Delivering Benefits at Speed Through Real-World Repurposing of Off-Patent Drugs: The COVID-19 Pandemic as a Case in Point

Rogosnitzky, Moshe; Berkowitz, Esther; Jadad, Alejandro R.

doi:10.2196/19199

Cited by 38 publications

(30 citation statements)

References 54 publications

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“…Unlike estrogens, progestogens lack demonstration of any mechanism of protection from COVID-19, has suppressive effects on both innate and cell-mediated immune responses, in particular inducing T-lymphocyte cell death [381], apparently do not have any major effect in the RAAS [382][383][384], although hormones with progesterone activity compete with aldosterone in the MR. Because of the suppressing effects on T-lymphocyte, progesterone should be discouraged for COVID-19, despite being currently evaluated for COVID-19 in hospitalized men [385].…”

Section: Discourage Use In Covid-19mentioning

confidence: 99%

Repurposing existing drugs for COVID-19: an endocrinology perspective

Cadegiani

2020

BMC Endocr Disord

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Background Coronavirus Disease 2019 (COVID-19) is a multi-systemic infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that has become a pandemic. Although its prevailing symptoms include anosmia, ageusia, dry couch, fever, shortness of brief, arthralgia, myalgia, and fatigue, regional and methodological assessments vary, leading to heterogeneous clinical descriptions of COVID-19. Aging, uncontrolled diabetes, hypertension, obesity, and exposure to androgens have been correlated with worse prognosis in COVID-19. Abnormalities in the renin-angiotensin-aldosterone system (RAAS), angiotensin-converting enzyme-2 (ACE2) and the androgen-driven transmembrane serine protease 2 (TMPRSS2) have been elicited as key modulators of SARS-CoV-2. Main text While safe and effective therapies for COVID-19 lack, the current moment of pandemic urges for therapeutic options. Existing drugs should be preferred over novel ones for clinical testing due to four inherent characteristics: 1. Well-established long-term safety profile, known risks and contraindications; 2. More accurate predictions of clinical effects; 3. Familiarity of clinical management; and 4. Affordable costs for public health systems. In the context of the key modulators of SARS-CoV-2 infectivity, endocrine targets have become central as candidates for COVID-19. The only endocrine or endocrine-related drug class with already existing emerging evidence for COVID-19 is the glucocorticoids, particularly for the use of dexamethasone for severely affected patients. Other drugs that are more likely to present clinical effects despite the lack of specific evidence for COVID-19 include anti-androgens (spironolactone, eplerenone, finasteride and dutasteride), statins, N-acetyl cysteine (NAC), ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), and direct TMPRSS-2 inhibitors (nafamostat and camostat). Several other candidates show less consistent plausibility. In common, except for dexamethasone, all candidates have no evidence for COVID-19, and clinical trials are needed. Conclusion While dexamethasone may reduce mortality in severely ill patients with COVID-19, in the absence of evidence of any specific drug for mild-to-moderate COVID-19, researchers should consider testing existing drugs due to their favorable safety, familiarity, and cost profile. However, except for dexamethasone in severe COVID-19, drug treatments for COVID-19 patients must be restricted to clinical research studies until efficacy has been extensively proven, with favorable outcomes in terms of reduction in hospitalization, mechanical ventilation, and death.

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Section: Discourage Use In Covid-19mentioning

confidence: 99%

Repurposing existing drugs for COVID-19: an endocrinology perspective

Cadegiani

2020

BMC Endocr Disord

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“…In the United States, the CDC projects that COVID-19 will be a top 10 leading cause of death for the year 2020. While we all eagerly await the development of a vaccine, scientists and clinicians have begun exploring “off-label” use of various drugs with that hope that strategic repurposing may help manage and treat COVID-19 [1] . Fenofibrate (a peroxisome proliferator-activated receptor alpha agonist) is one such medication that holds promise given its favorable effects on inflammation and endothelial function [1] .…”

Section: Introductionmentioning

confidence: 99%

“…While we all eagerly await the development of a vaccine, scientists and clinicians have begun exploring “off-label” use of various drugs with that hope that strategic repurposing may help manage and treat COVID-19 [1] . Fenofibrate (a peroxisome proliferator-activated receptor alpha agonist) is one such medication that holds promise given its favorable effects on inflammation and endothelial function [1] . Herein, exercise will be compared to fenofibrate as a possible therapeutic strategy to bolster resilience against (and help manage recovery from) COVID-19.…”

