Cyclosporine is listed among the immunomodulatory and anti-inflammatory agents considered within proposed pharmacological treatments for COVID-19.

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These agents were discussed as immunomodulatory or anti-inflammatory candidates within proposed pharmacological treatments for COVID-19. The group includes tocilizumab, chloroquine/hydroxychloroquine, colchicine, baricitinib, aviptadil, eculizumab, azithromycin, anakinra, pentoxifylline, theophylline, and cyclosporine.

Immunomodulatory and Anti-inflammatory Agents Considered for COVID-19

- Brand Name: Actemra
- Indication: treatment of rheumatoid arthritis and systemic juvenile arthritis
- Class: Interleukin-6 receptor inhibitor
- Mechanism: Tocilizumab is a monoclonal antibody that inhibits the binding of interleukin 6 (IL-6) to its receptor. The IL-6 pathway functions as a key part in regulating the inflammatory immune response in the lungs which, when activated, can cause damage and reduce respiratory functions. 
- Common AEs: Infections, hypertension, headache, and increase in liver enzymes
- Drug-Drug Interactions: Drugs metabolized by CYP3A4, 1A2, or 2C9
- Safety and Efficacy: Treatment in patients with severe SARS-CoV-2 is associated with a reduced need for oxygen, normalized lymphocyte counts and discharge from the hospital. Ongoing clinical trials are evaluating the efficacy and safety of the drug in COVID-19 patients. The drug was further associated with a reduction in fatality rate but an overall increase in risk for superinfections 

Tocilizumab

- Brand Name: Aralen (chloroquine) and Plaquenil (hydroxychloroquine)
- Indication: treatment of malaria and autoimmune diseases like lupus and rheumatoid arthritis 
- Class: Antimalarial agents
- Mechanism: Chloroquine and hydroxychloroquine interfere with the glycosylation of the enzyme ACE2 to reduce virus receptor binding. They may also inhibit enzymes like viral DNA and RNA polymerase and processes such as viral assembly and release. The accumulation of hydroxychloroquine in the cells increases the pH of organelles and prevents the processing of antigens (i.e. viral particles) prohibiting their entry to the cell.
- Common AEs: Heart disorders, liver impairment
- Drug-Drug Interactions: Digoxin, tricyclic antidepressants, antipsychotics, and class IA and III antiarrhythmics 
- Safety and Efficacy: Studies have suggested that chloroquine exhibits antiviral activity against SARS-CoV-2 and is effective in reducing viral replication in vitro. Chloroquine is recommended in the use of hospitalized patients and within clinical trials due to the risk of serious adverse reactions outside of these settings. The use of hydroxychloroquine is not recommended in hospitalized or nonhospitalized patients outside of clinical trials and data is limited and inconclusive. 

Chloroquine/Hydroxychloroquine

- Brand Name: Colcrys (tablet), Gloperba (oral solution), Mitigare (capsules)
- Indication: treatment of acute gouty arthritis and pericarditis
- Class: Anti-inflammatory agent
- Mechanism: Inhibit the metabolism and movement of granulocytes and inhibit neutrophil recruitment and regulation of white blood cell inflammatory activities. Colchicine binds tubulin stopping microtubule elongation to inhibit inflammasome activation, chemotaxis, and the migration of other substances necessary for inflammation.
- Common AEs: Diarrhea, GI bleeding, rashes, kidney damage, and liver damage
- Drug-Drug Interactions: CYP3A4 inhibitors and P-gp inhibitors
- Safety and Efficacy: Colchicine has the potential to reduce inflammatory responses in COVID-19 patients and thus reduce the cytokine storm. Its use in hospitalized adults with COVID-19 pneumonia and ARDS has been associated with increased survival. 

Colchicine

- Brand Name: Olumiant
- Indication: treatment of rheumatoid arthritis
- Class: Janus kinase 1 (JAK1) and 2 (JAK2) inhibitor
- Mechanism: Baricitinib inhibits the protein kinase associated with adapter protein 2 to prevent the binding of the virus to the alveolar surface in the lungs in COVID-19 infection. In rheumatoid arthritis it blocks the activation of proinflammatory mediators by inhibiting JAK 1 and 2 to reduce joint damage
- Common AEs: increased LDL cholesterol, upper respiratory tract infection, and nausea
- Drug-Drug Interactions: Organic anion transporter (OAT) 3 inhibitors
- Safety and Efficacy: Baricitinib may be useful in reduction of inflammation and cytokine levels. In comparison to standard care, a combination of this drug with lopinavir/ritonavir significantly reduced fatality and adverse reactions were not severe enough to stop treatment. 

