Uncomfortably Numb

For some time I’ve had a strange condition that even my doctor has not been able to explain. Nor has he suggested any tests that might put light on the matter.

Is it neurological or circulation? Or something else.

The tip of the ring finger on my right hand is numb. Sometimes it is itchy, as if bitten by a mosquito. I feel pressure if I touch it but it seems to have no operational pain receptors, as I can poke it with a pin without sensation other than a hint of pressure.

I have no explanation. But it seems ironic that the Romans and other old societies believed this finger is connected directly to the heart, which explains why it is the ring finger

It is difficult to photograph ones right hand with a cellphone, using ones left hand.

Something More Sinister Pt. 2

This morning Mehdi revealed what he was concerned about. He is still not happy with the latest blood test results. They may point towards myeloma. I’d never heard of it. I had to look it up.

The good news is that it is treatable.

So. Not diagnosed yet, but hypothesised. Referral to a specialist pending. Watch this space for developments.

Myeloma

A cancer of plasma cells.The plasma cells are a type of white blood cell in the bone marrow. With this condition, a group of plasma cells becomes cancerous and multiplies. The disease can damage the bones, immune system, kidneys and red blood cell count.


Treatable by a medical professional. Requires a medical diagnosis. Lab tests or imaging always required. For informational purposes only. Consult your local medical authority for advice.

Sources: Mayo Clinic and others. Learn more

The President’s Brain is Missing.

I doubt there is a sane person left who believes Trump has any sense, or any credibility, whatsoever. Following the news as it unfolds in the US is like watching some surreal black comedy.

It’s something Peter Sellars might have made with Stanley Kubrick – Dr Kidglove, or How I Learned to Stop Thinking and Follow the Trump.

COVID-19 CORONAVIRUS / DEATH TOLL 

Last updated: April 25, 2020, 09:17 GMT
Coronavirus Death Toll

197,694 people have died so far from the coronavirus COVID-19 outbreak as of April 25, 2020, 09:17 GMT.
There are currently 2,836,338 confirmed cases in 210 countries and territories . The fatality rate is still being assessed.

Follow the world-wide statistics, or country by country, here.

At the risk of being considered crepidarian: There is no doubt this COVID19 pandemic is just as scary as WHO said it could be. We are seeing now that the countries with the lowest infection and mortality curves are the ones with the best, and quickest lockdown response. Go New Zealand.

Now that testing is becoming more prevalent, and more reliable, many countries are finding evidence there is a significant proportion of asymptomatic infectious carriers among the apparently healthy population. These are not all being numbered among confirmed cases.

In our current world, this is about as apocalyptic as it gets.

I’m sure they said the same thing during the great flu pandemic of 1918 when about 500 million people or one-third of the world’s population became infected and the number of deaths worldwide was estimated to be at least 50 million.

The population of the world is exponentially greater now. So is the risk.

Stay safe out there. Good Luck.

Why Science Works

The chloroquine theory. Some real data, and an explanation of how and why it doesn’t work.

Thanks, Glenn for this.

Hopefully this takes some of air out of the hype machine:

https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v1

368 patients evaluated (all of them male, all over age 65, all veterans because that's where the data came from):

In this study, we found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19. An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone.

One interesting point this study does clarify; the original interest in chloroquine was because it is demonstrably effective in a petri dish; stops SARS-CoV-2 dead in its tracks. The difference is in a petri dish, they were getting concentrations of 4.5-17 µM, but the safe range in a human is around 1 µM. Trying to replicate the petri dish concentrations in living humans resulted in patients dying faster than COVID-19 would have killed them.

A Scholarly Analysis of a Classic PC* Poem

*PC = post coronavirus.

By a scholarly poet analyst.

The Poem:

I do not like you little fly
And I shall surely tell you why
You walk on shyte and things that die
And then you land upon my pie.

Don’t come here with your shitty feet
And walk across the things I eat
I just want pastry, gravy, meat,
Not hours upon a toilet seat

So shoo fly, do not bother me
Fly far away and let me be
I only want to eat my tea
Not
Campylobacter jejeuni.

Scholarly analysis:

The poet has used several literary devices to consolidate his theme. Firstly he has chosen to write only three quatrains with a simple aaaa bbbb cccc rhyme scheme. This sets out the poem in a deceptive, child-like simplicity, almost as if the it were a nursery rhyme, seemingly concealing rather than accentuating the depth and significance of the tragic theme.

