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1.
Front Immunol ; 13: 914265, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35874753

RESUMO

Background: Macrophage activation syndrome (MAS) is a severe complication of autoimmune diseases with high mortality. We report the effectiveness of baricitinib as an option for the maintenance therapy in MAS secondary to nodular panniculitis. Case summary: A 24-year-old female came to our hospital with repeated fever and a skin nodule on right tibial tuberosity. Results were notable for raised serum ferritin (SF), triglycerides (TG), elevated liver function enzymes, interleukin-6 (IL-6), interferon-γ (IFN-γ), soluble interleukin-2 receptor (sIL-2R) and decreased activity of NK cells. The pathological biopsy of the subcutaneous nodules indicated nodular panniculitis. Hemophagocytic cells were found in bone marrow aspiration. She was diagnosed as MAS secondary to nodular panniculitis. With the treatment of methylprednisolone (MP) and immunoglobulin, her symptoms and laboratory data gradually improved. Nevertheless, her disease relapsed when the MP dose was tapered. Regarding the usage of JAK inhibitors in MAS, we used baricitinib (JAK1/2 inhibitor) to treat MAS and her symptom and abnormal laboratory findings returned to normal. During follow-up, though the MP dose was tapered, she was stable without a MAS recurrence. Conclusion: The case report suggested baricitinib is an option for MAS in the maintenance therapy phase and is potentially beneficial to prevent recurrence.


Assuntos
Azetidinas , Síndrome de Ativação Macrofágica , Paniculite , Neoplasias Cutâneas , Adulto , Azetidinas/uso terapêutico , Feminino , Humanos , Síndrome de Ativação Macrofágica/diagnóstico , Síndrome de Ativação Macrofágica/tratamento farmacológico , Síndrome de Ativação Macrofágica/etiologia , Metilprednisolona/uso terapêutico , Purinas/uso terapêutico , Pirazóis , Neoplasias Cutâneas/complicações , Sulfonamidas , Adulto Jovem
2.
Eur J Dermatol ; 32(2): 237-243, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35866910

RESUMO

Background: Treatment with baricitinib in combination with topical corticosteroids previously showed greater improvements in itch and sleep versus placebo in adults with moderate-to-severe AD. Objectives: To assess whether improvements in itch and sleep translate to greater quality of life (QoL), productivity and treatment benefit in AD. Materials & Methods: In this post hoc analysis with data from BREEZE-AD7 (NCT03733301), itch and sleep improvements at Week 16 were defined by ≥4-point improvements in the Itch Numeric Rating Scale and ≥1.5 decreases in the number of night-time awakenings since baseline, respectively. Dermatology Life Quality Index, Work Productivity and Activity Impairment-AD and Patient Benefit Index (PBI) scores were compared in patients with and without improvements. Proportions were analysed using logistic regression with non-responder imputation. Changes from baseline were calculated using ANCOVA, with last observation carried forward. Least square mean PBI scores were assessed using ANOVA. Results: More patients with itch improvement versus no itch improvement reported no impact of AD on QoL (28.4% vs. 6.0%). Daily activity impairment was lower in patients with itch improvement (-39.6% vs. -15.6%). A greater proportion of patients with sleep improvement versus no sleep improvement had no AD-related impact on QoL (24.1% vs. 1.5%). Patients with sleep improvement had less daily activity impairment (-35.0% vs. -18.5%). Patients with itch and sleep improvements experienced greater treatment benefit. Conclusion: Patients with AD who experienced clinically meaningful improvements in itch and sleep following treatment had significantly better QoL, productivity and treatment benefit. Addressing these symptoms is important to achieving meaningful and patient-relevant improvements in well-being.


