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Bangrong Cai, Aimei Liao, Kyung-Ku Lee, Jae-Sam Ban, Hyun-Sam Yang, Young Jun Im, ChangJu Chun
A series of methotrexate-diosgenin conjugates was designed and synthesized to enhance the passive internalization of methotrexate (MTX) into transport-resistant cells. The inhibitory effects of these conjugates on dihydrofolate reductase (DHFR), and their anti-proliferation behaviors against a transport-resistant breast cancer cell line, MDA-MB-231, were investigated. All of the synthesized conjugates retained an ability to inhibit DHFR after the diosgenin substitution. The MTX conjugates were much more potent against methotrexate-resistant MDA-MB-231 cells than MTX...
October 19, 2016: Steroids
Yinghe Huo, Renske D Veldhuizen, Desiree M van der Heijde, Nick J Besselink, Johannes W G Jacobs, Jacob M van Laar, Max A Viergever, Koen L Vincken, Floris P Lafeber, Maria J H de Hair
OBJECTIVES: To compare as proof of concept the sensitivity to change of automated quantification of radiographic wrist and hand joint space width (JSW) with scoring JSW according to the Sharp/van der Heijde scoring method (SHS) in two strategy groups of a treat-to-target and tight-control early rheumatoid arthritis (RA) study. METHODS: Digital radiographs were assessed for JSW changes of 134 patients of the 236 patients participating in the second Computer Assisted Management in Early Rheumatoid Arthritis trial, of whom both baseline and year 2 radiographs were available (year 1 radiographs n=125)...
September 2016: Clinical and Experimental Rheumatology
Claudia Maria Hattinger, Elisa Tavanti, Marilù Fanelli, Serena Vella, Piero Picci, Massimo Serra
Antifolates are structural analogs of folates, which have been used as antitumor drugs for more than 60 years. The antifolate drug most commonly used for treating human tumors is methotrexate (MTX), which is utilized widely in first-line treatment protocols of high-grade osteosarcoma (HGOS). In addition to MTX, two other antifolates, trimetrexate and pemetrexed, have been tested in clinical settings for second-line treatment of recurrent HGOS with patients unfortunately showing modest activity. Areas covered: There is clinical evidence which suggsest that, like other chemotherapeutic agents, not all HGOS patients are equally responsive to antifolates and do not have the same susceptibility to experience adverse drug-related toxicities...
October 19, 2016: Expert Opinion on Drug Metabolism & Toxicology
Soumyarwit Manna, James J Augsburger, Zelia M Correa, Marwan F Al-Rjoub, Marepalli B Rao, Rupak K Banerjee
PURPOSE: The purpose of this study is to noninvasively evaluate the safety and toxicity of a chitosan (CS) and polylactic acid (PLA)-based sustained-release methotrexate (MTX) intravitreal microimplant in normal rabbit eyes using electroretinography (ERG). METHODS: PLA-coated CS-based microimplants containing 400 μg of MTX and placebo microimplants (without drug) were surgically implanted in the vitreous of the right and the left eyes, respectively, in each of the 8 New Zealand rabbits using minimally invasive technique...
October 18, 2016: Journal of Ocular Pharmacology and Therapeutics
Vibeke Strand, Eun Bong Lee, Roy Fleischmann, Rieke E Alten, Tamas Koncz, Samuel H Zwillich, David Gruben, Bethanie Wilkinson, Sriram Krishnaswami, Gene Wallenstein
OBJECTIVES: To compare patient-reported outcomes (PROs) in methotrexate (MTX)-naive patients (defined as no prior treatment or ≤3 doses) receiving tofacitinib versus MTX. METHODS: In the 24-month, phase III, randomised, controlled, ORAL Start trial (NCT01039688), patients were randomised 2:2:1 to receive tofacitinib 5 mg two times per day (n=373), tofacitinib 10 mg two times per day (n=397) or MTX (n=186). PROs assessed included Patient Global Assessment of disease (PtGA), pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and health-related quality of life (Short Form-36 [SF-36])...
2016: RMD Open
Tatsuhiro Yamamoto, Kotaro Shikano, Toshihiro Nanki, Shinichi Kawai
We investigated major determinants of the intracellular concentrations of methotrexate polyglutamates (MTXPGs) in patients with rheumatoid arthritis (RA). In 271 RA patients on stable oral low dose weekly pulse MTX therapy, the concentrations of MTXPGs in red blood cells (RBCs) were measured by liquid chromatography-electrospray ionization-tandem mass spectrometry. Polymerase chain reaction-restriction fragment length polymorphism analysis was performed to determine the genotypes of solute carrier family 19 member 1 (SLC19A1), folylpolyglutamate synthase (FPGS), and gamma-glutamyl hydrolase (GGH)...
