There are now at least three independent claims that bromhexine and likely ambroxol do not directly inhibit TMPRSS2.
This poses a mystery, as both work in cell culture and bromhexine did very well in the Iranian RCT.
Perhaps the effect is indirect:
researchgate.net/publication/64…
This poses a mystery, as both work in cell culture and bromhexine did very well in the Iranian RCT.
Perhaps the effect is indirect:
researchgate.net/publication/64…
Ambroxol triggers the release in the lungs of endogenous compounds known to be inhibitory to serine proteases.
As a cell-membrane-localized serine protease, TMPRSS2 would be fully exposed to them.
It likely gets inhibited likewise.
Bromhexine is metabolized to ambroxol.
As a cell-membrane-localized serine protease, TMPRSS2 would be fully exposed to them.
It likely gets inhibited likewise.
Bromhexine is metabolized to ambroxol.
@gstanchev @cispt2 @monarchdiaries @assur153 @YinPD @csentropy @AndyBiotech @houndcl
Ambroxol likely works as well as bromhexine, even though neither one likely directly inhibits TMPRSS2.
Ambroxol likely works as well as bromhexine, even though neither one likely directly inhibits TMPRSS2.
@mansarin @Dharmen46587056 @drakchaurasia
Ambroxol is likely not a TMPRSS2 inhibitor.
Instead, it triggers cells in the lungs to secrete substances that inhibit many serine proteases, likely including TMPRSS2.
Readily-available ambroxol may substitute for bromhexine.
Ambroxol is likely not a TMPRSS2 inhibitor.
Instead, it triggers cells in the lungs to secrete substances that inhibit many serine proteases, likely including TMPRSS2.
Readily-available ambroxol may substitute for bromhexine.
The combination of ambroxol's downstream secretory products at cell surface serine proteases (including any unknown ones that may also cleave Spike), plus an endosomal entry inhibitor like hydroxychloroquine or nitazoxanide, should largely block viral entry in the lungs.
@richardursomd @JamesTodaroMD
Hydroxychloroquine only blocks a side door, by interfering with endosomal acidification for acid hydrolases like Cathepsin L.
Ambroxol triggers release of endogenous serine protease inhibitors in the lungs, blocking the main entrance at TMPRSS2.
Hydroxychloroquine only blocks a side door, by interfering with endosomal acidification for acid hydrolases like Cathepsin L.
Ambroxol triggers release of endogenous serine protease inhibitors in the lungs, blocking the main entrance at TMPRSS2.
If both paths are barred, then the infection may be halted, even in hospital cases.
Putative minor routes are irrelevant:
- CypA-mediated entry at CD147 still needs a protease.
- Filopodia need Spike to be cleaved when they reach the neighboring cell.
Putative minor routes are irrelevant:
- CypA-mediated entry at CD147 still needs a protease.
- Filopodia need Spike to be cleaved when they reach the neighboring cell.
Ambroxol can be given safely in massive doses.
Doses of 500mg ambroxol have been proven safe and tolerable in humans.
Ambroxol is cheaply available throughout South Asia and Latin America.
Doses of 500mg ambroxol have been proven safe and tolerable in humans.
Ambroxol is cheaply available throughout South Asia and Latin America.
It hence appears highly probable that the most accessible high-efficacy antiviral treatment in mild and moderate COVID-19 may be nothing more than an old antimalarial and a particular type of cough syrup.
The Iranian bromhexine study above used hydroxychloroquine as part of the baseline treatment. Both routes would have been largely blocked.
If the virus is unable to infect new cells, even through filopodial transfer or other cell-cell fusion, then the infection is halted.
If the virus is unable to infect new cells, even through filopodial transfer or other cell-cell fusion, then the infection is halted.
Further corroboration of the serine protease inhibitory activity of the secretory products stimulated by ambroxol:
erj.ersjournals.com/content/19/5/9…
It works by prompting exocytosis of secretory vesicles from pneumocytes by a pH-based mechanism:
sciencedirect.com/science/articl…
erj.ersjournals.com/content/19/5/9…
It works by prompting exocytosis of secretory vesicles from pneumocytes by a pH-based mechanism:
sciencedirect.com/science/articl…
Importantly, and in contrast to what might be expected given the latter finding, ambroxol does *not* inhibit endosome acidification.
On the contrary: it may even promote it.
nature.com/articles/s4159…
Ambroxol has been widely investigated as an agent to enhance lysosomal function.
On the contrary: it may even promote it.
nature.com/articles/s4159…
Ambroxol has been widely investigated as an agent to enhance lysosomal function.
This suggests that endosomal entry inhibitors like, inter alia, hydroxychloroquine, chloroquine, mefloquine, amodiaquine, nitazoxanide, niclosamide, and so on are likely not redundant with the effects of ambroxol.
Hydroxychloroquine has been used off-label in attempts to treat pulmonary surfactant deficiencies, so it appears unlikely that it would interfere with ambroxol.
pubmed.ncbi.nlm.nih.gov/23719253/
sciencedirect.com/science/articl…
nejm.org/doi/pdf/10.105…
Efficacy is mixed but no harm was apparent.
pubmed.ncbi.nlm.nih.gov/23719253/
sciencedirect.com/science/articl…
nejm.org/doi/pdf/10.105…
Efficacy is mixed but no harm was apparent.
Meanwhile, ambroxol has also been used to prevent the formation of a hyaline membrane, a factor strongly contributing to ARDS.
ncbi.nlm.nih.gov/pmc/articles/P…
pubmed.ncbi.nlm.nih.gov/2662997/
ejog.org/article/0028-2…
Meta-analysis favors use of ambroxol in ARDS:
pubmed.ncbi.nlm.nih.gov/25174313/
ncbi.nlm.nih.gov/pmc/articles/P…
pubmed.ncbi.nlm.nih.gov/2662997/
ejog.org/article/0028-2…
Meta-analysis favors use of ambroxol in ARDS:
pubmed.ncbi.nlm.nih.gov/25174313/
See also:
