Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review | Clinical Pharmacy and Pharmacology | JAMA | JAMA Network
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    19 Comments for this article
    Richard Brown, MA (Cantab) MSc (Edin) | Farm Veterinarian Scotland
    I am surprised there is no mention of naproxen. The French may be about to start a trial with naproxen as a component of therapy (NCT04325633). Even if an RCT is not performed for Naproxen as a component, an epidemiological study should be performed to follow those who take naproxen long term (and who have been advised to continue to use it, ie some rheumatoid arthritis sufferers) and see if through this pandemic they have ( paradoxically) been less at risk.
    COVID-19 Angiotensin Paradigm can also be addressed
    Andrew Ashworth, MbChB | Bonhard Medical, Scotland
    This review of some pharmacological interventions (1) is a helpful summary but it restricts itself, perhaps based on the methodology, to interventions directed toward SARS-COV-2 virus itself and so does not include potential interventions to mitigate the clinical effects of COVID-19.

    SARS-COV-2 targets ACE2 and, while reduced expression of ACE2 has not been shown, the assumption of such a reduction is consistent with clinical findings. ACE2 converts inactivates Angiotensin II to Angiotensin 1-7.(3). Without ACE2, Angiotensin II causes contraction of smooth muscle via the phosphodiesterase 5 (PDE5) pathway (4) with vasoconstriction and cough.

    This ‘COVID-19 Angiotensin Paradigm”
    is consistent with clinical effects mediated by vasoconstriction:
    • Reduced gas exchange and therefore reduced oxygen supply to the systemic circulation
    • Reduced blood-borne immune response to the viral particles
    • Increased pressure in the Pulmonary artery with shunting of deoxygenated pulmonary arterial blood to the systemic circulation.
    - Bronchiolar smooth muscle-mediated cough

    Current pharmacological interventions appear to be focussed on antivirals. Current therapy relies on increasing alveolar oxygen concentration. If ACE2 fails to protect distal pulmonary vessels from Angiotensin II, then mitigating its effects has the immediate potential significantly to alter the progress of the disease. PDE-5 inhibitors are widely available and appear to have significant promise in addressing the increased exposure of pulmonary smooth muscle to Angiotensin II in COVID-19. There is an anecdotal report of a PDE5 inhibitor being used effectively in a similar historical case (5).

    PDE5 inhibitors in COVID-19 offer a means of treatment in poorer countries where ventilatory support is less available. A clinical trial is required.


    1. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. Published online April 13, 2020. doi:10.1001/jama.2020.6019(2)
    2. Hoffmann et al., 2020, Cell 181, 1–10 April 16, 2020 a 2020 Elsevier Inc.,
    3. Tikellis, C.,Thomas, M.C. Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease International Journal of Peptides Volume 2012, Article ID 256294, doi:10.1155/2012/256294
    4. Dongsoo Kima, Toru Aizawab, Heng Weic, et al. Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: A mechanism by which angiotensin II antagonizes cGMP signaling J Mol Cell Cardiol. 2005 January ; 38(1): 175–184. doi:10.1016/j.yjmcc.2004.10.013
    5. Ashworth AJ. Enhanced recovery from respiratory infection following treatment with a PDE-5 inhibitor: a single case study Prim Care Respir J 2012; 21(1): 17-18
    Pulmonary Delivery of Possible Therapeutic Agents for COVID-19
    Hasham Shafi, PhD Pharmaceutics | CSIR-Central drug research institute, University of Kashmir
    The review is well articulated and all therapeutic agents in trials or being used are discused. I would have expected researchers around the globe to give prime consideration to the route of drug delivery, It's well established that pulmonary delivery as a dry powder inhalation of some of the drug candidates can target these drugs directly to the site of infection and can reduce the drug dose especially in drugs with toxicity issues.
    Darunavir Has No Activity Against SARS-CoV-2
    Marcelo Radisic, MD | d.Institute, Instituto de Trasplante y Alta Complejidad / Sanatorio Finochietto. Buenos Aires, Argentina.
    Although darunavir is an effective inhibitor of the HIV-dimeric aspartyl protease, it has no demonstrated activity against SARS-CoV-2 protease, which is a cysteine protease. Darunavir has low affinity with the catalytic center of the SARS-CoV-2 protease active site.

