Antihelminthics
Amid the COVID-19 pandemic, the search for active molecules against the coronavirus should use advanced tools of computational biology and artificial intelligence for the recognition of drugs already approved and commercialized with potential effects on the replication of SARS-CoV-2 (386).
In this context, over the past few years, research has shown the antiviral potential in vitro, especially against RNA viruses, of Ivermectin, the best known and most widely used antiparasitic drug in human and veterinary medicine, with promising results against SARS-CoV-2 (387). The model of Vero/hSLAM cells infected with a SARS-CoV-2 isolate showed the ivermectin antiviral effect in which 24h-ivermectin treatment reduced 93% of RNA viral load in the cell supernatant and 99.8% of the intracellular viral RNA. The authors hypothesized that its probable mechanism of action occurs through the inhibition of nuclear import of importin-α/β1–mediated the IMPα/β1 heterodimer of viral proteins, as shown for other RNA viruses (387, 388). Corroborating, Lehrer and Rheinstein (389) identified the ivermectin docking site between the region of leucine 91 of viral spike and the histidine 378 of the ACE2 receptor, which may interfere with the attachment of the spike to the human cell membrane.
Although the in vitro proliferation inhibition effect of Ivermectin against SARS-CoV-2 has been shown, there is no evidence that the IC50 of ~ 2 µM determined by Caly and colleagues can be achieved in the clinic where pharmacokinetics studies showed that even the maximum tested dosage of 1700 μg/kg presented only 0.28μM of plasma concentration (390).
According to Navarro et al. (391), no adverse effects of high doses of ivermectin have so far been demonstrated in clinical studies with patients, with only a few transient ocular events in those who experienced high doses (up to 400 μg/kg). However, Duthaler et al. (392) demonstrated that the adverse effects of ivermectin in the body can vary according to the patient’s nutritional status, and the effects of high doses can be harmful, especially in patients with malnutrition levels. The general consensus of the authors is that further studies are needed to evaluate the efficacy and safety of ivermectin administered in high doses against SARS-CoV-2.
Xu et al. (386) published a review article regarding niclosamide, an old anthelmintic used to treat tapeworm infections, showing promising antiviral activity against various viral infections, such as SARS-CoV-1 and MERS-CoV. This drug has shown to act in vitro by enhancing autophagy and efficiently reducing MERS-CoV replication.
Originally developed as an antiprotozoal agent, nitazoxanide is another broad-spectrum antiviral agent that has been currently developed to treat influenza and other viral respiratory infections. Nitazoxanide exhibited in vitro activity against MERS-CoV by inhibiting the expression of viral N protein, in addition to reducing the production of IL-6 in an in vivo model (393, 394).
Despite the lack of studies in the literature showing the effect of these anthelmintics on the COVID-19 model, clinical trials have currently included this type of antiviral agent in many countries; there are 37 clinical trials using ivermectin alone or associated with hydroxychloroquine, and 19 with nitazoxanide. These studies are yet to be published and preliminary results are expected in the second half of 2020.