-
PloS One 2024This study aims to evaluate the efficacy and safety of JAK inhibitors in the treatment of patients with RA. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
This study aims to evaluate the efficacy and safety of JAK inhibitors in the treatment of patients with RA.
METHODS
The databases CNKI, VIP, Wanfang, CBM, and PubMed, Embase, Cochrane Library and Web of Science were searched to identify relevant randomized controlled trials (RCTs), all from the time of database creation to April 2024. Screening, data extraction, and risk of bias assessment (using Review Manager-5.3 software) were independently performed by at least two authors. The network meta-analysis was conducted using R 4.1.3 software. PROSPERO registration number: CRD42022370444.
RESULTS
Thirty-three RCTs included 15,961 patients The experimental groups involved six JAK inhibitors (filgotinib, tofacitinib, decernotinib, baricitinib, upadacitinib and peficitinib) and 12 interventions (different doses of the six JAK inhibitors), and the control group involved adalimumab (ADA) and placebo. Compared with placebo, all JAK inhibitors showed a significant increase in efficacy measures (ACR20/50/70). Compared with ADA, only tofacitinib, low-dose decernotinib, and high-dose peficitinib showed a significant increase in ACR20/50/70. Decernotinib ranked first in the SUCRA ranking of ACR20/50/70. In terms of safety indicators, only those differences between low-dose filgotinib and high-dose upadacitinib, low-dose tofacitinib and high-dose upadacitinib were statistically significant. Low-dose filgotinib ranked first in the SUCRA ranking with adverse events as safety indicators. Only the efficacy and safety of tofacitinib ranked higher among different SUCRA rankings.
CONCLUSION
Six JAK inhibitors have better efficacy than placebo. The superior efficacy of decernotinib and safety of low-dose filgotinib can be found in the SUCRA. However, there are no significant differences in safety between the different JAK inhibitors. Head-to-head trials, directly comparing one against each other, are required to provide more certain evidence.
Topics: Humans; Arthritis, Rheumatoid; Janus Kinase Inhibitors; Bayes Theorem; Pyrimidines; Piperidines; Network Meta-Analysis; Azetidines; Purines; Pyrroles; Pyrazoles; Sulfonamides; Randomized Controlled Trials as Topic; Treatment Outcome; Heterocyclic Compounds, 2-Ring; Niacinamide; Benzamides; Heterocyclic Compounds, 3-Ring; Antirheumatic Agents; Triazoles; Adamantane; Pyridines; Valine
PubMed: 38905267
DOI: 10.1371/journal.pone.0305621 -
Organic Letters Jun 2024We disclose an efficient nickel catalytic system for expediting the coupling of alkynes with fluoroalkyl hydrazones and boronic acids, thus facilitating the synthesis of...
We disclose an efficient nickel catalytic system for expediting the coupling of alkynes with fluoroalkyl hydrazones and boronic acids, thus facilitating the synthesis of stereospecific α-fluoroalkyl-alkene derivatives. 3-Pyrazoles might be involved as key intermediates through a nitrogen-releasing process, enabling subsequent coupling with boronic acids to afford 1,2-difunctional alkenes in a highly efficient and step-economical fashion. This tandem platform demonstrates broad functional group tolerance, including complex natural products and drug-like molecules.
PubMed: 38904403
DOI: 10.1021/acs.orglett.4c01975 -
Frontiers in Immunology 2024An 8-year-old female child presented with patchy hair loss for 1 year, accompanied by eyebrow loss for 6 months. Microscopic examination of the hair confirmed the...
An 8-year-old female child presented with patchy hair loss for 1 year, accompanied by eyebrow loss for 6 months. Microscopic examination of the hair confirmed the features of active stage alopecia areata, with a Severity of Alopecia Tool (SALT) score of 70%. The diagnosis was severe alopecia areata. The patient had a history of atopic dermatitis since infancy, with recurrent episodes of scattered papules and pruritus for 8 years. Initial treatment involved subcutaneous injections of dupilumab 300mg every 2 weeks for 6 months, resulting in a reduction of SALT score to 20% and improvement of atopic dermatitis symptoms. Discontinuation of Dupilumab and initiation of daily oral Baricitinib at a dose of 2mg for a duration of 5 months. According to the SALT score evaluation, the severity of hair loss was less than 10% and there was significant regrowth of hair. No significant adverse reactions were observed during the treatment period.
