with acute lymphocytic leukemia. All responders to induction therapy were randomized to treatment with 2400 rad of cranial irradiation plus intrathecal methotrexate or to treatment with intermediate-dose methotrexate plus intrathecal methotrexate, as prophylaxis for involvement of the central nervous system and other sanctuary areas. Complete responders were stratified into either standard-risk or increased-risk groups on the basis of age and white-cell count at presentation. Among patients with standard risk, hematologic relapses occurred in 9 of 117 given methotrexate and 24 ofmore » 120 given irradiation. The rate of central-nervous-system relapse was higher in the methotrexate group (23 of 117) than in the irradiation group. Among patients with increased risk, radiation offered greater protection to the central nervous system than methotrexate; there was no difference in the rate of hematologic relapse. Methotrexate offered better protection against systemic relapse in standard-risk patients and better protection against testicular relapse overall, but it offered less protection against relapses in the central nervous system than cranial irradiation.« less

The 46 kDa dimeric protein from Variovorax paradoxus shows faster methotrexate degrading activity in its nanoform compare to the native enzyme.

PubMed

Bayineni, Venkata Krishna; Venkatesh, Krishna; Sahu, Chandan Kumar; Kadeppagari, Ravi-Kumar

2016-04-01

Methotrexate degrading enzymes are required to overcome the toxicity of the methotrexate while treating the cancer. The enzyme from Variovorax paradoxus converts the methotrexate in to non toxic products. Methotrexate degrading enzyme from V. paradoxus is a dimeric protein with a molecular mass of 46 kDa and it acts on casein and gelatin. This enzyme is optimally active at pH 7.5 and 40°C and nanoparticles of this enzyme were prepared by desolvation-crosslinking method. Enzyme nanoparticles could degrade methotrexate faster than the native enzyme and they show lower Km compare to the native enzyme. Enzyme nanoparticles show better thermostability and they were stable for much longer time in the serum compare to the native enzyme. Enzyme nanoparticles show better functionality than the native enzyme while clearing the methotrexate added to the serum suggesting their advantage over the native enzyme for the therapeutic and biotechnological applications. Copyright © 2016 Elsevier Inc. All rights reserved.

Methotrexate-induced mucositis in acute leukemia patients is not associated with the MTHFR 677T allele in Mexico.

PubMed

Ruiz-Argüelles, Guillermo J; Coconi-Linares, Lucia Nancy; Garcés-Eisele, Javier; Reyes-Núñez, Virginia

2007-10-01

Methylenetetrahydrofolate reductase (MTHFR) has two common variants with reduced activity due to polymorphisms at nucleotides 677 and 1298. Both affect folate metabolism and thus remethylation of homocysteine, but are also thought to affect nucleotide synthesis and DNA methylation. Methotrexate (MTX), which interrupts folate metabolism, is used in the treatment of a variety of diseases including acute lymphoblastic leukemia (ALL), but exerts in some patients toxic effects on fast dividing tissues such as mucosal epithelia. The enhanced toxicity may be due to cooperative effects between MTX and MTHFR variants. Accordingly, it has been reported that carrying the 677T allele of the MTHFR is a risk factor for MTX-associated mucositis. As in the Mexican population, which is characterized by a high prevalence of the 677T MTHFR variant, several of its commonly associated defects have not been observed, we investigated the relationship between MTX toxicity and the 677T allele. Out of 28 patients with ALL (CC: 2, CT: 10, TT: 16), 16 had episodes of MTX-associated mucositis (CC: 0, CT: 6, TT: 10). Neither at the gene level nor at the genotype level was a significant association with mucositis found. It may be postulated that the risk of higher MTX toxicity in patients with decreased MTHFR activity could be neutralized by the normally folate rich diet in Mexico.

An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

PubMed

Warren, Richard B; Mrowietz, Ulrich; von Kiedrowski, Ralph; Niesmann, Johannes; Wilsmann-Theis, Dagmar; Ghoreschi, Kamran; Zschocke, Ina; Falk, Thomas M; Blödorn-Schlicht, Norbert; Reich, Kristian

2017-02-04

Methotrexate is one of the most commonly used systemic drugs for the treatment of moderate to severe psoriasis; however, high-quality evidence for its use is sparse and limited to use of oral dosing. We aimed to assess the effect of an intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis. We did this prospective, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial (METOP) at 16 sites in Germany, France, the Netherlands, and the UK. Eligible patients were aged 18 years or older, had a diagnosis of chronic plaque psoriasis for at least 6 months before baseline, had currently moderate to severe disease, and were methotrexate treatment-naive. Participants were randomly assigned (3:1), via a computer-generated random number sequence integrated into an electronic data capture system, to receive either methotrexate at a starting dose of 17·5 mg/week or placebo for the first 16 weeks, followed by methotrexate treatment of all patients up to 52 weeks (methotrexate-methotrexate vs placebo-methotrexate groups). Dose escalation to 22·5 mg/week was allowed after 8 weeks of methotrexate treatment if patients had not achieved at least a 50% reduction in baseline Psoriasis Area and Severity Index score (PASI), with corresponding volume increases in placebo injections. Treatment was combined with folic acid 5 mg/week. Group allocation was concealed from participants and investigators from the time of randomisation until an interim database lock at week 16, and was open label from week 16 onwards, with no masking of participants or investigators. The primary efficacy endpoint was a 75% reduction in PASI score (PASI 75) from baseline to week 16. We did analysis by modified intention to treat, with non-responder imputation. This study is registered with EudraCT, number 2012-002716-10. Between Feb 22, 2013, and May 13, 2015, we randomly assigned 120 patients to receive methotrexate (n=91) or placebo (n=29). At week 16, a PASI 75 response was achieved in 37 (41%) patients in the methotrexate group compared with three (10%) patients in the placebo group (relative risk 3·93, 95% CI 1·31-11·81; p=0·0026). Subcutaneous methotrexate was generally well tolerated; no patients died or had serious infections, malignancies, or major adverse cardiovascular events. Serious adverse events were recorded in three (3%) patients who received methotrexate for the full 52 week treatment period. Our findings show a favourable 52 week risk-benefit profile of subcutaneous methotrexate in patients with psoriasis. The route of administration and the intensified dosing schedule should be considered when methotrexate is used in this patient group. Medac. Copyright © 2017 Elsevier Ltd. All rights reserved.

Methotrexate and Pregnancy

MedlinePlus

... methotrexate to draw firm conclusions. One 2009 review paper reported no increase in miscarriage or birth defect ... methotrexate in the first trimester. While reassuring, this paper does not mean there is no risk for ...

Pneumocystis jirovecii pneumonia induced by low-dose methotrexate in a patient with chronic urticaria.

PubMed

Wang, Sheng-Huei; Tang, Shih-En; Li, Yu-Huei; Wei, Kuang-Yu; Chang, Chan-Yuan

2017-01-01

Methotrexate has immunosuppressive effects and is administered for refractory chronic urticaria. We present a case of Pneumocystis jirovecii pneumonia in a patient with refractory chronic urticaria managed by low-dose weekly methotrexate treatment (total cumulative dose 195mg). Our study highlights the importance of providing prompt diagnosis and treatment of Pneumocystis jirovecii pneumonia in patients with chronic urticaria under methotrexate therapy.

Methotrexate Is a JAK/STAT Pathway Inhibitor

PubMed Central

Thomas, Sally; Fisher, Katherine H.; Snowden, John A.; Danson, Sarah J.; Brown, Stephen; Zeidler, Martin P.

2015-01-01

Background The JAK/STAT pathway transduces signals from multiple cytokines and controls haematopoiesis, immunity and inflammation. In addition, pathological activation is seen in multiple malignancies including the myeloproliferative neoplasms (MPNs). Given this, drug development efforts have targeted the pathway with JAK inhibitors such as ruxolitinib. Although effective, high costs and side effects have limited its adoption. Thus, a need for effective low cost treatments remains. Methods & Findings We used the low-complexity Drosophila melanogaster pathway to screen for small molecules that modulate JAK/STAT signalling. This screen identified methotrexate and the closely related aminopterin as potent suppressors of STAT activation. We show that methotrexate suppresses human JAK/STAT signalling without affecting other phosphorylation-dependent pathways. Furthermore, methotrexate significantly reduces STAT5 phosphorylation in cells expressing JAK2 V617F, a mutation associated with most human MPNs. Methotrexate acts independently of dihydrofolate reductase (DHFR) and is comparable to the JAK1/2 inhibitor ruxolitinib. However, cells treated with methotrexate still retain their ability to respond to physiological levels of the ligand erythropoietin. Conclusions Aminopterin and methotrexate represent the first chemotherapy agents developed and act as competitive inhibitors of DHFR. Methotrexate is also widely used at low doses to treat inflammatory and immune-mediated conditions including rheumatoid arthritis. In this low-dose regime, folate supplements are given to mitigate side effects by bypassing the biochemical requirement for DHFR. Although independent of DHFR, the mechanism-of-action underlying the low-dose effects of methotrexate is unknown. Given that multiple pro-inflammatory cytokines signal through the pathway, we suggest that suppression of the JAK/STAT pathway is likely to be the principal anti-inflammatory and immunosuppressive mechanism-of-action of low-dose methotrexate. In addition, we suggest that patients with JAK/STAT-associated haematological malignancies may benefit from low-dose methotrexate treatments. While the JAK1/2 inhibitor ruxolitinib is effective, a £43,200 annual cost precludes widespread adoption. With an annual methotrexate cost of around £32, our findings represent an important development with significant future potential. PMID:26131691

Drug interaction between celecoxib and methotrexate in organic anion transporter 3-transfected renal cells and in rats in vivo.

PubMed

Maeda, Akimitsu; Tsuruoka, Shuichi; Ushijima, Kentarou; Kanai, Yoshikatsu; Endou, Hitoshi; Saito, Kazuyuki; Miyamoto, Etsuko; Fujimura, Akio

2010-08-25

Methotrexate has a clinically important pharmacokinetic interaction with nonsteroidal anti-inflammatory drugs (NSAIDs) mainly through its competition for tubular secretion via the renal organic anion transporter 3 (OAT3). We have previously reported the usefulness of OAT3-transfected renal tubular cells for screening of the drugs which interfere with the pharmacokinetics of methotrexate. Celecoxib, a cyclooxygenase (COX) 2 inhibitor, has not been reported to interact with methotrexate, but the mechanisms are unclear why the interaction did not occur. The purpose of this study was to evaluate the effect of celecoxib on methotrexate tubular secretion using a renal cell line stably expressing human OAT3 (S2-hOAT3), and to evaluate the pharmacokinetic interaction of the two drugs in rats. [3H]methotrexate uptake into S2-hOAT3 cells was significantly inhibited by celecoxib in a concentration-dependent manner and the Ki value was 35.3 microM. However, methotrexate serum concentrations and urinary excretion of methotrexate over 24 h in rats were not affected by celecoxib (50, 200 mg/kg). Celecoxib serum concentrations were increased by the increase in celecoxib dosage and the maximum drug concentration (Cmax) was 20.6 microM (celecoxib 200 mg/kg), which did not reach the Ki value obtained in the in vitro study. These results indicated that celecoxib inhibited the secretion of methotrexate via hOAT3, which suggested that celecoxib was a substrate of hOAT3. However, co-administration of the two drugs at clinical dosage did not affect the pharmacokinetics of methotrexate, because the serum concentrations did not reach the Ki value. Although the accumulation study using S2-hOAT3 cells was useful to predict the interaction between the new drug and methotrexate in vivo, a comparison of the Ki value with the Cmax in clinical dosage was necessary to evaluate the degree of this interaction. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Predictive factors for the methotrexate treatment outcome in ectopic pregnancy: A comparative study of 400 cases.

PubMed

Bonin, Lucie; Pedreiro, Cécile; Moret, Stéphanie; Chene, Gautier; Gaucherand, Pascal; Lamblin, Géry

2017-01-01

We sought to evaluate the global success rate of intramuscular methotrexate for the treatment of ectopic pregnancy, identify factors predictive of treatment success or failure, and study methotrexate tolerability in a large patient cohort. For this single-center retrospective observational study, we retrieved the records of all women who had a clinically or echographically confirmed ectopic pregnancy with a Fernandez score <13 and who were treated according to a 1mg/kg intramuscular single-dose methotrexate protocol. Medical treatment failure was defined by an obligation to proceed to laparoscopy. Needing a second injection was not considered to be medical treatment failure. Between February 2008 and November 2013 (69 months), 400 women received methotrexate for ectopic pregnancy. The medical treatment protocol was effective for 314 patients, i.e., an overall success rate of 78.5%. A single methotrexate dose was sufficient for 63.5% of the women and a second dose was successful for 73.2% of the remaining women. The medical treatment success rate fell as initial hCG levels climbed. The main factors associated with methotrexate failure included day (D) 0, D4 and D7 hCG levels, pretherapeutic blood progesterone, hematosalpinx at D0 and pain at D7. Early favorable kinetics of hCG levels was predictive of success. Methotrexate treatment was successful in 90% of women who had D0 hCG <1000IU/l. Methotrexate tolerability was good, with only 9% of the women reporting non-severe adverse effects. The fertility rate with delivery after medical treatment for ectopic pregnancy was 80.7%. In this study, we showed that an initial hCG value <1000IU/l and favorable early HCG kinetics were predictive factors for the successful medical treatment of ectopic pregnancy by methotrexate, and hematosalpinx and pretherapeutic blood progesterone >5ng/ml at diagnosis were predictive of its failure. We also confirmed good tolerability for single-dose methotrexate protocols. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Refractory acute leukaemia in adults treated with sequential colaspase and high-dose methotrexate.

PubMed

Yap, B S; McCredie, K B; Benjamin, R S; Bodey, G P; Freireich, E J

1978-09-16

Thirty-nine adults with acute leukaemia who had relapsed when receiving extensive chemotherapy were treated with a combination of methotrexate and colaspase (L-asparaginase) given sequentially. Patients initially received 50-80 mg/m(2) methotrexate, followed three hours later by intravenous colaspase, 40 000 IU/m(2). Seven days later intravenous methotrexate, 120 mg/m(2) was given. Each dose of methotrexate was followed 24 hours later by colaspase, and the two-day course of treatment was repeated every 7-14 days. The methotrexate dose was increased to tolerance by increments of 40 mg/m(2) with each course, while the colaspase dose remained constant unless abnormal liver function developed, when it was reduced by half.Overall, 18 out of 39 patients achieved complete remission (46%). Of these, 13 out of 21 (62%) had acute lymphoblastic leukaemia, three out of seven (43%) acute undifferentiated leukaemia, and two out of 11 (18%) acute myeloblastic leukaemia. The median duration of complete remission was 20 weeks and the median duration of survival in complete responders was 45 weeks. The median number of courses needed to achieve complete remission was three. The maximum tolerated dose of methotrexate was 400 mg/m(2) (median 200 mg/m(2)). Major side effects were due to colaspase. Methotrexate in doses of up to 400 mg/m(2) caused minimal myelosuppression and stomatitis, which suggested that colaspase given sequentially provides relative protection from methotrexate toxicity without the need for folinic acid (citrovorum factor) rescue.The combination of sequential colaspase and methotrexate is highly effective in reinducing remission in patients with acute lymphoblastic leukaemia or acute undifferentiated leukaemia. The regimen is easy to administer and relatively non-toxic, so it is suitable for use in outpatients, either alone or combined with other agents.

Comparative efficacy and incremental cost per responder of methotrexate versus apremilast for methotrexate-naïve patients with psoriasis.

PubMed

Armstrong, April W; Betts, Keith A; Sundaram, Murali; Thomason, Darren; Signorovitch, James E

2016-10-01

To our knowledge, no clinical trials directly compare apremilast with methotrexate (the standard of care for initial systemic treatment of psoriasis). We sought to compare apremilast's relative efficacy with that of methotrexate for moderate to severe psoriasis. An anchor-based indirect comparison was conducted for 75% improvement in Psoriasis Area and Severity Index score from baseline to week 16 (PASI 75) rates for systemic-naïve patients from Efficacy and Safety Trial Evaluating the Effects of apreMilast in psoriasis (ESTEEM) 1 and 2 (apremilast vs placebo) and Comparative study of HumirA vs. Methotrexate vs Placebo In psOriasis patieNts (CHAMPION) (adalimumab vs methotrexate vs placebo) trials. The difference-in-difference in PASI 75 response rates was calculated as the difference between the ESTEEM apremilast and placebo rates and the CHAMPION methotrexate versus placebo rates. Number needed to treat and incremental drug cost per responder were also estimated. No statistically significant difference was found between apremilast and methotrexate in PASI 75 (risk difference 13.1%; 95% confidence interval -1.8% to 28.0%; P = .09). Number needed to treat with apremilast versus methotrexate to gain 1 additional PASI 75 responder was 7.6. Annual incremental drug cost of this responder was estimated at $187,888.33. Few trials compare systemic-naïve patients. Only direct medication costs were considered. There was no statistical evidence of greater efficacy for apremilast versus methotrexate. The $187,888 incremental cost per PASI 75 may exceed what payers are willing to pay. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Enhanced antitumor efficacy of poly(D,L-lactide-co-glycolide)-based methotrexate-loaded implants on sarcoma 180 tumor-bearing mice

PubMed Central

Gao, Li; Xia, Lunyang; Zhang, Ruhui; Duan, Dandan; Liu, Xiuxiu; Xu, Jianjian; Luo, Lan

2017-01-01

Purpose Methotrexate is widely used in chemotherapy for a variety of malignancies. However, severe toxicity, poor pharmacokinetics, and narrow safety margin of methotrexate limit its clinical application. The aim of this study was to develop sustained-release methotrexate-loaded implants and evaluate antitumor activity of the implants after intratumoral implantation. Materials and methods We prepared the implants containing methotrexate, poly(D,L-lactide-co-glycolide), and polyethylene glycol 4000 with the melt-molding technique. The implants were characterized with regards to drug content, morphology, in vitro, and in vivo release profiles. Differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) were carried out to investigate the physicochemical properties of the implants. Furthermore, the antitumor activity of the implants was tested in a sarcoma 180 mouse model. Results The implants were prepared as solid rods. Scanning electron microscopy images showed a smooth surface of the implant, suggesting that methotrexate was homogeneously dispersed in the polymeric matrix. The results of DSC and FTIR indicated that no significant interaction between methotrexate and the polymer was observed in the implants. Both in vitro and in vivo release profiles of the implants were characterized by burst release followed by sustained release of methotrexate. Intratumoral implantation of methotrexate-loaded implants could efficiently delay tumor growth. Moreover, an increase in the dose of implants led to a higher tumor suppression rate without additional systemic toxicity. Conclusion These results demonstrate that methotrexate-loaded implants had significant antitumor efficacy in a sarcoma 180 mouse model without dose-limiting side effects, and suggest that the implants could be potentially applied as an intratumoral delivery system to treat cancer. PMID:29118572

Levoleucovorin Injection

MedlinePlus

... injection is used to prevent harmful effects of methotrexate (Rheumatrex, Trexall) when methotrexate is used to to treat certain types of ... people who have accidentally received an overdose of methotrexate or similar medications. Levoleucovorin injection is in a ...

Efficacy and safety of methotrexate in alopecia areata*

PubMed Central

Hammerschmidt, Mariana; Mulinari Brenner, Fabiane

2014-01-01

BACKGROUND Alopecia areata is a chronic disorder of the hair follicles and nails, of unknown etiology, with clear autoimmune components and genetic factors. Several therapeutic options have been suggested; however, no treatment is able to modify the disease course. Methotrexate is an immunosuppressant used in various dermatoses and recently introduced as a therapeutic option for alopecia areata. OBJECTIVES To evaluate the efficacy and safety of methotrexate in alopecia areata. METHODS In a retrospective, non-controlled study, we evaluated 31 patients with alopecia areata in current or prior treatment with methotrexate to assess the therapeutic response according to sex, age, pattern of alopecia areata, disease duration, cumulative dose of methotrexate, use of systemic corticosteroids or other treatments, and drug safety. RESULTS Regrowth greater than 50% was observed in 67.7% of patients, with the best responses observed in those with <5 years of disease progression (79%), age over 40 years (73.3%), male patients (72.8%), cumulative dose of methotrexate 1000-1500 mg, and multifocal alopecia areata (93%). Among patients receiving systemic corticosteroids in combination with methotrexate, 77.3% had greater than 50% regrowth, compared with 44.4% in those who used methotrexate alone. The therapeutic dose ranged from 10-25 mg/week. No patient had serious adverse effects. Relapse was observed in 33.3% of patients with more than 50% regrowth. CONCLUSION Methotrexate appears to be a promising and safe medication for the treatment of severe alopecia areata when used alone or in combination with corticosteroids. PMID:25184911

Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children

DOE Office of Scientific and Technical Information (OSTI.GOV)

Freeman, A.I.; Weinberg, V.; Brecher, M.L.

1983-03-03

We compared two regimens with respect to their ability to prolong disease-free survival in 506 children and adolescents with acute lymphocytic leukemia. All responders to induction therapy were randomized to treatment with 2400 rad of cranial irradiation plus intrathecal methotrexate or to treatment with intermediate-dose methotrexate plus intrathecal methotrexate, as prophylaxis for involvement of the central nervous system and other sanctuary areas. Patients were then treated with a standard maintenance regimen. Complete responders were stratified into either standard-risk or increased-risk groups on the basis of age and white-cell count at presentation. Among patients with standard risk, hematologic relapses occurred inmore » 9 of 117 given methotrexate and 24 of 120 given irradiation (P less than 0.01). The rate of central-nervous-system relapse was higher in the methotrexate group (23 of 117) than in the irradiation group (8 of 120) (P . 0.01). Among patients with increased risk, radiation offered greater protection to the central nervous system than methotrexate (P . 0.03); there was no difference in the rate of hematologic relapse. In both risk strata the frequency of testicular relapse was significantly lower in the methotrexate group (1 patient) than the radiation group (10 patients) (P . 0.01). Methotrexate offered better protection against systemic relapse in standard-risk patients and better protection against testicular relapse overall, but it offered less protection against relapses in the central nervous system than cranial irradiation.« less

First-line chemotherapy in low-risk gestational trophoblastic neoplasia

PubMed Central

Alazzam, Mo’iad; Tidy, John; Hancock, Barry W; Osborne, Raymond; Lawrie, Theresa A

2014-01-01

Background This is an update of a Cochrane review that was first published in Issue 1, 2009. Gestational trophoblastic neoplasia (GTN) is a rare but curable disease arising in the fetal chorion during pregnancy. Most women with low-risk GTN will be cured by evacuation of the uterus with or without single-agent chemotherapy. However, chemotherapy regimens vary between treatment centres worldwide and the comparable benefits and risks of these different regimens are unclear. Objectives To determine the efficacy and safety of first-line chemotherapy in the treatment of low-risk GTN. Search methods In September 2008, we electronically searched the Cochrane Gynaecological Cancer Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL Issue 3, 2008), MEDLINE and EMBASE. In addition, we searched online trial registers, conference proceedings and reference lists of identified studies. We re-ran these searches in February 2012 for this updated review. Selection criteria For the original review, we included randomised controlled trials (RCTs), quasi-RCTs and non-RCTs that compared first-line chemotherapy for the treatment of low-risk GTN. For this updated version of the review, we included only RCTs. Data collection and analysis Two review authors independently assessed studies for inclusion and extracted data to a pre-designed data extraction form. Meta-analysis was performed by pooling the risk ratio (RR) of individual trials. Main results We included five moderate to high quality RCTs (517 women) in the updated review. These studies all compared methotrexate with dactinomycin. Three studies compared weekly intramuscular (IM) methotrexate with bi-weekly pulsed intravenous (IV) dactinomycin (393 women), one study compared five-day IM methotrexate with bi-weekly pulsed IV dactinomycin (75 women) and one study compared eight-day IM methotrexate-folinic acid (MTX-FA) with five-day IV dactinomycin (49 women). Overall, dactinomycin was associated with significantly higher rates of primary cure than methotrexate (five studies, 513 women; RR 0.64, 95% Confidence Interval (CI) 0.54 to 0.76). Methotrexate was associated with significantly more treatment failure than dactinomycin (five studies, 513 women; RR 3.81, 95% CI 1.64 to 8.86). We consider this evidence to be of a moderate quality. There was no significant difference between the two groups with respect to nausea (four studies, 466 women; RR 0.61, 95% CI 0.29 to 1.26) or any of the other individual side-effects reported, although data for all of these outcomes were insufficient and too heterogeneous to be conclusive. No severe adverse effects (SAEs) occurred in either group in three out of the five included studies and there was no significant difference in SAEs between the groups overall (five studies, 515 women; RR 0.35, 95% CI 0.08 to 1.66; I2 = 60%), however, there was a trend towards fewer SAEs in the methotrexate group. We considered this evidence to be of a low quality due to substantial heterogeneity and low consistency in the occurrence/reporting of SAEs between trials. Authors’ conclusions Dactinomycin is more likely to achieve a primary cure in women with low-risk GTN, and less likely to result in treatment failure, compared with methotrexate. There is limited evidence relating to side-effects, however, the pulsed dactinomycin regimen does not appear to be associated with significantly more side-effects than the low-dose methotrexate regimen and therefore should compare favourably to the five- and eight-day methotrexate regimens in this regard. We consider pulsed dactinomycin to have a better cure rate than, and a side-effect profile at least equivalent to, methotrexate when used for first-line treatment of low-risk GTN. Data from a large ongoing trial of pulsed dactinomycin compared with five- and eight-day methotrexate regimens is likely to have an important impact on our confidence in these findings. PMID:22786502

Effects of methotrexate on the viscoelastic properties of single cells probed by atomic force microscopy.

PubMed

Li, Mi; Liu, Lianqing; Xiao, Xiubin; Xi, Ning; Wang, Yuechao

2016-10-01

Methotrexate is a commonly used anti-cancer chemotherapy drug. Cellular mechanical properties are fundamental parameters that reflect the physiological state of a cell. However, so far the role of cellular mechanical properties in the actions of methotrexate is still unclear. In recent years, probing the behaviors of single cells with the use of atomic force microscopy (AFM) has contributed much to the field of cell biomechanics. In this work, with the use of AFM, the effects of methotrexate on the viscoelastic properties of four types of cells were quantitatively investigated. The inhibitory and cytotoxic effects of methotrexate on the proliferation of cells were observed by optical and fluorescence microscopy. AFM indenting was used to measure the changes of cellular viscoelastic properties (Young's modulus and relaxation time) by using both conical tip and spherical tip, quantitatively showing that the stimulation of methotrexate resulted in a significant decrease of both cellular Young's modulus and relaxation times. The morphological changes of cells induced by methotrexate were visualized by AFM imaging. The study improves our understanding of methotrexate action and offers a novel way to quantify drug actions at the single-cell level by measuring cellular viscoelastic properties, which may have potential impacts on developing label-free methods for drug evaluation.

Phase II Trial of Oral Aminopterin for Adults and Children with Refractory Acute Leukemia

PubMed Central

Cole, Peter D.; Drachtman, Richard A.; Smith, Angela K.; Cate, Sarah; Larson, Richard A.; Hawkins, Douglas S.; Holcenberg, John; Kelly, Kara; Kamen, Barton A.

2010-01-01

Purpose To determine the antileukemic activity of weekly oral aminopterin in patients with refractory acute leukemia; to describe the pharmacodynamic properties of aminopterin; and to contrast the intracellular metabolism of aminopterin and methotrexate by patients’ blasts in vitro. Experimental Design Forty-six patients were enrolled in three strata: children with acute lymphoblastic leukemia (ALL), adults with ALL, and patients with acute myeloid leukemia (AML).Aminopterin was given weekly, in two doses of 2mg/m2, 12 hours apart. Limited sampling pharmacokinetic analysis was done during the first week of therapy. Accumulation of [3H]aminopterin and [3H]methotrexate by leukemic blasts was studied in vitro. Results Six of 22 children with ALL (27%; 95% confidence interval, 8–47%) had clinically significant responses. None of those with AML and only two of 11 adults with ALL had responses meeting protocol definitions, although peripheral blast counts tended to decrease with therapy in all groups. Mucosal toxicity was minimal, even with limited use of leucovorin rescue. Complete bioavailability of aminopterin was confirmed, with a mean area under the curve of 0.52 ± 0.03 µmol hour/L after oral dosing. No relationship between aminopterin pharmacokinetics and response was seen. In vitro, aminopterin showed more consistent metabolism by leukemic blasts to polyglutamates than methotrexate. Lineage-specific differences in the pattern of intracellular antifolylpolyglutamates were observed. Conclusions Weekly oral aminopterin has significant activity among children with refractory ALL. With greater cellular accumulation and metabolism, more reliable bioavailability than methotrexate, and tolerable toxicity at this dose and schedule, aminopterin deserves further study as a potent alternative to methotrexate. PMID:16299240

Interaction of methotrexate with trypsin analyzed by spectroscopic and molecular modeling methods

NASA Astrophysics Data System (ADS)

Wang, Yanqing; Zhang, Hongmei; Cao, Jian; Zhou, Qiuhua

2013-11-01

Trypsin is one of important digestive enzymes that have intimate correlation with human health and illness. In this work, the interaction of trypsin with methotrexate was investigated by spectroscopic and molecular modeling methods. The results revealed that methotrexate could interact with trypsin with about one binding site. Methotrexate molecule could enter into the primary substrate-binding pocket, resulting in inhibition of trypsin activity. Furthermore, the thermodynamic analysis implied that electrostatic force, hydrogen bonding, van der Waals and hydrophobic interactions were the main interactions for stabilizing the trypsin-methotrexate system, which agreed well with the results from the molecular modeling study.

Dietary L-arginine supplementation reduces Methotrexate-induced intestinal mucosal injury in rat.

PubMed

Koppelmann, Tal; Pollak, Yulia; Mogilner, Jorge; Bejar, Jacob; Coran, Arnold G; Sukhotnik, Igor

2012-04-30

Arginine (ARG) and nitric oxide maintain the mucosal integrity of the intestine in various intestinal disorders. In the present study, we evaluated the effects of oral ARG supplementation on intestinal structural changes, enterocyte proliferation and apoptosis following methotrexate (MTX)-induced intestinal damage in a rat. Male rats were divided into four experimental groups: Control rats, CONTR-ARG rats, were treated with oral ARG given in drinking water 72 hours before and 72 hours following vehicle injection, MTX rats were treated with a single dose of methotrexate, and MTX-ARG rats were treated with oral ARG following injection of MTX. Intestinal mucosal damage, mucosal structural changes, enterocyte proliferation and enterocyte apoptosis were determined 72 hours following MTX injection. RT-PCR was used to determine bax and bcl-2 mRNA expression. MTX-ARG rats demonstrated greater jejunal and ileal bowel weight, greater ileal mucosal weight, greater ileal mucosal DNA and protein levels, greater villus height in jejunum and ileum and crypt depth in ileum, compared to MTX animals. A significant decrease in enterocyte apoptosis in the ileum of MTX-ARG rats (vs MTX) was accompanied by decreased bax mRNA and protein expression and increased bcl-2 protein levels. Treatment with oral ARG prevents mucosal injury and improves intestinal recovery following MTX- injury in the rat.

Methotrexate-loxoprofen interaction: involvement of human organic anion transporters hOAT1 and hOAT3.

PubMed

Uwai, Yuichi; Taniguchi, Risa; Motohashi, Hideyuki; Saito, Hideyuki; Okuda, Masahiro; Inui, Ken-ichi

2004-10-01

Human organic anion transporters hOAT1 (SLC22A6) and hOAT3 (SLC22A8) are responsible for renal tubular secretion of an antifolic acid methotrexate, and are considered to be involved in drug interaction of methotrexate with nonsteroidal anti-inflammatory drugs (NSAIDs). In our hospital, a delay of methotrexate elimination was experienced in a patient with Hodgkin's disease, who took loxoprofen, a commonly used NSAID in Japan, which suggested a cause. In this study, we examined the drug interaction via hOAT1 and hOAT3, using Xenopus laevis oocytes. hOAT1 and hOAT3 mediated the methotrexate transport with low affinity (K(m) of 724.0 muM) and high affinity (K(m) of 17.2 muM), respectively. Loxoprofen and its trans-OH metabolite, an active major metabolite, markedly inhibited the methotrexate transport by both transporters. Their inhibition concentrations (IC(50)) were in the range of the therapeutic levels. These findings suggest that loxoprofen retards the elimination of methotrexate, at least in part, by inhibiting hOAT1 and hOAT3.

Sustained release of methotrexate through liquid-crystalline folate nanoparticles.

PubMed

Misra, Rahul; Mohanty, Sanat

2014-09-01

To make chemotherapy more effective, sustained release of the drug is desirable. By controlling the release rates, constant therapeutic levels can be achieved which can avoid re-administration of drug. This helps to combat tumors more effectively with minimal side effects. The present study reports the control release of methotrexate through liquid-crystalline folate nanoparticles. These nanoparticles are composed of highly ordered folate self-assembly which encapsulate methotrexate molecules. These drug molecules can be released in a controlled manner by disrupting this assembly in the environment of monovalent cations. The ordered structure of folate nanoparticles offers low drug losses of about 4-5%, which is significant in itself. This study reports the size-control method of forming methotrexate encapsulated folate nanoparticles as well as the release of methotrexate through these nanoparticles. It has been demonstrated that methotrexate release rates can be controlled by controlling the size of the nanoparticles, cross-linking cation and cross-linking concentration. The effect of different factors like drug loading, release medium, and pH of the medium on methotrexate release rates was also studied.

Comparison of intra-articular methotrexate with intra-articular triamcinolone hexacetonide by thermography.

PubMed

Bird, H A; Ring, E F; Daniel, R; Bacon, P A

1977-01-01

A comparison of intra-articular methotrexate and intra-articular triamcinolone hexacetonide was made in 42 arthritic patients with persistent bilateral knee effusions. One knee was injected with either 5 mg methotrexate (two injections of 2.5 mg a week apart) or a single injection of 20 mg triamcinolone. An objective assessment of both knees was made by quantitative thermography at 0,3,7,14 and 21 days. Joints injected with triamcinolone showed a greater fall in thermographic index (T.I) than the joints injected with methotrexate, which showed similar change to the non-injected knee joints in both groups. Four patients received larger doses of methotrexate, up to 20 mg, though the fall in T.I. was still less than the mean fall for triamcinolone injected joints. Peak venous blood levels of methotrexate were reached 1 hour after intra-articular injection, and a sphygmomanometer cuff inflated around the leg above the injected knee for periods of up to 1 hour did not appreciably delay this. Methotrexate had no immediate anti-inflammatory effect, even in psoriatic arthropathy, and did not give the relief of intra-articular steroid.

Evaluation of aprepitant for acute chemotherapy-induced nausea and vomiting in children and adolescents with acute lymphoblastic leukemia receiving high-dose methotrexate.

PubMed

Felix-Ukwu, Femi; Reichert, Kate; Bernhardt, M Brooke; Schafer, Eric S; Berger, Amanda

2018-02-01

Chemotherapy-induced nausea and vomiting (CINV) negatively impacts patients' quality of life. The emetogenicity of high-dose methotrexate in children and adolescents with cancer is incompletely characterized. At our institution, a number of patients with acute lymphoblastic leukemia (ALL) have received aprepitant with courses of high-dose methotrexate after poor CINV control with prior courses. We conducted a retrospective cohort analysis on patients with ALL who received methotrexate 5 g/m 2 /dose with and without concomitant aprepitant at Texas. Children's Hospital between October 1, 2010 and January 31, 2016. We identified 16 patients who received a total of 69 courses of methotrexate. An enhanced antiemetic regimen containing aprepitant was administered with 42 methotrexate courses and resulted in a 54% reduction in the use of as-needed antiemetics (P = 0.002, 95% CI: 21-89%). There were no statistically significant differences in methotrexate area under the curve values (2,209 μM⋅hr/l ± 151 vs. 2,051 μM⋅hr/l ± 94, P = 0.355) or end-infusion methotrexate concentrations (80.5 μM ± 5.6 vs. 74.7 μM ± 3.2, P = 0.335) in patients receiving a standard versus an enhanced antiemetic regimen. The addition of aprepitant reduces both CINV and the use of rescue antiemetics. Aprepitant does not appear to affect the pharmacokinetics of methotrexate. Granisetron was prescribed more frequently than ondansetron, but selection of secondary and tertiary agents, if any, was highly variable. © 2017 Wiley Periodicals, Inc.

Induction of cytogenetic damage in human lymphocytes in vitro and of antineoplastic effects in Ehrlich ascites tumor cells in vivo treated by methotrexate, hyperthermia and/or caffeine.

PubMed

Maskaleris, T; Lialiaris, T; Triantaphyllidis, C

1998-12-03

The synergistic effect of methotrexate (at concentrations between 3. 1 and 100 nM) and its combinations with caffeine (618 microM) and/or hyperthermia (42 degreesC for 2 h) on the frequency of sister chromatid exchanges (SCEs), the proliferating rate index and the mitotic index in cultured human lymphocytes, was examined. Also, the in vivo antineoplastic effects of methotrexate (at a concentration of 0.45 microg/g body weight) and its combination with caffeine (120 microg/g body weight), both on the survival time and the increase of the weight of tumor of BALB/c mice inoculated with Ehrlich ascites tumor cells was examined in the present study. The results indicated that: (a) the triple combination of methotrexate, caffeine and hyperthermia synergistically increased the levels of SCEs and exerted cytostatic and cytotoxic action and (b) the combination of methotrexate and caffeine significantly increased the survival span of the mice inoculated with Ehrlich ascites tumor cells and reduced the increase of the weight of their tumors at rates higher than in the case of methotrexate by itself. It is suggested that the above triple combination (methotrexate plus caffeine plus hyperthermia) could achieve increased effectiveness of methotrexate, better therapy results, and could be successfully applied in the treatment of various types of cancer. Copyright 1998 Elsevier Science B.V.

A decade of Australian methotrexate dosing errors.

PubMed

Cairns, Rose; Brown, Jared A; Lynch, Ann-Maree; Robinson, Jeff; Wylie, Carol; Buckley, Nicholas A

2016-06-06

Accidental daily dosing of methotrexate can result in life-threatening toxicity. We investigated methotrexate dosing errors reported to the National Coronial Information System (NCIS), the Therapeutic Goods Administration Database of Adverse Event Notifications (TGA DAEN) and Australian Poisons Information Centres (PICs). A retrospective review of coronial cases in the NCIS (2000-2014), and of reports to the TGA DAEN (2004-2014) and Australian PICs (2004-2015). Cases were included if dosing errors were accidental, with evidence of daily dosing on at least 3 consecutive days. Events per year, dose, consecutive days of methotrexate administration, reasons for the error, clinical features. Twenty-two deaths linked with methotrexate were identified in the NCIS, including seven cases in which erroneous daily dosing was documented. Methotrexate medication error was listed in ten cases in the DAEN, including two deaths. Australian PIC databases contained 92 cases, with a worrying increase seen during 2014-2015. Reasons for the errors included patient misunderstanding and incorrect packaging of dosette packs by pharmacists. The recorded clinical effects of daily dosage were consistent with those previously reported for methotrexate toxicity. Dosing errors with methotrexate can be lethal and continue to occur despite a number of safety initiatives in the past decade. Further strategies to reduce these preventable harms need to be implemented and evaluated. Recent suggestions include further changes in packet size, mandatory weekly dosing labelling on packaging, improving education, and including alerts in prescribing and dispensing software.

Golimumab, a human antibody to tumour necrosis factor α given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study

PubMed Central

Keystone, E C; Genovese, M C; Klareskog, L; Hsia, E C; Hall, S T; Miranda, P C; Pazdur, J; Bae, S-C; Palmer, W; Zrubek, J; Wiekowski, M; Visvanathan, S; Wu, Z; Rahman, M U

2009-01-01

Objective: The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate therapy. Methods: Patients were randomly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules (group 1, n  =  133), golimumab 100 mg injections plus placebo capsules (group 2, n  =  133), golimumab 50 mg injections plus methotrexate capsules (group 3, n  =  89), or golimumab 100 mg injections plus methotrexate capsules (group 4, n  =  89). Injections were administered subcutaneously every 4 weeks. The co-primary endpoints were the proportion of patients with 20% or greater improvement in the American College of Rheumatology criteria (ACR20) at week 14 and the change from baseline in the health assessment questionnaire-disability index (HAQ-DI) score at week 24. Results: The proportion of patients who achieved an ACR20 response at week 14 was 33.1% in the placebo plus methotrexate group, 44.4% (p = 0.059) in the golimumab 100 mg plus placebo group, 55.1% (p = 0.001) in the golimumab 50 mg plus methotrexate group and 56.2% (p<0.001) in the golimumab 100 mg plus methotrexate group. At week 24, median improvements from baseline in HAQ-DI scores were 0.13, 0.13 (p = 0.240), 0.38 (p<0.001) and 0.50 (p<0.001), respectively. During the placebo-controlled portion of the study (to week 16), serious adverse events occurred in 2.3%, 3.8%, 5.6% and 9.0% of patients and serious infections occurred in 0.8%, 0.8%, 2.2% and 5.6%, respectively. Conclusion: The addition of golimumab to methotrexate in patients with active RA despite methotrexate therapy significantly reduced the signs and symptoms of RA and improved physical function. PMID:19066176

Preventing and Managing Toxicities of High-Dose Methotrexate.

PubMed

Howard, Scott C; McCormick, John; Pui, Ching-Hon; Buddington, Randall K; Harvey, R Donald

2016-12-01

: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m 2 , is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%-12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated. High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m 2 , is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity. ©AlphaMed Press.

Lack of pharmacokinetic interaction between rofecoxib and methotrexate in rheumatoid arthritis patients.

PubMed

Schwartz, J I; Agrawal, N G; Wong, P H; Bachmann, K A; Porras, A G; Miller, J L; Ebel, D L; Sack, M R; Holmes, G B; Redfern, J S; Gertz, B J

2001-10-01

Rofecoxib is a highly selective and potent inhibitor of cyclooxgenase-2 (COX-2). Methotrexate is a disease-modifying agent with a narrow therapeutic index frequently prescribed for the management of rheumatoid arthritis. The objective of this study was to investigate the influence of clinical doses of rofecoxib on the pharmacokinetics of methotrexate in patients with rheumatoid arthritis. This was a randomized, double-blind, placebo-controlled study in 25 rheumatoid arthritis patients on stable doses of methotrexate. Patients received oral methotrexate (7.5 to 20 mg) on days -1, 7, 14, and 21. Nineteen patients received rofecoxib 12.5, 25, and 50 mg once daily on days 1 to 7, 8 to 14, and 15 to 21, respectively. Six patients received placebo on days 1 to 21 only to maintain a double-blinded design for assessment of adverse experiences. Plasma and urine samples were analyzed for methotrexate and its major although inactive metabolite, 7-hydroxymethotrexate. The AUC(0-infinity) geometric mean ratios (GMR) and their 90% confidence intervals (90% CI) (rofecoxib + methotrexate/methotrexate alone) for day 7/day -1, day 14/day -1, and day 21/day -1, for rofecoxib 12.5, 25, and 50 mg, were 1.03 (0.93, 1.14), 1.02 (0.92, 1.12), and 1.06 (0.96, 1.17), respectively (p > 0.2 for all comparisons to day -1). All AUC(0-infinity), GMR and Cmax GMR 90% CIs fell within the predefined comparability limits of (0.80, 1.25). Similar results were observed for renal clearance of methotrexate and 7-hydroxymethotrexate at the highest dose of rofecoxib tested (50 mg). It was concluded that rofecoxib at doses of 12.5, 25, and 50 mg once daily has no effect on the plasma concentrations or renal clearance (tested at the highest dose of rofecoxib) of methotrexate in rheumatoid arthritis patients.

Preventing and Managing Toxicities of High-Dose Methotrexate

PubMed Central

McCormick, John; Pui, Ching-Hon; Buddington, Randall K.; Harvey, R. Donald

2016-01-01

High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%–12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated. Implications for Practice: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity. PMID:27496039

Outcomes of conception subsequent to methotrexate treatment for an unruptured ectopic pregnancy.

PubMed

Svirsky, Ran; Ben-Ami, Ido; Berkovitch, Matitiahu; Halperin, Reuvit; Rozovski, Uri

2017-11-01

To assess the risk of adverse pregnancy outcomes in subsequent pregnancies among women treated with methotrexate for ectopic pregnancy. In a retrospective single-center study, data were assessed for women treated with methotrexate for ectopic pregnancy at Asaf Harofe Medical Center, Zerifin, Israel, between May 2004 and May 2014. Overall, 226 women were treated with methotrexate for ectopic pregnancy and subsequently conceived. The median time from treatment to conception was 10 months (range 1-120 months), and 127 women conceived within 12 months of treatment. Except for early missed abortion-which affected 23 (10.2%) pregnancies-adverse pregnancy outcomes such as fetal malformations were rare. The frequency of early abortion was lowest for women who conceived within 6 months of treatment with methotrexate (3/93, 3.2%), increased between 6 and 23 months (15/83, 18.1%), and remained high thereafter (7/50, 14.0%; P=0.006). The frequency of fetal malformation in a subsequent pregnancy was low among women treated with methotrexate for ectopic pregnancy. The frequency of early missed abortion was lowest during the first 6 months after treatment with methotrexate. © 2017 International Federation of Gynecology and Obstetrics.

Methotrexate-associated lymphoproliferative disorder.

PubMed

Kaneko, Yuko

2017-01-01

Methotrexate-associated lymphproliferative disorder (MTX-LPD) is a rare but critical complication developing in patients treated with methotrexate. Now that methotrexate is an anchor drug in the management of rheumatoid arthritis and become commonly used, MTX-LPD cases have increased. Many things has been unclear such as incidence, demographic characters, and risk factors. However, as the researches increased, several interesting topics has been demonstrated like associations with Epsteiin-Barr virus and with cell-mediated immunity. This report reviews newly the latest findings and future challenges on MTX-LPD.

Real-World Treatment Patterns for Golimumab and Concomitant Medications in Japanese Rheumatoid Arthritis Patients.

PubMed

Okazaki, Masateru; Kobayashi, Hisanori; Ishii, Yutaka; Kanbori, Masayoshi; Yajima, Tsutomu

2018-06-01

The aim of this study was to investigate real-world treatment patterns for use of golimumab and concomitant medications in Japanese patients with rheumatoid arthritis. This study was a post hoc retrospective analysis from post-marketing surveillance data on 2350 Japanese patients with moderate/severe rheumatoid arthritis who received golimumab for 24 weeks. The study population was divided based on initiation treatment or dose adjustment patterns with golimumab, methotrexate, or oral glucocorticoids. Logistic regression analysis revealed that the baseline factors associated with administration of golimumab (100 mg) were higher body weight, failure of prior biological therapy (bio-failure), no previous methotrexate use, and respiratory disease, while previous methotrexate use and absence of renal impairment or respiratory disease were associated with concomitant methotrexate therapy, and previous glucocorticoid use was associated with concomitant glucocorticoid therapy. The following associations were identified with regard to dose adjustment during treatment: bio-failure, no previous methotrexate use, previous csDMARDs use, presence of respiratory disease, allergy history, and higher CRP for golimumab dose escalation; shorter disease duration, previous GC, and no previous methotrexate use for methotrexate dose escalation; no prior biological therapy and renal impairment for methotrexate dose reduction; no previous GC use for glucocorticoid dose escalation; and absence of Steinbrocker's stage II/III/IV, absence of Steinbrocker's class II, no bio-failure, and no previous csDMARDs use for glucocorticoid dose reduction. This study revealed that various baseline factors were associated with initiation of treatment and dose adjustment of golimumab, methotrexate, or oral glucocorticoids, reflecting both the treatment strategies of physicians for improving RA symptoms and/or reducing adverse events. Janssen Pharmaceutical K.K. and Mitsubishi Tanabe Pharma Corporation.

Photoaffinity analogues of methotrexate as folate antagonist binding probes. 2. Transport studies, photoaffinity labeling, and identification of the membrane carrier protein for methotrexate from murine L1210 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Price, E.M.; Freisheim, J.H.

1987-07-28

A membrane-derived component of the methotrexate/one-carbon-reduced folate transport system in murine L1210 cells has been identified by using a photoaffinity analogue of methotrexate. The compound, a radioiodinated 4-azidosalicylyl derivative of the lysine analogue of methotrexate, is transported into murine L1210 cells in a temperature-dependent, sulfhydryl reagent inhibitable manner with a K/sub t/ of 506 +/- 79 nM and a V/sub max/ of 17.9 +/- 4.2 pmol min/sup -1/ (mg of total cellular protein)/sup -1/. Uptake of the iodinated compound at 200 nM is inhibited by low amounts of methotrexate. The parent compounds of the iodinated photoprobe inhibit (/sup 3/H)methotrexate uptake,more » with the uniodinated 4-azidosalicylyl derivative exhibiting a K/sub i/ of 66 +/- 21 nM. UV irradiation, at 4 /sup 0/C, of a cell suspension that had been incubated with the probe results in the covalent modification of a 46K-48K protein. This can be demonstrated when the plasma membranes from the labeled cells are analyzed via sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. Labeling of this protein occurs half-maximally at a reagent concentration that correlates with the K/sub t/ for transport of the iodinated compound. Protection against labeling of this protein by increasing amounts of methotrexate parallels the concentration dependence of inhibition of photoprobe uptake by methotrexate. Evidence that, in the absence of irradiation and at 37/sup 0/C, the iodinated probe is actually internalized is demonstrated by the labeling of two soluble proteins (M/sub r/ 38K and 21K) derived from the cell homogenate supernatant.« less

Effects of Intraventricular Methotrexate on Neuronal Injury and Gene Expression in a Rat Model: Findings From an Exploratory Study.

PubMed

Moore, Ida M Ki; Merkle, Carrie J; Byrne, Howard; Ross, Adam; Hawkins, Ashley M; Ameli, Sara S; Montgomery, David W

2016-10-01

Central nervous system (CNS)-directed treatment for acute lymphoblastic leukemia, used to prevent disease recurrence in the brain, is essential for survival. Systemic and intrathecal methotrexate, commonly used for CNS-directed treatment, have been associated with cognitive problems during and after treatment. The cortex, hippocampus, and caudate putamen, important brain regions for learning and memory, may be involved in methotrexate-induced brain injury. Objectives of this study were to (1) quantify neuronal degeneration in selected regions of the cortex, hippocampus, and caudate putamen and (2) measure changes in the expression of genes with known roles in oxidant defense, apoptosis/inflammation, and protection from injury. Male Sprague Dawley rats were administered 2 or 4 mg/kg of methotrexate diluted in artificial cerebrospinal fluid (aCSF) or aCSF only into the left cerebral lateral ventricle. Gene expression changes were measured using customized reverse transcription (RT)(2) polymerase chain reaction arrays. The greatest percentage of degenerating neurons in methotrexate-treated animals was in the medial region of the cortex; percentage of degenerating neurons in the dentate gyrus and cornu ammonis 3 regions of the hippocampus was also greater in rats treated with methotrexate compared to perfusion and vehicle controls. There was a greater percentage of degenerating neurons in the inferior cortex of control versus methotrexate-treated animals. Eight genes involved in protection from injury, oxidant defense, and apoptosis/inflammation were significantly downregulated in different brain regions of methotrexate-treated rats. To our knowledge, this is the first study to investigate methotrexate-induced injury in selected brain regions and gene expression changes using a rat model of intraventricular drug administration. © The Author(s) 2016.

Methotrexate causes acute hyperplasia of enterochromaffin cells containing substance P in the intestinal mucosa of rats.

PubMed

Machida, Takuji; Takano, Yuho; Iizuka, Kenji; Machida, Maiko; Hirafuji, Masahiko

2017-03-01

This study aimed to investigate the acute and chronic effect of methotrexate on the intestinal substance P metabolism after a single administration to rats. Methotrexate caused a significant increase in the number of substance P-containing cells in the ileal mucosa both at 24 and 96 h. Most of enterochromaffin cells expressing l-tryptophan hydroxylase contained substance P. The expression of Tac1 mRNA was increased by methotrexate at 24 h, but not at 96 h. Thus, methotrexate causes acute hyperplasia of enterochromaffin cells in the intestinal mucosa of rats with a transient increase in the production of substance P. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Methotrexate for the treatment of pediatric alopecia areata.

PubMed

Landis, Erin T; Pichardo-Geisinger, Rita O

2018-03-01

Alopecia areata is a form of nonscarring hair loss that occurs in pediatric and adult patients, with presentation varying from round or ovoid patches of alopecia to alopecia totalis or universalis. While frustrating for patients, it can also be frustrating for clinicians to treat, as there is no definitive treatment. Dermatologists are very familiar with the use of methotrexate for psoriasis and other inflammatory skin diseases, and this medication is generally well tolerated in children. This study presents a case series reviewing the efficacy of methotrexate in our pediatric patients with alopecia areata, making use of a retrospective chart review design from 2011 to 2016. In this data set, 8/14 subjects (57%) experienced good regrowth with methotrexate, while 3/14 (21%) had a response that could not be assessed due to loss to follow-up or premature discontinuation of the medication. No cases discontinued the medication due to recognized methotrexate side effects. This review suggests methotrexate is a generally safe and often effective medication in pediatric alopecia areata.

Initial Experience With Low-Dose Methotrexate as an Adjuvant Treatment for Rapidly Recurrent Nonvasculitic Laryngotracheal Stenosis.

PubMed

Rosow, David E; Ahmed, Jamal

2017-02-01

Adult laryngotracheal stenosis (LTS) is typically managed surgically, but some patients fail treatment because of rapid restenosis or granulation tissue formation. The need for frequent surgery or tracheostomy reduces the quality of life in these patients and poses a significant challenge for the treating physician. New adjuvant treatments are required to reduce the surgical burden of this condition. To examine whether patients with rapidly recurrent nonvasculitic LTS who fail surgical management of their stenosis (ie, requiring dilation more frequently than every 6 months) experience longer intervals between surgical procedures when receiving adjuvant treatment with low-dose methotrexate. This study was a retrospective case series study of patients treated with methotrexate from January 2014 to January 2016 at a tertiary academic medical center. Participants were 10 patients with LTS without any diagnosis of vasculitis or granulomatous disease who underwent low-dose methotrexate therapy. Once-weekly treatment with oral methotrexate, 15 or 20 mg. The mean number of days between operations before and after starting methotrexate therapy was compared. Clinical courses and adverse effects of each patient were also reviewed. Among 10 patients, the mean (SD) age at the outset of study inclusion was 52 (19) years; 8 were female and 2 were male. All 10 patients experienced some clinical improvement. Three patients who were previously tracheostomy dependent were able to be decannulated. Two other patients who were tracheostomy dependent and had failed endoscopic management of their granulation tissue had complete resolution. In 6 patients who underwent at least 1 surgical procedure before and after the initiation of methotrexate treatment, the mean (SD) interval between operations increased from 61 (35) days (95% CI, 26-96 days) before starting methotrexate therapy to 312 (137) days (95% CI, 175-449 days) after starting methotrexate therapy, for an absolute difference of 251 (58) days (95% CI, 193-309 days). The median number of days between surgical procedures was 44 days before starting methotrexate therapy and 289 days after starting methotrexate therapy. Adverse effects observed included mild hair thinning and onychomycosis in 2 patients and herpes zoster infection in 1 patient. Low-dose methotrexate appears to be an effective adjunct to surgery in select patients with LTS that is resistant to surgical management and leads to a substantial increase in the number of days between surgical procedures. The patient and clinician must be aware of the adverse effects of methotrexate therapy and balance these factors against the risk of poorly controlled airway stenosis. Randomized, placebo-controlled, double-blind trials are needed to examine whether the clinical efficacy in this series of patients translates to a larger population.

Cardiovascular event risk assessment in psoriasis patients treated with tumor necrosis factor-α inhibitors versus methotrexate.

PubMed

Wu, Jashin J; Guérin, Annie; Sundaram, Murali; Dea, Katherine; Cloutier, Martin; Mulani, Parvez

2017-01-01

Psoriasis is associated with increased risk for cardiovascular disease. To compare major cardiovascular event risk in psoriasis patients receiving methotrexate or tumor necrosis factor-α inhibitor (TNFi) and to assess TNFi treatment duration impact on major cardiovascular event risk. Adult psoriasis patients with ≥2 TNFi or methotrexate prescriptions in the Truven MarketScan Databases (Q1 2000-Q3 2011) were classified as TNFi or methotrexate users. The index date for each of these drugs was the TNFi initiation date or a randomly selected methotrexate dispensing date, respectively. Cardiovascular event risks and cumulative TNFi effect were analyzed by using multivariate Cox proportional-hazards models. By 12 months, TNFi users (N = 9148) had fewer cardiovascular events than methotrexate users (N = 8581) (Kaplan-Meier rates: 1.45% vs 4.09%: P < .01). TNFi users had overall lower cardiovascular event hazards than methotrexate users (hazard ratio = 0.55; P < .01). Over 24 months' median follow-up, every 6 months of cumulative exposure to TNFis were associated with an 11% cardiovascular event risk reduction (P = .02). Lack of clinical assessment measures. Psoriasis patients receiving TNFis had a lower major cardiovascular event risk compared to those receiving methotrexate. Cumulative exposure to TNFis was associated with a reduced risk for major cardiovascular events. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Regulatory aspects of the glutamylation of methotrexate in cultured hepatoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nimec, Z.; Galivan, J.

1983-10-15

The glutamylation of methotrexate has been evaluated in H35 hepatoma cells in vitro as a function of the conditions of culture. Glutamylation yields methotrexate polyglutamate with two to five additional glutamate residues and is a saturable process. The rate of glutamylation increases little above 10 microM extracellular methotrexate which corresponds to an intracellular concentration of approximately 4 microM. The rate of glutamylation measured over a 6-h period was stimulated by a reduction in cellular folates and prior incubation of the cells with insulin. Glutamylation was also more rapid in dividing cultures than in confluent cells. The combination of insulin inclusionmore » and folate reduction, which was additive, caused approximately a fourfold increase in the rate of glutamylation over control cells under the conditions tested. The maximal rate of methotrexate glutamylation, which was 100 nmol/g/h, occurred in folate-depleted, insulin-supplemented cells. Supplementing folate-depleted cells with reduced folate coenzymes caused the glutamylation to be reduced by more than 90%. In addition to showing that folates can modify the rates of methotrexate polyglutamate formation, data are presented suggesting that methotrexate polyglutamates can regulate their own synthesis. The consequences of the formation of these retained forms of methotrexate in H35 hepatoma cells and the effects of potential regulators of this process are discussed in terms of the glutamylation of folates in the cells and the chemotherapeutic effects of antifolates.« less

Risk of Nonmelanoma Skin Cancer Associated With the Use of Immunosuppressant and Biologic Agents in Patients With a History of Autoimmune Disease and Nonmelanoma Skin Cancer.

PubMed

Scott, Frank I; Mamtani, Ronac; Brensinger, Colleen M; Haynes, Kevin; Chiesa-Fuxench, Zelma C; Zhang, Jie; Chen, Lang; Xie, Fenglong; Yun, Huifeng; Osterman, Mark T; Beukelman, Timothy; Margolis, David J; Curtis, Jeffrey R; Lewis, James D

2016-02-01

Immune dysfunction underlies the pathogenesis of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Immunosuppressive therapy is the standard of care for these diseases. Both immune dysfunction and therapy-related immunosuppression can inhibit cancer-related immune surveillance in this population. Drug-induced immunosuppression is a risk factor for nonmelanoma skin cancer (NMSC), particularly squamous cell tumors. For patients with a history of NMSC, data are limited on the effect of these drugs on the risk of additional NMSCs. To determine the relative hazard of a second NMSC in patients with RA or IBD who use methotrexate, anti-tumor necrosis factor (anti-TNF) therapy, or thiopurines after an initial NMSC. In this retrospective cohort study, we studied 9460 individuals with RA or IBD enrolled in Medicare from January 1, 2006, through December 31, 2012. Exposure to methotrexate, thiopurines, anti-TNFs, sulfasalazine, hydroxychloroquine, abatacept, or rituximab after the incident NMSC surgery. A second NMSC occurring 1 year or more after the incident NMSC using Cox proportional hazards regression models. Among 9460 individuals (6841 with RA and 2788 with IBD), the incidence rate of a second NMSC per 1000 person-years was 58.2 (95% CI, 54.5-62.1) and 58.9 (95% CI, 53.2-65.2) in patients with RA and IBD, respectively. Among patients with RA, methotrexate used in conjunction with other medications was associated with an increased risk of a second NMSC (hazard ratio [HR], 1.60; 95% CI, 1.08-2.37). Adjusted for other medications, the risk of NMSC increased with 1 year or more of methotrexate use (HR, 1.24; 95% CI, 1.04-1.48). Compared with methotrexate alone, the addition of anti-TNF drugs was significantly associated with risk of NMSC (HR, 1.49; 95% CI, 1.03-2.16). Abatacept and rituximab were not associated with increased NMSC risk. The nonsignificant HRs for 1 year or more of thiopurine and anti-TNF use for IBD were 1.49 (95% CI, 0.98-2.27) and 1.36 (95% CI, 0.76-2.44), respectively. Methotrexate use is associated with an increased risk of a second NMSC. Anti-TNF use may increase the risk of a second NMSC when used with methotrexate for RA. Further long-term studies are required before one can conclude that thiopurine and/or anti-TNF do not increase the risk of a second NMSC in patients with IBD.

Dietary L-arginine supplementation reduces Methotrexate-induced intestinal mucosal injury in rat

PubMed Central

2012-01-01

Background Arginine (ARG) and nitric oxide maintain the mucosal integrity of the intestine in various intestinal disorders. In the present study, we evaluated the effects of oral ARG supplementation on intestinal structural changes, enterocyte proliferation and apoptosis following methotrexate (MTX)-induced intestinal damage in a rat. Methods Male rats were divided into four experimental groups: Control rats, CONTR-ARG rats, were treated with oral ARG given in drinking water 72 hours before and 72 hours following vehicle injection, MTX rats were treated with a single dose of methotrexate, and MTX-ARG rats were treated with oral ARG following injection of MTX. Intestinal mucosal damage, mucosal structural changes, enterocyte proliferation and enterocyte apoptosis were determined 72 hours following MTX injection. RT-PCR was used to determine bax and bcl-2 mRNA expression. Results MTX-ARG rats demonstrated greater jejunal and ileal bowel weight, greater ileal mucosal weight, greater ileal mucosal DNA and protein levels, greater villus height in jejunum and ileum and crypt depth in ileum, compared to MTX animals. A significant decrease in enterocyte apoptosis in the ileum of MTX-ARG rats (vs MTX) was accompanied by decreased bax mRNA and protein expression and increased bcl-2 protein levels. Conclusions Treatment with oral ARG prevents mucosal injury and improves intestinal recovery following MTX- injury in the rat. PMID:22545735

Effect of etodolac on methotrexate pharmacokinetics in patients with rheumatoid arthritis.

PubMed

Anaya, J M; Fabre, D; Bressolle, F; Bologna, C; Alric, R; Cocciglio, M; Dropsy, R; Sany, J

1994-02-01

To determine if the pharmacokinetics of methotrexate (MTX) is modified by the coadministration of etodolac. MTX (10 mg) was administered intramuscularly in the absence and presence of steady state levels of etodolac in 19 patients with rheumatoid arthritis. MTX levels were assayed by fluorescence polarization immunoassay. Concentrations of 7-hydroxymethotrexate (7-OH-MTX) were assayed by a reverse phase high performance liquid chromatography method. The unbound fraction was determined by ultrafiltration. When etodolac was coadministered with MTX, the highest observed concentration decreased and the mean residence time increased to become statistically significant. However, these differences are not of great clinical importance especially given that the area under the curve and clearances were unchanged. There were no significant differences in binding protein and 7-OH-MTX concentrations between MTX with and without etodolac administration. The pharmacokinetics of MTX is slightly modified by coadministration of etodolac. Moreover, no clinical toxicity was observed.

Environmental contamination with methotrexate in Canadian community pharmacies.

PubMed

Merger, Delphine; Tanguay, Cynthia; Langlois, Éric; Lefebvre, Michel; Bussières, Jean-François

2013-01-01

To evaluate environmental contamination with methotrexate, cyclophosphamide, and ifosfamide in Quebec, Canada, community pharmacies and to describe hazardous drug handling practices in these pharmacies. Three standardized sites were sampled in each participating community pharmacy. Samples were analyzed for the presence of cyclophosphamide, ifosfamide, and methotrexate by high-performance liquid chromatography tandem mass spectrometry. The limits of detection were 0.10, 0.12, and 0.41 ng/mL for cyclophosphamide, ifosfamide, and methotrexate, respectively. Nine working practices were assessed. 20 community pharmacies participated in the study, and 60 samples were analyzed. No traces of cyclophosphamide or ifosfamide were detected. Traces of methotrexate were found in 12 of 20 pharmacies (60%). Of the 20 pharmacies, 8 (40%) had a storage space reserved for hazardous drugs and none had a preparation area reserved for handling methotrexate tablets. All of the participating community pharmacies had a tablet counter reserved for the handling of hazardous drugs, and all pharmacies cleaned their tablet counter reserved for handling hazardous drugs after use. None of the pharmacies cut or crushed methotrexate tablets. The growing number of hazardous drugs represents a challenge for community pharmacies. Community pharmacists must be made aware of their presence and the need to comply with personal protection measures to reduce staff occupational exposure to hazardous drugs.

CCL20 and IL22 Messenger RNA Expression After Adalimumab vs Methotrexate Treatment of Psoriasis

PubMed Central

Goldminz, Ari M.; Suarez-Farinas, Mayte; Wang, Andrew C.; Dumont, Nicole; Krueger, James G.; Gottlieb, Alice B.