    Janssen, the manufacturer of darunavir, has reported that results from a single center, open label, randomised controlled trial conducted at Shanghai Public Health Clinical Center (SPHCC) testing darunavir and cobicistat (DRV/c) in treating 30 COVID-19 patients showed that DRV/c was not effective (1). In addition, the in-vitro antiviral activity of darunavir against SARS-CoV-2 was assessed and darunavir showed no activity
    against SARS-CoV-2 at clinically relevant concentrations (EC50>100 μM).

    These data do not support the use of darunavir for the treatment of COVID-19


    1., accessed April 4th, 2020
    Is Remdesivir the Answer for COVID-19?
    Sarosh Ahmed Khan, MBBS; MD; FACP; FRCP Edin | Naseem Medical Center, Baghe Mehtab, Srinagar, Kashmir 190019
    The anti-viral drug remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, had until now shown only in vitro activity against SARS-CoV-2. It had also been tried in non-clinical models in ebola and other coronaviruses (SARS-CoV and MERSCoV) (1,2). It was investigated in Ebola virus infection & found to have a favorable clinical safety profile, as reported on the basis of experience in about 500 persons (volunteers and patients) (3,4).

    But a recent small industry-conducted (Gilead Sciences) study appeared to show efficacy in seriously ill COVID-19 patients (5) . About 2/3rd of patients given the drug on compassionate-use
    basis showed signs of clinical improvement. Patients had confirmed COVID-19 with an O2-sat of =< 94% while they were breathing ambient air or were receiving O2 support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered IV on day 1, followed by 100 mg daily for the remaining 9 days. Of the 61 patients who received at least one dose of Remdesivir, data from 8 was not analyzed. At baseline, 57% were receiving mechanical ventilation(MV) and 8% were receiving ECMO. During a median follow-up of 18 days, 68% patients had an improvement in O2-support class, including 57% receiving MV who were extubated. A total of 25 patients were discharged, & 7 died; mortality was 18% among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation.

    The downsides:
    1. Small size of the cohort
    2. Viral load data to confirm the antiviral effects of remdesivir or any association between baseline viral load & viral suppression were not collected
    3. The duration of remdesivir therapy was not uniform
    4. Shorter duration of therapy (e.g., 5 vs 10 days) was not studied 
    5. 60% reported adverse events including raised liver enzymes, diarrhea, rash, renal impairment, & hypotension. AEs were more common in patients receiving invasive ventilation. Of 23% who had serious AEs, common ones were multi-organ dysfunction syndrome, septic shock, acute kidney injury, & hypotension. 4 patients had to stop treatment because of these
    6. The study did not have a control arm so we don't know the contribution of other factors like type of supportive care (concomitant medications or variations in ventilatory practices) & differences in institutional treatment protocols & thresholds for hospitalization

    Pharma companies seeing the desperate need of a drug have come up with a new name for “off-label use”: compassionate-use

    We may not be able to draw definitive conclusions, but if these caveats are taken care of, it seems that remdesivir may have clinical benefit in patients with severe Covid-19


    1. de Wit E et al. Prophylactic & therapeutic Remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A 2020; 117: 6771-6
    2. Sheahan TP et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic & zoonotic coronaviruses. Sci Tran Med 2017; 9(396): eaal3653
    3. Mulangu S et al. A randomized, controlled trial of Ebola virus disease therapeutics. NEJM 2019; 381: 2293-303
    4. EMA. Summary on compassionate use: Remdesivir Gilead. April 3 2020
    5. Grein J et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. NEJM April 10 2020 DOI: 10.1056/NEJMoa2007016
    Novel CoViD Impairment of hypoxic pulmonary vasoconstriction hypothesis
    Darren Emerick, MBBS | University of Queensland
    Working on the hypothesis that novel CoViD unusually causes impairment of hypoxic pulmonary vasoconstriction, COVID-19 would be a hyperaemic pneumonia, resulting in major ventilation-perfusion mismatch.

    Therapies that may modulate hypoxic pulmonary vasoconstriction include:

    Buffered L-lactic acid infusion [+R shift ODC]
    Angiotensin II infusion
    Beta 2 agonist infusion
    TASK-1 channel blockers eg doxapram, almitrine, 2-phenyl-3-(piperazinomethyl)imidazo[1,2-a]pyridine derivatives [Bayer phase 1 trials]
    Desferrioxamine infusion
    Hyperthermia [+R shift ODC]
    Methanandamide/Anandamide infusion
    Bupivacaine infusion

    [ET-1 infusion seems unlikely to represent a therapeutic strategy for enhancing HPV during acute (<4 h) hypoxia]
    What Does "Most Promising" Mean?
    Marlowe Fox, JD, MS | None
    This meta-analysis seems to be an important splash of cold water on potential treatments. In particular, the HCQ/CQ trials that resulted in statistically significant p-values but failed to control/adjust for several confounding variables (1,2). However, the description of remdesivir as the "most promising treatment” seems to have even less empirical support.

