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New insights into the antiviral effects of chloroquine

Savarino et al., Lancet Infect. Dis., doi:10.1016/S1473-3099(06)70361-9

Feb 2006

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HCQ for COVID-19

1st treatment shown to reduce risk in March 2020

^*, now with p < 0.00000000001 from 418 studies, recognized in 46 countries.

Lower risk for mortality, hospitalization, progression, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine treatments. ^* >10% efficacy, ≥3 studies.

5,000+ studies for 104 treatments. c19hcq.org

Update to 2003 paper. Hypothesis of CQ inhibiting SARS replication has been confirmed in two in-vitro studies. CQ affected an early stage of SARS replication.

38 preclinical studies support the efficacy of HCQ for COVID-19:

11 In Silico studies1-11

24 In Vitro studies1,12-34

3 In Vivo animal studies16,26,35

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1. González-Paz et al., Biophysical Analysis of Potential Inhibitors of SARS-CoV-2 Cell Recognition and Their Effect on Viral Dynamics in Different Cell Types: A Computational Prediction from In Vitro Experimental Data, ACS Omega, doi:10.1021/acsomega.3c06968.acs.org, doi.org.

2. Alkafaas et al., A study on the effect of natural products against the transmission of B.1.1.529 Omicron, Virology Journal, doi:10.1186/s12985-023-02160-6.biomedcentral.com, doi.org.

3. Guimarães Silva et al., Are Non-Structural Proteins From SARS-CoV-2 the Target of Hydroxychloroquine? An in Silico Study, ACTA MEDICA IRANICA, doi:10.18502/acta.v61i2.12533.kne-publishing.com, doi.org.

4. Nguyen et al., The Potential of Ameliorating COVID-19 and Sequelae From Andrographis paniculata via Bioinformatics, Bioinformatics and Biology Insights, doi:10.1177/11779322221149622.sagepub.com, doi.org.

5. Navya et al., A computational study on hydroxychloroquine binding to target proteins related to SARS-COV-2 infection, Informatics in Medicine Unlocked, doi:10.1016/j.imu.2021.100714.sciencedirect.com, doi.org.

6. Yadav et al., Repurposing the Combination Drug of Favipiravir, Hydroxychloroquine and Oseltamivir as a Potential Inhibitor Against SARS-CoV-2: A Computational Study, Research Square, doi:10.21203/rs.3.rs-628277/v1.researchsquare.com, doi.org.

7. Hussein et al., Molecular Docking Identification for the efficacy of Some Zinc Complexes with Chloroquine and Hydroxychloroquine against Main Protease of COVID-19, Journal of Molecular Structure, doi:10.1016/j.molstruc.2021.129979.sciencedirect.com, doi.org.

8. Baildya et al., Inhibitory capacity of Chloroquine against SARS-COV-2 by effective binding with Angiotensin converting enzyme-2 receptor: An insight from molecular docking and MD-simulation studies, Journal of Molecular Structure, doi:10.1016/j.molstruc.2021.129891.sciencedirect.com, doi.org.

9. Noureddine et al., Quantum chemical studies on molecular structure, AIM, ELF, RDG and antiviral activities of hybrid hydroxychloroquine in the treatment of COVID-19: molecular docking and DFT calculations, Journal of King Saud University - Science, doi:10.1016/j.jksus.2020.101334.sciencedirect.com, doi.org.

10. Tarek et al., Pharmacokinetic Basis of the Hydroxychloroquine Response in COVID-19: Implications for Therapy and Prevention, European Journal of Drug Metabolism and Pharmacokinetics, doi:10.1007/s13318-020-00640-6.springer.com, doi.org.

11. Rowland Yeo et al., Impact of Disease on Plasma and Lung Exposure of Chloroquine, Hydroxychloroquine and Azithromycin: Application of PBPK Modeling, Clinical Pharmacology & Therapeutics, doi:10.1002/cpt.1955.wiley.com, doi.org.

12. Hitti et al., Hydroxychloroquine attenuates double-stranded RNA-stimulated hyper-phosphorylation of tristetraprolin/ZFP36 and AU-rich mRNA stabilization, Immunology, doi:10.1111/imm.13835.wiley.com, doi.org.

13. Yan et al., Super-resolution imaging reveals the mechanism of endosomal acidification inhibitors against SARS-CoV-2 infection, ChemBioChem, doi:10.1002/cbic.202400404.wiley.com, doi.org.