Subtle.

He uses internal rhymes, assonance and alliteration to establish a rhythm that seems to support the nursery rhyme theme, belying once again the significance, indeed, the very the depths of despair and desolation plumbed in the work. For it is important to know that this opus was written during the great pandemic of 2020, when people around the world sat isolated in in their homes, afraid of death, and talking to flies. And dying.

He hauntingly starts the first and third verses with clever literary references to great literary works written before; one an ancient Latin tale of distrust*, translated and extemporised, it is said, by Tom Brown himself during his schooldays, and the other a song now considered racist, by Brigham Bishop. It was ostensibly about a fly and a negro soldier in Company B during the American civil war. It may have deeper, darker meaning. He was not the boogie woogie bugle boy.

Both references reflect and project the anxiety and stress of the poet’s own times.

It is known the poet suffered a serious bout of Campylobacter diarrhoea shortly before he wrote this poem. It was severe, and lasted eight days, at the end of which he was beginning to fear he might not just pass more crap than should really be in one man at any one time, but actually pass away.

When he survived, and recovered, he wrote an ode in gratitude

The poem ends with both a bit of scientific erudition, and poetic licence with the pronunciation of jejeuni.

Masterful.

So this poem can be seen not as simple doggerel, but a deep and meaningful metaphor describing the poet’s state of mind, and the state of the world around him, in which the pie represents a life full of happiness and fulfilment (meat and gravy), the fly a wandering traveller, unknowingly infected – or perhaps a thoughtless fucking food vendor who made a ham and egg burger after not washing his hands after using the toilet on Friday the 20th of last month at about 06:30 just after I picked up Lyn at the airport – (sorry!) – thus unintentionally bringing chaos and pain with him.

The brevity of the poem mirrors the brevity of life itself. The three verses represent the three stages of life; childhood, maturity and decrepitude, also known in literary circles as beginning, middle and end. The poet pulls no punches here.

In the poem, the toilet seat is a subtle metaphor for social isolation enforced as Lockdown, that leaves people sitting alone and lonely at home, unable to leave. Unable to be in company.

“Eat my tea” is a metaphor for “live my life”.

Campylobacter jejeuni is clearly also a metaphor, and a clever one at that, for the dread COVID 19 coronavirus that threatens the enjoyment of life itself.

By cleverly not mentioning toilet paper, a necessity when one has the trots, the poet brings it to mind by carefully not juxtaposing shitty and toilet seat in the same verse. This reminds us of the vast amounts of paper (read money) that the pandemic is costing society.

My word this guy packs a lot of meaning between a few lines.

Image Stolen from Internet

You didn’t know I could be so bloody deceptively deep.

Poem and scholarly analysis © 2020 ARF

*Non amo te, Sabidi, nec possum dicere quare.
Hoc tantum possum dicere: non amo te.

I do not love thee Doctor Fell, Why this is I cannot tell, but this I know, and know full well. I do not love thee Doctor Fell.

Don’t Panic.

We have normality. I repeat, we have normality.

Anything you still can’t cope with is therefore your own problem.

Douglas Adams

After the great double excision on Monday, Mehdi was concerned that the deeper procedure may infect, so he prescribed a prophylactic course of antibiotics, which I started taking that very day. I had confidently assured him that never in my sorry life had I an adverse reaction to antibiotics. I’ve had a lot of antibiotics.

I was so sure that when the diarrhoea started, I blamed my own cooking. I fed perfectly good nasi goreng to the wildlife.

Worse: I, the greatest food safety expert of the post HACCP age, doubted himself.

For that afternoon and the next two days, I spent my time hurrying to the latrine, sanitising all the surfaces I touched, and dozing in an increasingly weak stage of lassitude. Drinking water, black coffee and coke, eating bread and marmite.

I began to suffer chills and cold sweats, fever, disorientation weakness and lassitude, and generally feeling poorly.

I was concerned for my kidneys, so I drank copiously (which has consequences) and checked my bp regularly.

My blood pressure was fluctuating but when it dropped to 78/54 and an hour later had only recovered to 89/56, I began to worry.

I rang the surgery; the receptionist suggested I ring the COVID-19 1800 number.

I called the COVID-19 1800 number. The young person ran me through the questionnaire, and despite some ‘yes’ replies she assured me I was not COVID material,

Therefore I was of no interest to her. She wished me well, having more important things to do.

