Remdesivirs in vitro studies were one of the reaso
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Posted On: 06/07/2021 9:10:58 AM
Remdesivirs in vitro studies were one of the reasons it was quickly studied for Covid 19. Unfotunately further studies showed it lack efficacy against Covid 19. Why?
Remdesivir's poor clinical showing in spite of relative good in vitro studies is due to its hepatic toxicity which limits higher dosing and its relatively complicated conversion to its active metabolite requires an intracellular conversion.
https://www.statnews.com/2020/05/14/gilead-sh...-ancestor/
"Remdesivir’s lackluster results in patients with advanced Covid-19 in the NIAID-sponsored trial and the finding that it provided no statistically significant benefit in a clinical trial conducted in China among patients with severe Covid-19 symptoms are likely due to the suboptimal level of active GS-441524 triphosphate in the lungs. Patients with advanced or severe Covid-19 generally have a high viral load in their lungs and would need a high concentration of GS-441524 triphosphate to combat it. The benefit of using GS-441524 over remdesivir is that GS-441524 can almost certainly be given at much higher doses due to its lower toxicity. This would result in more conversion to the active compound, GS-441524 triphosphate, in the lungs."
Remdesivir IC 50 in vitro is .77um, but it has to enter the host cells to prevent intracellular viral reproduction. Remdesivir is a prodrug and is converted inside the cell to its active metabolite which is estimated to have an IC 50 of 38um to 231um or 7.7um in other studies, well below that of Brilacidin's IC 50 of .565um.
Its pharmacology explains Remdesivir's poor clinical performance in spite of a relatively good in vitro IC 50.
In addition Remdesivir's hepatotoxicity limits higher dosing.
"Assuming similar distribution and accumulation ratios of remdesivir and Nuc-TP in the lung between humans and monkeys, an optimistic estimation of Nuc-TP in the human lung tissues is 2 to 3-fold higher at a steady state than that observed in the monkey lung tissues [1]. This suggests that an IV dose of 200 mg remdesivir in a human may only achieve a suboptimal concentration of active form of Nuc-TP of <?2–5 µM in the human lung tissues (TableIII). Given that the intracellular volume (0.54 l) is 46% of the total volume of the lung (1.17 l) [17], the intracellular concentration of Nuc-TP in the human lung may be only at 4–10 µM (TableIII), which may be below the estimated intracellular IC50 and IC90 of Nuc-TP. Unfortunately, systemic adverse effects such as hepatotoxicity preclude escalation of the remdesivir dose to more than 200 mg/day."
The following article demonstrates these findings in great detail.
https://link.springer.com/article/10.1208/s12248-020-00459-8
Fortunately Brilacidin is not limited by these factors.
Its virucidal mechanism of action means it kills Covid19 on contact. It does not have to be converted to an active form so with infusion it kills the virus at first in the serum. With its good pharmcokinetics and high SI number it is well distributed throughout the body and kills the virus in the extracellular spaces as well as inside the cells. It was shown in the Viruses publication to block entry of Covid19 in the cells. And, computer modeling suggests it can disrupts the viral M-protein of Covid19 to prevent viral replication.
These multiple mechanisms of action, high SI number and safety all should make Brilacidin a superior antiviral, but also be active against Covid variants. It should make viral resistance much less likely.
We will know for sure soon.
GLTA, Farrell
Remdesivir's poor clinical showing in spite of relative good in vitro studies is due to its hepatic toxicity which limits higher dosing and its relatively complicated conversion to its active metabolite requires an intracellular conversion.
https://www.statnews.com/2020/05/14/gilead-sh...-ancestor/
"Remdesivir’s lackluster results in patients with advanced Covid-19 in the NIAID-sponsored trial and the finding that it provided no statistically significant benefit in a clinical trial conducted in China among patients with severe Covid-19 symptoms are likely due to the suboptimal level of active GS-441524 triphosphate in the lungs. Patients with advanced or severe Covid-19 generally have a high viral load in their lungs and would need a high concentration of GS-441524 triphosphate to combat it. The benefit of using GS-441524 over remdesivir is that GS-441524 can almost certainly be given at much higher doses due to its lower toxicity. This would result in more conversion to the active compound, GS-441524 triphosphate, in the lungs."
Remdesivir IC 50 in vitro is .77um, but it has to enter the host cells to prevent intracellular viral reproduction. Remdesivir is a prodrug and is converted inside the cell to its active metabolite which is estimated to have an IC 50 of 38um to 231um or 7.7um in other studies, well below that of Brilacidin's IC 50 of .565um.
Its pharmacology explains Remdesivir's poor clinical performance in spite of a relatively good in vitro IC 50.
In addition Remdesivir's hepatotoxicity limits higher dosing.
"Assuming similar distribution and accumulation ratios of remdesivir and Nuc-TP in the lung between humans and monkeys, an optimistic estimation of Nuc-TP in the human lung tissues is 2 to 3-fold higher at a steady state than that observed in the monkey lung tissues [1]. This suggests that an IV dose of 200 mg remdesivir in a human may only achieve a suboptimal concentration of active form of Nuc-TP of <?2–5 µM in the human lung tissues (TableIII). Given that the intracellular volume (0.54 l) is 46% of the total volume of the lung (1.17 l) [17], the intracellular concentration of Nuc-TP in the human lung may be only at 4–10 µM (TableIII), which may be below the estimated intracellular IC50 and IC90 of Nuc-TP. Unfortunately, systemic adverse effects such as hepatotoxicity preclude escalation of the remdesivir dose to more than 200 mg/day."
The following article demonstrates these findings in great detail.
https://link.springer.com/article/10.1208/s12248-020-00459-8
Fortunately Brilacidin is not limited by these factors.
Its virucidal mechanism of action means it kills Covid19 on contact. It does not have to be converted to an active form so with infusion it kills the virus at first in the serum. With its good pharmcokinetics and high SI number it is well distributed throughout the body and kills the virus in the extracellular spaces as well as inside the cells. It was shown in the Viruses publication to block entry of Covid19 in the cells. And, computer modeling suggests it can disrupts the viral M-protein of Covid19 to prevent viral replication.
These multiple mechanisms of action, high SI number and safety all should make Brilacidin a superior antiviral, but also be active against Covid variants. It should make viral resistance much less likely.
We will know for sure soon.
GLTA, Farrell
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