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https://www.readbyqxmd.com/read/28523588/advances-in-the-development-of-janus-kinase-inhibitors-in-inflammatory-bowel-disease-future-prospects
#1
Mathurin Flamant, Josselin Rigaill, Stephane Paul, Xavier Roblin
Inflammatory bowel disease (IBD) is caused by a dysregulation of the immune system, inducing the production of proinflammatory cytokines and adhesion molecules. A better understanding of the mucosal immune response in IBD has led to the development of new drugs directed at inflammatory cytokines and leukocyte-trafficking molecules. Beyond tumor necrosis factor antagonists and anti-integrin molecules, which act by blocking the interaction between gut-specific lymphocytes and their receptor on vascular endothelium, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway represents a new target in IBD...
May 18, 2017: Drugs
https://www.readbyqxmd.com/read/28513630/ibd-tofacitinib-effective-in-ulcerative-colitis
#2
Conor A Bradley
No abstract text is available yet for this article.
May 17, 2017: Nature Reviews. Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28513593/jak3-deficiency-blocks-innate-lymphoid-cell-development
#3
M L Robinette, M Cella, J B Telliez, T K Ulland, A D Barrow, K Capuder, S Gilfillan, L-L Lin, L D Notarangelo, M Colonna
Loss-of-function mutations in the tyrosine kinase JAK3 cause autosomal recessive severe combined immunodeficiency (SCID). Defects in this form of SCID are restricted to the immune system, which led to the development of immunosuppressive JAK inhibitors. We find that the B6.Cg-Nr1d1(tm1Ven)/LazJ mouse line purchased from Jackson Laboratories harbors a spontaneous mutation in Jak3, generating a SCID phenotype and an inability to generate antigen-independent professional cytokine-producing innate lymphoid cells (ILCs)...
May 17, 2017: Mucosal Immunology
https://www.readbyqxmd.com/read/28511169/efficiency-comparison-of-tofacitinib-and-budesonid-in-treatment-of-nonspecific-ulcerative-colitis
#4
Andriy M Bratasiuk, Antonina I Niroda
INTRODUCTION: A constant interest to explore NUC is caused by the global trend showing a rise in colitis mobidity rate. According to a series of epidemiological studies, the highest incidence of NUC occurs in young age groups, which leads to significant loss of working capacity and high level of incapacitation. One of the leading roles in the pathogenesis of this disease is reportedly played by immunogenetic theory. To date, the main practical technique of NUC diagnostics is colonoscopy...
2017: Wiadomości Lekarskie: Organ Polskiego Towarzystwa Lekarskiego
https://www.readbyqxmd.com/read/28503977/emerging-treatments-for-ulcerative-colitis-a-systematic-review
#5
Damianos G Kokkinidis, Eftychia E Bosdelekidou, Sotiria Maria Iliopoulou, Alexandros G Tassos, Pavlos T Texakalidis, Konstantinos P Economopoulos, Antonis A Kousoulis
OBJECTIVES: Various investigational medicinal products have been developed for ulcerative colitis (UC). Our aim was to systematically evaluate novel pharmacological therapeutic agents for the treatment of UC. MATERIAL AND METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations were followed. A search of the medical literature was conducted in the MEDLINE database for original research papers published between 01 January 2010 and 31 October 2014...
May 14, 2017: Scandinavian Journal of Gastroenterology
https://www.readbyqxmd.com/read/28490712/application-of-physiologically-based-pharmacokinetic-modeling-for-the-prediction-of-tofacitinib-exposure-in-japanese
#6
Misaki Suzuki, Susanna Tse, Midori Hirai, Yoichi Kurebayashi
Tofacitinib (3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3 -oxopropanenitrile) is an oral Janus kinase inhibitor that is approved in countries including Japan and the United States for the treatment of rheumatoid arthritis, and is being developed across the globe for the treatment of inflammatory diseases. In the present study, a physiologically-based pharmacokinetic model was applied to compare the pharmacokinetics of tofacitinib in Japanese and Caucasians to assess the potential impact of ethnicity on the dosing regimen in the two populations...