2018-01-01

IMPORTANCE Methotrexate is a first-line systemic agent for treating of psoriasis, although its onset of effects is slower and overall it is less effective than tumor necrosis factor blockers. OBJECTIVE To differentiate the response of psoriatic disease to adalimumab and methotrexate sodium. DESIGN, SETTING, AND PARTICIPANTS Single-center, randomized, assessor-blind, 2-arm clinical trial of 30 patients from the outpatient dermatology center of Tufts Medical Center, enrolled from August 18, 2009, to October 11, 2011. Patients aged 18 to 85 years with chronic plaque-type psoriasis, a minimum Physician Global Assessment score of 3 (higher scores indicate more severe disease), and a psoriatic plaque of at least 2 cm were randomized in a 1:1 fashion to receive subcutaneous adalimumab or oral methotrexate. Skin biopsy specimens obtained at baseline and weeks 1, 2, 4, and 16 were given a histologic grade by blinded assessors to evaluate treatment response. Analyses were conducted from April 16, 2013, to January 5, 2015. INTERVENTIONS A 16-week course of subcutaneous adalimumab (40 mg every 2 weeks after a loading dose) or low-dosage oral methotrexate sodium (7.5–25 mg/wk). MAIN OUTCOMES AND MEASURES Changes in genomic, immunohistochemical, and messenger RNA (mRNA) profiles. RESULTS Methotrexate responders experienced significant downregulation of helper T-cell– related (TH1, TH17, and TH22) mRNA expression compared with methotrexate nonresponders. Comparisons among adalimumab-treated patients were limited by the number of nonresponders (n = 1). Between adalimumab and methotrexate responders, we found no significant differences in gene expression at any study point or in the expression of T-cell–related mRNA at week 16. Adalimumab responders demonstrated early downregulation of chemokine (C-C motif) ligand 20 (CCL20) mRNA (mean [SE] at week 2, −1.83 [0.52], P < .001; week 16, −3.55 [0.54], P < .001) compared with late downregulation for methotrexate responders (week 2, 0.02 [0.51], P = .96; week 16, −2.96 [0.51], P < .001). Similar differences were observed with interleukin 22 (IL22) mRNA showing early downregulation for adalimumab responders (week 2, −3.17 [1.00], P < .001; week 16, −3.58 [1.00], P < .001) compared with late downregulation for methotrexate responders (week 2, −0.44 [0.68], P = .64; week 16, −5.14 [0.68], P < .001). Analysis of variance findings for key mRNA and immunohistochemical marker expression over the study course were significant only for CCL20 (P = .03) and IL22 (P = .006) mRNA comparing adalimumab and methotrexate responders. CONCLUSIONS AND RELEVANCE Methotrexate is an immunomodulator with effects on helper T-cell signaling in psoriasis. Similar genomic and immunohistochemical response signatures and levels of mRNA downregulation at study completion among adalimumab and methotrexate responders suggest a disease-driven instead of therapeutic-driven pathway regulation. Adalimumab and methotrexate responses are differentiated by patterns of normalization of CCL20 and IL22 mRNA expression and may explain the varied onset and degree of clinical responses by each treatment. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00932113 PMID:25946554

Long-term efficacy and safety of certolizumab pegol in Japanese rheumatoid arthritis patients with an inadequate response to methotrexate: 52-week results from an open-label extension of the J-RAPID study

PubMed Central

Tanaka, Yoshiya; Yamamoto, Kazuhiko; Takeuchi, Tsutomu; Yamanaka, Hisashi; Ishiguro, Naoki; Eguchi, Katsumi; Watanabe, Akira; Origasa, Hideki; Shoji, Toshiharu; Miyasaka, Nobuyuki; Koike, Takao

2014-01-01

Abstract Objectives. To evaluate the long-term efficacy and safety of certolizumab pegol (CZP) plus methotrexate treatment and to assess the efficacy of two CZP maintenance dosing schedules in Japanese rheumatoid arthritis (RA) patients with an inadequate response to methotrexate. Methods. J-RAPID double-blind patients were entered into an open-label extension (OLE) study. Patients withdrawn due to lack of efficacy at 16 weeks and double-blind completers without a week-24 American College of Rheumatology (ACR) 20 response received CZP 200 mg every other week (Q2W) plus methotrexate. Double-blind completers with week-24 ACR20 responses were randomized to CZP 200 mg Q2W plus methotrexate or CZP 400 mg every 4 weeks plus methotrexate. Results. The ACR20/ACR50/ACR70 response rates of double-blind completers (n = 204) were 89.7%/67.2%/36.3% at OLE entry and 95.6%/84.8%/58.3% at 52 weeks, respectively. Other clinical, functional and radiographic outcomes were sustained with long-term CZP plus methotrexate. Long-term treatment with CZP was well-tolerated with no new unexpected adverse events observed. The efficacy and safety of CZP treatment were similar between the two dosing schedules. Conclusions. Continued CZP administration with methotrexate maintained efficacy over 52 weeks and was well-tolerated for Japanese RA patients. No obvious differences in clinical efficacy and safety were observed between the two dosing schedules, giving flexibility in maintenance administration schedules. PMID:24593170

Examination of the effect of increasing doses of etoricoxib on oral methotrexate pharmacokinetics in patients with rheumatoid arthritis.

PubMed

Schwartz, Jules I; Agrawal, Nancy G B; Wong, P H; Miller, Jutta; Bachmann, Kenneth; Marbury, Thomas; Hoelscher, David; Cavanaugh, Paul F; Gottesdiener, Keith

2009-10-01

The authors designed 2 randomized controlled studies to examine the effects of etoricoxib 60 to 120 mg daily on methotrexate pharmacokinetics in 50 rheumatoid arthritis (RA) patients on stable doses of methotrexate (7.5-20 mg). Patients received oral methotrexate at baseline and on days 7 and 14. In study 1, patients received etoricoxib 60 mg (days 1-7) and then 120 mg (days 8-14); in study 2, patients received etoricoxib 90 mg (days 1-7) and then 120 mg (days 8-14). For study 1, the AUC(0-infinity) geometric mean ratio (GMR) (90% confidence interval [CI]) for day 7 versus baseline was 1.01 (0.91, 1.12) for etoricoxib 60 mg; the area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) GMR (90% CI) for day 14 was 1.28 (1.15, 1.42) for etoricoxib 120 mg. For study 2, the AUC(0-infinity) GMR (90% CI) for day 7 versus baseline was 1.07 (1.01, 1.13) for etoricoxib 90 mg; the AUC(0-infinity) GMR (90% CI) for day 14 was 1.05 (0.99, 1.11) for etoricoxib 120 mg. In summary, etoricoxib 60 and 90 mg had no effect on methotrexate plasma concentrations. Although no effect on methotrexate pharmacokinetics was observed with etoricoxib 120 mg in study 2, GMR AUC(0-infinity) fell outside the prespecified bounds in study 1. Standard monitoring of methotrexate-related toxicity should be continued when etoricoxib and methotrexate are administered concurrently, especially with doses >90 mg etoricoxib.

A single-blinded trial of methotrexate versus azathioprine as steroid-sparing agents in generalized myasthenia gravis

PubMed Central

2011-01-01

Background Long-term immunosuppression is often required in myasthenia gravis (MG). There are no published trials using methotrexate (MTX) in MG. The steroid-sparing efficacy of azathioprine (AZA) has been demonstrated after 18-months of starting therapy. However, AZA is considered expensive in Africa. We evaluated the steroid-sparing efficacy of MTX (17.5 mg weekly) compared with AZA (2.5 mg/kg daily) in subjects recently diagnosed with generalized MG by assessing their average monthly prednisone requirements. Methods The primary outcome was the average daily prednisone requirement by month between the two groups. Prednisone was given at the lowest dose to manage MG symptoms and adjusted as required according to protocol. Single-blinded assessments were performed 3-monthly for 2-years to determine the quantitative MG score and the MG activities of daily living score in order to determine those with minimal manifestations of MG. Results Thirty-one subjects (AZA n = 15; MTX n = 16) satisfied the inclusion criteria but only 24 were randomized. Baseline characteristics were similar. There was no difference between the AZA- and MTX-groups in respect of prednisone dosing (apart from months 10 and 12), in quantitative MG Score improvement, proportions in sustained remission, frequencies of MG relapses, or adverse reactions and/or withdrawals. The MTX-group received lower prednisone doses between month 10 (p = 0.047) and month 12 (p = 0.039). At month 12 the prednisone dose per kilogram bodyweight in the MTX-group (0.15 mg/kg) was half that of the AZA-group (0.31 mg/kg)(p = 0.019). Conclusions This study provides evidence that in patients with generalized MG methotrexate is an effective steroid-sparing agent 10 months after treatment initiation. Our data suggests that in generalized MG methotrexate has similar efficacy and tolerability to azathioprine and may be the drug of choice in financially constrained health systems. Trial registration SANCTR:DOH-27-0411-2436 PMID:21819556

Unilateral Salpingectomy and Methotrexate Are Associated With a Similar Recurrence Rate of Ectopic Pregnancy in Patients Undergoing In Vitro Fertilization.

PubMed

Irani, Mohamad; Robles, Alex; Gunnala, Vinay; Spandorfer, Steven D

To determine whether different treatment approaches of ectopic pregnancy (EP), particularly unilateral salpingectomy and methotrexate, affect its recurrence rate in patients undergoing in vitro fertilization (IVF). A retrospective cohort study (Canadian Task Force classification II-2). An academic medical center. Patients with a history of a previous EP who achieved pregnancy after IVF cycles between January 2004 and August 2015 were included. The recurrence rate of EP was compared between patients who underwent different treatment approaches for a previous EP. IVF. A total of 594 patients were included. Seventeen patients had a recurrence of EP (2.9%). Patients with a history of ≥2 EPs were associated with a significantly higher recurrence rate of EP than those with 1 previous EP (8.5% vs. 1.8%; p = .01; odds ratio [OR] = 2.2; 95% confidence interval [CI], 1.2-4.4). Patients who underwent unilateral salpingectomy (n = 245) had a comparable recurrence rate of EP after IVF with those who received methotrexate (n = 283) (3.6% vs. 2.8%; p = .5; OR = 1.3; 95% CI, 0.4-3.4). This OR remained unchanged after adjusting for patient's age, number of previous EPs, number of transferred embryos, and peak estradiol level during stimulation (adjusted OR = 1.4; 95% CI, 0.5-3.8). None of the patients who underwent bilateral salpingectomy (n = 45) or salpingostomy (n = 21) had a recurrence of EP after IVF. The recurrence rate of EP significantly correlates with the number of previous EPs. Treatment of EP with methotrexate has a comparable recurrence rate of EP after IVF with unilateral salpingectomy. Therefore, the risk of recurrence should not be a reason to favor salpingectomy over methotrexate in this population. Copyright © 2017 AAGL. Published by Elsevier Inc. All rights reserved.

Effects of a biologic agent in a patient with rheumatoid arthritis after treatment for methotrexate-associated B-cell lymphoma: a case report.

PubMed

Kuroda, Takeshi; Sato, Hiroe; Nakatsue, Takeshi; Wada, Yoko; Murakami, Shuichi; Nakano, Masaaki; Narita, Ichiei

2014-04-11

Several studies have suggested an increased risk of malignant tumor in patients with rheumatoid arthritis. It has been also reported that rheumatoid arthritis patients have a high incidence of lymphoma compared with the general population, and that patients receiving methotrexate, which is the anchor drug for rheumatoid arthritis treatment, can develop lymphoproliferative disease. Nevertheless, management of rheumatoid arthritis after treatment for methotrexate-associated lymphoma has not been fully investigated. We here report a patient with rheumatoid arthritis who developed malignant lymphoma associated with methotrexate therapy. Moreover, we describe the use of a biologic agent for a rheumatoid arthritis patient after treatment for lymphoma associated with methotrexate. A 60-year-old Japanese man with a 20-year history of rheumatoid arthritis was admitted to our hospital with a left inguinal tumor. Open biopsy was performed and a biopsy specimen revealed diffuse large B-cell lymphoma. As our patient had received methotrexate for 4 years, we diagnosed the lymphoproliferative disease as being methotrexate-related. This lymphoma was not associated with Epstein- Barr virus by Epstein-Barr virus-encoded ribonucleic acid in-situ hybridization, but this patient was an Epstein-Barr virus carrier, regarding serological testing. The lymphoma went into complete remission after 6 courses of rituximab plus cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone/prednisolone therapy. Two years later, however, rheumatoid arthritis activity gradually increased and was not controlled with salazosulfapyridine. Etanercept was administered in view of its possible effect on B-cells, and this reduced the level of disease activity without recurrence of lymphoma. The management of rheumatoid arthritis after treatment for methotrexate-associated lymphoma has not been fully investigated yet. Etanercept appeared to be safe because of its B-cell effect, but further observation is necessary to make a firm conclusion. Further accumulation of cases is needed to clarify which biologics are safe and effective for treatment of methotrexate-associated B-cell lymphoma.

Methotrexate-induced Hypersensitivity Pneumonitis appearing after 30 years of use: a case report.

PubMed

Salehi, Mashal; Miller, Robertha; Khaing, Myint

2017-06-28

Methotrexate has been implicated in a variety of lung complications, one of which is hypersensitivity pneumonitis. Hypersensitivity pneumonitis most often occurs within the first year of starting low-dose orally administered methotrexate. We present a case of methotrexate-induced hypersensitivity pneumonitis after 30 years of methotrexate use, which is the first case to be reported so far. A 77-year-old African American woman with a history of rheumatoid arthritis presented with progressively worsening shortness of breath and nonproductive cough. She was on a daily dose of 2.5 mg of methotrexate that had been orally administered for the last 30 years. A physical examination was significant for fever of 38.2 °C (100.8 °F), tachycardia, bilateral basal crackles, and oxygen saturation of 88% on room air. A laboratory work up was significant for normal white blood cell count, increased eosinophil count of 18.3%, and erythrocyte sedimentation rate of 111 mm/hour. Sputum cultures were negative for any bacterial pathogens including acid-fast bacilli. Influenza and respiratory syncytial viral infection were ruled out. A (1-3)-B-D-glucan assay (Fungitell®) was within normal limits. Pulmonary embolism was ruled out and echocardiography was normal. A chest X-ray showed hazy opacity with prominent reticulation within the upper lung fields bilaterally, right greater than the left with no pleural effusion. Lung computed tomography revealed nonspecific bilateral upper lung opacification. A pulmonary function test was significant for no obstruction, normal maximum voluntary ventilation, and no restriction, with mildly decreased diffusion. Methotrexate was stopped, and our patient was started on prednisone 60 mg orally administered daily with dramatic clinical and radiologic improvement. Methotrexate-induced hypersensitivity pneumonitis usually occurs in the initial few weeks to months of starting treatment with methotrexate; however, it can occur late during therapy too, and prompt diagnosis is crucial as it is a reversible condition when diagnosed early.

Cetuximab Prevents Methotrexate-Induced Cytotoxicity in Vitro through Epidermal Growth Factor Dependent Regulation of Renal Drug Transporters

PubMed Central

2017-01-01

The combination of methotrexate with epidermal growth factor receptor (EGFR) recombinant antibody, cetuximab, is currently being investigated in treatment of head and neck carcinoma. As methotrexate is cleared by renal excretion, we studied the effect of cetuximab on renal methotrexate handling. We used human conditionally immortalized proximal tubule epithelial cells overexpressing either organic anion transporter 1 or 3 (ciPTEC-OAT1/ciPTEC-OAT3) to examine OAT1 and OAT3, and the efflux pumps breast cancer resistance protein (BCRP), multidrug resistance protein 4 (MRP4), and P-glycoprotein (P-gp) in methotrexate handling upon EGF or cetuximab treatment. Protein kinase microarrays and knowledge-based pathway analysis were used to predict EGFR-mediated transporter regulation. Cytotoxic effects of methotrexate were evaluated using the dimethylthiazol bromide (MTT) viability assay. Methotrexate inhibited OAT-mediated fluorescein uptake and decreased efflux of Hoechst33342 and glutathione-methylfluorescein (GS-MF), which suggested involvement of OAT1/3, BCRP, and MRP4 in transepithelial transport, respectively. Cetuximab reversed the EGF-increased expression of OAT1 and BCRP as well as their membrane expressions and transport activities, while MRP4 and P-gp were increased. Pathway analysis predicted cetuximab-induced modulation of PKC and PI3K pathways downstream EGFR/ERBB2/PLCg. Pharmacological inhibition of ERK decreased expression of OAT1 and BCRP, while P-gp and MRP4 were increased. AKT inhibition reduced all transporters. Exposure to methotrexate for 24 h led to a decreased viability, an effect that was reversed by cetuximab. In conclusion, cetuximab downregulates OAT1 and BCRP while upregulating P-gp and MRP4 through an EGFR-mediated regulation of PI3K-AKT and MAPKK-ERK pathways. Consequently, cetuximab attenuates methotrexate-induced cytotoxicity, which opens possibilities for further research into nephroprotective comedication therapies. PMID:28493713

Cetuximab Prevents Methotrexate-Induced Cytotoxicity in Vitro through Epidermal Growth Factor Dependent Regulation of Renal Drug Transporters.

PubMed

Caetano-Pinto, Pedro; Jamalpoor, Amer; Ham, Janneke; Goumenou, Anastasia; Mommersteeg, Monique; Pijnenburg, Dirk; Ruijtenbeek, Rob; Sanchez-Romero, Natalia; van Zelst, Bertrand; Heil, Sandra G; Jansen, Jitske; Wilmer, Martijn J; van Herpen, Carla M L; Masereeuw, Rosalinde

2017-06-05

The combination of methotrexate with epidermal growth factor receptor (EGFR) recombinant antibody, cetuximab, is currently being investigated in treatment of head and neck carcinoma. As methotrexate is cleared by renal excretion, we studied the effect of cetuximab on renal methotrexate handling. We used human conditionally immortalized proximal tubule epithelial cells overexpressing either organic anion transporter 1 or 3 (ciPTEC-OAT1/ciPTEC-OAT3) to examine OAT1 and OAT3, and the efflux pumps breast cancer resistance protein (BCRP), multidrug resistance protein 4 (MRP4), and P-glycoprotein (P-gp) in methotrexate handling upon EGF or cetuximab treatment. Protein kinase microarrays and knowledge-based pathway analysis were used to predict EGFR-mediated transporter regulation. Cytotoxic effects of methotrexate were evaluated using the dimethylthiazol bromide (MTT) viability assay. Methotrexate inhibited OAT-mediated fluorescein uptake and decreased efflux of Hoechst33342 and glutathione-methylfluorescein (GS-MF), which suggested involvement of OAT1/3, BCRP, and MRP4 in transepithelial transport, respectively. Cetuximab reversed the EGF-increased expression of OAT1 and BCRP as well as their membrane expressions and transport activities, while MRP4 and P-gp were increased. Pathway analysis predicted cetuximab-induced modulation of PKC and PI3K pathways downstream EGFR/ERBB2/PLCg. Pharmacological inhibition of ERK decreased expression of OAT1 and BCRP, while P-gp and MRP4 were increased. AKT inhibition reduced all transporters. Exposure to methotrexate for 24 h led to a decreased viability, an effect that was reversed by cetuximab. In conclusion, cetuximab downregulates OAT1 and BCRP while upregulating P-gp and MRP4 through an EGFR-mediated regulation of PI3K-AKT and MAPKK-ERK pathways. Consequently, cetuximab attenuates methotrexate-induced cytotoxicity, which opens possibilities for further research into nephroprotective comedication therapies.

Interaction of Human Hemoglobin with Methotrexate

NASA Astrophysics Data System (ADS)

Zaharia, M.; Gradinaru, R.

2015-05-01

This study focuses on the interaction between methotrexate and human hemoglobin using steady-state ultraviolet-visible and fluorescence quenching methods. Fluorescence quenching was found to be valuable in assessing drug binding to hemoglobin. The quenching of methotrexate is slightly smaller than the quenching observed with related analogs (dihydrofolate and tetrahydrofolate). The quenching studies were performed at four different temperatures and various pH values. The number of binding sites for tryptophan is ~1. Parameter-dependent assays revealed that electrostatic forces play an essential role in the methotrexate-hemoglobin interaction. Furthermore, the complex was easily eluted using gel filtration chromatography.

Curcumin and folic acid abrogated methotrexate induced vascular endothelial dysfunction.

PubMed

Sankrityayan, Himanshu; Majumdar, Anuradha S

2016-01-01

Methotrexate, an antifolate drug widely used in rheumatoid arthritis, psoriasis, and cancer, is known to cause vascular endothelial dysfunction by causing hyperhomocysteinemia, direct injury to endothelium or by increasing the oxidative stress (raising levels of 7,8-dihydrobiopterin). Curcumin is a naturally occurring polyphenol with strong antioxidant and anti-inflammatory action and therapeutic spectra similar to that of methotrexate. This study was performed to evaluate the effects of curcumin on methotrexate induced vascular endothelial dysfunction and also compare its effect with that produced by folic acid (0.072 μg·g(-1)·day(-1), p.o., 2 weeks) per se and in combination. Male Wistar rats were exposed to methotrexate (0.35 mg·kg(-1)·day(-1), i.p.) for 2 weeks to induce endothelial dysfunction. Methotrexate exposure led to shedding of endothelium, decreased vascular reactivity, increased oxidative stress, decreased serum nitrite levels, and increase in aortic collagen deposition. Curcumin (200 mg·kg(-1)·day(-1) and 400 mg·kg(-1)·day(-1), p.o.) for 4 weeks prevented the increase in oxidative stress, decrease in serum nitrite, aortic collagen deposition, and also vascular reactivity. The effects were comparable with those produced by folic acid therapy. The study shows that curcumin, when concomitantly administered with methotrexate, abrogated its vascular side effects by preventing an increase in oxidative stress and abating any reduction in physiological nitric oxide levels.

Formation of methotrexate-PLLA-PEG-PLLA composite microspheres by microencapsulation through a process of suspension-enhanced dispersion by supercritical CO2

PubMed Central

Chen, Ai-Zheng; Wang, Guang-Ya; Wang, Shi-Bin; Li, Li; Liu, Yuan-Gang; Zhao, Chen

2012-01-01

Background The aim of this study was to improve the drug loading, encapsulation efficiency, and sustained-release properties of supercritical CO2-based drug-loaded polymer carriers via a process of suspension-enhanced dispersion by supercritical CO2 (SpEDS), which is an advanced version of solution-enhanced dispersion by supercritical CO2 (SEDS). Methods Methotrexate nanoparticles were successfully microencapsulated into poly (L-lactide)-poly(ethylene glycol)-poly(L-lactide) (PLLA-PEG-PLLA) by SpEDS. Methotrexate nanoparticles were first prepared by SEDS, then suspended in PLLA-PEG-PLLA solution, and finally microencapsulated into PLLA-PEG-PLLA via SpEDS, where an “injector” was utilized in the suspension delivery system. Results After microencapsulation, the composite methotrexate (MTX)-PLLA-PEG-PLLA microspheres obtained had a mean particle size of 545 nm, drug loading of 13.7%, and an encapsulation efficiency of 39.2%. After an initial burst release, with around 65% of the total methotrexate being released in the first 3 hours, the MTX-PLLA-PEG-PLLA microspheres released methotrexate in a sustained manner, with 85% of the total methotrexate dose released within 23 hours and nearly 100% within 144 hours. Conclusion Compared with a parallel study of the coprecipitation process, microencapsulation using SpEDS offered greater potential to manufacture drug-loaded polymer microspheres for a drug delivery system. PMID:22787397

Rheumatoid arthritis-related interstitial lung disease (RA-ILD): methotrexate and the severity of lung disease are associated to prognosis.

PubMed

Rojas-Serrano, Jorge; Herrera-Bringas, Denisse; Pérez-Román, Diana I; Pérez-Dorame, Renzo; Mateos-Toledo, Heidegger; Mejía, Mayra

2017-07-01

Interstitial lung disease (ILD) is a severe rheumatoid arthritis (RA) manifestation. The worst survival has been associated with usual interstitial pneumonia (UIP) definitive pattern in high-resolution chest tomography (HRCT) scans. Moreover, the use of methotrexate in RA-ILD is controversial. Our aim was to evaluate prognostic factors including methotrexate in an RA-ILD cohort and their association with survival. RA-ILD patients referred for medical evaluation and treatment at a single center were included. At the baseline, pulmonary function tests were carried out and a HRCT was obtained. A radiologist evaluated the ILD tomographic pattern and the extent of lung disease. Patients were considered as receiving methotrexate therapy if this drug was specifically prescribed for the treatment of RA-ILD at the beginning of follow up. Seventy-eight patients were included. UIP definite pattern in HRCT was not associated to worse survival. Variables associated with mortality reflected the severity of lung disease. Treatment with methotrexate was associated with survival (HR 0.13, 95% CI 0.02-0.64); older patients had worse prognosis (HR 1.04, 95% CI 1.003-1.09). After adjusting for confounding variables, methotrexate was strongly associated with survival. Methotrexate treatment during follow up was associated with survival. The severity of lung disease and not the tomographic pattern is associated with mortality; older patients had worse prognosis.

Use of methotrexate in patients with uveitis.

PubMed

Ali, A; Rosenbaum, J T

2010-01-01

Methotrexate has been frequently employed to treat ocular inflammatory diseases including uveitis, scleritis, and orbital inflammatory disease. It is effective for intraocular lymphoma when given directly into the eye. No study has assessed its efficacy for eye disease in a randomised, placebo controlled design. This report reviews the literature relevant to methotrexate's utility in the treatment of ocular inflammatory disease.

Direct Determination of Vibrational Density of States Change on Ligand Binding to a Protein

NASA Astrophysics Data System (ADS)

Balog, Erika; Becker, Torsten; Oettl, Martin; Lechner, Ruep; Daniel, Roy; Finney, John; Smith, Jeremy C.

2004-07-01

The change in the vibrational density of states of a protein (dihydrofolate reductase) on binding a ligand (methotrexate) is determined using inelastic neutron scattering. The vibrations of the complex soften significantly relative to the unbound protein. The resulting free-energy change, which is directly determined by the density of states change, is found to contribute significantly to the binding equilibrium.

Efficacy and Safety of Second-Line 5-Day Dactinomycin in Case of Methotrexate Failure for Gestational Trophoblastic Neoplasia.

PubMed

Prouvot, Catherine; Golfier, François; Massardier, Jérôme; You, Benoit; Lotz, Jean-Pierre; Patrier, Sophie; Devouassoux, Mojgan; Schott, Anne-Marie; Hajri, Touria; Bolze, Pierre-Adrien

2018-06-01

The objective of this study was to evaluate the characteristics and outcomes of patients treated for gestational trophoblastic neoplasia (GTN) with second-line 5-day dactinomycin after failed first-line 8-day methotrexate. From 1999 to 2017, patients with methotrexate resistant GTN treated with second line dactinomycin were identified at the French Trophoblastic Disease Reference Center. Using univariate and multivariate analysis, we identified significant predictive factors of second line dactinomycin failure. A total of 877 GTN patients were treated with first-line 8-day methotrexate, of which 103 required second-line 5-day dactinomycin for methotrexate failure. Complete response was observed in 78 patients (75.7% [95% confidence interval, 66.3-83.6]; P < 0.0001), whereas 25 needed third-line treatment, 13 for dactinomycin resistance and 12 for post-dactinomycin relapse. Overall survival of patients treated with dactinomycin was 100%. An interval of greater than or equal to 7 months between antecedent pregnancy termination and methotrexate initiation was a predictive factor significantly associated with second-line dactinomycin failure in multivariate analysis (exact odds ratio, 9.17 [95% confidence interval, 1.98-50.70]; P = 0.0029). No grades 4 and 5 adverse effects were experienced and the most common toxicity being grade 1 nausea (14.6%). Given a 75.7% complete response rate in methotrexate failed low-risk GTN patients treated with second-line dactinomycin and an overall survival rate of 100% after third-line treatment, the use of dactinomycin should be favored as second-line, regardless of human chorionic gonadotropin level at the time of dactinomycin initiation. However, an interval between the termination of the antecedent pregnancy and methotrexate initiation longer than 6 months should encourage considering alternative therapeutic strategies.

Evaluation of the effect of losartan and methotrexate combined therapy in adjuvant-induced arthritis in rats.

PubMed

Refaat, Rowaida; Salama, Mona; Abdel Meguid, Elham; El Sarha, Ashgan; Gowayed, Mennatallah

2013-01-05

There is increasing body of evidence documenting the involvement of angiotensin II in inflammatory diseases. Moreover the up-regulation of angiotensin II AT(1) receptors in the synovium of rheumatoid arthritis patients has been previously described. This study aimed at investigating the anti-inflammatory effect of losartan, the selective angiotensin II AT(1) receptor blocker, and comparing the efficacy of methotrexate alone and in combination with losartan in adjuvant arthritis in rats. Twelve days post adjuvant injection, Sprague-Dawley rats were treated with methotrexate (1mg/kg/week), losartan (20mg/kg/day) and their combination for 15 days. Severity of arthritis was assessed by hind paw swelling, arthrogram scores. Serum was analyzed for measurement of albumin, C-reactive protein (CRP), nitrite/nitrate concentrations, interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), aspartate transaminase (AST) and alanine transaminase (ALT). Histopathological examination was done for hind paws and livers. Methotrexate and losartan monotherapies significantly reduced all parameters of inflammation and arthritis with better results in the methotrexate group except for the transaminases where losartan caused more significant reduction in their serum levels. The combined therapy showed better results than methotrexate and losartan alone. Hind paws showed better improvement of inflammatory cell infiltration and bone resorption in the combined therapy group. Disturbances in liver architecture and fibrosis caused by adjuvant arthritis were reverted to normal status in the combined therapy group in contrast to losartan and methotrexate monotherapies. In conclusion, methotrexate and losartan combined therapy provided more effective anti-inflammatory and hepatoprotective effects than either drug alone. Copyright © 2012 Elsevier B.V. All rights reserved.

Long term safety of methotrexate in routine clinical care: discontinuation is unusual and rarely the result of laboratory abnormalities

PubMed Central

Yazici, Y; Sokka, T; Kautiainen, H; Swearingen, C; Kulman, I; Pincus, T

2005-01-01

Objective: To analyse patients with rheumatoid arthritis, treated with methotrexate in a weekly academic rheumatology clinic over 13 years, for continuation of courses and reasons for discontinuation. Methods: All 248 patients with an analysable longitudinal course who took methotrexate in standard care between 1990 and 2003 were studied. Continuation of courses was analysed using life tables. All abnormal and severely abnormal values for aspartate aminotransferase (AST) >40 U/l, >80 U/l, albumin <35 g/l, <30 g/l, white blood cell (WBC) count <4.0x109/l, <3.0x109/l, and platelet count <150x109/l, <100x109/l, were identified. Responses of the clinician and subsequent laboratory values were reviewed. Results: Over 1007 person-years, the probability of continuing methotrexate over five years was 79% (95% confidence interval, 72% to 84%). Severe laboratory abnormalities occurred in 2.9 per 100 person-years, specifically 0.9 for AST >80 U/l, 1.1 for albumin <30 g/l, 0.7 for WBC <3.0x109/l, and 0.3 for platelets <100x109/l. No severe laboratory abnormality progressed to further severity or clinical disease. Permanent discontinuations of methotrexate occurred in 46 patients (19%), 26 (10% of all patients) for adverse effects, 15 (32.6%) for inefficacy; only two discontinuations resulted from laboratory abnormalities, both of WBC, possibly from other sources. Conclusions: Methotrexate was associated with a high rate of continuation, and few clinically significant laboratory abnormalities. Discontinuation primarily reflected clinical rather than laboratory findings. Vigilance for methotrexate toxicity is required but methotrexate appears among the safest treatments for rheumatoid arthritis. PMID:15208176

Safety and efficacy of ocrelizumab in rheumatoid arthritis patients with an inadequate response to methotrexate or tumor necrosis factor inhibitors: a systematic review and meta-analysis.

PubMed

Abushouk, Abdelrahman Ibrahim; Ahmed, Hussien; Ismail, Ammar; Elmaraezy, Ahmed; Badr, Ahmed Said; Gadelkarim, Mohamed; Elnenny, Mohammed

2017-07-01

We conducted this systematic reviews and meta-analysis to investigate the safety and efficacy of ocrelizumab in patients with active rheumatoid arthritis (RA) who exhibited resistance or intolerance to methotrexate or biological therapy. We performed a web-based literature search of PubMed, Google Scholar, EBSCO, Scopus, Embase, and Web of science for studies that compared ocrelizumab plus methotrexate versus methotrexate plus placebo in RA patients. Data were extracted from eligible studies and pooled as risk ratios (RR), using RevMan software. Pooling data from four RCTs (2230 patients) showed that ocrelizumab plus methotrexate were superior to methotrexate plus placebo at 24 weeks in terms of improvement on the American college of rheumatology (ACR20, ACR50, and ACR70) criteria (p < 0.00001), disease activity score 28-ESR (RR = 3.77, 95% CI [2.47, 5.74], p < 0.00001), and Sharp/van der Heijde radiological score (RR = 1.63, 95% CI [1.43, 1.85], p < 0.00001). These effects were consistent among all ocrelizumab doses. The rates of serious adverse events were comparable between the ocrelizumab and placebo containing groups (RR = 1, 95% CI [0.78, 1.28], p = 0.98). However, infusion related reactions were significantly higher in ocrelizumab group (RR = 2.13, 95% CI [1.69, 2.68], p < 0.00001), compared to placebo group. The combination of ocrelizumab plus methotrexate was superior to methotrexate plus placebo on all clinical and radiographic improvement scales. The incidence of adverse events, including serious adverse events, was comparable between both groups. Future trials should investigate the efficacy of ocrelizumab alone and develop strategies to alleviate its related infusion reactions.

Interaction between rhein acyl glucuronide and methotrexate based on human organic anion transporters.

PubMed

Yuan, Yuan; Yang, Hua; Kong, Linghua; Li, Yuan; Li, Ping; Zhang, Hongjian; Ruan, Jianqing

2017-11-01

Rhein, a major bioactive compound of many medicinal herbs and the prodrug of diacerein, is often used with low dose of methotrexate as drug combination to treat rheumatoid arthritis. In this study, potential drug-drug interaction between methotrexate and rhein was investigated based on organic anion transporters (OAT). Our study demonstrated that rhein acyl glucuronide (RAG), the major metabolite of rhein in the human blood circulation, significantly inhibited the uptake of p-aminohippurate in hOAT1 transfected cells with IC 50 value of 691 nM and estrone sulfate uptake in hOAT3 transfected cells with IC 50 value of 78.5 nM. As the substrate of both hOAT1 and hOAT3, the methotrexate transport was significantly inhibited by RAG in hOAT1 transfected cells at 50 μM and hOAT3 transfected cells at 1 μM by 69% and 87%, respectively. Further in vivo study showed that after co-administrated with RAG in rats the AUC 0-24 values of methotrexate increased from 3109 to 5370 ng/mL*hr and the t 1/2 was prolonged by 40.5% (from 7.4 to 10.4 h), demonstrating the inhibitory effect of RAG on methotrexate excretion. In conclusion, rhein acyl glucuronide could significantly decrease the transport of methotrexate by both hOAT1 and hOAT3. The combination use of rhein, diacerein or other rhein-containing herbs with methotrexate may cause obvious drug-drug interaction and require close monitoring for potential drug interaction in clinical practice. Copyright © 2017 Elsevier B.V. All rights reserved.

HER2 specific delivery of methotrexate by dendrimer conjugated anti-HER2 mAb

NASA Astrophysics Data System (ADS)

Shukla, Rameshwer; Thomas, Thommey P.; Desai, Ankur M.; Kotlyar, Alina; Park, Steve J.; Baker, James R., Jr.

2008-07-01

Herceptin, a humanized monoclonal antibody that binds to human growth factor receptor-2 (HER2), was covalently attached to a fifth-generation (G5) polyamidoamine dendrimer containing the cytotoxic drug methotrexate. The specific binding and internalization of this conjugate labeled with FITC was clearly demonstrated in cell lines overexpressing HER2 by flow cytometry as well as confocal microscopic analysis. In addition, binding and uptake of antibody conjugated dendrimers was completely blocked by excess non-conjugated herceptin. The dendrimer conjugate was also shown to inhibit the dihydrofolate reductase with similar activity to methotrexate. Co-localization experiments with lysotracker red indicate that antibody conjugate, although internalized efficiently into cells, has an unusually long residence time in the lysosome. Somewhat lower cytotoxicity of the conjugate in comparison to free methotrexate was attributed to the slow release of methotrexate from the conjugate and its long retention in the lysosomal pocket.

Methotrexate: Underused and ignored?

PubMed Central

Herfarth, Hans H; Long, Millie D; Isaacs, Kim L

2015-01-01

For greater than a decade, methotrexate has been known to be an effective therapeutic agent in the treatment of steroid dependent active Crohn's disease. However, international data on medication utilization suggest that this drug is rarely used in clinical practice for an indication of Crohn's disease. This review investigates the potential reasons for the underuse of methotrexate in patients with inflammatory bowel diseases. PMID:23295701

Methotrexate therapy for chronic noninfectious uveitis: analysis of a case series of 160 patients.

PubMed

Samson, C M; Waheed, N; Baltatzis, S; Foster, C S

2001-06-01

To evaluate the outcomes of patients with chronic noninfectious uveitis unresponsive to conventional antiinflammatory therapy who were treated with methotrexate. Retrospective noncomparative interventional case series. All patients with chronic noninfectious uveitis treated with methotrexate at a single institution from 1985 to 1999. Charts of patients seen on the Ocular Immunology & Uveitis Service at the Massachusetts Eye & Ear Infirmary were reviewed. Patients with chronic uveitis of noninfectious origin treated with methotrexate were included in the study. Control of inflammation, steroid-sparing effect, visual acuity, adverse reactions. A total of 160 patients met the inclusion criteria. Control of inflammation was achieved in 76.2% of patients. Steroid-sparing effect was achieved in 56% of patients. Visual acuity was maintained or improved in 90% of patients. Side effects requiring discontinuation of medication occurred in 18% of patients. Potentially serious adverse reactions occurred in only 8.1% of patients. There was neither long-term morbidity nor mortality caused by methotrexate. Methotrexate is effective in the treatment of chronic noninfectious uveitis that fails to respond to conventional steroid treatment. It is an effective steroid-sparing immunomodulator, is a safe medication, and is well tolerated.

Preparation and characterization of PLGA-β-CD polymeric nanoparticles containing methotrexate and evaluation of their effects on T47D cell line.

PubMed

Gorjikhah, Fatemeh; Azizi Jalalian, Farid; Salehi, Roya; Panahi, Yunes; Hasanzadeh, Arash; Alizadeh, Effat; Akbarzadeh, Abolfazl; Davaran, Soodabeh

2017-05-01

Among all cancers that affect women, breast cancer has most mortality rate. It is essential to attain more safe and efficient anticancer drugs. Recent advances in medical nanotechnology and biotechnology have caused in novel improvements in breast and other cancer drug delivery. Methotrexate is an anticancer drug that prevents the dihydrofolate reductase enzyme, which inhibits in the formation of DNA, RNA and proteins which have poor water-solubility. For enhancing the solubility and stability of drugs in delivery systems, we used methotrexate-loaded PLGA- beta-cyclodextrin nanoparticles. The PLGA- beta-cyclodextrin nanoparticles were synthesized by a double emulsion method and characterized with FT-IR and SEM. T47D breast cancer cell lines were treated with equal concentrations of methotrexate-loaded PLGA- beta-cyclodextrin nanoparticles and free methotrexate. MTT assay confirmed that methotrexate-loaded PLGA- beta-cyclodextrin nanoparticles enhanced cytotoxicity and drug delivery in T47D breast cancer cells. These results indicate that encapsulated drugs could be effective in controlled drug release for a sustained period would serve the purpose for long-term treatment of many diseases such as breast cancer.

Efficacy of etanercept in preventing relapse of uveitis controlled by methotrexate.

PubMed

Foster, C Stephen; Tufail, Fehma; Waheed, Nadia Khalida; Chu, David; Miserocchi, Elisabetta; Baltatzis, Stefanos; Vredeveld, Cindy M

2003-04-01

To evaluate the efficacy of etanercept vs placebo in preventing relapses of uveitis in patients taking methotrexate with control of uveitis and whose methotrexate dosage was being tapered. Patients with chronic or recurrent noninfectious uveitis with inflammation controlled by low-dose methotrexate were randomized to either the drug or placebo group in a double-masked manner, given a methotrexate taper schedule, and followed for 24 weeks. The main outcome measures were control of inflammation, visual acuity, and adverse reactions. Data were analyzed both as an attempt-to-treat analysis and an analysis only of those patients who completed the study. A total of 20 patients were randomized to the drug and placebo groups. Relapse of uveitis occurred in 3 of 10 patients in the treatment group and 5 of 10 patients in the control group. Two patients in the treatment group withdrew prematurely from the study due to adverse effects. There was no significant difference between the treatment and placebo groups with regard to the rate of relapse and the final visual acuity. No patient suffered from any irreversible, long-term morbidity or mortality. Etanercept has no significant efficacy over placebo in preventing relapses of uveitis in patients being tapered from methotrexate.

Methotrexate as a first-line corticosteroid-sparing therapy in a cohort of uveitis and scleritis.

PubMed

Kaplan-Messas, Audrey; Barkana, Yaniv; Avni, Isaac; Neumann, Ron

2003-06-01

To evaluate the clinical experience with methotrexate as a first-line corticosteroid-sparing drug in patients with resistant ocular inflammation. We retrospectively studied 39 consecutive patients with uveitis (n = 36) or scleritis (n = 3) who were treated with methotrexate following inadequate control with corticosteroids lasting five years. Criteria for initiating treatment with methotrexate and defining outcome were strictly defined. The cohort included 21 females and 18 males, all Caucasians, with a mean age of 26.6 years (range: 3-73 years). Patients were followed up for 21.5 +/- 12.6 months. Treatment was discontinued due to side effects in 10 patients (26%). Of the remaining 29 patients, full or partial control of inflammation was achieved in 23 (79%). Response to treatment was observed after a mean of 2.4 +/- 0.8 months. Ten patients were fully controlled and discontinued methotrexate therapy after a mean of 20.9 +/- 9.2 months, with no recurrence of inflammation. Use of topical and systemic corticosteroids was markedly reduced in responsive patients. Methotrexate is recommended as a first-line adjunct to or replacement of systemic corticosteroids in the treatment of ocular inflammation.

RFC1 80G>A is a genetic determinant of methotrexate efficacy in rheumatoid arthritis: a human genome epidemiologic review and meta-analysis of observational studies.

PubMed

Kung, Tabitha N; Dennis, Jessica; Ma, Yiqing; Xie, Gang; Bykerk, Vivian; Pope, Janet; Thorne, Carter; Keystone, Edward; Siminovitch, Katherine A; Gagnon, France

2014-05-01

Associations have been reported between candidate genes and the response to methotrexate (MTX) in rheumatoid arthritis (RA) patients, but most of the studies have been small and have yielded conflicting results. This study was undertaken to provide a systematic review of all genetic variant associations with MTX efficacy and toxicity, and to conduct a meta-analysis evaluating the most commonly studied single-nucleotide polymorphism for which prior cumulative analysis has been lacking. A systematic review and meta-analysis were performed to identify genetic variant associations with MTX efficacy and toxicity. Studies were identified from the Medline, EMBase, HuGENet Navigator, and Cochrane Library databases through December 2012, and from the 2009-2011 abstracts of the American College of Rheumatology and the European League Against Rheumatism annual meeting proceedings. Additional unpublished genotype data from a Canadian cohort of patients with early RA were also included. Among the 87 identified studies examining genetic associations with MTX efficacy and toxicity, the reduced folate carrier 1 gene (RFC1) variant 80G>A (Arg(27) His, rs1051266) was selected for random-effects meta-analysis. RFC1 80G>A was associated with MTX efficacy in both the recessive model (odds ratio [OR] 1.42, 95% confidence interval [95% CI] 1.04-1.93) and the additive model (OR 1.28, 95% CI 1.10-1.49). Restriction of the sensitivity analyses to studies that involved Caucasian subjects only and that used similar outcome measures (MTX failure versus nonfailure) maintained and improved the associations in both models. No significant association between RFC1 80G>A and MTX toxicity was detected. In these analyses of available data from observational studies, RFC1 80G>A was found to be associated with MTX efficacy, but not toxicity, in RA patients. This variant merits further prospective analysis as a potential predictor of MTX efficacy. Variability in the definitions of response in pharmacogenetic studies is a source of data heterogeneity that should be addressed. Copyright © 2014 by the American College of Rheumatology.

Development and validation of a turbulent flow chromatography and tandem mass spectrometry method for the quantitation of methotrexate and its metabolites 7-hydroxy methotrexate and DAMPA in serum

PubMed Central

Schofield, Ryan C.; Ramanathan, Lakshmi V.; Murata, Kazunori; Grace, Marie; Fleisher, Martin; Pessin, Melissa S.; Carlow, Dean C.

2016-01-01

A rapid and simple turbulent flow liquid chromatography (TFC–LC) method implementing positive heated electrospray ionization (HESI) for the accurate and precise determination of methotrexate (MTX), 7-hydroxy methotrexate (7-OH MTX), and 4-amino-4-deoxy-N10-methylpteroic acid (DAMPA) concentrations in serum was developed. MTX was isolated from serum samples (100 μL) after protein precipitation with methanol containing formic acid and internal standard (MTX-D3) followed by centrifugation. The supernatant was injected into the turbulent flow liquid chromatography which is followed by electrospray positive ionization tandem mass spectrometry (TFC–LC–MS/MS) and quantified using a six-point calibration curve. For MTX and DAMPA the assays were linear from 10 to 1000 nmol/L and for 7-OH MTX from 20 to 2000 nmol/L. Dilutions of 10, 100 and 1000-fold were validated giving a clinically reportable range of 10 nmol/L to 5 × 105 nmol/L. Within-day and between-day precisions at concentrations spanning the analytical measurement ranges were less than 10% for all three analytes. MTX, DAMPA and 7-OH MTX were sufficiently stable under all relevant analytical conditions. No significant matrix effect was observed during the method validation. The TFC–LC-MS/MS MTX method was also compared with three other clinically validated MTX assays: a dihydrofolate reductase (DHFR) inhibition assay, an immunoassay based on fluorescence polarization and a previously developed LC–MS/MS assay. PMID:26322588

Protective effects of propolis on methotrexate-induced testis injury in rat.

PubMed

Sönmez, Mehmet Fatih; Çilenk, Kübra Tuğçe; Karabulut, Derya; Ünalmış, Sunay; Deligönül, Erkan; Öztürk, İsmet; Kaymak, Emin

2016-04-01

Propolis is an adhesive substance which is collected and used by honeybees. Propolis is a potent antioxidant and a free radical scavenger. This study was designed to determine whether propolis could protect against dysfunction and oxidative stress induced by methotrexate-induced injury in rat testis. A total of 40 male Wistar albino rats were divided into four groups: group 1 was the untreated control. On the eighth day of the experiment, groups 2 and 3 received single intraperitoneal injections of methotrexate (MTX) at 20mg/kg. Groups 3 and 4 received 100mg/kg/day propolis (by oral gavage) for 15 days by the first day of the experimental protocol. Then the rats were decapitated under anesthesia, and their testes were removed. The histopathological and biochemical analysis along with apoptosis assessment of testis tissues were compared. Immunohistochemical analysis of Heat shock protein-70 (HSP-70) and Proliferating Cell Nuclear Antigen (PCNA) were performed. The phenolic characterization of propolis was performed by Liquid chromatography-mass spectrometry (LC-MS/MS). Methotrexate caused tended to increase in malondialdehyde level and in the number of apoptotic cells; it also caused a decrease in MSTD and JTBS, PCNA and HSP-70 expression and xanthine oxidase levels in group 2. Propolis prevented the rise in malondialdehyde, xanthine oxidase levels and HSP-70 expression and improved testicular morphology and JTBS. It was found that, methorexate gives rise to serious damage in the testes and propolis is a potent antioxidant agent in preventing testicular injury. Copyright © 2016. Published by Elsevier Masson SAS.

Comparing ultraviolet light A photo(chemo)therapy with Methotrexate protocol in childhood localized scleroderma: Evidence from systematic review and meta-analysis approach.

PubMed

Marrani, Edoardo; Foeldvari, Ivan; Lopez, Jordi Anton; Cimaz, Rolando; Simonini, Gabriele

2018-03-14

Localized scleroderma is a skin fibrosing disorder that, if untreated, may result in severe disability. The purpose of this systematic review is to compare the present evidence concerning the effectiveness of Methotrexate versus phototherapy, alone or associated with Psoralen, in childhood localized scleroderma. A systematic search between January 1996 and May 2017 was performed to identify studies investigating the efficacy of Methotrexate (MTX) or phototherapy (UVA) for treating localized scleroderma with onset ≤18 years. Due to a lack of validated clinical criteria, four clinical response criteria were used to assess the treatment efficacy as primary outcome. We determined a combined estimate of the proportion of children responding to MTX and UVA. A total of 19 studies was included (8 MTX; 11 UVA). In the methotrexate group, 193 children were included in the analysis; in the phototherapy group, a total of 48 treated children. For both groups age, disease subtype, glucocorticoids (GCs) use, and side effects of treatment were also analyzed. The meta-analysis suggested that UVA and MTX protocols have both a favorable effect in active lesions of childhood localized scleroderma. However, MTX resulted significantly superior to UVA, with or without Psoralen. Our study supports the combination of MTX and GCs in patients with a high risk of complication. Phototherapy with UVA1 could represent a therapeutic option in patients with limited scleroderma, where lesions do not cross joints and they do not lead to potential cosmetic changes. Copyright © 2018 Elsevier Inc. All rights reserved.

Toxicity of aggressive multimodality therapy including cisplatinum, bleomycin and methotrexate with radiation and/or surgery for advanced head and neck cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weichselbaum, R.R.; Posner, M.R.; Ervin, T.J.

1982-05-01

A combined modality regimen employing induction chemotherapy with cisplatinum, bleomycin and methotrexate followed by surgery and/or radiation therapy was initiated in patients with advanced squamous cell carcinoma of the head and neck. In the first 23 patients treated with this program there was a 90% response rate to induction chemotherapy (9% CR and 81% PR). Toxicity associated with radiotherapy, but not surgery, was increased with 11 of 23 patients (48%) who experienced some toxicity during or immediately after radiotherapy. Mucositis was worse than expected and severe delayed mucositis was seen in 2 patients, one of whom required hospitalization. Late complications,more » possibly related to therapy included one myocardial infarction and one episode of hypoglycemia, both of which were fatal. One other patient voluntarily failed to take prescribed oral leucovorin, dying of unrescued methotrexate toxicity during adjuvant therapy, a questionable suicide. Further follow-up analysis of failure will be necessary to determine if the value of a combined modality regimen in producing an increased cure rate and long term survival will out weigh increased toxicity.« less

Methotrexate increases expression of cell cycle checkpoint genes via Jun-N-terminal kinase activation

PubMed Central

Spurlock, Charles F.; Tossberg, John T.; Fuchs, Howard A.; Olsen, Nancy J.; Aune, Thomas M.

2011-01-01

Objective To assess defects in expression of critical cell cycle checkpoint genes and proteins in subjects with rheumatoid arthritis relative to presence or absence of methotrexate medication and assess the role of Jun N-terminal kinase in methotrexate induction of these genes. Methods Flow cytometry analysis was used to quantify changes in intracellular proteins, measure reactive oxygen species (ROS), and determine apoptosis in different lymphoid populations. Quantitative reverse transcriptase polymerase chain reaction (Q-RT-PCR) was employed to determine changes in cell cycle checkpoint target genes. Results RA subjects express lower baseline levels of MAPK9, TP53, CDKN1A, CDKN1B, CHEK2, and RANGAP1 messenger RNA (mRNA) and total JNK protein. MAPK9, TP53, CDKN1A, and CDKN1B mRNA expression, but not CHEK2, and RANGAP1, is higher in patients on low-dose MTX therapy. Further, JNK levels inversely correlate with CRP levels in RA patients. In tissue culture, MTX induces expression of both p53 and p21 by JNK2 and JNK1-dependent mechanisms, respectively, while CHEK2 and RANGAP1 are not induced by MTX. MTX also induces ROS production, JNK activation, and sensitivity to apoptosis in activated T cells. Supplementation with tetrahydrobiopterin blocks these MTX-mediated effects. Conclusions Our findings support the notion that MTX restores some, but not all of the proteins contributing to cell cycle checkpoint deficiencies in RA T cells by a JNK dependent pathway. PMID:22183962

Effectiveness of nanoencapsulated methotrexate against osteosarcoma cells: in vitro cytotoxicity under dynamic conditions.

PubMed

Mitxelena-Iribarren, O; Hisey, C L; Errazquin-Irigoyen, M; González-Fernández, Y; Imbuluzqueta, E; Mujika, M; Blanco-Prieto, M J; Arana, S

2017-06-01

Cancer is a leading cause of mortality in the world, with osteosarcoma being one of the most common types among children between 1 and 14 years old. Current treatments including preoperative chemotherapy, surgery and postoperative chemotherapy produce several side effects with limited effectiveness. The use of lipid nanoparticles as biodegradable shells for controlled drug delivery shows promise as a more effective and targeted tumor treatment. However, in vitro validation of these vehicles is limited due to fluid stagnation in current techniques, in which nanoparticles sediment onto the bottom of the wells killing the cells by asphyxiation. In the current series of experiments, results obtained with methotrexate-lipid nanoparticles under dynamic assay conditions are presented as a promising alternative to current free drug based therapies. Effects on the viability of the U-2 OS osteosarcoma cell line of recirculation of cell media, free methotrexate and blank and methotrexate containing lipid nanoparticles in a 11 μM concentration were successfully assessed. In addition, several designs for the microfluidic platform used were simulated using COMSOL-Multiphysics, optimized devices were fabricated using soft-lithography and simulated parameters were experimentally validated. Nanoparticles did not sediment to the bottom of the platform, demonstrating the effectiveness of the proposed system. Moreover, encapsulated methotrexate was the most effective treatment, as after 72 h the cell population was reduced nearly 40% while under free methotrexate circulation the cell population doubled. Overall, these results indicate that methotrexate-lipid nanoparticles are a promising targeted therapy for osteosarcoma treatment.

Evaluation of Novel Agents Which Target Neovasculature of Breast Tumors

DTIC Science & Technology

2006-04-01

chemotherapeutic agents including cyclophosphamide, methotrexate, anthracycline, cytarabine , paclitaxel, and corticosteroids [29]. To determine whether the...anthracycline, cytarabine , paclitaxel, and corticosteroids [29]. Sasaki et al reported that the level of Bcl-2 in cancer cells was an indicator of 5-FU

Systematic review and meta-analysis of the efficacy and safety of leflunomide and methotrexate in the treatment of rheumatoid arthritis.

PubMed

Alfaro-Lara, Roberto; Espinosa-Ortega, Hector Fabricio; Arce-Salinas, César Alejandro

2017-08-31

To assess the efficacy and side effects of methotrexate and leflunomide in patients with rheumatoid arthritis (RA) as the first disease-modifying antirheumatic drug (DMARD). We performed a systematic review and meta-analysis of clinical studies that included patients who took methotrexate, leflunomide, placebo or another DMARD for RA treatment. A systematic review yielded 1971 articles from databases; once completely reviewed, 73 trials that completed inclusion criteria were selected. In structured workshops for discussion and assessment of each article, 6 could be meta-analyzed for the primary and secondary outcomes: achievement of American College of Rheumatology (ACR) 20 and its core set components; and change of serum C-reactive protein (CRP) levels, Health Assessment Questionnaire Disability Index (HAQ-Di), liver enzyme aspartate transaminase/alanine transaminase ratio, new gastrointestinal (GI) side effects and infections. A total of 1984 patients were included: 986 took leflunomide and 998 methotrexate. The probability of achieving ACR 20 had an odds ratio (OR) of 0.88 (95% confidence interval [CI] 0.74, 1.06) with a trend toward favoring methotrexate; reduction of the swollen joint count was greater for methotrexate: mean difference=0.82 (95%CI 0.24, 1.39); tender joint count, physician global assessment, HAQ-Di, and serum CRP levels revealed no significant difference between groups. Increased liver enzymes were more frequent in the leflunomide group, OR=0.38 (95%CI 0.27, 0.53), and new GI complaints were more common with methotrexate (OR=1.44; 95%CI 1.17, 1.79). There was no difference in the incidence of non-severe infections. Leflunomide used as the first DMARD in RA seemed to be as efficacious as methotrexate; only the reduction of swollen joint count was more marked for methotrexate. Leflunomide was linked to a greater increase in liver enzymes, but there were fewer GI complaints. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Predictive factors of relapse in low-risk gestational trophoblastic neoplasia patients successfully treated with methotrexate alone.

PubMed

Couder, Florence; Massardier, Jérôme; You, Benoît; Abbas, Fatima; Hajri, Touria; Lotz, Jean-Pierre; Schott, Anne-Marie; Golfier, François

2016-07-01

Patients with 2000 FIGO low-risk gestational trophoblastic neoplasia are commonly treated with single-agent chemotherapy. Methotrexate is widely used in this indication in Europe. Analysis of relapse after treatment and identification of factors associated with relapse would help understand their potential impacts on 2000 FIGO score evolution and chemotherapy management of gestational trophoblastic neoplasia patients. This retrospective study analyzes the predictive factors of relapse in low-risk gestational trophoblastic neoplasia patients whose hormone chorionic gonadotropin (hCG) normalized with methotrexate alone. Between 1999 and 2014, 993 patients with gestational trophoblastic neoplasia were identified in the French Trophoblastic Disease Reference Center database, of which 465 were low-risk patients whose hCG normalized with methotrexate alone. Using univariate and multivariate analysis we identified significant predictive factors for relapse after methotrexate. The Kaplan-Meier method was used to plot the outcome of patients. The 5-year recurrence rate of low-risk gestational trophoblastic neoplasia patients whose hCG normalized with methotrexate alone was 5.7% (confidence interval [IC], 3.86-8.46). Univariate analysis identified an antecedent pregnancy resulting in a delivery (HR = 5.96; 95% CI, 1.40-25.4, P = .016), a number of methotrexate courses superior to 5 courses (5-8 courses vs 1-4: HR = 6.19; 95% CI, 1.43-26.8, P = .015; 9 courses and more vs 1-4: HR = 6.80; 95% CI, 1.32-35.1, P = .022), and hCG normalization delay centered to the mean as predictive factors of recurrence (HR = 1.27; 95% CI, 1.09-1.49, P = .003). Multivariate analysis confirmed the type of antecedent pregnancy and the number of methotrexate courses as independent predictive factors of recurrence. A low-risk gestational trophoblastic neoplasia arising after a normal delivery had an 8.66 times higher relapse risk than that of a postmole gestational trophoblastic neoplasia (95% CI, 1.98-37.9], P = .0042). A patient who received 5-8 courses of methotrexate had a 6.7 times higher relapse risk than a patient who received 1-4 courses (95% CI, 1.54-29.2, P = .011). A patient who received 9 courses or more had an 8.1 times higher relapse risk than a patient who received 1-4 courses of methotrexate (95% CI, 1.54-42.6, P = .014). Low-risk gestational trophoblastic neoplasia following a delivery and patients who need more than 4 courses of methotrexate to normalization are at a higher risk of relapse than other low-risk patients. Allotting a higher score to the "antecedent pregnancy" FIGO item should be considered for postdelivery gestational trophoblastic neoplasia. Further analysis of the need for consolidation courses is warranted. Copyright © 2016 Elsevier Inc. All rights reserved.

Long-term survival in primary CNS lymphoma treated by high-dose methotrexate monochemotherapy: role of STAT6 activation as prognostic determinant.

PubMed

Yang, Seung-Ho; Lee, Kun Soo; Kim, Il Sup; Hong, Jae Taek; Sung, Jae Hoon; Son, Byung Chul; Lee, Sang Won; Hong, Yong-Kil

2009-03-01

We report a single-center experience of 16 immunocompetent patients diagnosed with primary central nervous system lymphoma and treated with monochemotherapy with high-dose methotrexate (MTX) and deferred radiotherapy. MTX was given at a dose of 8.0 g/m2 for induction and at a dose of 3.5-8.0 g/m2 for maintenance. There were eight complete responses (CR), one partial response, one stable disease, and six patients whose tumors progressed in spite of the chemotherapy. At final follow-up, five of five CRs were alive and well without radiotherapy, with median follow-up of 26 months. Overall survival in eight non-CRs treated with the subsequent radiotherapy was 36 months. In the immunohistochemical study, STAT6 was positively expressed in 8 out of 13 cases. They included all non-CRs and two CRs. This observation suggests that STAT6 expression can be used as a prognostic determinant for MTX chemotherapy.

Safety of intrathecal administration of cytosine arabinoside and methotrexate in dogs and cats.

PubMed

Genoni, S; Palus, V; Eminaga, S; Cherubini, G B

2016-09-01

The objective of the study was to retrospectively evaluate the short-term safety of intrathecal administration of cytosine arabinoside alone or in combination with methotrexate in dogs and cats. One hundred and twelve dogs and eight cats admitted between September 2008 and December 2013, diagnosed with suspected inflammatory (meningoencephalomyelitis of unknown aetiology) or neoplastic disease affecting brain or spinal cord and treated with an intrathecal administration of cytosine arabinoside alone or in combination with methotrexate were included in the study. Recorded information regarding possible adverse events during administration while recovering from anaesthesia and during hospitalization period were evaluated. The results showed that one patient developed generalized tonic-clonic seizure activity after administration of cytosine arabinoside and methotrexate during recovery from anaesthesia, however responded to intravenous administration of diazepam. On the base of our results we can conclude that intrathecal administration of cytosine arabinoside alone or in combination with methotrexate is a safe procedure in dogs and cats. © 2014 John Wiley & Sons Ltd.

Sequential use of hemoperfusion and single-pass albumin dialysis can safely reverse methotrexate nephrotoxicity.

PubMed

Chan, Winnie Kwai Yu; Hui, Wun Fung

2016-10-01

High-dose methotrexate therapy (HDMTX) is a common form of chemotherapy used in children with high-grade malignancy such as osteosarcoma. Treatment with HDMTX requires careful monitoring of drug levels with folinic acid (leucovorin) rescue therapy. Toxicity from methotrexate is not uncommon and sometimes causes significant morbidity and mortality. We report an 11-year-old child whose 24-h post-HDMTX serum level was 651.8 μmol/L (recommended level <20 μmol/L), which was complicated by septic shock and progressive renal and liver failure. As carboxypeptidase (glucarpidase) was not available locally, she was treated with the sequential use of charcoal hemoperfusion (CHP) and single-pass albumin dialysis (SPAD). The patient recovered without complications. Both liver and renal function recovered with no significant late sequelae. CHP and SPAD are effective extracorporeal methods of removing methotrexate. They provide alternative treatment options for critical care nephrologists in the management of methotrexate toxicity.

Design, synthesis of methotrexate-diosgenin conjugates and biological evaluation of their effect on methotrexate transport-resistant cells.

PubMed

Cai, Bangrong; Liao, Aimei; Lee, Kyung-Ku; Ban, Jae-Sam; Yang, Hyun-Sam; Im, Young Jun; Chun, ChangJu

2016-12-01

A series of methotrexate-diosgenin conjugates was designed and synthesized to enhance the passive internalization of methotrexate (MTX) into transport-resistant cells. The inhibitory effects of these conjugates on dihydrofolate reductase (DHFR), and their anti-proliferation behaviors against a transport-resistant breast cancer cell line, MDA-MB-231, were investigated. All of the synthesized conjugates retained an ability to inhibit DHFR after the diosgenin substitution. The MTX conjugates were much more potent against methotrexate-resistant MDA-MB-231 cells than MTX. Conjugate 18, containing a disulfide bond, exhibited the most potent anti-proliferative and DHFR inhibitory effects (IC 50 =4.1μM and 17.21nM, respectively). Anti-proliferative activity was higher in the conjugate with a longer space linker (conjugate 21) than those with shorter linkers (conjugates 19 and 20). These results suggest that diosgenin conjugation of MTX may be an effective way to overcome its transport resistance in cancer cells. Copyright © 2016 Elsevier Inc. All rights reserved.

Glucarpidase

MedlinePlus

Glucarpidase is used to prevent harmful effects of methotrexate (Rheumatrex, Trexall) in patients with kidney disease who are receiving methotrexate to treat certain types of cancer. Glucarpidase is ...

The safety of intraocular methotrexate in silicone-filled eyes.

PubMed

Hardwig, Paul W; Pulido, Jose S; Bakri, Sophie J

2008-10-01

Intraocular methotrexate has been safely used in eyes with primary CNS lymphoma (PCNSL), and in eyes with uveitis and proliferative diabetic retinopathy. Dosing in silicone-filled eyes was reduced from a standard 400 microg intravitreal injection due to concerns of toxicity. The present study reports the visual results of non-PCNSL, silicone-filled eyes treated with intravitreal methotrexate using cumulative dosages ranging from 200 microg to 1,200 microg. In this retrospective case series, all patients with silicone-filled eyes who received intraocular methotrexate were included. Patients were observed with serial ophthalmic examinations. Best-corrected visual acuity was measured by Snellen acuity. Pretreatment acuities were compared to those obtained at last follow-up. The cohort included 12 patients (13 eyes) with disease other than PCNSL. The cumulative dose of intraocular methotrexate in any one patient ranged from 200 microg to 1,200 microg. Mean follow-up was 9 months (median, 10 months; range, 2 weeks to 16 months). Best-corrected vision at last follow-up was either stable or improved from pretreatment acuity in 12 of 13 eyes. Preservation of acuity in 12 of 13 study eyes suggests that intravitreal methotrexate in a cumulative dose of up to 1,200 microg is safe in silicone-filled eyes.

Clinical Efficacy and Safety of Methotrexate versus Hydroxychloroquine in Preventing Lichen Planopilaris Progress: A Randomized Clinical Trial

PubMed Central

Naeini, Farahnaz Fatemi; Saber, Mina; Asilian, Ali; Hosseini, Sayed Mohsen

2017-01-01

Background: Lichen planopilaris is an inflammatory cicatricial alopecia, and its management is a challenge for dermatologists. We aimed to compare the efficacy of methotrexate and hydroxychloroquine on refractory lichen planopilaris. Methods: In a randomized clinical trial, 29 patients were randomly allocated to receive either 15 mg methotrexate/week or 200 mg hydroxychloroquine twice a day for 6 months. Side effects, symptoms/signs, and laboratory tests were assessed periodically. Lichen Planopilaris Activity Index (LPPAI) was measured before intervention and at 2, 4, and 6 months after. The changes from baseline to the end of the study were analyzed within each group and between the two groups by per-protocol and intention-to-treat analysis. Results: After 2 months, mean (standard deviation [SD]) decrease in LPPAI in methotrexate group was significantly more than that in hydroxychloroquine group (1.68 [1.24] vs. 0.8 [0.71], respectively, P = 0.047). Furthermore, after 6 months, mean (SD) decrease in LPPAI in methotrexate group was significantly higher than that in hydroxychloroquine group (3.3 [2.09] vs. 1.51 [0.91], respectively, P = 0.01). The following symptoms/signs showed significant improvements in frequency and/or severity in methotrexate group after intervention: pruritus (P = 0.007), erythema (P = 0.01), perifollicular erythema (P = 0.01), perifollicular scaling (P = 0.08), spreading (P = 0.001), and follicular keratosis (P = 0.04). In hydroxychloroquine group, only erythema (P = 0.004) showed significant improvement. Conclusions: Methotrexate was more effective than hydroxychloroquine in treating refractory lichen planopilaris. PMID:28584619

Methotrexate iontophoresis versus coal tar ointment in palmoplantar psoriasis: A pilot study.

