Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected *notes to self

[link to www.sciencedirect.com (secure)]

Scutellaria lateriflora

Trease and Evans' Pharmacognosy

Chapter 13 - Plant cell and tissue culture; biochemical conversions; clonal propagation

[link to www.sciencedirect.com (secure)]

[link to basicmedicalkey.com (secure)]


Nature of metabolites produced

Sometimes compounds not detected in the original plant appear in the cultures; thus, a new coumarin, rutacultin, has been isolated from suspension cell cultures of Ruta graveolens, two new chalcones have been characterized from static (callus) cultures of Glycyrrhiza echinata, sesquiterpene lactones from Andrographis paniculata cultures, new minor alkaloids and anthraquinones from Cinchona ledgeriana and C. pubescens, and tropane alkaloids, not previously obtained from the species, from belladonna root-cell suspension cultures. Recently the novel compound (2-glyceryl)-O-coniferaldehyde has been obtained from cultures of Artemisia annua and Tanacetum parthenium (L. K. Sy and G. D. Brown, Phytochemistry, 1999, 50, 781) and the quinone- methide triterpenes, tingenone and 22-hydroxytingenone, from callus cultures of Catha edulis

[link to www.sciencedirect.com (secure)]

Chalcones
Chalcones are another interesting class of compounds that have shown activity against cysteine proteases (vide supra).

...

Drugs for Parasitic Infections: Advances in the Discovery of New Antimalarials
M.A. Avery, ... K.M. Muraleedharan, in Reference Module in Chemistry, Molecular Sciences and Chemical Engineering, 2016

Chalcones
Interest in chalcones as antimalarial drug candidates started after the discovery of antimalarial activity associated with licochalcone A (127, Figure 32), a natural product isolated from Chinese licorice root.449
...
The results from this study suggest the following trends: (i) the presence of electron-withdrawing substituents on ring A or a quinoline ring at this location favors good activity; (ii) in general, the presence of electron donating groups on ring B is associated with better antimalarial activity; and (iii) an α,β-unsaturated ketone bridge is essential for activity. The most potent compound identified from this study was chalcone with an IC50 value of 0.23 ± 0.01 μM against drug-resistant strains of P. falciparum.


-----------



[link to malariajournal.biomedcentral.com (secure)]

In vitro anti-malarial efficacy of chalcones: cytotoxicity profile, mechanism of action and their effect on erythrocytes

he anti-malarial property of chalcone was first reported after an in vitro evaluation of an oxygenated chalcone, “licochalcone A” exclusively obtained from Chinese licorice, as an anti-malarial agent against chloroquine sensitive and chloroquine resistant Plasmodium strains.


The results showed significant reduction in the production of haemozoin when infected erythrocytes were treated with chloroquine and three other potent derivatives (2, 6, and 7), compared to untreated infected erythrocytes. This also suggests the similar mechanism of anti-malarial action of chalcones as the chloroquine does.

NF-KB pathway

[link to mmrjournal.biomedcentral.com (secure)]


(MDA5) and nucleotidyltransferase cyclic GMP-AMP synthase (cGAS) [63] are responsible for the recognition of viral RNA and DNA in the cytoplasm. These complex signalling recruit adaptors, including TIR-domain-containing adaptor protein including IFN-β (TRIF), mitochondrial antiviral-signalling protein (MAVS) [64] and stimulator of interferon genes protein (STING) [65] to trigger downstream cascades molecules, involving adaptor molecule MyD88 and lead to the activation of the transcription factor nuclear factor-κB (NF-KB) and interferon regulatory factor 3 (IRF3) and the production of type I Interferons (IFN-α /β) and a series of pro-inflammatory cytokines [66]. Hence, virus-cell interactions produce a diverse set of immune mediators against the invading virus [67]. Innate immunity is needed in a precise regulation to eliminate the virus, otherwise will result in immunopathology.

...

Of note, an anatomy report of COVID-19 pneumonia corpse [70] indicated that COVID-19 caused an inflammatory response in the lower airway and led to lung injury. Collectively, the virus particles invade the respiratory mucosa firstly and infect other cells, triggering a series of immune responses and the production of cytokine storm in the body, which may be associated with the critical condition of COVID-19 patients.
....