Baricitinib

- Brand Name: N/A
- Indication: treatment if erectile dysfunction, acute lung damage, and sarcoidosis
- Class: Vasoactive intestinal polypeptide analogue (Vasodilator)
- Mechanism: Avipatadil inhibits proinflammatory cytokines like IL-6 and tumor necrosis factor (TNF) alpha, protects against HCL induced fluid retention in the lungs, and inhibits the activation of protease enzymes essential in programmed cell death
- Common AEs: N/A
- Drug-Drug Interactions: N/A
- Safety and Efficacy: Aviptadil studies have shown that the drug is highly concentrated in the lung where it can inhibit IL-6 and TNF-alpha and protects against fluid retention in the lungs. Clinical studies for COVID-19 infection are ongoing

Aviptadil

- Brand Name: Soliris 
- Indication: treatment of atypical haemolytic uraemic syndrome, neuromyelitis spectrum disorders, and myasthenia gravis
- Class: Monoclonal antibody
- Mechanism: Eculizumab inhibits part of the complement cascade involved in the inflammatory response to treat multiple autoimmune disorders
- Common AEs: headache, infection anaemia, GI events, flu like symptoms, and reduced WBC count
- Drug-Drug Interactions: Rituximab and intravenous human immunoglobulin
- Safety and Efficacy: The role of the complement cascade in COVID-19 is unclear but it is believed that its inhibition may function well as a therapeutic approach to disease management. This medication will be tested in the treatment of people with severe SARS-CoV-2

Eculizumab

- Brand Name: Azasite, Zithromax, Zmax
- Indication: treatment of respiratory, genitourinary, and intestine infections
- Class: Macrolide Antibacterial
- Mechanism: Macrolides like azithromycin may have an immunomodulatory effect on lung inflammatory disorders. They may also decrease the inflammatory response associated with viral infections. Azithromycin may inhibit cytokines thus reducing chemotaxis of neutrophils to the lungs, increase neutrophil cell death, and decrease reactive oxygen species production.
- Common AEs: Cardiac arrhythmias 
- Drug-Drug Interactions: significant drug interactions
- Safety and Efficacy: Data on the use of azithromycin in COVID-19 is limited and inconclusive and at times yield similar results to standard care when in combination with hydroxychloroquine. In fact, there was an increased risk of cardiac events in comparison to standard care. 

Azithromycin 

- Brand Name: Kineret
- Indication: treatment of rheumatoid arthritis and neonatal onset multisystem inflammatory disease
- Class: Interleukin-1 antagonist
- Mechanism: Anakinra  competitively inhibits the binding of proinflammatory cytokines, IL-alpha and beta, to the IL-1 receptor which may help reduce cytokine storms
- Common AEs: rash, headache, upper respiratory tract infection
- Drug-Drug Interactions: significant drug interactions 
- Safety and Efficacy: Use of anakinra in comparison to standard care alone increased 21-day survival in patients with moderate to severe COVID-19, improved respiratory function, and decreased ventilation death.

Anakinra

- Brand Name(s): Trental, Pentoxil, Pentoxifylline SR
- Indication: Treatment of intermittent claudication (cramping with exercise due to obstruction of the arteries) of the limbs
- Class: Hemorrheologic agent
- Mechanism: Pentoxifylline is a phosphodiesterase inhibitor that helps blood flow more easily in narrowed arteries and inhibits various proinflammatory mediators like interleukin 6
- Common AEs: dizziness, headache, nausea, stomach discomfort (very favorable adverse effect profile)
- Drug-Drug Interactions: moderate drug interactions with aspirin, metoprolol, clopidogrel, etc.
- Safety and Efficacy: Use in COVID-19 patients associated with a higher ROX or ratio of oxygen saturation score, a lower mortality rate, and lower C reactive protein values indicating less inflammation in the body. Data supports testing of the drug in clinical trials.

Pentoxifylline

- Brand Name(s): Elixophyllin, Elixophylline, Pukmophyllin, Quibron-T, Theo-24, Theolair, Uniphyl
- Indication: Treatment of asthma, COPD, and bronchospasm
- Class: Bronchodilator
- Mechanism: Theophylline is a phosphodiesterase inhibitor with bronchodilatory effects and anti-inflammatory properties. It relaxes the smooth muscle of the airways and lung blood vessels and diminishes the response of the lungs to allergens, histamine, and adenosine (inflammatory mediators). 
- Common AEs: dizziness, fainting, nausea, vomiting, rapid pulse, heart arrhythmias, chest pain 
- Drug-Drug Interactions: Moderate drug interactions with esomeprazole, albuterol, etc.
- Safety and Efficacy: Use in COVID-19 patients associated with a higher ROX or ratio of oxygen saturation score, a lower mortality rate, and lower C reactive protein values indicating less inflammation in the body. Data supports testing of the drug in clinical trials.

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