PubMed

Haseena, K; George, Sandhya; Riyaz, Najeeba; Sasidharanpillai, Sarita; Puthussery, Paul V

2017-01-01

Palmoplantar psoriasis is often disabling and refractory to conventional therapy. Systemic drugs are indicated in its severe form, but side effects are a concern with their use. Methotrexate is one such systemic drug which is effective and cheap. To reduce systemic toxicity, methotrexate has been tried topically but results have been inconsistent due to poor drug penetration into the skin by passive diffusion. Iontophoresis may enhance its absorption and efficacy. To evaluate the efficacy and safety of topical methotrexate iontophoresis in comparison with coal tar ointment in the treatment of palmoplantar psoriasis. Thirty-one patients with palmar and/or plantar psoriasis were selected for the study and 28 patients completed it. The side having more severe involvement was treated while the other palm/sole served as a control. Iontophoresis using methotrexate solution was carried out on the study palm/sole with the injectable preparation of methotrexate (50 mg/2 ml) once a week for the first 4 weeks and subsequently every two weeks, for a total of six sittings. The control palm/sole was treated with coal tar ointment on other days. Erythema, scaling, induration and fissuring scores were noted in both groups before and after treatment. Both study and control groups showed decreases in scores but the reduction was more in the study group, the difference being statistically significant. Drawbacks of our study include the small sample size and the lack of follow-up. The study and control arms were not exactly matched and the study was not blinded. Methotrexate iontophoresis was safe and more effective than coal tar ointmentin palmoplantarpsoriasis.

Risk of Adverse Pregnancy Outcome After Paternal Exposure to Methotrexate Within 90 Days Before Pregnancy.

PubMed

Eck, Lasse Karlsen; Jensen, Thomas Bo; Mastrogiannis, Dimitrios; Torp-Pedersen, Arendse; Askaa, Bjarke; Nielsen, Torben Kjær; Poulsen, Henrik Enghusen; Jimenez-Solem, Espen; Andersen, Jon Trærup

2017-04-01

To study the association between paternal exposure to methotrexate within the 90-day period before pregnancy and congenital malformations and stillbirth in the offspring. We conducted a nationwide register study. Our cohort consisted of all live births in Denmark between 1997 and 2011 identified from the Medical Birth Registry. Methotrexate-exposed fathers were identified from the National Prescription Registry. From the national Hospital Registry we identified paternity, live births, and stillbirths as well as discharge diagnoses on congenital malformations. We identified 849,676 live births with known paternity. There were 127 live births of methotrexate-exposed fathers. Of these, four (3.2%) had major malformations compared with 28,814 (3.4%) of the unexposed. The odds ratio (OR) for major congenital malformation among exposed fathers compared with unexposed was 0.93 (95% confidence interval [CI] 0.34-2.51) and when adjusted for year of birth, maternal age, educational length, household income, and parity, the adjusted OR was 1.01 (95% CI 0.37-2.74). There were no stillbirths in the methotrexate-exposed group compared with 2,541 (0.3%) in the unexposed group and no increased risk of preterm birth (adjusted OR 1.31, 95% CI 0.66-2.59) among the children from exposed fathers. We found no association between paternal exposure to methotrexate within 90 days before pregnancy and congenital malformations, stillbirths, or preterm birth. Available data suggest that prepregnancy paternal methotrexate exposure should not be of major concern. Multinational recommendations should be changed accordingly.

Leucovorin

MedlinePlus

Leucovorin is used to prevent harmful effects of methotrexate (Rheumatrex, Trexall; cancer chemotherapy medication) when methotrexate is used to treat certain types of cancer. Leucovorin is also used to ...

Two-Year Safety and Efficacy Experience in Patients with Methotrexate-Resistant Active Rheumatoid Arthritis Treated with Etanercept and Conventional Disease-Modifying Anti-rheumatic Drugs in the Latin American Region.

PubMed

Machado, Daniel A; Guzman, Renato; Xavier, Ricardo M; Simon, Jesus A; Mele, Linda; Shen, Qi; Pedersen, Ronald; Kotak, Sameer; Vlahos, Bonnie

2016-01-01

Although long-term data are available from biologic studies in North American/European populations with rheumatoid arthritis (RA), long-term findings in Latin American RA populations are limited. To examine long-term safety/efficacy of etanercept, methotrexate, and/or other disease-modifying anti-rheumatic drugs (DMARDs) in Latin American patients with moderate-to-severe active RA. In the first phase of this open-label study, patients were randomized to etanercept 50 mg weekly plus methotrexate or conventional DMARD (hydroxychloroquine or sulfasalazine) plus methotrexate for 24 weeks. At the start of the second phase (week 24), investigators selected a treatment regimen that included any combination/dosage of etanercept, methotrexate, hydroxychloroquine, or sulfasalazine based on previous treatment response, preference, and local product labeling, and was continued for the 104-week extension. In the extension, in the group previously randomized to etanercept-plus-methotrexate therapy, etanercept was continued in 259/260 patients; methotrexate continued in 260/260; and hydroxychloroquine and sulfasalazine added in 8/260 and 3/260, respectively. In the group previously randomized to conventional DMARD-plus-methotrexate therapy, conventional DMARD was discontinued in 86/126 and etanercept added in 105/126. Among etanercept-exposed patients (total exposure, 798.1 patient-year [PY]), rates of adverse events, serious adverse events, and serious infections per PY were 1.7, 0.07, and 0.02 events per PY. In both groups, after treatment modification was permitted, clinical response rates and improvements in clinical/patient-reported outcomes from baseline were sustained to week 128. After investigators were permitted to modify treatment, etanercept was part of the treatment regimen in 95% of patients. Continuation or addition of etanercept in the 2-year extension resulted in a consistently good risk:benefit profile. Open-Label Study Comparing Etanercept to Conventional Disease Modifying Antirheumatic Drug (DMARD) Therapy; ClinicalTrials.gov, number NCT00848354; https://clinicaltrials.gov/ct2/show/NCT00848354.

A randomized clinical trial comparing methotrexate and mycophenolate mofetil for noninfectious uveitis.

PubMed

Rathinam, Sivakumar R; Babu, Manohar; Thundikandy, Radhika; Kanakath, Anuradha; Nardone, Natalie; Esterberg, Elizabeth; Lee, Salena M; Enanoria, Wayne T A; Porco, Travis C; Browne, Erica N; Weinrib, Rachel; Acharya, Nisha R

2014-10-01

To compare the relative effectiveness of methotrexate and mycophenolate mofetil for noninfectious intermediate uveitis, posterior uveitis, or panuveitis. Multicenter, block-randomized, observer-masked clinical trial. Eighty patients with noninfectious intermediate, posterior, or panuveitis requiring corticosteroid-sparing therapy at Aravind Eye Hospitals in Madurai and Coimbatore, India. Patients were randomized to receive 25 mg weekly oral methotrexate or 1 g twice daily oral mycophenolate mofetil and were monitored monthly for 6 months. Oral prednisone and topical corticosteroids were tapered. Masked examiners assessed the primary outcome of treatment success, defined by achieving the following at 5 and 6 months: (1) ≤0.5+ anterior chamber cells, ≤0.5+ vitreous cells, ≤0.5+ vitreous haze and no active retinal/choroidal lesions in both eyes, (2) ≤10 mg of prednisone and ≤2 drops of prednisolone acetate 1% a day, and (3) no declaration of treatment failure because of intolerability or safety. Additional outcomes included time to sustained corticosteroid-sparing control of inflammation, change in best spectacle-corrected visual acuity, resolution of macular edema, adverse events, subgroup analysis by anatomic location, and medication adherence. Forty-one patients were randomized to methotrexate and 39 to mycophenolate mofetil. A total of 67 patients (35 methotrexate, 32 mycophenolate mofetil) contributed to the primary outcome. Sixty-nine percent of patients achieved treatment success with methotrexate and 47% with mycophenolate mofetil (P = 0.09). Treatment failure from adverse events or tolerability was not different by treatment arm (P = 0.99). There were no differences between treatment groups in time to corticosteroid-sparing control of inflammation (P = 0.44), change in best spectacle-corrected visual acuity (P = 0.68), or resolution of macular edema (P = 0.31). There was no statistically significant difference in corticosteroid-sparing control of inflammation between patients receiving methotrexate or mycophenolate mofetil. However, there was a 22% difference in treatment success favoring methotrexate. Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

The development of a questionnaire to evaluate rheumatoid arthritis patient's knowledge about methotrexate.

PubMed

Fayet, Françoise; Savel, Carine; Rodere, Malory; Pereira, Bruno; Abdi, Dihya; Mathieu, Sylvain; Tournadre, Anne; Soubrier, Martin; Dubost, Jean-Jacques

2016-03-01

Assess knowledge concerning methotrexate in rheumatoid arthritis patients by means of a questionnaire. Methotrexate is the standard drug for rheumatoid arthritis treatment. It has potentially serious side effects that can be largely prevented by making sure that patients are well informed and comply with prescription guidelines. Cross-sectional survey. A questionnaire on methotrexate (mode of action, administration, drug interactions), side effects, monitoring and lifestyle implications was offered to all the rheumatoid arthritis patients treated with the drug seen between March and September 2013 in a large hospital in France. One hundred and eighty-three patients (143 women), mean age 60 (13·5) years, with a median disease duration of 12 years [7-20] and treated with methotrexate for eight years [5-13] took part. Methotrexate was identified as a disease-modifying antirheumatic drug by 78% of the patients. The weekly administration method was well assimilated (97%); 67% indicated that the rationale for folic acid was to reduce treatment toxicity. Only 21% knew that trimethoprim was contraindicated. Half were aware of the haematologic risk and 36% were aware of the risk of hypersensitivity pneumonitis. There was knowledge concerning laboratory testing (80%), but 54% thought they were only being monitored for rheumatoid arthritis activity. Only 13% of the men, but 90% of the women, of childbearing age knew that contraception was essential, and 75% indicated that alcohol consumption should be limited. A low knowledge score correlated significantly with age and low educational level. It was independent of sex, duration of treatment for rheumatoid arthritis. Rheumatoid arthritis patient's knowledge concerning methotrexate is poor, particularly for the most serious side effects (haematologic and hypersensitivity pneumonitis), interactions with trimethoprim, and in men, the need for contraception. Patient knowledge concerning methotrexate should be regularly checked and supported using the different therapeutic education tools available, especially when patients are older people and have had limited schooling. © 2015 John Wiley & Sons Ltd.

A Randomized Clinical Trial Comparing Methotrexate and Mycophenolate Mofetil for Non-Infectious Uveitis

PubMed Central

Rathinam, Sivakumar R; Babu, Manohar; Thundikandy, Radhika; Kanakath, Anuradha; Nardone, Natalie; Esterberg, Elizabeth; Lee, Salena M; Enanoria, Wayne TA; Porco, Travis C; Browne, Erica N; Weinrib, Rachel; Acharya, Nisha R

2014-01-01

Objective To compare the relative effectiveness of methotrexate and mycophenolate mofetil for non-infectious intermediate uveitis, posterior uveitis, or panuveitis. Design Multicenter, block-randomized, observer-masked clinical trial Participants Eighty patients with non-infectious intermediate, posterior or panuveitis requiring corticosteroid-sparing therapy at Aravind Eye Hospitals in Madurai and Coimbatore, India. Intervention Patients were randomized to receive 25mg weekly oral methotrexate or 1g twice daily oral mycophenolate mofetil and were monitored monthly for 6 months. Oral prednisone and topical corticosteroids were tapered. Main Outcome Measures Masked examiners assessed the primary outcome of treatment success, defined by achieving the following at 5 and 6 months: (1) ≤0.5+ anterior chamber cells, ≤0.5+ vitreous cells, ≤0.5+ vitreous haze and no active retinal/choroidal lesions in both eyes, (2) ≤ 10 mg of prednisone and ≤ 2 drops of prednisolone acetate 1% a day and (3) no declaration of treatment failure due to intolerability or safety. Additional outcomes included time to sustained corticosteroid-sparing control of inflammation, change in best spectacle-corrected visual acuity, resolution of macular edema, adverse events, subgroup analysis by anatomic location, and medication adherence. Results Forty-one patients were randomized to methotrexate and 39 to mycophenolate mofetil. A total of 67 patients (35 methotrexate, 32 mycophenolate mofetil) contributed to the primary outcome. Sixty-nine percent of patients achieved treatment success with methotrexate and 47% with mycophenolate mofetil (p=0.09). Treatment failure due to adverse events or tolerability was not significantly different by treatment arm (p=0.99). There were no statistically significant differences between treatment groups in time to corticosteroid-sparing control of inflammation (p=0.44), change in best spectacle-corrected visual acuity (p=0.68), and resolution of macular edema (p=0.31). Conclusions There was no statistically significant difference in corticosteroid-sparing control of inflammation between patients receiving methotrexate or mycophenolate mofetil. However, there was a 22% difference in treatment success favoring methotrexate. PMID:24917273

Growth hormone and nutrition as protective agents against methotrexate induced enteritis.

PubMed

Ortega, M; de Segura, I A; Vázquez, I; López, J M; De Miguel, E

2001-03-01

To determine whether exogenously administered growth hormone can reduce or prevent chemotherapy-induced intestinal mucosa injury. The expected results will allow to consider its potential clinical use. Experimental and randomized study. Experimental Surgery Service, La Paz University Hospital. Adult Wistar rats weighing 250-300 g. A chemotherapy protocol with methotrexate (MTX) (120 mg/kg) was employed. Animals fed either with a normoproteic or a hyperproteic liquid diet were treated with either saline or growth hormone (1 mg/kg/day) since three days before until four days after chemotherapy. Animals were sacrificed seven days after MTX administration for tissue sampling. Co-administration of growth hormone and a hyperproteic diet increased intestinal crypt proliferation and reduced MTX-induced apoptosis. Jejunal mucosal structure (morphometry), proliferation (Ki-67) and apoptosis (TUNNEL) were assessed.

Preparation and characterization of conjugated polyamidoamine-MPEG-methotrexate for potential drug delivery system

NASA Astrophysics Data System (ADS)

Mohd Sabri, Siti Noorzidah bt; Abu, Norhidayah; Mastor, Azreena; Hisham, Siti Farhana; Noorsal, Kartini

2012-07-01

Star polymers have unique characteristics due to their well-defined size and tailor ability which makes these polymers attractive candidates as carriers in drug delivery system applications. This work focuses on attaching a drug to the star polymer (polyamidoamine). The conjugation of polyamidoamine (PAMAM, generation 4) with methotrexate (MTX) (model drug) was studied in which monomethyl polyethylene glycol (MPEG) was used as a linker to reduce the toxicity of dendrimer. Conjugation starts with attaching the drug to the linker and followed by further conjugation with the polyamidoamine (PAMAM) dendrimer. The conjugation of PAMAM-PEG-MTX was confirmed through UV-Vis, FTIR, 1H NMR and DSC. The loading capacities and release profile of this conjugate were determined using 1H NMR and UV spectrometer.

Afatinib versus methotrexate in older patients with second-line recurrent and/or metastatic head and neck squamous cell carcinoma: subgroup analysis of the LUX-Head & Neck 1 trial.

PubMed

Clement, P M; Gauler, T; Machiels, J P; Haddad, R I; Fayette, J; Licitra, L F; Tahara, M; Cohen, E E W; Cupissol, D; Grau, J J; Guigay, J; Caponigro, F; de Castro, G; de Souza Viana, L; Keilholz, U; Del Campo, J M; Cong, X J; Ehrnrooth, E; Vermorken, J B

2016-08-01

In the phase III LUX-Head & Neck 1 (LHN1) trial, afatinib significantly improved progression-free survival (PFS) versus methotrexate in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients progressing on/after platinum-based therapy. This report evaluates afatinib efficacy and safety in prespecified subgroups of patients aged ≥65 and <65 years. Patients were randomized (2:1) to 40 mg/day oral afatinib or 40 mg/m(2)/week intravenous methotrexate. PFS was the primary end point; overall survival (OS) was the key secondary end point. Other end points included: objective response rate (ORR), patient-reported outcomes, tumor shrinkage, and safety. Disease control rate (DCR) was also assessed. Of 483 randomized patients, 27% (83 afatinib; 45 methotrexate) were aged ≥65 years (older) and 73% (239 afatinib; 116 methotrexate) <65 years (younger) at study entry. Similar PFS benefit with afatinib versus methotrexate was observed in older {median 2.8 versus 2.3 months, hazard ratio (HR) = 0.68 [95% confidence interval (CI) 0.45-1.03], P = 0.061} and younger patients [2.6 versus 1.6 months, HR = 0.79 (0.62-1.01), P = 0.052]. In older and younger patients, the median OS with afatinib versus methotrexate was 7.3 versus 6.4 months [HR = 0.84 (0.54-1.31)] and 6.7 versus 6.2 months [HR = 0.98 (0.76-1.28)]. ORRs with afatinib versus methotrexate were 10.8% versus 6.7% and 10.0% versus 5.2%; DCRs were 53.0% versus 37.8% and 47.7% versus 38.8% in older and younger patients, respectively. In both subgroups, the most frequent treatment-related adverse events were rash/acne (73%-77%) and diarrhea (70%-80%) with afatinib, and stomatitis (43%) and fatigue (31%-34%) with methotrexate. Fewer treatment-related discontinuations were observed with afatinib (each subgroup 7% versus 16%). A trend toward improved time to deterioration of global health status, pain, and swallowing with afatinib was observed in both subgroups. Advancing age (≥65 years) did not adversely affect clinical outcomes or safety with afatinib versus methotrexate in second-line R/M HNSCC patients. NCT01345682 (ClinicalTrials.gov). © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Self-targeted salinomycin-loaded DSPE-PEG-methotrexate nanomicelles for targeting both head and neck squamous cell carcinoma cancer cells and cancer stem cells.

PubMed

Zhu, Minhui; Chen, Shicai; Hua, Libo; Zhang, Caiyun; Chen, Mengjie; Chen, Donghui; Dong, Yinmei; Zhang, Yingying; Li, Meng; Song, Xianmin; Chen, Huaiwen; Zheng, Hongliang

2017-02-01

To target both head and neck squamous cell carcinoma (HNSCC) cells and cancer stem cells (CSCs) by salinomycin-loaded DSPE-PEG-MTX (synthesized using DSPE-PEG2000-NH2 and methotrexate) nanomicelles (M-SAL-MTX). The characterization, antitumor activity and mechanism of M-SAL-MTX were evaluated. M-SAL-MTX showed enhanced inhibitory effect toward both HNSCC CSCs and non-CSCs compared with a single treatment of methotrexate and salinomycin. In nude mice-bearing HNSCC xenografts, M-SAL-MTX suppressed tumor growth more effectively than other controls including combination of methotrexate and salinomycin. Therefore, M-SAL-MTX may provide a strategy for treating HNSCC by targeting both HNSCC CSCs and HNSCC cells.

Improving treatment with methotrexate in rheumatoid arthritis-development of a multimedia patient education program and the MiRAK, a new instrument to evaluate methotrexate-related knowledge.

PubMed

Ciciriello, Sabina; Buchbinder, Rachelle; Osborne, Richard H; Wicks, Ian P

2014-02-01

To develop and test an evidence-based, multimedia patient education program (MPEP) about methotrexate (MTX) treatment for rheumatoid arthritis (RA) and a new measure of patient knowledge [Methotrexate in Rheumatoid Arthritis Knowledge test (MiRAK)]. The content of the MPEP and MiRAK was guided by concept-mapping workshops with patients (N = 24), literature review, health professional, and expert linguistic input. The MPEP and MiRAK underwent multiple stages of testing and revision with patients and health professionals. The MiRAK was administered to RA patients (N = 169) and its properties examined using the Rasch analyses. A subset of respondents (N = 131) repeated the MiRAK to determine test-retest reliability. A before-after pilot study with patients who had recently started MTX (N = 31) tested responsiveness of the MiRAK and feasibility and acceptability of the MPEP. A DVD of 24-minutes duration was produced that presents detailed, evidence-based information about MTX. The Rasch analyses of the 60 MiRAK items revealed that these could be summated into a single score. The MiRAK had good model fit, supporting internal construct validity, good internal consistency (person separation index; 0.84), test-retest reliability (ICC; 0.89), and ability to detect change (ES; 2.38). The before-after study suggested that patients could self-administer the MPEP, with the majority finding it informative and easy to use. We developed a MPEP about MTX treatment for RA, which was found to be user-friendly and easily implementable. The MiRAK is a new scale, testing a broad spectrum of MTX knowledge. Analyses revealed strong evidence for its validity and reliability. Copyright © 2014 Elsevier Inc. All rights reserved.

Affinity labeling of the folate-methotrexate transporter from Leishmania donovani

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beck, J.T.; Ullman, B.

1989-08-22

An affinity labeling technique has been developed to identify the folate-methotrexate transporter of Leishmania donovani promastigotes using activated derivatives of the ligands. These activated derivatives were synthesized by incubating folate and methotrexate with a 10-fold excess of 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC) for 10 min at ambient temperature in dimethyl sulfoxide. When intact wild-type (DI700) Leishmania donovani or preparations of their membranes were incubated with a 0.4 {mu}M concentration of either activated ({sup 3}H)folate or activated ({sup 3}H)methotrexate, the radiolabeled ligands were covalently incorporated into a polypeptide with a molecular weight of approximately 46,000, as demonstrated by SDS-polyacrylamide gel electrophoresis. No affinity labelingmore » of a 46,000-dalton protein was observed when equimolar concentrations of activated radiolabeled ligands were incubated with intact cells or membranes prepared from a methotrexate-resistant mutant clone of Leishmania donovani, MTXA5, that is genetically defective in folate-methotrexate transport capability. Time course studies indicated that maximal labeling of the 46,000-dalton protein occurred within 5-10 min of incubation of intact cells with activated ligand. These studies provide biochemical evidence that the folate-methotrexate transporter of Leishmania donovani can be identified in crude extracts by an affinity labeling technique and serve as a prerequisite to further analysis of the transport protein by providing a vehicle for subsequent purification of this membrane carrier. Moreover, these investigations suggest that the affinity labeling technique using EDC-activated ligands may be exploitable to analyze other cell surface binding proteins in Leishmania donovani, as well as in other organisms.« less

Synthesis of protein-coated biocompatible methotrexate-loaded PLA-PEG-PLA nanoparticles for breast cancer treatment

PubMed Central

Massadeh, Salam; Alaamery, Manal; Al-Qatanani, Shatha; Alarifi, Saqer; Bawazeer, Shahad; Alyafee, Yusra

2016-01-01

Background PLA-PEG-PLA triblock polymer nanoparticles are promising tools for targeted dug delivery. The main aim in designing polymeric nanoparticles for drug delivery is achieving a controlled and targeted release of a specific drug at the therapeutically optimal rate and choosing a suitable preparation method to encapsulate the drug efficiently, which depends mainly on the nature of the drug (hydrophilic or hydrophobic). In this study, methotrexate (MTX)-loaded nanoparticles were prepared by the double emulsion method. Method Biodegradable polymer polyethylene glycol-polylactide acid tri-block was used with poly(vinyl alcohol) as emulsifier. The resulting methotrexate polymer nanoparticles were coated with bovine serum albumin in order to improve their biocompatibility. This study focused on particle size distribution, zeta potential, encapsulation efficiency, loading capacity, and in vitro drug release at various concentrations of PVA (0.5%, 1%, 2%, and 3%). Results Reduced particle size of methotrexate-loaded nanoparticles was obtained using lower PVA concentrations. Enhanced encapsulation efficiency and loading capacity was obtained using 1% PVA. FT-IR characterization was conducted for the void polymer nanoparticles and for drug-loaded nanoparticles with methotrexate, and the protein-coated nanoparticles in solid state showed the structure of the plain PEG-PLA and the drug-loaded nanoparticles with methotrexate. The methotrexate-loaded PLA-PEG-PLA nanoparticles have been studied in vitro; the drug release, drug loading, and yield are reported. Conclusion The drug release profile was monitored over a period of 168 hours, and was free of burst effect before the protein coating. The results obtained from this work are promising; this work can be taken further to develop MTX based therapies.

Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative

PubMed Central

Visser, K; Katchamart, W; Loza, E; Martinez-Lopez, J A; Salliot, C; Trudeau, J; Bombardier, C; Carmona, L; van der Heijde, D; Bijlsma, J W J; Boumpas, D T; Canhao, H; Edwards, C J; Hamuryudan, V; Kvien, T K; Leeb, B F; Martín-Mola, E M; Mielants, H; Müller-Ladner, U; Murphy, G; Østergaard, M; Pereira, I A; Ramos-Remus, C; Valentini, G; Zochling, J; Dougados, M

2009-01-01

Objectives: To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders. Methods: 751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007–8 consisting of three separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of methotrexate in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005–7 American College of Rheumatology/European League Against Rheumatism meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford levels of evidence. Each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. Results: A total of 16 979 references was identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of methotrexate were formulated. Nine recommendations were specific for rheumatoid arthritis (RA), including the work-up before initiating methotrexate, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the perioperative period and before/during pregnancy. One recommendation concerned methotrexate as a steroid-sparing agent in other rheumatic diseases. Conclusions: Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use. PMID:19033291

Itolizumab in combination with methotrexate modulates active rheumatoid arthritis: safety and efficacy from a phase 2, randomized, open-label, parallel-group, dose-ranging study.

PubMed

Chopra, Arvind; Chandrashekara, S; Iyer, Rajgopalan; Rajasekhar, Liza; Shetty, Naresh; Veeravalli, Sarathchandra Mouli; Ghosh, Alakendu; Merchant, Mrugank; Oak, Jyotsna; Londhey, Vikram; Barve, Abhijit; Ramakrishnan, M S; Montero, Enrique

2016-04-01

The objective of this study was to assess the safety and efficacy of itolizumab with methotrexate in active rheumatoid arthritis (RA) patients who had inadequate response to methotrexate. In this open-label, phase 2 study, 70 patients fulfilling American College of Rheumatology (ACR) criteria and negative for latent tuberculosis were randomized to four arms: 0.2, 0.4, or 0.8 mg/kg itolizumab weekly combined with oral methotrexate, and methotrexate alone (2:2:2:1). Patients were treated for 12 weeks, followed by 12 weeks of methotrexate alone during follow-up. Twelve weeks of itolizumab therapy was well tolerated. Forty-four patients reported adverse events (AEs); except for six severe AEs, all others were mild or moderate. Infusion-related reactions mainly occurred after the first infusion, and none were reported after the 11th infusion. No serum anti-itolizumab antibodies were detected. In the full analysis set, all itolizumab doses showed evidence of efficacy. At 12 weeks, 50 % of the patients achieved ACR20, and 58.3 % moderate or good 28-joint count Disease Activity Score (DAS-28) response; at week 24, these responses were seen in 22 and 31 patients. Significant improvements were seen in Short Form-36 Health Survey and Health Assessment Questionnaire Disability Index scores. Overall, itolizumab in combination with methotrexate was well tolerated and efficacious in RA for 12 weeks, with efficacy persisting for the entire 24-week evaluation period. (Clinical Trial Registry of India, http://ctri.nic.in/Clinicaltrials/login.php , CTRI/2008/091/000295).

Resumption of High-dose Methotrexate after Acute Kidney Injury and Glucarpidase Use in Pediatric Oncology Patients

PubMed Central

Christensen, Anthony M.; Pauley, Jennifer L.; Molinelli, Alejandro R.; Panetta, John C.; Ward, Deborah A.; Stewart, Clinton F.; Hoffman, James M.; Howard, Scott C.; Pui, Ching-Hon; Pappo, Alberto S.; Relling, Mary V.; Crews, Kristine R.

2013-01-01

Background High-dose methotrexate (HDMTX)-induced acute kidney injury is a rare but life-threatening complication. The methotrexate rescue agent glucarpidase rapidly hydrolyzes methotrexate to inactive metabolites. We retrospectively reviewed glucarpidase use in pediatric cancer patients at our institution and evaluated whether subsequent resumption of HDMTX was tolerated. Methods Clinical data and outcomes of all patients who received glucarpidase after HDMTX administration were reviewed. Results Of 1,141 patients treated with 4,909 courses of HDMTX, 20 patients (1.8% of patients, 0.4% of courses) received 22 doses of glucarpidase. The median glucarpidase dosage was 51.6 units/kg (range, 13 – 65.6 units/kg). At the time of administration, the median plasma methotrexate concentration was 29.1 µM (range, 1.3 – 590.6 µM). Thirteen of the 20 patients received a total of 39 courses of HDMTX therapy after glucarpidase. The median time to complete methotrexate excretion was 355 hours (range, 244 – 763 hours) for the HDMTX course during which glucarpidase was administered, 90 hours (range, 66 – 268 hours) for the next HDMTX course, and 72 hours (range, 42 – 116 hours) for subsequent courses. The median peak serum creatinine during these HDMTX courses was 2.2 mg/dL (range, 0.8 – 9.6 mg/dL), 0.8 mg/dL (range, 0.4 – 1.6 mg/dL), and 0.6 mg/dL (range, 0.4 – 0.9 mg/dL), respectively. One patient experienced nephrotoxicity upon rechallenge with HDMTX. Renal function eventually returned to baseline in all patients and no patient died as a result of methotrexate toxicity. Conclusion It is possible to safely resume HDMTX therapy after glucarpidase treatment for HDMTX-induced acute kidney injury. PMID:22252903

Protective effects of amifostine and cyclooxygenase-1 inhibitor against normal human epidermal keratinocyte toxicity induced by methotrexate and 5-fluorouracil.

PubMed

Maiguma, Takayoshi; Kaji, Hiroaki; Makino, Kazutaka; Teshima, Daisuke

2009-07-01

Our study aimed to find more effective protective agents against mucosa toxicity induced by methotrexate and 5-fluorouracil. We focused on the relationship between oral mucositis and keratinocyte injury and examined methotrexate and 5-fluorouracil-induced cytotoxicity in normal human epidermal keratinocyte cell lines. Cell viability and superoxide radical activity were measured based on converting WST-1 (4-[3-(4-indophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzen disulfonate) to a water-soluble formazan dye. DNA synthesis by 5-bromo-2'-deoxyuridine incorporation was measured as an indirect parameter of cell proliferation. Allopurinol and amifostine were used as the radical scavengers. l-glutamine was used as a mucosa-protective agent. A cyclooxygenase inhibitor interrupting the production of hydroxyl radicals in the arachidonic acid cascade was also examined. 5-fluorouracil and methotrexate caused cytotoxicity due to the activation of intracellular superoxide radicals specifically on normal human epidermal keratinocytes. From the electron spin resonance study, it was found that allopurinol was a superoxide radical scavenger, while amifostine was hydroxyl radical scavenger. Allopurinol showed no effect on the cytotoxicity due to 5-fluorouracil and methotrexate. The cell injury induced by methotrexate was restored by amifostine. However, the cell injury induced by 5-fluorouracil was markedly recovered by a selective cyclooxygenase-1 inhibitor compared to amifostine. It was suggested that amifostine and cyclooxygenase-1 inhibitor could be useful protective agents against methotrexate and 5-fluorouracil chemotherapeutic toxicity. Additionally, this in vitro cell injury model using normal human epidermal keratinocytes may be useful for understanding the pathophysiology of oral mucositis induced by chemotherapeutic agents.

Effects of repeated administration of chemotherapeutic agents tamoxifen, methotrexate, and 5-fluorouracil on the acquisition and retention of a learned response in mice

PubMed Central

Foley, John J.; Clark-Vetri, Rachel; Raffa, Robert B.

2011-01-01

Rationale A number of cancer chemotherapeutic agents have been associated with a loss of memory in breast cancer patients although little is known of the causality of this effect. Objectives To assess the potential cognitive effects of repeated exposure to chemotherapeutic agents, we administered the selective estrogen receptor modulator tamoxifen or the antimetabolite chemotherapy, methotrexate, and 5-fluorouracil, alone and in combination to mice and tested them in a learning and memory assay. Methods Swiss-Webster male mice were injected with saline, 32 mg/kg tamoxifen, 3.2 or 32 mg/kg methotrexate, 75 mg/kg 5-fluorouracil, 3.2 or 32 mg/kg methotrexate in combination with 75 mg/kg 5-fluorouracil once per week for 3 weeks. On days 23 and 24, mice were tested for acquisition and retention of a nose-poke response in a learning procedure called autoshaping. In addition, the acute effects of tamoxifen were assessed in additional mice in a similar procedure. Results The chemotherapeutic agents alone and in combination reduced body weight relative to saline treatment over the course of 4 weeks. Repeated treatment with tamoxifen produced both acquisition and retention effects relative to the saline-treated group although acute tamoxifen was without effect except at a behaviorally toxic dose. Repeated treatment with methotrexate in combination with 5-fluorouracil produced effects on retention, but the magnitude of these changes depended on the methotrexate dose. Conclusions These data demonstrate that repeated administration of tamoxifen or certain combination of methotrexate and 5-fluorouracil may produce deficits in the acquisition or retention of learned responses which suggest potential strategies for prevention or remediation might be considered in vulnerable patient populations. PMID:21537942

Retrospective analysis of factors that affect the success of single-dose methotrexate treatment in ectopic pregnancy

PubMed Central

Var, Altan; Özyurt, Ramazan; Şık, Bulat Aytek; Kumbasar, Serkan; Sever, Erman; Deveci, Mustafa; Çöt, Özgür; Salman, Süleyman; Güzel, Yılmaz

2015-01-01

Objective: Detection of factors that affect the success of single-dose methotrexate treatment in ectopic pregnancy. Materials and Methods: We investigated 99 patients who had been treated with single-dose methotrexate for ectopic pregnancy in our clinic between January 2009 and June 2014. Demographic, clinical, and laboratory results of possible factors that affect treatment success were retrospectively analyzed. Successfully and unsuccessfully treated patients were compared based on their pre-treatment results. Results: The success rate of single-dose methotrexate treatment was found to be 70.7%. No significant difference was found between succesfully and unsuccessfully treated patients before treatment in terms of factors such as gestational weeks, mass size, presence of yolk sac, and presence of free fluid (p=0.224, p=0.201, p=0.200, p=0.200). Serum β-hCG values in patients whose treatment was unsuccessful was found to be higher compared with the successfully treated group (mean β-hCG value of unsuccessful group: 4412±3501 mIU/mL; mean β-hCG value of successful group: 1079±942 mIU/mL; p<0.001). Conclusion: Single-dose methotrexate treatment is an effective and reliable method in the treatment of ectopic pregnancy. Elevation of serum β-hCG value stands as the main prognostic factor that affects the success of single-dose methotrexate treatment. PMID:28913072

The effects of milk thistle on hepatic fibrosis due to methotrexate in rat.

PubMed

Ghaffari, Ali Reza; Noshad, Hamid; Ostadi, Ali; Ghojazadeh, Morteza; Asadi, Parviz

2011-06-01

Extracts of milk thistle (MT), Silybum marianum, have been used as medical remedies since the time of ancient Greece. Methotrexate is a potentially hepatotxic drug. To clarify the hepatoprotective effects of MT on methotrexate. From January 2010 to April 2010, 30 male rats were recruited into three 10-rat subgroups in Tabriz University of Medical Sciences. Normal saline was injected intraperitoneally in the first group (A; the controls); intraperitoneal methotrexate plus oral MT extract were administered to the second group (B) and intraperitoneal methotrexate alone was given to the third group (C). Pre- and post-interventional measuring of serum parameters were carried out every 15 days. After six weeks, the rats were decapitated and histopathological evaluation of liver was done. Serum liver enzymes (AST, ALT), alkaline phosphatase, total and direct bilirubin, creatinine and BUN were measured on days 0, 15, 30, 45. They were significantly higher in the group C, comparing with other two groups. Serum albumin was the least in group C animals as well. There were no significant differences between groups A and B. The mean±SD fibrosis score using semi-quantitative scoring system (SSS) was 1.25±0.46, 1.40±0.52 and 6.70±0.82, in groups A, B and C, respectively (p<0.001). MT extract can effectively prevent methotrexate-induced liver dysfunction and fibrosis in rats.

Comparable Efficacy With Varying Dosages of Glucarpidase in Pediatric Oncology Patients

PubMed Central

Scott, Jeffrey R.; Zhou, Yinmei; Cheng, Cheng; Ward, Deborah A.; Swanson, Hope D.; Molinelli, Alejandro R.; Stewart, Clinton F.; Navid, Fariba; Jeha, Sima; Relling, Mary V.; Crews, Kristine R.

2016-01-01

Background Glucarpidase rapidly reduces methotrexate plasma concentrations in patients experiencing methotrexate-induced renal dysfunction. Debate exists regarding the role of glucarpidase in therapy given its high cost. The use of reduced-dose glucarpidase has been reported, and may allow more institutions to supply this drug to their patients. This report explores the relationship between glucarpidase dosage and patient outcomes in pediatric oncology patients. Methods The authors evaluated data from 26 patients who received glucarpidase after high-dose methotrexate. Decrease in plasma methotrexate concentrations and time to renal recovery were evaluated for an association with glucarpidase dosage, which ranged from 13 to 90 units/kg. Results No significant relationship was found between glucarpidase dosage (units/kg) and percent decrease in methotrexate plasma concentrations measured by TDx (P >0.1) or HPLC (P >0.5). Patients who received glucarpidase dosages <50 units/kg had a median percent reduction in methotrexate plasma concentration of 99.4% (range, 98–100) measured by HPLC compared to a median percent reduction of 99.4% (range, 77.2–100) in patients who received ≥50 units/kg. Time to SCr recovery was not related to glucarpidase dosage (P >0.8). Conclusions The efficacy of glucarpidase in the treatment of HDMTX-induced kidney injury was not dosage-dependent in this retrospective analysis of pediatric oncology patients. Pediatr Blood Cancer 2015;62:1518–1522. PMID:25631103

Success rates of single-dose methotrexate and additional dose requirements among women with first and previous ectopic pregnancies.

PubMed

Cirik, Derya Akdag; Kinay, Tugba; Keskin, Ugur; Ozden, Eda; Altay, Metin; Gelisen, Orhan

2016-04-01

To compare the success of the single-dose methotrexate regimen and the requirement for a second or third dose of methotrexate between women with their first ectopic pregnancy (EP) and those with previous EP. In a retrospective cohort study, data were analyzed from women treated for EP by single-dose methotrexate at a Turkish tertiary referral center between January 2010 and December 2013. Data were compared between women with at least one previous EP and those with their first EP. The success rate of the protocol in the first and previous EP groups was similar: 93.0% (320/344) and 87.3% (48/55), respectively. History of previous EP was not a predictor of treatment failure. However, the requirement for additional methotrexate doses was significantly higher in the previous EP group (16/48 [33.4%]) than in the first EP group (55/320 [17.2%]; P=0.03). Multivariate analysis showed that history of tubal surgery (P=0.006) and initial levels of the β-subunit of human chorionic gonadotropin (P=0.001) were significant predictors of treatment failure. Although the single-dose regimen had similar success rates in the previous EP and first EP groups, additional doses of methotrexate were more frequently required in the previous EP group. Copyright © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Methotrexate intercalated ZnAl-layered double hydroxide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chakraborty, Manjusha; Dasgupta, Sudip; Soundrapandian, Chidambaram

2011-09-15

The anticancerous drug methotrexate (MTX) has been intercalated into an ZnAl-layered double hydroxide (LDH) using an anion exchange technique to produce LDH-MTX hybrids having particle sizes in the range of 100-300 nm. X-ray diffraction studies revealed increases in the basal spacings of ZnAl-LDH-MTX hybrid on MTX intercalation. This was corroborated by the transmission electron micrographs, which showed an increase in average interlayer spacing from 8.9 A in pristine LDH to 21.3 A in LDH-MTX hybrid. Thermogravimetric analyses showed an increase in the decomposition temperature for the MTX molecule in the LDH-MTX hybrid indicating enhanced thermal stability of the drug moleculemore » in the LDH nanovehicle. The cumulative release profile of MTX from ZnAl-LDH-MTX hybrids in phosphate buffer saline (PBS) at pH 7.4 was successfully sustained for 48 h following Rigter-Peppas model release kinetics via diffusion. - Graphical abstract: ZnAl-layered double hydroxide intercalated with methotrexate ({approx}34% loading) promises the possibility of use of ZnAl-LDH material as drug carrier and in controlled delivery. Highlights: > ZnAl-layered double hydroxide methotrexate nanohybrid has been synthesized. > XRD and TEM studies on nanohybrid revealed successful intercalation of methotrexate. > TG and CHN analyses showed {approx}34 wt% of methotrexate loading into the nanohybrid. > Possibility of use of ZnAl-LDH material as drug carrier and in delivery.« less

Tofacitinib

MedlinePlus

Tofacitinib is used alone or with other medications to treat rheumatoid arthritis (condition in which the body ... be treated with methotrexate (Otrexup, Rasuvo, Trexall) alone. Tofacitinib is also used with methotrexate or other similar ...

Continuous low-dose cyclophosphamide and methotrexate combined with celecoxib for patients with advanced cancer

PubMed Central

Khan, O A; Blann, A D; Payne, M J; Middleton, M R; Protheroe, A S; Talbot, D C; Taylor, M; Han, C; Patil, M; Harris, A L

2011-01-01

Background: Combined therapy of metronomic cyclophosphamide, methotrexate and high-dose celecoxib targeting angiogenesis was used in a phase II trial. Methods: Patients with advanced cancer received oral cyclophosphamide 50 mg o.d., celecoxib 400 mg b.d. and methotrexate 2.5 mg b.d. for two consecutive days each week. Response was determined every 8 weeks; toxicity was evaluated according to CTC version 2.0. Plasma markers of inflammation, coagulation and angiogenesis were measured. Results: Sixty-seven of 69 patients were evaluable for response. Twenty-three patients had stable disease (SD) after 8 weeks, but there were no objective responses to therapy. Median time to progression was 57 days. There was a low incidence of toxicities. Among plasma markers, levels of tissue factor were higher in the SD group of patients at baseline, and levels of both angiopoietin-1 and matrix metalloproteinase-9 increased in the progressive disease group only. There were no changes in other plasma markers. Conclusion: This metronomic approach has negligible activity in advanced cancer albeit with minimal toxicity. Analysis of plasma markers indicates minimal effects on endothelium in this trial. These data for this particular regimen do not support basic tenets of metronomic chemotherapy, such as the ability to overcome resistant tumours by targeting the endothelium. PMID:21587257

Continuous low-dose cyclophosphamide and methotrexate combined with celecoxib for patients with advanced cancer.

PubMed

Khan, O A; Blann, A D; Payne, M J; Middleton, M R; Protheroe, A S; Talbot, D C; Taylor, M; Kirichek, O; Han, C; Patil, M; Harris, A L

2011-06-07

Combined therapy of metronomic cyclophosphamide, methotrexate and high-dose celecoxib targeting angiogenesis was used in a phase II trial. Patients with advanced cancer received oral cyclophosphamide 50 mg o.d., celecoxib 400 mg b.d. and methotrexate 2.5 mg b.d. for two consecutive days each week. Response was determined every 8 weeks; toxicity was evaluated according to CTC version 2.0. Plasma markers of inflammation, coagulation and angiogenesis were measured. Sixty-seven of 69 patients were evaluable for response. Twenty-three patients had stable disease (SD) after 8 weeks, but there were no objective responses to therapy. Median time to progression was 57 days. There was a low incidence of toxicities. Among plasma markers, levels of tissue factor were higher in the SD group of patients at baseline, and levels of both angiopoietin-1 and matrix metalloproteinase-9 increased in the progressive disease group only. There were no changes in other plasma markers. This metronomic approach has negligible activity in advanced cancer albeit with minimal toxicity. Analysis of plasma markers indicates minimal effects on endothelium in this trial. These data for this particular regimen do not support basic tenets of metronomic chemotherapy, such as the ability to overcome resistant tumours by targeting the endothelium.

Methotrexate

MedlinePlus

... and sometimes other medications to treat severe active rheumatoid arthritis (RA; a condition in which the body attacks ... to stop scales from forming. Methotrexate may treat rheumatoid arthritis by decreasing the activity of the immune system.

Current treatment of juvenile rheumatoid arthritis.

PubMed

Ilowite, Norman T

2002-01-01

Prognostic factors in juvenile rheumatoid arthritis (JRA) include polyarticular onset, polyarticular disease course, and rheumatoid factor positivity; in the systemic onset subtype, persistence of systemic features at 6 months after onset confers a worse prognosis. Timely diagnosis and appropriate aggressive treatment of patients with poor prognostic features improve quality of life and outcome. After nonsteroidal anti-inflammatory drugs, methotrexate is the most commonly used second-line agent. However, approximately one third of patients do not respond to methotrexate adequately. Randomized, placebo-controlled, clinical trials in patients with JRA are few, but one such trial with the tumor necrosis factor inhibitor etanercept shows that this drug is effective and well-tolerated. Other recently approved agents for rheumatoid arthritis, including infliximab, leflunomide, celecoxib, and rofecoxib, have not been adequately studied in pediatric patients, and the role of these agents in children with JRA remains to be determined.

A Case of Subacute Encephalopathy Developing After Treatment With Clofarabine and Methotrexate That Resolved With Corticosteroids.

PubMed

Tzachanis, Dimitrios; Haider, Mintallah; Papazisis, Georgios

2016-01-01

This is the case of a 24-year-old woman with relapsed acute undifferentiated leukemia who developed subacute encephalopathy with hemiparesis and dysarthria after treatment with high dose and intrathecal methotrexate, clofarabine, and cytarabine that resolved rapidly and completely after the administration of corticosteroids. We hypothesize that clofarabine might predispose to methotrexate-induced central nervous system toxicity by increasing endothelial permeability (capillary leak syndrome) and suggest that corticosteroids are effective in the treatment of this type of encephalopathy.

Methotrexate Injection

MedlinePlus

... and sometimes other medications to treat severe active rheumatoid arthritis (RA; a condition in which the body attacks ... to stop scales from forming. Methotrexate may treat rheumatoid arthritis by decreasing the activity of the immune system.

Two-Year Safety and Efficacy Experience in Patients with Methotrexate-Resistant Active Rheumatoid Arthritis Treated with Etanercept and Conventional Disease-Modifying Anti-rheumatic Drugs in the Latin American Region

PubMed Central

Machado, Daniel A.; Guzman, Renato; Xavier, Ricardo M.; Simon, Jesus A.; Mele, Linda; Shen, Qi; Pedersen, Ronald; Kotak, Sameer; Vlahos, Bonnie

2016-01-01

Background: Although long-term data are available from biologic studies in North American/European populations with rheumatoid arthritis (RA), long-term findings in Latin American RA populations are limited. Objective: To examine long-term safety/efficacy of etanercept, methotrexate, and/or other disease-modifying anti-rheumatic drugs (DMARDs) in Latin American patients with moderate-to-severe active RA. Methods: In the first phase of this open-label study, patients were randomized to etanercept 50 mg weekly plus methotrexate or conventional DMARD (hydroxychloroquine or sulfasalazine) plus methotrexate for 24 weeks. At the start of the second phase (week 24), investigators selected a treatment regimen that included any combination/dosage of etanercept, methotrexate, hydroxychloroquine, or sulfasalazine based on previous treatment response, preference, and local product labeling, and was continued for the 104-week extension. Results: In the extension, in the group previously randomized to etanercept-plus-methotrexate therapy, etanercept was continued in 259/260 patients; methotrexate continued in 260/260; and hydroxychloroquine and sulfasalazine added in 8/260 and 3/260, respectively. In the group previously randomized to conventional DMARD-plus-methotrexate therapy, conventional DMARD was discontinued in 86/126 and etanercept added in 105/126. Among etanercept-exposed patients (total exposure, 798.1 patient-year [PY]), rates of adverse events, serious adverse events, and serious infections per PY were 1.7, 0.07, and 0.02 events per PY. In both groups, after treatment modification was permitted, clinical response rates and improvements in clinical/patient-reported outcomes from baseline were sustained to week 128. Conclusion: After investigators were permitted to modify treatment, etanercept was part of the treatment regimen in 95% of patients. Continuation or addition of etanercept in the 2-year extension resulted in a consistently good risk:benefit profile. Trial Registration: Open-Label Study Comparing Etanercept to Conventional Disease Modifying Antirheumatic Drug (DMARD) Therapy; ClinicalTrials.gov, number NCT00848354; https://clinicaltrials.gov/ct2/show/NCT00848354 PMID:27006728

Structural comparison of complexes of methotrexate analogues with Lactobacillus casei dihydrofolate reductase by two-dimensional /sup 1/H NMR at 500 MHz

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hammond, S.J.; Birdsall, B.; Feeney, J.

1987-12-29

The authors have used two-dimensional (2D) NMR methods to examine complexes of Lactobacillus casei dihydrofolate reductase and methotrexate (MTX) analogues having structural modifications of the benzoyl ring and also the glutamic acid moiety. Assignments of the /sup 1/H signals in the spectra of the various complexes were made by comparison of their 2D spectra with those complexes containing methotrexate where we have previously assigned resonances from 32 of the 162 amino acid residues. In the complexes formed with the dihalomethotrexate analogues, the glutamic acid and pteridine ring moieties were shown to bind to the enzyme in a manner similar tomore » that found in the methotrexate-enzyme complex. Perturbations in /sup 1/H chemical shifts of protons in Phe-49, Leu-54, and Leu-27 and the methotrexate H7 and NMe protons were observed in the different complexes and were accounted for by changes in orientation of the benzoyl ring in the various complexes. Binding of oxidized or reduced coenzyme to the binary complexes did not result in different shifts for Leu-27, Leu-54, or Leu-19 protons, and thus, the orientation of the benzoyl ring of the methotrexate analogues is not perturbed greatly by the presence of either oxidized or reduced coenzyme. In the complex with the ..gamma..-monoamide analog, the /sup 1/H signals of assigned residues in the protein had almost identical shifts with the corresponding protons in the methotrexate-enzyme complex for all residues except His-28 and, to a lesser extent, Leu-27. This indicates that while the His-28 interaction with the MTX ..gamma..-CO/sub 2//sup -/ is no longer present in this complex with the ..gamma..-amide, there has not been a major change in the overall structure of the two complexes. This behavior contrasts to that of the ..cap alpha..-amide complex where /sup 1/H signals from protons in several amino acid residues are different compared with their values in the complex formed with methotrexate.« less

Efficacy of adalimumab in young children with juvenile idiopathic arthritis and chronic uveitis: a case series.

PubMed

La Torre, Francesco; Cattalini, Marco; Teruzzi, Barbara; Meini, Antonella; Moramarco, Fulvio; Iannone, Florenzo

2014-05-24

Juvenile idiopathic arthritis is a relatively common chronic disease of childhood, and is associated with persistent morbidity and extra-articular complications, one of the most common being uveitis. The introduction of biologic therapies, particularly those blocking the inflammatory mediator tumor necrosis factor-α, provided a new treatment option for juvenile idiopathic arthritis patients who were refractory to standard therapy such as non-steroidal anti-inflammatory drugs, corticosteroids and/or methotrexate. The first case was a 2-year-old girl with juvenile idiopathic arthritis and uveitis who failed to respond to treatment with anti-inflammatories, low-dose corticosteroids and methotrexate, and had growth retardation. Adalimumab 24 mg/m2 every 2 weeks and prednisone 0.5 mg/kg/day were added to methotrexate therapy; steroid tapering and withdrawal started after 1 month. After 2 months the patient showed good control of articular and ocular manifestations, and she remained in remission for 1 year, receiving adalimumab and methotrexate with no side effects, and showing significant improvement in growth. Case 2 was a 9-year-old boy with an 8-year history of juvenile idiopathic arthritis and uveitis that initially responded to infliximab, but relapse occurred after 2 years off therapy. After switching to adalimumab, and adjusting doses of both adalimumab and methotrexate based on body surface area, the patient showed good response and corticosteroids were tapered and withdrawn after 6 months; the patient remained in remission taking adalimumab and methotrexate. The final case was a 5-year-old girl with juvenile idiopathic arthritis for whom adalimumab was added to methotrexate therapy after three flares of uveitis. The patient had two subsequent episodes of uveitis that responded well to local therapy, but was then free of both juvenile idiopathic arthritis and uveitis symptoms, allowing methotrexate and then adalimumab to be stopped; the patient remained in drug-free remission. This report includes the first published case of the use of adalimumab in a child aged <3 years. Our clinical experience further supports the use of biologic therapy for the management of juvenile idiopathic arthritis and uveitis in children as young as two years of age.

Cellular uptake of Clostridium botulinum C2 toxin: membrane translocation of a fusion toxin requires unfolding of its dihydrofolate reductase domain.

PubMed

Haug, Gerd; Wilde, Christian; Leemhuis, Jost; Meyer, Dieter K; Aktories, Klaus; Barth, Holger

2003-12-30

The Clostridium botulinum C2 toxin is the prototype of the family of binary actin-ADP-ribosylating toxins. C2 toxin is composed of two separated nonlinked proteins. The enzyme component C2I ADP-ribosylates actin in the cytosol of target cells. The binding/translocation component C2II mediates cell binding of the enzyme component and its translocation from acidic endosomes into the cytosol. After proteolytic activation, C2II forms heptameric pores in endosomal membranes, and most likely, C2I translocates through these pores into the cytosol. For this step, the cellular heat shock protein Hsp90 is essential. We analyzed the effect of methotrexate on the cellular uptake of a fusion toxin in which the enzyme dihydrofolate reductase (DHFR) was fused to the C-terminus of C2I. Here, we report that unfolding of C2I-DHFR is required for cellular uptake of the toxin via the C2IIa component. The C2I-DHFR fusion toxin catalyzed ADP-ribosylation of actin in vitro and was able to intoxicate cultured cells when applied together with C2IIa. Binding of the folate analogue methotrexate favors a stable three-dimensional structure of the dihydrofolate reductase domain. Pretreatment of C2I-DHFR with methotrexate prevented cleavage of C2I-DHFR by trypsin. In the presence of methotrexate, intoxication of cells with C2I-DHFR/C2II was inhibited. The presence of methotrexate diminished the translocation of the C2I-DHFR fusion toxin from endosomal compartments into the cytosol and the direct C2IIa-mediated translocation of C2I-DHFR across cell membranes. Methotrexate had no influence on the intoxication of cells with C2I/C2IIa and did not alter the C2IIa-mediated binding of C2I-DHFR to cells. The data indicate that methotrexate prevented unfolding of the C2I-DHFR fusion toxin, and thereby the translocation of methotrexate-bound C2I-DHFR from endosomes into the cytosol of target cells is inhibited.

Methotrexate for ocular inflammatory diseases.

PubMed

Gangaputra, Sapna; Newcomb, Craig W; Liesegang, Teresa L; Kaçmaz, R Oktay; Jabs, Douglas A; Levy-Clarke, Grace A; Nussenblatt, Robert B; Rosenbaum, James T; Suhler, Eric B; Thorne, Jennifer E; Foster, C Stephen; Kempen, John H

2009-11-01

To evaluate the outcome of treatment with methotrexate for noninfectious ocular inflammation. Retrospective cohort study. Patients with noninfectious ocular inflammation managed at 4 tertiary ocular inflammation clinics in the United States observed to add methotrexate as a single, noncorticosteroid immunosuppressive agent to their treatment regimen, between 1979 and 2007, inclusive. Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics, including dosage, route of administration of methotrexate, and main outcome measures, were obtained for every eye of every patient at every visit via medical record review by trained expert reviewers. Control of inflammation, corticosteroid-sparing effects, and incidence of and reason for discontinuation of therapy. Among 384 patients (639 eyes) observed from the point of addition of methotrexate to an anti-inflammatory regimen, 32.8%, 9.9%, 21.4%, 14.6%, 15.1%, and 6.3%, respectively, had anterior uveitis, intermediate uveitis, posterior or panuveitis, scleritis, ocular mucous membrane pemphigoid, and other forms of ocular inflammation. In these groups, complete suppression of inflammation sustained for >or=28 days was achieved within 6 months in 55.6%, 47.4%, 38.6%, 56.4%, 39.5%, and 76.7%, respectively. Corticosteroid-sparing success (sustained suppression of inflammation with prednisone

In vivo anti-psoriatic activity, biodistribution, sub-acute and sub-chronic toxicity studies of orally administered methotrexate loaded chitin nanogel in comparison with methotrexate tablet.

PubMed

Panonnummal, Rajitha; Jayakumar, R; Anjaneyan, Gopikrishnan; Sabitha, M

2018-04-15

The anti-psoriatic efficacy of orally administered methotrexate loaded chitin nanogel (MCNG) was evaluated (two doses- 2.715 mg/kg and 5.143 mg/kg) and compared against orally administered methotrexate tablet MTX (5.143 mg/kg). MCNG at both dose levels of 2.715 mg/kg and 5.143 mg/kg exhibited significant anti-psoriatic activity which is very much comparable with MTX, caused normalization of histological features and inflammatory score associated with induced psoriasis. Biodistribution studies revealed the presence of drug in serum and in vital organs at all the three cases with highest amount in MCNG at 5.143 mg/kg dose, followed by MTX tablet and are lowest in MCNG at 2.715 mg/kg dose. MCNG at the highest dose of 5.143 mg/kg caused liver, lung and kidney toxicities on sub acute toxicity studies and MTX tablet was found to be toxic on liver and lung on sub chronic toxicity studies. MCNG 2.715 mg/kg was found to be safe on both sub acute and sub chronic administrations, suggesting that it can provide sufficient serum and tissue level of methotrexate necessary to clear psoriatic lesions, without inducing systemic toxicity and expected to be a better alternative for orally administered conventional methotrexate tablet for patients who need systemic medications for psoriasis. Copyright © 2018. Published by Elsevier B.V.

Evidence for two interconverting protein isomers in the methotrexate complex of dihydrofolate reductase from Escherichia coli

DOE Office of Scientific and Technical Information (OSTI.GOV)

Falzone, C.J.; Benkovic, S.J.; Wright, P.E.

1991-02-26

Two-dimensional {sup 1}H NMR methods and a knowledge of the X-ray crystal structure have been used to make resonance assignments for the amino acid side chains of dihydrofolate reductase from Escherichia coli complexed with methotrexate. The H7 proton on the pteridine ring of methotrexate was found to have NOEs to the methyl protons of Leu-28 which were assigned by using the L28F mutant. These NOEs indicated that the orientation of the methotrexate pteridine ring is similar in both solution and crystal structures. During the initial assignment process, it became evident that many of the resonances in this complex, unlike thosemore » of the folate complex, are severally broadened or doubled. The observation of two distinct sets of resonances in a ratio of approximately 2:1 was attributed to the presence of two protein isomers. Many of the side chains with clearly doubled resonances were located in the {beta}-sheet and the active site. Preliminary studies on the apoprotein also revealed doubled resonances in the absence of the inhibitor, indicating the existence of the protein isomers prior to methotrexate binding. In contrast to the methotrexate complex, the binary complex with folate and the ternary MTX-NADPH-DHFR complex presented a single enzyme form. These results are proposed to reflect the ability of folate and NADPH to bind predominantly to one protein isomer.« less

Methotrexate treatment in progressive tubal ectopic pregnancies and hCG-related clinicosurgical implications.

PubMed

Dogan, Askin; Gulhan, Ibrahim; Uyar, Ibrahim; Ekin, Atalay; Gezer, Cenk; Bilgin, Muzaffer; Taner, Cüneyt E; Ertas, Ibrahim E

2016-06-01

Our aim was to evaluate the relationship between the success of methotrexate treatment and β-hCG levels in progressive tubal ectopic pregnancies. We defined a retrospective cohort of 394 progressive tubal ectopic pregnancy patients treated with methotrexate. A single-dose methotrexate protocol using 50 mg/m(2) was administered to patients with progressive tubal ectopic pregnancy. Surgery was performed in patients who exhibited signs of acute abdomen due to tubal rupture. Of 394 patients that received methotrexate treatment, 335 (84.6%) responded to medical treatment, while the remaining 59 (15.36%) underwent surgery due to treatment failure. β-hCG levels in the failure group were significantly higher as compared with the success group at Day 1, Day 4, and Day 7 (2116±3157 vs. 4178±3422, 2062±3551 vs. 4935±4103, and 1532±3007 vs. 3900±4783, respectively). The receiver operating characteristics curve for β-hCG levels at Day 1 was 0.738, with a cutoff value of 1418 mIU/mL, while sensitivity and specificity values reached the optimum for treatment success (83.1% and 59.4%, respectively). Medical treatment with methotrexate achieved an 85.02% success rate for the treatment of progressive tubal ectopic pregnancy, while success rates for medical treatment decreased significantly when initial β-hCG levels were >1418 mIU/mL. Copyright © 2016. Published by Elsevier Taiwan.

Evaluation of ototoxicity of intratympanic administration of Methotrexate in rats.

PubMed

Eren, Sabri Baki; Dogan, Remzi; Yenigun, Alper; Veyseller, Bayram; Tugrul, Selahattin; Ozturan, Orhan; Aydin, Mehmet Serif

2017-09-01

Methotrexate is a dihydrofolate reductase enzyme inhibitor with very high selectivity, and it is an antiproliferative folic acid antagonist used for the treatment of autoimmune diseases. In this study, our objective was to evaluate the effect of intratympanic Methotrexate application in the inner ear. This study was planned as an animal study. This study performed in a tertiary referral center. 24 healthy female rats were used in our study. They were separated into three groups. 0.2 cc intratympanic saline was applied to both ears of Group 1. Paracentesis was applied to the tympanic membrane in both ears of Group 2. 0.2 cc intratympanic Methotrexate was applied to both ears of Group 3. At the beginning of the study, Distortion-product otoacoustic emissions (DPOAE) and Auditory brainstem response (ABR) of all rats were measured and then again on the 5th, 10th and 15th day. Histologic examinations of all groups were compared. There was not any significant difference between basal DPOAE and ABR measurement values of the groups and the results were measured again on the 5th, 10th and 15th day (p > 0.05). There was no difference between the groups in terms of histology. The intratympanic Methotrexate injection does not have any ototoxic effect on inner ear. We assume that intratympanic Methotrexate could be used safely on inner ear diseases in which steroid treatment is contraindicated or not effective. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of oral glutamine on enterocyte turnover during methotrexate-induced mucositis in rats.

PubMed

Sukhotnik, Igor; Mogilner, Jorge G; Karry, Rahel; Shamian, Benhoor; Lurie, Michael; Kokhanovsky, Natalie; Ure, Benno M; Coran, Arnold G

2009-01-01

The objective of this study was to evaluate the effects of oral glutamine in preventing intestinal mucosal damage caused by methotrexate (MTX) in rats. Male Sprague-Dawley rats were divided into 3 experimental groups: control rats, rats treated intraperitoneally with MTX (MTX rats) and rats treated with oral glutamine in the drinking water (2%) 72 h following intraperitoneal injection of a single dose of MTX (MTX-glutamine rats). Intestinal mucosal damage (Park's injury score), mucosal structural changes, enterocyte proliferation and enterocyte apoptosis were determined 72 h following MTX injection. RT-PCR was used to determine Bax and Bcl-2 mRNA expression. MTX-glutamine rats demonstrated greater jejunal and ileal mucosal weight and mucosal DNA, greater ileal villus height and crypt depth, and a greater index of proliferation in the jejunum and ileum compared to MTX animals. A significant decrease in enterocyte apoptosis in the ileum of MTX-glutamine rats (vs. MTX) was accompanied by decreased Bax and increased Bcl-2 mRNA expression. Treatment with oral glutamine prevents mucosal injury and improves intestinal recovery following MTX injury in the rat.

Methotrexate Reduced TNF Bioactivity in Rheumatoid Arthritis Patients Treated with Infliximab

PubMed Central

Rinaudo-Gaujous, Mélanie; Thomas, Thierry

2017-01-01

Objectives. To evaluate methotrexate effect on tumor necrosis factor (TNF) alpha bioactivity during infliximab (IFX) therapy in rheumatoid arthritis (RA) patients and to correlate TNF bioactivity with antibody towards IFX (ATI) development and RA clinical response. Materials and Methods. Thirty-nine active women RA patients despite conventional synthetic disease modifying antirheumatic drugs (csDMARDs) requiring IFX therapy were enrolled, and clinical data and blood samples were recorded at baseline (W0) and at 6 weeks (W6), W22, and W54 of IFX treatment. TNF bioactivity as well as IFX trough and ATI concentrations were assessed on blood samples. Results. TNF bioactivity decreased from W0 to W54 with a large range from W22 at the time of ATI detection. From W22, TNF bioactivity was lower in presence of methotrexate as csDMARD compared to other csDMARDs. IFX trough concentration increased from W0 to W54 with a large range from W22, similarly to TNF bioactivity. Methotrexate therapy prevented ATI presence at W22 and reduced TNF bioactivity compared to other csDMARDs (p = 0.002). Conclusion. This suggests that methotrexate plays a key role in TNF bioactivity and against ATI development. PMID:28352145

Therapy of primary CNS lymphoma with methotrexate-based chemotherapy and deferred radiotherapy: preliminary results.

PubMed

Cher, L; Glass, J; Harsh, G R; Hochberg, F H

1996-06-01

Disease-free survival in primary CNS lymphoma has improved with the advent of methotrexate-based pre-irradiation chemotherapy. Prolonged response durations have been noted in six of eight patients refusing radiation therapy in two of our prior series. We have treated an additional 11 patients with methotrexate-based chemotherapy without subsequent planned irradiation. Some received maintenance chemotherapy. Most have had durable responses with little or no toxicity. Prolonged responses can be maintained without radiation therapy, thus avoiding potential long-term radiation toxicity.

Herpes simplex type 2 encephalitis and methotrexate medication: a fortuitous or causative association in a patient with spondyloarthritis?

