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. Healy^2,3, 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

Summary

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.