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Tofacitinib

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https://www.readbyqxmd.com/read/29205421/systematic-review-with-network-meta-analysis-comparative-assessment-of-tofacitinib-and-biological-therapies-for-moderate-to-severe-ulcerative-colitis
#1
S Bonovas, T Lytras, G Nikolopoulos, L Peyrin-Biroulet, S Danese
BACKGROUND: Biological therapies have improved the care of patients with ulcerative colitis (UC). Tofacitinib, an oral small-molecule Janus kinase inhibitor, is potentially a new treatment option. AIM: To comparatively assess efficacy and harm of tofacitinib and biologics (infliximab, adalimumab, golimumab and vedolizumab) in adult patients not previously exposed to TNF antagonists. METHODS: We performed a comprehensive search of PubMed, Embase, Scopus, clinical trial registries, regulatory authorities' websites and major conference proceedings, through August 2017, to identify randomised, placebo-controlled or head-to-head trials assessing tofacitinib or biologics as induction and/or maintenance therapy in moderate-to-severe UC...
December 4, 2017: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29205406/systematic-review-and-network-meta-analysis-first-and-second-line-pharmacotherapy-for-moderate-severe-ulcerative-colitis
#2
S Singh, M Fumery, W J Sandborn, M H Murad
BACKGROUND: There are limited data to inform positioning of agents for treating moderate-severe ulcerative colitis (UC). AIM: To assess comparative efficacy and safety of different therapies as first-line (biologic-naïve) and second-line (prior exposure to anti-tumour necrosis factor(TNF)-α) agents for moderate-severe UC, through a systematic review and network meta-analysis, and appraise quality of evidence (QoE) using grading of recommendations, assessment, development and evaluation (GRADE) approach...
December 4, 2017: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29196988/analysis-of-spontaneous-postmarket-case-reports-submitted-to-the-fda-regarding-thromboembolic-adverse-events-and-jak-inhibitors
#3
Abril Verden, Mo Dimbil, Robert Kyle, Brian Overstreet, Keith B Hoffman
INTRODUCTION: The Janus kinase (JAK) inhibitor baricitinib is approved in Europe and Japan for the treatment of rheumatoid arthritis. In April 2017, the US FDA expressed concern about thromboembolic events (deep venous thrombosis [DVT] and pulmonary embolism [PE]) observed in placebo-controlled clinical trials of baricitinib. The European and Japanese labels for baricitinib were recently updated to include a precaution related to potential thromboembolic events in patients at risk. Given that the FDA-approved drugs tofacitinib and ruxolitinib are in the same class, we conducted a safety review of the FDA's Adverse Event Reporting System (FAERS) to assess postmarketing reporting rates for related thromboembolic risks...
December 2, 2017: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
https://www.readbyqxmd.com/read/29182790/validation-of-the-itch-severity-item-as-a-measurement-tool-for-pruritus-in-patients-with-psoriasis-results-from-a-phase-3-tofacitinib-program
#4
Sonja Ständer, Thomas Luger, Joseph C Cappelleri, Andrew G Bushmakin, Carla Mamolo, Michael A Zielinski, Anna M Tallman, Gil Yosipovitch
Tofacitinib is an oral Janus kinase inhibitor. This post-hoc analysis aimed to investigate the psychometric properties of the Itch Severity Item (ISI), a numeric rating scale from 0 (no itching) to 10 (worst possible itching) for pruritus in psoriasis, and review the effect of tofacitinib on pruritus in patients with psoriasis participating in Phase 3 studies (n = 3,641). The ISI showed high test-retest reliability (intra-class correlation coefficient: 0.84). The clinically important difference was defined as a 1...
November 28, 2017: Acta Dermato-venereologica
https://www.readbyqxmd.com/read/29171774/advances-in-treating-psoriasis-in-the-elderly-with-small-molecule-inhibitors
#5
Abigail Cline, Leah A Cardwell, Steven R Feldman
Due to the chronic nature of psoriasis, the population of elderly psoriasis patients is increasing. However, many elderly psoriatic patients are not adequately treated because management is challenging as a result of comorbidities, polypharmacy, and progressive impairment of organ systems. Physicians may hesitate to use systemic or biologic agents in elderly psoriasis patients because of an increased risk of adverse events in this patient population. Small molecule medications are emerging as promising options for elderly patients with psoriasis and other inflammatory conditions...