Assuntos
Dermatite Atópica , Fármacos Dermatológicos , Corticosteroides/uso terapêutico , Adulto , Azetidinas , Dermatite Atópica/complicações , Dermatite Atópica/diagnóstico , Dermatite Atópica/tratamento farmacológico , Fármacos Dermatológicos/uso terapêutico , Método Duplo-Cego , Humanos , Prurido/diagnóstico , Prurido/tratamento farmacológico , Prurido/etiologia , Purinas , Pirazóis , Qualidade de Vida , Índice de Gravidade de Doença , Sulfonamidas , Resultado do Tratamento
3.
Artigo em Russo | MEDLINE | ID: mdl-35904305

RESUMO

Despite significant success in the treatment of multiple sclerosis achieved in the recent years, the issues of therapy for progressive forms of the disease are far from being resolved. The first medication with proven efficiency at SPMS is the oral selective sphingosine 1 phosphate (S1P) receptor modulator siponimod. Before the registration of siponimod in Russia, Novartis company organized a «Managed access program to enable siponimod in patients with secondary progressive multiple sclerosis without satisfactory alternative therapy¼. For the period from September 2020 to May 2021, 10 patients with SPMS with exacerbations were included in the programme by RAS. The results of the treatment of the patients under the programme were similar to the results of previously controlled studies. The medication was well tolerated and the expected side effects (mainly lymphopenia and Elevated transaminases) were not more severe than moderate and were stopped by temporary cancel of the current treatment or concomitant therapy. During 1 year of therapy, the stabilization of condition of all patients and positive dynamics was noticed, including a decrease in the EDSS score in 44% of patients. Despite the limited number of patients and time of observation, the safety and efficacy of siponimod in patients with SPMS are quite high. The use of the medication in routine clinical practice does not require extraordinary methods of observation and control, but nevertheless includes genetic examination before the prescription of therapy, regular monitoring of clinical blood and biochemical parameters.


Assuntos
Azetidinas , Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Azetidinas/efeitos adversos , Compostos de Benzil/uso terapêutico , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico
5.
Lancet ; 400(10349): 359-368, 2022 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-35908569

RESUMO

BACKGROUND: We aimed to evaluate the use of baricitinib, a Janus kinase (JAK) 1-2 inhibitor, for the treatment of patients admitted to hospital with COVID-19. METHODS: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised with COVID-19 in the UK. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was done, which included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. The RECOVERY trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936) and is ongoing. FINDINGS: Between Feb 2 and Dec 29, 2021, from 10 852 enrolled, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% were receiving tocilizumab (with planned use within the next 24 h recorded for a further 9%). Overall, 514 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0·87; 95% CI 0·77-0·99; p=0·028). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of eight previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths), in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0·57; 95% CI 0·45-0·72). Including the results from RECOVERY in an updated meta-analysis of all nine completed trials (involving 11 888 randomly assigned patients and 1485 deaths) allocation to baricitinib or another JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0·80; 95% CI 0·72-0·89; p<0·0001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no significant excess of thrombosis, or other safety outcomes. INTERPRETATION: In patients hospitalised with COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth. FUNDING: UK Research and Innovation (Medical Research Council) and National Institute of Health Research.


Assuntos
COVID-19 , Inibidores de Janus Quinases , Azetidinas , COVID-19/tratamento farmacológico , Hospitais , Humanos , Inibidores de Janus Quinases/uso terapêutico , Purinas , Pirazóis , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2 , Sulfonamidas , Resultado do Tratamento
6.
Indian J Pharmacol ; 54(3): 183-193, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35848689

