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Sample records for methotrexate mtx treatment

  1. Determinants for drug survival of methotrexate in patients with psoriasis, split according to different reasons for discontinuation: results of the prospective MTX-CAPTURE

    NARCIS (Netherlands)

    Otero, M.E.; Reek, J.M.P.A. van den; Seyger, M.M.B.; Kerkhof, P.C.M. van de; Kievit, W.; Jong, E.M.G.J. de

    2017-01-01

    BACKGROUND: 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. OBJECTIVES: To describe 5-year drug survival for MTX in patients with psoriasis, split

  2. Weekly vs. daily administration of oral methotrexate (MTX) for generalized plaque psoriasis: a randomized controlled clinical trial.

    Science.gov (United States)

    Radmanesh, Mohammad; Rafiei, Behnam; Moosavi, Zahra-Beigum; Sina, Niloofar

    2011-10-01

    Methotrexate (MTX) treatment for psoriasis is most often administered weekly, because the drug has been considered more hepatotoxic when taken daily. However, some patients may tolerate smaller, more frequent doses better. To study the efficacy and toxicity of daily vs. weekly MTX. In a randomized controlled trial, 101 patients with generalized plaque psoriasis received oral MTX 2.5 mg daily for weeks, 4 weeks and monthly for a total of 4 months. Changes in PASI scores were classified into three categories: >75% improvement was considered significant; 25-75% moderate; and <25% poor. Sixty Group 1 patients and 81 Group 2 patients showed a significant response (P-value 0.001); 19 patients in Group 1 and 14 in Group 2 responded moderately; 22 patients in Group 1 and six patients from Group 2 responded poorly. Forty-five patients in Group 1 and 33 in Group 2 developed transient increases in liver enzymes (P-value 0.11). Nausea, headache, fatigue, and gastrointestinal upset were noted in four Group 1 patients and 30 Group 2 patients (P-value 0.0001). Nausea, vomiting, headache, and fatigue were significantly less common side effects in our patients who received MTX daily, but liver enzyme abnormalities were less common, and clinical efficacy was greater in the patients who received MTX weekly. © 2011 The International Society of Dermatology.

  3. Identification and characterization of the direct interaction between methotrexate (MTX and high-mobility group box 1 (HMGB1 protein.

    Directory of Open Access Journals (Sweden)

    Yuki Kuroiwa

    Full Text Available BACKGROUND: Methotrexate (MTX is an agent used in chemotherapy of tumors and autoimmune disease including rheumatoid arthritis (RA. In addition, MTX has some anti-inflammatory activity. Although dihydrofolate reductase (DHFR is a well-known target for the anti-tumor effect of MTX, the mode of action for the anti-inflammatory activity of MTX is not fully understood. METHODOLOGY/RESULT: Here, we performed a screening of MTX-binding proteins using T7 phage display with a synthetic biotinylated MTX derivative. We then characterized the interactions using surface plasmon resonance (SPR analysis and electrophoretic mobility shift assay (EMSA. Using a T7 phage display screen, we identified T7 phages that displayed part of high-mobility group box 1 (HMGB1 protein (K86-V175. Binding affinities as well as likely binding sites were characterized using genetically engineered truncated versions of HMGB1 protein (Al G1-K87, Bj: F88-K181, indicating that MTX binds to HMGB1 via two independent sites with a dissociation constants (KD of 0.50±0.03 µM for Al and 0.24 ± 0.01 µM for Bj. Although MTX did not inhibit the binding of HMGB1 to DNA via these domains, HMGB1/RAGE association was impeded in the presence of MTX. These data suggested that binding of MTX to part of the RAGE-binding region (K149-V175 in HMGB1 might be significant for the anti-inflammatory effect of MTX. Indeed, in murine macrophage-like cells (RAW 264.7, TNF-α release and mitogenic activity elicited by specific RAGE stimulation with a truncated monomeric HMGB1 were inhibited in the presence of MTX. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that HMGB1 is a direct binding protein of MTX. Moreover, binding of MTX to RAGE-binding region in HMGB1 inhibited the HMGB1/RAGE interaction at the molecular and cellular levels. These data might explain the molecular basis underlying the mechanism of action for the anti-inflammatory effect of MTX.

  4. Complete Remission of Methotrexate-Related Epstein-Barr-Virus-Associated Hodgkin-Like Lymphoma following Withdrawal of MTX Coupled with Clarithromycin Administration

    Directory of Open Access Journals (Sweden)

    Nobuo Takemori

    2012-01-01

    Full Text Available Patients with rheumatoid arthritis (RA are known to develop lymphoproliferative disorders (LPDs during the course of illness, particularly in cases treated with methotrexate (MTX for long periods. We describe a case of MTX-related Epstein-Barr-virus-(EBV- associated LPD resembling Hodgkin’s lymphoma (HL, in which a dramatic complete remission was achieved after withdrawal of MTX coupled with clarithromycin (CAM administration. Withdrawal of MTX coupled with CAM administration seemed to be effective for treating MTX-related EBV-associated LPDs. In particular, an immunomodulative effect of CAM might have been involved in achieving complete remission.

  5. Treatment efficacy and methotrexate-related toxicity in patients with rheumatoid arthritis receiving methotrexate in combination with adalimumab.

    Science.gov (United States)

    Burmester, Gerd R; Kaeley, Gurjit S; Kavanaugh, Arthur F; Gabay, Cem; MacCarter, Daryl K; Nash, Peter; Takeuchi, Tsutomu; Goss, Sandra L; Rodila, Ramona; Chen, Kun; Kupper, Hartmut; Kalabic, Jasmina

    2017-01-01

    Treatment of rheumatoid arthritis (RA) with a combination of methotrexate (MTX)+adalimumab (ADA) is more effective than ADA monotherapy. We assessed the toxicity of different doses of MTX and treatment efficacy of ADA+MTX in two trials. Data originated from CONCERTO, in patients with early RA initiating ADA+ 2.5, 5, 10 or 20 mg/week MTX for 26 weeks; and MUSICA, in patients with an inadequate response to MTX initiating ADA+ 7.5 or 20 mg/week MTX for 24 weeks. Efficacy was assessed by the American College of Rheumatology 50 (ACR50). Patient-reported MTX-related toxicity information was collected at each visit on 18 prespecified MTX-related adverse events (AE) in the MTX label. In CONCERTO, ACR50 rates increased over time, ranging from 54% to 68% at week 26, while AE rates remained steady, ranging from 2.4% to 17.8% at week 26. Of 395 patients, 113 (28.6%) reported 345 MTX-related AEs, including one serious AE (SAE, excessive fatigue and/or malaise); 10 AEs (in two patients) led to study discontinuation. In MUSICA, ACR50 rates increased over time, and were 32.3% and 37.5% at week 24, while MTX-related AE rates remained steady and were 6.5% at week 24. Of 309 patients, 71 (23%) reported 185 MTX-related AEs, including 5 SAEs (four infections and one fever/chills); six AEs (in four patients) led to study discontinuation. In patients with RA initiating ADA+MTX combination, treatment efficacy was achieved and increased throughout both trials, while rates of MTX-related AEs remained steady. MTX-related AEs were observed in up to 30% of patients and most were mild. MTX was discontinued by 0.5%-1.3% of patients. MUSICA (NCT01185288), CONCERTO (NCT01185301), Post results.

  6. Time to treatment as an important factor for the response to methotrexate in juvenile idiopathic arthritis.

    Science.gov (United States)

    Albers, H M; Wessels, J A M; van der Straaten, R J H M; Brinkman, D M C; Suijlekom-Smit, L W A; Kamphuis, S S M; Girschick, H J; Wouters, C; Schilham, M W; le Cessie, S; Huizinga, T W J; Ten Cate, R; Guchelaar, H J

    2009-01-15

    Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug in juvenile idiopathic arthritis (JIA). Currently, individual response to MTX cannot be reliably predicted. Identification of clinical and genetic factors that influence the response to MTX could be helpful in realizing the optimal treatment for individual patients. A cohort of 128 JIA patients treated with MTX were studied retrospectively. Eleven clinical parameters and genotypes of 6 single nucleotide polymorphisms in 5 genes related to the mechanism of action of MTX were compared between MTX responders and nonresponders using a multivariate regression analysis. The time from diagnosis to start of MTX treatment, physician's global assessment at baseline, and the starting dose were significantly associated with the response to MTX at 6 months after initiation. Patients with a shorter time from diagnosis to start of MTX and a higher disease activity according to the physician but with a lower MTX dose showed an increased response. The effect of the starting dose on MTX response seemed to be mainly due to the influence of the systemic JIA subtype. The time from diagnosis to start of MTX treatment and physician's global assessment at baseline were highly correlated. Therefore, the precise effect size of each independent variable could not be determined. In children with JIA, the time from diagnosis to start of MTX appears to be an important factor for MTX response. Our results suggest that an earlier start of MTX treatment will lead to an increased response.

  7. EFFICACY OF LOW-DOSE METHOTREXATE TREATMENT IN BIRDSHOT CHORIORETINOPATHY

    NARCIS (Netherlands)

    Rothova, Aniki; Ossewaarde-van Norel, Annette; Los, Leonoor I.; Berendschot, Tos T. J. M.

    Purpose: To ascertain the effect of treatment with methotrexate (MTX) on the visual prognosis of birdshot chorioretinopathy (BSCR). Methods: Retrospective case series of 76 consecutive patients with HLA-A29-positive BSCR, of whom 46 were followed for at least 5 years and 18 for longer than 10 years.

  8. Inhibition by methotrexate (MTX) polyglutamates (PGS) of folate-dependent biosyntheses in L1210 Leukemia cells

    International Nuclear Information System (INIS)

    Matherly, L.H.; Barlowe, C.K.; Goldman, I.D.

    1986-01-01

    The inhibition of folate-dependent pathways by MTX PGS was evaluated in folate-depleted L1210 cells incubated with (6S)5-formyl(CHO)tetrahydrofolate(FH 4 )(5μM). The accumulation of MTX PGS during exposure to MTX (10μM;3h) inhibited cell growth (>70%) under these conditions. In the presence of 5-CHO-FH 4 , carbon transfer from 14 C-formate or 3- 14 C-serine into purines, dTMP, and amino acids was suppressed following MTX-pretreatment, suggesting the formation of only low levels of FH 4 to drive these reactions. In cells treated with MTX (6S)5-CHO-[ 3 H]-FH 4 was metabolized predominantly to 10-CHO-[ 3 H]-FH 4 . While intracellular dihydrofolate (FH 2 ) increased 10-fold, indicating a block at FH 2 reductase by MTX PGS, FH 2 represented only 20% of the total metabolites of 5-CHO-FH 4 . The incorporation of 14 C from 5-[ 14 C]-CHO-FH 4 into serine and methionine was not affected by the presence of intracellular MTX PGS, however, carbon transfer into dTMP and purine nucleotides was reduced (50-60%). These findings demonstrate that MTX pretreatment inhibits de novo nucleotide and amino acid biosynthetic pathways even when high levels of reduced folates are present. The data suggest a suppression of dTMP synthase and the purine transformylase(s) by MTX and/or FH 2 PGS that accumulate in drug-treated cells. Inhibition of the purine biosynthetic steps appears to trap 10-CHO-FH 4 , limiting FH 4 for the synthesis of dTMP, serine, and methionine

  9. Uterine Artery Embolization Combined with Local Methotrexate and Systemic Methotrexate for Treatment of Cesarean Scar Pregnancy with Different Ultrasonographic Pattern

    International Nuclear Information System (INIS)

    Lian Fan; Wang Yu; Chen Wei; Li Jiaping; Zhan Zhongping; Ye Yujin; Zhu, Yunxiao; Huang Jia; Xu Hanshi; Yang Xiuyan; Liang Liuqin; Yang Jianyong

    2012-01-01

    Purpose: This study was designed to compare the effectiveness of systemic methotrexate (MTX) with uterine artery embolization (UAE) combined with local MTX for the treatment of cesarean scar pregnancy (CSP) with different ultrasonographic pattern, and to indicate the preferable therapy in CSP patients. Methods: The results of 21 CSP cases were reviewed. All subjects were initially administrated with systemic MTX (50 mg/m 2 body surface area). UAE combined with local MTX was added to the patients who had failed systemic MTX. The transvaginal ultrasonography data were retrospectively assessed, and two different ultrasonographic patterns were found: surface implantation and deep implantation of amniotic sac. The management and its effectiveness for patients with the two ultrasonographic patterns were studied retrospectively. Ultrasound scan and serum β-hCG were monitored during follow-up. Data were analyzed with the Student’s t test. Results: Nine patients were successfully treated with systemic MTX. The remaining 12 cases were successfully treated with additional UAE combined with local MTX. According to the classification by Vial et al. of CSP on ultrasonography, most surface implanted CSPs (8/11, 72.7%) could be successfully treated with systemic MTX, whereas most deeply implanted CSPs (9/10, 90%) had failed systemic MTX but still could be successfully treated with additional UAE combined with local MTX. All patients recovered without severe side effects. Most patients with a future desire for reproduction achieved subsequent pregnancy. Conclusions: For CSP patients suitable for nonsurgical treatment, UAE combined with local MTX would be the superior option compared with systemic MTX in the cases with deep implantation of amniotic sac.

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

    Science.gov (United States)

    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 ( 14 years). 5 g/m2/24 h treatments resulted in higher serum and CSF MTX and 7-OH-MTX levels (P treatments did not alter MTX or 7-OH-MTX levels. 7-OH-MTX levels were correlated with nephrotoxicity (r = 0.36, P children aged older than 14 years (P 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.

  11. Methotrexate treatment provokes apoptosis of proliferating keratinocyte in psoriasis patients.

    Science.gov (United States)

    Elango, Tamilselvi; Thirupathi, Anand; Subramanian, Swapna; Ethiraj, Purushoth; Dayalan, Haripriya; Gnanaraj, Pushpa

    2017-08-01

    Psoriasis is a chronic inflammatory skin disease characterized by hyper proliferation of keratinocytes. Recent data show that the epidermis thickening in psoriasis may be related to imbalance of homeostasis caused by abnormal apoptotic process. Maintenance of keratinocyte apoptotic process is very important in psoriasis. Methotrexate (MTX) has been used for many years to restore the normal skin in psoriasis condition. However, the exact mechanism of MTX in psoriasis condition is poorly understood. The aim of this study was to examine the role of MTX on keratinocyte apoptosis pathway in psoriasis patients. A total of 58 psoriasis vulgaris patients were recruited for this study. Nonlesional skin biopsies served as control. Skin biopsies of psoriatic patients were collected and analyzed for cytosolic, mitochondria and total cytochrome c by ELISA. Expression of caspase-9, NFκBp65, pAkt1 by western blot, real-time PCR and immunohistochemical analysis of c-FLIP protein was analyzed in nonlesional and lesional skin biopsies before (day 0) and after (at the end of 6 and 12 weeks) MTX treatment. After MTX treatment, a significant increase in cytochrome c was observed when compared with before MTX treatment in psoriasis patients (p psoriasis by controlling the acanthosis.

  12. Intra-arterial infusion of MTX for the treatment of cesarean scar pregnancy: a comparative study between different doses

    International Nuclear Information System (INIS)

    Gu Weijin; Wang Haiyun; Wan Jun; Zhang Lei; Wang Ying; Wang Wei; Ji Fang; Ji Lihua

    2010-01-01

    Objective: To investigate the effective dose of methotrexate (MTX) via intra-arterial infusion for the treatment of cesarean scar pregnancy. Methods: Thirty-six cases of incisional scar pregnancy at the gestational age of 5-9 weeks received bilateral uterine arterial infusion of MTX. According to the dose of MTX used, the patients were randomly and equally divided into four groups with MTX dose of 60, 100, 150 and 200 mg respectively. After the perfusion was completed the embolization of both uterine arteries with Gelfoam was carried out until the uterine arteries were no longer visualized on DSA. Uterine curettage was conducted within 1-7 days after the treatment. Results: In one week after the procedure, the difference in the decreasing rate of serum β-HCG and progesterone between group 60 mg and group 200 mg was of statistical significance (P 0.05). The hospitalization days of group 60 mg was the longest, while that of group 200 mg was the shortest. Conclusion: The recommended dose of MTX used via intra-arterial infusion in treating cesarean scar pregnancy is 200 mg. The interventional procedure can kill the embryo tissue and quickly lower the serum β-HCG and progesterone levels,it can also shorten the patient's hospitalization time. (authors)

  13. Methotrexate resistance in relation to treatment outcome in childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Wojtuszkiewicz, Anna; Peters, Godefridus J; van Woerden, Nicole L

    2015-01-01

    BACKGROUND: Methotrexate (MTX) eradicates leukemic cells by disrupting de novo nucleotide biosynthesis and DNA replication, resulting in cell death. Since its introduction in 1947, MTX-containing chemotherapeutic regimens have proven instrumental in achieving curative effects in acute lymphoblast...... resistant to MTX at diagnosis may allow for tailoring novel treatment strategies to individual leukemia patients....... leukemia (ALL). However, drug resistance phenomena pose major obstacles to efficacious ALL chemotherapy. Moreover, clinically relevant molecular mechanisms underlying chemoresistance remain largely obscure. Several alterations in MTX metabolism, leading to impaired accumulation of this cytotoxic agent...... in tumor cells, have been classified as determinants of MTX resistance. However, the relation between MTX resistance and long-term clinical outcome of ALL has not been shown previously. METHODS: We have collected clinical data for 235 childhood ALL patients, for whom samples taken at the time of diagnosis...

  14. Methotrexate transport mechanisms: the basis for targeted drug delivery and ß-folate-receptor-specific treatment.

    Science.gov (United States)

    Fiehn, C

    2010-01-01

    Methotrexate (MTX) plays a pivotal role in the treatment of rheumatoid arthritis (RA). The transport mechanisms with which MTX reaches is target after application are an important part of MTX pharmacology and its concentration in target tissue such as RA synovial membrane might strongly influence the effectiveness of the drug. Physiological plasma protein binding of MTX to albumin is important for the distribution of MTX in the body and relative high concentrations of the drug are found in the liver. However, targeted drug delivery into inflamed joints and increased anti-arthritic efficiency can be obtained by covalent coupling of MTX ex-vivo to human serum albumin (MTX-HSA) or in-vivo to endogenous albumin mediated through the MTX-pro-drug AWO54. High expression of the folate receptor β (FR-β) on synovial macrophages of RA patients and its capacity to mediate binding and uptake of MTX has been demonstrated. To further improve drug treatment of RA, FR-β specific drugs have been developed and were characterised for their therapeutic potency in synovial inflammation. Therefore, different approaches to improve folate inhibitory and FR-β specific therapy of RA beyond MTX are in development and will be described.

  15. Methotrexate is an effective treatment for chronic uveitis associated with juvenile idiopathic arthritis.

    Science.gov (United States)

    Foeldvari, Ivan; Wierk, Angela

    2005-02-01

    To assess the effectiveness of methotrexate (MTX) in the treatment of juvenile idiopathic arthritis (JIA) associated uveitis, which is still one of the most common causes of visual impairment. A retrospective chart review of patients with the diagnosis of uveitis associated with JIA between July 1, 2002, and December 31, 2002. Four hundred sixty-seven patients with JIA were followed. Thirty-eight had uveitis: 31 associated with oligoarticular JIA and 7 with psoriatic JIA. Twenty-five of the 38 patients received MTX; in 23 patients uveitis was the indication for MTX therapy. In the MTX treated group 46/50 eyes had uveitis, the mean (range) age at onset of uveitis was 7.82 years (1.8-15.8), and the mean age at onset of arthritis was 7.25 years (1.25-15.7). MTX treatment was started an average of 11.4 months (0-72) after the onset of uveitis. The mean MTX dose was 15.6 mg/m2. Remission occurred after 4.25 months (1-12). Mean duration of remission was 10.3 months (3-27). The total duration of MTX therapy was 661 months and patients were in remission for 417/661 months. In 6 patients MTX was discontinued after 12 months of remission. Four patients were still in remission after 7.5 months (1-14). MTX seems to be an effective therapy for JIA associated uveitis.

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

    International Nuclear Information System (INIS)

    Beane, Olivia S.; Fonseca, Vera C.; Darling, Eric M.

    2014-01-01

    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 vascular 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

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

    Energy Technology Data Exchange (ETDEWEB)

    Beane, Olivia S. [Center for Biomedical Engineering, Brown University, Providence, RI (United States); Fonseca, Vera C. [Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI (United States); Darling, Eric M., E-mail: Eric_Darling@brown.edu [Center for Biomedical Engineering, Brown University, Providence, RI (United States); Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI (United States); Department of Orthopaedics, Brown University, Providence, RI (United States); School of Engineering, Brown University, Providence, RI (United States)

    2014-10-01

    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 vascular 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

  18. Methotrexate in the treatment of penile carcinoma.

    Science.gov (United States)

    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.

  19. In vivo pharmacological evaluation and efficacy study of methotrexate-encapsulated polymer-coated layered double hydroxide nanoparticles for possible application in the treatment of osteosarcoma.

    Science.gov (United States)

    Ray, Sayantan; Saha, Suman; Sa, Biswanath; Chakraborty, Jui

    2017-04-01

    Considering the existing drawbacks of methotrexate (MTX) with respect to its solubility and toxicity, we incorporated it in a nanoceramic matrix, Mg-Al-layered double hydroxide (LDH) to form LDH-MTX nanoparticles, and the same was in turn encapsulated in a nontoxic and biodegradable polymer, poly (D,L-lactide-co-glycolide) (PLGA), to arrest the initial burst release and dose-dumping-related toxicity, already reported by our group. Our present study was designed to evaluate the pharmacokinetics, tissue distribution, survival rate of the test animals, and antitumor efficacy of the PLGA-LDH-MTX nanoparticles and its counterpart without LDH, PLGA-MTX nanoparticles compared with bare MTX. The median lethal dose (LD 50 ) of the former was higher, compared with bare MTX, using Balb/c nude mice, indicating it to be completely safe for use. Also, a comparative pharmacokinetic and antitumour efficacy study using MTX, PLGA-MTX, and PLGA-LDH-MTX nanoparticles in osteosarcoma-induced Balb/c nude mice in vivo demonstrated superiority of PLGA-LDH-MTX as compared to PLGA-MTX and bare MTX. The results suggest that PLGA-LDH-MTX nanoparticles might exhibit potential advantages over the present-day chemotherapy over bare MTX, for the possibility of treatment of osteosarcoma.

  20. Relapse rate of uveitis post-methotrexate treatment in juvenile idiopathic arthritis.

    Science.gov (United States)

    Kalinina Ayuso, Viera; van de Winkel, Evelyne Leonce; Rothova, Aniki; de Boer, Joke Helena

    2011-02-01

    To evaluate the efficacy of methotrexate (MTX) and the effect of its withdrawal on relapse rate of uveitis associated with juvenile idiopathic arthritis (JIA). Retrospective case series. Data of 22 pediatric JIA patients who were being treated with MTX for active uveitis were studied retrospectively. Relapse rate after the withdrawal of MTX was established. Anterior chamber (AC) inflammation, topical steroid use during the first year of MTX treatment, and associations of relapses after the withdrawal were evaluated statistically. Duration of MTX treatment and its withdrawal was determined individually in collaboration with a rheumatologist with an intention to continue the treatment for at least 1 year and to withdraw in case of inactivity of uveitis and arthritis. Inactivity of uveitis was defined as the presence of ≤0.5+ cells in the AC. Eighteen patients (18/22; 82%) showed improvement of their uveitis with a significant decrease in activity of AC inflammation after a minimal period of 3 months of MTX treatment. A topical steroid-sparing effect was observed when MTX was administered for a period of 3 to 9 months. MTX was discontinued because of inactive uveitis in 13 patients. In 9 patients (8/13; 69%) a relapse of uveitis was observed after a mean time of 7.5 months (± SD 7.3). Six patients (6/13; 46%) had a relapse within the first year after the withdrawal. Relapse-free survival after withdrawal of MTX was significantly longer in patients who had been treated with MTX for more than 3 years (P = .009), children who were older than 8 years at the moment of withdrawal (P = .003), and patients who had an inactivity of uveitis of longer than 2 years before withdrawal of MTX (P = .033). Longer inactivity under MTX therapy was independently protective for relapses after the withdrawal (hazard ratio = 0.07; 95% confidence interval 0.01-0.86; P = .038), which means that 1-year increase of duration of inactive uveitis before the withdrawal of MTX results in a

  1. The treatment of tubal pregnancy by MTX drug perfusion and vascular embolization

    International Nuclear Information System (INIS)

    Dan Jian; Ke Yaojun; Tan Wei; Jiang Ling

    2001-01-01

    Objective: To study the feasibility of the treatment of tubule pregnancy by interventional technique. Methods: By using Seldinger's method, 40 cases of tubule pregnancy received super selective angiography of uterine artery, followed by perfusion of methotrexate (MTX) through the catheter and embolization of uterine artery with gelatin sponge. The concentration of serum β-HCG, the change of pelvic cavity, and the open condition of oviduct were regularly monitored postoperatively. Results: Angiographic findings of tubule pregnancy were classified into 3 types. type I, no abnormal vascular appearance were found in 3 cases (7.5%). Type II, patchy vascular staining of villi in parauterine area was observed in 4 cases (10.0%). Type III, a round vacuolar staining of villi surrounded by small blood vessels in parauterine area occurred in 33 cases (82.5%). The cure rate in total 40 cases achieved 97.5% (39/40). After treatment, the mean time that the serum β-HCG concentration returned to normal was (7.66 +- 2.01) d and the mean time that the menstruation returned to normal was (29.78 +- 7.14) d. In 21 cases who hoped their fertility remaining intact, the oviduct were verified open by hysterosalpingography (HSG) in 20 cases, the open rate was 95.24%. Conclusion: The treatment of tubule pregnancy by interventional technique was proved no harmful effect to reproductive organs and would expect to preserve fertility. This method could resolve the difficult problem of celiac hemorrhage which making conservative treatment impossible and internal hemorrhage happened in the course of traditional conservative therapy leading to treatment failure finally. This method might be a new conception and a choice to treat tubal pregnancy through artery

  2. Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE)).

    Science.gov (United States)

    Emery, P; Deodhar, A; Rigby, W F; Isaacs, J D; Combe, B; Racewicz, A J; Latinis, K; Abud-Mendoza, C; Szczepanski, L J; Roschmann, R A; Chen, A; Armstrong, G K; Douglass, W; Tyrrell, H

    2010-09-01

    This phase III study evaluated the efficacy and safety of rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to MTX and who were naïve to prior biological treatment. Patients with active disease on stable MTX (10-25 mg/week) were randomised to rituximab 2 x 500 mg (n=168), rituximab 2 x 1000 mg (n=172), or placebo (n=172). From week 24, patients not in remission (Disease Activity Score (28 joints) > or =2.6) received a second course of rituximab; patients initially assigned to placebo switched to rituximab 2 x 500 mg. The primary end point was American College of Rheumatology 20 (ACR20) response at week 24. All patients were followed until week 48. At week 24, both doses of rituximab showed statistically superior efficacy (p<0.0001) to placebo (ACR20: 54%, 51% and 23%; rituximab (2 x 500 mg) + MTX, rituximab (2 x 1000 mg) + MTX and placebo + MTX, respectively). Secondary end points were also significantly improved for both rituximab groups compared with placebo. Further improvements in both rituximab arms were observed from week 24 to week 48. Rituximab + MTX was well tolerated, demonstrating comparable safety to placebo + MTX through to week 24, and between rituximab doses through to week 48. Rituximab (at 2 x 500 mg and 2 x 1000 mg) plus MTX significantly improved clinical outcomes at week 24, which were further improved by week 48. No significant differences in either clinical or safety outcomes were apparent between the rituximab doses.

  3. Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naïve with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE))

    Science.gov (United States)

    Emery, P; Deodhar, A; Rigby, W F; Isaacs, J D; Combe, B; Racewicz, A J; Latinis, K; Abud-Mendoza, C; Szczepański, L J; Roschmann, R A; Chen, A; Armstrong, G K; Douglass, W; Tyrrell, H

    2010-01-01

    Objectives This phase III study evaluated the efficacy and safety of rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to MTX and who were naïve to prior biological treatment. Methods Patients with active disease on stable MTX (10–25 mg/week) were randomised to rituximab 2×500 mg (n=168), rituximab 2×1000 mg (n=172), or placebo (n=172). From week 24, patients not in remission (Disease Activity Score (28 joints) ≥2.6) received a second course of rituximab; patients initially assigned to placebo switched to rituximab 2×500 mg. The primary end point was American College of Rheumatology 20 (ACR20) response at week 24. All patients were followed until week 48. Results At week 24, both doses of rituximab showed statistically superior efficacy (p<0.0001) to placebo (ACR20: 54%, 51% and 23%; rituximab (2×500 mg) + MTX, rituximab (2×1000 mg) + MTX and placebo + MTX, respectively). Secondary end points were also significantly improved for both rituximab groups compared with placebo. Further improvements in both rituximab arms were observed from week 24 to week 48. Rituximab + MTX was well tolerated, demonstrating comparable safety to placebo + MTX through to week 24, and between rituximab doses through to week 48. Conclusions Rituximab (at 2×500 mg and 2×1000 mg) plus MTX significantly improved clinical outcomes at week 24, which were further improved by week 48. No significant differences in either clinical or safety outcomes were apparent between the rituximab doses. PMID:20488885

  4. Mercaptopurine metabolite levels are predictors of bone marrow toxicity following high-dose methotrexate therapy of childhood acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Vang, Sophia Ingeborg; Schmiegelow, Kjeld; Frandsen, Thomas

    2015-01-01

    High-dose methotrexate (HD-MTX) courses with concurrent oral low-dose MTX/6-mercaptopurine (6MP) for childhood acute lymphoblastic leukaemia (ALL) are often followed by neutro- and thrombocytopenia necessitating treatment interruptions. Plasma MTX during HD-MTX therapy guides folinic acid rescue ...

  5. Disease activity, physical function, and radiographic progression after longterm therapy with adalimumab plus methotrexate: 5-year results of PREMIER

    NARCIS (Netherlands)

    van der Heijde, Désirée; Breedveld, Ferdinand C.; Kavanaugh, Arthur; Keystone, Edward C.; Landewé, Robert; Patra, Kaushik; Pangan, Aileen L.

    2010-01-01

    To evaluate the efficacy and safety of initial combination treatment with adalimumab (ADA) and methotrexate (MTX) versus monotherapy with ADA or MTX during an open-label extension of PREMIER. Patients with early rheumatoid arthritis (RA) received blinded ADA plus MTX, ADA alone, or MTX alone for 2

  6. Successful treatment of methotrexate intolerance in juvenile idiopathic arthritis using eye movement desensitization and reprocessing - treatment protocol and preliminary results.

    Science.gov (United States)

    Höfel, Lea; Eppler, Bruno; Storf, Magdalena; Schnöbel-Müller, Elizabeth; Haas, Johannes-Peter; Hügle, Boris

    2018-02-13

    Methotrexate (MTX), commonly used in juvenile idiopathic arthritis (JIA), frequently has to be discontinued due to intolerance with anticipatory and associative gastrointestinal adverse effects. Eye Movement Desensitization and Reprocessing (EMDR) is a psychological method where dysfunctional experiences and memories are reprocessed by recall combined with bilateral eye movements. The objective of this study was to assess efficacy of EMDR for treatment of MTX intolerance in JIA patients. We performed an open prospective study on consecutive JIA patients with MTX intolerance. Intolerance was determined using the Methotrexate Intolerance Severity Score (MISS) questionnaire prior to treatment, directly after treatment and after four months. Health-related quality of life was determined using the PedsQL prior to and four months after treatment. Patients were treated according to an institutional EMDR protocol with 8 sessions over two weeks. Changes in MISS and PedsQL were analyzed using non-parametric statistics. Eighteen patients with MTX intolerance (median MISS at inclusion 16.5, IQR = 11.75-20.25) were included. Directly after treatment, MTX intolerance symptoms were significantly improved (median MISS 1 (IQR = 0-2). After four months, median MISS score was at 6.5 (IQR = 2.75-12.25, p = 0.001), with 9/18 patients showing MISS scores ≥6. Median PedsQL after 4 months improved significantly from 77.6% to 85.3% (p = 0.008). MTX intolerance in children with JIA was effectively treated using an EMDR protocol, with lasting effect over a period of 4 months. EMDR treatment can potentially increase quality of life of affected patients and enable continued MTX treatment.

  7. Methotrexate for the Treatment of Pediatric Crohn's Disease: A Systematic Review and Meta-analysis.

    Science.gov (United States)

    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.

  8. Glucarpidase treatment for methotrexate intoxication: a case report and review of the literature

    NARCIS (Netherlands)

    Boelens, A. D.; Mathôt, R. A. A.; Vlaar, A. P. J.; Bouman, C. S. C.

    2018-01-01

    High-dose methotrexate (MTX) induced acute kidney injury can lead to sustained high systemic MTX levels and severe toxicity. A 39-year-old man with lymphoblastic T-cell lymphoma was admitted to our intensive care unit with elevated serum creatinine and prolonged high serum MTX levels. Standard

  9. A randomised comparative study of the short term clinical and biological effects of intravenous pulse methylprednisolone and infliximab in patients with active rheumatoid arthritis despite methotrexate treatment

    OpenAIRE

    Durez, P; Nzeusseu, T; Lauwerys, B; Manicourt, D; Verschueren, P; Westhovens, R; Devogelaer, J; Houssiau, F

    2004-01-01

    OBJECTIVES: To compare the short term clinical and biological effects of intravenous (i.v.) pulse methylprednisolone (MP) and infliximab (IFX) in patients with severe active rheumatoid arthritis (RA) despite methotrexate (MTX) treatment. METHODS: Patients with active RA despite MTX treatment were randomly allocated to receive a single i.v. infusion of MP (1 g) or three i.v. infusions of IFX (3 mg/kg) on weeks 0, 2, and 6. Patients were "blindly" evaluated for disease activity measures. Qualit...

  10. Methotrexate loaded polyether-copolyester dendrimers for the treatment of gliomas: enhanced efficacy and intratumoral transport capability.

    Science.gov (United States)

    Dhanikula, Renu Singh; Argaw, Anteneh; Bouchard, Jean-Francois; Hildgen, Patrice

    2008-01-01

    Therapeutic benefit in glial tumors is often limited due to low permeability of delivery systems across the blood-brain barrier (BBB), drug resistance, and poor penetration into the tumor tissue. In an attempt to overcome these hurdles, polyether-copolyester (PEPE) dendrimers were evaluated as drug carriers for the treatment of gliomas. Dendrimers were conjugated to d-glucosamine as the ligand for enhancing BBB permeability and tumor targeting. The efficacy of methotrexate (MTX)-loaded dendrimers was established against U87 MG and U 343 MGa cells. Permeability of rhodamine-labeled dendrimers and MTX-loaded dendrimers across the in vitro BBB model and their distribution into avascular human glioma tumor spheroids was also studied. Glucosylated dendrimers were found to be endocytosed in significantly higher amounts than nonglucosylated dendrimers by both the cell lines. IC 50 of MTX after loading in dendrimers was lower than that of the free MTX, suggesting that loading MTX in PEPE dendrimers increased its potency. Similar higher activity of MTX-loaded glucosylated and nonglucosylated dendrimers was found in the reduction of tumor spheroid size. These MTX-loaded dendrimers were able to kill even MTX-resistant cells highlighting their ability to overcome MTX resistance. In addition, the amount of MTX-transported across BBB was three to five times more after loading in the dendrimers. Glucosylation further increased the cumulative permeation of dendrimers across BBB and hence increased the amount of MTX available across it. Glucosylated dendrimers distributed through out the avascular tumor spheroids within 6 h, while nonglucosylated dendrimers could do so in 12 h. The results show that glucosamine can be used as an effective ligand not only for targeting glial tumors but also for enhanced permeability across BBB. Thus, glucosylated PEPE dendrimers can serve as potential delivery system for the treatment of gliomas.

  11. USE OF SUBCUTANEOUS METHOTREXATE FOR THE TREATMENT OF PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS: THE REMARCA TRIAL

    Directory of Open Access Journals (Sweden)

    D. E. Karateev

    2016-01-01

    Full Text Available The early administration of methotrexate (MTX and the use of its high (by the rheumatology practice standards doses contribute to the enhanced efficiency of therapy and the reduced severity of rheumatoid arthritis (RA. One of the important merits of MTX in the treatment of RA is the possibility of adjusting its dose and choosing its (oral or subcutaneous administration routes, which makes it possible to individualize treatment. Particular emphasis has been recently placed just on a subcutaneous MTX formulation that creates prerequisites for substantially improving the efficiency of RA therapy. The paper gives the data of the REMARCA (Russian investigation of methotrexate and biologicals for early active arthritis trial assessing the results of RA treatment in the use of the subcutaneous MTX dosage form as a first-line drug and in the elaboration of management tactics for this disease.Subjects and methods. The investigation included 191 patients (34 men and 157 women with active RA; of whom 51.8% had very early RA (< 6 months' disease duration. 115 patients with RA completed a 24-month follow-up period; and their data were analyzed in more detail.Results and discussion. The findings may substantiate treatment policy based on the prescription of subcutaneous MTX (without previously administering its oral formulation in patients with early RA and high disease activity, starting the drug at 15 mg/week and rapidly escalating with the highest tolerable doses during 4-8 weeks, which allows remission (or low disease activity in the majority of patients without using glucocorticoids and biological agents.

  12. Methotrexate Associated Renal Impairment Is Related to Delayed Elimination of High-Dose Methotrexate

    Directory of Open Access Journals (Sweden)

    Shi-Long Yang

    2015-01-01

    Full Text Available Although Methotrexate (MTX is an effective drug for the treatment of acute lymphoblastic leukemia (ALL, the toxicity remains a significant problem. In this prospective study, fifty-four patients with ALL were enrolled. 3 g or 5 g MTX/m2 was administered over 24 hours. Serum MTX concentrations were determined in 24, 48, and 96 hours after MTX infusion. Serum creatinine concentrations and creatinine clearance rate (CCR were determined before and 24 and 48 hours after MTX infusion. A total of 173 courses of MTX infusion were administered. The serum creatinine concentrations did not change much after MTX infusion while the CCR was gradually decreased. MTX clearance status was independently related to CCR decrease, with the risk of 8.07 to develop renal impairment in patients with delayed MTX elimination. Serum creatinine concentration, serum creatinine ratio, CCR, and CCR ratio at 24 hours were all related to MTX elimination delay. Patients with serum creatinine level >35.0 μmol/L, creatinine ratio >1.129, or CCR <100.0 mL/min were more likely to undergo MTX elimination delay. In conclusion, MTX could induce transient renal impairment and compromised renal function will delay MTX clearance. The serum creatinine concentration and the ratio and CCR are useful tools for evaluating MTX elimination status.

  13. Discovery – Methotrexate: Chemotherapy Treatment for Cancer

    Science.gov (United States)

    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.

  14. Methotrexate in Alopecia Areata: A Report of Three Cases

    OpenAIRE

    Batalla, Ana; Fl?rez, ?ngeles; Abalde, Teresa; V?zquez-Veiga, Hugo

    2016-01-01

    There are few studies about systemic treatment in severe cases of alopecia areata (AA), especially in the pediatric population. Although there is more experience with systemic corticosteroids, recent reports have suggested methotrexate (MTX) as an alternative treatment, with a relatively good outcome. We describe three cases of AA in children treated with MTX, two of them with successful results.

  15. Methotrexate for the treatment of juvenile idiopathic arthritis: process to approval for JIA indication in Japan.

    Science.gov (United States)

    Mori, Masaaki; Naruto, Takuya; Imagawa, Tomoyuki; Murata, Takuji; Takei, Syuji; Tomiita, Minako; Itoh, Yasuhiko; Fujikawa, Satoshi; Yokota, Shumpei

    2009-01-01

    Methotrexate (MTX), the primary treatment for the articular-type juvenile idiopathic arthritis (JIA), is effective and brings about radiological improvement. Patient compliance is good, and it is recognized that its known side effects, namely, disruption of liver function and induction of pulmonary lesions, are unlikely to be severe at the low MTX doses that are administered. In Japan, MTX was granted approval in 1999 by the then Ministry of Health and Welfare specifically for treating rheumatoid arthritis in adult patients, allowing it be generally used in medical institutions for patients having National Health Insurance. However, in the pediatric field, its use outside the indications has so far been unavoidable, and has been left to the discretion of the physician. Finally, at the present conference, expansion of the indications of MTX for JIA was approved in Japan. It is noteworthy that this expansion of indications was achieved without requiring clinical trials on children sponsored by the pharmaceutical company: it was achieved rather by collecting necessary information through ongoing efforts (including collection and analysis of information about approval status in foreign countries, adequate evidence from the literature, implementation of a clinical use survey in Japan, etc.). It also merits attention that the maximum dose (10 mg/m2) was set on the basis of pharmacokinetic data from children, rather than relying on the dosing method and dose for adults.

  16. Treatment of cervical pregnancy with ultrasound-guided local methotrexate injection.

    Science.gov (United States)

    Yamaguchi, M; Honda, R; Erdenebaatar, C; Monsur, M; Honda, T; Sakaguchi, I; Okamura, Y; Ohba, T; Katabuchi, H

    2017-12-01

    Cervical pregnancy (CP) is a rare type of ectopic pregnancy. While methotrexate (MTX) is generally the first-line method of choice for clinically stable women, there is still no consensus on the most appropriate treatment for this abnormal pregnancy. The aim of this study was to investigate the efficacy of a single local MTX injection under transvaginal ultrasound guidance for the initial treatment of CP and to assess post-treatment fertility. We reviewed retrospectively 15 patients with CP treated with local MTX injection under transvaginal ultrasound guidance. In all patients, the serum human chorionic gonadotropin (hCG) levels were monitored and the gestational sac was evaluated using ultrasonography after treatment. Magnetic resonance imaging (MRI) was performed as necessary. We evaluated the patients' clinical characteristics and clinical course after treatment, the efficacy of the treatment and the post-treatment fertility in patients desiring subsequent pregnancy. The median estimated gestational age at the time of MTX injection was 6 + 2 (range, 5 + 2 to 11 + 0) weeks. All 15 patients were treated successfully, without the need for blood transfusion or surgical procedures; however, three patients required an additional local MTX injection due to a poor decline in serum hCG level following the initial injection, while one patient required uterine artery embolization due to persistent vaginal bleeding and an enlarging gestational sac with blood vessels visible on contrast-enhanced MRI. The mean time following initial MTX injection for hCG normalization was 43.8 (95% CI, 33.3-54.3) days and for resumption of menses was 68.4 (95% CI, 51.9-84.9) days. Seven of the 10 women desiring subsequent pregnancy following treatment had uneventful pregnancy, one became pregnant but miscarried spontaneously at 8 weeks of gestation, one was treated by laparoscopic surgery after diagnosis of a tubal pregnancy and one did not conceive. A single, ultrasound

  17. Intraocular methotrexate in the treatment of uveitis and uveitic cystoid macular edema.

    Science.gov (United States)

    Taylor, Simon R J; Habot-Wilner, Zohar; Pacheco, Patricio; Lightman, Sue L

    2009-04-01

    A pilot study to evaluate the use of intravitreal methotrexate (MTX) for the treatment of uveitis and uveitic cystoid macular edema (CME). Prospective, consecutive, interventional case series. Fifteen eyes of 15 patients with a unilateral exacerbation of noninfectious intermediate, posterior uveitis, or panuveitis and/or CME such that visual acuity (VA) was 20/40 or worse, together with a history of increased intraocular pressure (IOP) in response to corticosteroid administration. Intravitreal injection of 400 microg in 0.1 ml MTX. The primary outcome measure was VA (using the Early Treatment Diabetic Retinopathy Study chart). Other outcome measures included ocular inflammation scores, time to relapse, levels of systemic corticosteroid and immunosuppressive therapy, and ocular coherence tomography. Potential complications of intravitreal MTX injection, including cataract progression, vitreous hemorrhage, retinal detachment, and corneal epitheliopathy, were assessed. VA improved at all time points and was statistically significant at the 3- and 6-month follow-up examinations. The mean visual improvement was 4 lines at 3 months and 4.5 lines at 6 months, with no statistical difference between the best VA obtained after MTX injection and after previous corticosteroid treatment, including intravitreal triamcinolone acetate injection. Five patients relapsed after a median of 4 months; a similar improvement was seen after re-injection. Ocular inflammation scores improved at all time points, and systemic immunosuppressive medication was reduced in 3 of 7 patients taking this at the start of the trial. In patients with uveitis and uveitic CME, intravitreal MTX can improve VA and reduce CME and, in some patients, allows the reduction of immunosuppressive therapy. Relapse occurs at a median of 4 months in some patients, but reinjection has similar efficacy.

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

    Science.gov (United States)

    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.

  19. The Influence of Methotrexate Treatment on Male Fertility and Pregnancy Outcome After Paternal Exposure.

    Science.gov (United States)

    Grosen, Anne; Kelsen, Jens; Hvas, Christian Lodberg; Bellaguarda, Emanuelle; Hanauer, Stephen B

    2017-04-01

    Inflammatory bowel disease incidence peaks during the reproductive years. Methotrexate (MTX) is frequently used for inflammatory bowel disease, but its use during pregnancy is contraindicated in women because of teratogenic effects. The aim of this review is to investigate the influence of MTX on male fertility and pregnancy outcomes after paternal MTX exposure. A systematic literature search was performed by applying 2 focus areas, "methotrexate" and "male fertility or pregnancy outcome." Terms and keywords were used both as MeSH terms and free-text searches. Pertinent articles were searched for additional relevant references. In animal studies, MTX induces aberrations in sperm DNA that have not been identified in humans. The effects of MTX on human sperm quality have only been described in case reports. A transient adverse effect on sperm quality with low-dose MTX has been reported, but several other cases have not found harmful effects of MTX. MTX has not been measured in human sperm ejaculates; yet, the risk of a direct toxic effect on the fetus through MTX-contaminated seminal plasma seems negligible. Until now, 284 pregnancies with paternal MTX exposure have been reported. The outcomes were 248 live births and a total of 13 malformations, with no overt indication of MTX embryopathy. This review reveals the lack of studies on the safety of MTX with regard to male reproduction. It is not clear whether MTX transiently influences male fertility and sperm DNA integrity, and more studies are needed. Comparative cohort studies found no increased risk of adverse pregnancy outcomes.

  20. Pharmacology and optimization of thiopurines and methotrexate in inflammatory bowel disease

    DEFF Research Database (Denmark)

    Coskun, Mehmet; Steenholdt, Casper; de Boer, Nanne K.

    2016-01-01

    Improving the efficacy and reducing the toxicity of thiopurines and methotrexate (MTX) have been areas of intense basic and clinical research. An increased knowledge on pharmacodynamics and pharmacokinetics of these immunomodulators has optimized treatment strategies in inflammatory bowel disease...

  1. Fatal pulmonary fibrosis complicating low dose methotrexate therapy for rheumatoid arthritis

    NARCIS (Netherlands)

    van der Veen, M. J.; Dekker, J. J.; Dinant, H. J.; van Soesbergen, R. M.; Bijlsma, J. W.

    1995-01-01

    We report the fatal disease course of 2 aged patients with rheumatoid arthritis (RA). Both had respiratory complaints after 10-15 weeks of treatment with methotrexate (MTX). After withdrawal of MTX, and despite the use of corticosteroids and ventilatory support, both died of respiratory failure.

  2. EEG with extreme delta brush in young female with methotrexate neurotoxicity supports NMDA receptor involvement

    DEFF Research Database (Denmark)

    Schmidt, Lisbeth Samsø; Kjær, Troels W; Schmiegelow, Kjeld

    2017-01-01

    Sub-acute neurotoxicity is a well-known complication to high-dose and intrathecal methotrexate (MTX) treatment of children with leukemia. Symptoms can be treated safely by dextromethorphan, a non-competitive antagonist to N-methyl-D-aspartic acid receptor (NMDAR). In a female with subacute MTX...

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

    Science.gov (United States)

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

    2012-04-01

    To compare the efficacy and safety of treatment with infliximab plus methotrexate with methotrexate alone in methotrexate-naive patients with active psoriatic arthritis (PsA). 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. At week 16, 86.3% of patients receiving infliximab plus methotrexate and 66.7% of those receiving methotrexate alone achieved an ACR20 response (palone experienced a 75% or greater improvement in PASI (palone group. 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.

  4. Methotrexate

    Science.gov (United States)

    ... lymphoma, and leukemia (cancer that begins in the white blood cells). Methotrexate is in a class of ... In case of overdose, call the poison control helpline at 1-800-222-1222. Information is also available online at https://www.poisonhelp.org/help. If the victim has ...

  5. Combined Treatment of MCF-7 Cells with AICAR and Methotrexate, Arrests Cell Cycle and Reverses Warburg Metabolism through AMP-Activated Protein Kinase (AMPK and FOXO1.

    Directory of Open Access Journals (Sweden)

    Tamás Fodor

    Full Text Available Cancer cells are characterized by metabolic alterations, namely, depressed mitochondrial oxidation, enhanced glycolysis and pentose phosphate shunt flux to support rapid cell growth, which is called the Warburg effect. In our study we assessed the metabolic consequences of a joint treatment of MCF-7 breast cancer cells with AICAR, an inducer of AMP-activated kinase (AMPK jointly with methotrexate (MTX, a folate-analog antimetabolite that blunts de novo nucleotide synthesis. MCF7 cells, a model of breast cancer cells, were resistant to the individual application of AICAR or MTX, however combined treatment of AICAR and MTX reduced cell proliferation. Prolonged joint application of AICAR and MTX induced AMPK and consequently enhanced mitochondrial oxidation and reduced the rate of glycolysis. These metabolic changes suggest an anti-Warburg rearrangement of metabolism that led to the block of the G1/S and the G2/M transition slowing down cell cycle. The slowdown of cell proliferation was abolished when mitotropic transcription factors, PGC-1α, PGC-1β or FOXO1 were silenced. In human breast cancers higher expression of AMPKα and FOXO1 extended survival. AICAR and MTX exerts similar additive antiproliferative effect on other breast cancer cell lines, such as SKBR and 4T1 cells, too. Our data not only underline the importance of Warburg metabolism in breast cancer cells but nominate the AICAR+MTX combination as a potential cytostatic regime blunting Warburg metabolism. Furthermore, we suggest the targeting of AMPK and FOXO1 to combat breast cancer.

  6. Preliminary study for predicting better methotrexate efficacy in Japanese patients with rheumatoid arthritis

    OpenAIRE

    Hashiguchi, Masayuki; Tsuru, Tomomi; Miyawaki, Kumika; Suzaki, Midori; Hakamata, Jun; Shimizu, Mikiko; Irie, Shin; Mochizuki, Mayumi

    2016-01-01

    Background Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammatory status, joint destruction, disability, and pain. Methotrexate (MTX) has been confirmed to reduce disease activity and delay or stabilize the development of bone erosions. However, major drawbacks are that patients show great interindividual variability in response to MTX and the unpredictable occurrence of side effects. A strategy for personalized MTX treatment to predict its efficacy a...

  7. 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.

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  9. Utilization of Subcutaneous Methotrexate in Rheumatoid Arthritis Patients After Failure or Intolerance to Oral Methotrexate: A Multicenter Cohort Study.

    Science.gov (United States)

    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.

  10. PEG capped methotrexate silver nanoparticles for efficient anticancer activity and biocompatibility.

    Science.gov (United States)

    Muhammad, Zarmina; Raza, Abida; Ghafoor, Sana; Naeem, Ayesha; Naz, Syeda Sohaila; Riaz, Sundus; Ahmed, Wajiha; Rana, Nosheen Fatima

    2016-08-25

    Nanocarriers endow tremendous benefits to the drug delivery systems depending upon the specific properties of either component. These benefits include, increase in the drug blood retention time, reduced efflux, additional toxicity and targeted delivery. Methotrexate (MTX) is clinically used for cancer treatment. Higher dosage of MTX results in hepatic and renal toxicity. In this study methotrexate silver nanoparticles (Ag-MTX) coated with polyethylene glycol (PEG) are synthesized and characterized. Their anticancer activity and biocompatibility is also evaluated. Ag-MTX nanoparticles are synthesized by chemical reduction method. They are characterized by Ultraviolet-Visible Spectroscopy and Fourier Transform Infrared Spectroscopy. Average size of PEG coated Ag-MTX nanoparticles (PEG-Ag-MTX nanoparticles) is 12nm. These particles exhibited improved anticancer activity against MCF-7 cell line. Hemolytic activity of these particles was significantly less than MTX. PEG-Ag-MTX nanoparticles are potential nanocarrier of methotrexate which may offer MTX based cancer treatment with reduced side effects. In-vivo investigations should be carried out to explore them in detail. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. High prevalence of methotrexate intolerance in juvenile idiopathic arthritis : development and validation of a methotrexate intolerance severity score

    NARCIS (Netherlands)

    Bulatović, Maja; Heijstek, Marloes W; Verkaaik, Marleen; van Dijkhuizen, E H Pieter; Armbrust, Wineke; Hoppenreijs, Esther P A; Kamphuis, Sylvia; Kuis, Wietse; Egberts, Toine C G; Sinnema, Gerben; Rademaker, Carin M A; Wulffraat, Nico M

    OBJECTIVE: To design and validate a new questionnaire for identifying patients with methotrexate (MTX) intolerance, and to determine the prevalence of MTX intolerance in patients with juvenile idiopathic arthritis (JIA) using this questionnaire. METHODS: The MTX Intolerance Severity Score (MISS)

  12. High prevalence of methotrexate intolerance in juvenile idiopathic arthritis: development and validation of a methotrexate intolerance severity score

    NARCIS (Netherlands)

    Bulatovic, M.; Heijstek, M.W.; Verkaaik, M.; Dijkhuizen, E.H. van; Armbrust, W.; Hoppenreijs, E.P.A.H.; Kamphuis, S.; Kuis, W.; Egberts, T.C.; Sinnema, G.; Rademaker, C.M.A.; Wulffraat, N.M.

    2011-01-01

    OBJECTIVE: To design and validate a new questionnaire for identifying patients with methotrexate (MTX) intolerance, and to determine the prevalence of MTX intolerance in patients with juvenile idiopathic arthritis (JIA) using this questionnaire. METHODS: The MTX Intolerance Severity Score (MISS)

  13. Reduced hepatotoxicity by total glucosides of paeony in combination treatment with leflunomide and methotrexate for patients with active rheumatoid arthritis.

    Science.gov (United States)

    Chen, Zhu; Li, Xiang-Pei; Li, Zhi-Jun; Xu, Liang; Li, Xiao-Mei

    2013-03-01

    Combination use of methotrexate (MTX) and leflunomide (LEF) has been proved effective in the treatment of active rheumatoid arthritis (RA). However, previous trials have documented that both are associated with increased incidence of liver toxicity. As active compounds extracted from the roots of the traditional Chinese herb Paeonia lactiflora Pall, total glucosides of paeony (TGP) have been shown to have anti-inflammatory, hepatoprotective and immuno-regulatory activities, without evident toxicity or side effects. In this 24-week, open label, randomized multicenter clinical trial, we investigated the efficacy of TGP and the protective effect on hepatotoxicity in the combination treatment with LEF and MTX for patients with active RA. A total of 204 patients with active RA (DAS28>3.2) recruited from 3 regional referral centers were enrolled and received MTX and LEF combination therapy (MTX 10 mg/week plus LEF 20 mg/day) with or without TGP for up to 24 weeks by randomization. Hepatotoxicity was defined as an increase of at least 1.5-fold the upper limits of normal (ULN) of alanine aminotransferase (ALT) or aspartate aminotransferase (AST). Significantly less frequent hepatotoxicity was observed in patients with TGP than those without (9.5% vs 34.8%, p 1.5 to ≤2 times and >2 to ≤3 times the ULN were lower in TGP group than the control (1.9% vs 10.1%, 2.9% vs 12.4%, p TGP group achieved a European League Against Rheumatism (EULAR) good response or moderate response at 12 weeks, although there is no statistical significance. Similar results were observed at 24 weeks. Our preliminary study demonstrates the hepatoprotective and additive role of TGP in combination with MTX and LEF in the treatment of active RA. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Lazić Jelena

    2017-01-01

    Full Text Available Despite remarkable progress in survival of children with acute lymphoblastic leukemia (ALL which has reached about 85%, early toxicity and relapse rate remain issues that need to to be resolved. Genetic variants are important factors influencing the metabolism of cytotoxic drugs in ALL treatment. Variants in genes coding for methotrexate (MTX-metabolizing enzymes are under constant scientific interest due to their potential impact on drug toxicity and relapse rate. We investigated methylenetetrahydrofolate reductase (MTHFR c.677C>T and MTHFR c.1298A>C variants as pharmacogenetic markers of MTX toxicity and predictors of relapse. The study enrolled 161 children with ALL, treated according to the current International Berlin-Frankfurt-Munster group (BFM for diagnostics and treatment of leukemia and lymphoma protocols. Genotyping was performed using PCRRFLP and allele-specific PCR assays. Our results revealed similar distributions of MTHFR c.677C>T and MTHFR c.1298A>C genotypes among 104 healthy individuals as compared to pediatric ALL patients. A lower incidence of early MTX toxicity was noted in the MTHFR c.677TT genotype (p=0.017, while MTHFR c.1298A>C genotypes were not associated with MTX toxicity. Carriers of any MTHFR c.677C>T and MTHFR c.1298A>C genotypes did not experience decreased overall survival (OAS or higher relapse rates. Genetic variants in the MTHFR gene are not involved in leukemogenesis in pediatric ALL. The presence of the MTHFR c.677TT genotype was recognized as a predictive factor for decreased MTX toxicity during the intensification phase of therapy. Neither MTHFR c.677C>T nor MTHFR c.1298A>C genotypes correlated with an increased number of toxic deaths or relapse rate. Our study emphasizes the importance of implementing pharmacogenetic markers in order to optimize pediatric ALL therapy. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. III 41004

  15. Total glucosides of paeony can reduce the hepatotoxicity caused by Methotrexate and Leflunomide combination treatment of active rheumatoid arthritis.

    Science.gov (United States)

    Xiang, Nan; Li, Xiao-Mei; Zhang, Miao-Jia; Zhao, Dong-Bao; Zhu, Ping; Zuo, Xiao-Xia; Yang, Min; Su, Yin; Li, Zhan-Guo; Chen, Zhu; Li, Xiang-Pei

    2015-09-01

    Total glucosides of paeony (TGP) have been confirmed to exert anti-inflammatory and hepatoprotective effects. Methotrexate (MTX) and Leflunomide (LEF) combination has a better efficacy in the treatment of active rheumatoid arthritis (RA), but hepatotoxicity was observed. In this study, we investigated the effect of TGP on hepatic dysfunction caused by MTX and LEF in patients with active RA. A total of 268 patients with active RA (disease activity score in 28 joints, DAS28>3.2) were enrolled in this study. All patients were randomly assigned to two groups, the therapeutic group in which patients were treated with TGP (1.8 g/day) combined with MTX and LEF (MTX 10mg/week plus LEF 20mg/day) while in the control group, patients were treated without TGP up to 12 weeks. The efficacy and liver abnormalities were observed. The incidence of abnormal liver function within 12 weeks in TGP group was significantly lower than that in control group (11.38% vs 23.26%, P=0.013). The proportion of patients with ALT/AST >3 times ULN (upper limits of normal) was significantly lower in TGP group than control group (1.63% vs 7.75%, P=0.022). More patients achieved remission, good and moderate response in TGP group than control group at 4, 8 and 12 weeks, but the difference was not significant (P>0.05). The proportions of all adverse events were comparable in the two groups except for diarrhea. Our study demonstrates that TGP can significantly reduce the incidence and severity of liver damage caused by MTX+LEF in the treatment of active RA patients. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Prediction of methotrexate intolerance in juvenile idiopathic arthritis: a prospective, observational cohort study.

    Science.gov (United States)

    van Dijkhuizen, Evert Hendrik Pieter; Bulatović Ćalasan, Maja; Pluijm, Saskia M F; de Rotte, Maurits C F J; Vastert, Sebastiaan J; Kamphuis, Sylvia; de Jonge, Robert; Wulffraat, Nico M

    2015-01-01

    Methotrexate (MTX) is an effective and safe drug in the treatment of juvenile idiopathic arthritis (JIA). Despite its safety, MTX-related gastrointestinal adverse effects before and after MTX administration, termed MTX intolerance, occur frequently, leading to non-compliance and potentially premature MTX termination. The aim of this study was to construct a risk model to predict MTX intolerance. In a prospective JIA cohort, clinical variables and single nucleotide polymorphisms were determined at MTX start. The Methotrexate Intolerance Severity Score was employed to measure MTX intolerance in the first year of treatment. MTX intolerance was most prevalent at 6 or 12 months after MTX start, which was defined as the outcome for the prediction model. The model was developed in 152 patients using multivariable logistic regression analysis and subsequently internally validated using bootstrapping. The prediction model included the following predictors: JIA category, antinuclear antibody, parent/patient assessment of pain, Juvenile Arthritis Disease Activity Score-27, thrombocytes, alanine aminotransferase and creatinine. The model classified 77.5% of patients correctly, and 66.7% of patients after internal validation by bootstrapping. The lowest predicted risk of MTX intolerance was 18.9% and the highest predicted risk was 85.9%. The prediction model was transformed into a risk score (range 0-17). At a cut-off of ≥6, sensitivity was 82.0%, specificity 56.1%, positive predictive value was 58.7% and negative predictive value 80.4%. This clinical prediction model showed moderate predictive power to detect MTX intolerance. To develop into a clinically usable tool, it should be validated in an independent cohort and updated with new predictors. Such an easy-to-use tool could then assist clinicians in identifying patients at risk to develop MTX intolerance, and in turn to monitor them closely and intervene timely in order to prevent the development of MTX intolerance

  17. Leflunomide is associated with a higher flare rate compared to methotrexate in the treatment of chronic uveitis in juvenile idiopathic arthritis.

    Science.gov (United States)

    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.

  18. Methotrexate treatment may prevent uveitis onset in patients with juvenile idiopathic arthritis: experiences and subgroup analysis in a cohort with frequent methotrexate use.

    Science.gov (United States)

    Kostik, Mikhail M; Gaidar, Ekaterina V; Hynnes, Alla Y; Dubko, Margarita F; Masalova, Vera V; Snegireva, Ludmil S; Chikova, Irina A; Isupova, Eugenia A; Nikitina, Tatiana N; Serogodskaya, Elena D; Kalashnikova, Olga V; Ravelli, Angelo; Chasnyk, Vyacheslav G

    2016-01-01

    To re-evaluate the ability of methotrexate (MTX) to prevent the onset of uveitis in Russian children with juvenile idiopathic arthritis (JIA). The clinical charts for all consecutive patients who received a stable management for at least 2 years with or without MTX were reviewed. Patients who were given systemic medications other than MTX (except NSAID) and patients with systemic arthritis, rheumatoid factor-positive arthritis, or enthesitis-related arthritis were excluded. Each patient was examined after at least a 2-year follow-up period after the first visit to establish whether uveitis had occurred. A total of 281 patients with a median disease duration of 3.8 years were included. 191 patients (68%) were treated with MTX. During the observation period, 64 patients (22.8%) developed uveitis, a median of 1.6 year after disease onset. The frequency of uveitis was lower in MTX-treated than in MTX-untreated patients (11.5% vs. 46.7%, respectively, OR=6.7 (95%CI:3.7-12.3), p=0.0000001). Survival analysis confirmed that patients treated with MTX had a lower probability of developing uveitis (HR=4.35, p=0.000001). In subgroup analysis it was shown that MTX was more preventive in boys than in girls, and in patients with JIA onset age of over 5 years compared to those with disease onset less than 5 years. The data of survival analysis of MTX prevention has shown that benefits do not depend on the number of active joints and ANA status. MTX therapy may prevent the onset of uveitis in children with JIA. Further randomised controlled trials are required to confirm our results.

  19. Adverse effects of methotrexate in three psoriatic arthritis patients.

    Science.gov (United States)

    Maejima, Hideki; Watarai, Akira; Nakano, Toshiaki; Katayama, Chieko; Nishiyama, Hiromi; Katsuoka, Kensei

    2014-04-01

    Methotrexate, a folic acid analogue with anti-proliferative and anti-inflammatory effects, is commonly used to treat patients with severe destructive psoriatic arthritis and has considerable efficacy. Combined anti-tumor necrosis factor and MTX therapy result in less treatment discontinuation due to adverse events. Despite its efficacy, MTX may result in adverse effects including hepatic, pulmonary, and renal toxicity as well as lymphoproliferative disorders and predisposition to infection. We herein report rare adverse effects of MTX treatment, specifically asymptomatic pulmonary tuberculosis, renal cell carcinoma, and lateral uveitis, in three psoriatic arthritis patients treated with MTX. MTX is an important drug for the treatment for psoriatic arthritis patient, but an awareness of the possible adverse effects is needed.

  20. The investigation of antimicrobial peptides expression and its related interaction with methotrexate treatment in patients with psoriasis vulgaris.

