There is insufficient evidence that chloroquine is an effective COVID-19 treatments and it may increase risk of negative outcomes

- Findings in support of chloroquine as a treatment for COVID-19
- Findings opposed to chloroquine as a treatment for COVID-19
- Using Molecular Docking to Determine the Mechanism of Action of Hydroxychloroquine/Chloroquine on SARS-CoV-2
- Chloroquine Mechanism of action/Target
- Toxicities of Chloroquine 

Chloroquine as treatment for COVID-19

- Zn is a lewis acid, meaning it accepts electrons
- Zn2+ is stable
- Zn2+ is able to cause apoptosis
- Zn activates the NF-kB pathway, which results in the formation of cytokines that cause inflammation
- Zn inhibits the entry of the COVID-19 virus
- 10 uM Zn-sulfate and Zinc-acetate can cut down RNA replication by 50%
- Chloroquine can be used to prevent functioning of ACE2 receptors (which then prevents inflammation)
- Chloroquine, similar to zinc, prevents the virus from being replicated
- When non-protonated, chloroquine is considered to be found in acidic organelles (located in golgi apparatus, lysosomes)
- Chloroquine can transport zinc ions and increases the uptake of those ions through lysosomes
- Zinc and chloroquine, when combined, results in death of malignant cells due to an increase in chloroquine cytotoxicity
- Ovarian cancer was treated with chloroquine containing zinc chloride. Normal cells/ non malignant cells contained extremely low levels of Zinc without chloroquine
- Zinc directly inhibits the replication of the COVID-19 virus


Potential use of zinc and chloroquine in treating COVID-19

Chloroquine, and hydroxychloroquine, have become recent treatments for COVID-19, and as of June 2020, chloroquine appears to be effective in the limitation of SARS-CoV-2 reproduction in vitro. A study from February 2020 showed good efficacy from chloroquine phosphate in over 100 Chinese patients. French doctors also identified relatively good efficacy in 20 COVID-19 patients who received hydroxychloroquine.  

The major treatments studied so far include: chloroquine phosphate, hydroxychloroquine sulfate, and carrimycin (all varying in dosage and delivery system). However, more data (particularly safety data) from high-quality clinical trials is still needed. 

Hamilton College

New treatment strategies in addition to antiviral therapy has potential to significantly improve clinical outcome. One of those new potential treatments is immunomodulatory therapy. Immunomodulatory agents for the reduction of cytokine storms combined with antiviral agents could aid in the treatment process. 

- Corticosteroids
- Chloroquine
- Tocilizumab
- Proposed Doses for COVID-19 Immunomodulatory Therapy 

Immunomodulatory Therapy for the Reduction of Cytokine Storms and COVID-19 Treatment

Chloroquine and hydroxychloroquine are known for treating malaria but are actually no longer effective against malaria parasites due to the development of resistance. They are now used to treat autoimmune diseases. Recently, they are considered to treat viral infections, mores specifically COVID-19, due to their low toxicity, affordability, great tolerability, and their ability to regulate the immune system. Both are soluble in water with hydroxychloroquine being slightly more soluble than chloroquine. Chloroquine and hydroxychloroquine are known to have long half-lives of 38 days and 54 days, respectively. They can easily build up in tissue after prolonged exposure but are metabolized by the liver and excreted through urine. Some possible side effects include keropathy, maculopathy, and retinopathy.

Chloroquine and Hydroxychloroquine

Zhao, M. (2020). Cytokine storm and immunomodulatory therapy in COVID-19: role of chloroquine and anti-IL-6 monoclonal antibodies. International journal of antimicrobial agents. doi: 10.1016/j.ijantimicag.2020.105982 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161506/

Cytokine Storm and Immunomodulatory therapy in COVID-19: Role of Chloroquine and Anti-IL-6 Monoclonal Antibodies

Cortegiani, A., Ingoglia, G., Ippolito, M., Giarratano, A., & Einav, S. (2020). A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. Journal of critical care.
https://www.sciencedirect.com/science/article/pii/S0883944120303907?casa_token=n7EfbAxBA2gAAAAA:YZJgk6lUqjRhiHlSJctxrfxiZ6hz5cciHU9fxtroqdo7OlIBaaKuhzbmNjz-_BD4lv2ljbusTA


A Systematic Review of the Efficacy and Safety of Chloroquine for the Treatment of COVID-19 

The most commonly used drugs for immunomodulatory therapy are corticosteroids, which in COVID-19 patients can suppress the host immune system and delay viral clearance. Through the findings of two recent patient studies, it is now believed that corticosteroid usage is beneficial in severe cases of COVID-19 (particularly in patients with ARDS), not in patients with mild cases of COVID-19. Therefore, corticosteroids are only recommended for patients in critical conditions. 

