A3- and A2B-fluorocorroles: synthesis, X-ray characterization and antiviral activity evaluation against human cytomegalovirus infection.
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ABSTRACT:
SUBMITTER: Kappler-Gratias S
PROVIDER: S-EPMC7496305 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundTo address the emergence of SARS-CoV-2, multiple clinical trials in humans were rapidly started, including those involving an oral treatment by nitazoxanide, despite no or limited pre-clinical evidence of antiviral efficacy.MethodsIn this work, we present a complete pre-clinical evaluation of the antiviral activity of nitazoxanide against SARS-CoV-2.FindingsFirst, we confirmed the in vitro efficacy of nitazoxanide and tizoxanide (its active metabolite) against SARS-CoV-2. Then, we demonstrated nitazoxanide activity in a reconstructed bronchial human airway epithelium model. In a SARS-CoV-2 virus challenge model in hamsters, oral and intranasal treatment with nitazoxanide failed to impair viral replication in commonly affected organs. We hypothesized that this could be due to insufficient diffusion of the drug into organs of interest. Indeed, our pharmacokinetic study confirmed that concentrations of tizoxanide in organs of interest were always below the in vitro EC50.InterpretationThese preclinical results suggest, if directly applicable to humans, that the standard formulation and dosage of nitazoxanide is not effective in providing antiviral therapy for Covid-19.FundingThis work was supported by the Fondation de France "call FLASH COVID-19", project TAMAC, by "Institut national de la santé et de la recherche médicale" through the REACTing (REsearch and ACTion targeting emerging infectious diseases), by REACTING/ANRS MIE under the agreement No. 21180 ('Activité des molécules antivirales dans le modèle hamster'), by European Virus Archive Global (EVA 213 GLOBAL) funded by the European Union's Horizon 2020 research and innovation program under grant agreement No. 871029 and DNDi under support by the Wellcome Trust Grant ref: 222489/Z/21/Z through the COVID-19 Therapeutics Accelerator".
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Project description:Patients treated with allogeneic hematopoietic cell transplantation (HCT) are at risk of cytomegalovirus (CMV) reactivation and disease, which results in increased morbidity and mortality. Although universal antiviral prophylaxis against CMV improves outcomes in solid organ transplant recipients, data have been conflicting regarding such prophylaxis in patients undergoing allogeneic HCT. We conducted a systematic review of randomized trials of prophylactic antivirals against CMV after allogeneic HCT to summarize the evolution of the field over the last 35 years and evaluate the prophylactic potential of antiviral agents against CMV after allogeneic HCT. Electronic databases were queried from database inception through 31 December 2017. For included studies, incidence of CMV infection and all-cause mortality were collected as primary outcomes; CMV disease incidence, use of preemptive therapy, and drug toxicities were collected as secondary outcomes. Nineteen clinical trials conducted between 1981 and 2017 involving a total of 4173 patients were included for review. Prophylactic strategies included use of acyclovir, valacyclovir, ganciclovir, maribavir, brincidofovir, and letermovir compared with placebo or a comparator antiviral. Fourteen trials that compared antiviral prophylaxis with placebo demonstrated overall effectiveness in reducing incidence of CMV infection (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.42-0.58), CMV disease (OR, 0.56; 95% CI, 0.40-0.80), and use of preemptive therapy (OR, 0.51; 95% CI, 0.42-0.62; 6 trials); however, none demonstrated reduction in all-cause mortality (OR, 0.96; 95% CI, 0.78-1.18) except the phase 3 trial of letermovir (week-24 OR, 0.59; 95% CI, 0.38-0.98). Additional research is warranted to determine patient groups most likely to benefit from antiviral prophylaxis and its optimal deployment after allogeneic HCT.
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