14. Mohd Abd Razak et al., In Vitro Anti-SARS-CoV-2 Activities of Curcumin and Selected Phenolic Compounds, Natural Product Communications, doi:10.1177/1934578X231188861.sagepub.com, doi.org.

15. Alsmadi et al., The In Vitro, In Vivo, and PBPK Evaluation of a Novel Lung-Targeted Cardiac-Safe Hydroxychloroquine Inhalation Aerogel, AAPS PharmSciTech, doi:10.1208/s12249-023-02627-3.springer.com, doi.org.

16. Wen et al., Cholinergic α7 nAChR signaling suppresses SARS-CoV-2 infection and inflammation in lung epithelial cells, Journal of Molecular Cell Biology, doi:10.1093/jmcb/mjad048.oup.com, doi.org.

17. Kamga Kapchoup et al., In vitro effect of hydroxychloroquine on pluripotent stem cells and their cardiomyocytes derivatives, Frontiers in Pharmacology, doi:10.3389/fphar.2023.1128382.frontiersin.org, doi.org.

18. Milan Bonotto et al., Cathepsin inhibitors nitroxoline and its derivatives inhibit SARS-CoV-2 infection, Antiviral Research, doi:10.1016/j.antiviral.2023.105655.sciencedirect.com, doi.org.

19. Miao et al., SIM imaging resolves endocytosis of SARS-CoV-2 spike RBD in living cells, Cell Chemical Biology, doi:10.1016/j.chembiol.2023.02.001.sciencedirect.com, doi.org.

20. Yuan et al., Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture, Communications Biology, doi:10.1038/s42003-022-03841-8.nature.com, doi.org.

21. Faísca et al., Enhanced In Vitro Antiviral Activity of Hydroxychloroquine Ionic Liquids against SARS-CoV-2, Pharmaceutics, doi:10.3390/pharmaceutics14040877.mdpi.com, doi.org.

22. Delandre et al., Antiviral Activity of Repurposing Ivermectin against a Panel of 30 Clinical SARS-CoV-2 Strains Belonging to 14 Variants, Pharmaceuticals, doi:10.3390/ph15040445.mdpi.com, doi.org.

23. Purwati et al., An in vitro study of dual drug combinations of anti-viral agents, antibiotics, and/or hydroxychloroquine against the SARS-CoV-2 virus isolated from hospitalized patients in Surabaya, Indonesia, PLOS One, doi:10.1371/journal.pone.0252302.plos.org, doi.org.

24. Zhang et al., SARS-CoV-2 spike protein dictates syncytium-mediated lymphocyte elimination, Cell Death & Differentiation, doi:10.1038/s41418-021-00782-3.nature.com, doi.org.

25. Dang et al., Structural basis of anti-SARS-CoV-2 activity of hydroxychloroquine: specific binding to NTD/CTD and disruption of LLPS of N protein, bioRxiv, doi:10.1101/2021.03.16.435741.biorxiv.org, doi.org.

26. Shang et al., Inhibitors of endosomal acidification suppress SARS-CoV-2 replication and relieve viral pneumonia in hACE2 transgenic mice, Virology Journal, doi:10.1186/s12985-021-01515-1.biomedcentral.com, doi.org.

27. Wang et al., Chloroquine and hydroxychloroquine as ACE2 blockers to inhibit viropexis of 2019-nCoV Spike pseudotyped virus, Phytomedicine, doi:10.1016/j.phymed.2020.153333.nih.gov, doi.org.

28. Sheaff, R., A New Model of SARS-CoV-2 Infection Based on (Hydroxy)Chloroquine Activity, bioRxiv, doi:10.1101/2020.08.02.232892.biorxiv.org, doi.org.

29. Ou et al., Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2, PLOS Pathogens, doi:10.1371/journal.ppat.1009212.plos.org, doi.org.

30. Andreani et al., In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect, Microbial Pathogenesis, doi:10.1016/j.micpath.2020.104228.sciencedirect.com, doi.org.

31. Clementi et al., Combined Prophylactic and Therapeutic Use Maximizes Hydroxychloroquine Anti-SARS-CoV-2 Effects in vitro, Front. Microbiol., 10 July 2020, doi:10.3389/fmicb.2020.01704.frontiersin.org, doi.org.

32. Liu et al., Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discovery 6, 16 (2020), doi:10.1038/s41421-020-0156-0.nature.com, doi.org.

33. Yao et al., In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Clin. Infect. Dis., 2020 Mar 9, doi:10.1093/cid/ciaa237.oup.com, doi.org.

