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A short introduction to Ambroxol:
Ambroxol is indicated as "secretolytic therapy in bronchopulmonary diseases associated with abnormal mucus secretion and impaired mucus transport. It promotes mucus clearance, facilitates expectoration and eases productive cough, allowing patients to breathe freely and deeply" [1] Ambroxol is also used as a local analgesic for sore throat in the form of lozenges. It's available OTC in most parts of the world, but doesn't seem to be available in the US. It has been in medical use since 1979. Normal daily dosages tend to range from 30mg to 75mg.
A short introduction to how SARS-CoV-2 infects cells:
It has been reported that the SARS-CoV-2 uses a receptor called ACE2 to enter cells. In order to use the ACE2 receptor, the virus needs to be primed by something called a protease. [2] [3] One prominent protease is called TMPRSS2.[4] An in vitro study (meaning in a test tube) showed that a TMPRSS2 inhibitor called Camostat (an approved drug in Japan used for chronic pancreatitis and postoperative reflux esophagitis) blocked the virus from entering cells. [2] Many influenza viruses also use TMPRSS2 to enter cells. [4] However, there are various other endogenous airway proteases that can prime both SARS-CoV-1 [5] (very similar to SARS-CoV-2, most likely translatable) and various influenza viruses.
How Ambroxol might prevent/treat COVID-19
Ambroxol have been shown to up-regulate the levels of the endogenous protease inhibitors that the body produce. [6] Ambroxol's up-regulation of these defensive molecules have been shown to increase the survivability of mice exposed to lethal levels of influenza virus. [6] [7] The daily dosage found to be most effective (higher dosage being less effective) was 10mg/kg, which for humans would be equivalent to 0,8 mg/kg[8], meaning 64mg ambroxol for someone who weighs 80kg. It have also been shown to inhibit rhinovirus infection (common cold) in cultures of human tracheal epithelial cells by various mechanisms. [9] One of these mechanisms (reducing acidic endosomes) might have effects against SARS-CoV-2: "We observed potent inhibition of SARS-CoV S-mediated transduction by two different classes of lysosomotropic agents in multiple cell lines, strongly suggesting that SARS-CoV glycoprotein requires acidification of endosomes for entry." [10]
"Ambroxol is a lysosomotropic drug of clinical use to treat conditions of productive cough for its mucolytic action. Ambroxol triggers the exocytosis of lysosomes via neutralization of lysosomal pH and calcium release from acidic calcium stores. Presumably for this reason, Ambroxol was also found to improve cellular function in some disease of lysosomal origin such as Parkinson's or lysosomal storage disease."[11]
In 2006, a Japanese study looked at the effect of ambroxol vs 2 other drugs regarding the incidence of upper respiratory tract infection (URTI) during 1 year (41 subjects in total). The ambroxol group had 66% less URTIs compared to one drug and 73% less URTIs compared to the other drug. [12]
Ambroxol may be an ACE2 binding agent according to an artificial intelligence drug target screening done by researchers at the School of Basic Medicine Sciences at Peking University. [13] [14] [15] This has not been tested in vitro to my knowledge.
Chinese hospitals are already using ambroxol in the treatment of moderate and severe COVID-19 patients, according the "Handbook of COVID-19 Prevention and Treatment", produced by the First Affiliated Hospital, Zhejiang University School of Medicine. The dosage is 30 mg x 2 (60mg total)/day i.v, equivalent to 76mg oral immediate release ambroxol / day [16].
According to a newly released paper by researches from IBM, computer simulations indicate that ambroxol (among ∼20 other compounds) may inhibit SARS-CoV-2’s main protease. "Currently, it is well known that the SARS-CoV-2’s main protease (Mpro) constitutes one of the most attractive antiviral drug targets, because the viral maturation almost exclusively relies on the Mpro’s activity." [17]
And now, the most interesting paper to date; ambroxol was one of 90 compounds found to inhibit SARS-CoV-2 replication in an in vitro screening of 1,520 approved drugs, according to a pre-print paper released 7 days ago. [18] The concentration used to test the drugs was 10µM.