RESUMO

OBJECTIVES: Psoriasis is a chronic infectious skin disease triggered by an autoimmune process involving T-cell-mediated hyper-proliferation of keratinocytes. The objective of this study is to assess the modulation of programmed death 1 (PD-1) and its ligand programmed cell death ligand 1 (PD-L1) through JAK/STAT pathway during the development of a psoriasis-like disease by both in vitro and in vivo model. Baricitinib, a known inhibitor of JAK1 and JAK2, was used to study the impact on PD-1 and PD-L1. MATERIALS AND METHODS: Human peripheral blood mononuclear cells (PBMC) were stimulated with either anti-CD3/CD28 or PMA/Ionomycin, to modulate level of PD-1 and PD-L1 under psoriasis-like condition. Interferon-gamma (IFNγ) was used to treat HaCaT cells to mimic the diseased keratinocytes found in Psoriatic patients. Psoriasis was induced with Imiquimod (IMQ) in animal model to study the cross-talk between different cell types and pathways. RESULTS: Expression levels of PD-1 and PD-L1 in PBMC, and secretion of cytokines, namely tumor necrosis factor-α (TNFα), IFNγ, interleukin (IL)-6, and IL-1 ß, were down-regulated on treatment with baricitinib. Further, in IFNγ-treated HaCaT cells (keratinocytes) mRNA levels of KRT-17 and PD-L1 were up-regulated.). Interestingly, in IFNγ-treated HaCat cells baricitinib decreased the levels of inflammatory cytokines such as IL-1 ß, IL-6, and TNFα along with KRT-17 and PD-L1. On IFNγ-treatment. Data from both PBMC and HaCaT suggest an anti-inflammatory role for this compound. Accordingly, baricitinib was able to alleviate disease symptom in IMQ induce mice model of psoriasis. As a consequence of baricitinib treatment down-regulation of p-STAT3, PD- and PD-L1 expression levels were observed. CONCLUSION: This study demonstrates a crosstalk between JAK/STAT and PD-1/PD-L1 pathways. It also demonstrates that cytokines such as IFNγ and IL-17 are down-regulated by baricitinib. We believe decreased expressions of PD-1 and PD-L1 may be a consequence of baricitinib-induced down-regulation of IFNγ and IL-17. More importantly, our data from the acute model of psoriasis indicates that PD-L1 behaves as a T-cell-associated T-cell-associated surrogate activation marker rather than immunosuppressive marker in early phase of psoriasis. Therefore it does not exhibit a causal relationship to disease.


Assuntos
Interleucina-17 , Psoríase , Animais , Apoptose , Azetidinas , Antígeno B7-H1/efeitos adversos , Antígeno B7-H1/metabolismo , Citocinas/metabolismo , Humanos , Imiquimode/efeitos adversos , Interleucina-17/efeitos adversos , Interleucina-17/metabolismo , Interleucina-1beta/efeitos adversos , Interleucina-1beta/metabolismo , Janus Quinases/metabolismo , Leucócitos Mononucleares/metabolismo , Ligantes , Camundongos , Receptor de Morte Celular Programada 1/metabolismo , Psoríase/tratamento farmacológico , Purinas , Pirazóis , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Sulfonamidas , Fator de Necrose Tumoral alfa
7.
Ann Intern Med ; 175(6): JC64, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35667076

RESUMO

SOURCE CITATION: Ely EW, Ramanan AV, Kartman CE, et al. Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial. Lancet Respir Med. 2022;10:327-36. 35123660.


Assuntos
COVID-19 , Oxigenação por Membrana Extracorpórea , Adulto , Azetidinas , COVID-19/tratamento farmacológico , Humanos , Purinas , Pirazóis , SARS-CoV-2 , Sulfonamidas
11.
Regul Toxicol Pharmacol ; 133: 105210, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35700864