May 9, 2017: Kobe Journal of Medical Sciences
https://www.readbyqxmd.com/read/28481462/biologics-or-tofacitinib-for-people-with-rheumatoid-arthritis-naive-to-methotrexate-a-systematic-review-and-network-meta-analysis
#7
REVIEW
Jasvinder A Singh, Alomgir Hossain, Amy S Mudano, Elizabeth Tanjong Ghogomu, Maria E Suarez-Almazor, Rachelle Buchbinder, Lara J Maxwell, Peter Tugwell, George A Wells
BACKGROUND: Biologic disease-modifying anti-rheumatic drugs (biologics) are highly effective in treating rheumatoid arthritis (RA), however there are few head-to-head biologic comparison studies. We performed a systematic review, a standard meta-analysis and a network meta-analysis (NMA) to update the 2009 Cochrane Overview. This review is focused on the adults with RA who are naive to methotrexate (MTX) that is, receiving their first disease-modifying agent. OBJECTIVES: To compare the benefits and harms of biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib versus comparator (methotrexate (MTX)/other DMARDs) in people with RA who are naive to methotrexate...
May 8, 2017: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/28480503/quantitative-evaluations-of-time-course-and-treatment-effects-of-systemic-agents-for-psoriasis-a-model-based-meta-analysis
#8
T Checchio, S Ahadieh, P Gupta, J Mandema, L Puig, R Wolk, H Valdez, H Tan, S Krishnaswami, A Tallman, M Kaur, K Ito
Aggregate data model-based meta-analysis is a regression approach to compare the dose-response and/or time-course across different treatments using summary level data from the literature. Literature search and systematic review following the Cochrane approach yielded 912 sources for investigational and approved treatments for psoriasis. In addition, data for tofacitinib were obtained from an internal database. Tofacitinib is an oral Janus kinase inhibitor. Two mathematical models were developed for Psoriasis Area and Severity Index (PASI) response in moderate to severe psoriasis patients to quantify the time to maximum effect for PASI75 and to evaluate the dose-response relationship for PASI responders (PASI50, PASI75, PASI90, PASI100) at Week 12...
May 8, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28475384/optimizing-pharmacologic-management-of-inflammatory-bowel-disease
#9
Shannon Chang, Stephen Hanauer
As our medical armamentarium for IBD continues to expand, it is essential that clinicians understand both optimizing and sequencing of individual and combination therapeutic approaches with available medications. Areas covered: This review summarizes dosing strategies and therapeutic drug monitoring for pharmacologic optimization in IBD. Aminosalicylates remain first-line therapies for mild-to-moderate UC but have limited evidence of efficacy in CD. Budesonide provides an alternative to aminosalicylates when targeted to appropriate sites in the distal small bowel and colon, as do conventional corticosteroids when applied rectally...
June 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28472115/efficacy-and-safety-at-24-weeks-of-daily-clinical-use-of-tofacitinib-in-patients-with-rheumatoid-arthritis
#10
Naoki Iwamoto, Sosuke Tsuji, Ayuko Takatani, Toshimasa Shimizu, Shoichi Fukui, Masataka Umeda, Ayako Nishino, Yoshiro Horai, Tomohiro Koga, Shin-Ya Kawashiri, Toshiyuki Aramaki, Kunihiro Ichinose, Yasuko Hirai, Mami Tamai, Hideki Nakamura, Kaoru Terada, Tomoki Origuchi, Katsumi Eguchi, Yukitaka Ueki, Atsushi Kawakami
OBJECTIVE: We evaluated the efficacy and safety of tofacitinib in patients with rheumatoid arthritis (RA) in a real-world setting. METHODS: Seventy consecutive patients, for whom tofacitinib was initiated between November 2013 and May 2016, were enrolled. All patients fulfilled the 2010 ACR/EULAR classification criteria for RA. All patients received 5 mg of tofacitinib twice daily and were followed for 24 weeks. Clinical disease activity indicated by disease activity score (DAS)28-ESR, the simplified disease activity index, and the clinical disease activity index as well as adverse events (AEs) were evaluated...
2017: PloS One
https://www.readbyqxmd.com/read/28467881/tofacitinib-for-ulcerative-colitis-a-promising-step-forward
#11
EDITORIAL
Sonia Friedman
New England Journal of Medicine, Volume 376, Issue 18, Page 1792-1793, May 2017.
