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Use of a selective type V phosphodiesterase inhibitor, PAPiSOL (E4021), in the treatment of pulmonary hypertension in the canine.

Daniel Swartz , Sandra Sexton, Leslie Curtin, Bryan Perry

Pulmonary hypertension (PH) is a progressive disease characterized by chronic elevation in pulmonary arterial pressure (PAP). This disease is poorly recognized in dogs with limited economical and effective treatment available. The secondary messenger cyclic guanosine monophosphate (cGMP), which regulates pulmonary and systemic pressures, is itself regulated by type 5 Phosphodiesterase (PDE-5). In dogs, an intravenous (IV) infusion of U46619 induces pulmonary arterial constriction. Using a selective phosphodiesterase inhibitor (PDI) PAPiSOL (E4021) orally is an effective treatment for decreasing an induced elevated PAP in the dog. Animals:This study was approved by the Institutional Animal Care and Use Committee. We performed a total of 15 studies in 5 Class A, purpose bred, SPF Beagles, male and female. Methods:A dose of 2.5 mg was administered as a dissolved tablet through an oral gastric tube (Tablet) or as a dissolvable strip placed in the buccal cavity (Strip). An acute model of PH was created using the infusion of thromboxane A2 mimetic, U46619. Results:The IV infusion of U46619 caused a dose dependent increase in PAP and a concomitant increase in pulmonary vascular resistance (PVR). Following the stabilization of an elevated PAP, the simultaneous oral treatment with PAPiSOL (E4021) attenuated the level of PAP and PVR. The resultant decrease in PAP with oral treatment with PAPiSOL (E4021) was small in relation to the modest decreases in PVR. Conclusion:These results demonstrated an effective treatment of PH with oral PAPiSOL (E4021) as well, identified PVR as the responsive pulmonary vascular variable.