I rang 000. In a very reasonable time a paramedic in an ambulance pulled up outside my plot. He was originally from my birthplace, Woking. How about that?

He asked all the questions again, plus more. He inspected my meds, and made the rattle when you walk joke, while he hooked me up to the portable machine that goes Ping!

Once that piece of medical tech is deployed, one knows all will be well. One is in the hands of an expert. They don’t let just anybody play with that.

He then gave me the most well considered and carefully reasoned explanation of why he believed I had at last found an antibiotic that did not agree with me.

By the end of tomorrow I hope to know he is right.

Twelve Monkeys

It’s happening.

Good for NZ.

A THOUGHT FOR TODAY:

Many people consider the things government does for them to be social progress but they regard the things government does for others as socialism.

Earl Warren, Chief Justice of the US Supreme Court (19 Mar 1891-1974) 

Wonder of the Week 2

An Effective Treatment for Coronavirus (COVID-19)

Thanks to Glenn for bringing this to my attention.

Presented by: James M. Todaro, MD (Columbia MD, jtodaro2@gmail.com) and Gregory J. Rigano, Esq. (grigano1@jhu.edu)

In consultation with Stanford University School of Medicine, UAB School of Medicine and National Academy of Sciences researchers.

March 13, 2020

SPANISH: https://docs.google.com/document/d/e/2PACX-1vR1adodKPhWalV9djnerI2x_v1LGgGyhZZxpl0O5r-ZNyDdagqFq1rTCxXBqaeicfxgvypDOqKCZVyV/pub

        Translation by: Celia Martínez-Aceves (Yale B.S. Candidate 2021; celia.martinez-aceves@yale.edu),  Martín Martínez (MIT B.S. 2017 ; martin.martinez.mit@gmail.com)

ITALIAN: https://docs.google.com/document/d/e/2PACX-1vSjPNh_WX6FXUIE3OaA3ScsW7yIH3-SpZyYzElNQUNuJvDmD9eFzM29mVXeaYRY-rjGv52wkrZNa7tb/pub

        Translation by: Google Translate and edited by Ross Shulman, Cornell University MS ’20 ross.shulman@gmail.com

Summary

Recent guidelines from South Korea and China report that chloroquine is an effective antiviral therapeutic treatment against Coronavirus Disease 2019.  Use of chloroquine (tablets) is showing favorable outcomes in humans infected with Coronavirus including faster time to recovery and shorter hospital stay.  US CDC research shows that chloroquine also has strong potential as a prophylactic (preventative) measure against coronavirus in the lab, while we wait for a vaccine to be developed.  Chloroquine is an inexpensive, globally available drug that has been in widespread human use since 1945 against malaria, autoimmune and various other conditions.   

Chloroquine: C18H26ClN3

Background

The U.S. CDC and World Health Organization have not published treatment measures against Coronavirus disease 2019 (“COVID-19”).  Medical centers are starting to have issues with traditional protocols.  Treatments, and ideally a preventative measure, are needed.   South Korea and China have had significantly more exposure and time to analyze diagnostic, treatment and preventative options.  The U.S., Europe and the rest of the world can learn from their experience.  According to former FDA commissioner, board member of Pfizer and Illumina, Scott Gotlieb MD, the world can learn the most about COVID-19 by paying closest attention to the response of countries that have had significant exposure to COVID-19 before the U.S. and Europe.[1]

As per the U.S. CDC, “Chloroquine (also known as chloroquine phosphate) is an antimalarial medicine… Chloroquine is available in the United States by prescription only… Chloroquine can be prescribed for either prevention or treatment of malaria. Chloroquine can be prescribed to adults and children of all ages. It can also be safely taken by pregnant women and nursing mothers.”[2]

CDC research also shows that “chloroquine can affect virus infection in many ways, and the antiviral effect depends in part on the extent to which the virus utilizes endosomes for entry. Chloroquine has been widely used to treat human diseases, such as malaria, amoebiosis, HIV, and autoimmune diseases, without significant detrimental side effects.”[3]

The treatment guidelines of both South Korea and China against COVID-19 are generally consistent, outlining chloroquine as an effective treatment.