November 24, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/29162613/the-jak1-2-inhibitor-ruxolitinib-reverses-interleukin-6-mediated-suppression-of-drug-detoxifying-proteins-in-cultured-human-hepatocytes
#6
Marie Febvre-James, Arnaud Bruyere, Marc Le Vee, Olivier Fardel
The inflammatory cytokine interleukin (IL)-6, which basically activates the JAK/STAT signaling pathway, is well-known to repress expression of hepatic cytochromes P-450 (CYPs) and transporters. Therapeutic proteins, like mAbs targeting IL-6 or its receptor, have been consequently demonstrated to restore full hepatic detoxification capacity, which results in inflammatory disease-related drug-drug interactions (idDDIs). In the present study, we investigated whether ruxolitinib, a small drug acting as a JAK1/2 inhibitor and currently used in the treatment of myeloproliferative neoplasms, may also counteract IL-6 repressing effects towards hepatic detoxifying systems...
November 21, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29151519/tofacitinib-therapy-for-rheumatoid-arthritis-a-direct-comparison-study-between-biologic-na%C3%A3-ve-and-experienced-patients
#7
Shunsuke Mori, Tamami Yoshitama, Yukitaka Ueki
Objective This study was designed to directly compare the outcomes of tofacitinib therapy for methotrexate-refractory rheumatoid arthritis (RA) between biologic-naïve patients and patients who had experienced an inadequate response to biological agents. Methods We prospectively enrolled and followed 113 patients who had a high or moderate clinical disease activity index (CDAI) (36 biologic-naïve patients and 77 biologic-experienced patients). Patients received 5 mg of tofacitinib twice daily. Effectiveness and adverse events were examined at month 6 of treatment...
November 20, 2017: Internal Medicine
https://www.readbyqxmd.com/read/29145097/lc-esi-ms-ms-determination-of-defactinib-a-novel-fak-inhibitor-in-mice-plasma-and-its-application-to-a-pharmacokinetic-study-in-mice
#8
Gurulingappa Hallur, Natarajan Tamizharasan, Suresh P Sulochana, Neeraj Kumar Saini, Mohd Zainuddin, Ramesh Mullangi
A sensitive, specific, selective and rapid LC-ESI-MS/MS method has been developed and validated for the quantification of defactinib in mice plasma using (13)C3,(15)N-tofacitinib as an internal standard (I.S.). Sample preparation was accomplished through a liquid-liquid extraction process. Baseline chromatographic resolution of defactinib and the I.S. was achieved on an Atlantis dC18 column using an isocratic mobile phase comprising 0.2% formic acid in water and acetonitrile (25:75, v/v) delivered at a flow rate of 0...
November 10, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29142036/effect-of-glucocorticoids-on-the-clinical-and-radiographic-efficacy-of-tofacitinib-in-patients-with-rheumatoid-arthritis-a-posthoc-analysis-of-data-from-6-phase-iii-studies
#9
Christina Charles-Schoeman, Désirée van der Heijde, Gerd R Burmester, Peter Nash, Cristiano A F Zerbini, Carol A Connell, Haiyun Fan, Kenneth Kwok, Eustratios Bananis, Roy Fleischmann
OBJECTIVE: Tofacitinib has been investigated for the treatment of rheumatoid arthritis (RA) in phase III studies in which concomitant glucocorticoids (GC) were allowed. We analyzed the effect of GC use on efficacy outcomes in patients with RA receiving tofacitinib and/or methotrexate (MTX) or conventional synthetic disease-modifying antirheumatic drugs (csDMARD) in these studies. METHODS: Our posthoc analysis included data from 6 phase III studies (NCT01039688; NCT00814307; NCT00847613; NCT00853385; NCT00856544; NCT00960440)...
November 15, 2017: Journal of Rheumatology
https://www.readbyqxmd.com/read/29139090/tofacitinib-a-review-in-rheumatoid-arthritis
#10
Sohita Dhillon
Tofacitinib (Xeljanz(®)) is a potent, selective JAK inhibitor that preferentially inhibits Janus kinase (JAK) 1 and JAK3. In the EU, oral tofacitinib 5 mg twice daily is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant of, one or more DMARDs. Several clinical studies of ≤ 24 months' duration showed that tofacitinib monotherapy (as first- or second-line treatment) and combination therapy with a conventional synthetic DMARD (csDMARD; as second- or third-line treatment) was effective in reducing signs and symptoms of disease and improving health-related quality of life (HR-QOL), with benefits sustained during long-term therapy (≤ 96 months)...
