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

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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.

License

Due to urgency, certain parts of this publication are taken directly from their attributed source. Cite them accordingly.

In all other circumstances, the GNU General Public License v3.0 applies.

Informational Purposes Only
[1] https://www.cnbc.com/video/2020/03/02/coronavirus-testing-emergency-room-doctor-cdc-department-health-squawk-box.html

[2] https://www.cdc.gov/malaria/resources/pdf/fsp/drugs/Chloroquine.pdf

[3] Vincent, Martin J et al. “Chloroquine is a potent inhibitor of SARS coronavirus infection and spread.” Virology journal vol. 2 69. 22 Aug. 2005, doi:10.1186/1743-422X-2-69 , https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1232869/#B15. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today’s diseases? Lancet Infect Dis. 2003;3:722–727. doi: 10.1016/S1473-3099(03)00806-5.

[4] http://www.koreabiomed.com/news/articleView.html?idxno=7428

[5] https://www.ncbi.nlm.nih.gov/pubmed/32075365/ ; http://www.nhc.gov.cn/yzygj/s7653p/202002/0293d017621941f6b2a4890035243730.shtml translated as https://www.chinalawtranslate.com/en/chloroquine-phosphate/ ; Novel Coronavirus Pneumonia Diagnosis and Treatment Plan (Provisional 7th Edition)

translated ashttps://www.chinalawtranslate.com/en/coronavirus-treatment-plan-7/ ; https://www.clinicaltrialsarena.com/news/coronavirus-covid-19-choroquine-data/ .

[6] https://www.clinicaltrialsarena.com/news/coronavirus-covid-19-choroquine-data/ . This research must be confirmed and furthermore ruled out that the subjects that had negative viral nucleic acid tests might not have been infected with C-19.

[7] http://www.koreabiomed.com/news/articleView.html?idxno=7428

[8] Novel Coronavirus Pneumonia Diagnosis and Treatment Plan (Provisional 7th Edition)translated as https://www.chinalawtranslate.com/en/coronavirus-treatment-plan-7/

[9] https://www.ncbi.nlm.nih.gov/pubmed/32075365/ Guangdong Provincial Science and Technology Department and Guangdong Provincial Health and Health Commission’s Multicenter Collaboration Group on Chloroquine Phosphate for New Coronavirus Pneumonia. Expert Consensus on Chloroquine Phosphate for New Coronavirus Pneumonia [J / OL]. Chinese Journal of Tuberculosis and Respiratory Medicine, 2020,43 (2020-02-20) .http: //rs.yiigle.com/yufabiao/1182323.htm.

[10] US CDC, Vincent MJ , Bergeron E , Benjannet S , et Al .Chloroquine IS A potent inhibitor of SARS coronavirus Infection and Spread of[J].Virology Journal,2005,2(. 1):69.The DOI: 10.1186 / 1743-422X-2-69 . Keyaerts E , Vijgen L , Maes P , et Al .The In Journal Severe acute Inhibition of Respiratory syndrome coronavirus by chloroquine[J].Biochem Biophys Res Communications,2004,323(. 1):0-268.The DOI: 10.1016 / j.bbrc .2004.08.085 .

[11] All research from this section is from: US CDC, Vincent MJ , Bergeron E , Benjannet S , et Al .Chloroquine IS A potent inhibitor of SARS coronavirus Infection and Spread of[J].Virology Journal,2005,2(. 1):69.The DOI:10.1186 / 1743-422X-2-69

[12] All research from this section is from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147684/ , https://virologyj.biomedcentral.com/articles/10.1186/s12985-019-1182-0#citeas ,https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1232869/#B15 , https://www.nature.com/articles/s41422-020-0282-0 , Thomas R. Broker, PhD, Stanford University School of Medicine, Telephone discussion March 12, 2020 , https://www.sciencealert.com/genetic-analysis-shows-wuhan-coronavirus-is-similar-to-sars .

[13] https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/872567/medicines_that_cannot_be_parallel_exported_from_th e_uk_13_march_2020.csv/preview

[14] http://doc.irasia.com/listco/hk/tfkf/announcement/a224851-e_01312ann_20200203(20200203_1952).pdf

[15] All information in this section is from: https://www.sciencealert.com/genetic-analysis-shows-wuhan-coronavirus-is-similar-to-sars , https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147684/ , https://virologyj.biomedcentral.com/articles/10.1186/s12985-019-1182-0#citeas , Thomas R. Broker, PhD, Stanford University School of Medicine, Telephone discussion March 12, 2020.

[16] https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/006002s044lbl.pdf , https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=006002 , https://www.cdc.gov/malaria/resources/pdf/fsp/drugs/Chloroquine.pdf

[17] See Safety citations.

[18] Steve Schow PhD, https://sparkmed.stanford.edu/about-spark/who-we-are/ . Email correspondence March 2020.