World J Mens Health. 2020 Jul;38(3):254-255. English.
Published online Jun 04, 2020.
Copyright © 2020 Korean Society for Sexual Medicine and Andrology
Editorial

Phosphodiesterase Type 5 Inhibitors and COVID-19: Are They Useful In Disease Management?

Nicola Mondaini
    • Urology Unit, Villa Donatello Hospital, Florence, Italy.
Received May 12, 2020; Revised May 17, 2020; Accepted May 17, 2020.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

COVID-19 is an acronym formed by “CO” for “corona,” “VI” for “virus,” and “D” for disease. The “19” represents 2019, the year when the infection started [1]. Recently, Varga et al [1] showed the presence of viral elements within endothelial cells and an accumulation of inflammatory cells. These findings suggest that infection with SARS-CoV-2 (the virus that causes COVID-19) facilitates the induction of endotheliitis in several organs as a direct consequence of viral involvement (as noted based on the presence of viral bodies) and activation of the host inflammatory response. This progressive endothelial thromboinflammatory syndrome involves the microvascular bed of many vital organs, leading to multiple organ failure and death. This is the principle of interstitial pneumonitis that progresses to pulmonary failure [2]. Yang et al [3] recently published a small, but very informative systematic review and meta-analysis on the prevalence of comorbidities associated with COVID-19 infections in China, and they reported that diabetes was prevalent in 8% of cases, highlighting that this is somewhat in line with the prevalence of diabetes (10.9%) in Chinese adults. Diabetes in fact causes endothelial damage; for this reason, patients with diabetes who already have a damaged endothelium are probably more sensitive to the effects of COVID-19 [4].

Patients with diabetes often also have erectile dysfunction, which is nothing more than endothelial dysfunction, and in such patients, the use of phosphodiesterase-5 (PDE5) inhibitors is recommended to treat erectile dysfunction. Thus, like diabetes, the presence of erectile dysfunction could also represent a symptom to be taken into consideration when predicting the prognosis of patients with COVID-19. This possibility points to a potential role of PDE5 inhibitors in the management of COVID-19 [5]. The PDE5 inhibitor sildenafil citrate is a vasodilator that was approved in 1998 for treating erectile dysfunction and more recently received an indication for pulmonary arterial hypertension and idiopathic pulmonary fibrosis [6]. Sildenafil is currently under investigation in a phase 3 trial in patients with COVID-19 (NCT04304313), which will help clarify its therapeutic potential [5]. The goal of sildenafil treatment is to prevent or perhaps block the progression of fibrosis and to improve respiratory parameters in patients. Tadalafil has also shown PDE5 inhibition with an IC50 of 5 nM. It possesses high selectivity for PDE5 versus PDE1–4 and PDE6. In particular, tadalafil is more selective against PDE5 than PDE6, whereas sildenafil shows similar potency to inhibit PDE5 and PDE6 [7]. Theoretically, the once-daily use of tadalafil, which is a long acting drug, could be useful to improve tissue vascularization and to combat fibrosis. Tadalafil is probably less effective in the acute phase, but could lend itself to use once daily for possible prevention in patients with erectile dysfunction who are not interested in sexual activity, and for similar purposes it could be administered to all discharged patients recovering from COVID-19.

For this reason, daily tadalafil could be a possible post-infection treatment, as its pharmacokinetic parameters, such as half-life and efficacy, make it an ideal candidate. No clear evidence exists regarding the possibility of SARS-CoV-2 infection in the testes, where sclerosis could result in fertility problems.

Therefore, my suggestion is to evaluate the use of daily tadalafil in future trials to block or prevent endothelial sclerosis in COVID-19 patients.

Notes

Conflict of Interest:The author has nothing to disclose.

References

    1. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020;395:1417–1418.
    1. Ciceri F, Beretta L, Scandroglio AM, Colombo S, Landoni G, Ruggeri A, et al. Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS): an atypical acute respiratory distress syndrome working hypothesis. Crit Care Resusc 2020;22:95–97.
    1. Yang J, Zheng Y, Gou X, Pu K, Chen Z, Guo Q, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis 2020;94:91–95.
    1. Kumar A, Arora A, Sharma P, Anikhindi SA, Bansal N, Singla V, et al. Is diabetes mellitus associated with mortality and severity of COVID-19? A meta-analysis. Diabetes Metab Syndr 2020;14:535–545.
    1. Rogosnitzky M, Berkowitz E, Jadad AR. Delivering benefits at speed through real-world repurposing of off-patent drugs: the COVID-19 pandemic as a case in point. JMIR Public Health Surveill 2020;6:e19199
    1. Idiopathic Pulmonary Fibrosis Clinical Research Network. Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, et al. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med 2010;363:620–628.
    1. Ahmed NS. Tadalafil: 15 years' journey in male erectile dysfunction and beyond. Drug Dev Res 2019;80:683–701.

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