Repurposing of FDA approved drugs as COVID-19 therapeutics: Safety concerns and contraindications of drugs in clinical trials

Repurposing of FDA approved drugs as COVID-19 therapeutics: Safety concerns and contraindications of drugs in clinical trials Ravinder Naik Dharavath, Meenu Dutt, Sunil Kumar, Priya Badyal, Nitin Rawat, Tanzeer Kaur, Shweta Sharma, Mahendra Bishnoi, Kanwaljit Chopra 1 Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014 India. 2 Forensic Toxicology Department, Institute of Forensic Science & Criminology, Panjab University, Chandigarh160014 India. 3 Department of Biophysics, Panjab University, Chandigarh-160014 India. 4 Food and Nutritional Biotechnology Laboratory, National Agri-Food Biotechnology Institute (NABI), SAS Nagar, Punjab-140306 India.

Notably, there are more than one hundred ongoing clinical trials are registered to evaluate the anti-COVID potential of hydroxychloroquine [25]. Antiparasitic antimalarial drugs are the most explored drugs for drug repurposing after antivirals due to their ability to interfere with various pathways involved in coronavirus infection and immunomodulatory properties [26,27]. The possible mechanisms of action of antiparasitic drugs including prevention of viral entry (chloroquine & hydroxychloroquine) [28], inhibition of non-structural proteins (mefloquine), endoribonuclease inhibition (mefloquine), blocking the post-translational viral maturation (nitazoxanide), inhibiting CoV main protease (niclosamide), inhibition of importin α/β1-mediated nuclear import of viral proteins (ivermectin), and inhibition of CoV papain-like protease (levamisole) [24,29].
Adverse drug reactions are as important as their beneficial effects while choosing for any kind of pharmacotherapy, and antiparasitic drugs are no exception. Well-known adverse effects of these pharmacological agents include gastrointestinal disturbances (e.g., nausea, vomiting, abdominal pain), hypersensitivity reactions, and blood-related adverse events [15,30]. As these drugs remain for a longer period in the body, the side effects such as Stevens-Johnson syndrome, and encephalopathy associated with antiparasitic use should be noticed carefully. The use of chloroquine and hydroxychloroquine should be avoided in COVID patients with existing heart conditions. On the other hand, the use of mefloquine in patients with existing psychiatric issues and depression ( Table 2).

Antimicrobial drugs
Antimicrobials and antibiotics are widely used drugs for the treatment of microbial infectious diseases caused by bacteria, viruses, and protozoan parasites. In general, most of the antimicrobials are known to be less effective or ineffective against viral infections. Still, the need for promising anti-COVID therapeutics made the researchers revisit the antimicrobial agents and evaluate them for their antiviral properties. Very few antimicrobial drugs were found to be beneficial against the COVID-19 employing preliminary in silico, and in vitro screening [31]. These antimicrobial drugs were found to exert their anti-COVID effects by preventing the viral entry (Povidone-iodine) or by inhibition of CoV main protease (Azithromycin & Atovaquone) or by interfering with viral replication Antimicrobials are well known for their skin (anaphylaxis, pruritus & urticaria), GI (irritation, and abdominal pain), blood-related adverse events. Furthermore, dose-dependent hepato-renal toxicities and antimicrobial resistance are associated with their inappropriate clinical use. Antimicrobial agents such as azithromycin administration may cause QT-interval prolongation and palpitations, whereas, the chronic use of nitazoxanide may lead to tachycardia (Table 3). Moreover, the use of drugs in COVID patients with pre-existing conditions related to liver, kidney, and heart should be strictly monitored or ceased, if needed (Table 3) [15,30].

Immunosuppressants
It could be possible that the hyperactivation of the immune system in COVID patients is responsible for the severe damages caused by SARS-CoV-2 infection [34]. Comorbid cardiometabolic health conditions (diabetes, hypertension, obesity, and heart ailment) in conjunction with the hyperactive immune system among multiple organ systems may exaggerate the mortality among the COVID patients [35,36]. Immunosuppression, through several cytokine axes, seems to have improved the well-being of CoV infected people in the clinical set-up. These drugs are well-known to exert their immunosuppressant actions via their anti-inflammatory abilities by reduction of cytokine secretion that essential for recruitment and differentiation of different immune cells.
However, the immunosuppressants at therapeutic doses may exert adverse effects, including skin rashes, GI disturbances, fluid accumulation, negative neurological effects (confusions and insomnia), blood, and blood vessel-related effects. Furthermore, the chronic administration of these agents may lead to some serious side effects such as myocardial infarction, liver, and kidney damage. Thalidomide, a well-known teratogen and use of which may lead to some life-threatening side effects such as opportunistic infections (pneumonia), congestive heart disease, renal failure, pulmonary embolism, and may even lead to coma. On the other hand, the use of immunosuppressants is contraindicated in immunocompromised patients, pregnancy, and people who are already suffering from any major organ failure (Table 4).

