Abstract
In a letter to the Editor in Journal of Aerosol Medicine and Pulmonary Drug Delivery, Volume 34, Number 4, 2021 (pp. 1–3), Ferro et al. describe a patient with severe respiratory insufficiency caused by SARS-CoV-2 infection, who improved greatly (without tracheal intubation) by administration of nebulized phosphodiesterase-3-(PDE3-)inhibitor enoximone.
Using enoximone as a treatment for respiratory insufficiency due to SARS-CoV-2 infection was earlier described by Beute et al.(1) and suggested by Giorgi et al.(2) Beute et al. describe systemic delivery of PDE3, whereas Ferro used a nebulized administration form.
Both are limited cases, but significant for the treatment of SARS-CoV-2–induced respiratory insufficiency, especially when linked to evidence of the efficiency of enoximone in asthma and status asthmaticus. A potent vasodilator, enoximone proved to be an equally potent bronchodilator, extremely suitable in respiratory diseases, even in low doses.(1,3,4)
Ferro et al. used nebulized administration, choosing to minimize systemic exposure.
Some considerations:
In severe bronchoconstriction, it is very difficult to reach the affected areas of the lungs; repeated nebulized administration might eventually push the drug to the distal parts of the lungs, but this may take several days—a crucial fact in COVID-19; systemic delivery would have immediate result, despite airway obstruction. Nebulized form suggests airway treatment only, but phosphodiesterases are expressed in restricted cells in several organs—for example, PDE3 is expressed in smooth muscle cells, immune cells, cardiovascular cells, and in the lungs. This means that PDE3 inhibition might, in a way, be called local therapy, even when administered systemically. In contrast, as there is no first-pass effect (through the liver), pharmacokinetical clearance and metabolization of nebulized delivery happen similar to IV (systemic) administration, with eventual excretion through the kidneys.(5)
Ferro et al. mention a possible danger in nebulized administration for caregivers because of droplet dispersion. Another consideration might be enoximone's pH of 12; this can be a contraindication for administering it directly to lung tissue, even nebulized; oral or IV administration has a lower impact on this point, without affecting the drug's efficacy.
Ferro's article provides a valuable addition to the therapeutic use of enoximone in COVID-19. However, given the above, systemic (IV or oral) administration seems preferable, as enoximone also plays a supporting and favorable role in targeting several other levels of the cascade involved in the SARS-CoV-2 respiratory condition, due to its therapeutic width.
Obviously, more (clinical) research is required. Given the ongoing pandemic situation, there is an urgent need to interfere in the SARS-CoV-2 pathophysiology to revert or maybe even prevent the emergent sequelae leading to mechanical ventilation often followed by death. Because of its observed efficacy, already at (very) low doses, PDE3 inhibitor enoximone represents an interesting treatment option for symptomatic COVID-19 patients, which is easily realizable in hospital and nursing homes as well as in outpatient/primary care settings.
Footnotes
Authors' Contributions
J.B. and A.K. contributed equally. Both authors meet the authorship criteria.
Author Disclosure Statement
J.B. is a scientific/clinical advisor for and indirect shareholder in BMR B.V. BMR B.V. has patents pending for several respiratory indications. A.K.J. is a scientific advisor for BMR B.V.; relatives of A.K.J. also have an interest in BMR B.V. None of the authors have a relation to the manufacturer of enoximone (Perfan®, Carinopharm GmbH, Elze, Germany).
Funding Information
No funding was received for this article.