Systems and Clinical Pharmacology of COVID-19 Therapeutic Candidates: A Clinical and Translational Medicine Perspective

Abstract

Over 50 million people have been infected with the SARS-CoV-2 virus, while around 1 million have died due to COVID-19 disease progression. COVID-19 presents flu-like symptoms that can escalate, in about 7 e10 days from onset, into a cytokine storm causing respiratory failure and death. Although social distancing reduces transmissibility, COVID-19 vaccines and therapeutics are essential to regain socioeconomic normalcy. Even if effective and safe vaccines are found, pharmacological interventions are still needed to limit disease severity and mortality. Integrating current knowledge and drug candidates (approved drugs for repositioning among >35 candidates) undergoing clinical studies (>3000 registered in ClinicalTrials.gov), we employed Systems Pharmacology approaches to project how antivirals and immunoregulatory agents could be optimally evaluated for use. Antivirals are likely to be effective only at the early stage of infection, soon after exposure and before hospitalization, while immunomodulatory agents should be effective in the later-stage cytokine storm. As current antiviral candidates are administered in hospitals over 5e7 days, a long-acting combination that targets multiple SARS-CoV-2 lifecycle steps may provide a long-lasting, single-dose treatment in outpatient settings. Long-acting therapeutics may still be needed even when vaccines become available as vaccines are likely to be approved based on a 50% efficacy target.

Beneficial immune-regulatory effects of novel strains of Aureobasidium pullulans AFO-202 and N-163 produced beta glucans in Sprague Dawley rats

“…Speci c targeted molecules acting on a speci c component of a biochemical pathway during immune enhancement or immune suppression have been reported by many studies [18], but their safety as a drug molecule in situations such as the COVID-19 pandemic may take longer to assess in routine clinical practice. Furthermore, a combination approach involving more than one molecule or agent might face technical and regulatory hurdles [19].…”

The Quest for System-Theoretical Medicine in the COVID-19 Era

“…Regardless of the details available on subtypes of cells, receptors, signaling molecules etc., there is lot of evidence of the antagonistic organization and regulation of an integrative neurophysiological, endocrine, and immune system. The integration of these subsystems has implications for neurophysiological complications, excess mortality rates, and polypharmacological treatment for COVID-19 (77,(82)(83)(84) but also the assessment of potential novel vaccines such as the mRNA vaccines and their short-and long-term adverse effects due to mass vaccination, e.g., autoimmune reactions and neurophysiological manifestations (82,(85)(86)(87)(88). The interaction of the neurophysiological, endocrine, and immune system is discussed in the following.…”

Antiviral Therapeutic Approaches for SARS-CoV-2 Infection: A Systematic Review

“…Up to the present day we lack an etiological treatment against COVID-19, which is why the therapeutic strategies used are being oriented in three main directions [ 27 ].…”

“…One way is trying to reduce or eliminate the SARS-CoV-2 viral load using molecules capable of interfering with viral replication. Another way is using immune therapies that allow regulating the inflammatory response and finally, the other therapeutic strategy used is symptomatic treatment, for example, providing oxygen [ 27 ]. Antiviral drugs are considered useful in the early stages of the disease when active viral replication is still prevalent.…”

“…Antiviral drugs are considered useful in the early stages of the disease when active viral replication is still prevalent. However, in later stages a pro-inflammatory process stands out, where the use of immunomodulatory agents is being evaluated [ 27 ].…”