Research paper – On the Efficacy of Tonic Water in Fighting Covid-19

Drinking tonic water could possibly “be more effective at ‘flattening the curve’ than any measures taken thus far.”
– Clyde Mason
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Research paper – On the Efficacy of Tonic Water in Fighting Covid-19

Clyde Mason

Ok, here’s the paper I’d written up as research when Covid 19 first came to prominence.

I first searched how coronaviruses infect cells, and learned that in order for the virus to infect a cell, the cell must first ‘invite it in’ by supplying a pH gradient in the form of a sialic acid moiety (which all our cells do because ACE2 is the enzyme which up-regulates blood pressure).

I then searched for the enzymatic pathways by which coronaviruses infect cells and learned it was via the ACE2 enzymatic pathway (the TMPRSS2 pathway was discovered later in another Covid 19 virus variant).

I then searched for everyday products which would act as enzymatic inhibitors, leading me to quinine.

After it was discovered that some variants of the Covid 19 virus can also use the TMPRSS2 enzymatic pathway, I researched everyday products which inhibit that, but didn’t find much, so I searched for prescription medication which does so, leading me to camostat mesylate.

———-

Quinine is a natural product derived from the bark of the cinchona tree. It is rapidly absorbed in the body, which can cause side effects in large enough doses. It also has a half-life in the body of only ~18 hours, so frequent dosing is necessitated.

Chloroquine is quinine produced synthetically and altered slightly to produce a new molecule for patenting purposes (naturally-occurring products could not be patented, and thus were not profitable to drug companies). The end product in the body is still quinine.

Chloroquine is an amine acidotropic form of quinine that was synthesized in Germany by Bayer in 1934 and emerged approximately 70 years ago as an effective substitute for natural quinine [4]. Natural quinine was so cheap that mass production wasn’t sufficiently profitable until after 1941.

Chloroquine is a non-enzymatically bioactivated form of quinine. Since the body must bioactivate it into quinine, it isn’t as rapidly absorbed as quinine, reducing to some degree the side effects due to rapid absorption. This also increases the half-life in the body, allowing less frequent dosage schedules.

In acting against malaria, chloroquine becomes protonated after it passes through a cell wall. In Plasmodium Falciparum (the parasite causing malaria), chloroquine enters through the parasite’s digestive vacuole, becomes protonated, cannot pass back out of the digestive vacuole, builds up in the parasite, and prevents detoxification of heme, which increases acidity within the parasite to the point that the parasite is damaged. [15][16]

Hydroxychloroquine is a prodrug form of chloroquine. It is metabolized in the body into chloroquine. The additional metabolic steps necessary to break down the molecule slows down the bioactivation of the resultant chloroquine into quinine (and hence the rate of absorption of the quinine), reducing toxicity caused by rapid absorption, but hydroxychloroquine is also ~1.6 to 8.8 times less active in the body against Plasmodium Falciparum. [15]

https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7189851/bin/gr1_lrg.jpg
(C) chloroquine, (D) hydroxychloroquine

Quinine was used in India in the form of a drink known as Indian tonic water to treat / prevent malaria. The British, colonizing India at the time, added gin, giving us gin and tonic.

By the 1930s Dutch plantations in Java were producing 22 million pounds per year of cinchona bark, or 97% of the world’s quinine production. When Japan invaded Java in 1941, natural quinine supplies dwindled, necessitating mass production of synthetic derivatives. [8]

Quinine is eliminated mainly by hepatic metabolism [1]. Seven metabolites have been identified with 3-hydroxyquinine being the major metabolite [1]. Other majority metabolites are (10R)-10,11-dihydroxyquinine and (10S)-10,11-dihydroxyquinine [2].

Quinine acts against malaria by targeting its purine nucleoside phosphorylase enzyme (PfPNP) [3], but it has other effects in the body which act against coronavirus.

Namely, it targets angiotensin-converting enzyme 2 (ACE2) [4], interfering with sialic acid biosynthesis [4]. SARS, MERS and Covid-19 use sialic acid moieties as receptors, so quinine (and its synthetic counterparts) work to prevent viral attachment to cell receptors.

https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7189851/bin/ga1_lrg.jpg

Hydroxychloroquine / Chloroquine / quinine can also act on the immune system through cell signalling and regulation of pro-inflammatory cytokines. [4]

It also acts to increase zinc uptake, which has anti-viral effects. Quinine used to be sold, prior to the FDA banning it for this use, as a treatment for leg cramps. The mechanism of action is increased uptake of zinc, calcium and magnesium by reducing hepatic metabolism [10]. Now it is recommended to directly ingest zinc, calcium and magnesium for leg cramps rather than taking quinine. [9]

This may be why people infected with Covid-19 experience a loss of the sense of taste (and smell, since the two senses are intricately connected) [11][12]. They become acutely zinc deficient.