    It also begs the question of what constitutes the “most promising treatment.” Does it mean:

    1. Best in-vitro effects (best mechanistic explanation/identification of mediator)
    2. Highest probability of similar in-vivo effects
    3. Robust empirical support (sample size; sufficiently articulated methods/evaluation procedures; controlling for comorbidities, symptom
    onset, prescriptions i.e. RAAS inhibitors; statistical significance)
    4. Probability of non-toxic, low side effect dosing
    5. Availability, cost-effectiveness, other pragmatic concerns
    6. Potential for prophylactic use as well
    7. Reducing the contagious phase of the infected

    And if this was the case, why did the article not articulate as much in its methods? This would obviate any concern of an ad hoc conclusion or any other potential bias.

    Remdesivir’s “promise” seems to be based on its “potent” in vitro effects against SARS-CoV-2 as well as two studies in which a total of four patients received remdesivir (3,4). In one study, a 35 y/o healthy male, after progressively worsening symptoms, received treatment on day 7 of hospital admission (day 11 of symptom onset). Within 24 hours, the patient’s oxygen saturation went from 90% to 96%, and he was taken off supplemental oxygen (3). In the other study 12 patients were examined, of which 3 received the treatment. The study was plagued by confounding variables. Not to mention, all 12 patients recovered (4). It should be noted that these studies are only footnoted in the article.

    Whatever the HCQ trials were lacking, they offered at least some scientific rigor (1,2). The article criticizes the French study (2) for “a small sample size…the removal of 6 patients in the hydroxychloroquine group...” Similarly, it critiques the Wuhan study: “At day 7, virologic clearance was similar, with 86.7% vs 93.3% clearance for the hydroxychloroquine plus standard of care group and standard care group, respectively (P > .05).” However, the Wuhan study’s most noteworthy findings may have been the average reduction of about 1 day in fever and coughing, both of which were supported by p-values of 0.0008 and .0016 respectively (1). Assuming these results are accurate, cutting a day off symptoms could substantially decrease the infection rate as well as increase the availability of hospital resources. There are certainly concerns with the Wuhan study—p-hacking or HARKING could very well have been involved—but the same problems exist with the remdesivir reports.

    With no clinical trials that sufficiently control for confounding variables, the most promising treatment would likely be the one with the most empirically supported mechanism (mediator). I would be interested in a meta-analysis that surveyed all the potential causal mechanisms, whether they be anti-viral or inhibition/blocking somewhere along the RAAS-pathway (5).


    Androgen Pathway Targets and Incomplete TMPRSS2 Inhibitors list
    Carlos Wambier, MD, PhD | Warren Alpert Medical School, Brown University
    This article mentions Transmembrane Protease Serine 2 (TMPRSS2) but fails to address the pivotal role of androgen receptor (RA) activation for transcription of the TMPRSS2 gene. The androgen pathway is key to individual vulnerability, since androgen-promoted proteins are increasingly expressed after puberty (1).

    Clinical signs of androgen expression such as androgenic alopecia (2) could be strictly linked to vulnerability.

    Thus, targeting any step of the androgen pathway with the following agents may theoretically increase host resistance:

    LH (GnRH) analogues: Degarelix, Goserelin, Leuprolide, Leuprorelin, Nafarelin 
    Testosterone (steroidogenesis) inhibitors: Ketoconazole, Fluconazole, Itraconazole 
    5-alpha reductase inhibitors: Dutasteride, Finasteride 
    RA inhibitors:
    Spironolactone, Bicalutamide, Darolutamide, Enzalutamide, Flutamide, Nilutamide: 

    All of which are used for androgenic suppression.

    Finally, the first TMPRSS2 inhibitor described was bromhexine, a common cough medication (3), to add to camostat, a new drug.

    The list above indexes the main medications that might be used to target the androgen pathway of viral entry in cells (through TMPRSS2 priming of both viral spike and ACE2) (1).

    Studies for male prophylaxis with medications that have a favorable side-effect profile (5-alpha reductase inhibitors), and in life-threatening circumstances, chemical castration, as done in metastatic prostate cancer, could also be tested in clinical trials.