Section: Introductionmentioning

confidence: 99%

Exercise as medicine for COVID-19: On PPAR with emerging pharmacotherapy

Heffernan

Jae

2020

Medical Hypotheses

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Coronavirus disease 2019 (COVID-19) may have a metabolic origin given strong links with risk factors such as lipids and glucose and co-morbidities such as obesity and type 2 diabetes mellitus. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein mediates viral cellular entry via the ACE2 receptor. The cytoplasmic tail of this spike protein is heavily palmitoylated. Emerging studies suggest that SARS-CoV-2 alters lipid metabolism in the lung epithelial cells by modulating peroxisome proliferator-activated receptor alpha (PPARα), possibly contributing to lipotoxicity, inflammation and untoward respiratory effects. Disruption of this process may affect palmitoylation of SARS-CoV spike protein and thus infectivity and viral assembly. COVID-19 is also increasingly being recognized as a vascular disease, with several studies noting prominent systemic endothelial dysfunction. The pathogenesis of endothelial dysfunction may also be linked to COVID-19-mediated metabolic and inflammatory effects. Herein, exercise will be compared to fenofibrate as a possible therapeutic strategy to bolster resilience against (and help manage recovery from) COVID-19. This paper will explore the hypothesis that exercise may be a useful adjuvant in a setting of COVID-19 management/rehabilitation due to its effects on PPARα and vascular endothelial function.

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“…The PDE-5 inhibitor sildenafil, a vasodilator that is approved for treating erectile dysfunction and pulmonary arterial hypertension [249] , is also evaluated in a phase 3 trial for patients with mild to severe COVID-19 [NCT04304313]. In fact, sildenafil has a wide range of anti-inflammatory, antioxidant, and vasodilatory actions resulting in cardioprotective effects and improved pulmonary circulation [250] , [251] , [252] .…”

Section: Drugs Used To Treat the Acute Respiratory Distress Cytokinementioning

confidence: 99%

Approaching coronavirus disease 2019: Mechanisms of action of repurposed drugs with potential activity against SARS-CoV-2

Lisi¹,

Lacal

Barbaccia

et al. 2020

Biochemical Pharmacology

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On March 11, 2020, the World Health Organization (WHO) declared the severe acute respiratory syndrome caused by coronavirus 2 (SARS-CoV-2) a global pandemic. As of July 2020, SARS-CoV-2 has infected more than 14 million people and provoked more than 590,000 deaths, worldwide. From the beginning, a variety of pharmacological treatments has been empirically used to cope with the life-threatening complications associated with Corona Virus Disease 2019 (COVID-19). Thus far, only a couple of them and not consistently across reports have been shown to further decrease mortality, respect to what can be achieved with supportive care. In most cases, and due to the urgency imposed by the number and severity of the patients' clinical conditions, the choice of treatment has been limited to repurposed drugs, approved for other indications, or investigational agents used for other viral infections often rendered available on a compassionate-use basis. The rationale for drug selection was mainly, though not exclusively, based either i) on the activity against other coronaviruses or RNA viruses in order to potentially hamper viral entry and replication in the epithelial cells of the airways, and/or ii) on the ability to modulate the excessive inflammatory reaction deriving from dysregulated host immune responses against the SARS-CoV-2. In several months, an exceptionally large number of clinical trials have been designed to evaluate the safety and efficacy of anti-COVID-19 therapies in different clinical settings (treatment or pre-and post-exposure prophylaxis) and levels of disease severity, but only few of them have been completed so far. This review focuses on the molecular mechanisms of action that have provided the scientific rationale for the empirical use and evaluation in clinical trials of structurally different and often functionally unrelated drugs during the SARS-CoV-2 pandemic.

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Delivering Benefits at Speed Through Real-World Repurposing of Off-Patent Drugs: The COVID-19 Pandemic as a Case in Point

Cited by 38 publications

References 54 publications

Repurposing existing drugs for COVID-19: an endocrinology perspective

Repurposing existing drugs for COVID-19: an endocrinology perspective

Exercise as medicine for COVID-19: On PPAR with emerging pharmacotherapy

Approaching coronavirus disease 2019: Mechanisms of action of repurposed drugs with potential activity against SARS-CoV-2

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