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Title: Interaction of therapeutic agents with PDE inhibitors in models of pulmonary arterial hypertension
Author: Rupasinghe, B. Y. I.
ISNI:       0000 0004 8502 3075
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2015
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Pulmonary arterial hypertension (PAH) is a highly proliferative, incurable vascular disease ultimately leading to right heart failure and death. Increased expression of phosphodiesterase (PDE) 5 activity in PAH patients has been targeted successfully by selective inhibitors (e.g. sildenafil), but like all treatments, these ultimately fail. What is not clearly understood is if the efficacy of PDE 5 inhibitors might be accentuated by their interaction with prostacyclin analogues and novel soluble guanylate cyclase (sGC) simulators. Initially, I investigated the combined use of existing therapeutic agents with PDE inhibitors to determine whether it is possible to inhibit proliferation of human pulmonary arterial smooth muscle cells (hPASMCs) from PAH patients to a greater degree than current therapeutic agents given singularly. I then went on to use the most anti-proliferative combination in a hypoxic mouse model of PAH to determine their hemodynamic effects. The anti-proliferative effect of the PDE 5 inhibitor sildenafil (10ìM) was greatly potentiated by BAY 41-2272 (1ìM) but even more so by treprostinil (1ìM). The sildenafil and treprostinil combination also elevated basal levels of cAMP, a secondary messenger involved in anti-proliferation and vasodilation. This combination also reversed chronic hypoxia induced RVSP increases in mice without affecting systemic pressure. Sildenafil and treprostinil as a combination therapy has been shown to be both beneficial as an anti-proliferative agent in vitro and also effective in reversing pulmonary pressures without affecting the systemic pressure. We envisage that this combination therapy will prove to be more effective in patients than singular drug treatment.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available