PubMed

Lupo, Julien; Dos Santos, Ophélie; Germi, Raphaele; Baccard-Longère, Monique; Stahl, Jean-Paul; Epaulard, Olivier; Morand, Patrice

2017-01-01

It is unclear whether immunosuppression is a risk factor for herpes encephalitis. Herein, we describe a rare case of herpes simplex virus type 2 encephalitis in a patient treated with low-dose methotrexate for HLA-B27-associated spondyloarthritis. The patient was successfully treated with acyclovir but presented sequelae of encephalitis. Here we discuss the possible role of low-dose methotrexate therapy as a risk factor of neurological herpes reactivation and severe disease. The host-related and viral risk factors are also addressed.

[Hemiparesis and facial palsy caused by methotrexate].

PubMed

Rueda Arenas, E; García Corzo, J; Franco Ospina, L

2013-12-01

Methotrexate used in the treatment of acute lymphocytic leukemia, can cause neurotoxicity, including a rare presentation with hemiparesis. We describe two teenagers, who during the implementation of the M phase of the protocol, suffered hemiparesis, facial paresis and dysarthria which quickly reversed. Leukemia involvement of the central nervous system and stroke, were ruled out. We briefly review the pathophysiology of methotrexate neurotoxicity, the characteristics of the focal paresis presentation and magnetic resonance image findings. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

Cost-minimisation analysis of subcutaneous methotrexate versus biologic therapy for the treatment of patients with rheumatoid arthritis who have had an insufficient response or intolerance to oral methotrexate.

PubMed

Fitzpatrick, Ray; Scott, David Gi; Keary, Ian

2013-11-01

This study aims to model the economic impact of subcutaneous methotrexate (SC MTX) or a biologic over a 12-month period using a hypothetical population of rheumatoid arthritis patients who failed to tolerate or respond to oral MTX and were suitable candidates for biologic therapy. A decision-based model was developed using current National Institute for Health and Clinical Excellence (NICE) guidance to determine the management of this hypothetical UK population. Published data on the continuation rates of SC MTX and biologics were used to compare the costs of the two treatment options. The economic model used a cost-minimisation methodology from a UK National Health Service (NHS) perspective, with the cost of all drugs and resources being estimated on this basis. Sensitivity analyses were also performed to determine the effects of changing key assumptions on the mean cost differences. The routine use of SC MTX following oral MTX failure has the potential to save an estimated £7,197 per patient in the first year of therapy and £9.3m per year nationally in new patients. Sensitivity analyses support the robustness of the results. The results of this study suggest that routine use of SC MTX following oral MTX failure has the potential to provide considerable savings to the NHS through optimised use of MTX first-line therapy. It is proposed, therefore, that patients should start on oral MTX with a subsequent switch to SC MTX in the case of an insufficient response or tolerability issues, before introducing a biologic agent.

Serum creatinine and creatinine clearance for predicting plasma methotrexate concentrations after high-dose methotrexate chemotherapy for the treatment for childhood lymphoblastic malignancies.

PubMed

Xu, Wei-qun; Zhang, Ling-yan; Chen, Xue-ying; Pan, Bin-hua; Mao, Jun-qing; Song, Hua; Li, Jing-yuang; Tang, Yong-min

2014-01-01

Monitoring of plasma methotrexate (MTX) concentrations allows for therapeutic adjustments in treating childhood acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) with high-dose MTX (HDMTX). We tested the hypothesis that assessment of creatinine clearance (CrCl) and/or serum Cr may be a suitable means of monitoring plasma MTX concentrations. All children in the study had ALL or NHL, were in complete remission, and received HDMTX (3 or 5 g/m(2))+leucovorin. Plasma MTX concentrations were measured at 24, 48, and 96 h. CrCl was determined at 24 and 48 h. Correlations between 24- and 48-h plasma MTX concentrations and CrCl and serum Cr concentrations were determined. CrCl and serum Cr concentrations were compared over time between children who had delayed and non-delayed MTX elimination. A total of 105 children were included. There were significant negative correlations between CrCl at 24 and 48 h and plasma MTX concentrations at 24 (both p < 0.001) and 48 h (both p < 0.001). There were significant positive correlations between serum Cr concentrations at both 24 and 48 h and plasma MTX concentrations at 24 (both p < 0.001) and 48 h (both p < 0.001). There were 88 (30.2 %) instances of elimination delay. Children with elimination delay had significantly lower CrCl and higher Cr concentrations at 24 and 48 h compared with children without elimination delay (all p < 0.05). Our findings suggest that, with further refinement, assessment of renal function may be a useful means of monitoring plasma MTX concentrations during HDMTX for ALL and NHL.

Reduction of non-specific adsorption of drugs to plastic containers used in bioassays or analyses.

PubMed

Fukazawa, Tominaga; Yamazaki, Yuri; Miyamoto, Yohei

2010-01-01

Non-specific adsorption (NSA) of drugs to plastic or glass containers used in clinical use is well known, but methods for reducing NSA have been rarely reported. We assessed the NSA to various containers and then investigated methods to reduce NSA. Probe drugs (methotrexate, warfarin, chloroquine, propranolol, verapamil, digoxin and paclitaxel) dissolved in water were incubated in conventional or low-adsorption containers for 4h at 4 degrees C and the NSA was determined by HPLC. They were also dissolved in aqueous methanol or acetonitrile and the NSA to a conventional polypropylene microplate was determined. Finally, tissue culture microplates were coated with silane coupling agents and the effects of the coatings were evaluated. Hydrophobic drugs (paclitaxel, verapamil and digoxin) were highly adsorbed to conventional plastic microplates, but in addition to hydrophobic drugs, positively charged drugs were well adsorbed to the tissue culture microplate. Low-adsorption microplates could reduce NSA below 15%, but positively charged or neutral hydrophobic drugs showed relatively higher adsorption. Acetonitrile showed stronger NSA inhibition than that of methanol, but the peak shapes of methotrexate and chloroquine were broadened and split. Among the silane coupling agents, GPTMS suppressed the NSA below 10%. Also, AATMS resembled the NSA pattern of GPTMS, but it increased the adsorption of methotrexate to 29%. On conventional plastic microplates, NSA is mainly driven by hydrophobic interactions, but on tissue culture microplates and low-adsorption microplates, in addition to hydrophobic interactions, ionic interactions play a role in the NSA. Therefore, to reduce the NSA to plastic containers, both hydrophobic and ionic interactions should be reduced using amphiphilic organic solvents or neutral and hydrophilic coatings. 2010 Elsevier Inc. All rights reserved.

Stability of four standardized preparations of methotrexate, cytarabine, and hydrocortisone for intrathecal use.

PubMed

Olmos-Jiménez, Raquel; Espuny-Miró, Alberto; Díaz-Carrasco, María Sacramento; Fernández-Varón, Emilio; Valderrey-Pulido, Manuel; Cárceles-Rodríguez, Carlos

2016-10-01

Intrathecal administration of methotrexate, cytarabine, and hydrocortisone is commonly used to treat and prevent central nervous system involvement in leukemias and lymphomas. The use of intrathecal solutions with pH and osmolarity values close to physiologic range of CSF (pH 7.31-7.37, osmolarity 281-306 mOsm/kg) and standardization of the methotrexate, cytarabine, and hydrocortisone doses in children and adults based on age is highly recommended. Stability studies of standardized intrathecal mixtures under these conditions have not yet been published. The purpose of this study was to evaluate the physical and chemical stabilities of four standardized mixtures of methotrexate, cytarabine, and hydrocortisone stored at 2-8℃ and 25℃ up to 7 days after preparation. Four different standardized intrathecal mixtures were prepared and stored at 2-8℃ and 25℃ and protected from light. Triplicate samples were taken at different times and precipitation, appearance, color, pH, and osmolarity were analyzed. Methotrexate, cytarabine, and hydrocortisone concentrations were measured using a modified high-performance liquid chromatography method. No variation greater than 10% of the initial concentration of methotrexate, cytarabine, and hydrocortisone was observed in any of the four standardized mixtures for the 7 days of study when stored at 2-8℃ and 25℃ and protected from light. The osmolarity of the four preparations was within the physiologic range of CSF for 7 days at both 2-8℃ and 25℃. The pH values close to the physiologic range of CSF were stable for 48 h at 25℃ and for 120 h at 2-8℃. Triple intrathecal standardized preparations of methotrexate, cytarabine, and hydrocortisone sodium phosphate are physically and chemically stable at 25℃ for 48 h and at 2-8℃ for 5 days. © The Author(s) 2015.

Teaching methotrexate self-injection with a web-based video maintains patient care while reducing healthcare resources: a pilot study.

PubMed

Katz, Steven J; Leung, Sylvia

2015-01-01

The aim of the study was to compare standard nurse-led methotrexate self-injection patient education to a web-based methotrexate self-injection education video in conjunction with standard teaching on patient self-confidence for self-injection, as well as patient satisfaction, patient knowledge and teaching time. Consecutive rheumatology patients seen for methotrexate self-injection education were enrolled. Prior to education, patient self-confidence for self-injection, age, gender and education were recorded. Patients were randomized 1:1 to standard teaching or the intervention: a 12-min methotrexate self-injection education video followed by further in-person nurse education. Patients recorded their post-education confidence for self-injection, satisfaction with the teaching process and answered four specific questions testing knowledge on methotrexate self-injection. The time spent providing direct education to the patient was recorded. Twenty-nine patients participated in this study: 15 had standard (C) teaching and 14 were in the intervention group (I). Average age, gender and education level were similar in both groups. Both groups were satisfied with the quality of teaching. There was no difference in pre-confidence (C = 5.5/10 vs. I = 4.7/10, p = 0.44) or post-confidence (C = 8.8, I = 8.8, p = 0.93) between the groups. There was a trend toward improved patient knowledge in the video group versus the standard group (C = 4.7/6, I = 5.5/6, p = 0.15). Nurse teaching time was less in the video group (C = 60 min, I = 44 min, p = 0.012), with men requiring longer education time than women across all groups. An education video may be a good supplement to standard in-person nurse teaching for methotrexate self-injection. It equals the standard teaching practise with regard to patient satisfaction, confidence and knowledge while decreasing teaching time by 25 %.

Effects of methotrexate upon inflammatory parameters induced by carrageenan in the mouse model of pleurisy.

PubMed Central

Dalmarco, Eduardo Monguilhott; Fröde, Tânia Silvia; Medeiros, Yara Santos

2002-01-01

BACKGROUND: The model of pleurisy induced by carrageenan exhibits a biphasic response (4 and 48 h) and permits the quantification of exudate, cell migration and certain enzymes such as myeloperoxidase (MPO) and adenosine-deaminase (ADA) that are markers of activated leukocytes. AIMS: The present study evaluates whether there exists, in the pleurisy model, a significant inhibition of ADA and MPO enzymes, leukocyte kinetics and other markers of inflammation [nitric oxide (NO) levels, exudation] caused by methotrexate treatment by the intraperitoneal (i.p.) route. METHODS: The pleurisy was induced by carrageenan (1%) in mice, and the parameters were analyzed 4 and 48 h after. RESULTS: After the induction of inflammation (4 h), methotrexate (20 mg/kg, i.p., 24 h before pleurisy induction) inhibited the leukocyte infiltration (p < 0.05), NO levels and MPO activity (p < 0.01), but not ADA activity and fluid leakage (p > 0.05). Regarding the second phase of pleurisy (48 h), methotrexate (40 mg/kg, i.p., 0.5 h before pleurisy induction) inhibited the leukocyte infiltration (p < 0.05), fluid leakage, NO levels (p < 0.01), and ADA and MPO activity (p < 0.05). CONCLUSIONS: These findings support the evidence that the acute administration of methotrexate has an important systemic anti-inflammatory activity in the studied inflammatory model. This effect was due to a significant inhibition on both neutrophil and mononuclear cells, being less marked in relation to exudation 48 h after. In relation to the enzymes studied and to NO levels, the findings support the evidence that methotrexate inhibits both enzymes (MPO and ADA) from leukocytes at the site of injury, thus reflecting the activation of both neutrophils and lymphocytes, respectively. Furthermore, the inhibiting effect on NO in both phases of pleurisy induced by carrageenan (4 and 48 h) indicates that methotrexate acts on constitutive and/or inducible NO synthases by means of different cells of the pleural cavity. PMID:12467522

Comparison of systemic and local methotrexate treatments in cesarean scar pregnancies: time to change conventional treatment and follow-up protocols.

PubMed

Uludag, Semih Z; Kutuk, Mehmet S; Ak, Mehmet; Ozgun, Mahmut T; Dolanbay, Mehmet; Aygen, Ercan M; Sahin, Yılmaz

2016-11-01

The aim of this study was to compare the use of systemic and local methotrexate in the treatment of cesarean scar pregnancy. In this retrospective cohort study, we collected the data of 44 patients with cesarean scar pregnancy. The patients were grouped according to treatment modality: Group 1, local methotrexate injection (n=17) and Group 2, systemic methotrexate (n=27). The groups were compared with respect to side effects, recovery time, reproductive outcome, and treatment cost. The mean gestational age at diagnosis (6.4±0.93 vs. 5.4±0.80 weeks, p=0.001), pretreatment serum β-human chorionic gonadotrophin level [27,970 (11,010-39,421) vs. 7606 (4725-16,996) mIU/mL, p=0.001], and lesion size (2.74±1.36 and 1.28±0.55cm, p=0.001) were higher in Group 1. All patients were cured by primary therapy without additional surgery. The mean times for β-human chorionic gonadotrophin normalization, the uterine-mass disappearance, were significantly shorter in Group 1 than in Group 2 (6.17±1.55 vs. 8.11±2.0 weeks, p=0.001 and 10.47±4.14 vs. 13.40±4.44 weeks, p=0.002, respectively). The cost of treatment was similar between groups (281.133±112.123$ vs. 551.134±131.792$, p=0.76). The total pregnancy rates were not different between groups (5/16, 31.4% vs. 6/11, 54.6%, p=0.301). One recurrent cesarean scar pregnancy occurred after systemic methotrexate. Oral ulcers, the most common side effect, were seen in seven patients in Group 2. Even though treatment success and reproductive outcomes are similar, local methotrexate is superior to systemic methotrexate with regard to recovery time, side effects, and treatment costs, even in patients with unfavorable pretreatment prognostic predictors. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial.

PubMed

Ravelli, Angelo; Davì, Sergio; Bracciolini, Giulia; Pistorio, Angela; Consolaro, Alessandro; van Dijkhuizen, Evert Hendrik Pieter; Lattanzi, Bianca; Filocamo, Giovanni; Verazza, Sara; Gerloni, Valeria; Gattinara, Maurizio; Pontikaki, Irene; Insalaco, Antonella; De Benedetti, Fabrizio; Civino, Adele; Presta, Giuseppe; Breda, Luciana; Marzetti, Valentina; Pastore, Serena; Magni-Manzoni, Silvia; Maggio, Maria Cristina; Garofalo, Franco; Rigante, Donato; Gattorno, Marco; Malattia, Clara; Picco, Paolo; Viola, Stefania; Lanni, Stefano; Ruperto, Nicolino; Martini, Alberto

2017-03-04

Little evidence-based information is available to guide the treatment of oligoarticular juvenile idiopathic arthritis. We aimed to investigate whether oral methotrexate increases the efficacy of intra-articular corticosteroid therapy. We did this prospective, open-label, randomised trial at ten hospitals in Italy. Using a concealed computer-generated list, children younger than 18 years with oligoarticular-onset disease were randomly assigned (1:1) to intra-articular corticosteroids alone or in combination with oral methotrexate (15 mg/m 2 ; maximum 20 mg). Corticosteroids used were triamcinolone hexacetonide (shoulder, elbow, wrist, knee, and tibiotalar joints) or methylprednisolone acetate (ie, subtalar and tarsal joints). We did not mask patients or investigators to treatment assignments. Our primary outcome was the proportion of patients in the intention-to-treat population who had remission of arthritis in all injected joints at 12 months. This trial is registered with European Union Clinical Trials Register, EudraCT number 2008-006741-70. Between July 7, 2009, and March 31, 2013, we screened 226 participants and randomly assigned 102 to intra-articular corticosteroids alone and 105 to intra-articular corticosteroids plus methotrexate. 33 (32%) patients assigned to intra-articular corticosteroids alone and 39 (37%) assigned to intra-articular corticosteroids and methotrexate therapy had remission of arthritis in all injected joints (p=0·48). Adverse events were recorded for 20 (17%) patients who received methotrexate, which led to permanent treatment discontinuation in two patients (one due to increased liver transaminases and one due to gastrointestinal discomfort). No patient had a serious adverse event. Concomitant administration of methotrexate did not augment the effectiveness of intra-articular corticosteroid therapy. Future studies are needed to define the optimal therapeutic strategies for oligoarticular juvenile idiopathic arthritis. Italian Agency of Drug Evaluation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Polyamidoamine dendrimer conjugated chitosan nanoparticles for the delivery of methotrexate.

PubMed

Leng, Zhen-Hua; Zhuang, Qian-Fen; Li, Yan-Chao; He, Zeng; Chen, Zhao; Huang, Sai-Peng; Jia, Hong-Ying; Zhou, Jian-Wei; Liu, Yang; Du, Li-Bo

2013-10-15

Encapsulating anticancer drugs to synthetic polymer is a promising approach to improve the efficiency and reduce the side effects of anticancer drugs. In this study, novel chitosan derivatives with polyamidoamine moieties (CS-PAMAM) were synthesized and characterized by morphology, particle size, and zeta potential. Then the anticancer drug-methotrexate-encapsulated CS-PAMAM was prepared by hydrophobic-hydrophilic interactions. The drug release assay showed that the amount of the methotrexate release from CS-PAMAM was pH depended. Meanwhile, the cell viability assay illustrated that CS-PAMAM was suitable for the drug delivery because of its low cytotoxicity on cells. Moreover, our results showed that the CS-PAMAM could significantly improve the cytotoxicity of free methotrexate on A549 cells. These results demonstrate that CS-PAMAM may provide a suitable platform for the water-insoluble drug delivery. Copyright © 2013 Elsevier Ltd. All rights reserved.

Phase I-II study of carboplatin vincristine methotrexate and bleomycin (COMB) in carcinoma of the cervix.

PubMed Central

Rustin, G. J.; Newlands, E. S.

1988-01-01

Platinum based combination chemotherapy has been associated with a high response rate in patients with cervical carcinoma. To determine whether the toxicity could be reduced but the efficacy maintained carboplatin 200 mg m-2 was substituted for cisplatin in a regimen that was repeated two weekly and also contained vincristine, methotrexate and bleomycin. Twenty-four patients with squamous cell carcinoma of the cervix of whom 17 had relapsed following radiotherapy were studied. Only 5 of the 19 evaluable patients had a partial response (26%, 95 confidence limits 45.7-6.3%) compared to 30 of 43 (70%, 84-56%) who received a cisplatin combination in a previous study (P less than 0.01) (Rustin et al., 1987). Carboplatin as given in the COMB regimen appears less effective than cisplatin containing combinations for squamous cell carcinoma of the cervix. PMID:2465019

Pediatric morphea (localized scleroderma): review of 136 patients.

PubMed

Christen-Zaech, Stéphanie; Hakim, Miriam D; Afsar, F Sule; Paller, Amy S

2008-09-01

Morphea is an autoimmune inflammatory sclerosing disorder that may cause permanent functional disability and disfigurement. We sought to determine the clinical features of morphea in a large pediatric cohort. We conducted a retrospective chart review of 136 pediatric patients with morphea from one center, 1989 to 2006. Most children showed linear morphea, with a disproportionately high number of Caucasian and female patients. Two patients with rapidly progressing generalized or extensive linear morphea and arthralgias developed restrictive pulmonary disease. Initial oral corticosteroid treatment and long-term methotrexate administration stabilized and/or led to disease improvement in most patients with aggressive disease. Retrospective analysis, relatively small sample size, and risk of a selected referral population to the single site are limitations. These data suggest an increased prevalence of morphea in Caucasian girls, and support methotrexate as treatment for problematic forms. Visceral manifestations rarely occur; the presence of progressive problematic cutaneous disease and arthralgias should trigger closer patient monitoring.

Protective effect of alpha-lipoic acid in methotrexate-induced ovarian oxidative injury and decreased ovarian reserve in rats.

PubMed

Soylu Karapinar, Oya; Pinar, Neslihan; Özcan, Oğuzhan; Özgür, Tümay; Dolapçıoğlu, Kenan

2017-08-01

To determine whether the possible oxidative effect of methotrexate (Mtx) on ovary and to evaluate the effectiveness of alpha lipoic acid (ALA), which may be useful in many oxidative stress models. Thirty-two female Wistar-albino rats were randomly divided into four groups; control group, alpha lipoic acid group (ALA 100 mg/kg, 10 days), multiple dose Mtx group (Mtx 1 mg/kg 1, 3, 5, 7 days) and Mtx and ALA group (Mtx 1 mg/kg 1, 3, 5, 7 days and ALA 100 mg/kg, 10 days). Serum total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI), tumor necrosis factor-alpha (TNF-α), tissue malondialdehyde (MDA) and activities of glutathione peroxidase (GSH-Px) and catalase (CAT) and anti-Mullerian hormone (AMH) and total ovarian follicle count were evaluated. Mtx administration caused a significant decrease in TAS, a significant increase in TOS and OSI, a significant increase in MDA levels and a decrease in GSH-Px and CAT activity. Moreover the proinflammatory cytokine (TNF-α) was increased in the Mtx group. And AMH values and total follicle count were significantly decreased in Mtx group. However, ALA treatment reversed biochemical results and AMH levels and total follicle count. Alpha lipoic acid ameliorates methotrexate induced oxidative damage of ovarian in rats.

Methotrexate for topical application in an extemporaneous preparation.

PubMed

Wohlrab, Johannes; Neubert, Reinhard H H; Michael, Julia; Naumann, Sandy

2015-09-01

The antifolate agent methotrexate is routinely used for systemic therapy of cancer and chronic inflammatory diseases. Successful topical use has been described for individual therapeutic attempts, in case series, and small studies, especially for mycosis fungoides (premycotic stage) and lymphomatoid papulosis. With respect to its clinical use in selected treatment scenarios, there have been no approved preparations or regulated instructions for pharmaceutical compounding. Two high performance liquid chromatography methods were established for the determination of the active substance within a galenic formulation as well as within extracts of biological material. Suitable vehicles for epicutaneous application were developed and preclinically tested for stability, release, and pharmacokinetics of the active substance as well as their safety. The tests show that methotrexate may be readily incorporated into "Basiscreme DAC". It remains stable up to a concentration of 0.5%. This preparation releases enough active substance to achieve relevant local bioavailability in the respective target compartments of the skin. There is no evidence of safety risks due to relevant systemic bioavailability after topical application on a limited area of the skin. In summary, this approved prescription for extemporaneous preparation complies with the requirements of the German Ordinance on the Operation of Pharmacies (Article 7 ApBetrO), and the available data proves its stability and pharmaceutical quality. © 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

5-Aminoimidazole-4-carboxamide ribonucleotide-transformylase and inosine-triphosphate-pyrophosphatase genes variants predict remission rate during methotrexate therapy in patients with juvenile idiopathic arthritis.

PubMed

Pastore, Serena; Stocco, Gabriele; Moressa, Valentina; Zandonà, Luigi; Favretto, Diego; Malusà, Noelia; Decorti, Giuliana; Lepore, Loredana; Ventura, Alessandro

2015-04-01

For children with juvenile idiopathic arthritis (JIA) who fail to respond to methotrexate, the delay in identifying the optimal treatment at an early stage of disease can lead to long-term joint damage. Recent studies indicate that relevant variants to predict methotrexate response in JIA are those in 5-aminoimidazole-4-carboxamide ribonucleotide-transformylase (ATIC), inosine-triphosphate-pyrophosphatase (ITPA) and solute-liquid-carrier-19A1 genes. The purpose of the study was, therefore, to explore the role of these candidate genetic factors on methotrexate response in an Italian cohort of children with JIA. Clinical response to methotrexate was evaluated as clinical remission stable for a 6-month period, as ACRPed score and as change in Juvenile Arthritis Disease score. The most relevant SNPs for each gene considered were assayed on patients' DNA. ITPA activity was measured in patients' erythrocytes. Sixty-nine patients with JIA were analyzed: 52.2 % responded to therapy (ACRPed70 score), while 37.7 % reached clinical remission stable for 6 months. ATIC rs2372536 GG genotype was associated with improved clinical remission (adjusted p value = 0.0090). For ITPA, rs1127354 A variant was associated with reduced clinical remission: (adjusted p value = 0.028); this association was present even for patients with wild-type ITPA and low ITPA activity. These preliminary results indicate that genotyping of ATIC rs2372536 and ITPA rs1127354 variants or measuring ITPA activity could be useful to predict methotrexate response in children with JIA after validation by further prospective studies on a larger patient cohort.

Medical management of ectopic pregnancy with single-dose and 2-dose methotrexate protocols: human chorionic gonadotropin trends and patient outcomes.

PubMed

Mergenthal, Michelle C; Senapati, Suneeta; Zee, Jarcy; Allen-Taylor, Lynne; Whittaker, Paul G; Takacs, Peter; Sammel, Mary D; Barnhart, Kurt T

2016-11-01

Ectopic pregnancy, although rare, is an important cause of female morbidity and mortality and early, effective treatment is critical. Systemic methotrexate has become widely accepted as a safe and effective alternative to surgery in the stable patient. As the number and timing of methotrexate doses differ in the 3 main medical treatment regimens, one might expect trends in serum human chorionic gonadotropin and time to resolution to vary depending on protocol. Furthermore, human chorionic gonadotropin trends and time to resolution may predict ultimate treatment success. This study hypothesized that the 2-dose methotrexate protocol would be associated with a faster initial decline in serum human chorionic gonadotropin levels and a shorter time to resolution compared to the single-dose protocol. A prospective multicenter cohort study included clinical data from women who received medical management for ectopic pregnancy. Rates of human chorionic gonadotropin change and successful pregnancy resolution were assessed. Propensity score modeling addressed confounding by indication, the potential for differential assignment of patients with better prognosis to the single-dose methotrexate protocol. In all, 162 ectopic pregnancies were in the final analysis; 114 (70%) were treated with the single-dose methotrexate and 48 (30%) with the 2-dose protocol. Site, race, ethnicity, and reported pain level were associated with differential protocol allocation (P < .001, P = .011, P < .001, and P = .035, respectively). Women had similar initial human chorionic gonadotropin levels in either protocol but the mean rate of decline of human chorionic gonadotropin from day 0 (day of administration of first dose of methotrexate) to day 7 was significantly more rapid in women who received the single-dose protocol compared to those treated with the 2-dose protocol (mean change -31.3% vs -10.4%, P = .037, adjusted for propensity score and site). The 2 protocols had no significant differences in success rate or time to resolution. In a racially and geographically diverse group of women, the single- and double-dose methotrexate protocols had comparable outcomes. The more rapid human chorionic gonadotropin initial decline in the single-dose group suggested these patients were probably at lower risk for ectopic rupture than those getting the 2-dose protocol. A prospective randomized controlled design is needed to remove confounding by indication. Copyright © 2016 Elsevier Inc. All rights reserved.

Functionalized gold nanoparticles for topical delivery of methotrexate for the possible treatment of psoriasis.

PubMed

Bessar, Hagar; Venditti, Iole; Benassi, Luisa; Vaschieri, Cristina; Azzoni, Paola; Pellacani, Giovanni; Magnoni, Cristina; Botti, Elisabetta; Casagrande, Viviana; Federici, Massimo; Costanzo, Antonio; Fontana, Laura; Testa, Giovanna; Mostafa, Fawzia Farag; Ibrahim, Samia Ali; Russo, Maria Vittoria; Fratoddi, Ilaria

2016-05-01

Gold nanoparticles (AuNPs) represent an effective choice for topical drug delivery systems thanks to their small size, general non-toxicity, ease of functionalization and high surface to volume ratio. Even if systemic, methotrexate still plays an important role in psoriasis treatment: its topical use shows insufficient percutaneus penetration owing to limited passive diffusion, high molecular weight and dissociation at physiological pH. The aim of our study was to design a new drug delivery nanocarrier for Methotrexate and to improve its solubility, stability and biodistribution. AuNPs were on purpose prepared with a hydrophilic stabilizing layer, in order to improve the colloidal stability in water. Water-soluble gold nanoparticles functionalized by sodium 3-mercapto-1-propansulfonate (Au-3MPS) were prepared and loaded with methotrexate (MTX). The loading efficiency of MTX on Au-3MPS was assessed in the range 70-80%, with a fast release (80% in one hour). The release was studied up to 24h reaching the value of 95%. The Au-3MPS@MTX conjugate was fully characterized by spectroscopic techniques (UV-vis, FTIR) and DLS. Preliminary toxicity tests in the presence of keratinocytes monolayers allowed to assess that the used Au-3MPS are not toxic. The conjugate was then topically used on C57BL/6 mouse normal skin in order to trace the absorption behavior. STEM images clearly revealed the distribution of gold nanoparticles inside the cells. In vitro studies showed that Methotrexate conjugated with Au-3MPS is much more efficient than Methotrexate alone. Moreover, DL50, based on MTT analysis, is 20 folds reduced at 48 h, by the presence of nanoparticles conjugation. UV-vis spectra for in vivo tracing of the conjugate on bare mouse skin after 24h of application, show increased delivery of Methotrexate in the epidermis and dermis using Au-3MPS@MTX conjugate, compared to MTX alone. Moreover we observed absence of the Au-3MPS in the dermis and in the epidermis, suggesting that these layers of the skin do not retain the nanoparticles. Based on our data, we found that the novel Au-3MPS@MTX conjugate is an effective non-toxic carrier for the satisfactory percutaneous absorption of Methotrexate and could help in possible topical treatment of psoriasis. Copyright © 2016 Elsevier B.V. All rights reserved.

Methotrexate for Ocular Inflammatory Diseases

PubMed Central

Gangaputra, Sapna; Newcomb, Craig W.; Liesegang, Teresa L.; COT; CRC; Kaçmaz, R. Oktay; Jabs, Douglas A.; Levy-Clarke, Grace A.; Nussenblatt, Robert B.; Rosenbaum, James T.; Suhler, Eric B.; Thorne, Jennifer E.; Foster, C. Stephen; Kempen, John H.

2013-01-01

Purpose To evaluate the outcome of treatment with methotrexate for noninfectious ocular inflammation. Design Retrospective cohort study. Participants Patients with noninfectious ocular inflammation managed at 4 tertiary ocular inflammation clinics in the United States observed to add methotrexate as a single, noncorticosteroid immunosuppressive agent to their treatment regimen, between 1979 and 2007, inclusive. Methods Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics, including dosage, route of administration of methotrexate, and main outcome measures, were obtained for every eye of every patient at every visit via medical record review by trained expert reviewers. Main Outcome Measures Control of inflammation, corticosteroid-sparing effects, and incidence of and reason for discontinuation of therapy. Results Among 384 patients (639 eyes) observed from the point of addition of methotrexate to an anti-inflammatory regimen, 32.8%, 9.9%, 21.4%, 14.6%, 15.1%, and 6.3%, respectively, had anterior uveitis, intermediate uveitis, posterior or panuveitis, scleritis, ocular mucous membrane pemphigoid, and other forms of ocular inflammation. In these groups, complete suppression of inflammation sustained for ≥28 days was achieved within 6 months in 55.6%, 47.4%, 38.6%, 56.4%, 39.5%, and 76.7%, respectively. Corticosteroid-sparing success (sustained suppression of inflammation with prednisone ≤10 mg/d) was achieved within 6 months among 46.1%, 41.3%, 20.7%, 37.3%, 36.5%, and 50.9%, respectively. Overall, success within 12 months was 66% and 58.4% for sustained control and corticosteroid sparing ≤10 mg), respectively. Methotrexate was discontinued within 1 year by 42% of patients. It was discontinued owing to ineffectiveness in 50 patients (13%); 60 patients (16%) discontinued because of side effects, which typically were reversible with dose reduction or discontinuation. Remission was seen in 43 patients, with 7.7% remitting within 1 year of treatment. Conclusions Our data suggest that adding methotrexate to an anti-inflammatory regimen not involving other noncorticosteroid immunosuppressive drugs is moderately effective for management of inflammatory activity and for achieving corticosteroid-sparing objectives, although many months may be required for therapeutic success. Methotrexate was well tolerated by most patients, and seems to convey little risk of serious side effects during treatment. Financial Disclosure(s) The authors have no proprietary or commercial interests in any of the materials discussed in this article. PMID:19748676

Efficacy of adalimumab in young children with juvenile idiopathic arthritis and chronic uveitis: a case series

PubMed Central

2014-01-01

Background Juvenile idiopathic arthritis is a relatively common chronic disease of childhood, and is associated with persistent morbidity and extra-articular complications, one of the most common being uveitis. The introduction of biologic therapies, particularly those blocking the inflammatory mediator tumor necrosis factor-α, provided a new treatment option for juvenile idiopathic arthritis patients who were refractory to standard therapy such as non-steroidal anti-inflammatory drugs, corticosteroids and/or methotrexate. Case presentations The first case was a 2-year-old girl with juvenile idiopathic arthritis and uveitis who failed to respond to treatment with anti-inflammatories, low-dose corticosteroids and methotrexate, and had growth retardation. Adalimumab 24 mg/m2 every 2 weeks and prednisone 0.5 mg/kg/day were added to methotrexate therapy; steroid tapering and withdrawal started after 1 month. After 2 months the patient showed good control of articular and ocular manifestations, and she remained in remission for 1 year, receiving adalimumab and methotrexate with no side effects, and showing significant improvement in growth. Case 2 was a 9-year-old boy with an 8-year history of juvenile idiopathic arthritis and uveitis that initially responded to infliximab, but relapse occurred after 2 years off therapy. After switching to adalimumab, and adjusting doses of both adalimumab and methotrexate based on body surface area, the patient showed good response and corticosteroids were tapered and withdrawn after 6 months; the patient remained in remission taking adalimumab and methotrexate. The final case was a 5-year-old girl with juvenile idiopathic arthritis for whom adalimumab was added to methotrexate therapy after three flares of uveitis. The patient had two subsequent episodes of uveitis that responded well to local therapy, but was then free of both juvenile idiopathic arthritis and uveitis symptoms, allowing methotrexate and then adalimumab to be stopped; the patient remained in drug-free remission. Conclusion This report includes the first published case of the use of adalimumab in a child aged <3 years. Our clinical experience further supports the use of biologic therapy for the management of juvenile idiopathic arthritis and uveitis in children as young as two years of age. PMID:24886032

Occupational Exposure to Chemotherapy of Pharmacy Personnel at a Single Centre

PubMed Central

Ramphal, Raveena; Bains, Tejinder; Goulet, Geneviève; Vaillancourt, Régis

2015-01-01

Background: Cyclophosphamide is one of the most commonly used chemotherapy drugs worldwide. Data concerning environmental contamination and biological exposure of pharmacy personnel to this and other chemotherapy drugs are limited. Objectives: To determine whether pharmacy personnel involved in preparing and checking cyclophosphamide doses were more likely to have detectable levels of this drug in their urine than non-oncology pharmacy personnel with no known contact with the drug, and to compare the degree of surface contamination with cyclophosphamide, methotrexate, and ifosfamide in the oncology pharmacy of a tertiary care pediatric hospital, where chemotherapy doses were prepared, and the main (control) pharmacy in the same institution, where no chemotherapy was prepared. Methods: Biological exposure to cyclophosphamide was compared between pharmacy personnel who did and did not handle this drug by determining whether participants had detectable amounts of cyclophosphamide in their urine. Environmental exposure to chemotherapy drugs was assessed by using surface wipes to determine the degree of surface contamination with various chemotherapy agents in the oncology pharmacy and the main (control) pharmacy. Results: On initial testing, cyclophosphamide was detected in the urine of all pharmacy personnel (n = 7 oncology personnel, n = 5 control personnel). However, it was determined that all control personnel had been exposed to the oncology pharmacy on the day of testing. Repeat testing of these individuals revealed no positive samples among those not exposed to the oncology pharmacy on the day of repeat testing. The sole positive result on retesting of control personnel was for a participant who had been exposed to the oncology pharmacy on the retest day. Surface wipe testing revealed contamination of the oncology pharmacy with cyclophosphamide and methotrexate before and after cleaning, as well as contamination with ifosfamide after cleaning. The main (control) pharmacy showed no evidence of contamination with cyclophosphamide, methotrexate, or ifosfamide. Conclusions: The findings suggest that environmental contamination plays a role in biological exposure to cyclophosphamide. Measures to reduce environmental contamination from chemotherapy and biological exposure of pharmacy personnel when handling chemotherapy agents should be identified and implemented as a priority. PMID:25964681

Cytomegalovirus-induced infectious mononucleosis-like syndrome in a rheumatoid arthritis patient treated with methotrexate and infliximab.

PubMed

Shimojima, Yasuhiro; Ishii, Wataru; Matsuda, Masayuki; Nakazawa, Hideyuki; Ikeda, Shu-Ichi

2010-01-01

We report a patient with rheumatoid arthritis (RA) who developed cytomegalovirus (CMV)-induced infectious mononucleosis-like syndrome (IMLS) while being treated with methotrexate and infliximab. She suddenly developed intermittent high fever and general fatigue with liver dysfunction, remarkable lymphocytosis and laboratory data suggestive of CMV reactivation. Her clinical symptoms quickly improved after the cessation of methotrexate and infliximab without the use of anti-viral drugs such as ganciclovir. CMV-induced IMLS might be a cause of persistent fever in RA patients, particularly when biologics are used for treatment.

The acitretin and methotrexate combination therapy for psoriasis vulgaris achieves higher effectiveness and less liver fibrosis.

PubMed

An, Jingang; Zhang, Dingwei; Wu, Jiawen; Li, Jiong; Teng, Xiu; Gao, Xiaomin; Li, Ruilian; Wang, Xiuying; Xia, Linlin; Xia, Yumin

2017-07-01

Both acitretin and methotrexate are effective in ameliorating psoriatic lesion. However, their combination has been seldom reported in the treatment of psoriasis because of the warning regarding the potential hepatotoxicity of the drug interactions. This study was designed to investigate the effectiveness of such combination therapy for psoriasis vulgaris, and the potential benefit as well as side effect during the treatment. Thirty-nine patients with psoriasis vulgaris were treated with acitretin, methotrexate or their combination or as control. Similarly, K14-VEGF transgenic psoriasis-like mice were treated with these drugs. Human primary keratinocytes and hepatic stellate cells were used for analyzing their effect in vitro. The results showed that the combination therapy exhibited higher effectiveness in remitting skin lesion, but did not significantly affect the liver function of both patients and mice. Moreover, the combination groups showed less elevation of profibrotic factors in sera when compared with methotrexate alone groups accordingly. Furthermore, primary keratinocytes expressed more involucrin as well as loricrin and proliferated more slowly on the combined stimulation. Interestingly, such combination treatment induced lower expression of profibrotic factors in hepatic stellate cells. In conclusion, the acitretin-methotrexate combination therapy for psoriasis vulgaris can achieve higher effectiveness and result in less liver fibrosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Apoptosis Induction and Gene Expression Profile Alterations of Cutaneous T-Cell Lymphoma Cells following Their Exposure to Bortezomib and Methotrexate

PubMed Central

Kontsioti, Frieda; Konsta, Eugene; Vikentiou, Miriam; Spathis, Aris; Papageorgiou, Sotiris; Vasilatou, Diamantina; Gkontopoulos, Konstantinos; Mpazani, Efthimia; Karakitsos, Petros; Rigopoulos, Dimitrios; Dimitriadis, George

2017-01-01

Mycosis fungoides (MF) and its leukemic variant Sézary syndrome (SS) comprise the majority of CTCL, a heterogenous group of non-Hodgkins lymphomas involving the skin. The CTCL’s resistance to chemotherapy and the lack of full understanding of their pathogenesis request further investigation. With the view of a more targeted therapy, we evaluated in vitro the effectiveness of bortezomib and methotrexate, as well as their combination in CTCL cell lines, regarding apoptosis induction. Our data are of clinical value and indicate that the bortezomib/methotrexate combinational therapy has an inferior impact on the apoptosis of CTCL compared to monotherapy, with bortezomib presenting as the most efficient treatment option for SS and methotrexate for MF. Using PCR arrays technology, we also investigated the alterations in the expression profile of genes related to DNA repair pathways in CTCL cell lines after treatment with bortezomib or methotrexate. We found that both agents, but mostly bortezomib, significantly deregulate a large number of genes in SS and MF cell lines, suggesting another pathway through which these agents could induce apoptosis in CTCL. Finally, we show that SS and MF respond differently to treatment, verifying their distinct nature and further emphasizing the need for discrete treatment approaches. PMID:28107479

Safety of Systemic Agents for the Treatment of Pediatric Psoriasis.

PubMed

Bronckers, Inge M G J; Seyger, Marieke M B; West, Dennis P; Lara-Corrales, Irene; Tollefson, Megha; Tom, Wynnis L; Hogeling, Marcia; Belazarian, Leah; Zachariae, Claus; Mahé, Emmanuel; Siegfried, Elaine; Philipp, Sandra; Szalai, Zsuzsanna; Vleugels, Ruth Ann; Holland, Kristen; Murphy, Ruth; Baselga, Eulalia; Cordoro, Kelly; Lambert, Jo; Alexopoulos, Alex; Mrowietz, Ulrich; Kievit, Wietske; Paller, Amy S

2017-11-01

Use of systemic therapies for moderate to severe psoriasis in children is increasing, but comparative data on their use and toxicities are limited. To assess patterns of use and relative risks of systemic agents for moderate to severe psoriasis in children. A retrospective review was conducted at 20 centers in North America and Europe, and included all consecutive children with moderate to severe psoriasis who used systemic medications or phototherapy for at least 3 months from December 1, 1990, to September 16, 2014. The minimal core data set included age, sex, severity of psoriasis, systemic interventions, monitoring, adverse events (AEs), and reason for discontinuation. For 390 children (203 girls and 187 boys; mean [SD] age at diagnosis, 8.4 [3.7] years) with psoriasis who used 1 or more systemic medications, the mean interval between diagnosis and starting systemic therapy was 3.0 years. Methotrexate was used by 270 patients (69.2%), biologic agents (primarily etanercept) by 106 (27.2%), acitretin by 57 (14.6%), cyclosporine by 30 (7.7%), fumaric acid esters by 19 (4.9%), and more than 1 medication was used by 73 (18.7%). Of 270 children taking methotrexate, 130 (48.1%) reported 1 or more AEs associated with methotrexate, primarily gastrointestinal (67 [24.8%]). Folic acid 6 days per week (odds ratio, 0.16; 95% CI, 0.06-0.41; P < .001) or 7 days per week (OR, 0.21; 95% CI, 0.08-0.58; P = .003) protected against gastrointestinal AEs more than once-weekly folic acid, regardless of the total weekly dosage. Methotrexate-associated hepatic transaminase elevations were associated with obesity (35 of 270 patients [13.0%]), but a folic acid regimen was not. Injection site reactions occurred in 20 of 106 patients (18.9%) treated with tumor necrosis factor inhibitors, but did not lead to discontinuation of treatment. Having 1 or more AEs related to medication, gastrointestinal AE, laboratory abnormality, or AE leading to discontinuation of the drug was more likely with methotrexate than tumor necrosis factor inhibitors, but having 1 or more infections related to medication (predominantly upper airway) was less likely. Six patients developed a serious treatment-related AE (methotrexate, 3; fumaric acid esters, 2; and adalimumab, 1), but methotrexate and biologic agents were taken for a mean duration that was 2-fold greater than the mean duration for cyclosporine or fumaric acid esters. No patient developed tuberculosis or a malignant neoplasm. Medication-related AEs occur less often with tumor necrosis factor inhibitors than with methotrexate. Folic acid administration 6 or 7 times per week protected more against methotrexate-induced gastrointestinal AEs than did weekly administration. A prospective registry is needed to track the long-term risks of systemic agents for pediatric psoriasis.

Comparison of pharmacokinetics and toxicity after high-dose methotrexate treatments in children with acute lymphoblastic leukemia.

PubMed

Csordas, Katalin; Hegyi, Marta; Eipel, Oliver T; Muller, Judit; Erdelyi, Daniel J; Kovacs, Gabor T

2013-02-01

We carried out a detailed comparative study of the pharmacokinetics and toxicity of methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX) after high-dose intravenous methotrexate (HD-MTX) in children with acute lymphoblastic leukemia (ALL). Overall, 65 children were treated with 5 g/m2/24 h MTX and 88 children were treated with 2 g/m2/24 h MTX according to ALL-BFM 95 and ALL IC-BFM 2002 protocols (mean age: 6.4 years, range 1.0-17.9 years). A total of 583 HD-MTX courses were analyzed. Serum MTX and 7-OH-MTX levels were measured at 24, 36, and 48 h, and cerebrospinal fluid (CSF) MTX levels were determined 24 h after the initiation of the infusion. The area under the concentration-time curve was calculated. Hepatotoxicity, nephrotoxicity, and bone marrow toxicity were estimated by routine laboratory tests. We investigated pharmacokinetics and toxicity in distinct age groups (< 6 and > 14 years). 5 g/m2/24 h treatments resulted in higher serum and CSF MTX and 7-OH-MTX levels (P < 0.05). The CSF penetration rate of MTX was independent of the MTX dose [2.3% (95% confidence interval: 1.7-2.5%) vs. 2.8% (95% confidence interval: 2.4-3%)]. The CSF MTX concentration was correlated with the 24 h MTX serum level (r = 0.38, P < 0.0001). Repeated treatments did not alter MTX or 7-OH-MTX levels. 7-OH-MTX levels were correlated with nephrotoxicity (r = 0.36, P < 0.0001). Higher MTX levels and toxicity occurred more frequently in children aged older than 14 years (P < 0.05). Therapeutic serum and CSF MTX concentrations can be achieved more reliably with 5 g/m2/24 h treatments. To predict the development of toxicity, monitoring of the level of the 7-OH-MTX is useful. Monitoring of pharmacokinetics is essential to prevent the development of severe adverse events in adolescents.

Adipose-derived stem cells retain their regenerative potential after methotrexate treatment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beane, Olivia S.; Fonseca, Vera C.; Darling, Eric M., E-mail: Eric_Darling@brown.edu

In musculoskeletal tissues like bone, chemotherapy can impair progenitor cell differentiation and proliferation, resulting in decreased bone growth and mineralization throughout a patient's lifetime. In the current study, we investigated the effects of chemotherapeutics on adipose-derived stem cell (ASC) function to determine whether this cell source could be a candidate for repairing, or even preventing, chemotherapy-induced tissue damage. Dose-dependent proliferation rates of ASCs and normal human fibroblasts (NHFs) were quantified after treatment with cytarabine (CY), etoposide (ETO), methotrexate (MTX), and vincristine (VIN) using a fluorescence-based assay. The influence of MTX on the multipotency of ASCs and freshly isolated stromal vascularmore » fraction (SVF) cells was also evaluated using lineage-specific stains and spectrophotometry. ASC and NHF proliferation were equally inhibited by exposure to CY and ETO; however, when treated with MTX and VIN, ASCs exhibited greater resistance. This was especially apparent for MTX-treated samples, with ASC proliferation showing no inhibition for clinically relevant MTX doses ranging from 0.1 to 50 μM. Additional experiments revealed that the differentiation potential of ASCs was not affected by MTX treatment and that upregulation of dihydrofolate reductase possibly contributed to this response. Moreover, SVF cells, which include ASCs, exhibited similar resistance to MTX impairment, with respect to cellular proliferation, clonogenicity, and differentiation capability. Therefore, we have shown that the regenerative properties of ASCs resist the cytotoxicity of MTX, identifying these cells as a potential key for repairing musculoskeletal damage in patients undergoing chemotherapy. - Highlights: • Long-term effects of chemotherapeutics can include musculoskeletal dysfunction. • A screen of common drugs showed disparate effects on ASCs and fibroblasts. • One drug, methotrexate, did not impair ASC growth characteristics or multipotency. • Upregulation of dihydrofolate reductase may enable ASC methotrexate resistance. • ASCs thus pose a possible means to ameliorate long-term tissue damage.« less

The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis

PubMed Central

Roubille, Camille; Richer, Vincent; Starnino, Tara; McCourt, Collette; McFarlane, Alexandra; Fleming, Patrick; Siu, Stephanie; Kraft, John; Lynde, Charles; Pope, Janet; Gulliver, Wayne; Keeling, Stephanie; Dutz, Jan; Bessette, Louis; Bissonnette, Robert; Haraoui, Boulos

2015-01-01

The objective of this systematic literature review was to determine the association between cardiovascular events (CVEs) and antirheumatic drugs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA)/psoriasis (Pso). Systematic searches were performed of MEDLINE, EMBASE and Cochrane databases (1960 to December 2012) and proceedings from major relevant congresses (2010–2012) for controlled studies and randomised trials reporting confirmed CVEs in patients with RA or PsA/Pso treated with antirheumatic drugs. Random-effects meta-analyses were performed on extracted data. Out of 2630 references screened, 34 studies were included: 28 in RA and 6 in PsA/Pso. In RA, a reduced risk of all CVEs was reported with tumour necrosis factor inhibitors (relative risk (RR), 0.70; 95% CI 0.54 to 0.90; p=0.005) and methotrexate (RR, 0.72; 95% CI 0.57 to 0.91; p=0.007). Non-steroidal anti-inflammatory drugs (NSAIDs) increased the risk of all CVEs (RR, 1.18; 95% CI 1.01 to 1.38; p=0.04), which may have been specifically related to the effects of rofecoxib. Corticosteroids increased the risk of all CVEs (RR, 1.47; 95% CI 1.34 to 1.60; p<0.001). In PsA/Pso, systemic therapy decreased the risk of all CVEs (RR, 0.75; 95% CI 0.63 to 0.91; p=0.003). In RA, tumour necrosis factor inhibitors and methotrexate are associated with a decreased risk of all CVEs while corticosteroids and NSAIDs are associated with an increased risk. Targeting inflammation with tumour necrosis factor inhibitors or methotrexate may have positive cardiovascular effects in RA. In PsA/Pso, limited evidence suggests that systemic therapies are associated with a decrease in all CVE risk. PMID:25561362

Taurine protects against methotrexate-induced toxicity and inhibits leukocyte death

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cetiner, Mustafa; Sener, Goeksel; Sehirli, A. Ozer

2005-11-15

The efficacy of methotrexate (MTX), a widely used cytotoxic chemotherapeutic agent, is often limited by severe side effects and toxic sequelae. Regarding the mechanisms of these side effects, several hypotheses have been put forward, among which oxidative stress is noticeable. The present study was undertaken to determine whether taurine, a potent free radical scavenger, could ameliorate MTX-induced oxidative injury and modulate immune response. Following a single dose of methotrexate (20 mg/kg), either saline or taurine (50 mg/kg) was administered for 5 days. After decapitation of the rats, trunk blood was obtained and the ileum, liver, and kidney were removed tomore » measure malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity, and collagen content, as well as histological examination. Our results showed that MTX administration increased the MDA, MPO activity, and collagen contents and decreased GSH levels in all tissues (P < 0.001), while these alterations were reversed in taurine-treated group (P < 0.05-0.01). Elevated (P < 0.001) TNF-{alpha} level observed following MTX treatment was depressed with taurine (P < 0.01). Oxidative burst of neutrophils stimulated by phorbol myristate acetate was reduced in saline-treated MTX group (P < 0.001), while taurine abolished this effect. Similarly, flow cytometric measurements revealed that leukocyte apoptosis and cell death were increased in MTX-treated animals, while taurine reversed these effects (P < 0.05). Reduced cellularity in bone marrow samples of MTX-treated group (P < 0.01) was reversed back to control levels in taurine-treated rats. Severe degeneration of the intestinal mucosa, liver parenchyma, glomerular, and tubular epithelium observed in saline-treated group was improved by taurine treatment. In conclusion, it appears that taurine protects against methotrexate-induced oxidant organ injury and inhibits leukocyte apoptosis and may be of therapeutic potential in alleviating the systemic side effects of chemotherapeutics.« less

Cost effectiveness of etanercept (Enbrel) in combination with methotrexate in the treatment of active rheumatoid arthritis based on the TEMPO trial.

PubMed

Kobelt, G; Lindgren, P; Singh, A; Klareskog, L

2005-08-01

To estimate the cost effectiveness of combination treatment with etanercept plus methotrexate in comparison with monotherapies in patients with active rheumatoid arthritis (RA) using a new model that incorporates both functional status and disease activity. Effectiveness data were based on a 2 year trial in 682 patients with active RA (TEMPO). Data on resource consumption and utility related to function and disease activity were obtained from a survey of 616 patients in Sweden. A Markov model was constructed with five states according to functional status (Health Assessment Questionnaire (HAQ)) subdivided into high and low disease activity. The cost for each quality adjusted life year (QALY) gained was estimated by Monte Carlo simulation. Disease activity had a highly significant effect on utilities, independently of HAQ. For resource consumption, only HAQ was a significant predictor, with the exception of sick leave. Compared with methotrexate alone, etanercept plus methotrexate over 2 years increased total costs by 14,221 euros and led to a QALY gain of 0.38. When treatment was continued for 10 years, incremental costs were 42,148 euros for a QALY gain of 0.91. The cost per QALY gained was 37,331 euros and 46,494 euros, respectively. The probability that the cost effectiveness ratio is below a threshold of 50,000 euros/QALY is 88%. Incorporating the influence of disease activity into this new model allows better assessment of the effects of anti-tumour necrosis factor treatment on patients' general wellbeing. In this analysis, the cost per QALY gained with combination treatment with etanercept plus methotrexate compared with methotrexate alone falls within the acceptable range.

The role of bicarbonate anions in methotrexate degradation via UV/TiO2: Mechanisms, reactivity and increased toxicity.

PubMed

Lai, Webber Wei-Po; Hsu, Ming-Hao; Lin, Angela Yu-Chen

2017-04-01

Bicarbonate anion (HCO 3 - ) is a major constituent in wastewater and natural water matrices, and the aim of this study was to investigate its roles in the degradation of the antineoplastic agent methotrexate via UV/TiO 2 . A comprehensive investigation of reaction mechanisms was performed by conducting scavenger experiments and substructure reactivity and Microtox ® toxicity tests. In the presence of HCO 3 - , the methotrexate degradation rate substantially increased, indicating the involvement of CO 3 - . The estimated second-order rate constants of methotrexate with CO 3 - and OH were 1.4 × 10 7  M -1  s -1 and 8.7 × 10 9  M -1  s -1 , respectively. Both the valence hole (h vb + ) and OH resulted in the generation of CO 3 - . Initial transformation pathways of methotrexate were proposed, including the addition of atomic oxygen, hydroxylation, deamination, CC cleavage and CN cleavage. CN cleavage at the aniline moiety (the N(13) position) is the primary decomposition pathway, leading to an aminopterin yield of 43%. CO 3 - preferentially reacted with the 4-aminobenzamide (ABZ) moiety and generated toxic byproducts during the later stages of decomposition, which was not observed in the UV/TiO 2 system. The reactivity of the three methotrexate substructures decreased in the following order in the presence of HCO 3 - : ABZ ≫ DHP ≫ LG∼0; however, without HCO 3 - , the following order was observed: ABZ ∼ DHP > LG. The results of this work suggest that the increase in toxicity induced by the presence of HCO 3 - likely occurs in many other OH-based advanced oxidation processes in wastewater containing pharmaceutical cocktails with ABZ moieties. Copyright © 2017 Elsevier Ltd. All rights reserved.

Methotrexate versus cyclophosphamide for remission maintenance in ANCA-associated vasculitis: A randomised trial.

PubMed

Maritati, Federica; Alberici, Federico; Oliva, Elena; Urban, Maria L; Palmisano, Alessandra; Santarsia, Francesca; Andrulli, Simeone; Pavone, Laura; Pesci, Alberto; Grasselli, Chiara; Santi, Rosaria; Tumiati, Bruno; Manenti, Lucio; Buzio, Carlo; Vaglio, Augusto

2017-01-01

The treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is based on remission-induction and remission-maintenance. Methotrexate is a widely used immunosuppressant but only a few studies explored its role for maintenance in AAV. This trial investigated the efficacy and safety of methotrexate as maintenance therapy for AAV. In this single-centre, open-label, randomised trial we compared methotrexate and cyclophosphamide for maintenance in AAV. We enrolled patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), the latter with poor-prognosis factors and/or peripheral neuropathy. Remission was induced with cyclophosphamide. At remission, the patients were randomised to receive methotrexate or to continue with cyclophosphamide for 12 months; after treatment, they were followed for another 12 months. The primary end-point was relapse; secondary end-points included renal outcomes and treatment-related toxicity. Of the 94 enrolled patients, 23 were excluded during remission-induction or did not achieve remission; the remaining 71 were randomised to cyclophosphamide (n = 33) or methotrexate (n = 38). Relapse frequencies at months 12 and 24 after randomisation were not different between the two groups (p = 1.00 and 1.00). Relapse-free survival was also comparable (log-rank test p = 0.99). No differences in relapses were detected between the two treatments when GPA+MPA and EGPA were analysed separately. There were no differences in eGFR at months 12 and 24; proteinuria declined significantly (from diagnosis to month 24) only in the cyclophosphamide group (p = 0.0007). No significant differences in adverse event frequencies were observed. MTX may be effective and safe for remission-maintenance in AAV. clinicaltrials.gov NCT00751517.

Protective effects of methotrexate against ischemic cardiovascular disorders in patients treated for rheumatoid arthritis or psoriasis: novel therapeutic insights coming from a meta-analysis of the literature data

PubMed Central

Vecchis, Renato De; Baldi, Cesare; Palmisani, Leonardo

2016-01-01

Objective: The association between chronic use of methotrexate and decreased risk of ischemic cardiovascular events (CVE) among patients with psoriatic or rheumatoid arthritis (RA) was investigated using a systematic review and meta-analysis. Methods: The studies should have recruited adults receiving methotrexate, followed up for at least one year. Moreover, studies should have reported “hard” cardiovascular endpoints, by evaluating the cardiovascular outcomes of the habitual users of the drug or of new users compared with patients with the same disease who had never used methotrexate. The outcome of interest was the overall pooled odds ratio (OR) of major adverse cardiovascular events, i.e., a composite of new- onset angina, acute coronary syndrome, need for percutaneous or surgical coronary revascularization, stroke, and cardiovascular death. The study was performed according to the PRISMA statement. Results: Seven observational studies, mostly engaging patients with RA, were included in the meta-analysis. The pooled odds ratio (OR) was 0.73 (95% CI=0.70- 0.77 p<0.001). When stratified meta-analysis models were assessed, the pooled OR was 0.80 (95% CI=0.66-0.97; p=0.022) for studies adjusting for clinical severity of RA. Furthermore, the OR was even more significant after adjustment for concomitant use of other drugs specific for RA (OR=0.71, 95% CI=0.67-0.75, p<0.001). Conclusion: Methotrexate at low doses, such those used for maintenance therapy of RA, predicted a decreased risk of CVE. Since methotrexate doesn’t interfere with blood lipids, platelet aggregation or insulin resistance, the protective association may originate from mechanisms other than those exerted by antiplatelet drugs or statins. PMID:26467356

[Intrathecal methotrexate in breast cancer meningeal carcinomatosis - Experience with a new administration schedule].

PubMed

Cochereau, Delphine; Da Costa, Sabrina; Le Maignan, Christine; Gauthier, Hélène; Cochereau, Jérôme; Espié, Marc; Giacchetti, Sylvie; Teixeira, Luis

2016-05-01

Methotrexate represents the standard intrathecal treatment of breast cancer meningeal carcinomatosis. However, its optimal schedule remains undefined. The aim of the present study was to evaluate results obtained with the methotrexate schedule used in Saint-Louis hospital (Paris). Patients followed in Saint-Louis hospital for breast cancer and who received intrathecal methotrexate were included in this retrospective monocentric study. Intrathecal treatment received contained methotrexate 12 mg/day (days: 1-5) and then 15 mg/week until progression or toxicity. Between 2003 and 2015, 41 patients were included. Primitive tumours were RH+/HER2-, HER2+ and triple-negative in respectively 66%, 14%, 5% and 15% of patients, 22% of them had meningeal carcinomatosis as metastatic disease initial manifestation. Objective response rate was 54%, median overall survival was 4.0 mois [CI 95%: 3-7.3] and 1-year survival rate was 15.2% (11.4%, 50% et 0% in RH+/HER2-, HER2+ and triple-negative subgroups; HR=0.45 [0.21-0.97] between HER2+ and RH+/HER2-). In univariate analysis, prognostic factors were brain involvement (p=0.049), initial cerebrospinal fluid protein level (p=0.0002) and concomitant systemic treatment received (p=0.049). This intrathecal methotrexate schedule demonstrates a similar median overall survival as the one obtained with a dose-dense schedule and an improved quality of life. Nevertheless, as the objective response and 1-year survival rates are slightly inferior, a dose-dense schedule remains still preferred in HER2+ patients or in those harboring a mainly meningeal progression. Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Intraocular methotrexate can induce extended remission in some patients in noninfectious uveitis.

PubMed

Taylor, Simon R J; Banker, Alay; Schlaen, Ariel; Couto, Cristobal; Matthe, Egbert; Joshi, Lavnish; Menezo, Victor; Nguyen, Ethan; Tomkins-Netzer, Oren; Bar, Asaf; Morarji, Jiten; McCluskey, Peter; Lightman, Sue

2013-01-01

To assess the outcomes of the intravitreal administration of methotrexate in uveitis. Multicenter, retrospective interventional case series of patients with noninfectious uveitis. Thirty-eight eyes of 30 patients were enrolled, including a total of 54 intravitreal injections of methotrexate at a dose of 400 µg in 0.1 mL. The primary outcome measure was visual acuity. Secondary outcome measures included control of intraocular inflammation and cystoid macular edema, time to relapse, development of adverse events, and levels of systemic corticosteroid and immunosuppressive therapy. Methotrexate proved effective in controlling intraocular inflammation and improving vision in 30 of 38 eyes (79%). The side effect profile was good, with no reported serious ocular adverse events and only one patient having an intraocular pressure of >21 mmHg. Of the 30 eyes that responded to treatment, 8 relapsed, but 22 (73%) entered an extended period of remission, with the Kaplan-Meier estimate of median time to relapse for the whole group being 17 months. The eight eyes that relapsed were reinjected and all responded to treatment. One eye relapsed at 3 months, but 7 eyes again entered extended remission. Of the 14 patients on systemic therapy at the start of the study, 8 (57%) were able to significantly reduce this following intravitreal methotrexate injection. In patients with uveitis and uveitic cystoid macular edema, intravitreal MTX can effectively improve visual acuity and reduce cystoid macular edema and, in some patients, allows the reduction of immunosuppressive therapy. Some patients relapse at 3 to 4 months, but a large proportion (73%) enter an extended period of remission of up to 18 months. This larger study extends the results obtained from previous smaller studies suggesting the viability of intravitreal methotrexate as a treatment option in uveitis.

78 FR 13347 - Clinical Chemistry and Clinical Toxicology Devices Panel of the Medical Devices Advisory...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-27

... as isoniazid test strips. Isoniazid test strips are considered pre-Amendment devices since they were... as methotrexate enzyme immunoassays. Methotrexate enzyme immunoassays are considered pre- Amendment... and PCP radioimmunoassays. PCP enzyme immunoassays and PCP radioimmunoassays are considered pre...

A porphyrin-based metal–organic framework as a pH-responsive drug carrier

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Wenxin; Hu, Quan; Jiang, Ke

A low cytotoxic porphyrin-based metal–organic framework (MOF) PCN-221, which exhibited high PC12 cell viability via 3-(4,5-dimethylthiazol-2-yl)−2,5-diphenyl tetrazolium (MTT) assay, was selected as an oral drug carrier. Methotrexate (MTX) was chosen as the model drug molecule which was absorbed into inner pores and channels of MOFs by diffusion. PCN-221 showed high drug loading and sustained release behavior under physiological environment without “burst effect”. The controlled pH-responsive release of drugs by PCN-221 revealed its promising application in oral drug delivery. - Graphical abstract: The porous crystals PCN-221 with pore openings (MOF) PCN-221 was prepared exhibiting low cytotoxicity. PCN-221 showed high drug Methotrexatemore » loading and controlled pH-responsive release of Methotrexate. - Highlights: • A porphyrin-based metal–organic framework (MOF) PCN-221 was prepared showing low cytotoxicity. • PCN-221 showed high drug Methotrexate loading. • PCN-221 showed controlled pH-responsive release of Methotrexate.« less

Methotrexate in Atherogenesis and Cholesterol Metabolism

PubMed Central

Coomes, Eric; Chan, Edwin S. L.; Reiss, Allison B.

2011-01-01

Methotrexate is a disease-modifying antirheumatic drug commonly used to treat inflammatory conditions such as rheumatoid arthritis which itself is linked to increased cardiovascular risk. Treatments that target inflammation may also impact the cardiovascular system. While methotrexate improves cardiovascular risk, inhibition of the cyclooxygenase (COX)-2 enzyme promotes atherosclerosis. These opposing cardiovascular influences may arise from differing effects on the expression of proteins involved in cholesterol homeostasis. These proteins, ATP-binding cassette transporter (ABC) A1 and cholesterol 27-hydroxylase, facilitate cellular cholesterol efflux and defend against cholesterol overload. Methotrexate upregulates expression of cholesterol 27-hydroxylase and ABCA1 via adenosine release, while COX-2 inhibition downregulates these proteins. Adenosine, acting through the A2A and A3 receptors, may upregulate proteins involved in reverse cholesterol transport by cAMP-PKA-CREB activation and STAT inhibition, respectively. Elucidating underlying cardiovascular mechanisms of these drugs provides a framework for developing novel cardioprotective anti-inflammatory medications, such as selective A2A receptor agonists. PMID:21490773

Severe neurotoxicity following intrathecal methotrexate with nitrous oxide sedation in a child with acute lymphoblastic leukemia.

PubMed

Löbel, U; Trah, J; Escherich, G

2015-03-01

Systemic and intrathecal methotrexate is widely used in treatment protocols for childhood acute lymphoblastic leukemia. Its side effects vary in characteristics, intensity and time of onset, and depend on the administration route. Interactions with several drugs are known. Side effects of nitrous oxide sedation, often used for moderately painful procedures, typically occur after long time use and include neurological symptoms. We present a child who experienced a severe and long-lasting neurotoxicity after the third intrathecal application of methotrexate with short sedation by nitrous oxide during induction therapy for acute lymphoblastic leukemia. Symptoms completely resolved after 12 months. © 2014 Wiley Periodicals, Inc.

