Inhaled combination of sildenafil and rosiglitazone improves pulmonary hemodynamics, cardiac function, and arterial remodeling

Abstract

Currently, dual- or triple-drug combinations comprising different vasodilators are the mainstay for the treatment of pulmonary arterial hypertension (PAH). However, the patient outcome continues to be disappointing because the existing combination therapy cannot restrain progression of the disease. Previously, we have shown that when given as a monotherapy, long-acting inhaled formulations of sildenafil (a phosphodiesterase-5 inhibitor) and rosiglitazone (a peroxisome proliferator receptor-γ agonist) ameliorate PAH in rats. Thus, with a goal to develop a new combination therapy, we prepared and characterized poly(lactic-co-glycolic acid) (PLGA)-based long-acting inhalable particles of sildenafil and rosiglitazone. We then assessed the efficacy of the combinations of sildenafil and rosiglitazone, given in plain forms or as PLGA particles, in reducing mean pulmonary arterial pressure (mPAP) and improving pulmonary arterial remodeling and right ventricular hypertrophy (RVH) in Sugen 5416 plus hypoxia-induced PAH rats. After intratracheal administration of the formulations, we catheterized the rats and measured mPAP, cardiac output, total pulmonary resistance, and RVH. We also conducted morphometric studies using lung tissue samples and assessed the degree of muscularization, the arterial medial wall thickening, and the extent of collagen deposition. Compared with the plain drugs, given via the pulmonary or oral route as a single or dual combination, PLGA particles of the drugs, although given at a longer dosing interval compared with the plain drugs, caused more pronounced reduction in mPAP without affecting mean systemic pressure, improved cardiac function, slowed down right heart remodeling, and reduced arterial muscularization. Overall, PLGA particles of sildenafil and rosiglitazone, given as an inhaled combination, could be a viable alternative to currently available vasodilator-based combination therapy for PAH.

Current and future treatments of pulmonary arterial hypertension

“…Nevertheless, the quest for novel therapeutics exploiting PPAR‐γ signalling continues. An inhaled therapy combining sildenafil and rosiglitazone was successfully applied in rats with PH in a recently published study (Rashid, Nozik‐Grayck, McMurtry, Stenmark, & Ahsan, 2019).…”

PulmoBind Imaging Measures Reduction of Vascular Adrenomedullin Receptor Activity with Lack of effect of Sildenafil in Pulmonary Hypertension

“…However, other investigators found that oral sildenafil at 50 mg/kg once daily for 14 days did provide positive pulmonary vascular remodeling with reduced percentage of muscularization, reduced medial hypertrophy and reduced number of occluded small arteries 17 . More recently, beneficial arteriolar remodeling was also present with chronic inhaled sildenafil in short or long acting formulations in the same model 18 . Adrenomedullin (AM) is a 52 amino acids peptide with vasodilator and anti-proliferative actions.…”

Xinmai 'an extract enhances the efficacy of sildenafil in the treatment of pulmonary arterial hypertension via inhibiting MAPK signalling pathway

“…Sildenafil is a highly selective phosphodiesterase-5 inhibitor, which can enhance the cGMP pathway, ultimately affect the synthesis and release of vasoactive factor NO, and regulate the level of free Ca 2þ in cells, resulting in vascular dilatation and reduction of pulmonary artery pressure (Gao et al 2020). It has been proven that sildenafil alone or in combination with other drugs has a certain effect on various types of pulmonary hypertension, and its price is cheaper than prostacyclin drugs and endothelin receptor antagonists (Rashid et al 2019). Therefore, its clinical application prospects, especially the effect of combined use with other drugs is compelling.…”

“…It has been proven that sildenafil alone or in combination with other drugs has a certain effect on various types of pulmonary hypertension, and its price is cheaper than prostacyclin drugs and endothelin receptor antagonists (Rashid et al. 2019 ). Therefore, its clinical application prospects, especially the effect of combined use with other drugs is compelling.…”