Specifically, according to the Korea Biomedical Review, in February 2020 in South Korea, the COVID-19 Central Clinical Task Force, composed of physicians and experts treating patients agreed upon treatment principles for patients with COVID-19.[4]  In China, the General Office of the National Health Commission, General Office of the State Administration of Traditional Chinese Medicine as well as a Multi-Center Collaborative Group of Guangdong Provincial Department of Science and Technology and Guangdong Provincial Health Comp and the China National Center for Biotechnology Development have established effective treatment measures based on human studies.[5]

 According to their research (reported in Clinical Trials Arena), 

“Data from the drug’s [chloroquine] studies showed ‘certain curative effect’ with ‘fairly good efficacy’ … patients treated with chloroquine demonstrated a better drop in fever, improvement of lung CT images, and required a shorter time to recover compared to parallel groups.  The percentage of patients with negative viral nucleic acid tests was also higher with the anti-malarial drug…  Chloroquine has so far shown no obvious serious adverse reactions in more than 100 participants in the trials…  Chloroquine was selected after several screening rounds of thousands of existing drugs.  Chloroquine is undergoing further trials in more than ten hospitals in Beijing, Guangdong province and Hunnan province.”[6]

Treatment Guidelines from South Korea[7]

According to the Korea Biomedical Review, the South Korean COVID-19 Central Clinical Task Force guidelines are as follows:

1.        If patients are young, healthy, and have mild symptoms without underlying conditions, doctors can observe them without antiviral treatment;

2.        If more than 10 days have passed since the onset of the illness and the symptoms are mild, physicians do not have to start an antiviral medication;

3.        However, if patients are old or have underlying conditions with serious symptoms, physicians should consider an antiviral treatment. If they decide to use the antiviral therapy, they should start the administration as soon as possible:

… chloroquine 500mg orally per day.

4.        As chloroquine is not available in Korea, doctors could consider hydroxychloroquine 400mg orally per day (Hydroxychloroquine is an analog of chloroquine used against malaria, autoimmune disorders, etc.  It is widely available as well).

5.        The treatment is suitable for 7 – 10 days, which can be shortened or extended depending on clinical progress.

Notably, the guidelines mention other antivirals as further lines of defense, including anti-HIV drugs.

Treatment Guidelines from China[8]

According to China’s Novel Coronavirus Pneumonia Diagnosis and Treatment Plan, 7th Edition, the treatment guidelines are as follows:

1. Treatment for mild cases includes bed rest, supportive treatments, and maintenance of caloric intake. Pay attention to fluid and electrolyte balance and maintain homeostasis. Closely monitor the patient’s vitals and oxygen saturation.

2. As indicated by clinical presentations, monitor the hematology panel, routine urinalysis, CRP, biochemistry (liver enzymes, cardiac enzymes, kidney function), coagulation, arterial blood gas analysis, chest radiography, and so on. Cytokines can be tested, if possible.

3. Administer effective oxygenation measures promptly, including nasal catheter, oxygen mask, and high flow nasal cannula. If conditions allow, a hydrogen-oxygen gas mix (H2/O2: 66.6%/33.3%) may be used for breathing.

4. Antiviral therapies: 

… chloroquine phosphate (adult 18-65 years old weighing more than 50kg: 500mg twice daily for 7 days; bodyweight less than 50kg: 500mg twice daily for day 1 and 2, 500mg once daily for day 3 through 7) …

Additionally, the Guangdong Provincial Department of Science and Technology and the Guangdong Provincial Health and Health Commission issued a report stating “Expert consensus on chloroquine phosphate for new coronavirus pneumonia: … clinical research results show that chloroquine improves the success rate of treatment and shortens the length of patient’s hospital stay.”[9]  The report further goes on to cite research from the US CDC from 2005 as well as research from the University of Leuven University in Belgium regarding chloroquine’s effectiveness against SARS coronavirus at the cellular level.[10]

Like the South Korean guidelines, notably, other antivirals (e.g. anti-HIV drugs) are listed as further lines of defense.  The most research thus far has been around chloroquine.

Chloroquine as a prophylactic (preventative) measure against COVID-19[11]

According to research by the US CDC, chloroquine has strong antiviral effects on SARS coronavirus, both prophylactically and therapeutically.  SARS coronavirus has significant similarities to COVID-19.  Specifically, the CDC research was completed in primate cells using chloroquine’s well known function of elevating endosomal pH.  The results show that “We have identified chloroquine as an effective antiviral agent for SARS-CoV in cell culture conditions, as evidenced by its inhibitory effect when the drug was added prior to infection or after the initiation and establishment of infection. The fact that chloroquine exerts an antiviral effect during pre- and post-infection conditions suggest that it is likely to have both prophylactic and therapeutic advantages.”