Chloroquine is a repurposed drug with great potential to treat COVID-19. Chloroquine has been used to treat malaria for many years [78], with a mechanism that is not well understood against some viral infections. Several possible mechanisms are investigated: Chloroquine can inhibit pH-dependent steps of the replication of several viruses [79], with a potent effect on SARS-CoV infection and spread [80]. Moreover, chloroquine has immunomodulatory effects, suppressing the production/release of TNF-α and IL-6. It also works as a novel class of autophagy inhibitor [81], which may interfere with viral infection and replication. Several studies have found that chloroquine interfered with the glycosylation of cellular receptors of SARS-CoV [80] and functioned at both entry and at post-entry stages of the COVID-19 infection in Vero E6 cells [82]. A combination of remdesivir and chloroquine was proven to effectively inhibit the recently emerged SARS-CoV-2 in vitro.
.....

Additionally, clinicians combined Chinese and Western medicine treatment including lopinavir/ritonavir (Kaletra®), arbidol, and Shufeng Jiedu Capsule (SFJDC, a traditional Chinese medicine) and gained significant improvement in pneumonia associated symptoms in Shanghai Public Health Clinical Center, China

-------------------------------------------------

[link to www.ncbi.nlm.nih.gov (secure)]

Shufeng Jiedu Capsule

Shufeng Jiedu Capsule protect against acute lung injury by suppressing the MAPK/NF-KB pathway.


-------------------------------

[link to www.researchgate.net (secure)]

Table 2. Active constituents of Shufeng Jiedu Capsule and responding signaling pathways (MAPK and NF-KB pathway)

Polygonum cuspidatum (Japanese knotweed)
----resveratrol
----emodin
----rhein
----quercetin

Forsythia suspensa (Forsythia)
-----rutin

Bupleurum chinense DC. (Hare's ear)
-----kaempferol
-----quercetin

Glycyrrhiza uralensis (licorice)
-----liquiritigenin
-----liquiritin

[link to onlinelibrary.wiley.com (secure)]

NF-KB modulators from Valeriana officinalis

sesquiterpenes: acetylvalerenolic acid (1), valerenal (2) and valerenic acid (3), 1 and 3 were active as inhibitors of NF-KB at a concentration of 100 µg/mL. Acetylvalerenolic acid (1) reduced NF-KB activity to 4%, whereas valerenic acid (3) reduced NF-KB activity to 25%.

[link to www.researchgate.net (secure)]

Terpenoids: natural inhibitors of NF-kB signaling
with anti-inflammatory and anticancer potential

Artemisinin
Artemisolide
Costunolide
Elephantopins
Ergolide
Helenalin - Arnica
Huperzine
Humulene - Cannabis, Hops, sage, and ginseng
Parthenolide - hawthorn, feverfew
Nepalolide
Valerenic - Valerian
Zerumbone - Ginger

-----


Avicins
Betulinic acid - birch/chaga
Boswellic acid
Celastrol
Ginsenosides - Ginseng
Glycyrrhizin - Licorice
Lupeol - Dandelion root
Saikosaponins - Bupuleurum
Ursolic acid - Rosemary/Sage/Apple/OreganoCranberry etc



---

Conclusions
There is a vast literature indicating that plant-derived
terpenoids can inhibit signaling via the NF-kB system
and hence possess beneficial therapeutic effects
against inflammatory diseases and cancer. However,
we should be cautious and aware that plants do not
synthesize terpenoids for our benefit but for their own
defense against insects [147] and environmental
threats. Some of the terpenoids are agricultural
pesticides, such as juvenile hormone, and many of
them can have toxic side-effects, as with the sesquiterpene lactones. One interesting question is why
plants might have devised the terpenoids, and attempt
to suppress NF-kB signaling, as a way of combating
hostile insects. One novel answer could be that
terpenoids are intended to destroy the immune system
of the invaders and probably also to disrupt morphogenesis mediated via NF-kB signaling.
One alarming example of the dangers which may lie in
the use of natural NF-kB inhibitors is the case of
thalidomide....

