Expert Opinion

Treatment of Coronavirus Disease 2019: Shooting in the Dark

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The identification of effective interventions against the coronavirus disease 2019 (COVID-19) pandemic has become a health priority. The rational treatment of a disease is based on the knowledge of its pathophysiology, the identification of a therapeutic target and the confirmation of the efficacy and safety of the selected therapeutic intervention in randomised controlled trials. However, we are facing the COVID-19 pandemic without a clear understanding of the pathophysiology of the disease. As we are fighting against a viral infection, drugs previously developed or approved to treat other viral infections or that exhibit a broad-spectrum antiviral activity, anti-inflammatory drugs and drugs against cytokine storm are currently being tested. Unfortunately, the efficacy and safety of these medications remain uncertain, and some may increase the risk of cardiovascular complications in patients with COVID-19. Thus, at the present time, due to the lack of solid scientific data to support a therapeutic strategy, we truly are shooting in the dark with the treatment of COVID-19. We must wait for the results of ongoing randomised, controlled studies before the widespread adoption of these drugs. In the meantime, investigational anti-COVID-19 drugs should be used in hospitals or as part of clinical trials.

Disclosure:JT is on the European Cardiology Review editorial board. This work was supported by grants from the Institute of Health Carlos III (PI16/00398 and CB16/11/00303).



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Correspondence Details:Juan Tamargo, Department of Pharmacology, School of Medicine, Universidad Complutense, Instituto de Investigación Sanitaria Gregorio Marañón, CIBERCV, 28040 Madrid, Spain. E:

Open Access:

This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

When the cause of the sickness is unknown, only a miracle can cure it.Don Quixote, Miguel de Cervantes, 1605.

The coronavirus 2019 (COVID-19) pandemic was caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1,2 COVID-19 rapidly spread from China to most countries around the world, and on 11 March 2020 the WHO declared a global pandemic. The COVID-19 pandemic has already had a major negative impact on global health systems and the economy.3 From a pharmacological point of view, the rational treatment of a disease is based on the knowledge of its pathophysiology, the identification of a therapeutic target and trial confirmation of the effectiveness of the intervention. Indeed, under normal circumstances, well-designed randomised controlled trials (RCTs) are key to confirm that a pharmacological intervention directed at a selected target is effective and safe. However, these are not normal times and we find ourselves facing a pandemic caused by a virus of which we know very little, and for which there is no clear understanding of the pathogenesis or pathophysiology of the diseases triggered by COVID-19. Moreover, little is known regarding the short- and long-term clinical consequences of the disease and why different individuals respond so differently to the aggression of the virus. Without specific effective therapies for COVID-19 we are facing a very large death toll and the collapse of many health services worldwide.

As a result of the severity of the problem, in the past few months numerous drugs have been proposed that might be effective in the treatment of COVID-19 (Table 1). However, due to the lack of true scientific data to support a therapeutic strategy for COVID-19, it has become apparent that we truly are shooting in the dark. This article aims to convey my reflections on the current situation from a clinical pharmacologist’s viewpoint. Several issues have attracted my attention since the initial reports emerged from China at the time of rapid death progression in that country.

The Ibuprofen Story

On 14 March 2020 the French Health Minister, Olivier Véran, claimed on Twitter that anti-inflammatory drugs such as ibuprofen or cortisone could be an aggravating factor in people with COVID-19.4 A few days later, on 18 March, the WHO recommended using paracetamol instead of ibuprofen. On 19 March, the WHO updated its advice on the official Twitter account: “Based on currently available information, WHO does not recommend against the use of ibuprofen”.5 Finally, on 14 April, the Commission on Human Medicines Expert Working Group on COVID-19 concluded that there is currently insufficient evidence to link ibuprofen or other non-steroidal anti-inflammatory drugs, with a susceptibility to contracting COVID-19 or the worsening of its symptoms.6

Use of Renin-Angiotensin-Aldosterone System Inhibitors in COVID-19 Patients

The angiotensin-converting enzyme 2 (ACE2) is the receptor responsible for SARS-CoV entry into cells, and because ACE2 expression increases in patients treated with ACE inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs), it was hypothesised in a letter published in The Lancet Respiratory Medicine that patients treated with agents capable of increasing ACE2 availability/density such as ACEIs, ARBs, and ibuprofen could be at higher risk of developing severe and fatal COVID-19 infection.7–9 Furthermore, the authors added that ACEIs can modify the adaptive immune response and suggested that long-term use of ACEIs might suppress the adaptive immune response in individuals affected by COVID-19. The article caused great consternation among patients and physicians alike. Although it was somewhat ‘reasonable’ on theoretical grounds, there is no clinical or scientific evidence to indicate that treatment with these important medications should be abandoned or discontinued in patients affected by SARS-CoV-2 infection.10,11

