Repurposing existing drugs for COVID-19: an endocrinology perspective

Abstract

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.

Azithromycin with nitazoxanide, hydroxychloroquine or ivermectin, with or without dutasteride, for early stage COVID-19: an open-label prospective observational study in males with mild-to-moderate COVID-19 (The Pre-AndroCoV Male Trial).

“…Disease duration was notably higher in AGA males not treated with dutasteride, in accordance with literature (5,6,14,16,17), whereas the chronic use of dutasteride likely prevented the appearance of symptoms in almost all patients, possibly due to its indirect inhibitory effects on the expression of TMPRSS-2, a protein that facilitates the SARS-CoV-2 entry in the cells. This is in full correspondence with recent literature on dutasteride ability to diminish severe COVID-19 in hospitalized patients (18).…”

“…The natural course of SARS-CoV-2 has been divided into three major stages: the rst one encompasses the period of SARS-CoV-2 viral infectivity and spread; the second stage corresponds to an exacerbated, diffuse and dysfunctional in ammatory reaction to SARS-CoV-2, while the third stage represents the COVID-19 induced acute lung injury per se (14).…”

“…Multiple drugs have been proposed to improve COVID-19 clinical outcomes, from the demonstration of speci c in vitro antiviral activity against SARS-CoV-2, through clinical observations, or following mechanistical rationale (14). Among these drugs, azithromycin, in association with hydroxychloroquine or ivermectin, have been the most attempted drug combinations to decrease COVID-19 severity and complications (15).…”

Hydroxychloroquine, nitazoxanide and ivermectin have similar effects in early COVID-19: a head-to-head comparison of the Pre-AndroCoV Trial.

“…The investigation of androgenic phenotypes and chronic use of AA is critical importance to determine COVID-19 disease course (2,(9)(10)(11), since both have demonstrated to modulate the clinical presentation, including improvement of outcomes in COVID-19 in chronic use of AA (26). This nding is expected since TMPRSS-2, a cell surface protein that primes to the spike protein of SARS-CoV-2 and facilitates its cell entry, is strongly regulated by androgens, and is consequently underexpressed in chronic AA users.…”

“…Coronavirus Disease 2019 (COVID-19) is a multi-systemic infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that leads to a wide variety of symptoms in the upper and lower respiratory tract, gastrointestinal, neurological, and musculoskeletal systems, although unspeci c symptoms in other systems may also appear (1)(2)(3)(4).…”