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Tofacitinib

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https://www.readbyqxmd.com/read/29458040/pharmacological-inhibition-of-jak3-enhances-the-antitumor-activity-of-imatinib-in-human-chronic-myeloid-leukemia
#1
Kenta Yagi, Akira Shimada, Toshiaki Sendo
Imatinib (IMA) is the standard treatment for CML; however, stopping IMA sometimes results in disease relapse, which suggests that leukemic stem cells (LSCs) remain in such patients, even after complete molecular remission has been achieved. Therefore, new strategies will be required to eradicate LSCs. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is part of the BCR-ABL signaling network, and it is activated in CML, especially in LSCs. JAK2 is known to be associated with CML survival, but the role of JAK3 in CML remains unknown...
February 16, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29454012/immunologic-effects-of-chronic-administration-of-tofacitinib-a-janus-kinase-inhibitor-in-cynomolgus-monkeys-and-rats-comparison-of-juvenile-and-adult-responses
#2
Mark Collinge, Douglas J Ball, Christopher J Bowman, Andrea L Nilson, Zaher A Radi, W Mark Vogel
Tofacitinib, an oral Janus kinase (JAK) inhibitor for treatment of rheumatoid arthritis, targets JAK1, JAK3, and to a lesser extent JAK2 and TYK2. JAK1/3 inhibition impairs gamma common chain cytokine receptor signaling, important in lymphocyte development, homeostasis and function. Adult and juvenile cynomolgus monkey and rat studies were conducted and the impact of tofacitinib on immune parameters (lymphoid tissues and lymphocyte subsets) and function (T-dependent antibody response (TDAR), mitogen-induced T cell proliferation) assessed...
February 14, 2018: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/29452839/development-of-selective-inhibitors-for-the-treatment-of-rheumatoid-arthritis-r-3-3-methyl-7h-pyrrolo-2-3-d-pyrimidin-4-yl-amino-pyrrolidin-1-yl-3-oxopropanenitrile-as-a-jak1-selective-inhibitor
#3
Chieyeon Chough, Misuk Joung, Sunmin Lee, Jaemin Lee, Jong Hoon Kim, B Moon Kim
A series of 3(R)-aminopyrrolidine derivatives were designed and synthesized for JAK1-selective inhibitors through the modification of tofacitinib's core structure, (3R,4R)-3-amino-4-methylpiperidine. From the new core structures, we selected (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a scaffold for further SAR studies. From biochemical enzyme assays and liver microsomal stability tests, (R)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile (6) was chosen for further in vivo test through oral administration...
February 3, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29452121/an-open-label-pilot-study-to-evaluate-the-efficacy-of-tofacitinib-in-moderate-to-severe-patch-type-alopecia-areata-totalis-and-universalis
#4
A Jabbari, F Sansaricq, J Cerise, J C Chen, A Bitterman, G Ulerio, J Borbon, R Clynes, A M Christiano, J Mackay-Wiggan
Alopecia areata (AA) is a common autoimmune disease, with a lifetime risk of ∼2%. In AA, the immune systems targets the hair follicle, resulting in clinical hair loss. AA prognosis is unpredictable, and currently there is no definitive treatment. Our previous whole genome expression studies identified active immune circuits in AA lesions, including common γ-chain cytokine and IFN pathways. Since these pathways are mediated through JAK kinases, we prioritized clinical exploration of small molecule JAK inhibitors...
February 13, 2018: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29434279/oncogenic-activation-of-jak3-stat-signaling-confers-clinical-sensitivity-to-prn371-a-novel-selective-and-potent-jak3-inhibitor-in-natural-killer-t-cell-lymphoma
#5
M -L Nairismägi, M E Gerritsen, Z M Li, G C Wijaya, B K H Chia, Y Laurensia, J Q Lim, K W Yeoh, X S Yao, W L Pang, A Bisconte, R J Hill, J M Bradshaw, D Huang, T L L Song, C C Y Ng, V Rajasegaran, T Tang, Q Q Tang, X J Xia, T B Kang, B T Teh, S T Lim, C K Ong, J Tan
Aberrant activation of the JAK3-STAT signaling pathway is a characteristic feature of many hematological malignancies. In particular, hyperactivity of this cascade has been observed in natural killer/T-cell lymphoma (NKTL) cases. Although the first-in-class JAK3 inhibitor tofacitinib blocks JAK3 activity in NKTL both in vitro and in vivo, its clinical utilization in cancer therapy has been limited by the pan-JAK inhibition activity. To improve the therapeutic efficacy of JAK3 inhibition in NKTL, we have developed a highly selective and durable JAK3 inhibitor PRN371 that potently inhibits JAK3 activity over the other JAK family members JAK1, JAK2, and TYK2...
