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As of November 2021, there were 21 million confirmed active cases of COVID-19, including 77,016 patients in serious or critical condition (virusncov.com). However, there are no effective oral drugs for the treatment of severe COVID 19 patients. We here discuss the mechanism of action for Proxalutaminde to treat mild, moderate and severe COVID-19 Patients. Cellular entry and infection of SARS-CoV-2 virus are mediated by two key proteins in host cells, angiotensin converting enzyme 2 (ACE2), a host transmembrane protein, providing the binding sites for SARS-CoV-2 on the host cell surface, and transmembrane protease serine 2 protein (TMPRSS2), priming the S protein of SARS-Cov-2 to facilitate the viral entry into the host cells. Both ACE2 and TMPRSS2 proteins are regulated by androgen receptor (AR) signaling. Previously, Proxalutamide has been reported to downregulate the expression of ACE2 and TMPRSS2 in cells derived from prostate, lung cancer and normal lung epithelial cells. In this study, we demonstrate that Proxalutamide inhibited the infection of SARS-COV-2 wild type, alpha and delta variants, with IC50s of 69, 48 and 39 nM, respectively. Moreover, Proxalutamide reduced SARS-COV-2 viral load in outpatients with COVID-19 (82% viral RT-PCR negative rate in active group vs. 31% in placebo group after treatment for 7 days (p-value<0.0001). Severe COVID-19 disease leads to cytokine storm resulting in pulmonary inflammation and extensive damage in lung and other organs. Anti-inflammatory drugs, including Baricitinib and dexamethasone, have shown limited clinical benefit for hospitalized COVID-19 patients. Therefore, more effective drugs are in urgent need for patients suffering from severe COVID-19. Recently, Proxalutamide has been reported to reduce the mortality rate (HR=0.16) and lung injury (by 57%, active drug vs placebo groups) in hospitalized patients with COVID-19 in an IIT phase III study. We presented here the mechanism of action of Proxalutamide for targeting cytokine storm in severe COVID-19 patients. Proxalutamide was demonstrated to activate nuclear factor erythroid 2-related factor 2 (Nrf2) in macrophages, which stimulates the antioxidant response element (ARE) for reducing cytokine storm-induced organ damage in COVID-19. In addition, Proxalutamide inhibited TNF alpha and IL-6 expression and blocked INF gamma signaling by downregulating STAT1 expression in immune cells. Importantly, Proxalutamide reduced inflammatory cells in lungs in a Poly (I:C), pseudoviral induced-lung injury animal models. Further, Proxalutamide decreased C-reactive protein, D-Dimer and improved lymphocyte count, biomarkers for COVID-19 progression in clinical studies. Together, these results provide a strong rationale for the treatment of severe COVID-19 patients with Proxalutamide.
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There are nearly 1200 species of sea cucumber in the world's seas. Among these creatures included in the Holothuroidea class, 37 species show distribution in the Mediterranean and Aegean Sea. The purpose of this study is to determine the chemical content and biological potent of five sea cucumber species, Holothuria tubulosa, Holothuria poli, Holothuria mammata, Holothuria sanctori and Stichopus regalis which were collected from the Aegean Sea. The detailed flavonoid, phenolic and triterpene contents were determined by LCHR/MS. Cytotoxic activities against several cancer cell lines, MDA-MB-231, PC-3, A549, PANC-1, HEPG2 and a healthy cell line CCD-34LU were performed by MTT method. Antiviral activities of the samples were measured as virucidal activity against avian coronavirus by in ovo. According to the results of LC-HRMS analysis, H. sanctori, H. poli and S. regalis had the richest chemical content diversity in terms of examined triterpene compounds. Fumaric acid was detected as the most abundant substance in all sea cucumber species. H. tubulosa had a highly toxic effect on all the tested cells. The best cytotoxic activity on A549 cells was seen in H. mammata, H. sanctori and H. poli. H. sanctori also showed a significant toxic effect against PANC-1, MDA-MB-231, HepG2 and A549 cells, whereas the IC50 value in CCD-34LU cells was above 50 mu g/mL for this sample. The n-butanol extracts of sea cucumber species reduced hemagglutination (HA) virus titer between 1-fold to 4-fold in log2-based at all tested concentrations. The best inhibited virus HA titer results were found in H. tubulosa at 5 mu g/g. According to these results we have obtained, the extracts of sea cucumbers may be used in many fields such as medicine, food, cosmetics in the future. This study is also very important in terms of being a guide for all studies on the use, processing and production of sea cucumbers and detailed isolation and purification studies on sea cucumber species from Turkey.