    Science.gov (United States)

    Ozlu, Emin; Karadag, Ayse Serap; Ozkanli, Seyma; Oguztuzun, Serpil; Akbulak, Ozge; Uzuncakmak, Tugba Kevser; Demirkan, Serkan; Akdeniz, Necmettin

    2017-12-01

    Psoriasis is a chronic, inflammatory and immune-mediated disease. Recently, the role of antimicrobial peptides (AMPs) such as human beta defensins (hBDs) in the pathogenesis of psoriasis has been investigated. We aimed to evaluate the expression profiles of hBD-1 and hBD-2 in psoriatic skin before and after methotrexate (MTX) therapy and to compare healthy controls. Immunohistochemical expressions of hBD-1 and hBD-2 were assessed in 16 patients with psoriasis vulgaris and 20 normal skin biopsies from healthy controls. The patients were administered a 12 week of MTX and skin biopsy samples were obtained from the lesional skin of the patients pre-/posttreatment and normal body of the healthy controls. The median (range) Psoriasis Area and Severity Index (PASI) value was 21.6 (8.2-27.7) before the treatment whereas; 3.05 (1-23.4) after the treatment. hBD-1 expression in psoriasis patients was significantly higher as compared to the healthy controls before treatment (p psoriasis patients and healthy controls in terms of hBD-2 expression before treatment (p > 0.05). No significant difference was observed between before-after MTX treatment in terms of hBD-1 and hBD-2 expression levels in psoriasis patients (p > 0.05). These findings suggest a role for hBD-1 in psoriasis pathogenesis. But MTX treatment does not affect on hBD-1 and hBD-2 expressions. Further studies are needed to assess the roles of these AMPs in psoriasis etiopathogenesis.

  1. CD5-Positive Primary Intraocular B-Cell Lymphoma Arising during Methotrexate and Tumor Necrosis Factor Inhibitor Treatment

    Directory of Open Access Journals (Sweden)

    Kenji Nagata

    2015-09-01

    Full Text Available Purpose: To report a case of CD5+ primary intraocular B-cell lymphoma arising during methotrexate (MTX and tumor necrosis factor (TNF inhibitor treatment in a young patient with rheumatoid arthritis and uveitis. Case Presentation: A 39-year-old woman treated with MTX and a TNF inhibitor for rheumatoid arthritis and uveitis had steroid-resistant vitreous opacity. A vitreous sample was obtained by using diagnostic vitrectomy and was categorized as class V based on cytologic examination. Flow cytometric analysis of the vitreous sample revealed that abnormal cells were CD5+, CD10-, CD19+, CD20+ and immunoglobulin light-chain kappa+, suggesting the diagnosis of CD5+ primary intraocular B-cell lymphoma. Polymerase chain reaction (PCR detected immunoglobulin heavy-chain gene rearrangement. Epstein-Barr virus (EBV DNA was detected in the vitreous sample by using PCR, and immunohistochemistry revealed EBV latent membrane protein-1 expression in the abnormal cells infiltrating the vitreous. Optic nerve invasion was observed on magnetic resonance imaging. Conclusion: Primary intraocular lymphoma (PIOL may develop in patients receiving MTX and TNF inhibitor treatment. EBV infection may play an important role in the pathogenesis of PIOL arising during immunosuppressive therapy.

  2. Protection of the Peyer's patch-associated crypt and villus epithelium against methotrexate-induced damage is based on its distinct regulation of proliferation

    NARCIS (Netherlands)

    Renes, Ingrid B.; Verburg, Melissa; Bulsing, Nathalie P.; Ferdinandusse, Sacha; Büller, Hans A.; Dekker, Jan; Einerhand, Alexandra W. C.

    2002-01-01

    The crypt and villus epithelium associated with Peyer's patches (PPs) is largely spared from methotrexate (MTX)-induced damage, compared with the non-patch (NP) epithelium. To assess the mechanism(s) preventing damage to the PP epithelium after MTX treatment, epithelial proliferation, apoptosis, and

  3. Interaction of nonsteroidal anti-inflammatory drugs with multidrug resistance protein (MRP) 2/ABCC2- and MRP4/ABCC4-mediated methotrexate transport.

    NARCIS (Netherlands)

    El-Sheikh, A.A.K.; Heuvel, J.J.M.W. van den; Koenderink, J.B.; Russel, F.G.M.

    2007-01-01

    Methotrexate (MTX) has been used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of inflammatory diseases as well as malignancies. Especially at high MTX dosages, severe adverse effects with this combination may occur, usually resulting from an impaired renal

  4. A U-HPLC-ESI-MS/MS-based stable isotope dilution method for the detection and quantitation of methotrexate in plasma

    NARCIS (Netherlands)

    E. den Boer (Ethan); S.G. Heil (Sandra); B.D. van Zelst (Bertrand); P. Schneider (Petra); B.C.P. Koch (Birgit); M.L. te Winkel (Mariël Lizet); M.M. van den Heuvel-Eibrink (Marry); T.M. Luider (Theo); R. de Jonge (Robert)

    2012-01-01

    textabstractINTRODUCTION: High-dose methotrexate (MTX) is used in the treatment of proliferative diseases such as acute lymphoblastic leukemia. Therapeutic drug monitoring of plasma MTX is important to monitor efficacy and adverse events. The authors aimed to develop a liquid chromatography,

  5. Folate, homocysteine, and cobalamin status in patients with rheumatoid arthritis treated with methotrexate, and the effect of low dose folic acid supplement

    DEFF Research Database (Denmark)

    Hornung, Nete; Ellingsen, Torkell; Stengaard-Pedersen, Kristian

    2004-01-01

    OBJECTIVE: To investigate the effect of methotrexate (MTX) treatment of rheumatoid arthritis (RA) on folate metabolism, and to determine the effect of low dose folic acid on toxicity, efficacy, and folate status. METHODS: A 52-week prospective study of 81 patients with RA treated with MTX and self...

  6. Effects of Incorporating Carboxymethyl Chitosan into PMMA Bone Cement Containing Methotrexate.

    Directory of Open Access Journals (Sweden)

    Bo-Ming Liu

    Full Text Available Treatment of bone metastases usually includes surgical resection with local filling of methotrexate (MTX in polymethyl methacrylate (PMMA cement. We investigated whether incorporating carboxymethyl chitosan (CMCS in MTX-PMMA cement might overcome disadvantages associated with MTX. To determine the optimal CMCS+MTX concentration to suppress the viability of cancer cells, an integrated microfluidic chip culturing highly metastatic lung cancer cells (H460 was employed. The mechanical properties, microstructure, and MTX release of (CMCS+MTX-PMMA cement were evaluated respectively by universal mechanical testing machine, scanning electron microscopy (SEM, and incubation in simulated body fluid with subsequent HPLC-MS. Implants of MTX-PMMA and (CMCS+MTX-PMMA cement were evaluated in vivo in guinea pig femurs over time using spiral computed tomography with three-dimensional image reconstruction, and SEM at 6 months. Viability of H460 cells was significantly lowest after treatment with 57 μg/mL CMCS + 21 μg/mL MTX, which was thus used in subsequent experiments. Incorporation of 1.6% (w/w CMCS to MTX-PMMA significantly increased the bending modulus, bending strength, and compressive strength by 5, 2.8, and 5.2%, respectively, confirmed by improved microstructural homogeneity. Incorporation of CMCS delayed the time-to-plateau of MTX release by 2 days, but increased the fraction released at the plateau from 3.24% (MTX-PMMA to 5.34%. Relative to the controls, the (CMCS+MTX-PMMA implants integrated better with the host bone. SEM revealed pores in the cement of the (CMCS+MTX-PMMA implants that were not obvious in the controls. In conclusion, incorporation of CMCS in MTX-PMMA appears a feasible and effective modification for improving the anti-tumor properties of MTX-PMMA cement.

  7. Microbubbles coupled to methotrexate-loaded liposomes for ultrasound-mediated delivery of methotrexate across the blood–brain barrier

    Directory of Open Access Journals (Sweden)

    Wang X

    2014-10-01

    Full Text Available Xiang Wang,1 Ping Liu,1 Weixiao Yang,1 Lu Li,1 Peijing Li,2 Zheng Liu,1 Zhongxiong Zhuo,1 Yunhua Gao1 1Department of Ultrasound, Xinqiao Hospital of the Third Military Medical University, Chongqing, 2Department of Ultrasound, General Hospital of the Jinan Military Area, Jinan, People’s Republic of China Abstract: Methotrexate (MTX is the single most effective agent for the treatment of primary central nervous system lymphoma. Currently, the delivery of MTX to the brain is achieved by high systemic doses, which cause severe long-term neurotoxicity, or intrathecal administration, which is highly invasive and may lead to infections or hemorrhagic complications. Acoustically active microbubbles have been developed as drug carriers for the noninvasive and brain-targeted delivery of therapeutics. However, their application is limited by their low drug-loading capacity. To overcome this limitation, we prepared microbubbles coupled to MTX-loaded liposomes using ZHIFUXIAN, a novel type of microbubbles with a superior safety profile and long circulation time. MTX-liposome-coupled microbubbles had a high drug-loading capacity of 8.91%±0.86%, and their size (2.64±0.93 µm in diameter was suitable for intravenous injection. When used with ultrasound, they showed more potent in vitro cytotoxicity against Walker-256 cancer cells than MTX alone or MTX-loaded liposomes. When Sprague-Dawley rats were exposed to sonication, administration of these MTX-liposome-coupled microbubbles via the tail vein led to targeted disruption of the blood–brain barrier without noticeable tissue or capillary damage. High-performance liquid chromatography analysis of the brain MTX concentration showed that MTX delivery to the brain followed the order of MTX-liposome-coupled microbubbles + ultrasound (25.3±2.4 µg/g > unmodified ZHIFUXIAN + MTX + ultrasound (18.6±2.2 µg/g > MTX alone (6.97±0.75 µg/g > MTX-liposome-coupled microbubbles (2.92±0.39 µg/g. Therefore

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

    Science.gov (United States)

    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.

  9. Topical methotrexate pretreatment enhances the therapeutic effect of topical 5-aminolevulinic acid-mediated photodynamic therapy on hamster buccal pouch precancers

    OpenAIRE

    Deng-Fu Yang; Jeng-Woei Lee; Hsin-Ming Chen; Yih-Chih Hsu

    2014-01-01

    Topical 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is effective for treatment of human oral precancerous lesions. This animal study aimed to assess whether topical methotrexate (MTX) pretreatment could enhance the therapeutic effect of topical ALA-PDT on hamster buccal pouch precancerous lesions. Methods: Twenty hamster buccal pouch precancerous lesions were treated with either topical ALA-PDT with topical MTX pretreatment (topical MTX-ALA-PDT group, n = 10) or topical A...

  10. The optimal cutoff serum level of human chorionic gonadotropin for efficacy of methotrexate treatment in women with extrauterine pregnancy.

    Science.gov (United States)

    Sagiv, Ron; Debby, Abraham; Feit, Hagit; Cohen-Sacher, Bina; Keidar, Ran; Golan, Abraham

    2012-02-01

    To evaluate the efficacy of methotrexate treatment for extrauterine pregnancy and define criteria for prediction of success. Of 829 patients with an ectopic pregnancy admitted to E. Wolfson Medical Center, Holon, Israel, from January 1997 through December 2009, 238 had asymptomatic tubal pregnancies and increasing serum β-human chorionic gonadotropin (βhCG) levels. These patients were treated with a single intramuscular injection of 50mg of methotrexate (MTX) per square meter of body surface. Success was defined as undetectable βhCG levels without the need for a surgical intervention. The groups of patients successfully treated (n=167 [70%]) and unsuccessfully treated (n=71 [30%]) were compared. They were similar regarding age and gravidity. The initial serum βhCG level was significantly higher in the latter group than in the former (3798 mIU/mL vs. 1601 mIU/mL, Pinitial βhCG levels were less than 1000 mIU/mL, 71% when they were between 1000 and 2000 mIU/mL, and only 59% when they were between 2000 and 3000 mIU/mL. Methotrexate treatment is a safe and effective alternative to surgery. However, patients with initial βhCG levels higher than 2000 mIU/mL should only be offered the surgical approach. Copyright © 2011. Published by Elsevier Ireland Ltd.

  11. Efficient delivery of anticancer drug MTX through MTX-LDH nanohybrid system

    Science.gov (United States)

    Oh, Jae-Min; Park, Man; Kim, Sang-Tae; Jung, Jin-Young; Kang, Yong-Gu; Choy, Jin-Ho

    2006-05-01

    We have been successful to intercalate anticancer drug, methotrexate (MTX), into layered double hydroxides (LDHs), Mg2Al(OH)6(NO3)·0.1H2O, through conventional co-precipitation method. Layered double hydroxides (LDHs) are endowed with great potential for delivery vector, since their cationic layers lead to safe reservation of biofunctional molecules such as drug molecules or genes. And their ion exchangeability and solubility in acidic media (pHosteosarcoma cell culture lines (Saos-2 and MG-63) and the normal one (human fibroblast) were used for in vitro test. The anticancer efficacy of MTX intercalated LDHs (MTX-LDH nanohybrids) was also estimated in vitro by the bioassay such as MTT and BrdU (5-bromo-2-deoxyuridine) with the bone cancer cell culture lines (Saos-2 and MG-63). According to the toxicity test results, LDHs do not harm to both the normal and cancer cells upto the concentration of 500 ug/mL. The anticancer efficacy test for the MTX-LDH nanohybrids turn out to be much more effective in cell suppression compared to the MTX itself. According to the cell-line tests, the MTX-LDH shows same drug efficacy to the MTX itself in spite of the low concentration by ˜5000 times. Such a high cancer suppression effect of MTX-LDH hybrid is surely due to the excellent delivery efficiency of inorganic delivery vector, LDHs.

  12. Methotrexate for rheumatoid arthritis patients who are on hemodialysis.

    Science.gov (United States)

    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.

  13. Methotrexate osteopathy in long-term, low-dose methotrexate treatment for psoriasis and rheumatoid arthritis

    NARCIS (Netherlands)

    Zonneveld, I. M.; Bakker, W. K.; Dijkstra, P. F.; Bos, J. D.; van Soesbergen, R. M.; Dinant, H. J.

    1996-01-01

    In dermatology and rheumatology, methotrexate is frequently prescribed in low dosages per week; in oncology, high dosages per week are prescribed. Methotrexate osteopathy was first reported in children with leukemia treated with high doses of methotrexate. In animal studies, low doses of

  14. Protective Effects of Vitamin E on Methotrexate-Induced Jejunal Mucosal Damage in Rats.

    Science.gov (United States)

    Burcu, Busra; Kanter, Mehmet; Orhon, Zeynep Nur; Yarali, Oguzhan; Karabacak, Rukiye

    2016-04-01

    To investigate the possible protective effects of Vitamin E (Vit E) on oxidative stress and jejunal damage in the rat intestinal mucosa after methotrexate (MTX)-induced enterotoxicity. Rats were divided into 3 groups: control, MTX, and MTX+ Vit E; each group contained 8 animals. The control group was given physiological serum in addition to sunflower oil for 3 days. The second group was given sunflower oil with intragastric tube daily, followed by MTX injection (20 mg/kg intraperitoneally). To the third group, starting 3 days before injection, Vit E was given dissolved in sunflower oil (600 mg/kg orally) in addition to MTX injection. Four days after MTX injection the anesthetized rats were sacrificed, and the tissue samples obtained from their jejunums were investigated for histological and biochemical analysis. Vit E treatment significantly decreased the elevated tissue malondialdehyde levels and increased the reduced glutathione peroxidase and superoxide dismutase activities in comparison to the MTX-treated group. MTX treatment caused severe histopathological injury including mucosal erosions, inflammatory cell infiltration, necrosis, hemorrhage, and villous congestion. Vit E treatment significantly attenuated the severity of intestinal injury caused by MTX via inhibiting induced nitric oxide synthase levels and NF-κB p65 activation. Because of its reconstructing and antioxidant effects, Vit E pretreatment may have protective effects in the intestinal tissue of MTX-treated rats.

  15. Use of biotin targeted methotrexate–human serum albumin conjugated nanoparticles to enhance methotrexate antitumor efficacy

    Science.gov (United States)

    Taheri, Azade; Dinarvand, Rassoul; Nouri, Faranak Salman; Khorramizadeh, Mohammad Reza; Borougeni, Atefeh Taheri; Mansoori, Pooria; Atyabi, Fatemeh

    2011-01-01

    Biotin molecules could be used as suitable targeting moieties in targeted drug delivery systems against tumors. To develop a biotin targeted drug delivery system, we employed human serum albumin (HSA) as a carrier. Methotrexate (MTX) molecules were conjugated to HSA. MTX-HSA nanoparticles (MTX-HSA NPs) were prepared from these conjugates by cross-linking the HSA molecules. Biotin molecules were then conjugated on the surface of MTX-HSA NPs. The anticancer efficacy of biotin targeted MTX-HSA NPs was evaluated in mice bearing 4T1 breast carcinoma. A single dose of biotin targeted MTX-HSA NPs showed stronger in vivo antitumor activity than non-targeted MTX-HSA NPs and free MTX. By 7 days after treatment, average tumor volume in the biotin targeted MTX-HSA NPs-treated group decreased to 17.6% of the initial tumor volume when the number of attached biotin molecules on MTX-HSA-NPs was the highest. Average tumor volume in non-targeted MTX-HSA NPs-treated mice grew rapidly and reached 250.7% of the initial tumor volume. Biotin targeted MTX-HSA NPs increased the survival of tumor-bearing mice to 47.5 ± 0.71 days and increased their life span up to 216.7%. Mice treated with biotin targeted MTX-HSA NPs showed slight body weight loss (8%) 21 days after treatment, whereas non-targeted MTX-HSA NPs treatment at the same dose caused a body weight loss of 27.05% ± 3.1%. PMID:21931482

  16. The clinical efficacy of methotrexate and 5-fluorouracil in the interventional treatment of uterine incisional pregnancy after cesarean section: a comparative study

    International Nuclear Information System (INIS)

    Zhang Lei; Gu Weijin; Wan Jun; Ji Lihua; Wang Haiyun; Wang Ying; Ji Fang; Chen Qing

    2012-01-01

    Objective: To compare the interventional therapeutic efficacy of methotrexate (MTX) with that of 5-fluorouracil (5-FU) in treating uterine incisional pregnancy after cesarean section. Methods: A total of 92 patients with uterine incisional pregnancy after cesarean section, who were admitted to the hospital during the period from 2007 to 2010, were randomly divided into two groups: group MTX and group 5-FU. Patients in group MTX (n=46) received intra-arterial infusion of MTX (60-200) mg, which was followed by arterial embolization. Patients in group 5-FU (n=46) received intra-arterial infusion of 5-FU (1000-1250) mg, which was followed by arterial embolization. After the treatment the serum β-HCG and progesterone levels were determined daily for three succeeding days. The patients were followed up for three months. The clinical results were compared between the two groups. Results: The cure rates in group MTX and group 5-FU were 97.2% and 100%, respectively. No significant difference in cure rate existed between the two groups (P>0.05). A rapid fall in the serum β-HCG and progesterone levels within 1-3 days after the treatment were detected in 40 cases of group MTX and 38 cases of group 5-FU, and the decreasing extent was over 50%-80%, but the difference between the two groups was not significant (P>0.05). At the operation day, all patients of both groups had abdominal pain, and three patients in group MTX and 2 patients in 5-FU group had nausea and vomiting, but the difference between the two groups was not significant (P>0.05). During the follow-up period, no significant difference in the recovery time of the mental cycle and the hormone levels were found between the two groups (P>0.05). Conclusion: For the interventional treatment of uterine incisional pregnancy after cesarean section, the use of MTX has the same clinical efficacy as the use of 5-FU does. (authors)

  17. Methotrexate for the Treatment of Thyroid Eye Disease

    Directory of Open Access Journals (Sweden)

    Diego Strianese

    2014-01-01

    Full Text Available Background/Aim. To evaluate the efficacy of methotrexate for the treatment of thyroid eye disease (TED. Methods. 36 consecutive patients with active TED, previously treated with corticosteroids but stopped due to the occurrence of side effects, were commenced on methotrexate therapy. Two different weekly doses were administered depending on the weight of the patient (7.5 mg or 10 mg. Clinical activity score (7-CAS, visual acuity (VA, ocular motility, exophthalmos, and eyelid position were retrospectively evaluated at 3, 6, and 12 months and compared with baseline data. Results. There was a statistically significant improvement in 7-CAS at 3, 6, and 12 months after treatment (P<0.0001. There was no significant change in visual acuity. Ocular motility disturbances improved at 6 and 12 months (P<0.001. There was no significant change in exophthalmos (mean 24 mm, SD 3 mm or eyelid position (marginal reflex distance mean 6 mm, SD 1.5 mm during the follow-up period. No side effects were registered. Conclusions. Methotrexate therapy is effective in reducing CAS and ocular motility disturbances. No significant improvement in proptosis or eyelid retraction should be expected from this treatment. Eventually, it might be considered a suitable alternative treatment in TED for patients who cannot tolerate steroids.

  18. Biochemical criteria of toxicity of therapy with high doses of methotrexate in children with osteosarcoma

    Directory of Open Access Journals (Sweden)

    A. M. Strizhevskaya

    2015-01-01

    Full Text Available Methotrexate (Mtx is a cytotoxic drug from the group of antimetabolites, folic acid antagonists. High-dose (HD Mtx in pediatric oncology are used for the treatment of osteosarcoma (OS, and other types of tumors. This therapy has allowed to achieve a five-year relapse-free survival rates up to 80 % in patients with OS. However, the high toxicity of Mtx is a serious constraint in achieving the maximum therapeutic effect, which in most cases poses the occurrence of side effects in patients on various organs and systems. Treatment should be under strict laboratory monitoring, primarily therapeutic drug monitoring the concentration of Mtx in serum.246 children (boys – 125, girls – 121 aged 5 to 16 years with osteosarcoma (mean age 12.2 years who were treated in N.N. Blokhin Russian Cancer Research Center from 2006 to 2013. Patients were conducted from 1 to 8 courses HD Mtx at a dose of 8 or 12 g/m2 , administered within 4 h of infusion on the background of alkaline prehydrate. Leucovorin was administered intravenously, every 6 hours, starting 24 h from the start of the Mtx infusion. 1137 courses of HD Mtx were conducted with FPIA method (analyzer TDx/Flx, Abbott, USA. The technique of monitoring of homocysteine (Hcy in the blood serum by analyzer Vitros 5/1FS (Johnson & Johnson, USA during the entire course of high-dose Mtx was tested. In groups calculated pharmacokinetic parameters Mtx were tested: area under the pharmacokinetic curve (MtxAUC, clearance of methotrexate (ClMtx, the elimination half-life (T1/2 and the total time of excretion (Ttotal. Normal excretion of Mtx was revealed at 1050 courses Mtx, corresponding to the following values: 4 h – 1109 ± 283 μmol/l; 24 h – 4,67 ± 0,95 μmol/l; 42 h – 0,38 ± 0.16 µmol/l; 48 h – less than 0,23 ± 0.04 µmol/l; 72 h of 0.07 ± 0,03 µmol/l; 96 h of 0.03 ± 0.01 µmol/l. At 87 courses identified delayed Mtx excretion, accounting for 7.6 % of all courses. In all measured parameters

  19. Methotrexate in the treatment of peripheral arthritis in ulcerative colitis

    Directory of Open Access Journals (Sweden)

    R. Scarpa

    2011-06-01

    Full Text Available Objective: To evaluate efficacy of methotrexate treatment in peripheral arthritis of ulcerative colitis. Methods: We studied 18 patients (10/8 M/F; mean age: 38.90 yrs; range: 21-65 yrs, with peripheral arthritis (14 with polyarticular, 4 with oligoarticular subset associate ulcerative colitis. Methotrexate 20 mg/week was administered in our patients, who were already receiving mesalazina for inflammatory bowel disease. At baseline, after 3 (T1, 6 (T2 and 12 months (T3 serological parameters (ESR and CRP, functional status (HAQ and disease activity (VAS, GH, Ritchie articular index were evaluated. Results: During the therapy a significant improvement was observed in disease activity, functional status and serological parameters since T1. ESR and CRP did not change at T2 and T3. Instead VAS, GH, Ritchie articular index and HAQ had a significant and gradual improvement from T1 to T3. Conclusion: Methotrexate treatment was efficacious in the treatment of peripheral arthritis associate ulcerative colitis. This drug induced improvement in disease activity, functional status and serological parameters after 3 months of therapy.

  20. Enzymatic assay for methotrexate in erythrocytes

    DEFF Research Database (Denmark)

    Schrøder, H; Heinsvig, E M

    1985-01-01

    Methotrexate (MTX) accumulates in erythrocytes in MTX-treated patients. We present a modified enzymatic assay measuring MTX concentrations between 10 and 60 nmol/l in erythrocytes, adapted for a centrifugal analyser (Cobas Bio). About 40 patient's samples could be analysed within 1 h. The detection...

  1. A novel platform designed by Au core/inorganic shell structure conjugated onto MTX/LDH for chemo-photothermal therapy.

    Science.gov (United States)

    Tian, De-Ying; Wang, Wei-Yuan; Li, Shu-Ping; Li, Xiao-Dong; Sha, Zhao-Lin

    2016-05-30

    A novel platform making up of methotrexate intercalated layered double hydroxide (MTX/LDH) hybrid doped with gold nanoparticles (NPs) may have great potential both in chemo-photothermal therapy and the simultaneous drug delivery. In this paper, a promising platform of Au@PDDA-MTX/LDH was developed for anti-tumor drug delivery and synergistic therapy. Firstly, Au NPs were coated using Layer-by-Layer (LbL) technology by alternate deposition of poly (diallyldimethylammonium chloride) (PDDA) and MTX molecules, and then the resulting core-shell structures (named as Au@PDDA-MTX) were directly conjugated onto the surface of MTX/LDH hybrid by electrostatic attraction to afford Au@PDDA-MTX/LDH NPs. Here MTX was used as both the agent for surface modification and the anti-tumor drug for chemotherapy. The platform of Au@PDDA-MTX/LDH NPs not only had a high drug-loading capacity, but also showed excellent colloidal stability and interesting pH-responsive release profile. In vitro drug release studies demonstrated that MTX released from Au@PDDA-MTX/LDH was relatively slow under normal physiological pH, but it was enhanced significantly at a weak acidic pH value. Furthermore, the combined treatment of cancer cells by using Au@PDDA-MTX/LDH for synergistic hyperthermia ablation and chemotherapy was demonstrated to exhibit higher therapeutic efficacy than either single treatment alone, underscoring the great potential of the platform for cancer therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Comparing the effects of tofacitinib, methotrexate and the combination, on bone marrow oedema, synovitis and bone erosion in methotrexate-naive, early active rheumatoid arthritis: results of an exploratory randomised MRI study incorporating semiquantitative and quantitative techniques

    DEFF Research Database (Denmark)

    Conaghan, Philip G.; Ostergaard, Mikkel; Bowes, Michael A.

    2016-01-01

    OBJECTIVES: To explore the effects of tofacitinib-an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA)-with or without methotrexate (MTX), on MRI endpoints in MTX-naive adult patients with early active RA and synovitis in an index wrist or hand. METHODS: In this exploratory......, phase 2, randomised, double-blind, parallel-group study, patients received tofacitinib 10 mg twice daily + MTX, tofacitinib 10 mg twice daily + placebo (tofacitinib monotherapy), or MTX + placebo (MTX monotherapy), for 1 year. MRI endpoints (Outcome Measures in Rheumatology Clinical Trials RA MRI score...... differences in RAMRIS bone marrow oedema (BME) at month 6 were -1.55 (90% CI -2.52 to -0.58) for tofacitinib + MTX and -1.74 (-2.72 to -0.76) for tofacitinib monotherapy (both ptofacitinib + MTX...

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

    Directory of Open Access Journals (Sweden)

    Aurea Lima

    2015-06-01

    Full Text Available 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.

  4. Methotrexate information booklet study 2008.

    LENUS (Irish Health Repository)

    Mohammad, A

    2012-02-01

    INTRODUCTION: I n order to assess the value of using the methotrexate information booklet, we conducted a single blind prospective controlled trial of the patients attending two rheumatology services. METHODS: The active-arm (n=40) used the MTX information booklet for the patients\\' education and the control-arm (n=38) did not. Patients\\' interviews were conducted over a 6-month period using an MTX-questionnaire. RESULTS: The entire active-arm patients (100%) were taking folic-acid and 32 (80%) knew the reason why they were taking folic-acid vs. [30 (79%) and 10 (26%) in the control-arm]. In the active-arm 35 (88%) knew the reason for their monthly blood tests vs. 18 (47%) in the control-arm. The entire active-arm was aware of the need for contraception use and MTX-side effects vs. 23 (60%) and 15 (40%) in the control-arm respectively. CONCLUSIONS: The use of the MTX information booklet in our cohort improved their understanding of the treatment.

  5. Involvement of Multiple Transporters-mediated Transports in Mizoribine and Methotrexate Pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Teruo Murakami

    2012-08-01

    Full Text Available Mizoribine is administered orally and excreted into urine without being metabolized. Many research groups have reported a linear relationship between the dose and peak serum concentration, between the dose and AUC, and between AUC and cumulative urinary excretion of mizoribine. In contrast, a significant interindividual variability, with a small intraindividual variability, in oral bioavailability of mizoribine is also reported. The interindividual variability is mostly considered to be due to the polymophisms of transporter genes. Methotrexate (MTX is administered orally and/or by parenteral routes, depending on the dose. Metabolic enzymes and multiple transporters are involved in the pharmacokinetics of MTX. The oral bioavailability of MTX exhibits a marked interindividual variability and saturation with increase in the dose of MTX, with a small intraindividual variability, where the contribution of gene polymophisms of transporters and enzymes is suggested. Therapeutic drug monitoring of both mizoribine and MTX is expected to improve their clinical efficacy in the treatment of rheumatoid arthritis.

  6. Methotrexate diethyl ester-loaded lipid-core nanocapsules in aqueous solution increased antineoplastic effects in resistant breast cancer cell line.

    Science.gov (United States)

    Yurgel, Virginia C; Oliveira, Catiuscia P; Begnini, Karine R; Schultze, Eduarda; Thurow, Helena S; Leon, Priscila M M; Dellagostin, Odir A; Campos, Vinicius F; Beck, Ruy C R; Guterres, Silvia S; Collares, Tiago; Pohlmann, Adriana R; Seixas, Fabiana K

    2014-01-01

    Breast cancer is the most frequent cancer affecting women. Methotrexate (MTX) is an antimetabolic drug that remains important in the treatment of breast cancer. Its efficacy is compromised by resistance in cancer cells that occurs through a variety of mechanisms. This study evaluated apoptotic cell death and cell cycle arrest induced by an MTX derivative (MTX diethyl ester [MTX(OEt)2]) and MTX(OEt)2-loaded lipid-core nanocapsules in two MTX-resistant breast adenocarcinoma cell lines, MCF-7 and MDA-MB-231. The formulations prepared presented adequate granulometric profile. The treatment responses were evaluated through flow cytometry. Relying on the mechanism of resistance, we observed different responses between cell lines. For MCF-7 cells, MTX(OEt)2 solution and MTX(OEt)2-loaded lipid-core nanocapsules presented significantly higher apoptotic rates than untreated cells and cells incubated with unloaded lipid-core nanocapsules. For MDA-MB-231 cells, MTX(OEt)2-loaded lipid-core nanocapsules were significantly more efficient in inducing apoptosis than the solution of the free drug. S-phase cell cycle arrest was induced only by MTX(OEt)2 solution. The drug nanoencapsulation improved apoptosis induction for the cell line that presents MTX resistance by lack of transport receptors.

  7. Cerebral venous and sinus thrombosis with cerebrospinal fluid circulation block after the first methotrexate administration by lumbar puncture

    International Nuclear Information System (INIS)

    Bienfait, H.P.; Gijtenbeek, J.M.M.; Bent, M.J. van; Bruin, H.G. de; Voogt, P.J.; Pillay, M.

    2002-01-01

    We report a patient treated for small lymphocytic lymphoma/leukemia with cerebral venous and sinus thrombosis (CVST) after lumbar puncture with intrathecal administration of methotrexate (MTX). He also developed a cerebrospinal fluid flow block. This is the first report of an association between lumbar puncture and intrathecally administered MTX and the development of CVST. Intrathecal treatment in this patient was discontinued and he was successfully treated with high-dose low-molecular-weight heparin subcutaneously. (orig.)

  8. Palonosetron for the prevention of nausea and vomiting in children with acute lymphoblastic leukemia treated with high dose methotrexate

    DEFF Research Database (Denmark)

    Nadaraja, Sambavy; Mamoudou, Aissata Diop; Thomassen, Harald

    2012-01-01

    High dose methotrexate (HD-MTX), used in the treatment of children with acute lymphoblastic leukemia (ALL), is moderately emetogenic. First generation 5-HT(3) receptor antagonists are effective prophylactic agents but require multiple administrations. Palonosetron has a half life of 36-42 hours...... of palonosetron (5 µg/kg) for the prevention of chemotherapy-induced nausea and vomiting in children 18 years of age with ALL treated with HD-MTX, 5 g/m(2)....

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

    Science.gov (United States)

    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.

  10. Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by background methotrexate dose group.

    Science.gov (United States)

    Fleischmann, R; Mease, P J; Schwartzman, S; Hwang, L-J; Soma, K; Connell, C A; Takiya, L; Bananis, E

    2017-01-01

    Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This post hoc analysis investigated the effect of methotrexate (MTX) dose on the efficacy of tofacitinib in patients with RA. ORAL Scan (NCT00847613) was a 2-year, randomized, Phase 3 trial evaluating tofacitinib in MTX-inadequate responder (IR) patients with RA. Patients received tofacitinib 5 or 10 mg twice daily (BID), or placebo, with low (≤12.5 mg/week), moderate (>12.5 to tofacitinib 5 mg BID (N = 321), tofacitinib 10 mg BID (N = 316), or placebo (N = 160); 242, 333, and 222 patients received low, moderate, and high MTX doses, respectively. At months 3 and 6, ACR20/50/70 response rates were greater for both tofacitinib doses vs placebo across all MTX doses. At month 3, mean changes from baseline in CDAI and HAQ-DI were significantly greater for both tofacitinib doses vs placebo, irrespective of MTX category; improvements were maintained at month 6. Both tofacitinib doses demonstrated improvements in DAS28-4(ESR), and less structural progression vs placebo, across MTX doses at month 6. Tofacitinib plus MTX showed greater clinical and radiographic efficacy than placebo in MTX-IR patients with RA, regardless of MTX dose.

  11. Synthesis and Evaluation of Hydrogen Peroxide Sensitive Prodrugs of Methotrexate and Aminopterin for the Treatment of Rheumatoid Arthritis

    DEFF Research Database (Denmark)

    Peiró Cadahía, Jorge; Bondebjerg, Jon; Hansen, Christian A.

    2018-01-01

    A series of novel hydrogen peroxide sensitive prodrugs of methotrexate (MTX) and aminopterin (AMT) were synthesized and evaluated for therapeutic efficacy in mice with collagen induced arthritis (CIA) as a model of chronic rheumatoid arthritis (RA). The prodrug strategy selected is based on ROS...... assays. Selected candidates showed moderate to good solubility, high chemical and enzymatic stability, and therapeutic efficacy comparable to the parent drugs in the CIA model. Importantly, the prodrugs displayed the expected safer toxicity profile and increased therapeutic window compared to MTX and AMT...

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

    Science.gov (United States)

    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.

  13. Methotrexate: an effective monotherapy for refractory generalized morphea

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    Platsidaki E

    2017-05-01

    Full Text Available Eftychia Platsidaki, Vassiliki Tzanetakou, Anargyros Kouris, Panagiotis G Stavropoulos Department of Dermatology and Venereology, Andreas Syggros Hospital, University of Athens, Athens, Greece Introduction: Morphea is an inflammatory skin disorder characterized by excessive collagen deposition. Although treatment algorithms for morphea subtypes have been suggested, no consistent recommendations are available. This study attempts to evaluate the clinical efficacy of methotrexate (MTX as monotherapy in refractory generalized morphea. Methods: It is a retrospective study, including 20 patients who had already been treated with various topical and systemic therapies with minimal clinical improvement. Patients received orally MTX at a of dosage 15 mg once weekly. Duration of the use, dosage of MTX, and adverse events were recorded. Clinical assessment of skin lesions was performed and documented. Results: The mean disease duration was 27 months before the initiation of MTX treatment. After 12 months of therapy, very good response was achieved in 6 patients (30%, good response in 10 patients (50%, and fair response in 2 patients (10%, while 2 patients (10% had failed treatment. Patients were followed up for a mean time interval of 21 months. No serious adverse event was recorded. Conclusion: MTX has been already proved to be an effective and well-tolerated treatment in pediatric patients with morphea. The majority of the group of adult patients showed very good and good improvement when treated with MTX. Although this is an uncontrolled study, MTX monotherapy was considered a safe and effective treatment for the management of this specific clinical subset of morphea in adults. Keywords: methotrexate, adults, generalized morphea

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

    Science.gov (United States)

    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.

  15. Evaluation of the Efficacy of Combined Therapy of Methotrexate and Etanercept versus Methotrexate as a Mono-Therapy.

    Science.gov (United States)

    Rexhepi, Sylejman; Rexhepi, Mjellma; Rexhepi, Blerta; Sahatçiu-Meka, Vjollca; Mahmutaj, Vigan

    2018-05-20

    This study aims to evaluate the efficacy of Methotrexate (MTX) alone and combined therapy with Etanercept (ETN) and Methotrexate in patients with active rheumatoid arthritis (RA). In the randomised control study, conducted in the period from March 2014 until March 2016, we evaluated the efficacy of the treatment of patients with RA with MTX as monotherapy and combination treatment with MTX and ETN. In the Clinic of Rheumatology in Prishtina, 90 adult patients with RA were treated in combination with ETN (doses of 50 mg subcutaneously/weekly), with oral MTX (doses up to 20 mg weekly), and MTX alone (doses up to 20 mg weekly) during this period of two years. Clinical response was assessed using European League against Rheumatism (EULAR)/American College of Rheumatology (ACR) Criteria and the Disease Activity Score (DAS28). Radiographic changes were measured in the beginning and at the end of the study using Larsen's method. Of the cohort groups of 90 patients, mean age of 55.63, 15 patients, (16.6 %) were treated with combined therapy (ETN plus MTX) and 75 patients (83.3%) with monotherapy (MTX). After two years of treatment the group with combined therapy resulted with improvement of acute phase reactants as erythrocyte sedimentation rate (ESR) for the first hour (41.1 vs. 10.3 mm/hour) and C - reactive protein (CRP) (40.8 vs. 6 mg/liter), and compared to the group treated with monotherapy, there were no significant changes (ESR: 45.7 vs 34.3 mm/hour; CRP: 48 vs 24 mg/liter). Before the treatment, the severity of the disease was high, wherein the group with combined therapy DAS28 was 5.32, compared to the monotherapy group whom DAS28 was 5.90. After 2 years of treatment, we had significant changes in the results of DAS28, wherein the group treated with ETN plus MTX DAS28 was 2.12 ± 0.15, while in the group of patients treated with MTX DAS28 were 3.75 ± 0.39 (t = 13.03; df = 58; p < 0.0001). The group with combined therapy showed no evidence of radiographic

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

    Science.gov (United States)

    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.

  17. Efficacy of tofacitinib monotherapy in methotrexate-naive patients with early or established rheumatoid arthritis

    NARCIS (Netherlands)

    Fleischmann, Roy M.; Huizinga, Tom W. J.; Kavanaugh, Arthur F.; Wilkinson, Bethanie; Kwok, Kenneth; DeMasi, Ryan; van Vollenhoven, Ronald F.

    2016-01-01

    Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib monotherapy was previously shown to inhibit structural damage, reduce clinical signs and symptoms of RA, and improve physical functioning over 24 months in methotrexate (MTX)-naive adult

  18. Use of mycophenolate mofetil in patients with severe localized scleroderma resistant or intolerant to methotrexate

    NARCIS (Netherlands)

    Mertens, Jorre S.; Marsman, Diane; van de Kerkhof, Peter C M; Hoppenreijs, Esther P A H; Knaapen, Hanneke K A; Radstake, Timothy R D; de Jong, Elke M G J; Seyger, Marieke M B

    2016-01-01

    To assess the efficacy and safety of mycophenolate mofetil (MMF) in patients with localized scleroderma (LoS) resistant or intolerant to previous treatment with methotrexate (MTX). A case series of patients with LoS treated with MMF. Outcome was assessed through clinical examination. Adverse events

  19. A systemic review and meta-analysis of the clinical efficacy and safety of total glucosides of peony combined with methotrexate in rheumatoid arthritis.

    Science.gov (United States)

    Feng, Zhi-Tao; Xu, Juan; He, Guo-Chao; Cai, San-Jin; Li, Juan; Mei, Zhi-Gang

    2018-01-01

    To assess the efficacy and safety of the combination of total glucoside of peony (TGP) and methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). Randomized controlled trial (RCT) data on the traditional Chinese active component TGP combined with MTX vs. MTX alone for the treatment of RA was collected by searching the Pubmed, Embase, Cochrane Library, CNKI, VIP Journals database, and Wanfang database up to February 2017. Study selection, data extraction, data synthesis, and data analyses were performed according to the Cochrane standards. A total of eight RCTs involving 522 participants were included in this meta-analysis. Compared with MTX alone, the use of TGP combined with MTX exhibited better therapeutic effects for the treatment of RA (P = 0.004). In addition, TGP combined with MTX caused a more significant decrease in erythrocyte sedimentation rate (ESR) (P TGP and MTX combination group (P = 0.0007). Our study demonstrates that TGP combined with MTX is more effective than MTX alone for the treatment of RA. Nevertheless, the adverse effects of the combination of TGP and MTX need to be further assessed. Due to the poor methodological quality of included trials, well-designed, multi-center, and large-scale RCTs are necessary to draw a more definitive conclusion.

  20. The use of low dose methotrexate in children with chronic anterior and intermediate uveitis.

    Science.gov (United States)

    Malik, A R; Pavesio, C

    2005-07-01

    To assess the efficacy of low dose methotrexate (MTX) therapy for children with chronic anterior and intermediate uveitis. A retrospective case review of 10 children who received MTX for chronic uveitis at a tertiary referral centre was performed. The following data were recorded for each patient: age, sex, race, duration of uveitis, primary diagnosis, anatomical localisation of uveitis, corticosteroid therapy, dose range of MTX, duration of MTX therapy, and side effects of MTX therapy. Several clinical parameters were evaluated to study the effect of MTX. These included visual acuity, anterior chamber inflammation, and topical and oral corticosteroid requirement. After MTX VA of 6/6 or better was present in 100% right eyes and 80% left eyes (p = 0.055 and p = 0.016, respectively). Anterior chamber inflammation decreased in 60% of children after MTX (p = 0.0168). The requirement of topical steroid decreased from a mean of 5.6 times a day before MTX to 1.5 times a day after MTX (p = 0.005). The dose of oral steroid decreased from a mean of 18 mg per day to 2.85 mg per day (p = 0.012). The most common adverse effect was nausea (20%). No patient required discontinuation of MTX because of side effects. MTX is effective and safe for chronic anterior and intermediate uveitis in children. An increase awareness of its efficacy is required among paediatricians and ophthalmologists to prevent sight threatening complication of chronic uveitis and its treatment with long term use of steroids.

  1. The role of Wnt/β-catenin signaling in enterocyte turnover during methotrexate-induced intestinal mucositis in a rat.

    Directory of Open Access Journals (Sweden)

    Igor Sukhotnik

    Full Text Available BACKGROUND/AIMS: Intestinal mucositis is a common side-effect in patients who receive aggressive chemotherapy. The Wnt signaling pathway is critical for establishing and maintaining the proliferative compartment of the intestine. In the present study, we tested whether Wnt/β-catenin signaling is involved in methotrexate (MTX-induced intestinal damage in a rat model. METHODS: Non-pretreated and pretreated with MTX Caco-2 cells were evaluated for cell proliferation and apoptosis using FACS analysis. Adult rats were divided into three experimental groups: Control rats; MTX-2 animals were treated with a single dose of MTX given IP and were sacrificed on day 2, and MTX-4 rats were treated with MTX similar to group B and were sacrificed on day 4. Intestinal mucosal damage, mucosal structural changes, enterocyte proliferation, and enterocyte apoptosis were measured at sacrifice. Real Time PCR and Western blot was used to determine the level of Wnt/β-catenin related genes and protein expression. RESULTS: In the vitro experiment, treatment with MTX resulted in marked decrease in early cell proliferation rates following by a 17-fold increase in late cell proliferation rates compared to early proliferation. Treatment with MTX resulted in a significant increase in early and late apoptosis compared to Caco-2 untreated cells. In the vivo experiment, MTX-2 and MTX-4 rats demonstrated intestinal mucosal hypoplasia. MTX-2 rats demonstrated a significant decrease in FRZ-2, Wnt 3A Wnt 5A, β-catenin, c-myc mRNA expression and a significant decrease in β-catenin and Akt protein levels compared to control animals. Four days following MTX administration, rats demonstrated a trend toward a restoration of Wnt/β-catenin signaling especially in ileum. CONCLUSIONS: Wnt/β-catenin signaling is involved in enterocyte turnover during MTX-induced intestinal mucositis in a rat.

  2. Uterine arterial methotrexate infusion and embolization in the treatment of uterine adenomyosis

    International Nuclear Information System (INIS)

    Xie Jingyan; Wang Suzheng; Chen Jingfang; Xuan Yinghua; Lou Wensheng; Gu Jianping

    2008-01-01

    Objective: To study the efficacy of treating different types of uterine adenomyosis with transcatheter local infusion of methotrexate (MTX) combined with uterine arterial embolization under guidance of digital subtraction angiography (DSA). Methods: 33 cases were primarily screened out according to clinical symptoms and color Doppler and then further diagnosis as diffuse or local adenomyosis were undertaken with super selective uterine arterial angiography. The patients were then treated with uterine arterial local infusion (50 mg MTX)and embolization with PVA microsphere (diameter 450-650 μm), individually. Finally, the comparison between the preoperative and postoperative menstruation volumes, the degrees of dysmenorrheal, uterine sizes and the levels of sexual hormones of diffuse and local adenomyosis was carried out. Results: The uterine arterial local infusion of MTX combined with embolization showed no chemotherapeutic side effects. In all cases, there were decrease of menstruation amount, alleviated dysmenorrhea, reduction of uterine size, and the efficacy was more evident in diffuse adenomyosis (P<0.05). Conclusions: Micro-invasive interventional technique combined with drug therapy is promising for diffuse and local adenomyosis especially for the former. (authors)

  3. Anti-tumor Study of Chondroitin Sulfate-Methotrexate Nanogels

    Science.gov (United States)

    Wang, Jinyu; Zhao, Weibo; Chen, Haixiao; Qin, An; Zhu, Peizhi

    2017-10-01

    Self-assembly nanogels (NGs) were formed by bioconjugating methotrexate (MTX) with chondroitin sulfate (CS). MTX-CS NGs can greatly enhance the solubility and improve the delivery efficacy of MTX due to the CD44 binding property of CS. Vivo experiments revealed that MTX-CS NGs showed less toxicity than MTX. MTX-CS NGs can improve the anti-tumor effect while reducing the side effects of MTX. Due to their CD44 binding property, chondroitin sulfate-drug conjugates could be a promising and efficient platform for improving the solubility of sparingly soluble drug molecules as well as targeted delivery to cancer cells and tumor tissues.

  4. P-gp, MRP2 and OAT1/OAT3 mediate the drug-drug interaction between resveratrol and methotrexate

    Energy Technology Data Exchange (ETDEWEB)

    Jia, Yongming [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044 (China); Liu, Zhihao; Wang, Changyuan; Meng, Qiang; Huo, Xiaokui; Liu, Qi; Sun, Huijun [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian 116044 (China); Sun, Pengyuan; Yang, Xiaobo; Ma, Xiaodong [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044 (China); Liu, Kexin, E-mail: kexinliu@dlmedu.edu.cn [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian 116044 (China)

    2016-09-01

    The purpose of present study was to investigate the effect of resveratrol (Res) on altering methotrexate (MTX) pharmacokinetics and clarify the related molecular mechanism. Res significantly increased rat intestinal absorption of MTX in vivo and in vitro. Simultaneously, Res inhibited MTX efflux transport in MDR1-MDCK and MRP2-MDCK cell monolayers, suggesting that the target of drug interaction was MDR1 and MRP2 in the intestine during the absorption process. Furthermore, there was a significant decrease in renal clearance of MTX after simultaneous intravenous administration. Similarly, MTX uptake was markedly inhibited by Res in rat kidney slices and hOAT1/3-HEK293 cell, indicating that OAT1 and OAT3 were involved in the drug interaction in the kidney. Additionally, concomitant administration of Res decreased cytotoxic effects of MTX in hOAT1/3-HEK293 cells, and ameliorated nephrotoxicity caused by MTX in rats. Conversely, intestinal damage caused by MTX was not exacerbated after Res treatment. In conclusion, Res enhanced MTX absorption in intestine and decreased MTX renal elimination by inhibiting P-gp, MRP2, OAT1 and OAT3 in vivo and in vitro. Res improved MTX-induced renal damage without increasing intestinal toxicity. - Highlights: • DDI between MTX and Res will occur when they are co-administered. • The first targets of the DDI are P-gp and MRP2 located in intestine. • The second targets of the DDI are OAT1 and OAT3 in kidney. • Res improved MTX-induced renal damage without increasing intestinal toxicity.

  5. Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats

    Directory of Open Access Journals (Sweden)

    Maranhão RC

    2017-05-01

    Full Text Available Raul C Maranhão,1,2 Maria C Guido,1 Aline D de Lima,1 Elaine R Tavares,1 Alyne F Marques,1 Marcelo D Tavares de Melo,3 Jose C Nicolau,3 Vera MC Salemi,3 Roberto Kalil-Filho3 1Laboratory of Metabolism and Lipids, 2Faculty of Pharmaceutical Sciences, 3Heart Failure Unit, Clinical Cardiology Division, Heart Institute (InCor, Medical School Hospital, University of São Paulo, São Paulo, Brazil Purpose: Acute myocardial infarction (MI is accompanied by myocardial inflammation, fibrosis, and ventricular remodeling that, when excessive or not properly regulated, may lead to heart failure. Previously, lipid core nanoparticles (LDE used as carriers of the anti-inflammatory drug methotrexate (MTX produced an 80-fold increase in the cell uptake of MTX. LDE-MTX treatment reduced vessel inflammation and atheromatous lesions induced in rabbits by cholesterol feeding. The aim of the study was to investigate the effects of LDE-MTX on rats with MI, compared with commercial MTX treatment.Materials and methods: Thirty-eight Wistar rats underwent left coronary artery ligation and were treated with LDE-MTX, or with MTX (1 mg/kg intraperitoneally, once/week, starting 24 hours after surgery or with LDE without drug (MI-controls. A sham-surgery group (n=12 was also included. Echocardiography was performed 24 hours and 6 weeks after surgery. The animals were euthanized and their hearts were analyzed for morphometry, protein expression, and confocal microscopy.Results: LDE-MTX treatment achieved a 40% improvement in left ventricular (LV systolic function and reduced cardiac dilation and LV mass, as shown by echocardiography. LDE-MTX reduced the infarction size, myocyte hypertrophy and necrosis, number of inflammatory cells, and myocardial fibrosis, as shown by morphometric analysis. LDE-MTX increased antioxidant enzymes; decreased apoptosis, macrophages, reactive oxygen species production; and tissue hypoxia in non-infarcted myocardium. LDE-MTX increased adenosine

  6. TUG1 mediates methotrexate resistance in colorectal cancer via miR-186/CPEB2 axis.

    Science.gov (United States)

    Li, Changfeng; Gao, Yongjian; Li, Yongchao; Ding, Dayong

    2017-09-16

    Colorectal cancer (CRC) is a common malignancy, most of which remain unresponsive to chemotherapy. Methotrexate (MTX) is one of the earliest cytotoxic drugs and serves as an anti-metabolite and anti-folate chemotherapy for various types of cancer. However, MTX resistance prevents its clinical application in cancer therapy. Thereby, overcoming the drug resistance is an alternative strategy to maximize the efficacy of MTX therapies in clinics. Long non-coding RNAs (lncRNAs) have gained widespread attention in recent years. More and more evidences have shown that lncRNAs play regulatory roles in various biological activities and disease progression including drug resistance in cancer cells. Here, we observed lncRNA TUG1 was associated to the MTX resistant in colorectal cancer cells. Firstly, quantitative analysis indicated that TUG1 was significantly increased in tumors which were resistant to MTX treatment. TUG1 knockdown re-sensitized the MTX resistance in colorectal cancer cells, which were MTX-resistant colorectal cell line. Furthermore, bioinformatics analysis showed that miR-186 could directly bind to TUG1, suggesting TUG1 might worked as a ceRNA to sponge miR-186. Extensively, our study also showed that CPEB2 was the direct target of miR-186 in colorectal cancer cells. Taken together, our study suggests that lncRNA TUG1 mediates MTX resistance in colorectal cancer via miR-186/CPEB2 axis. Copyright © 2017. Published by Elsevier Inc.

  7. Methotrexate therapy may prevent the onset of uveitis in juvenile idiopathic arthritis.

    Science.gov (United States)

    Papadopoulou, Charalampia; Kostik, Mikhail; Böhm, Marek; Nieto-Gonzalez, Juan Carlos; Gonzalez-Fernandez, Maria Isabel; Pistorio, Angela; Martini, Alberto; Ravelli, Angelo

    2013-09-01

    To evaluate whether early treatment with methotrexate (MTX) prevents the onset of uveitis in children with juvenile idiopathic arthritis. The clinical charts of all consecutive patients seen between January 2002 and February 2011 who had a disease duration uveitis had occurred. A total of 254 patients with a median disease duration of 0.3 year were included. Eighty-six patients (33.9%) were treated with MTX, whereas 168 patients (66.1%) did not receive MTX. During the 2-year follow-up, 211 patients (83.1%) did not develop uveitis, whereas 43 patients (16.9%) had uveitis a median of 1.0 year after the first visit. The frequency of uveitis was lower in MTX-treated than in MTX-untreated patients (10.5% vs 20.2%, respectively, P = .049). Survival analysis confirmed that patients treated with MTX had a lower probability of developing uveitis. Early MTX therapy may prevent the onset of uveitis in children with juvenile idiopathic arthritis. Because our study may be affected by confounding by indication, the potential of MTX to reduce the incidence of ocular disease should be investigated in a randomized controlled trial. Copyright © 2013 Mosby, Inc. All rights reserved.

  8. A retrospective review of methotrexate-induced hepatotoxicity among patients with psoriasis in a tertiary dermatology center in Malaysia.

    Science.gov (United States)

    Ng, Lim Chui; Lee, Yin Yin; Lee, Chew Kek; Wong, Su-Ming

    2013-01-01

    Methotrexate (MTX) is a common and efficacious systemic agent used for the treatment of moderate to severe psoriasis. Nevertheless, its use is associated with the risk of hepatotoxicity. This study was performed to study the association of MTX dose with regards to hepatotoxicity as evidenced by deranged transaminases. This was a retrospective review of patients with psoriasis on MTX from 2000 to 2009 at the outpatient dermatology clinic, University Malaya Medical Centre (UMMC). We analyzed patients' demography, serial laboratory investigations, liver ultrasounds, and liver biopsies of patients on MTX. Sixty-six of 710 (9.30%) patients with psoriasis were prescribed MTX throughout the 10-year period. Among them 57.6% developed deranged transaminases, with six requiring MTX withdrawal due to hepatotoxicity. The mean cumulative dose of MTX at the detection of liver enzyme derangement was 552.3 ± 596.1 mg. A high proportion of patients on MTX had deranged transaminases. However, the number of serious events was low. We concluded from this study that the use of MTX is relatively safe in patients with moderate to severe psoriasis. © 2013 The International Society of Dermatology.

  9. Induction therapy with adalimumab plus methotrexate for 24 weeks followed by methotrexate monotherapy up to week 48 versus methotrexate therapy alone for DMARD-naive patients with early rheumatoid arthritis: HIT HARD, an investigator-initiated study.

    Science.gov (United States)

    Detert, Jacqueline; Bastian, Hans; Listing, Joachim; Weiß, Anja; Wassenberg, Siegfried; Liebhaber, Anke; Rockwitz, Karin; Alten, Rieke; Krüger, Klaus; Rau, Rolf; Simon, Christina; Gremmelsbacher, Eva; Braun, Tanja; Marsmann, Bettina; Höhne-Zimmer, Vera; Egerer, Karl; Buttgereit, Frank; Burmester, Gerd-R

    2013-06-01

    To investigate the long-term effects of induction therapy with adalimumab (ADA) plus methotrexate (MTX) in comparison with placebo (PBO) plus MTX in DMARD-naïve patients with active early rheumatoid arthritis (RA). Patients with active early RA (disease duration of ≤12 months) were randomly assigned to receive 40 mg ADA subcutaneously every other week (eow) plus MTX 15 mg/week subcutaneously or PBO plus MTX subcutaneously at 15 mg/week over 24 weeks. Thereafter, all patients received MTX monotherapy up to week 48. The primary outcome was the Disease Activity Score 28 (DAS28) at week 48. Secondary outcomes included proportions of patients in remission (DAS28Health Assessment Questionnaire (HAQ) score and radiographic progression. 87 patients were assigned to ADA/MTX and 85 patients to PBO/MTX. At baseline, DAS28 was 6.2±0.8 in the ADA/MTX and 6.3±0.9 in the PBO/MTX groups. At week 24, treatment with ADA/MTX compared with PBO/MTX resulted in a greater reduction in DAS28 (3.0±1.2 vs 3.6±1.4; p=0.009) and other secondary outcomes such as DAS28 remission rate (47.9% vs 29.5%; p=0.021) and HAQ (0.49±0.6 vs 0.72±0.6; p=0.0014). At week 48, the difference in clinical outcomes between groups was not statistically significant (DAS28: 3.2±1.4 vs 3.4±1.6; p=0.41). Radiographic progression at week 48 was significantly greater in patients administered PBO/MTX (Sharp/van der Heijde score: ADA/MTX 2.6 vs PBO/MTX 6.4; p=0.03, Ratingen score: 1.7 vs 4.2; p=0.01). A greater reduction in radiographic progression after initial combination therapy with ADA and MTX was seen at week 48, even after discontinuation of ADA treatment at week 24. This sustained effect was not found at the primary endpoint (DAS28 reduction).

  10. Birth outcomes after preconception paternal exposure to methotrexate

    DEFF Research Database (Denmark)

    Winter, Rachel W; Larsen, Michael Due; Magnussen, Bjarne

    2017-01-01

    BACKGROUND: Methotrexate (MTX), a folic acid antagonist, is often prescribed for moderate to severe inflammatory related diseases. The safety of paternal MTX use prior to conception is unknown. This study, using the National Danish Registries, aimed to examine the association between paternal MTX...

  11. Sustained Response Following Discontinuation of Methotrexate in Patients With Rheumatoid Arthritis Treated With Subcutaneous Tocilizumab: Results From a Randomized, Controlled Trial.

    Science.gov (United States)

    Kremer, Joel M; Rigby, William; Singer, Nora G; Birchwood, Christine; Gill, Darcy; Reiss, William; Pei, Jinglan; Michalska, Margaret

    2018-03-25

    To evaluate whether tocilizumab (TCZ) monotherapy is non-inferior to TCZ + methotrexate (MTX) in maintaining clinical response in patients with rheumatoid arthritis (RA) who achieve low disease activity with TCZ+MTX. Patients with RA who experienced an inadequate response to MTX received MTX plus TCZ 162 mg subcutaneous. At 24 weeks, patients who achieved Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) ≤3.2 were randomized to receive TCZ monotherapy or continue TCZ+MTX until week 52. The primary outcome was the comparison of mean change in DAS28-ESR from weeks 24 to 40 between the TCZ monotherapy and TCZ+MTX arms (non-inferiority margin of 0.6). Secondary outcomes included DAS28-ESR worsening ≥1.2, achievement of DAS28-ESR <2.6 and ≤3.2 and safety and immunogenicity. Of 718 patients enrolled, 294 were randomized at week 24 (TCZ monotherapy, n = 147; TCZ+MTX, n = 147). The mean changes in DAS28-ESR from weeks 24 to 40 were 0.46 and 0.14 in the TCZ monotherapy and TCZ+MTX arms, respectively (weighted difference between the groups, 0.318 [95% CI 0.045, 0.592]); discontinuing MTX in TCZ responders was non-inferior to continuing MTX. Safety events were broadly similar between the randomized treatment groups; the most common serious adverse event was infection, occurring in 2.1% of patients in the TCZ monotherapy group and 2.2% in the TCZ+MTX group. Patients with RA receiving TCZ+MTX who achieve low disease activity can discontinue MTX without significant worsening of disease activity in the 16 weeks following MTX discontinuation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  12. Reversible acute methotrexate leukoencephalopathy: atypical brain MR imaging features

    International Nuclear Information System (INIS)

    Ziereisen, France; Damry, Nash; Christophe, Catherine; Dan, Bernard; Azzi, Nadira; Ferster, Alina

    2006-01-01

    Unusual acute symptomatic and reversible early-delayed leukoencephalopathy has been reported to be induced by methotrexate (MTX). We aimed to identify the occurrence of such atypical MTX neurotoxicity in children and document its MR presentation. We retrospectively reviewed the clinical findings and brain MRI obtained in 90 children treated with MTX for acute lymphoblastic leukaemia or non-B malignant non-Hodgkin lymphoma. All 90 patients had normal brain imaging before treatment. In these patients, brain imaging was performed after treatment completion and/or relapse and/or occurrence of neurological symptoms. Of the 90 patients, 15 (16.7%) showed signs of MTX neurotoxicity on brain MRI, 9 (10%) were asymptomatic, and 6 (6.7%) showed signs of acute leukoencephalopathy. On the routine brain MRI performed at the end of treatment, all asymptomatic patients had classical MR findings of reversible MTX neurotoxicity, such as abnormal high-intensity areas localized in the deep periventricular white matter on T2-weighted images. In contrast, the six symptomatic patients had atypical brain MRI characterized by T2 high-intensity areas in the supratentorial cortex and subcortical white matter (n=6), cerebellar cortex and white matter (n=4), deep periventricular white matter (n=2) and thalamus (n=1). MR normalization occurred later than clinical recovery in these six patients. In addition to mostly asymptomatic classical MTX neurotoxicity, MTX may induce severe but reversible unusual leukoencephalopathy. It is important to recognize this clinicoradiological presentation in the differential diagnosis of acute neurological deterioration in children treated with MTX. (orig.)

  13. Methotrexate induces DNA damage and inhibits homologous recombination repair in choriocarcinoma cells

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    Xie L

    2016-11-01

    Full Text Available Lisha Xie,1,* Tiancen Zhao,1,2,* Jing Cai,1 You Su,1 Zehua Wang,1 Weihong Dong1 1Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 2Department of Obstetrics and Gynecology, Central Hospital of Wuhan, Wuhan, China *These authors contributed equally to this work Objective: The objective of this study was to investigate the mechanism of sensitivity to methotrexate (MTX in human choriocarcinoma cells regarding DNA damage response. Methods: Two choriocarcinoma cancer cell lines, JAR and JEG-3, were utilized in this study. An MTX-sensitive osteosarcoma cell line MG63, an MTX-resistant epithelial ovarian cancer cell line A2780 and an MTX-resistant cervical adenocarcinoma cell line Hela served as controls. Cell viability assay was carried out to assess MTX sensitivity of cell lines. MTX-induced DNA damage was evaluated by comet assay. Quantitative reverse transcription polymerase chain reaction was used to detect the mRNA levels of BRCA1, BRCA2, RAD51 and RAD52. The protein levels of γH2AX, RAD 51 and p53 were analyzed by Western blot. Results: Remarkable DNA strand breaks were observed in MTX-sensitive cell lines (JAR, JEG-3 and MG63 but not in MTX-resistant cancer cells (A2780 and Hela after 48 h of MTX treatment. Only in the choriocarcinoma cells, the expression of homologous recombination (HR repair gene RAD51 was dramatically suppressed by MTX in a dose- and time-dependent manner, accompanied with the increase in p53. Conclusion: The MTX-induced DNA strand breaks accompanied by deficiencies in HR repair may contribute to the hypersensitivity to chemotherapy in choriocarcinoma. Keywords: choriocarcinoma, chemotherapy hypersensitivity, DNA double-strand break, RAD51, p53

  14. A single center experience of methotrexate in the treatment of Crohn's disease and ulcerative colitis: a case for subcutaneous administration.

    Science.gov (United States)

    Nathan, Debbie M; Iser, John H; Gibson, Peter R

    2008-06-01

    Methotrexate (MTX) is used as a second-line immuno-modulator in patients with inflammatory bowel disease when purine analogs are not tolerated or lack efficacy. High-level evidence indicates efficacy for intramuscular administration in Crohn's disease, but there are few reports of experience with subcutaneous delivery. This study aimed to evaluate the response to and tolerance of MTX where subcutaneous administration was the preferred option. The records of all patients treated with MTX were evaluated with regard to the dose, duration, response, and tolerance to MTX. Remission was defined as improvement in symptoms with no corticosteroid requirement for 3 months or ability to wean off steroids. MTX was initiated in 45 patients with Crohn's disease and 23 ulcerative colitis (median age, 46 years; range, 20-80 years; 54% men) because of intolerance (69%) or resistance (31%) to purine analogues. MTX was initiated in 74% of patients in doses of 25 mg (33) or 20 mg (17), administered by subcutaneous self-injection in 90% of subjects. Remission was achieved in 24 of 45 (53%) with Crohn's disease and 11 of 23 (48%) with ulcerative colitis. An additional four (9%) patients with Crohn's disease and three patients (13%) with ulcerative colitis demonstrated symptomatic improvement and/or ability to decrease corticosteroid dose. While nine patients ceased therapy and nine successfully reduced their doses due to intolerance, three of four patients had no adverse effects. Subcutaneous delivery was well accepted. Subcutaneously administered MTX exhibits apparent efficacy, acceptance, tolerance, and safety in patients with Crohn's disease or ulcerative colitis who are steroid-dependent and where purine analogs have been ineffective or intolerable.

  15. Taurine protects against methotrexate-induced toxicity and inhibits leukocyte death

    International Nuclear Information System (INIS)

    Cetiner, Mustafa; Sener, Goeksel; Sehirli, A. Ozer; Eksioglu-Demiralp, Emel; Ercan, Feriha; Sirvanci, Serap; Gedik, Nursal; Akpulat, Sertac; Tecimer, Tuelay; Yegen, Berrak C.

