Synergistic interferon alpha-based drug combinations inhibit SARS-CoV-2 and other viral infections in vitro

There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. In the present study, we found that recombinant human interferon-alpha (IFNa) triggers intrinsic and extrinsic cellular antiviral responses, as well as reduces replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. Although IFNa alone was insufficient to completely abolish SARS-CoV-2 replication, combinations of IFNa with remdesivir or other antiviral agents (EIDD-2801, camostat, cycloheximide, or convalescent serum) showed strong synergy and effectively inhibited SARS-CoV-2 infection in human lung epithelial Calu-3 cells. Furthermore, we showed that the IFNa-remdesivir combination suppressed virus replication in human lung organoids, and that its single prophylactic dose attenuated SARS-CoV-2 infection in lungs of Syrian hamsters. Transcriptome and metabolomic analyses showed that the combination of IFNa-remdesivir suppressed virus-mediated changes in infected cells, although it affected the homeostasis of uninfected cells. We also demonstrated synergistic antiviral activity of IFNa2a-based combinations against other virus infections in vitro. Altogether, our results indicate that IFNa2a-based combination therapies can achieve higher efficacy while requiring lower dosage compared to monotherapies, making them attractive targets for further pre-clinical and clinical development.

Identification of novel antiviral drug combinations in vitro and tracking their development

Combination therapies have become a standard for the treatment for HIV and HCV infections. They are advantageous over monotherapies due to better efficacy and reduced toxicity, as well as the ability to prevent the development of resistant viral strains and to treat viral co-infections. Here, we identify several new synergistic combinations against emerging and re-emerging viral infections in vitro. We observed synergistic activity of nelfinavir with investigational drug EIDD-2801 and convalescent serum against SARS-CoV-2 infection in human lung epithelial Calu-3 cells. We also demonstrated synergistic activity of vemurafenib combination with emetine, homoharringtonine, gemcitabine, or obatoclax against echovirus 1 infection in human lung epithelial A549 cells. We also found that combinations of sofosbuvir with brequinar and niclosamide were synergistic against HCV infection in hepatocyte derived Huh-7.5 cells, whereas combinations of monensin with lamivudine and tenofovir were synergistic against HIV-1 infection in human cervical TZM-bl cells. Finally, we present an online resource that summarizes novel and known antiviral drug combinations and their developmental status. Overall, the development of combinational therapies could have a global impact improving the preparedness and protection of the general population from emerging and re-emerging viral threats.

Current Allogeneic Hematopoietic Stem Cell Transplantation for Pediatric Acute Lymphocytic Leukemia: Success, Failure and Future Perspectives-A Single-Center Experience, 2008 to 2016.

Hematopoietic stem cell transplantation (HSCT) is the only curative option for a subset of patients with high-risk or relapsed acute lymphoblastic leukemia (ALL). Given evolving practices, it is important to continually evaluate outcomes for pediatric ALL following HSCT. Outcomes after HSCT are influenced by the type of donor used as this determines the degree and method of T cell depletion used and, consequently, specific transplant-related morbidities. We retrospectively analyzed HSCT data from our center for transplants performed between January 2008 and May 2016, comparing outcomes among different donor types. One hundred and twenty-four pediatric patients underwent HSCT from a matched sibling donor (MSD; n = 48), an unrelated matched donor (UMD; n = 56), or a haploidentical donor (n = 20). We observed a similar 3-year event-free survival (EFS) for MSD recipients (of .64) and for UMD recipients (.62), but a significantly lower EFS for recipients of haploidentical transplants (.35; P = .01). Relapse was the main cause of HSCT failure and was significantly higher in the haploidentical donor group (.47 versus .19 for MSD and .24 for UMD; P = .02). Treatment-related mortality was evenly distributed among the donor groups (.17, .16, and .15 for the MSD, UMD, and haploidentical groups, respectively). Rates of infection-related mortality were lower than previously reported. Relapse is the main obstacle for successful HSCT in the contemporary era, and this effect is most evident in recipients of haploidentical donor grafts. Newer methods to improve graft-versus-leukemia effect are being evaluated and will need to be incorporated into the management of high-risk patients.

Alleviation of ascorbic acid-induced gastric high acidity by calcium ascorbate in vitro and in vivo

Ascorbic acid is one of the most well-known nutritional supplement and antioxidant found in fruits and vegetables. Calcium ascorbate has been developed to mitigate the gastric irritation caused by the acidity of ascorbic acid. The aim of this study was to compare calcium ascorbate and ascorbic acid, focusing on their antioxidant activity and effects on gastric juice pH, total acid output, and pepsin secretion in an in vivo rat model, as well as pharmacokinetic parameters. Calcium ascorbate and ascorbic acid had similar antioxidant activity. However, the gastric fluid pH was increased by calcium ascorbate, whereas total acid output was increased by ascorbic acid. In the rat pylorus ligation-induced ulcer model, calcium ascorbate increased the gastric fluid pH without changing the total acid output. Administration of calcium ascorbate to rats given a single oral dose of 100 mg/kg as ascorbic acid resulted in higher plasma concentrations than that from ascorbic acid alone. The area under the curve (AUC) values of calcium ascorbate were 1.5-fold higher than those of ascorbic acid, and the C(max) value of calcium ascorbate (91.0 ng/ml) was higher than that of ascorbic acid (74.8 ng/ml). However, their T(max) values were similar. Thus, although calcium ascorbate showed equivalent antioxidant activity to ascorbic acid, it could attenuate the gastric high acidity caused by ascorbic acid, making it suitable for consideration of use to improve the side effects of ascorbic acid. Furthermore, calcium ascorbate could be an appropriate antioxidant substrate, with increased oral bioavailability, for patients with gastrointestinal disorders.