Gupta Nilesh, Rashid Jahidur, Nozik-Grayck Eva, McMurtry Ivan F, Stenmark Kurt R, Ahsan Fakhrul
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center , 1300 Coulter Drive, Amarillo, Texas 79106, United States.
Developmental Lung Biology, Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Departments of Medicine and Pediatrics, University of Colorado, Denver , Anschutz Medical Campus, Aurora, Colorado 80045, United States.
Mol Pharm. 2017 Mar 6;14(3):830-841. doi: 10.1021/acs.molpharmaceut.6b01061. Epub 2017 Feb 17.
Currently, two or more pulmonary vasodilators are used to treat pulmonary arterial hypertension (PAH), but conventional vasodilators alone cannot reverse disease progression. In this study, we tested the hypothesis that a combination therapy comprising a vasodilator plus a therapeutic agent that slows pulmonary arterial remodeling and right heart hypertrophy is an efficacious alternative to current vasodilator-based PAH therapy. Thus, we encapsulated a cocktail of superoxide dismutase (SOD), a superoxide scavenger, and fasudil, a specific rho-kinase inhibitor, into a liposomal formulation equipped with a homing peptide, CAR. We evaluated the effect of the formulations on pulmonary hemodynamics in monocrotaline-induced PAH rats (MCT-induced PAH) and assessed the formulation's efficacy in slowing the disease progression in Sugen-5416/hypoxia-induced PAH rats (SU/hypoxia-induced PAH). For acute studies, we monitored both mean pulmonary and systemic arterial pressures (mPAP and mSAP) for 2 to 6 h after a single dose of the plain drugs or formulations. In chronic studies, PAH rats received plain drugs every 48 h and the formulations every 72 h for 21 days. In MCT-induced PAH rats, CAR-modified liposomes containing fasudil plus SOD elicited a more pronounced, prolonged, and selective reduction in mPAP than unmodified liposomes and plain drugs did. In SU/hypoxia-induced PAH rats, the formulation produced a >50% reduction in mPAP and slowed right ventricular hypertrophy. When compared with individual plain drugs or combination, CAR-modified-liposomes containing both drugs reduced the extent of collagen deposition, muscularization of arteries, increased SOD levels in the lungs, and decreased the expression of pSTAT-3 and p-MYPT1. Overall, CAR-modified-liposomes of SOD plus fasudil, given every 72 h, was as efficacious as plain drugs, given every 48 h, suggesting that the formulation can reduce the total drug intake, systemic exposures, and dosing frequency.
目前，两种或更多种肺血管扩张剂被用于治疗肺动脉高压（PAH），但仅使用传统血管扩张剂无法逆转疾病进展。在本研究中，我们检验了这样一种假设，即一种包含血管扩张剂加上一种减缓肺动脉重塑和右心室肥厚的治疗药物的联合疗法，是当前基于血管扩张剂的PAH治疗的有效替代方案。因此，我们将超氧化物歧化酶（SOD，一种超氧化物清除剂）和法舒地尔（一种特异性 Rho 激酶抑制剂）的混合物封装到一种配备有归巢肽CAR的脂质体制剂中。我们评估了该制剂对野百合碱诱导的PAH大鼠（MCT诱导的PAH）肺血流动力学的影响，并评估了该制剂在减缓苏金-5416/低氧诱导的PAH大鼠（SU/低氧诱导的PAH）疾病进展方面的疗效。对于急性研究，我们在单次给予普通药物或制剂后2至6小时监测平均肺动脉压和体动脉压（mPAP和mSAP）。在慢性研究中，PAH大鼠每48小时接受普通药物，每72小时接受制剂，持续21天。在MCT诱导的PAH大鼠中，含有法舒地尔加SOD的CAR修饰脂质体比未修饰脂质体和普通药物引起更显著、更持久且更具选择性的mPAP降低。在SU/低氧诱导的PAH大鼠中，该制剂使mPAP降低>50%，并减缓了右心室肥厚。与单独的普通药物或联合用药相比，含有两种药物的CAR修饰脂质体减少了胶原沉积程度、动脉肌化，增加了肺中SOD水平，并降低了pSTAT-3和p-MYPT1的表达。总体而言，每72小时给予一次的SOD加 法舒地尔的CAR修饰脂质体与每48小时给予一次的普通药物效果相同，这表明该制剂可以减少总药物摄入量、全身暴露量和给药频率。