Stevens-Johnson Syndrome associated with methotrexate treatment for acute lymphoblastic leukemia: a case report.

PubMed

Akıncı, Burcu; Siviş, Zuhal Ö; Şahin, Akkız; Karapınar, Deniz Y; Balkan, Can; Kavaklı, Kaan; Aydınok, Yeşim

2018-06-01

Toxic epidermal necrolysis and Stevens-Johnson syndrome are rare mucocutaneous diseases which are associated with a prolonged course and potentially lethal outcome. They are mostly drug induced and mortality rates are very high. Although mostly skin is involved, multiple organ systems such as cardiovascular, pulmonary, gastrointestinal, and urinary systems may be affected. Here, we report a case of Stevens- Johnson Syndrome associated with methotrexate treatment who developed acute cardiac failure and gastrointestinal hemorrhage beside skin findings. He had been treated with intravenous immunglobulin and methylprednisolone succesfully and continued chemotherapy with methotrexate treatment again. Sociedad Argentina de Pediatría.

Patient-derived osteosarcoma cells are resistant to methotrexate.

PubMed

Dos Santos Cavalcanti, Amanda; Meohas, Walter; Ribeiro, Gabriele de Oliveira; de Sá Lopes, Ana Cristina; Gholamin, Sharareh; Razavi, Mostafa; Hanae Kasai Brunswick, Taís; Avan, Amir; Matheus Guimarães, João Antonio; Leite Duarte, Maria Eugenia; Kahn, Suzana Assad

2017-01-01

Osteosarcoma is the most common primary bone tumor in children and young adults. The median survival of osteosarcoma patients has not significantly improved since 1990, despite administration of different classes of chemotherapy agents, such as methotrexate, cisplatin and doxorubicin. Cancer stem cells (CSCs) are responsible for the resistance of osteosarcoma to chemotherapy and OCT4, SOX2 and SSEA4 have been used to identify CSCs in osteosarcoma. Here, we used low-passage patient-derived osteosarcoma cells and osteosarcoma cells directly isolated from patients before and after chemotherapy treatments to evaluate the effects of chemotherapy on stem cell markers expression. We demonstrate that primary osteosarcoma cells are resistant to methotrexate treatment and sensitive to cisplatin and doxorubicin in vitro. We also verified that cisplatin and doxorubicin reduce the expression of SOX2 and OCT4 in primary osteosarcoma cells whereas methotrexate does not alter SOX2 and OCT4 expression, however it increases SSEA4 expression in primary osteosarcoma cells. Finally, we found that, although the combination treatment cisplatin plus doxorubicin inhibited the in vivo growth of osteosarcoma cells in NOD-SCID gamma mice subcutaneously injected with SaOs2, the combination treatment cisplatin plus doxorubicin plus methotrexate did not inhibit the in vivo growth of these cells. These observations may provide an explanation for the poor response of osteosarcomas to chemotherapy and point to the need of reevaluating the therapeutic strategies for human osteosarcomas.

Patient-derived osteosarcoma cells are resistant to methotrexate

PubMed Central

dos Santos Cavalcanti, Amanda; Meohas, Walter; Ribeiro, Gabriele de Oliveira; de Sá Lopes, Ana Cristina; Gholamin, Sharareh; Razavi, Mostafa; Hanae Kasai Brunswick, Taís; Avan, Amir; Matheus Guimarães, João Antonio; Leite Duarte, Maria Eugenia

2017-01-01

Osteosarcoma is the most common primary bone tumor in children and young adults. The median survival of osteosarcoma patients has not significantly improved since 1990, despite administration of different classes of chemotherapy agents, such as methotrexate, cisplatin and doxorubicin. Cancer stem cells (CSCs) are responsible for the resistance of osteosarcoma to chemotherapy and OCT4, SOX2 and SSEA4 have been used to identify CSCs in osteosarcoma. Here, we used low-passage patient-derived osteosarcoma cells and osteosarcoma cells directly isolated from patients before and after chemotherapy treatments to evaluate the effects of chemotherapy on stem cell markers expression. We demonstrate that primary osteosarcoma cells are resistant to methotrexate treatment and sensitive to cisplatin and doxorubicin in vitro. We also verified that cisplatin and doxorubicin reduce the expression of SOX2 and OCT4 in primary osteosarcoma cells whereas methotrexate does not alter SOX2 and OCT4 expression, however it increases SSEA4 expression in primary osteosarcoma cells. Finally, we found that, although the combination treatment cisplatin plus doxorubicin inhibited the in vivo growth of osteosarcoma cells in NOD-SCID gamma mice subcutaneously injected with SaOs2, the combination treatment cisplatin plus doxorubicin plus methotrexate did not inhibit the in vivo growth of these cells. These observations may provide an explanation for the poor response of osteosarcomas to chemotherapy and point to the need of reevaluating the therapeutic strategies for human osteosarcomas. PMID:28934267

Retrospective analysis: Conservative treatment of placenta increta with methotrexate.

PubMed

Zhang, Chunhua; Li, Hongyan; Zuo, Changting; Wang, Xietong

2018-05-01

To evaluate the efficacy of conservative treatment with methotrexate against placenta increta by two different routes of administration through retrospective analysis. A total of 54 women diagnosed with placenta increta after vaginal delivery were enrolled in this retrospective study. The participants accepted conservative management with methotrexate through either intravenous injection or local multi-point injection under ultrasound guidance. The treatment was considered effective if no hysterectomy was mandatory during the follow-up period. Out of the 54 cases, 21 patients were treated with methotrexate intravenously (group 1), and 33 patients received local multi-point injection to the placenta increta under ultrasound guidance (group 2). No maternal death occurred. In group 1, 10 patients expelled the placentas spontaneously, 7 patients underwent uterine curettage and 4 patients underwent hysterectomy for uncontrollable post-partum hemorrhage and infection. In group 2, 25 patients expelled placentas spontaneously and 8 patients underwent uterine curettage with no incidence of hysterectomy. The success rate in group 1 and group 2 was 17/21 and 33/33, respectively. The average time of the spontaneous placenta expulsion was 79.13 ± 29.87 days in group 1 and 42.42 ± 31.83 days in group 2. Local multi-point methotrexate injection under ultrasound guidance is a better alternative for patients with placenta increta, especially for preserving fertility. © 2018 Japan Society of Obstetrics and Gynecology.

The impact of salpingectomy and single-dose systemic methotrexate treatments on ovarian reserve in ectopic pregnancy.

PubMed

Sahin, Cagdas; Taylan, Enes; Akdemir, Ali; Ozgurel, Banu; Taskıran, Dilek; Ergenoglu, Ahmet M

2016-10-01

To investigate the effects of salpingectomy and methotrexate treatments on ovarian reserve in ectopic pregnancy. In this prospective study, a total of 131 patients with ectopic pregnancy were divided into 3 groups of methotrexate (MTX) only (Group-1, n: 55), salpingectomy only (Group-2, n: 61), and salpingectomy following MTX (Group-3, n: 15). Pretreatment and post-treatment anti-Müllerian hormone (AMH) levels were evaluated. Significant differences in AMH levels were detected between group 1 and group 2 (2.52±1.28 vs. 1.96±1.66, p=0.043), and group 1 and group 3 (2.52±1.28 vs. 1.77±0.76, p=0.035) at one month postoperative. However, these differences disappeared at the 3rd postoperative month. When AMH levels were compared within the same group, postoperative one month AMH levels were significantly lower than the preoperative AMH levels only in group 3 (p=0.03). However, this difference also disappeared at the 3rd postoperative month. Systemic single-dose methotrexate treatment, unilateral salpingectomy, and salpingectomy following methotrexate administration in ectopic pregnancy were reassuring based on pretreatment and post-treatment AMH levels. Current medical and surgical treatment approaches do not have an obvious negative effect on ovarian reserve. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Magnetic- and pH-responsive κ-carrageenan/chitosan complexes for controlled release of methotrexate anticancer drug.

PubMed

Mahdavinia, Gholam Reza; Mosallanezhad, Amirabbas; Soleymani, Moslem; Sabzi, Mohammad

2017-04-01

The aim of the present work was to develop green carriers for methotrexate using κ-carrageenan/chitosan complexes. Magnetic Fe 3 O 4 nanoparticles were first synthesized in the presence of κ-carrageenan through in situ method. Then, the obtained magnetic κ-carrageenan was crosslinked using the polycation chitosan biopolymer. The physical and structural properties of hydrogels were investigated by FTIR, XRD, SEM, TEM, TGA, and VSM techniques. The pH-dependent swelling behavior of hydrogels was examined in various buffer solutions. All of the prepared hydrogels showed a high swelling capacity in basic solutions. The introduction of magnetite nanoparticles into κ-carrageenan/chitosan complexes had a significant effect on the swelling capacity of magnetic hydrogels, as the water absorbency of hydrogels decreased with increasing magnetite content. Methotrexate as an anticancer and model drug was loaded on hydrogels and the release profiles were investigated at pH=7.4 and 5.3. The methotrexate encapsulation efficiency was increased by increasing magnetite and chitosan contents. The results demonstrated that the release of methotrexate from magnetic hydrogels is pH-dependent with a high release content at pH=7.4. The release profiles were analyzed by Peppas's empirical model and the release of drug from hydrogels followed Fickian type of diffusion mechanism at both pHs. Copyright © 2017 Elsevier B.V. All rights reserved.

Impact of 24 months of anti-TNF therapy versus methotrexate on body weight in patients with rheumatoid arthritis: a prospective observational study.

PubMed

Sfriso, Paolo; Caso, Francesco; Filardo, Giuseppe Sebastiano; Botsios, Costantino; Costa, Luisa; Scarpa, Raffaele; Todesco, Silvano; Spinella, Paolo; Oliviero, Francesca; Punzi, Leonardo

2016-06-01

To evaluate the impact of anti-TNF-α therapy on the body weight of rheumatoid arthritis (RA) patients following 24 months of treatment. Data were collected on all RA patients included in the Veneto Region's Registry of Biological Therapy from January 2007 to July 2012. Inclusion criteria were: start of monotherapy with adalimumab, etanercept, or methotrexate, no previous use of biologic therapy, and at least 24 months of treatment. At baseline, 12, and 24 months, each patient completed a questionnaire about physical activity, smoking, alcohol, and food habits. One hundred and thirty-one RA patients in monotherapy with etanercept (n = 47), adalimumab (n = 44), and methotrexate (n = 40) were enrolled for this study. After 24 months of therapy, there was an increase of weight only in patients treated with anti-TNF-α. Patients on etanercept and adalimumab therapy showed a risk to gain weight six times greater compared to those on methotrexate therapy. The results of present study show that the use of anti-TNF-α in RA patients can be associated to a significant increase of body weight. This increase is not shown in patients under treatment with methotrexate. A more careful evaluation of weight changes needs to be considered in RA patients under anti-TNF-α treatment.

Combination chemotherapy with methotrexate and vinblastine for surgically unresectable, aggressive fibromatosis.

PubMed

Park, Kyong-Hwa; Choi, Yoon Ji; Kim, Kwan-Woo; Ro, Kyung-Han; Kang, Chang Ho; Song, Sang-Heon; Park, Jong Hoon

2016-09-01

To elucidate the clinical benefit and safety of low-dose chemotherapy using methotrexate and vinblastine in patients (mostly adults) with progressive and/or symptomatic fibromatosis. Patients were enrolled if they were treated with methotrexate and vinblastine chemotherapy for recurrences after surgical excision or newly diagnosed aggressive fibromatosis that was not amenable to surgical resection at the Korea University Medical Center from May 2008 to February 2016. Twenty-two patients were treated with this regimen, and 21 were eligible for safety and efficacy analysis. Eleven (52%) of 21 patients showed a documented partial response (PR), and 11 showed stable disease (SD) by the end of treatment. All the patients who achieved PR reported a significant reduction in pain and improvement in the function of the affected lesions. Median progression-free survival was not reached at the time of analysis. The most common adverse event was abnormalities of the liver transaminases (overall 84.2%). The most common grade 3 or higher toxicity was neutropenia (36.8%), but no febrile neutropenic event was observed. The elevated levels of transaminases were normalized by reducing the dose of methotrexate or delaying treatment. Low-dose chemotherapy with methotrexate and vinblastine for 1 year was effective and well tolerated by adult patients with aggressive, recurrent fibromatosis. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Bisphosphonate-associated osteonecrosis of jaw reoccurrence after methotrexate therapy: a case report.

PubMed

Alsalleeh, Fahd; Keippel, Jeffery; Adams, Lyde; Bavitz, Bruce

2014-09-01

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-known complication caused by amino-bisphosphonate therapy. We document one case of BRONJ associated with oral administration of methotrexate, a known immunosuppressive drug used to treat rheumatoid arthritis. A 66-year-old woman was referred for evaluation and endodontic surgery of recently re-treated tooth 13. Tooth 14 was extracted 3 months prior, and the extraction site had not completely healed. Her medical history revealed rheumatoid arthritis and osteoporosis. She had been taking Fosamax (alendronate) 70 mg daily. Because of adequate root canal therapy of tooth 13, endodontic surgery was performed. Five months after apicoectomy, her symptoms had not changed. Tooth 13 was extracted, and the socket healed without complications. The socket of extracted tooth 14 was also healing. At the 3-month recall visit, bone exposure and purulent discharge at the site of extracted tooth 14 were noted. The patient had recently received methotrexate. The methotrexate was discontinued, and she was given course of amoxicillin. At the 18-month follow-up, the healing progressed, and the wound was closed. A medication that suppresses the immune system such as methotrexate may complicate the management of BRONJ. Once a diagnosis of BRONJ is made, a closely monitored conservative approach is recommended. Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Effects of antineoplastic drugs on Lactobacillus casei and radioisotopic assays for serum folate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carmel, R.

1978-02-01

Microbiologic assay, usually employing Lactobacillus casei, remains the standard assay for serum folate to date. Among its disadvantages have been falsely low results in patients receiving bacteriostatic agents such as antibiotics. This study examined whether commonly used antineoplastic drugs had similar effect. Methotrexate and 5-fluorouracil depressed microbiologic serum folate levels. No effect was found for adriamycin, bleomycin, BCNU, cyclophosphamide, cytosine arabinoside, vincristine, vinblastine, mechlorethamine, mithramycin, hydroxyurea, and hydrocortisone. None of the drugs affected radioassay except methotrexate, which produced falsely high folate results. Thus, it appears that L. casei assay for folate becomes unreliable in patients receiving 5-fluorouracil and radioisotopic assaymore » becomes unreliable in those receiving methotrexate.« less

Successful treatment of an unresectable inflammatory myofibroblastic tumor of the frontal bone using a cyclooxygenase-2 inhibitor and methotrexate.

PubMed

Kusunoki-Nakamoto, Fumiko; Matsukawa, Takashi; Tanaka, Masaki; Miyagawa, Toji; Yamamoto, Tomotaka; Shimizu, Jun; Ikemura, Masako; Shibahara, Junji; Tsuji, Shoji

2013-01-01

Inflammatory myofibroblastic tumor (IMT) is a disease characterized by tumorous lesions consisting of myofibroblastic spindle cells and inflammatory cells that occur primarily in the soft tissues and viscera of children and young adults. Total excision is the most effective therapy. Steroids have been used to treat unresectable lesions with some success. We herein report a case of IMT involving the frontal bone accompanied by pachymeningitis. The tumor was characterized by an aggressive clinical course that was refractory to prednisolone. Performing total excision seemed difficult. Celecoxib and methotrexate were effective treatments. Our experience suggests the efficacy of celecoxib and methotrexate as alternatives for treating unresectable IMT.

Protective effect of aged garlic extract on the small intestinal damage of rats induced by methotrexate administration.

PubMed

Horie, T; Matsumoto, H; Kasagi, M; Sugiyama, A; Kikuchi, M; Karasawa, C; Awazu, S; Itakura, Y; Fuwa, T

1999-08-01

The methotrexate (MTX) administration to rats causes the damage of small intestine. The small intestinal damage was evaluated by measuring the intestinal permeability of the poorly absorbable compound, fluorescein isothiocyanate (FITC)-labeled dextran (average molecular weight, 4,400) (FD-4) using the in vitro everted intestine technique and by determining the FD-4 that appeared in plasma using the in situ closed loop intestine technique. The MTX administration to rats fed with the standard laboratory diet increased the small intestinal permeability of FD-4 due to the damage of the small intestine. Interestingly, the permeability of FD-4, when MTX was administered to rats fed with the aged garlic extract containing diet, was depressed almost to the level of control rats without the MTX treatment. The present study showed that the aged garlic extract protected the small intestine from the damage induced by the action of MTX on the crypt cells.

Cyclophosphamide, vincristine, methotrexate with leucovorin rescue, and cytarabine (COMLA) combination sequential chemotherapy for advanced diffuse histiocytic lymphoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sweet, D.L.; Golomb, H.M.; Ultmann, J.E.

A program of combination sequential chemotherapy using cyclophosphamide, vincristine, methotrexate with leucovorin rescue, and cytarabine (COMLA) was administered to 42 previously untreated patients with advanced diffuse histiocytic lymphoma. Twenty-three patients achieved a complete remission as determined by strict clinical restaging criteria. The observed median duration of survival for the complete responders is longer than 33 months. Eight patients achieved a partial response, with a median survival longer than 21 months. Eleven patients showed no response, with a median survival of 5 months. Toxicity was acceptable. None of the responders have shown central nervous system relapse. There was no difference inmore » response rates between patients with stage III or IV lymphoma or between asymptomatic or symptomatic patients. The COMLA program produces a high rate of complete and durable remissions and should be considered as an initial form of management of patients with advanced diffuse histiocytic lymphoma.« less

pH and salivary sodium bicarbonate during the administration protocol for methotrexate in children with leukemia.

PubMed

Rojas de Morales, Thais; Navas, Rita; Viera, Ninoska; Alvarez, Carmen Julia; Chaparro, Neira; Griman, Dariana

2007-10-01

To analyze the behavior of pH and sodium bicarbonate (NAHCO3) in the saliva of patients with leukemia during the administration protocol for Methotrexate (Mtx). A controlled clinical essay was carried out on 23 patients between 4 and 18 years of age with high-risk Acute Lymphoblastic Leukemia. Sampling was carried out at To: basal condition; T1: 12 hours after intravenous administration of sodium bicarbonate, before administering Mtx and T2: 3 hours after administering Mtx, the time of maximum concentration. Chiron-Diagnostic 378 equipment was used to determine pH and sodium bicarbonate. The data was interpreted using Analysis of Variance at the 5% significance level. The highest values of sodium bicarbonate were observed at T2, with salivary pH levels remaining within neutrality ranges, diminishing slightly in T1. CONCLUSION. In this study, the dose of sodium bicarbonate considered in the administration protocol of 3 g /m2 Mtx, kept sodium bicarbonate levels in saliva at normal levels and pH neutral.

Biological Impact of Senescence Induction in Prostate Cancer

DTIC Science & Technology

2010-01-01

with decreasing compound concentrations. Data showing chlorhexidine, bithionol, cytarabine and crassin acetate effectively inhibited proliferation...senescence with 25 nM doxorubicin were included as a positive control. Of the candi- date compounds, methotrexate, cytarabine , chlorhexidine, and IC261...then normalized to expression in untreated cells. Candidate compounds: methotrexate (MET), chlorhexadine (CHL), crassin acetate (CRA), cytarabine

Discovery – Methotrexate: Chemotherapy Treatment for Cancer

Cancer.gov

Prior to the 1950s, treatment for the majority of cancers was limited to either surgery or the use of radiation. The discovery of the use of methotrexate in curing a rare cancer marked the first time a cancer had been cured. This led to the development of many of today’s common cancer treatments.

Microemulsions for Colorectal Cancer Treatments. General Considerations and Formulation of Methotrexate.

PubMed

Flores, Sergio E; Rial-Hermida, M Isabel; Ramirez, Jorge C; Pazos, Alejandro; Concheiro, Angel; Alvarez-Lorenzo, Carmen; Peralta, René D

2016-01-01

Microemulsions combine the advantages of emulsions with those of nanocarriers, overcoming the stability problems of the former and providing facile scalable systems with compartments adequate for high drug loadings. Recently, microemulsions are gaining attention in the formulation of anticancer drugs not only for topical treatment, but also for systemic delivery as well as for the development of theranostic systems. The aim of this paper is two-fold. First, an updated review about general features, preparation, characterization and pharmaceutical applications, with a special focus on colorectal cancer, is provided. Second, a case study of formulation of methotrexate in microemulsions is presented. Various essential oils (menthol, trans-anethole, α-tocopherol) and surfactants (TPGS-1000, Maxemul 6112, Noigen RN-20) were investigated for the preparation of o/w microemulsions for the delivery of methotrexate, and the ability of methotrexate-loaded microemulsions to inhibit cancer cell growth was then evaluated. Disregarding the surfactants used, menthol and trans-anethole led to cytotoxic microemulsions, whereas α-tocopherol based-formulations induced cell proliferation. These findings highlight the role that the oily component may play in the efficacy and safety of the microemulsions.

Optical properties of cytostatic drugs used in cancer treatment

NASA Astrophysics Data System (ADS)

Pascu, Mihail-Lucian; Mogos, Ioan; Enescu, Mironel; Staicu, Angela; Truica, Sorina; Voicu, Letitia; Gazdaru, Doina M.; Pascu, Mihaela O.; Radu, Alina

2001-10-01

A spectroscopical characterization of methotrexate, cytostatic drug used frequently in cancer therapy, was performed. The absorption, emission and excitation spectra were measured for methotrexate solutions in natural saline and sodium hydroxide at concentration in the range 10-5 M -10-6 M and pH 8.4. The absorption bands are noticed in the spectral range 250 nm - 450 nm. The fluorescence excitation was made at 340 nm and 370 nm; the fluorescence emission was detected in the spectral range 400 nm - 500 nm with a maximum at 450 nm. The behavior of absorption and fluorescence spectra of methotrexate solution exposed to uv-visible light was investigated. The irradiation was made using an Xe lamp (emission between 325 nm and 420 nm and power density of 11 mW/cm2). The exposure time was between 15 min. and 3 h. Major modifications on absorption bands for irradiation times longer than 1 hour were observed. Furthermore, the methotrexate solutions become strongly fluorescent after irradiation. The observed changes are not linear with the exposure time indicating complex photochemical processes which implies, at least, one intermediate product.

St. John's wort significantly increased the systemic exposure and toxicity of methotrexate in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Shih-Ying; Juang, Shin-Hun; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan

2012-08-15

St. John's wort (SJW, Hypericum perforatum) is one of the popular nutraceuticals for treating depression. Methotrexate (MTX) is an immunosuppressant with narrow therapeutic window. This study investigated the effect of SJW on MTX pharmacokinetics in rats. Rats were orally given MTX alone and coadministered with 300 and 150 mg/kg of SJW, and 25 mg/kg of diclofenac, respectively. Blood was withdrawn at specific time points and serum MTX concentrations were assayed by a specific monoclonal fluorescence polarization immunoassay method. The results showed that 300 mg/kg of SJW significantly increased the AUC{sub 0−t} and C{sub max} of MTX by 163% and 60%,more » respectively, and 150 mg/kg of SJW significantly increased the AUC{sub 0−t} of MTX by 55%. In addition, diclofenac enhanced the C{sub max} of MTX by 110%. The mortality of rats treated with SJW was higher than that of controls. In conclusion, coadministration of SJW significantly increased the systemic exposure and toxicity of MTX. The combined use of MTX with SJW would need to be with caution. -- Highlights: ► St. John's wort significantly increased the AUC{sub 0−t} and C{sub max} of methotrexate. ► Coadministration of St. John's wort increased the exposure and toxicity of methotrexate. ► The combined use of methotrexate with St. John's wort will need to be with caution.« less

Drug resistance following irradiation of RIF-1 tumors: Influence of the interval between irradiation and drug treatment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hopwood, L.E.; Davies, B.M.; Moulder, J.E.

1990-09-01

RIF-1 tumors contain a small number of cells (1 to 100 per 10(6) cells) that are resistant to 5-fluorouracil, methotrexate, or adriamycin. The frequency of drug-resistant cells among individual untreated tumors is highly variable. Radiation, delivered in vivo at doses of 3 to 12 Gy, increases the frequency of methotrexate- and 5-fluorouracil-resistant cells, but not the frequency of adriamycin-resistant cells. The magnitude of induction of 5-fluorouracil and methotrexate resistance shows a complex dependence on the radiation dose and on the interval between irradiation and assessment of drug resistance. For a dose of 3 Gy, induced 5-fluorouracil and methotrexate resistance ismore » seen only after an interval of 5 to 7 days, whereas for a dose of 12 Gy, high levels of induced resistance are observed 1 to 3 days after irradiation. The maximum absolute risk for induction of resistance is 4 per 10(4) cells per Gy for methotrexate, and 3 per 10(6) cells per Gy for 5-fluorouracil. These results indicate that tumor hypoxia may play a role in the increased levels of drug resistance seen after irradiation, and that both genetic and environmental factors may influence radiation-induction of drug resistance. These studies provide essential data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be caused by radiation-induced drug resistance.« less

Predicting success of methotrexate treatment by pretreatment HCG level and 24-hour HCG increment.

PubMed

Levin, Gabriel; Saleh, Narjes A; Haj-Yahya, Rani; Matan, Liat S; Avi, Benshushan

2018-04-01

To evaluate β-human chorionic gonadotropin (β-HCG) level and its 24-hour increment as predictors of successful methotrexate treatment for ectopic pregnancy. Data were retrospectively reviewed from women with ectopic pregnancy who were treated by single-dose methotrexate (50 mg/m 2 ) at a university hospital in Jerusalem, Israel, between January 1, 2000, and June 30, 2015. Serum β-HCG before treatment and its percentage increment in the 24 hours before treatment were compared between treatment success and failure groups. Sixty-nine women were included in the study. Single-dose methotrexate treatment was successful for 44 (63.8%) women. Both mean β-HCG level and its 24-hour increment were lower for women with successful treatment than for those with failed treatment (respectively, 1224 IU\\L vs 2362 IU\\L, P=0.018; and 13.5% vs 29.6%, P=0.009). Receiver operator characteristic curve analysis yielded cutoff values of 1600 IU\\L and 14% increment with a positive predictive value of 75% and 82%, respectively, for treatment success. β-HCG level and its 24-hour increment were independent predictors of treatment outcome by logistic regression (both P<0.01). A β-HCG increment of less than 14% in the 24 hours before single-dose methotrexate and serum β-HCG of less than 1600 IU\\L were found to be good predictors of treatment success. © 2017 International Federation of Gynecology and Obstetrics.

Enhanced and Selective Antiproliferative Activity of Methotrexate-Functionalized-Nanocapsules to Human Breast Cancer Cells (MCF-7).

PubMed

de Oliveira, Catiúscia P; Büttenbender, Sabrina L; Prado, Willian A; Beckenkamp, Aline; Asbahr, Ana C; Buffon, Andréia; Guterres, Silvia S; Pohlmann, Adriana R

2018-01-04

Methotrexate is a folic acid antagonist and its incorporation into nanoformulations is a promising strategy to increase the drug antiproliferative effect on human breast cancer cells by overexpressing folate receptors. To evaluate the efficiency and selectivity of nanoformulations containing methotrexate and its diethyl ester derivative, using two mechanisms of drug incorporation (encapsulation and surface functionalization) in the in vitro cellular uptake and antiproliferative activity in non-tumoral immortalized human keratinocytes (HaCaT) and in human breast carcinoma cells (MCF-7). Methotrexate and its diethyl ester derivative were incorporated into multiwall lipid-core nanocapsules with hydrodynamic diameters lower than 160 nm and higher drug incorporation efficiency. The nanoformulations were applied to semiconfluent HaCaT or MCF-7 cells. After 24 h, the nanocapsules were internalized into HaCaT and MCF-7 cells; however, no significant difference was observed between the nanoformulations in HaCaT (low expression of folate receptors), while they showed significantly higher cellular uptakes than the blank-nanoformulation in MCF-7, which was the highest uptakes observed for the drug functionalized-nanocapsules. No antiproliferative activity was observed in HaCaT culture, whereas drug-containing nanoformulations showed antiproliferative activity against MCF-7 cells. The effect was higher for drug-surface functionalized nanocapsules. In conclusion, methotrexate-functionalized-nanocapsules showed enhanced and selective antiproliferative activity to human breast cancer cells (MCF-7) being promising products for further in vivo pre-clinical evaluations.

Long non-coding RNA LUCAT1 modulates methotrexate resistance in osteosarcoma via miR-200c/ABCB1 axis.

PubMed

Han, Zhe; Shi, Liying

2018-01-01

Long non-coding RNAs (lncRNAs) have been verified to participate in the tumorigenesis of multiple cancers. Nevertheless, the deepgoing role molecular mechanisms of lncRNAs on osteosarcoma chemoresistance remain unclear. In present study, we investigate the function of lncRNA LUCAT1 on osteosarcoma methotrexate (MTX) resistant phenotype and discover the potential regulatory mechanism. Results showed that LUCAT1 was up-regulated in MTX-resistant cells (MG63/MTX, HOS/MTX) compared to that in parental cells. LncRNA LUCAT1 and ABCB1 protein expression levels were both up-regulated when induced by different concentration of methotrexate. In vitro and vivo, LUCAT1 knockdown decreased the expression levels drug resistance related genes (MDR1, MRP5, LRP1), proliferation, invasion and tumor growth of osteosarcoma cells. Bioinformatics tools and luciferase assay reveled that miR-200c both targeted the 3'-UTR of LUCAT1 and ABCB1 mRNA, suggesting the modulation of LUCAT1 on ABCB1 through sponging miR-200c. Rescue experiments confirmed the combined role of LUCAT1, miR-200c and ABCB1 on osteosarcoma proliferation, invasion and methotrexate resistance. Overall, results indicate the vital role of LUCAT1 in the methotrexate resistance regulation through miR-200c/ABCB1 pathway, providing a novel insight and treatment strategy for osteosarcoma drug resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

[Late sequelae of central nervous system prophylaxis in children with acute lymphoblastic leukemia: high doses of intravenous methotrexate versus radiotherapy of the central nervous system--review of literature].

PubMed

Zając-Spychała, Olga; Wachowiak, Jacek

2012-01-01

Acute lymphoblastic leukemia is the most common malignancy in children. All current therapy regimens used in the treatment of childhood acute lymphoblastic leukemia include prophylaxis of the central nervous system. Initially it was thought that the best way of central nervous system prophylaxis is radiotherapy. But despite its effectiveness this method, may cause late sequelae and complications. In the programme currently used in Poland to treat acute lymphoblastic leukemia, prophylactic radiotherapy has been reduced by 50% (12 Gy) and is used only in patients stratified into the high risk group and in patients diagnosed as T-cell ALL (T-ALL). Complementary to radiotherapy, intrathecal methotrexate is given alone or in combination with cytarabine and hydrocortisone is given, as well as systemic chemotherapy with intravenous methotrexate is administered in high or medium doses (depending on risk groups and leukemia immunophenotype). Recent studies have shown that high dose irradiation of the central nervous system impairs cognitive development causing memory loss, visuomotor coordination impairment, attention disorders and reduction in the intelligence quotient. It has been proved that the degree of cognitive impairment depends on the radiation dose directed to the medial temporal lobe structures, particularly in the hippocampus and the surrounding cortex. Also, methotrexate used intravenously in high doses, interferes with the metabolism of folic acid which is necessary for normal development and the optimal functioning of neurons in the central nervous system. It has been proved that patients who have been treated with high doses of methotrexate are characterized by reduced memory skills and a lower intelligence quotient. The literature data concerning long term neuroanatomical abnormalities and neuropsychological deficits are ambiguous, and there is still no data concerning current methods of central nervous system prophylaxis with low doses of irradiation in combination with high doses of intravenous methotrexate.

Palmar-plantar erythrodysesthesia syndrome following treatment with high-dose methotrexate or high-dose cytarabine.

PubMed

Karol, Seth E; Yang, Wenjian; Smith, Colton; Cheng, Cheng; Stewart, Clinton F; Baker, Sharyn D; Sandlund, John T; Rubnitz, Jeffrey E; Bishop, Michael W; Pappo, Alberto S; Jeha, Sima; Pui, Ching-Hon; Relling, Mary V

2017-09-15

Palmar-plantar erythrodysesthesia syndrome (PPES) is an uncommon side effect of high-dose cytarabine or methotrexate. Prior case reports of PPES have been limited, and the predisposing factors for the development of PPES remain unknown. A review of databases identified 22 patients (1.3%) who developed 39 episodes of PPES among 1720 patients after treatment with high-dose cytarabine or methotrexate. Symptoms lasted a mean of 6.4 days. Hands and feet were both involved in 68% of the initial episodes. Parenteral opioids were required for pain control by 27% of the patients. In comparison with the 1698 children treated with similar therapy, the children who developed PPES were older (mean age at diagnosis, 14.3 vs 7.7 years; P = 7.5 × 10 -7 ). The frequency of PPES was less common in patients receiving methotrexate alone (7 of 946 or 0.7%) versus cytarabine (7 of 205 or 3.4%; P = .005) but was not different for those receiving both high-dose methotrexate and cytarabine (8 of 569 or 1.4%; P = .32). Prolonged infusions of methotrexate were associated with less frequent PPES in comparison with rapid infusions (P = 1.5 × 10 -5 ), as was the co-administration of dexamethasone with cytarabine (P = 2.5 × 10 -6 ). Self-described race and sex were not associated with PPES. In a multivariate analysis, older age and high-dose cytarabine administration without dexamethasone remained associated with PPES (P = 1.1 × 10 -4 and P = .038, respectively). A genome-wide association study did not identify any associations with PPES meeting the genome-wide significance threshold, but top variants were enriched for skin expression quantitative trait loci, including rs11764092 in AUTS2 (P = 6.45 × 10 -5 ). These data provide new insight into the incidence of PPES as well as its risk factors. Cancer 2017;123:3602-8. © 2017 American Cancer Society. © 2017 American Cancer Society.

Role of day 4 HCG as an early predictor of success after methotrexate therapy for ectopic pregnancies.

PubMed

Girija, S; Manjunath, A P; Salahudin, A; Jeyaseelan, L; Gowri, V; Abu-Heija, A; Al Kharusi, L

2017-08-01

To validate whether change in serum HCG levels between days 0 and 4 confer any prognostic value during methotrexate therapy and to quantify its change. This is a retrospective study of 48 tubal ectopic pregnancies treated with single dose methotrexate protocol at University Hospital, Muscat, Oman from January 2012 to December 2013. The clinical outcome was analyzed based on the complete resolution of HCG levels or need for additional doses of methotrexate or recourse to surgery. The percentage change in HCG levels between days 0 and 4 (HCG index) of methotrexate were calculated and receiver operator characteristics curve was plotted to identify the best cutoff levels. In order to get a robust 95% confidence interval, bootstrap method using R software was done using 1000 re-sampling. ROC curve and the predictive values were estimated using MEDCALC software. The mean HCG level on day 4 is significantly higher in treatment failure group (4254±4095 IU/L vs. 2109±3646 IU/L, P=0.008). The HCG levels between day 0 and 4 decreased in 42.7% (21/48) of cases and 80.9% of these cases had treatment success. The HCG levels increased in 57.4% (27/48) of cases and 33.3% of these cases had treatment success. (P=0.001). A 10 percent decline in day 4 HCG levels predict the treatment success with sensitivity of 77% and Specificity 81%. The area under the ROC curve was 0.82 (95% CI: 0.67-0.92), (P<0.001). The success with single dose of methotrexate therapy for tubal ectopic pregnancies was predicted early in the course of treatment by following three key findings: the absolute mean HCG values on day 4, decrease in HCG level from day 0 to 4 and 10% or more fall in day 4 HCG levels. Copyright © 2017 Elsevier B.V. All rights reserved.

Mycophenolate mofetil after methotrexate failure or intolerance in the treatment of scleritis and uveitis.

PubMed

Sobrin, Lucia; Christen, William; Foster, C Stephen

2008-08-01

To evaluate the outcomes of treatment with mycophenolate mofetil in patients with scleritis and uveitis refractory to or intolerant of methotrexate. Retrospective noncomparative case series. Eighty-five patients with scleritis and/or uveitis who failed with or did not tolerate methotrexate and were subsequently treated with mycophenolate mofetil between 1998 and 2006. We reviewed medical records of patients who were treated with mycophenolate mofetil after methotrexate intolerance or failure at one tertiary uveitis referral practice. We recorded dose and duration of methotrexate and mycophenolate mofetil therapy, inflammation grade, Snellen visual acuity (VA), use of other immunomodulatory therapy, and adverse events. Multivariate logistic regression was used to identify factors associated with inflammation control. Control of inflammation, steroid-sparing effect, VA, and adverse effects were assessed. Inflammation was controlled with mycophenolate mofetil in 47 patients (55%), with 5 achieving durable remission off all medication. In multivariate logistic regression analysis that adjusted for gender and age, the odds of inflammation control were lower for patients with scleritis (odds ratio [OR], 0.19; 95% confidence interval [CI], 0.04-0.93; P = 0.04) than for patients without scleritis. Among patients without scleritis, the odds of inflammation control were lower for patients with juvenile idiopathic arthritis (JIA)-associated uveitis (OR, 0.14; CI, 0.02-0.81, P = 0.03) compared to patients without JIA-associated uveitis. Eight of the 11 patients (73%) who were taking concomitant prednisone were able to taper their dose to <10 mg daily. Visual acuity declined in a greater percentage of patients who were unresponsive to mycophenolate mofetil (29%) compared with that of patients who responded to mycophenolate mofetil (9%). Side effects requiring discontinuation of mycophenolate mofetil occurred in 18 patients (21%). Mycophenolate mofetil was effective in controlling inflammation in approximately half of the patients who had previously failed with or did not tolerate methotrexate. The odds of inflammation control were less in patients with the diagnoses of scleritis and JIA.

Methotrexate-treated ectopic pregnancy: beta human chorionic gonadotropin serum changes as a success predictor using a mathematical model validation.

PubMed

Kovaleva, Aleksandra; Irishina, Natalia; Pereira, Augusto; Cuesta-Guardiola, Tatiana; Ortiz-Quintana, Luis

2017-03-01

Surgical rescue of methotrexate-treated ectopic pregnancy is necessary when tubal rupture or medical therapy failure is detected during post-therapeutic monitoring. It is known that an increased beta human chorionic gonadotropin (β-hCG) concentration is the most important factor associated with treatment failure. Therefore, we suggested that relative changes in serum β-hCG could predict a successful result of medical treatment, leading to facilitation of the decision to forgo the prospect of possible surgical rescue. A retrospective observational study of 115 patients with an ectopic pregnancy who were treated with a single dosage protocol of 50mg/m 2 of methotrexate injected intramuscularly was performed at Puerta de Hierro University Hospital and Gregorio Marañón University General Hospital. Standard statistical tests were applied in order to evaluate the relative changes in β-hCG concentration between the 1st and the 4th days following methotrexate injection. Methotrexate treatment has a 95% probability to be successful if the relative change of β-hCG from the 1st to the 4th day of monitoring is within the following interval: [-1.02; 0.15]. Moreover, if the values of β-hCG-relative change from 1st to 4th day of monitoring are within [0.54; 1.2], it assures a negative result of treatment with 95% probability. Therefore, the value 0.15 (15%) of β-hCG relative change can be considered a cut-off value for a positive result to treatment. Our data support that negative β-hCG relative changes on the 4th day of treatment likely predict a successful result of methotrexate therapy, with a cut-off point of 0.15. Expectant management should be carried out in these cases if no clinical indications of surgery are presented. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

[Medical management of interstitiel pregnancy by in situ methotrexate].

PubMed

Debras, E; Fernandez, H; Pourcelot, A-G; Houllier, M; Capmas, P

2016-09-01

Interstitial pregnancy accounts for 3 to 11% of ectopic pregnancy; these pregnancies are the more frequently non-tubal ectopic pregnancy. Medical treatment can be used in case of unruptured interstitial pregnancy and is used more and more frequently to avoid hemorrhagic risk and risk of conversion to radical surgery when a surgical management is decided. However, a larger use of methotrexate in interstitial pregnancy and conditions of use are not clearly defined. The aim of this study is to report a series of unruptured interstitial pregnancy managed by in situ injection of methotrexate. This retrospective observational study included women treated for an interstitial pregnancy between 2010 and 2013 in a teaching hospital. Medical management used was an in situ injection of methotrexate (1mg/kg) guided by vaginal sonography plus an intramuscular injection of methotrexate (1mg/kg) in the 48hours following in situ injection and 600mg of mifepristone when progesterone blood rate was more than 9ng/mL. A great decrease of serum hCG without surgery was considered a success. Fourteen women had an interstitial pregnancy during the study period. Six were managed surgically in 5 cases for suspicion of uterine rupture and one for pregnancy of unknown location. Eight women had a medical management and the success rate was 100%. Mean time for decrease of serum hCG until 2 UI/L was 54.4 days [34.0-74.8]. No uterine rupture or immediate complication was reported. Five women out of 8 had a spontaneous pregnancy after management of interstitial pregnancy. Medical management by in situ injection of methotrexate under sonographic guidance with an intramuscular injection within the 48hours following the in situ injection and mifepristone when ectopic pregnancy was active can be proposed in first-line therapy in case of unruptured interstitial pregnancy. This treatment has a great efficiency and low rate of complications. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Shock wave-induced ATP release from osteosarcoma U2OS cells promotes cellular uptake and cytotoxicity of methotrexate.

PubMed

Qi, Baochang; Yu, Tiecheng; Wang, Chengxue; Wang, Tiejun; Yao, Jihang; Zhang, Xiaomeng; Deng, Pengfei; Xia, Yongning; Junger, Wolfgang G; Sun, Dahui

2016-10-03

Osteosarcoma is the most prevalent primary malignant bone tumor, but treatment is difficult and prognosis remains poor. Recently, large-dose chemotherapy has been shown to improve outcome but this approach can cause many side effects. Minimizing the dose of chemotherapeutic drugs and optimizing their curative effects is a current goal in the management of osteosarcoma patients. In our study, trypan blue dye exclusion assay was performed to investigate the optimal conditions for the sensitization of osteosarcoma U2OS cells. Cellular uptake of the fluorophores Lucifer Yellow CH dilithium salt and Calcein was measured by qualitative and quantitative methods. Human MTX ELISA Kit and MTT assay were used to assess the outcome for osteosarcoma U2OS cells in the present of shock wave and methotrexate. To explore the mechanism, P2X7 receptor in U2OS cells was detected by immunofluorescence and the extracellular ATP levels was detected by ATP assay kit. All data were analyzed using SPSS17.0 statistical software. Comparisons were made with t test between two groups. Treatment of human osteosarcoma U2OS cells with up to 450 shock wave pulses at 7 kV or up to 200 shock wave pulses at 14 kV had little effect on cell viability. However, this shock wave treatment significantly promoted the uptake of Calcein and Lucifer Yellow CH by osteosarcoma U2OS cells. Importantly, shock wave treatment also significantly enhanced the uptake of the chemotherapy drug methotrexate and increased the rate of methotrexate-induced apoptosis. We found that shock wave treatment increased the extracellular concentration of ATP and that KN62, an inhibitor of P2X7 receptor reduced the capacity methotrexate-induced apoptosis. Our results suggest that shock wave treatment promotes methotrexate-induced apoptosis by altering cell membrane permeability in a P2X7 receptor-dependent manner. Shock wave treatment may thus represent a possible adjuvant therapy for osteosarcoma.

The Canadian Methotrexate and Etanercept Outcome Study: a randomised trial of discontinuing versus continuing methotrexate after 6 months of etanercept and methotrexate therapy in rheumatoid arthritis

PubMed Central

Pope, Janet E; Haraoui, Boulos; Thorne, J Carter; Vieira, Andrew; Poulin-Costello, Melanie; Keystone, Edward C

2014-01-01

Objective To determine if withdrawing methotrexate (MTX) after 6 months of combination etanercept (ETN)+MTX, in MTX-inadequate responders with active rheumatoid arthritis (RA), is non-inferior to continuing ETN+MTX. Methods Tumour necrosis factor-inhibitor naïve RA patients with disease activity score 28 (DAS28)≥3.2, swollen joint count≥3, despite stable MTX, were treated with ETN+MTX for 6 months, followed by randomisation to either continue ETN+MTX or switch to ETN monotherapy for an additional 18 months. The primary endpoint was change in DAS28 from 6-month randomisation to 12 months. The non-inferiority margin of change in DAS28 was 0.6, with prespecified analyses (DAS28<3.2 vs DAS28≥3.2). Results 205 patients were randomised. DAS28 was stable in patients on ETN+MTX and increased slightly in patients on ETN monotherapy from 6 to 12 months. Non-inferiority was not achieved, with an adjusted difference of 0.4 (0.1 to 0.7) between the ETN and the ETN+MTX groups, for the month 6–12 change in DAS28. However, patients who achieved low disease activity (LDA; DAS28<3.2) at 6 months had a similar disease activity at 12 months, whether on monotherapy or combination therapy (DAS28 change 0.7 ETN vs 0.57 ETN+MTX, p=0.8148). Conversely, for patients who did not reach LDA at 6 months, those on ETN monotherapy had increased disease activity at 12 months, while disease activity continued to decrease for patients on combination therapy, at 12 months (DAS28 change 0.4 ETN vs −0.4 ETN+MTX, p=0.0023). Conclusions Non-inferiority was not achieved. Withdrawing MTX after 6 months of continuation ETN+MTX in MTX inadequate responders did not yield the same degree of improvement between 6 and 12 months compared with continuing ETN+MTX. Trial Registration ClinicalTrials.gov−NCT00654368. PMID:23979914

The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis.

PubMed

Roubille, Camille; Richer, Vincent; Starnino, Tara; McCourt, Collette; McFarlane, Alexandra; Fleming, Patrick; Siu, Stephanie; Kraft, John; Lynde, Charles; Pope, Janet; Gulliver, Wayne; Keeling, Stephanie; Dutz, Jan; Bessette, Louis; Bissonnette, Robert; Haraoui, Boulos

2015-03-01

The objective of this systematic literature review was to determine the association between cardiovascular events (CVEs) and antirheumatic drugs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA)/psoriasis (Pso). Systematic searches were performed of MEDLINE, EMBASE and Cochrane databases (1960 to December 2012) and proceedings from major relevant congresses (2010-2012) for controlled studies and randomised trials reporting confirmed CVEs in patients with RA or PsA/Pso treated with antirheumatic drugs. Random-effects meta-analyses were performed on extracted data. Out of 2630 references screened, 34 studies were included: 28 in RA and 6 in PsA/Pso. In RA, a reduced risk of all CVEs was reported with tumour necrosis factor inhibitors (relative risk (RR), 0.70; 95% CI 0.54 to 0.90; p=0.005) and methotrexate (RR, 0.72; 95% CI 0.57 to 0.91; p=0.007). Non-steroidal anti-inflammatory drugs (NSAIDs) increased the risk of all CVEs (RR, 1.18; 95% CI 1.01 to 1.38; p=0.04), which may have been specifically related to the effects of rofecoxib. Corticosteroids increased the risk of all CVEs (RR, 1.47; 95% CI 1.34 to 1.60; p<0.001). In PsA/Pso, systemic therapy decreased the risk of all CVEs (RR, 0.75; 95% CI 0.63 to 0.91; p=0.003). In RA, tumour necrosis factor inhibitors and methotrexate are associated with a decreased risk of all CVEs while corticosteroids and NSAIDs are associated with an increased risk. Targeting inflammation with tumour necrosis factor inhibitors or methotrexate may have positive cardiovascular effects in RA. In PsA/Pso, limited evidence suggests that systemic therapies are associated with a decrease in all CVE risk. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Protective effects of Rutin against methanol induced acute toxic optic neuropathy: an experimental study.

PubMed

Taşlı, Nurdan Gamze; Çimen, Ferda Keskin; Karakurt, Yücel; Uçak, Turgay; Mammadov, Renad; Süleyman, Bahadır; Kurt, Nezahat; Süleyman, Halis

2018-01-01

To determine the effects of Rutin on methanol induced optic neuropathy and compare the results with the effects of ethanol. Totally 30 rats were divided into 5 groups, with 6 rats in each group as follows: healthy controls (C), methotrexate (MTX), methotrexate+methanol (MTM), methotrexate+methanol+ethanol (MTME) and methotrexate+ methanol+Rutin (MTMR). In all rabbits except those of the control group, MTX, diluted in sterile serum physiologic, 0.3 mg/kg per oral was applied for 7d by the aid of a tube. After this procedure to the rats of MTM, MTME and MTMR groups, 20% methanol with a dose of 3 g/kg per oral was given by the aid of a tube. In MTME group, 4h after the application of methanol, 20% ethanol was applied by the same way with a dose of 0.5 g/kg. On the other hand, in MTMR group 4h after the application of methanol, Rutin, which was dissolved in distilled water, was applied by the same way with a dose of 50 mg/kg. There were statistically significant differences in tissue 8-hydroxy-2 deoxyguanine (8-OHdG), interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), myeloperoxidase (MPO). glutathione peroxidase (tGSH) and superoxide dismutase (SOD) levels between groups ( P <0.001). In MTMR group tissue 8-OHdG, IL-1β, MDA, and MPO levels were similar with the healthy controls but significantly different than the other groups. In histopathological evaluations, in MTX group there was moderate focal destruction, hemorrhage and decrease in number of astrocytes and oligodendrocytes; in MTM group there was severe destruction and edema with decrease in number of astrocytes and oligodendrocytes; in MTME group there was mild hemorrhage, mild edema, mildly dilated blood vessels with congestion while in MTMR group, optic nerve tissue was resembling the healthy controls. Rutin may prevent methanol-induced optic neuropathy via anti-inflammatory effects and decreasing the oxidative stress. New treatment options are warranted in this disease to avoid loss of vision in patients.

High-dose methotrexate therapy of childhood acute lymphoblastic leukemia: lack of relation between serum methotrexate concentration and creatinine clearance.

PubMed

Joannon, Pilar; Oviedo, Iris; Campbell, Myriam; Tordecilla, Juan

2004-07-01

The objectives of this study were: (1) to analyze the relation of serum methotrexate (MTX) concentration with creatinine clearance, (2) to compare the leucovorin rescue dose administered to the patients based on creatinine clearance, with the one calculated according to serum MTX levels, and (3) to determine MTX-related toxicity. Thirty children with high-risk non-B acute lymphoblastic leukemia (ALL) treated according to the national protocol (PINDA 92) based on ALL BFM 90, were randomized to receive consolidation with four doses of either 1 or 2 g/m(2) MTX as a 24-hr infusion, at 2-week intervals (group M1 and M2, respectively). Serum MTX concentrations were measured at 24, 42, and 48 hr after beginning the infusion and were analyzed retrospectively. The creatinine clearance was calculated after 12-hr intravenous hydration prior to each MTX dose. Leucovorin dosage was adjusted according to creatinine clearance. Serum MTX concentrations at 24, 42, and 48 hr after starting the infusion were not related to creatinine clearance in both treatment groups. Leucovorin rescue administered according to creatinine clearance was excessive in 43% in group M1 and in 51% in group M2, as compared to the dose calculated according to serum MTX levels. No serious clinical complications were observed. These results suggest that creatinine clearance is not a good parameter to calculate leucovorin rescue. MTX-related toxicity in this group of patients receiving a dose of 1 or 2 g/m(2) and rescued with leucovorin without monitoring serum MTX levels was acceptable. Copyright 2004 Wiley-Liss, Inc.

The role of nanoparticles in the albumin-cytarabine and albumin-methotrexate interactions.

PubMed

Pentak, Danuta; Maciążek-Jurczyk, Małgorzata; Zawada, Zygmunt H

2017-04-01

Understanding the interactions which occur between nanomaterials and biomolecules is one of the most important issues in nanotechnology. Determining the properties of nanoparticles obtained through the use of novel methods and defining the scope of their application as drug carriers has important practical significance. Nanoparticles containing methotrexate and cytarabine obtained by a modified reverse-phase evaporation method (mREV) were characterized through the use of the UV/Vis and NMR methods. Obtained results confirmed high degree of analysed drugs encapsulation. The encapsulation efficiencies of cytarabine (AraC) and methotrexate (MTX) in L DPPC/AraC/MTX were found to be 86.30% (AraC) and 86.00% (MTX). The increased permeability of the phospholipid membranes, resulting from physico-chemical properties and the location of the drug, as well as from the physico-chemical properties of the phospholipids themselves, has been confirmed by increase in the length of the T1 relaxation time of protons in the N + (CH 3 ) 3 group. The study of analysed drugs release process from the liposomes has been made for bovine serum albumin, both in the absence (dBSA) and in the presence of fatty acid (BSA). Moreover two types of kinetic models (Bhaskar equation and Rigter-Peppas equation) have been used. Based on the study it has been concluded that mathematical modelling of drug release can be very helpful in speeding up product development and in better understanding the mechanisms controlling drug release from advanced delivery systems. Copyright © 2016 Elsevier B.V. All rights reserved.

Determination of Methotrexate, 7-Hydroxymethotrexate, and 2,4-Diamino-N10-methylpteroic Acid by LC-MS/MS in Plasma and Cerebrospinal Fluid and Application in a Pharmacokinetic Analysis of High-Dose Methotrexate

PubMed Central

Roberts, Michael S.; Selvo, Nicholas S.; Roberts, Jessica K.; Daryani, Vinay M.; Owens, Thandranese S.; Harstead, K. Elaine; Gajjar, Amar; Stewart, Clinton F.

2017-01-01

A rapid and robust method for measuring methotrexate (MTX) and its two primary metabolites, 7-hydroxymethotrexate (7-OHMTX) and 2,4-diamino-N10-methylpteroic acid (DAMPA), was developed for use in pharmacokinetic studies of plasma and cerebrospinal fluid samples collected from infants with malignant brain tumors. Sample aliquots (100μL) were prepared for bioanalysis of MTX and metabolites using a Waters Oasis HLB microelution SPE plate. Chromatography was performed using a Phenomenex Synergi Polar-RP 4μ 75 × 2.0mm ID column heated to 40°C. A rapid gradient elution on a Shimadzu HPLC system was used, with mobile phase A consisting of water/formic acid (100/0.1 v/v) and mobile phase B consisting of acetonitrile/formic acid (100/0.1 v/v). Column eluent was analyzed using AB Sciex QTRAP 5500 instrumentation in electrospray ionization mode. The ion transitions (m/z) monitored were 455.2→308.1, 471.1→324.1, and 326.2→175.1 for MTX, 7-OHMTX, and DAMPA respectively. The method was linear over a range of 0.0022 – 5.5 μM for MTX, 0.0085 – 21 μM for 7-OHMTX, and 0.0031 – 7.7 μM for DAMPA. The method was applied to the analysis of serial plasma samples obtained from infants diagnosed with malignant brain tumors receiving high-dose MTX and results were compared to MTX concentrations from a TDx-FLx FPIA. PMID:28824272

Prevalence of positive ppd in a cohort of rheumatoid arthritis patients.

PubMed

Tamborenea, Maria Natalia; Tate, Guillermo; Mysler, Eduardo; Debonis, Jose; Schijedman, Adrian

2010-03-01

The main objective of this study is to determine the prevalence of positive and anergic tuberculin skin test (ppd) in a rheumatoid arthritis cohort of patients (RA) and assess the association among ppd results and clinical and treatment variables. Patients with RA diagnosis were included. The ppd was done by Mantoux method. Positive result was considered when indurations were equal or greater than 5 mm. Anergic reaction was defined when the indurations was 0 mm. We included 105 patients (N = 105). The prevalence of positive ppd was 12.4% (n = 13), while the 87.6% (n = 92) presented a negative result. The 69.5% (n = 73) of the population were anergic to ppd. Patients with negative result received higher steroids dosages than patients with positive ppd (p < 0.04). In the multivariable model, the steroids dosage was a significant and independent predictor of negative ppd (p = 0.021, OR 0.72, 95% CI 0.55-0.95). Anergic and non-anergic patients were separated in groups, and a new analysis was done. The higher dosage of methotrexate was associated to tuberculine anergy (p = 0.025). In the multivariable model, the methotrexate dosage was a significant and independent predictor of tuberculine anergy (p = 0.005, OR 1.14, 95% CIs 1.04-1.24). In conclusion, in our cohort, the prevalence of positive ppd was lower than others studies. Among analyzed variables, the high steroid dose was a significant and independent predictor of negative ppd. The methotrexate treatment and dose were associated with ppd anergy.

A Bayesian Analysis of a Randomized Clinical Trial Comparing Antimetabolite Therapies for Non-Infectious Uveitis.

PubMed

Browne, Erica N; Rathinam, Sivakumar R; Kanakath, Anuradha; Thundikandy, Radhika; Babu, Manohar; Lietman, Thomas M; Acharya, Nisha R

2017-02-01

To conduct a Bayesian analysis of a randomized clinical trial (RCT) for non-infectious uveitis using expert opinion as a subjective prior belief. A RCT was conducted to determine which antimetabolite, methotrexate or mycophenolate mofetil, is more effective as an initial corticosteroid-sparing agent for the treatment of intermediate, posterior, and pan-uveitis. Before the release of trial results, expert opinion on the relative effectiveness of these two medications was collected via online survey. Members of the American Uveitis Society executive committee were invited to provide an estimate for the relative decrease in efficacy with a 95% credible interval (CrI). A prior probability distribution was created from experts' estimates. A Bayesian analysis was performed using the constructed expert prior probability distribution and the trial's primary outcome. A total of 11 of the 12 invited uveitis specialists provided estimates. Eight of 11 experts (73%) believed mycophenolate mofetil is more effective. The group prior belief was that the odds of treatment success for patients taking mycophenolate mofetil were 1.4-fold the odds of those taking methotrexate (95% CrI 0.03-45.0). The odds of treatment success with mycophenolate mofetil compared to methotrexate was 0.4 from the RCT (95% confidence interval 0.1-1.2) and 0.7 (95% CrI 0.2-1.7) from the Bayesian analysis. A Bayesian analysis combining expert belief with the trial's result did not indicate preference for one drug. However, the wide credible interval leaves open the possibility of a substantial treatment effect. This suggests clinical equipoise necessary to allow a larger, more definitive RCT.

Safe adalimumab therapy for rheumatoid arthritis in a patient with pre-existing multiple myeloma.

PubMed

Mielke, Frank; Schweigert, Marcus

2008-04-01

We report on a patient with rheumatoid arthritis (RA) who was treated with adalimumab and retrospectively diagnosed as having a multiple myeloma. In addition to the determination of clinical symptoms, investigations included radiography of the thorax, spine, hands and feet, arthrosonography, determination of laboratory parameters (including C-reactive protein levels and presence of antibodies against cyclic citrullinated peptide), cytogenetics and electrocardiography. RA was initially diagnosed in 1988. Stage II and stage III RA were diagnosed for the left and right foot, respectively, in 1996. Joints of both hands were diagnosed with stage I RA; both wrists and some finger joints showed signs of synovitis. Plasmocytoma was diagnosed in 2004; however, investigation of medical records revealed evidence of multiple myeloma 8 years earlier, in 1996. RA was originally treated with gold, sulfasalazine, azathioprin and glucocorticoid. Methotrexate was later used in addition to cortisone and then in combination with a selective cyclo-oxygenase-2 inhibitor. A combination therapy consisting of adalimumab (40 mg every 2 weeks), methotrexate (15 mg weekly) and a cyclo-oxygenase-2 inhibitor (rofecoxib 25 mg daily until July 2004, etoricoxib 90 mg daily from October 2004) was started in November 2003. Adalimumab therapy was interrupted for 6 months owing to safety concerns, but was resumed after a careful risk-benefit assessment.

Polymorphisms at the Ligand Binding Site of the Vitamin D Receptor Gene and Osteomalacia

PubMed Central

Ak, Duygu Gezen; Kahraman, Hakkí; Dursun, Erdinç; Duman, Belgin Süsleyici; Erensoy, Nevin; Alagöl, Faruk; Tanakol, Refik; Yılmazer, Selma

2005-01-01

Vitamin D receptor (VDR) gene polymorphisms have been suggested as possible determinants of bone mineral density (BMD) and calcium metabolism. In this study, our aim was to determine whether there is an association between VDR gene polymorphism and osteomalacia or not. We determined ApaI and TaqI polymorphisms in the vitamin D receptor gene in 24 patients with osteomalacia and 25 age-matched healthy controls. Serum calcium, phosphorus, ALP, PTH, 25OHD levels were also examined. We used PCR and RFLP methods to test for an association between osteomalacia and polymorphisms within, intron 8 and exon 9 of the VDR gene. When the control and patients were compared for their ApaI and TaqI genotypes there was no relationship between VDR gene allelic polymorphisms and osteomalacia. Whereas a nearly significant difference for A allele was found in the allellic distribution of the patients (p = 0.08). Also no association between biochemical data and VDR gene polymorphisms was observed. PMID:16403954

Musculoskeletal involvement in sarcoidosis*, **

PubMed Central

Nessrine, Akasbi; Zahra, Abourazzak Fatima; Taoufik, Harzy

2014-01-01

Sarcoidosis is a multisystem inflammatory disorder of unknown cause. It most commonly affects the pulmonary system but can also affect the musculoskeletal system, albeit less frequently. In patients with sarcoidosis, rheumatic involvement is polymorphic. It can be the presenting symptom of the disease or can appear during its progression. Articular involvement is dominated by nonspecific arthralgia, polyarthritis, and Löfgren's syndrome, which is defined as the presence of lung adenopathy, arthralgia (or arthritis), and erythema nodosum. Skeletal manifestations, especially dactylitis, appear mainly as complications of chronic, multiorgan sarcoidosis. Muscle involvement in sarcoidosis is rare and usually asymptomatic. The diagnosis of rheumatic sarcoidosis is based on X-ray findings and magnetic resonance imaging findings, although the definitive diagnosis is made by anatomopathological study of biopsy samples. Musculoskeletal involvement in sarcoidosis is generally relieved with nonsteroidal anti-inflammatory drugs or corticosteroids. In corticosteroid-resistant or -dependent forms of the disease, immunosuppressive therapy, such as treatment with methotrexate or anti-TNF-α, is employed. The aim of this review was to present an overview of the various types of osteoarticular and muscle involvement in sarcoidosis, focusing on their diagnosis and management. PMID:24831403

Epstein Barr virus-positive mucocutaneous ulcer of the colon associated Hodgkin lymphoma in Crohn's disease.

PubMed

Moran, Neil R; Webster, Bradley; Lee, Kenneth M; Trotman, Judith; Kwan, Yiu-Lam; Napoli, John; Leong, Rupert W

2015-05-21

Epstein Barr virus (EBV) positive mucocutaneous ulcers (EBVMCU) form part of a spectrum of EBV-associated lymphoproliferative disease. They have been reported in the setting of immunosenescence and iatrogenic immunosuppression, affecting the oropharyngeal mucosa, skin and gastrointestinal tract (GIT). Case reports and series to date suggest a benign natural history responding to conservative management, particularly in the GIT. We report an unusual case of EBVMCU in the colon, arising in the setting of immunosuppression in the treatment of Crohn's disease, with progression to Hodgkin lymphoma 18 mo after cessation of infliximab. The patient presented with multiple areas of segmental colonic ulceration, histologically showing a polymorphous infiltrate with EBV positive Reed-Sternberg-like cells. A diagnosis of EBVMCU was made. The ulcers failed to regress upon cessation of infliximab and methotrexate for 18 mo. Following commencement of prednisolone for her Crohn's disease, the patient developed widespread Hodgkin lymphoma which ultimately presented as a life-threatening lower GIT bleed requiring emergency colectomy. This is the first report of progression of EBVMCU to Hodgkin lymphoma, in the setting of ongoing iatrogenic immunosuppression and inflammatory bowel disease.

Methylenetetrahydrofolate reductase gene haplotypes affect toxicity during maintenance therapy for childhood acute lymphoblastic leukemia in Japanese patients.

PubMed

Tanaka, Yoichi; Manabe, Atsushi; Nakadate, Hisaya; Kondoh, Kensuke; Nakamura, Kozue; Koh, Katsuyoshi; Kikuchi, Akira; Komiyama, Takako

2014-05-01

Abstract The aim of this study was to investigate the influence of daily 6-mercaptopurine (6-MP) and low-dose weekly methotrexate (MTX) combination treatment and methylenetetrahydrofolate reductase (MTHFR) haplotypes on toxicity during maintenance therapy in Japanese childhood acute lymphoblastic leukemia (ALL). We retrospectively analyzed the MTHFR C677T and A1298C polymorphisms and influence of haplotypes on toxicity in 73 patients. Patients with the MTHFR 677TT and 677CT + 1298AC were associated with severe liver toxicity (p = 0.014, odds ratio [OR] = 3.82, 95% confidence interval [CI] = 1.27-11.46) and more rapid onset of liver toxicity (p = 0.010). Patients with MTHFR 677TT and 677CT + 1298AC were associated with lower frequency of 6-MP and MTX dose reduction due to leukopenia (p < 0.05). No difference was observed in average drug doses in the MTHFR genotypes. In conclusion, the MTHFR C677T and A1298C haplotypes might be useful for monitoring adverse effects in childhood ALL maintenance therapy in Japanese patients.

[Personalized drug therapy-directed clinical pharmacology research based on genetic polymorphisms and pharmacokinetics analysis].

PubMed

Hayashi, Hideki

2013-01-01

In this decade, the field of pharmacogenomics (PGx), which is related to pharmacokinetics (PK) or pharmacodynamics (PD), has attracted much attention because it may provide a possible explanation for individual differences in the clinical efficacy of drugs. For the development of personalized drug therapy, it is important to accumulate evidence from PK/PD/PGx analysis in clinical trials. Warfarin (WF) is one of the most widely prescribed anticoagulants for the prevention and treatment of venous and arterial thromboembolism. However, large interindividual and interethnic differences have been observed in the WF dose required to elicit the anticoagulant effect. We investigated the factors influencing the WF maintenance dose in Japanese patients. Our study confirmed a large interindividual variability in the WF maintenance dose that was due to a VKORC1 1639 G>A polymorphism and differences in body weight, age, and serum albumin. In addition, we found that the CYP4F2 genotype affects the plasma concentration of menaquinone-4, and that this finding was correlated with the WF sensitivity index in Japanese pediatric patients. Methotrexate (MTX) is an antifolate that is widely used to treat rheumatoid arthritis (RA) and cancer. The response to low-dose MTX demonstrated wide interpatient variability; however, the contributing factors remain unclear. We found that the frequency of the RFC1 80A allele was higher in RA patients treated with MTX alone compared with patients who received biological disease-modifying antirheumatic drugs (bDMARDs). This finding may support the combined use of bDMARDs and MTX. Further large-scale prospective clinical trials are required to confirm these findings.