34. Wang (B) et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res. 30, 269–271, doi:10.1038/s41422-020-0282-0.nature.com, doi.org.

35. Shu-Han Lin et al., Inhalable Chitosan-Based Hydrogel as a Mucosal Adjuvant for Hydroxychloroquine in the Treatment for SARS-CoV-2 Infection in a Hamster Model, Journal of Microbiology, Immunology and Infection, doi:10.1016/j.jmii.2023.08.001.sciencedirect.com, doi.org.

Savarino et al., 1 Feb 2006, peer-reviewed, 5 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

This Paper HCQ All

Abstract: Reﬂection and Reaction empirically, because of its activity against most of the causative ﬁlamentous fungi and its time-tested experience.7,8,10 Newer agents may be useful when microbiological diagnosis is established (eg, voriconazole for Aspergillus spp, posaconazole for zygomycetes), although further studies are required. Lastly, Van Damme and Hartman refer to noma (chancrum oris), a devastating necrotising destructive process of the face typically affecting young malnourished children in Africa. This condition has been presented in a recent excellent review by Baratti-Mayer and colleagues.14 We thank Van Damme and Hartman for their interest in our paper, and their comments which allowed us to elaborate upon the most important topic of rapidly progressive SSTIs. 10 Donald C Vinh, John M Embil 11 DCV and JME are at the Section of Infectious Diseases, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. Correspondence to: Dr John Embil, Infection Prevention and Control Unit, Health Sciences Centre, MS 673-820 Sherbrook Street, Winnipeg, Manitoba, R3A 1R9, Canada. Tel +1 204 787 4654; fax +1 204 787 4699; jembil@hsc.mb.ca 1 2 3 4 5 6 7 8 9 12 13 14 Vinh DC, Embil JM. Rapidly progressive soft tissue infections. Lancet Infect Dis 2005; 5: 501–13. Djupesland PG. Necrotizing fasciitis of the head and neck—report of three cases and review of the literature. Acta Otolaryngol 2000; 543 (suppl): 186–89. Kimura AC, Pien FD. Head and neck cellulitis in hospitalized adults. Am J Otolaryngol 1993; 14: 343–49. Broadhurst LE, Erickson RL, Kelley PW. Decreases in invasive Haemophilus inﬂuenzae diseases in US Army children, 1984 through 1991. JAMA 1993; 269: 227–31. Givner LB. Periorbital versus orbital cellulitis. Pediatr Infect Dis J 2002; 21: 1157–58. Lipsky BA, Berendt AR, Derry HG, et al. Infectious Diseases of America guideline: diagnosing and treating diabetic foot infections. Clin Infect Dis 2004; 39: 885–910. Johnson MA, Lyle G, Hanly M, et al. Aspergillus: a rare primary organism in soft-tissue infections. Am Surg 1998; 64: 122–26. Gettleman LK, Shetty AK, Prober CG. Posttraumatic invasive Aspergillus fumigatus wound infection. Pediatr Infect Dis J 1999; 18: 745–47. Sawyer RG, Schenk WG 3rd, Adams RB, et al. Aspergillus ﬂavus wound infection following repair of a ruptured duodenum in a nonimmunocompromised host. Scand J Infect Dis 1992; 24: 805–09. Heinz T, Perfect J, Schell W, et al. Soft-tissue fungal infections: surgical management of 12 immunocompromised patients. Plast Reconstr Surg 1996; 97: 1391–99. Safdar A. Progressive cutaneous hyalohyphomycosis due to Paecilomyces lilacinus: rapid response to treatment with caspofungin and itraconazole. Clin Infect Dis 2002; 34: 1415–17. Losee JE, Selber J, Vega S, et al. Primary cutaneous mucormycosis: guide to surgical management. Ann Plast Surg 2002; 49: 385–90. Andresen D, Donaldson A, Choo L, et al. Multifocal cutaneous mucormycosis complicating polymicrobial wound infections in a tsunami survivor from Sri Lanka. Lancet 2005; 365: 876–78. Baratti-Mayer D, Pittet B, Montandon D, et al. Noma: an “infectious” disease of unknown aetiology. Lancet Infect Dis 2003; 3: 419–31. New insights into the antiviral effects of chloroquine In a paper published 2 years ago in this journal, some of us described the potentially therapeutic beneﬁts of the quinoline antimalarial chloroquine in viral diseases such as HIV-1/AIDS and severe acute respiratory syndrome (SARS).1..

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