- Findings in support of using HCQ for COVID-19 treatment
- Findings opposed to use of HCQ for COVID-19 treatment 
- HCQ Mechanism of action
- Toxicities of HCQ

Findings Related to the Use of Hydroxychloroquine (HCQ) as treatment for COVID-19

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.

Syracuse University

Michigan State University

- Amlodipine
- Apilimod
- Arbidol + lopinavir/ritonavir 
- Azithromycin
- Azithromycin+Hydroxychloroquine
- Camostat mesylate
- Chloroquine
- Chloroquine + macrolide (Azithromycin or clarithromycin)
- Clofazimine
- Colchicine
- Corticosteroids 
- Diltiazem
- Dexamethasone
- Famotidine
- Favipiravir
- Felodipine 
- Heparin
- Hydroxychloroquine
- Interferon-α2b 
- Lopinavir-Ritonavir
- Nifedipine
- Nitazoxanide
- Oseltamivir
- Propolis
- Rapamycin
- Remdesivir
- Ribavirin
- Tocilizumab
- Verapamil
- Statin
-Tofacitinib

Use of existing drugs to mitigate COVID-19

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

Geleris, J., Sun, Y., Platt, J., Zucker, J., Baldwin, M., Hripcsak, G., Labella, A., Manson, D., Kubin, C., Barr, R., Sobieszczyk, M., & Schluger, N. ((2020). Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. The New England Journal of Medicine. DOI: 10.1056/NEJMoa2012410 
https://www.nejm.org/doi/full/10.1056/nejmoa2012410

Observational Study of Hydroxychloroquine in Hospitalized Patients with COVID-19

Sanders, J. M., Monogue, M. L., Jodlowski, T. Z., & Cutrell, J. B. (2020). Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. Jama, 323(18), 1824-1836.
doi:10.1001/jama.2020.6019
https://jamanetwork.com/journals/jama/fullarticle/2764727/

Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19)


Remdesivir, an antiviral drug developed by Gilead Sciences, is undergoing various clinical trials to assess its effectiveness in treating COVID-19. Preliminary studies suggest high expectations for drug efficacy and it has been authorized to treat severe infections in the U.S. and Japan.

- Early randomized trials are unable to provide evidence for reducing time to clinical improvement, clearance of virus, or mortality
- Adverse health effects
- Results concerning Remdesivir benefits 
- Availability of Remdesivir 
- Global production of Remdesivir 
- Global clinical trials map
- Intracellular processing of Remdesivir 
- Toxicities of Remdesivir 

Findings about use of Remdesivir as COVID-19 intervention

This combination of drugs does not appear to improve COVID-19 outcomes and may increase risk of negative outcomes.

- findings in support
- findings opposed
- findings indicate no significant difference in comparison to standard care 

Azithromycin (AZM) + Hydroxychloroquine (HCQ) as treatment for COVID-19

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

There is insufficient evidence that this therapy improves COVID-19 outcomes and may increase risk of other negative outcomes

-Studies in favor
- Studies opposed

Chloroquine + macrolide (Azithromycin or clarithromycin) as a treatment for COVID-19

Anticoagulants like heparin may improve outcomes in COVID-19 patients. Many patients exhibit unusual clotting patterns that may be alleviated by use of anticoagulants.  Heparin has been shown to directly bind to the S1 subunit of SARS-CoV-2 S protein which may interfere with its ability to infect cells.

Heparin as a treatment for COVID-19

Interferon-α2b is a broad spectrum anti-virals responsible for having direct inhibitory effects on viral replication. In addition, IFN-α2b promotes an immune response in order to clear a viral infection.

- Findings in support 
- Finding opposed 

Interferon-α2b Treatment for COVID-19

Dexamethasone is a steroid evaluated for use in improving outcomes for COVID-19 patients through mitigating the inflammatory response during infection.

- 28-day mortality and other clinical outcomes in a randomized controlled trial of patients in the UK through the RECOVERY project
- Financial benefits 

Dexamethasone as a treatment for COVID -19

Arbidol is an antiviral drug that binds to the antigenic protein hemagglutinin and prevents host cell adhesion and membrane fusion and is used to treat influenza. Lopinavir and ritonavir are HIV protease inhibitors that target 3CL protease. 