Caffeic acid phenethyl ester

Cinnamomum verum

From SARS to MERS, Thrusting Coronaviruses into the Spotlight

5.4. S Protein-Based Therapeutics for SARS-CoV and MERS-CoV
Despite the presence of extensive research reporting on SARS-CoV and MERS-CoV therapies, it was not possible to establish whether treatments benefited patients during their outbreak. In the absence of fundamental, clinically proven, effective antiviral therapy against SARS-CoV and MERS-CoV, patients mainly receive supportive care supplemented by diverse combinations of drugs. Several approaches are being considered to treat infections of SARS-CoV

Procyanidins and butanol extract of Cinnamomi Cortex inhibit SARS-CoV infection

[link to www.ncbi.nlm.nih.gov (secure)]

[link to www.jstage.jst.go.jp (secure)]

Caffeic Acid Phenethyl Ester Suppresses the Production of Proinflammatory Cytokines in Hypertrophic Adipocytes through
Lipopolysaccharide-Stimulated Macrophages

Grape polyphenols and propolis mixture inhibits inflammatory mediator release from human leukocytes and reduces clinical scores in experimental arthritis

[link to www.sciencedirect.com (secure)]



Abstract

Polyphenols from red fruits and bee-derived propolis (PR) are bioactive natural products in various in vitro and in vivo models. The present study shows that hematotoxicity-free doses of grape polyphenols (GPE) and PR differentially decreased the secretion of pro-inflammatory cytokines from activated human peripheral blood leucocytes. While GPE inhibited the monocytes/macrophage response, propolis decreased both monokines and interferon γ (IFNγ) production. When used together, their distinct effects lead to the attenuation of all inflammatory mediators, as supported by a significant modulation of the transcriptomic profile of pro-inflammatory genes in human leukocytes. To enforce in vitro data, GPE + PR were tested for their ability to improve clinical scores and cachexia in chronic rat adjuvant-induced arthritis (AA). Extracts significantly reduced arthritis scores and cachexia, and this effect was more significant in animals receiving continuous low doses compared to those receiving five different high doses. Animals treated daily had significantly better clinical scores than corticoid-treated rats. Together, these findings indicate that the GPE + PR combination induces potent anti-inflammatory activity due to their complementary immune cell modulation.

Thread: Hard facts: Drug affinities for covid19 - what works and what not?

nsaids coronavirus ACE2

[link to core.ac.uk (secure)]

Antiviral Natural Products and Herbal Medicines
Liang‑Tzung Lin1
,Wen‑Chan Hsu2
, Chun‑Ching Lin2
1
Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
2
School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan



Coronavirus Saikosaponins (A, B2
, C, D) against HCoV‑22E9 Saikosaponin B2
inhibits viral attachment and
penetration stages
[14]
Lycoris radiata and its active component
lycorine, Artemisia annua, Pyrrosia lingua, and
Lindera aggregata against SARS‑CoV
Unclear [15]
Phenolic compounds of Isatis indigotica against
SARS‑CoV
SARS‑CoV 3CL protease inhibitor [16]
Amentoflavone isolated from Torreya nucifera
against SARS‑CoV
SARS‑CoV 3CL protease inhibitor [17]
Myricetin and scutellarein against SARS‑CoV SARS‑CoV helicase inhibitor [18]
Houttuynia cordata water extract against
SARS‑CoV
SARS‑CoV 3CL protease inhibitor; viral
polymerase inhibitor