October 18, 2016: Scientific Reports
Luis Sala-Icardo, Amalia Lamana, Ana María Ortiz, Elena García Lorenzo, Pablo Moreno Fresneda, Rosario García-Vicuña, Isidoro González-Álvaro
OBJECTIVE: 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). PATIENTS AND METHODS: We analyzed 1415 visits from 350 patients of the PEARL (Princesa Early Arthritis Register Longitudinal) study: (732 with MTX, 683 without MTX)...
October 14, 2016: Reumatología Clinica
Luis Rodriguez-Rodriguez, Leticia Leon, Jose Ivorra-Cortes, Alejandro Gómez, Jose Ramon Lamas, Esperanza Pato, Juan Angel Jover, Lydia Abásolo
OBJECTIVES: To assess the mortality rate (MR) and the mortality risk of a rheumatoid arthritis (RA) inception cohort, with and without biologic agents (BAs). Other factors associated to mortality were also investigated. METHODS: Retrospective longitudinal study of RA patients, attending the rheumatology outpatient clinic of a tertiary Hospital (Madrid), collected over 5 years (2000-2004), and followed from the diagnosis of RA up to the patients' death, lost to follow-up or September 2013...
October 7, 2016: Clinical and Experimental Rheumatology
Gerd Horneff, Ariane Klein, Prasad T Oommen, Anton Hospach, Ivan Foeldvari, Isa Feddersen, Kirsten Minden
OBJECTIVES: While tumour necrosis factor (TNF)-α-inhibitor treatment improved outcome of juvenile idiopathic arthritis (JIA) management markedly, concerns have been raised about an association of TNF-α-inhibitor treatment and an increased risk for malignancies especially lymphoma. METHODS: Cases of suspected malignancies documented in the German Biker Registry are reviewed in detail. RESULTS: Until Dec 31, 2015, 3695 JIA patients were prospectively followed with a total of more than 13,198 observation years...
September 8, 2016: Clinical and Experimental Rheumatology
Bart V J Cuppen, Johannes W G Jacobs, Evert-Jan Ter Borg, Anne C A Marijnissen, Johannes W J Bijlsma, Floris P J G Lafeber, Jacob M van Laar
OBJECTIVES: Despite the success of TNF-alpha inhibitor (TNFi) treatment in rheumatoid arthritis (RA), a substantial number of patients necessitate discontinuation. Prediction thereof would be clinically relevant and guide the decision whether to start TNFi treatment. METHODS: Data were used from the observational BiOCURA cohort, in which patients initiating biological treatment were enrolled and followed up for one year. In the model development cohort (n=192), a model predicting TNFi discontinuation was built using Cox-regression with backward selection (p<0...
October 7, 2016: Clinical and Experimental Rheumatology
A J Kivitz, S R Gutierrez-Ureña, J Poiley, M C Genovese, R Kristy, K Shay, X Wang, J P Garg, A Zubrzycka-Sienkiewicz
OBJECTIVE: To evaluate efficacy and safety of orally administered once-daily peficitinib in combination with methotrexate (MTX) in patients with moderate-to-severe rheumatoid arthritis (RA) who had an inadequate response to MTX. METHODS: In this multinational, phase IIb, randomized, double-blind, placebo-controlled, dose-ranging trial, patients with RA (N=378) were treated with peficitinib 25 mg, 50 mg, 100 mg, 150 mg + MTX, or matching placebo + MTX once daily for 12 weeks (NCT01554696)...
October 16, 2016: Arthritis & Rheumatology
Takao Koike, Masayoshi Harigai, Naoki Ishiguro, Shigeko Inokuma, Syuji Takei, Tsutomu Takeuchi, Hisashi Yamanaka, Yoshinari Takasaki, Tsuneyo Mimori, Katsutoshi Hiramatsu, Shuichi Komatsu, Yoshiya Tanaka
INTRODUCTION: There is insufficient evidence regarding the appropriate dose of methotrexate (MTX) required to achieve specific treatment goals in patients with rheumatoid arthritis (RA) receiving biologic drugs in Japan. The present study aimed to assess the dose-response effect of MTX in combination with adalimumab (ADA) to achieve low disease activity (LDA) and/or remission at 24 weeks in RA patients. METHODS: This analysis used data of the ADA all-case survey in Japan (n = 7740), and 5494 patients who received ADA and MTX were classified into five groups by weighted average MTX dose (>0-<4, 4-<6, 6-<8, 8-< 10, and ≥10 mg/week)...
June 2016: Rheumatol Ther
Yueqin Han, Yanping Zhu, Jinshen Wang, Yanqin Han, Daogang Qin, Qiaozhi Yang, Xiaojing Sun, Lijun Chen
OBJECTIVES: To investigate the efficacy of interleukin 11 (IL-11) towards the high dose methotrexate (HDMTX)-concurrent rat small intestinal mucositis and its impacts on the proliferation of the human T-lymphoblastic leukemia (CEM) cell line. MATERIALS AND METHODS: 95 Wistar rats were randomly divided into five groups, the normal control group (A), the methotrexate (MTX) control group (B), the IL-11-pre-treated high-dose group (C), the post-IL-11-treatment high-dose group (D) and the post-IL-11-treatment low-dose group (E)...