Drugs Under Development for the Treatment of COVID-19

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The above examples are of concern, given that they led to confusing and contradictory recommendations, created uncertainty among prescribers and increased mistrust in medical decisions among the general public. They may also fuel the proliferation of false information or imaginative uses for medications or substances that may not only be ineffective but also extremely dangerous and life-threatening.

As expected, scientists all over the world are assessing whether drugs that inhibit SARS-CoV-2 in vitro (even when their effects in vivo may remain uncertain), agents with broad-spectrum antiviral actions, previously developed and approved for the treatment of other viral infections (particularly RNA viruses, i.e. influenza and HIV) or drugs approved for other clinical indications that exhibit potent broad-spectrum antiviral effects (i.e. chloroquine, hydrochloroquine, ivermectin) might also be effective against SARS-CoV-2 (Table 1). Azithromycin was also tested in this context because its early use is known to reduce the likelihood of recurrent severe episodes of lower respiratory tract illness.12 The race to find an effective medication is progressing at high speed, but the risk is that the quality of the research could be compromised by the anxiety driving some of the research projects.

Severe pneumonia caused by human coronavirus is often associated with massive inflammatory cell infiltration, increased plasma concentration of inflammatory cytokines/chemokines and multiorgan failure, resulting in acute lung injury and acute respiratory distress syndrome.13,14 Indeed, high virus titres and deregulated cytokine/chemokine responses cause a cytokine storm, which results in high morbidity and mortality due to immunopathology.1,14,15 Furthermore, a recent meta-analysis found that measurement of circulating interleukin-6 (IL-6) may predict disease progression in COVID-19 patients.16 This suggests that besides controlling viral load, novel strategies directed at attenuating the cytokine storm (e.g. IL-6 receptor antagonists, immunosuppressants, interferons, fingolimod) may possibly improve clinical outcome, although these medications can increase the risk of secondary infection.

Table 2 summarises the mechanisms of action, the main adverse effects and potential interactions with other cardiovascular drugs,
of drugs currently under clinical investigation for the treatment of COVID-19.

Some Pharmacological Reflections

COVID-19 is a new pandemic and to date, no specific drug (or vaccine) has been found to be effective. Therefore, there is no solid evidence at this point in time that allows treating physicians to use COVID-19-specific treatments, thus management should include the prompt implementation of proven infection prevention and control measures and supportive care, ranging from symptomatic outpatient management to full intensive care support.17 At the onset of the COVID-19 outbreak and in view of the lack of specific treatment for this new coronavirus, SARS-CoV-2, antiviral screening programs identified many antiviral agents that showed in vitro activity against SARS-CoV-2. These drugs are presently being tested in ongoing clinical trials. Several issues have emerged in relation to the strategies that are currently being implemented.

The first is whether the antiviral effects reported in vitro could also be achieved in vivo. Sometimes the concentrations at which these agents inhibit SARS-CoV in vitro are much higher (‘supratherapeutic’) than the therapeutic plasma levels reached at the recommended doses. Thus, it is possible that plasma levels with meaningful activity against SARS-CoV in vitro would not be achieved in vivo without potentially adverse effects. This may be the case for ivermectin and ribavirin. 18 Furthermore, several drugs under development or already approved for other indications, exhibiting a broad-spectrum antiviral activity, are now being tested in COVID-19 patients even when their efficacy and safety in in vivo models or in patients is uncertain. Some antivirals (favipiravir, baloxavir) show no activity against SARS-CoV-2 in vitro at concentrations under 100 μmol/l, but they are, however, being tested in ongoing trials.19 It would not be surprising if the results were disappointing.

Main Pharmacological Characteristics of Some Proposed Drugs for Treating COVID-19

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Main Pharmacological Characteristics of Some Proposed Drugs for Treating COVID-19

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The second is how the pharmacokinetic properties of many of the currently investigated drugs, which were studied in healthy volunteers or in patients affected with the disease for which the drug was initially approved, behave in COVID-19 patients.