CORONAVIRUS
CoV is an enveloped, positive‑sense single‑stranded RNA(ss‑
RNA) virus belonging to the Coronaviridae family. The CoV
family consists of several species and causes upper respiratory
tract and gastrointestinal infections in mammals and birds. In
humans, it mainly causes common cold, but complications in‑
cluding pneumonia and SARS can occur.[11] The known human
CoV (HCoV) includes HCoV‑229E, ‑OC43, ‑NL63, ‑HKU1,
and the more widely known severe acute respiratory syndrome
coronavirus (SARS‑CoV) which caused a global threat with
high mortality in 2003.[12] In 2012, the World Health Organiza‑
tion (WHO) designated a sixth type of HCoV infection identified as
the Middle East respiratory syndrome coronavirus (MERS‑CoV)
which is associated with high fatality.[13]
There are no specific treatments for CoV infection and pre‑
ventive vaccines are still being explored. Thus, the situation
reflects the need to develop effective antivirals for prophylaxis
and treatment of CoV infection. We have previously reported
that saikosaponins (A, B2
, C, and D), which are naturally occur‑
ring triterpene glycosides isolated from medicinal plants such
as Bupleurum spp. (柴胡 Chái Hu), Heteromorpha spp., and
Scrophularia scorodonia (玄參 Xuán Shēn), exert antiviral ac‑
tivity against HCoV‑22E9.[14] Upon co‑challenge with the virus,
these natural compounds effectively prevent the early stage of
HCoV‑22E9 infection, including viral attachment and penetration.
Extracts from Lycoris radiata (石蒜 Shí Suàn), Artemisia annua
(黃花蒿 Huáng Huā Hāo), Pyrrosia lingua (石葦 Shí Wěi), and
Lindera aggregata (烏藥 Wū Yào) have also been documented to
display anti–SARS‑CoV effect from a screening analysis using hun‑
dreds of Chinese medicinal herbs.[15] Natural inhibitors against the
SARS‑CoV enzymes, such as the nsP13 helicase and 3CL protease,
have been identified as well and include myricetin, scutellarein,
and phenolic compounds from Isatis indigotica (板藍根 Bǎn Lán
Gēn) and Torreya nucifera (榧 Fěi).[16‑18] Other anti‑CoV natural
medicines include the water extract from Houttuynia cordata
(魚腥草 Yu Xīng Cǎo), which has been observed to exhibit several
antiviral mechanisms against SARS‑CoV, such as inhibiting the
viral 3CL protease and blocking the viral RNA‑dependent RNA
polymerase activity.[19]

[link to core.ac.uk (secure)]

There are no specific treatments for CoV infection and pre‑
ventive vaccines are still being explored. Thus, the situation
reflects the need to develop effective antivirals for prophylaxis
and treatment of CoV infection. We have previously reported
that saikosaponins (A, B2
, C, and D), which are naturally occur‑
ring triterpene glycosides isolated from medicinal plants such
as Bupleurum

Chloroquine treatment + doses

Didier raoult
@raoult_didier
Several states have already included hydroxychloroquine or chloroquine in their therapeutic recommendations for the treatment of Covid-19 as soon as symptoms of the virus are detected.

[link to twitter.com (secure)]


French decree on chloroquine

[link to www.legifrance.gouv.fr (secure)]



LE Monde on Chloroquine

[link to www.lemonde.fr (secure)]



Thread: HUGE! French Study finds Hydroxychloroquine EVERY PATIENT in Study Group of 80

propolis and grape seed extract for the storm

Caffeic acid phenethyl ester (CAPE), the main component of propolis

Thread: Surgeon Duc C. Vuong, explains how the Corona virus kills you. URGENT INFO, get in here GLP

Determination of catechins in matcha green tea by micellar electrokinetic chromatography


Catechins in green tea are known to have many beneficial health properties. Recently, it has been suggested that matcha has greater potential health benefits than other green teas. Matcha is a special powdered green tea used in the Japanese tea ceremony. However, there has been no investigation to quantitate the catechin intake from matcha compared to common green teas. We have developed a rapid method of analysis of five catechins and caffeine in matcha using micellar electrokinetic chromatography. Results are presented for water and methanol extractions of matcha compared with water extraction of a popular green tea. Using a mg catechin/g of dry leaf comparison, results indicate that the concentration of epigallocatechin gallate (EGCG) available from drinking matcha is 137 times greater than the amount of EGCG available from China Green Tips green tea, and at least three times higher than the largest literature value for other green teas.


Zinc Ionophore Activity of Quercetin and Epigallocatechin-gallate:
[link to pubs.acs.org (secure)]
In order to confirm that the polyphenols transport zinc cations across the plasma membrane independently of plasma membrane zinc transporters, QCT, epigallocatechin-gallate, or clioquinol (CQ), alone and combined with zinc, were added to unilamellar dipalmitoylphosphocholine/cholesterol liposomes loaded with membrane-impermeant FluoZin-3. Only the combinations of the chelators with zinc triggered a rapid increase of FluoZin-3 fluorescence within the liposomes, thus demonstrating the ionophore action of QCT, epigallocatechin-gallate, and CQ on lipid membrane systems.

