Adenosine is a potent endogenous regulator of inflammation and tissue repair. Adenosine, which is released from injured and hypoxic tissue or in response to toxins and medications, may induce pulmonary fibrosis in mice, presumably via interaction with a specific adenosine receptor. We therefore determined whether adenosine and its receptors contribute to the pathogenesis of hepatic fibrosis. As in other tissues and cell types, adenosine is released in vitro in response to the fibrogenic stimuli ethanol (40 mg dl−1) and methotrexate (100 nM). Adenosine A2A receptors are expressed on rat and human hepatic stellate cell lines and adenosine A2A receptor occupancy promotes collagen production by these cells. Liver sections from mice treated with the hepatotoxins carbon tetrachloride (CCl4) (0.05 ml in oil, 50 : 50 v : v, subcutaneously) and thioacetamide (100 mg kg−1 in PBS, intraperitoneally) released more adenosine than those from untreated mice when cultured ex vivo. Adenosine A2A receptor‐deficient, but not wild‐type or A3 receptor‐deficient, mice are protected from development of hepatic fibrosis following CCl4 or thioacetamide exposure. Similarly, caffeine (50 mg kg−1 day−1, po), a nonselective adenosine receptor antagonist, and ZM241385 (25 mg kg−1 bid), a more selective antagonist of the adenosine A2A receptor, diminished hepatic fibrosis in wild‐type mice exposed to either CCl4 or thioacetamide. These results demonstrate that hepatic adenosine A2A receptors play an active role in the pathogenesis of hepatic fibrosis, and suggest a novel therapeutic target in the treatment and prevention of hepatic cirrhosis. British Journal of Pharmacology (2006) 148, 1144–1155. doi:

Background Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov , NCT04327388 ; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 1...

The significant global presence of atypical pathogens and the better outcomes associated with antimicrobial regimens with atypical coverage support empiric therapy for all hospitalized patients with CAP with a regimen that covers atypical pathogens.

.Conclusion. These results demonstrate that adenosine A 2A receptors play an active role in the pathogenesis of dermal fibrosis and suggest a novel therapeutic target in the treatment and prevention of dermal fibrosis in diseases such as scleroderma.Adenosine, a product of ATP catabolism, is released from cells and tissues under conditions of stress or hypoxia and is a potent endogenous physiologic and pharmacologic mediator. Adenosine regulates cellular and organ function via interaction with a family of 4 G protein-coupled receptors, A 1 , A 2A , A 2B , and A 3.

Results. MTX increased 27-hydroxylase message and completely blocked NS398-induced down-regulation of 27-hydroxylase (mean ؎ SEM 112.8 ؎ 13.1% for NS398 plus MTX versus 71.1 ؎ 4.3% for NS398 alone; P < 0.01). MTX also negated COX-2 inhibitor-mediated down-regulation of ABCA1. The ability of MTX to reverse inhibitory effects on 27-hydroxylase and ABCA1 was blocked by the adenosine A 2A receptor-specific antagonist ZM241385. MTX also prevented NS398 and IFN␥ from increasing transformation of lipid-laden THP-1 macrophages into foam cells.Conclusion. This study provides evidence supporting the notion of an atheroprotective effect of MTX. Through adenosine A 2A receptor activation, MTX promotes reverse cholesterol transport and limits foam cell formation in THP-1 macrophages. This is the first reported evidence that any commonly used medication can increase expression of antiatherogenic reverse cholesterol transport proteins and can counteract the effects of COX-2 inhibition. Our results suggest that one mechanism by which MTX protects against cardiovascular disease in rheumatoid arthritis patients is through facilitation of cholesterol outflow from cells of the artery wall.Methotrexate (MTX) has a long history of use in the treatment of various immunologic diseases, and has been used to treat rheumatoid arthritis (RA) and psoDr.

Objective. Evidence from in vitro, in vivo, and clinical studies indicates that adenosine mediates, at least in part, the antiinflammatory effects of methotrexate (MTX), although the biochemical events involved have not been fully elucidated. This study was undertaken to investigate whether MTX exerts antiinflammatory effects in mice that lack ecto-5-nucleotidase (ecto-5-NT) (CD73) and are unable to convert AMP to adenosine extracellularly, in order to determine whether adenosine is generated intracellularly and transported into the extracellular space or is generated from the extracellular dephosphorylation of AMP to adenosine.Methods. Male CD73 gene-deficient mice and age-matched wild-type mice received intraperitoneal injections of saline or MTX (1 mg/kg/week) for 5 weeks. Air pouches were induced on the back by subcutaneous injection of air; 6 days later, inflammation was induced by injection of carrageenan.Results. Fewer leukocytes, but higher levels of tumor necrosis factor ␣ (TNF␣), accumulated in the air pouches of vehicle-treated CD73-deficient mice compared with those of wild-type mice. As expected, MTX treatment reduced the number of leukocytes and TNF␣ levels in the exudates and increased exudate adenosine concentrations in wild-type mice. In contrast, MTX did not reduce exudate leukocyte counts or TNF␣ levels or increase exudate adenosine levels in CD73-deficient mice.Conclusion. These results demonstrate that the antiinflammatory actions of MTX are mediated, at least in part, by increased release of adenine nucleotides that are hydrolyzed extracellularly to adenosine via an ecto-5-NT-dependent pathway.Low-dose weekly methotrexate (MTX) is a mainstay in the treatment of rheumatoid arthritis and other inflammatory diseases, with a relatively safe profile compared with other therapies (1).

This paper presents a comprehensive performance study of polylactic acid (PLA) biocomposites, obtained by solvent casting, containing a novel silver-based antimicrobial layered silicate additive for use in active food packaging applications. The silver-based nanoclay showed strong antimicrobial activity against Gram-negative Salmonella spp. Despite the fact that no exfoliation of the silver-based nanoclay in PLA was observed, as suggested by transmission electron microscopy (TEM) and wide angle X-ray scattering (WAXS) experiments, the additive dispersed nicely throughout the PLA matrix to a nanoscale, yielding nanobiocomposites. The films were highly transparent with enhanced water barrier and strong biocidal properties. Silver migration from the films to a slightly acidified water medium, considered an aggressive food simulant, was measured by stripping voltammetry. Silver migration accelerated after 6 days of exposure. Nevertheless, the study suggests that migration levels of silver, within the specific migration levels referenced by the European Food Safety Agency (EFSA), exhibit antimicrobial activity, supporting the potential application of this biocidal additive in active food-packaging applications to improve food quality and safety.

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