November 14, 2017: Drugs
https://www.readbyqxmd.com/read/29136293/efficacy-and-safety-of-tofacitinib-for-moderate-to-severe-plaque-psoriasis-a-systematic-review-and-meta-analysis-of-randomized-controlled-trials
#11
REVIEW
C-M Kuo, T-H Tung, S-H Wang, C-C Chi
The effects of tofacitinib in treating moderate-to-severe plaque psoriasis were unclear. We aimed to assess the effects of tofacitinib in treating moderate-to-severe plaque psoriasis. We searched PubMed, Cochrane Central Register of Controlled Trials, and EMBASE for relevant randomised controlled trials (RCTs), and conducted a systematic review and meta-analysis. Four RCTs with 2,724 participants were included. Compared to placebo, tofacitinib significantly improved psoriasis (≥ 75% reduction in the Psoriasis Area and Severity Index score: 5 mg BID: risk difference (RD) 0...
November 14, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/29108908/tofacitinib-2-ointment-a-topical-janus-kinase-inhibitor-for-the-treatment-of-alopecia-areata-a-pilot-study-of-10-patients
#12
Lucy Y Liu, Brittany G Craiglow, Brett A King
No abstract text is available yet for this article.
November 3, 2017: Journal of the American Academy of Dermatology
https://www.readbyqxmd.com/read/29106440/identification-of-pmn-released-mutagenic-factors-in-a-co-culture-model-for-colitis-associated-cancer
#13
Nicolas Granofszky, Michaela Lang, Vineeta Khare, Gerald Schmid, Theresa Scharl, Franziska Ferk, Kristine Jimenez, Siegfried Knasmüller, Christoph Campregher, Christoph Gasche
Microsatellite instability (MSI) is present in ulcerative colitis and colitis-associated colorectal cancers. Certain factors released by polymorphonuclear cells (PMN) may drive mucosal frameshift mutations resulting in MSI and cancer. Here, we applied a co-culture system with PMNs and colon epithelial cells to identify such culprit factors. Subjecting HCT116+chr3 and HCEC-1CT MSI-reporter cell lines harboring mono-, di- or tetranucleotide DNA repeats linked to EGFP to activated PMNs induced frameshift mutations within all repeats, as quantified by flow cytometry...
November 2, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/29094282/tofacitinib-a-new-oral-therapy-for-psoriasis
#14
REVIEW
Alexandra Azevedo, Tiago Torres
Psoriasis is a common, chronic, immune-mediated disease associated with several comorbidities. Biologic therapy revolutionized the treatment of moderate-to-severe psoriasis, improving physical and emotional burden of the disease. Still, there are unmet needs in the treatment of psoriasis regarding long-term efficacy, tolerability, safety, route of administration, and cost. The increased knowledge of the pathogenesis of the intracellular metabolic pathways allowed the development of new compounds that inhibit certain intracellular proteins involved in the immune response...
November 1, 2017: Clinical Drug Investigation
https://www.readbyqxmd.com/read/29080806/t-cell-mediated-immune-response-to-pneumococcal-conjugate-vaccine-pcv-13-and-tetanus-toxoid-vaccine-in-patients-with-moderate-to-severe-psoriasis-during-tofacitinib-treatment
#15
Kevin Winthrop, Neil Korman, William Abramovits, Scott T Rottinghaus, Huaming Tan, Annie Gardner, Geoffrey Mukwaya, Mandeep Kaur, Hernan Valdez
BACKGROUND: Psoriasis is often treated with immunomodulatory therapies that may affect immune response to common antigens. Tofacitinib is an oral Janus kinase inhibitor. OBJECTIVE: To characterize the effect of long-term exposure to tofacitinib 10 mg twice daily (BID) on T cell function in psoriasis patients. METHODS: Patients completing at least 3 months' continuous treatment with tofacitinib 10 mg BID were vaccinated with T cell-dependent vaccines (monovalent tetanus toxoid and 13-valent pneumococcal conjugate [PCV-13])...
October 25, 2017: Journal of the American Academy of Dermatology
https://www.readbyqxmd.com/read/29079427/correlation-and-cluster-analysis-of-immunomodulatory-drugs-based-on-cytokine-profiles
#16
Fredrik K Wallner, Malin Hultquist Hopkins, Nina Woodworth, Therese Lindvall Bark, Peter Olofsson, Andreas Tilevik
Drug discovery is a constant struggle to overcome hurdles posed by the complexity of biological systems. One of these hurdles is to find and understand the molecular target and the biological mechanism of action. Although the molecular target has been determined, the true biological effect may be unforeseen also for well-established drugs. Hence, there is a need for novel ways to increase the knowledge of the biological effects of drugs in the developmental process. In this study, we have determined cytokine profiles for 26 non-biological immunomodulatory drugs or drug candidates and used these profiles to cluster the compounds according to their effect in a preclinical ex vivo culture model of arthritis...