    Some patients present with increased risk of thrombosis from androgen blockade. A phytochemical compound, quercetin-3-β-O-D-glucoside (isoquercetin), with antiviral activity against Zika and Ebola virus(4,5), inhibits the androgen receptor (6) and targets extracellular protein disulfide isomerase (PDI), improving markers of coagulation in advanced cancer patients (7). PDI is a thiol isomerase secreted by vascular cells, that is required for thrombus formation.

    1. Wambier CG, Goren A. SARS-COV-2 infection is likely to be androgen mediated. J Am Acad Dermatol. April 2020. doi:10.1016/j.jaad.2020.04.032
    2. Goren A, McCoy J, Wambier CG, et al. What does androgenetic alopecia have to do with COVID-19? An insight into a potential new therapy. Dermatol Ther. April 2020:e13365. doi:10.1111/dth.13365
    3. Lucas JM, Heinlein C, Kim T, et al. The Androgen-Regulated Protease TMPRSS2 Activates a Proteolytic Cascade Involving Components of the Tumor Microenvironment and Promotes Prostate Cancer Metastasis. Cancer Discov. 2014;4(11):1310-1325. doi:10.1158/2159-8290.CD-13-1010
    4. Qiu X, Kroeker A, He S, et al. Prophylactic efficacy of quercetin 3-β-O-D-glucoside against Ebola virus infection. Antimicrob Agents Chemother. 2016;60(9):5182-5188. doi:10.1128/AAC.00307-16
    5. Wong G, He S, Siragam V, et al. Antiviral activity of quercetin-3-β-O-D-glucoside against Zika virus infection. Virol Sin. 2017;32(6):545-547. doi:10.1007/s12250-017-4057-9
    6. Xing N. Quercetin inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Carcinogenesis. 2001. doi:10.1093/carcin/22.3.409
    7. Zwicker JI, Schlechter BL, Stopa JD, et al. Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer. JCI insight. 2019;4(4):1-12. doi:10.1172/jci.insight.125851
    Reconsider Corticosteroids
    Lei Zhang, M.D. | Tianjin Cancer Institution and Hospital
    People have a negative attitude towards use of corticosteroids for COVID-19 (1) for several reasons. First is that the original protocol in SARS used large doses (2) with potential for serious complications, including femoral head necrosis, secondary infections, etc. (3) with outcomes attributed to SARS rather than the treatment. Secondly, no potential effective antiviral drugs such as remdesivir were developed at the time when SARS broke out, (4) so large doses undoubtedly caused an increase in viral replication and delay in viral clearance (5).

    Postmortem analysis of COVID-19 patients has confirmed the lung tissue injury caused by cytokine storms
    and the formation of acute respiratory distress syndrome (ARDS) (6), which is a problem that antiviral drugs cannot solve. Twenty years ago, methylprednisolone therapy was proven effective for improving lung injury and reducing mortality in ARDS (7). Recently, in treatment of COVID-19, it has also been reported that the use of steroids, especially low-dose therapy, can effectively reverse the condition of severe patients and reduce death. (8) (9) If we could change the traditional usage pattern, adopt early low-dose corticosteroids therapy, and use them with effective antiviral drugs, the mortality rate of severe COVID-19 patients might be reduced .