RESUMO

PURPOSE: Our aim is to build a physiologically based pharmacokinetic and JAK2 occupancy model (PBPK-JO) to simultaneously predict pharmacokinetic (PK) and pharmacodynamic (PD) changes of baricitinib (BAR) in healthy humans when co-administrated with kidney transporters OAT3 and MATE2-K inhibitors, and in patients with hepatic and renal impairment. METHODS: Probenecid and vandetanib were selected as OAT3 and MATE2-K competitive inhibitors, respectively. The PBPK-JO model was built using physicochemical and biochemical properties of BAR, and then verified by observed clinical PK. Finally, the model was applied to determine optimal dosing regimens in various clinical situations. RESULTS: Here, we have successfully simulated PK and JAK2 occupancy profiles in humans by PBPK-JO model. Moreover, this modelling reproduced every observed PK data, and every mean relative deviation (MRD) was below 2. The simulation suggested that PK of BAR had a significant change (2.22-fold increase), however PD only had a slight increase of 1.14-fold. Additionally, the simulation also suggested that vandetanib was almost unlikely to affect the PK and PD of BAR. In simulations of hepatic and renal impairment patients, the predictions suggested that significant changes in the PK and PD of BAR occurred. However, there was a lower fold increase in JAK2 occupancy than in PK in patients relative to healthy individuals. CONCLUSION: Administration dose adjustment of BAR when co-administrated with OAT3 inhibitors or in patients with hepatic or renal impairment should combine PK and PD changes of BAR, instead of only considering PK alteration.


Assuntos
Azetidinas , Modelos Biológicos , Simulação por Computador , Humanos , Janus Quinase 2 , Rim , Proteínas de Membrana Transportadoras , Purinas , Pirazóis , Sulfonamidas
12.
Target Oncol ; 17(3): 283-293, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35715627

RESUMO

BACKGROUND: The MAPK pathway is an emerging target across a number of adult and pediatric tumors. Targeting the downstream effector of MAPK, MEK1, is a proposed strategy to control the growth of MAPK-dependent tumors. OBJECTIVE: iMATRIX-cobi assessed the safety, pharmacokinetics, and anti-tumor activity of cobimetinib, a highly selective MEK inhibitor, in children and young adults with relapsed/refractory solid tumors. PATIENTS AND METHODS: This multicenter Phase I/II study enrolled patients aged 6 months to < 30 years with solid tumors with known/expected MAPK pathway involvement. Patients received cobimetinib tablet or suspension formulation on Days 1-21 of a 28-day cycle. Dose escalation followed a rolling 6 design. The primary endpoint was safety; secondary endpoints were pharmacokinetics and anti-tumor activity. RESULTS: Of 56 enrolled patients (median age 9 years [range 3-29]), 18 received cobimetinib tablets and 38 cobimetinib suspension. Most common diagnoses were low-grade glioma (LGG; n = 32, including n = 12 in the expansion cohort) and plexiform neurofibroma within neurofibromatosis type 1 (n = 12). Six patients (11 %) experienced dose-limiting toxicities (including five ocular toxicity events), which established a pediatric recommended Phase II dose (RP2D) of 0.8 mg/kg tablet and 1.0 mg/kg suspension. Most frequently reported treatment-related adverse events were gastrointestinal and skin disorders. Steady state mean exposure (Cmax, AUC0-24) of cobimetinib at the RP2D (1.0 mg/kg suspension) was ~ 50 % lower than in adults receiving the approved 60 mg/day dose. Overall response rate was 5.4 % (3/56; all partial responses in patients with LGG). CONCLUSIONS: The safety profile of cobimetinib in pediatrics was similar to that reported in adults. Clinical activity was observed in LGG patients with known/suspected MAPK pathway activation. Cobimetinib combination regimens may be required to improve response rates in this pediatric population. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02639546, registered December 24, 2015.


Assuntos
Azetidinas , Neoplasias , Piperidinas , Adolescente , Adulto , Azetidinas/efeitos adversos , Azetidinas/uso terapêutico , Criança , Pré-Escolar , Inibidores Enzimáticos/uso terapêutico , Glioma/tratamento farmacológico , Humanos , Dose Máxima Tolerável , Recidiva Local de Neoplasia , Neoplasias/tratamento farmacológico , Pediatria , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Comprimidos , Adulto Jovem
13.
Cell Rep ; 39(11): 110945, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35688145

