Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center , Amarillo, Texas.
Department of Pediatrics, University of Colorado Anschutz Medical Campus , Aurora, Colorado.
Am J Physiol Lung Cell Mol Physiol. 2019 Jan 1;316(1):L119-L130. doi: 10.1152/ajplung.00381.2018. Epub 2018 Oct 11.
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.
目前，包含不同血管扩张剂的双联或三联药物组合是肺动脉高压（PAH）治疗的主要方法。然而，由于现有联合疗法无法抑制疾病的进展，患者的预后仍然令人失望。之前，我们已经表明，当作为单一疗法使用时，长效吸入型西地那非（一种磷酸二酯酶-5 抑制剂）和罗格列酮（一种过氧化物酶体增殖物激活受体-γ 激动剂）制剂可改善大鼠的 PAH。因此，为了开发新的联合疗法，我们制备并表征了西地那非和罗格列酮的基于聚乳酸-共-乙醇酸（PLGA）的长效吸入性颗粒。然后，我们评估了西地那非和罗格列酮的组合，以普通形式或 PLGA 颗粒形式给予，在降低平均肺动脉压（mPAP）和改善 Sugen 5416 加低氧诱导的 PAH 大鼠的肺动脉重塑和右心室肥厚（RVH）方面的疗效。在给予制剂后经气管内给药，我们通过导管测量 mPAP、心输出量、总肺阻力和 RVH。我们还使用肺组织样本进行形态计量学研究，并评估了肌化程度、动脉中膜壁增厚和胶原沉积程度。与通过肺部或口服途径给予的普通药物相比，作为单一或双重组合给予的 PLGA 药物颗粒，尽管与普通药物相比，给药间隔较长，但可更显著地降低 mPAP，而不影响平均全身血压，改善心功能，减缓右心重塑，并减少动脉肌化。总体而言，作为吸入组合给予的西地那非和罗格列酮的 PLGA 颗粒可能是目前基于血管扩张剂的 PAH 联合疗法的可行替代方案。