February 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29424301/novel-therapeutic-approaches-in-rheumatoid-arthritis-role-of-janus-kinases-inhibitors
#6
Felice Rivellese, Antonio Lobasso, Letizia Barbieri, Bianca Liccardo, Amato De Paulis, Francesca Wanda Rossi
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation and hyperplasia, autoantibody production, cartilage and bone destruction and several systemic features. Cardiovascular, pulmonary, psychological, and muscle involvement are the main comorbidities of RA and are responsible for the severity of the disease and long-term prognosis. Pharmacological treatment of rheumatic diseases has evolved remarkably over the past years. In addition, the widespread adoption of treat to target and tight control strategies has led to a substantial improvement of outcomes, so that drug-free remission is nowadays a realistic goal in the treatment of RA...
February 9, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29417755/safety-signal-detection-and-evaluation-in-clinical-development-programs-a-case-study-of-tofacitinib
#7
Gorana Dasic, Thomas Jones, Vera Frajzyngier, Ricardo Rojo, Ann Madsen, Hernan Valdez
Adverse events are anticipated during a clinical development program. Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We describe here the process undertaken by Pfizer to investigate a safety signal for pancreatic cancer with tofacitinib. Potential cases of pancreatic cancer across indications from Pfizer's clinical trials and safety databases were identified and underwent in-depth case review and external expert consultation. The magnitude of the signal was quantified...
February 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29417430/effect-of-discontinuation-or-initiation-of-methotrexate-or-glucocorticoids-on-tofacitinib-efficacy-in-patients-with-rheumatoid-arthritis-a-post-hoc-analysis
#8
Roy Fleischmann, Jürgen Wollenhaupt, Stanley Cohen, Lisy Wang, Haiyun Fan, Vara Bandi, John Andrews, Liza Takiya, Eustratios Bananis, Michael E Weinblatt
INTRODUCTION: 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. METHODS: 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...
February 7, 2018: Rheumatology and Therapy
https://www.readbyqxmd.com/read/29399328/jak-inhibitors-for-the-treatment-of-myeloproliferative-neoplasms-and-other-disorders
#9
REVIEW
William Vainchenker, Emilie Leroy, Laure Gilles, Caroline Marty, Isabelle Plo, Stefan N Constantinescu
JAK inhibitors have been developed following the discovery of the JAK2 V617F in 2005 as the driver mutation of the majority of non- BCR-ABL1 myeloproliferative neoplasms (MPNs). Subsequently, the search for JAK2 inhibitors continued with the discovery that the other driver mutations ( CALR and MPL ) also exhibited persistent JAK2 activation. Several type I ATP-competitive JAK inhibitors with different specificities were assessed in clinical trials and exhibited minimal hematologic toxicity. Interestingly, these JAK inhibitors display potent anti-inflammatory activity...
2018: F1000Research
https://www.readbyqxmd.com/read/29387870/rapid-repigmentation-of-vitiligo-using-tofacitinib-plus-low-dose-narrowband-uv-b-phototherapy
#10
Sa Rang Kim, Henry Heaton, Lucy Y Liu, Brett A King
No abstract text is available yet for this article.
January 31, 2018: JAMA Dermatology
https://www.readbyqxmd.com/read/29386436/-analysis-of-time-to-onset-of-interstitial-lung-disease-after-the-administration-of-small-molecule-molecularly-targeted-drugs
#11
Fusao Komada
The aim of this study was to investigate the time-to-onset of drug-induced interstitial lung disease (DILD) following the administration of small molecule molecularly-targeted drugs via the use of the spontaneous adverse reaction reporting system of the Japanese Adverse Drug Event Report database. DILD datasets for afatinib, alectinib, bortezomib, crizotinib, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, osimertinib, sorafenib, sunitinib, temsirolimus, and tofacitinib were used to calculate the median onset times of DILD and the Weibull distribution parameters, and to perform the hierarchical cluster analysis...
2018: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/29383118/phosphoproteome-profiling-reveals-critical-role-of-jak-stat-signaling-in-maintaining-chemoresistance-in-breast-cancer
#12
Augusto S Nascimento, Luisa L Peres, Alessandra V S Fari, Renato Milani, Rodrigo A Silva, Celio Jr da Costa Fernandes, Maikel P Peppelenbosch, Carmen V Ferreira-Halder, Willian F Zambuzzi
Breast cancer is responsible for 25% of cancer cases and 15% of cancer death among women. Treatment is usually prolonged and hampered by the development of chemoresistance. The molecular mechanisms maintaining the chemoresistant phenotype remains, however, largely obscure. As kinase signaling in general is highly drugable, identification of kinases essential for maintaining chemoresistance could prove therapeutically useful. Hence we compared cellular kinase activity in chemotherapy resistant MCF7Res cells to chemotherapy-sensitive MCF cells using a peptide array approach that provides an atlas of cellular kinase activities and consequently, predominant pathways can be identified...