RESUMO

SARS-CoV-2-infected subjects are generally asymptomatic during initial viral replication but may suffer severe immunopathology after the virus has receded and monocytes have infiltrated the airways. In bronchoalveolar lavage fluid from severe COVID-19 patients, monocytes express mRNA encoding inflammatory mediators and contain SARS-CoV-2 transcripts. We leverage a human small airway model of infection and inflammation, whereby primary blood monocytes transmigrate across SARS-CoV-2-infected lung epithelium to characterize viral burden, gene expression, and inflammatory mediator secretion by epithelial cells and monocytes. In this model, lung-infiltrating monocytes acquire SARS-CoV-2 from the epithelium and upregulate expression and secretion of inflammatory mediators, mirroring in vivo data. Combined use of baricitinib (Janus kinase inhibitor) and remdesivir (nucleoside analog) enhances antiviral signaling and viral clearance by SARS-CoV-2-positive monocytes while decreasing secretion of proneutrophilic mediators associated with acute respiratory distress syndrome. These findings highlight the role of lung-infiltrating monocytes in COVID-19 pathogenesis and their importance as a therapeutic target.


Assuntos
COVID-19 , Azetidinas , COVID-19/tratamento farmacológico , Humanos , Mediadores da Inflamação , Pulmão/patologia , Monócitos , Purinas , Pirazóis , SARS-CoV-2 , Sulfonamidas
14.
CNS Drugs ; 36(7): 703-719, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35725892

RESUMO

Siponimod is a selective sphingosine 1-phosphate receptor subtype 1 (S1P1) and 5 (S1P5) modulator approved in the United States and the European Union as an oral treatment for adults with relapsing forms of multiple sclerosis (RMS), including active secondary progressive multiple sclerosis (SPMS). Preclinical and clinical studies provide support for a dual mechanism of action of siponimod, targeting peripherally mediated inflammation and exerting direct central effects. As an S1P1 receptor modulator, siponimod reduces lymphocyte egress from lymph nodes, thus inhibiting their migration from the periphery to the central nervous system. As a result of its peripheral immunomodulatory effects, siponimod reduces both magnetic resonance imaging (MRI) lesion (gadolinium-enhancing and new/enlarging T2 hyperintense) and relapse activity compared with placebo. Independent of these effects, siponimod can penetrate the blood-brain barrier and, by binding to S1P1 and S1P5 receptors on a variety of brain cells, including astrocytes, oligodendrocytes, neurons, and microglia, exert effects to modulate neural inflammation and neurodegeneration. Clinical data in patients with SPMS have shown that, compared with placebo, siponimod treatment is associated with reductions in levels of neurofilament light chain (a marker of neuroaxonal damage) and thalamic and cortical gray matter atrophy, with smaller reductions in MRI magnetization transfer ratio and reduced confirmed disability progression. This review examines the preclinical and clinical data supporting the dual mechanism of action of siponimod in RMS.


Assuntos
Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Azetidinas , Compostos de Benzil/farmacologia , Encéfalo/diagnóstico por imagem , Humanos , Inflamação/tratamento farmacológico , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Recidiva
15.
Mult Scler Relat Disord ; 64: 103966, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35724530

RESUMO

OBJECTIVES: The aim of this study was to investigate the short- and long-term effects of siponimod on autonomic nervous system (ANS) function, in people with secondary progressive multiple sclerosis (pwSPMS) METHODS: The following ANS tests were performed in 26 pwSPMS: a 10 min supine resting position, Valsalva maneuver, deep breathing test and a 10 min tilt-up table test. Heart rate variability (HRV) was performed for the 10 min in supine resting position (M0) and for a 3 h period after siponimod treatment initiation (M0s1-6). All ANS tests were repeated after at least 6 months of treatment with siponimod (M6). RESULTS: In all 6 intervals after siponimod ingestion (M0s1-6), standard deviation of NN intervals (SDNN) was higher compared to M0. After 6 months of continuous treatment with siponimod, SDNN was significantly lower compared to M0. At M6, Valsalva ratio and respiratory sinus arrhythmia were lower compared to M0 values (1.510±0.338 vs 1.864±0.456, p=0.003 and 7.969±2.865 vs 13.091±4.687, p<0.001, respectively). Cardiovagal index was significantly higher at M6 compared to M0 (1 (range 0-2) vs 0 (range 0-1), p=0.008, respectively). Active Magnetic Resonance Imaging (MRI) one year prior to starting siponimod was a positive predictor of M6 SDNN and Adrenergic Index (AI) at M0 was a negative predictor of M6 SDNN. CONCLUSION: This study has shown an inverse relationship in short- versus long-term effects of siponimod on ANS function. A shift towards parasympathetic predominance was observed during the first three hours after ingestion, while after 6 or more months of continuous treatment with siponimod, a shift towards sympathetic predominance was observed.


