stereomatch | 15 points
A systematic review of experimental evidence for antiviral effects of ivermectin and an in‐silico analysis of ivermectin's possible mode of action against SARS‐CoV‐2[-] passfailboat | 4 points
This is excellent. So many "big brains" have been critical of the clinical evidence for lack of a proposed mechanism. The fact that anti-viral properties are found in vivo at standard therapeutic doses further supports this against those who reference the in vitro studies and the 100x dosage.
[-] [deleted] | 1 points
[deleted]
[-] stereomatch | 7 points | Jan 20 2021 20:37:04
Here is a section where they revisit the question of in vitro (higher doses required) vs in vivo performance of Ivermectin:
In 6-8 week-old BALB/c mice and 30 day-old piglets, ivermectin (0.2 mg/kg) caused a significant reduction in the replication and viral DNA copies in visceral organs following infection with Suid herpesvirus and Porcine circovirus respectively. Interestingly, these data are discordant with results from in vitro tests where micromolar concentrations of ivermectin were required to inhibit viral replication of Porcine circovirus in PK-15 cells and Suid herpesvirus in BHK-21 cells. This suggests that for some viral infections, ivermectin at currently recommended therapeutic doses may exert efficacy in vivo even if effective concentrations in vitro are not attainable without causing considerable toxicity. This argument has also been advanced previously, and it seems plausible because the proposed antiviral mechanism targets mammalian cell proteins that are important for intracellular transport. These critical functions are then hijacked by viruses to enhance viral replication. The fact that ivermectin may serve as a mammalian host-directed antiviral agent implies that reducing viral load by even a modest amount at a low dose could be supplementary in enhancing the immune system in fighting viral infections. Indeed, immune stimulatory effects of ivermectin have been documented [50], with treatment at 0.2 mg/kg significantly enhancing antibody production against sheep red blood cells as well as helper T-lymphocyte and macrophage dependent responses in the CD-1 strain of mice.
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[-] No-Sandwich-777 | 2 points | Jan 21 2021 05:22:57
" With regard to coronaviruses and the possible mode of action of ivermectin by blocking the NLS of importin α, we can only find one efficiently functional NLS in the co-factor protein nsp8 that is not logically rapidly sequestered for other viral functions. Three proteins of SARS-CoV-2 had apparent or mock NLS; nsp8, ORF6 and the nucleocapsid protein N. Logically, mostly these proteins will be utilized quickly for other functions outside the nucleus and only minor leakage into the nucleus would occur except for possibly nsp8 that does not have an essential role, just a co-factor role outside the nucleus and this needs closer scrutiny. It appears the application of ivermectin should have a clinical effect that is poorly understood at the moment. Of considerable interest is the paper of Giri et al. on the intrinsically disordered protein regions of the SARS-like coronaviruses examined by a computational approach [34]. Completely independently, using vastly different methods, they identified only the nucleocapsid N, nsp8 and ORF 6 as proteins of high intrinsic disorder. We were not aware of this publication when conducting our review, so we find it incongruous that the same proteins were identified by total independent scientific approaches and different goals. This intriguing co-incidence deserves further scrutiny.
Conclusion
This review provides a critical assessment of the potential for repurposing ivermectin (a clinically approved drug for parasitic infections) as a broad-spectrum antiviral drug. Molecular studies have identified the inhibition of nuclear translocation of viral proteins, facilitated by mammalian host processes as the main target. Other off-target effects such as stimulation of immune responses against viral infections are possible but have not been directly investigated. The bulk of current knowledge in this field comes from in vitro studies done by infecting cell cultures. Testing of the antiviral effects of ivermectin in in vivo animal infection models is very limited but the available data is promising and, this may be particularly true for infections with arboviruses. Given that viral infections remain one of the major causes of economic loses in medicine and agriculture, the potential to develop ivermectin as an additional antiviral agent should be pursued with an emphasis of pre-clinical trials in validated models of infection. However, given the coronavirus attack on importin β, the use of ivermectin to further block importin α, seems counter-intuitive to being a high priority treatment in the clinical arena without further pharmacological investigation of ivermectin. Nevertheless, there does appear to be a functional NLS in ORF1ab encoding the cleaved protein nsp8 which would be hampered by ivermectin and this should be examined further as a priority. "
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