The study shows that chloroquine is effective in preventing SARS-CoV infection in cell culture if the drug is added to the cells 24 h prior to infection. 

FIGURE 1

Prophylactic effect of chloroquine. Vero E6 cells pre-treated with chloroquine for 20 hrs. Chloroquine-containing media were removed and the cells were washed with phosphate buffered saline before they were infected with SARS-CoV (0.5 multiplicity of infection) for 1 h in the absence of chloroquine. Virus was then removed and the cells were maintained in Opti-MEM (Invitrogen) for 16–18 h in the absence of chloroquine. SARS-CoV antigens were stained with virus-specific HMAF, followed by FITC-conjugated secondary antibodies. (A) The concentration of chloroquine used is indicated on the top of each panel. (B) SARS-CoV antigen-positive cells at three random locations were captured by using a digital camera, the number of antigen-positive cells was determined, and the average inhibition was calculated. Percent inhibition was obtained by considering the untreated control as 0% inhibition. The vertical bars represent the range of SEM.

In the case of chloroquine treatment prior to infection, the impairment of terminal glycosylation of ACE2 may result in reduced binding affinities between ACE2 and SARS-CoV spike protein and negatively influence the initiation of SARS-CoV infection.  The cell surface expression of under-glycosylated ACE2 and its poor affinity to SARS-CoV spike protein may be the primary mechanism by which infection is prevented by drug pretreatment of cells prior to infection.

In addition, the study also shows that chloroquine was very effective even when the drug was added 3–5 h after infection, suggesting an antiviral effect even after the establishment of infection.

Figure 2

Post-infection chloroquine treatment reduces SARS-CoV infection and spread. Vero E6 cells were seeded and infected as described for Fig. 1 except that chloroquine was added only after virus adsorption. Cells were maintained in Opti-MEM (Invitrogen) containing chloroquine for 16–18 h, after which they were processed for immunofluorescence. (A) The concentration of chloroquine is indicated on the top. (B) Percent inhibition and SEM were calculated as in Fig. 1B. (C) The effective dose (ED50) was calculated using commercially available software (Grafit, version 4, Erithacus Software).

When chloroquine is added after infection, it can rapidly raise the pH and subvert on-going fusion events between virus and endosomes, thus inhibiting the infection.  When added after the initiation of infection, it likely affects the endosome-mediated fusion, subsequent virus replication, or assembly and release.  Specifically, rapid elevation of endosomal pH and abrogation of virus-endosome fusion may be the primary mechanism by which virus infection is prevented under post-treatment conditions.

The US CDC study goes on to conclude that: 

“The infectivity of coronaviruses other than SARS-CoV are also affected by chloroquine, as exemplified by the human CoV-229E [15]. The inhibitory effects observed on SARS-CoV infectivity and cell spread occurred in the presence of 1–10 μM chloroquine, which are plasma concentrations achievable during the prophylaxis and treatment of malaria (varying from 1.6–12.5 μM) [26] and hence are well tolerated by patients.  Chloroquine, a relatively safe, effective and cheap drug used for treating many human diseases including malaria, amoebiasis and human immunodeficiency virus is effective in inhibiting the infection and spread of SARS CoV in cell culture.”

COVID-19 and Chloroquine: Mechanisms of Action[12]

COVID-19 in a single stranded, positive strain RNA virus with a protein shell and membrane.  The genome is of the same sense of the mRNA.  It goes through a lifecycle where incoming viral COVID genome has to become double stranded RNA and the new strand becomes the new strand for the new mRNA.  There are significant similarities between COVID-19 and SARS coronavirus.  Both COVID-19 and SARS-like coronaviruses have machinery for regulating their own replication and production of their proteins.  Coronavirus depends on the breakdown of macromolecules such as proteins.  Specifically, the virus depends on turning over the host proteins to trigger response for available building blocks to make their own proteins or nucleic acids.  They break down due to low PH catalyzed by hydrolysis. Additionally, coronaviruses have non-structural proteins that are not part of the capsid (protein shell of the virus).  These non-structural proteins are regulatory proteins that take over the host cell and suppress the immune system of the host (similar to HIV).  Coronavirus can create growth factor like mechanisms (e.g. cytokines) to optimize the growth environment in the cell to favor it.