In the rush to find a treatment, several ongoing trials are being conducted with drugs that were developed but not approved as yet, or were approved to treat other non-COVID-19 diseases (repurposed agents). However, the half maximum effective concentrations and the recommended doses of these drugs against different viruses are quite different and are based on the particular type of infectious disease. Therefore, the question is how will the most effective and safer dose be calculated in patients with COVID-19? In fact, doses of a given drug may differ in different trials. For example, the dose of chloroquine used to treat COVID-19 varies from 500 mg orally twice daily for 5–10 days to a loading dose of 400 mg twice daily for 1 day followed by 200 mg twice daily for 4 days.20–22 Thus, studies are needed to determine the optimal dose range for the drugs used in the treatment of COVID-19 patients.

We must keep in mind that patients with COVID-19 and pre-existing cardiovascular disease have an increased risk of developing severe symptoms and death, and COVID-19 itself is associated with several cardiovascular complications, including acute myocardial injury, myocarditis, arrhythmias and venous thromboembolism.8,23 Some drugs tested in ongoing trials produce serious cardiovascular and non-cardiovascular adverse effects (hepatotoxicity, neutropenia and increased risk of infection), which clearly represents a clinical challenge (Table 2). It is also recommended to avoid the coadministration of drugs that prolong the QT interval (azithromycin with chloroquine/hydroxychloroquine) and to prescribe chloroquine/hydroxychloroquine, which can produce serious cardiovascular events, only in-hospital or as part of a clinical trial, in patients with COVID-19.

Although corticosteroids were not initially recommended for COVID-19 patients because of the lack of proven benefit and potential harm with these drugs, the RECOVERY Collaborative Group has very recently shown that in hospitalised patients with COVID-19, the use of dexamethasone for up to 10 days resulted in lower 28-day mortality than usual care among those who were receiving either invasive mechanical ventilation or oxygen alone at randomisation.24

Interestingly, the safety profile of drugs not already approved by the Food and Drug Administration (FDA) or the European Medicines Agency is based on limited published evidence, so that their safety profile remains uncertain and we must await the results of ongoing prospective, randomised, controlled studies before the widespread adoption of these drugs.25 Additionally, some drugs (HIV protease inhibitors, IL-6 receptor antagonists) inhibit or induce the activity of some cytochrome P450 3A4 enzymes and increase or decrease, respectively, the exposure of multiple drugs that are substrates of such isoforms (Table 2). Therefore, investigational anti-COVID-19 therapeutics should be used only in approved, RCTs.

Almost on a daily basis, case reports, observational or small retrospective, non-randomised studies are published in major journals and non peer-reviewed journals. Albeit describing interesting cases and findings, many of these articles suffer from serious methodological problems, including lack of blinding, small sample size (<50 patients per group) and marked variations in the inclusion/exclusion criteria, presence of background therapy and varied treatment regimens (different doses, different duration of therapy and different routes of administration), which makes it difficult to ascertain the true treatment effect. Furthermore, the effects of current treatments on quality of life and drug safety are underreported. This variability can explain why even studies performed in the same country with the combination of hydroxychloroquine and azithromycin may lead to contradictory results. 26,27 Additionally, the non-standardised collection of clinical data limits the conclusions from retrospective analysis. As an example, one trial recruiting 21 patients concluded that 91% of patients were discharged on average 13.5 days after the treatment with tocilizumab (400 mg IV), with most patients receiving only one dose; however, the lack of a comparator group limits the interpretation of these results.28

Furthermore, sometimes the preliminary exciting results of one study are not confirmed in other trials. This may indeed be the case of remdesivir. In 53 patients hospitalised for severe COVID-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 68% of patients.29 These promising results led to a Phase III trial in China. Surprisingly, on 23 April 2020, the WHO reported the preliminary results of a Phase III Chinese trial but this report was quickly withdrawn, suggesting that remdesivir did not have beneficial effects in COVID-19 patients or that it was not able reduce the virus in the bloodstream. Interestingly, the researchers responsible for the study indicated that they had not approved its posting. This is a good example of how rushing to obtain results can lead to speculation and unhelpful rumours about the effectiveness of drugs. Nevertheless, on 1 May 2020, the FDA issued an Emergency Use Authorisation for emergency use of remdesivir for the treatment of hospitalised COVID-19 patients.30 Ongoing clinical trials will define which patients will best benefit from remdesivir treatment.


