PDE3-inhibitor enoximone prevented mechanical ventilation in patients with SARS-CoV-2 pneumonia

Abstract

Background: Standard care in severe SARS-CoV-2 pneumonia complicated by severe dyspnea and respiratory failure, consists of symptom reduction, ultimately supported by mechanical ventilation. Patients with severe SARS-CoV-2, a prominent feature of COVID-19, show several similar symptoms to Critical Asthma Syndrome (CAS) patients, such as pulmonary edema, mucus plugging of distal airways, decreased tissue oxygenation, (emergent) exhaustion due to severe dyspnea and respiratory failure. Prior application of elective phosphodiesterase (PDE)3-inhibitors milrinone and enoximone in patients with CAS yielded rapid symptomatic relief and reverted the need for mechanical ventilation, due to their bronchodilator and anti-inflammatory properties. Based on these observations, we hypothesized that enoximone may be beneficial in the treatment of patients with severe SARS-CoV-2 pneumonia and prominent CAS-features. Methods: In this case report enoximone was administered to four consecutive patients (1 M; 3 F; 46-70 y) with emergent respiratory failure due to SARS-CoV-2 pneumonia. Clinical outcome was compared with three controls who received standard care only. Results: After an intravenous bolus of enoximone 20 mg followed by 10 mg/h via perfusor, a rapid symptomatic relief was observed: two out of four patients recovered within a few hours, the other two (with comorbid COPD GOLD II/III) responded within 24-36 h. Compared to the controls, in the enoximone-treated patients respiratory failure and further COVID-19-related deterioration was reverted and mechanical ventilation was prevented, leading to reduced hospital/ICU time. Discussion: Our preliminary observations suggest that early intervention with the selective PDE3-inhibitor enoximone may help to revert respiratory failure as well as avert mechanical ventilation, and reduces ICU/hospital time in patients with severe SARS-CoV-2 pneumonia. Our findings warrant further research on the therapeutic potential of PDE3-inhibition, alone or in combination with other anti-COVID-19 strategies.

The Potential Role of Aerosolized Phosphodiesterase 3 Inhibitor Enoximone in the Management of Coronavirus Disease 2019 Hypoxemia: A Case Report

“…(3) Beute et al reported four cases of severe respiratory insufficiency related to SARS-CoV-2 pneumonia in which the endovenous administration of enoximone prevented mechanical ventilation. (4) In our case we administered aerosolized enoximone basing on the pharmacodynamic idea that inhaled administration of PDE inhibitors applies the drug directly to the site of action minimizing systemic exposure and increasing the therapeutic index. In particular, the need to restore vasodilation in aerated lungs makes inhaled route as the potential perfect way of drug administration in COVID-19 pneumonia.…”

Role of Multifunctional Cytoskeletal Filaments in Coronaviridae Infections: Therapeutic Opportunities for COVID-19 in a Nutshell

“…In line with the above, colchicine (see above) attenuates the inflammatory response by interfering with pathways that include the TNFα-induced nuclear factor κΒ (NF-κΒ) pathway [ 39 ]. The PDE3-inhibitors, milrinone and enoximone, are reported to help treat respiratory failure in patients with severe SARS-CoV-2 pneumonia [ 40 ]. PDE3-inhibitors prevent microvascular leakage (via a normalization of the cytoskeleton by increasing intracellular cAMP) and increase the ciliary beat frequency of the epithelial cells within the respiratory tract ([ 40 ] and references therein); moreover, the anti-inflammatory properties of PDE3-inhibitors may help prevent the cytokine storm [ 41 ].…”

“…The PDE3-inhibitors, milrinone and enoximone, are reported to help treat respiratory failure in patients with severe SARS-CoV-2 pneumonia [ 40 ]. PDE3-inhibitors prevent microvascular leakage (via a normalization of the cytoskeleton by increasing intracellular cAMP) and increase the ciliary beat frequency of the epithelial cells within the respiratory tract ([ 40 ] and references therein); moreover, the anti-inflammatory properties of PDE3-inhibitors may help prevent the cytokine storm [ 41 ]. Finally, dexamethasone has been shown to preserve the intestinal mucosal barrier and to shorten the length of hospitalization of COVID-19 patients [ 42 ].…”

Phosphodiesterase-3 Inhibitor Enoximone in SARS-CoV-2 Infection

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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.

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“…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.…”