[link to blogs.sciencemag.org (secure)]

CHEMICAL NEWS
Chloroquine, Past and Present
By Derek Lowe 20 March, 2020

-----------------------------------

Ron T says:
24 March, 2020 at 8:40 pm
Derek, my wife says I need to contact CDC or someone with my successful use of Cinchona Bark tea (quinine quinidine) against my unconfirmed Covid infection.

I believe my case shows evidence of the efficacy of Quinine because on Day 6-12 I had much improved symptoms after developing a concrete lung feeling and on Day 5 a drowining feeling. But when I stopped the Quinine for 24 hours on Day 12. (out of concern for the recent press about side effects), within 24 hours I went to having severe breathing difficulties and literally feeling like I was drowning. I made the choice to drink the tea as preferable to dying. An hour later I was able to sleep. Now 37 hours later I feel excellent.

My urgent care visits in Day 3 and 14 both showed completely clear lungs with no hint of any infection.

My oxygen on Day 14 was still 99% even though I felt slightly hypoxic. Is there some way the fingertip oxygen test was fooled by the virus? I read a chinese paper referenced below that somehow covid attacks hemoglobin. It’s above my education level.

Please help me understand why these worked. I hear the zinc allowed in theory and the endosome prevention theory. What do you think is really going on?

And please email me who I should contact. I believe this is evidence – the stopping and starting of quinine correlating exactly to my symptoms is evidence.

[link to chemrxiv.org (secure)]

On Day 1 I woke up with “concrete chest tightness”. On Day 3 I was not tested for covid because I never had a fever.

On Day 5 I woke up gasping for air.

On Day 6 I bought Red Cinchona Bark tea and took the “traditional dose” I researched online (1-3 grams day). By the afternoon I had immediate improvement.

Day 6-12 I had no chest tightness, but had strange symptoms moving through parts of my body, such as a moving full feeling in various parts of my lungs.

Day 12 stopped Quinine out of fear for mis dose, QT prolongation etc

Day 12-14 above. Once I show no symptoms for three days I can leave self quarantine.



Reply
Deborah Hernandez says:
26 March, 2020 at 10:50 pm
Thanks for this Ron T. I came across some leg cramp pills from Hylands that has the cinchona ingredient in them for my girlfriend when her lungs were hurting so bad that she couldn’t hardly move. They would not even see her at the doctor for the same reasons you say, no fever. I started researching and found out about this Peruvian bark. Went out immediately and purchased this over the counter leg cramp medicine. It has been 2 days now of taking it and she feels like a new Person! She is by no way healed yet but her pain has diminished and she is on the upswing. Cant believe it!

She is trying to help by telling people and I feel like trying to tell the CDC will for certain go upon deaf ears. She has existing health problems due to a car accident causing her to be more susceptible to infection. She is missing half of one of her lungs and doesn’t have a spleen.

It is nice to see someone experiencing the same results. She felt immensely better in the hour after her first dose.




Becky says:
25 March, 2020 at 12:23 am
Ron t….. I have cinchona bark what is as your tea recipe and dosage



Reply
Ron T says:
25 March, 2020 at 10:44 am
I found online the traditional cinchona tea recipe/dose was 1-3 grams a day for malaria. I used this dose because I found Chinas current recommended dose of hChloroquine for covid was the same dose widely used for once you have malaria (not the prophylactic malaria dose which is much less.)

Chemistry people on here could look it up (please do) but near as I could tell 1 gram of red cinchona equals about 1 400mg hchloroquine pill. So I’m doing 1 gram of tea in morning and 1 gram at night.

Warning: 6 grams is fatal!

To measure I used 1/4 a teaspoon for 1 gram. Steep in boiling water for 7 minutes. I include large and small bark particles evenly, avoid just using dust because the dose will be too strong.