Corticosteroids or Steroidal anti-inflammatory drugs
Corticosteroids are considered lifesaving drugs and used in the treatment of health conditions such as bronchial asthma, chronic obstructive pulmonary disease (COPD), and various autoimmune disorders (e.g., rheumatoid arthritis). Corticosteroids produce their beneficial health effects via their anti-inflammatory and Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 18 June 2020 doi:10.20944/preprints202006.0232.v1 immunomodulatory properties; hence they are also known as steroidal anti-inflammatory drugs. Nevertheless, the hyperactive host immune system is the primary target of these drugs. The corticosteroids mainly act by reducing the cytokine secretion from the infected host cells (dexamethasone, budesonide & hydrocortisone), or by inhibition of cyclooxygenase (COX)-2 synthesis (methylprednisolone), or by anti-inflammatory cum antioxidant properties to prevent the pulmonary interstitial fibrosis (prednisone) [39]. However, the pleiotropic modes of action of corticosteroids may be one of the important reasons behind their repurposing.
Corticosteroids are known to act by multiple mechanisms and can produce side effects at an even greater magnitude. However, the noteworthy side effects include Cushing's syndrome, osteoporosis, acute adrenal insufficiency, hyperglycemia, depression, atrial fibrillation, acute kidney injury, and opportunistic fungal infections [15,30]. The contraindications are always looked forward to prior to their administration to patients with underlying conditions osteoporosis, cerebral palsy, acute respiratory distress syndrome, less active immune system, prior tuberculosis, and pregnant women (Table 5) [40].

Non-steroidal anti-inflammatory drugs (NSAIDs)
NSAIDs are one of the most commonly prescribed classes of medication for the management of pain and inflammation. These drugs fundamentally modulate the immune system through their anti-inflammatory properties, mainly by inhibiting the cyclooxygenases (COX-1/2), enzymes that regulate the synthesis of prostaglandins, and other prostanoids, such as thromboxanes [15]. Duet to the physiological roles of COX-2 (inflammation, pain, and fever) and COX-1 (platelet aggregation), COX-1/2 inhibitors are thought to be promising drugs for the treatment of COVID. The NSAIDs are considered safe as compared to steroidal anti-inflammatory drugs. However, these drugs are used to provide symptomatic relief to the patients but not specific therapeutic options of COVID [41,42]. The NSAID drug, which is currently under trials, mainly acts by inhibition of platelet aggregation (aspirin, enoxaparin, tinzaparin, and defibrotide) via inhibition of COX-1 or by reducing the inflammation through inhibition of COX-2 (Ibuprofen, dexmedetomidin and formeterol).
The well-recorded adverse effects of NSAIDs include gastric irritation, Reyes Syndrome in children, respiratory and metabolic acidosis, anaphylactic shock, liver damage, hypertension, and renal impairment. On the other hand, anti-coagulant anti-inflammatory heparin analogues may lead to hemorrhage across multiple organ systems (Table   6). NSAIDs under trials for drug repurposing are diversely contraindicated in special populations such as children, pregnant women, people suffering from cardiac ailments, hepato-renal failure, and bone marrow depression (Table   6).