- Combined therapy of arbidol and lopinavir/ritonavir, rather than lopinavir/ritonavir only, have shown to improve COVID-19 outcomes significantly.
- Arbidol monotherapy may be superior to lopinavir/ritonavir in treating COVID-19 
- Toxicities of Arbidol 
- Toxicities of Lopinavir/Ritonavir 
- Scaffold morphing of arbidol to create analogues for treatment of COVID-19


Arbidol + lopinavir/ritonavir as treatment for COVID-19

Ivermectin+Azithromycin+Hydroxychloroquine treatment was shown to result in a better cure rate and shorter hospital stay compared to control.
- groups used
- results demonstrating better cure rate
- results demonstrating shorter hospital stay
- important considerations

Ivermectin+Azithromycin+Hydroxychloroquine Treatment for COVID-19

The purpose of this drug is to hinder the viral RNA polymerase that is dependent on RNA. There is a lack of data for the activity of ribavirin with COVID-19; therefore, its effect must be studied further. There are also safety concerns for this drug. The combination of this inconclusive data and the safety concerns for Ribavirin give it limited merit for treating COVID-19. 

Ribavirin as a treatment for COVID-19

This drug is an antiviral used to treat the flu. It has yet to show any in-vitro activity against COVID-19. Therefore, it is not a likely treatment for the novel coronavirus. 

Oseltamivir as a treatment for COVID-19


This drug has had in vitro activity against MERS and SARS-CoV-2. Due to its antiviral activity, immunomodulatory effects, and safeness, it is a potential treatment option for COVID-19. More research still needs to be done though with this drug. 

Nitazoxanide as a treatment for COVID-19

This drug works by hindering the host serine proteins, TMPRSS2, thus prohibiting the nCoV cell entry in vitro. Future research needs to be done though with this drug to indicate if it can be a COVID-19 treatment. 


Camostat mesylate as a treatment for COVID-19


This drug works by hindering the viral RNA polymerase, thus stopping viral replication. It requires doses at the higher end of the dosing range to tread COVID-19. Overall, it is well tolerated, but it may have some mild effects. With limited clinical experience for treating COVID-19, Favipiravir is not accessible in the US for clinical use. 

- Toxicities of Favipiravir 
- Favipiravir mechanism of action 

Favipiravir as a treatment for COVID-19

Corticosteroids are used to minimize host inflammatory responses in the lungs that can have damaging effects on the lungs and respiratory system. The corticosteroids, however, can cause delayed viral clearance and a larger risk of secondary infection. The evidence for the use of corticosteroids with COVID-19 is also limited. Due to their potential harm and the lack of proven helpfulness, it is overall not recommended to use corticosteroids on COVID-19 patients. 
Studies have shown that using corticosteroids has reduced deaths by 35% in ventilated patients and by 20% among those receiving oxygen only compared with those in the standard care group. In addition, 93% improvement in the intervention group in days when organ support was not needed.


Corticosteroids as a treatment for COVID-19

Many researchers believe that antibodies from recovered COVID-19 patients could be useful with free virus and infected cell immune clearance. Because more safety and efficacy trials need to take place before immunoglobulin therapy is used as a COVID-19 treatment, on March 24th, 2020 the FDA requested emergency investigational new drug application and screener donors for COVID-19 containing plasma. 

Immunoglobulin Therapy as a treatment for COVID-19

Due to a lack of clinical trials with interferon and conflicting in-vitro and animal data with the drug, interferon cannot be recommended as a treatment for COVID-19 currently. 


Interferon

In a study from France, 12 patients in stage 2b or 3 COVID-19 associated pneumonia were treated with i.v. anakinra and compared to 10 patients receiving standard-of-care treatment. Those within the experimental group significantly improved clinically, experienced no deaths, and experienced decreased usage of mechanical ventilation. The main drawback of the study is the small sample size.

Application of Anakinra to Treat Inflammation-Associated Respiratory Failure in COVID-19

Remdesivir is a nucleotide analog that inhibits viral RNA-dependent RNA polymerase (RDRP) and has strong potential to be a therapeutic for COVID-19. 
Replication of the single-stranded RNA genome of SARS-CoV-2 depends on an RDRP. Remdesivir is a prodrug that, after metabolized to remdesivir triphosphate, acts as an analog of ATP, competing for incorporation by RDRP and interfering with viral RNA replication.

There have been successful case reports for the drug’s use against COVID-19, and clinical trials are continuing to evaluate its safety and efficacy. In fact, the National Institution of Health (NIH) is currently conducting an adaptive, randomized, double-blind placebo-controlled trial with remdesivir. The drug at this time is not currently FDA approved. Therefore, it can only be obtained by compassionate use, expanded access, or enrollment in a clinical trial.  


Remedesivir may reduce time for clinical improvement and decrease mortality. It has no effect on need for ventilation or length of hospital stay.

