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Tofacitinib Inhibits the Activation and Cellular Trafficking of STATs Stimulated by rhIL-6 in Normal and Immortalized Human ChondrocytesThorpe, Jessica 07 September 2020 (has links)
No description available.
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Inhalational Delivery of a JAK3 Inhibitor for the Novel Treatment of Asthma and the Investigation of Pharmaceutical Salts in HFA Propellant SystemsYounis, Usir, Younis, Usir January 2018 (has links)
Asthma is a significant lung disease involving chronic inflammation and remodeling of the airways, resulting in reduced quality of life for those who suffer from the condition. Current therapeutic guidelines suggest the use of inhaled corticosteroids for long-term anti-inflammatory relief to manage moderate to severe chronic asthma; however, inhaled corticosteroids fail to provide prophylactic or reversal treatment of damaged airways incurred by chronic asthma as well as exhibiting adverse side effects (skeletal complications, diabetes, and weight gain).Therefore, there is a need for a new type of drug therapy to address these gaps in the treatment of chronic asthma. There is growing interest aimed towards the inhibition of the Janus Kinase and Signal Transducer and Activator of Transcription (JAK-STAT) pathway for the treatment of asthma. Despite the promising opportunity to investigate this new pathway towards this clinical application, no published work is available using an established and characterized JAK 1/3 inhibitor for the treatment of chronic asthma delivered via inhalation.
This work investigated tofacitinib citrate, a selective JAK 3 inhibitor, and its potential to be delivered locally to the lungs for the treatment of chronic asthma. Several preformulation studies were conducted to determine the basic physical and chemical properties of the compound and its free base, tofacitinib, for proper inhalational formulation development. The drug was delivered to BALB/c mice challenged with house dust mite (HDM) allergen via nebulization utilizing a nose-only chamber. After a three week dosing schedule, mice treated with tofacitinib citrate exhibited an increase in monocyte cell numbers with a simultaneous decrease in eosinophil cell count, gathered from BAL fluid. Further, the experimental groups treated with tofacitinib citrate had a decrease in total protein concentrations in comparison to the experimental groups that were only challenged with HDM or were both exposed to HDM and vehicle. These findings demonstrated that the proper formulation was developed for nebulized delivery of tofacitinib citrate, and that the compound was capable of reducing total protein concentrations and eosinophil cell recruitment, both recognized as biomarkers for an asthmatic response. Although significant work is still needed to be done, these data hold promise for the potential of a locally delivered JAK 3 inhibitor as a treatment for chronic asthma.
Further, the solubility of tofacitinib citrate and five other pharmaceutical salts were determined in HFA 134a, HFA 227, and DFP with varying cosolvent content (0-20% v/v ethanol). The experimental solubilities of the free acid and base compounds were larger than the solubilities of their respective salts in all three systems for tofacitinib, albuterol, and salicylic acid. Warfarin, phenytoin, and ciprofloxacin had similar solubilities with their respective salt forms. Solubilities also increased with increasing cosolvent concentration for all compounds investigated. The model propellant, DFP, provided a slightly stronger correlation of solubility values with HFA 134a in comparison to HFA 227. The observed solubility values were also compared to calculated values obtained from the ideal solubility model, where it was determined that the observed solubility was indeed also dependent on its surrounding solvent interactions and not solely on its ideal solubility (melting point). While some physical changes were observed for the pharmaceutical salts in HFA 134a and 227, more quantitative studies are needed for a larger database of compounds to better understand the factors that contribute to the solubility of pharmaceutical salts (and their correlation to DFP), in HFA-based systems. This information could potentially contribute to a predictive model, saving time and money during the process of pMDI formulation development.
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The role of JAK1 and JAK3 in CD8⁺ effector T cellsRollings, Christina January 2016 (has links)
The aim of this project was to explore the role of the tyrosine kinases JAK1 and JAK3 in cytokine signalling, focusing on interleukin-2 signalling in CD8<sup>+</sup> effector T lymphocytes. Initial experiments compared the effects of the pan JAK1/JAK3 inhibitor tofacitinib, the selective JAK1 inhibitor GSK186, and the selective JAK3 inhibitor GSK192 on IL-2 control of effector CD8+ cytotoxic T cells (CTL). On the basis of these preliminary data, a detailed analysis of the effect of tofacitinib on effector CD8<sup>+</sup> T lymphocytes was performed. Phosphorylation events regulated by tofacitinib were identified using mass spectrometry analysis of SILAC (stable isotope labelling with amino acids in cell culture) labelled CTL. Tofacitinib regulated a selective number of phosphorylation sites, with less than 1.2% of the CTL phosphoproteome significantly regulated by tofacitinib treatment following 4hrs tofacitinib treatment. Proteins with downregulated phosphorylation sites were enriched in functions related to the Jak-STAT signalling, regulation of gene expression, and MAPK signalling cascades. Proteins with upregulated phosphorylations were also enriched in functions related to regulation of gene transcription. The proteome of tofacitinib treated CTL was defined by label free mass spectrometry. Approximately 4.5% of the CTL proteome was significantly regulated following 24 hours tofacitinib treatment, suggesting tofacitinib regulates the expression of a selective subset of proteins. Tofacitinib treatment resulted in the downregulation of proteins involved in ribosome biosynthesis, steroid biosynthesis, regulation of transcription and the cell cycle; and the upregulation of proteins with hydrolase activity, and with roles in the lysosome and extracellular exosomes. The phosphoproteomic and proteomic data demonstrates that JAK kinase dependent IL-2 signalling regulates essential processes in CTL by controlling a selective number of phosphorylation events and proteins. Validation of proteins identified as regulated following tofacitinib treatment identified new targets of IL-2 signalling in CTL, including the transcription factor NFIL3. NFIL3 was shown to be upregulated in CD8<sup>+</sup> T lymphocytes following stimulation with IL-2 and regulated perforin and CD62L expression, suggesting a role in the regulation of CTL effector function.