August 2016: Iranian Journal of Basic Medical Sciences
Wei-Yuan Wang, Xiu-Fen Zhao, Xiao-Han Ju, Yu Wang, Lin Wang, Shu-Ping Li, Xiao-Dong Li
A novel morphology change of Au-methotrexate (Au-MTX) conjugates that could transform from nanochains to discrete nanoparticles was achieved by a simple, one-pot, and hydrothermal growth method. Herein, MTX was used efficiently as a complex-forming agent, reducing agent, capping agent, and importantly a targeting anticancer drug. The formation mechanism suggested a similarity with the molecular imprinting technology. The Au-MTX complex induced the MTX molecules to selectively adsorb on different crystal facets of gold nanoparticles (AuNPs) and then formed gold nanospheres...
October 12, 2016: International Journal of Pharmaceutics
A J Ruiz-Padilla, J I Gamez-Nava, A M Saldaña-Cruz, J D Murillo-Vazquez, M L Vazquez-Villegas, S A Zavaleta-Muñiz, B T Martín-Márquez, J M Ponce-Guarneros, N A Rodriguez Jimenez, A Flores-Chavez, F Sandoval-Garcia, J C Vasquez-Jimenez, E G Cardona-Muñoz, S E Totsuka-Sutto, L Gonzalez-Lopez
Objective. To evaluate the association of -174G/C IL-6 polymorphism with failure in therapeutic response to methotrexate (MTX) or leflunomide (LEF). This prospective, observational cohort included 96 Mexican-Mestizo patients with moderate or severe rheumatoid arthritis (RA), initiating MTX or LEF, genotyped for IL-6 -174G/C polymorphism by PCR-RFLP. Therapeutic response was strictly defined: only if patients achieved remission or low disease activity (DAS-28 < 3.2). Results. Patients with MTX or LEF had significant decrement in DAS-28 (p < 0...
2016: BioMed Research International
R Fleischmann, P J Mease, S Schwartzman, L-J Hwang, K Soma, C A Connell, L Takiya, E Bananis
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 <17.5 mg/week), or high (≥17...
October 12, 2016: Clinical Rheumatology
Andrea Picchianti Diamanti, Milica Markovic, Giuseppe Argento, Simonetta Giovagnoli, Alberto Ricci, Bruno Laganà, Raffaele D'Amelio
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that can present different extrarticular manifestations involving heart, lungs and kidneys. In recent years there has been a growing awareness of the central role played by the lungs in the onset and progression of RA. In particular interstitial lung disease (ILD) is a common pulmonary manifestation that may be related to the inflammatory process itself, infectious complications and to the treatments used. Management of patients with ILD/RA is still a challenge for clinicians, both synthetic [mainly methotrexate (MTX), leflunomide] and biologic immunosuppressors [mainly anti-tumor necrosis factor (TNF)α] have in fact been related to the onset or worsening of lung diseases with conflicting data...
October 12, 2016: Therapeutic Advances in Respiratory Disease
Rafael Alfonso-Cristancho, Nigel Armstrong, Ramesh Arjunji, Rob Riemsma, Gill Worthy, Rita Ganguly, Jos Kleijnen
Our aim was to establish the comparative effectiveness of rheumatoid arthritis (RA) biologics, using a systematic review and network meta-analysis. The systematic review used randomized controlled trials (RCTs) in adults with RA who failed treatment with conventional disease-modifying agents for rheumatoid disease (cDMARDs). We compared the effectiveness of abatacept, adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, and rituximab to tocilizumab, a recent biologic with a different mechanism of action (anti-IL-6 receptor)...
October 10, 2016: Clinical Rheumatology
Yao Wang, Ping Huang, Minxi Hu, Wei Huang, Xinyuan Zhu, Deyue Yan
The distinct and complementary biochemical mechanisms of folic acid analog methotrexate (MTX) and cytidine analog gemcitabine (GEM) make their synergistic combination effectively. 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...
October 10, 2016: Bioconjugate Chemistry
Roy Fleischmann, Michael Schiff, Désirée van der Heijde, Cesar Ramos-Remus, Alberto Spindler, Marina Stanislav, Cristiano A F Zerbini, Sirel Gurbuz, Christina Dickson, Stephanie de Bono, Douglas Schlichting, Scott Beattie, Wen-Ling Kuo, Terence Rooney, William Macias, Tsutomu Takeuchi
Objective This Phase 3 study evaluated baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX in patients with active rheumatoid arthritis (RA) with no or minimal prior conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) and naive to biologic DMARDs. Methods Patients (N=588) were randomized 4:3:4 (MTX: baricitinib 4 mg once daily: baricitinib 4 mg + MTX) for 52 weeks. The primary endpoint assessment was noninferiority of baricitinib monotherapy to MTX based on American College of Rheumatology 20% (ACR20) response at Week 24...
October 9, 2016: Arthritis & Rheumatology
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