Protein kinase inhibitors
kinases have been identified as important drug targets for treating different forms of human ailments such as cancer, autoimmune and inflammatory diseases because of their (kinases) crucial role in signal transduction and control of different cellular functions [43]. Besides, recent studies on the evaluation of the anti-COVID potential of protein kinase inhibitors have suggested that the kinase inhibitors may offer benefits against CoV infection.
Numerous virtual screening and in vitro studies have stated that these drugs might be able to prevent the viral entry into the host cell via inhibition of CoV main protease/type-II transmembrane serine protease or by inhibiting the Janus kinase (JAK½) or Serine/threonine (MARK1) kinase (Table 6) [44][45][46]. Based on the available pieces of evidence, these protein kinase inhibitors are taken up for drug repurposing and are also being investigated in clinical trials.
Anaemia, thrombocytopenia, splenomegaly, hepatomegaly, atrial fibrillation, hypersensitivity, opportunistic infections, pain in extremity, memory impairment, insomnia, depression, and haemorrhage are the key adverse drug reactions associated with the use of protein kinase inhibitors. Further, drug resistance with these drugs is also a concern but uncommon. The use of kinase inhibitors is strictly contraindicated in patients with underlying Mycobacterium (Tuberculosis) infection, hypertension, vital organ failure (liver or kidney), and hypersensitivity to the drug (Table 7).

Other drugs
In addition to various classes of drugs discussed above, this section includes other drugs that are capable of alleviating the clinical symptoms of COVID that are currently under various clinical trials. All these drug acts by different mechanisms of action which include, decreasing the availability of the ACE-2 receptors for the CoV infarction, kidney damage, angioedema, and hypotension (see Table 8 for detailed information on drug-specific ADR). Information on contraindications related to the use of these drugs in special populations and health conditions should be considered before commencing the treatment (Table 8).        Inhibits neuraminidase enzyme that helps the release of viral replicates from the host cells [8,61].
Hypersensitive to drug, pregnancy. Anti-parasitic agent for Strongyloidiasis.
Anti-helminthic Table 4. List of immunosuppressant drugs in clinical trials against COVID-19; their mechanism(s) of action, adverse drug reactions, and contraindications.
Hypersensitive to drug, Immunocompromised patients.
Prophylaxis therapy to prevent graft rejection.
Pregnancy, hepatic failure, renal insufficiency. Children below 2 years of age, and immunocompromised patients.
Immunosuppressive drug to prevent graft rejection and acute dermatitis.
Pregnancy, and immunocompromised patients. immunosuppressant and antiangiogenic. Table 5. List of corticosteroids in clinical trials against COVID-19; their mechanism(s) of action, adverse drug reactions, and contraindications.

Drug candidate -No. of Ongoing clinical trials Target & MoA against COVID-19 Adverse drug reactions Contraindications/Special populations Current indications
Dexamethasone-12 Inflammatory modulation by reducing the cytokine secretion [71].
Anti-inflammatory and immunosuppressive for the treatment of asthma, arthritis, atopic dermatitis, contact dermatitis.
An anti-inflammatory drug used to treat ulcerative colitis, acute severe asthma.

Methylprednisolone-25
Reduction of inflammatory cytokine release in the lungs by suppressing the synthesis of cyclooxygenase (COX)-2 [56,72]. Pregnancy, hypersensitive to drug, diabetic and immunocompromised patients.

Similar to
Methylprednisolone.
Hypersensitive to drug, immunocompromised patients.

Drug candidate -No. of Ongoing clinical trials Purpose & MoA against COVID-19 Adverse drug reactions Contraindications/Special populations Current indications
Aspirin-8 Anti-inflammatory and via inhibition of platelet aggregation [74].
Should not be given along with anticoagulants such as Warfarin, as it may lead to excessive bleeding.
Liver failure and hypertensive patients being treated with diuretics [15].

Enoxaparin-22 Tinzaparin-24
Pulmonary coagulopathy with ARDS in COVID patients is fatal. Prophylactic use of heparins will improve the blood oxygenation to reduce the mortality rate among COVID patients [75].   inhibitor as antidiabetic.
Patients with renal failure should be critically monitored in asthmatic patients.
Cholinesterase inhibitor for the treatment of Myasthenia gravis.
Patients with comorbid Liver and kidney impairments [86].
HMGA CoA reductase inhibitor for the treatment of hypercholesterolemia & Hypertriglyceridemia.

Sildenafil-1
Via vasodilation by activation of nitric oxide (NO) release, thereby decreasing pulmonary artery pressure and, as a result, lower pulmonary capillary hydrostatic pressure [52].
Should not be used in patients with "Retinal degenerative diseases." PDE-5 Inhibitor for erectly dysfunction and pulmonary hypertension treatment.

Spironolactone-3
As a replacement of angiotensin receptor blockers in hypertensive patients. As it doesn't lead to the overexpression of ACE-2 receptors in the lungs [87].