    1, Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review [published online ahead of print, 2020 Apr 13]. JAMA. 2020;10.1001/jama.2020.6019. doi:10.1001/jama.2020.6019
    2, Sung JJ, Wu A, Joynt GM, et al. Severe acute respiratory syndrome: report of treatment and outcome after a major outbreak. Thorax.2004;59(5):414–420.
    3, Hong N, Du XK. Avascular necrosis of bone in severe acute respiratory syndrome. Clin Radiol. 2004;59(7):602–608. doi:10.1016/j.crad.2003.12.008
    4, Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19 [published online ahead of print, 2020 Apr 10]. N Engl J Med. 2020;10.1056/NEJMoa2007016.doi:10.1056/NEJMoa2007016
    5, Lee N, Allen Chan KC, Hui DS, Ng EK, Wu A, et al. (2004) Effects of early corticosteroid treatment on plasma SARS-associated coronavirus RNA concentrations in adult patients. J Clin Virol 31: 304–309.
    6, Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020 Feb 18 [Epub ahead of print].
    7, Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1998;280(2):159–165. doi:10.1001/jama.280.2.159
    8, Zheng C, Wang J, Guo H, et al. Risk-adapted Treatment Strategy For COVID-19 Patients [published online ahead of print, 2020 Mar 27]. Int J Infect Dis. 2020;S1201-9712(20)30179-X. doi:10.1016/j.ijid.2020.03.047
    9, Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. Published online March 13,
    The Social Life of SARS-Cov-2 With Therapeutic Implications
    Arturo Tozzi, Pediatrician | University of North Texas
    Viruses may spread not just as single particles, but also as collective aggregates (Segredo-Otero and Sanjuán, 2019; Andreu-Moreno and Sanjuán, 2020). These assemblies stand for “viral communities” with enhanced infectious capacity and improved spread compared with “free” viral particles (Cuevas et al., 2020). It is well known that coronavirus particles are able to stick together through virion-virion binding and to form aggregates. In particular, their particles tightly adhere with their projections sticking into each other, forming a mosaic patch that leads virions to squeeze and lose their spherical shape (Lin et al., 2004; Groneberg et al., 2005). It has been shown that, when SARS-Cov-2 grows in supernatants of infected cells, virions tend to aggregate in small globular assemblies that progressively give rise to larger net-like aggregates (Peter Doherty Institute for Infection and Immunity,

    The ability to build particles assemblies and achieve collective dynamical behavior may provide invaluable advantages to SARS-Cov-2. The squeezing in their spherical shape allows particles to achieve a best package, increasing their number in a given amount of host fluids and maximizing viral load. SARS-CoV-2 positive patients with few/no symptoms and modest levels of detectable viral RNA in the oropharynx have been described (Zou et al., 2020). This finding, together with the observation that SARS-CoV-2 displays a well-known decay rate both in aerosols and various surfaces (van Doremalen et al., 2020), suggests the possibility that reduced viral loads could be correlated with decreased viral ability to build particles clustering. The globular-like arrangement of multiple SARS-CoV-2 virions may provide another advantage against host immunity and environmental offenses: even if immune systems or environmental factors engage the external core of the viral assembly, an inner viral sanctuary might be spared from further damages. It is noteworthy that, while VSV multi-virion complexes occur unfrequently in standard cell cultures, they are abundant in other fluids such as saliva (Cuevas et al., 2020). Further, it might be hypothesized that the lower symptomatic response in children to COVID-19 (Huang et al., 2020; Bi et al., 2020) could be correlated with local factors endowed in the pediatric respiratory airways that are able to scatter the viral assemblies responsible for symptoms severity. In sum, clustered SARS-Cov-2 dissemination stands for a potential target leading to novel antiviral strategies able to mechanically disrupt virionic assemblies.

    Arturo Tozzi
    Center for Nonlinear Science, Department of Physics, University of North Texas, Denton, Texas, USA

    James F. Peters
    Department of Electrical and Computer Engineering, University of Manitoba
    Department of Mathematics, Adıyaman University, 02040 Adıyaman, Turkey

    Isabella Annesi-Maesano
    French NIH (INSERM), EPAR Department, IPLESP, INSERM
    Sorbonne University, Paris, France.

    Gennaro D'Amato
    Division of Respiratory and Allergic Diseases, Department of Chest Diseases, High Specialty A. Cardarelli Hospital, Napoli, Italy
    Medical School of Specialization in Respiratory Diseases, University on Naples Federico II.
    Clarification on Angiotensin Receptor Blockers' Proposed Role in SARS-CoV-2
    James Cutrell, MD | UT Southwestern Medical Center, Dallas, Texas
    We would like to clarify a statement in our current review on page E7 which reads, “In contrast, angiotensin receptor blockers could theoretically provide clinical benefit via blockade of ACE2 receptors.”

    One proposed mechanism for angiotensin receptor blockers' (ARBs') amelioration of SARS-CoV-2 lung injury stems from ARB inhibition of the angiotensin receptor 1 (AT1R), not direct inhibition of the ACE2 receptor. This blockade in theory dampens angiotensin II mediated AT1R activation and downstream signaling that underlies SARS-CoV-2 mediated lung injury. An additional purported ARB mechanism of lung protection is ACE2 upregulation and subsequent increased conversion of angiotensin II
    to angiotensin 1-7, a known vasodilator. These clinical benefits of ARBs have not been established but are being studied in ongoing clinical trials.

    This clarification does not affect the clinical recommendations in our review which are concordant with major clinical societies and practice guidelines recommending continued therapy with ACE inhibitors or ARBs in patients already on these agents.

