Researchers have discovered that treprostinil palmitil inhalation suspension (TPIS), an inhaled prostacyclin analog, improved pulmonary vascular hemodynamics and cardiac performance while decreasing pulmonary vascular remodeling and right heart hypertrophy in rats induced with conditions mimicking pulmonary arterial hypertension (PAH). Results of the study were published in the European Journal of Pharmacology.
PAH is characterized by the progressive remodeling of the pulmonary vasculature, leading to an increase in pulmonary vascular resistance that eventually causes right-sided heart failure and death. There are a number of treatment options available, but none of them have been proven to be disease-modifying.
In a recent study using rat models, the intravenous (IV) infusion of treprostinil managed to significantly improve pulmonary hemodynamics but failed to inhibit pulmonary vasculature remodeling. The rats in that study were challenged with Sugen 5416 combined with hypoxia (Su/Hx), a combination that results in conditions resembling PAH. The partial success of the IV infusion of treprostinil led researchers to question whether the problem was the insufficient penetration of treprostinil into lung tissue. They decided to investigate whether the administration of the drug through inhalation would improve its efficacy.
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The researchers induced PAH-like conditions in their rat models by giving them a single subcutaneous injection of Sugen 5416 (Su) in dimethyl sulfoxide (DMSO) at 20 mg/kg, followed by 3 weeks of exposure to a 10% O2/balance N2 gas mixture to induce hypoxia. The rats were then transitioned to normoxic air breathing for either 5 or 10 weeks. Another group of rats received oral sildenafil, a standard phosphodiesterase-5 (PDE5) inhibitor, at a dose of 50 mg/kg. The control group received 100% dimethyl sulfoxide (2 mL/kg) and normoxic air breathing.
To formulate the TPIS, researchers used a stock concentration of 0.3 mg/mL in phosphate-buffered saline (PBS) with dilutions made for nebulization at concentrations of 0.3 and 1 mM. A 12-port nose-only inhalation system and an Aeroneb Pro nebulizer were used to administer the inhaled TPIS and PBS.
The results demonstrated that the inhalation of TPIS was successful in reducing PAH pathology. To summarize their findings, the authors of the study wrote, “In both the 8- and 13-week experiments, TPIS at inhaled doses ranging from 39.6 to 134.1 μg/kg, [once-a-day], dose-dependently improved pulmonary vascular hemodynamics, reduced the increase in right heart size, enhanced cardiac performance, and attenuated most of the histological changes induced by the Su/Hx challenge.” Overall, TPIS also performed better than sildenafil.
How does inhaled TPIS perform better than the IV administration of the drug? Researchers theorized that it was because inhaled TPIS was better able to act on local mechanisms in the lungs, leading directly to the benefits described in this study.
Reference
Corboz MR, Plaunt AJ, Malinin V, et al. Treprostinil palmitil inhibits the hemodynamic and histopathological changes in the pulmonary vasculature and heart in an animal model of pulmonary arterial hypertension. Eur J Pharmacol. Published online September 8, 2021. doi:10.1016/j.ejphar.2021
