ABSTRACT
BackgroundSARS-CoV-2 viral entry may disrupt angiotensin II (Ang II) homeostasis in part via ACE2 downregulation, potentially contributing to COVID-19 induced lung injury. Preclinical models of viral pneumonias that utilize ACE2 demonstrate Ang II type 1 receptor (AT1R) blockade mitigates lung injury, though observational COVID-19 data addressing the effect of AT1R blockade remain mixed. MethodsMulticenter, blinded, placebo-controlled randomized trial of losartan (50 mg PO twice daily for 10 days) versus placebo. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already taking a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible. The primary outcome was the imputed partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity, oxygen, ventilator, and vasopressor-free days, and mortality. Losartan pharmacokinetics (PK) and RAAS components [Ang II, angiotensin-(1-7) (Ang-(1-7)), ACE, ACE2] were measured in a subgroup of participants. FindingsFrom April 2020 - February 2021, 205 participants were randomized, 101 to losartan and 104 to placebo. Compared to placebo, losartan did not significantly affect PaO2/FiO2 ratio at 7 days [difference of -24.8 (95% -55.6 to 6.1; p=0.12)]. Losartan did not improve any secondary clinical outcome, but worsened vasopressor-free days. PK data were consistent with appropriate steady-state concentrations, but we observed no significant effect of losartan on RAAS components. InterpretationInitiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury does not improve PaO2 / FiO2 ratio at 7 days. These data may have implications for ongoing clinical trials. Trial RegistrationLosartan for Patients With COVID-19 Requiring Hospitalization (NCT04312009), https://clinicaltrials.gov/ct2/show/NCT04312009
ABSTRACT
Effective therapies for COVID-19 are urgently needed. Presently there are more than 800 COVID-19 clinical trials globally, many with drug combinations, resulting in an empirical process with an enormous number of possible combinations. To identify the most promising potential therapies, we developed a biophysical model for the SARS-CoV-2 viral cycle and performed a sensitivity analysis for individual model parameters and all possible pairwise parameter changes (162 = 256 possibilities). We found that model-predicted virion production is fairly insensitive to changes in most viral entry, assembly, and release parameters, but highly sensitive to some viral transcription and translation parameters. Furthermore, we found a cooperative benefit to pairwise targeting of transcription and translation, predicting that combined targeting of these processes will be especially effective in inhibiting viral production.Competing Interest StatementThe authors have declared no competing interest.View Full Text