Multi-agent chemotherapy overcomes glucocorticoid resistance conferred by a BIM deletion polymorphism in pediatric acute lymphoblastic leukemia.

PubMed

Soh, Sheila Xinxuan; Lim, Joshua Yew Suang; Huang, John W J; Jiang, Nan; Yeoh, Allen Eng Juh; Ong, S Tiong

2014-01-01

A broad range of anti-cancer agents, including glucocorticoids (GCs) and tyrosine kinase inhibitors (TKIs), kill cells by upregulating the pro-apoptotic BCL2 family member, BIM. A common germline deletion in the BIM gene was recently shown to favor the production of non-apoptotic BIM isoforms, and to predict inferior responses in TKI-treated chronic myeloid leukemia (CML) and EGFR-driven lung cancer patients. Given that both in vitro and in vivo GC resistance are predictive of adverse outcomes in acute lymphoblastic leukemia (ALL), we hypothesized that this polymorphism would mediate GC resistance, and serve as a biomarker of poor response in ALL. Accordingly, we used zinc finger nucleases to generate ALL cell lines with the BIM deletion, and confirmed the ability of the deletion to mediate GC resistance in vitro. In contrast to CML and lung cancer, the BIM deletion did not predict for poorer clinical outcome in a retrospective analysis of 411 pediatric ALL patients who were uniformly treated with GCs and chemotherapy. Underlying the lack of prognostic significance, we found that the chemotherapy agents used in our cohort (vincristine, L-asparaginase, and methotrexate) were each able to induce ALL cell death in a BIM-independent fashion, and resensitize BIM deletion-containing cells to GCs. Together, our work demonstrates how effective therapy can overcome intrinsic resistance in ALL patients, and suggests the potential of using combinations of drugs that work via divergent mechanisms of cell killing to surmount BIM deletion-mediated drug resistance in other cancers.

Effects of methylenetetrahydrofolate reductase gene polymorphisms on toxicities during consolidation therapy in pediatric acute lymphoblastic leukemia in a Chinese population.

PubMed

Liu, Shu-Guang; Li, Zhi-Gang; Cui, Lei; Gao, Chao; Li, Wei-Jing; Zhao, Xiao-Xi

2011-06-01

This study aimed to investigate whether there was a correlation between the genotype or haplotype of the methylenetetrahydrofolate reductase gene (MTHFR) and toxicities during consolidation therapy or plasma methotrexate (MTX) levels at 48 h after the first dose of MTX infusion. We retrospectively genotyped 181 children with newly diagnosed acute lymphoblastic leukemia (ALL) who were treated with the Chinese Children's Leukemia Group protocol. In standard- and medium-risk treatment branches, the 677T carriers (CT + TT) had a higher risk of developing thrombocytopenia when compared with carriers of the CC genotype (odds ratio [OR] 5.21, 95% confidence interval [CI] 1.18-23.01, p = 0.017). The 1298AC/CC genotypes were associated with a decrease in skin toxicity, as compared with the common AA genotype (p = 0.037). An estimation of haplotype frequencies showed that there was no 677T-1298C haplotype in the population. A lower frequency of anemia (OR 0.44, 95% CI 0.21-0.90, p = 0.025) and lower MTX level (p = 0.044) were observed in patients with the 677C-1298C haplotype than in those without. High plasma MTX level was correlated with anemia (p = 0.011) and neutropenia (p = 0.044). In the high-risk group, the polymorphisms or plasma MTX levels were not correlated with any toxicity. Taken together, our data demonstrate that genotyping of MTHFR and measurement of plasma MTX levels might be useful to optimize MTX therapy.

Unexpected toxicity of combined modality therapy for small cell carcinoma of the lung. A Southwest oncology group study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Livingston, R.B.; Mira, J.; Haas, C.

1979-09-01

Combination chemotherapy with cyclophosphamide, vincristine, methotrexate and Adriamycin was delivered to 35 patients with small-cell carcinoma of the lung (28 with extensive and 7 with limited disease), including elective administration of intrathecal methotrexate. Whole-brain irradiation (3000 rad in 10 fractions) was then administered, with concomitant systemic cyclophosphamide and methotrexate for patients with extensive disease. Those with limited disease received concomitant chest irradiation without chemotherapy. Maintenance therapy then involved cyclophosphamide 750 mg/m/sup 2/ day 1, and methotrexate 30 mg/m/sup 2/ days 1 and 8, every 3 weeks. In only 2 patients reinduction was carried out at 24 weeks with the originalmore » chemotherapy. Myelosuppression was severe; there were at least 2 drug-related deaths from this cause in the induction period, and 15 febrile episodes with leukopenia. Stomatitis was more frequent and more severe in ''maintenance'' than in ''induction'' courses, especially the first maintenance course which was given with concomitant whole-brain irradiation. In addition, 13 episodes of unusual toxicity occurred in close temporal relation to systemic methotrexate administration, usually associated with stomatitis, in patients who were on maintenance therapy. These included 3 episodes of loss of consciousness, 4 of generalized erythroderma, 2 of ''flu''-like syndrome, and 1 each of the following: fatal, bilateral interstitial pneumonia; reversible, eosinophilic pleural effusion; acute myocardial infarction; and renal compromise with hematuria. As a result of this unexpected and protean toxicity, the pilot study was discontinued. However, at this time seven patients (4 with extensive and 3 with limited disease) remain in complete remission.« less

Effects of dexamethasone, celecoxib, and methotrexate on the histology and metabolism of bone tissue in healthy Sprague Dawley rats.

PubMed

Liu, Yanzhi; Cui, Yang; Chen, Yan; Gao, Xiang; Su, Yanjie; Cui, Liao

2015-01-01

To investigate the long-term effects of three antiarthritics, namely dexamethasone, celecoxib, and methotrexate on the histology and metabolism of intact bone tissue in rats. Thirty-two 12-week-old healthy female Sprague Dawley rats were randomly allocated into four groups: 1) control (saline, daily); 2) dexamethasone (2 mg/kg, twice weekly); 3) celecoxib (50 mg/kg, daily); and 4) methotrexate (0.5 mg/kg, twice weekly). The drugs were administered to the rats for 12 weeks and the animals were weighed on a weekly basis. The femurs and lumbar vertebrae were harvested for bone mineral density and bone mechanical properties analyses. The proximal tibiae were processed for bone histomorphometry and micro-computed tomography analyses. The following results were obtained: 1) dexamethasone strongly inhibited bone formation rate accompanied with a decrease in bone mineral density and bone biomechanical properties; 2) celecoxib stimulated bone resorption, leading to a decrease of bone mass and femur biomechanic properties; and 3) methotrexate caused bone loss and bone quality deterioration to a lesser extent due to the increase of the bone turnover rate on the proximal tibial metaphysis of the rats. This study provides a comparative profile of the long-term effects of clinical doses of celecoxib, methotrexate, and dexamethasone on intact skeletons of the rats. The results indicate that the three antiarthritics have varying degrees of side effects on bone metabolism, and these findings will help physicians to learn more about the potential effects of antiarthritics on bone metabolism.

Methotrexate for rheumatoid arthritis patients who are on hemodialysis.

PubMed

Al-Hasani, Hasanein; Roussou, Euthalia

2011-12-01

Methotrexate (MTX) can be toxic to patients suffering from end stage renal disease (ESRD) on hemodialysis even at low doses. This increase in toxicity is more notable in terms of bone marrow suppression in the form of pancytopenia. Many methods of elimination including dialysis itself have been proven ineffective, and alternate treatments with anti-TNF alpha blockers can be considered.

Investigating methotrexate toxicity within a randomized double-blinded, placebo-controlled trial: rationale and design of the Cardiovascular Inflammation Reduction Trial-Adverse Events (CIRT-AE) Study

USDA-ARS?s Scientific Manuscript database

Background: The role of low dose methotrexate (LDM) in potential serious toxicities remains unclear despite its common use. Prior observational studies investigating LDM toxicity compared LDM to other active drugs. Prior placebo-controlled clinical trials of LDM in inflammatory conditions were not l...

A novel mechanism of toxic injury to the Papez circuit from chemotherapy.

PubMed

Kwan, Benjamin Yin Ming; Krings, Timo; Bernstein, Mark; Mandell, Daniel M

2015-04-01

Toxic effects of chemotherapy delivered via Ommaya reservoir include pericatheter necrosis and toxic leukoencephalopathy. Imaging evidence of toxicity is often asymptomatic, but can be clinically consequential. A young patient, treated for cerebrospinal fluid relapse of acute lymphoblastic leukemia with methotrexate and cytarabine via Ommaya reservoir, presented with acute deterioration of short-term memory. MRI demonstrated extra-ventricular Ommaya catheter position and typical methotrexate-induced changes in the deep white matter, but also signal alteration in the forniceal columns and mammillary bodies, components of the Papez circuit. This case presents a novel mechanism of chemotherapy-induced neurotoxicity associated with extra-ventricular Ommaya catheter position. Specifically, the clinical and imaging findings suggest that extra-ventricular Ommaya catheter position may lead to a direct methotrexate-induced toxicity to the Papez circuit. This provides further clinical evidence of the function of the circuit. The possibility that this patient received a supratherapeutic dose of methotrexate may explain why this presentation with profound memory impairment is not more common. However, this case also provides a potential explanation for patients who receive standard dose chemotherapy via extra-ventricular Ommaya catheter and develop milder memory loss. Copyright © 2014 Elsevier Ltd. All rights reserved.

Screening of cytoprotectors against methotrexate-induced cytogenotoxicity from bioactive phytochemicals.

PubMed

Gu, Shaobin; Wu, Ying; Yang, Jianbo

2016-01-01

As a well known anti-neoplastic drug, the cytogenotoxicity of methotrexate (MTX) has received more attention in recent years. To develop a new cytoprotector to reduce the risk of second cancers caused by methotrexate, an umu test combined with a micronucleus assay was employed to estimate the cytoprotective effects of ten kinds of bioactive phytochemicals and their combinations. The results showed that allicin, proanthocyanidins, polyphenols, eleutherosides and isoflavones had higher antimutagenic activities than other phytochemicals. At the highest dose tested, the MTX genetoxicity was suppressed by 34.03%∼67.12%. Of all the bioactive phytochemical combinations, the combination of grape seed proanthocyanidins and eleutherosides from Siberian ginseng as well as green tea polyphenols and eleutherosides exhibited stronger antimutagenic effects; the inhibition rate of methotrexate-induced genotoxicity separately reached 74.7 ± 6.5% and 71.8 ± 4.7%. Pretreatment of Kunming mice with phytochemical combinations revealed an obvious reduction in micronucleus and sperm abnormality rates following exposure to MTX (p < 0.01). Moreover, significant increases in thymus and spleen indices were observed in cytoprotector candidates in treated groups. The results indicated that bioactive phytochemicals combinations had the potential to be used as new cytoprotectors.

The Role of Folate Transport in Antifolate Drug Action in Trypanosoma brucei*

PubMed Central

Dewar, Simon; Sienkiewicz, Natasha; Ong, Han B.; Wall, Richard J.; Horn, David

2016-01-01

The aim of this study was to identify and characterize mechanisms of resistance to antifolate drugs in African trypanosomes. Genome-wide RNAi library screens were undertaken in bloodstream form Trypanosoma brucei exposed to the antifolates methotrexate and raltitrexed. In conjunction with drug susceptibility and folate transport studies, RNAi knockdown was used to validate the functions of the putative folate transporters. The transport kinetics of folate and methotrexate were further characterized in whole cells. RNA interference target sequencing experiments identified a tandem array of genes encoding a folate transporter family, TbFT1–3, as major contributors to antifolate drug uptake. RNAi knockdown of TbFT1–3 substantially reduced folate transport into trypanosomes and reduced the parasite's susceptibly to the classical antifolates methotrexate and raltitrexed. In contrast, knockdown of TbFT1–3 increased susceptibly to the non-classical antifolates pyrimethamine and nolatrexed. Both folate and methotrexate transport were inhibited by classical antifolates but not by non-classical antifolates or biopterin. Thus, TbFT1–3 mediates the uptake of folate and classical antifolates in trypanosomes, and TbFT1–3 loss-of-function is a mechanism of antifolate drug resistance. PMID:27703008

Safety profile of methotrexate in inflammatory bowel disease.

PubMed

Gabbani, Tommaso; Deiana, Simona; Lunardi, Sarah; Manetti, Natalia; Annese, Vito

2016-10-01

Methotrexate, which was initially developed in 1948 for the treatment of leukemia, is known to be an immunomodulatory and anti-inflammatory drug. It has been widely used for over 60 years as both a low and high-dose therapy in chronic inflammatory diseases. The aim of this review was to analyze and summarize the available data specifically on the safety of this drug in the management of inflammatory bowel diseases. A structured search of articles was conducted using the PubMed database up to April 2016. All articles in English with isolated or combined keywords were included according to their relevance to the aims of this study. Numerous of studies have established the efficacy of parenteral methotrexate in the management of steroid-dependent and steroid-resistant Crohn's disease, either for inducing or maintaining remission. However, its efficacy in ulcerative colitis has not been properly investigated. Additionally, methotrexate has been shown to reduce the effect of immunization with anti-TNF agents when combined. The drug has potential advantages over thiopurines such as its weekly administration, a possible shorter time of action, low cost, decreased risk for malignancy and overall a comparable safety profile.

Resolution of recalcitrant uveitic optic disc edema following administration of methotrexate: two case reports.

PubMed

Woo, Se Joon; Kim, Mi Jeung; Park, Kyu Hyung; Lee, Yun Jong; Hwang, Jeong-Min

2012-02-01

A 13-year-old male and a 15-year-old female presented with optic disc edema associated with chronic recurrent uveitis. While the ocular inflammation responded to high doses of oral prednisolone, the disc edema showed little improvement. After oral administration of methotrexate, the disc edema and ocular inflammation were resolved, and the dose of oral corticosteroid could be reduced.

Determinants for drug survival of methotrexate in patients with psoriasis, split according to different reasons for discontinuation: results of the prospective MTX-CAPTURE.

PubMed

Otero, M E; van den Reek, J M; Seyger, M M; van de Kerkhof, P C; Kievit, W; de Jong, E M

2017-08-01

As methotrexate (MTX) is a widely used treatment for psoriasis, it is important to gain insight into the reasons for the discontinuation of MTX and to understand the determinants for drug survival. To describe 5-year drug survival for MTX in patients with psoriasis, split according to different reasons for discontinuation, and to identify the determinants for drug survival. Data were extracted from a prospective psoriasis registry of patients treated with MTX (MTX-CAPTURE). Drug survival was analysed using Kaplan-Meier estimates and the determinants for discontinuation were analysed using Cox regression analysis. Analyses were split according to the reason for discontinuation: side-effects or ineffectiveness. We included 85 patients treated with MTX, with a maximum treatment duration of 5·2 years. The overall drug survival rates were 63%, 30% and 15% after 1, 3 and 5 years, respectively. The median survival was 1·8 years. Overall, 55 patients (65%) discontinued MTX for the following reasons: side-effects (35%), ineffectiveness (26%), combination of side-effects and ineffectiveness (13%), other reasons (16%) and 11% were lost to follow-up. The most reported side-effects were gastrointestinal symptoms, despite the use of folic acid in 99% of patients. Based on univariate analysis, a high Psoriasis Area and Severity Index score and a high score on the visual analogue scale for disease severity at baseline were possible determinants for a short drug survival. Drug survival of MTX was low with 15% of patients 'on drug' after 5 years. Side-effects alone or in combination with inadequate disease control were more important in the context of treatment discontinuation than inadequate disease control alone. © 2017 British Association of Dermatologists.

Celecoxib, a specific COX-2 inhibitor, has no significant effect on methotrexate pharmacokinetics in patients with rheumatoid arthritis.

PubMed

Karim, A; Tolbert, D S; Hunt, T L; Hubbard, R C; Harper, K M; Geis, G S

1999-12-01

To determine the effects of celecoxib, a specific inhibitor of cyclooxygenase 2 (COX-2) on the renal clearance and plasma pharmacokinetic profile of stable methotrexate (MTX) doses in patients with rheumatoid arthritis (RA). Fourteen adult female patients with RA taking a stable weekly dose of MTX (5 to 15 mg/wk) for a minimum of 3 months were randomized to receive concomitantly either celecoxib (200 mg BID) or placebo for a period of 7 days in a single blind, 2 period crossover study of MTX pharmacokinetics and renal clearance. The plasma pharmacokinetic profile of MTX did not change significantly when celecoxib or a placebo was coadministered. The mean renal clearance of MTX alone, 7.98+/-2.18 l/h, was virtually unchanged by coadministration of celecoxib (7.94+/-1.61 l/h) or placebo (7.97+/-1.19 l/h). Celecoxib has no significant effect on the pharmacokinetics or renal clearance of MTX in patients with RA, although these results should be confirmed in prospective studies of elderly and renally impaired patients.

Prevention of methotrexate-induced nephrotoxicity by concomitant administration of garlic aqueous extract in rat.

PubMed

Ahmed, Walaa; Zaki, Amr; Nabil, Taghred

2015-01-01

Methotrexate (MTX) has been widely used for treatment of cancer and rheumatoid arthritis, but its use has been limited by its nephrotoxicity. This study was carried out to determine whether garlic exerts a protective effect against MTX-induced nephrotoxicity. Nephrotoxicity was induced in rats after a single i.p. injection of MTX (20 mg/kg). Garlic extract (1 mL/100 g b.w.) was given orally for 7 days before and after MTX administration. Serum samples were collected to evaluate urea, creatinine, sodium, phosphorous, potassium, and calcium. Reduced glutathione, catalase, adenosine deaminase, nitric oxide, and malondialdehyde were measured in renal tissue. Tubular injury was evaluated by histopathological examination. MTX increased urea and creatinine levels and led to imbalances in some electrolytes. It also depleted renal antioxidant enzyme levels and increased malondialdehyde, adenosine deaminase, and nitric oxide levels. Histopathological examination showed glomerular and tubular alterations. Pretreatment with garlic significantly improved renal function and increased renal antioxidant enzyme activities. Furthermore, garlic reduced renal oxidative stress and prevented alterations in renal morphology. Garlic treatment has a reversible biochemical and histological effect upon MTX-induced nephrotoxicity.

Design and stability study of a paediatric oral solution of methotrexate 2 mg/ml.

PubMed

Vrignaud, Sandy; Briot, Thomas; Launay, Aurélie; Kempf, Marie; Lagarce, Frédéric

2015-06-20

Oral paediatric forms development by pharmaceutical industry is still insufficient. The present study was performed to propose an adapted and pleasant formulation of liquid oral formulation of MTX. The solution is composed of injectable methotrexate, water, Ora Sweet(®) and sodium bicarbonate. After 120 days storage, pH remained stable at about 8 in all formulations, insuring no risk of MTX precipitation. MTX content in solution formulation, determined by high performance liquid chromatography measurements, remained in the specifications of >90% of the initial concentration when stored at 4 and 25°C. Forced degradation of MTX by heat and acidic conditions allowed formation and detection of degradation products by the analytical method. Microbial study of the preparation shows that the solution remains in the specifications during all the storage, or after one sample each week during one month, eventually indicating the microbial properties are not affected by patient use. To conclude, we here propose a new MTX liquid formulation stable for at least 120 days. Copyright © 2015 Elsevier B.V. All rights reserved.

1HNMR study of methotrexate serum albumin (MTX SA) binding in rheumatoid arthritis

NASA Astrophysics Data System (ADS)

Sułkowska, A.; Maciążek-Jurczyk, M.; Bojko, B.; Równicka, J.; Sułkowski, W. W.

2008-11-01

Rheumatoid arthritis (RA) is an immunologically depended disease. It is characterized by a chronic, progressive inflammatory process. Methotrexate (4-amino-10-methylfolic acid, MTX) is the modifying drug used to treat RA. The aim of the presented studies is to determine the low affinity binding site of MTX in bovine (BSA) and human (HSA) serum albumin with the use of proton nuclear magnetic resonance ( 1HNMR) spectroscopy. The analysis of 1HNMR spectra of MTX in the presence of serum albumin (SA) allows us to observe the interactions between aromatic rings of the drug and the rings of amino acids located in the hydrophobic subdomains of the protein. On the basis of the chemical shifts σ [ppm] and the relaxation times T1 [s] of drug protons the hydrophobic interaction between MTX-SA and the stoichiometric molar ratio of the complex was evaluated. This work is a part of a spectroscopic study on MTX-SA interactions [A. Sułkowska, M. Maciążek, J. Równicka, B. Bojko, D. Pentak, W.W. Sułkowski, J. Mol. Struct. 834-836 (2007) 162-169].

Methotrexate for the Treatment of Pediatric Crohn's Disease: A Systematic Review and Meta-analysis.

PubMed

Colman, Ruben J; Lawton, Rachel C; Dubinsky, Marla C; Rubin, David T

2018-04-23

Methotrexate (MTX) is an immunomodulator used for the treatment of pediatric inflammatory bowel disease (IBD). There are currently no RCTs that assess the treatment efficacy of methotrexate within the pediatric IBD patient population. This systematic review and meta-analysis assesses the efficacy of MTX therapy among the existing pediatric literature. A systematic literature search was performed using MEDLINE and the Cochrane library from inception until March 2016. Synonyms for 'pediatric', 'methotrexate' and 'IBD' were utilized as both free text and MESH search terms. The studies included contained clinical remission (CR) rates for MTX treatment of pediatric IBD patients 18 yrs old, as mono- or combination therapy. Case studies with <10 patients were excluded. Quality assessment was performed with the Newcastle-Ottawa Scale. Meta-analysis calculated pooled CR rates. A random-effects meta-analysis with forest plots was performed using R. Fourteen (11 monotherapy, 1 combination therapy, 2 both; n = 886 patients) observational studies were eligible out of 202 studies. No interventional studies were identified. The pooled achieved CR rate for pediatric CD patients on monotherapy within 3-6 months was 57.7% (95% CI 48.2-66.6%), (P =0.22; I2 = 29.8%). The CR was 37.1% (95% CI 29.5-45.5%), (P = 0.20; I2 = 37.4%) for maintenance therapy at 12 months. Sub-analysis could not identify CR differences between MTX administration types, thiopurine exposure. This meta-analysis demonstrated that, over 50% of pediatric Crohn's disease patients induced with methotrexate achieved clinical remission, while 12-month remission rate was only 37%. Prospective controlled interventional trials should assess treatment efficacy among patient subgroups. 10.1093/ibd/izy078_video1izy078.video15774883936001.

Breast cancer leptomeningeal metastasis: the results of combined treatment and the comparison of methotrexate and liposomal cytarabine as intra-cerebrospinal fluid chemotherapy.

PubMed

Niwińska, Anna; Rudnicka, Halina; Murawska, Magdalena

2015-02-01

This was a prospective observational study to assess the results of the treatment of patients with breast cancer leptomeningeal metastasis (LM) and to compare the efficacy of methotrexate and liposomal cytarabine in patients treated intrathecally by lumbar puncture. In this prospective observational study, 149 consecutive patients with breast cancer and LM treated between the years 1999 and 2011 were assessed. Multimodality treatment methods were used: systemic therapy in 77 patients, radiotherapy in 92 patients, intrathecal methotrexate in 81 patients, and intrathecal liposomal cytarabine in 15 patients. The median survival of all patients was 4.2 months. The median survival of patients in whom systemic intravenous/oral treatment was used was 6 months, in those who did not have systemic treatment, the median survival was 2 months (P < .001). The median survival of patients treated with intrathecal methotrexate was 4.2 months; in patients treated with intrathecal liposomal cytarabine, the median survival was 4.6 months, and in patients who did not receive intrathecal treatment, the median survival was 3.7 months (P = .717). Median survival after whole-brain radiotherapy was 4.6 months and with no radiotherapy, it was 3.2 months (P = .028). Multivariate analysis revealed a Karnofsky performance status (KPS) of > 70. Systemic intravenous/oral treatment and bone as a site of metastasis were factors prolonging survival from LM. Among treatment methods, only systemic therapy prolonged survival in patients with LM. Neither radiotherapy nor lumbar intrathecal therapy influenced survival in those patients; however, both methods alleviated signs and symptoms of LM. No difference in survival was observed in patients treated intrathecally with methotrexate and those treated with liposomal cytarabine. Treatment with both drugs was comparable. Copyright © 2015 Elsevier Inc. All rights reserved.

Methotrexate-cytarabine-dexamethasone combination chemotherapy with or without rituximab in patients with primary central nervous system lymphoma.

PubMed

Sun, Xuefei; Liu, Jing; Wang, Yaming; Bai, Xueyan; Chen, Yuedan; Qian, Jun; Zhu, Hong; Liu, Fusheng; Qiu, Xiaoguang; Sun, Shengjun; Ji, Nan; Liu, Yuanbo

2017-07-25

High-dose methotrexate based chemotherapy is the standard treatment for patients with newly diagnosed primary central nervous system lymphoma (PCNSL). The role of rituximab is controversial because of its large size, which limits its penetration of the blood-brain barrier. In this study, we investigated the efficacy and tolerability of adding rituximab to methotrexate-cytarabine-dexamethasone combination therapy (RMAD regimen). The patients treated with RMAD had a complete remission rate of 66.7% after induction chemotherapy; this rate was only 33.3% in patients treated with MAD alone (p = .011). The most common grade 1-3 adverse events were similar and included hematologic toxicity, increased aminotransferase levels, and gastrointestinal reactions. Multivariate analysis revealed that rituximab treatment was associated with longer progression-free survival (PFS, p = .005) but not overall survival (OS). Additionally, we observed that elevated serum lactate dehydrogenase was associated with shorter OS and PFS. We retrospectively analyzed 60 immunocompetent patients with newly diagnosed PCNSL at Beijing Tiantan Hospital, Capital Medical University from January 2010 to June 2016. Twenty-four patients received 3-6 courses of 3.5 g/m2 methotrexate on day 1; 0.5-1 g/m2 cytarabine on day 2; and 5-10 mg dexamethasone on days 1, 2 and 3. Thirty-six patients received the same combination plus rituximab 375 mg/m2 on day 0. All patients repeated the treatment every 3 weeks. High-dose methotrexate based chemotherapy with rituximab yields a higher complete remission rate and does not increase serious toxicities. PFS benefits from the addition of rituximab. OS has an increasing trend in patients treated with rituximab without statistical significance.

Initiation of TNF Inhibitor Therapy and Change in Physiologic Measures in Psoriasis

PubMed Central

Wu, Jashin J.; Liu, Liyan; Asgari, Maryam M.; Curtis, Jeffrey R.; Harrold, Leslie; Salman, Craig; Herrinton, Lisa J.

2014-01-01

Background Psoriasis may predispose to cardiovascular disease and diabetes. However, the role of TNF inhibitor in mediating this risk is controversial. Objective To assess this relationship, we estimated change in metabolic physiologic measures before and after initiation of TNF inhibitor therapy compared with methotrexate therapy among psoriasis patients. Methods We conducted a retrospective cohort study, 2007–2012, using computerized clinical data for 1,274 new users of TNF inhibitor and 979 new users of methotrexate therapy to compare change in blood pressure, lipids, triglycerides, fasting plasma glucose, and body mass index before and after start of TNF inhibitors or methotrexate. The study was restricted to new users. We computed within-person change in each measure, so that each patient served as their own control. In addition, we compared TNF inhibitor patients to methotrexate patients, by computing the adjusted difference in their group means. In secondary analyses, we examined phototherapy as a comparator. Results Among starters of TNF inhibitor and MTX therapy, within-person change in physiologic measures at 6 months did not differ significantly. We observed no important or significant changes in any of the physiologic measures with initiation of TNF inhibitor compared with methotrexate. The same results were found in subgroup analyses focused on men, and on those with hypertension, diabetes mellitus, or obesity. The same results were observed with phototherapy, except that diastolic blood pressure declined by 0.6 mm Hg within-person during the 6 months after starting phototherapy (p<0.05). Conclusions The study provides no evidence for improvement of physiologic measures associated with the metabolic syndrome resulting from TNF inhibitor use for psoriasis. PMID:24708441

Concurrent use of methotrexate and celecoxib increases risk of silent liver fibrosis in rheumatoid arthritis patients with subclinical reduced kidney function.

PubMed

Park, Jin Su; Park, Min-Chan; Park, Yong-Beom; Lee, Soo-Kon; Lee, Sang-Won

2014-01-01

We evaluated the effects of concurrent use of methotrexate and celecoxib on silent liver and kidney damages in rheumatoid arthritis (RA) patients. We enrolled 92 RA patients with normal laboratory results related to liver and kidney functions, who had received methotrexate and celecoxib concurrently over 6 months. Liver stiffness measurement (LSM) using transient elastography and ultrasonography were performed along with blood and urine tests. Estimated glomerular filtration rate (eGFR) was calculated by both the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) equations. Initial eGFR represented kidney function at the time of the initiation of celecoxib. The cutoff for abnormal LSM values was adopted as 5.3 kPa. The optimal cutoff of each eGFR for abnormal LSM values was also calculated. The median age of patients was 55 years old (74 women). The median LSM was 4.4 kPa and the median eGFRs and median initial eGFRs ranged from 89 to 99 mL/min/1.73 m(2). The cumulative doses of methotrexate and celecoxib and their concurrent administration duration did not affect LSM values and eGFRs. Both eGFRs were significantly associated with LSM values. Patients with initial eGFR(CKD-EPI), initial eGFR(MDRD), and eGFR(CKD-EPI) below each optimal cutoff had significantly high risks for silent liver fibrosis (RR 9.4, 10.3, and 4.4, p < 0.001, respectively). Both initial eGFRs (CKD-EPI and MDRD) and eGFR (CKD-EPI) were significant predictors for the development of silent liver fibrosis in RA patients who had received methotrexate and celecoxib concurrently for at least 6 months.

Single-center, single-dose, open-label, randomized, two-period crossover study on the bioavailability of methotrexate administered using a novel prefilled, needle-free delivery system.

PubMed

Bienvenu, Boris; Aouba, Achille; Gottenberg, Jacques-Eric; Verstuyft, Celine

2017-04-01

Zeneo 1 is a needle-free injection device. We performed a pharmacokinetic study to investigate the bioequivalence of methotrexate administered subcutaneously using either the needle-free injection device or a conventional needle and syringe. This was a single-dose, open-label, laboratory-blind, randomized crossover study performed in adult healthy volunteers. Each participant received two methotrexate injections (each 25 mg), one via needle-free injection device and one via conventional injection, with a 21-28 day wash-out interval between dosing. For each participant, the administration site for both injections was either the abdomen or the thigh. The primary pharmacokinetic outcome parameters were AUC (0- t ) and C max . Bioequivalence was assessed by standard criteria: whether 90% confidence intervals of geometric mean ratios for the two administration methods were within 80-125%. Fifty-two individuals completed the study. Bioequivalence criteria were met for AUC (0- t ) , for the overall analysis (both injection sites: 90% confidence interval: 99.4-103.1%), and for each injection site separately. Bioequivalence was similarly demonstrated with AUC (0-∞) . Bioequivalence criteria for C max were fulfilled for abdominal administration but not for the overall analysis. Injection via the needle-free injection device was well tolerated. Limitations include conducting the study in healthy volunteers and the relatively small subject number (albeit satisfactory for bioequivalence). This study shows that methotrexate injection via needle-free injection device is bioequivalent to a conventional needle and syringe in relation to AUC (0- t ) and AUC (0-∞) . Studies of needle-free injection device use in patients requiring methotrexate therapy are planned.

Comparison of alternative βhCG follow-up protocols after single-dose methotrexate therapy for tubal ectopic pregnancy.

PubMed

Şükür, Yavuz Emre; Koyuncu, Kazibe; Seval, Mehmet Murat; Çetinkaya, Esra; Dökmeci, Fulya

2017-12-01

To evaluate the performances of five different βhCG follow-up protocols after single-dose methotrexate therapy for tubal ectopic pregnancy (EP). Data of patients who received single-dose methotrexate therapy for tubal EP at a university hospital between January 2011 and July 2016 were reviewed. A 'successful methotrexate treatment' was defined if the EP treated with no need for surgery. The performances of different protocols were tested by comparing with the currently used '15% βhCG decrease between days 4 and 7' protocol. The tested follow-up protocols were '20, 25%, and any βhCG decrease between days 0/1 and 7' and '20% and any βhCG decrease between days 0/1 and 4'. Among the 96 patients evaluated, 12 (12.5%) required second dose. Totally, 91 (94.8%) patients treated successfully with no need for surgery. Four patients were operated within 4 days following the second dose. One patient who did not need second dose according to the standard follow-up protocol was operated on the 10th day due to rupture (specificity = 80%). Two protocols, namely '20% βhCG decrease between days 0/1 and 7' and 'any βhCG decrease between days 0/1 and 7' did not show statistically significant differences from the index protocol regarding the number of patients who should be assigned to 2nd dose. 'Any βhCG decrease between days 0/1 and 7' protocol may substitute the currently used one to decide second dose methotrexate in tubal EP management. Omitting 4th day measurement seems to be more convenient and cost effective.

Trophoblastic Tumors of the Uterus—Problems of Methotrexate Therapy

PubMed Central

Johnson, F. Deborah; Jacobs, Edwin M.; Silliphant, William M.

1968-01-01

Nineteen patients with trophoblastic tumors of the uterus were evaluated at the University of California San Francisco Medical Center. Eight patients, admitted before 1956, did not receive chemotherapy; the mortality rate was 87.5 per cent. Ten of the remaining 11 patients were given intermittent, intensive Methotrexate therapy; actinomycin D and vincristine were used in treating two patients in whom resistance to Methotrexate developed. The mortality was 10 per cent. Toxicity was a prominent factor but was completely reversible when chemotherapy was stopped. None of the patients showed recurrent disease during follow-up evaluation eight months to five years and eight months after therapy was completed. It is postulated that continuing chemotherapy four to six months after the chorionic gonadotropin titer becomes negative decreases recurrent disease. ImagesFigure 1.Figure 2.Figure 3.Figure 3.Figure 3. PMID:18730089

[Fiessinger-Leroy-Reiter syndrome with non-obstructive cardiomyopathy treated with methotrexate].

PubMed

Blétry, O; De Prost, Y; Scheuble, C; Frank, R; Godeau, P

1979-07-01

The case of a 50 year old male with the Fiessinger-Leroy-Reiter syndrome, ankylosing spondylitis and generalised pustular psoriasis is reported. This condition wax complicated by non-obstructive cardiomyopathy, congestive cardiac failure and first-degree atrioventricular block, the site of which was localised by electrophysiological studies (nodal block with an infrahisian conduction defect). After failure of several therapeutic regimes, a spectacular improvement was obtained with Methotrexate associated with a diuretic; the signs of heart failure regressed and the cardiomyopathy stablised. A parallel improvement was seen in the skin, cardiac and articular lesions and has been maintained with an 18 months follow-up. Left ventricular performance was studied by echocardiography. The mechanism of the beneficial effect of Methotrexate is unclear; this therapeutic trial is to be extended to include other cases of primary cardiomyopathy without obstruction.

Thermal, spectroscopic, and ab initio structural characterization of carprofen polymorphs.

PubMed

Bruni, Giovanna; Gozzo, Fabia; Capsoni, Doretta; Bini, Marcella; Macchi, Piero; Simoncic, Petra; Berbenni, Vittorio; Milanese, Chiara; Girella, Alessandro; Ferrari, Stefania; Marini, Amedeo

2011-06-01

Commercial and recrystallized polycrystalline samples of carprofen, a nonsteroidal anti-inflammatory drug, were studied by thermal, spectroscopic, and structural techniques. Our investigations demonstrated that recrystallized sample, stable at room temperature (RT), is a single polymorphic form of carprofen (polymorph I) that undergoes an isostructural polymorphic transformation by heating (polymorph II). Polymorph II remains then metastable at ambient conditions. Commercial sample is instead a mixture of polymorphs I and II. The thermodynamic relationships between the two polymorphs were determined through the construction of an energy/temperature diagram. The ab initio structural determination performed on synchrotron X-Ray powder diffraction patterns recorded at RT on both polymorphs allowed us to elucidate, for the first time, their crystal structure. Both crystallize in the monoclinic space group type P2(1) /c, and the unit cell similarity index and the volumetric isostructurality index indicate that the temperature-induced polymorphic transformation I → II is isostructural. Polymorphs I and II are conformational polymorphs, sharing a very similar hydrogen bond network, but with different conformation of the propanoic skeleton, which produces two different packing. The small conformational change agrees with the low value of transition enthalpy obtained by differential scanning calorimetry measurements and the small internal energy computed with density functional methods. Copyright © 2011 Wiley-Liss, Inc.

Utilization of Subcutaneous Methotrexate in Rheumatoid Arthritis Patients After Failure or Intolerance to Oral Methotrexate: A Multicenter Cohort Study.

PubMed

Branco, Jaime C; Barcelos, Anabela; de Araújo, Filipe Pombo; Sequeira, Graça; Cunha, Inês; Patto, José Vaz; Oliveira, Margarida; Mateus, Margarida Pratas; Couto, Maura; Nero, Patrícia; Pinto, Patrícia; Monteiro, Paulo; Castelão, Walter; Félix, Jorge; Ferreira, Diana; Almeida, João; Silva, Maria João

2016-01-01

Low-dose weekly methotrexate (MTX) is the mainstay in the therapy of rheumatoid arthritis (RA). It can be given via oral, intramuscular or subcutaneous (SC) route. This study sought to determine the real-world pattern of treatment with SC MTX in Portuguese adult patients with active RA. Utilization of Metoject(®) in Rheumatoid Arthritis (UMAR) was a non-interventional, cohort multicenter study with retrospective data collection. Eligible patients had active RA, at least 18 years of age, and started SC MTX treatment in 2009 or 2010 after failure or intolerance to oral MTX. Data were collected from patient's clinical records. Both non-parametric and parametric survival methods were used to obtain a detailed understanding of SC MTX treatment duration. Fifty patients were included, of which only 9 discontinued SC MTX during the study follow-up period. The probability of discontinuation after 1, 2, and 3 years of treatment of SC MTX treatment is expected to be 6.10%, 8.50%, and 23.20%, respectively. The extrapolated median duration of SC MTX using an exponential model was 106.4 months/8.87 years. Mean dose of SC MTX was 18.36 mg. The reasons for treatment discontinuation were occurrence of adverse events in six patients and lack of efficacy in three. The long treatment duration of SC MTX highlights its excellent tolerability compared to oral MTX, especially concerning the frequent adverse gastrointestinal events of MTX. Furthermore, long MTX treatment duration provides the opportunity to postpone or even avoid expensive therapies with biologics. The results obtained from the UMAR study provide important information for the utilization and public financing of SC MTX in Portugal.

Highly Effective Auger-Electron Therapy in an Orthotopic Glioblastoma Xenograft Model using Convection-Enhanced Delivery

PubMed Central

Thisgaard, Helge; Halle, Bo; Aaberg-Jessen, Charlotte; Olsen, Birgitte Brinkmann; Therkelsen, Anne Sofie Nautrup; Dam, Johan Hygum; Langkjær, Niels; Munthe, Sune; Någren, Kjell; Høilund-Carlsen, Poul Flemming; Kristensen, Bjarne Winther

2016-01-01

Glioblastoma, the most common and malignant primary brain tumor, always recurs after standard treatment. Therefore, promising new therapeutic approaches are needed. Short-range Auger-electron-emitters carry the ability of causing highly damaging radiation effects in cells. The aim of this study was to test the effect of [125I]5-Iodo-2'-deoxyuridine (125I-UdR, a radioactive Auger-electron-emitting thymidine analogue) Auger-therapy on immature glioblastoma spheroid cultures and orthotopic xenografted glioblastoma-bearing rats, the latter by means of convection-enhanced delivery (CED). Moreover, we aimed to determine if the therapeutic effect could be enhanced when combining 125I-UdR therapy with the currently used first-line chemotherapeutic agent temozolomide. 125I-UdR significantly decreased glioblastoma cell viability and migration in vitro and the cell viability was further decreased by co-treatment with methotrexate and/or temozolomide. Intratumoral CED of methotrexate and 125I-UdR with and without concomitant systemic temozolomide chemotherapy significantly reduced the tumor burden in orthotopically xenografted glioblastoma-bearing nude rats. Thus, 100% (8/8) of the animals survived the entire observation period of 180 days when subjected to the combined Auger-chemotherapy while 57% (4/7) survived after the Auger-therapy alone. No animals (0/8) treated with temozolomide alone survived longer than 50 days. Blood samples and post-mortem histology showed no signs of dose-limiting adverse effects. In conclusion, the multidrug approach consisting of CED of methotrexate and 125I-UdR with concomitant systemic temozolomide was safe and very effective leading to 100% survival in an orthotopic xenograft glioblastoma model. Therefore, this therapeutic strategy may be a promising option for future glioblastoma therapy. PMID:27924163

Highly Effective Auger-Electron Therapy in an Orthotopic Glioblastoma Xenograft Model using Convection-Enhanced Delivery.

PubMed

Thisgaard, Helge; Halle, Bo; Aaberg-Jessen, Charlotte; Olsen, Birgitte Brinkmann; Therkelsen, Anne Sofie Nautrup; Dam, Johan Hygum; Langkjær, Niels; Munthe, Sune; Någren, Kjell; Høilund-Carlsen, Poul Flemming; Kristensen, Bjarne Winther

2016-01-01

Glioblastoma, the most common and malignant primary brain tumor, always recurs after standard treatment. Therefore, promising new therapeutic approaches are needed. Short-range Auger-electron-emitters carry the ability of causing highly damaging radiation effects in cells. The aim of this study was to test the effect of [ 125 I]5-Iodo-2'-deoxyuridine ( 125 I-UdR, a radioactive Auger-electron-emitting thymidine analogue) Auger-therapy on immature glioblastoma spheroid cultures and orthotopic xenografted glioblastoma-bearing rats, the latter by means of convection-enhanced delivery (CED). Moreover, we aimed to determine if the therapeutic effect could be enhanced when combining 125 I-UdR therapy with the currently used first-line chemotherapeutic agent temozolomide. 125 I-UdR significantly decreased glioblastoma cell viability and migration in vitro and the cell viability was further decreased by co-treatment with methotrexate and/or temozolomide. Intratumoral CED of methotrexate and 125 I-UdR with and without concomitant systemic temozolomide chemotherapy significantly reduced the tumor burden in orthotopically xenografted glioblastoma-bearing nude rats. Thus, 100% (8/8) of the animals survived the entire observation period of 180 days when subjected to the combined Auger-chemotherapy while 57% (4/7) survived after the Auger-therapy alone. No animals (0/8) treated with temozolomide alone survived longer than 50 days. Blood samples and post-mortem histology showed no signs of dose-limiting adverse effects. In conclusion, the multidrug approach consisting of CED of methotrexate and 125 I-UdR with concomitant systemic temozolomide was safe and very effective leading to 100% survival in an orthotopic xenograft glioblastoma model. Therefore, this therapeutic strategy may be a promising option for future glioblastoma therapy.

Identification of 7 Proteins in Sera of RA Patients with Potential to Predict ETA/MTX Treatment Response

PubMed Central

Obry, Antoine; Hardouin, Julie; Lequerré, Thierry; Jarnier, Frédérique; Boyer, Olivier; Fardellone, Patrice; Philippe, Peggy; Marcelli, Christian; Loët, Xavier Le; Vittecoq, Olivier; Cosette, Pascal

2015-01-01

Objective: The recent growth of innovating biologics has opened fascinating avenues for the management of patients. In rheumatoid arthritis, many biologics are currently available, the choice of which being mostly determined empirically. Importantly, a given biologic may not be active in a fraction of patients and may even provoke side effects. Here, we conducted a comparative proteomics study in attempt to identify a predictive theranostic signature of non-response in patients with rheumatoid arthritis treated by etanercept/methotrexate combination. Methods: A serum sample was collected prior to treatment exposure from a cohort of 22 patients with active RA. A proteomic “label free” approach was then designed to quantitate protein biomarkers using mass spectrometry. To verify these results, a relative quantification followed by an absolute quantification of interesting protein candidates were performed on a second cohort. The criterion of judgment was the response to etanercept/methotrexate combination according to the EULAR criteria assessed at 6 months of treatment. Results: These investigations led to the identification of a set of 12 biomarkers with capacity to predict treatment response. A targeted quantitative analysis allowed to confirm the potential of 7 proteins from the latter combination on a new cohort of 16 patients. Two highly discriminating proteins, PROS and CO7, were further evaluated by ELISA on this second cohort. By combining the concentration threshold of each protein associated to a right classification (responders vs non-responders), the sensitivity and specificity reached 88.9 % and 100 %, respectively. Conclusion: Prior to methotrexate/etanercept treatment, abundance of several sera proteins, notably PROS and CO7, were associated to response status of RA patients 6 month after treatment initiation. PMID:26379787

Treatment Algorithms in Systemic Lupus Erythematosus.

PubMed

Muangchan, Chayawee; van Vollenhoven, Ronald F; Bernatsky, Sasha R; Smith, C Douglas; Hudson, Marie; Inanç, Murat; Rothfield, Naomi F; Nash, Peter T; Furie, Richard A; Senécal, Jean-Luc; Chandran, Vinod; Burgos-Vargas, Ruben; Ramsey-Goldman, Rosalind; Pope, Janet E

2015-09-01

To establish agreement on systemic lupus erythematosus (SLE) treatment. SLE experts (n = 69) were e-mailed scenarios and indicated preferred treatments. Algorithms were constructed and agreement determined (≥50% respondents indicating ≥70% agreement). Initially, 54% (n = 37) responded suggesting treatment for scenarios; 13 experts rated agreement with scenarios. Fourteen of 16 scenarios had agreement as follows: discoid lupus: first-line therapy was topical agents and hydroxychloroquine and/or glucocorticoids then azathioprine and subsequently mycophenolate (mofetil); uncomplicated cutaneous vasculitis: initial treatment was glucocorticoids ± hydroxychloroquine ± methotrexate, followed by azathioprine or mycophenolate and then cyclophosphamide; arthritis: initial therapy was hydroxychloroquine and/or glucocorticoids, then methotrexate and subsequently rituximab; pericarditis: first-line therapy was nonsteroidal antiinflammatory drugs, then glucocorticoids with/without hydroxychloroquine, then azathioprine, mycophenolate, or methotrexate and finally belimumab or rituximab, and/or a pericardial window; interstitial lung disease/alveolitis: induction was glucocorticoids and mycophenolate or cyclophosphamide, then rituximab or intravenous gamma globulin (IVIG), and maintenance followed with azathioprine or mycophenolate; pulmonary hypertension: glucocorticoids and mycophenolate or cyclophosphamide and an endothelin receptor antagonist were initial therapies, subsequent treatments were phosphodiesterase-5 inhibitors and then prostanoids and rituximab; antiphospholipid antibody syndrome: standard anticoagulation with/without hydroxychloroquine, then a thrombin inhibitor for venous thrombosis, versus adding aspirin or platelet inhibition drugs for arterial events; mononeuritis multiplex and central nervous system vasculitis: first-line therapy was glucocorticoids and cyclophosphamide followed by maintenance with azathioprine or mycophenolate, and then rituximab, IVIG, or plasmapheresis; and serious lupus nephritis: first-line therapy was glucocorticoids and mycophenolate, then cyclophosphamide then rituximab. We established variable agreement on treatment approaches. For some treatment decisions there was good agreement between experts even if no randomized controlled trial data were available. © 2015, American College of Rheumatology.

A Bayesian Analysis of a Randomized Clinical Trial Comparing Antimetabolite Therapies for Non-Infectious Uveitis

PubMed Central

Browne, Erica N; Rathinam, Sivakumar R; Kanakath, Anuradha; Thundikandy, Radhika; Babu, Manohar; Lietman, Thomas M; Acharya, Nisha R

2017-01-01

Purpose To conduct a Bayesian analysis of a randomized clinical trial (RCT) for non-infectious uveitis using expert opinion as a subjective prior belief. Methods A RCT was conducted to determine which antimetabolite, methotrexate or mycophenolate mofetil, is more effective as an initial corticosteroid-sparing agent for the treatment of intermediate, posterior, and pan- uveitis. Before the release of trial results, expert opinion on the relative effectiveness of these two medications was collected via online survey. Members of the American Uveitis Society executive committee were invited to provide an estimate for the relative decrease in efficacy with a 95% credible interval (CrI). A prior probability distribution was created from experts’ estimates. A Bayesian analysis was performed using the constructed expert prior probability distribution and the trial’s primary outcome. Results 11 of 12 invited uveitis specialists provided estimates. Eight of 11 experts (73%) believed mycophenolate mofetil is more effective. The group prior belief was that the odds of treatment success for patients taking mycophenolate mofetil were 1.4-fold the odds of those taking methotrexate (95% CrI 0.03 – 45.0). The odds of treatment success with mycophenolate mofetil compared to methotrexate was 0.4 from the RCT (95% confidence interval 0.1–1.2) and 0.7 (95% CrI 0.2–1.7) from the Bayesian analysis. Conclusions A Bayesian analysis combining expert belief with the trial’s result did not indicate preference for one drug. However, the wide credible interval leaves open the possibility of a substantial treatment effect. This suggests clinical equipoise necessary to allow a larger, more definitive RCT. PMID:27982726

[Relapsing polychondritis. A case report of a patient treated with methotrexate and celecoxib].

PubMed

Cervera Castillo, Hernando; Torres Caballero, Verónica

2005-01-01

Relapsing polychondritis is a rare illness in which the cartilaginous tissues such as auricles, nose, laryngotracheal structures, joints and others, are affected. Customary treatment is based on corticosteroids and traditional antiinflammatory agents including aspirin and indomethacin. We describe a case of relapsing polychondritis in an 82-year-old man with associated diabetes mellitus and special features treated successfully with alternative therapy based on methotrexate and celecoxib.

Resolution of Recalcitrant Uveitic Optic Disc Edema Following Administration of Methotrexate: Two Case Reports

PubMed Central

Kim, Mi Jeung; Park, Kyu Hyung; Lee, Yun Jong; Hwang, Jeong-Min

2012-01-01

A 13-year-old male and a 15-year-old female presented with optic disc edema associated with chronic recurrent uveitis. While the ocular inflammation responded to high doses of oral prednisolone, the disc edema showed little improvement. After oral administration of methotrexate, the disc edema and ocular inflammation were resolved, and the dose of oral corticosteroid could be reduced. PMID:22323889

Dietary polyphenols influence antimetabolite agents: methotrexate, 6-mercaptopurine and 5-fluorouracil in leukemia cell lines

PubMed Central

Mahbub, Amani; Le Maitre, Christine; Haywood-Small, Sarah; Cross, Neil; Jordan-Mahy, Nicola

2017-01-01

Polyphenols have been previously shown to sensitize leukemia cell lines to topoisomerase inhibitors. Here, we assess the effects of five polyphenols when used alone and in combination with antimetabolites: methotrexate, 6-mercaptopurine and 5-fluorouracil; in lymphoid and myeloid leukemia cells lines, and non-tumor control cells. The effects of combined treatments were investigated on ATP and glutathione levels, cell-cycle progression, DNA damage and apoptosis. Polyphenols antagonized methotrexate and 6-mercaptopurine induced cell-cycle arrest and apoptosis in most leukemia cell lines. This was associated with reduced DNA damage and increased glutathione levels, greater than that seen following individual treatments alone. In contrast, 5-fluorouracil when combined with quercetin, apigenin and rhein caused synergistic decrease in ATP levels, induction of cell-cycle arrest and apoptosis in some leukemia cell lines. However, antagonistic effects were observed when 5-fluorouracil was combined with rhein and cis-stilbene in myeloid cell lines. The effects were dependant on polyphenol type and chemotherapy agent investigated, and cell type treated. Interestingly treatment of non-tumor control cells with polyphenols protected cells from antimetabolite treatments. This suggests that polyphenols modulate the action of antimetabolite agents; more importantly they antagonized methotrexate and 6-mercaptopurine actions, thus suggesting the requirement of polyphenol-exclusion during their use. PMID:29285220

Methotrexate Induces Apoptosis in Organ-Cultured Nasal Polyps Via the Fas Pathway.

PubMed

Heo, Kyung Wook; Park, Seong Kook; Lee, Yeo Myeong; Choe, Si Hong; Gu, Pyung Mo; Hong, Tae Ui; Hur, Dae Young

2017-05-01

Methotrexate (MTX) is very effective when used to treat chronic inflammatory diseases, and also induces apoptosis in nasal polyps (NPs). Increasing evidence suggests that Fas-Fas ligand (FasL) interactions activate multiple pathways involved in the regulation of immune and inflammatory cell functions. The aim of the present study was to identify pathways activated by Fas signaling when NPs were treated with MTX. Nasal polyps tissues were cultured using an air-liquid interface organ culture method. Cultures were maintained in the absence or presence of MTX (10 or 100 μM) for 24 hours. The authors used the reverse transcription-polymerase chain reaction method and Western blotting to identify pathways activated by Fas when NPs were treated with MTX. The Fas mRNA expression ratio was unchanged upon MTX treatment, but the FasL mRNA expression ratio was significantly higher in MTX-treated than nontreated polyps. In addition, the expression levels of the Fas and FasL proteins were significantly higher in polyps treated with both 10 and 100 μM MTX compared with nontreated polyps. Methotrexate induces apoptosis in NPs via the Fas pathway. Future studies should explore the topical use of MTX for NP control. Methotrexate may be a useful alternative steroid-sparing agent for the treatment of NPs.

Life-threatening interaction between the root extract of Pueraria lobata and methotrexate in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chiang, H.-M.; Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan; Fang, S.-H.

2005-12-15

Isoflavone supplements are nowadays widely used as alternative for hormone replacement therapy. However, the safety remains unanswered. This study attempted to investigate the effect of Pueraria lobata root decoction (PLRD), an isoflavone-rich herb, on the pharmacokinetics of methotrexate (MTX), a bicarboxylate antimetabolite with narrow therapeutic window. Rats were orally and intravenously given methotrexate alone and coadministered with PLRD. Blood samples were withdrawn via cardiopuncture at specific time points after drug administration. Serum methotrexate concentrations were assayed by specific monoclonal fluorescence polarization immunoassay method. Pharmacokinetic parameters were calculated using noncompartment model of WINNONLIN for both oral and intravenous data of MTX.more » Our results showed that coadministration of 4.0 g/kg and 2.0 g/kg of PLRD significantly increased the AUC{sub 0-t} by 207.8% and 127.9%, prolonged the mean residence time (MRT) by 237.8 and 155.2%, respectively, finally resulted in surprisingly high mortalities of 57.1% and 14.3% in rats. When MTX was given intravenously, the coadministration of PLRD at 4.0 g/kg significantly increased the half-life by 53.9% and decreased the clearance by 47.9%. In conclusion, the coadministration of PLRD significantly decreased the elimination and resulted in markedly increased exposure of MTX in rats.« less

Inverse Correlation of Population Similarity and Introduction Date for Invasive Ascidians

PubMed Central

Silva, Nathan; Smith, William C.

2008-01-01

The genomes of many marine invertebrates, including the purple sea urchin and the solitary ascidians Ciona intestinalis and Ciona savignyi, show exceptionally high levels of heterozygosity, implying that these populations are highly polymorphic. Analysis of the C. savignyi genome found little evidence to support an elevated mutation rate, but rather points to a large population size contributing to the polymorphism level. In the present study, the relative genetic polymorphism levels in sampled populations of ten different ascidian species were determined using a similarity index generated by AFLP analysis. The goal was to determine the range of polymorphism within the populations of different species, and to uncover factors that may contribute to the high level of polymorphism. We observe that, surprisingly, the levels of polymorphism within these species show a negative correlation with the reported age of invasive populations, and that closely related species show substantially different levels of genetic polymorphism. These findings show exceptions to the assumptions that invasive species start with a low level of genetic polymorphism that increases over time and that closely related species have similar levels of genetic polymorphism. PMID:18575620

Efficacy and safety of adalimumab every other week versus methotrexate once weekly in children and adolescents with severe chronic plaque psoriasis: a randomised, double-blind, phase 3 trial.

PubMed

Papp, Kim; Thaçi, Diamant; Marcoux, Danielle; Weibel, Lisa; Philipp, Sandra; Ghislain, Pierre-Dominique; Landells, Ian; Hoeger, Peter; Kotkin, Carol; Unnebrink, Kristina; Seyger, Marieke; Williams, David

2017-07-01

Adalimumab is indicated for the treatment of moderate to severe psoriasis in adults. We assessed the efficacy and safety of adalimumab in children and adolescents with severe plaque psoriasis. This randomised, double-blind, multiperiod, phase 3 trial was done at 38 clinics in 13 countries. Patients (aged ≥4 to <18 years) with severe plaque psoriasis who had not responded to topical therapy were randomly assigned with an interactive voice or web-response system (1:1:1) to receive adalimumab 0·8 mg/kg or 0·4 mg/kg subcutaneously at week 0, then every other week starting at week 1, or oral methotrexate once weekly (0·1-0·4 mg/kg) for 16 weeks. Randomisation was stratified by history of etanercept treatment, with a block size of three. Responders were withdrawn from treatment (for up to 36 weeks) and re-treated with adalimumab (for 16 weeks) if disease became uncontrolled. Ranked primary efficacy endpoints were the proportion of patients who achieved at least 75% improvement from baseline in Psoriasis Area and Severity Index (PASI75) score and clear or minimal physician global assessment (PGA) score at week 16, comparing adalimumab 0·8 mg/kg with methotrexate. Efficacy analysis was by intention to treat, and safety analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01251614, and has been completed. Between Dec 14, 2010, and Feb 5, 2015, 114 patients were randomly assigned to adalimumab 0·8 mg/kg (n=38), adalimumab 0·4 mg/kg (n=39) or methotrexate (n=37). At week 16, PASI75 was achieved in 22 (58%) of 38 patients in the adalimumab 0·8 mg/kg group compared with 12 (32%) of 37 patients in the methotrexate group (p=0·027). 23 (61%) of 38 patients in the adalimumab 0·8 mg/kg group and 15 (41%) of 37 in the methotrexate group achieved clear or minimal PGA (p=0·083). In the adalimumab 0·4 mg/kg group, 17 (44%) of 39 patients achieved PASI75 and 16 (41%) achieved clear or minimal PGA. The most frequent adverse events were infections (17 [45%] of 38 in the adalimumab 0·8 mg/kg group during initial treatment; 22 [56%] of 39 in the adalimumab 0·4 mg/kg group; 21 [57%] of 37 in the methotrexate group). Three serious adverse events were reported, all in patients in the adalimumab 0·4 mg/kg group, and were not judged to be related to study drug. Treatment with adalimumab 0·8 mg/kg in children and adolescents with severe plaque psoriasis provided significant improvements in PASI75 and a non-significant increase in the proportion of patients who achieved clear or minimal PGA compared with methotrexate. No new safety risks were identified. AbbVie. Copyright © 2017 Elsevier Ltd. All rights reserved.

The investigation of epsilon toxin effects on different cancerous cell lines and its synergism effect with methotrexate.

PubMed

Shekarsaraei, Azin Gholami; Hasannia, Sadegh; Pirooznia, Nazanin; Ataiee, Fariba

2014-01-01

The overall goal of this study is to use a bacterial toxin as drug delivery agents for chemotherapy drugs and overcome the development of resistance to these medicines. COR-L105 and MDA-MB 231 which are epithelial-like were used in this study. Cytotoxicity assays were performed by 3-(4, 5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) as metabolic indicator. The toxin was essential to kill 50% (CT50) and IC 50 value (inhibition growth value) for methotrexate were determined as optical density at 540 nm. Epsilon toxin-loaded PLGA nanoparticles were prepared using non-aqueous technique. Surface morphology, in vitro drug release, and encapsulation efficiency of the nanoparticles was determined. Results confirmed that using non-toxic concentration of epsilon toxin, resistance to cancerous cell decreased significantly, which could be an important result in cancer therapy. The synergistic effect of MTX and epsilon toxin showed that bio toxins can be used as supplement with chemical drugs and increase the effect of chemotherapy. The results illustrated that application of PLGA as drug delivery system due to its controlled release properties was beneficial. These finding proposed that due to the ease of local accessibility of lung tumors with aerosol drug delivery, biotoxins can directly be used with chemotherapy drugs in aerosol form.

Drug loading and release on tumor cells using silk fibroin-albumin nanoparticles as carriers

NASA Astrophysics Data System (ADS)

Subia, B.; Kundu, S. C.

2013-01-01

Polymeric and biodegradable nanoparticles are frequently used in drug delivery systems. In this study silk fibroin-albumin blended nanoparticles were prepared using the desolvation method without any surfactant. These nanoparticles are easily internalized by the cells, reside within perinuclear spaces and act as carriers for delivery of the model drug methotrexate. Methotrexate loaded nanoparticles have better encapsulation efficiency, drug loading ability and less toxicity. The in vitro release behavior of methotrexate from the nanoparticles suggests that about 85% of the drug gets released after 12 days. The encapsulation and loading of a drug would depend on factors such as size, charge and hydrophobicity, which affect drug release. MTT assay and conjugation of particles with FITC demonstrate that the silk fibroin-albumin nanoparticles do not affect the viability and biocompatibility of cells. This blended nanoparticle, therefore, could be a promising nanocarrier for the delivery of drugs and other bioactive molecules.

Interaction of anticancer drug methotrexate with nucleic acids analyzed by multi-spectroscopic method

NASA Astrophysics Data System (ADS)

Cai, Changqun; Chen, Xiaoming; Gong, Hang

2009-02-01

Methotrexate (MTX) as an antifolate, which is widely used as chemotherapeutic drugs. A high-dose MTX therapy has a direct toxicity influence on the non-germinal cells, especially the liver cells. It is known that the inject dose for adults is 10-30 mg and is half for children for routine use, while our experiments showed that the optimum dosage of MTX which enhanced the RLS intensities to the maximum is 4.54 ng ml -1. The interaction of methotrexate (MTX) with nucleic acids in aqueous solution in the presence of cetyltrimethylammonium bromide (CTMAB), a kind of cationic surfactant similar to the Human cells, were investigated based on the measurements of resonance light scattering (RLS), UV-vis, fluorescence and NMR spectra, etc. The interaction has been proved to give a ternary complex of MTX-CTMAB-DNA in BR buffer (pH 9.30), which exhibits strong enhanced RLS signals at 339.5 nm.

Genetically-determined polymorphism of nonspecific esterases and phosphoglucomutase in eight introduced breeds of the silkworm, Bombyx mori, raised in Bulgaria.

PubMed

Staykova, Teodora

2008-01-01

Isoenzymes are very suitable markers for the study of the inter-breed diversity of the silkworm Bombyx mon L. (Lepidoptera: Bombycidae). More than 250 breeds are raised in Bulgaria, which are not very well studied with regard to their isoenzymic polymorphism. Polymorphism of nonspecific esterases from pupal haemolymph was analyzed, as well as of phosphoglucomutase from different organs of larvae, pupae and imago, from eight introduced breeds. Electrophoresis in polyacrylamide gels was used. A polylocus control of nonspecific esterases, and possible monolocus control of phosphoglucomutase was ascertained. Biallele and triallele polymorphism of phosphoglucomutase locus and in three of the esterase loci was determined. The allelic frequencies of the polymorphic loci in each breed were analyzed. Inter-breed differences were found in different allelic frequencies, different heterozygosity and polymorphism.

Physiologically based pharmacokinetic modelling of methotrexate and 6-mercaptopurine in adults and children. Part 2: 6-mercaptopurine and its interaction with methotrexate.

PubMed

Ogungbenro, Kayode; Aarons, Leon

2014-04-01

6-mercaptopurine (6-MP) is a purine antimetabolite and prodrug that undergoes extensive intracellular metabolism to produce thionucleotides, active metabolites which have cytotoxic and immunosuppressive properties. Combination therapies involving 6-MP and methotrexate have shown remarkable results in the cure of childhood acute lymphoblastic leukaemia (ALL) in the last 30 years. 6-MP undergoes very extensive intestinal and hepatic metabolism following oral dosing due to the activity of xanthine oxidase leading to very low and highly variable bioavailability and methotrexate has been demonstrated as an inhibitor of xanthine oxidase. Despite the success recorded in the use of 6-MP in ALL, there is still lack of effect and life threatening toxicity in some patients due to variability in the pharmacokinetics of 6-MP. Also, dose adjustment during treatment is still based on toxicity. The aim of the current work was to develop a mechanistic model that can be used to simulate trial outcomes and help to improve dose individualisation and dosage regimen optimisation. A physiological based pharmacokinetic model was proposed for 6-MP, this model has compartments for stomach, gut lumen, enterocyte, gut tissue, spleen, liver vascular, liver tissue, kidney vascular, kidney tissue, skin, bone marrow, thymus, muscle, rest of body and red blood cells. The model was based on the assumption of the same elimination pathways in adults and children. Parameters of the model include physiological parameters and drug-specific parameter which were obtained from the literature or estimated using plasma and red blood cell concentration data. Age-dependent changes in parameters were implemented for scaling and variability was also introduced on the parameters for prediction. Inhibition of 6-MP first-pass effect by methotrexate was implemented to predict observed clinical interaction between the two drugs. The model was developed successfully and plasma and red blood cell concentrations were adequately predicted both in terms of mean prediction and variability. The predicted interaction between 6-MP and methotrexate was slightly lower than the reported clinical interaction between the two drugs. The model can be used to predict plasma and tissue concentration in adults and children following oral and intravenous dosing and may ultimately help to improve treatment outcome in childhood ALL patients.

Outpatient endometrial aspiration: an alternative to methotrexate for pregnancy of unknown location.