December 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29377257/exposure-response-characterisation-of-tofacitinib-efficacy-in-moderate-to-severe-ulcerative-colitis-results-from-a-dose-ranging-phase-2-trial
#13
Arnab Mukherjee, Anasuya Hazra, Mike K Smith, Steven W Martin, Diane R Mould, Chinyu Su, Wojciech Niezychowski
BACKGROUND AND AIMS: Tofacitinib is an oral, small molecule JAK inhibitor being investigated for UC. In a phase 2 dose-ranging study, tofacitinib demonstrated efficacy vs placebo as UC induction therapy. In this post-hoc analysis, we aimed to compare tofacitinib dose and plasma concentration as predictors of efficacy and identify covariates that determined efficacy in patients with UC. METHODS: One- and two-compartment pharmacokinetic models, with first-order absorption and elimination, were evaluated to describe plasma tofacitinib concentration-time data at baseline and week 8...
January 28, 2018: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29361154/bone-remodelling-locus-minori-or-unappreciated-potential-of-tofacitinib
#14
Maria I Bokarewa, Malin C Erlandsson
No abstract text is available yet for this article.
January 17, 2018: Rheumatology
https://www.readbyqxmd.com/read/29352846/the-janus-kinase-inhibitor-tofacitinib-inhibits-tnf-%C3%AE-induced-gliostatin-expression-in-rheumatoid-fibroblast-like-synoviocytes
#15
Yohei Kawaguchi, Yuko Waguri-Nagaya, Naoe Tatematsu, Yusuke Oguri, Masaaki Kobayashi, Masahiro Nozaki, Kiyofumi Asai, Mineyoshi Aoyama, Takanobu Otsuka
OBJECTIVES: Gliostatin (GLS) is known to have angiogenic and arthritogenic activity, and GLS expression levels in serum from patients with rheumatoid arthritis (RA) are significantly correlated with the disease activity. Tofacitinib is a novel oral Janus kinase (JAK) inhibitor and is effective in treating RA. However, the mechanism of action of tofacitinib in fibroblast-like synoviocytes (FLSs) has not been elucidated. The purpose of this study was to investigate the modulatory effects of tofacitinib on serum GLS levels in patients with RA and GLS production in FLSs derived from patients with RA...
January 15, 2018: Clinical and Experimental Rheumatology
https://www.readbyqxmd.com/read/29341526/-the-internal-medicine-articles-that-struck-us-the-most-in-2017
#16
Vanessa Kraege, Evrim Jaccard, Alain Kenfak, Elisabeth Stamm, Fanny Blondet, Grégoire Humair, Plamena Tasheva, Oriane Aebischer, Sabine Giroud, Jonathan Tschopp, Claudio Sartori
2017 has continued to bring important progress in all areas of internal medicine, impacting our daily practice. From bedside screening for beta-lactam allergies, to statins as primary prevention in the elderly, SGLT2 inhibitors in heart failure, azithromycin in severe asthmatics and tofacitinib in ulcero-haemorrhagic recto-colitis, internal medicine journals are full of novelties. Every year, the chief residents of the CHUV internal medicine ward meet up to share their readings: here is their selection of eleven articles, chosen, summarized and commented for you...
January 17, 2018: Revue Médicale Suisse
https://www.readbyqxmd.com/read/29341281/editorial-tofacitinib-and-biologics-for-moderate-to-severe-ulcerative-colitis-what-is-best-in-class
#17
EDITORIAL
H H Tsai
No abstract text is available yet for this article.
February 2018: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29341277/editorial-tofacitinib-and-biologics-for-moderate-to-severe-ulcerative-colitis-what-is-best-in-class-authors-reply
#18
EDITORIAL
S Bonovas, T Lytras, G Nikolopoulos, L Peyrin-Biroulet, S Danese
No abstract text is available yet for this article.
February 2018: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29325464/the-clinical-course-of-patients-with-rheumatoid-arthritis-who-underwent-orthopaedic-surgeries-under-disease-control-by-tofacitinib
#19
Keiichiro Nishida, Ryozo Harada, Yoshihisa Nasu, Ayumu Takeshita, Ryuichi Nakahara, Masamitsu Matsumeda, Toshifumi Ozaki
No abstract text is available yet for this article.
January 11, 2018: Modern Rheumatology
https://www.readbyqxmd.com/read/29318514/the-impact-of-biologics-and-tofacitinib-on-cardiovascular-risk-factors-and-outcomes-in-patients-with-rheumatic-disease-a-systematic-literature-review
#20
REVIEW
Michael Nurmohamed, Ernest Choy, Sadiq Lula, Blerina Kola, Ryan DeMasi, Paola Accossato
INTRODUCTION: Rheumatic diseases are autoimmune, inflammatory diseases often associated with cardiovascular (CV) disease, a major cause of mortality in these patients. In recent years, treatment with biologic and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs), either as monotherapy or in combination with other drugs, have become the standard of treatment. In this systematic literature review, we evaluated the effect of treatment with biologic or tofacitinib on the CV risk and outcomes in these patients...
January 9, 2018: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
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