The half life is 6 hours

The Gram-positive soil bacterium Streptomyces avermitilis produces geosmin

(avermectins Abamectin Doramectin Emamectin Ivermectin #Selamectin milbemycins Moxidectin Milbemycin oxime)

Avermectin
From Wikipedia, the free encyclopedia
Jump to navigationJump to search

Ivermectin, one of the avermectins
The avermectins are a series of drugs and pesticides used to treat parasitic worms and insect pests. They are a 16-membered macrocyclic lactone derivatives with potent anthelmintic and insecticidal properties.[1][2] These naturally occurring compounds are generated as fermentation products by Streptomyces avermitilis, a soil actinomycete. Eight different avermectins were isolated in four pairs of homologue compounds, with a major (a-component) and minor (b-component) component usually in ratios of 80:20 to 90:10.[2] Other anthelmintics derived from the avermectins include ivermectin, selamectin, doramectin, eprinomectin, moxidectin, and abamectin.

Half of the 2015 Nobel Prize in Physiology or Medicine was awarded to William C. Campbell and Satoshi Ōmura for discovering avermectin, "the derivatives of which have radically lowered the incidence of river blindness and lymphatic filariasis, as well as showing efficacy against an expanding number of other parasitic diseases."[3]

Glycyrrhiza glabra Fabaceae Licorice-Root; Licorice; Smooth Licorice; Commom Licorice Leaf 100-1000

nicotinic acid

niacin

[link to pubchem.ncbi.nlm.nih.gov (secure)]

[link to www.heighpubs.org (secure)]


Acute mountain sickness may cause headache, insomnia, dizziness, nausea, vomiting
and fatigue. While HACE is more serious stage where brain swelling occurs and it is
potentially fatal

In one of our study, Das et al. [2], has shown that hypobaric hypoxia induces
working memory impairment. Study reported that endogenous ligand HMGB1 get
upregulated in Rats’ brain when exposed to hypobaric hypoxia while treatment with
andrographolide an active constituents of a plant Andrographis paniculata inhibit
the expressions of HMGB1. The decreased expression HMGB1 leads to decreased
expression of NF-kB and secretion of pro-inϐlammatory cytokines, therefore decreased
apoptosis.
Thus, neuroinϐlammation induced neurodegeneration may be prevented by the
use of andrographolide. In conclusion, endogenous ligands of TLRs could be important
therapeutic target for prevention of high altitude induced memory impairment.

[link to www.sciencedirect.com (secure)]

Pathogenic role of HMGB1 in SARS?


Pathogenic role of HMGB1 in SARS?
An excessive immune response to acute coronavirus infection appears to be the fatal factor in patients who die of SARS [18], [19], [20], [21]. Autopsy of SARS patients revealed signs of diffuse alveolar damage, airspace edema, and bronchiolar fibrin [19], [20], [21]. Our hypothesis is that initial acute coronavirus infection of alveolar endothelial cells or macrophages leads to cell injury via virus-mediated cytolysis, which is accompanied by HMGB1 release from damaged cells (Fig. 2). Extracellular HMGB1, as a mediator of acute lung injury [13], subsequently mediates injurious pulmonary inflammatory responses including neutrophil infiltration, derangement of epithelial barrier, lung edema, and lung injury. Collectively, these injurious pulmonary inflammatory responses may consequently lead to respiratory failure, and death.

Figure 2. Hypothetical role of HMGB1 in the pathogenesis of SARS. HMGB1 is released from coronavirus infected cells, and then stimulates excessive inflammatory responses.

[link to www.ncbi.nlm.nih.gov (secure)]

Protective Effect of Glycyrrhizin, a Direct HMGB1 Inhibitor, on Focal Cerebral Ischemia/Reperfusion-Induced Inflammation, Oxidative Stress, and Apoptosis in Rats


[link to www.ncbi.nlm.nih.gov (secure)]

Glycyrrhizin binds to high-mobility group box 1 protein and inhibits its cytokine activities.
Mollica L1, De Marchis F, Spitaleri A, Dallacosta C, Pennacchini D, Zamai M, Agresti A, Trisciuoglio L, Musco G, Bianchi ME.

etc