Topics: Humans; Alopecia Areata; Dermatitis, Atopic; Female; Purines; Child; Azetidines; Pyrazoles; Sulfonamides; Antibodies, Monoclonal, Humanized; Treatment Outcome; Severity of Illness Index; Drug Therapy, Combination
PubMed: 38903518
DOI: 10.3389/fimmu.2024.1395288 -
BioRxiv : the Preprint Server For... Apr 2024The cannabinoid CB2 receptor (CB2R) is a potential therapeutic target for distinct forms of tissue injury and inflammatory diseases. To thoroughly investigate the role...
The cannabinoid CB2 receptor (CB2R) is a potential therapeutic target for distinct forms of tissue injury and inflammatory diseases. To thoroughly investigate the role of CB2R in pathophysiological conditions and for target validation , optimal pharmacological tool compounds are essential. Despite the sizable progress in the generation of potent and selective CB2R ligands, pharmacokinetic parameters are often neglected for studies. Here, we report the generation and characterization of a tetra-substituted pyrazole CB2R full agonist named RNB-61 with high potency ( 0.13-1.81 nM, depending on species) and a peripherally restricted action due to P-glycoprotein mediated efflux from the brain. H and C labelled RNB-61 showed apparent values < 4 nM towards human CB2R in both cell and tissue experiments. The >6000-fold selectivity over CB1 receptors and negligible off-targets , combined with high oral bioavailability and suitable systemic pharmacokinetic (PK) properties, prompted the assessment of RNB-61 in a mouse ischemia-reperfusion model of acute kidney injury (AKI) and in a rat model of chronic kidney injury/inflammation and fibrosis (CKI) induced by unilateral ureteral obstruction. RNB-61 exerted dose-dependent nephroprotective and/or antifibrotic effects in the AKI/CKI models. Thus, RNB-61 is an optimal CB2R tool compound for preclinical studies with superior biophysical and PK properties over generally used CB2R ligands.
PubMed: 38903103
DOI: 10.1101/2024.04.26.591311 -
BMC Neurology Jun 2024Edaravone dexborneol has been reported as an effective neuroprotective agent in the treatment of acute ischemic stroke (AIS). This study aimed at investigating the...
BACKGROUND
Edaravone dexborneol has been reported as an effective neuroprotective agent in the treatment of acute ischemic stroke (AIS). This study aimed at investigating the impact of edaravone dexborneol on functional outcomes and systematic inflammatory response in AIS patient.
METHODS
All participants were recruited from the AISRNA study (registered 21/11/2019, NCT04175691 [ClinicalTrials.gov]) between January 2022 and December 2022. The AIS patients were divided into two groups based on whether they received the treatment of edaravone dexborneol (37.5 mg/12 hours, IV) within 48 h after stroke onset. Inflammatory response was determined by detecting levels of cytokines (interleukin-2 [IL-2], IL-4, IL-5, IL-8, IL-6, IL-10, IL-12p70, IL-17, tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ], IFN-α, and IL-1β) within 14 days after stroke onset.
RESULTS
Eighty-five AIS patients were included from the AISRNA study. Patients treated with edaravone dexborneol showed a significantly higher proportion of modified Rankin Scale score < 2 compared to those who did not receive this treatment (70.7% versus 47.8%; P = 0.031). Furthermore, individuals receiving edaravone dexborneol injection exhibited lower expression levels of interleukin (IL)-1β, IL-6, and IL-17, along with higher levels of IL-4 and IL-10 expression during the acute phase of ischemic stroke (P < 0.05). These trends were not observed for IL-2, IL-5, IL-8, IL-12p70, tumor necrosis factor-α, interferon-γ [IFN-γ], and IFN-α (P > 0.05).
CONCLUSIONS
Treatment with edaravone dexborneol resulted in a favorable functional outcome at 90 days post-stroke onset when compared to patients without this intervention; it also suppressed proinflammatory factors expression while increasing anti-inflammatory factors levels.
TRIAL REGISTRATION
ClinicalTrials.gov NCT04175691. Registered November 21, 2019, https://www.
CLINICALTRIALS
gov/ct2/show/NCT04175691 .