It generally takes 4 to 5 days to completely flush quinine from the body [5]. The consumption of 10 oz. of tonic water can result in a quinine positive urine sample for a period of up to 96 hours (4 days) after intake. [5] Approximately 20% of quinine is excreted unmetabolized [6]. It has a half-life of approximately 18 hours [6].

Quinine in tonic water in the US is limited to 83 mg / liter [7].

Thus, we can make a simple linear extrapolation, assuming a half-life of 18 hours and ingestion of 83 mg / day. This means that after 24 hours, approximately 27.67% of the amount from the prior day remains in the system. Thus it accumulates until the body is excreting as much as is ingested. That occurs after approximately 5 days, when the in-body dosage varies between 124.5 mg immediately after ingestion to 41.5 mg immediately prior to the next ingestion.

https://i.imgur.com/zYZFjYL.png

Is that enough to have a prophylactic effect?

Well, the National Institutes of Health state that chloroquine is “a potent inhibitor of SARS coronavirus infection” [4a][13] and since SARS binds to the same cell receptors as Covid-19, and since chloroquine is a synthetic version of quinine, it would appear that it should work.

Pretreatment with 0.1, 1, and 10 μM chloroquine reduced infectivity by 28%, 53%, and 100%, respectively. [13]

The EC90 value of chloroquine against the 2019-nCoV in Vero E6 cells was 6.90 μM, which can be clinically achievable as demonstrated in the plasma of rheumatoid arthritis patients who received 500 mg administration. [14]

Interpolating the dosage of 500 mg to 6.9 μM concentration, for a dosage of 124.5 mg daily (83 mg from tonic water, the remainder being that remaining in the body from prior dosages), that should give a concentration of ~1.71 μM, reducing infectivity by ~60% immediately after ingestion of 1 L of Indian tonic water, decreasing over the next 24 hours to ~.47 μM, with a reduced infectivity of ~40%, per [13].

That would be more effective at ‘flattening the curve’ than any measures taken thus far. Covid19 has a R0 of ~2.2… so we could conceivably reduce that (assuming an average reduced infectivity of 50%) to ~1.1, effectively completely ‘flattening the curve’.

Given that no doctor is going to give you chloroquine or hydroxychloroquine as a prophylactic measure due to low supplies during a coronavirus pandemic, using Indian tonic water containing quinine to reduce infectivity would seem to be a prudent preventative measure.

The wrap-up: It would appear that quinine interferes with sialic acid biosynthesis, which the Covid19 virus takes advantage of to attach to cell receptors. If the virus has a more difficult time attaching to cells, that allows the immune system to clear the virus without having to simultaneously deal with a rapidly-spreading infection.

Addendum: It should be noted that Covid-19 (unlike SARS, MERS and the 2003 Covid virus) can utilize a second enzymatic pathway to infect cells. It is the TMPRSS2 enzyme pathway. So utilizing chloroquine or hydroxychloroquine to inhibit the ACE2 enzyme pathway, while also taking a TMPRSS2 inhibitor (camostat mesylate, for example) will act to more effectively block the virus’s ability to infect cells, thus allowing the immune system to clear the virus without also dealing with a rapidly-spreading infection. [17][18]

[1] https://www.drugs.com/npp/quinine.html

[2] https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2710.2007.00788.x

[3] https://blogs.sciencemag.org/pipeline/archives/2019/01/22/quinines-target

[4] https://www.sciencedirect.com/science/article/pii/S0924857920300881
[4a] https://pubmed.ncbi.nlm.nih.gov/16115318/

[5] https://friendslab.com/quinine-use-and-detection/

[6] https://www.drugbank.ca/drugs/DB00468

[7] https://en.wikipedia.org/wiki/Tonic_water

[8] https://en.wikipedia.org/wiki/Quinine

[9] https://healthfully.com/287838-leg-cramps-magnesium-calcium.html

[10] https://www.webmd.com/drugs/2/drug-19765/cal-mag-zinc-ii-oral/details/list-interaction-details/dmid-455/dmtitle-aluminum-and-magnesium-antacids-quinidine-quinine/intrtype-drug

[11] https://academic.oup.com/jn/article/131/2/305/4687001

[12] https://www.businessinsider.com/coronavirus-symptoms-loss-of-smell-taste-covid-19-anosmia-hyposmia-2020-3?op=1

[13] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1232869/

[14] https://www.nature.com/articles/s41422-020-0282-0

[15] https://academic.oup.com/jac/article/52/2/188/719755

[16] https://www.reddit.com/r/pharmacology/comments/6ehf0q/is_chloroquine_considered_a_prodrug/

[17] https://www.biorxiv.org/content/10.1101/2020.07.22.216150v1.full.pdf

[18] https://clinicaltrials.gov/ct2/show/NCT04321096

_________

Also from Clyde Mason:
https://www.iceagenow.info/you-can-use-tonic-to-fight-covid-19-says-reader/

The post Research paper – On the Efficacy of Tonic Water in Fighting Covid-19 appeared first on Ice Age Now.

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January 23, 2021 at 11:59AM

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