    1. Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. Published online March, 4, 2020. doi:10.1002/ddr.21656

    2. Patel AB, Verma A. COVID-19 and Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: What is the Evidence? JAMA. Published online March 24, 2020. doi:10.1001/jama.2020.4812
    CONFLICT OF INTEREST: Dr. Cutrell received non-financial support from Regeneron and Gilead outside the submitted work.
    Absence of Effective Treatment
    Eduardo Quinteros, MD. Board IM Cardio | Internal Medicine and Critical care, Clinica Mayo Bell Ville, Argentina
    After reading this review I thought the title might better be "Absence of Probable Treatments for COVID19." People are desperate for an oseltamivir for SARS-CoV-2, and medical journals become repositories of letters and reviews with 70-patient studies that are too limited to provide a solution. Some comments are at the level of what you hear in a supermarket line, spreading more confusion. We'd do well to remember the first principle of medicine: first, do no harm.
    Is There Evidence for Treatment with Hydroxychloroquine & Azithromycin?
    John Baer, M.D. |
    Regarding the hydroxychloroquine-azithromycin study cited (ref 16), I have concerns. I recommend having a look at the methods & the detailed patient data present at the end of the draft of the paper (Supplementary Table 1: This table is not included in the final publication. Method of testing was cell culture cytotoxicity, then PCR of the supernatant. Lots of room for false positive and negatives, e.g. some patients in both the control and treatment groups oscillated between positive and negative; is "POS" a patient with cytotoxicity alone, without PCR confirmation? There is lots of missing and heterogeneous data in the control group. The methods and detailed patient data raise significant questions about whether there was a treatment effect.
    Statins and COVID-19
    Timo Strandberg, MD, PhD | Universities of Helsinki and Oulu, and Helsinki University Hospital
    Sanders et al present various pharmacologic possibilities to prevent and treat COVID-19 (1). They do not mention statin treatment, which is a potential way to improve host resistance without directly attacking the virus (2).

    Statins have favorable effects on endothelium dysfunction and may also prevent thromboembolic complications (3). Although statins have anti-inflammatory and immunomodulatory properties and their use has been associated with less complications during infections (2), I don’t believe that statins would act as direct antimicrobial agents in COVID-19. But a considerable portion of patients have cardiovascular diseases or diabetes, and statins are evidence-based treatment to reduce
    morbidity and mortality in those individuals (4). Statin treatment is also associated with mortality benefit among older, frail patients (5), a considerable group of COVID-19 victims.

    That low cholesterol is associated with worse prognosis in many acute diseases and in frailty is no argument to avoid statin treatment, because the mechanisms of ‘endogenous’ (due to acute conditions, frailty) and ‘exogenous’ (caused by statins) cholesterol reduction are different (6).

    Statins are well-known, generally safe, cheap, and effective drugs. However, adherence is frequently not optimal due to, for example, fake information on the internet and social media. I think appropriate use of statins among patients with cardiovascular risk should be actively promoted during the COVID-19 pandemia.


    1. Sanders JM, Monogue ML, Jodlowski TZ, et al. Pharmacologic treatments for coronavirus disease 2019 (COVID-19)A Review. JAMA. Published online April 13, 2020. doi:10.1001/jama.2020.6019
    2. Fedson DS. Treating the host response to emerging virus disease: lessons learned from sepsis, pneumonia, influenza and Ebola. Ann Transl Med 2016;4:421
    3. Kunutsor SK, Seidu S, Khunti K. Statins and primary prevention of venous thromboembolism: a systematic review and meta-analysis. Lancet Haematol. 2017 Feb;4(2):e83-e93. doi: 10.1016/S2352-3026(16)30184-3.
    4. Cholesterol Treatment Trialists' Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet. 2019;393(10170):407-415
    5. Strandberg TE. Deprescribing statins-Is it ethical? J Am Geriatr Soc. 2016;64(9):1926-7.
    6. Gnanenthiran SR, Ng ACC, Cumming R, et al. Low total cholesterol is associated with increased major adverse cardiovascular events in men aged ≥70 years not taking statins. Heart. 2019 Oct 13. pii: heartjnl-2019-315449. doi: 10.1136/heartjnl-2019-315449
    CONFLICT OF INTEREST: Collaborations (research, consultative, educational) with companies (including Amgen, Merck, Orion, Sanofi, Servier) and other entities interested in cholesterol-lowering. I take a statin daily.
    Vitamin C
    Harri Hemila, MD,PhD | University of Helsinki
    The literature summarizing a possible role for vitamin C in COVID-19 is briefly summarized at
    Disappointing Review
    Todd Clark, MD | ER Physician in Private Hospital System with Academic Affiliations
    Disappointing review mostly in its overemphasis of certain weak therapies (remdesivir for one), and complete omission of other promising therapies (vitamin C (Dr. Marik’s critical care protocol) and heparin (DIC prevention), to name a few).