It is this part of the coronavirus’ replicative path that chloroquine inhibits.  Notably, because of its nitrogen structure, chloroquine has the unique ability to get into cells and cross endosomal membranes.  Once inside, nitrogens in chloroquine (and quinines in general) prevent acidification by absorbing a high amount of hydrogens that simply then interact with nitrogen and then chloroquine becomes positively charged – an ionic interaction which makes it harder for the endosome to become acidified.  The result is a buffer that holds it at the higher pH and prevents it from becoming acidic enough to be functional.  To summarize, because chloroquine has a multitude of extra nitrogens, once it crosses the membrane and enters an organelle, the organelle is prevented from reaching a lower pH.  The organelle’s enzymes cannot work because the donor group will be a hydrogen ion, disabling the hydrolysis required for coronavirus replication.  This means that all kinds of events in the cell are incapable of performing optimally, including viral replication. 

Chloroquine’s entrance into the organelle likely constipates the whole system.  An analogy is that the virus is like a garbage facility which has to break down and burn up the garbage and if it cannot, the garbage piles up and the city becomes paralyzed.  This is likely the case for any virus, cancer cells or any other condition that is dependent on turning over the worn out or incorrectly synthesized proteins.

The UK has banned the export of Chloroquine[13]

As of February 26, 2020, the UK government has added chloroquine to the list of medicines that cannot be parallel exported from the UK.  Chloroquine was never on this list before.  This likely happened because of the growing body of evidence of chloroquine’s effectiveness against coronavirus.

China prioritizes internal use of Active Pharmaceutical Ingredients (APIs) including Chloroquine[14]

In early February, Chongqing Kangle Pharmaceutical was requested by the Ministry of Industry and Information Technology, Consumption Division to promptly increase the manufacturing and production of the active pharmaceutical ingredients chloroquine phosphate despite slowed production during the Chinese New Year. 

Key Risks and Tradeoffs

There has been massive de-stabilization of society due to COVID-19. 

Mutations[15]

RNA viruses are subject to fairly high mutation rates as RNA based genomes do not copy themselves faithfully, thereby accumulating mutations quickly which can lead to failure of the virus (analogy: unaudited software code will often eventually fail due to a critical error) or can lead to a stronger mutation – which is likely what has happened in 2020 (when coronavirus “jumped” from animal to human; it is doubtful that this has occurred because of the use of chloroquine) as we have have two forms of COVID-19 (“more aggressive” and “less aggressive”).  If the replication quality of RNA virus like coronavirus can be destabilized this will likely cause it to self destruct, but there is always the risk that the virus mutates to become more aggressive.

Treating COVID-19 with chloroquine, as is being done in South Korea and China does have the potential to lead to a mutation.  The mutation can either be beneficial or harmful to humans.    In this particular case, chloroquine is likely being used to destabilize the replication quality of COVID-19, providing significant potential for COVID-19 to self-destruct, which would likely bide more time for health systems worldwide to increase capacity and equipment as well as allow time for the public release of a vaccine.  All precaution must be taken into account for the risk of escape where COVID-19 comes out stronger.

Manufacturing

Chloroquine and its analogs has been manufactured and distributed at global scale since approximately 1945.  While there has recently been a shortage of N95 protective masks, medical systems can adjust and dramatically increase the supply of chloroquine in the world.  Chloroquine tablets and intravenous formulations are generic and easy to produce.

Safety[16]

Chloroquine is a prescription drug.  It can have side effects and has contraindications.  One often cited side effect is chloroquine retinopathy, which can result in permanent vision loss after high cumulative doses of chloroquine. However, retinal damage is extremely rare in patients with a total dosage under 400g (dosage level only reached after years of treatment). Medical professionals must be consulted before use of chloroquine. Chloroquine tablets are readily available in the U.S. and have never been removed from the market. Intravenous chloroquine was taken off the market in the USA pre-2000 because of the absence of acute malarial infections in the USA – there was no use for the intravenous form.  It can easily be brought back to the market.

Formulation Optimizations[17]

Tablet vs. Intravenous

Currently chloroquine is most widely administered in tablet form (chloroquine phosphate.  While readily available, the issue is that when the tablet is ingested, it must be processed through the stomach and be taken up by the small intestine, for which then it enters the blood and subsequently the respiratory system.  Because of the metabolism, this takes time and there is a loss of chloroquine delivery to the respiratory system (where COVID-19 replicates).