10µM = 0,00001 molar. Ambroxol hydrochloride's molar mass is 414.56 g/mol [19].
414.56 * 0,00001=0,0041456 g/L ambroxol.
0,0041456 g/L = 4145,6 ng/ml ambroxol.
What's the concentration of ambroxol in lung tissues at normal dosages? According to one paper[20], the concentration of ambroxol in the bronchoalveolar lavage fluid was 135ng/ml after 2 weeks of 60mg ambroxol x 2 (120mg/day). They also state that a dilution factor of 50 can be applied to estimate tissue distribution. That would mean 135*50=6750ng/ml ambroxol in the lung tissue after 120mg ambroxol/day. Another study referenced in the same paper stated that ambroxol concentrate in pulmonary tissue (aka the lungs) at levels up to 20 times that in blood (plasma according to other papers referring to the same study [21]). The maximum plasma level after ingesting 1 x 30 mg immediate release ambroxol is reported to be around 60 ng/ml [22]. That would extrapolate to 60*20=1200ng/ml ambroxol in lung tissue after ingesting 30mg ambroxol.
This indicates that ambroxol may have antiviral effects against SARS-CoV-2 at concentrations achievable with normal dosages.
There seems to be an epidemiologic study underway in China evaluating ambroxol's potential in the treatment of COVID-19, sponsered by Boehringer Ingelheim, one of the world's largest pharmaceutical companies. [23]
Ambroxol have also been shown to have a wide range of anti-inflammatory properties [24] [25], and to reduce elastase release by human neutrophils by 40% at 10µM [26], the same concentration used in the SARS-CoV-2 in vitro study above. "Elastase breaks down elastin, an elastic fibre that, together with collagen, determines the mechanical properties of connective tissue." [27] Ambroxol have also been shown in mice to improve neuronal survival and reduces white matter damage through suppressing endoplasmic reticulum stress in microglia after intracerebral hemorrhage. [28]
Ambroxol can be bought OTC from German pharmacies, you can find some here. Many pharmacies do not send to addresses outside of Germany, but some do. One such pharmacy is www.bodfeld-apotheke.de.
Ambroxol is indicated as "secretolytic therapy in bronchopulmonary diseases associated with abnormal mucus secretion and impaired mucus transport. It promotes mucus clearance, facilitates expectoration and eases productive cough, allowing patients to breathe freely and deeply" [1] Ambroxol is also used as a local analgesic for sore throat in the form of lozenges. It's available OTC in most parts of the world, but doesn't seem to be available in the US. It has been in medical use since 1979. Normal daily dosages tend to range from 30mg to 75mg.
A short introduction to how SARS-CoV-2 infects cells:
It has been reported that the SARS-CoV-2 uses a receptor called ACE2 to enter cells. In order to use the ACE2 receptor, the virus needs to be primed by something called a protease. [2] [3] One prominent protease is called TMPRSS2.[4] An in vitro study (meaning in a test tube) showed that a TMPRSS2 inhibitor called Camostat (an approved drug in Japan used for chronic pancreatitis and postoperative reflux esophagitis) blocked the virus from entering cells. [2] Many influenza viruses also use TMPRSS2 to enter cells. [4] However, there are various other endogenous airway proteases that can prime both SARS-CoV-1 [5] (very similar to SARS-CoV-2, most likely translatable) and various influenza viruses.