Assuntos
Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Sistema Nervoso Autônomo , Azetidinas , Compostos de Benzil/farmacologia , Compostos de Benzil/uso terapêutico , Frequência Cardíaca/fisiologia , Humanos , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico
16.
Molecules ; 27(9)2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35566200

RESUMO

In this work it is demonstrated that enantiomerically enriched N-alkyl 2-oxazolinylazetidines undergo exclusive α-lithiation, and that the resulting lithiated intermediate is chemically stable but configurationally labile under the given experimental conditions that afford enantioenriched N-alkyl-2,2-disubstituted azetidines. Although this study reveals the configurational instability of the diastereomeric lithiated azetidines, it points out an interesting stereoconvergence of such lithiated intermediates towards the thermodynamically stable species, making the overall process highly stereoselective (er > 95:5, dr > 85:15) after trapping with electrophiles. This peculiar behavior has been rationalized by considering the dynamics at the azetidine nitrogen atom, the inversion at the C-Li center supported by in situ FT-IR experiments, and DFT calculations that suggested the presence of η3-coordinated species for diastereomeric lithiated azetidines. The described situation contrasted with the demonstrated stability of the smaller lithiated aziridine analogue. The capability of oxazolinylazetidines to undergo different reaction patterns with organolithium bases supports the model termed "dynamic control of reactivity" of relevance in organolithium chemistry. It has been demonstrated that only 2,2-substituted oxazolinylazetidines with suitable stereochemical requirements could undergo C=N addition of organolithiums in non-coordinating solvents, leading to useful precursors of chiral (er > 95:5) ketoazetidines.


Assuntos
Azetidinas , Lítio , Nitrogênio , Espectroscopia de Infravermelho com Transformada de Fourier , Estereoisomerismo
17.
Nat Commun ; 13(1): 2764, 2022 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-35589714

RESUMO

2 + 2 Photocycloadditions are idealized, convergent construction approaches of 4-membered heterocyclic rings, including azetidines. However, methods of direct excitation are limited by the unfavorable photophysical properties of imines and electronically unbiased alkenes. Here, we report copper-catalyzed photocycloadditions of non-conjugated imines and alkenes to produce a variety of substituted azetidines. Design principles allow this base metal-catalyzed method to achieve 2 + 2 imine-olefin photocycloaddition via selective alkene activation through a coordination-MLCT pathway supported by combined experimental and computational mechanistic studies.


Assuntos
Alcenos , Azetidinas , Catálise , Cobre , Iminas
18.
Sci Rep ; 12(1): 7843, 2022 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-35551258

RESUMO

As there are no clear on-target mechanisms that explain the increased risk for thrombosis and viral infection or reactivation associated with JAK inhibitors, the observed elevated risk may be a result of an off-target effect. Computational approaches combined with in vitro studies can be used to predict and validate the potential for an approved drug to interact with additional (often unwanted) targets and identify potential safety-related concerns. Potential off-targets of the JAK inhibitors baricitinib and tofacitinib were identified using two established machine learning approaches based on ligand similarity. The identified targets related to thrombosis or viral infection/reactivation were subsequently validated using in vitro assays. Inhibitory activity was identified for four drug-target pairs (PDE10A [baricitinib], TRPM6 [tofacitinib], PKN2 [baricitinib, tofacitinib]). Previously unknown off-target interactions of the two JAK inhibitors were identified. As the proposed pharmacological effects of these interactions include attenuation of pulmonary vascular remodeling, modulation of HCV response, and hypomagnesemia, the newly identified off-target interactions cannot explain an increased risk of thrombosis or viral infection/reactivation. While further evidence is required to explain both the elevated thrombosis and viral infection/reactivation risk, our results add to the evidence that these JAK inhibitors are promiscuous binders and highlight the potential for repurposing.