    2005-01-01

    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 to 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-α 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

  16. Similar Improvements in Patient-Reported Outcomes Among Rheumatoid Arthritis Patients Treated with Two Different Doses of Methotrexate in Combination with Adalimumab: Results From the MUSICA Trial.

    Science.gov (United States)

    Kaeley, Gurjit S; MacCarter, Daryl K; Goyal, Janak R; Liu, Shufang; Chen, Kun; Griffith, Jennifer; Kupper, Hartmut; Garg, Vishvas; Kalabic, Jasmina

    2018-06-01

    In patients with rheumatoid arthritis (RA), combination treatment with methotrexate (MTX) and adalimumab is more effective than MTX monotherapy. From the patients' perspective, the impact of reduced MTX doses upon initiating adalimumab is not known. The objective was to evaluate the effects of low and high MTX doses in combination with adalimumab initiation on patient-reported outcomes (PROs), in MTX-inadequate responders (MTX-IR) with moderate-to-severe RA. MUSICA was a randomized, double-blind, controlled trial evaluating the efficacy of 7.5 or 20 mg/week MTX, in combination with adalimumab for 24 weeks in MTX-IR RA patients receiving prior MTX ≥ 15 mg/week for ≥ 12 weeks. PROs were recorded at each visit, including physical function, health-related quality-of-life, work productivity, quality-of-sleep, satisfaction with treatment medication, sexual impairment due to RA, patient global assessment of disease activity (PGA), and patient pain. Last observation carried forward was used to account for missing values. At baseline, patients in both MTX dosage groups had similar demographics, disease characteristics, and PRO scores. Overall, initiation of adalimumab led to significant improvements from baseline in the PROs assessed for both MTX dosage groups. Improvements in presenteeism from baseline were strongly correlated with corresponding improvements in SF-36 (vitality), pain, and physical function. Physical and mental well-being had a good correlation with improvement in sleep. Overall, improvements in disease activity from baseline were correlated with improvements in several PROs. The addition of adalimumab to MTX in MTX-IR patients with moderate-to-severe RA led to improvements in physical function, quality-of-life, work productivity, quality of sleep, satisfaction with treatment medication, and sexual impairment due to RA, regardless of the concomitant MTX dosage. AbbVie. Clinicaltrials.gov identifier, NCT01185288.

  17. Ameliorating Role of Caffeic Acid Phenethyl Ester (CAPE Against Methotrexate-Induced Oxidative Stress in the Sciatic Nerve, Spinal Cord and Brain Stem Tissues of Rats

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    Ertuğrul Uzar

    2010-03-01

    Full Text Available OBJECTIVE: Methotrexate (MTX-associated neurotoxicity is an important clinical problem in cancer patients, but the mechanisms of MTX-induced neurotoxicity are not yet known exactly. The aims of this study were (1 to investigate the possible role of malondialdehyde (MDA, superoxide dismutase (SOD enzyme, glutathione peroxidase (GSH-Px and catalase (CAT in the pathogenesis of MTX-induced neurotoxicity and (2 to determine whether there is a putative protective effect of caffeic acid phenethyl ester (CAPE on MTX-induced neurotoxicity in the spinal cord, brainstem and sciatic nerve of rats. METHODS: A total of 19 adult Wistar male rats were divided into three experimental groups. Group I, control group; Group II, MTX-treated group; and Group III, MTX + CAPE-treated group. MTX was administered to the MTX and MTX + CAPE groups intraperitoneally (IP with a single dose of 20 mg/kg on the second day of the experiment. CAPE was administered to the MTX + CAPE group IP with a dose of 10 μmol/kg for 7 days. RESULTS: In the sciatic nerve and spinal cord tissue, CAT and GSH-Px activities were increased in the MTX group in comparison with the control group. CAPE treatment with MTX significantly decreased CAT and GSH-Px activities in the neuronal tissues of rats in comparison with the MTX group. In the spinal cord and brainstem tissues, SOD activity in the MTX group was decreased in comparison with the control group, but in the sciatic nerve, there was no significant difference. In the spinal cord and brainstem of rats, SOD activity was increased in the CAPE + MTX group when compared with the MTX group. The level of MDA was higher in the MTX group than in the control group. CAPE administration with MTX injection caused a significant decrease in MDA level when compared with the MTX group. CONCLUSION: These results reveal that MTX increases oxidative stress in the sciatic nerve, spinal cord and brainstem of rats and that CAPE has a preventive effect on the

  18. Leukoencephalopathy in childhood hematopoietic neoplasm caused by moderate-dose methotrexate and prophylactic cranial radiotherapy -- an MR analysis

    International Nuclear Information System (INIS)

    Matsumoto, Ko; Takahashi, Shoki; Sato, Atsushi; Imaizumi, Masue; Higano, Shuichi; Sakamoto, Kiyohiko; Asakawa, Hiroshi; Tada, Keiya

    1995-01-01

    Purpose: The main purpose of this study was to determine influential factors related to minor leukoencephalopathy (LEP) caused by moderate-dose methotrexate (MTX) and prophylactic cranial radiotherapy (CRT) in childhood hematopoietic malignancies. We also compared the incidence of LEP following this treatment to that reported in the literature following treatment with high-dose MTX alone. Methods and Materials: Thirty-eight pediatric patients of hematopoietic malignancies (37 acute lymphoblastic leukemias, 1 non-Hodgkin lymphoma) who were given CRT (18-24 Gy) as well as prophylactic intrathecal and per os MTX were studied for leukoencephalopathy by magnetic resonance (MR) imaging. All the patients were free from grave neuropsychiatric disturbances. The data were examined to elucidate the influential ones of five factors (patients' age, doses of intrathecal and per os MTX, dose of CRT, interval between treatment, and MR study) to develop LEP using multiple regression analysis. To compare the effect of moderate-dose MTX and prophylactic CRT on LEP to that of high-dose MTX alone, we conducted literature review. Results: Seven out of 38 patients (18%) developed LEP. From multiple regression analysis and partial correlation coefficients, the age and CRT dose seemed influential in the subsequent development of LEP. The incidence of LEP following treatment with moderate-dose MTX and prophylactic CRT appears to be less than that reported in the literature following treatment with intravenous high-dose MTX. However, even moderate-dose MTX in combination with CRT can result in a significant incidence of MR-detectable LEP, particularly in children 6 years of age or younger receiving 24 Gy. Conclusion: Leukoencephalopathy was caused by moderate-dose MTX and prophylactic CRT in pediatric patients, probably less frequently than by high-dose MTX treatment alone. The influential factors were patient's age and CRT dose

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Salam Massadeh

    2016-06-01

    Full Text Available 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.

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

    Science.gov (United States)

    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.

  2. Methotrexate: the emerging drug of choice for serious rheumatoid arthritis.

    Science.gov (United States)

    Salach, R H; Cash, J M

    1994-01-01

    The recently recognized high morbidity and unexpected mortality associated with rheumatoid arthritis (RA) has spurred new interest in more aggressive, early treatment of this disease. Methotrexate (MTX) has rapidly become the rheumatologist's drug of choice for serious RA because of its favorable efficacy to toxicity ratio and rapid onset of action compared with other second-line agents. The initial concerns about hepatic fibrosis and cirrhosis in psoriatic patients has subsided somewhat as long-term liver toxicity data are accumulating in patients with RA. Routine liver biopsy with incremental doses of MTX is no longer recommended. Potential for severe lung, hematologic, and infectious complications exists, mandating careful monitoring of RA patients taking MTX.

  3. Risk factors for oral methotrexate failure in patients with inflammatory polyarthritis: results from a UK prospective cohort study.

    Science.gov (United States)

    Bluett, James; Sergeant, Jamie C; MacGregor, Alex J; Chipping, Jacqueline R; Marshall, Tarnya; Symmons, Deborah P M; Verstappen, Suzanne M M

    2018-03-20

    Oral methotrexate (MTX) is the first-line therapy for patients with rheumatoid arthritis (RA). However, approximately one quarter of patients discontinue MTX within 12 months. MTX failure, defined as MTX cessation or the addition of another anti-rheumatic drug, is usually due adverse event(s) and/or inefficacy. The aims of this study were to evaluate the rate and predictors of oral MTX failure. Subjects were recruited from the Norfolk Arthritis Register (NOAR), a primary care-based inception cohort of patients with early inflammatory polyarthritis (IP). Subjects were eligible if they commenced MTX as their first DMARD and were recruited between 2000 and 2008. Patient-reported reasons for MTX failure were recorded and categorised as adverse event, inefficacy or other. The addition of a second DMARD during the study period was categorised as failure due to inefficacy. Cox proportional hazards regression models were used to assess potential predictors of MTX failure, accounting for competing risks. A total of 431 patients were eligible. The probability of patients remaining on MTX at 2 years was 82%. Competing risk analysis revealed that earlier MTX failure due to inefficacy was associated with rheumatoid factor (RF) positivity, younger age at symptom onset and higher baseline disease activity (DAS-28). MTX cessation due to an adverse event was less likely in the RF-positive cohort. RF-positive inflammatory polyarthritis patients who are younger with higher baseline disease activity have an increased risk of MTX failure due to inefficacy. Such patients may require combination therapy as a first-line treatment.

  4. Effect of Discontinuation or Initiation of Methotrexate or Glucocorticoids on Tofacitinib Efficacy in Patients with Rheumatoid Arthritis: A Post Hoc Analysis.

    Science.gov (United States)

    Fleischmann, Roy; Wollenhaupt, Jürgen; Cohen, Stanley; Wang, Lisy; Fan, Haiyun; Bandi, Vara; Andrews, John; Takiya, Liza; Bananis, Eustratios; Weinblatt, Michael E

    2018-06-01

    Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We evaluated the effect of concomitant methotrexate (MTX) or glucocorticoid (GC) use on tofacitinib clinical efficacy. Data were pooled from two open-label, long-term extension studies of tofacitinib 5 or 10 mg twice daily in patients with RA. Response according to Clinical Disease Activity Index (CDAI) was assessed separately in patients who discontinued (no MTX/GC use within 30 days prior to year-3 visit; assessment at month 3/year 3) or initiated (on/before year 3; assessment at initiation and year 3) MTX/GC. By year 3, among patients receiving background MTX at baseline, 186/1608 (11.6%) discontinued MTX, and 319/1434 (22.2%) patients receiving GC at baseline discontinued GC. Overall, 70.4/69.1% of patients who discontinued/continued MTX and 72.7/65.9% who discontinued/continued GC achieved CDAI remission or low disease activity (LDA) at year 3. Month 3 remission/LDA rates were maintained at year 3 in the majority of patients, irrespective of MTX/GC discontinuation/continuation. By year 3, 6.2% of patients receiving tofacitinib without MTX at baseline had initiated concomitant MTX, and 25.1% receiving tofacitinib without GC initiated GC; 69.0% and 45.4% initiating MTX or GC, respectively, had a CDAI-defined incomplete response prior to initiation. RA signs/symptoms improved following MTX initiation; only modest improvement was observed with GC initiation. Patients achieving remission/LDA with tofacitinib may discontinue MTX or GC and maintain treatment response. Patients with an incomplete response may benefit from adding concomitant MTX. Pfizer Inc. Study A3921024 [NCT00413699] and Study A3921041 [NCT00661661].

  5. High-dose methotrexate following intravitreal methotrexate administration in preventing central nervous system involvement of primary intraocular lymphoma.

    Science.gov (United States)

    Akiyama, Hiroki; Takase, Hiroshi; Kubo, Fumito; Miki, Tohru; Yamamoto, Masahide; Tomita, Makoto; Mochizuki, Manabu; Miura, Osamu; Arai, Ayako

    2016-10-01

    In order to prevent central nervous system (CNS) involvement and improve the prognosis of primary intraocular lymphoma (PIOL), we prospectively evaluated the efficacy of combined therapy using intravitreal methotrexate (MTX) and systemic high-dose MTX on treatment-naïve PIOL. Patients with newly diagnosed PIOL whose lymphoma was limited to the eyes were enrolled. The patients were treated with weekly intravitreal MTX until the ocular lesions were resolved, followed by five cycles of systemic high-dose MTX (3.5 g/m 2 ) every other week. Ten patients were enrolled in this study and completed the treatment. All patients achieved complete response for their ocular lesions with rapid decrease of intravitreal interleukin-10 concentration. Adverse events of intravitreal and systemic high-dose MTX were mild and tolerable. With a median follow-up of 29.5 months, four patients (40%) experienced the CNS disease development and the mean CNS lymphoma-free survival (CLFS) time was 51.1 months. Two-year CLFS, which was the primary end-point of the study, was 58.3% (95% confidence interval, 23.0-82.1%). In contrast, eight patients were treated with intravitreal MTX alone in our institute, and their 2-year CLFS was 37.5% (95% confidence interval, 8.7-67.4%). In conclusion, systemic high-dose MTX following intravitreal MTX is feasible and might be effective in preventing CNS involvement of PIOL. Further arrangements are worth considering in order to improve the effects. This study was registered with UMIN Clinical Trials Registry (UMIN000003921). © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  6. Methotrexate in patients with rheumatoid arthritis in Spain: Subanalysis of the AR Excellence project.

    Science.gov (United States)

    Tornero-Molina, Jesús; Andreu, José Luis; Martín-Martínez, María-Auxiliadora; Corominas, Héctor; Pérez Venegas, José Javier; Román-Ivorra, José Andrés; Sánchez-Alonso, Fernando

    2017-12-19

    The AR Excellence project evaluates clinical monitoring in patients with rheumatoid arthritis (RA) in Spain. The aim of the study was to analyze the use of methotrexate (MTX) in the AR Excellence cohort and to compare it with current recommendations. We collected data from RA patients who initiated treatment with MTX. They included demographics, dose and routes of administration, switching among them, highest dose in each route, combinations with other disease-modifying antirheumatic drugs (DMARDs), time to combination with another DMARD (either conventional or biological) and adverse events. Six hundred twenty-five patients with RA (mean age 55 years; 70.6% women) were included, with an average disease duration of 21 months. Ninety percent of the patients initiated treatment with MTX. Therapy was begun with a mean dose of 11mg per week; this initial dose was increased in 58% of the individuals. The average time to reach the full dose of MTX (20mg a week) was 6,67 months. Time to combination of MTX with another DMARD, either synthetic or biological, was 3 months. In all, 67.4% of the patients received oral MTX and the route was subcutaneous in 18.6%. In 12% of the cases, there was a change in the route of administration after a period of 6 months. In 544 patients, folate supplements were added to MTX; MTX-related adverse events were detected in 17.3% of the patients. MTX is currently the pivotal treatment in RA. The subanalysis of the AR Excellence project demonstrates that MTX escalation to its full doses is not done with adequate speed. The subcutaneous route is used in a small proportion of patients. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

  7. A randomised comparative study of the short term clinical and biological effects of intravenous pulse methylprednisolone and infliximab in patients with active rheumatoid arthritis despite methotrexate treatment.

    Science.gov (United States)

    Durez, P; Nzeusseu Toukap, A; Lauwerys, B R; Manicourt, D H; Verschueren, P; Westhovens, R; Devogelaer, J-P; Houssiau, F A

    2004-09-01

    To compare the short term clinical and biological effects of intravenous (i.v.) pulse methylprednisolone (MP) and infliximab (IFX) in patients with severe active rheumatoid arthritis (RA) despite methotrexate (MTX) treatment. Patients with active RA despite MTX treatment were randomly allocated to receive a single i.v. infusion of MP (1 g) or three i.v. infusions of IFX (3 mg/kg) on weeks 0, 2, and 6. Patients were "blindly" evaluated for disease activity measures. Quality of life (QoL) was evaluated through the SF-36 health survey. Serum matrix metalloproteinase-3 (MMP-3) titres were measured at baseline, weeks 2 and 6. Compared with baseline, significant improvement was noted in all activity measures, including serum C reactive protein (CRP) titres, in the IFX group only. At week 14, 6/9 (67%) and 4/9 (44%) IFX patients met the ACR20 and 50 response criteria, while this was the case in only 1/12 (8%) and 0/12 (0%) MP patients, respectively (ptreatment, whereas some did so in the IFX group. Serum MMP-3 titres significantly decreased (41% drop) at week 6 in the IFX group, while no changes were seen in patients given MP. This short term randomised comparative study demonstrates that TNF blockade is better than MP pulse therapy in a subset of patients with severe refractory RA, with improvement in not only clinical parameters of disease activity but also biological inflammatory indices, such as serum CRP and MMP-3 titres.

  8. [Weekly low-dose methotrexate in rheumatoid arthritis. Review of the literature].

    Science.gov (United States)

    Manganelli, P; Troise Rioda, W

    1993-10-01

    Methotrexate (MTX) is an antifolic drug that in recent years has been largely employed in the treatment of Rheumatoid Arthritis (RA). Both short and long term clinical trials have demonstrated its efficacy and good tolerability. It induces a significant improvement of all clinical variables and a decrease in the erythrocyte sedimentation rate and other acute phase reactants with a steroid sparing effect. The probability of continuing MTX therapy for up to 5 years is 46-55% whereas that of continuing gold, hydroxychloroquine, sulfasalazine or D-penicillamine therapy is less than 20%. MTX is a rapidly acting drug with a clinical response within 4 weeks and a plateau phase after 6 months of therapy. Discontinuation of long-term MTX therapy induces a flare-up of the disease so that patients receiving long-term MTX must continue the drug to maintain clinical benefits. In spite of its clinical efficacy, MTX does not seem to have a significant effect on disease progression as determined radiographically. In this respect, MTX appears to have some superiority when compared to azathioprine, but not when compared to gold salts. MTX has been employed in patients with RA unresponsive to other Disease-Modifying Antirheumatic Drugs (DMARDs), but according to some recent views on the therapeutic strategy of RA, it could be used in early RA as a first choice drug. Toxic effects are the main reason in limiting long-term MTX treatment. Hepatic toxicity is one of the more common side-effects of MTX, but the recognition of its "risk factors" such as alcohol abuse, may reduce it. Acute pneumonitis is one of the more severe complications of MTX therapy and may be life-threatening. In RA patients treated with MTX are also reported complications of immunosuppression, such as Pneumocystis carinii pneumonia whose clinical-radiological picture may be similar to that of acute pneumonitis. The mechanism of action of low-dose weekly MTX in RA is still unclear, but it might be more

  9. Methotrexate-induced Pancytopenia in Two Patients with Renal Dysfunction

    OpenAIRE

    Yusuf OĞUZ; Tayfun EYİLETEN; Murat KARAMAN; Seyid Ahmet AY; Mahmut İlker YILMAZ

    2011-01-01

    Methotrexate (MTX) is cleared primarily by renal excretion. The excretion of MTX is delayed in subjects with renal dysfunction and elevated plasma MTX concentrations develop which lead to bone marrow toxicities and possible pancytopenia. In this case report, we presented two advanced age patients with MTX-induced pancytopenia. The first patient on hemodialysis was diagnosed with seronegative arthritis while the second patient with congestive heart failure was diagnosed with rheumatoid arthrit...

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

    Directory of Open Access Journals (Sweden)

    Askin Dogan

    2016-06-01

    Full Text Available 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/m2 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.

  11. The Effectiveness of Intraocular Methotrexate in the Treatment of Posterior Uveitis in Behçet’s Disease Patients Compared to Retrobulbar Steroids Injection

    Directory of Open Access Journals (Sweden)

    Hossam El Din Mohamed Khalil

    2016-01-01

    Full Text Available Aim of Work. To evaluate the efficacy of intravitreal methotrexate (MTX compared to retrobulbar triamcinolone acetonide (TAA, in controlling posterior segment involvement and inducing remissions among Behçet’s disease (BD patients. Study Design. This is a cross-sectional nonrandomized comparative study. Patients and Methods. 31 adult BD male patients with a mean disease duration of 5.45 years who presented with bilateral posterior segment involvement were included. Each patient received intravitreal injection of 400 μg/0.1 mL (MTX for the right eye (Group A and 1 mL of retrobulbar 40 mg/mL TAA for the left eye (Group B. Results. 90% of eyes showed complete improvement of anterior chamber reaction, whereas an improvement in vitreous activity in 77% with no significant differences between both groups (p≤0.1. BCVA improved in 77.4% eyes (Group A compared to 87.1% (Group B (p≤0.4. Relapses were noted in 11 eyes (35.5%, in group A, with the mean duration of remission being 19.1 weeks ± 2.13 compared to 7.35±2.8 in 20 eyes (64.5% in group B (p≤0.1. Conclusion. No statistical differences were found between both treatment modalities; however, based on clinical observations, intravitreal MTX may ensure better control of inflammatory reaction and may encourage longer remission as compared to retrobulbar TAA in BD patients.

  12. Methotrexate-induced acute toxic leukoencephalopathy

    Directory of Open Access Journals (Sweden)

    Parag R Salkade

    2012-01-01

    Full Text Available Acute lymphoblastic leukemia (ALL is one of the most common malignancies of childhood, which is treated with high doses of methotrexate (MTX, as it crosses the blood-brain barrier and can be administered intravenously and via intrathecal route to eradicate leukemic cells from central nervous system (CNS. Additionally, high doses of MTX not only prevent CNS recurrence but also hematologic relapses. Although, standard treatment protocol for ALL includes multimodality therapy, MTX is usually associated with neurotoxicity and affects periventricular deep white matter region. Methotrexate-induced ′acute toxic leukoencephalopathy′ has varying clinical manifestations ranging from acute neurological deficit to seizures or encephalopathy. Diffusion weighted magnetic resonance imaging (DW-MRI is widely available and routinely used in clinical practice to identify acute stroke and also to distinguish acute stroke from non-stroke like conditions. We report a local teenage Chinese girl who developed 2 discrete episodes of left upper and lower limb weakness with left facial nerve paresis after receiving the 2 nd and 3 rd cycle of high dose of intravenous and intrathecal methotrexate, without having cranial irradiation. After each episode of her neurological deficit, the DW-MRI scan showed focal restricted diffusion in right centrum semiovale. Her left sided focal neurological deficit and facial nerve paresis almost completely subsided on both these occasions within 3 days of symptom onset. Follow-up DW-MRI, after her neurological recovery, revealed almost complete resolution of previously noted restricted diffusion in right centrum semiovale, while the lesion was not evident on concurrent T2W (T2-weighted and FLAIR (Fluid-Attenuated Inversion recovery sequences, nor showed any post contrast enhancement on post gadolinium enhanced T1W (T1-weighted sequences. No residual neurological deficit or intellectual impairment was identified on clinical follow up

  13. MTX final report

    Energy Technology Data Exchange (ETDEWEB)

    Hooper, E.B. [ed.; Allen, S.L.; Brown, M.D.; Byers, J.A.; Casper, T.A.; Cohen, B.I.; Cohen, R.H.; Fenstermacher, M.E.; Foote, J.H.; Hoshino, K. [and others

    1994-01-01

    The MTX experiment was proposed in 1986 to apply high frequency microwaves generated by a free-electron laser (FEL) to electron cyclotron resonance heating (ECRH) in a high field, high density tokamak. As the absorption of microwaves at the electron cyclotron resonance requires high frequencies, the opportunity of applying a free-electron laser has appeal as the device is not limited to frequencies in the microwave or long millimeter wavelength regions, in contrast to many other sources. In addition, the FEL is inherently a high power source of microwaves, which would permit single units of 10 MW or more, optimum for reactors. Finally, it was recognized early in the study of the application of the FEL based on the induction linear accelerator, that the nonlinear effects associated with the intense pulses of microwaves naturally generated would offer several unique opportunities to apply ECRH to current drive, MHD control, and other plasma effects. It was consequently decided to adapt the induction accelerator based FEL to heating and controlling the tokamak, and to conduct experiments on the associated physics. To this end, the Alcator C tokamak was moved from the Massachusetts Institute of Technology (MIT) to the Lawrence Livermore National Laboratory where it was installed in Building 431 and operated from March, 1989, until the conclusion of the experiment in October, 1992. The FEL, based on the ETA-11 accelerator and IMP wiggler was brought into operation by the LLNL Electron Beam Group and power injected into the tokamak during an experimental run in the Fall, 1989. Following an upgrade by the MTX group, a second experimental run was made lasting from the Winter, 1992 through the end of the experiment. Significant contributions to the ECRH experiments were made by the Japan Atomic Energy Research Institute (JAERI).

  14. MTX final report

    International Nuclear Information System (INIS)

    Hooper, E.B.; Allen, S.L.; Brown, M.D.; Byers, J.A.; Casper, T.A.; Cohen, B.I.; Cohen, R.H.; Fenstermacher, M.E.; Foote, J.H.; Hoshino, K.

    1994-01-01

    The MTX experiment was proposed in 1986 to apply high frequency microwaves generated by a free-electron laser (FEL) to electron cyclotron resonance heating (ECRH) in a high field, high density tokamak. As the absorption of microwaves at the electron cyclotron resonance requires high frequencies, the opportunity of applying a free-electron laser has appeal as the device is not limited to frequencies in the microwave or long millimeter wavelength regions, in contrast to many other sources. In addition, the FEL is inherently a high power source of microwaves, which would permit single units of 10 MW or more, optimum for reactors. Finally, it was recognized early in the study of the application of the FEL based on the induction linear accelerator, that the nonlinear effects associated with the intense pulses of microwaves naturally generated would offer several unique opportunities to apply ECRH to current drive, MHD control, and other plasma effects. It was consequently decided to adapt the induction accelerator based FEL to heating and controlling the tokamak, and to conduct experiments on the associated physics. To this end, the Alcator C tokamak was moved from the Massachusetts Institute of Technology (MIT) to the Lawrence Livermore National Laboratory where it was installed in Building 431 and operated from March, 1989, until the conclusion of the experiment in October, 1992. The FEL, based on the ETA-11 accelerator and IMP wiggler was brought into operation by the LLNL Electron Beam Group and power injected into the tokamak during an experimental run in the Fall, 1989. Following an upgrade by the MTX group, a second experimental run was made lasting from the Winter, 1992 through the end of the experiment. Significant contributions to the ECRH experiments were made by the Japan Atomic Energy Research Institute (JAERI)

  15. Methotrexate for uveitis associated with juvenile idiopathic arthritis: value and requirement for additional anti-inflammatory medication.

    Science.gov (United States)

    Heiligenhaus, A; Mingels, A; Heinz, C; Ganser, G

    2007-01-01

    To study the value of methotrexate (MTX) and the requirement for additional anti-inflammatory drugs for the treatment of severe chronic iridocyclitis associated with juvenile idiopathic arthritis (JIA). Institutional study of 35 consecutive patients with JIA started on MTX as the single systemic immunosuppressive drug for the treatment of associated iridocyclitis. The clinical epidemiologic data, course of visual acuity (VA), development of complications, and the need for additional anti-inflammatory drugs were analyzed. Mean follow-up with MTX treatment was 27.6 months. Uveitic complications were present in 31 patients before MTX treatment. With MTX, quiescence of uveitis was obtained with (n=21) or without (n=4) additional topical steroids. Additional systemic immunosuppressive drugs were required in another 7 patients: cyclosporine A (n=4), azathioprine (n=1), infliximab (n=1), or etanercept (n=1). Three patients had active uveitis at the end of the follow-up period. During MTX therapy, uveitis first developed in the unaffected fellow eyes in 2 patients, and secondary glaucoma or ocular hypertension occurred in 7 patients. The VA deteriorated in 6, improved in 13, and was stable in the remaining eyes. The data suggest that MTX is very effective in controlling inflammation of uveitis in patients with JIA. However, additional topical steroids or systemic immunosuppressive drugs are often required.

  16. The effect of methotrexate on the bone healing of mandibular condylar process fracture: an experimental study in rats.

    Science.gov (United States)

    Cavalcanti, Samantha Cristine Santos X B; Corrêa, Luciana; Mello, Suzana Beatriz Veríssimo; Luz, João Gualberto C

    2014-10-01

    Methotrexate (MTX) is an anti-metabolite used in rheumatology and oncology. High doses are indicated for oncological treatment, whereas low doses are indicated for chronic inflammatory diseases. This study evaluated the effect of two MTX treatment schedules on the bone healing of the temporomandibular joint fracture in rats. Seventy-five adult male Wistar rats were used to generate an experimental unilateral medially rotated condylar fracture model that allows an evaluation of bone healing and the articular structures. The animals were subdivided into three groups that each received one of the following treatments intraperitoneally: saline (1 mL/week), low-dose MTX (3 mg/kg/week) and high-dose MTX (30 mg/kg). The histological study comprised fracture site and temporomandibular joint evaluations and bone neoformation was evaluated by histomorphometric analysis. A biochemical parameter of bone formation was also assessed. When compared with saline, high-dose MTX delayed bone fracture repairs. In this latter group, after 90 days, the histological analysis revealed atrophy of the fibrocartilage and the presence of fibrous tissue in the joint space. The histomorphometric analysis revealed diminished bone neoformation. The alkaline phosphatase levels also decreased after MTX treatment. It was concluded that high-dose MTX impaired mandibular condyle repair and induced degenerative articular changes. Copyright © 2014 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

  17. Changes in serum lipids in patients with rheumatoid arthritis treated with a combination of tocilizumab and methotrexate compared with methotrexate alone for 24 weeks of observation

    Directory of Open Access Journals (Sweden)

    E. V. Udachkina

    2015-11-01

    Full Text Available Background. According to the some studies tocilizumab therapy (TCZ in patients with rheumatoid arthritis (RA is accompanied by deterioration of blood lipid profile. Aim. To study changes in serum lipid parameters in patients with RA treated with a combination of tocilizumab and methotrexate compared with methotrexate alone for 24 weeks of observation. Material and methods. Patients (n=72 with RA were included into the pilot non-randomized 24-week study and divided in two groups: 1 TCZ+MTX group (n=39; women 30; median age 51 [43-55] years; 6 i.v. infusions of TCZ 8 mg/kg + МТX 10-20 mg/week; 2 MTX group (n=33; women 23; mеdian age 56 [48-63] years; MTX 7.5-20 mg/week. Results. At the baseline, similar proatherogenic blood profile was observed in both groups. The patients of MTX group more frequently took statins (n=19; 57.6% compared with the group TCZ+MTX (n=7; 18%, (p<0.05. The lipid levels correlated positively with traditional risk factors (p<0.05. RA activity and duration correlated negatively with high density lipoprotein cholesterol (HDL-C, (p<0.05. Good/satisfactory anti-inflammatory effect was achieved in both groups after 24 weeks of treatment. Patients of TCZ+MTX group showed an increase in total cholesterol and HDL-C levels by 11% and 110%, respectively and decrease in plasma atherogenic index (PAI by 47%, (p<0.05. HDL-C level increased by 22% and PAI decreased by 16% in patients of MTX group (p<0.05. Among patients of MTX group without statin therapy HDL-C as well as non-HDL-C levels were increased by 24% and 27%, respectively (p<0.05; PAI did not change significantly in this subgroup. Among patients of MTX group treated with statins isolated increase in HDL-C level by 22% and decrease in PAI by 37.3% (p<0.05 were observed. A number of patients with achieved target levels of all studied lipid parameters did not change significantly in both groups. Conclusions. TCZ+MTX combined therapy as well as MTX monotherapy are associated

  18. Microwave hyperthermia enhancement of methotrexate absorption in rat brains

    International Nuclear Information System (INIS)

    Lin, J.C.; Yuen, M.K.; Jung, D.T.

    1987-01-01

    The author studied enhanced absorption of methotrexate (MTX) in brains of male Wistar (10 weeks old, 500g) subjected to microwave hyperthermia. The rat was anesthetized using 40 mg/kg of sodium pentobarbital, IP and was placed in a stereotaxic head holder. Microwave energy (2450 MHz, 2.6 W/cm/sup 2/, CW) were applied directly to the left side of the rat's head by a coaxial applicator for 20 min. The body temperature was kept at 37.8 0 C. The brain temperature recorded in a similar group of animals using a Vitek probe was about 45 0 C. Three different MTX dosages, 50, 100 and 200 mg/kg, were injected intravenously immediately following microwave irradiation into three groups of rats in 1.5, 3 and 6 min., respectively. MTX was allowed to circulate for five min. before brains were removed for analysis. Standard HPLC procedures were applied to samples from anterior and posterior left hemisphere of the cerebrum, and the cerebellum. Samples from the right hemisphere were used for controls. The average absorption at the posterior left hemisphere was found to be 2.4, 9.6 and 12.4μg of MTX/g of brain tissue for 50, 100 and 200 mg/kg, respectively. These results indicate that MTX absorption is significantly increased in rat brains subjected to microwave hyperthermia treatment

  19. Four-year experience with methotrexate exposures.

    Science.gov (United States)

    LoVecchio, Frank; Katz, Kenneth; Watts, David; Wood, Ian

    2008-09-01

    Unintentional methotrexate (MTX) acute oral overdose is rarely reported. We conducted a retrospective chart review of all human exposure calls (>150,000 charts) for MTX ingestions reported to our Poison Center during 2000-2003. Thirteen patients met the criteria. The average amount of MTX ingested was 13.03 mg (data from 7 cases), and the average patient age was 43 years (20 months to 80 years). No significant toxicities occurred. Although intravenous MTX toxicity can be severe, this does not appear to be a phenomenon associated with either acute unintentional or suicidal oral ingestion.

  20. Methotrexate: an option for preventing the recurrence of acute anterior uveitis.

    Science.gov (United States)

    Muñoz-Fernández, S; García-Aparicio, A M; Hidalgo, M V; Platero, M; Schlincker, A; Bascones, M L; Pombo, M; Morente, P; Sanpedro, J; Martín-Mola, E

    2009-05-01

    To evaluate the efficacy of methotrexate (MTX) in preventing the recurrence of acute anterior uveitis (AAU). This prospective, open, longitudinal study included patients from June 2002 to March 2005 who had either three or more episodes of AAU in the previous year, or a recurrence of AAU within 3 months before starting the trial. We excluded uveitis of infectious origin, masquerade syndromes, and patients with contraindications to MTX. The response criteria were defined as an absence of symptoms and the presence of a normal ophthalmologic examination. The study outcome compared the number of flare-ups of uveitis over an MTX-treated for 1 year to the number of flare-ups of the same group during the previous year without MTX. A total of 571 patients with uveitis were evaluated during the period of the study, and 10 fulfilled the inclusion criteria. One patient refused the treatment, and nine completed the study. The mean number of recurrences in the pre-MTX year was 3.4 (SD: 0.52), which was significantly reduced to 0.89 (SD: 1.17) in the year of treatment (P=0.011). MTX treatment seems to reduce the number of flare-ups in patients with recurrent AAU.

  1. Methotrexate-Induced Accumulation of Fluorescent Annexin V in Collagen-Induced Arthritis

    Directory of Open Access Journals (Sweden)

    Andreas Wunder

    2005-01-01

    Full Text Available We examined the accumulation of Cy5.5-labeled annexin V in the paws of mice with and without collagen-induced arthritis, with and without methotrexate (MTX treatment, by near-infrared fluorescence imaging. Fluorescence reflectance imaging (FRI of paws was performed 48 hr after MTX injection and at 10 min and 3 hr after the injection of Cy5.5-annexin V (1 nmol dye per mouse. With arthritic paws, MTX treatment caused a 7-fold increase in fluorescence intensity compared with the paws of untreated mice and a 4-fold increase compared to nonarthritic paws of MTX-treated mice (p < .001 each. Tissue samples of paws were examined histologically for Cy5.5 fluorescence and by TUNEL staining for apoptosis. Cy5.5-annexin V was seen in the hyperplastic synovia of MTX-treated mice, and TUNEL staining for apoptosis showed apoptotic cells in the hyperplastic synovia. Monitoring the uptake of Cy5.5-annexin V in arthritic paws by FRI provided a method of assessing a response to MTX, a response that was readily quantitated with simple instrumentation and that occurred before conventional measurements of treatment response.

  2. The combination of etanercept and methotrexate increases the effectiveness of treatment in active psoriasis despite inadequate effect of methotrexate therapy

    DEFF Research Database (Denmark)

    Zachariae, Claus; Mørk, Nils-Jørgen; Reunala, Timo

    2008-01-01

    Many patients with moderate-to-severe plaque psoriasis do not respond adequately to methotrexate monotherapy. This pilot study, with a small patient population, was performed to evaluate the effectiveness and safety of etanercept and methotrexate combination in patients with plaque psoriasis...

  3. Direct antioxidant properties of methotrexate: Inhibition of malondialdehyde-acetaldehyde-protein adduct formation and superoxide scavenging

    Directory of Open Access Journals (Sweden)

    Matthew C. Zimmerman

    2017-10-01

    Full Text Available Methotrexate (MTX is an immunosuppressant commonly used for the treatment of autoimmune diseases. Recent observations have shown that patients treated with MTX also exhibit a reduced risk for the development of cardiovascular disease (CVD. Although MTX reduces systemic inflammation and tissue damage, the mechanisms by which MTX exerts these beneficial effects are not entirely known. We have previously demonstrated that protein adducts formed by the interaction of malondialdehyde (MDA and acetaldehyde (AA, known as MAA-protein adducts, are present in diseased tissues of individuals with rheumatoid arthritis (RA or CVD. In previously reported studies, MAA-adducts were shown to be highly immunogenic, supporting the concept that MAA-adducts not only serve as markers of oxidative stress but may have a direct role in the pathogenesis of inflammatory diseases. Because MAA-adducts are commonly detected in diseased tissues and are proposed to mitigate disease progression in both RA and CVD, we tested the hypothesis that MTX inhibits the generation of MAA-protein adducts by scavenging reactive oxygen species. Using a cell free system, we found that MTX reduces MAA-adduct formation by approximately 6-fold, and scavenges free radicals produced during MAA-adduct formation. Further investigation revealed that MTX directly scavenges superoxide, but not hydrogen peroxide. Additionally, using the Nrf2/ARE luciferase reporter cell line, which responds to intracellular redox changes, we observed that MTX inhibits the activation of Nrf2 in cells treated with MDA and AA. These studies define previously unrecognized mechanisms by which MTX can reduce inflammation and subsequent tissue damage, namely, scavenging free radicals, reducing oxidative stress, and inhibiting MAA-adduct formation.

  4. The Australasian Psoriasis Collaboration view on methotrexate for psoriasis in the Australasian setting.

    Science.gov (United States)

    Rademaker, Marius; Gupta, Monisha; Andrews, Megan; Armour, Katherine; Baker, Chris; Foley, Peter; Gebauer, Kurt; George, Jacob; Rubel, Diana; Sullivan, John

    2017-08-01

    The Australasian Psoriasis Collaboration reviewed methotrexate (MTX) in the management of psoriasis in the Australian and New Zealand setting. The following comments are based on expert opinion and a literature review. Low-dose MTX (< 0.4 mg/kg per week) has a slow onset of action and has moderate to good efficacy, together with an acceptable safety profile. The mechanism of action is anti-inflammatory, rather than immunosuppressive. For pretreatment, consider testing full blood count (FBC), liver and renal function, non-fasting lipids, hepatitis serology, HbA1c and glucose. Body mass index and abdominal circumference should also be measured. Optional investigations in at-risk groups include an HIV test, a QuantiFERON-TB Gold test and a chest X-ray. In patients without complications, repeat the FBC at 2-4 weeks, then every 3-6 months and the liver/renal function test at 3 months and then every 6 months. There is little evidence that a MTX test dose is of value. Low-dose MTX rarely causes clinically significant hepatotoxicity in psoriasis. Most treatment-emergent liver toxicity is related to underlying metabolic syndrome and non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. Alcohol itself is not contraindicated, but should be limited to < 20 gm/day. [Correction added on 6 January 2017, after first online publication: '20 mg/day' has been corrected to '20 gm/day'.] Although MTX is a potential teratogen post-conception, there is little evidence for this pre-conception. MTX does not affect the quality of sperm. There is no evidence that MTX reduces healing, so there is no specific need to stop MTX peri-surgery. MTX may be used in combination with cyclosporine, acitretin, prednisone and anti-tumour necrosis factor biologics. © 2016 The Australasian College of Dermatologists.

  5. Modifications in Lipid Levels Are Independent of Serum TNF-α in Rheumatoid Arthritis: Results of an Observational 24-Week Cohort Study Comparing Patients Receiving Etanercept Plus Methotrexate or Methotrexate as Monotherapy

    Directory of Open Access Journals (Sweden)

    Norma Alejandra Rodriguez-Jimenez

    2014-01-01

    Full Text Available Objective. To compare the modifications in lipids between patients with rheumatoid arthritis (RA receiving etanercept plus methotrexate (ETA + MTX versus methotrexate (MTX and their relationship with serum levels of tumor necrosis factor-alpha (TNF-α. Methods. In an observational cohort study, we compared changes in lipid levels in patients receiving ETA + MTX versus MTX in RA. These groups were assessed at baseline and at 4 and 24 weeks, measuring clinical outcomes, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C, low-density lipoprotein cholesterol, and TNF-α. Results. Baseline values for lipid levels were similar in both groups. HDL-C levels increased significantly only in the ETA + MTX group (from 45.5 to 50.0 mg/dL at 4 weeks, a 10.2% increase, P<0.001, and to 56.0 mg/dL at 24 weeks, a 25.1% increase, P<0.001, while other lipids underwent no significant changes. ETA + MTX also exhibited a significant increase in TNF-α (44.8 pg/mL at baseline versus 281.4 pg/mL at 24 weeks, P<0.001. The MTX group had no significant changes in lipids or TNF-α. Significant differences in HDL-C between groups were observed at 24 weeks (P=0.04 and also in TNF-α  (P=0.01. Conclusion. HDL-C levels increased significantly following treatment with ETA + MTX, without a relationship with decrease of TNF-α.

  6. Influence of combined therapy with prospidin and methotrexate on radiological progression, functional status and quality of life in pts with rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    O. V. Simonova

    2004-01-01

    Full Text Available Objective. To evaluate influence of combination therapy with prospidin (P and methotrexate (MTX on X-ray progression, functional status (FS and quality of life (QL in patients with rheumatoid arthritis (RA in comparison with MTX monotherapy. Material and methods. 143 RA pts (129 female and 14 male were studied. Of them, there were. Mean age was 45.5±5.l years. Average duration of the disease was 4.5 years. 20 pts had II and 123 - 111 degree of RA activity. The second X-ray stage according to Steinbroker dominated. 72 pts of group I received P+MTX combination therapy. The therapy included intravenous drip-feed of P 200-300 mg per week in 200ml of 5% glucose and MTX 10 mg per week 1M. The maintaining therapy included P 100-200 mg per week IM and MTX 10 mg per week. 71 patients of group II received MTX monotherapy 10 mg per week. X-ray progression assessment was performed according to Sharp method. FS was evaluated with the HAQ questionnaire, Lee test. QL was evaluated with SF-36 scale. Pts were examined before and after I, 2, 3, 6 and 12 months of treatment. Results. There was no increase of X-ray progression of the disease in case of P+MTX therapy as compared with MTX monotherapy. Both methods resulted in improvement of FS parameters and physical health. Combination therapy significantly improved psychological health as well.

  7. Efficacy of tofacitinib monotherapy in methotrexate-naive patients with early or established rheumatoid arthritis

    OpenAIRE

    Fleischmann, Roy M; Huizinga, Tom W J; Kavanaugh, Arthur F; Wilkinson, Bethanie; Kwok, Kenneth; DeMasi, Ryan; van Vollenhoven, Ronald F

    2016-01-01

    Introduction Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib monotherapy was previously shown to inhibit structural damage, reduce clinical signs and symptoms of RA, and improve physical functioning over 24?months in methotrexate (MTX)-naive adult patients with RA. In this post hoc analysis, we compared efficacy and safety of tofacitinib in patients with early (disease duration

  8. Plasma MicroRNA Profiles in Patients with Early Rheumatoid Arthritis Responding to Adalimumab plus Methotrexate vs Methotrexate Alone

    DEFF Research Database (Denmark)

    Sode, Jacob; Krintel, Sophine B; Carlsen, Anting Liu

    2018-01-01

    OBJECTIVE: The aim was to identify plasma (i.e., cell-free) microRNA (miRNA) predicting antitumor necrosis and/or methotrexate (MTX) treatment response in patients enrolled in an investigator-initiated, prospective, double-blinded, placebo-controlled trial (The OPERA study, NCT00660647). METHODS......: We included 180 disease-modifying antirheumatic drug-naive patients with early rheumatoid arthritis (RA) randomized to adalimumab (ADA; n = 89) or placebo (n = 91) in combination with MTX. Plasma samples before and 3 months after treatment initiation were analyzed for 91 specific mi...... multivariate miRNA models were able to predict response to ADA treatment after 3 and 12 months, with 63% and 82% area under the ROC curves, respectively. CONCLUSION: We identified miR-27a-3p as a potential predictive biomarker of ACR/EULAR remission in patients with early RA treated with ADA in combination...

  9. Novel methotrexate soft nanocarrier/fractional erbium YAG laser combination for clinical treatment of plaque psoriasis.

    Science.gov (United States)

    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.

  10. Double-blind, randomized, controlled, pilot study comparing classic ayurvedic medicine, methotrexate, and their combination in rheumatoid arthritis.

    Science.gov (United States)

    Furst, Daniel E; Venkatraman, Manorama M; McGann, Mary; Manohar, P Ram; Booth-LaForce, Cathryn; Sarin, Reshmi; Sekar, P G; Raveendran, K G; Mahapatra, Anita; Gopinath, Jidesh; Kumar, P R Krishna

    2011-06-01

    To compare classic Ayurveda, methotrexate (MTX), and their combination in a double-blind, randomized, double-dummy, pilot trial in rheumatoid arthritis (RA) for 36 weeks. Forty-three seropositive RA patients by American College of Rheumatology (ACR) criteria with disease duration of less than 7 years were assigned to the following treatment groups: MTX plus Ayurvedic placebo (n = 14), Ayurveda plus MTX placebo (n = 12), or Ayurveda plus MTX (n = 17). Outcomes included the Disease Activity Score (DAS28-CRP), ACR20/50/70, and Health Assessment Questionnaire--Disability Index. All measures were obtained every 12 weeks for 36 weeks. Analyses included descriptive statistics, analysis of variance, χ², or Student t test. The unique features of this study included the development of placebos for each Ayurvedic pharmacological dosage form and individualization of Ayurvedic therapy. All groups were comparable at baseline in demographics and disease characteristics. There were no statistically significant differences among the 3 groups on the efficacy measures. ACR20 results were MTX 86%, Ayurveda 100%, and combination 82%, and DAS28-CRP response were MTX -2.4, Ayurveda -1.7, and combination -2.4. Differences in adverse events among groups were also not statistically significant, although the MTX groups experienced more adverse event (MTX 174, Ayurveda 112, combination 176). No deaths occurred. In this first-ever, double-blind, randomized, placebo-controlled pilot study comparing Ayurveda, MTX, and their combination, all 3 treatments were approximately equivalent in efficacy, within the limits of a pilot study. Adverse events were numerically fewer in the Ayurveda-only group. This study demonstrates that double-blind, placebo-controlled, randomized studies are possible when testing individualized classic Ayurvedic versus allopathic treatment in ways acceptable to western standards and to Ayurvedic physicians. It also justifies the need for larger studies.

  11. Effect of methotrexate combined with ginger, silymarin or propolis on ...

    African Journals Online (AJOL)

    The present study was performed to evaluate the effect of three natural antioxidants on the adverse effect of methotrexate (MTX) in normal liver cells. TaqMan RT-PCR technology was used to estimate the mRNA expression levels for three genes after rats injection with a single dose of 20 mg/kg b.w MTX or the same MTX ...

  12. Long-term survival of methotrexate in psoriatic arthritis

    Directory of Open Access Journals (Sweden)

    N. Battafarano

    2011-06-01

    Full Text Available Objective. The purpose of this study was to evaluate the long-term survival rate of Methotrexate (MTX in the peripheral joint involvement of psoriatic arthritis (PsA in a setting of everyday clinical practice. Methods. This was an observational restrospective study performed using the data from a dermatological-rheumatological PsA clinic. All of the patients evaluated at this clinic from March 1997 to December 2007 who were started on MTX alone, had a three-year follow-up time or had discontinued the therapy were included into the survey. Results. Of the 174 evaluable patients, 104 (59.8% were still taking MTX after three years of treament. The reasons of therapy discontinuation in the remaining 70 (40.2% patients were: 34 (19.5% lost-to-follow-up, 18 (10.3% adverse events, 14 (8% inefficacies, and 4 (2.3% deaths (none related to the therapy. MTX was effective in controlling joint inflammation but not in preventing their deterioration. Overall, adverse events were recorded in 43 patients (36.4% of the 114 patients with a three-year follow-up. No serious side effect occurred in the study population. Conclusions. The results of this study showed that, in a setting of clinical pratice, MTX had a good three-year performance in patients with peripheral PsA. Almost 60% of them were still taking this drug at the end of the study period and the toxicity was more than acceptable. In our opinion, MTX might be considered the non-biological DMARD of choice for the treatment of this condition. However it should be used earlier and at higher doses.

  13. Endogenous metabolites that are substrates of organic anion transporter's (OATs) predict methotrexate clearance.

    Science.gov (United States)

    Muhrez, Kienana; Benz-de Bretagne, Isabelle; Nadal-Desbarats, Lydie; Blasco, Hélène; Gyan, Emmanuel; Choquet, Sylvain; Montigny, Frédéric; Emond, Patrick; Barin-Le Guellec, Chantal

    2017-04-01

    Variable pharmacokinetics of high-dose-methotrexate (MTX) is responsible for severe toxicities. Unpredictable overexposure still occurs during some courses despite having controlled the main factors known to play a role in its elimination. The aim of our study was to evaluate whether the urine metabolomic profile measured at the time of MTX administration is predictive of the drug's clearance and/or of treatment-related toxicity. We analyzed the urine content of endogenous metabolites before MTX administration in a cohort of adult patients treated for lymphoid malignancies. Individual MTX clearance (MTX CL ) was estimated from population pharmacokinetic analyses of therapeutic drug monitoring data. We determined the urine metabolite content by gas chromatography-mass spectrometry (GC-MS) and applied Partial Least Square (PLS) analysis to assess the relationship between the urine metabolome and MTX CL . External validation was applied to evaluate the performances of the PLS model. We used orthogonal partial least squares discriminant analysis (OPLS-DA) to distinguish patients with normal or delayed elimination, and patients with or without toxicity. Sixty-two patients were studied. We obtained a very good prediction of individual MTX clearance using a set of 28 metabolites present in patient urine at baseline. The mean prediction error and precision were -0.36% and 21.4%, respectively, for patients not included in the model. The model included a set of endogenous organic anions, of which the tubular secretion depends on organic anion transporter (OAT) function. Our analyses did not allow us to discriminate between patients with or without delayed elimination or those who did or did not experience toxicity. Urinary metabolomics can be informative about an individual's ability to clear MTX. More broadly, it paves the way for the development of a biomarker of tubular secretion, easily measurable from endogenous substances. Copyright © 2016 Elsevier Ltd. All rights

  14. Neurologic sequelae of methotrexate and ionizing radiation: a new classification

    International Nuclear Information System (INIS)

    Bleyer, W.A.

    1981-01-01

    Therapy for prevention of central nervous system (CNS) leukemia has had a dramatic effect on disease-free survival in children with acute lymphoblastic leukemia (ALL). Now, a majority of children may be in complete remission indefinitely, having completed therapy years ago. Unfortunately, some of these long-term survivors have residual neurologic dysfunction, varying in severity from the not uncommon occurrence of mild intellectual deficit to the fortunately rare instance of debilitating leukoencephalopathy. To help identify inciting factors and ultimately render CNS prophylaxis less neurotoxic, this article attempts to categorize the types of neurotoxicities reported in patients treated with methotrexate (MTX) and ionizing radiation. A variety of clinical syndromes are described and related temporally to these treatment modalities. Analyzed in this way, combinations including CNS irradiation appear to be the most neurotoxic. The safest methods are the single modalities, of which high-dose iv MTX may be the least neurotoxic

  15. The role of methotrexate in resolving ocular inflammation after specific therapy for presumed latent syphilitic uveitis and presumed tuberculosis-related uveitis.

    Science.gov (United States)

    Sahin, Ozlem; Ziaei, Alireza

    2014-07-01

    This study was designed to investigate whether the antiinflammatory and antiproliferative activity of oral and intravitreal methotrexate (MTX) suppresses intraocular inflammation in patients with presumed latent syphilitic uveitis and presumed tuberculosis-related uveitis. Interventional prospective study including three cases with presumed latent syphilitic uveitis treated with intravenous penicillin and oral MTX, and two cases with presumed tuberculosis-related uveitis treated with standard antituberculosis therapy and intravitreal MTX injections. Treatment efficacy of all cases was assessed by best-corrected visual acuity, fundus fluorescein angiography, and optical coherence tomography. Four eyes of 3 patients with presumed latent syphilitic uveitis had improved best-corrected visual acuity, suppression of intraocular inflammation, and resolution of cystoid macular edema in 6 months with oral MTX therapy. No recurrence of intraocular inflammation was observed in 6 months to 18 months of follow-up period after cessation of MTX. Two eyes of two patients with presumed tuberculosis-related uveitis showed improved best-corrected visual acuity, suppression of intraocular inflammation, and resolution of cystoid macular edema after intravitreal injections of MTX. No recurrence of intraocular inflammation was observed in 6 months to 8 months of follow-up period after cessation of antituberculous therapy. For the first time in the treatment of presumed latent syphilitic uveitis and presumed tuberculosis-related uveitis, we believe that MTX might have an adjunctive role to suppress intraocular inflammation, reduce uveitic macular edema, and prevent the recurrences of the diseases.

  16. Successful Management of Tubal Ectopic Pregnancy with Transvaginal Sonography Guided Intracardiac KCL Injection and Systemic Methotrexate - A Case Report

    Directory of Open Access Journals (Sweden)

    Sumesh Choudhary

    2014-01-01

    Full Text Available Background: Methotrexate (Mtx is an accepted modality for conservative treatment of ectopic pregnancy. However, there is no consensus regarding its use in live ectopic pregnancy and high serum beta-human chorionic gonadotrophin (β-hCG titres. Concurrent use of intra-sac hypertonic KCl, to produce cardiac asystole with systemic Mtx potentially improve outcome in live ectopic gestations with very high serum β-hCG titres. Here a successful management of live ectopic pregnancy in a 25-year-old nulliparous woman, with very high β-hCG titres (29502.04mIU/mL, using ultrasound-guided intra-cardiac potassium chloride (KCl injection and systemic Mtx is reported. No treatment related complications were encountered. However, individualized treatment with a stringent follow-up regime is mandatory in such cases.

  17. Mycophenolate mofetil after methotrexate failure or intolerance in the treatment of scleritis and uveitis.

    Science.gov (United States)

    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 methotrexate. The odds of inflammation control were less in patients with the diagnoses of scleritis and JIA.

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

    Science.gov (United States)

    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.

  19. Topically applied methotrexate is rapidly delivered into skin by fractional laser ablation

    DEFF Research Database (Denmark)

    Taudorf, Elisabeth Hjardem; Lerche, Catharina; Vissing, Anne-Cathrine

    2015-01-01

    Objectives: Methotrexate (MTX) is a chemotherapeutic and anti-inflammatory drug that may cause systemic adverse effects. This study investigated kinetics and biodistribution of MTX delivered topically by ablative fractional laser (AFXL). Methods: In vitro passive diffusion of 10 mg/ml MTX (1 w...... sections, donor and receiver compartments. Fluorescence microscopy of UVC-activated MTX-fluorescence and desorption electro-spray ionization mass spectrometry imaging (DESI-MSI) evaluated MTX biodistribution. Results: AFXL-processed skin facilitated rapid MTX delivery through cone-shaped microchannels.......30 mg/cm3, p = 0.002). Transdermal permeation was

  20. Overview and guidelines of off-label use of methotrexate in ectopic pregnancy: report by CNGOF.

    Science.gov (United States)

    Marret, Henri; Fauconnier, Arnaud; Dubernard, Gil; Misme, Hélène; Lagarce, Laurence; Lesavre, Magali; Fernandez, Hervé; Mimoun, Camille; Tourette, Claire; Curinier, Sandra; Rabishong, Benoit; Agostini, Aubert

    2016-10-01

    Our objective is to describe off-label use of methotrexate in ectopic pregnancy treatment using evidence based medicine. The patient group includes all women with a pregnancy outside the usual endometrium, or of unknown location. Method used was a Medline search on ectopic pregnancy managed using methotrexate treatment; evidence synthesis was done based on this current literature analysis. Level of evidence (LE) were given according to the centre for evidence base medicine rules. Grade was proposed for guidelines but no recommendation was possible as misoprostol is off label use for all the indications studied. In the absence of any contraindication, the protocol recommended for medical treatment of ectopic pregnancy is a single intramuscular injection of methotrexate (MTX) at a dosage of 1mg/kg or 50mg/m(2) (Grade A). It can be repeated once at the same dose should the hCG concentration not fall sufficiently. Pretreatment laboratory results must include a complete blood count and kidney and liver function tests (in accordance with its marketing authorization). MTX is an alternative to conservative treatment such as laparoscopic salpingotomy for uncomplicated tubal pregnancy (Grade A) with pretreatment hCG levels≤5000IU/l (Grade B). Expectant management is preferred for hCG levelslocation persisting more than 10days in an asymptomatic woman who has an hCG level>2000IU/l, routine MTX treatment is an option. MTX is not indicated for combination with treatments such as mifepristone or potassium. Copyright © 2016. Published by Elsevier Ireland Ltd.

  1. Nanomedical strategy to prolong survival period, heighten cure rate, and lower systemic toxicity of S180 mice treated with MTX/MIT.

    Science.gov (United States)

    Song, Ning; Zhao, Ming; Wang, Yuji; Hu, Xi; Wu, Jianhui; Jiang, Xueyun; Li, Shan; Cui, Chunying; Peng, Shiqi

    2016-01-01

    In spite of the usual combination form of methotrexate (MTX)/mitoxantrone (MIT) and various complex combination regimens of MTX/MIT with other anticancer drugs, the survival period, cure rate, and systemic toxicity still need to be improved. For this purpose, a nanostructured amino group-modified mesoporous silica nanoparticles (MSNN)-MTX/MIT was designed. In the preparation, the surface of mesoporous silica nanoparticles (MSNs) was modified with amino groups to form MSNN. The covalent modification of the amino groups on the surface of MSNN with MTX resulted in MSNN-MTX. The loading of MIT into the surface pores of MSNN-MTX produced nanostructured MSNN-MTX/MIT. Compared with the usual combination form (MTX/MIT), nanostructured MSNN-MTX/MIT increased the survival period greatly, heightened the cure rate to a great extent, and lowered the systemic toxicity of the treated S180 mice, significantly. These superior in vivo properties of nanostructured MSNN-MTX/MIT over the usual combination form (MTX/MIT) were correlated with the former selectively releasing MTX and MIT in tumor tissue and inside cancer cells in vitro. The chemical structure and the nanostructure of MSNN-MTX/MIT were characterized using infrared and differential scanning calorimeter spectra as well as transmission electron microscope images, respectively.

  2. Comparing the effects of tofacitinib, methotrexate and the combination, on bone marrow oedema, synovitis and bone erosion in methotrexate-naive, early active rheumatoid arthritis: results of an exploratory randomised MRI study incorporating semiquantitative and quantitative techniques.

    Science.gov (United States)

    Conaghan, Philip G; Østergaard, Mikkel; Bowes, Michael A; Wu, Chunying; Fuerst, Thomas; van der Heijde, Désirée; Irazoque-Palazuelos, Fedra; Soto-Raices, Oscar; Hrycaj, Pawel; Xie, Zhiyong; Zhang, Richard; Wyman, Bradley T; Bradley, John D; Soma, Koshika; Wilkinson, Bethanie

    2016-06-01

    To explore the effects of tofacitinib-an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA)-with or without methotrexate (MTX), on MRI endpoints in MTX-naive adult patients with early active RA and synovitis in an index wrist or hand. In this exploratory, phase 2, randomised, double-blind, parallel-group study, patients received tofacitinib 10 mg twice daily + MTX, tofacitinib 10 mg twice daily + placebo (tofacitinib monotherapy), or MTX + placebo (MTX monotherapy), for 1 year. MRI endpoints (Outcome Measures in Rheumatology Clinical Trials RA MRI score (RAMRIS), quantitative RAMRIS (RAMRIQ) and dynamic contrast-enhanced (DCE) MRI) were assessed using a mixed-effect model for repeated measures. Treatment differences with ptofacitinib + MTX and -1.74 (-2.72 to -0.76) for tofacitinib monotherapy (both ptofacitinib + MTX and -0.52 (-1.46 to 0.41) for tofacitinib monotherapy (both p>0.05 vs MTX monotherapy). Treatment differences in RAMRIQ synovitis were statistically significant at month 3, consistent with DCE MRI findings. Less deterioration of RAMRIS and RAMRIQ erosive damage was seen at months 6 and 12 in both tofacitinib groups versus MTX monotherapy. These results provide consistent evidence using three different MRI technologies that tofacitinib treatment leads to early reduction of inflammation and inhibits progression of structural damage. NCT01164579. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  3. Biodegradable chitosan and polylactic acid-based intraocular micro-implant for sustained release of methotrexate into vitreous: analysis of pharmacokinetics and toxicity in rabbit eyes.

    Science.gov (United States)

    Manna, Soumyarwit; Banerjee, Rupak K; Augsburger, James J; Al-Rjoub, Marwan F; Donnell, Anna; Correa, Zelia M

    2015-08-01

    The purpose of this study was to evaluate the pharmacokinetics and toxicity of a chitosan (CS) and polylactic acid (PLA) based methotrexate (MTX) intravitreal micro-implant in an animal model using rabbit eyes. CS- and PLA-based micro-implants containing 400 μg of MTX were fabricated using lyophilization and dip-coating techniques. The micro-implants were surgically implanted in the vitreous of eight New Zealand rabbits employing minimally invasive technique. The PLA-coated CS-MTX micro-implant was inserted in the right eye and the placebo micro-implant in the left eye of each rabbit. Two rabbits were euthanized at each pre-determined time point post-implantation (days 5, 12, 19, and 33) for pharmacokinetics and histopathology evaluation. A therapeutic concentration of MTX (0.1-1.0 μM) in the vitreous was detected in the rabbit eyes studied for 33 days. The MTX release from the coated micro-implants followed a first order kinetics (R (2) ~ 0.88), implying that MTX release depends on the concentration of MTX in the micro-implant. Histopathological analysis of the enucleated eyes failed to show any signs of infection or tissue toxicity in any of the specimens. The PLA-coated CS-MTX micro-implants were able to deliver therapeutic release of MTX for a period of more than 1 month without detectable toxicity in a rabbit model. The micro-implants can be further investigated as a prospective alternative to current treatment protocols of repeated intravitreal MTX injections in intraocular disorders such as primary intraocular lymphoma, and selected cases of non-microbial intraocular inflammation.

  4. Attenuation of Methotrexate-Induced Embryotoxicity and Oxidative Stress by Ethyl Pyruvate

    Directory of Open Access Journals (Sweden)

    Najafi Gholamreza

    2016-07-01

    Full Text Available Background Methotrexate (MTX, as an anti-folate agent, is widely used in the treatment of rheumatic disorders and malignant tumors, however it damages reproductive sys- tem in mice. The aim of this research was to study the effects of ethyl pyruvate (EP on embryo development and oxidative stress changes in the testis of mice treated with MTX. Materials and Methods In this experimental study, thirty-two adult male Naval Medical Research Institute mice, with average weight of 26 ± 2 g, were divided into four groups. The first group (control received distilled water (0.1 ml/mice/day, while the second group was intraperitoneally (IP treated with 20 mg/kg MTX once per week. The third group was IP treated with 40 mg/kg/day EP, and the fourth group was IP treated with both 20 mg/kg MTX and 40 mg/kg/day EP for 30 days. At the end of treatment fertilization rate and embryonic development were evaluated. Differences between these groups were assessed by ANOVA using the SPSS software package for Windows with a Tukey-Kramer multiple post-hoc comparison test. Results MTX treatment caused significant (P<0.05 increase in malondialdehyde (MDA and reduced catalase (CAT, as well as leading to in vitro fertilization (IVF and embryonic development. The improved effects of EP on the IVF were determined by the reduced level of MDA (index of oxidative stress and significant increased level of CAT (a key antioxidant. We observed significant increase in fertilization rate and embryonic development in the treated group with both MTX and EP. Conclusion It is suggested that EP can be useful in ameliorating testicular damages and embryotoxicity induced by MTX. These effects could be attributed to its antioxidant properties.

  5. Reduction of oxidative stress by an ethanolic extract of leaves of Piper betle (Paan) Linn. decreased methotrexate-induced toxicity.

    Science.gov (United States)

    De, Soumita; Sen, Tuhinadri; Chatterjee, Mitali

    2015-11-01

    Methotrexate (MTX), a folate antagonist, is currently used as first line therapy for autoimmune diseases like rheumatoid arthritis and psoriasis, but its use is limited by the associated hepatotoxicity. As leaves of Piper betle, belonging to family Piperaceae, have antioxidant and anti-inflammatory properties, the present study was undertaken to investigate the potential of Piper betle leaf extract (PB) in attenuating MTX-induced hepatotoxicity. Rats pre-treated with PB (50 or 100 mg kg(-1) b.w., p.o.) were administered with a single dose of MTX (20 mg kg(-1), b.w., i.p.) and its hepatoprotective efficacy was compared with folic acid (1 mg kg(-1) b.w., i.p.), conventionally used to minimize MTX-induced toxicity. MTX-induced hepatotoxicity was confirmed by increased activities of marker enzymes, alanine transaminase, aspartate transaminase, and alkaline phosphatase which were remitted by pre-treatment with PB and corroborated with histopathology. Additionally, MTX-induced hepatic oxidative stress which included increased generation of reactive oxygen species, enhanced lipid peroxidation, depleted levels of glutathione and decreased activities of antioxidant enzymes was effectively mitigated by PB, indicative that its promising antioxidant-mediated hepatoprotective activity was worthy of future pharmacological consideration.