Topics: Humans; Edaravone; Male; Ischemic Stroke; Female; Aged; Middle Aged; Cytokines; Neuroprotective Agents; Treatment Outcome; Inflammation
PubMed: 38902691
DOI: 10.1186/s12883-024-03712-1 -
Communications Biology Jun 2024AMPK is a well-known energy sensor regulating cellular metabolism. Metabolic disorders such as obesity and diabetes are considered detrimental factors that reduce...
AMPK is a well-known energy sensor regulating cellular metabolism. Metabolic disorders such as obesity and diabetes are considered detrimental factors that reduce fecundity. Here, we show that pharmacologically induced in vitro activation (by metformin) or inhibition (by dorsomorphin) of the AMPK pathway inhibits or promotes activation of ovarian primordial follicles in cultured murine ovaries and human ovarian cortical chips. In mice, activation of primordial follicles in dorsomorphin in vitro-treated ovaries reduces AMPK activation and upregulates Wnt and FOXO genes, which, interestingly, is associated with decreased phosphorylation of β-catenin. The dorsomorphin-treated ovaries remain of high quality, with no detectable difference in reactive oxygen species production, apoptosis or mitochondrial cytochrome c oxidase activity, suggesting safe activation. Subsequent maturation of in vitro-treated follicles, using a 3D alginate cell culture system, results in mature metaphase eggs with protruding polar bodies. These findings demonstrate that the AMPK pathway can safely regulate primordial follicles by modulating Wnt and FOXO genes, and reduce β-catenin phosphorylation.
Topics: Animals; Female; Mice; Ovarian Follicle; AMP-Activated Protein Kinases; Pyrimidines; Pyrazoles; Humans; Up-Regulation; Forkhead Transcription Factors; Wnt Proteins; beta Catenin; Phosphorylation; Mice, Inbred C57BL; Metformin; Wnt Signaling Pathway
PubMed: 38902324
DOI: 10.1038/s42003-024-06418-9 -
European Journal of Medicinal Chemistry Jun 2024The identification of chemically different inhibitors that target the colchicine site of tubulin is still of great value for cancer treatment. Combretastatin A-4(CA-4),...
The identification of chemically different inhibitors that target the colchicine site of tubulin is still of great value for cancer treatment. Combretastatin A-4(CA-4), a naturally occurring colchicine-site binder characterized by its structural simplicity and biological activity, has served as a structural blueprint for the development of novel analogues with improved safety and therapeutic efficacy. In this study, a library of forty-eight 4-phenyl-5-quinolinyl substituted triazole, pyrazole or isoxazole analouges of CA-4, were synthesized and evaluated for their cytotoxicity against Esophageal Squamous Cell Carcinoma (ESCC) cell lines. Compound C11, which features a 2-methyl substitution at the quinoline and carries an isoxazole ring, emerged as the most promising, with 48 h ICs of less than 20 nmol/L against two ESCC cell lines. The findings from EBI competitive assay, CETA, and in vitro tubulin polymerization assay of C11 are consistent with those of the positive control colchicine, demonstrating the clear affinity of compound C11 to the colchicine binding site. The subsequent cellular-based mechanism studies revealed that C11 significantly inhibited ESCC cell proliferation, arrested cell cycle at the M phase, induced apoptosis, and impeded migration. Experiments conducted in vivo further confirmed that C11 effectively suppressed the growth of ESCC without showing any toxicity towards the selected animal species. Overall, our research suggests that the tubulin polymerization inhibitor incorporating quinoline and the isoxazole ring may deserve consideration for cancer therapy.
PubMed: 38901104
DOI: 10.1016/j.ejmech.2024.116611 -
Science (New York, N.Y.) Jun 2024Unleashing antitumor T cell activity by checkpoint inhibitor immunotherapy is effective in cancer patients, but clinical responses are limited. Cytokine signaling...
Unleashing antitumor T cell activity by checkpoint inhibitor immunotherapy is effective in cancer patients, but clinical responses are limited. Cytokine signaling through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway correlates with checkpoint immunotherapy resistance. We report a phase I clinical trial of the JAK inhibitor ruxolitinib with anti-PD-1 antibody nivolumab in Hodgkin lymphoma patients relapsed or refractory following checkpoint inhibitor immunotherapy. The combination yielded a best overall response rate of 53% (10/19). Ruxolitinib significantly reduced neutrophil-to-lymphocyte ratios and percentages of myeloid suppressor cells but increased numbers of cytokine-producing T cells. Ruxolitinib rescued the function of exhausted T cells and enhanced the efficacy of immune checkpoint blockade in preclinical solid tumor and lymphoma models. This synergy was characterized by a switch from suppressive to immunostimulatory myeloid cells, which enhanced T cell division.
