Aerosolised Phosphodiesterase 3 Inhibitor Enoximone in the Treatment of COVID-19 Pneumonia: In Vitro Evaluations Supporting Clinical Evidence

  1. M. Piras1, B. Grassiri1, C. Migone1, Y. Zambito1, A. M. Healy2,3, C. Ehrhardt3, P. Roncucci4 and B. Ferro4

1Department of Pharmacy, University of Pisa, Pisa/56126, Italy.

2SSPC, The Science Foundation Ireland Research Centre for Pharmaceuticals, Ireland.

3School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland

4Departments of Anesthesia and Critical Care, Spedali Riuniti Livorno Estav Nordovest, Livorno/57121, Italy


Enoximone (ENOX) is a phosphodiesterase-3 (PDE-3) inhibitor, which is clinically applied in congestive heart failure, having vasodilating and positive inotropic activity. It is commercially available as an i.v. aqueous formulation (PERFAN®), containing ethanol and propylene glycerol as co-solvents. The aim of this work is to support the encouraging clinical preliminary results observed with the off-label pulmonary administration of PERFAN®, through the inhalation route, in patients affected by COVID-19-related acute respiratory distress syndrome (CARDS). PERFAN® aerosolisation was characterised in terms of delivered dose, aerodynamic droplet size distribution and applied to in vitro models dedicated to IVIV correlation. The results demonstrate that ENOX is capable of a local direct effect on human pulmonary epithelial cell line NCI-H441, increasing intracellular cAMP levels and providing protection from oxidative stress. Furthermore, the delivered drug permeates across the in vitro monolayer model, suggesting good in vivo bioavailability to achieve a vasodilatory effect. It was also noted that the in vivo effect is due to about ~30% of the delivered PERFAN® dose (50 mg), since ENOX precipitates rapidly in the nebuliser cup during the aerosolisation. However, the droplets produced on nebulisation have a MMAD of 5 mm and GSD of 2, indicating a favourable size and size distribution for deposition in the bronchi-alveolar region. Beyond the beneficial exploitation of the off-label PERFAN® administration, this research opens up future development of ENOX inhalable medicines.

Key Message

This work suggests that pulmonary administration of ENOX has a positive local effect in patients with severe COVID-19 pneumonia and that the drug could be used off-label. The main limiting aspect of PERFAN® aerosolisation is the precipitation of enoximone crystals in the nebuliser cup, reducing the delivered dose.