  6. Diosmin Attenuates Methotrexate-Induced Hepatic, Renal, and Cardiac Injury: A Biochemical and Histopathological Study in Mice

    Science.gov (United States)

    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

  7. A Combination of Surgery And Methotrexate for Successful Treatment of a Caesarean Scar Ectopic Pregnancy.

    LENUS (Irish Health Repository)

    Tadesse, WG

    2018-06-01

    Caesarean scar ectopic pregnancy (CSEP) is one of the rarest forms of ectopic pregnancies. With rising caesarean delivery (CD) rates worldwide, there is an increase in the incidence of CSEP. Patients usually present with painless vaginal bleeding and often misdiagnosed as spontaneous miscarriage. The use of ultrasonography with colour flow Doppler helps in the differential diagnosis. Different treatment options are described in the literature, although there is insufficient evidence regarding the best approach. We report the diagnosis and management of a case of CSEP in a woman with four previous CD who presented with vaginal bleeding and lower abdominal cramps at six weeks of gestation. She was treated with laparoscopic and ultrasound guided aspiration of the gestational sac and local injection of methotrexate supplemented by intramuscular methotrexate injection.

  8. Comparison of intelligence quotient in children surviving leukemia who received different prophylactic central nervous system treatments

    OpenAIRE

    Nahid, Reisi; Leila, Khalilian

    2012-01-01

    Background: Neurocognitive deficits and decrease in intelligence quotient (IQ) is one of the complication of prophylactic central nervous system (CNS) treatment in acute lymphoblastic leukemia (ALL) patients. In this study, we compare the IQ in survivors of ALL that were treated with different prophylactic CNS treatments. Materials and Methods : We compared 43 long-term survivors of ALL: 21 survivors with intrathecal methotrexate (IT MTX) as CNS prophylaxis, 22 with IT MTX+1800-2400 rads c...

  9. Successful combination treatment of a patient with progressive juvenile localized scleroderma (morphea) using imatinib, corticosteroids, and methotrexate.

    Science.gov (United States)

    Inamo, Yasuji; Ochiai, Toyoko

    2013-01-01

    We report a case of progressive juvenile localized scleroderma (JLS or morphea) treated with a combination of imatinib, corticosteroids, and methotrexate. This therapy halted the progressive skin thickening and the hand and finger joint deformity in the early stages of the disease. We conclude that imatinib used in addition to standard treatment with systemic corticosteroids and methotrexate may be of therapeutic benefit for individuals with JLS. © 2012 Wiley Periodicals, Inc.

  10. Computed tomography of the brain following prophylactic treatment with irradiation therapy and intraspinal metho-trexate in children with acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Lund, E.; Hamborg-Pedersen, B.

    1984-01-01

    In 28 children with acute lymphoblastic leukemia (ALL) computed tomography (CT) was performed in order to demonstrate possible cerebral changes following treatment with prophylactic irradiation and intraspinal methotrexate (MTX). The time of CT-scan examination varied from 1 year and 1 month to 10 years and 1 month after diagnosis of ALL. The age of the children ranged from 3 years and 11 months to 14 years and 5 months. Six children had normal CT scans, 12 children had slight atrophylike changes, and nine had severe cerebral atrophy. Two patients in the latter group presented an enlarged ventricular system as well. In one patient intracerebral calcification was the only pathologic finding. The severe changes were seen in children of all age groups, but predominantly-in children with a short duration of their disease, severe symptoms, and frequent marrow relapse. Changes induced by steroid therapy may be reversible. No satisfactory explanation of the demonstrated cerebral pathologic findings can be given, except that they are the consequences of the combination of total therapy and severity of disease in the individual patient. Measurement of attenuation coefficients in grey and white matter shows increasing values with age during childhood. A combination of decreasing attenuation coefficients, especially in the white matter, and the finding of severe atrophy seems to be a bad prognostic sign. (orig.)

  11. Serum Creatinine Versus Plasma Methotrexate Levels to Predict Toxicities in Children Receiving High-dose Methotrexate.

    Science.gov (United States)

    Tiwari, Priya; Thomas, M K; Pathania, Subha; Dhawan, Deepa; Gupta, Y K; Vishnubhatla, Sreenivas; Bakhshi, Sameer

    2015-01-01

    Facilities for measuring methotrexate (MTX) levels are not available everywhere, potentially limiting administration of high-dose methotrexate (HDMTX). We hypothesized that serum creatinine alteration after HDMTX administration predicts MTX clearance. Overall, 122 cycles in 50 patients of non-Hodgkin lymphoma or acute lymphoblastic leukemia aged ≤18 years receiving HDMTX were enrolled prospectively. Plasma MTX levels were measured at 12, 24, 36, 48, 60, and 72 hours; serum creatinine was measured at baseline, 24, 48, and 72 hours. Correlation of plasma MTX levels with creatinine levels and changes in creatinine from baseline (Δ creatinine) were evaluated. Plasma MTX levels at 72 hours showed positive correlation with serum creatinine at 48 hours (P = .011) and 72 hours (P = .013) as also Δ creatinine at 48 hours (P = .042) and 72 hours (P = .045). However, cut-off value of either creatinine or Δ creatinine could not be established to reliably predict delayed MTX clearance. Greater than 50% Δ creatinine at 48 and 72 hours significantly predicted grade 3/4 leucopenia (P = .036 and P = .001, respectively) and thrombocytopenia (P = .012 and P = .009, respectively) but not mucositis (P = .827 and P = .910, respectively). Delayed MTX elimination did not predict any grade 3/4 toxicity. In spite of demonstration of significant correlation between serum creatinine and Δ creatinine with plasma MTX levels at 72 hours, cut-off value of either variable to predict MTX delay could not be established. Thus, either of these cannot be used as a surrogate for plasma MTX estimation. Interestingly, Δ creatinine effectively predicted hematological toxicities, which were not predicted by delayed MTX clearance.

  12. Extracorporeal photochemotherapy and methotrexate in the treatment of atypical oral lichen planus

    Directory of Open Access Journals (Sweden)

    A. V. Molochkov

    2017-01-01

    Full Text Available Background: Some authors have successfully used methotrexate in the treatment of atypical oral lichen planus (LP and noted its good tolerability. High clinical efficacy of the extracorporeal photochemotherapy (ECP has been also reported in the treatment of such patients. However, there is no information on the long-term results of methotrexate and ECP and their combination in the treatment of atypical LP. Aim: To study clinical efficacy and long-term results of the combination of routine therapy with the ECP course and a single injection of methotrexate at a dose of 10 mg in patients with atypical LP of the oral cavity and the skin. Materials and methods: This was a prospective study with an active control. Eighteen (18 patients with various forms of atypical LP of the oral cavity (hypertrophic, erosive/ulcerative, exudative/hyperemic forms and the skin (hypertrophic, pigmented, atrophic, follicular forms were administered the combination of routine therapy (chloroquine, doxycycline, vitamin B6, topical corticosteroids, an ECP course, and a single injection of methotrexate at a dose of 10 mg. Two hours before the ECP session all patients were given 8-methoxypsoralen. Peripheral mononuclear cells were isolated with a cell separator and treated with ultraviolet radiation (λ = 320–400 nm, then the monocyte cell mass was re-infused to the patient. The treatment course included 4 sessions performed every other day. A single injection of methotrexate was given in the middle of the ECP course. Clinical efficacy was assessed with the Thongprasom scale of activity of the disease and by visual analog scale (VAS for pain assessment in patients with oral lesions. Results: The treatment was well tolerated and was not associated with methotrexate-related immune abnormalities. At one month after the 4th ECP session, the mean Thongprasom score was decreased from 5 to 2.2 ± 1.2 (p < 0.001. At Week 24 after the treatment, 15 (83.2% of

  13. A randomised controlled trial of the clinical effectiveness, safety and cost-effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis (SYCAMORE Trial).

    Science.gov (United States)

    Ramanan, Athimalaipet V; Dick, Andrew D; Benton, Diana; Compeyrot-Lacassagne, Sandrine; Dawoud, Dalia; Hardwick, Ben; Hickey, Helen; Hughes, Dyfrig; Jones, Ashley; Woo, Patricia; Edelsten, Clive; Beresford, Michael W

    2014-01-09

    Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA are at risk of inflammation of the uvea in the eye (uveitis). Overall, 20% to 25% of paediatric uveitis is associated with JIA. Major risk factors for development of uveitis in JIA are oligoarticular pattern of arthritis, an age at onset of arthritis of less than seven years of age, and antinuclear antibody positivity. In the initial stages of mild to moderate inflammation the uveitis is asymptomatic. This has led to current practice of screening all children with JIA for uveitis. Approximately 12% to 38% of patients with JIA develop uveitis in seven years following onset of arthritis. In 30% to 50% of children with JIA-associated uveitis structural complications are present at diagnosis. Furthermore about 50% to 75% of those with severe uveitis will eventually develop visual impairment secondary to ocular complications such as cataract and glaucoma. Defining the severity of inflammation and structural complications in uveitis patients is now possible following Standardised Uveitis Nomenclature (SUN) guidelines, and modified to incorporate the consensus of end point and outcome criteria into the design of randomised trials. Despite current screening and therapeutic options (pre-biologics) 10% to 15% of children with JIA-associated uveitis may develop bilateral visual impairment and certified legally blind. To date, there remains no controlled trial evidence of benefits of biologic therapy. This study will randomise 154 patients aged 2 to 18 years with active JIA-associated uveitis (despite methotrexate (MTX) treatment for at least 12 weeks). All participants will be treated for 18 months, with follow up of 3 years from randomisation (continuing on MTX throughout). All participants will receive a stable dose of MTX and in addition either adalimumab (20 mg/0.8 ml for patientstreatment of juvenile idiopathic arthritis associated uveitis. ISRCTN10065623.

  14. Topical methotrexate pretreatment enhances the therapeutic effect of topical 5-aminolevulinic acid-mediated photodynamic therapy on hamster buccal pouch precancers.

    Science.gov (United States)

    Yang, Deng-Fu; Lee, Jeng-Woei; Chen, Hsin-Ming; Hsu, Yih-Chih

    2014-09-01

    Topical 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is effective for treatment of human oral precancerous lesions. This animal study aimed to assess whether topical methotrexate (MTX) pretreatment could enhance the therapeutic effect of topical ALA-PDT on hamster buccal pouch precancerous lesions. Twenty hamster buccal pouch precancerous lesions were treated with either topical ALA-PDT with topical MTX pretreatment (topical MTX-ALA-PDT group, n = 10) or topical ALA-PDT alone (topical ALA-PDT group, n = 10). The intracellular protoporphyrin IX (PpIX) level in another 12 precancerous lesions (n = 6 for either the topical MTX-ALA or topical ALA group) was monitored by fluorescence spectroscopy. The intracellular PpIX reached its peak level in precancerous lesions 6.5 hours and 2.5 hours after topical ALA application for the topical MTX-ALA group (5.63-fold higher in the lesion than in the normal mucosa) and topical ALA group (2.42-fold higher in the lesion than in the normal mucosa), respectively. The complete response rate of precancerous lesions was 80% for the topical MTX-ALA-PDT group and 70% for the topical ALA-PDT group. In addition, the topical MTX-ALA-PDT group required a significantly lower mean treatment number (2.1 ± 0.6) to achieve complete response than the topical ALA-PDT group (4.4 ± 1.3, p topical MTX-ALA-PDT group had a lower recurrence rate (12.5%) than the topical ALA-PDT group (28.6%). We conclude that topical MTX-pretreatment can increase intracellular PpIX production in hamster buccal pouch precancerous lesions and significantly improves the outcomes of the precancerous lesions treated with topical ALA-PDT. Copyright © 2014. Published by Elsevier B.V.

  15. Carvacrol and Pomegranate Extract in Treating Methotrexate-Induced Lung Oxidative Injury in Rats

    Science.gov (United States)

    Şen, Hadice Selimoğlu; Şen, Velat; Bozkurt, Mehtap; Türkçü, Gül; Güzel, Abdulmenap; Sezgi, Cengizhan; Abakay, Özlem; Kaplan, Ibrahim

    2014-01-01

    Background This study was designed to evaluate the effects of carvacrol (CRV) and pomegranate extract (PE) on methotrexate (MTX)-induced lung injury in rats. Material/Methods A total of 32 male rats were subdivided into 4 groups: control (group I), MTX treated (group II), MTX+CRV treated (group III), and MTX+PE treated (group IV). A single dose of 73 mg/kg CRV was administered intraperitoneally to rats in group III on Day 1 of the investigation. To group IV, a dose of 225 mg/kg of PE was administered via orogastric gavage once daily over 7 days. A single dose of 20 mg/kg of MTX was given intraperitoneally to groups II, III, and IV on Day 2. The total duration of experiment was 8 days. Malondialdehyde (MDA), total oxidant status (TOS), total antioxidant capacity (TAC), and oxidative stress index (OSI) were measured from rat lung tissues and cardiac blood samples. Results Serum and lung specimen analyses demonstrated that MDA, TOS, and OSI levels were significantly greater in group II relative to controls. Conversely, the TAC level was significantly reduced in group II when compared to the control group. Pre-administering either CRV or PE was associated with decreased MDA, TOS, and OSI levels and increased TAC levels compared to rats treated with MTX alone. Histopathological examination revealed that lung injury was less severe in group III and IV relative to group II. Conclusions MTX treatment results in rat lung oxidative damage that is partially counteracted by pretreatment with either CRV or PE. PMID:25326861

  16. Virgin coconut oil supplementation attenuates acute chemotherapy hepatotoxicity induced by anticancer drug methotrexate via inhibition of oxidative stress in rats.

    Science.gov (United States)

    Famurewa, Ademola C; Ufebe, Odomero G; Egedigwe, Chima A; Nwankwo, Onyebuchi E; Obaje, Godwin S

    2017-03-01

    The emerging health benefit of virgin coconut oil (VCO) has been associated with its potent natural antioxidants; however, the antioxidant and hepatoprotective effect of VCO against methotrexate-induced liver damage and oxidative stress remains unexplored. The study explored the antioxidant and hepatoprotective effects of VCO against oxidative stress and liver damage induced by anticancer drug methotrexate (MTX) in rats. Liver damage was induced in Wistar rats pretreated with dietary supplementation of VCO (5% and 15%) by intraperitoneal administration of MTX (20mg/kg bw) on day 10 only. After 12days of treatment, assays for serum liver biomarkers (aminotransferases), alkaline phosphatase, albumin and total protein as well as hepatic content of malondialdehyde, reduced glutathione and antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) were carried out. Liver was used to examine histopathological changes. MTX administration induced significant increase in serum liver enzymes along with marked decrease in albumin and total protein compared to control group. Hepatic activities of antioxidant enzymes were significantly decreased, while malondialdehyde increased significantly. Treatment with VCO supplemented diet prior to MTX administration attenuated MTX-induced liver injury and oxidative stress evidenced by significant improvements in serum liver markers, hepatic antioxidant enzymes and malondialdehyde comparable to control group. Histopathological alterations were prevented and correlated well with the biochemical indices. The study suggests antioxidant and hepatoprotective effects of VCO supplementation against hepatotoxicity and oxidative damage via improving antioxidant defense system in rats. Our findings may have beneficial application in the management of hepatotoxicity associated with MTX cancer chemotherapy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  17. Anti-TNFα agents and methotrexate in spondyloarthritis related uveitis in a Chinese population.

    Science.gov (United States)

    Lian, Fan; Zhou, Jun; Wei, Cui; Wang, Yu; Xu, Hanshi; Liang, Liuqin; Yang, Xiuyan

    2015-11-01

    This study seeks to evaluate the clinical characteristics of spondyloarthritis (SpA)-related uveitis in a cohort from South China and to assess the efficacy and safety of therapies based on TNF blockers. SpA patients with uveitis admitted to a south China hospital were enrolled. Demographic information, clinical characteristics, laboratory findings, intraocular inflammation, visual acuity, macular thickness, and treatments were documented. Of the 1,036 SpA patients reviewed, 182 had uveitis. Ankylosing spondylitis (AS) was the most common subtype. Unilateral uveitis was found in 51 cases (51/182, 28.0%), and unilateral alternating uveitis was found in 75 cases (75/182, 41.2%). Half of the cases were recurrent uveitis (52.2%), and acute onset was common (76.4%). The most serious complication was vision loss (0.5%). No significant difference in disease activity was found between the SpA patients with or without uveitis. Predominant improvements were found in cases treated with all three anti-TNFs (infliximab, adalimumab, and etanercept) and anti-TNFs plus methotrexate (MTX). Monotherapy of methotrexate was not adequate for inducing remission. Monotherapy of etanercept was not as effective as adalimumab and infliximab, mainly in the prevention of recurrence. No significant difference in effectiveness was found among the three anti-TNFs if MTX was added. Etanercept plus MTX were well tolerated. Infliximab and adalimumab were associated with more tuberculosis and/or hepatitis flares. Uveitis is common in SpA patients. Severe complications may develop in prolonged and intractable cases. Treatments based on anti-TNFs had good clinical response, and better safety documentation were observed in etanercept plus MTX compared to the other two anti-TNF monoclonal antibodies plus MTX.

  18. Ameliorative Effects of Hydroalcoholic Extract of Lavandula officinalis L. on Methotrexate-Induced Oxidative Stress in Rats

    Directory of Open Access Journals (Sweden)

    Mojtaba Kalantar, Saeed Shirali, Amin Hasanvand , Masoud Valizadeh , Ramin Tavakoli , Marzieh Asadi , Mehdi Goudarzi

    2017-03-01

    Full Text Available Background: Methotrexate as a chemotherapy drug can causes chronic liver damage and oxidative stress. The aim of this study was to evaluate the protective effect of hydroalcoholic extract of Lavandula officinalis on methotrexate-induced oxidative stress in rats. Methods: In this experimental study, thirty five Wistar male rats weighting 200-250 g were randomly divided into 5 groups (n = 7 in each group. Negative control group (normal saline 5ml/kg; positive control group received normal salin orally for 10 days, and a single dose of methotrexate (MTX, 20mg/kg, i.p. was administrated on the 9th day. Groups 3-5 received respectively 100, 200 and 400 mg/kg of Lavandula officinalis extract (LOE orally for 10 days, and a single dose of MTX was injected on the 9th day. 24 h after the last injection, animals were sacrificed. Blood samples were collected to determine serum AST, ALT and ALP levels. Malondialdehyde (MDA, glutathione (GSH levels and catalase (CAT, superoxide dismutase (SOD and glutathione peroxidase (GPx activity were assayed in liver tissue. A portion of liver was maintained in 10% formalin for Hematoxylin and Eosin (H&E staining and histological examination. Results: The result obtained from current study was showed a significant increase in the levels of AST, ALT, ALP, MDA and decrease of GSH, CAT and SOD by MTX administration. Pre-treatment with LOE showed reduction in the levels of AST, ALT, ALP, MDA and increase of GSH, CAT and SOD in all doses but the most significant alteration was observed in doses of 200 and 400 mg/kg (P<0.05. Histological results showed that methotrexate could lead to liver damage. Also the hepatoprotective effect of the LOE was confirmed by the histological examination of the liver. Conclusion: Our results indicate that hydroalcoholic extract of Lavandula officinalis have produced amelioration in biochemical and oxidative stress parameters against MTX -induced oxidative stress.

  19. Adherence to methotrexate in rheumatoid arthritis

    DEFF Research Database (Denmark)

    Bliddal, Henning; Eriksen, Stine A; Christensen, Robin

    2015-01-01

    Objectives. To study adherence to methotrexate (MTX) and factors of importance thereof in patients with rheumatoid arthritis (RA). Methods. Patients with a hospital diagnosis of RA (ICD10 codes M05.X or M06.X) after January 1, 1997, and aged ≥18 years at the date of first diagnosis...

  20. A long-term follow-up study of methotrexate in juvenile localized scleroderma (morphea).

    Science.gov (United States)

    Zulian, Francesco; Vallongo, Cristina; Patrizi, Annalisa; Belloni-Fortina, Anna; Cutrone, Mario; Alessio, Maria; Martino, Silvana; Gerloni, Valeria; Vittadello, Fabio; Martini, Giorgia

    2012-12-01

    Recent studies report that methotrexate (MTX) is beneficial in the treatment of juvenile localized scleroderma (JLS) but little is known about its long-term effectiveness. We assessed the therapeutic role of MTX in children with JLS who were followed up for a prolonged period. A cohort of patients with JLS, previously enrolled in a double-blind, randomized controlled trial and treated with oral MTX (15 mg/m(2)/wk) and prednisone (1 mg/kg/d, maximum 50 mg) for the first 3 months, were prospectively followed up. Lesions were evaluated clinically, with infrared thermography, and by a computerized skin score. Response to treatment was defined as: (1) no new lesions; (2) skin score rate less than 1; and (3) decrease in lesion temperature by at least 10% compared with baseline. Clinical remission (CR) on medication was defined when response was maintained, on treatment, for at least 6 months, and complete CR when response was maintained, without treatment, for at least 6 months. Of 65 patients treated with MTX, 48 (73.8%) were responders, 10 (15.4%) relapsed by 24 months since MTX start, and 7 (10.8%) were lost to follow-up. Among the responders, 35 (72.9%) maintained CR for a mean of 25 months and 13 (27.1%) were in CR on medication. Adverse effects seen in 28 patients (48.3%) were generally mild and never required treatment discontinuation. The use of objective measures not widely available, such as infrared thermography and computerized skin score, makes it difficult to compare data from previous studies. Long-term MTX therapy is beneficial and well tolerated for JLS. Copyright © 2012 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  1. Effect of certolizumab pegol with methotrexate on home and work place productivity and social activities in patients with active rheumatoid arthritis.

    Science.gov (United States)

    Kavanaugh, Arthur; Smolen, Josef S; Emery, Paul; Purcaru, Oana; Keystone, Edward; Richard, Lance; Strand, Vibeke; van Vollenhoven, Ronald F

    2009-11-15

    To assess the impact of certolizumab pegol (CZP), a novel PEGylated anti-tumor necrosis factor, in combination with methotrexate (MTX) on productivity outside and within the home, and on participation in family, social, and leisure activities in adult patients with rheumatoid arthritis (RA). The efficacy and safety of CZP (200 mg and 400 mg) plus MTX were assessed in 2 phase III, multicenter, double-blind, placebo-controlled trials (Rheumatoid Arthritis Prevention of Structural Damage [RAPID] 1 and RAPID 2). The novel, validated, RA-specific Work Productivity Survey (WPS-RA) was used to assess work place and home productivity. WPS-RA responses were collected at baseline and every 4 weeks until withdrawal/study completion. At baseline, 41.6% and 39.8% of subjects were employed outside the home in RAPID 1 and RAPID 2, respectively. Compared with placebo plus MTX, CZP plus MTX significantly reduced work absenteeism and presenteeism among patients working outside the home. Significant reductions in number of household days lost, household days with productivity reduced by >/=50%, and days lost due to RA for participation in family, social, and leisure activities were reported by patients in active treatment relative to placebo plus MTX. Improvements in all measures were observed with CZP plus MTX as early as week 4, and maintained until the study end (12 months in RAPID 1, 6 months in RAPID 2). Findings were consistent with clinical improvements with CZP plus MTX in both trials. CZP plus MTX improved productivity outside and within the home and resulted in more participation in social activities compared with placebo plus MTX. These observations suggest that considerable indirect cost gains might be achieved with this therapeutic agent in RA.

  2. St. John's wort significantly increased the systemic exposure and toxicity of methotrexate in rats

    International Nuclear Information System (INIS)

    Yang, Shih-Ying; Juang, Shin-Hun; Tsai, Shang-Yuan; Chao, Pei-Dawn Lee; Hou, Yu-Chi

    2012-01-01

    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 0−t and C max of MTX by 163% and 60%, respectively, and 150 mg/kg of SJW significantly increased the AUC 0−t of MTX by 55%. In addition, diclofenac enhanced the C 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 0−t and C 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.

  3. Assessment by MRI of inflammation and damage in rheumatoid arthritis patients with methotrexate inadequate response receiving golimumab: results of the GO-FORWARD trial

    DEFF Research Database (Denmark)

    Conaghan, Philip G; Emery, Paul; Østergaard, Mikkel

    2011-01-01

    To evaluate golimumab's effect on MRI-detected inflammation and structural damage in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX).......To evaluate golimumab's effect on MRI-detected inflammation and structural damage in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX)....

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

    Science.gov (United States)

    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.

  5. Combination of Mangifera indica L. extract supplementation plus methotrexate in rheumatoid arthritis patients: a pilot study.

    Science.gov (United States)

    López Mantecón, Ana M; Garrido, Gabino; Delgado-Hernández, René; Garrido-Suárez, Bárbara B

    2014-08-01

    The purpose of the present study was to evaluate the possible therapeutic effects and the safety of Mangifera indica extract (Vimang tablets, 300 mg) combined with methotrexate (MTX) on reducing disease activity in rheumatoid arthritis (RA). Twenty patients with active RA underwent a year of treatment with MTX (12.5 mg/week) associated to non-steroidal anti-inflammatory drugs (NSAIDs) and/or prednisone (5-10 mg/day) were randomly allocated to the experimental group (n=10), that received the extract supplementation (900 mg/day) or preceding usual treatment (n=10) during 180 days. RA activity was evaluated using the tender and swollen joint counts, erythrocyte sedimentation rate, disease activity score-28 (DAS 28), visual analogue scale (VAS) and health assessment questionnaire (HAQ). Treatment's efficacy was demonstrated with ACR criteria. Only the patients of MTX-Vimang group revealed statistically significant improvement in DAS 28 parameters with respect baseline data but no differences were observed between groups. ACR improvements amounted 80% only in MTX-Vimang group at the 90 days (pVimang group, 100% of patients decreased NSAIDs administration (p<0.01) and 70% of those eradicated gastrointestinal side effects (p<0.01) ensuing of the preceding treatment. Other adverse effects were not reported. Copyright © 2013 John Wiley & Sons, Ltd.

  6. Methotrexate Toxicity in Growing Long Bones of Young Rats: A Model for Studying Cancer Chemotherapy-Induced Bone Growth Defects in Children

    Directory of Open Access Journals (Sweden)

    Chiaming Fan

    2011-01-01

    Full Text Available The advancement and intensive use of chemotherapy in treating childhood cancers has led to a growing population of young cancer survivors who face increased bone health risks. However, the underlying mechanisms for chemotherapy-induced skeletal defects remain largely unclear. Methotrexate (MTX, the most commonly used antimetabolite in paediatric cancer treatment, is known to cause bone growth defects in children undergoing chemotherapy. Animal studies not only have confirmed the clinical observations but also have increased our understanding of the mechanisms underlying chemotherapy-induced skeletal damage. These models revealed that high-dose MTX can cause growth plate dysfunction, damage osteoprogenitor cells, suppress bone formation, and increase bone resorption and marrow adipogenesis, resulting in overall bone loss. While recent rat studies have shown that antidote folinic acid can reduce MTX damage in the growth plate and bone, future studies should investigate potential adjuvant treatments to reduce chemotherapy-induced skeletal toxicities.

  7. TARGETED INFORMATION ON METHOTREXATE AND LIFTING ALCOHOL RESTRICTIONS IN PATIENTS WITH RA AND PSA IS SAFE AND REDUCES PATIENTS' NEGATIVE BELIEFS

    DEFF Research Database (Denmark)

    Larsen, Janni Lisander; Nordin, Henrik

    Background Research regarding potential interaction between use of Methotrexate (MTX) and alcohol consumption is sparse (1-2, 5). Nevertheless patients traditionally are advised against alcohol intake while on MTX for safety reasons. Furthermore MTX generally is perceived by doctors and patients ...

  8. Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions

    NARCIS (Netherlands)

    Breedveld, Pauline; Zelcer, Noam; Pluim, Dick; Sönmezer, Ozgür; Tibben, Matthijs M.; Beijnen, Jos H.; Schinkel, Alfred H.; van Tellingen, Olaf; Borst, Piet; Schellens, Jan H. M.

    2004-01-01

    The antifolate drug methotrexate (MTX) is transported by breast cancer resistance protein (BCRP; ABCG2) and multidrug resistance-associated protein1-4 (MRP1-4; ABCC1-4). In cancer patients, coadministration of benzimidazoles and MTX can result in profound MTX-induced toxicity coinciding with an

  9. Diagnostics data management on MTX

    International Nuclear Information System (INIS)

    Butner, D.N.; Brown, M.D.; Casper, T.A.; Meyer, W.H.; Moller

    1992-01-01

    This paper reports on the Microwave Tokamak Experiment (MTX), a magnetic fusion energy research experiment to explore electron cyclotron heating using a free electron laser operating in the microwave range. The diagnostic data from MTX is acquired and processed by a distributed, multivendor, computer network. Each shot of the experiment produces data files containing up to 15 megabytes of data. Typically half-second shots are taken every 5 minutes with 50 to 60 shots taken on a single day. As many as 80 full data short have been taken on a good day. Data files are created on Hewlett-Packard (HP) computers running Unix, HP computers running BASIC, and a Digital Equipment Corporation (DEC) VAXcluster running VMS. A small portion of the data acquired on the HP systems is immediately stored in a data system on the VAXcluster, but most data is held and processed on the computer on which it was acquired. A commercial database program running on the VAXcluster maintains a history of the data files created for each shot

  10. Estrogen-Related Receptor Alpha Confers Methotrexate Resistance via Attenuation of Reactive Oxygen Species Production and P53 Mediated Apoptosis in Osteosarcoma Cells

    Directory of Open Access Journals (Sweden)

    Peng Chen

    2014-01-01

    Full Text Available Osteosarcoma (OS is a malignant tumor mainly occurring in children and adolescents. Methotrexate (MTX, a chemotherapy agent, is widely used in treating OS. However, treatment failures are common due to acquired chemoresistance, for which the underlying molecular mechanisms are still unclear. In this study, we report that overexpression of estrogen-related receptor alpha (ERRα, an orphan nuclear receptor, promoted cell survival and blocked MTX-induced cell death in U2OS cells. We showed that MTX induced ROS production in MTX-sensitive U2OS cells while ERRα effectively blocked the ROS production and ROS associated cell apoptosis. Our further studies demonstrated that ERRα suppressed ROS induction of tumor suppressor P53 and its target genes NOXA and XAF1 which are mediators of P53-dependent apoptosis. In conclusion, this study demonstrated that ERRα plays an important role in the development of MTX resistance through blocking MTX-induced ROS production and attenuating the activation of p53 mediated apoptosis signaling pathway, and points to ERRα as a novel target for improving osteosarcoma therapy.

  11. Portuguese recommendations for the use of methotrexate in rheumatic diseases - 2016 update.

    Science.gov (United States)

    Duarte, Ana Catarina; Santos-Faria, Daniela; Gonçalves, Maria João; Sepriano, Alexandre; Mourão, Ana Filipa; Duarte, Cátia; Neves, Joana Sousa; Águeda, Ana Filipa; Ribeiro, Pedro Avila; Daniel, Alexandra; Neto, Adriano; Cordeiro, Ana; Rodrigues, Ana; Barcelos, Anabela; Silva, Cândida; Ponte, Cristina; Vieira-Sousa, Elsa; Teixeira, Filipa; Oliveira-Ramos, Filipa; Araújo, Filipe; Barcelos, Filipe; Canhão, Helena; Santos, Helena; Ramos, João; Polido-Pereira, Joaquim; Tavares-Costa, José; Melo Gomes, José António; Cunha-Miranda, Luís; Costa, Lúcia; Cerqueira, Marcos; Cruz, Margarida; Santos, Maria José; Bernardes, Miguel; Oliveira, Paula; Abreu, Pedro; Figueira, Ricardo; Barros, Rita; Falcão, Sandra; Pinto, Patrícia; Pimenta, Sofia; Capela, Susana; Teixeira, Vitor; Fonseca, João Eurico

    2017-01-01

    Methotrexate (MTX) is the first-line drug in the treatment of rheumatoid arthritis (RA) and the most commonly prescribed disease modifying anti-rheumatic drug. Moreover, it is also used as an adjuvant drug in patients under biologic therapies, enhancing the efficacy of biologic agents. To review the literature and update the Portuguese recommendations for the use of MTX in rheumatic diseases first published in 2009. The first Portuguese guidelines for the use of MTX in rheumatic diseases were published in 2009 and were integrated in the multinational 3E Initiative (Evidence Expertise Exchange) project. The Portuguese rheumatologists based on literature evidence and consensus opinion formulated 13 recommendations. At a national meeting, the recommendations included in this document were further discussed and updated. The document resulting from this meeting circulated to all Portuguese rheumatologists, who anonymously voted online on the level of agreement with the updated recommendations. Results presented in this article are mainly in accordance with previous guidelines, with some new information regarding hepatitis B infection during MTX treatment, pulmonary toxicity monitoring, hepatotoxicity management, association with hematologic neoplasms, combination therapy and tuberculosis screening during treatment. The present recommendations combine scientific evidence with expert opinion and attained desirable agreement among Portuguese rheumatologists. The regular update of these recommendations is essential in order to keep them a valid and useful tool in daily practice.

  12. Pancytopenia after low dose methotrexate therapy in a hemodialysis patient: case report and review of literature.

    Science.gov (United States)

    Yang, Ching-Ping; Kuo, Mei-Chuan; Guh, Jinn-Yuh; Chen, Hung-Chun

    2006-01-01

    Methotrexate (MTX) is widely used in the treatment of rheumatoid arthritis (RA) with a side effect of pancytopenia. However, only a few cases of severe pancytopenia caused by low-dose MTX therapy have been reported, and the condition is rarely reported in uremic patients on dialysis therapy. We thereby report a hemodialysis patient who developed severe pancytopenia after oral treatment with low-dose MTX for RA. A 55-year-old woman who had been on regular hemodialysis treatment for 7 yr suffered from RA for 10 yr. She was regularly treated with celecoxib, prednisolone, and sulfasalazine in the past year. Because of the increasing arthralgia, 7.5 mg per week MTX was prescribed 3 months before admission. Stomatitis, fever, general fatigue, multiple skin carbuncles, and easy bruising developed after a cumulative dose of 90 mg. Pancytopenia was found at admission and the nadir of white blood cell count was 250/microL with 28% neutrophils, hematocrit was 22%, and platelet count was 6000/microL. Eosinophil counts increased from 11.5% initially to 26.1% on the sixth admission day. Transfusion with red blood cells and platelets, and appropriate antibiotics and folic acid were prescribed. She continued receiving regular hemodialysis and eventually recovered within 3 weeks.

  13. Uncommon toxicity of low-dose methotrexate: case report

    Directory of Open Access Journals (Sweden)

    Zohreh Yousefi

    2015-10-01

    Full Text Available Background: Standard treatment of Gestational Trophoblastic Disease (GTD is chemotherapy. Single-agent chemotherapy regime including Methotrexate (MTX or Actinomycin. Single-agent is widely used in treatment of persistent trophoblastic disease. We reported an uncommon toxicity of low-dose single-agent methotrexate in a patient. Case Presentation: A 20-year-old woman, primary gravid after two months missed period and spotting with diagnosis of incomplete abortion with uterine size equivalent of ten weeks pregnancy (8-10 cm underwent evacuation curettage. In serial follow-up, based on rise of beta-hCG titer and absence of metastatic disease, it was categorized as low-risk persistent trophoblastic disease. She was referred to gynecology oncology center of Ghaem Hospital, Mashhad University of Medical Sciences in May 2014. Because of rise of beta-hCG titer, after complete metastatic work-up and lack of disease in other sites, persistent disease was diagnosed and candidate for chemotherapy (single agent low-dose. The patient received first course of therapy with MTX (50 mg/m², intra muscular. Unfortunately, after two days of treatment she developed uncommon severe toxicity, fever, severe nausea and vomiting, tachycardia, and generalized weakness. Also, we found hematologic abnormality (WBC: -14000-15000 µI, platelet- 540 µI and sever neutropenia, and abnormal rising in liver function test (SGOT, SGPT (three to four times and renal function test (BUN and Creatinine (two times. In addition, she had disseminated erosive lesion in all of body especially in face. Due to the fatal side effects of chemotherapy, she was admitted to intensive care unit (ICU. Fortunately, after two to three weeks, she was improved by conservative management. After few weeks beta-hCG titer was in normal limit. However she had normal serial beta-hCG in one year of follow-up. Conclusion: It is important to emphasis unpredictable side effects of chemotherapy with low

  14. Value of ultrasonography as a marker of early response to abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate

    DEFF Research Database (Denmark)

    D'Agostino, Maria-Antonietta; Wakefield, Richard J; Berner-Hammer, Hilde

    2016-01-01

    OBJECTIVES: To study the responsiveness of a combined power Doppler and greyscale ultrasound (PDUS) score for assessing synovitis in biologic-naïve patients with rheumatoid arthritis (RA) starting abatacept plus methotrexate (MTX). METHODS: In this open-label, multicentre, single-arm study......, patients with RA (MTX inadequate responders) received intravenous abatacept (∼10 mg/kg) plus MTX for 24 weeks. A composite PDUS synovitis score, developed by the Outcome Measures in Rheumatology-European League Against Rheumatism (OMERACT-EULAR)-Ultrasound Task Force, was used to evaluate individual joints......-week treatment period. The earliest PDUS sign of improvement in synovitis was at week 1 (mean change in GLOESS (MCPs 2-5): -0.7 (95% CIs -1.2 to -0.1)), with continuous improvement to week 24. Early improvement was observed in the component scores (power Doppler signal at week 1, synovial hyperplasia...

  15. Combined Systemic and Hysteroscopic Intra-Amniotic Injection of Methotrexate Associated with Hysteroscopic Resection for Cervical Pregnancy: A Cutting-Edge Approach for an Uncommon Condition.

    Science.gov (United States)

    Di Spiezio Sardo, Attilio; Vieira, Mariana da Cunha; Laganà, Antonio Simone; Chiofalo, Benito; Vitale, Salvatore Giovanni; Scala, Mariamaddalena; De Falco, Marianna; Nappi, Carmine; Catena, Ursula; Bifulco, Giuseppe

    2017-02-01

    This case report of a 36-year-old woman with a diagnosis of cervical pregnancy describes a novel approach to this rare form of ectopic pregnancy, which was successfully treated with systemic and local methotrexate (MTX) therapy combined with hysteroscopic resection. After local and systemic administration of MTX, the patient underwent hysteroscopic resection of the cervical pregnancy using a 27 bipolar resectoscope with a 4-mm loop. The cervical pregnancy was completely treated, and satisfactory hemostasis was achieved with electrocoagulation. The reported case and literature review demonstrate that the combination of systemic and local (hysteroscopic) administration of MTX with hysteroscopic resection could offer the possibility of a safe, successful, minimally invasive, and fertility-sparing surgical treatment for cervical pregnancy.

  16. Methotrexate diethyl ester-loaded lipid-core nanocapsules in aqueous solution increased antineoplastic effects in resistant breast cancer cell line

    Directory of Open Access Journals (Sweden)

    Yurgel VC

    2014-03-01

    Full Text Available Virginia C Yurgel,1,* Catiuscia P Oliveira,2,* Karine R Begnini,1 Eduarda Schultze,1 Helena S Thurow,1 Priscila MM Leon,1 Odir A Dellagostin,1 Vinicius F Campos,1 Ruy CR Beck,2 Silvia S Guterres,2 Tiago Collares,1 Adriana R Pohlmann,2–4 Fabiana K Seixas11Programa de Pós-Graduação em Biotecnologia (PPGB, Grupo de Pesquisa em Oncologia Celular e Molecular, Laboratório de Genômica Funcional, Biotecnologia/Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil; 2Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; 3Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; 4Centro de Nanociência e Nanotecnologia, CNANO-UFRGS, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil*These authors contributed equally to this workAbstract: Breast cancer is the most frequent cancer affecting women. Methotrexate (MTX is an antimetabolic drug that remains important in the treatment of breast cancer. Its efficacy is compromised by resistance in cancer cells that occurs through a variety of mechanisms. This study evaluated apoptotic cell death and cell cycle arrest induced by an MTX derivative (MTX diethyl ester [MTX(OEt2] and MTX(OEt2-loaded lipid-core nanocapsules in two MTX-resistant breast adenocarcinoma cell lines, MCF-7 and MDA-MB-231. The formulations prepared presented adequate granulometric profile. The treatment responses were evaluated through flow cytometry. Relying on the mechanism of resistance, we observed different responses between cell lines. For MCF-7 cells, MTX(OEt2 solution and MTX(OEt2-loaded lipid-core nanocapsules presented significantly higher apoptotic rates than untreated cells and cells incubated with unloaded lipid-core nanocapsules. For MDA-MB-231

  17. Liposomal Cytarabine Induces Less Neurocognitive Dysfunction Than Intrathecal Methotrexate in an Animal Model

    DEFF Research Database (Denmark)

    Thomsen, Anna M; Gulinello, Maria E; Wen, Jing

    2018-01-01

    Liposomal cytarabine is currently being tested clinically as an alternative to intrathecal (IT) methotrexate (MTX) for preventing relapse within the central nervous system among patients with acute lymphoblastic leukemia. To compare the toxicity and cognitive deficits caused by IT MTX versus lipo...

  18. Bioavailability of higher dose methotrexate comparing oral and subcutaneous administration in patients with rheumatoid arthritis

    NARCIS (Netherlands)

    Hoekstra, Monique; Haagsma, C.; Neef, C; Proost, Johannes H; Knuif, A.; van der Laar, M.

    Objective. To determine the bioavailability of higher oral doses of methotrexate (MTX) in adult patients with rheumatoid arthritis (RA). Methods. A pharmacokinetic analysis was performed in 15 patients with RA taking a stable dose of MTX (greater than or equal to25 mg weekly). Separated by 2 weeks,

  19. Solid lipid nanoparticles by coacervation loaded with a methotrexate prodrug: preliminary study for glioma treatment.

    Science.gov (United States)

    Battaglia, Luigi; Muntoni, Elisabetta; Chirio, Daniela; Peira, Elena; Annovazzi, Laura; Schiffer, Davide; Mellai, Marta; Riganti, Chiara; Salaroglio, Iris Chiara; Lanotte, Michele; Panciani, Pierpaolo; Capucchio, Maria Teresa; Valazza, Alberto; Biasibetti, Elena; Gallarate, Marina

    2017-03-01

    Methotrexate-loaded biocompatible nanoparticles were tested for preliminary efficacy in glioma treatment. Behenic acid nanoparticles, prepared by the coacervation method, were loaded with the ester prodrug didodecylmethotrexate, which was previously tested in vitro against glioblastoma human primary cultures. Nanoparticle conjugation with an ApoE mimicking chimera peptide was performed to obtain active targeting to the brain. Biodistribution studies in healthy rats assessed the superiority of ApoE-conjugated formulation, which was tested on an F98/Fischer glioma model. Differences were observed in tumor growth rate (measured by MRI) between control and treated rats. In vitro tests on F98 cultured cells assessed their susceptibility to treatment, with consequent apoptosis, and allowed us to explain the apoptosis observed in glioma models.

  20. Optimization of methotrexate loaded niosomes by Box-Behnken design: an understanding of solvent effect and formulation variability.

    Science.gov (United States)

    Zidan, Ahmed S; Mokhtar Ibrahim, Mahmoud; Megrab, Nagia A El

    2017-09-01

    Dermal drug delivery system which localizes methotrexate (MTX) in the skin is advantageous in topical treatment of psoriasis. The aim of the current study was to understand dilution effects and formulation variability for the potential formation of niosomes from proniosome gels of MTX. Box-Behnken's design was employed to prepare a series of MTX proniosome gels of Span 40, cholesterol (Chol-X 1 ) and Tween 20 (T20-X 2 ). Short chain alcohols (X 3 ), namely ethanol (Et), propylene glycol (Pg) and glycerol (G) were evaluated for their dilution effects on proniosomes. The responses investigated were niosomal vesicles size (Y 1 ), MTX entrapment efficiency percent (EE%-Y 2 ) and zeta potential (Y 3 ). MTX loaded niosomes were formed immediately upon hydration of the proniosome gels with the employed solvents. Addition of Pg resulted in a decrease of vesicular size from 534 nm to 420 nm as Chol percentage increased from 10% to 30%, respectively. In addition, increasing the hydrophilicity of the employed solvents was enhancing the resultant zeta potential. On the other hand, using Et in proniosomal gels would abolish Chol action to increase the zeta potential value and hence less stable niosomal dispersion was formed. The optimized formula of MTX loaded niosomes showed vesicle size of 480 nm, high EE% (55%) and zeta potential of -25.5 mV, at Chol and T20 concentrations of 30% and 23.6%, respectively, when G was employed as the solvent. Hence, G was the solvent of choice to prepare MTX proniosomal gels with a maintained stability and highest entrapment.

  1. Analysis of association between polymorphisms of MTHFR, MTHFD1 and RFC1 genes and efficacy and toxicity of methotrexate in rheumatoid arthritis patients

    Directory of Open Access Journals (Sweden)

    Vejnovic Dubravka

    2016-01-01

    Full Text Available A folate analogue methotrexate (MTX is the most commonly used disease-modifying drug in the treatment of rheumatoid arthritis. However, the clinical response of RA patients treated with MTX shows interindividual differences and 30% of patients discontinue therapy due to the side effects. In a group of 184 RA patients treated with MTX we have investigated whether polymorphisms in MTHFR (rs1801133, rs1801131, MTHFD1 (rs2236225 and RFC1 (rs144320551 genes may have impact on MTX efficacy and/or adverse drugs 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 and all adverse drug events were recorded. Patients were genotyped for selected polymorphism by PCR-RFLP method. According to the EULAR response criteria after 6 months of MTX therapy 146 (79.3% patients were classified as responders, (17 patients (11.6% were good and 129 patients (88.4% were moderate responders and 38 patients (20.7% as non-responders. ADEs were observed in 53 (28.8% patients. The majority of ADEs were mild (36 (19.56% patients to moderate (12 (6.25% patients. Five patients (2.7% had serious ADEs. Association studies have been conducted between obtained genotypes and the efficacy and toxicity of MTX. We have observed no association between polymorphisms and efficacy or toxicity of MTX in RA patients. [Projekat Ministarstva nauke Republike Srbije, br. 175091

  2. Comparative efficacy and safety of tofacitinib, with or without methotrexate, in patients with active rheumatoid arthritis: a Bayesian network meta-analysis of randomized controlled trials.

    Science.gov (United States)

    Lee, Young Ho; Bae, Sang-Cheol; Song, Gwan Gyu

    2015-12-01

    This study aimed to assess the relative efficacy and safety of tofacitinib 5 and 10 mg twice daily, or in combination with methotrexate (MTX), in patients with active RA. Randomized controlled trials (RCTs) examining the efficacy and safety of tofacitinib in patients with active RA were included in this network meta-analysis. We performed a Bayesian network meta-analysis to combine the direct and indirect evidence from the RCTs. Ten RCTs including 4867 patients met the inclusion criteria. There were 21 pairwise comparisons including 11 direct comparisons of seven interventions. The ACR20 response rate was significantly higher in the tofacitinib 10 mg + MTX group than in the placebo and MTX groups (OR 7.56, 95 % credible interval (CrI) 3.07-21.16; OR 3.67, 95 % CrI 2.60-5.71, respectively). Ranking probabilities based on the surface under the cumulative ranking curve (SUCRA) indicated that tofacitinib 10 mg + MTX had the highest probability of being the best treatment for achieving the ACR20 response rate (SUCRA = 0.9254), followed by tofacitinib 5 mg + MTX (SUCRA = 0.7156), adalimumab 40 mg + MTX (SUCRA = 0.6097), tofacitinib 10 mg (SUCRA = 0.5984), tofacitinib 5 mg (SUCRA = 0.4749), MTX (SUCRA = 0.1674), and placebo (SUCRA = 0.0086). In contrast, the safety based on the number of withdrawals due to adverse events did not differ significantly among the seven interventions. Tofacitinib, at dosages 5 and 10 mg twice daily, in combination with MTX, was the most efficacious intervention for active RA and was not associated with a significant risk for withdrawals due to adverse events.

  3. Uveitis Events During Adalimumab, Etanercept, and Methotrexate Therapy in Juvenile Idiopathic Arthritis: Data From the Biologics in Pediatric Rheumatology Registry.

    Science.gov (United States)

    Foeldvari, Ivan; Becker, Ingrid; Horneff, Gerd

    2015-11-01

    Uveitis is a major extraarticular quality of life-restricting manifestation of juvenile idiopathic arthritis (JIA). The aim of the study is to describe the occurrence of uveitis in JIA patients receiving tumor necrosis factor inhibitors or methotrexate (MTX). Patients' characteristics, treatment, and the reported first occurrence of uveitis as an adverse event were searched in the Biologics in Pediatric Rheumatology Registry. The rates per exposed patients, exposure time, and time until event were calculated. Uveitis was reported as an adverse event in 75 of 3,467 patients; 51 of 2,844 patients were receiving MTX, 37 of 1,700 patients were receiving etanercept, and 13 of 364 patients were receiving adalimumab. Patients with uveitis were younger (mean ± SD age 4.6 ± 4.2 versus 7.4 ± 4.5 years; P uveitis diagnosis before starting treatment more often had a uveitis event (n = 28, 8.4%; OR 8.5, P uveitis event occurred: 11 while taking MTX (3.2 per 1,000 patient-years), 2 while taking etanercept monotherapy (1.9 per 1,000 patient-years), and 3 while taking etanercept and MTX combination (0.9 per 1,000 patient-years). A new uveitis event occurred early in the disease course after a median disease duration of 1.5 years (interquartile range [IQR] 1.3-3.8) while taking etanercept and 1.8 years (IQR 1.8-2.1) for the MTX cohort. A recurrent uveitis event was reported after a disease duration of 7.6 years (IQR 4.3-10.0) in the etanercept cohort and 4.8 years (IQR 1.0-5.8) in the MTX cohort. Univariate analysis showed that MTX, but not etanercept or adalimumab, led to a lower rate of uveitis. Patients with a history of uveitis had higher risks for uveitis events while taking both etanercept and adalimumab. Methotrexate turned out to be protective. Few patients developed a first uveitis event while taking etanercept, while the rate is comparable to that with MTX. Uveitis may not be attributed to be an adverse drug reaction to etanercept. © 2015, American

  4. Age at natural menopause in women on long-term methotrexate therapy for rheumatoid arthritis.

    Science.gov (United States)

    Banas, Tomasz; Hajdyla-Banas, Iwona; Pitynski, Kazimierz; Niewegłowska, Dorota; Juszczyk, Grzegorz; Ludwin, Artur; Knafel, Anna; Ludwin, Inga

    2016-10-01

    The aim of the study was to compare the natural menopause ages of healthy women with those of women with methotrexate (MTX)-treated rheumatoid arthritis (RA), and to specifically assess the effect of disease onset and activity and the use of MTX on the age of the last menstruation. We performed a retrospective review of medical records to identify the ages at which menopause occurred in women with premenopausal RA treated with MTX and in women with postmenopausal onset, irrespective of therapy. Natural menopause ages were also compared between participants with and without RA. Women with premenopausal onset of RA underwent menopause at a significantly younger age than did healthy women (P Menopause also occurred at younger ages in participants with postmenopausal disease onset than in healthy controls (P = 0.012). The study suggested that menopause age was positively correlated with the age at which RA was diagnosed (R = 0.51; P menopause (P = 0.008). The age at which menopause occurs in a patient with RA depends on the patient's age at the time of disease onset and its duration, but is not influenced by MTX treatment.

  5. Diagnostics data management on MTX

    International Nuclear Information System (INIS)

    Butner, D.N.; Brown, M.D.; Casper, T.A.; Meyer, W.H.; Moller, J.M.

    1991-09-01

    The Microwave Tokamak Experiment (MTX) is a magnetic fusion energy research experiment to explore electron cyclotron heating using a free electron laser operating in the microwave range. The diagnostic data from MTX is acquired and processed by a distributed, multivendor, computer network. Each shot of the experiment produces data files containing up to 15 megabytes of data. Typically half-second shots are taken every 5 minutes with 50 to 60 shots taken on a single day. As many as 80 full data shots have been taken on a good day. Data files are created on Hewlett-Packard (HP) computers running Unix, HP computers running BASIC, and a Digital Equipment Corporation (DEC) VAXcluster running VMS. A small portion of the data acquired on the HP systems is immediately stored in a data system on the VAXcluster, but most data is held and processed on the computer on which it was acquired. A commercial database program running on the VAXcluster maintains a history of the data files created for each shot. During the night, data files on all computers are compressed to about one-third their original size and the files on the HP computers are transferred to the VAXcluster. When enough data has accumulated, all data files that have not been previously archived are archived to 8 mm magnetic tape. Once the data is on the VAXcluster, a single defined procedure call may be used to obtain data that was taken on any of the computers in the network. Data that has been archived to tape is maintained on disk for a few days. Users may specify that certain shots be designated ''goodshots,'' whose data files will be maintained on disk for a longer period of time. If a user requests data for a shot that is no longer on disk, retrieval processes on the VAXcluster determine which tapes contain the data, request the computer operator to load the tapes if necessary, and retrieve the files from the tapes. The data is then available for processing by programs running on any computer in the network

  6. Success and spontaneous pregnancy rates following systemic methotrexate versus laparoscopic surgery for tubal pregnancies: A randomized trial

    DEFF Research Database (Denmark)

    Krag Moeller, Lars Bo; Moeller, Charlotte; Thomsen, Sten Grove

    2009-01-01

    . A total of 106 women diagnosed with ectopic pregnancy (EP). Methods. Between March 1997 and September 2000, 1,265 women were diagnosed with EP, 395 (31%) were eligible, 109 (9%) were randomized of whom 106 had an EP. The study was originally powered to a sample size of 422 patients. The women were......Objective. To determine which treatment should be offered to women with a non-ruptured tubal pregnancy: a single dose of methotrexate (MTX) or laparoscopic surgery. Design. Prospective, randomized, open multicenter study. Setting. Seven Danish departments of obstetrics and gynecology. Sample...... (n.s.). Conclusions. In women with an EP, who are hemodynamically stable and wishing to preserve their fertility, medical treatment with single dose MTX tends to be equal to treatment with laparoscopic surgery regarding success rate, complications, and subsequent fertility. Although the two treatment...

  7. The Analysis of Efficacy and Failure Factors of Uterine Artery Methotrexate Infusion and Embolization in Treatment of Cesarean Scar Pregnancy

    Directory of Open Access Journals (Sweden)

    Xiao An

    2013-01-01

    Full Text Available Objectives. This study observes therapeutic efficacy of uterine artery embolization combined with MTX infusion which terminates cesarean scar pregnancy (CSP and induces three factors which probably relate to failure. Methods. Twenty-three CSP patients were treated with combined uterine artery MTX infusion and embolization. Among them six patients with severe hemorrhage were immediately treated with interventional operation. Clinical effects were estimated by symptoms, serum -hCG, ultrasound, and MR. Results. Interventional treatments were technologically successful in 22 patients except one. Immediate hemostasis was achieved in all 6 patients with massive colporrhagia. No occurrence of infection and uterine necrosis was observed, but 12 women suffered abdominal pains. Nineteen patients’ uteri were preserved, whereas four underwent hysterectomy eventually. Conclusions. Transcatheter arterial chemoembolization is effective to treat high-risk CSP in preference to hysterectomy. To achieve more successful outcomes, three factors should be highlighted: adequate MTX dosage, appropriate embolic material, and complete embolization of target arteries that supply blood to embryo in the scar.

  8. Interferon versus methotrexate in intermediate uveitis with macular edema: results of a randomized controlled clinical trial.

    Science.gov (United States)

    Mackensen, Friederike; Jakob, Eva; Springer, Christina; Dobner, Bianca C; Wiehler, Ute; Weimer, Petra; Rohrschneider, Klaus; Fiehn, Christoph; Max, Regina; Storch-Hagenlocher, Brigitte; Becker, Matthias D

    2013-09-01

    To compare interferon (IFN) beta with methotrexate (MTX) in the treatment of intermediate uveitis with macular edema. Monocentric, prospective, randomized, controlled clinical trial. Specialized uveitis center at the University of Heidelberg. PATIENT OR STUDY POPULATION: Patients with either primary intermediate uveitis or uveitis associated with multiple sclerosis. MAIN INCLUSION CRITERIA: Visual acuity of 20/30 or worse (0.2 logarithm of the minimal angle of resolution) and macular edema of more than 250 μm (central 1-mm in optical coherence tomography; Stratus). Randomization into either IFN beta 44 μg subcutaneously 3 times weekly or 20 mg MTX subcutaneously once weekly. At 3 months, the primary outcome parameter of mean change in visual acuity was evaluated and efficacy was determined. Secondary parameters were macular edema by optical coherence tomography, inflammatory activity, and retinal sensitivity by microperimetry (MP-1; Nidek). In case of treatment failure, switching to the other treatment arm was possible. Nineteen patients were included. Ten were randomized to MTX, and 9 were randomized to IFN beta. At 3 months, visual acuity improved a mean 0.31 logarithm of the minimal angle of resolution (range, -0.02 to -0.96, 15.6 letters on the Early Treatment Diabetic Retinopathy Study chart) in the IFN beta group versus a mean 0.09 logarithm of the minimal angle of resolution (range, 0.12 to -0.38, 4.7 letters) in the MTX arm (P = .0435, Mann-Whitney U test). Macular thickness decreased by a mean of 206 μm (range, -41 to -416 μm) in the IFN arm, but increased by 47 μm (range, 108 to -28 μm) in the MTX group (P treatment of macular edema in the setting of intermediate uveitis. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Evidence-based recommendations for treatment with methotrexate in rheumatic disorders

    DEFF Research Database (Denmark)

    Madsen, Ole Rintek; Faurschou, Mikkel; Loft, Anne Gitte

    2010-01-01

    The aim of this study was to develop 3E (Evidence, Expertise, Exchange) recommendations (RCs) on the use of methotrexate in rheumatic disorders and to assess the agreement among Danish rheumatologists.......The aim of this study was to develop 3E (Evidence, Expertise, Exchange) recommendations (RCs) on the use of methotrexate in rheumatic disorders and to assess the agreement among Danish rheumatologists....

  10. Laser-assisted delivery of topical methotrexate - in vitro investigations

    DEFF Research Database (Denmark)

    Taudorf, Elisabeth Hjardem

    2016-01-01

    of the correlation between laser parameters and tissue effects was used to deliver methotrexate (MTX) topically through microscopic ablation zones (MAZs) of precise dimensions. MTX is a well-known chemotherapeutic and anti-inflammatory drug that may cause systemic adverse effects, and topical delivery is thus......Ablative fractional lasers (AFXL) are increasingly used to treat dermatological disorders and to facilitate laser-assisted topical drug delivery. In this thesis, laser-tissue interactions generated by stacked pulses with a miniaturized low-power 2,940 nm AFXL were characterized (study I). Knowledge...... zones of varying thickness. The ratio of skin deposition versus transdermal permeation was constant, regardless of MAZ depth. Impact of transport kinetics on AFXL-assisted topical MTX delivery: MTX accumulated rapidly in AFXL-processed skin. MTX was detectable in mid-dermis after 15 min. and saturated...

  11. Systemic methotrexate to treat ectopic pregnancy does not affect ovarian reserve.

    Science.gov (United States)

    Oriol, Bárbara; Barrio, Ana; Pacheco, Alberto; Serna, José; Zuzuarregui, José Luis; Garcia-Velasco, Juan A

    2008-11-01

    To evaluate whether methotrexate (MTX) compromises ovarian reserve and future reproductive outcome in women undergoing assisted reproductive technology (ART), when it is used as first-line treatment for ectopic pregnancy (EP). Prospective, observational study. University-affiliated private IVF unit. Twenty-five women undergoing IVF-ICSI who were treated with MTX (1 mg/kg IM) for an EP after ART. Evaluation of reproductive outcome and serum anti-Müllerian hormone (AMH) levels. Serum AMH was evaluated before administering MTX and >or=1 week after the resolution of the EP. Reproductive outcome was evaluated by comparing subsequent IVF-ICSI cycles after EP resolution. Serum AMH levels, cycle length, gonadotropin dose required, peak serum E(2) level, oocytes collected, and embryos obtained. Serum AMH levels before MTX were not statistically significantly different from those after treatment (3.7 +/- 0.3 ng/mL vs. 3.9 +/- 0.3 ng/mL). Patients undergoing a subsequent cycle after systemic treatment for EP had similar cycle durations (10.3 vs. 10.8 d), gonadotropin requirements (2,775 vs. 2,630.3 IU), peak E(2) levels (1,884.3 vs. 1,523.6 pg/mL), number of oocytes retrieved (12.1 vs. 10.5), and total number of embryos obtained (7.1 vs. 6.5). Single-dose MTX is a safe first-treatment choice that does not compromise future reproductive outcomes in women who are diagnosed with EP after ART.

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

    Science.gov (United States)

    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 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.

  13. Endogenous inspired biomineral-installed hyaluronan nanoparticles as pH-responsive carrier of methotrexate for rheumatoid arthritis.

    Science.gov (United States)

    Alam, Md Mahmudul; Han, Hwa Seung; Sung, Shijin; Kang, Jin Hee; Sa, Keum Hee; Al Faruque, Hasan; Hong, Jungwan; Nam, Eon Jeong; Kim, In San; Park, Jae Hyung; Kang, Young Mo

    2017-04-28

    Methotrexate (MTX), an anchor drug for rheumatoid arthritis (RA), has been suffered from refractoriness and high toxicity limiting effective dosage. To mitigate these challenges, the ability to selectively deliver MTX to arthritis tissue is a much sought-after modality for the treatment of RA. In this study, we prepared mineralized nanoparticles (MP-HANPs), composed of PEGylated hyaluronic acid (P-HA) as the hydrophilic shell, 5β-cholanic acid as the hydrophobic core, and calcium phosphate (CaP) as the pH-responsive mineral. Owing to the presence of CaP as the diffusion barrier, mineralized HANPs revealed the pH-responsiveness of release kinetics of MTX across neutral to acidic conditions. HANPs were internalized via receptor-mediated endocytosis in macrophages which involved molecular redundancy among major hyaladherins, including CD44, stabilin-2, and RHAMM. Following endocytosis, MP-HANPs loaded with doxorubicin revealed pH-dependent demineralization followed by dramatic acceleration of drug release into the cytosol compared to other HANPs. Furthermore, an in vivo study showed a significantly high paw-to-liver ratio of fluorescent intensity after systemic administration of MP-HANP-Cy5.5, indicating improved biodistribution of nanoparticles into arthritic paws in collagen-induced arthritis mice. Treatment with MTX-loaded MP-HANPs ameliorated inflammatory arthritis with remarkable safety at high dose of MTX. We highlight the distinct advantages of combining key benefits of biomineralization and PEGylation with HA-based nanoparticles for arthritis-selective targeting, thus suggesting MP-HANPs as a promising carrier of MTX for treatment of RA. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Design and optimization of topical methotrexate loaded niosomes for enhanced management of psoriasis: application of Box-Behnken design, in-vitro evaluation and in-vivo skin deposition study.

    Science.gov (United States)

    Abdelbary, Aly A; AbouGhaly, Mohamed H H

    2015-05-15

    Psoriasis, a skin disorder characterized by impaired epidermal differentiation, is regularly treated by systemic methotrexate (MTX), an effective cytotoxic drug but with numerous side effects. The aim of this work was to design topical MTX loaded niosomes for management of psoriasis to avoid systemic toxicity. To achieve this goal, MTX niosomes were prepared by thin film hydration technique. A Box-Behnken (BB) design, using Design-Expert(®) software, was employed to statistically optimize formulation variables. Three independent variables were evaluated: MTX concentration in hydration medium (X1), total weight of niosomal components (X2) and surfactant: cholesterol ratio (X3). The encapsulation efficiency percent (Y1: EE%) and particle size (Y2: PS) were selected as dependent variables. The optimal formulation (F12) displayed spherical morphology under transmission electron microscopy (TEM), optimum particle size of 1375.00 nm and high EE% of 78.66%. In-vivo skin deposition study showed that the highest value of percentage drug deposited (22.45%) and AUC0-10 (1.15 mg.h/cm(2)) of MTX from niosomes were significantly greater than that of drug solution (13.87% and 0.49 mg.h/cm(2), respectively). Moreover, in-vivo histopathological studies confirmed safety of topically applied niosomes. Concisely, the results showed that targeted MTX delivery might be achieved using topically applied niosomes for enhanced treatment of psoriasis. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Action of methotrexate and tofacitinib on directly stimulated and bystander-activated lymphocytes.