Topics: Adult; Aged; Animals; Female; Humans; Male; Mice; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Synergism; Hodgkin Disease; Immune Checkpoint Inhibitors; Immunotherapy; Janus Kinase Inhibitors; Janus Kinases; Nitriles; Nivolumab; Programmed Cell Death 1 Receptor; Pyrazoles; Pyrimidines; T-Lymphocytes; Mice, Inbred C57BL; Mice, Inbred BALB C
PubMed: 38900864
DOI: 10.1126/science.ade8520 -
Archiv Der Pharmazie Jun 2024The design and synthesis of a library of 21 novel benzenesulfonamide-bearing 3-functionalized pyrazole-linked 1,2,3-triazole derivatives as dual inhibitors of cathepsin...
The design and synthesis of a library of 21 novel benzenesulfonamide-bearing 3-functionalized pyrazole-linked 1,2,3-triazole derivatives as dual inhibitors of cathepsin B and carbonic anhydrase enzymes are reported. The target 1,2,3-triazole-linked pyrazolic esters (16) were synthesized by the condensation of 1,2,3-triazolic diketo esters with 4-hydrazinobenzenesulfonamide hydrochloride, and these were further converted into the corresponding carboxylic acid (17) and carboxamide (18) analogs. The synthesized compounds were assayed in vitro for their inhibition potential against human carbonic anhydrase (hCA) isoforms I, II, IX, and XII. They were found to be potent inhibitors at the low nanomolar level against the cancer-related hCA IX and XII and to be selective towards the cytosolic isoform hCA I. The physiologically important isoform hCA II was potently inhibited by all the newly synthesized compounds showing K values ranging between 0.8 and 561.5 nM. The ester derivative 16c having 4-fluorophenyl (K = 5.2 nM) was the most potent inhibitor of hCA IX, and carboxamide derivative 18b (K = 2.2 nM) having 4-methyl substituted phenyl was the most potent inhibitor of hCA XII. The newly synthesized compounds exhibited potent cathepsin B inhibition at 10 M concentration. In general, the carboxamide derivatives (18) showed higher % inhibition as compared with the corresponding ester derivatives (16) and carboxylic acid derivatives (17) for cathepsin B. The interactions of the target compounds with the active sites of cathepsin B and CA were studied through molecular docking studies. Further, the in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness properties of the target compounds were also studied.
PubMed: 38900588
DOI: 10.1002/ardp.202400114 -
Langmuir : the ACS Journal of Surfaces... Jul 2024Herein, we present a highly efficient dual-functionalized acid-base nanocatalyst, denoted as FeO@GLYMO-HEPES, featuring sulfuric acid and tertiary amines as its dual...
Herein, we present a highly efficient dual-functionalized acid-base nanocatalyst, denoted as FeO@GLYMO-HEPES, featuring sulfuric acid and tertiary amines as its dual functional components. This catalyst is synthesized through the immobilization of 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) as the source of these functionalities onto magnetite (FeO) using 3-glycidoxypropyltriethoxysilane (GLYMO) as a linker. Characterization studies confirm the integrity of the FeO core, with the GLYMO-HEPES coating exhibiting no phase changes. Furthermore, FeO@GLYMO-HEPES nanoparticles demonstrate a uniform size distribution without aggregation. Notably, the catalyst exhibits remarkable stability up to 200 °C and possesses a saturation magnetization value of 31.5 emu/g, facilitating easy recovery via magnetic separation. These findings underscore the potential of FeO@GLYMO-HEPES as a versatile and recyclable nanocatalyst for various applications. Its catalytic ability was evaluated in the synthesis of various pyrano[2,3-]pyrazoles and 2-amino-3-cyano-4-chromenes through a tandem Knorr-Knoevenagel-Michael-Thorpe-Ziegler-type heterocyclization mechanism, using different aldehydes. A wide range of fused heterocycles was synthesized having good to excellent yields. The process is cost-effective, safe, sustainable, and scalable, and the catalyst can be reused up to five times. The prepared catalyst was found to be highly stable and heterogeneous and showed good recyclability.
PubMed: 38900039
DOI: 10.1021/acs.langmuir.4c00563