    Remdesivir study patients were cherry-picked and would have gotten better without the drug.

    Only 15 comments after over 700,000 views of this article is alarming as well. Hoping people aren’t just taking what is written here as gospel.
    Biased Review
    Dinesh Ranjan, MD, FACS | PRAN Philanthropic Clinic
    Sanders and colleagues have published a detailed review of pharmacologic treatment options for Covid-19 in JAMA (1). Two drugs, hydroxychloroquine (HCQ) and remdesivir, have garnered most attention by medical journals and public media lately. While the French study touting HCQ with azithromycin had several shortcomings (2), it was hailed by President Trump regardless. The academic medicine, medical journals and main-stream media have condemned HCQ. In contrast however, remdesivir seems to have caught the fancy of the same group who seem to be willing to ignore the shortcomings of remdesivir data. This double standard is evident in this review.

    authors state that they reviewed English language”articles catalogued in PubMed. However, they cite a Chinese language paper not catalogued in PubMed, showing no benefit with HCQ (3). They appear to ignore other English language papers supporting HCQ. Finally, the authors conclude that they “do not support adoption” of HCQ/Azithromycin “without additional studies”.

    In contrast, when discussing remdesivir; the authors recommend that “inclusion of this agent for treatment of Covid-19 may be considered”. This recommendation is based upon “anticipated results from RCTs” and “successful case reports” in Covid-19 patients. Recommendations are based on anticipated results? And the successful case reports they state includes a study of 3 (out of 7 hospitalized) patients, without any difference in outcome. The authors, while making a case for its antiviral properties, state that remdesivir was used in clinical trials in Ebola – but they fail to mention that their cited reference did not include humans (4). They mention other single case reports of remdesivir use in Ebola. Unfortunately, they neglect to mention that the definitive study on Ebola therapeutics: a randomized trial of four therapeutic options, had not supported Remdesivir (5). Surely, a search in PubMed had brought up this NEJM paper? Why was this ignored while the authors were using single case reports to support remdesivir?

    That remdesivir has become the favorite in journals and media is obvious (6). And it may yet be the best option for our patients once we have results from trials. We just wish that the reviews and recommendations published in respected journals will use an even-handed approach and not be openly cherry-picking information to support possible preexisting biases.


    1. Sanders JM, Monogue ML, Jodlowski TZ et al. JAMA. 2020 Apr 13. doi: 10.1001/jama.2020.6019.
    2. Gautret P, Lagier JC, Parola P et al. . Int J Antimicrob Agents. 2020 Mar 20:105949. doi: 10.1016/j.ijantimicag.2020
    3. Chen J,Liu D,Liu L, etal. J Zhejiang Univ (MedSci). Published on line March 6, 2020.doi:10.3785/j
    4. https://www.who. int/ebola/drc-2018/summaries-of-evidenceexperimental-therapeutics.pdf
    5. Mulangu S, Dodd LE, Davey RT. Randomized, Controlled Trial of Ebola Virus Disease Therapeutics N Engl J Med. 2019 Dec 12;381(24):2293-2303
    6. 7. Grein J, Ohmagari N, Shin D et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020 Apr 10. doi: 10.1056/NEJMoa2007016
    Be Humble, Alert, and Creative!
    Bert Govig, MD, MPH | McGill University
    Thanks to Dr Sanders and his team for this clear paper and particularly for repetition of the fundamental point: there is no known treatment for COVID-19 ... RCTs are needed.

