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Drug repurposing is a cost-effective process to identify therapeutic candidates during a medical crisis or pandemic. The supercomputing platform, EXaSCale smArt pLatform Against paThogEns for CoronaVirus (EXSCALATE4CoV;E4C), was used to identify drug candidates for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. E4C identified raloxifene as having great therapeutic potential, confirmed by in vitro data, which led to the progression of clinical trials to assess its efficacy. Raloxifene met the primary virologic endpoint in the treatment of early mild coronavirus disease 2019 (COVID-19), and although additional clinical trials are needed to confirm these results, there is evidence in support of in silico drug repurposing to provide cost-effective and rapid drug screening to identify treatment options for the pandemic and future pandemics. © 2023, The Author(s), under exclusive license to Springer Nature Switzerland AG.
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Introduction: The clinical progression of severe coronavirus disease 2019 (COVID-19) is associated with uncontrolled activation of inflammatory cytokines that results in excessive tissue injury, among which is interleukin-8 (IL-8). Aim(s): To assess the efficacy and safety of reparixin, an inhibitor of IL-8 receptors, as add-on therapy to the standard of care for severe COVID-19 pneumonia. Method(s): This was a Phase 3, multicenter, randomized, placebo-controlled study in hospitalized adult patients with COVID-19 requiring oxygen support and/or noninvasive ventilation. From February to July 2021, patients were randomized 2:1 to oral reparixin or placebo in addition to the standard of care for up to 21 days or until hospital discharge. The primary endpoint was the proportion of patients alive and free of respiratory failure. This study was funded by Dompe Farmaceutici SpA (ClinicalTrials.gov: NCT04878055). Result(s): Of the 278 randomized patients, 185 patients in the reparixin group and 94 patients in the placebo group were included in the primary intention-to-treat analysis. The proportion of patients alive and free of respiratory failure at day 28 was greater in the reparixin group but not statistically significant (n=152 (89.4%) vs. n=71 (85.5%), OR: 1.63, 95% CI: 0.75 - 3.51, p= 0.2). While time to recovery was not different between groups, patients who received reparixin had a lower intensive care unit admission rate. Reparixin was well-tolerated. Conclusion(s): This trial did not meet the primary efficacy endpoint due to the low mortality in both arms, yet reparixin showed a promising trend towards limiting disease progression. A confirmatory Phase 3 study is currently underway.
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Rationale: Severe coronavirus disease 2019 (COVID-19) is associated with significant morbidity attributed from the complications of acute respiratory distress syndrome. Poor outcomes in severe COVID-19 patients have been related to cytokine release syndrome, which may be mediated by CX- C chemokine ligand 8/interleukin 8 (CXCL8/IL-8) acting through C-X-C chemokine receptor types 1 and 2 (CXCR1/2). The aim of this clinical trial was to determine if CXCR 1/2 blockade by reparixin, an IL-8 inhibitor, can improve clinical outcomes in hospitalized patients with severe COVID-19 pneumonia. Methods: This was a Phase 2, open-label, adaptive, multicenter, randomized trial in hospitalized adult patients, conducted in Italy and Brazil, with severe COVID-19 pneumonia between May and November 2020. Eligible patients had respiratory distress (respiratory rate ≥30 breaths/minute without oxygen and/or partial arterial oxygen pressure (PaO2)/fraction of inspiration O2 (FiO2) >100 to <300 mmHg), pneumonia confirmed by chest imaging, and elevated inflammatory markers. Patients were randomized 2:1 to receive oral reparixin 1200mg three times daily or the standard of care (SOC) for up to 21 days. Patients were followed for up to seven days after the end of treatment. The primary endpoint was defined as a composite of clinical events: use of supplemental oxygen, need for mechanical ventilation, intensivecare unit admission, and/or use of rescue medication. This study was funded by Dompé Farmaceutici SpA (ClinicalTrials.gov: NCT04794803). Results: Fifty-five patients were enrolled and included in the final analysis comparing reparixin (n = 36) to the SOC (n = 19). The rate of clinical events was statistically significantly lower in the reparixin group compared to the SOC group (16.7% [95% CI: 6.4-32.8%] vs 42.1% [95% CI: 20.3-66.5%], p=0.02). After controlling for covariates, this statistical significance was maintained with a hazard ratio of 0.33 (95% CI, 0.11 to 0.99;p = 0.047). Reparixin treatment appeared to be well-tolerated with no discontinuation of therapy. Conclusions: In patients with severe COVID-19, reparixin led to a significant improvement in clinical outcomes when compared to the SOC. The results of this phase 2 study allowed progression to a Phase 3 clinical trial to further explore the efficacy and safety of reparixin for the treatment of severe COVID- 19.
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This review aimed to gather information about the biological effects of bovine colostrum (BC) supplementation for improving the respiratory health in humans and the potential role of bioactive molecules from BC as adjunctive therapy for SARS-CoV-2 infection (Coronavirus Disease 2019–COVID-19). Several studies have shown that BC supplementation is effective against infections and respiratory allergies, as well as in attenuating immunosuppression caused by intense exercise in high-performance athletes. The major immune system modulation proteins present in BC are immunoglobulins, lactoferrin and transforming growth factor-β (TGF-β). Studies have revealed that lactoferrin is effective in combating SARS-CoV-2. Hyperimmune colostrum may constitute an alternative way to produce specific antibodies against COVID-19. Based on the immune system boosting ability as well as anti-inflammatory, antioxidant and antiviral/antibacterial activities, we suggest that well designed, randomized, placebo-controlled, multicenter clinical trials should be done to verify the safety and effectiveness of BC supplements against SARS-CoV-2 infection. © 2021 The Author(s). Published with license by Taylor and Francis Group, LLC.
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Background The deterioration of patients with coronavirus disease 2019 (COVID-19) has been hypothesized to be due to cytokine release syndrome including interleukin-6 (IL-6). Tocilizumab (TCZ) is an IL-6 inhibitor that may be a potential therapy for COVID-19. Methods Patients hospitalized for COVID-19 and treated with TCZ between March 1, 2020, and March 26, 2020, at an academic medical center in New York City were described. Patients were categorized as severe illness or critical illness based on previously described definitions. Outcomes assessed included respiratory status improvement, laboratory values, discharge, or death. Results A total of 12 patients were included in this case series. Ten patients were classified as critical and 2 as severe. Eight (n = 6 critical and n = 2 severe) patients had improvements in respiratory symptoms after receiving TCZ and were discharged, but 4 patients expired despite receiving therapy. All patients had an elevation in IL-6 and C-reactive protein levels before TCZ treatment. After TCZ treatment, there was a significant decrease in C-reactive protein levels (P = 0.002) and an increase in aspartate aminotransferase (P = 0.18) and alanine aminotransferase (P = 0.006) levels. Patients who received TCZ treatment later in their hospitalization course had a poor outcome. Conclusions Tocilizumab may play a role in treating patients with COVID-19 with elevated IL-6 levels, who are classified as severely ill and treated early in their disease course. The risks of adverse events and economic burdens should also be evaluated.