    Science.gov (United States)

    Piscianz, Elisa; Candilera, Vanessa; Valencic, Erica; Loganes, Claudia; Paron, Greta; De Iudicibus, Sara; Decorti, Giuliana; Tommasini, Alberto

    2016-07-01

    Chronic inflammation associated with autoimmune activation is characteristic of rheumatic diseases from childhood to adulthood. In recent decades, significant improvements in the treatment of these types of disease have been achieved using disease modifying anti-rheumatic drugs (DMARDs), such as methotrexate (MTX) and, more recently, using biologic inhibitors. The recent introduction of kinase inhibitors (for example, tofacitinib; Tofa) further increases the available ARDs. However, there are patients that do not respond to any treatment strategies, for whom combination therapies are proposed. The data regarding the combined action of different drugs is lacking and the knowledge of the mechanisms of ARDs and their actions upon pathogenic lymphocytes, which are hypothesized to sustain disease, is poor. An in vitro model of inflammation was developed in the current study, in which stimulated and unstimulated lymphocytes were cultured together, but tracked separately, to investigate the action of MTX and Tofa on the two populations. By analysing lymphocyte proliferation and activation, and cytokine secretion in the culture supernatants, it was established that, due to the presence of activated cells, unstimulated cells underwent a bystander activation that was modulated by the ARDs. Additionally, varying administration schedules were demonstrated to affect lymphocytes differently in vitro, either directly or via bystander activation. Furthermore, MTX and Tofa exerted different effects; while MTX showed an antiproliferative effect, Tofa marginally effected activation, although only a slight antiproliferative action, which could be potentiated by sequential treatment with MTX. Thus, it was hypothesized that these differences may be exploited in sequential therapeutic strategies, to maximize the anti‑rheumatic effect. These findings are notable and must be accounted for, as bystander‑activated cells in vivo could contribute to the spread of autoimmune activation

  16. Saccharomyces boulardii ameliorates clarithromycin- and methotrexate-induced intestinal and hepatic injury in rats.

    Science.gov (United States)

    Duman, Deniz Güney; Kumral, Zarife Nigâr Özdemir; Ercan, Feriha; Deniz, Mustafa; Can, Güray; Cağlayan Yeğen, Berrak

    2013-08-28

    Saccharomyces boulardii is a probiotic used for the prevention of antibiotic-associated diarrhoea. We aimed to investigate whether S. boulardii could alter the effects of clarithromycin (CLA) and methotrexate (MTX) on oro-caecal intestinal transit and oxidative damage in rats. Rats were divided into two groups receiving a single dose of MTX (20 mg/kg) or CLA (20 mg/kg per d) for 1 week. Groups were treated with either saline or S. boulardii (500 mg/kg) twice per d throughout the experiment. The control group was administered only saline. Following decapitation, intestinal transit and inflammation markers of glutathione (GSH), malondialdehyde and myeloperoxidase were measured in intestinal and hepatic tissues. CLA and MTX increased intestinal transit, while S. boulardii treatment slowed down CLA-facilitated transit back to control level. Both MTX and CLA increased lipid peroxidation while depleting the antioxidant GSH content in the hepatic and ileal tissues. Conversely, lipid peroxidation was depressed and GSH levels were increased in the ileal and hepatic tissues of S. boulardii-treated rats. Increased ileal neutrophil infiltration due to MTX and CLA treatments was also reduced by S. boulardii treatment. Histological analysis supported that S. boulardii protected intestinal tissues against the inflammatory effects of both agents. These findings suggest that S. boulardii ameliorates intestinal injury and the accompanying hepatic inflammation by supporting the antioxidant state of the tissues and by inhibiting the recruitment of neutrophils. Moreover, a preventive effect on MTXinduced toxicity is a novel finding of S. boulardii, proposing it as an adjunct to chemotherapy regimens.

  17. Effects of Resveratrol on Methotrexate-Induced Testicular Damage in Rats

    Directory of Open Access Journals (Sweden)

    Esin Yuluğ

    2013-01-01

    Full Text Available This study investigated the probable protective effects of resveratrol (RES, an antioxidant, against methotrexate- (MTX- induced testis damage. Twenty-four male Sprague Dawley rats were randomly divided into four groups: control, RES, MTX, and MTX + RES groups. Rats were sacrificed at the end of the experiment. Plasma and tissue malondialdehyde (MDA levels, superoxide dismutase (SOD and catalase (CAT activity in tissue, testicular histopathological damage scores, and testicular and epididymal epithelial apoptotic index (AI were evaluated. The MTX group had significantly higher plasma and tissue MDA levels and significantly lower SOD and CAT activity than those of the control group. In the MTX + RES group, plasma and tissue MDA levels decreased significantly and SOD activity rose significantly compared to the MTX group. The MTX group had significantly lower Johnsen’s testicular biopsy score (JTBS values than those of the control group. JTBS was significantly higher in the MTX + RES group than in the MTX group. AI increased in the testis and epididymis in the MTX group and significantly decreased in the MTX + RES group. Our results indicate that RES has protective effects against MTX-induced testis damage at the biochemical, histopathological, and apoptotic levels.

  18. MTX [Microwave Tokamak Experiment] plasma diagnostic system

    International Nuclear Information System (INIS)

    Rice, B.W.; Hooper, E.B.; Brooksby, C.A.

    1987-01-01

    In this paper, a general overview of the MTX plasma diagnostics system is given. This includes a description of the MTX machine configuration and the overall facility layout. The data acquisition system and techniques for diagnostic signal transmission are also discussed. In addition, the diagnostic instruments planned for both an initial ohmic-heating set and a second FEL-heating set are described. The expected range of plasma parameters along with the planned plasma measurements will be reviewed. 7 refs., 5 figs

  19. Methotrexate intolerance in oral and subcutaneous administration in patients with juvenile idiopathic arthritis: a cross-sectional, observational study.

    Science.gov (United States)

    van Dijkhuizen, E H Pieter; Pouw, Juliëtte N; Scheuern, Andrea; Hügle, Boris; Hardt, Sven; Ganser, Gerd; Kümmerle-Deschner, Jasmin Beate; Horneff, Gerd; Holzinger, Dirk; Bulatović Ćalasan, Maja; Wulffraat, Nico M

    2016-01-01

    Methotrexate (MTX) is the cornerstone disease-modifying anti-rheumatic drug (DMARD) in juvenile idiopathic arthritis (JIA). In Dutch patients, MTX intolerance occurred frequently and was associated with subcutaneous (SC) administration. The aim of this study was to assess the prevalence of MTX intolerance and its association with the route of administration in a German cohort of JIA patients. A cross-sectional study of JIA patients on MTX was performed. Primary outcome was MTX intolerance, which was determined using the validated Methotrexate Intolerance Severity Score (MISS) questionnaire. The prevalence of gastrointestinal adverse effects and MTX intolerance was compared between patients on MTX SC and MTX administered orally (PO). Of 179 JIA patients on MTX, 73 (40.8%) were intolerant. The odds of MTX intolerance were higher in patients using MTX exclusively SC compared to exclusively PO (adjusted odds ratio 3.37 [95% confidence interval 1.19-10.0]). There was strong evidence that the former experienced more behavioural complaints (76.1% vs. 47.4%, p=0.001) and weak evidence that they experienced more abdominal pain after MTX intake (43.5% vs. 27.4%, p=0.056). The prevalence of MTX intolerance was high and exclusively SC administration of MTX was associated with MTX intolerance and behavioural adverse effects. The prevalence of gastrointestinal adverse effects was at least as high as in patients on MTX PO. The frequently held assumption that SC causes fewer side effects than PO seems unwarranted. Definite answers about the differences between SC and PO administration with respect to safety and efficacy should be obtained by randomised trials.

  20. [Recommendations for the use of methotrexate in patients with juvenile idiopathic arthritis].

    Science.gov (United States)

    Calvo, I; Antón, J; López Robledillo, J C; de Inocencio, J; Gamir, M L; Merino, R; Lacruz, L; Camacho, M; Rua, M J; Bustabad, S; Díaz Cordovés-Rego, G

    2016-03-01

    To develop a consensus document of recommendations for the use of methotrexate (MTX) in patients with juvenile idiopathic arthritis (JIA). A group of eleven experts proposed several clinical questions on the use of MTX in patients with JIA. A systematic review was conducted and the evidence and recommendations for each question were extracted. The results were discussed and validated by the experts in a work session to establish the final recommendations. MTX is recommended as the first drug for inducing remission in JIA, and its indication should be made according to the clinical category of the patient. Prior to treatment, it is recommended to perform a complete blood count, including white cells, levels of liver enzymes, serum creatinine, and other analytical parameters according to specific risk factors. Treatment should be initiated with a dose of 10-15 mg/m(2)/week. In cases of uveitis or polyarthritis, an initial dose of 15 mg/m(2)/week should be considered. For a better bioavailability and tolerability, it is preferable to administer MTX parenterally if the dose is ≥15 mg/m(2)/week. It is necessary to periodically perform an analytical monitoring of the patient and to assess possible alterations in liver enzymes to make changes if necessary. Combinations with biological agents may be necessary, as well as the concomitant addition of folic or folinic acid. This document describes the main recommendations for the appropriate use of MTX in JIA patients, according to scientific evidence and clinical experience. Copyright © 2015 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

  1. Double-modulation of 5-Fluorouracil by methotrexate and leucovorin in advanced colorectal-carcinoma.

    Science.gov (United States)

    Leone, B; Romero, A; Rabinovich, M; Vallejo, C; Bianco, A; Perez, J; Rodriguez, R; Cuevas, M; Machiavelli, M; Paris, A; Lacava, J

    1993-11-01

    A phase II trial was performed to evaluate the efficacy and toxicity of a double modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) and leucovorin (LV) as first line chemotherapy in advanced colorectal carcinoma. Between January 1990, and April 1992, 42 patients with metastatic or advanced recurrent (inoperable) colorectal cancer were entered into the study. Therapy consisted of a sequential combination of MTX, LV and 5-FU. MTX was administered at a dose of 150 mg/m2 over 20 minutes I.V. infusion at hour (h) 0, followed 19 h later by LV 50 mg/m2 over 2 h infusion. 5-FU 900 mg/m2 was given by I.V. push injection at h 20. Starting 24 h after MTX administration all patients received LV 15 mg/m2 intramuscularly every 6 h for six doses. Treatment was repeated every 15 days until progressive disease, severe toxicity, or death. Four patients were considered not evaluable for response. Objective regression (OR) was observed in 14 of 38 patients (37%, 95% confidence interval 23-53%). Two patients (5%) obtained complete response (CR) and 12 (32%) partial response (PR). Median time to treatment failure was 6 months (range 1-21). Median survival for the whole group of patients was 13 months (range 1-27). Toxicity was within acceptable limits but one therapy-related death due to severe leukopenia and sepsis was observed. Double modulation of 5-FU with MTX and low dose of LV is an active regimen against advanced colorectal carcinoma and represents a promising strategy that should be further explored.

  2. Survival of tumor-bearing mice exposed to heavy water or heavy water plus methotrexate

    International Nuclear Information System (INIS)

    Laissue, J.A.; Buerki, H.; Berchtold, W.

    1982-01-01

    Moderate body deuteration combined with a cytostatic drug [methotrexate (MTX)] significantly increases the survival time of young adult DBA/2 mice bearing transplantable P815. L5178Y, or L1210 tumors. Neoplastic cells were grown in vitro from tumor stock and injected i.p. into mice from two groups, one drinking tap water, and other drinking 30% heavy water in tap water. One-half of the animals in each of these two groups was given a single injection of MTX (4 mg/kg body weight) on 3 consecutive days per week. At death, extension of primary and metastatic tumors was examined and was found to be macro- and microscopically comparable in the corresponding groups. The mean survival time of untreated mice drinking tap water was about 2 weeks following injection of the fast-growing P815, L5178Y, or L1210 (V) tumors and approximately 5 weeks after injection of cells from a slower-growing L1210 subline. Body deuteration alone roughly doubled the survival time solely of mice bearing this L1210 subline. Treatment with MTX approximately doubled the mean survival time of hosts bearing one of the fast-growing tumors. Combined treatment with heavy water and MTX increased the mean survival time of the mice in all groups by 15 to 125% as compared to control values. The reasons for this effect are unknown. However, heavy water has been shown to exert antimitotic activity and to depress the incorporation of radioactive precursors into DNA of proliferating mammalian cells. The depression of antibody formation following antigenic stimulation and the reduction in numbers of nonneoplastic lymphoid cells of mice following moderate body deuteration may have contributed to the enhancement of MTX activity in addition to other effects of deuterium

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

    International Nuclear Information System (INIS)

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

    1983-01-01

    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 of 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

  4. Purine biosynthesis in L1210 leukemia cells is inhibited by 7-hydroxymethotrexate (7-OH-MTX) polyglutamates (PGS)

    International Nuclear Information System (INIS)

    Seither, R.L.; Matherly, L.H.; Goldman, I.D.

    1986-01-01

    The biochemical basis for 7-OH-MTX cytotoxicity was examined in L1210 tumor cells. Cells were exposed to 100 μM 7-OH-MTX (approx. 50% growth inhibition) or 10 μM methotrexate (MTX) (approx. 95% growth inhibition) for 6 hrs to allow high levels of PGS to accumulate. Dihydrofolate reductase (DHFR) activity was assessed by dihydrofolate (FH 2 ) pools labeled with 5-formyl-[ 3 H]-tetrahydrofolate (5μM) or 3 H-folic acid (1 μM). FH 2 was not elevated above control levels in 7-OH-MTX treated cells, in contrast to MTX treated cells in which FH 2 increased 4- to 7-fold. 3 H-Deoxyuridine incorporation into DNA was not inhibited in cells containing high levels (11.5 nmol/g dry wt.) of 7-OH-MTX tetraglutamate (7-OH-4-NH 2 -10-CH 3 -PteGlu 4 ), well in excess of the DHFR-binding capacity (7.3 +/- 0.9 nmol/g), indicating a normal rate of thymidylate synthesis. Although small amounts of 7-OH-MTX and its PGS were bound to DHFR in L1210 cells, as assessed by gel filtration, there was evidence for the preferential binding of 7-OH-MTX tetraglutamate. In all cases this was well below the DHFR binding capacity, consistent with normal rates of deoxyuridine metabolism and FH 2 levels in the cell. Incorporation of 14 C-formate (60 min) into thymidylate and amino acids was unaffected by 7-OH-MTX, yet incorporation into purines was inhibited over 50%, supporting a block(s) in de novo purine biosynthesis

  5. Bioavailibility of higher dose methotrexate comparing oral and subcutaneous route of administration in patients with rheumatoid arthritis

    NARCIS (Netherlands)

    Hoekstra, Monique; Hoekstra, M.; Haagsma, Cees; Neef, Cees; Proost, Johannes; van de Laar, Mart A F J; Knuif, Antonius

    2004-01-01

    OBJECTIVE: To determine the bioavailability of higher oral doses of methotrexate (MTX) in adult patients with rheumatoid arthritis (RA). METHODS: A pharmacokinetic analysis was performed in 15 patients with RA taking a stable dose of MTX (> or = 25 mg weekly). Separated by 2 weeks, a pharmacokinetic

  6. Implementation Study of Patient-Ready Syringes Containing 25 mg/mL Methotrexate Solution for Use in Treating Ectopic Pregnancy

    Directory of Open Access Journals (Sweden)

    R. Respaud

    2014-01-01

    Full Text Available Background. Ectopic pregnancy (EP is a significant cause of morbidity and mortality during the first trimester of pregnancy. Small unruptured tubal pregnancies can be treated medically with a single dose of methotrexate (MTX. Objective. The aim of this study was to evaluate the stability of a 25 mg/mL solution of MTX to devise a secure delivery circuit for the preparation and use of this medication in the management of EP. Method. MTX solutions were packaged in polypropylene syringes, stored over an 84-day period, and protected from light either at +2 to +8°C or at 23°C. We assessed the physical and chemical stability of the solutions at various time points over the storage period. A pharmaceutical delivery circuit was implemented that involved the batch preparation of MTX syringes. Results. We show that 25 mg/mL MTX solutions remain stable over an 84-day period under the storage conditions tested. Standard doses were prepared, ranging from 50 mg to 100 mg. The results of this study suggest that MTX syringes can be prepared in advance by the pharmacy, ready to be dispensed at any time that a diagnosis of EP is made. Conclusion. The high stability of a 25 mg/mL MTX solution in polypropylene syringes makes it possible to implement a flexible and cost-effective delivery circuit for ready-to-use preparations of this drug, providing 24-hour access and preventing treatment delays.

  7. Effect of N-Feruloylserotonin and Methotrexate on Severity of Experimental Arthritis and on Messenger RNA Expression of Key Proinflammatory Markers in Liver

    Directory of Open Access Journals (Sweden)

    Ľudmila Pašková

    2016-01-01

    Full Text Available Rheumatoid arthritis (RA is a chronic inflammatory disease, leading to progressive destruction of joints and extra-articular tissues, including organs such as liver and spleen. The purpose of this study was to compare the effects of a potential immunomodulator, natural polyphenol N-feruloylserotonin (N-f-5HT, with methotrexate (MTX, the standard in RA therapy, in the chronic phase of adjuvant-induced arthritis (AA in male Lewis rats. The experiment included healthy controls (CO, arthritic animals (AA, AA given N-f-5HT (AA-N-f-5HT, and AA given MTX (AA-MTX. N-f-5HT did not affect the body weight change and clinical parameters until the 14th experimental day. Its positive effect was rising during the 28-day experiment, indicating a delayed onset of N-f-5HT action. Administration of either N-f-5HT or MTX caused reduction of inflammation measured as the level of CRP in plasma and the activity of LOX in the liver. mRNA transcription of TNF-α and iNOS in the liver was significantly attenuated in both MTX and N-f-5HT treated groups of arthritic rats. Interestingly, in contrast to MTX, N-f-5HT significantly lowered the level of IL-1β in plasma and IL-1β mRNA expression in the liver and spleen of arthritic rats. This speaks for future investigations of N-f-5HT as an agent in the treatment of RA in combination therapy with MTX.

  8. Biochemical modulation of 5-fluorouracil by methotrexate in patients with advanced gastric carcinoma.

    Science.gov (United States)

    Pérez, J E; Lacava, J A; Dominguez, M E; Rodriguez, R; Barbieri, M R; Ortiz, E H; Romero Acuña, L A; Langhi, M J; Romero Acuña, J M; Vallejo, C T; Leone, B A; Machiavelli, M R; Romero, A O

    1998-10-01

    A phase II trial was conducted to evaluate the efficacy and toxicity of a modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) (with leucovorin (LV) rescue) as first-line chemotherapy in patients with locally advanced (inoperable) or metastatic gastric carcinoma. From July 1993 through August 1996, 36 patients with advanced gastric carcinoma received a regimen that consisted of: MTX 200 mg/m2 diluted in 250 ml normal saline by intravenous infusion over 20 minutes at hour 0; 5-FU 1,200 mg/m2 intravenous push injection at hour 20. Beginning 24 hours after MTX administration all patients received LV 15 mg/m2 intramuscularly every 6 hours for six doses. Cycles were repeated every 15 days. One patient was not assessable for response. Objective regression was observed in 15 of 37 patients (43%; 95% confidence interval, 26%-60%). One patient (3%) achieved complete response and 14 (40%) achieved partial response. No change was recorded in 14 patients (40%) and progressive disease was noted in six patients (17%). The median time to treatment failure was 7 months and the median survival was 12 months. Toxicity was within acceptable limits but one therapy-related death resulting from severe leukopenia occurred. The dose-limiting toxicity was mucositis. Five episodes of grade 3 or 4 stomatitis were observed and caused dosage modifications of MTX and 5-FU. Biochemical modulation of 5-FU by MTX appears as an attractive modality in patients with advanced gastric cancer. Further investigation both in experimental and clinical fields is needed to clearly define its role and to design the best modulatory strategy.

  9. Efficacy of royal jelly on methotrexate-induced systemic oxidative ...

    African Journals Online (AJOL)

    The aim of this present study is to investigate the mucositis caused by methotrexate (MTX), as well as whether the application of royal jelly (RJ) has a protective effect on oxidative stress. This present study included six groups each consisted of 12 Wistar rats. Distilled water (po: peroral) was given to the 1st group as placebo ...

  10. Carrier-bound Methotrexate. IV. Antiproliferative Activity of ...

    African Journals Online (AJOL)

    NJD

    Polymeric conjugates of methotrexate (MTX) with macromolecular carriers, ... The water-soluble conjugates, crudely fractionated by aqueous dialysis, possess mass-average molecular masses in ..... for 20 h in an ice bath and another 3 h at room temperature. ... with excess Et2O-hexane (2:1) afforded a resinous product,.

  11. Methotrexate pharmacogenetics in Uruguayan adults with hematological malignant diseases.

    Science.gov (United States)

    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.

  12. Protective Effects of Erythropoietin and N-Acetylcysteine on Methotrexate-Induced Lung Injury in Rats

    Directory of Open Access Journals (Sweden)

    Hasan Kahraman

    2013-03-01

    Full Text Available Objective: Methotrexate (MTX is known to have deleterious side effects on lung tissue. We aimed to investigate the effects of erythropoietin (EPO and N-acetyl-cysteine (NAC on MTX-induced lung injury in rats. Study Design: Animal experiment. Material and Methods: Twenty-six female Sprague-Dawley rats were divided into 4 groups. Sham group, 0.3 mL saline; MTX group, 5 mg/kg MTX; EPO group, 5mg/kg MTX and 2000 IU/kg EPO; NAC group, 5 mg/kg MTX and 200 mg/kg NAC were administered once daily for 4 consecutive days. Malondialdehyde (MDA, superoxide dismutase (SOD, catalase (CAT and inflammation and congestion scores in lung tissues were evaluated. Results: In MTX group MDA were significantly higher, CAT and SOD were significantly lower than in sham, EPO and NAC groups (p0.005. In group MTX both scores were significantly higher than in sham (p<0.005. The congestion score of group MTX was significantly higher than those of group EPO and NAC (p<0.005. Conclusion: EPO and NAC have significant preventive effects on MTX-induced lung injury in rats. Decreased antioxidant capacity and increased MDA level may cause the oxidative damage in MTX group. Also, higher antioxidant capacity and lower MDA level may be a response to oxidative stress in EPO and NAC groups.

  13. Plasma level of CXC-chemokine CXCL12 is increased in rheumatoid arthritis and is independent of disease activity and methotrexate treatment

    DEFF Research Database (Denmark)

    Hansen, IB; Ellingsen, T; Hornung, N

    2006-01-01

    ' duration, and 50 sex and age matched healthy controls. ELISA for CXCL12 was performed on plasma prior to and after 16 and 28 weeks of MTX treatment in the patients with RA and once in controls. RESULTS: The p-CXCL12 was 1855 +/- 145 pg/ml in RA patients and 1273 +/- 79 pg/ml in controls (p

  14. Thymidylate synthase genetic polymorphism and plasma total homocysteine level in a group of Turkish patients with rheumatoid arthritis: relationship with disease activity and methotrexate toxicity.

    Science.gov (United States)

    Borman, Pınar; Taşbaş, Özgur; Karabulut, Halil; Tukun, Ajlan; Yorgancıoğlu, Rezan

    2015-01-01

    The polymorphism of thymidylate synthase (TS) gene and homocysteine are reported to have a relationship to methotrexate (MTX) metabolism, with conflicting results. The aim of this study was to determine homocysteine levels and the frequency of TS gene triple repeat (TS3R) and double repeat (TS2R) polymorphisms in a group of Turkish RA patients and evaluate its association with MTX toxicity and disease activity. Sixty-four patients with RA and 31 control subjects with a mean age of 48.7 ± 12.5 and 46.2 ± 13.4 years, were enrolled to the study. Demographic characteristics were obtained and number of patients with MTX-related adverse affects, were recorded in the patient group. The homocysteine levels and TS2R/TS3R polymorphisms of the TS gene were analyzed and the distribution of genotypes according to MTX toxicity and disease activity, were determined. The demographic properties were similar between the patient and control subjects. Folic acid supplementation with a mean dose of 5mg folic acid/week, was present in all patients. Thirty-six of the 64 patients showed adverse effects to MTX treatment. The frequency of TS2R and TS3R polymorphisms were found to be similar in the patient and control groups. TS2R and TS3R gene polymorphisms were found to be similar in patients with and without MTX-related adverse events. The mean homocysteine level was also similar in patients with and without TS gene polymorphism, but was found to be higher (12.45μmol/L vs 10.7μmol/L) in patients with MTX-related side effects than in patients without side effects. The mean level of homocysteine was correlated with levels of ESR in the patient group. In conclusion, homocysteine levels might effect the disease activity and toxicity of MTX but 2R and 3R polymorphisms in the TS gene, were not related with MTX-related toxicity in RA patients receiving folate supplementation. Further studies are needed to illuminate the polymorphisms in other enzymes that might be responsible from the MTX

  15. High Efficacy of Methotrexate in Patients with Recurrent Idiopathic Acute Anterior Uveitis: a Prospective Study.

    Science.gov (United States)

    Bachta, Artur; Kisiel, Bartłomiej; Tłustochowicz, Mateusz; Raczkiewicz, Anna; Rękas, Marek; Tłustochowicz, Witold

    2017-02-01

    To evaluate prospectively the efficacy of methotrexate (MTX) in the treatment of recurrent idiopathic acute anterior uveitis (RIAAU). Nineteen out of 22 RIAAU patients completed the study (two patients withdrew their consent shortly after study initiation, one patient discontinued after 4 weeks because of the adverse effects). All patients were treated with MTX in a starting dose of 15 mg/week, increased to target dose of 25 mg/week after 4 weeks. In patients taking systemic corticosteroids (CS) the dose was gradually tapered (by 2.5 mg every week) until discontinuation. The mean follow-up period was 3.3 years (19-59 months). Sixteen patients (84 %) remained flare-free on MTX therapy. In the remaining three patients the mean interval between flares increased from 4.8 to 18.3 months. Systemic CS were tapered off in all patients. The number of acute anterior uveitis flares in the whole cohort decreased from 2.12 to 0.11/patient-year (p treatment of RIAAU.

  16. Extended duration of prehydration does not prevent nephrotoxicity or delayed drug elimination in high-dose methotrexate infusions

    DEFF Research Database (Denmark)

    Mikkelsen, Torben Stamm; Mamoudou, Aissata Diop; Tuckuviene, Ruta

    2014-01-01

    Alkalized hydration is used as supportive care to prevent renal toxicity during infusions with high-dose methotrexate (HDMTX). In children with acute lymphoblastic leukemia (ALL), the hydration is commonly initiated 4 hours before start of the methotrexate (MTX) infusion. To test if longer durati...

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

    Science.gov (United States)

    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

  18. H19 mediates methotrexate resistance in colorectal cancer through activating Wnt/β-catenin pathway

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Ke-feng [Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong (China); Liang, Wei-Cheng [School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong (China); Feng, Lu [Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (China); Pang, Jian-xin [School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515 (China); Waye, Mary Miu-Yee [School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong (China); Zhang, Jin-Fang [Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (China); Fu, Wei-Ming, E-mail: fuweiming76@smu.edu.cn [School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515 (China)

    2017-01-15

    Colorectal cancer (CRC) is a common malignancy, most of which remain unresponsive to chemotherapy. As one of the earliest cytotoxic drugs, methotrexate (MTX) serves as an anti-metabolite and anti-folate chemotherapy for various cancers. Unfortunately, MTX resistance prevents its clinical application in cancer therapy. Thereby, overcoming the drug resistance is an alternative strategy to maximize the therapeutic efficacy of MTX in clinics. Long noncoding RNAs (lncRNAs) have gained widespread attention in recent years. More and more emerging evidences have demonstrated that they play important regulatory roles in various biological activities and disease progression including drug resistance. In the present study, a MTX-resistant colorectal cell line HT-29 (HT-29-R) was developed, which displayed the active proliferation and shortened cell cycle. LncRNA H19 was found to be significantly upregulated in this resistant cell line. Further investigation showed that H19 knockdown sensitized the MTX resistance in HT-29-R cells while its overexpression improved the MTX resistance in the parental cells, suggesting that H19 mediate MTX resistance. The Wnt/β-catenin signaling was activated in HT-29-R cells, and H19 knockdown suppressed this signaling in the parental cells. In conclusion, H19 mediated MTX resistance via activating Wnt/β-catenin signaling, which help to develop H19 as a promising therapeutic target for MTX resistant CRC. - Highlights: • A methotrexate (MTX) -resistant colorectal cancer cell line HT-29 (HT-29-R) has been developed. • H19 was upregulated in HT-29-R cells. • H19 mediated MTX resistance in colorectal cancer (CRC). • Wnt/β-catenin pathway was involved in the H19-mediated MTX resistance in CRC cells.

  19. H19 mediates methotrexate resistance in colorectal cancer through activating Wnt/β-catenin pathway

    International Nuclear Information System (INIS)

    Wu, Ke-feng; Liang, Wei-Cheng; Feng, Lu; Pang, Jian-xin; Waye, Mary Miu-Yee; Zhang, Jin-Fang; Fu, Wei-Ming

    2017-01-01

    Colorectal cancer (CRC) is a common malignancy, most of which remain unresponsive to chemotherapy. As one of the earliest cytotoxic drugs, methotrexate (MTX) serves as an anti-metabolite and anti-folate chemotherapy for various cancers. Unfortunately, MTX resistance prevents its clinical application in cancer therapy. Thereby, overcoming the drug resistance is an alternative strategy to maximize the therapeutic efficacy of MTX in clinics. Long noncoding RNAs (lncRNAs) have gained widespread attention in recent years. More and more emerging evidences have demonstrated that they play important regulatory roles in various biological activities and disease progression including drug resistance. In the present study, a MTX-resistant colorectal cell line HT-29 (HT-29-R) was developed, which displayed the active proliferation and shortened cell cycle. LncRNA H19 was found to be significantly upregulated in this resistant cell line. Further investigation showed that H19 knockdown sensitized the MTX resistance in HT-29-R cells while its overexpression improved the MTX resistance in the parental cells, suggesting that H19 mediate MTX resistance. The Wnt/β-catenin signaling was activated in HT-29-R cells, and H19 knockdown suppressed this signaling in the parental cells. In conclusion, H19 mediated MTX resistance via activating Wnt/β-catenin signaling, which help to develop H19 as a promising therapeutic target for MTX resistant CRC. - Highlights: • A methotrexate (MTX) -resistant colorectal cancer cell line HT-29 (HT-29-R) has been developed. • H19 was upregulated in HT-29-R cells. • H19 mediated MTX resistance in colorectal cancer (CRC). • Wnt/β-catenin pathway was involved in the H19-mediated MTX resistance in CRC cells.

  20. 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

    Directory of Open Access Journals (Sweden)

    Kotnik Barbara Faganel

    2017-09-01

    Full Text Available 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.

  1. Comparison of weakness progression in inclusion body myositis during treatment with methotrexate or placebo

    NARCIS (Netherlands)

    Badrising, UA; Maat-Schieman, MLC; Ferrari, MD; Zwinderman, AH; Wessels, JAM; Breedveld, FC; van Doorn, PA; van Engelen, BGM; Hoogendijk, JE; Howeler, CJ; de Jager, AE; Jennekens, FGI; Koehler, PJ; de Visser, M; Viddeleer, A; Verschuuren, JJ; Wintzen, AR

    We investigated whether 5 to 20mg per week oral methotrexate could slow down disease progression in 44 patients with inclusion body myositis in a randomized double-blind placebo-controlled study over 48 weeks. Mean change of quantitative muscle strength testing sum scores was the primary study

  2. Protective effects of vitamin E and Cornus mas fruit extract on methotrexate-induced cytotoxicity in sperms of adult mice

    Directory of Open Access Journals (Sweden)

    Leila Zarei

    2014-03-01

    Full Text Available This study was aimed to assess the protective effects of Cornus mas fruit extract (CMFE and vitamin E (Vit E on sperm quality parameters in the methotrexate (MTX-treated mice. Forty-eight young adult male mice (8-12 weeks were randomly divided into six groups including control and test groups. The control group received normal saline orally , and the test groups were treated MTX (20 mg kg-1, ip, once weekly, MTX + CMFE (250 mg kg-1, MTX + CMFE (500 mg kg-1, MTX + CMFE (1000 mg kg-1, and MTX + Vit E (100 IU kg-1, po for 35 consecutive days. On day 35, after euthanasia the epididymal sperms were isolated. Then the total mean sperm count, sperm viability and motility were determined. The total antioxidant capacity (TAOC of all experimental groups were also evaluated. The MTX-treated animals showed a significant changes in all parameters of sperm quality assessment compared to the control group. Both Vit E and CMFE were able to protect from MTX-induced effects on sperm maturity and DNA damage. Co-administration of MTX and CMFE and/or Vit E resulted in protection from MTX-reduced TAOC. In conclusion, these data suggested that MTX administration could adversely affect the sperm quality. Moreover, the protective effect of Vit E and CMFE on MTX-induced sperm toxicity was also documented.

  3. Poloxamer surface modified trimethyl chitosan nanoparticles for the effective delivery of methotrexate in osteosarcoma.

    Science.gov (United States)

    Li, Shenglong; Xiong, Yuyuan; Zhang, Xiaojing

    2017-06-01

    The present work is an effort to explore the poloxamer-modified trimethyl chitosan (TMC) encapsulated MTX for osteosarcoma treatment in order to improve the therapeutic efficacy and minimize severe toxicity associated with the clinical usage of MTX. The methotrexate-loaded pluronic-chitosan nanoparticles (MTCN) was nanosized and exhibited a controlled release of drug from the carrier system. The MTCN showed higher accumulation in cell cytoplasm region evident by the high red fluorescence indicating its uptake through energy-dependent endocytosis process. MTCN exhibited the increased cytotoxicity in MG63 cells compared free MTX due to its enhanced cellular uptake. Especially, MTCN exhibited a superior apoptosis effect with bright chromatin condensation and nuclear fragmentation was observed and showed remarkably higher apoptosis (∼48%) compared to that of free drug. The results of this investigation clearly demonstrate that the poloxamer-modified trimethyl chitosan (TMC) seems to have a great potential as a drug carrier in cancer chemotherapy. The present research work offers immense scope for further exploitation of poloxamer-modified trimethyl chitosan (TMC) in future for the development of nanoparticulate drug delivery system for cancer chemotherapy. Copyright © 2017. Published by Elsevier Masson SAS.

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

    Science.gov (United States)

    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.

  5. adverse effects of low dose methotrexate in rheumatoid arthritis patients

    International Nuclear Information System (INIS)

    Gilani, S.T.; Khan, D.A.; Khan, F.A.; Ahmed, M.

    2012-01-01

    To determine the frequency of adverse effects attributed to Methotrexate (MTX) toxicity and serum minimum toxic concentration with low dose MTX in Rheumatoid Arthritis (RA) patients. Study Design: Cross-sectional observational study. Place and Duration of Study: Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology, Rawalpindi, from March 2010 to March 2011. Methodology: One hundred and forty adult patients of RA receiving low dose MTX (10 mg/week) for at least 3 months, ere included by consecutive sampling. Blood samples were collected 2 hours after the oral dose of MTX. Serum alanine transaminase and creatinine were analyzed on Hitachi and blood counts on Sysmex analyzer. Serum MTX concentration was measured on TDX analyzer. Results: Out of one hundred and forty patients; 68 males (49%) and 72 females (51%), 38 developed MTX toxicity (27%), comprising of hepatotoxicity in 12 (8.6%), nephrotoxicity in 3 (2.1%), anaemia in 8 (5.7%), leucopenia in 2 (1.4%), thrombocytopenia in 3 (2.1%), pancytopenia in 2 (1.4%), gastrointestinal adverse effects in 5 (3.6%) and mucocutaneous problems in 3 (2.1%). Receiver operating characteristic curve revealed serum minimum toxic concentration of MTX at cutoff value of 0.71 mu mol/l with a sensitivity of 71% and specificity of 76%. Conclusion: Adverse effects of low dose MTX were found in 27% of RA patients, mainly comprising of hepatotoxicity and haematological problems. MTX toxicity can be detected by therapeutic drug monitoring of serum concentration of 0.71 mu mol/l with sensitivity of 71% and specificity of 76% in the patients on low dose MTX maintenance therapy. (author)

  6. A histological evaluation on osteogenesis and resorption of methotrexate-loaded calcium phosphate cement in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Li Dong; Yang Zhiping; Li Xin; Li Zhenfeng; Li Jianmin [Department of Orthopedics, Qilu Hospital of Shandong University, Shandong (China); Yang Jingyan, E-mail: yangzhiping@medmail.com.c [Department of Pathology, 2nd Affiliated Hospital of Shandong University, Shandong (China)

    2010-04-15

    In this study, we investigated the resorption of in vivo methotrexate-loaded calcium phosphate cement (MTX-CPC) implants and their effect on osteogenesis. MTX-CPC implants containing 1% methotrexate (MTX) (weight/weight) were preset and implanted into the femoral condyle of rabbits. Calcium phosphate cement (CPC) without MTX was used as the control. The femurs were harvested at day 1 and at 1, 3 and 6 months after implantation and radiological examination were performed. Decalcified sections were examined by hematoxylin and eosin (HE) staining, alkaline phosphatase (ALPase) immunohistochemistry and tartrate-resistant acid phosphatase (TRAPase) enzyme histochemistry. Then, we performed histomorphometric analysis, including determination of the percentage of newly formed bone and osteoblast and osteoclast counts. The results indicated that MTX-CPC implants were biocompatible, biodegradable and osteoconducive. However, MTX release from the implantation site inhibited osteogenesis in the initial period; this inhibition weakened with time, and no difference was observed between CPC and MTX-CPC at 6 months after implantation. Hence, MTX-CPC is an excellent material for filling defects and can be used for preparing effective drug delivery systems to achieve local control of invasive bone tumors.

  7. Comparison of central nervous system prophylaxis with cranial radiation and intrathecal methotrexate versus intrathecal methotrexate alone in acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Muriel, F.S.; Svarch, E.; Pavlovsky, S.

    1983-01-01

    In acute lymphoblastic leukemia, central nervous system prophylaxis with irradiation plus intrathecal methotrexate (i.t. MTX) reduces the incidence of CNS relapse to 7%-15%. However, increased evidence of CNS delayed toxicity was recognized mainly in children as CT scan abnormalities and neuropsychologic alterations. Two questions were analyzed: (1) Will further doses of i.t. methotraxate and dexamethasone (i.t. MTX-DMT) decrease the incidence of CNS relapse. (2) Is i.t. MTX-DMT given during induction and maintenance as effective as cranium irradiation plus i.t. MTX-DMT. Incidence of primary CNS relapse in i.t. MTX-DMT-treated patients with a WBC count 50,000, it was 16% in the treated group and 19% in the control group. These patients were compared with patients which had received 3 doses of i.t. MTX-DMT alone during induction, 3 doses weekly during the first month of remission, and quarterly thereafter. The incidence of leukemia at 60 mo in patients with a WBC count 50,000 at 48 mo was 28% and 42% in the irradiated and nonirradiated group respectively. Complete remission remained at 15% and 16% respectively of patients disease-free at 48 mo. We conclude that (A) after cranial irradiation plus i.t. MTX-DMT X 5, the use of additional doses of i.t. MTX-DMT is not of further benefit in preventing CNS relapse; (B) use of i.t. MTX-DMT alone compares with cranial irradiation plus i.t. MTX-DMT in incidence of CNS relapse; and (C) relapse-free survival and survival in patients with a WBC count < 50.000 were significantly longer in those without cranial irradiation

  8. 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

    Science.gov (United States)

    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

  9. Pharmacological and therapeutic properties of carrier bound methotrexate against tumor confined to a third space body compartment.

    Science.gov (United States)

    Chu, B C; Howell, S B

    1981-11-01

    The pharmacokinetics and therapeutic effectiveness of methotrexate (MTX) and MTX covalently bound to bovine serum albumin (MTX-BSA) and poly-l-lysine, MW 3,000 (MTX-PLL 3K) or MW 40,000 to 60,000 (MTX-PLL 40-60K) were compared when these drugs were injected directly into the pleural cavities of BDF1 mice containing the L1210 tumor. Simultaneous measurements od drug levels in both pleural fluid and blood after a single dose demonstrated that free MTX and MTX-PLL 3K were cleared from the pleural cavity and blood within 4 hr, MTX-PLL 40K-60K was cleared within 2 hr, and MTX-BSA was still present in the tumor compartment at 48 hr. The coupling of MTX to these carriers increased its toxicity by extending the half-life of MTX-BSA within the animal and by incorporating a toxic PLL derivative as a carrier. At equitoxic doses, a single dose of MTX-BSA gave a peak increase in lifespan (ILS) of 50% (at 35 mg/kg) compared with a peak ILS of 30 to 35% for both free drug (at 95 mg/kg) and the MTX-PLL derivatives (at 1.4-6 mg/kg). Systemic administration of sufficient leucovorin to provide partial marrow protection compromised the antitumor activity of both MTX and MTX-BSA in the pleural cavity, and although leucovorin permitted higher doses to be used, this resulted in only a small increase in peak ILS for MTX-BSA on a single dose schedule.

  10. Methotrexate osteopathy

    Energy Technology Data Exchange (ETDEWEB)

    Schwartz, A.M.; Leonidas, J.C.

    1984-01-01

    Methotrexate osteopathy is an uncommon complication of long-term oral maintenance therapy for childhood neoplasms, most commonly acute lymphocytic leukemia. It is characterized by severe lower extremity pain and by osteoporosis particularly involving the lower extremities and thick dense provisional zones of calcification and growth arrest lines resembling scurvy. Fractures may occur. The appearance must be distinguished from recurrent or metastatic disease.

  11. Methotrexate osteopathy

    International Nuclear Information System (INIS)

    Schwartz, A.M.; Leonidas, J.C.; Tufts Univ., Boston, MA

    1984-01-01

    Methotrexate osteopathy is an uncommon complication of long-term oral maintenance therapy for childhood neoplasms, most commonly acute lymphocytic leukemia. It is characterized by severe lower extremity pain and by osteoporosis particularly involving the lower extremities and thick dense provisional zones of calcification and growth arrest lines resembling scurvy. Fractures may occur. The appearance must be distinguished from recurrent or metastatic disease. (orig.)

  12. Nonmetastatic osteosarcoma of the extremity. Neoadjuvant chemotherapy with methotrexate, cisplatin, doxorubicin and ifosfamide. An Italian Sarcoma Group study (ISG/OS-Oss).

    Science.gov (United States)

    Ferrari, Stefano; Meazza, Cristina; Palmerini, Emanuela; Tamburini, Angela; Fagioli, Franca; Cozza, Raffaele; Ferraresi, Virginia; Bisogno, Gianni; Mascarin, Maurizio; Cefalo, Graziella; Manfrini, Marco; Capanna, Rodolfo; Biagini, Roberto; Donati, Davide; Picci, Piero

    2014-01-01

    Based on the results of the ISG/OS-1 study, the MAP regimen (methotrexate [MTX], doxorubicin [ADM] and cisplatin [CDP] with the addition of ifosfamide [IFO] in poor-responder patients) was investigated in patients with nonmetastatic osteosarcoma of the extremity (ISG/OS-Oss study). Compared with the ISG/OS-1 study (cumulative doses: ADM 420 mg/m(2), MTX 120 g/m(2), CDP 600 mg/m(2), IFO 30 g/m(2)), the ISG/OS-Oss study reduced the number of MTX cycles from 10 to 5 (cumulative MTX dose: 60 g/m(2)) in order to diminish treatment duration and toxicity. From January 2007 to June 2011, 171 patients (median age 16 years, 60% males) were registered. The limb salvage rate was 94% and the good pathologic response rate 51% (these figures were 92% and 48%, respectively, in the ISG/OS-1 study). At a median follow-up of 39 months (range, 4-80), the 5-year overall survival rate was 80% (95% CI, 73%-87%) and the event-free survival was 50% (95% CI, 39%-59%). For comparison, the 5-year overall and event-free survival rates in ISG/OS-1 were 73% (95% CI, 65%-81%) and 64% (95% CI, 56%-73%), respectively. This study confirms that in nonmetastatic osteosarcoma of the extremity, conservative surgery in more than 90% and a good pathologic response rate of 50% can be expected with primary chemotherapy based on the MAP regimen. The response and resection rates in the ISG/OS-Oss study are in the same range as those of the previous study, whereas the event-free survival is lower than that previously achieved. Since the only difference between the two studies was the cumulative dose of postoperatively given MTX, our data support the importance of the cumulative dose of MTX in the MAP regimen.

  13. Combined regional chemotherapy and radiation therapy in the treatment of epidermoid carcinoma in the oro-facial region

    Energy Technology Data Exchange (ETDEWEB)

    Danko, J; Satko, I [Komenskeho Univ., Bratislava (Czechoslovakia). Lekarska Fakulta; Durkovsky, J [Institute of Clinical Oncology, Bratislava (Czechoslovakia)

    1979-01-01

    Treatment was studied of oro-facial epidermoid carcinoma by combined chemo- and radiotherapy and eventual surgery. Cytostatic drugs were applied intraarterially. After a monocytostatic treatment trial with Methotrexate (MTX), a combined cytostatic program was developed alternating two cytostatic drugs, viz., MTX and Bleomycin (BLM). The usefulness of chemotherapy and its inclusion in the treatment of epidermoid carcinoma in the oro-facial region was found justified for combined therapy. The selected intraarterial administration, however, is not suitable for routine application. For this reason, the combination irradiation or surgical therapy with chemotherapy was adopted.

  14. Hand bone loss in early rheumatoid arthritis during a methotrexate-based treat-to-target strategy with or without adalimumab-a substudy of the optimized treatment algorithm in early RA (OPERA) trial

    DEFF Research Database (Denmark)

    Ørnbjerg, L M; Østergaard, M; Jensen, T

    2017-01-01

    This study aims to investigate 1-year hand bone loss (HBL1-year) in early rheumatoid arthritis (RA) patients treated with a methotrexate (MTX) and intra-articular triamcinolone treat-to-target strategy +/- adalimumab and to determine if HBL6months is associated with radiographic progression after 2...... associated with ∆TSS after 2 years (β = -0.086 (95% confidence interval = -0.15; -0.025) TSS unit/mg/cm(2) increase, p = 0.006) but not with presence of radiographic progression (∆TSS >0) (OR 0.96 (0.92-1.0), p = 0.10). In early RA patients treated with a methotrexate-based treat-to-target strategy...

  15. Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate

    OpenAIRE

    Humphreys, Jenny H; Warner, Alexander; Costello, Ruth; Lunt, Mark; Verstappen, Suzanne M M; Dixon, William G

    2017-01-01

    Background Patients with rheumatoid arthritis (RA) who take methotrexate (MTX) are advised to limit their alcohol intake due to potential combined hepatotoxicity. However, data are limited to support this. The aim of this study was to quantify the risk of developing abnormal liver blood tests at different levels of alcohol consumption, using routinely collected data from primary care. Methods Patients with RA in the Clinical Practice Research Datalink starting MTX between 1987 and 2016 were i...

  16. COMPARATIVE EVALUATION OF THE EFFICACY AND SAFETY OF TREATMENT USING ADALIMUMAB IN COMBINATION WITH METHOTREXATE AND METHOTREXATE MONOTHERAPY IN CHILDREN WITH POLYARTICULAR JUVENILE IDIOPATHIC ARTHRITIS IN COMBINATION WITH UVEITIS

    Directory of Open Access Journals (Sweden)

    V. А. Kel’tsev

    2014-01-01

    Full Text Available Juvenile idiopathic arthritis (JIA is the most common rheumatic disease in children and it is characterized by a primary lesion of the joints, organs and tissues with the formation of multiple organ failure of varying severity. The article describes the results of studying the efficacy and safety of adalimumab in combination with methotrexate (n = 26 and methotrexate monotherapy (n = 17 when treating the patients with polyarticular JIA and uveitis refractory to the basic immunosuppressive therapy. It was shown that the combination therapy induced the remission of arthritis in children with JIA in a shorter period of time. After 1 year, the disease remission was recorded in 42% of children in the treatment group and in 18% of children in the comparison group, the uveitis remission — in 26 (54% of 48 eyes and 2 (7% of 28 eyes with signs of lesions, respectively. It should be noted that adalimumab in combination with methotrexate was well tolerated and no serious adverse effects were recorded. Thus, the introduction of adalimumab in the treatment regimen of children with JIA and uveitis refractory to the basic immunosuppressive therapy allowed for the rapid disease remission while preserving the effect in a significant number of patients during the following year.

  17. Recommendations by the Spanish Society of Rheumatology for the management of patients diagnosed with rheumatoid arthritis who cannot be treated with methotrexate.

    Science.gov (United States)

    García-Vicuña, Rosario; Martín-Martínez, María Auxiliadora; Gonzalez-Crespo, María Rosa; Tornero-Molina, Jesús; Fernández-Nebro, Antonio; Blanco-García, Francisco Javier; Blanco-Alonso, Ricardo; Marsal-Barril, Sara

    To establish a set of recommendations for the management of patients diagnosed with rheumatoid arthritis (RA) who cannot be treated with methotrexate (MTX) due to contraindications, drug toxicity or lack of adherence, and to establish therapeutic strategies more effective and safer in these RA patients. A qualitative analysis of the scientific evidence available to June 2015. The 2-round Delphi technique of consensus was used to collect and establish expert opinion based on the participants' clinical experience when only low quality evidence was available. A total of eighteen recommendations were developed for the management of this patient profile. Fourteen of these recommendations were related to drug safety aspects. Recommendations on contraindication and toxicity of MTX have been updated. The experts recommend the use of biological monotherapy, a preferred treatment option, in patients whose profiles reveal a contraindication, intolerance or circumstances that prevent us against the use of MTX. There is some high-quality scientific evidence that supports contraindication and establishes certain conditions of MTX use in RA patients with specific clinical profiles. Copyright © 2016. Publicado por Elsevier España, S.L.U.

  18. Fifteen chord FIR polarimetry system on MTX

    International Nuclear Information System (INIS)

    Rice, B.W.

    1992-03-01

    A far-infrared (FIR) polarimeter diagnostic has been added to an existing fifteen chord interferometer on the Microwave Tokamak Experiment (MTX). The polarimeter utilizes a new technique for determination of the Faraday rotation angle based on phase measurements of a rotating polarization ellipse. This technique allows the rotation angle to be determined even in the presence of signal amplitude variations caused by refraction. The implementation of this instrument requires no new detectors and minimal optics, making it quite inexpensive to add on to existing multichord interferometers. The MTX polarimeter has been operating for about a year and has achieved a resolution of ≤0.2 degrees with a bandwidth of ≅1 kHz and a chord spacing of 1.5 cm. Typical Faraday rotation angles on MTX are in the range of 5--15 degrees. To obtain the poloidal field, the line-integrated density and Faraday rotation profiles are inverted in a manner consistent with the Grad-Shafranov equilibrium to first order in the inverse aspect-ratio expansion. Profile measurements during normal ohmic operation are presented

  19. Delayed methotrexate excretion in infants and young children with primary central nervous system tumors and postoperative fluid collections.

    Science.gov (United States)

    Wright, Karen D; Panetta, John C; Onar-Thomas, Arzu; Reddick, Wilburn E; Patay, Zoltan; Qaddoumi, Ibrahim; Broniscer, Alberto; Robinson, Giles; Boop, Frederick A; Klimo, Paul; Ward, Deborah; Gajjar, Amar; Stewart, Clinton F

    2015-01-01

    High-dose methotrexate (HD-MTX) has been used to treat children with central nervous system tumors. Accumulation of MTX within pleural, peritoneal, or cardiac effusions has led to delayed excretion and increased risk of systemic toxicity. This retrospective study analyzed the association of intracranial post-resection fluid collections with MTX plasma disposition in infants and young children with brain tumors. Brain MRI findings were analyzed for postoperative intracranial fluid collections in 75 pediatric patients treated with HD-MTX and for whom serial MTX plasma concentrations (MTX) were collected. Delayed plasma excretion was defined as (MTX) ≥1 μM at 42 hours (h). Leucovorin was administered at 42 h and then every 6 h until (MTX) collections present. Population average (inter-individual variation) MTX clearance was 96.0 ml/min/m² (41.1 CV %) and increased with age. Of the patients with intracranial fluid collections, 24 had delayed excretion; only 2 of the 17 without fluid collections (P collection, total leucovorin dosing, or hydration fluids between those with and without toxicity. Although an intracranial fluid collection is associated with delayed MTX excretion, HD-MTX can be safely administered with monitoring of infants and young children with intracranial fluid collections. Infants younger than 1 year may need additional monitoring to avoid toxicity.

  20. Does methotrexate administration for ectopic pregnancy after in vitro fertilization impact ovarian reserve or ovarian responsiveness?

    Science.gov (United States)

    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.

  1. Preparation of Multifunctional Fe@Au Core-Shell Nanoparticles with Surface Grafting as a Potential Treatment for Magnetic Hyperthermia

    Directory of Open Access Journals (Sweden)

    Ren-Jei Chung

    2014-01-01

    Full Text Available Iron core gold shell nanoparticles grafted with Methotrexate (MTX and indocyanine green (ICG were synthesized for the first time in this study, and preliminarily evaluated for their potential in magnetic hyperthermia treatment. The core-shell Fe@Au nanoparticles were prepared via the microemulsion process and then grafted with MTX and ICG using hydrolyzed poly(styrene-alt-maleic acid (PSMA to obtain core-shell Fe@Au-PSMA-ICG/MTX nanoparticles. MTX is an anti-cancer therapeutic, and ICG is a fluorescent dye. XRD, TEM, FTIR and UV-Vis spectrometry were performed to characterize the nanoparticles. The data indicated that the average size of the nanoparticles was 6.4 ± 09 nm and that the Au coating protected the Fe core from oxidation. MTX and ICG were successfully grafted onto the surface of the nanoparticles. Under exposure to high frequency induction waves, the superparamagnetic nanoparticles elevated the temperature of a solution in a few minutes, which suggested the potential for an application in magnetic hyperthermia treatment. The in vitro studies verified that the nanoparticles were biocompatible; nonetheless, the Fe@Au-PSMA-ICG/MTX nanoparticles killed cancer cells (Hep-G2 via the magnetic hyperthermia mechanism and the release of MTX.

  2. Preparation of Multifunctional Fe@Au Core-Shell Nanoparticles with Surface Grafting as a Potential Treatment for Magnetic Hyperthermia.

    Science.gov (United States)

    Chung, Ren-Jei; Shih, Hui-Ting

    2014-01-24

    Iron core gold shell nanoparticles grafted with Methotrexate (MTX) and indocyanine green (ICG) were synthesized for the first time in this study, and preliminarily evaluated for their potential in magnetic hyperthermia treatment. The core-shell Fe@Au nanoparticles were prepared via the microemulsion process and then grafted with MTX and ICG using hydrolyzed poly(styrene-alt-maleic acid) (PSMA) to obtain core-shell Fe@Au-PSMA-ICG/MTX nanoparticles. MTX is an anti-cancer therapeutic, and ICG is a fluorescent dye. XRD, TEM, FTIR and UV-Vis spectrometry were performed to characterize the nanoparticles. The data indicated that the average size of the nanoparticles was 6.4 ± 09 nm and that the Au coating protected the Fe core from oxidation. MTX and ICG were successfully grafted onto the surface of the nanoparticles. Under exposure to high frequency induction waves, the superparamagnetic nanoparticles elevated the temperature of a solution in a few minutes, which suggested the potential for an application in magnetic hyperthermia treatment. The in vitro studies verified that the nanoparticles were biocompatible; nonetheless, the Fe@Au-PSMA-ICG/MTX nanoparticles killed cancer cells (Hep-G2) via the magnetic hyperthermia mechanism and the release of MTX.

  3. Mechanisms of immunological eradication of a syngeneic guinea pig tumor. II. Effect of methotrexate treatment and T cell depletion of the recipient on adoptive immunity

    International Nuclear Information System (INIS)

    Shu, S.; Fonseca, L.S.; Hunter, J.T.; Rapp, H.J.

    1983-01-01

    The influence of methotrexate on the development of immunity to the line 10 hepatoma was studied in guinea pigs. Chronic methotrexate treatment had no apparent effect on the ability of immune guinea pigs to suppress the growth of inoculated tumor cells. In contrast, the same methotrexate regimen inhibited the development of tumor immunity if started before the 8th day after immunization with a vaccine containing viable line 10 cells admixed with Bacillus Calmette-Guerin (BCG) cell walls. Thus, methotrexate selectively inhibited the afferent limb of the immune response. In adoptive transfer experiments, methotrexate-treated recipient guinea pigs were capable of being passively sensitized with immune spleen cells, indicating that the primary cell-mediated immune response of the recipient was not required for adoptive immunity. The contribution of recipient T cells in adoptive immunity was further investigated in guinea pigs deleted of T cells by thymectomy, irradiation, and bone marrow reconstitution. Despite demonstrable deficiency in T lymphocyte reactions, B animals were fully capable of rejecting tumors after transfer of immune cells. These results suggest that the expression of adoptive immunity was independent of recipient T cell participation. In addition, sublethal irradiation of immune spleen cells prior to adoptive transfer abolished their efficacy. Proliferation of transferred immune cells in the recipient may be essential for expression of adoptive immunity

  4. Transporter-mediated interaction of indican and methotrexate in rats

    Directory of Open Access Journals (Sweden)

    Shiuan-Pey Lin

    2018-04-01

    Full Text Available Indican (indoxyl-β-D-glucoside is present in several Chinese herbs e.g. Isatis indigotica, Polygonum tinctorium and Polygonum perfoliatum. The major metabolite of indican was indoxyl sulfate (IS, an uremic toxin which was a known substrate/inhibitor of organic anion transporter (OAT 1, OAT 3 and multidrug resistance-associated protein (MRP 4. Methotrexate (MTX, an important immunosuppressant with narrow therapeutic window, is a substrate of OAT 1, 2, 3, 4 and MRP 1, 2, 3, 4. We hypothesized that IS, the major metabolite of oral indican, might inhibit the renal excretion of MTX mediated by OAT 1, OAT 3 and MRP 4. Therefore, this study investigated the effect of oral indican on the pharmacokinetics of MTX. Rats were orally given MTX with and without indican (20.0 and 40.0 mg/kg in a parallel design. The serum MTX concentration was determined by a fluorescence polarization immunoassay. For mechanism clarification, phenolsulfonphthalein (PSP, 5.0 mg/kg, a probe substrate of OAT 1, OAT 3, MRP 2 and MRP 4, was intravenously given to rats with and without a intravenous bolus of IS (10.0 mg/kg to measure the effect of IS on the elimination of PSP. The results indicated that 20.0 and 40.0 mg/kg of oral indican significantly increased the area under concentration–time curve0-t (AUC0-t of MTX by 231% and 259%, prolonged the mean residence time (MRT by 223% and 204%, respectively. Furthermore, intravenous IS significantly increased the AUC0-t of PSP by 204% and decreased the Cl by 68%. In conclusion, oral indican increased the systemic exposure and MRT of MTX through inhibition on multiple anion transporters including OAT 1, OAT 3 and MRP 4 by the major metabolite IS. Keywords: Indican, Indoxyl sulfate, Methotrexate, Anion transporters, Pharmacokinetics

  5. Delayed High-dose Methotrexate Excretion and Influencing Factors in Osteosarcoma Patients

    Directory of Open Access Journals (Sweden)

    Wei Zhang

    2016-01-01

    Conclusions: Precaution of delayed excretion of MTX is needed during osteosarcoma treatment using HD-MTX. An optimal individualized rescue strategy can be created with consideration of gender, age, and C24 h.

  6. Factors Associated with Myelosuppression Related to Low-Dose Methotrexate Therapy for Inflammatory Rheumatic Diseases

    Science.gov (United States)

    Mori, Shunsuke; Hidaka, Michihiro; Kawakita, Toshiro; Hidaka, Toshihiko; Tsuda, Hiroyuki; Yoshitama, Tamami; Migita, Kiyoshi; Ueki, Yukitaka

    2016-01-01

    Objective Severe myelosuppression is a serious concern in the management of rheumatic disease patients receiving methotrexate (MTX) therapy. This study was intended to explore factors associated with the development of MTX-related myelosuppression and its disease severity. Methods We retrospectively examined a total of 40 cases of MTX-related myelosuppression that had been filed in the registries of participating rheumatology and hematology divisions. Data before onset were compared with those of 120 controls matched for age and sex. Cytopenia was graded according to the National Cancer Institute criteria for adverse events. Data before and at onset were compared between the severe and non-severe groups. Results Non-use of folic acid supplements, concurrent medications, and low renal function were significantly associated with the development of myelosuppression (p disease severity was not dependent on MTX doses. Serum albumin levels and folic acid supplementation are the important factors affecting the severity of MTX-related pancytopenia and neutropenia. PMID:27128679

  7. Effect of methotrexate conjugated PAMAM dendrimers on the viability of MES-SA uterine cancer cells

    Directory of Open Access Journals (Sweden)

    Samreen Khatri

    2014-01-01

    Full Text Available The aim of this work was to synthesize methotrexate (MTX-polyamidoamine (PAMAM dendritic nanoconjugates and to study their effect on cell viability in uterine sarcoma cells. The amide-bonded PAMAM dendrimer-MTX conjugates were prepared by conjugation between the amine-terminated G5 dendrimer and the carboxylic groups of the MTX using a dicyclohexylcarbodiimide coupling reaction. The formation of conjugates was evaluated by ultraviolet (UV and 1 H nuclear magnetic resonance ( 1 H NMR spectroscopy studies. The cell survival of MES-SA cells, a uterine sarcoma cell line, was evaluated in the presence of the dendrimer-MTX nanoconjugate, using appropriate controls. The UV and 1 H NMR study confirmed the formation of covalent bonds between the drug and the dendrimer. The cell viability study indicated that the nanoconjugates had significantly improved cell killing compared to the free MTX.

  8. St. John's wort significantly increased the systemic exposure and toxicity of methotrexate in rats

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Shih-Ying [Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan (China); Juang, Shin-Hun [Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan (China); Department of Medical Research, China Medical University Hospital, Taichung, Taiwan (China); Tsai, Shang-Yuan; Chao, Pei-Dawn Lee [School of Pharmacy, China Medical University, Taichung, Taiwan (China); Hou, Yu-Chi, E-mail: hou5133@gmail.com [School of Pharmacy, China Medical University, Taichung, Taiwan (China); Department of Medical Research, China Medical University Hospital, Taichung, Taiwan (China)

    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%, 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.

  9. Microfluidic platform for dynamic in vitro optimization of methotrexate-loaded lipid nanoparticle delivery for personalized osteosarcoma treatment

    Energy Technology Data Exchange (ETDEWEB)

    Muñoz-Hernando, M.; Macias, P.; Abella, M.; Desco, M.; Sharpe, S.; Vaquero, J.J.; Muñoz-Barrutia, M.

    2016-07-01

    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. The use of lipid nanoparticles as biodegradable shells for controlled drug delivery shows promise as a more effective and targeted tumor treatment. However, current techniques for in vitro testing of these vehicles have shown little validity due to their static nature, in which nanoparticles sediment onto the bottom of the wells and kill the cells via asphyxiation, hiding the real effect achieved by the nanoparticles. In this work, a microfluidic platform capable of determining the optimum dose of methotrexate-loaded lipid nanoparticles in osteosarcoma treatment is presented as a promising alternative to current nanoparticle characterization assays. (Author)

  10. 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.

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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

  13. Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs

    DEFF Research Database (Denmark)

    Singh, Jasvinder A; Hossain, Alomgir; Tanjong Ghogomu, Elizabeth

    2016-01-01

    , tocilizumab) and small molecule tofacitinib, versus comparator (MTX, DMARD, placebo (PL), or a combination) in adults with rheumatoid arthritis who have failed to respond to methotrexate (MTX) or other disease-modifying anti-rheumatic drugs (DMARDs), i.e., MTX/DMARD incomplete responders (MTX.......78)) were similarly inconclusive and downgraded to low quality for both imprecision and indirectness.Main results text shows the results for tofacitinib and differences between medications. AUTHORS' CONCLUSIONS: Based primarily on RCTs of 6 months' to 12 months' duration, there is moderate quality evidence...

  14. Long-term safety of etanercept and adalimumab compared to methotrexate in patients with juvenile idiopathic arthritis (JIA).

    Science.gov (United States)

    Klotsche, Jens; Niewerth, Martina; Haas, Johannes-Peter; Huppertz, Hans-Iko; Zink, Angela; Horneff, Gerd; Minden, Kirsten

    2016-05-01

    Published evidence on the long-term safety of etanercept (ETA) and adalimumab (ADA) in patients with polyarticular juvenile idiopathic arthritis (pJIA) is still limited. To investigate the rates of serious adverse events (SAE) and of events of special interest (ESI) under ETA and ADA treatment. Patients with pJIA were prospectively observed in the national JIA biological register, Biologika in der Kinderrheumatologie, and its follow-up register, Juvenile arthritis Methotrexate/Biologics long-term Observation. We calculated the relative risks of SAE and ESI for ETA and ADA compared with methotrexate (MTX). Among the 1414 patients treated with ETA (n=1414; 4461 exposure years (EY)) and ADA (n=320; 493 EY), significantly more SAE, infections and medically important infections were observed (ETA: 4.5, 5.7, 0.9; ADA: 4.7, 11.4, 0.4 per 100 EY) compared with those treated with MTX alone (n=1455; 2.907 EY; 2.6, 5.5, 0.5 per 100 EY). The risk for malignancies was not significantly increased for ETA and ADA compared with MTX (0.09, 0.27 and 0.07/100 person-years). Patients under ETA monotherapy developed more frequently incident inflammatory bowel disease (IBD) and incident uveitis (0.5 and 0.8/100 EY) than patients treated by ETA in combination with MTX (0.1 and 0.2/100 EY) or MTX alone (0.03 and 0.1/100 EY). Our data confirm the acceptable long-term tolerability of ETA and ADA in pJIA. However, whether the onset of IBD and uveitis during ETA monotherapy is a paradoxical effect or an inadequate response to therapy remains unclear and requires further investigation in this growing cohort. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  15. Methotrexate for ocular inflammatory diseases.