Remdesivir as a treatment for COVID-19


Hydroxychloroquine as Treatment for COVID-19

Tocilizumab inhibits Interleukin-6 (IL-6) which may mitigate the extreme inflammatory response among COVID-19 patients. 

- Outcomes among 100 severe COVID-19 patients in Brescia, Italy during 10-day follow-up after Tocilizumab infusion

- Figure illustrating how Tocilizumab calms the inflammatory storm by blocking IL-6 receptors

- Severe COVID-19 cases and the impact of tocilizumab

- Toxicities of TCZ

- Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study

- Case Report of Tocilizumab for COVID-19 Pneumonia in a Non Small Cell Lung Cancer Patient Treated with Chemo-Immunotherapy

- Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state

Tocilizumab (TCZ) As a Treatment for COVID-19

Previously used drugs approved by the FDA have been repurposed in order to be tested against COVID-19. However, clinical trials are underway for several anti-malarial drugs in order to test their effects against the disease.

In silico approaches that are currently used for drug repurposing, including molecular docking, molecular dynamics, and computational chemistry, constitute valuable tools to aid preclinical and clinical studies of nanomaterials directed for disease treatment. 


Drug re-purposing against COVID-19

Famotidine, a histamine-2 receptor antagonist, is a widely available, cheap over the counter drug. It is currently being investigated as a treatment for COVID-19. Computer simulations have identified a 3-chymotrypsin-like protease as a potential target for famotidine in the fight against COVID-19.  

- A retrospective cohort study of non-hospitalized COVID-19 patients taking Famotidine

Famotidine as a treatment for COVID-19 

Statin inhibits HMG-CoA reductase and is used to lower cholesterol. It has anti-inflammatory and immunomodulatory properties and also increases the cellular expression of ACE2. Further studies should be conducted to learn about the full effects of this drug.

Statin as a treatment for COVID-19

Chloroquine 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.  There is current no strong evidence to support this hypothesis, and unfavorable effects have been observed in COVID-19 patients taking the drug.   

Chloroquine as Treatment for COVID-19

Amlodipine is a dihydropyridine calcium channel blocker that is commonly used to treat hypertension. Also, amlodipine has shown to be a safe and effective pulmonary vasodiltor in patients with chronic obstructive pulmonary disease and has shown to lead to an improvement in the right heart function. This drug is currently undergoing clinical trials to test its effectiveness against coronavirus. 

- A retrospective review of elderly COVID-19 patients receiving either amlodipine or nifedipine to investigate effects on mortality, hospitalization, and overall progression of the disease

Amlodipine as a treatment for COVID-19 treatment 

Nifedipine, a dihydropyridine calcium channel blocker, is widely used to treat hypertension. Studies have shown that nifedipine can increase pulmonary vasodilation without lowering arterial oxygenation levels or causing systemic hypotension in patients that experience pulmonary hypertension from chronic airflow limitation. Nifedipine is currently being investigated as a treatement for COVID-19 

- A retrospective review of elderly COVID-19 patients receiving either amlodipine or nifedipine to investigate effects on mortality, hospitalization, and overall progression of the disease


Nifedipine as a treatment for COVID-19

In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. 

Lopinavir-Ritonavir as a treatment for COVID-19

Clofazimine is an FDA-approved drug that has been used to treat leprosy for many years. It is also a drug that is being clinically tested because of its potential in treating COVID-19.


Clofazimine as a Treatment for COIVD-19

Rapamycin, also commonly known as sirolimus, is an FDA-approved antibiotic that has proven to be effective in preventing immunosuppressive and antiproliferative properties for diseases such as tuberous sclerosis, psoriasis, and malignancy.

In fact, Dr. Nir Barzilai, a professor at the Albert Einstein College of Medicine, claims that “rapamycin could decrease severity of coronavirus in the elderly by 50%.”


Rapamycin as a Treatment for COVID-19

Apilimod, also known as LAM-002A is an anti-cancer drug that is viewed to have high potential in effectively treating COVID-19.

In fact, Dr. Sumit Chanda, a lead investigator at the Sanford Burnham Prebys Medical Discovery Institute claims that apilimod is one of the top candidates to represent a treatment option for COVID-19. 


Apilimod as a Treatment for COVID-19

- Propolis is a compound produced by honey bees that has been widely used as an immune booster and antiviral compound. Multiple aspects of propolis demonstrate its potential as an effective treatment for Covid-19. 

Findings about use of Propolis as a therapeutic treatment for Covid-19

Azithromycin (AZM) appears to have no significant effect on COVID-19 outcomes, but its use does not increase the risk of other negative health outcomes in patients.

Azithromycin (AZM) as treatment for 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. 

Chloroquine and 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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