Assuntos
Antirreumáticos , Inibidores de Janus Quinases , Trombose , Viroses , Antirreumáticos/efeitos adversos , Azetidinas , Humanos , Inibidores de Janus Quinases/efeitos adversos , Aprendizado de Máquina , Diester Fosfórico Hidrolases , Piperidinas , Purinas , Pirazóis , Pirimidinas , Sulfonamidas , Trombose/induzido quimicamente
19.
Arthritis Res Ther ; 24(1): 112, 2022 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-35578304

RESUMO

BACKGROUND: Patients with systemic lupus erythematosus (SLE) have substantial unmet medical need. Baricitinib is a Janus kinase (JAK)1 and 2 inhibitor that was shown to have therapeutic benefit in patients with SLE in a phase II clinical trial. The purpose of this study was to evaluate the median change from baseline in conventional serologic biomarkers in subgroups and the overall population of baricitinib-treated patients with SLE, and the SLE Responder Index-4 (SRI-4) response by normalization of anti-dsDNA. METHODS: Data were assessed from the phase II trial I4V-MC-JAHH (NCT02708095). The median change from baseline in anti-dsDNA, IgG, and other conventional serologic markers was evaluated over time in patients who had elevated levels of markers at baseline, and in all patients for IgG. Median change from baseline for baricitinib treatments were compared with placebo. Among patients who were anti-dsDNA positive at baseline, SRI-4 responder rate was compared for those who stayed positive or achieved normal levels by week 24. RESULTS: Significant decreases of anti-dsDNA antibodies were observed in response to baricitinib 2 mg and 4 mg compared to placebo beginning at weeks 2 (baricitinib 2 mg = - 14.3 IU/mL, placebo = 0.1 IU/mL) and 4 (baricitinib 4 mg = - 17.9 IU/mL, placebo = 0.02 IU/mL), respectively, continuing through week 24 (baricitinib 2 mg = - 29.6 IU/mL, baricitinib 4 mg = - 15.1 IU/mL, placebo=3.0 IU/mL). Significant reductions from baseline of IgG levels were found for baricitinib 4 mg-treated patients compared to placebo at weeks 12 (baricitinib 4 mg = - 0.65 g/L, placebo = 0.09 g/L) and 24 (baricitinib 4 mg = - 0.60 g/L, placebo = - 0.04 g/L). For patients who were anti-dsDNA positive at baseline, no relationship between achieving SRI-4 responder and normalization of anti-dsDNA was observed by week 24. CONCLUSIONS: Baricitinib treatment resulted in a rapid and sustained significant decrease in anti-dsDNA antibodies compared to placebo among those with positive anti-dsDNA antibodies at baseline, as well as a significant decrease in IgG levels in the 4 mg group at weeks 12 and 24. These data suggest that baricitinib may influence B cell activity in SLE. Further studies are needed to evaluate if reductions in anti-dsDNA levels with baricitinib treatment reflect the impact of baricitinib on B cell activity. TRIAL REGISTRATION: NCT02708095 .


Assuntos
Lúpus Eritematoso Sistêmico , Anticorpos Antinucleares , Azetidinas , Biomarcadores , DNA , Método Duplo-Cego , Humanos , Imunoglobulina G/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Purinas , Pirazóis , Índice de Gravidade de Doença , Sulfonamidas , Resultado do Tratamento
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