    Science.gov (United States)

    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 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. 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

  16. The METEX study: Methotrexate versus expectant management in women with ectopic pregnancy: A randomised controlled trial

    Directory of Open Access Journals (Sweden)

    Visser Harry

    2008-06-01

    Full Text Available Abstract Background Patients with ectopic pregnancy (EP and low serum hCG concentrations and women with a pregnancy of unknown location (PUL and plateauing serum hCG levels are commonly treated with systemic methotrexate (MTX. However, there is no evidence that treatment in these particular subgroups of women is necessary as many of these early EPs may resolve spontaneously. The aim of this study is whether expectant management in women with EP or PUL and with low but plateauing serum hCG concentrations is an alternative to MTX treatment in terms of treatment success, future pregnancy, health related quality of life and costs. Methods/Design A multicentre randomised controlled trial in The Netherlands. Hemodynamically stable patients with an EP visible on transvaginal ultrasound and a plateauing serum hCG concentration Discussion This trial will provide guidance on the present management dilemmas in women with EPs and PULs with low and plateauing serum hCG concentrations. Trial registration Current Controlled Trials ISRCTN 48210491

  17. MTX microwave-electric-field diagnostic

    International Nuclear Information System (INIS)

    Odajima, Kazuo; Ohasa, Kazumi; Shiho, Makoto

    1990-06-01

    A joint Japan-U.S. project is in progress to measure the high electric fields produced by a free-electron laser beam of GW-peak-power level when injected into the plasma of the Microwave Tokamak Experiment (MTX) at the Lawrence Livermore National Laboratory in California. In this report, we discuss the planned method of measurement and the status of the work. The equipment needed is either well along in the design stage or is being built. We plan to test out the combined operation of all components in Japan before shipping to Livermore. Although the measurement appears difficult for a variety of technical and physics reasons, calculations indicate that it should be possible. (author)

  18. Dioscin enhances methotrexate absorption by down-regulating MDR1 in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Lijuan, E-mail: jlwang1979@163.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning (China); Wang, Changyuan, E-mail: wangcyuan@163.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning (China); Peng, Jinyong, E-mail: jinyongpeng2005@163.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning (China); Liu, Qi, E-mail: llaqii@yahoo.com.cn [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning (China); Meng, Qiang, E-mail: mengq531@yahoo.cn [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning (China); Sun, Huijun, E-mail: sunhuijun@hotmail.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning (China); Huo, Xiaokui, E-mail: huoxiaokui@163.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning (China); and others

    2014-06-01

    The purpose of this study was to investigate the enhancing effect of dioscin on the absorption of methotrexate (MTX) and clarify the molecular mechanism involved in vivo and in vitro. Dioscin increased MTX chemosensitivity and transepithelial flux in the absorptive direction, significantly inhibiting multidrug resistance 1 (MDR1) mRNA and protein expression and MDR1 promoter and nuclear factor κ-B (NF-κB) activities in Caco-2 cells. Moreover, inhibitor κB-α (IκB-α) degradation was inhibited by dioscin. Dioscin enhanced the intracellular concentration of MTX by down-regulating MDR1 expression through a mechanism that involves NF-κB signaling pathway inhibition in Caco-2 cells. Dioscin strengthened MTX absorption by inhibiting MDR1 expression in rat intestine. In addition, even though MTX is absorbed into the enterocytes, there was no increase in toxicity observed, and that, in fact, decreased toxicity was seen. - Highlights: • Dioscin raised MTX concentration by inhibiting MDR1 in Caco-2 cells. • Dioscin suppresses MDR1 by inhibiting NF-κB signaling pathway in Caco-2 cells. • Dioscin can enhance MTX absorption via inhibiting MDR1 in vivo and in vitro. • Dioscin did not increase MTX-induced gastrointestinal mucosal toxicity.

  19. Lymphatic transport and lymph node targeting of methotrexate-conjugated PEGylated dendrimers are enhanced by reducing the length of the drug linker or masking interactions with the injection site.

    Science.gov (United States)

    Ryan, Gemma M; McLeod, Victoria M; Mehta, Dharmini; Kelly, Brian D; Stanislawski, Pauline C; Owen, David J; Kaminskas, Lisa M; Porter, Christopher J H

    2017-11-01

    Drug conjugation to dendrimer-based delivery systems has been shown to enhance delivery to the lymphatic system after subcutaneous administration. Dendrimer interaction with components of the interstitium at the injection site, however, may prevent drainage from the injection site. The current study sought to vary the length of a linker employed to conjugate methotrexate (MTX) to a PEGylated dendrimer, in an attempt to reduce MTX interaction with interstitial binding sites and enhance lymphatic drainage. Dendrimers with shorter linkers resulted in higher lymphatic drainage, presumably via shielding of interaction sites by the PEG mantle, but were not retained in lymph nodes. Improved drainage of dendrimers with longer linkers was achieved through coadministration with dextran to mask interactions at the injection site while maintaining retention within the node. Enhanced drug exposure to the lymph node has the potential to enhance the treatment of lymph-node resident cancer metastases. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Measures of 6-mercaptopurine and methotrexate maintenance therapy intensity in childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Nielsen, Stine Nygaard; Grell, Kathrine; Nersting, Jacob

    2016-01-01

    PURPOSE: Normal white blood cell counts (WBC) are unknown in children with acute lymphoblastic leukemia (ALL). Accordingly, 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy is adjusted by a common WBC target of 1.5-3.0 × 10(9)/L. Consequently, the absolute degree...

  1. Use of methotrexate in patients with uveitis.

    Science.gov (United States)

    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.

  2. Nodulose por Metotrexato Methotrexate Induced Nodulosis

    Directory of Open Access Journals (Sweden)

    Fernanda Guidolin

    2005-08-01

    Full Text Available A nodulose por metotrexato (MTX é um dos efeitos colaterais pouco conhecidos do uso desse medicamento em doses baixas. Embora classicamente descrita em casos de artrite reumatóide, tem aparecido, também, em outras doenças reumáticas. Descreve-se aqui um caso de nodulose por MTX em uma paciente com artrite reumatóide soropositiva, que utilizava esse medicamento há um ano, com bom controle do processo articular. Segue-se uma breve revisão sobre o assunto.Methotrexate-induced nodulosis is a rare side effect of this drug when it is used in low doses. Although classically described in rheumatoid arthritis patients, it may also appear in other rheumatic disorders. We describe a seropositive rheumatoid arthritis patient who developed methotrexate-induced nodulosis after using this drug for a year, with good control of articular symptoms. This case presentation is followed by a brief revision on the subject.

  3. Double modulation of 5-fluorouracil by methotrexate and high-dose L-leucovorin in advanced colorectal cancer.

    Science.gov (United States)

    Romero, A O; Perez, J E; Cuevas, M A; Lacava, J A; Sabatini, C L; Dominguez, M E; Rodriguez, R; Barbieri, M R; Ortiz, E H; Salvadori, M A; Acuña, L A; Acuña, J M; Langhi, M J; Amato, S; Machiavelli, M R; Leone, B A; Vallejo, C T; Lorusso, V; DeLena, M

    1998-02-01

    A phase II trial was performed to evaluate the efficacy and toxicity of a double modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) and L-leucovorin (L-LV) in patients with advanced recurrent (inoperable) or metastatic colorectal carcinoma (ACC). Between July 1993 and October 1995, 41 patients with ACC received a regimen that consisted of MTX 150 mg/m2 i.v., infused over a 20-minute period at hour 0, followed 19 hours later by L-LV 250 mg/m2 in a 2-hour i.v. infusion. 5-FU, 900 mg/m2, was administered by i.v. push injection at hour 20. Beginning 24 hours after MTX administration, all patients received four doses of L-LV, 15 mg/m2 i.m., every 6 hours. Cycles were repeated every 15 days. Two patients were not assessable for response. Objective regression was observed in 11 of 39 (28%) patients, [95% confidence interval (CI), 14-42%]. One (2%) patient achieved complete response (CR) and 10 (26%) partial response (PR). No change was recorded in 15 (39%) patients and progressive disease was noted in 13 (33%) patients. The median time to treatment failure was 6 months and the median survival time was 10 months. Toxicity was within acceptable limits, but one therapy-related death due to severe leukopenia was observed. The dose-limiting toxicity was mucositis. Eight episodes of grade 3 or 4 stomatitis were observed, and were responsible for dosage modifications of MTX and 5-FU. In conclusion, further in experimental and clinical studies are clearly necessary in order to design the best modulatory strategy of 5-FU.

  4. Role of sonography in the recognition, assessment, and treatment of cesarean scar ectopic pregnancies.

    Science.gov (United States)

    McKenna, David A; Poder, Liina; Goldman, Mindy; Goldstein, Ruth B

    2008-05-01

    Cesarean scar ectopic pregnancies (CSEPs) are rare but may have serious adverse consequences and are therefore important to promptly recognize on sonography. We aim to describe the typical sonographic appearances. Potential treatments are discussed, including sonographic guidance for transcervical injection of methotrexate (MTX) into the gestational sac. Two patients with CSEPs were treated with systemic and intra-amniotic administration of MTX under sonographic guidance. Both patients were followed clinically after medical treatment, resulting in low maternal morbidity and mortality. Considering the increasing rate of cesarean delivery and the increased risk of CSEPs, sonologists should be familiar with the sonographic appearances of a pregnancy implanted into the cesarean scar. We show how to correctly diagnose scar implantation and describe how to perform sonographically guided transcervical injection of MTX.

  5. Comparison of central nervous system prophylaxis with cranial radiation and intrathecal methotrexate versus intrathecal methotrexate alone in acute lymphoblastic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Muriel, F.S.; Svarch, E.; Pavlovsky, S.; Eppinger-Helft, M.; Braier, J.; Vergara, B.; Garay, G.; Kvicala, R.; Divito, J.M.; Failace, R.

    1983-08-01

    In acute lymphoblastic leukemia, central nervous system prophylaxis with irradiation plus intrathecal methotrexate (i.t. MTX) reduces the incidence of CNS relapse to 7%-15%. However, increased evidence of CNS delayed toxicity was recognized mainly in children as CT scan abnormalities and neuropsychologic alterations. Two questions were analyzed: (1) Will further doses of i.t. methotraxate and dexamethasone (i.t. MTX-DMT) decrease the incidence of CNS relapse. (2) Is i.t. MTX-DMT given during induction and maintenance as effective as cranium irradiation plus i.t. MTX-DMT. Incidence of primary CNS relapse in i.t. MTX-DMT-treated patients with a WBC count < 50,000 and in the untreated group was 11%. In patients with a WBC count > 50,000, it was 16% in the treated group and 19% in the control group. These patients were compared with patients which had received 3 doses of i.t. MTX-DMT alone during induction, 3 doses weekly during the first month of remission, and quarterly thereafter. The incidence of leukemia at 60 mo in patients with a WBC count < 50,000 was 20% in the irradiated group and 32% in the group with i.t. MTX-DMT alone. The relapse-free survival at 60 mo was 26% and 41%, respectively, (p < 0.0005). The incidence in patients with a WBC count > 50,000 at 48 mo was 28% and 42% in the irradiated and nonirradiated group respectively. Complete remission remained at 15% and 16% respectively of patients disease-free at 48 mo. We conclude that (A) after cranial irradiation plus i.t. MTX-DMT X 5, the use of additional doses of i.t. MTX-DMT is not of further benefit in preventing CNS relapse; (B) use of i.t. MTX-DMT alone compares with cranial irradiation plus i.t. MTX-DMT in incidence of CNS relapse; and (C) relapse-free survival and survival in patients with a WBC count < 50.000 were significantly longer in those without cranial irradiation.

  6. Myelotoxicity after high-dose methotrexate in childhood acute leukemia is influenced by 6-mercaptopurine dosing but not by intermediate thiopurine methyltransferase activity

    DEFF Research Database (Denmark)

    Levinsen, Mette; Rosthøj, Susanne; Nygaard, Ulrikka

    2015-01-01

    Purpose: Through enhancement of 6-mercaptopurine (6MP) bioavailability and inhibition of purine de novo synthesis, high-dose methotrexate (HD-MTX) may increase incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6MP. Patients with intermediate activity of thiopurine...... methyltransferase (TPMTIA) have higher cytosol 6-thioguanine nucleotide levels. We investigated toxicity following HD-MTX during MTX/6MP maintenance therapy in relation to 6MP and TPMT. Methods: Using linear mixed models, we explored myelo- and hepatotoxicity in relation to 6MP dosage and TPMT phenotype following 1......,749 HD-MTX courses to 411 children with acute lymphoblastic leukemia on maintenance therapy. Results: The degree of myelosuppression following HD-MTX was similar for patients with TPMTIA and patients with high TPMT activity (TPMTHA), when HD-MTX started with same blood counts and 6MP doses. However...

  7. Evaluation of the Efficacy of Combined Therapy of Methotrexate and Etanercept versus Methotrexate as a Mono-Therapy

    Directory of Open Access Journals (Sweden)

    Sylejman Rexhepi

    2018-04-01

    CONCLUSIONS: Based on our results achieved during 2 years we can conclude that ETN in combination with MTX reduced disease activity, slowed radiographic progression and improved clinical manifestations more effectively than MTX alone. No serious adverse events were noticed in the group with combination treatment.

  8. Population PK/PD model of homocysteine concentrations after high-dose methotrexate treatment in patients with acute lymphoblastic leukemia.

    Directory of Open Access Journals (Sweden)

    Hauke Rühs

    Full Text Available Elevated homocysteine concentrations have been associated with methotrexate-induced neurotoxicity. Based on methotrexate and homocysteine plasma concentrations of 494 children with acute lymphoblastic leukemia treated with high-dose methotrexate in the TOTAL XV study, a pharmacokinetic/pharmacodynamic (PK/PD model was built with NONMEM. Several compartment and indirect response models were investigated. The pharmacokinetic disposition of methotrexate was best described by a two-compartment model. Homocysteine concentrations were included by an indirect response model where methotrexate inhibition of the homocysteine elimination rate was described by an E(max model. The homocysteine baseline level was found to be age-dependent. Simulations revealed that folinate rescue therapy does not affect peak concentrations of homocysteine but leads to a modestly reduced homocysteine exposure. In conclusion, our PK/PD model describes the increase of methotrexate-induced HCY concentrations with satisfactory precision and can be applied to assess the effect of folinate regimens on the HCY concentration-time course.

  9. Individualized toxicity-titrated 6-mercaptopurine increments during high-dose methotrexate consolidation treatment of lower risk childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Frandsen, Thomas Leth; Abrahamsson, Jonas; Lausen, Birgitte Frederiksen

    2011-01-01

    This study explored the feasibility and toxicity of individualized toxicity-titrated 6-mercaptopurine (6MP) dose increments during post-remission treatment with High-dose methotrexate (HDM) (5000 mg/m2, ×3) in 38 patients with Childhood (ALL). Patients were increased in steps of 25 mg 6MP/m2 per...... the remaining patients (P = 0·03). This study shows individualized toxicity-titrated 6MP dosing during consolidation is feasible without increased risk of toxicity....

  10. Cyclosporin-Methotrexate Compared with Cyclosporin-Methotrexate-Methylprednisolone Therapy for the Prophylaxis of Acute Graft-Versus Host Disease

    International Nuclear Information System (INIS)

    Khattab, N.F.

    2010-01-01

    Acute graft-versus host (GVHD) disease is a common immunologic complication, which occurs in 40-50% of the recipients of allogenic stem cell transplantation (SCT). The role of corticosteroid in the prevention of GVHD is not well established. We report here a study to determine whether the addition of methylprednisolone to the combination of cyclosporine (CSA) and methotrexate (MTX), methylp-rednisolone (MP) for the prophylaxis of acute GVHD would further decrease the incidence of acute GVHD. A group of patients (25 patients with acute myeloid leukemia (AML) and 12 patients with acute lymphocytic leukemia (ALL) that received CSA/MTX/MP started from 2004 to 2008, were compared to a historical group of patients (19 patient with acute myeloid leukemia (AML) and 12 patients with acute lymphocytic leukemia (ALL) that received GVHD prophylaxis in the form of CSA/MTX only from 1999 to 2003). The primary endpoint in this study was the develop-ment of GVHD and the secondary end point was overall and disease free survival. Both groups of patients were matched for age, sex, donor recipient sex, low risk patients and high risk patients. Although the incidence of acute GVHD in the MP -ve group was 35% versus 24% in the MP+ve group, there was no significant difference between them. The overall survival showed a significant difference between the 2 groups (p<0.05). It was 48% for the 2 drug regimen (CSA/MTX) vs. 81% for the three drug regimen (CSA/MTX/MP). There was a significant decrease in the relapse rate in patients on CSA/MTX/MP (p<0.05). In conclusion, the addition of MP (methylprednis-olone) to the combination of CSA/MTX did not affect the incidence of acute GVHD significantly in allogeneic SCT but surprisingly the incidence of survival and relapse was markedly increased and decreased respectively

  11. Lack of effect of methotrexate in budesonide-refractory collagenous colitis

    Directory of Open Access Journals (Sweden)

    Münch A

    2013-08-01

    Full Text Available Andreas Münch,1,* Johan Bohr,2,3,* Lina Vigren,4 Curt Tysk,2,3,* Magnus Ström1,* 1Division of Gastroenterology and Hepatology, Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköping University, Linköping, 2Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Örebro University, Örebro, 3School of Health and Medical Science, Örebro University, Örebro, 4Division of Gastroenterology, Department of Clinical Science, Lund University, Malmö, Sweden *These authors are members of the Swedish Organization for the study of Inflammatory Bowel Disease (SOIBD, a national organization for gastroenterologists, colorectal surgeons, and basic scientists Background: In most cases, collagenous colitis can be treated effectively with budesonide. However, some patients develop side effects or have chronic symptoms refractory to budesonide. This paper reports an open case series of patients intolerant or refractory to budesonide who were treated with methotrexate (MTX. Methods and patients: Nine patients (seven women with a median (range age of 62 (44–77 years were studied. Bowel movements were registered during 1 week prior to baseline and after 6 and 12 weeks’ treatment, enabling calculation of the mean bowel movements/day. All patients underwent colonoscopy with biopsies before inclusion to confirm diagnosis. Open treatment with MTX was given 15 mg subcutaneously weekly for 6 weeks and was increased to 25 mg for a further 6 weeks if symptoms were unresponsive to the first 6 weeks’ treatment. The endpoint was clinical remission, which was defined as a mean <3 stools/day and mean <1 watery stool/day/week at Week 12. The Short Health Scale was used at baseline and Week 12 to assess health-related quality of life. Results: Five patients fulfilled the treatment according to the protocol and four patients discontinued the study after 3–6 weeks because of adverse events. No patient achieved

  12. Effects of prophylactic treatment of central nervous system leukemia in children

    International Nuclear Information System (INIS)

    Abe, Yukiko; Asakura, Akio; Endo, Norio

    1982-01-01

    Thirty-five children with previously untreated ALL or AUL who received CNS prophylatic therapy with 3 treatment regiments were analyzed. After eutering complete remission, patients received CNS-prophylaxis with one of the following regimens: Goup A- cyclic high dose multichemotherapy plus intermittent intra-thecal methotrexate (MTX); Group B-craniospinal irradiation plus intermittent intrathecal MTX; Group C-intermittent high dose intravenous MTX. Incidence of CNS-leukemia and bone marrow relapse was less frequent in Group B. EEG abnormalities were seen in 38.5% of Group A, 40% of Group B, and 28.6% of Group C respectively, but the abnormalities were transient. IQs of three groups were above 100, but IQs of CNS-leukemia patients, especially VIQs had a tendency to be low. (author)

  13. Cost analysis of biologic drugs in rheumatoid arthritis first line treatment after methotrexate failure according to patients' body weight.

    Science.gov (United States)

    Román Ivorra, José Andrés; Ivorra, José; Monte-Boquet, Emilio; Canal, Cristina; Oyagüez, Itziar; Gómez-Barrera, Manuel

    2016-01-01

    The objective was to assess the influence of patients' weight in the cost of rheumatoid arthritis treatment with biologic drugs used in first line after non-adequate response to methotrexate. Pharmaceutical and administration costs were calculated in two scenarios: non-optimization and optimization of intravenous (IV) vials. The retrospective analysis of 66 patients from a Spanish 1,000 beds-hospital Rheumatology Clinic Service was used to obtain posology and weight data. The study time horizon was two years. Costs were expressed in 2013 euros. For an average 69kg-weighted patient the lowest cost corresponded to abatacept subcutaneous (SC ABA) (€21,028.09) in the scenario without IV vials optimization and infliximab (IFX) (€20,779.29) with optimization. Considering patients' weight in the scenario without IV vials optimization infliximab (IFX) was the least expensive drug in patients ranged 45-49kg, IV ABA in 50-59kg and SC ABA in patients over 60kg. With IV vials optimization IFX was the least expensive drug in patients under 69kg and SC ABA over 70kg. Assuming comparable effectiveness of biological drugs, patient's weight is a variable to consider, potentials savings could reach €20,000 in two years. Copyright © 2015 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

  14. Dosing algorithm to target a predefined AUC in patients with primary central nervous system lymphoma receiving high dose methotrexate.

    Science.gov (United States)

    Joerger, Markus; Ferreri, Andrés J M; Krähenbühl, Stephan; Schellens, Jan H M; Cerny, Thomas; Zucca, Emanuele; Huitema, Alwin D R

    2012-02-01

    There is no consensus regarding optimal dosing of high dose methotrexate (HDMTX) in patients with primary CNS lymphoma. Our aim was to develop a convenient dosing algorithm to target AUC(MTX) in the range between 1000 and 1100 µmol l(-1) h. A population covariate model from a pooled dataset of 131 patients receiving HDMTX was used to simulate concentration-time curves of 10,000 patients and test the efficacy of a dosing algorithm based on 24 h MTX plasma concentrations to target the prespecified AUC(MTX) . These data simulations included interindividual, interoccasion and residual unidentified variability. Patients received a total of four simulated cycles of HDMTX and adjusted MTX dosages were given for cycles two to four. The dosing algorithm proposes MTX dose adaptations ranging from +75% in patients with MTX C(24) 12 µmol l(-1). The proposed dosing algorithm resulted in a marked improvement of the proportion of patients within the AUC(MTX) target between 1000 and 1100 µmol l(-1) h (11% with standard MTX dose, 35% with the adjusted dose) and a marked reduction of the interindividual variability of MTX exposure. A simple and practical dosing algorithm for HDMTX has been developed based on MTX 24 h plasma concentrations, and its potential efficacy in improving the proportion of patients within a prespecified target AUC(MTX) and reducing the interindividual variability of MTX exposure has been shown by data simulations. The clinical benefit of this dosing algorithm should be assessed in patients with primary central nervous system lymphoma (PCNSL). © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

  15. Methotrexate Dosage Reduction Upon Adalimumab Initiation: Clinical and Ultrasonographic Outcomes from the Randomized Noninferiority MUSICA Trial.

    Science.gov (United States)

    Kaeley, Gurjit S; Evangelisto, Amy M; Nishio, Midori J; Goss, Sandra L; Liu, Shufang; Kalabic, Jasmina; Kupper, Hartmut

    2016-08-01

    To examine the clinical and ultrasonographic (US) outcomes of reducing methotrexate (MTX) dosage upon initiating adalimumab (ADA) in MTX-inadequate responders with moderately to severely active rheumatoid arthritis (RA). MUSICA (NCT01185288) was a double-blind, randomized, parallel-arm study of 309 patients with RA receiving MTX ≥ 15 mg/week for ≥ 12 weeks before screening. Patients were randomized to high dosage (20 mg/week) or low dosage (7.5 mg/week) MTX; all patients received 40 mg open-label ADA every other week for 24 weeks. The primary endpoint was Week 24 mean 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) to test for noninferiority of low-dosage MTX using a 15% margin. US images were scored using a 10-joint semiquantitative system incorporating OMERACT definitions for pathology, assessing synovial hypertrophy, vascularity, and bony erosions. Rapid improvement in clinical indices was observed in both groups after addition of ADA. The difference in mean DAS28-CRP (0.37, 95% CI 0.07-0.66) comparing low-dosage (4.12, 95% CI 3.88-4.34) versus high-dosage MTX (3.75, 95% CI 3.52-3.97) was statistically significant and non-inferiority was not met. Statistically significant differences were not detected for most clinical, functional, and US outcomes. Pharmacokinetic and safety profiles were similar. In MUSICA, Week 24 mean DAS28-CRP, the primary endpoint, did not meet non-inferiority for the low-dosage MTX group. Although the differences between the 2 MTX dosage groups were small, our study findings did not support routine MTX reduction in MTX inadequate responders initiating ADA.

  16. Maitotoxin-4, a Novel MTX Analog Produced by Gambierdiscus excentricus

    Directory of Open Access Journals (Sweden)

    Francesco Pisapia

    2017-07-01

    Full Text Available Maitotoxins (MTXs are among the most potent toxins known. These toxins are produced by epi-benthic dinoflagellates of the genera Gambierdiscus and Fukuyoa and may play a role in causing the symptoms associated with Ciguatera Fish Poisoning. A recent survey revealed that, of the species tested, the newly described species from the Canary Islands, G. excentricus, is one of the most maitotoxic. The goal of the present study was to characterize MTX-related compounds produced by this species. Initially, lysates of cells from two Canary Island G. excentricus strains VGO791 and VGO792 were partially purified by (i liquid-liquid partitioning between dichloromethane and aqueous methanol followed by (ii size-exclusion chromatography. Fractions from chromatographic separation were screened for MTX toxicity using both the neuroblastoma neuro-2a (N2a cytotoxicity and Ca2+ flux functional assays. Fractions containing MTX activity were analyzed using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS to pinpoint potential MTX analogs. Subsequent non-targeted HRMS analysis permitted the identification of a novel MTX analog, maitotoxin-4 (MTX4, accurate mono-isotopic mass of 3292.4860 Da, as free acid form in the most toxic fractions. HRMS/MS spectra of MTX4 as well as of MTX are presented. In addition, crude methanolic extracts of five other strains of G. excentricus and 37 other strains representing one Fukuyoa species and ten species, one ribotype and one undetermined strain/species of Gambierdiscus were screened for the presence of MTXs using low resolution tandem mass spectrometry (LRMS/MS. This targeted analysis indicated the original maitotoxin (MTX was only present in one strain (G. australes S080911_1. Putative maitotoxin-2 (p-MTX2 and maitotoxin-3 (p-MTX3 were identified in several other species, but confirmation was not possible because of the lack of reference material. Maitotoxin-4 was detected in all seven strains of G

  17. Antioxidant and anti-inflammatory effects of virgin coconut oil supplementation abrogate acute chemotherapy oxidative nephrotoxicity induced by anticancer drug methotrexate in rats.

    Science.gov (United States)

    Famurewa, Ademola C; Aja, Patrick M; Maduagwuna, Ekenechukwu K; Ekeleme-Egedigwe, Chima A; Ufebe, Odomero G; Azubuike-Osu, Sharon O

    2017-12-01

    Methotrexate (MTX) is an efficacious anticancer agent constrained in clinical use due to its toxicity on non-targeted tissue, a considerable source of worry to clinicians. Because the toxicity is associated with oxidative stress and inflammation, the study explored antioxidant and anti-inflammatory effect of virgin coconut oil (VCO) supplementation in nephrotoxicity induced by MTX in rats. Rats were randomized into 4 groups (n=6) as follows: Control group; MTX group injected with single dose of MTX (20mg/kg, ip) on day 14; VCO (5%)+MTX and VCO (15%)+MTX groups were pre-treated with VCO diet and injected with single dose of MTX (20mg/kg, ip) on day 14. After 3 days of MTX injection, serum kidney markers, renal activities of antioxidant enzymes and glutathione (GSH) content were determined. Lipid peroxidation level and inflammatory markers- interleukin-6 (IL-6), nitric oxide (NO) and C-reactive protein (CRP) were estimated in kidney. Histopathological alterations were examined for kidney damage. MTX nephrotoxicity was evidenced by markedly elevated serum renal markers along with significant decreases in renal GSH and activities of antioxidant enzymes confirmed by histopathology. Lipid peroxidation level, IL-6, NO and CRP markedly increased compared to control. VCO supplementation prior to MTX injection attenuated MTX-induced oxidative nephrotoxicity via prominent increases in GSH and antioxidant enzyme activities in a dose-dependent manner. The renal inflammatory markers and MDA depleted considerably compared to MTX control group. Histopathological alterations were mitigated to confirm the biochemical indices. VCO supplementation demonstrates nephroprotective activity by attenuating MTX oxidative nephrotoxicity via antioxidant and anti-inflammatory activities in kidney. Our results suggested that VCO may benefit cancer patients on MTX chemotherapy against kidney injury. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  18. Whole brain magnetization transfer histogram analysis of pediatric acute lymphoblastic leukemia patients receiving intrathecal methotrexate therapy

    Energy Technology Data Exchange (ETDEWEB)

    Yamamoto, Akira [Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto-shi Kyoto 606-8507 (Japan)]. E-mail: yakira@kuhp.kyoto-u.ac.jp; Miki, Yukio [Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto-shi Kyoto 606-8507 (Japan)]. E-mail: mikiy@kuhp.kyoto-u.ac.jp; Adachi, Souichi [Department of Pediatrics, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto-shi Kyoto 606-8507 (Japan)]. E-mail: sadachi@kuhp.kyoto-u.ac.jp (and others)

    2006-03-15

    Background and purpose: The purpose of this prospective study was to evaluate the hypothesis that magnetization transfer ratio (MTR) histogram analysis of the whole brain could detect early and subtle brain changes nonapparent on conventional magnetic resonance imaging (MRI) in children with acute lymphoblastic leukemia (ALL) receiving methotrexate (MTX) therapy. Materials and methods: Subjects in this prospective study comprised 10 children with ALL (mean age, 6 years; range, 0-16 years). In addition to conventional MRI, magnetization transfer images were obtained before and after intrathecal and intravenous MTX therapy. MTR values were calculated and plotted as a histogram, and peak height and location were calculated. Differences in peak height and location between pre- and post-MTX therapy scans were statistically analyzed. Conventional MRI was evaluated for abnormal signal area in white matter. Results: MTR peak height was significantly lower on post-MTX therapy scans than on pre-MTX therapy scans (p = 0.002). No significant differences in peak location were identified between pre- and post-chemotherapy imaging. No abnormal signals were noted in white matter on either pre- or post-MTX therapy conventional MRI. Conclusions: This study demonstrates that MTR histogram analysis allows better detection of early and subtle brain changes in ALL patients who receive MTX therapy than conventional MRI.

  19. Intervention of ginger or propolis ameliorates methotrexate-induced ileum toxicity.

    Science.gov (United States)

    Abdul-Hamid, Manal; Salah, Marwa

    2016-02-01

    The long-term clinical use of methotrexate (MTX) is restricted due to its severe intestinal toxicity. The protective effect of ginger or propolis on the toxicity induced by MTX is relatively less understood, so the possible protective effect of ginger or propolis, used separately, was investigated. A total of 60 male albino rats were divided into six groups as follows: (1) control group; (2) ginger group; (3) propolis group; (4) MTX group; (5) ginger + MTX group; and (6) propolis + MTX group. The present results show that MTX caused ileum injury, including shortening and fusion of the villi, inflammatory cell infiltration and goblet cell depletion. Administration of ginger or propolis ameliorated the MTX-induced ileum injury as shown by histological, immunohistochemical and ultrastructural investigations and statistical analysis. This is revealed by intact villi, which shows marked increase in brown colouration of proliferating cell nuclear antigen positive nuclei in the crypts region, improvement in the number of goblet cells and brush border length of ileum. The current results conclude the efficacy and safety of ginger and propolis, which may be due to their antioxidant properties. © The Author(s) 2013.

  20. Italian consensus on the recommendations about the use of methotrexate for the treatment of rheumatic diseases with a focus on rheumatoid arthritis: results from the “3E initiative”

    Directory of Open Access Journals (Sweden)

    C. Montecucco

    2011-06-01

    Full Text Available Objective: To develop a set of national evidence-based recommendations for the use of Methotrexate (MTX in daily clinical practice. Methods: A panel of 37 Italian Rheumatologists reviewed 10 international recommendations formulated during the “3E (Evidence, Expertise, Exchange initiative” for the year 2007-8, following a systematic literature search in Medline, Embase, Cochrane Library, and 2005-7 American College of Rheumatology/European League Against Rheumatism meeting abstracts and the revision of selected papers and the appraisal of Oxford levels of evidence. Moreover, the same panel by the same methodology formulated further 5 recommendations on topics previously selected by Italian representatives to 3E initiative. The agreement about the set of proposed recommendations was stated by a consensus process and the potential impact on clinical practice was assessed. Results: International Recommendations were analysed and changed when appropriate. In addition, 5 national recommendations were developed by identifying 6371 references, selecting and evaluating the 29 ones satisfying Evidence Based Medicine principles. Conclusions: A set of 15 national recommendations for the use of MTX in daily clinical practice was developed. These recommendations are evidence-based and integrate the expertise of a large panel of Italian rheumatologists.

  1. Comparative efficacy and safety of local and systemic methotrexate injection in cesarean scar pregnancy

    Directory of Open Access Journals (Sweden)

    Peng P

    2015-01-01

    Full Text Available Ping Peng,1 Ting Gui,1 Xinyan Liu,1 Weilin Chen,1 Zhenzhen Liu2 1Department of Obstetrics and Gynecology, 2Department of Ultrasonography, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China Objective: To investigate the efficacy of methotrexate (MTX injection in treatment of cesarean scar pregnancy (CSP. Method: A randomized controlled study was performed in 104 CSP patients receiving either local or systemic MTX injection at the Peking Union Medical College Hospital from the year 2008 to 2013. Results: Complete cure was defined as regression of ultrasonographic findings and normalization of serum β-hCG within 60 days. It was regarded as delayed cure if additional dilation and curettage (D&C was needed. The overall cure rate (complete cure plus delayed cure was 69.2% versus 67.3% for local injection versus systemic administration (P>0.05. The median time for serum β-hCG remission and uterine mass disappearance after systemic administration (42 [21–69] days and 40 [20–67] days were significantly lower than those receiving local injection (56 [24–92] days and 53 [23–88] days, with P=0.029 and 0.046, respectively. The mean pretreatment serum β-hCG (human chorionic gonadotropin level and lesion size in cured group (21,941±18,351 mIU/mL and 2.9±1.3 cm, respectively were significantly lower than those in the failed group (37,047±30,864 mIU/mL and 3.6±1.3 with P=0.038 and 0.044, respectively. Conclusion: MTX injection is effective in CSP treatment. Systemic administration shows similar overall cure rate compared to local injection, but requires shorter time for serum β-hCG remission and uterine mass disappearance. Keywords: cesarean scar pregnancy, methotrexate injection, local, systemic

  2. 甲氨蝶呤排泄延迟致多器官损伤%Delayed elimination of methotrexate induced multiple organ dysfunction

    Institute of Scientific and Technical Information of China (English)

    马晶晶; 高杰

    2016-01-01

    1例59岁男性患者因弥漫大B细胞淋巴瘤行大剂量甲氨蝶呤( MTX,15 g,8 g/m2)化疗。首次静脉滴注MTX约10 min(约0.8 g)时,患者出现头胀、面红、发冷,停药,静脉注射地塞米松5 mg,约5 min后症状缓解,继续滴注MTX,约10 min时再次出现相同症状,遂停药。第2次静脉滴注相同剂量MTX约10 min(约0.8 g)时上述症状复现,停药并给予对症治疗后缓解。停药后5 d,患者出现臀、骶尾处红斑、胸部丘脓疱疹,咽喉疼痛,MTX 血药浓度为0.38μmol/L;次日体温升至39.5℃,WBC 0.36×109/L,中性粒细胞计数0.22×109/L,scr 151μmol/L,粪便潜血试验阳性。考虑为MTX所致过敏反应及其排泄延迟所致多器官损伤。予亚叶酸钙100 mg静脉滴注、1次/6 h,同时予抗过敏、抗感染、营养支持等对症治疗。停药后14 d,患者皮疹基本消退,scr 96μmol/L;停药后26 d,患者WBC 6.34×109/L,中性粒细胞计数4.77×109/L,粪便潜血试验阴性。%A 59-year-old male patient with diffuse large B-cell lymphoma received IV infusion of high-dose methotrexate(MTX)15 g(8 g/m2 ). At the first treatment with an IV infusion of methotrexate about 10 min(about 0. 8 g),the patient presented with dizziness,flushing,and feeling of cold. MTX was stopped and IV injection of dexamethasone 5 mg was given and 5 minutes later,the patient's symptoms were improved. The IV infusion of MTX was continued and about 10 minutes later,the patient developed the above-mentioned symptoms again. MTX was stopped again. At the second treatment with the same dose of methotrexate about 10 min(about 0. 8 g),the above-mentioned symptoms recurred and relieved after MTX withdrawal and symptomatic treatments. On the 5th day after MTX withdrawal,the patient presented with erythema on buttocks and sacrum,bullous rash on chest,and throat ache and the MTX serum concentration was 0. 38μmol/L. On the 6th day after MTX withdrawal

  3. Life-threatening interaction between the root extract of Pueraria lobata and methotrexate in rats

    International Nuclear Information System (INIS)

    Chiang, H.-M.; Fang, S.-H.; Wen, K.-C.; Hsiu, S.-L.; Tsai, Shang-Yuan; Hou, Y.-C.; Chi, Y.-C.; Lee Chao, Pei-Dawn

    2005-01-01

    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. Our results showed that coadministration of 4.0 g/kg and 2.0 g/kg of PLRD significantly increased the AUC 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

  4. Efficacy of parenteral administration of bee venom in experimental arthritis in the rat: a comparison with methotrexate.

    Science.gov (United States)

    Yamasaki, Simone C; Mendes, Mariana T; Alponti, Rafaela F; Silveira, Paulo F

    2015-05-01

    The use of bee venom (BV) to treat inflammation and pain in arthritis has become increasingly common. This study aimed to compare the effects of BV and methotrexate (MTX), the most used disease-modifying anti-rheumatic drug, in arthritic rats. Edema, erythema, cyanosis, hyperalgesia, reduction of the body mass gain, high circulating tumor necrosis factor alpha (TNF-α) and anti-type II collagen antibodies (AACII), and altered activity of basic (APB) and neutral (APN) aminopeptidases and dipeptidyl peptidase IV (DPPIV) are present in arthritic rats. MTX and/or BV do not affect AACII in healthy or arthritic individuals, but restores TNF-α to normal levels in arthritic rats. BV restores body mass gain to normal levels and MTX ameliorates body mass gain. BV contains DPPIV. BV restores APN in synovial fluid (SF) and in soluble fraction (S) from synovial tissue (ST), and DPPIV in solubilized membrane-bound fraction (M) from peripheral blood mononuclear cells (PBMCs). MTX restores APN of SF, as well as ameliorates APB of S-PBMCs, APN of S-ST and DPPIV of M-PBMCs. The combination therapy does not overcome the effects of BV or MTX alone on the peptidase activities. Edema is ameliorated by MTX or BV alone. MTX, but not BV, is effective in reducing hyperalgesia. Data show that anti-arthritic effects of BV at non-acupoints are not negligible when compared with MTX. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Self-Delivery Nanoparticles of Amphiphilic Methotrexate-Gemcitabine Prodrug for Synergistic Combination Chemotherapy via Effect of Deoxyribonucleotide Pools.

    Science.gov (United States)

    Wang, Yao; Huang, Ping; Hu, Minxi; Huang, Wei; Zhu, Xinyuan; Yan, Deyue

    2016-11-16

    The distinct and complementary biochemical mechanisms of folic acid analog methotrexate (MTX) and cytidine analog gemcitabine (GEM) make their synergistic combination effective. Unfortunately, such a combination faces severe pharmacokinetic problems and several transportation barriers. To overcome these problems, a new strategy of amphiphilic small molecule prodrug (ASMP) is developed to improve their synergistic combination effect. The ASMP was prepared by the amidation of the hydrophilic GEM with the hydrophobic MTX at a fixed ratio. Owing to its inherent amphiphilicity, the MTX-GEM ASMP self-assembled into stable nanoparticles (ASMP-NPs) with high drug loading capacity (100%), in which the MTX and GEM could self-deliver without any carriers and release synchronously in cancer cells. In vitro studies showed that the MTX-GEM ASMP-NPs could greatly improve the synergistic combination effects by the reason of arresting more S phase of the cell cycle and reducing levels of deoxythymidine triphosphate (dTTP), deoxyadenosine triphosphate (dATP), and deoxycytidine triphosphate (dCTP). The stronger synergistic effects caused the higher cell cytotoxicity and apoptotic ratio, and circumvented the multidrug resistance (MDR) of tumor cells. Additionally, MTX-GEM ASMP-NPs could achieve the same anticancer effect with the greatly reduced dosage compared with the free drugs according to the dose-reduction index (DRI) values of MTX and GEM in MTX-GEM ASMP-NPs, which may be beneficial for reducing the side effects.

  6. Protective effect of Chlorogenic acid against methotrexate induced oxidative stress, inflammation and apoptosis in rat liver: An experimental approach.

    Science.gov (United States)

    Ali, Nemat; Rashid, Summya; Nafees, Sana; Hasan, Syed Kazim; Shahid, Ayaz; Majed, Ferial; Sultana, Sarwat

    2017-06-25

    Methotrexate (MTX) is a drug which is used to treat different types of cancers but hepatotoxicity limits its clinical use. Chlorogenic acid (CGA) is one of the most abundant naturally occurring polyphenols in the human diet. Here, we assessed the effect of CGA against MTX-induced hepatotoxicity and investigated the underlying possible mechanisms in Wistar Rats. Rats were pre-treated with CGA (50 or 100 mg kg/b.w) and administered a single dose of MTX (20 mg/kg, b.w.). MTX caused hepatotoxicity as evidenced by significant increase in serum toxicity markers, histopathological changes. decreased activities of anti-oxidant armory (SOD, CAT, GPx, GR) and GSH content. MTX significantly causes upregulation of iNOS, Cox-2, Bax and downregulation of Bcl-2 expressions, it causes higher caspase 3, 9 activities. However CGA pretreatment alleviates the hepatotoxicity by decreasing the oxidative stress. CGA inhibited Cox-2, iNOS, Bax, Bcl-2 and Caspases 3, 9 mediated inflammation and apoptosis, and improve the histology induced by MTX. Thus, these findings demonstrated the hepatoprotective nature of CGA by attenuating the pro-inflammatory and apoptotic mediators and improving antioxidant competence in hepatic tissue. These results imply that CGA has perfective effect against MTX-induced liver injury. Hence CGA supplementation might be helpful in abrogation of MTX toxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat

    NARCIS (Netherlands)

    Seigers, Riejanne; Schagen, Sanne B.; Beerling, Wieteke; Boogerd, Willem; Van Tellingen, Olaf; Van Dam, Frits S. A. M.; Koolhaas, Jaap M.; Buwalda, Bauke

    2008-01-01

    Methotrexate (MTX) is a cytostatic agent widely used in combination with other agents as adjuvant chemotherapy for breast cancer and is associated with cognitive impairment as a long-term side effect in some cancer patients. This paper aimed to identify a neurobiological mechanism possibly

  8. Rapid alleviation of signs and symptoms of rheumatoid arthritis with intravenous or subcutaneous administration of adalimumab in combination with methotrexate.

    NARCIS (Netherlands)

    Rau, R.; Simianer, S.; Riel, P.L.C.M. van; Putte, L.B.A. van de; Kruger, K.; Schattenkirchner, M.; Allaart, C.F.; Breedveld, F.C.; Kempeni, J.; Beck, K.; Kupper, H.

    2004-01-01

    OBJECTIVE: This randomized, placebo-controlled, double-blind, Phase 1 study assessed the magnitude, onset, and duration of response with intravenous (i.v.) and subcutaneous (s.c.) adalimumab (Humira, Abbott Laboratories) combined with methotrexate (MTX) in patients with active rheumatoid arthritis

  9. Changes in Ultrasonographic Vascularity Upon Initiation of Adalimumab Combination Therapy in Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate.

    Science.gov (United States)

    Kaeley, Gurjit S; Nishio, Midori J; Goyal, Janak R; MacCarter, Daryl K; Wells, Alvin F; Chen, Su; Kupper, Hartmut; Kalabic, Jasmina

    2016-11-01

    To assess joint disease activity by ultrasound (US) in patients with rheumatoid arthritis (RA) initiating treatment with adalimumab (ADA) plus methotrexate (MTX). Data for this post hoc analysis originated from the MUSICA trial (ClinicalTrials.gov identifier: NCT01185288), which evaluated the efficacy of initiating ADA (40 mg every other week) plus 7.5 or 20 mg/week MTX in 309 patients with RA with an inadequate response to MTX. Synovial vascularization over 24 weeks was assessed bilaterally at metacarpophalangeal joint 2 (MCP2), MCP3, MCP5, metatarsophalangeal joint 5, and the wrists by power Doppler US (PDUS). A semiquantitative 4-grade scale was used. Disease activity was assessed using the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) and Simplified Disease Activity Index (SDAI). The correlation between continuous variables was assessed using Pearson's correlation coefficient. After 24 weeks of treatment with ADA plus MTX, rapid improvements in the mean synovial vascularity score were observed; the greatest improvements were in MCP2 (-0.5), MCP3 (-0.4), and the wrist (-0.4). At week 24, patients with the lowest DAS28-CRP ( 0.9). Synovial vascularity scores correlated poorly with DAS28, swollen joint count in 66 joints (SJC66), SJC28, tender joint count in 68 joints (TJC68), TJC28, Clinical Disease Activity Index (CDAI), SDAI, physician's global assessment, patient's global assessment of pain, and disease duration (ρ < 0.2). Thirty-two (70%) of 46 patients with a DAS28-CRP of <2.6, and 11 (58%) of 19 patients with an SDAI indicating remission had at least 1 joint with a synovial vascularity score of ≥1. PDUS detects changes in synovial vascularity in RA patients treated with ADA plus MTX, and residual synovial vascularity in patients in whom clinical disease control has been achieved. © 2016 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

  10. Effects of Early Chemotherapeutic Treatment on Learning in Adolescent Mice: Implications for Cognitive Impairment and Remediation in Childhood Cancer Survivors

    Science.gov (United States)

    Bisen-Hersh, Emily B.; Hineline, Philip N.; Walker, Ellen A.

    2013-01-01

    Purpose Among children diagnosed with acute lymphoblastic leukemia (ALL) and given chemotherapy-only treatment, 40-70% of survivors experience neurocognitive impairment. The present study used a preclinical mouse model to investigate the effects of early exposure to common ALL chemotherapeutics methotrexate (MTX) and cytarabine (Ara-C) on learning and memory. Experimental Design Pre-weanling mouse pups were treated on postnatal day (PND) 14, 15, and 16 with saline, MTX, Ara-C, or a combination of MTX and Ara-C. Nineteen days following treatment (PND 35), behavioral tasks measuring different aspects of learning and memory were administered. Results Significant impairment in acquisition and retention over both short (1h) and long (24h) intervals, as measured by autoshaping and novel object recognition tasks, were found following treatment with MTX and Ara-C. Similarly, a novel conditional discrimination task revealed impairment in acquisition for chemotherapy-treated mice. No significant group differences were found following the extensive training component of this task, with impairment following the rapid training component occurring only for the highest MTX and Ara-C combination group. Conclusions Findings are consistent with clinical studies suggesting that childhood cancer survivors are slower at learning new information and primarily exhibit deficits in memory years after successful completion of chemotherapy treatment. The occurrence of mild deficits on a novel conditional discrimination task suggests that chemotherapy-induced cognitive impairment may be ameliorated through extensive training or practice. PMID:23596103

  11. Ceramic core with polymer corona hybrid nanocarrier for the treatment of osteosarcoma with co-delivery of protein and anti-cancer drug

    Science.gov (United States)

    Ram Prasad, S.; Sampath Kumar, T. S.; Jayakrishnan, A.

    2018-01-01

    For the treatment of metastatic bone cancer, local delivery of therapeutic agents is preferred compared to systemic administration. Delivery of an anti-cancer drug and a protein that helps in bone regeneration simultaneously is a challenging approach. In this study, a nanoparticulate carrier which delivers a protein and an anti-cancer drug is reported. Bovine serum albumin (BSA) as a model protein was loaded into hydroxyapatite (HA) nanoparticles (NPs) and methotrexate (MTX) conjugated to poly(vinyl alcohol) was coated onto BSA-loaded HA NPs. Coating efficiency was in the range of 10-17 wt%. In vitro drug release showed that there was a steady increase in the release of both BSA and MTX with 76% of BSA and 88% of MTX being released in 13 days. Cytotoxicity studies of the NPs performed using human osteosarcoma (OMG-63) cell line showed the NPs were highly biocompatible and exhibited anti-proliferative activity in a concentration-dependent manner.

  12. A review of tofacitinib efficacy in rheumatoid arthritis patients who have had an inadequate response or intolerance to methotrexate.

    Science.gov (United States)

    Fleischmann, Roy

    2017-10-01

    Tofacitinib is a pan JAK inhibitor with specificity for JAK3 over JAK1 over JAK2, which is approved in many countries for the treatment of rheumatoid arthritis (RA), including the United States and the European Union, either as monotherapy or in combination with conventional synthetic disease modifying anti-arthritis drugs (csDMARDs). Phase 2, 3 and 4 clinical trials have investigated the efficacy and safety of tofacitinib given either as monotherapy or in combination with csDMARDs. Areas covered: This review reports the safety, clinical, functional, and radiographic efficacy, of tofacitinib used as monotherapy in the treatment of adult patients with RA reported in the prospective, double-blind, controlled randomized trials reported to date. One critical clinical question is whether tofacitinib monotherapy has similar efficacy as tofacitinib in combination with methotrexate (MTX); this question has recently been addressed. A literature search on tofacitinib monotherapy was carried out using the PubMed database up to July 2017. Expert opinion: Although tofacitinib plus MTX is statistically more clinically effective, tofacitinib monotherapy is effective in many patients with RA.

  13. Methotrexate and epirubicin conjugates as potential antitumor drugs

    Directory of Open Access Journals (Sweden)

    Szymon Wojciech Kmiecik

    2017-07-01

    Full Text Available Introduction: The use of hybrid molecules has become one of the most significant approaches in new cytotoxic drug design. This study describes synthesis and characterization of conjugates consisting of two well-known and characterized chemotherapeutic agents: methotrexate (MTX and epirubicin (EPR. The synthesized conjugates combine two significant anticancer strategies: combinatory therapy and targeted therapy. These two drugs were chosen because they have different mechanisms of action, which can increase the anticancer effect of the obtained conjugates. MTX, which is a folic acid analog, has high cytotoxic properties and can serve as a targeting moiety that can reach folate receptors (FRs overexpresing tumor cells. Combination of nonselective drugs such as EPR with MTX can increase the selectivity of the obtained conjugates, while maintaining the high cytotoxic properties.Materials and methods: Conjugates were purified by RP-HPLC and the structure was investigated by MS and MS/MS methods. The effect of the conjugates on proliferation of LoVo, LoVo/Dx, MCF-7 and MV-4-11 human cancer cell lines was determined by SRB or MTT assay.Results: The conjugation reaction results in the formation of monosubstituted (α, γ and disubstituted MTX derivatives. In vitro proliferation data demonstrate that the conjugates synthesized in our study show lower cytotoxic properties than both chemotherapeutics used alone.Discussion: Epirubicin cytotoxicity was not observed in obtained conjugates. Effective drugs release after internalization needs further investigation.

  14. Advanced colorectal carcinoma. A prospective randomized trial of sequential methotrexate, 5-fluorouracil, and leucovorin versus 5-fluorouracil alone.

    Science.gov (United States)

    Machiavelli, M; Leone, B A; Romero, A; Rabinovich, M G; Vallejo, C T; Bianco, A; Pérez, J E; Rodríguez, R; Cuevas, M A; Alvarez, L A

    1991-06-01

    One hundred and twenty-five previously untreated patients bearing metastatic or advanced recurrent (inoperable) colorectal carcinoma and measurable disease were prospectively randomized. Those in arm A received 5-fluorouracil (5-FU), 1,200 mg/m2 i.v. infusion over 2 h, while those in arm B received methotrexate (MTX), 200 mg/m2 i.v. (push injection), followed 20 h later by 5-FU, 1,200 mg/m2 i.v. infusion over 2 h, plus calcium leucovorin (LV), 25 mg i.m. every 6 h for eight doses beginning 24 h after MTX administration. Cycles were repeated every 15 days. All patients receiving treatment were evaluable for toxicity and survival, and 118 patients were evaluable for response. The objective regression rate (complete plus partial response) was 12% (7 of 58) in arm A and 28% (17 of 60) in arm B (p = 0.049). No change was observed in 24% (14 of 58) in arm A and in 35% (21 of 60) in arm B (p = 0.28), while progressive disease was registered in 64% (37 of 58) and 37% (22 of 60) in arms A and B, respectively (p = 0.006). Median duration of response was 3 months in arm A and 5 months in arm B (p = 0.39). The median survival was 8.3 months in arm A and 11.2 months in arm B (p = 0.25). No statistically significant differences were found when objective regression and survival were related to site of primary tumor, performance status, and number of involved organs. There were two drug-related deaths in arm B due to severe myelosuppression followed by mucositis and sepsis. Of nonhematologic toxicities, diarrhea was more frequently observed in arm B, as were mucositis and infectious complications. Our results indicate that the sequential schedule MTX-5-FU-LV with 20-h intervals between MTX and 5-FU is superior in terms of objective regression to 5-FU alone given at the dose and schedule used in the present study. However, MTX-5-FU-LV did not have a significant impact on survival.

  15. Effects of early chemotherapeutic treatment on learning in adolescent mice: implications for cognitive impairment and remediation in childhood cancer survivors.

    Science.gov (United States)

    Bisen-Hersh, Emily B; Hineline, Philip N; Walker, Ellen A

    2013-06-01

    Among children diagnosed with acute lymphoblastic leukemia (ALL) and given chemotherapy-only treatment, 40% to 70% of survivors experience neurocognitive impairment. The present study used a preclinical mouse model to investigate the effects of early exposure to common ALL chemotherapeutics methotrexate (MTX) and cytarabine (Ara-C) on learning and memory. Preweanling mouse pups were treated on postnatal day (PND) 14, 15, and 16 with saline, MTX, Ara-C, or a combination of MTX and Ara-C. Nineteen days after treatment (PND 35), behavioral tasks measuring different aspects of learning and memory were administered. Significant impairment in acquisition and retention over both short (1 hour) and long (24 hours) intervals, as measured by autoshaping and novel object recognition tasks, was found following treatment with MTX and Ara-C. Similarly, a novel conditional discrimination task revealed impairment in acquisition for chemotherapy-treated mice. No significant group differences were found following the extensive training component of this task, with impairment following the rapid training component occurring only for the highest MTX and Ara-C combination group. Findings are consistent with those from clinical studies suggesting that childhood cancer survivors are slower at learning new information and primarily exhibit deficits in memory years after successful completion of chemotherapy. The occurrence of mild deficits on a novel conditional discrimination task suggests that chemotherapy-induced cognitive impairment may be ameliorated through extensive training or practice. ©2013 AACR

  16. The influence of folate pathway polymorphisms on high-dose methotrexate-related toxicity and survival in children with non-Hodgkin malignant lymphoma

    Science.gov (United States)

    Erculj, Nina; Kotnik, Barbara Faganel; Debeljak, Marusa; Jazbec, Janez; Dolzan, Vita

    2014-01-01

    Background We evaluated the influence of folate pathway polymorphisms on high-dose methotrexate (HD-MTX) related toxicity in paediatric patients with T-cell non-Hodgkin lymphoma (NHL). Patients and methods In total, 30 NHL patients were genotyped for selected folate pathway polymorphisms. Results Carriers of at least one MTHFR 677T allele had significantly higher MTX area under the time-concentration curve levels at third MTX cycle (P = 0.003). These patients were also at higher odds of leucopoenia (P = 0.006) or thrombocytopenia (P = 0.041) and had higher number of different HD-MTX-related toxicity (P = 0.035) compared to patients with wild-type genotype. Conclusions Our results suggest an important role of MTHFR 677C>T polymorphism in the development of HD-MTX-related toxicity in children with NHL. PMID:25177243

  17. The influence of folate pathway polymorphisms on high-dose methotrexate-related toxicity and survival in children with non-Hodgkin malignant lymphoma

    International Nuclear Information System (INIS)

    Erculj, Nina; Kotnik, Barbara Faganel; Debeljak, Marusa; Jazbec, Janez; Dolzan, Vita

    2014-01-01

    We evaluated the influence of folate pathway polymorphisms on high-dose methotrexate (HD-MTX) related toxicity in paediatric patients with T-cell non-Hodgkin lymphoma (NHL). In total, 30 NHL patients were genotyped for selected folate pathway polymorphisms. Carriers of at least one MTHFR 677T allele had significantly higher MTX area under the time-concentration curve levels at third MTX cycle (P = 0.003). These patients were also at higher odds of leucopoenia (P = 0.006) or thrombocytopenia (P = 0.041) and had higher number of different HD-MTX-related toxicity (P = 0.035) compared to patients with wild-type genotype. Our results suggest an important role of MTHFR 677C>T polymorphism in the development of HD-MTX-related toxicity in children with NHL

  18. Methotrexate for refractory prurigo nodularis

    Directory of Open Access Journals (Sweden)

    Mariam Al Zaabi

    2017-01-01

    Full Text Available Prurigo nodularis (PN is chronic unbearable inflammatory skin disease. Although it was described before a century, not many studies have been conducted regarding the systemic treatment of prurigo nodularis. A 64-year-old male patient has moderate to severe atopic dermatitis superimposed by disseminated pruritic nodules over the trunk and extremities. In spite of topical treatment and Phototherapy, patient condition was deteriorating. Therefore, the patient was treated with multimodalities including high potency topical steroid, intravenous antihistamine, cyclosporine and omalizumab without improvement. Thus the patient has been treated with methotrexate which led to remarkable improvement. Management of prurigo nodularis is often challenging as the etiology of PN in the majority of the cases is unknown. Conservative treatments are often inefficient. This case proves the efficacy of methotrexate in the management of prurigo nodularis.

  19. Rheumatoid Factor Positivity Is Associated with Increased Joint Destruction and Upregulation of Matrix Metalloproteinase 9 and Cathepsin K Gene Expression in the Peripheral Blood in Rheumatoid Arthritic Patients Treated with Methotrexate

    Directory of Open Access Journals (Sweden)

    Elena V. Tchetina

    2013-01-01

    Full Text Available We evaluated changes in gene expression of mTOR, p21, caspase-3, ULK1, TNFα, matrix metalloproteinase (MMP-9, and cathepsin K in the whole blood of rheumatoid arthritic (RA patients treated with methotrexate (MTX in relation to their rheumatoid factor status, clinical, immunological, and radiological parameters, and therapeutic response after a 24-month follow-up. The study group consisted of 35 control subjects and 33 RA patients without previous history of MTX treatment. Gene expression was measured using real-time RT-PCR. Decreased disease activity in patients at the end of the study was associated with significant downregulation of TNFα expression. Downregulation of mTOR was observed in seronegative patients, while no significant changes in the expression of p21, ULK1, or caspase-3 were noted in any RA patients at the end of the study. The increase in erosion numbers observed in the seropositive patients at the end of the follow-up was accompanied by upregulation of MMP-9 and cathepsin K, while seronegative patients demonstrated an absence of significant changes in MMP-9 and cathepsin K expression and no increase in the erosion score. Our results suggest that increased expression of MMP-9 and cathepsin K genes in the peripheral blood might indicate higher bone tissue destruction activity in RA patients treated with methotrexate. The clinical study registration number is 0120.0810610.

  20. Accuracy of Methotrexate Use in Rheumatoid Arthritis Patients in Emanuel Klampok Hospital based on Explicit Criteria

    Directory of Open Access Journals (Sweden)

    Rizki Puspitasari

    2014-09-01

    Full Text Available Methotrexate (MTX is the first line therapy for rheumatoid arthritis (RA as an antiinflammatory and immunosuppressant agent. The purpose of this study was to evaluate the use of MTX in patients with rheumatoid arthritis at Emanuel Klampok Hospital based on criteria, including the indication, process indicators, complication, and outcome indicators. The medical record from 13 inpatients and 27 outpatients who used MTX were compared with the criteria. The results of this study demonstrated that all of the patients had appropriately indications to use MTX. Patients with risk factors that lead to GI disorders, hepatotoxicity, and bone marrow toxicity were 35 patients, 19 patients, and 15 patients respectively. There were 32 patients used MTX with the correct dosage, meanwhile incorrect dosage was showed in 3 patients with ClCr 61–80 mL/minute, 2 patients with ClCr 51–60 mL/minute, 1 patient with ClCr 10–50 mL/minute, and 2 patients with SGPT >3 normal value. The interaction with NSAID was happened in 35 patients and the interaction with hepatotoxicity agents in 19 patients. Complication occurred in 7 patients with effects that occur were GI disorders and 1 patient with chirrosis. There were 10 patients with clinical complaints reduced and 2 patients with the better condition. Indication of use MTX had appropriately, but process indicators, complication, and outcome indicators still not appropriate.

  1. Agreement between Rheumatologist and Patient-reported Adherence to Methotrexate in a US Rheumatoid Arthritis Registry.

    Science.gov (United States)

    Curtis, Jeffrey R; Bharat, Aseem; Chen, Lang; Greenberg, Jeffrey D; Harrold, Leslie; Kremer, Joel M; Sommers, Tanya; Pappas, Dimitrios

    2016-06-01

    Rheumatologists have limited tools to assess medication adherence. The extent to which methotrexate (MTX) adherence is overestimated by rheumatologists is unknown. We deployed an Internet survey to patients with rheumatoid arthritis (RA) participating in a US registry. Patient self-report was the gold standard compared to MTX recorded in the registry. Response rate to the survey was 44%. Of 228 patients whose rheumatologist reported current MTX at the time of the most recent registry visit, 45 (19.7%) had discontinued (n = 19, 8.3%) or missed ≥ 1 dose in the last month (n = 26, 11.4%). For the subgroup whose rheumatologist also confirmed at the next visit that they were still taking MTX (n = 149), only 2.6% reported not taking it, and 10.7% had missed at least 1 dose. MTX use was misclassified for 13%-20% of patients, mainly because of 1 or more missed doses rather than overt discontinuation. Clinicians should be aware of suboptimal adherence when assessing MTX response.

  2. Characterization of disruptions in the Microwave Tokamak Experiment, MTX

    International Nuclear Information System (INIS)

    Hooper, E.B.; Makowski, M.A.

    1990-01-01

    The Microwave Tokamak Experiment (MTX) has a substantial number of fast diagnostics, especially for electrons, as part of its mission for pulsed, high-power electron cyclotron heating. As part of its contribution to ITER R ampersand D, these diagnostics are being used to characterize disruptions in MTX. This report is the first of two, with the second planned for submittal in September 1990, at the end of the ITER conceptual design activity. Here, we analyze the characteristics of disruptions during normal operation of MTX, discuss some new data pertaining to the ''Granetz limit,'' and describe preliminary data on ramped density shorts which will be used for fast measurements on density limit disruptions. The final report will discuss measurements using the fast diagnostics to characterize the disruption

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

    Science.gov (United States)

    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.

  4. Methods to Evaluate the Effect of Ethanol on the Folate Analogue: Fluorescein Methotrexate Uptake in Human Proximal Tubular Cells

    Directory of Open Access Journals (Sweden)

    Sivakumar JT Gowder

    2009-01-01

    Full Text Available Ethanol-induced folate deficiency is due to effects of ethanol on folate metabolism and absorption. We have already shown by using different methods that ethanol interferes with reabsorption of folate from the proximal tubule. In this study, we have used the folate analogue, the fluorescein methotrexate (FL-MTX, in order to evaluate effects of ethanol on FL-MTX uptake by the human proximal tubular (HPT cells by using a confocal microscope and fluoroskan microplate reader. Since endothelins (ETs play a major role in a number of diseases and also in the damage induced by a variety of chemicals, we have used endothelin-B (ET-B and protein kinase-C (PKC inhibitors to evaluate the role of endothelin in ethanol-mediated FL-MTX uptake by using fluoroskan microplate reader. Confocal microscope and fluoroskan studies reveal that cellular absorption of FL-MTX is concentration-dependent. Moreover, ethanol concentration has an impact on FL-MTX uptake. Fluoroskan studies reveal that the ethanol-induced decrease in FL-MTX uptake is reversed by adding the ET-B receptor antagonist (RES-701-1 or PKC-selective inhibitor (BIM. Thus, we can conclude that ethanol may act via ET and ET in turn may act via ET-B receptor and the PKC signaling pathway to impair FL-MTX transport.

  5. Liposomes containing alkylated methotrexate analogues for phospholipase A(2) mediated tumor targeted drug delivery

    DEFF Research Database (Denmark)

    Kaasgaard, Thomas; Andresen, Thomas Lars; Jensen, Simon Skøde

    2009-01-01

    of alkylated compounds in liposomes, it was demonstrated that the MTX-analogue partitioned into the water phase and thereby became available for cell uptake. It was concluded that liposomes containing alkylated MTX-analogues show promise as a drug delivery system, although the MTX-analogue needs to be more......Two lipophilic methotrexate analogues have been synthesized and evaluated for cytotoxicity against KATO III and HT-29 human colon cancer cells. Both analogues contained a C-16-alkyl chain attached to the gamma-carboxylic acid and one of the analogues had an additional benzyl group attached...... cytotoxicity was incorporated into liposomes that were designed to be particularly Susceptible to a liposome degrading enzyme, secretory phospholipase A(2) (sPLA(2)), which is found in high concentrations in tumors of several different cancer types. Liposome incorporation was investigated by differential...

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

    Science.gov (United States)

    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.

