Alarming situation has been caused due to the emergence of COVID-19 infection around the world. There is an urgency of developing a therapeutic strategy in order to control the spread of COVID-19. Towards that initiative, potential drugs like hydroxychloroquine, ivermectin and azithromycin have been tested by diverse group of researchers worldwide for their potential against novel coronavirus. The present report presents together the comprehensive knowledge derived from the major researches about the above drugs altogether in context of the current health emergency around the world. Hydroxychloroquine and ivermectin were known to act by creating the acidic environment and inhibiting the importin (IMPα/β1) mediated viral import. Azithromycin was found to act similar to the hydroxychloroquine as an acidotropic lipophilic weak base. All the three categories of drugs seemed to potentially act against novel coronavirus infection. However, their efficacies need to be studied in detail individually and in combination in-vivo in order to combat COVID-19 infection.
Caly, Druce (1) reported that ivermectin inhibited SARS-CoV-2 in vitro for up to 48 h using ivermectin at 5μM. The concentration resulting in 50% inhibition (IC50, 2 µM) was >35x higher than the maximum plasma concentration (Cmax) after oral administration of the approved dose of ivermectin when given fasted. Simulations were conducted using an available population pharmacokinetic model to predict total (bound and unbound) and unbound plasma concentration-time profiles after a single and repeat fasted administration of the approved dose of ivermectin (200 μg/kg), 60 mg, and 120 mg. Plasma total Cmax was determined and then multiplied by the lung:plasma ratio reported in cattle to predict the lung Cmax after administration of each single dose. Plasma ivermectin concentrations of total (bound and unbound) and unbound concentrations do not reach the IC50 , even for a dose level 10x higher than the approved dose. Even with the high lung:plasma ratio, ivermectin is unlikely to reach the IC50 in lungs after single oral administration of the approved dose (predicted lung: 0.0873 µM) or at doses 10x higher that the approved dose administered orally (predicted lung: 0.820 µM). In summary, the likelihood of a successful clinical trial using the approved dose of ivermectin is low. Combination therapy should be evaluated in vitro. Re-purposing drugs for use in COVID-19 treatment is an ideal strategy but is only feasible when product safety has been established and experiments of re-purposed drugs are conducted at clinically relevant concentrations.
Ivermectin is an antiparasitic drug that has shown also an effective pharmacological activity towards various infective agents, including viruses. This paper proposes an alternative mechanism of action for this drug that makes it capable of having an antiviral action, also against the novel coronavirus, in addition to the processes already reported in literature.
Although several clinical trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 h post infection with SARS-CoV-2 able to effect ~5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.
Importance: There is no established anti-viral therapy for treating COVID-19 illness.
Objective: To study the usefulness of Ivermectin, an antimicrobial therapy, in COVID-19 outcomes.
Design: An international, multicenter, observational propensity-score matched case-controlled study using prospectively collected data on patients diagnosed with COVID-19 between January 1, 2020 and March 31, 2020.
Setting: An international multi- institutional deidentified healthcare outcomes database.
Participants: Hospitalized patients diagnosed with COVID-19 determined by presence of a positive laboratory finding confirming SARS-CoV-2 infection.
Exposure: Ivermectin (150mcg/Kg) administered once compared with COVID-19 patients receiving medical therapy without ivermectin.
Main Outcome: The principal outcome was to assess the association of ivermectin administration with survival in COVID-19.
Results: The cohort (including 704 ivermectin treated and 704 controls) was derived from 169 hospitals across 3 continents with COVID-19 illness. The patients were matched for age, sex, race or ethnicity, comorbidities and a illness severity score (qSOFA). Of those requiring mechanical ventilation fewer patients died in the ivermectin group (7.3% versus 21.3%) and overall death rates were lower with ivermectin (1.4% versus 8.5%; HR 0.20 CI 95% 0.11-0.37, p<0.0001).
Conclusions and Relevance: The administration of ivermectin during COVID-19 illness in hospitalized patients is associated with a lower mortality and hospital length of stay. These findings require confirmation in randomized controlled trials.