When chloroquine is used intravenously against malaria (chloroquine hydrochloride), it is being mainlined directly into the blood stream so that it is distributing around the body within seconds, likely encountering the virus faster and at a higher concentration in the respiratory system.  Intravenous formulations are readily available and should be studied accordingly.

Further research should be carried out using chloroquine in nanoparticles and various fast, slow and sustained released formulations, as well as combinations of chloroquine and other molecules.

Repurposing other FDA approved drugs

As per Steve Schow PhD, Professor of Chemical and Systems Biology at Stanford University School of Medicine and Lead Advisor to Stanford’s SPARK Translational Research Program: 

“There are a number of related isoquinoline and quinoline drug family members who might exhibit the same general acid neutralizing effects. In addition certain antidepressants and antipsychotic drugs are known to accumulate in lysosomes via this acid-base process and might be effective here if the doses needed aren’t too high.”[18]

New Molecular Entity: Chloroquine analogs with more nitrogens 

The nitrogens in chloroquine and quinines in general prevent acidification by absorbing a high amount of hydrogens that then interact with nitrogen, and,in turn, transfer a positive charge to chloroquine.  This ionic interaction makes it harder and harder for the endosome to become acidified, therefore disrupting viral replication.  If more nitrogens are added, either by making extra branches of ionizable nitrogens or lengthening one of the chains by putting extra carbons and other nitrogens around it, this may have even greater effect.  The key issue will be whether there is a heavy change in bioavailability – will the new molecule be able to enter the cell and reach the right place with similar efficiency.

Conclusion

Chloroquine can both both prevent and treat malaria.  Chloroquine can prevent and treat coronavirus in primate cells (Figure 1 and Figure 2).  According to South Korean and China human treatment guidelines, chloroquine is effective in treating COVID-19.  Given chloroquine’s human safety profile and existence, it can be implemented today in the U.S., Europe and the rest of the world.  Medical doctors may be reluctant to prescribe chloroquine to treat COVID-19 since it is not FDA approved for this use.  The United States of America and other countries should immediately authorize and indemnify medical doctors for prescribing chloroquine to treat COVID-19.  We must explore whether chloroquine can safely serve as a preventative measure prior to infection of COVID-19 to stop further spread of this highly contagious virus.

More Sources

Griffero-Diaz’s F. , Hoschander SA , Brojatsch J .Endocytosis IS A Critical entry in STEP B of subgroup Avian leukosis viruses[J].J Virology,2003,76(24):12866-12876.The DOI: 10.1128 / jvi.76.24. 12866-12876.2002 .

Rodrigo D , Luiza H , Paula P , et al .Chloroquine, an Endocytosis Blocking Agent, Inhibits Zika Virus Infection in Different Cell Models[J].Viruses,2016,8(12):322-.DOI: 10.3390 / v8120322 .

Zhang S , Yi C , of Li C , et Al .Chloroquine inhibits the endosomal Viral an RNA Release and autophagy in-dependent Viral Replication and Effectively Prevents CARE OF to Fetal Transmission of Zika Virus. [J] Antiviral Res.2019;169:104 547. The DOI: 10.1016 /j.antiviral.2019.104547

Kono M , Tatsumi K , Imai AM , et al .Inhibition of human coronavirus 229E infection in human epithelial lung cells (L132) by chloroquine: involvement of p38 MAPK and ERK[J].Antiviral Res,2008,77(2):150-152.DOI: 10.1016 / j.antiviral.2007.10.011 .

Didier Raoult, et. al.  , Chloroquine and hydroxychloroquine as available weapons to fight COVID-19 International Journal of Antimicrobial Agents

Available online 4 March 2020, https://www.sciencedirect.com/science/article/pii/S0924857920300820?via%3Dihub#!

Next Steps from the Community

  1. Disseminate this publication amongst the medical community.  Get more feedback.
  2. Send this publication to your scientific contacts in South Korea and China – lets get more data, details, etc.  Science never ends.
  3. Translate this paper into all languages.
  4. Explore all options for use of chloroquine against any medical condition that depends on the turnover of worn out or incorrectly synthesized proteins.

Acknowledgements

Special thanks to Stanford University School of Medicine, SPARK Translational Research Program, Steve Schow, PhD, The Lab of Louise T. Chow, PhD and Thomas R. Broker, PhD, Bruce Bloom DDS, JD of HealX and Adrian Bye.

  

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