October 25, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29074274/cellular-and-functional-actions-of-tofacitinib-related-to-the-pathophysiology-of-hibernoma-development
#17
Zaher A Radi, W Mark Vogel, Phillip M Bartholomew, Petra Koza-Taylor, Alexandros Papanikolaou, Todd Wisialowski, Prashant Nambiar, Douglas J Ball
Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis. In the 2-year carcinogenicity study with tofacitinib, increased incidence of hibernoma (a neoplasm of brown adipose tissue [BAT]) was noted in female rats at ≥30 mg/kg/day (≥41x human exposure multiples). Thus, signaling pathways within BAT were investigated by measuring BAT: weight, cell proliferation biomarkers, content of basal and prolactin-induced phosphorylated Signal Transducer and Activator of Transcription (STAT), and uncoupling protein 1 (UCP-1)...
October 23, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/29051788/emerging-oral-targeted-therapies-in-inflammatory-bowel-diseases-opportunities-and-challenges
#18
REVIEW
Marcel Vetter, Markus F Neurath
To improve quality of life and prevent long-term risks in patients with inflammatory bowel diseases (IBDs: Crohn's disease, ulcerative colitis), it is essential to suppress inflammatory activity adequately. However, corticosteroids are only suitable for therapy of acute flares and the evidence for positive effects of immunosuppressive substances like azathioprine or 6-mercapropurine is mainly limited to maintenance of remission. In addition, only subgroups of patients benefit from biologicals targeting tumour necrosis factor α or α4β7 integrins...
October 2017: Therapeutic Advances in Gastroenterology
https://www.readbyqxmd.com/read/29045212/tofacitinib-or-adalimumab-versus-placebo-for-psoriatic-arthritis
#19
RANDOMIZED CONTROLLED TRIAL
Philip Mease, Stephen Hall, Oliver FitzGerald, Désirée van der Heijde, Joseph F Merola, Francisco Avila-Zapata, Dorota Cieślak, Daniela Graham, Cunshan Wang, Sujatha Menon, Thijs Hendrikx, Keith S Kanik
BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor that is under investigation for the treatment of psoriatic arthritis. We evaluated tofacitinib in patients with active psoriatic arthritis who previously had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs). METHODS: In this 12-month, double-blind, active-controlled and placebo-controlled, phase 3 trial, we randomly assigned patients in a 2:2:2:1:1 ratio to receive one of the following regimens: tofacitinib at a 5-mg dose taken orally twice daily (107 patients), tofacitinib at a 10-mg dose taken orally twice daily (104), adalimumab at a 40-mg dose administered subcutaneously once every 2 weeks (106), placebo with a blinded switch to the 5-mg tofacitinib dose at 3 months (52), or placebo with a blinded switch to the 10-mg tofacitinib dose at 3 months (53)...
October 19, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29045207/tofacitinib-for-psoriatic-arthritis-in-patients-with-an-inadequate-response-to-tnf-inhibitors
#20
RANDOMIZED CONTROLLED TRIAL
Dafna Gladman, William Rigby, Valderilio F Azevedo, Frank Behrens, Ricardo Blanco, Andrzej Kaszuba, Elizabeth Kudlacz, Cunshan Wang, Sujatha Menon, Thijs Hendrikx, Keith S Kanik
BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor that is under investigation for the treatment of psoriatic arthritis. We evaluated tofacitinib in patients with active psoriatic arthritis who had previously had an inadequate response to tumor necrosis factor (TNF) inhibitors. METHODS: In this 6-month randomized, placebo-controlled, double-blind, phase 3 trial, we randomly assigned 395 patients, in a 2:2:1:1 ratio, to four regimens: 5 mg of tofacitinib administered orally twice daily (132 patients); 10 mg of tofacitinib twice daily (132 patients); placebo, with a switch to 5 mg of tofacitinib twice daily at 3 months (66 patients); or placebo, with a switch to 10 mg of tofacitinib twice daily at 3 months (65 patients)...
October 19, 2017: New England Journal of Medicine
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