  7. Electrochemically controlled release of anticancer drug methotrexate using nanostructured polypyrrole modified with cetylpyridinium: Release kinetics investigation

    International Nuclear Information System (INIS)

    Alizadeh, Naader; Shamaeli, Ehsan

    2014-01-01

    A new simple strategy for direct electrochemical incorporation of chemotherapeutic methotrexate (MTX) into conductive polypyrrole (PPy) has been suggested for an electrochemically controlled loading and release system. Electropolymerization of MTX doped polypyrrole yielded poor quality with low efficiency of doping, but a well-doped, nanostructure and increased capacity of drug loading (24.5 mg g −1 ) has been obtained in the presence of cetylpyridinium (CP) as a modifier. When CP was preloaded onto PPy, the hydrophobic surface of the PPy serves as a backbone to which the hydrophobic chain of the CP can be attached. Electrostatic interaction between cationic CP with anionic MTX and aromatic interaction between pyridinium head of CP with pyrimidine and pyrazine rings of MTX increases drug doping. Then release kinetics were investigated at various applied potentials and temperatures. Kinetics analysis based on Avrami's equation showed that the drug release was controlled and accelerated by increasing temperature and negative potential and sustained by increasing positive potential. At open circuit condition, the release parameter (n) represented a diffusive mechanism and at applying electrochemical potentials, a first-order mode. Activation energy parameters (E a , ΔG ≠ , ΔH ≠ and ΔS ≠ ) and half-life time (t 1/2 ) of drug release are also analyzed as a function of applied potential. The nanostructured polymer films (PPy/CP/MTX) were characterized by several techniques: scanning electron microscopy, Furrier transforms Infrared, UV-vis spectroscopy. Overall, our results demonstrate that the PPy/CP/MTX films, combined with electrical stimulation, permit a programmable release of MTX by altering the interaction strength between the PPy/CP and MTX

  8. The impact of gallic acid on the methotrexate-induced kidney damage in rats

    Directory of Open Access Journals (Sweden)

    Halil Asci

    2017-10-01

    Full Text Available Prolonged use of an antineoplastic agent methotrexate (MTX, can cause numerous side effects such as nephrotoxicity. The aim of this study was to examine the effects of MTX on kidneys and demonstrate the protective effects of gallic acid (GA. Twenty-four, male, rats distributed into three groups. Each groups consisted eight rats and only saline was administered to the control group. The MTX group received a single dose (20 mg/kg MTX intraperitoneally. The MTX + GA group received same dose MTX and 100 mg/kg GA orally during the 7 days. Renal functions, oxidative stress markers, histopathological and immunohistochemical changes were evaluated at the end of the experiment. Blood urea nitrogen, creatinine, uric acid levels and tissue oxidative stress markers, total oxidant status and oxidative stress index levels significantly increased and total antioxidant status levels significantly decreased in MTX group compared with the control group. At the histopathological examination hemorrhages, tubular cell necrosis, glomerulosclerosis, inflammatory cell infiltrations and proteinous materials in tubules were noticed in MTX group. Immunohistochemical examination revealed that increased expressions of serum amyloid A (SAA, tumor necrosis factor alpha (TNF-α, prostaglandin E2 (PGE-2 and C-reactive protein (CRP in tubular epithelial cells of kidneys in this group. There were no immunoreaction with SAA and CRP, only small number of PGE-2 and TNF-α positive tubular epithelial cells were observed in MTX + GA group. In conclusion, all evidence suggested that oxidative stress caused MTX-induced nephrotoxicity and GA prevent the kidney from the nephrotoxicity due to its antioxidant and anti-inflammatory activities.

  9. Fluorescein-methotrexate transport in dogfish shark (Squalus acanthias) choroid plexus.

    Science.gov (United States)

    Baehr, Carsten H; Fricker, Gert; Miller, David S

    2006-08-01

    The vertebrate choroid plexus removes potentially toxic metabolites and xenobiotics from cerebrospinal fluid (CSF) to blood for subsequent excretion in urine and bile. We used confocal microscopy and quantitative image analysis to characterize the mechanisms driving transport of the large organic anion, fluorescein-methotrexate (FL-MTX), from bath (CSF-side) to blood vessels in intact lateral choroid plexus from dogfish shark, Squalus acanthias, an evolutionarily ancient vertebrate. With 2 microM FL-MTX in the bath, steady-state fluorescence in the subepithelium/vascular space exceeded bath levels by 5- to 10-fold, and fluorescence in the epithelial cells was slightly below bath levels. FL-MTX accumulation in both tissue compartments was reduced by NaCN, Na removal, and ouabain, but not by a 10-fold increase in medium K. Certain organic anions, e.g., probenecid, MTX, and taurocholate, reduced FL-MTX accumulation in both tissue compartments; p-aminohippurate and estrone sulfate reduced subepithelial/vascular accumulation, but not cellular accumulation. At low concentrations, digoxin, leukotriene C4, and MK-571 reduced fluorescence in the subepithelium/vascular space while increasing cellular fluorescence, indicating preferential inhibition of efflux over uptake. In the presence of 10 microM digoxin (reduced efflux, enhanced cellular accumulation), cellular FL-MTX accumulation was specific, concentrative, and Na dependent. Thus transepithelial FL-MTX transport involved the following two carrier-mediated steps: electroneutral, Na-dependent uptake at the apical membrane and electroneutral efflux at the basolateral membrane. Finally, FL-MTX accumulation in both tissue compartments was reduced by phorbol ester and increased by forskolin, indicating antagonistic modulation by protein kinase C and protein kinase A.

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

    Science.gov (United States)

    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

  11. Screening of cytoprotectors against methotrexate-induced cytogenotoxicity from bioactive phytochemicals.

    Science.gov (United States)

    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 phytochemicals combinations had the potential to be used as new cytoprotectors.

  12. 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.

    Science.gov (United States)

    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.

  13. Methotrexate induces poly(ADP-ribose) polymerase-dependent, caspase 3-independent apoptosis in subsets of proliferating CD4+ T cells

    DEFF Research Database (Denmark)

    Nielsen, C H; Albertsen, L; Bendtzen, K

    2007-01-01

    The mechanism of action of methotrexate (MTX) in autoimmune diseases (AID) is unclear. A pro-apoptotic effect has been demonstrated in mitogen-stimulated peripheral blood mononuclear cells (PBMC), but studies employing conventional antigens have disputed a pro-apoptotic effect. CD4+ T helper (Th)...

  14. Methotrexate use in allergic contact dermatitis: a retrospective study.

    Science.gov (United States)

    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.

  15. Carmustine and methotrexate in combination after whole brain radiation therapy in breast cancer patients presenting with brain metastases: a retrospective study

    Directory of Open Access Journals (Sweden)

    Poujol Sylvain

    2010-06-01

    Full Text Available Abstract Background Since 1999, patients presenting with brain metastases (BM from breast cancer (BC are treated in our institution with a carmustine (BCNU - methotrexate (MTX combination. We report here our clinical experience regarding this combination. Patients and Methods Patients were treated by a combination of BCNU 100 mg/m² on day 1 and MTX 600 mg/m² on day 1 and 15 of a 28 day cycle. Treatment was continued until progression or unacceptable toxicity. Results 50 patients were treated between 1999 and 2007. 94% of the patients presented with concomitant extra-cerebral disease. Median number of previous metastatic setting chemotherapy regimens was 2 (0-5. Median number of cycles was 3 (1-20. There were 11 objective responses (23% [95%CI 12-37] among 48 evaluable patients. Median progression-free survival and overall survival (OS were 4.2 (95%CI: 2.8-5.3 and 6.9 (4.2-10.7 months respectively, with a one-year OS rate of 32% (20-46. Median Relative Dose Intensity for BCNU and MTX were 0.98 (0.31-1.1 and 0.96 (0.57-1.66 respectively. There were 2 presumed treatment-related deaths. One patient developed febrile neutropenia. Performance status, BS-BM score and presence of liver metastases were associated with OS in univariate analysis. Conclusions This combination appears to be effective and well tolerated in good performance status BC patients presenting with BM.

  16. Studies of methotrexate-induced limb dysplasias utilizing a 51chromium release assay

    International Nuclear Information System (INIS)

    Brewton, R.G.; MacCabe, J.A.

    1990-01-01

    The folate antagonist methotrexate (MTX), widely used in chemotherapy, is a well-documented teratogen. However, the mechanism by which it exerts its effects is still unclear. Specifically, we have examined the cytotoxicity of MTX in vivo and in vitro and have looked at the relationship between cytotoxicity and teratogenesis. The chick embryo was utilized to examine the effects of the drug administered to carefully staged embryos. Embryos were exposed at stages 18-22 and examined on day 11 of incubation. Wings were malformed in a stage-dependent manner while legs were affected similarly at each stage used. A modification of the 51chromium-release assay was used to test the toxicity of MTX to limb cells in vitro. None of the tissues tested showed measurable toxicity in vitro even though the drug kills cells in vivo, thereby suggesting that MTX may be metabolized differently in vitro. Malformations induced by MTX do not seem to be due to changes in the amount of cell death taking place in the limb but may be caused by a transient inhibition of cell division

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

    Science.gov (United States)

    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.

  18. Protective Effects of Thymoquinone against Methotrexate-Induced Germ Cell Apoptosis in Male Mice

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    Fatemeh Sheikhbahaei

    2016-12-01

    Full Text Available Background: Toxic effects of anti-cancer and other drugs on the normal tissues could be reduced by the herbal plants and their fractions. This study investigated the protective effect of thymoquinone (TQ as a fraction of Nigella sativa on methotrexate (MTX- induced germ cell apoptosis in male mice. Materials and Methods: In this experimental study, thirty male Balb/c mice were divided randomly into 5 groups (n=6. A single dose of MTX (20 mg/kg and different concentrations of TQ were administrated for 4 consecutive days. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL assay was performed on paraffin embedded tissue sections to analysis the occurrence of apoptosis in the testis. Reverse transcription polymerase chain reaction (RT-PCR of apoptosis-related genes was performed with RNA extracted from testes of the mice. Statistical analysis was done using one-way ANOVA. Results: In the MTX group, there was a significant increase in morphologic sign of germ cell degeneration of tubules (48 ± 0.6%, apoptotic index (AI; 2.3 ± 0.6%, as well as mRNA expression of p53 (P=0.008, caspase 8 (P=0.002, caspase 3 (P=0.005, caspase 9 (P=0.000, bax (P=0.004 and the ratio of bax/bcl-2 (P=0.000, whereas there was an decrease in the expression of bcl-2 (P=0.003, as compared to control group. In MTX+TQ groups, the data showed that different concentrations of TQ could improve the harmful effects caused by the MTX. The best protective effects were achieved in MTX+TQ (10 mg/kg. Conclusion: TQ protects testicular germ cell against MTX-induced apoptosis by affecting related genes regulation.

  19. Failure Rate of Single Dose Methotrexate in Managment of Ectopic Pregnancy

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    Feras Sendy

    2015-01-01

    Full Text Available 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.

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

    Science.gov (United States)

    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.

  1. [Hemiparesis and facial palsy caused by methotrexate].

    Science.gov (United States)

    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.

  2. Short time administration of antirheumatic drugs - Methotrexate as a strong inhibitor of osteoblast's proliferation in vitro

    Directory of Open Access Journals (Sweden)

    Annussek Tobias

    2012-09-01

    Full Text Available Abstract Introduction Due to increasing use of disease modifying antirheumatic drugs (DMARDs as first line therapy in rheumatic diseases, dental and maxillofacial practitioner should be aware of drug related adverse events. Especially effects on bone-metabolism and its cells are discussed controversially. Therefore we investigate the in vitro effect of short time administration of low dose methotrexate (MTX on osteoblasts as essential part of bone remodelling cells. Methods Primary bovine osteoblasts (OBs were incubated with various concentrations of MTX, related to tissue concentrations, over a period of fourteen days by using a previously established standard protocol. The effect on cell proliferation as well as mitochondrial activity was assessed by using 3-(4, 5-dimethylthiazol-2-yl 2, 5-diphenyltetrazolium bromide (MTT assay, imaging and counting of living cells. Additionally, immunostaining of extracellular matrix proteins was used to survey osteogenic differentiation. Results All methods indicate a strong inhibition of osteoblast`s proliferation by short time administration of low dose MTX within therapeutically relevant concentrations of 1 to 1000nM, without affecting cell differentiation of middle-stage differentiated OBs in general. More over a significant decrease of cell numbers and mitochondrial activity was found at these MTX concentrations. The most sensitive method seems to be the MTT-assay. MTX-concentration of 0,01nM and concentrations below had no inhibitory effects anymore. Conclusion Even low dose methotrexate acts as a potent inhibitor of osteoblast’s proliferation and mitochondrial metabolism in vitro, without affecting main differentiation of pre-differentiated osteoblasts. These results suggest possible negative effects of DMARDs concerning bone healing and for example osseointegration of dental implants. Especially the specifics of the jaw bone with its high vascularisation and physiological high tissue metabolism

  3. Delayed elimination of high-dose methotrexate and use of carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Svahn, Thommy; Mellgren, Karin; Harila-Saari, Arja

    2017-01-01

    concentration decreased by 75% when measured with immune-based methods, and by 100% when measured with high-performance liquid chromatography. The median time from the start of Mtx infusion to plasma levels ≤ 0.2 μM was 228 hr (range: 48-438). The maximum increase in plasma creatinine was 375% (range: 100...... negative acute lymphoblastic leukemia (ALL) were treated according to the Nordic Organization for Pediatric Hematology and Oncology (NOPHO) ALL 2008 protocol, including administration of six to eight high-dose (5 g/m2 /24 hr) Mtx (HDMtx) courses. The protocol includes recommendations for CPDG2......-1,310). Creatinine peaked after a median of 48 hr (range: 36-86). Mtx elimination time was shorter in patients with body surface area creatinine increase (209 vs. 258 hr; P = 0.034). All patients normalized their renal function...

  4. Preliminary study of interventional treatment for tubal pregnancy

    International Nuclear Information System (INIS)

    Tang Yukuan; Chen Hanwei; Li Kaifang; Jiang Zaibo; Ma Zhuang; Liu Huanling

    2000-01-01

    Objective: To study the clinical value and methods of interventional treatment for tubal pregnancy. Methods: Two different methods were used in the interventional treatment of 18 patients with tubal pregnancy, which were transvaginal tubal intra-gestational methotrexate (MTX) injection and intra-utero-arterial MTX infusion. The former was selected for the treatment of 8 patients and the latter for 10 patients. Cook-fallopian tube catheterization set and the general angiographic catheters of 4.1 Fr Cobra were used. After the treatment, conditions of the patients, β-HCG level and ultrasound changes of the pregnant bladder were the main indexes for monitoring the therapeutic effect in this study. Results: The successful rate, cure rate, embryo killing rate reached 100%, 88.9%(16/18) and 94.4% (17/18) respectively. Two cases of intra-utero-arterial MTX infusion treatment failed, β-HCG was reduced to normal level with an average of 11.2 +- 11.6 d (3-28 d). In 10 cases, the ultrasound showed that the pregnancy bladder disappeared in 2-3 weeks, accounting for 76.9% (10/13). The longest time was 60 days. The range of menstruation recovery was 37 +- 9 d (21-50 d). Conclusions: Interventional treatment of tubal pregnancy is effective, reliable and easy for operation. It will be especially effective by arterial procedure. Interventional treatment will be a important method for terminating tubal pregnancy

  5. 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

    Energy Technology Data Exchange (ETDEWEB)

    Wahba, Sanaa M.R. [Zoology department, Women College, Ain-Shams University,11566 Cairo (Egypt); Darwish, Atef S., E-mail: atef_mouharam@sci.asu.edu.eg [Chemistry department, Faculty of Science, Ain Shams University, Cairo (Egypt); Shehata, Iman H. [Microbiology and Immunology Department, Faculty of Medicine, Ain-Shams University, Cairo (Egypt); Abd Elhalem, Sahar S. [Zoology department, Women College, Ain-Shams University,11566 Cairo (Egypt)

    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 0.5 mg/kg/week for 2.5 months, 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. - Highlights: • Opening the door to synthesize smart targeted drug deliveries against RA disease • Therapy action of MTX-laden lignin and Fe{sub 3}O{sub 4}/SiO{sub 2} composite toward RA disease • Procure selective targeted drug deliveries of near 100% curing against RA disease • Revolutionary clinical therapies for RA disease by inventive MTX-delivery models.

  6. 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

    International Nuclear Information System (INIS)

    Wahba, Sanaa M.R.; Darwish, Atef S.; Shehata, Iman H.; Abd Elhalem, Sahar S.

    2015-01-01

    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 0.5 mg/kg/week for 2.5 months, 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. - Highlights: • Opening the door to synthesize smart targeted drug deliveries against RA disease • Therapy action of MTX-laden lignin and Fe 3 O 4 /SiO 2 composite toward RA disease • Procure selective targeted drug deliveries of near 100% curing against RA disease • Revolutionary clinical therapies for RA disease by inventive MTX-delivery models

  7. PLGA-soya lecithin based micelles for enhanced delivery of methotrexate: Cellular uptake, cytotoxic and pharmacokinetic evidences.

    Science.gov (United States)

    Singh, Anupama; Thotakura, Nagarani; Kumar, Rajendra; Singh, Bhupinder; Sharma, Gajanand; Katare, Om Prakash; Raza, Kaisar

    2017-02-01

    Biocompatible and biodegradable polymers like PLGA have revolutionized the drug delivery approaches. However, poor drug loading and substantially high lipophilicity, pave a path for further tailing of this promising agent. In this regard, PLGA was feathered with biocompatible phospholipid and polymeric micelles were developed for delivery of Methotrexate (MTX) to cancer cells. The nanocarriers (114.6nm±5.5nm) enhanced the cytotoxicity of MTX by 2.13 folds on MDA-MB-231 cells. Confocal laser scanning microscopy confirmed the increased intracellular delivery. The carrier decreased the protein binding potential and enhanced the bioavailable fraction of MTX. Pharmacokinetic studies vouched substantial enhancement in AUC and bioresidence time, promising an ideal carrier to effectively deliver the drug to the site of action. The developed nanocarriers offer potential to deliver the drug in the interiors of cancer cells in an effective manner for improved therapeutic action. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Aggregation of gold nanoparticles followed by methotrexate release enables Raman imaging of drug delivery into cancer cells

    International Nuclear Information System (INIS)

    Durgadas, C. V.; Sharma, C. P.; Paul, W.; Rekha, M. R.; Sreenivasan, K.

    2012-01-01

    This study refers an aqueous synthesis of methotrexate (MTX)-conjugated gold nanoparticles (GNPs), their interaction with HepG2 cells, and the use of Raman imaging to observe cellular internalization and drug delivery. GNPs of average size 3.5–5 nm were stabilized using the amine terminated bifunctional biocompatible copolymer and amended by conjugating MTX, an anticancer drug. The nanoparticles were released MTX at a faster rate in acidic pH and subsequently found to form aggregates. The Raman signals of cellular components were found to be enhanced by the aggregated particles enabling the mapping to visualize site-specific drug delivery. The methodology seems to have potential in optimizing the characteristics of nanodrug carriers for emptying the cargo precisely at specified sites.Graphical AbstractDrug release induced particle aggregation enhances Raman signals to aid in imaging.

  9. Systemic high-dose methotrexate plus ifosfamide is highly effective for central nervous system (CNS) involvement of lymphoma

    OpenAIRE

    2008-01-01

    Abstract Patients with malignant central nervous system (CNS) involvement of lymphoma have a poor prognosis with intrathecal chemotherapy and radiation. In this paper, we report the results we obtained in such patients by intravenous chemotherapy with high-dose methotrexate and ifosfamide (HDMTX/IFO). The study involved a review of all patients who received HDMTX/IFO for CNS involvement of malignant lymphoma at our hospital. Therapy consisted of 4 g/m2 of MTX (4 h infu...

  10. Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis.

    Directory of Open Access Journals (Sweden)

    Kalle J Aaltonen

    Full Text Available Five-tumour necrosis factor (TNF-blockers (infliximab, etanercept, adalimumab, certolizumab pegol and golimumab are available for treatment of rheumatoid arthritis. Only few clinical trials compare one TNF-blocker to another. Hence, a systematic review is required to indirectly compare the substances. The aim of our study is to estimate the efficacy and the safety of TNF-blockers in the treatment of rheumatoid arthritis (RA and indirectly compare all five currently available blockers by combining the results from included randomized clinical trials (RCT.A systematic literature review was conducted using databases including: MEDLINE, SCOPUS (including EMBASE, Cochrane library and electronic search alerts. Only articles reporting double-blind RCTs of TNF-blockers vs. placebo, with or without concomitant methotrexate (MTX, in treatment of RA were selected. Data collected were information of patients, interventions, controls, outcomes, study methods and eventual sources of bias.Forty-one articles reporting on 26 RCTs were included in the systematic review and meta-analysis. Five RCTs studied infliximab, seven etanercept, eight adalimumab, three golimumab and three certolizumab. TNF-blockers were more efficacious than placebo at all time points but were comparable to MTX. TNF-blocker and MTX combination was superior to either MTX or TNF-blocker alone. Increasing doses did not improve the efficacy. TNF-blockers were relatively safe compared to either MTX or placebo.No single substance clearly rose above others in efficacy, but the results of the safety analyses suggest that etanercept might be the safest alternative. Interestingly, MTX performs nearly identically considering both efficacy and safety aspects with a margin of costs.

  11. Methotrexate and Pregnancy

    Science.gov (United States)

    ... increased risk for infertility, not birth defects. Low sperm count has been seen in some men using methotrexate. Most of these men were using high doses of the medication, as well as other medications used to treat cancer. Sperm levels returned to normal after the men stopped ...

  12. Individualized toxicity-titrated 6-mercaptopurine increments during high-dose methotrexate consolidation treatment of lower risk childhood acute lymphoblastic leukaemia. A Nordic Society of Paediatric Haematology and Oncology (NOPHO) pilot study

    DEFF Research Database (Denmark)

    Frandsen, Thomas L; Abrahamsson, Jonas; Lausen, Birgitte

    2011-01-01

    This study explored the feasibility and toxicity of individualized toxicity-titrated 6-mercaptopurine (6MP) dose increments during post-remission treatment with High-dose methotrexate (HDM) (5000 mg/m(2), ×3) in 38 patients with Childhood (ALL). Patients were increased in steps of 25 mg 6MP/m(2...... the remaining patients (P = 0·03). This study shows individualized toxicity-titrated 6MP dosing during consolidation is feasible without increased risk of toxicity....

  13. Countermeasures against methotrexate intolerance in juvenile idiopathic arthritis instituted by parents show no effect.

    Science.gov (United States)

    Scheuern, Andrea; Tyrrell, Pascal N; Haas, Johannes-Peter; Hügle, Boris

    2017-06-01

    A high proportion of children with JIA will develop intolerance to MTX with anticipatory and associative gastrointestinal adverse effects. Parents and physicians frequently try to alleviate these symptoms with a variety of countermeasures. The objective of this study was to investigate the course of MTX intolerance within a 6 month period, and the effects of countermeasures on MTX intolerance severity. We performed a prospective study of 196 consecutive JIA patients treated with MTX. Intolerance was determined using the Methotrexate Intolerance Severity Score (MISS) questionnaire. MISS and countermeasures instituted by parents or physicians were determined at four time points, each 2 months apart. Countermeasures, classified into four types (antiemetic drugs, covert dosing, taste masking and complementary medicine), were analysed using non-parametric statistics and mixed linear modelling, adjusted by propensity scoring for use of countermeasures. Ninety patients (46%) showed MTX intolerance, with 58 (64%) using countermeasures at time of inclusion. Median MISS at inclusion was 11 (interquartile range = 8.0-14.25), and did not change significantly over time. No significant difference in MISS score was observed between patients receiving countermeasures and those who did not. For specific countermeasures, MISS did not change significantly after introduction. Sensitivity analysis adjusting for propensity score indicated no significant association of MISS severity on parents' decision to implement any countermeasures. MTX intolerance was present in many children with JIA and symptoms decreased little in the short term. Various modalities used as countermeasures against nausea by parents showed no discernible effect. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  14. PROJECT: RECOMMENDATIONS ON TREATMENT OF RHEUMATOID ARTHRITIS DEVELOPED BY ALL-RUSSIAN PUBLIC ORGANIZATION «ASSOCIATION OF RHEUMATOLOGISTS OF RUSSIA» – 2014 (PART 1

    Directory of Open Access Journals (Sweden)

    E. L. Nasonov

    2015-01-01

    Full Text Available Authors report new recommendations of All-Russian Public Organization «Association of Rheumatologists of Russia» (ARR on treatment of rheumatoid arthritis (RA, which adapts contemporary concept accepted in the respective field of pharmacotherapy known as «Treat to Target». According to it, the main objective of RA pharmacotherapy is a remission (or low disease activity. To achieve it, disease modifying anti-rheumatic drugs (DMARD should be administered to all RA patients as early as possible, with efficacy monitoring and therapy correction according to the disease activity. Special attention has been paid to the use of methotrexate (MTX as «the gold standard» of RA pharmacotherapy and the key component of «Treat to Target» strategy. Early MTX administration (including subcutaneous injections should become an obligatory component of RA treatment at all stages of the disease. If MTX is not efficient or not well tolerated (including subcutaneous form of the drug as monotherapy or combined with conventional DMARD, biological agents should be used. Those include TNFα inhibitors, antagonist of interleukin-6 receptor (Tocilizumab, anti-B-cell drugs (Rituximab and agents blocking T-cell activation (Abatacept. Tofacitinib therapy (JAK inhibitor is indicated in patients who are resistant to conventional DMARDs and biologics. All biologics and Tofacitinib are more effective in combination with MTX (or other DMARD. 

  15. PROJECT: RECOMMENDATIONS ON TREATMENT OF RHEUMATOID ARTHRITIS DEVELOPED BY ALL-RUSSIAN PUBLIC ORGANIZATION «ASSOCIATION OF RHEUMATOLOGISTS OF RUSSIA» – 2014 (PART 1

    Directory of Open Access Journals (Sweden)

    E. L. Nasonov

    2016-01-01

    Full Text Available Authors report new recommendations of All-Russian Public Organization «Association of Rheumatologists of Russia» (ARR on treatment of rheumatoid arthritis (RA, which adapts contemporary concept accepted in the respective field of pharmacotherapy known as «Treat to Target». According to it, the main objective of RA pharmacotherapyis a remission (or low disease activity. To achieve it, disease modifying anti-rheumatic drugs (DMARD should be administered to all RA patients as early as possible, with efficacy monitoring and therapy correction according to the disease activity. Special attention has been paid to the use of methotrexate (MTX as «the gold standard» of RA pharmacotherapy and the key component of «Treat to Target» strategy. Early MTX administration (including subcutaneous injections should become an obligatory component of RA treatment at all stages of the disease. If MTX is not efficient or not well tolerated (including subcutaneous form of the drug as monotherapy or combined with conventional DMARD, biological agents should be used. Those include TNFα inhibitors, antagonist of interleukin-6 receptor (Tocilizumab, anti-B-cell drugs  Rituximab and agents blocking T-cell activation (Abatacept. Tofacitinib therapy (JAK inhibitor is indicated in patients who are resistant to conventional DMARDs and biologics. All biologics and Tofacitinib are more effective in combination with MTX (or other DMARD.

  16. Immunogenicity and safety of the inactivated hepatitis A vaccine in children with juvenile idiopathic arthritis on methotrexate treatment: a matched case-control study.

    Science.gov (United States)

    Maritsi, Despoina N; Coffin, Susan E; Argyri, Ioanna; Vartzelis, George; Spyridis, Nick; Tsolia, Maria N

    2017-01-01

    To describe the immunogenicity and side effects of immunisation against hepatitis A virus (HAV) in JIA patients on methotrexate treatment, who have not been previously exposed to HAV. Case-control study performed in JIA patients and healthy controls matched on age and gender. The subjects received two doses of inactivated anti-HAV vaccine (720 mIU/ml) intramuscularly at 0 and 6 months. Seroconversion, seroprotection rates and anti-HAV-IgG titres were measured at 1, 7 and 18 months. Children were monitored for adverse events. 83 JIA patients and 76 controls were enrolled in the study. At one month, seroprotection rates were lower in children with, as compared to those without JIA (48.2% vs. 65%; p=0.05). At 7 and 18 months, rates of seroprotection rose significantly and were similar in both groups. The titre of anti-HAV-IgG was lower in children with JIA than healthy children at all time points (pVaccines were well tolerated. Two doses of inactivated HAV vaccine were well tolerated and immunogenic in most immunosuppressed children with JIA; however, a single dose of HAV vaccine was insufficient to induce seroprotection in half of the patients. Further studies are required to analyse the long-term immunity against HAV in this population and optimal HAV immunisation regimen.

  17. Marrow transplantation for leukemia following fractionated total body irradiation. A comparative trial of methotrexate and cyclosporine

    International Nuclear Information System (INIS)

    Irle, C.; Deeg, H.J.; Buckner, C.D.; Swedish Hospital Medical Center, Seattle, WA; Veterans Administration Hospital, Seattle, WA; Washington Univ., Seattle

    1985-01-01

    Fifty-six patients, 30-47 yr of age, with leukemia in relapse received allogeneic marrow transplants from HLA-identical siblings. All patients were treated with cyclophosphamide (120 mg/kg) and 7 daily fractions of 2.25 Gy of total body irradiation (TBI) for seven consecutive days. Nine patients (16%) are currently alive, free of disease, 324-845 days from transplantation. Actuarial relapse and survival rates at 2 yr were 56% and 9.5% respectively. These data were not remarkably different from those in previous studies using 10 Gy of TBI administered as a single dose. Thirty patients were randomized to receive methotrexate (MTX) and 26 to receive cyclosporine (CSP) as postgrafting prophylaxis for acute graft-versus-host disease (GVHD). Probability of developing significant acute GVHD by day 100 post-transplant was 71% for patients in the MTX group and 45% for patients in the CSP group (p<0.05). Probability of relapse was 37% for patients in the MTX group and 70% for patients in the CSP group (p<0.05). Transplant-related deaths were more frequent in the MTX group and leukemic deaths more frequent in the CSP group although this may have been related to an uneven distribution of high-risk patients. Long term disease-free survival was comparable. (author)

  18. Preparation for propagation and absorption experiments in MTX

    International Nuclear Information System (INIS)

    Byers, J.A.; Cohen, R.H.; Fenstermacher, M.E.; Hooper, E.B.; Meassick, S.; Rognlien, T.D.; Smith, G.R.; Stallard, B.W.

    1989-04-01

    Preparatory calculations of microwave transmission through the MTX access duct, propagation of the waves through the plasma and the resulting power deposition profile on a calorimeter located on the tokamak inside wall have been performed. The microwave transmission calculations include the relative phase slippage of waveguide modes in the duct to determine the spatial structure of the wavefront at the duct exist. Ray-tracing calculations show substantial spreading of the beam in the poloidal direction at densities above 1.5 /times/ 10 20 m/sup /minus/3/, well within the range of the experiments. Initial experiments with low or high toroidal field (cyclotron resonance outside the plasma) will investigate both diffraction and refraction effects, without absorption. Estimates of the fractional absorption of the beam in the initial experiments with the cyclotron resonance at the plasma axis have also been made. 4 refs., 3 figs

  19. The MTX [Microwave Tokamak Experiment] data acquisition system

    International Nuclear Information System (INIS)

    Butner, D.N.; Drlik, M.; Brown, M.D.; Casper, T.A.; Meyer, W.H.; Moller, J.M.

    1989-01-01

    The diagnostic data from the MTX experiment is acquired and processed by an expandable, distributed, multivendor computer network. The system blends a variety of software into a coordinated, unified, and highly flexible design. Using modular software design techniques, we created a system stressing distributed processing, portability, and transparent data access. In our approach to modularity, we standardized communication interfaces between modules and separated generic tasks from machine and application-specific implementations. For flexible distributed processing, we used modular, portable software and LLNL facility that provides an interprocess communication system (IPCS) in the multivendor network. With transparent data access, any program can access data stored anywhere in the network without knowing the specific location. The computer hardware includes a DEC VAX cluster, HP workstations and HP desktop computers. We are using commercial software in addition to packages from MIT, ORNL, and LLNL. 4 refs., 4 figs

  20. Magnet power system for the Microwave Tokamak Experiment (MTX)

    International Nuclear Information System (INIS)

    Jackson, M.C.; Musslewhite, R.C.

    1987-01-01

    The system configuration, layout, and general philosophy for the MTX magnet power system is described. The vast majority of the magnet power equipment was quite successfully used on the ALCATOR-C experiment at the Massachusetts Institute of Technology. The AC power for the magnet system at MIT was obtained from a 225MVA alternator. The power for the system at LLNL is obtained directly from the local utility's 230 kV line. This installation, therefore, necessitates the addition of a great deal of equipment in ranges from new switchgear in the substation to using existing switchgear obtained from MIT as contractors for intershop electrical isolation as well as safety isolation for personnel entry into the experimental area. Additionally, some discussion is made of the unique layout of this facility and the tradeoffs made to accommodate them. 2 refs., 6 figs

  1. Methotrexate loading in chitosan nanoparticles at a novel pH: Response surface modeling, optimization and characterization.

    Science.gov (United States)

    Hashad, Rania A; Ishak, Rania A H; Geneidi, Ahmed S; Mansour, Samar

    2016-10-01

    The aim of this study was to assess the feasibility of employing a novel but critical formulation pH (6.2) to encapsulate an anionic model drug (methotrexate, MTX) into chitosan(Cs)-tripolyphosphate nanoparticles(NPs). A response surface methodology using a three-level full factorial design was applied studying the effects of two independent variables namely; Cs concentration and MTX concentration. The responses investigated were the entrapment efficiency (EE%), mean hydrodynamic particle size (PS), polydispersity index (PDI) and zeta potential (ZP). In order to simultaneously optimize the series of models obtained, the desirability function approach was applied with a goal to produce high percent of MTX encapsulated into highly charged Cs-TPP NPs of homogenous optimum PS. MTX-loaded CsNPs were successfully prepared at the novel pH applied. The suggested significant models were found quadratic for EE, PS and ZP responses, while 2-factor interaction model for PDI. The optimization overlay graph showed that the maximum global desirability, D=0.856, was reached when the conditions were set at high Cs and MTX concentration. Thus, the use of such optimized conditions, at this novel pH, achieved a maximum drug EE% (73.38%) into NPs characterized by optimum PS (232.6nm), small PDI value (0.195) and highly surface charged (+18.4mV). Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Engineering human T cells for resistance to methotrexate and mycophenolate mofetil as an in vivo cell selection strategy.

    Directory of Open Access Journals (Sweden)

    Mahesh Jonnalagadda

    Full Text Available Gene transfer and drug selection systems that enforce ongoing transgene expression in vitro and in vivo which are compatible with human pharmaceutical drugs are currently underdeveloped. Here, we report on the utility of incorporating human enzyme muteins that confer resistance to the lymphotoxic/immunosuppressive drugs methotrexate (MTX and mycophenolate mofetil (MMF in a multicistronic lentiviral vector for in vivo T lymphocyte selection. We found that co-expression of human dihydrofolate reductase (DHFR(FS; L22F, F31S and inosine monophosphate dehydrogenase II (IMPDH2(IY; T333I, S351Y conferred T cell resistance to the cytocidal and anti-proliferative effects of these drugs at concentrations that can be achieved clinically (up to 0.1 µM MTX and 1.0 µM MPA. Furthermore, using a immunodeficient mouse model that supports the engraftment of central memory derived human T cells, in vivo selection studies demonstrate that huEGFRt(+DHFR(FS+IMPDH2(IY+ T cells could be enriched following adoptive transfer either by systemic administration of MTX alone (4.4 -fold, MMF alone (2.9-fold, or combined MTX and MMF (4.9-fold. These findings demonstrate the utility of both DHFR(FS/MTX and IMPDH2(IY/MMF for in vivo selection of lentivirally transduced human T cells. Vectors incorporating these muteins in combination with other therapeutic transgenes may facilitate the selective engraftment of therapeutically active cells in recipients.

  3. Engineering human T cells for resistance to methotrexate and mycophenolate mofetil as an in vivo cell selection strategy.

    Science.gov (United States)

    Jonnalagadda, Mahesh; Brown, Christine E; Chang, Wen-Chung; Ostberg, Julie R; Forman, Stephen J; Jensen, Michael C

    2013-01-01

    Gene transfer and drug selection systems that enforce ongoing transgene expression in vitro and in vivo which are compatible with human pharmaceutical drugs are currently underdeveloped. Here, we report on the utility of incorporating human enzyme muteins that confer resistance to the lymphotoxic/immunosuppressive drugs methotrexate (MTX) and mycophenolate mofetil (MMF) in a multicistronic lentiviral vector for in vivo T lymphocyte selection. We found that co-expression of human dihydrofolate reductase (DHFR(FS); L22F, F31S) and inosine monophosphate dehydrogenase II (IMPDH2(IY); T333I, S351Y) conferred T cell resistance to the cytocidal and anti-proliferative effects of these drugs at concentrations that can be achieved clinically (up to 0.1 µM MTX and 1.0 µM MPA). Furthermore, using a immunodeficient mouse model that supports the engraftment of central memory derived human T cells, in vivo selection studies demonstrate that huEGFRt(+)DHFR(FS+)IMPDH2(IY+) T cells could be enriched following adoptive transfer either by systemic administration of MTX alone (4.4 -fold), MMF alone (2.9-fold), or combined MTX and MMF (4.9-fold). These findings demonstrate the utility of both DHFR(FS)/MTX and IMPDH2(IY)/MMF for in vivo selection of lentivirally transduced human T cells. Vectors incorporating these muteins in combination with other therapeutic transgenes may facilitate the selective engraftment of therapeutically active cells in recipients.

  4. Leukoencephalopathy and cortical leminar necrosis associated with intrathecal methotrexate and cranial irridiation

    International Nuclear Information System (INIS)

    Iqbal, Yasir; Al-Sudairy, Reem; Abdullah, Mohammad F.

    2003-01-01

    With the advent of chemotherapy, mortality rates in children with acute lymphoblastic leukemia have decreased . Though prophylactic treatment of central nervous system (CNS) to prevent leukemic infiltration has reduced the incidence of CNS relapse and improved the survival in pediatric acute lymphoblastic leukemia. We studied a unique case of neurotoxicity associated with prophylactic cranial irradiation and intrathecal MTX. This is the first reported case of pure MTX-related CLN.Perhaps the combination of MTX along with cranial irradiation, can result in increased neurotoxic effects. (author)

  5. The role of nanoparticles in the albumin-cytarabine and albumin-methotrexate interactions

    Energy Technology Data Exchange (ETDEWEB)

    Pentak, Danuta, E-mail: danuta.pentak@us.edu.pl [Department of Materials Chemistry and Chemical Technology, Institute of Chemistry, University of Silesia, Szkolna 9, 40-006 Katowice (Poland); Maciążek-Jurczyk, Małgorzata; Zawada, Zygmunt H. [School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Department of Physical Pharmacy, Jagiellońska 4, 41-200 Sosnowiec (Poland)

    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{sub 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{sup +}(CH{sub 3}){sub 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. - Graphical abstract: In vitro drug release profiles of different liposomal formulation. - Highlights: • Liposomes containing tested drugs can be obtained by mREV method. • High degree of encapsulation characterizes obtained liposomes. • Cytarabine and methotrexate release from liposomes followed both: diffusion and controlled mechanisms.

  6. Methotrexate-induced intestinal mucositis delays gastric emptying and gastrointestinal transit of liquids in awake rats

    Directory of Open Access Journals (Sweden)

    Pedro M. G. Soares

    2011-03-01

    Full Text Available CONTEXT: Methotrexate and other anticancer agents can induce intestinal mucositis, which is one of the most common limiting factor that prevent further dose escalation of the methotrexate. OBJECTIVES: To evaluate the gastric emptying and gastrointestinal transit of liquids in methotrexate-induced intestinal mucositis. METHODS: Wistar rats received methotrexate (2.5 mg/kg/day for 3 days, subcutaneously or saline. After 1, 3 and 7 days, sections of duodenum, jejunum and ileum were removed for assessment of epithelial damage and myeloperoxidase activity (biochemical marker of granulocyte infiltration. Others rats were pre-treated with methotrexate or saline, gavage-fed after 3 or 7 days with a standard test liquid meal, and sacrificed 10, 20 or 30-min later. Gastric and small intestine dye recoveries were measured by spectrophotometry. RESULTS: After 3 days of methotrexate, there was an epithelial intestinal damage in all segments, with myeloperoxidase activity increase in both in duodenum and ileum. Seven days after methotrexate, we observed a complete reversion of this intestinal damage. There was an increase in gastric dye recoveries after 10, 20, and 30-min post-prandial intervals after 3 days, but not after 7 days, of methotrexate. Intestine dye recoveries were decreased in the first and second segments at 10 min, in the third at 20 min, and in the second and third at 30 min, only after 3 days of methotrexate treatment. CONCLUSION: Methotrexate-induced intestinal mucositis delays gastric emptying and gastrointestinal transit of liquids in awake rats.

  7. Methotrexate for primary biliary cirrhosis

    DEFF Research Database (Denmark)

    Giljaca, Vanja; Poropat, Goran; Stimac, Davor

    2010-01-01

    Methotrexate has been used to treat patients with primary biliary cirrhosis as it possesses immunosuppressive properties. The previously prepared version of this review from 2005 showed that methotrexate seemed to significantly increase mortality in patients with primary biliary cirrhosis. Since...... that last review version, follow-up data of the included trials have been published....

  8. Facial symmetry evaluation after experimentally displaced condylar process fracture in methotrexate treated rats Avaliação da simetria facial após fratura experimental com desvio do processo condilar em ratos tratados com metotrexato

    Directory of Open Access Journals (Sweden)

    Samantha Cristine Santos Xisto Braga Cavalcanti

    2012-03-01

    Full Text Available PURPOSE: To investigate the facial symmetry of high and low dose methotrexate (MTX treated rats submitted to experimentally displaced mandibular condyle fracture through the recording of cephalometric measurements. METHODS: One hundred male Wistar rats underwent surgery using an experimental model of right condylar fracture. Animals were divided into four groups: A - saline solution (1mL/week; B - dexamethasone (DEX (0,15mg/Kg; C - MTX low dose (3 mg/Kg/week; D - MTX high dose (30 mg/Kg. Animals were sacrificed at 1, 7, 15, 30 and 90 days postoperatively (n=5. Body weight was recorded. Specimens were submitted to axial radiographic incidence, and cephalometric mensurations were made using a computer system. Linear measurements of skull and mandible, as well as angular measurements of mandibular deviation were taken. Data were subjected to statistical analyses among the groups, periods of sacrifice and between the sides in each group (α=0.05. RESULTS: Animals regained body weight over time, except in group D. There was reduction in the mandibular length and also changes in the maxilla as well as progressive deviation in the mandible in relation to the skull basis in group D. CONCLUSION: Treatment with high dose methotrexate had deleterious effect on facial symmetry of rats submitted to experimentally displaced condylar process fracture.OBJETIVO: Avaliar a simetria facial de ratos tratados com metotrexato (MTX, em dose alta e baixa, submetidos à fratura experimental do processo condilar com desvio por meio de mensurações cefalométricas. MÉTODOS: Cem ratos Wistar machos foram submetidos a procedimento cirúrgico utilizando modelo experimental de fratura de côndilo do lado direito. Os animais foram distribuídos em quatro grupos: A - soro fisiológico (1mL/semana; B - dexametasona (DEX (0,15mg/Kg; C - MTX baixa dose (3mg/Kg/semana; D - MTX alta dose (30mg/Kg. Os períodos de sacrifício foram de 1, 7, 15, 30 e 90 dias de pós-operatório (n=5

  9. A decrease in vitamin D levels is associated with methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia.

    Science.gov (United States)

    Oosterom, N; Dirks, N F; Heil, S G; de Jonge, R; Tissing, W J E; Pieters, R; van den Heuvel-Eibrink, M M; Heijboer, A C; Pluijm, S M F

    2018-06-19

    Children with acute lymphoblastic leukemia (ALL) are at increased risk of vitamin D deficiency, which might make them more susceptible to developing adverse events. Previous studies showed that low vitamin D levels were associated with an increased inflammatory mucosal state and impaired mucosal tissue barriers. We examined the prevalence of vitamin D deficiency and studied the association between vitamin D levels and methotrexate (MTX)-induced oral mucositis in pediatric ALL. We assessed 25-hydroxyvitamin D (25(OH)D 3 ) and 24,25-dihydroxyvitamin D (24,25(OH) 2 D 3 ) levels in 99 children with ALL before the start of 4 × 5 g/m 2 high-dose methotrexate (HD-MTX) (T0) and in 81/99 children after discontinuation of HD-MTX (T1). Two cutoff values for vitamin D deficiency exist: 25(OH)D 3 levels D deficiency occurred in respectively 8% ( 4 years of age as compared to children between 1 and 4 years of age. A decrease in 25(OH)D 3 levels during HD-MTX therapy was associated with developing severe oral mucositis (OR 1.6; 95% CI [1.1-2.4]). 25(OH)D 3 and 24,25(OH) 2 D 3 levels at T0 and the change in 24,25(OH) 2 D 3 levels during therapy were not associated with the development of severe oral mucositis. This study showed that vitamin D deficiency occurs frequently in pediatric ALL patients above the age of 4 years. A decrease in 25(OH)D 3 levels during MTX therapy was observed in children with ALL that developed severe oral mucositis.

  10. 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.

    Science.gov (United States)

    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

  11. Floating data acquisition system for microwave calorimeter measurements on MTX

    International Nuclear Information System (INIS)

    Sewall, N.R.

    1989-01-01

    A microwave calorimeter has been designed for making 140-GHz absorption measurements on the MTX. Measurement of the intensity and spatial distribution of the FEL-generated microwave beam on the inner wall will indicate the absorption characteristics of the plasma when heated with a 140 GHz FEL pulse. The calorimeter works by monitoring changes of temperature in silicon carbide tiles located on the inner wall of the tokamak. Thermistors are used to measure the temperature of each tile. The tiles are located inside the tokamak about 1 cm outside of the limiter radius at machine potential. The success of this measurement depends on our ability to float the data acquisition system near machine potential and isolate it from the rest of the vault ground system. Our data acquisition system has 48 channels of thermistor signal conditioning, a multiplexer and digitizer section, a serial data formatter, and a fiber-optic transmitter to send the data out. Additionally, we bring timing signals to the interface through optical fibers to tell it when to begin measurement, while maintaining isolation. The receiver is an HP 200 Series computer with a serial data interface; the computer provides storage and local display for the shot temperature profile. Additionally, the computer provides temporary storage of the data until it can be passed to a shared resource management system for archiving. 2 refs., 6 figs

  12. Floating data acquisition system for microwave calorimeter measurements on MTX

    International Nuclear Information System (INIS)

    Sewall, N.R.; Meassick, S.

    1989-01-01

    A microwave calorimeter has been designed for making 140-GHz absorption measurements on the MTX. Measurement of the intensity and spatial distribution of the FEL-generated microwave beam on the inner wall will indicate the absorption characteristics of the plasma when heated with a 140 GHz FEL pulse. The calorimeter works by monitoring changes of temperature in silicon carbide tiles located on the inner wall of the tokamak. Thermistors are used to measure the temperature of each tile. The tiles are located inside the tokamak about 1 cm outside of the limiter radius at machine potential. The success of this measurement depends on our ability to float the data acquisition system near machine potential and isolate it from the rest of the vault ground system. Our data acquisition system has 48 channels of thermistor signal conditioning, a multiplexer and digitizer section, a serial data formatter, and a fiber-optic transmitter to send the data out. Additionally, we bring timing signals to the interface through optical fibers to tell it when to begin measurement, while maintaining isolation. The receiver is an HP 200 series computer with a serial data interface; the computer provides storage and local display for the shot temperature profile. Additionally, the computer provides temporary storage of the data until it can be passed to a shared resource management system for archiving. 2 refs., 6 figs

  13. Methotrexate induces poly(ADP-ribose) polymerase-dependent, caspase 3-independent apoptosis in subsets of proliferating CD4+ T cells

    DEFF Research Database (Denmark)

    Nielsen, C H; Albertsen, L; Bendtzen, K

    2007-01-01

    The mechanism of action of methotrexate (MTX) in autoimmune diseases (AID) is unclear. A pro-apoptotic effect has been demonstrated in mitogen-stimulated peripheral blood mononuclear cells (PBMC), but studies employing conventional antigens have disputed a pro-apoptotic effect. CD4+ T helper (Th....... Exposure of CA-stimulated PBMC to MTX significantly increased their level of cleaved poly(ADP-ribose) polymerase (PARP), and a similar tendency was observed in TT-stimulated cells. Unlike CA and TT, the mitogen phytohaemagglutinin (PHA) induced proliferation of both CD4- and CD4+ T cells, and induced......) cells play a significant role in most AID. We therefore examined directly, by flow cytometry, the uptake of MTX by the T helper (Th) cells stimulated for 6 days with Candida albicans (CA) or tetanus toxoid (TT), and its consequences with respect to induction of apoptosis. While none of the resting Th...

  14. Long-term study of the impact of methotrexate on serum cytokines and lymphocyte subsets in patients with active rheumatoid arthritis: correlation with pharmacokinetic measures

    Science.gov (United States)

    Kremer, Joel M; Lawrence, David A; Hamilton, Robert; McInnes, Iain B

    2016-01-01

    Objective To describe changes in immune parameters observed during long-term methotrexate (MTX) therapy in patients with active rheumatoid arthritis (RA) and explore correlations with simultaneously measured MTX pharmacokinetic (PKC) parameters. Design Prospective, open-label, long-term mechanism of action study. Setting University clinic. Methods MTX was initiated at a single weekly oral dose of 7.5 mg and dose adjusted for efficacy and toxicity for the duration of the study. Standard measures of disease activity were performed at baseline and every 6–36 months. Serum cytokine measurements in blood together with lymphocyte surface immunophenotypes and stimulated peripheral blood mononuclear cell (PBMC) cytokine production were assessed at each clinical evaluation. Results Cytokine concentrations exhibited multiple significant correlations with disease activity measures over time. The strongest correlations observed were for interleukin (IL)-6 (r=0.45, p<0.0001 for swollen joints and r=0.32, p=0.002 for tender joints) and IL-8 (r=0.25, p=0.01 for swollen joints). Significant decreases from baseline were observed in serum IL-1B, IL-6 and IL-8 concentrations. The most significant changes were observed for IL-6 (p<0.001). Significant increases from baseline were observed in IL-2 release from PBMCs ex vivo (p<0.01). In parallel, multiple statistically significant correlations were observed between MTX PKC measures and immune parameters. The change in swollen joint count correlated inversely with the change in area under the curve (AUC) for MTX (r=−0.63, p=0.007). Conclusions MTX therapy of patients with RA is accompanied by a variety of changes in serum cytokine expression, which in turn correlate strongly with clinical disease activity and MTX pharmacokinetics (PKCs). These data strongly support the notion that MTX mediates profound and functionally relevant effects on the immunological hierarchy in the RA lesion. PMID:27335660

  15. The relationship between CNS prophylactic treatment and smoking behavior in adult survivors of childhood leukemia: a National Cancer Institute and Children's Cancer Group (NCI/CCG) study

    International Nuclear Information System (INIS)

    Tao, M.L.; Weiss, R.E.; Guo, M.D.; Byrne, J.; Mills, J.L.; Robison, L.L.; Zeltzer, L.K.

    1997-01-01

    Purpose/Objective: To determine the relationship of both cranial radiation dose (CRD) and intra-thecal methotrexate (IT-MTX) dose with smoking behavior in survivors of childhood acute lymphoblastic leukemia (ALL). Material and Methods: A retrospective cohort study was conducted by NCI/CCG with 593 young adult survivors (median age, 21.6 years), treated prior to age 20 years on CCG ALL protocols from 1970 to 1986, and 409 sibling controls (median age, 24.5 years). Subjects were telephone surveyed regarding risk-taking behaviors, including cigarette smoking. A previous report has compared the smoking behavior of survivors to controls; this report will focus on the association between CNS treatment variables and smoking behavior for survivors only. Contingency table analysis was used to determine the prevalence of having ever smoked regularly (i.e. ≥ 100 cigarettes total and daily use for ≥ 6 months) for each treatment group: combinations of CRD (0-18 Gy vs. 24 Gy) and IT-MTX (0 to ≤ 83 mg vs. >83 mg). Logistic regression analysis was used to examine CRD, IT-MTX dose, age at diagnosis and age at follow-up as predictors for smoking. Too few subjects received intravenous methotrexate to evaluate this as an explanatory variable. The analysis was done separately for survivors from treatment periods 1 and 2 (1970-77 and 1978-86, respectively) to control for the time period cohort effect (which we have previously demonstrated to be significant). These treatment period definitions also correlated with a shift in protocol treatment trends from 24 Gy to 0-18 Gy and lower dose IT-MTX to higher dose IT-MTX. Results: Among the survivors from treatment period 1 who received 24 Gy CRD, those treated with higher dose IT-MTX (>83 mg) were significantly more likely to have ever been regular smokers than those treated with no or lower dose IT-MTX (31% vs. 16%, p=0.016). Among survivors from treatment period 1 who received 0-18 Gy CRD, the smoking prevalence was also greater in

  16. Treatment of tubal pregnancy by uterine artery perfusion and embolization

    International Nuclear Information System (INIS)

    Ni Caifang; Zou Jianwei; Zhao Hui; Jin Yonghai; Zhu Xiaoli; Liu Yizhi; He Qi; Shen Zhongji

    2006-01-01

    Objective: To study the feasibility, safety, and efficacy of the treatment for tubal pregnancy by interventional technique of transuterine arterial catheterization perfusion and embolization. Methods: Using modified Seldinger technique, 42 cases of tubal pregnancy received super-selective angiography of uterine artery, followed by perfusion of 50-100 mg methotrexate (MTX) through the catheter and embolization of uterine artery with gelatin sponge. Before and after the procedure, changes of clinical symptoms, physical signs, value of β-hCG and size of pregnancy cyst of patients were studied. Concentrations of MTX in peripheral blood were studied at 0.5, 6, 12, 24, 36, 48 hours after the procedure. Results: 38 out of 42 cases were cured with successful rate of 90.5%(38/42). The average time of β-hCG decreasing to normal was 8.26 ± 2.04 days. The concentration of MTX in peripheral blood with 50 mg or 75 mg dosage could not be detected at 36 hours after the procedure but could be detected as 0.01 μmol/L at 48 hours after the procedure with a dosage of 100 mg. Conclusions: It is simple, safe and efficient in performing trans-uterine artery chemo-embolization for therapy of fallopian tubal pregnancy, especially for those who complicated with manipules bleeding and also as the first choice for prevention of high risk massive hemorrhage. (authors)

  17. Compliance with methotrexate treatment in patients with rheumatoid arthritis: influence of patients' beliefs about the medicine. A prospective cohort study

    DEFF Research Database (Denmark)

    de Thurah, Annette; Nørgaard, Mette; Harder, Ingegerd

    2010-01-01

    dose, years of school education, functional disability, use of folic acid, and co-morbidity. Crude and adjusted prevalence ratios (PR) with 95% confidence intervals (CI) were calculated by using log-binomial regression. The necessity and concern scales of the Beliefs about Medication Questionnaire were...... was seen after 9 months. The prevalence of having a CQR in the bottom quartile or not was almost equally distributed among patients who had high or low concerns about treatment at baseline. After 9 months, however, the prevalence of having a CQR in the bottom quartile was 18.9% for patients who had low...

  18. The Promise of Pharmacogenomics in Reducing Toxicity During Acute Lymphoblastic Leukemia Maintenance Treatment

    Directory of Open Access Journals (Sweden)

    Shoshana Rudin

    2017-04-01

    Full Text Available Pediatric acute lymphoblastic leukemia (ALL affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2–3 years. While the primary drugs used in the maintenance phase, 6-mercaptopurine (6-MP and methotrexate (MTX, are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity. For both drugs, pharmacogenomic factors have been identified that could explain a large amount of the variance in toxicity between patients, and may serve as effective predictors of toxicity during the maintenance phase of ALL treatment. 6-MP toxicity is associated with polymorphisms in the genes encoding thiopurine methyltransferase (TPMT, nudix hydrolase 15 (NUDT15, and potentially inosine triphosphatase (ITPA, which vary between ethnic groups. Moreover, MTX toxicity is associated with polymorphisms in genes encoding solute carrier organic anion transporter family member 1B1 (SLCO1B1 and dihydrofolate reductase (DHFR. Additional polymorphisms potentially associated with toxicities for MTX have also been identified, including those in the genes encoding solute carrier family 19 member 1 (SLC19A1 and thymidylate synthetase (TYMS, but their contributions have not yet been well quantified. It is clear that pharmacogenomics should be incorporated as a dosage-calibrating tool in pediatric ALL treatment in order to predict and minimize the occurrence of serious toxicities for these patients.

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

    International Nuclear Information System (INIS)

    Hammond, S.J.; Birdsall, B.; Feeney, J.; Searle, M.S.; Roberts, G.C.K.; Cheung, H.T.A.

    1987-01-01

    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 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 to that found in the methotrexate-enzyme complex. Perturbations in 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 γ-monoamide analog, the 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 γ-CO 2 - is no longer present in this complex with the γ-amide, there has not been a major change in the overall structure of the two complexes. This behavior contrasts to that of the α-amide complex where 1 H signals from protons in several amino acid residues are different compared with their values in the complex formed with methotrexate

  20. [Pharmacokinetic monitoring of 24-hour infusion of methotrexate in an adult population with non-Hodgkin lymphoma].

    Science.gov (United States)

    Fernández Megía, M J; Alós Almiñana, M; Esquer Borrás, J

    2004-01-01

    To describe the behavior and variability of methotrexate (MTX) pharmacokinetic parameters in patients with non-Hodgkin lymphoma (NHL) and to suggest a monitoring system to optimize sample collection using a bayesian method. Two adult patient groups diagnosed with different NHL types were studied. Group I was made up of 9 patients aged 53 +/- 16 years who received MTX at a mean dose of 1.652 +/- 327 mg per course. Group II was made up of 7 patients aged 53 +/- 14 years who received MTX at a mean dose of 1.862 +/- 220 mg per course. No statistically significant differences between groups were seen. Serum MTX measurements were performed using polarized immunofluorescence (TDx system). The pharmacokinetic analysis was performed using Abbottbase Pharmacokinetics Systems (PKS) software, adjusting experimental data according to a bicompartmental linear model for intravenous delivery using non-linear regression in Group I and Bayesian estimates in Group II. By estimating mean square error and linear regression between predicted and experimental concentrations, the capability of the Bayesian method implemented in PKS to predict plasma MTX concentration at 48 hours post-infusion was evaluated. The safety of MTX therapy was assessed using patient medical histories and then scoring toxicity using the WHO scale. Pharmacokinetic parameters obtained for group I included: alpha (h(-1)) = 0.38 +/- 0.12; beta (h(-1)) = 0.07 +/- 0.03; K12 (h(-1)) = 0.02 +/- 0.02; K21 (h(-1)) = 0.09 +/- 0.09; K13 (h(-1)) = 0.34 +/- 0.12; Vc (l/kg) = 0.53 +/- 0.23; Vss (l/kg) = 0.62 +/- 0.26; Cl (l/kg.h) = 0.16 +/- 0.06. The error for the PKS population model in measuring plasma MTX concentration at 48 hours post-infusion in Group II was calculated in accordance with three sampling schemes -12 h, 24 h, and both. It was -14.58 x 10(-3), -15.70 x 10(-3) and -14.67 x 10(-3), respectively. Eqm was 9.58 x 10(-3), 2.39 x 10(-3), and 1.02 x 10(-3), respectively. An MTX monitoring scheme is suggested based on

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

    Science.gov (United States)

    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

  2. Pancytopenia associated with low-dose methotrexate therapy – case reports

    Directory of Open Access Journals (Sweden)

    Marija Čeh

    2012-12-01

    Conclusions: With the increasing long-term use of methotrexate, it is important that patients should be monitored during treatment for haematological side-effects, as pancytopenia can be a late manifestation. Furthermore, more attention should be paid to risk factors predisposing hematological toxicity of methotrexate before commencing this drug

  3. MTX [Microwave Tokamak Experiment] diagnostic and auxiliary systems for confinement, transport, and plasma physics studies

    International Nuclear Information System (INIS)

    Hooper, E.B.; Allen, S.L.; Casper, T.A.; Thomassen, K.I.

    1989-01-01

    This note describes the diagnostics and auxiliary systems on the Microwave Tokamak Experiment (MTX) for confinement, transport, and other plasma physics studies. It is intended as a reference on the installed and planned hardware on the machine for those who need more familiarity with this equipment. Combined with the tokamak itself, these systems define the opportunities and capabilities for experiments in the MTX facility. We also illustrate how these instruments and equipment are to be used in carrying out the MTX Operations Plan. Near term goals for MTX are focussed on the absorption and heating by the microwave beam from the FEL, but the Plan also includes using the facility to study fundamental phenomena in the plasma, to control MHD activity, and to drive current noninductively

  4. Investigation of nano lipid vesicles of methotrexate for anti-rheumatoid activity

    Directory of Open Access Journals (Sweden)

    Prabhu P

    2012-01-01

    Full Text Available Prabhakara Prabhu1, Rakshith Shetty1, Marina Koland1, K Vijayanarayana3, KK Vijayalakshmi2, M Harish Nairy1, GS Nisha11Department of Pharmaceutics, Nitte University, NGSM Institute of Pharmaceutical Sciences, Paneer, Deralakatte, Mangalore, Karnataka, India; 2Department of Applied Zoology, Mangalore University, Konaje, Mangalore, Karnataka, India; 3Department of Pharmacy Practice, Manipal University, Manipal College of Pharmaceutical Sciences, Manipal, Karnataka, IndiaBackground: The purpose of this study was to formulate and evaluate nano lipid vesicles of methotrexate (MTX for its anti-rheumatoid activity.Methods: In this study the principle of both active as well as passive targeting using MTX-loaded stealth liposomes as per the magic gun approach was followed. Stealth liposomes of MTX were prepared by thin-film hydration method using a PEGylated phospholipid-like DSPE-MPEG 2000. Similarly, conventional liposomes were prepared using phospholipids like DPPC and DSPC. Conventional liposomes were coated with a hydrophilic biocompatible polymer like chitosan. They were investigated for their physical properties and in vitro release profile. Further, in vivo screening of the formulations for their anti-rheumatoid efficacy was carried out in rats. Rheumatoid arthritis was induced in male Wistar-Lewis rats using complete Freund’s adjuvant (1 mg/mL Mycobacterium tuberculosis, heat killed in mineral oil.Results: It was found that chitosan coating of the conventional liposomes increased the physical stability of the liposomal suspension as well as its entrapment efficiency. The size of the unsonicated lipid vesicles was found to be in the range of 8–10 µm, and the sonicated lipid vesicles in the range of 210–260 nm, with good polydispersity index. Further, chitosan-coated conventional liposomes and the PEGylated liposomes released the drug for a prolonged period of time, compared to the uncoated conventional liposomes. It was found that there

  5. 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.

    Science.gov (United States)

    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.

  6. Pharmacokinetics of methotrexate in the cerebrospinal fluid after intracerebroventricular administration in patients with meningeal carcinomatosis and altered cerebrospinal fluid flow dynamics

    International Nuclear Information System (INIS)

    Miller, K.T.; Wilkinson, D.S.

    1989-01-01

    Pharmacokinetic parameters of the distribution and elimination of intracerebroventricularly administered methotrexate (MTX) were evaluated in three patients with meningeal carcinomatosis. Abnormal cerebrospinal fluid (CSF) flow dynamics, which were not otherwise clinically evident, were diagnosed by 111In-diethylenetriaminepentaacetate radionuclide imaging. Alterations in CSF flow resulted in large changes in MTX distribution. Reduced cortical convexity (type III), spinal subarachnoid (type II), or ventricular (type I) CSF flow resulted in a prolongation of the single-pass mean residence time of MTX in the peripheral compartment by as much as eightfold and a reduction in intercompartmental clearance by 94-99%. Leptomeningeal carcinomatosis can affect both CSF MTX distribution and elimination, each to a different extent, within the same patient. Total MTX clearance from the CSF was reduced by 79-93% in the patients studied. A two-compartment pharmacokinetic model, with elimination occurring from the peripheral compartment, gave values for the distribution rate constant from the central to the peripheral compartment (k12), which decreased with the extent of CSF flow abnormality. However, the elimination rate constant from the peripheral compartment (k20) was reduced to an extent apparently independent of CSF flow abnormality (percentage reduction in k12 and k20, respectively: type III, 18 and 66; type II, 67 and 86; type I, 78 and 48). Inadequate distribution and locally high concentrations of MTX within the CSF may contribute to therapeutic failure and neurotoxicity. Monitoring of MTX levels in the CSF may be deceiving when samples are drawn from the site of injection, since the distribution kinetics are altered by abnormal CSF flow dynamics

  7. Synthesis and characterization of novel P(HEMA-LA-MADQUAT) micelles for co-delivery of methotrexate and Chrysin in combination cancer chemotherapy.

    Science.gov (United States)

    Davaran, Soodabeh; Fazeli, Hamed; Ghamkhari, Aliyeh; Rahimi, Fariborz; Molavi, Ommoleila; Anzabi, Maryam; Salehi, Roya

    2018-08-01

    A Novel poly [2-hydroxyethyl methacrylate-Lactide-dimethylaminoethyl methacrylate quaternary ammonium alkyl halide] [P(HEMA-LA-MADQUAT)] copolymer was synthesized through combination of ring opening polymerization (ROP) and 'free' radical initiated polymerization methods. This newly developed copolymer was fully characterized by FT-IR, 1 HNMR and 13 CNMR spectroscopy. Micellization of the copolymer was performed by dialysis membrane method and obtained micelles were characterized by FESEM, dynamic light scattering (DLS), zeta potential (ξ), and critical micelle concentration (CMC) measurements. This copolymer was developed with the aim of co-delivering two different anticancer drugs: methotrexate (MTX) and chrysin. In vitro cytotoxicity effect of MTX@Chrysin-loaded P(HEMA-LA-MADQUAT) was also studied through assessing the survival rate of breast cancer cell line (MCF-7) and DAPI staining assays. Cationic micelle (and surface charge of + 7.6) with spherical morphology and an average diameter of 55 nm and CMC of 0.023 gL -1 was successfully obtained. Micelles showed the drug loaded capacity around 87.6 and 86.5% for MTX and Chrysin, respectively. The cytotoxicity assay of a drug-free nanocarrier on MCF-7 cell lines indicated that this developed micelles were suitable nanocarriers for anticancer drugs. Furthermore, the MTX@Chrysin-loaded micelle had more efficient anticancer performance than free dual anticancer drugs (MTX @ chrysin), confirmed by MTT assay and DAPI stainingmethods. Therefore, we envision that this recently developed novel micelle can enhance the efficacy of chemotherapeutic agents, MTX and Chrysin, combination chemotherapy and has the potential to be used as an anticancer drug delivery system for in vivo studies. Therefore, this recently developed novel micelle can enhance the efficacy of chemotherapeutic agents, MTX and Chrysin, combination chemotherapy and has the potential to be used as an anticancer drug delivery system for in vivo studies.