    This sober fact is humbling. In our search for treatments we should remember:

    * Graphical illustration helps us think about these drugs, but should not fool us into thinking we understand the disease. It is quite likely that the drugs we will use to treat COVID-19 will work through unknown or unanticipated mechanisms. ACE inhibitors, Beta Blockers, statins, PDE-5 inhibitors, SGLT-2 inhibitors, and even hydroxy chloroquine
    are used today for purposes that were accidentally discovered after they were in clinical use.
    * Most of the candidate drugs will either have no effect or will cause harm. That is the nature of pharmacologic research. However we have hundreds of thousands of patients that will die from COVID and outcomes (particularly hard ones like death) drive power. We have the power, and the professional and moral mandate to rapidly eliminate drugs that don’t work until solutions are found. This requires focus, discipline, coordination, and leadership.
    * We should not ignore nonpharmacologic treatment. Prone ventilation seemed foolish until it worked. Similarly, we have discovered in clinical medicine that sleep, diet, stress, smoking, body weight, and a host of other behaviours dramatically influence health and disease. As we look for pharmacologic treatments for COVID-19 patients, we should cast our scientific gaze broadly. The goal is to save patients by all means possible.
    Sivelestat for ARDS in COVID-19
    Hiroyuki Okura, MD. | Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan
    This review provides comprehensive, useful and timely information to the doctors who are currently fighting against the devastating pandemic situation all over the world. While I was reading this review article I noticed that one drug commonly used for the treatment of acute respiratory distress syndrome (ARDS) in Japan is missing. The drug is sivelestat, a selective neutrophil elastase inhibitor, which is commercially available in Japan, but not in China, USA or European countries. Based on favorable results of a phase III trial (1), this drug was approved for the treatment of acute lung injury caused by systemic inflammatory response syndrome in Japan. On the other hand, because an international randomized trial failed to demonstrate efficacy of sivelestat in patients with moderate to severe acute respiratory distress syndrome (ARDS) (2), it has not been on the global market. Therefore, it is not surprising that there are no published reports regarding the use of sivelestat during treatment of ARDS caused by COVID-19 (as of May 8, 2020). A recent retrospective analysis using a Japanese nationwide administrative database (Diagnostic Procedure Combination; DPC) in 2012 demonstrated that the early (within 7 days) use of sivelestat may improve outcome in patients with acute lung injury/ ARDS (3). Although I do not have full access to the Japanese nationwide status of the drugs used for COVID-19, I found a case report (written in Japanese) describing 2 clinical cases who were successfully recovered after intensive treatments including use of sivelestat (4). As of May, 9, Japan is one of the countries with the lowest mortality rate due to COVID-19 (case-fatality rate of 3.6 % and deaths/100k population of 0.44) (5). Although exact mechanisms for the differences in mortality due to COVID-19 is unclear, the inter-country differences in the specific drugs used for ARDS such as sevelestat may, in-part, explain the differences in mortality.

    1. Tamakuma S, Shibaya T, Hirasawa H, Ogawa M, Nakashima M. A Phase Ⅲ Clinical Study of a Neutrophil Elastase lnhibitor;ONO-50460・Na in SIRS Patients. Rinsyoiyaku. 1998;14(2):289-318.
    2. Zeiher BG, Matsuoka S, Kawabata K, Repine JE. Neutrophil elastase and acute lung injury: prospects for sivelestat and other neutrophil elastase inhibitors as therapeutics. Crit Care Med. 2002;30(5 Suppl):S281-287.
    3. Kido T, Muramatsu K, Yatera K, et al. Efficacy of early sivelestat administration on acute lung injury and acute respiratory distress syndrome. Respirology. 2017;22(4):708-713.
    4. The Japanese Association for Infectious Diseases. case report ( Accessed on May 8, 2020.
    5. The Johns Hopkins Hospital. COVID-19 data analysis center. Mortality Analysis. ( Accessed on May 8, 2020.
    April 13, 2020

    Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review

    Author Affiliations
    • 1Department of Pharmacy, University of Texas Southwestern Medical Center, Dallas
    • 2Division of Infectious Diseases and Geographic Medicine, Department of Medicine, University of Texas Southwestern Medical Center, Dallas
    • 3Pharmacy Service, VA North Texas Health Care System, Dallas
    JAMA. 2020;323(18):1824-1836. doi:10.1001/jama.2020.6019

    Importance  The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected by SARS-CoV-2, clinicians need accurate evidence regarding effective medical treatments for this infection.

    Observations  No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomized trials. Oseltamivir has not been shown to have efficacy, and corticosteroids are currently not recommended. Current clinical evidence does not support stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with COVID-19.

    Conclusions and Relevance  The COVID-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918. The speed and volume of clinical trials launched to investigate potential therapies for COVID-19 highlight both the need and capability to produce high-quality evidence even in the middle of a pandemic. No therapies have been shown effective to date.