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The COVID-19 pandemic, which has reached 4 million global cases as of March 10, 2020, has become a worldwide problem. Turkey is one of the most affected (9th in the world) country with 139 771 cases. An intermittent curfew policy that differ for three age groups, and an intercity travel ban varying within the country have been implemented. The effects of changes in social life and industrial activity in terms of environmental pollution are not yet known. The short-term effects on PM2.5, PM10, SO2, NO2, NO, NOx, O3 and CO concentrations measured at 51 air quality measurement stations (AQMS) in 11 cities in March – April period of 2020 were statistically compared with that of the previous year. While PM2.5 (9/14 AQMS) and PM10 (29/35 AQMS) concentrations were not significantly affected, NO (12/24 AQMS), NO2 (20/29 AQMS), NOX (17/25 AQMS) concentrations were decreased, SO2 concentrations at half of the AQMSs (11/25) did not show a significant change. There were stations at which higher pollutant concentrations were measured in the study period in 2020 compared to that of 2019. Excess risks associated with PM2.5 and PM10 were estimated to be variable, albeit with a small difference. In conclusion, the heterogeneous actions taken in response to the COVID-19 pandemic resulted in mixed effects on ambient air quality. © 2021 The Author(s)
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In a prospective observational study (pre-AndroCoV Trial), the use of nitazoxanide, ivermectin and hydroxychloroquine demonstrated unexpected improvements in COVID-19 outcomes when compared to untreated patients. The apparent yet likely positive results raised ethical concerns on the employment of further full placebo controlled studies in early-stage COVID-19. The present analysis aimed to elucidate, through a comparative analysis with two control groups, whether full placebo-control randomized clinical trials (RCTs) on early-stage COVID-19 are still ethically acceptable. The Active group (AG) consisted of patients enrolled in the Pre-AndroCoV-Trial (n = 585). Control Group 1 (CG1) consisted of a retrospectively obtained group of untreated patients of the same population (n = 137), and Control Group 2 (CG2) resulted from a precise prediction of clinical outcomes based on a thorough and structured review of indexed articles and official statements. Patients were matched for sex, age, comorbidities and disease severity at baseline. Compared to CG1 and CG2, AG showed reduction of 31.5-36.5% in viral shedding (p < 0.0001), 70-85% in disease duration (p < 0.0001), and 100% in respiratory complications, hospitalization, mechanical ventilation, deaths and post-COVID manifestations (p < 0.0001 for all). For every 1000 confirmed cases for COVID-19, at least 70 hospitalizations, 50 mechanical ventilations and five deaths were prevented. Benefits from the combination of early COVID-19 detection and early pharmacological approaches were consistent and overwhelming when compared to untreated groups, which, together with the well-established safety profile of the drug combinations tested in the Pre-AndroCoV Trial, precluded our study from continuing employing full placebo in early COVID-19.
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Many Americans fail to get life-saving vaccines each year, and the availability of a vaccine for COVID-19 makes the challenge of encouraging vaccination more urgent than ever. We present a large field experiment (N = 47,306) testing 19 nudges delivered to patients via text message and designed to boost adoption of the influenza vaccine. Our findings suggest that text messages sent prior to a primary care visit can boost vaccination rates by an average of 5%. Overall, interventions performed better when they were 1) framed as reminders to get flu shots that were already reserved for the patient and 2) congruent with the sort of communications patients expected to receive from their healthcare provider (i.e., not surprising, casual, or interactive). The best-performing intervention in our study reminded patients twice to get their flu shot at their upcoming doctor's appointment and indicated it was reserved for them. This successful script could be used as a template for campaigns to encourage the adoption of life-saving vaccines, including against COVID-19.