Repurposing rosiglitazone, a PPAR-γ agonist and oral antidiabetic, as an inhaled formulation, for the treatment of PAH

Abstract

Peroxisome-proliferator-activated-receptor-gamma (PPAR-γ) is implicated, in some capacity, in the pathogenesis of pulmonary arterial hypertension (PAH). Rosiglitazone, an oral antidiabetic and PPAR-γ agonist, has the potential to dilate pulmonary arteries and to attenuate arterial remodeling in PAH. Here, we sought to test the hypothesis that rosiglitazone can be repurposed as inhaled formulation for the treatment of PAH. We have tested this conjecture by preparing and optimizing poly(lactic-co-glycolic) acid (PLGA) based particles of rosiglitazone, assessing the drug particles for pulmonary absorption, investigating the efficacy of the plain versus particulate drug formulation in improving the respiratory hemodynamics in PAH animals, and finally studying the effect of the drug in regulating the molecular markers associated with PAH pathogenesis. The optimized particles were slightly porous and spherical, and released 87.9% ± 6.7% of the drug in 24 h. The elimination half-life of the drug formulated in PLGA particles was 2.5-fold greater than that of the plain drug administered via the same route at the same dose. The optimized formulation, given via the pulmonary route, produced pulmonary selective vasodilation in PAH animals, but oral rosiglitazone had no effect in pulmonary hemodynamics. Rosiglitazone ameliorates the pathogenesis of PAH by balancing the molecular regulators involved in the vasoconstriction and vasodilation of human pulmonary arterial smooth muscle cells. All in all, data generated using intact animal and cellular models point to the conclusion that PLGA particles of an antidiabetic drug can be used for the treatment of a different disease, PAH.

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

“…IT sildenafil, IT plain drug combination, and IT combination particles reduced TPVR to half of that observed in saline-treated PAH rats. Reduction in TPVR produced by combination particles can be attributed to the sustained pulmonary vasodilation and inhibition of vascular remodeling by sildenafil and rosiglitazone at the local pulmonary vasculature (7,21,28,46,48). Altogether, our study indicates a functional deterioration of the cardiac parameters in Sugen-hypoxia-induced PAH and that sildenafil plus rosiglitazone improves the cardiac functional capacity in diseased rats.…”

“…Lack of effects in the oral plain drug combination group can be attributed to the poor absorption from the gastrointestinal tract. Combination particles, although given every 48 h, were as effective as the plain drug combination given once a day IT because PLGA particles released the drugs slowly but continuously over a longer period on the highly absorptive alveolar surface (20,44,46,48). The systemic arterial pressure remained unaltered perhaps because the doses of the drugs were too small to produce a measurable systemic effect.…”

“…Preparation and characterization of PLGA particles of sildenafil and rosiglitazone. Sildenafil-and rosiglitazone-loaded microparticles were prepared according to our previously established water-in-oilin-water (W 1/O/W2) double emulsion-solvent evaporation method (46,48). In short, 0.5 ml of an internal aqueous phase (W1) containing rosiglitazone maleate (20 mg/ml) or sildenafil citrate (20 mg/ml) in a mixture of methanol and double-deionized water (20:80) plus 0.5% polyethyleneimine (PEI) in water was first emulsified in a PLGA polymer solution in dichloromethane (organic phase) using a Branson Sonifier 450 (Branson Ultrasonics, Danbury, CT).…”

“…The inhaled formulations of various anti-PAH drugs including prostaglandin E 1 , fasudil, long-acting nitric oxide donors, and superoxide dismutase, when formulated as polymeric or lipidic particles, can minimize drops in systemic arterial pressure by restricting the drugs' vasodilatory effects within the pulmonary vasculature. In a recent study, we showed that by formulating it as inhalable particles, rosiglitazone, a peroxisome proliferator-activated receptor-␥ agonist that is reported to inhibit pul-monary arterial remodeling and arrest PAH progression (14,28,33,41,54), can be repurposed for the treatment of PAH (46). In a separate study, we demonstrated that inhaled poly-(lactic-co-glycolic acid) (PLGA) particles of sildenafil, an orally active phosphodiesterase type 5 inhibitor that is frequently used as monotherapy or in combination therapy for PAH (13), improve pulmonary hemodynamics in PAH rats when given at a reduced dose and longer dosing intervals (48).…”

“…As a continuation of the above two studies (46,48), wherein we assessed the feasibility of inhaled particulate formulations of rosiglitazone and sildenafil for the treatment of PAH, here we tested the hypothesis that a combination of sildenafil and rosiglitazone, when given as prolonged-release formulations via the pulmonary route, improves pulmonary hemodynamics, RVH, and pulmonary arterial remodeling. As such, we first prepared PLGA particles of sildenafil and rosiglitazone and assessed them for their suitability for administration via the pulmonary route.…”