PubMed

Insogna, Iris G; Farland, Leslie V; Missmer, Stacey A; Ginsburg, Elizabeth S; Brady, Paula C

2017-08-01

Pregnancies of unknown location with abnormal beta-human chorionic gonadotropin trends are frequently treated as presumed ectopic pregnancies with methotrexate. Preliminary data suggest that outpatient endometrial aspiration may be an effective tool to diagnose pregnancy location, while also sparing women exposure to methotrexate. The purpose of this study was to evaluate the utility of an endometrial sampling protocol for the diagnosis of pregnancies of unknown location after in vitro fertilization. A retrospective cohort study of 14,505 autologous fresh and frozen in vitro fertilization cycles from October 2007 to September 2015 was performed; 110 patients were diagnosed with pregnancy of unknown location, defined as a positive beta-human chorionic gonadotropin without ultrasound evidence of intrauterine or ectopic pregnancy and an abnormal beta-human chorionic gonadotropin trend (<53% rise or <15% fall in 2 days). These patients underwent outpatient endometrial sampling with Karman cannula aspiration. Patients with a beta-human chorionic gonadotropin decline ≥15% within 24 hours of sampling and/or villi detected on pathologic analysis were diagnosed with failing intrauterine pregnancy and had weekly beta-human chorionic gonadotropin measurements thereafter. Those patients with beta-human chorionic gonadotropin declines <15% and no villi identified were diagnosed with ectopic pregnancy and treated with intramuscular methotrexate (50 mg/m 2 ) or laparoscopy. Across 8 years of follow up, among women with pregnancy of unknown location, failed intrauterine pregnancy was diagnosed in 46 patients (42%), and ectopic pregnancy was diagnosed in 64 patients (58%). Clinical variables that included fresh or frozen embryo transfer, day of embryo transfer, serum beta-human chorionic gonadotropin at the time of sampling, endometrial thickness, and presence of an adnexal mass were not significantly different between patients with failed intrauterine pregnancy or ectopic pregnancy. In patients with failed intrauterine pregnancy, 100% demonstrated adequate postsampling beta-human chorionic gonadotropin declines; villi were identified in just 46% (n=21 patients). Patients with failed intrauterine pregnancy had significantly shorter time to resolution (negative serum beta-human chorionic gonadotropin) after sampling compared with patients with ectopic pregnancy (12.6 vs 26.3 days; P<.001). With the use of this safe and effective protocol of endometrial aspiration with Karman cannula, a large proportion of women with pregnancy of unknown location are spared methotrexate, with a shorter time to pregnancy resolution than those who receive methotrexate. Copyright © 2017 Elsevier Inc. All rights reserved.

A novel analytical method for pharmaceutical polymorphs by terahertz spectroscopy and the optimization of crystal form at the discovery stage.

PubMed

Ikeda, Yukihiro; Ishihara, Yoko; Moriwaki, Toshiya; Kato, Eiji; Terada, Katsuhide

2010-01-01

A novel analytical method for the determination of pharmaceutical polymorphs was developed using terahertz spectroscopy. It was found out that each polymorph of a substance showed a specific terahertz absorption spectrum. In particular, analysis of the second derivative spectrum was enormously beneficial in the discrimination of closely related polymorphs that were difficult to discern by powder X-ray diffractometry. Crystal forms that were obtained by crystallization from various solvents and stored under various conditions were specifically characterized by the second derivative of each terahertz spectrum. Fractional polymorphic transformation for substances stored under stressed conditions was also identified by terahertz spectroscopy during solid-state stability test, but could not be detected by powder X-ray diffractometry. Since polymorphs could be characterized clearly by terahertz spectroscopy, further physicochemical studies could be conducted in a timely manner. The development form of compound examined was determined by the results of comprehensive physicochemical studies that included thermodynamic relationships, as well as chemical and physicochemical stability. In conclusion, terahertz spectroscopy, which has unique power in the elucidation of molecular interaction within a crystal lattice, can play more important role in physicochemical research. Terahertz spectroscopy has a great potential as a tool for polymorphic determination, particularly since the second derivative of the terahertz spectrum possesses high sensitivity for pharmaceutical polymorphs.

Assessment of the rs4340 ACE gene polymorphism in acute coronary syndrome in a Western Mexican population.

PubMed

Valdez-Haro, A; Valle, Y; Valdes-Alvarado, E; Casillas-Muñoz, F; Muñoz-Valle, J F; Reynoso-Villalpando, G L; Flores-Salinas, H E; Padilla-Gutiérrez, J R

2017-09-27

Acute coronary syndrome (ACS) is considered one of the main causes of death worldwide. Contradictory findings concerning the impact of the angiotensin-converting enzyme (ACE) gene on cardiovascular diseases have been reported. Previous conclusions point out that the variability in results depends on ethnicity and genetic polymorphisms to determine the association of rs4340 polymorphisms of the ACE gene and ACE circulating levels in ACS. Genotyping of rs4340 polymorphisms was performed in a total of 600 individuals from Western Mexico divided into two groups: the ACS and the control group (CG). The polymorphisms were identified by polymerase chain reaction. Serum ACE concentration was determined by enzyme-linked immunosorbent assay. D/D carriers had higher ACE levels than I/I carriers (3.6 vs 2.8 ng/mL, P < 0.0021) in the CG. The D/D genotype of the rs4340 polymorphism is associated with higher ACE concentration levels; however, the polymorphism was not associated with ACS.

Fatal chickenpox pneumonia in an asthmatic patient on oral steroids and methotrexate.

PubMed Central

Gatnash, A. A.; Connolly, C. K.

1995-01-01

A 49 year old man with a long history of severe chronic asthma, treated with oral corticosteroids and weekly doses of methotrexate, contracted chickenpox from his son whose chickenpox rash had developed three weeks before presentation. Five days before admission the patient developed a vesicular skin rash which became extensive, with general malaise, bilateral pneumonia, and acute deterioration of his asthma. He died two weeks after admission despite treatment with acyclovir. Images PMID:7785019

Splenic Pregnancy: A New Minimally Invasive Approach to Treatment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Klang, Eyal, E-mail: eyalkla@hotmail.com; Keddel, Nicholas; Inbar, Yael

The spleen is a rare site of abdominal ectopic pregnancy. In a review of the literature, we found 16 published cases of primary splenic pregnancies. Of the cases identified, all received surgical intervention, with one case successfully treated with laparoscopic methotrexate injection, and the rest underwent splenectomy. We would like to present a case of primary splenic pregnancy in a 35-year-old woman successfully treated with percutaneous image-guided injection of methotrexate and KCl.

Exploring Virtual Worlds with Head-Mounted Displays

DTIC Science & Technology

1989-02-01

docking problem is important both to biochemists attempting to understand how proteins and nucleic acids work, and to chemists doing analytic drug design...then depressing the mouse button he is able to manipulate the methotrexate. A. long as the mouse button is depressed the methotrexate will follow the... depressing the mouse button outside of the drug’s "grabbing" volume. In this mode, both molecules move in concert. When the active site is positioned to

Modifying mesoporous silica nanoparticles to avoid the metabolic deactivation of 6-mercaptopurine and methotrexate in combinatorial chemotherapy.

PubMed

Wang, Wenjing; Fang, Chenjie; Wang, Xiaozhu; Chen, Yuxi; Wang, Yaonan; Feng, Wei; Yan, Chunhua; Zhao, Ming; Peng, Shiqi

2013-07-21

Mesoporous silica nanoparticles with amino and thiol groups (MSNSN) were prepared and covalently modified with methotrexate and 6-mercaptopurine to form 6-MP-MSNSN-MTX. In the presence of DTT, 6-MP-MSNSN-MTX gradually releases 6-MP. In rat plasma, 6-MP-MSNSN-MTX effectively inhibits the metabolic deactivation of 6-MP and MTX. 6-MP-MSNSN-MTX could be an agent for long-acting chemotherapy.

Annual Progress Report FY 93 (Walter Reed Army Medical Center, Department of Clinical Investigation). Clinical Investigation Program. Volume 2

DTIC Science & Technology

1993-01-01

Effect of Methotrexate on Expression of Interceilular Adhesion Molecule I in Interleukin- 1 Stimulated Cultured Human Cells KEYWORDS: methotrexate...on interleukin- 1 ( IL -I) induced ICAM-l expression in cultured human fibroblasts and adenocarcinoma cells. TECHNICAL APPROACH Expression of ICAM- 1 will...incubated with IL -l to stimulate ICAM-l expression. In general, the cells responded well. ICAM- 1 was readily detectable with monoclonal antibodies and flow

Increased sensitivity to apoptosis induced by methotrexate is mediated by Jun N-terminal kinase

PubMed Central

Spurlock, Charles F.; Aune, Zachary T.; Tossberg, John T.; Collins, Patrick L.; Aune, Jessica P.; Huston, Joseph W.; Crooke, Philip S.; Olsen, Nancy J.; Aune, Thomas M.

2011-01-01

Objective Low-dose methotrexate [MTX] is an effective therapy for rheumatoid arthritis yet its mechanism of action is incompletely understood. Here, we explored induction of apoptosis by MTX. Methods We employed flow cytometry to assess changes in levels of intracellular proteins, reactive oxygen species [ROS], and apoptosis.Quantitative polymerase chain reaction was usedtoassess changes in transcript levels of select target genes in response to MTX. Results MTX does not directly induce apoptosis but rather ‘primes’ cells for markedly increased sensitivity to apoptosis via either mitochondrial or death receptor pathways by a Jun N-terminal kinase [JNK]-dependent mechanism. Increased sensitivity to apoptosis is mediated, at least in part, by MTX-dependent production of reactive oxygen species, JNK activation and JNK-dependent induction of genes whose protein products promote apoptosis. Supplementation with tetrahydrobiopterin blocks these methotrexate-induced effects. Subjects with rheumatoid arthritis on low-dose MTX therapy express elevated levels of the JNK-target gene, JUN. Conclusions Our results support a model whereby methotrexate inhibits reduction of dihydrobiopterin to tetrahydrobiopterin resulting in increased production of ROS, increased JNK activity and increased sensitivity to apoptosis. The finding of increased JUN levels in subjects with RA taking low-dose MTX supports the notion that this pathway is activated by MTX, in vivo, and may contribute to efficacy of MTX in inflammatory disease. PMID:21618198

Does methotrexate administration for ectopic pregnancy after in vitro fertilization impact ovarian reserve or ovarian responsiveness?

PubMed

Boots, Christina E; Gustofson, Robert L; Feinberg, Eve C

2013-12-01

To evaluate the effects of methotrexate (MTX) on the future fertility of women undergoing IVF by comparing ovarian reserve and ovarian responsiveness in the IVF cycle before and after an ectopic pregnancy (EP) treated with MTX. Retrospective cohort study. Private reproductive endocrinology and infertility practice. Sixty-six women undergoing IVF before and after receiving MTX for an EP. Methotrexate administration and ovarian stimulation. Markers of ovarian reserve (day 3 FSH, antral follicle count), measures of ovarian responsiveness (duration of stimulation, peak E2 level, total dose of gonadotropins, number of oocytes retrieved, fertilization rate), and time from MTX administration to subsequent IVF cycle. There were no differences after MTX administration in body mass index (BMI), FSH, or antral follicle count. A greater dose of gonadotropins was used in the cycle after MTX, but there were no differences in numbers of oocytes retrieved or high quality embryos transferred. As expected, there was a slight increase in age in the subsequent IVF cycle. The pregnancy rates (PR) were comparable to the average PRs within the practice when combining all age groups. Methotrexate remains the first line of therapy for medical management of asymptomatic EP and does not compromise ovarian reserve, ovarian responsiveness, or IVF success in subsequent cycles. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Therapeutic Efficacy of Orally Delivered Doxorubicin Nanoparticles in Rat Tongue Cancer Induced by 4-Nitroquinoline 1-Oxide.

PubMed

Moradzadeh Khiavi, Monir; Rostami, Ahamd; Hamishekar, Hamed; Mesgari Abassi, Mehran; Aghbali, Amirala; Salehi, Roya; Abdollahi, Bita; Fotoohi, Soheila; Sina, Mahmud

2015-06-01

Oral cancer is one of the most significant cancers in the world, and squamous cell carcinoma makes up about 94% of oral malignancies. The aim of the present study was to compare the efficacy of doxorubicin plus methotrexate - loaded nanoparticles on tongue squamous cell carcinoma induced by 4NQO and compare it with the commercial doxorubicin and methotrexate delivered orally on seventy SD male rats. 70 rats were divided into five groups. During the study, the animals were weighed by a digital scale once a week. Number of mortalities was recorded in the data collection forms. At the end of the treatment, biopsy samples were taken from rat tongues in order to evaluate the severity of dysplasia and the extent of cell proliferation. The results were analyzed using ANOVA, descriptive statistics and chi-square test. No statistically significant difference was found in the mean weight of five groups (p>0.05). No significant relationship was found between groups and mortality rate (P = 0. 39). In addition, there was a significant relationship between groups and the degree of dysplasia (P <0.001). The statistical analysis showed a significant relationship between groups and the rate of cell proliferation (p <0.001). The results of the present study showed that the use of doxorubicin plus methotrexate - loaded nanoparticles orally had more therapeutic effects than commercial doxorubicin plus methotrexate.

DNA polymorphism identity determination using flow cytometry

DOEpatents

Nolan, John P.; White, P. Scott; Cai, Hong

2001-01-01

DNA polymorphism identity determination using flow cytometry. Primers designed to be immobilized on microspheres are allowed to anneal to the DNA strand under investigation, and are extended by either DNA polymerase using fluorescent dideoxynucleotides or ligated by DNA ligase to fluorescent reporter oligonucleotides. The fluorescence of either the dideoxynucleotide or the reporter oligonucleotide attached to the immobilized primer is measured by flow cytometry, thereby identifying the nucleotide polymorphism on the DNA strand.

Lack of Association Between Polymorphisms in Dopa Decarboxylase and Dopamine Receptor-1 Genes With Childhood Autism in Chinese Han Population.

PubMed

Yu, Hong; Liu, Jun; Yang, Aiping; Yang, Guohui; Yang, Wenjun; Lei, Heyue; Quan, Jianjun; Zhang, Zengyu

2016-04-01

Genetic factors play an important role in childhood autism. This study is to determine the association of single-nucleotide polymorphisms in dopa decarboxylase (DDC) and dopamine receptor-1 (DRD1) genes with childhood autism, in a Chinese Han population. A total of 211 autistic children and 250 age- and gender-matched healthy controls were recruited. The severity of disease was determined by Children Autism Rating Scale scores. TaqMan Probe by real-time polymerase chain reaction was used to determine genotypes and allele frequencies of single-nucleotide polymorphism rs6592961 in DDC and rs251937 in DRD1. Case-control and case-only studies were respectively performed, to determine the contribution of both single-nucleotide polymorphisms to the predisposition of disease and its severity. Our results showed that there was no significant association of the genotypes and allele frequencies of both single-nucleotide polymorphisms concerning childhood autism and its severity. More studies with larger samples are needed to corroborate their predicting roles. © The Author(s) 2015.

SdsA polymorph isolation and improvement of their crystal quality using nonconventional crystallization techniques

DOE Office of Scientific and Technical Information (OSTI.GOV)

De la Mora, Eugenio; Flores-Hernández, Edith; Jakoncic, Jean

SdsA, a sodium dodecyl sulfate hydrolase, from Pseudomonas aeruginosa was crystallized in three different crystal polymorphs and their three-dimensional structure was determined. The different polymorphs present different crystal packing habits. One of the polymorphs suggests the existence of a tetramer, an oligomeric state not observed previously, while the crystal packing of the remaining two polymorphs obstructs the active site entrance but stabilizes flexible regions of the protein. Nonconventional crystallization methods that minimize convection, such as counterdiffusion in polyvinyl alcohol gel coupled with the influence of a 500 MHz (10.2 T) magnetic field, were necessary to isolate the poorest diffracting polymorphmore » and increase its internal order to determine its structure by X-ray diffraction. In conclusion, the results obtained show the effectiveness of nonconventional crystallographic methods to isolate different crystal polymorphs.« less

Significance of 5,10-methylenetetrahydrofolate reductase gene variants in acute lymphoblastic leukemia in Indian population: an experimental, computational and meta-analysis.

PubMed

Bellampalli, Ravishankara; Phani, Nagaraja M; Bhat, Kamalakshi G; Prasad, Krishna; Bhaskaranand, Nalini; Guruprasad, Kanive P; Rai, Padmalatha S; Satyamoorthy, Kapaettu

2015-05-01

Acute lymphoblastic leukemia (ALL) arises due to several genetic alterations in progenitor cells, and methotrexate is frequently used as part of the treatment regimen. Although there is evidence for an effect of 5,10-methylenetetrahydrofolate reductase gene (MTHFR) C677T and A1298C variations on drug response in ALL, its risk association for ALL is still unresolved. In a case-control study of 203 patients with ALL and 246 controls and meta-analysis in the Indian population, we showed an insignificant association of MTHFR C677T and A1298C genotypes with childhood and adult ALL. Comprehensive in silico characterization of non-synonymous single nucleotide polymorphisms (nsSNPs) and SNPs of the 3' untranslated region (UTR) revealed nine nsSNPs as deleterious, and three SNPs in the 3'UTR could possibly alter the binding of miRNAs. The study revealed that several overlooked SNPs may contribute to the risk of ALL susceptibility and further studies of these SNPs with functional characterization in a large sample size are required to understand the significant role of MTHFR in ALL development.

FcγRIIIa Expression on Monocytes in Rheumatoid Arthritis: Role in Immune-Complex Stimulated TNF Production and Non-Response to Methotrexate Therapy

PubMed Central

Cooper, Dawn L.; Martin, Stephen G.; Robinson, James I.; Mackie, Sarah L.; Charles, Christopher J.; Nam, Jackie; Consortium, YEAR; Isaacs, John D.; Emery, Paul; Morgan, Ann W.

2012-01-01

Objective The expression of FcγRIIIa/CD16 may render monocytes targets for activation by IgG-containing immune complexes (IC). We investigated whether FcγRIIIa/CD16 was upregulated in rheumatoid arthritis (RA), associated with TNF production in response to IC-stimulation, and if this predicted response to methotrexate therapy. Methods FcγRIIIa/CD16 expression on CD14low and CD14++ monocytes was measured by flow cytometry in healthy controls and RA patients (early and long-standing disease). Intracellular TNF-staining was carried out after in vitro LPS or heat-aggregated immunoglobulin (HAG) activation. FcγRIIIa/CD16 expression pre- and post-steroid/methotrexate treatment was examined. Results Increased FcγRIIIa/CD16 expression on CD14++ monocytes in long-standing RA patients compared to controls was demonstrated (p = 0.002) with intermediate levels in early-RA patients. HAG-induced TNF-production in RA patients was correlated with the percentage of CD14++ monocytes expressing FcγRIIIa/CD16 (p<0.001). The percentage of CD14++ monocytes expressing FcγRIIIa/CD16 at baseline in early DMARD-naïve RA patients was negatively correlated with DAS28-ESR improvement 14-weeks post-methotrexate therapy (p = 0.003) and was significantly increased in EULAR non-responders compared to moderate (p = 0.01) or good responders (p = 0.003). FcγRIIIa/CD16 expression was not correlated with age, presence of systemic inflammation or autoantibody titers. Conclusion Increased FcγRIIIa/CD16 expression on CD14++ monocytes in RA may result in a cell that has increased responsiveness to IC-stimulation. This monocyte subset may contribute to non-response to methotrexate therapy. PMID:22235253

A randomized trial comparing methotrexate and vinblastine (MV) with cisplatin, methotrexate and vinblastine (CMV) in advanced transitional cell carcinoma: results and a report on prognostic factors in a Medical Research Council study. MRC Advanced Bladder Cancer Working Party.

PubMed Central

Mead, G. M.; Russell, M.; Clark, P.; Harland, S. J.; Harper, P. G.; Cowan, R.; Roberts, J. T.; Uscinska, B. M.; Griffiths, G. O.; Parmar, M. K.

1998-01-01

Transitional cell carcinomas may arise at any site within the urinary tract and are a source of considerable morbidity and mortality. In particular, patients with metastatic disease have a poor prognosis, with less than 5% alive at 5 years. A multicentre randomized trial comparing methotrexate and vinblastine (MV) with cisplatin, methotrexate and vinblastine (CMV) in advanced or metastatic transitional cell carcinoma was conducted in the UK. From April 1991 to June 1995, 214 patients were entered by 16 centres, 108 randomized to CMV and 106 to MV. A total of 204 patients have died. The hazard ratio (relative risk of dying) was 0.68 (95% CI 0.51-0.90, P-value = 0.0065) in favour of CMV. This translates to an absolute improvement in 1-year survival of 13%, 16% in MV and 29% in CMV. The median survival for CMV and MV was 7 months and 4.5 months respectively. Two hundred and eight patients objectively progressed or died. The hazard ratio was 0.55 (95% CI 0.41-0.73, P-value = 0.0001) in favour of CMV. Two hundred and nine patients symptomatically progressed or died. The hazard ratio was 0.48 (95% CI 0.36-0.64, P-value = 0.0001) in favour of CMV. The most important pretreatment factors influencing overall survival were WHO performance status and extent of disease. These two factors were used to derive a prognostic index which could be used to categorize patients into three prognostic groups. We conclude that the addition of cisplatin to methotrexate and vinblastine should be considered in patients with transitional cell carcinoma, taking into account the increased toxicity. PMID:9792152

Prognostic factors for primary central nervous system lymphomas treated with high-dose methotrexate-based chemo-radiotherapy.

PubMed

Lee, Jeunghun; Shishido-Hara, Yukiko; Suzuki, Kaori; Shimizu, Saki; Kobayashi, Keiichi; Kamma, Hiroshi; Shiokawa, Yoshiaki; Nagane, Motoo

2017-10-01

Primary central nervous system lymphoma (PCNSL) remains an aggressive and refractory tumor despite high-dose methotrexate-based chemo-radiotherapy. Age and performance status have been shown to be important clinical prognostic factors, however others, especially molecular factors, affecting the prognosis are still uncertain. We investigate clinical, neuroimaging and immunohistochemical data in tissue from 41 PCNSL patients treated primarily with methotrexate-based chemo-radiotherapy and evaluate the influence of potential prognostic factors on clinical outcome as well as correlation among these factors. Median progression-free survival (PFS) and overall survival (OS) were 29 and 73 months, respectively. Expression of the mismatch repair (MMR) proteins, MLH1, MSH2, MSH6 and PMS2, correlated tightly with each other and high expression of MSH2 was significantly associated with better OS and PFS (P = 0.005 and P = 0.007), while methotrexate metabolism-related proteins did not affect survival. In addition, low expression of PMS2 was an independent predictor of methotrexate resistance (P = 0.039). Among neuroimaging findings, involvement of the fornix and tegmentum/velum were significantly associated with poorer OS (P < 0.001 and P = 0.013) and PFS (P = 0.014 and P = 0.043, respectively). Germinal center B cell (GCB)-PCNSL subtype as opposed to non-GCB subtype, tended toward better survival. Regarding oncogenes, cMYC-positive cases showed unfavorable OS (P = 0.046). By multivariate analysis, MSH2 and involvement of the fornix were independent predictors for both OS and PFS, whereas tegmentum/velum location and cMYC expression were significantly associated with OS. Although further studies are needed, these results suggest that MMR protein expression, as well as specific deep locations and cMYC expression, may be a novel prognostic and predictive markers for PCNSL. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphisms as determinants for elevated total homocysteine concentrations in pregnant women.

PubMed

Barbosa, P R; Stabler, S P; Machado, A L K; Braga, R C; Hirata, R D C; Hirata, M H; Sampaio-Neto, L F; Allen, R H; Guerra-Shinohara, E M

2008-08-01

To examine the association between methylenetetrahydrofolate reductase (MTHFR) (C677T and A1298C), methionine synthase (MTR) A2756G and methionine synthase reductase (MTRR) A66G gene polymorphisms and total homocysteine (tHcy), methylmalonic acid (MMA) and S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) levels; and to evaluate the potential interactions with folate or cobalamin (Cbl) status. Two hundred seventy-five healthy women at labor who delivered full-term normal babies. Cbl, folate, tHcy, MMA, SAM and SAH were measured in serum specimens. The genotypes for polymorphisms were determined by PCR-restriction fragment length polymorphism (RFLP). Serum folate, MTHFR 677T allele and MTR 2756AA genotypes were the predictors of tHcy levels in pregnant women. Serum Cbl and creatinine were the predictors of SAM/SAH ratio and MMA levels, respectively. The gene polymorphisms were not determinants for MMA levels and SAM/SAH ratios. Low levels of serum folate were associated with elevated tHcy in pregnant women, independently of the gene polymorphisms. In pregnant women carrying MTHFR 677T allele, or MTHFR 1298AA or MTRR 66AA genotypes, lower Cbl levels were associated with higher levels of tHcy. Lower SAM/SAH ratio was found in MTHFR 677CC or MTRR A2756AA genotypes carriers when Cbl levels were lower than 142 pmol/l. Serum folate and MTHFR C677T and MTR A2576G gene polymorphisms were the determinants for tHcy levels. The interaction between low levels of serum Cbl and MTHFR (C677T or A1298C) or MTRR A66G gene polymorphisms was associated with increased tHcy.

Anionic clay as the drug delivery vehicle: tumor targeting function of layered double hydroxide-methotrexate nanohybrid in C33A orthotopic cervical cancer model

PubMed Central

Choi, Goeun; Piao, Huiyan; Alothman, Zeid A; Vinu, Ajayan; Yun, Chae-Ok; Choy, Jin-Ho

2016-01-01

Methotrexate (MTX), an anticancer agent, was successfully intercalated into the anionic clay, layered double hydroxides to form a new nanohybrid drug. The coprecipitation and subsequent hydrothermal method were used to prepare chemically, structurally, and morphologically well-defined two-dimensional drug-clay nanohybrid. The resulting two-dimensional drug-clay nanohybrid showed excellent colloidal stability not only in deionized water but also in an electrolyte solution of Dulbecco’s Modified Eagle’s Medium with 10% fetal bovine serum, in which the average particle size in colloid and the polydispersity index were determined to be around 100 and 0.250 nm, respectively. The targeting property of the nanohybrid drug was confirmed by evaluating the tumor-to-blood and tumor-to-liver ratios of the MTX with anionic clay carrier, and these ratios were compared to those of free MTX in the C33A orthotopic cervical cancer model. The biodistribution studies indicated that the mice treated with the former showed 3.5-fold higher tumor-to-liver ratio and fivefold higher tumor-to-blood ratio of MTX than those treated with the latter at 30 minutes postinjection. PMID:26855572

CSF drug levels for children with acute lymphoblastic leukemia treated by 5 g/m2 methotrexate. A study from the EORTC Children's Leukemia Cooperative Group.

PubMed

Milano, G; Thyss, A; Serre Debeauvais, F; Laureys, G; Benoit, Y; Deville, A; Dutour, C; Robert, A; Otten, J; Behar, C

1990-04-01

A multicenter EORTC study was conducted in children with acute lymphocytic leukemia to determine whether 5 g/m2 of methotrexate (MTX) (24 h i.v. infusion, four cycles) is an appropriate dosage for obtaining CSF drug concentrations approaching the critical cytotoxic level of 10(-6) M. A total of 193 cycles were analyzed for 58 patients. At the end of the 24 h infusion, the mean MTX serum level was 65.27 +/- 33.11 microM; the mean CSF MTX level was 1.47 +/- 1.1 microM; no significant difference in CSF MTX levels was observed between patients with (n = 20) and those without i.v. Ara-C (n = 38). The mean CSF MTX/serum MTX ratio was 0.029 +/- 0.027. CSF drug concentrations greater than or equal to 10(-6) M were achieved in 81% of the courses. The highest level was 8.4 X 10(-6) M. Only 5% of patients failed to achieve this drug concentration in at least one cycle. No significant correlation was observed between blood and CSF MTX levels. Mean CSF MTX levels were comparable from one cycle to another.

Supramolecular interaction of methotrexate with cucurbit[7]uril and analytical application

NASA Astrophysics Data System (ADS)

Chang, Yin-Xia; Zhang, Xiang-Mei; Duan, Xue-Chao; Liu, Fan; Du, Li-Ming

2017-08-01

The supramolecular interaction between cucurbit[7]uril (CB[7]) as the host and the anti-cancer drug methotrexate (MTX) as the guest was studied using fluorescence spectroscopy, UV-visible absorption spectroscopy, 1H NMR, 2D NOESY, and theoretical calculations. The experimental results confirmed the formation of 1:2 inclusion complex with CB[7] and indicated a simple and sensitive competitive method for the fluorescence detection of MTX. It was found that the fluorescence intensities of CB[7]-palmatine, CB[7]-berberine and CB[7]-coptisine were quenched linearly upon the addition of MTX. The linear ranges obtained in the detection of MTX were 0.1-15 μg mL- 1, 0.2-15 μg mL- 1, and 0.4-15 μg mL- 1 with detection limits of 0.03 μg mL-1, 0.06 μg mL-1, and 0.13 μg mL-1, respectively. This method can be used for the determination of MTX in biological fluids. These results suggested that cucurbit[7]uril is a promising drug carrier for targeted MTX delivery and monitoring, with improved efficacy and reduced toxicity in normal tissues.

Sugarcane bagasse lignin, and silica gel and magneto-silica as drug vehicles for development of innocuous methotrexate drug against rheumatoid arthritis disease in albino rats.

PubMed

Wahba, Sanaa M R; Darwish, Atef S; Shehata, Iman H; Abd Elhalem, Sahar S

2015-03-01

The present study clarifies co-therapy action of deliveries from their textural changes point of view. Methotrexate (MTX) was immobilized onto biodegradable lignin, silica gel and iron/silica nanocomposite. Loaded-MTX was i.p. injected into albino rats at doses of 0.25 and 0.5mg/kg/week for 2.5months, after which spleen, liver, testes and knee joint tissues were collected for tests. IFN-γ and IL-17A mRNA gene expressions in spleen in all biological samples were determined by RT-PCR. Physicochemical features of drug carriers were monitored by XRD, BET-PSD, SEM and TEM. Drug inflammatory-site targeting was found to be closely related to the physico-features of deliverers. The interlayered lignin of micro- and meso-pore channels directed MTX toward concealed infected cells in liver and testes tissues, while meso-structured silica flacks satisfied by gathering MTX around knee joints. The magneto-silica nanocomposite targeted MTX toward spleen tissue, which is considered as a lively factory for the production of electron rich compounds. Copyright © 2014 Elsevier B.V. All rights reserved.

Anionic clay as the drug delivery vehicle: tumor targeting function of layered double hydroxide-methotrexate nanohybrid in C33A orthotopic cervical cancer model.

PubMed

Choi, Goeun; Piao, Huiyan; Alothman, Zeid A; Vinu, Ajayan; Yun, Chae-Ok; Choy, Jin-Ho

2016-01-01

Methotrexate (MTX), an anticancer agent, was successfully intercalated into the anionic clay, layered double hydroxides to form a new nanohybrid drug. The coprecipitation and subsequent hydrothermal method were used to prepare chemically, structurally, and morphologically well-defined two-dimensional drug-clay nanohybrid. The resulting two-dimensional drug-clay nanohybrid showed excellent colloidal stability not only in deionized water but also in an electrolyte solution of Dulbecco's Modified Eagle's Medium with 10% fetal bovine serum, in which the average particle size in colloid and the polydispersity index were determined to be around 100 and 0.250 nm, respectively. The targeting property of the nanohybrid drug was confirmed by evaluating the tumor-to-blood and tumor-to-liver ratios of the MTX with anionic clay carrier, and these ratios were compared to those of free MTX in the C33A orthotopic cervical cancer model. The biodistribution studies indicated that the mice treated with the former showed 3.5-fold higher tumor-to-liver ratio and fivefold higher tumor-to-blood ratio of MTX than those treated with the latter at 30 minutes postinjection.

Cheilitis granulomatosa associated with lupus erythematosus discoid and treated with methotrexate: report of a case*

PubMed Central

Nazzaro, Gianluca; Muratori, Simona; Carrera, Carlo Giovanni; Coggi, Antonella; Gianotti, Raffaele

2015-01-01

We present the rare case of a 47-year-old patient, suffering from cheilitis granulomatosa and lupus erythematosus discoid: this association is really exceptional because only once reported in English literature. In addition, the treatment of cheilitis granulomatosa is a challenge for the dermatologist: the gold standard, represented by steroids, is in fact designed as a short-time option. Our report confi rms the good efficacy of methotrexate as a steroid-sparing agent. PMID:26312716

Severe Skin Toxicity in Pediatric Oncology Patients Treated with Voriconazole and Concomitant Methotrexate

PubMed Central

van Eijkelenburg, Natasha K. A.; Huitema, Alwin D. R.; Schellens, Jan H. M.; Schouten-van Meeteren, Antoinette Y. N.

2013-01-01

We report the occurrence of skin toxicities in pediatric oncology patients on concomitant treatment with voriconazole and methotrexate (MTX). Of 23 patients who received this combination, 11 patients suffered from cheilitis and/or photosensitivity. In contrast, only in 1 of 9 patients who received voriconazole without MTX was photosensitivity observed. A mechanism of action was not able to be identified. We describe two cases with severe skin toxicities. Caution is warranted when using voriconazole and concomitant MTX. PMID:23571545

Sonography of Methotrexate for Ectopics

NASA Astrophysics Data System (ADS)

Urzicǎ, Denise; Dorohoi, Dana-Ortansa

2007-04-01

Treatment unruptured ectopic pregnancy with methotrexate (MTX) and citrovorum factor is now an established alternative to surgical therapy. Serial measurements of serum beta-HCG and early ultrasound examination have allowed detection of early and unruptured tubal ectopic pregnancies, permitting treatment without removal of the tube. It is believed that preserving the tube increases the chance of subsequent live births. Our findings suggest that outpatient transvaginal intratubal methorexate administration can provide a safe and effective alternative to surgical treatment for patients with early and unruptured tubal ectopic pregnancy.

Methylenetetrahydrofolate reductase and thymidylate synthase genotypes and risk of acute graft-versus-host disease following hematopoietic cell transplantation for chronic myelogenous leukemia.

PubMed

Robien, Kim; Bigler, Jeannette; Yasui, Yutaka; Potter, John D; Martin, Paul; Storb, Rainer; Ulrich, Cornelia M

2006-09-01

Methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) play key roles in intracellular folate metabolism. Polymorphisms in these enzymes have been shown to modify toxicity of methotrexate (MTX) after hematopoietic cell transplantation. In this study, we evaluated the risk of acute graft-versus-host disease (GVHD) associated with genetic variation in recipient and donor MTHFR and TS genotypes to assess whether genotype alters the efficacy of MTX in acute GVHD prophylaxis. Data on the transplantation course were abstracted from medical records for 304 adults who received allogeneic hematopoietic cell transplants. MTHFR (C677T and A1298C) and TS (enhancer-region 28-base pair repeat, TSER, and 1494del6) genotypes were determined using polymerase chain reaction/restriction fragment length polymorphism and TaqMan assays. Multivariable logistic regression was used to assess the associations between genotypes and risk of acute GVHD. Compared with recipients with the wild-type MTHFR 677CC genotype, those with the variant 677T allele showed a decreased risk of detectable acute GVHD (677CT: odds ratio, 0.8; 95% confidence interval, 0.4-1.6; 677TT: odds ratio, 0.4; 95% confidence interval, 0.2-0.8; P for trend = .01). The variant MTHFR 1298C allele in recipients was associated with an increased risk of acute GVHD compared with the wild-type MTHFR 1298AA genotype (1298AC: odds ratio, 2.0; 95% confidence interval, 1.1-3.9; 1298CC: odds ratio, 3.6; 95% confidence interval, 1.0-12.7; P for trend < .01). No association with risk of acute GVHD was observed for donor MTHFR genotypes or for recipient or donor TS genotypes, with the exception of an increase in acute GVHD among recipients whose donors had the TSER 3R/2R genotype (odds ratio, 3.0; 95% confidence interval, 1.3-7.2). These findings indicate that host, but not donor, MTHFR genotypes modify the risk of acute GVHD in recipients receiving MTX, in a manner consistent with our previously reported associations between MTHFR genotypes and MTX toxicity. A direct trade-off between drug toxicity and drug efficacy may play a role. Alternatively, the systemic folate environment, regulated by host tissues, might influence donor T-cell growth and activity.

IL-6 pathway-driven investigation of response to IL-6 receptor inhibition in rheumatoid arthritis

PubMed Central

Wang, Jianmei; Platt, Adam; Upmanyu, Ruchi; Germer, Søren; Lei, Guiyuan; Rabe, Christina; Benayed, Ryma; Kenwright, Andrew; Hemmings, Andrew; Martin, Mitchell; Harari, Olivier

2013-01-01

Objectives To determine whether heterogeneity in interleukin-6 (IL-6), IL-6 receptor and other components of the IL-6 signalling pathway/network, at the gene, transcript and protein levels, correlate with disease activity in patients with rheumatoid arthritis (RA) and with clinical response to tocilizumab. Design Biomarker samples and clinical data for five phase 3 trials of tocilizumab were analysed using serum (3751 samples), genotype (927 samples) and transcript (217 samples) analyses. Linear regression was then used to assess the association between these markers and either baseline disease activity or treatment response. Results Higher baseline serum IL-6 levels were significantly associated (p<0.0001) with higher baseline DAS28, erythrocyte sedimentation rate, C reactive protein and Health Assessment Questionnaire in patients whose responses to disease-modifying antirheumatic drugs (DMARD-IR) and to antitumour necrosis factor (aTNF-IR) were inadequate and patients who were naive/responders to methotrexate (MTX). Higher baseline serum IL-6 levels were also significantly associated with better clinical response to tocilizumab (versus placebo) measured by cDAS28 in the pooled DMARD-IR (p<0.0001) and MTX-naive populations (p=0.04). However, the association with treatment response was weak. A threefold difference in baseline IL-6 level corresponded to only a 0.17-unit difference in DAS28 at week 16. IL-6 pathway single nucleotide polymorphisms and RNA levels also were not strongly associated with treatment response. Conclusions Our analyses illustrate that the biological activity of a disease-associated molecular pathway may impact the benefit of a therapy targeting that pathway. However, the variation in pathway activity, as measured in blood, may not be a strong predictor. These data suggest that the major contribution to variability in clinical responsiveness to therapeutics in RA remains unknown. PMID:23959753

Impact of genetic variants of ATP binding cassette B1, AICAR transformylase/IMP cyclohydrolase, folyl-polyglutamatesynthetase, and methylenetetrahydrofolatereductase on methotrexate toxicity.

PubMed

Sala-Icardo, Luis; Lamana, Amalia; Ortiz, Ana María; García Lorenzo, Elena; Moreno Fresneda, Pablo; García-Vicuña, Rosario; González-Álvaro, Isidoro

To analyze the effect of single nucleotide polymorphisms (SNPs) with well-known functional impact of methylenetetrahydrofolatereductase (MTHFR; rs1801131 and rs1801133), the membrane transporter ABCB1 (rs1045642), the AICAR transformylase/IMP cyclohydrolase (ATIC; rs2372536) and folyl-polyglutamatesynthetase (FPGS; rs1544105), on liver and bone marrow toxicity of methotrexate (MTX). We analyzed 1415 visits from 350 patients of the PEARL (Princesa Early Arthritis Register Longitudinal) study: (732 with MTX, 683 without MTX). The different SNPs were genotyped using specific TaqMan probes (Applied Biosystems). Multivariate analyzes were performed using generalized linear models in which the dependent variables were the levels of serum alanine aminotransferase (liver toxicity), leukocytes, platelets or hemoglobin (hematologic toxicity) and adjusted for clinical variables (disease activity, etc.), analytical (renal function, etc.), sociodemographic (age, sex, etc.) and genetic variants of MTHFR, ABCB1, ATIC and FPGS. The effect of these variables on the MTX doses prescribed throughout follow-up was also analyzed through multivariate analysis nested by visit and patient. When taking MTX, those patients carrying the CC genotype of rs1045642 in ABCB1 showed significantly higher GPT levels (7.1±2.0 U/L; P<.001). Carrying at least one G allele of rs1544105 in FPGS was associated with lower leukocyte (-0.67±0.32; 0.038), hemoglobin (-0.34±0.11g/dL; P=.002), and platelet (-11.8±4.7; P=.012) levels. The presence of the G allele of rs1544105 in FPGS, and the T allele of rs1801133 in MTHFR, was significantly associated with the use of lower doses of MTX. Our data suggest that genotyping functional variants in FGPS and MTHFR enzymes and the transporter ABCB1 could help to identify patients with increased risk of MTX toxicity. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Polymorphisms in candidate genes for type 2 diabetes mellitus in a Mexican population with metabolic syndrome findings.

PubMed

Sánchez-Corona, J; Flores-Martínez, S E; Machorro-Lazo, M V; Galaviz-Hernández, C; Morán-Moguel, M C; Perea, F J; Mújica-López, K I; Vargas-Ancona, L; Laviada-Molina, H A; Fernández, V; Pardío, J; Arroyo, P; Barrera, H; Hanson, R L

2004-01-01

The metabolic or insulin resistance syndrome, characterized by hypertension, dyslipidemia, glucose intolerance and hyperinsulinemia, may have genetic determinants. The insulin gene (INS), insulin receptor gene (INSR) and insulin receptor substrate 1 gene (IRS1) have been proposed as candidate genes. We examined eight polymorphisms in these genes in 163 individuals from Yucatan, Mexico; this population has a high prevalence of obesity, type 2 diabetes mellitus and dyslipidemia. Subjects were evaluated for body mass index (BMI) and blood pressure. Blood samples were collected to determine glucose, insulin, triglycerides and cholesterol levels, as well as for DNA isolation. Restriction fragment length polymorphisms in INS, INSR and IRS1 were identified by polymerase chain reaction and digestion with selected restriction enzymes. Among the eight polymorphisms analyzed, the PstI polymorphism in INS was significantly associated with hypertriglyceridemia and with the presence of at least one abnormality related to the metabolic syndrome (P=0.007 and 0.004, respectively). The MaeIII polymorphism in INS was associated with fasting hyperinsulinemia (P=0.045). In multilocus analyses including both INS polymorphisms, significant associations were seen with hypertriglyceridemia (P=0.006), hypercholesterolemia (P=0.031) and with presence of at least one metabolic abnormality (P=0.009). None of the polymorphisms in INSR or IRS1 was associated with any of these traits. These findings suggest that the insulin gene may be an important determinant of metabolic syndrome, and particularly of dyslipidemia, in this population.

DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): a prospective substudy of a phase 3 trial.

PubMed

Nielsen, Stine Nygaard; Grell, Kathrine; Nersting, Jacob; Abrahamsson, Jonas; Lund, Bendik; Kanerva, Jukka; Jónsson, Ólafur Gísli; Vaitkeviciene, Goda; Pruunsild, Kaie; Hjalgrim, Lisa Lyngsie; Schmiegelow, Kjeld

2017-04-01

Adjustment of mercaptopurine and methotrexate maintenance therapy of acute lymphoblastic leukaemia by leucocyte count is confounded by natural variations. Cytotoxicity is primarily mediated by DNA-incorporated thioguanine nucleotides (DNA-TGN). The aim of this study was to establish whether DNA-TGN concentrations in blood leucocytes during maintenance therapy are associated with relapse-free survival. In this substudy of the NOPHO ALL2008 phase 3 trial done in 23 hospitals in seven European countries (Denmark, Estonia, Finland, Iceland, Lithuania, Norway, and Sweden), we analysed data from centralised and blinded analyses of 6-mercaptopurine and methotrexate metabolites in blood samples from patients with non-high-risk childhood acute lymphoblastic leukaemia. Eligible patients were aged 1·0-17·9 years; had been diagnosed with non-high-risk precursor B-cell or T-cell leukaemia; had been treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol; and had reached maintenance therapy in first remission. Maintenance therapy was (mercaptopurine 75 mg/m 2 once per day and methotrexate 20 mg/m 2 once per week, targeted to a leucocyte count of 1·5-3·0 × 10 9 cells per L). We measured DNA-TGN and erythrocyte concentrations of TGN nucleotides, methylated mercaptopurine metabolites, and methotrexate polyglutamates. The primary objective was the association of DNA-TGN concentrations and 6-mercaptopurine and methotrexate metabolites with relapse-free survival. The secondary endpoint was the assessment of DNA-TGN concentration and 6-mercaptopurine and methotrexate metabolites during maintenance therapy phase 2. Between Nov 26, 2008 and June 14, 2016, 1509 patients from the NOPHO ALL2008 study were assessed for eligibility in the DNA-TGN substudy, of which 918 (89%) of 1026 eligible patients had at least one DNA-TGN measurement and were included in the analyses. Median follow-up was 4·6 years (IQR 3·1-6·1). Relapse-free survival was significantly associated with DNA-TGN concentration (adjusted hazard ratio 0·81 per 100 fmol/μg DNA increase, 95% CI 0·67-0·98; p=0·029). In patients with at least five blood samples, erythrocyte concentrations of TGN, methylated mercaptopurine metabolites, and methotrexate polyglutamates were associated with DNA-TGN concentration (all p<0·0001). Our results suggest the need for intervention trials to identify clinically applicable strategies for individualised drug dosing to increase DNA-TGN concentration, and randomised studies to investigate whether such strategies improve cure rates compared with current dose adjustments based on white blood cell counts. Danish Cancer Society, Childhood Cancer Foundation (Denmark), Childhood Cancer Foundation (Sweden), Nordic Cancer Union, Otto Christensen Foundation, University Hospital Rigshospitalet, and Novo Nordic Foundation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Novel methotrexate soft nanocarrier/fractional erbium YAG laser combination for clinical treatment of plaque psoriasis.

PubMed

Ramez, Shahenda A; Soliman, Mona M; Fadel, Maha; Nour El-Deen, Faisal; Nasr, Maha; Youness, Eman R; Aboel-Fadl, Dalea M

2018-02-15

Psoriasis is a commonly encountered chronic dermatological disease, presenting with inflammatory symptoms in patients. Systemic treatment of psoriasis is associated with several adverse effects, therefore the development of a customized topical treatment modality for psoriasis would be an interesting alternative to systemic delivery. The therapeutic modality explored in this article was the comparative treatment of psoriatic patients using nanoparticulated methotrexate in the form of jojoba oil-based microemulsion with or without fractional erbium YAG laser. Assessment parameters included follow-up photography for up to 8 weeks of treatment, estimation of the psoriasis severity [TES (thickness, erythema, scales)] score, and histopathological skin evaluation. The prepared methotrexate microemulsion was clinically beneficial and safe in treatment of psoriasis vulgaris. The concomitant use of the fractional laser provided improvement in the psoriatic plaques within shorter time duration (3 weeks compared to 8 weeks of treatment), presenting an alternative topical treatment modality for psoriasis vulgaris.

Measurement of Erythrocyte Methotrexate Polyglutamate Levels: Ready for Clinical Use in Rheumatoid Arthritis?

PubMed Central

Danila, Maria I.; Hughes, Laura B.; Brown, Elizabeth E.; Morgan, Sarah L.; Baggott, Joseph E.; Arnett, Donna K.; Bridges, S. Louis

2013-01-01

Methotrexate (MTX) is one of the most commonly prescribed and most effective drugs for the treatment of rheumatoid arthritis (RA). Given the partial response of many patients and the side effect profile of the drug, there is considerable interest in identification of biomarkers to guide MTX therapy in RA. Upon entering cells, MTX is polyglutamated. Measuring methotrexate polyglutamates (MTX PGs) levels in circulating red blood cells (RBC) has been proposed as an objective measure that can help to optimize MTX therapy in RA. There is conflicting data with regard to the clinical utility of measurement of MTX PGs measurements as a predictor of the efficacy or toxicity of low-dose MTX effects in RA. Should large, randomized clinical trials of this assay show consistent, reproducible, long-term correlations between MTX PG levels and efficacy and toxicity, this test could become a prominent tool for clinicians to optimize the use of MTX in RA. PMID:20665136

Modifying mesoporous silica nanoparticles to avoid the metabolic deactivation of 6-mercaptopurine and methotrexate in combinatorial chemotherapy

NASA Astrophysics Data System (ADS)

Wang, Wenjing; Fang, Chenjie; Wang, Xiaozhu; Chen, Yuxi; Wang, Yaonan; Feng, Wei; Yan, Chunhua; Zhao, Ming; Peng, Shiqi

2013-06-01

Mesoporous silica nanoparticles with amino and thiol groups (MSNSN) were prepared and covalently modified with methotrexate and 6-mercaptopurine to form 6-MP-MSNSN-MTX. In the presence of DTT, 6-MP-MSNSN-MTX gradually releases 6-MP. In rat plasma, 6-MP-MSNSN-MTX effectively inhibits the metabolic deactivation of 6-MP and MTX. 6-MP-MSNSN-MTX could be an agent for long-acting chemotherapy.Mesoporous silica nanoparticles with amino and thiol groups (MSNSN) were prepared and covalently modified with methotrexate and 6-mercaptopurine to form 6-MP-MSNSN-MTX. In the presence of DTT, 6-MP-MSNSN-MTX gradually releases 6-MP. In rat plasma, 6-MP-MSNSN-MTX effectively inhibits the metabolic deactivation of 6-MP and MTX. 6-MP-MSNSN-MTX could be an agent for long-acting chemotherapy. Electronic supplementary information (ESI) available: Experimental details of the synthesis and in vitro and in vivo assays. See DOI: 10.1039/c3nr00227f

Inhibitory effect of selective cyclooxygenase-2 inhibitor etoricoxib on human organic anion transporter 3 (hOAT3).

PubMed

Honjo, Hiroaki; Uwai, Yuichi; Iwamoto, Kikuo

2011-04-01

It is well known that nonsteroidal anti-inflammatory drugs (NSAIDs) delay the elimination of methotrexate. One of the mechanisms is thought to be inhibition of methotrexate uptake via human organic anion transporter 3 (hOAT3, SLC22A8) in the renal proximal tubule by NSAIDs. In this study, we evaluated the inhibitory effects of selective cyclooxygenase-2 inhibitor etoricoxib on hOAT3 by uptake experiments using Xenopus laevis oocytes. The injection of hOAT3 cRNA stimulated the uptake of methotrexate into the oocytes, and its transport was inhibited by etoricoxib. Etoricoxib inhibited estrone sulfate uptake by hOAT3 dose dependently, and the 50% inhibitory concentration was estimated to be 9.8 µM. Eadie-Hofstee plot analysis showed that etoricoxib inhibited hOAT3 in a competitive manner. These findings show that etoricoxib has inhibitory effect on hOAT3, and that the potential is comparable to that of traditional NSAIDs. ©2011 Bentham Science Publishers Ltd.

Thermodynamic Stability Analysis of Tolbutamide Polymorphs and Solubility in Organic Solvents.

PubMed

Svärd, Michael; Valavi, Masood; Khamar, Dikshitkumar; Kuhs, Manuel; Rasmuson, Åke C

2016-06-01

Melting temperatures and enthalpies of fusion have been determined by differential scanning calorimetry (DSC) for 2 polymorphs of the drug tolbutamide: FI(H) and FV. Heat capacities have been determined by temperature-modulated DSC for 4 polymorphs: FI(L), FI(H), FII, FV, and for the supercooled melt. The enthalpy of fusion of FII at its melting point has been estimated from the enthalpy of transition of FII into FI(H) through a thermodynamic cycle. Calorimetric data have been used to derive a quantitative polymorphic stability relationship between these 4 polymorphs, showing that FII is the stable polymorph below approximately 333 K, above which temperature FI(H) is the stable form up to its melting point. The relative stability of FV is well below the other polymorphs. The previously reported kinetic reversibility of the transformation between FI(L) and FI(H) has been verified using in situ Raman spectroscopy. The solid-liquid solubility of FII has been gravimetrically determined in 5 pure organic solvents (methanol, 1-propanol, ethyl acetate, acetonitrile, and toluene) over the temperature range 278 to 323 K. The ideal solubility has been estimated from calorimetric data, and solution activity coefficients at saturation in the 5 solvents determined. All solutions show positive deviation from Raoult's law, and all van't Hoff plots of solubility data are nonlinear. The solubility in toluene is well below that observed in the other investigated solvents. Solubility data have been correlated and extrapolated to the melting point using a semiempirical regression model. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Effect of transforming growth factor-alpha on enterocyte apoptosis is correlated with EGF receptor expression along the villus-crypt axis during methotrexate-induced intestinal mucositis in a rat.

PubMed

Sukhotnik, Igor; Shteinberg, Dan; Ben Lulu, Shani; Bashenko, Yulia; Mogilner, Jorge G; Ure, Benno M; Shaoul, Ron; Coran, Arnold G

2008-11-01

The purpose of the present study was to evaluate the effect of transforming-growth factor-alpha (TGF-alpha) on enterocyte apoptosis following methotrexate (MTX) induced intestinal mucositis in a rat and in Caco-2 cells. Non-pretreated and pretreated with MTX Caco-2 cells were incubated with increasing concentrations of TGF-alpha. Cell apoptosis was determined by FACS cytometry. Adult rats were divided into four groups: Control, Control-TGF-alpha, MTX, and MTX- TGF-alpha rats. Three days later rats were sacrificed. Enterocyte apoptosis were measured at sacrifice. RT-PCR and Western Blotting was used to determine the level of Bax and Bcl-2 mRNA and protein. Real time PCR was used to measure epidermal growth factor receptor (EGFr) expression along the villus-crypt axis. The in vitro experiment has shown that treatment with TGF-alpha of Caco-2 cells results in a significant inhibition of cell apoptosis in a dose-dependent manner. In vivo experiment, a decreased levels of apoptosis in MTX- TGF-alpha rats corresponded with the decrease in Bax and with the increase in Bcl-2 at both mRNA and protein levels. The inhibiting effect of TGF-alpha on enterocyte apoptosis was strongly correlated with EGFr expression along the villus-crypt axis. In conclusion, treatment with TGF-alpha inhibits enterocyte apoptosis following MTX- injury in the rat.

Therapeutic Efficacy of Orally Delivered Doxorubicin Nanoparticles in Rat Tongue Cancer Induced by 4-Nitroquinoline 1-Oxide

PubMed Central

Moradzadeh Khiavi, Monir; Rostami, Ahamd; Hamishekar, Hamed; Mesgari Abassi, Mehran; Aghbali, Amirala; Salehi, Roya; Abdollahi, Bita; Fotoohi, Soheila; Sina, Mahmud

2015-01-01

Purpose: Oral cancer is one of the most significant cancers in the world, and squamous cell carcinoma makes up about 94% of oral malignancies. The aim of the present study was to compare the efficacy of doxorubicin plus methotrexate - loaded nanoparticles on tongue squamous cell carcinoma induced by 4NQO and compare it with the commercial doxorubicin and methotrexate delivered orally on seventy SD male rats. Methods: 70 rats were divided into five groups. During the study, the animals were weighed by a digital scale once a week. Number of mortalities was recorded in the data collection forms. At the end of the treatment, biopsy samples were taken from rat tongues in order to evaluate the severity of dysplasia and the extent of cell proliferation. The results were analyzed using ANOVA, descriptive statistics and chi-square test. Results: No statistically significant difference was found in the mean weight of five groups (p>0.05). No significant relationship was found between groups and mortality rate (P = 0. 39). In addition, there was a significant relationship between groups and the degree of dysplasia (P <0.001). The statistical analysis showed a significant relationship between groups and the rate of cell proliferation (p <0.001). Conclusion: The results of the present study showed that the use of doxorubicin plus methotrexate - loaded nanoparticles orally had more therapeutic effects than commercial doxorubicin plus methotrexate. PMID:26236659

Multimodality therapy for medulloblastoma. [Efficacy and complications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thomas, P.R.M.; Duffner, P.K.; Cohen, M.E.

1980-02-15

Eight patients with recurrent medulloblastoma were treated with a chemotherapy regimen consisting of vincristine, BCNU, dexamethasone and intrathecal and intermediate dose intravenous methotrexate (500 mg/m/sup 2/). Five also received local low dose radiotherapy (RT). All 8 patients responded to treatment; 6 completely and 2 partially. These latter 2 were in their second and third recurrences. Three remain in remission. The median duration of response was 18.8 months, and median time from start of chemotherapy to death was 32 months using the Kaplan-Meier technique. In addition, 9 other patients with newly diagnosed medulloblastoma were treated with craniospinal radiation and the samemore » adjuvant chemotherapy as above. The first 5 patients also received intraventricular methotrexate and/or intravenous BCNU during radiotherapy. The toxicity in the 5 patients was very severe. There were three toxic deaths, one death from cancer; one patient survives disease-free, but he is demented. With the discontinuance of intraventricular methotrexate and the postponement of myelosuppressive chemotherapy until after the completion of radiotherapy, the regimen has been well tolerated. All 4 patients treated this way remain alive, well, and disease-free at intervals up to 36 months. We conclude that recurrent medulloblastomas are sensitive to multiagent chemotherapy and that prolonged remissions may occur. With primary adjuvant chemotherapy, extreme caution with myelosuppressive drugs must be exercised during the period of craniospinal radiotherapy. We also do not recommend the use of intraventricular methotrexate. When these two criteria were followed, the preliminary results with adjuvant chemotherapy appear encouraging.« less

Efficacy of Methotrexate in patients with plaque type psoriasis

PubMed Central

Haider, Sabiqa; Wahid, Zarnaz; Najam-us-Saher; Riaz, Farzana

2014-01-01

Objective: To assess the efficacy of Methotrexate in patients with plaque type psoriasis. Methods: This descriptive study was conducted in the department of Dermatology, Civil Hospital Karachi from September 2009 to March 2010. Seventy three patients between 18 to 50 years of age suffering from plaque type psoriasis with PASI score of >10 were included in the study after taking the informed consent. Oral methotrexate in a dose of 7.5 mg/week was given for 8 weeks. The data collected included demographic profile (age and gender), duration of disease, site of involvement, size of plaque, severity of plaque measured by Psoriasis Area and Severity Index (PASI) score before starting the treatment and at the end of treatment. Efficacy was labeled with a PASI score of ≤5 at the end of 8 weeks. Results: Out of 73 patients there were 45 (61.6%) males and 28 (38.4%) females. The mean ±SD age was 40.0±12.6 years. The mean baseline PASI score showed clear and comparable improvement from a mean ± SD PASI score of 14.8±4.2 to 4.9±4.3.Twenty nine (40%) patients had an almost complete remission during the 8 weeks of treatment. Partial remission was achieved in 44 (60%) patients. The clearance time for psoriasis ranged from 5-7 weeks (mean 6±0.89 weeks). Conclusion: Treatment with methotrexate for chronic plaque psoriasis brings satisfactory disease control and improved quality of life. PMID:25225524

Optimization of anti-cancer drugs and a targeting molecule on multifunctional gold nanoparticles.

PubMed

Rizk, Nahla; Christoforou, Nicolas; Lee, Sungmun

2016-05-06

Breast cancer is the most common and deadly cancer among women worldwide. Currently, nanotechnology-based drug delivery systems are useful for cancer treatment; however, strategic planning is critical in order to enhance the anti-cancer properties and reduce the side effects of cancer therapy. Here, we designed multifunctional gold nanoparticles (AuNPs) conjugated with two anti-cancer drugs, TGF-β1 antibody and methotrexate, and a cancer-targeting molecule, folic acid. First, optimum size and shape of AuNPs was selected by the highest uptake of AuNPs by MDA-MB-231, a metastatic human breast cancer cell line. It was 100 nm spherical AuNPs (S-AuNPs) that were used for further studies. A fixed amount (900 μl) of S-AuNP (3.8 × 10(8) particles/ml) was conjugated with folic acid-BSA or methotrexate-BSA. Methotrexate on S-AuNP induced cellular toxicity and the optimum amount of methotrexate-BSA (2.83 mM) was 500 μl. Uptake of S-AuNPs was enhanced by folate conjugation that binds to folate receptors overexpressed by MDA-MB-231 and the optimum uptake was at 500 μl of folic acid-BSA (2.83 mM). TGF-β1 antibody on S-AuNP reduced extracellular TGF-β1 of cancer cells by 30%. Due to their efficacy and tunable properties, we anticipate numerous clinical applications of multifunctional gold nanospheres in treating breast cancer.

Protective effect of propolis on methotrexate-induced kidney injury in the rat.

PubMed

Ulusoy, Hasan Basri; Öztürk, İsmet; Sönmez, Mehmet Fatih

2016-06-01

Objectives Propolis is a potent antioxidant and a free radical scavenger. Pharmacological induction of heat shock proteins (HSPs) has been investigated for restoring normal cellular function following an injury. In this study, effect of propolis on HSP-70 expression in methotrexate-induced nephrotoxicity and direct preventive effect of propolis in this toxicity were investigated. Material and methods A total of 40 male Wistar albino rats were divided into four groups: Group 1 was the untreated control. On the eighth day of the experiment, groups 2 and 3 received single intraperitoneal injections of methotrexate (MTX) at 20 mg/kg. Groups 3 and 4 received 100 mg/kg/day propolis (by oral gavage) for 15 d by the first day of the experimental protocol. Then the rats were decapitated under ketamine esthesia and their kidney tissues were removed. HSP-70 expression, apoptosis, and histopathological damage scores were then compared. Results MTX caused epithelial desquamation into the lumen of the tubules, dilatation, and congestion of the peritubular vessels and renal corpuscles with obscure Bowman's space. The number of apoptotic cells (p = 0.000) and HSP-70 (p = 0.002) expression were increased in group 2. Propolis prevented the rise in number of apoptotic cells (p = 0.017), HSP-70 (p = 0.000) expression, and improved kidney morphology. Conclusions It was found that methotrexate gives rise to serious damage in the kidney and propolis is a potent antioxidant agent in preventing kidney injury.

Optimization of anti-cancer drugs and a targeting molecule on multifunctional gold nanoparticles

NASA Astrophysics Data System (ADS)

Rizk, Nahla; Christoforou, Nicolas; Lee, Sungmun

2016-05-01

Breast cancer is the most common and deadly cancer among women worldwide. Currently, nanotechnology-based drug delivery systems are useful for cancer treatment; however, strategic planning is critical in order to enhance the anti-cancer properties and reduce the side effects of cancer therapy. Here, we designed multifunctional gold nanoparticles (AuNPs) conjugated with two anti-cancer drugs, TGF-β1 antibody and methotrexate, and a cancer-targeting molecule, folic acid. First, optimum size and shape of AuNPs was selected by the highest uptake of AuNPs by MDA-MB-231, a metastatic human breast cancer cell line. It was 100 nm spherical AuNPs (S-AuNPs) that were used for further studies. A fixed amount (900 μl) of S-AuNP (3.8 × 108 particles/ml) was conjugated with folic acid-BSA or methotrexate-BSA. Methotrexate on S-AuNP induced cellular toxicity and the optimum amount of methotrexate-BSA (2.83 mM) was 500 μl. Uptake of S-AuNPs was enhanced by folate conjugation that binds to folate receptors overexpressed by MDA-MB-231 and the optimum uptake was at 500 μl of folic acid-BSA (2.83 mM). TGF-β1 antibody on S-AuNP reduced extracellular TGF-β1 of cancer cells by 30%. Due to their efficacy and tunable properties, we anticipate numerous clinical applications of multifunctional gold nanospheres in treating breast cancer.

Prevalence of alpha actinin-3 gene (ACTN3) R577X and angiotensin converting enzyme (ACE) insertion / deletion gene polymorphisms in national and amateur Turkish athletes.

PubMed

Eroğlu, Onur; Zileli, Rayif; Nalbant, M Ali; Ulucan, Korkut

2018-04-30

Studies to date showed the importance of alpha- actinin-3 (ACTN3) R577X and angiotensin converting enzyme (ACE) ID polymorphisms on determining athletic performance. Therefore, in this study, we aimed to examine polymorphisms given to Turkish athletes and compare them with sedentary individuals. Genomic DNAs were extracted from peripheral blood by using commercially available DNA isolation kit (Macherey-Nagel, NucleoSpin®, Germany). For this study, a total of 84 volunteers (23 national athletes, 27 amateur athletes and 34 sedentary controls) was recruited.  ACE ID genotypes were determined by conventional polymerase chain reaction, and ACTN3 R577X polymorphisms by polymerase chain reaction- restriction fragment length polymorphism methodology.   In ACTN3 R577X polymorphism, RX was the dominating genotype, and we detected no RR genotype in national athletes. (no RR genotype was detected in national athletes) X allele is more frequent in national athletes and R allele was more frequent in both amateur athletes and control group. II genotype was more frequent in national athletes and in control group, whereas DD genotype was more frequent in amateur athletes for ACE ID polymorphism. When we consider alleles, D allele was found more frequently in amateur athletes and control group whereas I allele was more frequent in national athletes in ACE ID polymorphism. For ACTN3, X allele was superior to R allele. ACTN3 R577X and ACE ID polymorphisms were important biomarkers in determining athletic performance. However, our results in Turkish athletes suggest that ACE D allele and ACTN3 X alleles may be beneficial to athletes potentially, regardless of the distance they perform.

Comparison of CYP2C9, CYP2C19, CYP2D6, ABCB1, and SLCO1B1 gene-polymorphism frequency in Russian and Nanai populations

PubMed Central

Sychev, Dmitrij Alekseevitch; Shuev, Grigorij Nikolaevich; Suleymanov, Salavat Shejhovich; Ryzhikova, Kristina Anatol’evna; Mirzaev, Karin Badavievich; Grishina, Elena Anatol’evna; Snalina, Natalia Evgenievna; Sozaeva, Zhannet Alimovna; Grabuzdov, Anton Mikhailovich; Matsneva, Irina Andreevna

2017-01-01

Background The efficiency and safety of drug therapy depends on the peculiarities of functioning of the P450 cytochrome group and transporting proteins. There are significant differences for single-nucleotide polymorphism (SNP) frequency. Materials and methods We studied the peculiarities of P450 cytochrome polymorphisms, SLCO1B1 transporting protein, and P-glycoprotein carriage in healthy volunteers in the Nanai ethnic group living in Russia, and compared them to the carriage of SNPs in the Russian population according to literature data. Results After performing the real-time polymerase chain reactions on the samples from 70 healthy volunteers from the Nanai group, for the CYP2C9*2C430T polymorphism we determined 70 CC-genotype carriers. As for the CYP2C9*3A1075C polymorphism, we found 62 AA-genotype carriers and eight AC-genotype carriers. For the CYP2C19*2G681A polymorphism, we determined 39 GG-genotype carriers and 28 GA-genotype carriers, for the CYP2C19*3G636A polymorphism 58 GG-genotype carriers and 12 GA-genotype carriers, and for the CYP2C19*17C806T polymorphism 67 CC-genotype carriers and three CT-genotype carriers. For the CYP2D6*4G1846A polymorphism, the GG genotype had 68 carriers, and the GA genotype two carriers. For the ABCB1*6C3435T polymorphism, there were 19 CC-genotype carriers and 39 CT-genotype carriers. For the SLCO1B1*5T521C polymorphism, the TT genotype had 41 carriers and the CT genotype 25 carriers. The distribution of genotypes fitted the Hardy–Weinberg equilibrium for all the polymorphisms, except those of CYP2C9*2. There were also significant differences in allele frequencies for some polymorphisms between the Nanais and the Russians. Conclusion In the Nanai population, there are polymorphisms connected with the decrease in safety and efficiency of drug therapy. Studying the ethnic differences might influence the determination of priority in the introduction of pharmacogenetic tests in clinical practice in different regions of Russia. PMID:28435307

The Third Ambient Aspirin Polymorph

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shtukenberg, Alexander G.; Hu, Chunhua T.; Zhu, Qiang

Polymorphism in aspirin (acetylsalicylic acid), one of the most widely consumed medications, was equivocal until the structure of a second polymorph II, similar in structure to the original form I, was reported in 2005. Here, the third ambient polymorph of aspirin is described. Lastly, it was crystallized from the melt and its structure was determined using a combination of X-ray powder diffraction analysis and crystal structure prediction algorithms.

