Morsingjohns0140

Background Accumulating evidence proposed JAK inhibitors as therapeutic targets warranting rapid investigation. Objective This study evaluated the efficacy and safety of ruxolitinib, a Janus-associated kinase (JAK1/2) inhibitor, for COVID-19. Methods We conducted a prospective, multicenter, single-blind, randomized controlled phase II trial involving patients with severe COVID-19. Results Forty-three patients were randomly assigned (11) to receive ruxolitinib plus SoC treatment (22 patients) or placebo based on SoC treatment (21 patients). After exclusion of 2 patients (1 ineligible, 1 consent withdrawn) from the ruxolitinib group, 20 patients in intervention group and 21 patients in control group were included in the study. Treatment with ruxolitinib plus SoC was not associated with significantly accelerated clinical improvement in severe patients with COVID-19, although ruxolitinib recipients had a numerically faster clinical improvement. Eighteen (90%) patients from the ruxolitinib group showed CT improvement at D14 compared with 13 (61.9%) patients from the control group (P = 0.0495). Three patients in the control group died of respiratory failure, with 14.3% overall mortality at D28; no patients died in the ruxolitinib group. Ruxolitinib was well tolerated with low toxicities and no new safety signals. Levels of 7 cytokines were significantly decreased in the ruxolitinib group in comparison to the control group. Conclusions Although no statistical difference was observed, ruxolitinib recipients had a numerically faster clinical improvement. Significant chest CT improvement, a faster recovery from lymphopenia and favorable side-effect profile in ruxolitinib group were encouraging and informative to future trials to test efficacy of ruxolitinib in a larger population. This trial is registered at www.chictr.org.cn as ChiCTR-OPN-2000029580.Raloxifene hydrochloride (RH) is a selective oestrogen receptor modulator used for the treatment of osteoporosis. Suzetrigine Even though 60% of an oral dose is quickly absorbed via the gastrointestinal tract, the absolute bioavailability of RH is only 2-3% in humans due to extensive first-pass metabolism. Various approaches to improve RH bioavailability have been reported over the past few years; however, none have focused on the development of products for pulmonary administration. Therefore, in this study, submicron particles containing RH were produced for pulmonary administration with the aim to limit first-pass metabolism. Powders were produced by vibrational atomisation spray drying with a high process yield (>80%). The drug content was between 440 and 890 mg·g-1, and powders had a high encapsulation efficiency (>95%), mean particle size of 400-700 nm, low residual moisture (55%) and adequate mass median aerodynamic diameter for pulmonary delivery ( less then 5 μm). The pharmacokinetic study in male Wistar rats demonstrated an absolute bioavailability of 47.20% after pulmonary administration of the particles. Therefore, these submicron-sized powders are promising for pulmonary RH delivery as a dry powder medicine.Chemotherapeutic drugs for colorectal cancer(CRC) which is currently the third most lethal cancer globally, are administered intravenously (iv) due to their low oral bioavailability resulting from their physicochemical properties. Non-selective biodistribution and difficulties of parenteral administration reduce treatment efficacy. The aim of this work is to develop cyclodextrin (CD) based cationic nanoparticles (NPs) for CRC treatment with model drug camptothecin (CPT) that can be administered orally, protecting CPT through gastrointestinal tract (GIT), accumulating at mucus layer and providing an effective local treatment for the tumor area. NPs using two different amphiphilic CDs were prepared and coated with polyethylenimine (PEI) or chitosan (CS) to obtain positively charged surface for all formulations. Pre-formulation studies resulted in optimal formulation, CPT loaded Poly-β-CD-C6 NPs, with 135 nm diameter and zeta potential of + 40 mV. In vitro release study was designed to represent gastrointestinal pH and transit time revealing 52% of encapsulated CPT successfully delivered all the way to simulated colon. CPT bound to Poly-β-CD-C6 NPs exhibited higher cytotoxicity on HT-29 cells compared to equivalent CPT in solution. Caco-2 cell permeability studies showed 276% increase in CPT permeability and significantly higher mucosal penetration in cationic CD nanoparticle form.Non-injectable delivery of peptides and proteins is not feasible due to the limitations of large molecular mass, high hydrophilic properties, and gastrointestinal degradation. Therefore, proposing a new method to solve this problem is a burning issue. The objective of this study was to propose a novel protein delivery strategy to overcome the poor efficacy and irritation of buccal insulin delivery. In this study, we applied a conjugate of cell-penetrating peptides (LMWP) and insulin (INS-PEG-LMWP) for buccal delivery. INS-PEG-LMWP was prepared using insulin solution and mixture as references. The transport behaviour, in vivo bioactivity, hypoglycaemic effect, and safety of INS-PEG-LMWP were systematically characterised. An in vitro study demonstrated that the uptake and transportation of INS-PEG-LMWP across buccal mucosal multilayers significantly increased. By comparing the effects of different endocytic inhibitors on INS-PEG-LMWP uptake, the conjugate might be delivered via an energy independent, electrostatically adsorbed pathway. INS-PEG-LMWP's relative pharmacological bioavailability was high and its relative bioavailability was up to 26.86%, demonstrating no visible mucosal irritation. Cell-penetrating peptides are likely to become a reliable and safe tool for overcoming insulin's low permeability through the epithelial multilayers, the major barrier to buccal delivery.Repetitive traumatic brain injuries (TBIs) among military personnel have been linked to chronic behavioral and neurological symptoms, and poor health outcomes. Repetitive TBIs may impact inflammation, which may offer some explanation of the biological basis of these long-term risks, and may improve the care that is provided to these individuals. This study examines the concentrations of TNFα, IL-6 and IL-10 and associations with behavioral symptoms, including post-traumatic stress disorder symptoms and depression in a cohort of 106 military personnel and Veterans with a history of TBI. Group comparisons conducted for those with repetitive TBIs (> 3; n = 44), to participants with less than three TBIs (n = 29), and controls with no TBIs (n = 33). The primary outcomes were serum levels of inflammatory related proteins TNF-α, IL-6 and IL-10, TBI history, and PTSD symptoms. IL-6 mean concentration was significantly higher in the repetitive TBI group compared to those with 1-2 TBI or no TBI history (p = 0.050). Additionally, for participants with a history of TBI, PTSD symptom severity, specifically, intrusion (p = .