COVID-19 is a new pandemic and, to date, no specific drug has been found to be effective. The identification of effective interventions against COVID-19 (including vaccines) has become a public health priority. Scientists and physicians are facing the challenge to better understand the characteristics of this new virus and the pathophysiology of the disease that it causes, in order to identify possible therapeutic targets and effective therapeutic drugs and vaccines. Despite these efforts, at the present time, we are still shooting in the dark for the reasons mentioned here. Adequately powered randomised clinical trials are needed to establish the efficacy and safety of therapeutic agents prior to the widespread adoption of these therapies. Attempts should be made to develop suitable treatment protocols and to standardise datasets that could facilitate meaningful analysis of treatment effects and clinical outcomes.


  1. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497–506.
    Crossref | PubMed
  2. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382:727–33.
    Crossref | PubMed
  3. WHO. Coronavirus disease (COVID-2019) situation reports. 2020. (accessed 28 April 2020).
  4. Véran O. Twitter. 14 March 2020. (accessed 22 May 2020).
  5. Updated: WHO Now Doesn’t Recommend Avoiding Ibuprofen For COVID-19 Symptoms. (accessed 28 May 2020).
  6. Medicines and Healthcare products Regulatory Agency and Commission on Human Medicines. Commission on Human Medicines advice on ibuprofen and coronavirus (COVID-19). London: MHRA/CHM, 2020. (accessed 28 April 2020).
  7. Li XC, Zhang J, Zhuo JL. The vasoprotective axes of the renin-angiotensin system: physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res 2017;125:21–38.
    Crossref | PubMed
  8. Zheng YY, Ma YT, Zhang JY, et al. COVID-19 and the cardiovascular system. Nat Rev Cardiol 2020;17:259–60.
    Crossref | PubMed
  9. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?. Lancet Respir Med 2020;8:e21.
    Crossref | PubMed
  10. Danser AHJ, Epstein M, Batll ze D. Renin-angiotensin system blockers and the COVID-19 pandemic: at present there is no evidence to abandon renin-angiotensin system blockers. Hypertension 2020;75:1382–5.
    Crossref | PubMed
  11. European Society for Cardiology. Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers. 13 March 2020. (accessed 18 March 2020).
  12. Bacharier LB, Guilbert TW, Mauger DT, et al. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: a randomized clinical trial. JAMA 2015;314:2034–44.
    Crossref | PubMed
  13. Crayne CB, Albeituni S, Nichols KE, Cron RQ. The immunology of macrophage activation syndrome. Front Immunol 2019;10:119.
    Crossref | PubMed
  14. Chen X, Zhao B, Qu Y, et al. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients. Clin Infect Dis 2020; epub ahead of press.
    Crossref | PubMed
  15. Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 2017;39:529–39.
    Crossref | PubMed
  16. Ulhaq ZS, Soraya GV. Interleukin-6 as a potential biomarker of COVID-19 progression. Med Mal Infect 2020;50:382–3.
    Crossref | PubMed
  17. WHO. Clinical management of severe acute respiratory infection when COVID-19 is suspected. 2020. (accessed 28 April 2020).
  18. Momekov G, Momekova D. Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view. MedRxiv 17 April 2020 (accessed 22 May 2020).
  19. Choy KT, Wong AYL, Kaewpreedee P, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res 2020;178:104786.
    Crossref | PubMed
  20. Colson P, Rolain JM, Lagier JC, et al. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents 2020;55:105932.
    Crossref | PubMed
  21. Office of the National Health and Health Commission Office of the State Administration of Traditional Chinese Medicine. New coronavirus pneumonia diagnosis and treatment program (trial version 7) [in Chinese]. 2020. (accessed 22 May 2020).
  22. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020; epub ahead of press.
    Crossref | PubMed
  23. Driggin E, Madhavan MV, Bikdeli B, et al. Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic. J Am Coll Cardiol 2020;75:2352–71.
    Crossref | PubMed
  24. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with Covid-19 - preliminary report. N Engl J Med 2020; epub ahead of press.
    Crossref | PubMed
  25. Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. MedRxiv 23 April 2020 (accessed 22 May 2020).
  26. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020; epub ahead of press.
    Crossref | PubMed
  27. Molina JM, Delaugerre C, Le Goff J, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect 2020;50:384.
    Crossref | PubMed
  28. Xu, X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. 2020. (accessed 22 May 2020).
  29. Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med 2020; epub ahead of press.
    Crossref | PubMed
  30. Food and Drug Administration. Emergency use authorization for emergency use of remdesivir for the treatment of hospitalized 2019 coronavirus disease (COVID-19) patients. 1 May 2020. (accessed 22 May 2020).