May 4, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28467869/tofacitinib-as-induction-and-maintenance-therapy-for-ulcerative-colitis
#12
RANDOMIZED CONTROLLED TRIAL
William J Sandborn, Chinyu Su, Bruce E Sands, Geert R D'Haens, Séverine Vermeire, Stefan Schreiber, Silvio Danese, Brian G Feagan, Walter Reinisch, Wojciech Niezychowski, Gary Friedman, Nervin Lawendy, Dahong Yu, Deborah Woodworth, Arnab Mukherjee, Haiying Zhang, Paul Healey, Julian Panés
BACKGROUND: Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy. METHODS: We conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks...
May 4, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28465766/biologic-disease-modifying-antirheumatic-drugs-in-a-national-privately-insured-population-utilization-expenditures-and-price-trends
#13
Christopher B Atzinger, Jeff J Guo
BACKGROUND: Spending on biologic drugs is a significant driver of drug expenditures for payers in private health plans. Biologic disease-modifying antirheumatic drugs (DMARDs) are some of the most effective and costly treatments in a physician's arsenal. Understanding the total annual expenditure, the average cost per prescription, and the impact of cost-sharing is important for drug benefit managers. OBJECTIVE: To assess drug utilization, expenditures, out-of-pocket (OOP) cost, and price trends of biologic DMARDs in patients with rheumatoid arthritis (RA) in a large managed care organization...
February 2017: American Health & Drug Benefits
https://www.readbyqxmd.com/read/28461107/tofacitinib-attenuates-arthritis-manifestations-and-reduces-the-pathogenic-cd4-t-cells-in-adjuvant-arthritis-rats
#14
Smadar Gertel, Hussein Mahagna, Gidi Karmon, Abdulla Watad, Howard Amital
Rheumatoid arthritis (RA) is an autoimmune disease characterized by pronounced inflammation and leukocyte infiltration in affected joints. Tofacitinib is new agent, a selective inhibitor of Janus kinase (JAK) signaling pathways mediated by JAK1 and JAK3 and inhibits the key transcription factors STAT1 and STAT3. We investigated the action mechanisms of tofacitinib in rats with adjuvant-induced-arthritis (AIA). AIA-rats were treated orally with tofacitinib or with methotrexate. Arthritis severity and serum C-reactive protein (CRP) levels were evaluated, splenic cells were examined by flow cytometry and cytokines were analyzed by real-time PCR...
April 28, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28460083/estimated-medical-expenditure-and-risk-of-job-loss-among-rheumatoid-arthritis-patients-undergoing-tofacitinib-treatment-post-hoc-analyses-of-two-randomized-clinical-trials
#15
Regina Rendas-Baum, Mark Kosinski, Amitabh Singh, Charles A Mebus, Bethany E Wilkinson, Gene V Wallenstein
Objectives.: RA causes high disability levels and reduces health-related quality of life, triggering increased costs and risk of unemployment. Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. These post hoc analyses of phase 3 data aimed to assess monthly medical expenditure (MME) and risk of job loss for tofacitinib treatment vs placebo. Methods.: Data analysed were from two randomized phase 3 studies of RA patients (n = 1115) with inadequate response to MTX or TNF inhibitors (TNFi) receiving tofacitinib 5 or 10 mg twice daily, adalimumab (one study only) or placebo, in combination with MTX...
April 28, 2017: Rheumatology
https://www.readbyqxmd.com/read/28433687/steroid-resistance-of-airway-type-2-innate-lymphoid-cells-ilc2s-from-severe-asthma-the-role-of-thymic-stromal-cell-lymphopoietin-tslp
#16
Sucai Liu, Mukesh Verma, Lidia Michalec, Weimin Liu, Anand Sripada, Donald Rollins, James Good, Yoko Ito, HongWei Chu, Magdalena M Gorska, Richard J Martin, Rafeul Alam
BACKGROUND: ILC2s represent an important type 2 immune cell. Glucocorticoid regulation of human ILC2s is largely unknown. OBJECTIVE: To assess steroid resistance of human blood and airway ILC2s from asthmatic patients and examine its mechanism of induction. METHODS: We studied human blood and lung ILC2s from asthmatic and control subjects by flow cytometry and ELISA. RESULTS: Dexamethasone (Dex) inhibited (P=0.04) CRTH2 and type 2 cytokine expression by blood ILC2s stimulated with IL25 and IL33...
