Overall, heparin use did not improve outcomes. However, in severe COVID-19 cases with a sepsis-induced coagulopathy (SIC)  score of 4 or higher and patients with D-dimer levels above 6 times normal levels, heparin treatment reduced 28-day mortality rates.

- results for heparin vs. no anticoagulants by SIC score
- results for heparin vs. no anticoagulants by D-dimer level
- results for univariate analysis for other clotting factors
- patient characteristics
- SIC score
- methods
- discussion

Findings supporting heparin use in COVID-19 patients for patients at high risk of coagulopathy from retrospective study in Wuhan, China

- Prophylactic concentration: 0.1-0.4U/ml
- Therapeutic concentration: 0.3-0.7U/ml

IU: international units (arbitrary amount)

Prophylactic and Therapeutic Serum Concentrations of Unfractionated Heparin (UFH)

LMWHs include drugs such as dalteparin and enoxparin.

- Prophylactic concentration:  0.2-0.5IU/ml
- Therapeutic concentration: 0.5-1.2IU/ml 

IU: international units (arbitrary amount)

Prophylactic and Therapeutic Serum Concentrations of Low Molecular Weight Heparins (LMWH)

Partridge et al. have observed multiple heparin binding sites on the SARS-CoV-2 S protein, including:

- one at the furin cleavage site between the S1 and S2 subunits
- others in the S2 domain 
- others in the receptor binding domain (RBD)

SARS-CoV-2 S Protein May Have Multiple Heparin Binding Sites

In RT4 cells pre-treated with anti-ACE2 antibodies, unfractionated heparin strongly inhibited SARS-CoV-2 S1S2 protein binding, whereas the low-molecular-weight heparins dalteparin and enoxaparin acted as partial inhibitors and were less potent than unfractionated heparin.

Comparison of Unfractionated and Low-Molecular-Weight Heparins in Anti-ACE2-Treated RT4 Cells

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.

Michigan State University

University of Michigan - Ann Arbor

- 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

Heparin and heparan sulfate are structurally similar glycosaminoglycans that are physiologically relevant and have been used as pharmacological targets, especially in regards to cancer.  Heparin interacts with the protein antithrombin III (ATIII) and causes a conformation change that increases its ability to inhibit coagulation factors.  Consequently, heparin is used as an anticoagulant.  Heparan sulfate is involved in many processes.  It is notably involved in cell-to-cell extracellular membrane organization - the process in which cells adhere together - and cell proliferation via growth factor signaling.  These roles make it and its related enzymes key targets for drugs meant to prevent cancer metastasis.  

Heparin and Heparan Sulfate

Partridge, L. J., Urwin, L., Nicklin, M. J., James, D. C., Green, L. R., & Monk, P. N. (2020). ACE2-independent interaction of SARS-CoV-2 spike protein to human epithelial cells can be inhibited by unfractionated heparin. bioRxiv.
https://www.biorxiv.org/content/10.1101/2020.05.21.107870v2
doi: 10.1101/2020.05.21.107870

ACE2-independent interaction of SARS-CoV-2 spike protein to human epithelial cells can be inhibited by unfractionated heparin

Remdesivir, an antiviral drug developed by Gilead Sciences, has been evaluated in multiple clinical trials for treating COVID-19. Preliminary studies raised expectations for its efficacy, and it was granted emergency-use authorization to treat severe infections in the U.S. and Japan. Key findings on Remdesivir as a COVID-19 intervention include: early randomized trials unable to show reduced time to clinical improvement, viral clearance, or mortality; adverse health effects; study results on Remdesivir's benefits; availability constraints; global production; global clinical trial locations; and intracellular drug processing.

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 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

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

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


- 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.

Hydroxychloroquine as 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

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

Tocilizumab (TCZ) inhibits Interleukin-6 (IL-6), a mechanism that may mitigate the extreme inflammatory response among COVID-19 patients. Its application has been investigated across severe cases and hyperinflammatory states to assess its impact on fever reduction, oxygen requirements, and mortality, as well as to monitor potential toxicities.

Tocilizumab (TCZ) as a 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

There is insufficient evidence demonstrating that chloroquine is an effective treatment for COVID-19. Furthermore, its use as a therapeutic intervention may increase the risk of negative clinical outcomes in patients.

Chloroquine as a COVID-19 Therapy

Clofazimine, an FDA-approved drug traditionally used to treat leprosy, is undergoing clinical evaluation as a potential repurposed treatment for COVID-19.

Clofazimine as a Treatment for COVID-19

Rapamycin (sirolimus) is an FDA-approved immunosuppressant and mTOR inhibitor known for its immunosuppressive and antiproliferative properties, which are used to treat tuberous sclerosis, psoriasis, and certain malignancies. Because of these properties, researchers have investigated its potential to mitigate severe COVID-19, with some experts suggesting it could significantly reduce disease severity in elderly patients.

Rapamycin as a Treatment for COVID-19

Dexamethasone is a corticosteroid evaluated for improving outcomes in hospitalized COVID-19 patients by mitigating the damaging inflammatory response during infection. Key evidence and considerations include its effect on 28-day mortality and other clinical outcomes in the UK RECOVERY randomized controlled trial, and its low cost and wide availability as a treatment.

Dexamethasone as a treatment for COVID-19

The structural differences between the repeating units of heparin (a) and heparan sulfate (b) allow them to be involved in different physiological processes.  Key differences include:

- a sulfo group in heparin and an acetyl group in heparan sulfate at the N-position of the glucosamine
- sulfation at different positions
- epimerization (i.e. spatial rearrangement to chiral analog) of the C-5 uronic acid

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