  8. Selective sparing of goblet cells and paneth cells in the intestine of methotrexate-treated rats

    NARCIS (Netherlands)

    M. Verburg (Melissa); I.B. Renes (Ingrid); H.P. Meijer; J.A. Taminiau; H.A. Büller (Hans); A.W.C. Einerhand (Sandra); J. Dekker (Jan)

    2000-01-01

    textabstractProliferation, differentiation, and cell death were studied in small intestinal and colonic epithelia of rats after treatment with methotrexate. Days 1-2 after treatment were characterized by decreased proliferation, increased apoptosis, and decreased numbers and depths

  9. 超声支架引导下双腔取卵针囊内注射MTX配合米非司酮及中药治疗罕见部位异位妊娠6例分析%Ultrasound-guided Oocyte Retrieval Needles Intracapsular Injection Dual Chamber Bracket MTX Treatment with Mifepristone and Medicine Rare Analysis of Six Cases of Ectopic Pregnancy

    Institute of Scientific and Technical Information of China (English)

    刘海瑛; 王妍; 阿艳妮

    2014-01-01

    Objective To investigate the stable condition of rare ectopic pregnancy, If indicators meet the drug treatment ,intracapsular injecting and taking orally drug for conservative treatment to avoid the impact of operation trauma on organization. Method In the abdominal ultrasonography or transvaginal ultrasound support guided,pregnancy intracapsular injection of MTX with double cavity needle for take eggs combined with mifepristone and Chinese medicine treatment of rare ectopic pregnancy, understand the chance of changing into the operation treatment, the serumβ-HCG fall time and drug side effect incidence. Results The ultrasound accurate guided pregnancy intracapsular injection of MTX combined with mifepristone in treatment of ectopic pregnancy stable rare position, the serumβ-HCG decreases faster, side effects lighter, no increased chance to operation, the residuing focus absorbed completely after chinese medicine treatment. Conclusion Ultrasound-guided injection drug stents rare ectopic pregnancy small patient trauma, pain, easy operation, without anesthesia, the treatment can be repeated, safety, efficacy, and to the maximum extent possible to ensure that the patients with normal structure or function of tissues and organs, there is further studies need to accumulate more data for the treatment of indications scope, application of drugs and on another pregnancy impacts.%目的:探讨罕见部位异位妊娠病情稳定,指标符合药物治疗者行囊内注射配合口服药物保守治疗以避免手术创伤对组织的影响。方法在腹部超声支架或阴道超声支架引导下,行双腔取卵针妊娠囊内注射MTX配合米非司酮口服及中药活血化瘀治疗罕见部位异位妊娠,了解其转手术治疗概率,血β-HCG下降时间及药物不良反应发生情况。结果超声准确引导下妊娠囊内注射MTX配合米非司酮口服治疗罕见部位稳定异位妊娠,血β-HCG下降时间快,不良反应轻,转手术

  10. PROGNOSTIC FACTORS FOR PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMAS TREATED WITH HIGH-DOSE METHOTREXATE-BASED CHEMO-RADIOTHERAPY

    Science.gov (United States)

    Nagane, Motoo; Lee, Jeunghun; Shishido-Hara, Yukiko; Suzuki, Kaori; Shimizu, Saki; Umino, Michiru; Kobayashi, Keiichi; Shiokawa, Yoshiaki

    2014-01-01

    BACKGROUND: Chemotherapy with high-dose methotrexate (HD-MTX) followed by whole brain radiotherapy (WBRT) is a conventional approach to treat primary central nervous system lymphomas (PCNSL), but some tumors relapse early leading to unfavorable outcome. Several biomarkers have been identified as prognostic factors in PCNSL, however, the correlation of both clinical factors including those related to MTX metabolism and B-cell differentiation and oncogenic biomarkers with response to and outcome by therapy is yet unclear. METHODS: We investigated 32 immunocompetent patients (19 males, 13 females) with PCNSL (all diffuse large B-cell type) treated with HD-MTX based therapy with or without WBRT since 2000 in our institution. Paraffin-embedded formalin-fixed tumor tissue sections were stained immunohistochemically with antibodies against following factors: B-cell differentiation markers (CD10, Bcl-6, Mum-1, CD138); MTX metabolism-related (MRP family, LRP, DHFR); cell cycle-related (p27KIP1, MIB-1); drug resistance-related (MGMT, MLH1, MSH2, MSH6, PMS2); and oncogenes (Myc, Bcl-2). Correlation between positivity of these factors and clinical outcomes were evaluated using logrank test and cox regression analysis. RESULTS: Among these factors, complete response to HD-MTX was significantly associated with longer progression-free survival (PFS)(P = 0.0012), while Bcl-6 expression as well as histological subtype (non-germinal center B-cell, non-GCB) was closely correlated with shorter PFS. Age (>60) (P = 0.006) and MSH2 expression (P = 0.017) were found to be better predictor for overall survival (OS), but in multivariate analysis, they were no longer significant. Other factors involved in MTX metabolism, DNA repair enzymes, and oncogenes did not affect outcome. CONCLUSIONS: Non-GCB subtype and Bcl-6 expression may be associated with worse outcome in patients with PCNSL treated with HD-MTX, while MTX-metabolism related factors did not influence prognosis. Further

  11. Prophylactic CNS therapy in childhood leukemia. Randomized controlled study of high-dose intravenous methotrexate and cranial irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Yokoyama, Takashi; Hiyoshi, Yasuhiko [Kurume Univ., Fukuoka (Japan). School of Medicine; Fujimoto, Takeo

    1982-12-01

    This study was designed to evaluate the efficacy of CNS-prophylaxis with high-dose methotrexate (MTX). Seventy children with previously untreated acute lymphoblastic leukemia (ALL) entered to this study between July 1978 and December 1980. According to initial white blood count (WBC), they were stratified to induce remission with; vincristine and prednine in low initial WBC ( lt 25,000/mm/sup 3/) group and these two agents plus adriamycin in high initial WBC ( gt 25,000/mm/sup 3/) group. After inducing remission, 62 children who achieved CR, received different CNS-prophlaxis; using a regimen of three doses of weekly high-dose MTX (1,000 mg/m/sup 2/) 6-hour infusion, which was repeated every 12 weeks-Group A (n = 14); high-dose MTX followed by 2400 rad cranial irradiation plus three doses of i.t. MT X-Group B (n = 15), 2400 rad cranial irradiation plus three doses of i.t. MTX-Group C (n = 16), and in 17 patients with high initial WBC, same as in Group A-Group D (n = 17). During an intravenous 6-h infusion of MTX at a dose of 1,000 mg/m/sup 2/, the CSF concentration of MTX rose to 2.3 +- 2.4 x 10/sup -6/M after initiation of infusion and remained in 10/sup -7/ M level for 48 hours. CNS-leukemia terminated complete remission in one of 14 children in Group A, two of 15 in Group B, two of 16 in Group C and two of 17 in Group D. The cumulative incidence of CNS-leukemia at 20 months calculated by the technique of Kaplan and Meier was 0% in Group A, 18.1% in Group B, 7.1% in Group C and 50.8% in Group D. There was no statistical difference among Groups A, B and C. These data suggested that CNS-prophylaxis with high-dose intravenous MTX was effective as well as 2400 rad cranial irradiation plus three doses of i.t. MTX in childhood ALL with low initial WBC.

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

    Science.gov (United States)

    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.

  13. Current evidence of methotrexate efficacy in childhood chronic uveitis: a systematic review and meta-analysis approach.

    Science.gov (United States)

    Simonini, Gabriele; Paudyal, Priyamvada; Jones, Gareth T; Cimaz, Rolando; Macfarlane, Gary J

    2013-05-01

    To summarize evidence regarding the effectiveness of MTX in the treatment of childhood autoimmune chronic uveitis (ACU). A systematic search of articles between January 1990 and June 2011 was conducted using EMBASE, Ovid MEDLINE, Evidence-Based Medicine Reviews-ACP Journal Club, the Cochrane Library and EBM Reviews. Studies investigating the efficacy of MTX as a single immunosuppressant medication in the treatment of ACU refractory to therapy with topical treatment and/or systemic treatment in children (≤16 years) were eligible for inclusion. The primary outcome measure was the improvement of intraocular inflammation, expressed as Tyndall, as defined by the Standardization of Uveitis Nomenclature working group criteria. The effect measure for each study was the proportion of people classified as responders. We determined a combined estimate of the proportion of children in the eligible studies responding to MTX. The initial search identified 246 articles of which 52 were potentially eligible. Nine eligible articles, all retrospective chart reviews, remained in the analysis. The number of children in studies ranged from 3 to 25, and the dose of MTX varied from 7.5 to 30 mg/m2. Altogether, 95 of 135 children responded to MTX. The pooled analysis suggested that MTX has a favourable effect in the improvement of intraocular inflammation: the proportion of responding subjects was 0.73 (95% CI 0.66, 0.81). Although randomized controlled trials are needed, the available evidence supports the use of MTX in the treatment of childhood ACU: approximately three-quarters of patients on MTX can expect improvement in intraocular inflammation.

  14. A qualitative analysis of methotrexate self-injection education videos on YouTube.

    Science.gov (United States)

    Rittberg, Rebekah; Dissanayake, Tharindri; Katz, Steven J

    2016-05-01

    The aim of this study is to identify and evaluate the quality of videos for patients available on YouTube for learning to self-administer subcutaneous methotrexate. Using the search term "Methotrexate injection," two clinical reviewers analyzed the first 60 videos on YouTube. Source and search rank of video, audience interaction, video duration, and time since video was uploaded on YouTube were recorded. Videos were classified as useful, misleading, or a personal patient view. Videos were rated for reliability, comprehensiveness, and global quality scale (GQS). Reasons for misleading videos were documented, and patient videos were documented as being either positive or negative towards methotrexate (MTX) injection. Fifty-one English videos overlapped between the two geographic locations; 10 videos were classified as useful (19.6 %), 14 misleading (27.5 %), and 27 personal patient view (52.9 %). Total views of videos were 161,028: 19.2 % useful, 72.8 % patient, and 8.0 % misleading. Mean GQS: 4.2 (±1.0) useful, 1.6 (±1.1) misleading, and 2.0 (±0.9) for patient videos (p tool available, clinicians need to be familiar with specific resources to help guide and educate their patients to ensure best outcomes.

  15. Pharmacogenetic markers to predict the clinical response to methotrexate in south Indian Tamil patients with psoriasis.

    Science.gov (United States)

    Indhumathi, S; Rajappa, Medha; Chandrashekar, Laxmisha; Ananthanarayanan, P H; Thappa, D M; Negi, V S

    2017-08-01

    Despite the advent of several new systemic therapies, methotrexate remains the gold standard for the treatment of moderate to severe psoriasis. However, there exists a significant heterogeneity in individual response to methotrexate. There are no consistently reliable markers to predict methotrexate treatment response till date. We aimed to demonstrate the association of certain genetic variants in the HLA (HLA-A2, HLA-B17, and HLA-Cw6) and the non-HLA genes including T-helper (Th)-1, Th-2, Th-17 cytokine genes (IFN-γ, IL-2, IL-4, IL-10, IL-12B, and IL-23R), and T-regulatory gene (FOXP3) with the methotrexate treatment response in South Indian Tamil patients with psoriasis. Of the 360 patients recruited, 189 patients with moderate to severe psoriasis were treated with methotrexate. Of the 189 patients, 132 patients responded to methotrexate and the remaining 57 patients were non-responders. We analyzed the association of aforesaid polymorphisms with the methotrexate treatment outcome using binary logistic regression. We observed that there were significant differences between genotype frequencies of HLA-Cw6 and FOXP3 (rs3761548) among the responders compared to non-responders, with conservative estimation. We observed that pro-inflammatory cytokines such as IFN-γ, IL-2, IL-12, and IL-23 were markedly reduced with the use of methotrexate, in comparison to the baseline levels, while the plasma IL-4 levels were increased posttreatment. Our results serve as preliminary evidence for the clinical use of genetic markers as predictors of response to methotrexate in psoriasis. This might aid in the future in the development of a point-of-care testing (POCT) gene chip, to predict optimal treatment response in patients with psoriasis, based on their individual genotypic profile.

  16. The treatment of tubal pregnancy by interventional technique through uterine artery

    International Nuclear Information System (INIS)

    Li Lizhao; Zhang Yonghui; Chen Zhu; Ge Xiaobing; Li Jiehua

    2004-01-01

    Objective: To study the feasibility and the clinical effect of the treatment of tubule pregnancy by using interventional technique through selective uterine artery. Methods: By using seldinger's method, 48 cases received interventional treatment, followed by perfusion of methotrexate (MTX) 100 mg through Tube 4-5 F. The concentration of serum β-HCG, the changes of pelvic cavity, and the open condition of amnion by ultrasonic examination. Results: The cure rate of 47 cases was 97.92%. No serious reaction. After treatment, the mean time that the serum β-HCG concentration returned to normal was 14-28 days and the mean time was 18 days. Conclusion: The treatment of tubule pregnancy by interventional technique proved no harmful effect to reproductive organs and quick recovery. It is worth spreading

  17. Brief Report

    DEFF Research Database (Denmark)

    Faurschou, Mikkel; Westman, Kerstin; Rasmussen, Niels

    2012-01-01

    The NORAM (Nonrenal Wegener's Granulomatosis Treated Alternatively with Methotrexate [MTX]) trial demonstrated that MTX can replace cyclophosphamide (CYC) as remission-inducing treatment for patients with newly diagnosed early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Du...

  18. 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.

    Science.gov (United States)

    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.

  19. Simultaneous detection of folic acid and methotrexate by an optical sensor based on molecularly imprinted polymers on dual-color CdTe quantum dots.

    Science.gov (United States)

    Ensafi, Ali A; Nasr-Esfahani, Parisa; Rezaei, B

    2017-12-15

    In this work, molecularly imprinted polymers (MIPs) were used on the surface of cadmium telluride quantum dots (CdTe QDs) for the simultaneous determination of folic acid (FA) and methotrexate (MTX). For this purpose, two different sizes of CdTe QDs with emission peaks in the yellow (QD Y ) and orange (QD O ) spectral regions were initially synthesized and capped with MIPs. FA and MTX were used as templates for the synthesis of the two composites and designated as QD Y -MIPs and QD O -MIPs, respectively. Fourier transform infrared spectroscopy, transmission electron microscopy, and fluorescence spectroscopy were employed to characterize the composites. QD Y -MIPs and QD O -MIPs were then mixed (to form QDs-MIPs) and excited at identical excitation wavelengths; they emitted two different emission wavelengths without any spectral overlap. The fluorescence signals of QD Y -MIPs and QD O -MIPs diminished in intensity with increasing concentration of the corresponding template molecules. Under optimal conditions, the dynamic range was 0.5-20 μmol L -1 for FA and MTX, and the detection limits for FA and MTX were 32.0 nmol L -1 and 34.0 nmol L -1 , respectively. The reproducibility of the method was checked for 12.5 μmol L -1 of FA and MTX to find RSD values of 4.2% and 6.3%, respectively. Finally, the applicability of the method was checked using human blood plasma samples. Results indicated the successful application of the method as a fluorescent probe for the rapid and simultaneous detection of FA and MTX in real samples. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Clinical relevance of consolidation radiotherapy and other main therapeutic issues in primary central nervous system lymphomas treated with upfront high-dose methotrexate

    International Nuclear Information System (INIS)

    Reni, Michele; Ferreri, Andres J.M.; Guha-Thakurta, Nandita; Blay, Jean-Yves; Dell'Oro, Stefania; Biron, Pierre; Hochberg, Fred H.

    2001-01-01

    Purpose: To evaluate the optimal dose of methotrexate (MTX) and the efficacy of other drugs, intrathecal chemotherapy (CHT), and radiotherapy (RT) in primary brain lymphomas. Methods and Materials: Two hundred eighty-eight immunocompetent patients with histologically documented, previously untreated primary brain lymphomas, receiving CHT containing high-dose MTX (≥1 g/m 2 ) with or without RT were selected from 19 prospective series. The impact on survival of the MTX dose ( 2 vs.≥3 g/m 2 ), the main drugs, intrathecal CHT, and combination CHT (mono-CHT vs. poly-CHT) was assessed, according to the intention-to-treat principle. The role of post-CHT irradiation (immediate vs. delayed RT) was evaluated in 119 patients with a complete response to CHT. The whole brain and tumor bed dose ( 2 (p=0.04), thiotepa (p=0.03), and intrathecal CHT (p=0.03) improved the OS, and nitrosoureas (p 0.01) correlated with a worse survival. In multivariate analysis, limited to patients receiving MTX ≥3 g/m 2 , only the addition of cytarabine improved the OS; nitrosoureas reduced MTX efficacy. Of the 119 complete responders, 70 received immediate RT. A RT dose of ≥40 Gy to the whole brain or tumor bed did not improve OS. The 3-year OS was similar between the immediate and delayed RT groups. In multivariate analysis, RT delay had no negative impact on survival. Conclusions: MTX ≥3 g/m 2 seems to improve survival in primary brain lymphoma patients. The efficacy of additional drugs, except for cytarabine, remains unproved. Randomized trials are needed to confirm that RT withdrawal yields no detrimental effect in complete responders

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

    Science.gov (United States)

    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.

  2. Increased baseline RUNX2, caspase 3 and p21 gene expressions in the peripheral blood of disease-modifying anti-rheumatic drug-naïve rheumatoid arthritis patients are associated with improved clinical response to methotrexate therapy.

    Science.gov (United States)

    Tchetina, Elena V; Demidova, Natalia V; Markova, Galina A; Taskina, Elena A; Glukhova, Svetlana I; Karateev, Dmitry E

    2017-10-01

    To investigate the potential of the baseline gene expression in the whole blood of disease-modifying anti-rheumatic drug-naïve rheumatoid arthritis (RA) patients for predicting the response to methotrexate (MTX) treatment. Twenty-six control subjects and 40 RA patients were examined. Clinical, immunological and radiographic parameters were assessed before and after 24 months of follow-up. The gene expressions in the whole blood were measured using real-time reverse transcription polymerase chain reaction. The protein concentrations in peripheral blood mononuclear cells were quantified using enzyme-linked immunosorbent assay. Receiver operating characteristic curve analyses were used to suggest thresholds that were associated with the prediction of the response. Decreases in the disease activity at the end of the study were accompanied by significant increases in joint space narrowing score (JSN). Positive correlations between the expressions of the Unc-51-like kinase 1 (ULK1) and matrix metalloproteinase 9 (MMP-9) genes with the level of C-reactive protein and MMP-9 expression with Disease Activity Score of 28 joints (DAS28) and swollen joint count were noted at baseline. The baseline tumor necrosis factor (TNF)α gene expression was positively correlated with JSN at the end of the follow-up, whereas p21, caspase 3, and runt-related transcription factor (RUNX)2 were correlated with the ΔDAS28 values. Our results suggest that the expressions of MMP-9 and ULK1 might be associated with disease activity. Increased baseline gene expressions of RUNX2, p21 and caspase 3 in the peripheral blood might predict better responses to MTX therapy. © 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

  3. Índice orientador do tratamento sistêmico da gravidez ectópica íntegra com dose única de metotrexato Index for the systemic treatment of unruptured ectopic pregnancy with a single dose of methotrexate

    Directory of Open Access Journals (Sweden)

    Julio Elito Junior

    1998-04-01

    iguais a cinco estiveram todas relacionadas com o fracasso do tratamento. O índice orientador ajuda-nos a indicar os melhores casos para o tratamento medicamentoso. Não o aconselhamos, portanto, quando a nota for inferior ou igual a cinco; por outro lado, podemos predizer boa evolução do tratamento, quando a nota for superior a cinco.A prospective study was performed with 42 patients with unruptured ectopic pregnancy, which intended to elaborate an index to orient the systemic treatment with the administration of a single intramuscular dose of methotrexate (50 mg/m². Patients were monitored with beta-hCG titers on days 1, 4 and 7 after the methotrexate. When the titers of beta-hCG declined more than 15%, between days 4 and 7 after methotrexate, the patients were discharged and had an outpatient follow-up monitored with beta-hCG titers weekly until the titers were less than 5 mIU/ml, which represents success of the treatment. We prepared an index for the systemic treatment with methotrexate, with five parameters: (1 initial titers of beta-hCG; (2 aspects of the image at ultrasound (hematosalpinx, gestational sac, live embryo; (3 size of the mass; (4 free fluid in cul-de-sac; (5 collor doppler. Each parameter received a grade from 0 to 2. Grade 0 represented bad prognosis, favorable parameters received grade 2 and borderline parameters received grade one. The success rate with a single dose of methotrexate was 69.0% (29/42. The color doppler was performed in 20 of the 42 patients; in this group of 20 patients the success rate was 75.0% (15/20. In the 22 patients who were not submitted to the color doppler, the average grade of the score in the successful cases was 6.6, and in the unsuccessful it was 3.1. In the group who underwent the doppler (20 patients the average was 7.9 in the successful cases and 4.2 in the cases that failed. In the present study the cut-off grade was 5, for most of the patients with grades above 5 had a successful treatment (15/16 - 93

  4. Anionic clay as the drug delivery vehicle: tumor targeting function of layered double hydroxide-methotrexate nanohybrid in C33A orthotopic cervical cancer model.

    Science.gov (United States)

    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.

  5. Enhanced Anti-Tumoral Activity of Methotrexate-Human Serum Albumin Conjugated Nanoparticles by Targeting with Luteinizing Hormone-Releasing Hormone (LHRH) Peptide

    Science.gov (United States)

    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. PMID:21845098

  6. Impact of Antiinflammatory Treatment on the Onset of Uveitis in Juvenile Idiopathic Arthritis: Longitudinal Analysis From a Nationwide Pediatric Rheumatology Database.

    Science.gov (United States)

    Tappeiner, Christoph; Schenck, Sandra; Niewerth, Martina; Heiligenhaus, Arnd; Minden, Kirsten; Klotsche, Jens

    2016-01-01

    Based on a nationwide database, this study analyzed the influence of methotrexate (MTX), tumor necrosis factor (TNF) inhibitors, and a combination of the 2 medications on uveitis occurrence in juvenile idiopathic arthritis (JIA) patients. Data from the National Paediatric Rheumatological Database in Germany were used in this study. Between 2002 and 2013, data from JIA patients were annually documented at the participating pediatric rheumatologic sites. Patients with a JIA disease duration of treatment on the occurrence of uveitis was evaluated by discrete-time survival analysis. A total of 3,512 JIA patients (mean ± SD age 8.3 ± 4.8 years, 65.7% female, 53.2% antinuclear antibody positive, and mean ± SD age at arthritis onset 7.8 ± 4.8 years) fulfilled the inclusion criteria. Mean ± SD total followup time was 3.6 ± 2.4 years. Uveitis developed in a total of 180 patients (5.1%) within 1 year after arthritis onset. Uveitis onset after the first year was observed in another 251 patients (7.1%). Disease-modifying antirheumatic drug (DMARD) treatment in the year before uveitis onset significantly reduced the risk for uveitis as follows: MTX: hazard ratio (HR) 0.63, P = 0.022; TNF inhibitors: HR 0.56, P uveitis risk (HR 0.29, P uveitis onset. Early MTX use within the first year of disease and the combination of MTX with a TNF inhibitor had the highest protective effect. © 2016 The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

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

    OpenAIRE

    Štuhec, 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 noadverse 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. ...

  8. Yellow fever vaccine used in a psoriatic arthritis patient treated with methotrexate

    OpenAIRE

    Štuhec, Matej

    2015-01-01

    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 noadverse 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. ...

  9. Anionic clay as the drug delivery vehicle: tumor targeting function of layered double hydroxide-methotrexate nanohybrid in C33A orthotopic cervical cancer model

    Directory of Open Access Journals (Sweden)

    Choi G

    2016-01-01

    Full Text Available Goeun Choi,1 Huiyan Piao,1 Zeid A Alothman,2 Ajayan Vinu,3 Chae-Ok Yun,4 Jin-Ho Choy1 1Center for Intelligent Nano-Bio Materials, Department of Chemistry and Nano Science, Ewha Womans University, Seoul, Korea; 2Advanced Materials Research Chair, Chemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia; 3Future Industries Institute, University of South Australia, Mawson Lakes, SA, Australia; 4Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea Abstract: 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. Keywords: anionic clay, biodistribution, cervical cancer, colloidal stability, layered double hydroxide, methotrexate 

  10. Methotrexate encephalopathy: Two cases in adult cancer patients, who recovered with pathophysiologically based therapy

    Directory of Open Access Journals (Sweden)

    Shodeinde A Coker

    2017-05-01

    Full Text Available Background/Objectives: Neurotoxicity is a serious and sometimes fatal adverse effect that can occur following methotrexate treatment. We describe two adult patients with hematological malignancies with methotrexate encephalopathy who recovered with dextromethorphan therapy. Results: Case 1: A 24-year-old male with acute lymphoblastic leukemia developed the acute onset of bilateral facial weakness and slurred speech after his first treatment with high-dose intravenous methotrexate. The clinical scenario and a head magnetic resonance imaging supported a diagnosis of methotrexate encephalopathy. Treatment with dextromethorphan was coincident with recovery. Case 2: A 65-year-old female with recurrent diffuse large B-cell lymphoma was treated with high-dose intravenous methotrexate. Two weeks after a cycle, she developed hypoactive delirium, marked lethargy, ocular ataxia, and a right-sided facial weakness. Within 2 days of starting dextromethorphan, there was improvement with clinical recovery. Conclusions: These two cases suggest that N-methyl d-aspartate receptor activation by homocysteine may play an important role in the pathogenesis of methotrexate neurotoxicity.

  11. Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study

    DEFF Research Database (Denmark)

    Schmiegelow, Kjeld; Al-Modhwahi, Ibrahim; Andersen, Mette Klarskov

    2009-01-01

    Among 1614 children with acute lymphoblastic leukemia (ALL) treated with the Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL-92 protocol, 20 patients developed a second malignant neoplasm (SMN) with a cumulative risk of 1.6% at 12 years from the diagnosis of ALL. Nine of the 16...... acute myeloid leukemias or myelodysplastic syndromes had monosomy 7 (n = 7) or 7q deletions (n = 2). In Cox multivariate analysis, longer duration of oral 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy (P = .02; longest for standard-risk patients) and presence of high hyperdiploidy (P...

  12. Sequential optimization of methotrexate encapsulation in micellar nano-networks of polyethyleneimine ionomer containing redox-sensitive cross-links.

    Science.gov (United States)

    Abolmaali, Samira Sadat; Tamaddon, Ali; Yousefi, Gholamhossein; Javidnia, Katayoun; Dinarvand, Rasoul

    2014-01-01

    A functional polycation nanonetwork was developed for delivery of water soluble chemotherapeutic agents. The complexes of polyethyleneimine grafted methoxy polyethylene glycol (PEI-g-mPEG) and Zn(2+) were utilized as the micellar template for cross-linking with dithiodipropionic acid, followed by an acidic pH dialysis to remove the metal ion from the micellar template. The synthesis method was optimized according to pH, the molar ratio of Zn(2+), and the cross-link ratio. The atomic force microscopy showed soft, discrete, and uniform nano-networks. They were sensitive to the simulated reductive environment as determined by Ellman's assay. They showed few positive ζ potential and an average hydrodynamic diameter of 162±10 nm, which decreased to 49±11 nm upon dehydration. The ionic character of the nano-networks allowed the achievement of a higher-loading capacity of methotrexate (MTX), approximately 57% weight per weight, depending on the cross-link and the drug feed ratios. The nano-networks actively loaded with MTX presented some suitable properties, such as the hydrodynamic size of 117±16 nm, polydispersity index of 0.22, and a prolonged swelling-controlled release profile over 24 hours that boosted following reductive activation of the nanonetwork biodegradation. Unlike the PEI ionomer, the nano-networks provided an acceptable cytotoxicity profile. The drug-loaded nano-networks exhibited more specific cytotoxicity against human hepatocellular carcinoma cells if compared to free MTX at concentrations above 1 μM. The enhanced antitumor activity in vitro might be attributed to endocytic entry of MTX-loaded nano-networks that was found in the epifluorescence microscopy experiment for the fluorophore-labeled nano-networks.

  13. Installation and operation of the 400 kW 140 GHz gyrotron on the MTX experiment

    International Nuclear Information System (INIS)

    Ferguson, S.W.; Felker, B.; Jackson, M.C.; Petersen, D.E.; Sewall, N.R.; Stever, R.D.

    1991-09-01

    This paper describes the installation and operation of the 400 kW 140 GHz gyrotron used for plasma heating on the Microwave Tokamak Experiment (MTX) at Lawrence Livermore National Laboratory (LLNL). The Varian VGT-8140 gyrotron has operated at a power level of 400 kW for 100 ms in conjunction with MTX plasma shots. The gyrotron system is comprised of a high voltage (-80 kV) modulated power supply, a multistation CAMAC computer control, a 5-tesla superconducting magnet, a series of conventional copper magnets, a circulating fluorinert (FC75) window cooling system, a circulating oil cooling system, a water cooling system, and microwave frequency and power diagnostics. Additionally, a Vlasov launcher is used to convert the gyrotron TE 15,2 mode to a Gaussian beam. Two versions of the Vlasov launcher have been used on the gyrotron, one version designed by LLNL and one version designed by the Japan Atomic Energy Research Institute (JAERI). The Gaussian beam from the Vlasov launcher is transported to the MTX tokamak by a series of 5 mirrors in a 35-meter-long, high-efficiency, quasioptical beam transport system. A twist polarizer is built into one of the mirrors to adjust for horizontal polarization in the tokamak. No windows are used between the Vlasov reflector and the MTX tokamak. A laser alignment system is used to perform the initial system alignment. A summary of the design and operating characteristics of each of these systems is included. Also included is a summary of the system operation and performance

  14. Increased ghrelin but low ghrelin-reactive immunoglobulins in a rat model of methotrexate chemotherapy-induced anorexia

    Directory of Open Access Journals (Sweden)

    Marie François

    2016-07-01

    Full Text Available Background and aims: Cancer chemotherapy is commonly accompanied by mucositis, anorexia, weight loss and anxiety independently from cancer-induced anorexia-cachexia, further aggravating clinical outcome. Ghrelin is a peptide hormone produced in gastric mucosa that reaches the brain to stimulate appetite. In plasma, ghrelin is protected from degradation by ghrelin-reactive immunoglobulins (Ig. To analyze possible involvement of ghrelin in the chemotherapy-induced anorexia and anxiety, gastric ghrelin expression, plasma levels of ghrelin and ghrelin-reactive IgG were studied in rats treated with methotrexate (MTX.Methods: Rats received MTX (2.5 mg/kg, S.C. for three consecutive days and were killed 3 days later, at the peak of anorexia and weight loss. Control rats received phosphate-buffered saline. Preproghrelin mRNA expression in the stomach was analyzed by in situ hybridization. Plasma levels of ghrelin and ghrelin-reactive IgG were measured by immunoenzymatic assays and IgG affinity kinetics by surface plasmon resonance. Anxiety- and depression-like behaviors in MTX-treated anorectic and in control rats were evaluated in the elevated plus-maze and the forced-swim test, respectively.Results: In MTX-treated anorectic rats the number of preproghrelin mRNA-producing cells was found increased (by 51.3%, p<0.001 as well were plasma concentrations of both ghrelin and des-acyl-ghrelin (by 70.4%, p<0.05 and 98.3%, p<0.01, respectively. In contrast, plasma levels of total IgG reactive with ghrelin and des-acyl-ghrelin were drastically decreased (by 87.2% and 88.4%, respectively, both p<0.001, and affinity kinetics of these IgG were characterized by increased small and big Kd, respectively. MTX-treated rats displayed increased anxiety- but not depression-like behavior.Conclusion: MTX-induced anorexia, weight loss and anxiety are accompanied by increased ghrelin production and by a decrease of ghrelin-reactive IgG levels and affinity binding properties

  15. Microwave tokamak experiment (MTX) first year of operation and future plans

    International Nuclear Information System (INIS)

    Jackson, M.C.

    1989-01-01

    The Microwave Tokamak Experiment (MTX) at Lawrence Livermore National Laboratory (LLNL) began plasma operations in November 1988, and our main goal is the study of electron-cyclotron heating (ECH) in plasma discharges. The MTX tokamak was relocated from the Massachusetts Institute of Technology (MIT), and we have re-created plasma parameters that are similar to those generated while the tokamak was at MIT. After stable ohmic operation was achieved, single-pulse FEL heating experiments began. During this phase, the FEL operated at low power levels on the way to its ultimate goal of 2 GW and 140 GHz with a 30-ns pulse length. We have developed a number of new diagnostics to measure these fast FEL pulses and the resulting plasma effects. In this paper, we present results that show the correlation of MTX data with MIT data, some of the operational modifications and procedures used, results to date from preliminary tokamak operations with the FEL, and our near-term operational plans. 7 refs., 8 figs., 1 tab

  16. Effect of a treat-to-target strategy based on methotrexate and intra-articular betamethasone with or without additional cyclosporin on MRI-assessed synovitis, osteitis, tenosynovitis, bone erosion, and joint space narrowing in early rheumatoid arthritis: results from a 2-year randomized double

    DEFF Research Database (Denmark)

    Møller-Bisgaard, S.; Ejbjerg, B. J.; Eshed, I.

    2017-01-01

    Objectives: To investigate whether a treat-to-target strategy based on methotrexate (MTX) and intra-articular (IA) betamethasone suppresses magnetic resonance imaging (MRI)-determined measures of disease activity and reduces joint destruction in early rheumatoid arthritis (eRA) patients, and to i......Objectives: To investigate whether a treat-to-target strategy based on methotrexate (MTX) and intra-articular (IA) betamethasone suppresses magnetic resonance imaging (MRI)-determined measures of disease activity and reduces joint destruction in early rheumatoid arthritis (eRA) patients......, and to investigate whether concomitant cyclosporin A (CyA) provides an additional effect.Method: In the 2-year randomized, double-blind, treat-to-target trial CIMESTRA, 160 patients with eRA (intra-articular betamethasone and CyA, or placebo CyA. A total of 129 patients participated...

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Danuta Pentak

    2016-12-01

    Full Text Available 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 Transmittance2919/2850 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.

  19. Structures of dihydrofolate reductase-thymidylate synthase of Trypanosoma cruzi in the folate-free state and in complex with two antifolate drugs, trimetrexate and methotrexate

    Energy Technology Data Exchange (ETDEWEB)

    Senkovich, Olga; Schormann, Norbert; Chattopadhyay, Debasish; (UAB)

    2010-11-22

    The flagellate protozoan parasite Trypanosoma cruzi is the pathogenic agent of Chagas disease (also called American trypanosomiasis), which causes approximately 50 000 deaths annually. The disease is endemic in South and Central America. The parasite is usually transmitted by a blood-feeding insect vector, but can also be transmitted via blood transfusion. In the chronic form, Chagas disease causes severe damage to the heart and other organs. There is no satisfactory treatment for chronic Chagas disease and no vaccine is available. There is an urgent need for the development of chemotherapeutic agents for the treatment of T. cruzi infection and therefore for the identification of potential drug targets. The dihydrofolate reductase activity of T. cruzi, which is expressed as part of a bifunctional enzyme, dihydrofolate reductase-thymidylate synthase (DHFR-TS), is a potential target for drug development. In order to gain a detailed understanding of the structure-function relationship of T. cruzi DHFR, the three-dimensional structure of this protein in complex with various ligands is being studied. Here, the crystal structures of T. cruzi DHFR-TS with three different compositions of the DHFR domain are reported: the folate-free state, the complex with the lipophilic antifolate trimetrexate (TMQ) and the complex with the classical antifolate methotrexate (MTX). These structures reveal that the enzyme is a homodimer with substantial interactions between the two TS domains of neighboring subunits. In contrast to the enzymes from Cryptosporidium hominis and Plasmodium falciparum, the DHFR and TS active sites of T. cruzi lie on the same side of the monomer. As in other parasitic DHFR-TS proteins, the N-terminal extension of the T. cruzi enzyme is involved in extensive interactions between the two domains. The DHFR active site of the T. cruzi enzyme shows subtle differences compared with its human counterpart. These differences may be exploited for the development of

  20. The combined application of biological therapy and methotrexate in case of escape phenomenon progressing

    Directory of Open Access Journals (Sweden)

    Ponich E.S.

    2015-09-01

    Full Text Available Aim: the study of the efficacy of methotrexate in patients with the "escape effect" during the ustekinumab therapy. Materials and Methods. The results of methotrexate at a dose of 15-20mg/week in treatment of 4 patients receiving biologic and developed "escape effect". Ustekinumab is used as a hypodermic injection at a dose of 45 mg for a body weight of a patient no more than 100 kg, and 90 mg of body weight over 100 kg, at the zero week, the 4th week and then every 12 weeks. Patients control meets the standard management of patients in biological therapy. Results. The study shows that in the case of the resistance progressing when applying preparations of biological therapy, methotrexate is useful at a dose of 15-20mg/week for up to 6 months. The combined use of biologic therapy and methotrexate in the treatment of patients with psoriasis vulgaris, "escape effect" contributes to the marked regression of clinical symptoms and allows to control the process long enough, which is confirmed by the dynamics of the index PASI, BRS and DLQI. The combined method is highly safe, as evidenced by the lack of inhibition of hematopoiesis, the normal level of hepatic transaminases and serum creatinine, which greatly improves patient compliance in this type of therapy. Conclusion. The article presents the data of the combined application of biological medication therapy (ustekinumab and methotrexate for the treatment of patients with the common form of psoriasis vulgaris. In the case of the development of resistance of biological therapy recommended the appointment of methotrexate. The combined use of methotrexate and biologic therapy in the treatment of patients with psoriasis vulgaris contributes to marked regression of clinical symptoms and allows to control the process for a long time.

  1. Circulating levels of osteoprotegerin and sRANKL and the effect of methotrexate in patients with rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    Aadhaar Dhooria

    2018-01-01

    Conclusions: OPG levels are higher in RA patients and normalize in response to treatment with methotrexate. The initial higher levels of OPG may represent a compensatory mechanism to osteoclast activation; they normalize on reduction of disease activity.

  2. Sequential optimization of methotrexate encapsulation in micellar nano-networks of polyethyleneimine ionomer containing redox-sensitive cross-links

    Directory of Open Access Journals (Sweden)

    Abolmaali SS

    2014-06-01

    Full Text Available Samira Sadat Abolmaali,1 Ali Tamaddon,1,2 Gholamhossein Yousefi,1,2 Katayoun Javidnia,3 Rasoul Dinarvand41Department of Pharmaceutics, Shiraz School of Pharmacy, 2Center for Nanotechnology in Drug Delivery, 3Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; 4Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IranAbstract: A functional polycation nanonetwork was developed for delivery of water soluble chemotherapeutic agents. The complexes of polyethyleneimine grafted methoxy polyethylene glycol (PEI-g-mPEG and Zn2+ were utilized as the micellar template for cross-linking with dithiodipropionic acid, followed by an acidic pH dialysis to remove the metal ion from the micellar template. The synthesis method was optimized according to pH, the molar ratio of Zn2+, and the cross-link ratio. The atomic force microscopy showed soft, discrete, and uniform nano-networks. They were sensitive to the simulated reductive environment as determined by Ellman's assay. They showed few positive ζ potential and an average hydrodynamic diameter of 162±10 nm, which decreased to 49±11 nm upon dehydration. The ionic character of the nano-networks allowed the achievement of a higher-loading capacity of methotrexate (MTX, approximately 57% weight per weight, depending on the cross-link and the drug feed ratios. The nano-networks actively loaded with MTX presented some suitable properties, such as the hydrodynamic size of 117±16 nm, polydispersity index of 0.22, and a prolonged swelling-controlled release profile over 24 hours that boosted following reductive activation of the nanonetwork biodegradation. Unlike the PEI ionomer, the nano-networks provided an acceptable cytotoxicity profile. The drug-loaded nano-networks exhibited more specific cytotoxicity against human hepatocellular carcinoma cells if compared to free MTX at concentrations above 1 µM. The

  3. CAN INITIAL βHCG VALUES PREDICT THE NEED FOR SECOND DOSE OF METHOTREXATE IN MEDICAL MANAGEMENT OF ECTOPIC PREGNANCY?

    Directory of Open Access Journals (Sweden)

    Priya Narayanan

    2016-09-01

    Full Text Available INTRODUCTION Prediction of requirement of second dose of methotrexate in patients treated with single dose would help in guiding treatment and counseling. The aim of this study is to determine whether pretreatment beta HCG values can predict the need for second dose of methotrexate in medically managed ectopic pregnancy. MATERIALS AND METHODS 46 women with ectopic pregnancies who were managed medically were included. The median of beta HCG titres on day 1, day 4 and day 7 was assessed in patients who responded to single dose methotrexate and those who required a second dose. RESULTS Out of the 46 patients studied, 41 responded to medical treatment (success 91%. 14 out of 41 required second dose of methotrexate (34%. Two patients required third dose of methotrexate. Five patients required surgery. DISCUSSION The median of day 1 and day 4 beta HCG values were not statistically different between those who responded to single dose methotrexate and those who required a second dose. Only day 7 values were found to be different. CONCLUSION The beta-hCG titre on day 1 and day 4 is not a predictor of requirement of second dose of methotrexate.

  4. Treatment of initial parenchymal central nervous system involvement in systemic aggressive B-cell lymphoma.

    Science.gov (United States)

    Nijland, Marcel; Jansen, Anne; Doorduijn, Jeanette K; Enting, Roelien H; Bromberg, Jacoline E C; Kluin-Nelemans, Hanneke C

    2017-09-01

    Central nervous system (CNS) involvement in systemic B-cell non-Hodgkin lymphoma (B-NHL) at diagnosis (sysCNS) is rare. We investigated the outcome of 21 patients with sysCNS, most commonly diffuse large B-cell lymphoma, treated with high dose methotrexate (HD-MTX) and R-CHOP. The median number of cycles of HD-MTX and R-CHOP was 4 (range 1-8) and 6 (range 0-8), respectively. Consolidative whole brain radiotherapy (WBRT) was given to 33% (7/21) patients. With a median follow-up of 44 months the 3-year progression free survival (PFS) and overall survival (OS) were 45% (95%CI 34-56%) and 49% (95%CI 38-60%), respectively. Over 90% of patients had an unfavorable international prognostic index score, reflected by treatment-related mortality of 19% (4/21) and relapse-related mortality of 28% (6/21). The outcome of these patients was, however, unexpectedly good when compared to secondary CNS relapses. Prospective studies are needed to define the optimal treatment for patients with sysCNS, but its rarity might be challenging.

  5. Evaluation of Protective Activity of Curcumin in Reducing Methotrexate Induced Liver Cells Injury: An Experimental Study on Iraqi White Domestic Rabbits

    Directory of Open Access Journals (Sweden)

    Hussain Abady Aljebori

    2018-03-01

    Full Text Available Background: Hepatotoxicity is a common problem in medical practice, most of the commonly used drugs are potentially hepatotoxic. Although Methotrexate is a hepa- toxic drug, it is widely used in the treatment of many cancerous and non-cancerous conditions because of its cytotoxic and immunosuppressant activity. Curcumin con- tains a variety of natural substances with antioxidant properties, it is widely used in  folk medicine.Antioxidant activity of Curcumin can reduce liver cell injury induced by Methotrexate administration. Objective: The research aims to study the methotrexate hepatoxicity on rabbits, and the hepatoprotective activity of Curcumin. Materials and Methods: Thirty white domestic rabbits were bought from animal market and grouped randomly into three groups; control group received intraperitoneal normal saline, methotrexate group received 6.5 mg/Kgm body weight intraperitoneal methotrexate, and curcumin group received oral Curcumin in addition to intraperitoneal methotrexate. Results: The study showed abnormal liver function tests, INR, liver tissues oxida- tive markers, and liver cell injury on histopathology in Methotrexate group, and normal findings in Curcumin groups. Conclusion: It is concluded that the Methotrexate is a hepatotoxic drug. The results also shoe that the concomitant administration of Curcumin reduced hepatotoxicity. Recommendation: It is recommended to use of Curcumin in clinical practice as a food supplement to patient receiving methotrexate to reduce hepatotoxicity.

  6. Chemically crosslinked nanogels of PEGylated poly ethyleneimine (L-histidine substituted) synthesized via metal ion coordinated self-assembly for delivery of methotrexate: Cytocompatibility, cellular delivery and antitumor activity in resistant cells

    Energy Technology Data Exchange (ETDEWEB)

    Abolmaali, Samira Sadat, E-mail: s.abolmaali@gmail.com [Pharmaceutical Nanotechnology Department, Shiraz University of Medical Sciences, Shiraz 71345 (Iran, Islamic Republic of); Tamaddon, Ali Mohammad, E-mail: amtamadon@gmail.com [Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz 71345 (Iran, Islamic Republic of); Mohammadi, Samaneh, E-mail: samaneh.mohammadi1986@gmail.com [Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz 71345 (Iran, Islamic Republic of); Amoozgar, Zohreh, E-mail: zohreh_amoozgar@dfci.harvard.edu [Department of Cancer Immunology and Aids, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115 (United States); Dinarvand, Rasoul, E-mail: dinarvand@tums.ac.ir [Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 14174 (Iran, Islamic Republic of)

    2016-05-01

    Self-assembled nanogels were engineered by forming Zn{sup 2+}-coordinated micellar templates of PEGylated poly ethyleneimine (PEG-g-PEI), chemical crosslinking and subsequent removal of the metal ion. Creation of stable micellar templates is a crucial step for preparing the nanogels. To this aim, imidazole moieties were introduced to the polymer by Fmoc-L-histidine using carbodiimide chemistry. It was hypothesized the nanogels loaded with methotrexate (MTX), a chemotherapeutic agent, circumvent impaired carrier activity in HepG2 cells (MTX-resistant hepatocellular carcinoma). So, the nanogels were post-loaded with MTX and characterized by {sup 1}H-NMR, FTIR, dynamic light scattering-zeta potential, atomic force microscopy, and drug release experiments. Cellular uptake and the antitumor activity of MTX-loaded nanogels were investigated by flow cytometry and MTT assay. Discrete, spherical and uniform nanogels, with sizes about 77–83 nm and a relatively high drug loading (54 ± 4% w/w), showed a low polydispersity and neutral surface charges. The MTX-loaded nanogels, unlike empty nanogels, lowered viability of HepG2 cells; the nanogels demonstrated cell-cycle arrest and apoptosis comparably higher than MTX as free drug that was shown to be through i) cellular uptake of the nanogels by clathrin-mediated transport and ii) endosomolytic activity of the nanogels in HepG2 cells. These findings indicate the potential antitumor application of this preparation, which has to be investigated in-vivo. - Highlights: • Nanogel synthesis through chemical crosslinking of the transition metal ion coordinated polymer self-assembly • An enhanced cytocompatibility if compared to unmodified polymer • A noticeable endocytic cellular internalization and endosomolytic activity • A specific antitumor cytotoxicity, cell cycle arrest and apoptosis in resistant tumor cells.

  7. Impact of genetic variants of ATP binding cassette B1, AICAR transformylase/IMP cyclohydrolase, folyl-polyglutamatesynthetase, and methylenetetrahydrofolatereductase on methotrexate toxicity.

    Science.gov (United States)

    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.

  8. Methotrexate-loaded biodegradable nanoparticles: preparation ...

    Indian Academy of Sciences (India)

    Administrator

    In the present work, formulation and development of a novel methotrexate ... etc and also evaluated for its in vitro cytotoxic potential against U-343 MGa human neuronal glioblastoma ... 2.3a Particle size, polydispersity index and zeta poten-.

  9. Consensus Guideline for Use of Glucarpidase in Patients with High-Dose Methotrexate Induced Acute Kidney Injury and Delayed Methotrexate Clearance

    DEFF Research Database (Denmark)

    Ramsey, Laura B; Balis, Frank M; O'Brien, Maureen M

    2018-01-01

    Acute kidney injury due to high-dose methotrexate (HDMTX) is a serious, life-threatening toxicity that can occur in pediatric and adult patients. Glucarpidase is a treatment approved by the Food and Drug Administration for high methotrexate concentrations in the context of kidney dysfunction...... is above 30 µM, 42-hour concentration is above 10 µM, or 48-hour concentration is above 5 µM and the serum creatinine is significantly elevated relative to the baseline measurement (indicative of HDMTX-induced acute kidney injury), glucarpidase may be indicated. After a 36- to 42-hour HDMTX infusion......: Glucarpidase is a rarely used medication that is less effective when given after more than 60 hours of exposure to high-dose methotrexate, so predicting early which patients will need it is imperative. There are no currently available consensus guidelines for the use of this medication. The indication...

  10. Correlation of RAD51 and radiosensitization of methotrexate

    International Nuclear Information System (INIS)

    Du Liqing; Bai Jianqiang; Liu Qiang; Wang Yan; Zhao Peng; Chen Fenghua; Wang Hong; Fan Feiyue

    2012-01-01

    Objective: To evaluate the correlation between homologous recombination repair protein RAD51 and methotrexate-enhanced radiosensitivity. Methods: Western blot and RT-PCR assays were used to detect RAD51 expression in HOS osteosarcoma cells exposed to γ-ray irradiation alone and in combination with methotrexate. Colony formation assay was used to test the survival fraction of HOS cells exposed to γ-rays and methotrexate. Results: Methotrexate inhibited both protein and RNA expressions of RAD51, and the combination of radiation and methotrexate enhanced the inhibition of RAD51 expression. Moreover, transfection of cells with RAD51 gene decreased cellular sensitivity to methotrexate and γ-rays. The sensitizer enhancement ratios after irradiation in combination with methotrexate were 1.51 and 0.99, respectively. Methotrexate was a preferred radiosensitizer to HOS cell. Conclusions: RAD51 might be involved in the methotrexate-enhanced radiosensitivity. (authors)

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

    Science.gov (United States)

    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.

  12. Early medical abortion with methotrexate and misoprostol.

    Science.gov (United States)

    Borgatta, L; Burnhill, M S; Tyson, J; Leonhardt, K K; Hausknecht, R U; Haskell, S

    2001-01-01

    To evaluate the introduction of an early medical abortion program with methotrexate and misoprostol, using a standardized protocol. A total of 1973 women at 34 Planned Parenthood sites participated in a case series of early medical abortion. Ultrasound was used to confirm gestational age of less than 49 days from the first day of the last menstrual period. Women were given intramuscular methotrexate 50 mg/m(2) of body surface area on day 1, and then they inserted misoprostol 800 microg vaginally at home on day 5, 6, or 7. Women were advised to have a suction curettage if the pregnancy appeared viable 2 weeks after methotrexate or if any gestational sac persisted 4 weeks after methotrexate. Outcomes were complete medical abortion and suction curettage. Sixteen hundred fifty-nine women (84.1%) had a complete medical abortion, and 257 (13.0%) had suction curettage. The most common reason for curettage was patient option (8.9%). At 2 weeks after methotrexate use, 1.4% of women had curettage because of a viable pregnancy; at 4 weeks, 1.6% of women had curettage because of a persistent but nonviable pregnancy. One percent of women had curettage because of physician recommendation, most commonly for bleeding. Suction curettage rates decreased with site experience (P <.006) and were lower at early gestational ages (P <.004) and in nulliparous women (P <.004). Medical abortion with methotrexate and misoprostol is safe and effective and can be offered in a community setting.

  13. Superior outcome using cyclosporin A alone versus cyclosporin A plus methotrexate for post-transplant immunosuppression in children with acute leukemia undergoing sibling hematopoietic stem cell transplantation.

    Science.gov (United States)

    Weiss, Melissa; Steinbach, Daniel; Zintl, Felix; Beck, James; Gruhn, Bernd

    2015-06-01

    The outcome of cyclosporin A (CSA) alone (n = 19) as graft-versus-host disease (GVHD) prophylaxis was compared to that of CSA combined with methotrexate (MTX) (n = 43) in children with acute leukemia who underwent hematopoietic stem cell transplantation. All respective donors were HLA-identical siblings. All patients received CSA at a dose of 3 mg/kg/day starting on day -1. A CSA level of 80-130 ng/ml was aimed for. The 43 patients in the historical control were given an additional 10 mg/m(2) dosage of MTX on days 1, 3, 6, and 11. Patients who received CSA alone had a significantly reduced cumulative incidence of relapse (5 vs. 40 %; p = 0.002), a significantly increased 5-year event-free survival (84 vs. 35 %; p = 0.001), and a significantly increased 5-year overall survival (84 vs. 42 %; p = 0.004). The incidence of acute GVHD grade II-IV and chronic GVHD in patients in the CSA group was equivalent to the CSA+MTX group (26 vs. 19 %; p = 0.440, and 32 vs. 23 %; p = 0.428). In conclusion, post-transplant immunosuppression consisting of CSA alone is well tolerated and may contribute to a superior outcome.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  16. Curcumin Attenuates Methotrexate-Induced Hepatic Oxidative Damage in Rats

    International Nuclear Information System (INIS)

    HEMEIDA, R.A.M.; MOHAFEZ, O.M.

    2008-01-01

    In the present study, we have addressed the ability of curcumin to suppress MTX-induced liver damage. Hepatotoxicity was induced by injection of a single dose of MTX (20 mg/kg I.P.). MTX challenge induced liver damage that was well characterized histopathologically and biochemically. MTX increased relative liver/body weight ratio. Histologically, MTX produced fatty changes in hepatocytes and sinusoidal lining cells, mild necrosis and inflammation. Biochemically, the test battery entailed elevated activities of serum ALT and AST. Liver activities of superoxide dismutase (SOD), catalase (CAT) and level of reduced glutathione (GSH), were notably reduced, while lipid peroxidation, expressed as malondialdhyde (MDA) level was significantly increased. Administration of curcumin (100mg/kg, I.P.) once daily for 5 consecutive days after MTX challenge mitigated the injurious effects of MTX and ameliorated all the altered biochemical parameters. These results showed that administration of curcumin decreases MTX-induced liver damage probably via regulation of oxidant/anti-oxidant balance. In conclusion, the present study indicates that curcumin may be of therapeutic benefit against MTX-cytotoxicity.

  17. Case report: AREB in a patient with rheumatoid arthritis treated with methotrexate and infliximab

    Directory of Open Access Journals (Sweden)

    Giuseppe Rossi

    2011-09-01

    Full Text Available Anti TNF-a drugs seem to be the new frontier of Rheumatoid Arthritis (RA therapy. The association infliximab methotrexate has been approved for the treatment of RA not responding to the classic therapy, but the short clinical experience in using antiTNF-a molecules brings to segnalation of new risks or adverse events. We describe a case of a patient, treated for many years with classic RA therapy, which developed a refractory anemia after treatment with association infliximab-methotrexate.

  18. Efficacy of Methotrexate in patients with plaque type psoriasis

    Science.gov (United States)

    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

  19. Effect of biologic therapy on radiological progression in rheumatoid arthritis: what does it add to methotrexate?

    Directory of Open Access Journals (Sweden)

    Jones G

    2012-07-01

    Full Text Available Graeme Jones, Erica Darian-Smith, Michael Kwok, Tania WinzenbergMenzies Research Institute, University of Tasmania, Tasmania, AustraliaAbstract: There have been substantial advances in the treatment of rheumatoid arthritis in recent years. Traditional disease-modifying antirheumatic drugs (DMARDs have been shown to have small effects on the progression of radiographic damage. This quantitative overview summarizes the evidence for biologic DMARDS and radiographic damage either alone or in combination with methotrexate. Two outcomes were used (standardized mean difference and odds of progression. A total of 21 trials were identified of which 18 had useable data. For biologic monotherapy, tocilizumab, adalimumab, and etanercept were significantly better than methotrexate, with tocilizumab ranking first in both outcomes while golimumab was ineffective in both outcomes. For a biologic in combination with methotrexate compared with methotrexate alone, most therapies studied (etanercept, adalimumab, infliximab, certolizumab, tocilizumab, and rituximab were effective at slowing X-ray progression using either outcome, with infliximab ranking first in both outcomes. The exceptions to this were golimumab (no effect on standardized mean difference and abatacept (no effect on odds of progression. This effect was additional to methotrexate; thus, the overall benefit is moderate to large in magnitude, which is clearly of major clinical significance for sufferers of rheumatoid arthritis and supports the use of biologic DMARDs in those with a poor disease prognosis.Keywords: rheumatoid, trials, meta-analysis, radiographs, biologic, disease-modifying antirheumatic drugs, DMARDs

  20. The Cost-effectiveness of Sequences of Biological Disease-modifying Antirheumatic Drug Treatment in England for Patients with Rheumatoid Arthritis Who Can Tolerate Methotrexate.

    Science.gov (United States)

    Stevenson, Matt D; Wailoo, Allan J; Tosh, Jonathan C; Hernandez-Alava, Monica; Gibson, Laura A; Stevens, John W; Archer, Rachel J; Simpson, Emma L; Hock, Emma S; Young, Adam; Scott, David L

    2017-07-01

    To ascertain whether strategies of treatment with a biological disease-modifying antirheumatic drug (bDMARD) are cost-effective in an English setting. Results are presented for those patients with moderate to severe rheumatoid arthritis (RA) and those with severe RA. An economic model to assess the cost-effectiveness of 7 bDMARD was developed. A systematic literature review and network metaanalysis was undertaken to establish relative clinical effectiveness. The results were used to populate the model, together with estimates of Health Assessment Questionnaire (HAQ) score following European League Against Rheumatism response; annual costs, and utility, per HAQ band; trajectory of HAQ for patients taking bDMARD; and trajectory of HAQ for patients using nonbiologic therapy (NBT). Results were presented as those associated with the strategy with the median cost-effectiveness. Supplementary analyses were undertaken assessing the change in cost-effectiveness when only patients with the most severe prognoses taking NBT were provided with bDMARD treatment. The costs per quality-adjusted life-year (QALY) values were compared with reported thresholds from the UK National Institute for Health and Care Excellence of £20,000 to £30,000 (US$24,700 to US$37,000). In the primary analyses, the cost per QALY of a bDMARD strategy was £41,600 for patients with severe RA and £51,100 for those with moderate to severe RA. Under the supplementary analyses, the cost per QALY fell to £25,300 for those with severe RA and to £28,500 for those with moderate to severe RA. The cost-effectiveness of bDMARD in RA in England is questionable and only meets current accepted levels in subsets of patients with the worst prognoses.

  1. Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate.

    Science.gov (United States)

    Humphreys, Jenny H; Warner, Alexander; Costello, Ruth; Lunt, Mark; Verstappen, Suzanne M M; Dixon, William G

    2017-09-01

    Patients with rheumatoid arthritis (RA) who take methotrexate (MTX) are advised to limit their alcohol intake due to potential combined hepatotoxicity. However, data are limited to support this. The aim of this study was to quantify the risk of developing abnormal liver blood tests at different levels of alcohol consumption, using routinely collected data from primary care. Patients with RA in the Clinical Practice Research Datalink starting MTX between 1987 and 2016 were included. Hepatotoxicity was defined as transaminitis: alanine transaminase or aspartate aminotransferase more than three times the upper limit of normal. Crude rates of transaminitis were calculated per 1000 person-years, categorised by weekly alcohol consumption in units. Cox proportional hazard models tested the association between alcohol consumption and transaminitis univariately, then age and gender adjusted. 11 839 patients were included, with 530 episodes of transaminitis occurring in 47 090 person-years follow-up. Increased weekly alcohol consumption as a continuous variable was associated with increased risk of transaminitis, adjusted HR (95% CI) per unit consumed 1.01 (1.00 to 1.02); consuming between 15 and 21 units was associated with a possible increased risk of hepatotoxicity, while drinking >21 units per week significantly increased rates of transaminitis, adjusted HR (95% CI) 1.85 (1.17 to 2.93). Weekly alcohol consumption of risk of transaminitis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  2. Oral methotrexate/6-mercaptopurine may be superior to a multidrug LSA2L2 Maintenance therapy for higher risk childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study

    DEFF Research Database (Denmark)

    Schmiegelow, Kjeld; Heyman, Mats; Kristinsson, Jon

    2009-01-01

    The importance of maintenance therapy for higher risk childhood acute lymphoblastic leukemia (ALL) is uncertain. Between 1992 and 2001 the Nordic Society for Pediatric Haematology/Oncology compared in a nonrandomized study conventional oral methotrexate (MTX)/6-mercaptopurine (6MP) maintenance...... therapy (P=0.04) were both related to an increased risk of an event (overall P value of the Cox model: 0.003), whereas neither sex, age at diagnosis, administration of central nervous system irradiation, nor presence of a day 15 bone marrow with > or =25% versus

  3. Chemometrics-assisted Spectrofluorimetric Determination of Two Co-administered Drugs of Major Interaction, Methotrexate and Aspirin, in Human Urine Following Acid-induced Hydrolysis.

    Science.gov (United States)

    Maher, Hadir M; Ragab, Marwa A A; El-Kimary, Eman I

    2015-01-01

    Methotrexate (MTX) is widely used to treat rheumatoid arthritis (RA), mostly along with non-steroidal anti-inflammatory drugs (NSAIDs), the most common of which is aspirin or acetyl salicylic acid (ASA). Since NSAIDs impair MTX clearance and increase its toxicity, it was necessary to develop a simple and reliable method for the monitoring of MTX levels in urine samples, when coadministered with ASA. The method was based on the spectrofluorimetric measurement of the acid-induced hydrolysis product of MTX, 4-amino-4-deoxy-10-methylpteroic acid (AMP), along with the strongly fluorescent salicylic acid (SA), a product of acid-induced hydrolysis of aspirin and its metabolites in urine. The overlapping emission spectra were resolved using the derivative method (D method). In addition, the corresponding derivative emission spectra were convoluted using discrete Fourier functions, 8-points sin xi polynomials, (D/FF method) for better elimination of interferences. Validation of the developed methods was carried out according to the ICH guidelines. Moreover, the data obtained using derivative and convoluted derivative spectra were treated using the non-parametric Theil's method (NP), compared with the least-squares parametric regression method (LSP). The results treated with Theil's method were more accurate and precise compared with LSP since the former is less affected by the outliers. This work offers the potential of both derivative and convolution using discrete Fourier functions in addition to the effectiveness of using the NP regression analysis of data. The high sensitivity obtained by the proposed methods was promising for measuring low concentration levels of the two drugs in urine samples. These methods were efficiently used to measure the drugs in human urine samples following their co-administration.

  4. Methotrexate-Loaded Four-Arm Star Amphiphilic Block Copolymer Elicits CD8+ T Cell Response against a Highly Aggressive and Metastatic Experimental Lymphoma.

    Science.gov (United States)

    Hira, Sumit Kumar; Ramesh, Kalyan; Gupta, Uttam; Mitra, Kheyanath; Misra, Nira; Ray, Biswajit; Manna, Partha Pratim

    2015-09-16

    We have synthesized a well-defined four-arm star amphiphilic block copolymer [poly(DLLA)-b-poly(NVP)]4 [star-(PDLLA-b-PNVP)4] that consists of D,L-lactide (DLLA) and N-vinylpyrrolidone (NVP) via the combination of ring-opening polymerization (ROP) and xanthate-mediated reversible addition-fragmentation chain transfer (RAFT) polymerization. Synthesis of the polymer was verified by 1H NMR spectroscopy and gel permeation chromatography (GPC). The amphiphilic four-arm star block copolymer forms spherical micelles in water as demonstrated by transmission electron microscopy (TEM) and 1H NMR spectroscopy. Pyrene acts as a probe to ascertain the critical micellar concentration (cmc) by using fluorescence spectroscopy. Methotrexate (MTX)-loaded polymeric micelles of star-(PDLLA15-b-PNVP10)4 amphiphilic block copolymer were prepared and characterized by fluorescence and TEM studies. Star-(PDLLA15-b-PNVP10)4 copolymer was found to be significantly effective with respect to inhibition of proliferation and lysis of human and murine lymphoma cells. The amphiphilic block copolymer causes cell death in parental and MTX-resistant Dalton lymphoma (DL) and Raji cells. The formulation does not cause hemolysis in red blood cells and is tolerant to lymphocytes compared to free MTX. Therapy with MTX-loaded star-(PDLLA15-b-PNVP10)4 amphiphilic block copolymer micelles prolongs the life span of animals with neoplasia by reducing the tumor load, preventing metastasis and augmenting CD8+ T cell-mediated adaptive immune responses.

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

    Science.gov (United States)

    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 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.

  6. Sequential Proximal Tibial Stress Fractures associated with Prolonged usage of Methotrexate and Corticosteroids: A Case Report

    Directory of Open Access Journals (Sweden)

    Tan TJL

    2015-11-01

    Full Text Available Stress fractures of the proximal tibia metaphysis are rare in the elderly. We present a case of a 65-year old male who developed sequential proximal tibia stress fractures associated with prolonged usage of methotrexate and prednisolone within a span of 18 months. Magnetic Resonance Imaging revealed an incomplete stress fracture involving the medial proximal tibial region. The patient was treated with stemmed total knee arthroplasty (TKA bilaterally. Stress fractures should be considered in patients with atypical knee pain who have a history of methotrexate and prednisolone usage. TKA is an effective treatment in stress fractures of the proximal tibia.