April 19, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28407099/discontinuation-of-tofacitinib-after-achieving-low-disease-activity-in-patients-with-rheumatoid-arthritis-a-multicentre-observational-study
#17
Satoshi Kubo, Kunihiro Yamaoka, Koichi Amano, Shuji Nagano, Shigeto Tohma, Eiichi Suematsu, Hayato Nagasawa, Kanako Iwata, Yoshiya Tanaka
Objective.: To determine whether tofacitinib can be discontinued in patients with RA who achieve low disease activity (LDA). Methods.: RA patients with LDA after tofacitinib treatment in a phase III and long-term extension study were enrolled in this multicentre, non-randomized, open, prospective, observational study. The decision of discontinuation or continuation of tofacitinib was determined based on patient-physician decision making with informed consent. The primary endpoint was the proportion of patients who remained tofacitinib-free at post-treatment week 52...
April 12, 2017: Rheumatology
https://www.readbyqxmd.com/read/28396102/efficacy-of-tofacitinib-for-the-treatment-of-nail-psoriasis-two-52-week-randomized-controlled-phase-3-studies-in-patients-with-moderate-to-severe-plaque-psoriasis
#18
Joseph F Merola, Boni Elewski, Svitlana Tatulych, Shuping Lan, Anna Tallman, Mandeep Kaur
BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor. Efficacy and safety of tofacitinib in patients with moderate-to-severe plaque psoriasis have been demonstrated. OBJECTIVE: We sought to assess the efficacy of tofacitinib for the treatment of nail psoriasis over a period of 52 weeks. METHODS: In 2 identical phase 3 studies (OPT Pivotal 1 and 2), patients were randomized 2:2:1 to receive tofacitinib 5 mg, tofacitinib 10 mg, or placebo, twice daily...
April 7, 2017: Journal of the American Academy of Dermatology
https://www.readbyqxmd.com/read/28389165/cytomegalovirus-retinitis-followed-by-immune-recovery-uveitis-in-an-elderly-patient-with-rheumatoid-arthritis-undergoing-administration-of-methotrexate-and-tofacitinib-combination-therapy
#19
Kunio Yanagisawa, Yoshiyuki Ogawa, Mayumi Hosogai, Daisuke Todokoro, Takeki Mitsui, Akihiko Yokohama, Shoji Kishi, Hiroshi Handa
Cytomegalovirus (CMV) retinitis is an opportunistic ocular infection most commonly observed in patients infected with human immunodeficiency virus (HIV). We present a rare case of CMV retinitis that developed in a non-HIV patient with rheumatoid arthritis (RA). Over the preceding 5 months, a family doctor had been treating the 78-year-old male patient with a combination therapy of methotrexate (MTX) and tofacitinib (TOF). CMV retinitis occurred when the patient's CD4+ T cells were low (196 cells/μl), and preceded the onset of Pneumocystis pneumonia...
April 4, 2017: Journal of Infection and Chemotherapy: Official Journal of the Japan Society of Chemotherapy
https://www.readbyqxmd.com/read/28382662/successful-targeted-treatment-of-mast-cell-activation-syndrome-with-tofacitinib
#20
Lawrence B Afrin, Roger W Fox, Susan L Zito, Leo Choe, Sarah C Glover
Mast cell (MC) activation syndrome (MCAS) is a collection of illnesses of inappropriate MC activation with little to no neoplastic MC proliferation, distinguishing it from mastocytosis. MCAS presents as chronic, generally inflammatory multisystem polymorbidity likely driven in most by heterogeneous patterns of constitutively activating mutations in MC regulatory elements, posing challenges for identifying optimal mutation-targeted treatment in individual patients. Targeting commonly affected downstream effectors may yield clinical benefit independent of upstream mutational profile...
April 6, 2017: European Journal of Haematology
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