The decision must still be made carefully even in critical cases of COVID-19 due to their potential negative side effects. There is no available data illustrating the success of corticosteroids in SARS-CoV or MERS. 

Corticosteroids and COVID-19

Chloroquine and COVID-19

Immunomodulatory agents which directly targets cytokines involved in COVID-19 also have the potential to lower hyperinflammation in severe cases, which is important when elevated levels of IL6 in the blood has proved to be a predictor for fatal outcomes in COVID-19 patients. Tocilizumab, an antibody which blocks IL6 has been recommended for patients with severe or critical illness, extensive lesions in bilateral lungs, and confirmed elevated levels of IL6. A study on 20 patients with severe COVID-19 illustrated reduction in fever and lung lesion opacity and recovery of percentage of peripheral blood lymphocytes after treatment with tocilizumab. 

Tocilizumab and COVID-19

Proposed Doses for COVID-19 Immunomodulatory Therapy 

Hydroxychloroquine (HCQ) is a drug that is thought to prevent the SARS-CoV-2 virus from entering host cells through inhibiting the glycosylation of host receptors, proteolytic process, and endosomal acidification.  Safer and more potent in antiviral properties than aminoquinolines chloroquine, HCQ has been widely used for the treatment of malaria and rheumatic diseases. Due to its anti-inflammatory and antiviral effects, some sources also claim it can serve as effective treatment for COVID-19. On March 30, 2020, the US FDA issued an Emergency Use Authorization, which suggested using these drugs for patients with pneumonia, and after this event, HCQ has been widely used to treat COVID-19 patients around the world. However, no robust clinical studies have supported the effectiveness of this treatment.

Hydroxychloroquine as Treatment for COVID-19

A preclinical study done in 1982 showed that chloroquine was found in the highest concentration in lung tissue, leading to the proposition of chloroquine as a possible treatment for COVID-19 caused pneumonia. In vitro studies were then conducted using VeroE6 cells from the kidneys of African green monkeys. In these studies, hydroxychloroquine (EC50 = 0.72μM) appeared more effective than chloroquine (EC50=5.47μM) in countering COVID-19 in vitro. A recent study was done using the PBPK models. The maintenance dose, used to bring the concentration up in infected lung tissue, consist of a loading dose of 400mg of chloroquine followed by 200mg twice daily for four days. This is found to be more successful than if given 500mg twice daily for 5 days. EC90 of chloroquine against COVID-19 was 6.90μM in VeroE6 cells. The cytotoxic concentration (CC50) is 273.20μM for chloroquine and 249.50μM for hydroxychloroquine. Chloroquine was more effective in treating COVID-19 than hydroxychloroquine due to its higher selectivity index (CC50/EC50).

Results of Preclinical Studies on Chloroquine and Hydroxychloroquine

- Inhibits N-glycosylation to prevents ACE2 receptors from binding onto the surface of the host cell
- Prevents maturation of the viral spike proteins, which includes SARS-CoV-2, by inhibiting N-glycosylation
- CQ/HCQ prevents buildup of sialic acid, which is responsible for viral entry
- CQ inhibits PICALM action, decreasing viral entry
- In SARS-CoV-2, CQ/HCQ inhibits viral entry after the onset of the virus
- CQ may be able to prevent TGN vesicles from transporting the virus into the lungs (observed in the Chikungunya virus)
- CQ prevents p38 MAPK from  spreading the virus to the respiratory tract
- There was not a significant variation between the cytotoxicity of CQ and HCQ
- CQ may be more efficient at inhibition viral action compared to HCQ
- CQ and HCQ inhibit the maturation of endocytotic cells to transport the viral particles into the cell


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