The Third Ambient Aspirin Polymorph

DOE PAGES

Shtukenberg, Alexander G.; Hu, Chunhua T.; Zhu, Qiang; ...

2017-05-17

Polymorphism in aspirin (acetylsalicylic acid), one of the most widely consumed medications, was equivocal until the structure of a second polymorph II, similar in structure to the original form I, was reported in 2005. Here, the third ambient polymorph of aspirin is described. Lastly, it was crystallized from the melt and its structure was determined using a combination of X-ray powder diffraction analysis and crystal structure prediction algorithms.

Idealized powder diffraction patterns for cellulose polymorphs

USDA-ARS?s Scientific Manuscript database

Cellulose samples are routinely analyzed by X-ray diffraction to determine their crystal type (polymorph) and crystallinity. However, the connection is seldom made between those efforts and the crystal structures of cellulose that have been determined with synchrotron X-radiation and neutron diffrac...

The Role of Lattice Matching Techniques in the Characterization of Polymorphic Forms.

PubMed

Mighell, Alan D

2011-01-01

An inspection of the recent literature reveals that polymorphism is a frequently encountered phenomenon. The recognition of polymorphic forms plays a vital role in the materials sciences because such structures are characterized by different crystal packing and accordingly have different physical properties. In the pharmaceutical industry, recognition of polymorphic forms can be critical for, in certain cases, a polymorphic form of a drug may be an ineffective therapeutic agent due to its unfavorable physical properties. A check of the recent literature has revealed that in some cases new polymorphic forms are not recognized. In other instances, a supposedly new polymeric form is actually the result of an incorrect structure determination. Fortunately, lattice-matching techniques, which have proved invaluable in the identification and characterization of crystal structures, represent a powerful tool for analyzing polymorphic forms. These lattice-matching methods are based on either of two strategies: (a) the reduced cell strategy-the matching of reduced cells of the respective lattices or (b) the matrix strategy-the determination of a matrix or matrices relating the two lattices coupled with an analysis of the matrix elements. Herein, these techniques are applied to three typical cases-(a) the identification of a new polymorphic form, (b) the demonstration that a substance may not be a new polymorphic form due to missed symmetry, and (c) the evaluation of pseudo polymorphism because of a missed lattice. To identify new polymorphic forms and to prevent errors, it is recommended that these lattice matching techniques become an integral part of the editorial review process of crystallography journals.

Early non-response to certolizumab pegol in rheumatoid arthritis predicts treatment failure at one year. Data from a randomised phase III clinical trial.

PubMed

Berenbaum, Francis; Pham, Thao; Claudepierre, Pascal; de Chalus, Thibault; Joubert, Jean-Michel; Saadoun, Carine; Riou França, Lionel; Fautrel, Bruno

2018-01-01

To compare different early clinical criteria of non-response determined at three months as predictors of clinical failure at one year in patients with rheumatoid arthritis starting therapy with certolizumab pegol. Data were derived from a randomised Phase III clinical trial in patients with rheumatoid arthritis who failed to respond to methotrexate monotherapy. Patients included in this post-hoc analysis were treated with certolizumab pegol (400mg qd reduced to 200mg qd after one month) and with methotrexate. The study duration was twelve months. Response at three months was determined with the American College of Rheumatology-50, Disease Assessment Score-28 ESR, Health Assessment Questionnaire and the Clinical Disease Activity Index. The performance of these measures at predicting treatment failure at twelve months defined by the American College of Rheumatology-50 criteria was determined, using the positive predictive values as the principal evaluation criterion. Three hundred and eighty two patients were available for analysis and 225 completed the twelve-month follow-up. At Week 52, 149 (38.1%) patients met the American College of Rheumatology-50 response criterion. Positive predictive values ranged from 81% for a decrease in Health Assessment Questionnaire- Disability index score since baseline >0.22 to 95% for a decrease in Disease Assessment Score-28 score since baseline≥1.2. Sensitivity was≤70% in all cases. Performance of these measures was similar irrespective of the definition of treatment failure at 12months. Simple clinical measures of disease activity can predict future treatment failure reliably and are appropriate for implementing treat-to-target treatment strategies in everyday practice. Copyright © 2017 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

Glutamine attenuates the inhibitory effect of methotrexate on TLR signaling during intestinal chemotherapy-induced mucositis in a rat

PubMed Central

2014-01-01

Toll-like receptor 4 (TLR-4) is crucial in maintaining intestinal epithelial homeostasis, participates in a vigorous signaling process and heightens inflammatory cytokine output. The objective of this study was to determine the effects of glutamine (GLN) on TLR-4 signaling in intestinal mucosa during methotrexate (MTX)-induced mucositis in a rat. Male Sprague–Dawley rats were randomly assigned to one of four experimental groups of 8 rats each: 1) control rats; 2) CONTR-GLN animals were treated with oral glutamine given in drinking water (2%) 48 hours before and 72 hours following vehicle injection; 3) MTX-rats were treated with a single IP injection of MTX (20 mg/kg); and 4) MTX-GLN rats were pre-treated with oral glutamine similar to group B, 48 hours before and 72 hours after MTX injection. Intestinal mucosal damage, mucosal structural changes, enterocyte proliferation and enterocyte apoptosis were determined 72 hours following MTX injection. The expression of TLR-4, MyD88 and TRAF6 in the intestinal mucosa was determined using real time PCR, Western blot and immunohistochemistry. MTX-GLN rats demonstrated a greater jejunal and ileal mucosal weight and mucosal DNA, greater villus height in ileum and crypt depth and index of proliferation in jejunum and ileum, compared to MTX animals. The expression of TLR-4 and MyD88 mRNA and protein in the mucosa was significantly lower in MTX rats versus controls animals. The administration of GLN increased significantly the expression of TLR-4 and MyD88 (vs the MTX group). In conclusion, treatment with glutamine was associated with up-regulation of TLR-4 and MyD88 expression and a concomitant decrease in intestinal mucosal injury caused by MTX-induced mucositis in a rat. PMID:24742067

Leflunomide is associated with a higher flare rate compared to methotrexate in the treatment of chronic uveitis in juvenile idiopathic arthritis.

PubMed

Bichler, J; Benseler, S M; Krumrey-Langkammerer, M; Haas, J-P; Hügle, B

2015-01-01

Chronic anterior uveitis is a serious complication of juvenile idiopathic arthritis (JIA); disease flares are highly associated with loss of vision. Leflunomide (LEF) is used successfully for JIA joint disease but its effectiveness in uveitis has not been determined. The aim of this study was to determine whether LEF improves flare rates of uveitis in JIA patients compared to preceding methotrexate (MTX) therapy. A single-centre retrospective study of consecutive children with JIA and chronic anterior uveitis was performed. All children initially received MTX and were then switched to LEF. Demographic, clinical, and laboratory data, dose and duration of MTX and LEF therapy, concomitant medications and rate of anterior uveitis flares, as determined by an expert ophthalmologist, were obtained. Flare rates were compared using a generalized linear mixed model with a negative binomial distribution. A total of 15 children were included (80% females, all antinuclear antibody positive). The median duration of MTX therapy was 51 (range 26-167) months; LEF was given for a median of 12 (range 4-47) months. Anti-tumour necrosis factor (anti-TNF-α) co-medication was given to four children while on MTX. By contrast, LEF was combined with anti-TNF-α treatment in six children. On MTX, JIA patients showed a uveitis flare rate of 0.0247 flares/month, while LEF treatment was associated with a significantly higher flare rate of 0.0607 flares/month (p = 0.008). Children with JIA had significantly more uveitis flares on LEF compared to MTX despite receiving anti-TNF-α co-medication more frequently. Therefore, LEF may need to be considered less effective in controlling chronic anterior uveitis.

Clinical relevance of the interleukin 10 promoter polymorphisms in Chinese Han patients with major trauma: genetic association studies.

PubMed

Zeng, Ling; Gu, Wei; Chen, Kehong; Jiang, Dongpo; Zhang, Lianyang; Du, Dingyuan; Hu, Ping; Liu, Qing; Huang, Suna; Jiang, Jianxin

2009-01-01

An excessive inflammatory response is thought to account for the pathogenesis of sepsis and multiple organ dysfunction syndrome (MODS) after severe trauma. The interleukin-10 (IL-10) is a potent anti-inflammatory cytokine. The objectives of this prospective study were to investigate the distribution of IL-10 promoter polymorphisms in a cohort of 308 Chinese Han patients with major trauma, and to identify associations of IL-10 promoter polymorphisms with IL-10 production and incidence of sepsis and MODS. A total of 308 patients with major trauma were included in this study. The genotypes of polymorphisms -1082, -819 and -592 were determined by polymerase chain reaction-restriction fragment length polymorphism. The IL-10 levels in the supernatants were determined with enzyme-linked immunoabsorbent assay. The -1082A and -592A alleles were significantly associated with lower lipopolysaccharide-induced IL-10 production in an allele-dose dependent fashion. There was no significant difference for the -819 polymorphism. Except for the -1082 polymorphism, the -819 and -592 polymorphisms were not significantly associated with sepsis morbidity rate and MOD scores. Our results further confirm the functionality of the IL-10 promoter single nucleotide polymorphisms in relation to IL-10 production. They also suggest that individual difference in IL-10 production in trauma patients might be at least in part related to genetic variations in the IL-10 promoter region.

A Novel siRNA-Based Approach to Study Mechanisms of Resistance/Action of a New Drug in Treatment of Breast Cancer. Addendum

DTIC Science & Technology

2006-08-01

electroporation, were tested in the MCF-7 breast cancer cell line. The cell line was then treated with a lethal dose of ET-743 and cytarabine , however no...drugs with known mechanisms of resistance, methotrexate (MTX) and cytarabine , using a clonogenic assay and MCF-7 breast cancer cells. 3. To employ...Aim 2. To test the ability of the generated siRNA library by using two drugs with known mechanisms of resistance, methotrexate (MTX) and cytarabine

Metastatic bone lesion due to methotrexate and etanercept 24 years after breast cancer treatment

PubMed Central

Yano, Shuichi

2014-01-01

A 72-year-old woman with rheumatoid arthritis presented with lumbar vertebral bone metastasis 24 years after mammectomy and radiotherapy for breast cancer. She was treated with prednisolone and methotrexate (MTX) for 11 months to which 10 mg of etanercept twice a week was added for a further 8 months. On the basis of this result, the possibility of a metastatic bone lesion appearing many years after cancer treatment should be considered when planning MTX and etanercept therapy. PMID:24729113

A Case of the Cauda Equina Syndrome Associated With the Intrathecal Chemotherapy in a Patient With Primary Central Nervous System Lymphoma

PubMed Central

Park, Seunglee; Kang, Jung-Il; Bang, Hyun; Kim, Bo-Ram

2013-01-01

The intrathecal chemotherapy with methotrexate and cytarabine arabinoside is used for the treatment and prophylaxis of the primary central nervous system lymphoma. The therapy may induce neurotoxicity including the cauda equina syndrome. We report a case of a 58-year-old man with the diffuse large B-cell lymphoma, who developed the cauda equina syndrome after the administration of intrathecal methotrexate and cytarabine arabinoside, as diagnosed by the electrodiagnostic, urodynamic, and radiologic approaches. PMID:23869341

Life threatening acute pneumonitis during low dose methotrexate treatment for rheumatoid arthritis: a case report and review of the literature.

PubMed Central

Ridley, M G; Wolfe, C S; Mathews, J A

1988-01-01

A patient is described with definite rheumatoid arthritis (RA) who developed life threatening acute pneumonitis after receiving a total dose of only 12.5 mg methotrexate (MTX). This complication has been previously described, but this is probably the lowest reported dose before development of pneumonitis in a patient with RA. The possible significance of this case is discussed in the light of recent reports suggesting an increased susceptibility of patients with RA to the pulmonary toxicity of MTX. Images PMID:3052323

Effect of intravitreal methotrexate and rituximab on interleukin-10 levels in aqueous humor of treated eyes with vitreoretinal lymphoma.

PubMed

Raja, Harish; Snyder, Melissa R; Johnston, Patrick B; O'Neill, Brian P; Caraballo, Juline N; Balsanek, Joseph G; Peters, Brian E; Decker, Paul A; Pulido, Jose S

2013-01-01

Intraocular cytokines are promising diagnostic biomarkers of vitreoretinal lymphoma. Here, we evaluate the utility of IL-10, IL-6 and IL-10/IL-6 for discriminating lymphoma from uveitis and report the effects of intraocular methotrexate and rituximab on aqueous cytokine levels in eyes with lymphoma. This is a retrospective case series including 10 patients with lymphoma and 7 patients with uveitis. Non-parametric Mann-Whitney analysis was performed to determine statistical significance of difference in interleukin levels between lymphoma and uveitis. Compared to eyes with uveitis, eyes with lymphoma had higher levels of IL-10 (U = 7.0; two-tailed p = 0.004) and IL-10/IL-6 (U = 6.0; two-tailed p = 0.003), whereas IL-6 levels were more elevated, although insignificant, in those patients with uveitis than in lymphoma (U = 15.0; two-tailed p = ns). Using a receiver operating characteristic analysis to identify threshold values diagnostic for lymphoma, optimal sensitivity and specificity improved to 80.0% and 100%, respectively, for IL-10>7.025 pg/ml and 90.0% and 100.0%, respectively, for IL-10/IL-6>0.02718. In patients in whom serial interleukin levels were available, regular intravitreal treatment with methotrexate and rituximab was associated with reduction in IL-10 levels over time. In conclusion, optimal IL-10 and IL-10/IL-6 threshold values are associated with a diagnostic sensitivity ≥80% and specificity of 100%. Therefore, these cytokines may serve as a useful adjunct in the diagnosis of lymphoma. While negative IL-10 and IL-10/IL-6 values do not exclude a diagnosis of lymphoma, elevated levels do appear to be consistent with lymphoma clinically. Moreover, elevated levels of IL-10 in the setting of a clinically quiet eye may point to impending disease recurrence. Lastly, once lymphoma is diagnosed, IL-10 levels can be monitored over time to assess disease activity and therapeutic response.

Regulatory considerations of pharmaceutical solid polymorphism in Abbreviated New Drug Applications (ANDAs).

PubMed

Raw, Andre S; Furness, M Scott; Gill, Devinder S; Adams, Richard C; Holcombe, Frank O; Yu, Lawrence X

2004-02-23

A sponsor of an Abbreviated New Drug Application (ANDA) must have information to show that the proposed generic product and the innovator product are both pharmaceutically equivalent and bioequivalent, and therefore, therapeutically equivalent. Many pharmaceutical solids exist in several crystalline forms and thus exhibit polymorphism. Polymorphism may result in differences in the physico-chemical properties of the active ingredient and variations in these properties may render a generic drug product to be bioinequivalent to the innovator brand. For this reason, in ANDAs, careful attention is paid to the effect of polymorphism in the context of generic drug product equivalency. This review discusses the impact of polymorphism on drug product manufacturability, quality, and performance. Conclusions from this analysis demonstrate that pharmaceutical solid polymorphism has no relevance to the determination of drug substance "sameness" in ANDAs. Three decision trees for solid oral dosage forms or liquid suspensions are provided for evaluating when and how polymorphs of drug substances should be monitored and controlled in ANDA submissions. Case studies from ANDAs are provided which demonstrate the irrelevance of polymorphism to the determination of drug substance "sameness". These case studies also illustrate the conceptual framework from these decision trees and illustrate how their general principles are sufficient to assure both the quality and the therapeutic equivalence of marketed generic drug products.

NQR investigation and characterization of cocrystals and crystal polymorphs

NASA Astrophysics Data System (ADS)

Seliger, Janez; Žagar, Veselko; Asaji, Tetsuo

2013-05-01

The application of 14N NQR to the study of cocrystals and crystal polymorphs is reviewed. In ferroelectric and antiferroelectric organic cocrystals 14N NQR is used to determine proton position in an N-H...O hydrogen bond and proton displacement below TC. In cocrystal isonicitinamide - oxalic acid (2:1) 14N NQR is used to distinguish between two polymorphs and to determine the type of the hydrogen bond (N-...H-O). The difference in the 14N NQR spectra of cocrystal formers and cocrystal is investigated in case of carbamazepine, saccharin and carbamazepine - saccharin (1:1). The experimental resolution allows an unambiguous distinction between the 14N NQR spectrum of the cocrystal and the 14N NQR spectra of the cocrystal formers. The possibility of application of NQR and double resonance for the determination of the inhomogeneity of the sample and for the study of the life time of an unstable polymorph is discussed.

In Black South Africans from Rural and Urban Communities, the 4G/5G PAI-1 Polymorphism Influences PAI-1 Activity, but Not Plasma Clot Lysis Time

PubMed Central

de Lange, Zelda; Rijken, Dingeman C.; Hoekstra, Tiny; Conradie, Karin R.; Jerling, Johann C.; Pieters, Marlien

2013-01-01

Data on genetic and environmental factors influencing PAI-1 levels and their consequent effect on clot lysis in black African populations are limited. We identified polymorphisms in the promoter area of the PAI-1 gene and determined their influence on PAI-1act levels and plasma clot lysis time (CLT). We also describe gene-environment interactions and the effect of urbanisation. Data from 2010 apparently healthy urban and rural black participants from the South African arm of the PURE study were cross-sectionally analysed. The 5G allele frequency of the 4G/5G polymorphism was 0.85. PAI-1act increased across genotypes in the urban subgroup (p = 0.009) but not significantly in the rural subgroup, while CLT did not differ across genotypes. Significant interaction terms were found between the 4G/5G polymorphism and BMI, waist circumference and triglycerides in determining PAI-1act, and between the 4G/5G polymorphism and fibrinogen and fibrinogen gamma prime in determining CLT. The C428T and G429A polymorphisms did not show direct relationships with PAI-1act or CLT but they did influence the association of other environmental factors with PAI-1act and CLT. Several of these interactions differed significantly between rural and urban subgroups, particularly in individuals harbouring the mutant alleles. In conclusion, although the 4G/5G polymorphism significantly affected PAI-1act, it contributed less than 1% to the PAI-1act variance. (Central) obesity was the biggest contributor to PAI-1act variance (12.5%). Urbanisation significantly influenced the effect of the 4G/5G polymorphism on PAI-1act as well as gene-environment interactions for the C428T and G429A genotypes in determining PAI-1act and CLT. PMID:24386152

In black South Africans from rural and urban communities, the 4G/5G PAI-1 polymorphism influences PAI-1 activity, but not plasma clot lysis time.

PubMed

de Lange, Zelda; Rijken, Dingeman C; Hoekstra, Tiny; Conradie, Karin R; Jerling, Johann C; Pieters, Marlien

2013-01-01

Data on genetic and environmental factors influencing PAI-1 levels and their consequent effect on clot lysis in black African populations are limited. We identified polymorphisms in the promoter area of the PAI-1 gene and determined their influence on PAI-1act levels and plasma clot lysis time (CLT). We also describe gene-environment interactions and the effect of urbanisation. Data from 2010 apparently healthy urban and rural black participants from the South African arm of the PURE study were cross-sectionally analysed. The 5G allele frequency of the 4G/5G polymorphism was 0.85. PAI-1act increased across genotypes in the urban subgroup (p = 0.009) but not significantly in the rural subgroup, while CLT did not differ across genotypes. Significant interaction terms were found between the 4G/5G polymorphism and BMI, waist circumference and triglycerides in determining PAI-1act, and between the 4G/5G polymorphism and fibrinogen and fibrinogen gamma prime in determining CLT. The C428T and G429A polymorphisms did not show direct relationships with PAI-1act or CLT but they did influence the association of other environmental factors with PAI-1act and CLT. Several of these interactions differed significantly between rural and urban subgroups, particularly in individuals harbouring the mutant alleles. In conclusion, although the 4G/5G polymorphism significantly affected PAI-1act, it contributed less than 1% to the PAI-1act variance. (Central) obesity was the biggest contributor to PAI-1act variance (12.5%). Urbanisation significantly influenced the effect of the 4G/5G polymorphism on PAI-1act as well as gene-environment interactions for the C428T and G429A genotypes in determining PAI-1act and CLT.

An unusual type of polymorphism in a liquid crystal

DOE PAGES

Li, Lin; Salamonczyk, Miroslaw; Shadpour, Sasan; ...

2018-02-19

Polymorphism is a remarkable concept in chemistry, materials science, computer science, and biology. Whether it is the ability of a material to exist in two or more crystal structures, a single interface connecting to two different entities, or alternative phenotypes of an organism, polymorphism determines function and properties. In materials science, polymorphism can be found in an impressively wide range of materials, including crystalline materials, minerals, metals, alloys, and polymers. Here in this paper we report on polymorphism in a liquid crystal. A bent-core liquid crystal with a single chiral side chain forms two structurally and morphologically significantly different liquidmore » crystal phases solely depending on the cooling rate from the isotropic liquid state. On slow cooling, the thermodynamically more stable oblique columnar phase forms, and on rapid cooling, a not heretofore reported helical microfilament phase. Since structure determines function and properties, the structural color for these phases also differs.« less

An unusual type of polymorphism in a liquid crystal

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Lin; Salamonczyk, Miroslaw; Shadpour, Sasan

Polymorphism is a remarkable concept in chemistry, materials science, computer science, and biology. Whether it is the ability of a material to exist in two or more crystal structures, a single interface connecting to two different entities, or alternative phenotypes of an organism, polymorphism determines function and properties. In materials science, polymorphism can be found in an impressively wide range of materials, including crystalline materials, minerals, metals, alloys, and polymers. Here in this paper we report on polymorphism in a liquid crystal. A bent-core liquid crystal with a single chiral side chain forms two structurally and morphologically significantly different liquidmore » crystal phases solely depending on the cooling rate from the isotropic liquid state. On slow cooling, the thermodynamically more stable oblique columnar phase forms, and on rapid cooling, a not heretofore reported helical microfilament phase. Since structure determines function and properties, the structural color for these phases also differs.« less

Outcomes Associated with Reducing the Urine Alkalinization Threshold in Patients Receiving High-Dose Methotrexate.

PubMed

Drost, Sarah A; Wentzell, Jason R; Giguère, Pierre; McLurg, Darcy L; Sabloff, Mitchell; Kanji, Salmaan; Nguyen, Tiffany T

2017-06-01

Urine alkalinization increases methotrexate (MTX) solubility and reduces the risk of nephrotoxicity. The objectives of this study were to determine whether a reduction in the urine pH threshold from 8 to 7 in patients receiving high-dose methotrexate (HDMTX) results in a shorter length of hospital stay, delayed MTX clearance, or higher rates of nephrotoxicity; and to determine whether specific factors were associated with prolonged MTX clearance. Retrospective cohort study. Hematology service of a large university-affiliated teaching hospital in Ottawa, Canada. Sixty-five adults with 150 HDMTX exposures who had elective admissions for HDMTX between September 1, 2014, and December 18, 2015, were included. Thirty-four patients (with 79 HDMTX exposures) had their urine alkalinized to a pH of 8 or higher, and 31 patients (with 71 HDMTX exposures) had their urine alkalinized to a pH of 7 or higher, after an institutional change in the urine pH threshold from 8 to 7 was implemented on May 1, 2015. Data related to patient demographics, urine alkalinization, MTX serum concentration monitoring, hospital length of stay, and renal function were collected retrospectively from patients' electronic health records. Lowering the urine pH threshold from 8 to 7 did not significantly affect hospital length of stay (absolute difference 3.5 hrs, 95% confidence interval -4.0 to 10.9) or clearance of MTX (elimination rate constant 0.058 in the pH of 7 or higher group vs 0.064 in the pH of 8 or higher group, p=0.233). Nephrotoxicity rates were similar between groups (15.5% in the pH of 7 or higher group vs 10.1% in the pH of 8 or higher group, p=0.34). Higher MTX dose and interacting medications (e.g., proton pump inhibitors and sulfonamide antibiotics) were significantly associated with delayed MTX elimination. No significant differences in HDMTX-associated hospital length of stay, MTX clearance, or rates of nephrotoxicity were noted between patients in the urine pH of 7 or higher and 8 or higher groups. Interacting medications and higher MTX dose were associated with delayed MTX elimination, suggesting that a closer review of interacting medications before HDMTX administration may be warranted. © 2017 Pharmacotherapy Publications, Inc.

Potential applications for halloysite nanotubes based drug delivery systems

NASA Astrophysics Data System (ADS)

Sun, Lin

Drug delivery refers to approaches, formulations, technologies, and systems for transporting a drug in the body. The purpose is to enhance the drug efficacy and to reduce side reactions, which can significantly improve treatment outcomes. Halloysite is a naturally occurred alumino-silicate clay with a tubular structure. It is a biocompatible material with a big surface area which can be used for attachment of targeted molecules. Besides, loaded molecules can present a sustained release manner in solution. These properties make halloysite nanotubes (HNTs) a good option for drug delivery. In this study, a drug delivery system was built based on halloysite via three different fabrication methods: physical adsorption, vacuum loading and layer-by-layer coating. Methotrexate was used as the model drug. Factors that may affect performance in both drug loading and release were tested. Results showed that methotrexate could be incorporated within the HNTs system and released in a sustained manner. Layer-by-layer coating showed a better potential than the other two methods in both MTX loading and release. Besides, lower pH could greatly improve MTX loading and release while the increased number of polyelectrolytes bilayers had a limited impact. Osteosarcoma is the most common primary bone malignancy in children and adolescents. Postoperative recurrence and metastasis has become one of the leading causes for patient death after surgical remove of the tumor mass. A strategy could be a sustained release of chemotherapeutics directly at the primary tumor sites where recurrence would mostly occur. Then, this HNTs based system was tested with osteosarcoma cells in vitro to show the potential of delivering chemotherapeutics in the treatment of osteosarcoma. Methotrexate was incorporated within HNTs with a layer-bylayer coating technique, and drug coated HNTs were filled into nylon-6 which is a common material for surgical sutures in industry. Results showed that (1) methotrexate could be released in a sustained manner; (2) cytotoxicity test confirmed the biocompatibility of HNTs and methotrexate coated HNTs; (3) proliferation test confirmed the growth inhibition of released methotrexate on osteosarcoma cells; and (4) nylon-6 could prolong the sustained release of methotrexate from polyelectrolytes coated HNTs. Another application comes from the prevention of surgical site infection. It is a common complication in surgery, which may prolong hospital stay, increase mortality rate, and cause additional financial burden for patients. By directly releasing antibiotics at the surgical site, it is supposed to enhance the drug efficacy and improve the treatment outcome. Therefore, the same HNTs based system was tested with E. coli in vitro to show the potential of delivering antibiotics to enhance the prevention of surgical site infection. Nitrofurantoin was incorporated within HNTs using the layer-by-layer coating technique, and the drug coated HNTs were filled into nylon-6 again. Results showed that (1) nitrofurantoin could be incorporated with this HNTs based drug delivery system, and released in a sustained manner; (2) nylon-6 could prolong the sustained release of nitrofurantoin from polyelectrolytes coated HNTs; and (3) released nitrofurantoin could severely inhibit E. coil growth. Therefore, a tunable drug delivery system based on HNTs was developed, and a great potential of medical application in drug delivery was shown.

A polymorphism in a transporter of testosterone is a determinant of androgen independence in prostate cancer.

PubMed

Sharifi, Nima; Hamada, Akinobu; Sissung, Tristan; Danesi, Romano; Venzon, David; Baum, Caitlin; Gulley, James L; Price, Douglas K; Dahut, William L; Figg, William D

2008-08-05

To determine if patients with advanced prostate cancer carrying a polymorphism that codes for a more active testosterone transporter have less durable responses to androgen-deprivation therapy (ADT) than patients not carrying this polymorphism. We previously determined that a polymorphism in SLCO1B3 affects testosterone transport and that those men who have at least one wild-type T allele at the 334 T > G polymorphism in this gene have a shorter survival. We hypothesized that the T allele which increases testosterone transport would be associated with a shorter interval from ADT to androgen independence. We examined the association between this SLCO1B3 polymorphism and time from ADT to androgen independence, ADT to prostate-specific antigen (PSA) nadir and PSA nadir to androgen independence in 68 Caucasian patients with advanced prostate cancer who were treated with ADT with metastatic disease (D2) or biochemical failure with no metastatic disease (D0). When examined separately, patients in the individual stages tended to have a shorter time to androgen independence with the T allele in the D0 (P = 0.11) and D2 (P = 0.18) groups. Combining these groups and stratifying by stage yielded a statistically significant shorter time to androgen independence with the T allele (P = 0.048). A polymorphism in a transporter that increases testosterone import is associated with a shorter time to androgen independence in patients with prostate cancer who are treated with ADT.

Changes in Body Mass Related to the Initiation of Disease-Modifying Therapies in Rheumatoid Arthritis.

PubMed

Baker, Joshua F; Sauer, Brian C; Cannon, Grant W; Teng, Chia-Chen; Michaud, Kaleb; Ibrahim, Said; Jorgenson, Erik; Davis, Lisa; Caplan, Liron; Cannella, Amy; Mikuls, Ted R

2016-08-01

Unintentional weight loss is important and can be predictive of long-term outcomes in patients with rheumatoid arthritis (RA). This study was undertaken to assess how primary therapies for RA may influence changes in body mass index (BMI) in RA patients from a large administrative database. Unique dispensing episodes of methotrexate, prednisone, leflunomide, and tumor necrosis factor inhibitors (TNFi) administered to RA patients were identified from the US Department of Veterans Affairs pharmacy databases. Values for C-reactive protein (CRP) level and BMI closest to the time point within 30 days of the treatment course start date and at follow-up time points were linked. Missing laboratory values were imputed. Weight loss was defined as a decrease in BMI of >1 kg/m(2) . Regression models were used to evaluate changes in BMI during each drug treatment as compared to treatment with methotrexate. To assess the impact of confounding by indication, propensity scores for use of each drug were incorporated in analyses using matched-weighting techniques. In total, 52,662 treatment courses in 32,859 RA patients were identified. At 6 months from the date of prescription fill, weight gain was seen among patients taking methotrexate, those taking prednisone, and those taking TNFi. On average, compared to methotrexate-treated patients, prednisone-treated patients had significantly more weight gain, while leflunomide-treated patients demonstrated weight loss. In multivariable models, more weight loss (β = -0.41 kg/m(2) , 95% confidence interval [95% CI] -0.46, -0.36; P < 0.001) and a greater risk of weight loss (odds ratio 1.73, 95% CI 1.55, 1.79; P < 0.001) were evident among those receiving leflunomide compared to those receiving methotrexate. Treatment with prednisone was associated with greater weight gain (β = 0.072 kg/m(2) , 95% CI 0.042, 0.10; P < 0.001). These associations persisted in analyses adjusted for propensity scores and in sensitivity analyses. Leflunomide is associated with significantly more, but modest, weight loss, while prednisone is associated with greater weight gain compared to other therapies for RA. © 2016, American College of Rheumatology.

T-614, a novel immunomodulator, attenuates joint inflammation and articular damage in collagen-induced arthritis

PubMed Central

Du, Fang; Lü, Liang-jing; Fu, Qiong; Dai, Min; Teng, Jia-lin; Fan, Wei; Chen, Shun-le; Ye, Ping; Shen, Nan; Huang, Xin-fang; Qian, Jie; Bao, Chun-de

2008-01-01

Introduction T-614 is a novel oral antirheumatic agent for the treatment of rheumatoid arthritis. Whether it has immunomodulatory or disease-modifying properties and its mechanism of action are largely undetermined. Methods Rats with collagen-induced arthritis (CIA) were treated with T-614 (5 and 20 mg/kg) daily. Animals receiving methotrexate (1 mg/kg every 3 days) and the nonsteroidal anti-inflammatory agent nimesulide (10 mg/kg per day) were used as controls. A combination therapy group was treated with both T-614(10 mg/kg per day) and methotrexate (1 mg/kg every 3 days). Hind paw swelling was evaluated and radiographic scores calculated. Serum cytokine levels were assessed by Bio-plex analysis. Quantitative PCR was used to evaluate expression of mRNA for interferon-γ, IL-4 and IL-17. Serum IL-17 and anti-type II collagen antibodies (total IgG, IgG1, IgG2a, IgG2b and IgM) were measured using ELISA. Results Oral T-614 inhibited paw swelling and offered significant protection against arthritis-induced cartilage and bone erosion, comparable to the effects of methotrexate. CIA rats treated with T-614 exhibited decreases in both mRNA expression of IL-17 in peripheral blood mononuclear cells and lymph node cells, and circulating IL-17 in a dose-dependent manner. T-614 also reduced serum levels of tumor necrosis factor-α, IL-1β and IL-6. A synergistic effect was observed for the combination of methotrexate and T-614. In addition, T-614 (20 mg/kg per day) depressed production of anti-type II collagen antibodies and differentially affected levels of IgG2a subclasses in vivo, whereas IgM level was decreased without any change in the IgG1 level. Together, the findings presented here indicate that the novel agent T-614 has disease-modifying effects against experimental arthritis, as opposed to nimesulide. Conclusions Our data suggested that T-614 is an effective disease-modifying agent that can prevent bone/cartilage destruction and inflammation in in CIA rats. Combination with methotrexate markedly enhances the therapeutic effect of T-614. PMID:19019215

Risk of Serious Infection in Juvenile Idiopathic Arthritis Patients Associated With Tumor Necrosis Factor Inhibitors and Disease Activity in the German Biologics in Pediatric Rheumatology Registry.

PubMed

Becker, Ingrid; Horneff, Gerd

2017-04-01

To examine the effects of tumor necrosis factor inhibitors on the risk for serious infections and other influencing factors in a registry. Patients exposed for the first time to etanercept, adalimumab, or methotrexate and serious infections were identified in the German Biologic Registry for Pediatric Rheumatology (BIKER) registry. Serious infection rates per 1,000 observation-years and relative risks were calculated. Cox regression identified risk factors and provided hazard ratios (HRs) for occurrence of infections. A total of 3,350 patients with 5,919 observation-years fulfilled the inclusion criteria for the study. The first biologic agents were etanercept (1,720 cases) and adalimumab (177 cases). A total of 1,453 patients were treated with methotrexate and no biologic agent. In total, 28 serious infections were reported in 26 patients (4.7 per 1,000 patient-years), 5 with methotrexate (1.6 per 1,000 patient-years), 21 with etanercept (8.1 per 1,000 patient-years), and 2 with adalimumab (9.7 per 1,000 patient-years). Significant univariate risk factors for infection were therapy with biologic agents, disease duration before therapy start, corticosteroid medication, nonbiologic premedications, higher clinical Juvenile Arthritis Disease Activity Score including maximal 10 joints (cJADAS10) at therapy start, and higher mean cJADAS10 during therapy. In multivariate Cox regression, only biologic therapy and cJADAS10 at therapy start remained significant. Risk for infection was increased by etanercept (univariate HR 6.0 [95% confidence interval (95% CI) 2.0-17.5]) or adalimumab (HR 7.3 [95% CI 1.3-40.0]) compared to methotrexate as well as by an elevated cJADAS10 at therapy start (HR 1.1 [95% CI 1.0-1.2] per unit increase). The total rate of serious infections reported in the BIKER registry seems low. Treatment with etanercept or adalimumab increases the risk for serious infection slightly, compared to methotrexate. Disease activity expressed by cJADAS10 appears to be an independent risk factor. © 2016, American College of Rheumatology.

Adenovirally mediated p53 overexpression diversely influence the cell cycle of HEp-2 and CAL 27 cell lines upon cisplatin and methotrexate treatment.

PubMed

Kraljević Pavelić, Sandra; Marjanović, Marko; Poznić, Miroslav; Kralj, Marijeta

2009-12-01

p53 gene plays a crucial role in the response to therapy. Since it is inactivated in the majority of human cancers, it is strongly believed that the p53 mutations confer resistance to therapeutics. In this paper we analyzed the influence of two mechanistically diverse antitumor agents--cisplatin and methotrexate on the proliferation and cell cycle of two head and neck squamous cancer cell lines HEp-2 (wild type p53 gene, but HPV 18/E6-inactivated protein) and CAL 27 (mutated p53 gene), along with the influence of adenovirally mediated p53 overexpression in modulation of cisplatin and methoterexate effects, whereby subtoxic vector/compound concentrations were employed. p53 gene was introduced into tumor cells using adenoviral vector (AdCMV-p53). The cell cycle perturbations were measured by two parameter flow cytometry. The expression of p53, p21(WAF1/CIP1) and cyclin B1 proteins was examined using immunocytochemistry and western blot methods. In CAL 27 cells overexpression of p53 completely abrogated high S phase content observed in methotrexate-treated cells into a G1 and slight G2 arrest, while it sustained G2 arrest of the cells treated with cisplatin, along with the reduction of DNA synthesis and cyclin B1 expression. On the other hand, in HEp-2 cell line p53 overexpression slightly slowed down the progression through S phase in cells treated with methotrexate, decreased the cyclin B1 expression only after 24 h, and failed to sustain the G2 arrest after treatment with cisplatin alone. Instead, it increased the population of S phase cells that were not actively synthesizing DNA, sustained cyclin B1 expression and allowed the G2 cells to progress through mitosis. This study demonstrates that adenovirally mediated p53 overexpression at sub-cytotoxic levels enhanced the activity of low doses of cisplatin and methotrexate in HEp-2 and CAL 27 cells through changes in the cell cycle. However, the mechanisms of these effects differ depending on the genetic context and on the chemotherapeutics' modality of action.

Estimating the cost-effectiveness of 54 weeks of infliximab for rheumatoid arthritis.

PubMed

Wong, John B; Singh, Gurkirpal; Kavanaugh, Arthur

2002-10-01

To estimate the cost-effectiveness of infliximab plus methotrexate for active, refractory rheumatoid arthritis. We projected the 54-week results from a randomized controlled trial of infliximab into lifetime economic and clinical outcomes using a Markov computer simulation model. Direct and indirect costs, quality of life, and disability estimates were based on trial results; Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) database outcomes; and published data. Results were discounted using the standard 3% rate. Because most well-accepted medical therapies have cost-effectiveness ratios below $50,000 to $100,000 per quality-adjusted life-year (QALY) gained, results below this range were considered to be "cost-effective." At 3 mg/kg, each infliximab infusion would cost $1393. When compared with methotrexate alone, 54 weeks of infliximab plus methotrexate decreased the likelihood of having advanced disability from 23% to 11% at the end of 54 weeks, which projected to a lifetime marginal cost-effectiveness ratio of $30,500 per discounted QALY gained, considering only direct medical costs. When applying a societal perspective and including indirect or productivity costs, the marginal cost-effectiveness ratio for infliximab was $9100 per discounted QALY gained. The results remained relatively unchanged with variation of model estimates over a broad range of values. Infliximab plus methotrexate for 54 weeks for rheumatoid arthritis should be cost-effective with its clinical benefit providing good value for the drug cost, especially when including productivity losses. Although infliximab beyond 54 weeks will likely be cost-effective, the economic and clinical benefit remains uncertain and will depend on long-term results of clinical trials.

Cell-penetrating conjugates of pentaglutamylated methotrexate as potential anticancer drugs against resistant tumor cells.

PubMed

Szabó, Ildikó; Orbán, Erika; Schlosser, Gitta; Hudecz, Ferenc; Bánóczi, Zoltán

2016-06-10

The emerging resistance of tumor cells against methotrexate (MTX) is one of the major limitations of the MTX treatment of tumorous diseases. The disturbance in the polyglutamation which is a main step in the mechanism of methotrexate action is often the reason of the resistance. Delivery of polyglutamylated MTX into cells may evade the mechanisms that are responsible for drug resistance. In this study conjugates of methotrexate and its pentaglutamylated derivatives with cell-penetrating peptides - penetratin and octaarginine - were investigated. The cellular-uptake and in vitro cytostatic activity of conjugates were examined on breast cancer cell cultures (MDA-MB-231 as resistant and MCF-7 as sensitive cell culture). These cell cultures showed very different behaviour towards the conjugates. Although the presence of pentaglutamyl moiety significantly decreased the internalisation of conjugates, some of them were significantly active in vitro. All of the conjugates were able to penetrate in some extent into both cell types, but only the conjugates of penetratin showed in vitro cytostatic activity. The most effective conjugates were the MTX-Glu5-Penetratin(desMet) and MTX-Glu5-GFLG-Penetratin(desMet). The latter was effective on both cell cultures while the former was active only on the resistant tumor cells. Our results suggest that the translocation of polyglutamylated MTX may be a new way to treat sensitive and more importantly resistant tumors. While both penetratin and octaarginine peptides were successfully used to deliver several kinds of cargos earlier in our case the activity of penetratin conjugates was more pronounced. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Intrathecal trastuzumab (Herceptin) and methotrexate for meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer: a case report.

PubMed

Stemmler, Hans-Joachim; Mengele, Karin; Schmitt, Manfred; Harbeck, Nadia; Laessig, Dorit; Herrmann, Karin A; Schaffer, Pamela; Heinemann, Volker

2008-09-01

Leptomeningeal carcinomatosis represents a rare manifestation of metastatic breast cancer (MBC). We herewith report on a patient suffering from HER2 overexpressing MBC who received intrathecal methotrexate and trastuzumab for meningeal carcinomatosis. A 48-year-old woman was diagnosed with breast cancer in December 2002. Following surgery, six cycles of adjuvant FE100C plus irradiation and, subsequently for 1 year, trastuzumab were given. As a result of disseminated metastatic spread in October 2005, the patient received whole-brain radiotherapy for symptomatic central nervous system involvement, and was put on several trastuzumab-based combination regimens (capecitabine, vinorelbine, paclitaxel). In June 2006, the patient developed clinical signs of terminal cone involvement with overflow incontinence and paraparesis of the legs. Immediate radiation led to partial relief from clinical symptoms. Subsequently, the patient was put on the tyrosine kinase inhibitor lapatinib and capecitabine (August to October 2007), but on November 6th the patient suffered again from overflow incontinence and weakness of the legs. Failing to respond to lapatinib, the patient received gemcitabine/cisplatin and, additionally, was recommenced on intravenous trastuzumab. Owing to progressive leptomeningeal disease, the patient received repeated doses of intrathecal methotrexate and trastuzumab. Within 2 weeks and four intrathecal treatments, cerebrospinal fluid cytology showed the absence of tumor cells. Moreover, a striking clinical improvement with resolution of the paraparesis of the legs and overflow incontinence was observed. This case report gives details regarding the clinical course of a breast cancer patient who received intrathecal trastuzumab and methotrexate via lumbar puncture for meningeal carcinomatosis of HER2-overexpressing MBC.

Effects of fentanyl administration on locomotor response in horses with the G57C μ-opioid receptor polymorphism.

PubMed

Wetmore, Lois A; Pascoe, Peter J; Shilo-Benjamini, Yael; Lindsey, Jane C

2016-08-01

OBJECTIVE To determine the locomotor response to the administration of fentanyl in horses with and without the G57C polymorphism of the μ-opioid receptor. ANIMALS 20 horses of various breeds and ages (10 horses heterozygous for the G57C polymorphism and 10 age-, breed-, and sex-matched horses that did not have the G57C polymorphism). PROCEDURES The number of steps each horse took was counted over consecutive 2-minute periods for 20 minutes to determine a baseline value. The horse then received a bolus of fentanyl (20 μg/kg, IV), and the number of steps was again counted during consecutive 2-minute periods for 60 minutes. The mean baseline value was subtracted from each 2-minute period after fentanyl administration; step counts with negative values were assigned a value of 0. Data were analyzed by use of a repeated-measures ANOVA. RESULTS Data for 19 of 20 horses (10 horses with the G57C polymorphism and 9 control horses without the G57C polymorphism) were included in the analysis. Horses with the G57C polymorphism had a significant increase in locomotor activity, compared with results for horses without the polymorphism. There was a significant group-by-time interaction. CONCLUSIONS AND CLINICAL RELEVANCE Horses heterozygous for the G57C polymorphism of the μ-opioid receptor had an increased locomotor response to fentanyl administration, compared with the response for horses without this polymorphism. The clinical impact of this finding should be investigated.

Systemic treatment of papular dermatitis: A retrospective study.

PubMed

Moustafa, Farah A; Sandoval, Laura F; Jorizzo, Joseph L; Huang, William W

2015-10-01

Papular dermatitis is an intensely pruritic eruption that is often refractory to conventional therapy. The aim of this study was to evaluate the efficacy of different non-steroidal systemic therapies for long-term control of disease in patients with papular dermatitis. This was a single center, retrospective study involving a chart review of patients with a diagnosis of papular dermatitis who were prescribed systemic therapy between 1 January 2002 and 31 December 2012. Fourteen patients were identified that were treated with a systemic agent. Median duration of treatment was 25 months. Methotrexate was used first line in 12 patients, with control of disease achieved in eight patients with a dose between 2.5 and 10 mg weekly. Azathioprine and mycophenolate mofetil also provided control of disease when used as first-line therapy in the remaining two patients. While azathiopurine was effective in patients who failed methotrexate, gastrointestinal side effects limited its use long term. Low dose weekly methotrexate, as well as, azathioprine and mycophenolate mofetil are long-term treatment options for patients with papular dermatitis refractory to other therapies.

Encapsulation of methotrexate loaded magnetic microcapsules for magnetic drug targeting and controlled drug release

NASA Astrophysics Data System (ADS)

Chakkarapani, Prabu; Subbiah, Latha; Palanisamy, Selvamani; Bibiana, Arputha; Ahrentorp, Fredrik; Jonasson, Christian; Johansson, Christer

2015-04-01

We report on the development and evaluation of methotrexate magnetic microcapsules (MMC) for targeted rheumatoid arthritis therapy. Methotrexate was loaded into CaCO3-PSS (poly (sodium 4-styrenesulfonate)) doped microparticles that were coated successively with poly (allylamine hydrochloride) and poly (sodium 4-styrenesulfonate) by layer-by-layer technique. Ferrofluid was incorporated between the polyelectrolyte layers. CaCO3-PSS core was etched by incubation with EDTA yielding spherical MMC. The MMC were evaluated for various physicochemical, pharmaceutical parameters and magnetic properties. Surface morphology, crystallinity, particle size, zeta potential, encapsulation efficiency, loading capacity, drug release pattern, release kinetics and AC susceptibility studies revealed spherical particles of ~3 μm size were obtained with a net zeta potential of +24.5 mV, 56% encapsulation and 18.6% drug loading capacity, 96% of cumulative drug release obeyed Hixson-Crowell model release kinetics. Drug excipient interaction, surface area, thermal and storage stability studies for the prepared MMC was also evaluated. The developed MMC offer a promising mode of targeted and sustained release drug delivery for rheumatoid arthritis therapy.

Diosmin Attenuates Methotrexate-Induced Hepatic, Renal, and Cardiac Injury: A Biochemical and Histopathological Study in Mice

PubMed Central

Khalifa, Hesham A.; Al-Quraishy, Saleh A.

2017-01-01

The current study was designed to investigate the beneficial role of diosmin, a biologically active flavonoid, against methotrexate- (MTX-) induced hepatic, renal, and cardiac injuries in mice. Male Swiss albino mice received a single intraperitoneal injection of MTX (at 20 mg/kg, body weight) either alone or in combination with oral diosmin (at 50 or 100 mg/kg body weight, for 10 days). Serum was used to evaluate tissue injury markers, while hepatic, renal, and cardiac tissue samples were obtained for determination of antioxidant activity as well as histopathological examination. Diosmin treatment ameliorated the MTX-induced elevation of serum alkaline phosphatase, aminotransferases, urea, creatinine, lactate dehydrogenase, and creatine kinases as well as plasma proinflammatory cytokines (interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha). Additionally, both diosmin doses significantly reduced tissue levels of malondialdehyde and nitric oxide and increased those of glutathione, glutathione peroxidase, glutathione reductase, glutathione S-transferase, superoxide dismutase, and catalase, compared to the MTX-intoxicated group. Histopathological examination showed that diosmin significantly minimized the MTX-induced histological alterations and nearly restored the normal architecture of hepatic, renal, and cardiac tissues. Based on these findings, diosmin may be a promising agent for protection against MTX-induced cytotoxicity in patients with cancer and autoimmune diseases. PMID:28819543

Enhanced anti-tumoral activity of methotrexate-human serum albumin conjugated nanoparticles by targeting with Luteinizing Hormone-Releasing Hormone (LHRH) peptide.

PubMed

Taheri, Azade; Dinarvand, Rassoul; Atyabi, Fatemeh; Ahadi, Fatemeh; Nouri, Farank Salman; Ghahremani, Mohammad Hossein; Ostad, Seyed Nasser; Borougeni, Atefeh Taheri; Mansoori, Pooria

2011-01-01

Active targeting could increase the efficacy of anticancer drugs. Methotrexate-human serum albumin (MTX-HSA) conjugates, functionalized by luteinizing hormone-releasing hormone (LHRH) as targeting moieties, with the aim of specifically targeting the cancer cells, were prepared. Owing to the high expression of LHRH receptors in many cancer cells as compared to normal cells, LHRH was used as the targeting ligand in this study. LHRH was conjugated to MTX-HSA nanoparticles via a cross-linker. Three types of LHRH targeted nanoparticles with a mean particle size between 120-138 nm were prepared. The cytotoxicity of LHRH targeted and non-targeted nanoparticles were determined on the LHRH positive and negative cell lines. The internalization of the targeted and non-targeted nanoparticles in LHRH receptor positive and negative cells was investigated using flow cytometry analysis and fluorescence microscopy. The cytotoxicity of the LHRH targeted nanoparticles on the LHRH receptor positive cells were significantly more than non-targeted nanoparticles. LHRH targeted nanoparticles were also internalized by LHRH receptor positive cells significantly more than non-targeted nanoparticles. There were no significant differences between the uptake of targeted and non-targeted nanoparticles to the LHRH receptor negative cells. The active targeting procedure using LHRH targeted MTX-HSA nanoparticles could increase the anti-tumoral activity of MTX.

Low-dose chemotherapy with methotrexate and vinblastine for patients with desmoid tumors: relationship to CTNNB1 mutation status.

PubMed

Nishida, Yoshihiro; Tsukushi, Satoshi; Urakawa, Hiroshi; Hamada, Shunsuke; Kozawa, Eiji; Ikuta, Kunihiro; Ando, Yuichi; Ishiguro, Naoki

2015-12-01

This study was conducted to determine the efficacy and safety of low-dose chemotherapy with methotrexate (MTX) and vinblastine (VBL) for patients with desmoid tumors refractory to meloxicam treatment, focusing in particular on the relationship between the efficacy of this chemotherapy and catenin β-1 (CTNNB1) mutation status. Since March 2003, patients pathologically diagnosed with extraperitoneal desmoid tumors have been prospectively treated with meloxicam, a COX-2 inhibitor, at our institution. Patients with inoperable tumors who were resistant to meloxicam treatment underwent MTX and VBL therapy every other week. The responses of all patients were evaluated, and factors that were correlated with efficacy were analyzed, including CTNNB1 mutation status. Sixty-eight patients were prospectively treated with meloxicam. MTX + VBL therapy was administered in 15 patients. Six patients showed a partial response. Only one patient presented disease progression. A few patients showed grade 3-4 treatment-related toxicity with the administration of MTX and VBL every other week. Intriguingly, CTNNB1 status did not affect the efficacy of this treatment. MTX and VBL treatment every other week is well tolerated and achieved a favorable response in patients resistant to meloxicam treatment, regardless of CTNNB1 mutation status.

The effects of combined therapy of rheumatoid arthritis on the acute phase reactants.

PubMed

Rexhepi, Sylejman; Rexhepi, Mjellma; Sahatçiu-Meka, Vjollca; Pllana, Ejup; Dragusha, Gani; Gashi, Masar; Rexhepi, Blerta

2009-01-01

The paper presents the results of studies of acute phase reactants in the 60 treated patients with rheumatoid arthritis. Patients were divided into two groups, depending on the applied treatment: group I (n = 30) was treated with methotrexate, sulfasalazine and hydroxychloroquine, and group II (n = 30) with methotrexate. The results of our study shows that there is a statistically significant reduction in the value of acute phase reactants and clinical parameters after treatment in both investigated groups of patients, and also a significant statistical difference between the first and second group of treated patients.

Recurrent Bilateral Focal Myositis.

PubMed

Nagafuchi, Hiroko; Nakano, Hiromasa; Ooka, Seido; Takakuwa, Yukiko; Yamada, Hidehiro; Tadokoro, Mamoru; Shimojo, Sadatomo; Ozaki, Shoichi

This report describes a rare case of recurrent bilateral focal myositis and its successful treatment via methotrexate. A 38-year-old man presented myalgia of the right gastrocnemius in May 2005. Magnetic resonance imaging showed very high signal intensity in the right gastrocnemius on short-tau inversion recovery images. A muscle biopsy revealed inflammatory CD4+ cell-dominant myogenic change. Focal myositis was diagnosed. The first steroid treatment was effective. Tapering of prednisolone, however, repeatedly induced myositis relapse, which progressed to multiple muscle lesions of both lower limbs. Initiation of methotrexate finally allowed successful tapering of prednisolone, with no relapse in the past 4 years.

Recurrent Bilateral Focal Myositis

PubMed Central

Nagafuchi, Hiroko; Nakano, Hiromasa; Ooka, Seido; Takakuwa, Yukiko; Yamada, Hidehiro; Tadokoro, Mamoru; Shimojo, Sadatomo; Ozaki, Shoichi

2016-01-01

This report describes a rare case of recurrent bilateral focal myositis and its successful treatment via methotrexate. A 38-year-old man presented myalgia of the right gastrocnemius in May 2005. Magnetic resonance imaging showed very high signal intensity in the right gastrocnemius on short-tau inversion recovery images. A muscle biopsy revealed inflammatory CD4+ cell-dominant myogenic change. Focal myositis was diagnosed. The first steroid treatment was effective. Tapering of prednisolone, however, repeatedly induced myositis relapse, which progressed to multiple muscle lesions of both lower limbs. Initiation of methotrexate finally allowed successful tapering of prednisolone, with no relapse in the past 4 years. PMID:27853086

Covalent conjugation of graphene oxide with methotrexate and its antitumor activity

NASA Astrophysics Data System (ADS)

Wojtoniszak, M.; Urbas, K.; Perużyńska, M.; Kurzawski, M.; Droździk, M.; Mijowska, E.

2013-05-01

Here, we have functionalized graphene oxide with anticancer drug methotrexate through amide bonding. A kinetics of the drug release from graphene oxide in physiological solution - phosphate buffered saline (PBS) containing different biocompatible polymers have been investigated. Dispersion of MTX-GO in poly sodium-4-styrene sulfonate and poly ethylene glycol resulted in increase of the release time. The material was characterized with transmission electron microscopy, atomic force microscopy, Raman spectroscopy, Fourier transform infrared spectroscopy and UV-vis spectroscopy. Furthermore, antineoplastic action against human breast adenocarcinoma cell line MCF7 of MTX-GO and empty graphene oxide was explored.

Leflunomide is equally efficacious and safe compared to low dose rituximab in refractory rheumatoid arthritis given in combination with methotrexate: results from a randomized double blind controlled clinical trial.

PubMed

Wijesinghe, Harindu; Galappatthy, Priyadharshini; de Silva, Rajiva; Seneviratne, Suranjith L; Saravanamuttu, Ushagowry; Udagama, Preethi; Hart, Melanie; Kelleher, Peter; Senerath, Upul; Fernandopulle, Rohini; Weerasekera, Lilani P; Wijayaratne, Lalith S

2017-07-19

The standard dose of rituximab used in rheumatoid arthritis (RA) is 1000 mg but recent studies have shown that low dose (500 mg) is also effective. Efficacy of low dose rituximab in rheumatoid arthritis (RA) refractory to first-line non-biologic Disease Modifying Anti Rheumatic Drugs (DMARDs), compared to leflunomide is unknown. In a tertiary care referral setting, we conducted a randomized, double blind controlled clinical trial comparing the efficacy and safety of low-dose rituximab-methotrexate combination with leflunomide-methotrexate combination. Patients on methotrexate (10-20 mg/week) with a Disease Activity Score (DAS) > 3.2 were randomly assigned to rituximab (500 mg on days 1 and 15) or leflunomide (10-20 mg/day). The primary end-point was ACR20 at 24 weeks. Sample of 40 had 70% power to detect a 30% difference. ACR50, ACR70, DAS, EULAR good response, CD3 + (T cell), CD19 + (B cell) and CD19 + CD27+ (memory B cell) counts, tetanus and pneumococcal antibody levels were secondary end points. Baseline characteristics were comparable in the two groups. At week 24, ACR20 was 85% vs 84% (p = 0.93), ACR50 was 60% vs. 64% (p = 0.79) and ACR70 was 35% vs 32% (P = 0.84), in rituximab and in leflunomide groups respectively. Serious adverse events were similar. With rituximab there was significant reduction in B cells (p < 0.001), memory B cells (p < 0.001) and pneumococcal antibody levels (P < 0.05) without significant changes in T cells (p = 0.835) and tetanus antibody levels (p = 0.424) at 24 weeks. With leflunomide, significant reduction in memory B cells (p < 0.01) and pneumococcal antibody levels (p < 0.01) occurred without significant changes in B cells (P > 0.05), T cells (P > 0.05) or tetanus antibody levels (P > 0.05). Leflunomide-methotrexate combination is as efficacious as low-dose rituximab-methotrexate combination at 24 weeks, in RA patient's refractory to initial DMARDs. The high responses seen in both groups have favorable cost implications for patients in developing countries. Changes in immune parameters with leflunomide are novel and need further characterization. The trial was registered with the Sri Lanka Clinical Trials Registry (SLCTR), a publicly accessible primary registry linked to the registry network of the International Clinical Trials Registry Platform of the WHO (WHO-ICTRP) (registration number: SLCTR/2008/008 dated 16th May 2008).

Polymorphisms in GSTM1, GSTT1, GSTP1, and GSTM3 genes and breast cancer risk in northeastern Mexico.

PubMed

Jaramillo-Rangel, G; Ortega-Martínez, M; Cerda-Flores, R M; Barrera-Saldaña, H A

2015-06-11

Glutathione S-transferases (GSTs) are a family of phase II metabolizing enzymes involved in carcinogen detoxification and the metabolism of various bioactive compounds. Several genes that code for these enzymes are polymorphic in an ethnicity-dependent manner, with particular genotypes previously associated with an increased risk of breast cancer. The purpose of this study was to determine the frequencies of polymorphisms in the genes GSTM1, GSTT1, GSTP1, and GSTM3 and to investigate whether an association exists between these genes and breast cancer risk in subjects from northeastern Mexico. Genotypes were determined for 243 women with histologically confirmed breast cancer and 118 control subjects. Gene polymorphisms were analyzed using a DNA microarray. We found an increased breast cancer risk associated with the GSTM1 gene deletion polymorphism (OR = 2.19; 95%CI = 1.50-3.21; P = 0.001). No associations between the GSTT1, GSTP1, and GSTM3 genotypes and neoplasia risk were observed. In conclusion, we determined the genotype distribution of GST polymorphisms in control subjects and breast cancer patients from northeastern Mexico. The GSTM1 null genotype was associated with breast cancer risk. Our findings may be used to individualize breast cancer screening and therapeutic intervention in our population, which displays ethnic characteristics that differentiate it from other populations in Mexico.

Trial of Early Aggressive Therapy in Polyarticular Juvenile Idiopathic Arthritis

PubMed Central

Wallace, Carol A.; Giannini, Edward H.; Spalding, Steven J.; Hashkes, Philip J.; O’Neil, Kathleen M.; Zeft, Andrew S.; Szer, Ilona S.; Ringold, Sarah; Brunner, Hermine I.; Schanberg, Laura E.; Sundel, Robert P.; Milojevic, Diana; Punaro, Marilynn G.; Chira, Peter; Gottlieb, Beth S.; Higgins, Gloria C.; Ilowite, Norman T.; Kimura, Yukiko; Hamilton, Stephanie; Johnson, Anne; Huang, Bin; Lovell, Daniel J.

2011-01-01

OBJECTIVES To determine if aggressive treatment initiated early in the course of rheumatoid factor positive or negative polyarticular juvenile idiopathic arthritis (poly-JIA) can induce clinical inactive disease (CID) within 6 months. METHODS Between May 2007 and October 2010 a multi-center, prospective, double blind, randomized, placebo controlled trial of two aggressive treatments was conducted in 85 children aged 2 to 16 years with polyarticular JIA of less than 12 months duration. Patients received either methotrexate 0.5 mg/kg/wk SQ (40 mg max), etanercept 0.8 mg/kg/wk (50 mg max), prednisolone 0.5 mg/kg/d (60 mg max) tapered to 0 by 17 weeks (Arm 1), or methotrexate (same dose as Arm 1), etanercept placebo, and prednisolone placebo (Arm 2). The primary outcome was CID at 6 months. An exploratory phase determined the rate of clinical remission on medication (6 months of continuous CID) at 12 months. RESULTS By 6 months, 17 of 42 (40%) of patients in Arm 1 and 10 of 43 (23%) in Arm 2 had achieved CID (X2 = 2.91; p = 0.088). After 12 months, 9 patients in Arm 1 and 3 in Arm 2 achieved clinical remission on medication (p = 0.0534). There were no significant inter-arm differences in adverse events. CONCLUSIONS Although this study did not meet its primary endpoint, early aggressive therapy in this cohort of children with recent onset polyarticular JIA resulted in substantial proportions of patients in both arms achieving CID by 6 months and clinical remission on medication within 12 months of treatment. PMID:22183975

Effects of Streptococcus thermophilus TH-4 in a rat model of doxorubicin-induced mucositis.

PubMed

Wang, Hanru; Brook, Caitlin L; Whittaker, Alexandra L; Lawrence, Andrew; Yazbeck, Roger; Howarth, Gordon S

2013-08-01

Mucositis is a debilitating intestinal side effect of chemotherapeutic regimens. Probiotics have been considered a possible preventative treatment for mucositis. Streptococcus thermophilus TH-4 (TH-4), a newly identified probiotic, has been shown to partially alleviate mucositis induced by administration of the antimetabolite chemotherapy drug, methotrexate in rats; likely mediated through a mechanism of folate production. However, its effects against other classes of chemotherapy drug have yet to be determined. The authors investigated the effects of TH-4 in a rat model of mucositis induced by the anthracycline chemotherapy drug, doxorubicin. Gastrointestinal damage was induced in female Dark Agouti rats (148.3 ± 1.5 g) by intraperitoneal injection of doxorubicin (20 mg/kg). Animals recieved a daily oral gavage of TH-4 at 10(9) cfu/ml or skim milk (vehicle) from days 0 to 8. At day 6, rats were injected with either saline or doxorubicin. At kill, small intestinal tissues were collected for determination of sucrase and myeloperoxidase (MPO) activities and histological assessment. Body weight was significantly decreased by doxorubicin compared with normal controls (p < 0.05). Histological parameters, such as crypt depth and villus height, were also significantly decreased by doxorubicin. TH-4 partially prevented the loss of body weight induced by doxorubicin (2.3% compared with 4%), but provided no further therapeutic benefit. The minimal amelioration of doxorubicin-induced mucositis by TH-4 further supports folate production as a likely mechanism of TH-4 action against methotrexate-induced mucositis. Further studies into TH-4 are required to confirm its applicability to other conventional chemotherapy regimens.

MAOA and TNF-β gene polymorphisms are associated with photophobia but not osmophobia in patients with migraine.

PubMed

Ishii, Masakazu; Usami, Shino; Hara, Hajime; Imagawa, Atsuko; Masuda, Yutaka; Shimizu, Shuniichi

2014-06-01

Photophobia and osmophobia are typical symptoms associated with migraine, but the contributions of gene polymorphisms to these symptoms are not fully elucidated. We investigated whether the gene polymorphisms are involved in photophobia and osmophobia in patients with migraine. Ninety-one migraine patients and 119 non-headache healthy volunteers were enrolled. The 12 gene polymorphisms were determined by polymerase-chain-reaction (PCR) and PCR restriction-fragment-length polymorphism analysis. Photophobia and osmophobia were observed in 49 (54%) and 31 patients (34%), respectively. Distributions of monoamine oxidase A (MAOA) T941G and tumour necrosis factor-β (TNF-β) G252A polymorphisms were significantly different between patients with photophobia and controls. However, no gene polymorphism differences were observed between patients with osmophobia and controls. The MAOA T941G and TNF-β G252A gene polymorphisms appear to contribute to photophobia but not to osmophobia. We propose that different gene polymorphisms are responsible for photophobia and osmophobia symptoms during migraine.

Asymmetric Dispersal Can Maintain Larval Polymorphism: A Model Motivated by Streblospio benedicti

PubMed Central

Zakas, Christina; Hall, David W.

2012-01-01

Polymorphism in traits affecting dispersal occurs in a diverse variety of taxa. Typically, the maintenance of a dispersal polymorphism is attributed to environmental heterogeneity where parental bet-hedging can be favored. There are, however, examples of dispersal polymorphisms that occur across similar environments. For example, the estuarine polychaete Streblospio benedicti has a highly heritable offspring dimorphism that affects larval dispersal potential. We use analytical models of dispersal to determine the conditions necessary for a stable dispersal polymorphism to exist. We show that in asexual haploids, sexual haploids, and in sexual diploids in the absence of overdominance, asymmetric dispersal is required in order to maintain a dispersal polymorphism when patches do not vary in intrinsic quality. Our study adds an additional factor, dispersal asymmetry, to the short list of mechanisms that can maintain polymorphism in nature. The region of the parameter space in which polymorphism is possible is limited, suggesting why dispersal polymorphisms within species are rare. PMID:22576818