How Ambroxol might prevent/treat COVID-19
Ambroxol have been shown to up-regulate the levels of the endogenous protease inhibitors that the body produce. [6] Ambroxol's up-regulation of these defensive molecules have been shown to increase the survivability of mice exposed to lethal levels of influenza virus. [6] [7] The daily dosage found to be most effective (higher dosage being less effective) was 10mg/kg, which for humans would be equivalent to 0,8 mg/kg[8], meaning 64mg ambroxol for someone who weighs 80kg. It have also been shown to inhibit rhinovirus infection (common cold) in cultures of human tracheal epithelial cells by various mechanisms. [9] One of these mechanisms (reducing acidic endosomes) might have effects against SARS-CoV-2: "We observed potent inhibition of SARS-CoV S-mediated transduction by two different classes of lysosomotropic agents in multiple cell lines, strongly suggesting that SARS-CoV glycoprotein requires acidification of endosomes for entry." [10]
"Ambroxol is a lysosomotropic drug of clinical use to treat conditions of productive cough for its mucolytic action. Ambroxol triggers the exocytosis of lysosomes via neutralization of lysosomal pH and calcium release from acidic calcium stores. Presumably for this reason, Ambroxol was also found to improve cellular function in some disease of lysosomal origin such as Parkinson's or lysosomal storage disease."[11]
In 2006, a Japanese study looked at the effect of ambroxol vs 2 other drugs regarding the incidence of upper respiratory tract infection (URTI) during 1 year (41 subjects in total). The ambroxol group had 66% less URTIs compared to one drug and 73% less URTIs compared to the other drug. [12]
Ambroxol may be an ACE2 binding agent according to an artificial intelligence drug target screening done by researchers at the School of Basic Medicine Sciences at Peking University. [13] [14] [15] This has not been tested in vitro to my knowledge.
Chinese hospitals are already using ambroxol in the treatment of moderate and severe COVID-19 patients, according the "Handbook of COVID-19 Prevention and Treatment", produced by the First Affiliated Hospital, Zhejiang University School of Medicine. The dosage is 30 mg x 2 (60mg total)/day i.v, equivalent to 76mg oral immediate release ambroxol / day [16].
According to a newly released paper by researches from IBM, computer simulations indicate that ambroxol (among ∼20 other compounds) may inhibit SARS-CoV-2’s main protease. "Currently, it is well known that the SARS-CoV-2’s main protease (Mpro) constitutes one of the most attractive antiviral drug targets, because the viral maturation almost exclusively relies on the Mpro’s activity." [17]
And now, the most interesting paper to date; ambroxol was one of 90 compounds found to inhibit SARS-CoV-2 replication in an in vitro screening of 1,520 approved drugs, according to a pre-print paper released 7 days ago. [18] The concentration used to test the drugs was 10µM.
10µM = 0,00001 molar. Ambroxol hydrochloride's molar mass is 414.56 g/mol [19].
414.56 * 0,00001=0,0041456 g/L ambroxol.
0,0041456 g/L = 4145,6 ng/ml ambroxol.
What's the concentration of ambroxol in lung tissues at normal dosages? According to one paper[20], the concentration of ambroxol in the bronchoalveolar lavage fluid was 135ng/ml after 2 weeks of 60mg ambroxol x 2 (120mg/day). They also state that a dilution factor of 50 can be applied to estimate tissue distribution. That would mean 135*50=6750ng/ml ambroxol in the lung tissue after 120mg ambroxol/day. Another study referenced in the same paper stated that ambroxol concentrate in pulmonary tissue (aka the lungs) at levels up to 20 times that in blood (plasma according to other papers referring to the same study [21]). The maximum plasma level after ingesting 1 x 30 mg immediate release ambroxol is reported to be around 60 ng/ml [22]. That would extrapolate to 60*20=1200ng/ml ambroxol in lung tissue after ingesting 30mg ambroxol.
This indicates that ambroxol may have antiviral effects against SARS-CoV-2 at concentrations achievable with normal dosages.
There seems to be an epidemiologic study underway in China evaluating ambroxol's potential in the treatment of COVID-19, sponsered by Boehringer Ingelheim, one of the world's largest pharmaceutical companies. [23]
Ambroxol have also been shown to have a wide range of anti-inflammatory properties [24] [25], and to reduce elastase release by human neutrophils by 40% at 10µM [26], the same concentration used in the SARS-CoV-2 in vitro study above. "Elastase breaks down elastin, an elastic fibre that, together with collagen, determines the mechanical properties of connective tissue." [27] Ambroxol have also been shown in mice to improve neuronal survival and reduces white matter damage through suppressing endoplasmic reticulum stress in microglia after intracerebral hemorrhage. [28]
Ambroxol can be bought OTC from German pharmacies, you can find some here. Many pharmacies do not send to addresses outside of Germany, but some do. One such pharmacy is www.bodfeld-apotheke.de.
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