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Eficacia y seguridad del tratamiento con tofacitinib en pacientes con artritis psoriásica: Revisión sistemática / Efficacy and safety of treatment with tofacitinib in patients with psoriatic arthritis: Systematic reviewEscobar Candela, Andrea Alejandra, Gutierrez Velarde, Marysabelle 27 January 2021 (has links)
Objetivo: evaluar la eficacia y la seguridad del tofacitinib para el tratamiento de segunda línea en pacientes con artritis psoriásica.
Metodología: La búsqueda bibliográfica se llevó a cabo en Medline y Cochrane Library, utilizando los términos MeSH: “Psoriatic arthritis” AND “Tofacitinib”, se realizó un meta-análisis de efectos aleatorios para calcular los riesgos relativos (RR), diferencias de medias estandarizadas (DME) y sus respectivos intervalos de confianza al 95% (IC95%) a través del software de Review Manager, versión 5.2. Los criterios de inclusión utilizados fueron: diseño de tipo ensayo clínicos aleatorizado o estudios de cohorte, uso de tofacitinib como segunda línea de tratamiento, población mayor o igual a 18 años, inclusión de los desenlaces seleccionados, e idioma.
Resultados: se incluyó tres ensayos clínicos aleatorizados, en población adulta con artritis psoriásica activa según CASPAR, que compararon tofacitinib frente a placebo o adalimumab. En un periodo de seguimiento de tres meses, tofacitinib demostró eficacia frente a placebo en la mejora del compromiso articular (ACR20) tanto en dosis de 5 mg (RR: 1,77; IC95%: 1,39 a 2,44) como en dosis de 10 mg (RR: 1,89; IC95%: 1,49 a 2,39). Se encontró mejora significativa en la discapacidad a dosis de 10 mg (DME: -4,27; IC95%: -4,60 a -3,94) y en la calidad de vida. Frente a adalimumab, tofacitinib de 5mg fue inferior en los resultados de eficacia, mientras que la dosis de 10mg fue superior. Con relación a la seguridad, no se encontró diferencias en la presencia de algún efecto adverso, efecto adverso severo ni en discontinuación por efectos adversos.
Conclusión: tofacitinib en dosis de 5mg y 10mg mostró ser eficaz en el control del compromiso articular y mejora de la calidad de vida frente a placebo, en el tratamiento de segunda línea de artritis psoriásica, con similar perfil de seguridad. Número de registro de revisión sistemática en prospero: CRD42019122245. / Objective: to evaluate the efficacy and safety of tofacitinib for second-line treatment in patients with psoriatic arthritis.
Methodology: he bibliographic search was carried out in Medline and Cochrane Library, using the MeSH terms: “Psoriatic arthritis” AND “Tofacitinib”, a random effects meta-analysis was carried out to calculate the relative risks (RR), standardized mean differences ( SMD) and their respective 95% confidence intervals (95% CI) through Review Manager software, version 5.2. The inclusion criteria used were: design of a randomized clinical trial or cohort studies, use of tofacitinib as a second line of treatment, population older than or equal to 18 years, inclusion of selected outcomes, and language.
Results: three randomized clinical trials were included, in an adult population with active psoriatic arthritis according to CASPAR, which compared tofacitinib with placebo or adalimumab. In a three-month follow-up period, tofacitinib demonstrated efficacy compared to placebo in improving joint involvement (ACR20) both in 5 mg doses (RR: 1.77; 95% CI: 1.39 to 2.44) and in 10 mg dose (RR: 1.89; 95% CI: 1.49 to 2.39). A significant improvement was found in disability at a dose of 10 mg (SMD: -4.27; 95% CI: -4.60 to -3.94) and in quality of life. Compared to adalimumab, the 5mg tofacitinib was lower in efficacy results, while the 10mg dose was higher. Regarding safety, no differences were found in the presence of any adverse effect, severe adverse effect, or in discontinuation due to adverse effects.
Conclusion: tofacitinib in doses of 5mg and 10mg was shown to be effective in controlling joint involvement and improving quality of life compared to placebo, in the second-line treatment of psoriatic arthritis, with a similar safety profile. Prospero Systematic Review Registry Number: CRD42019122245. / Tesis
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