Intratracheally Administered Peptide-Modified Lipid Admixture Containing Fasudil and/or DETA NONOate Ameliorates Various Pathologies of Pulmonary Arterial Hypertension.
Intratracheally Administered Peptide-Modified Lipid Admixture Containing Fasudil and/or DETA NONOate Ameliorates Various Pathologies of Pulmonary Arterial Hypertension.
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DOI：
10.3390/ph16121656
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发表时间：
2023-11-28
期刊：
影响因子：
--
通讯作者：
Ahsan F
中科院分区：
文献类型：
--
作者：
Sarkar T;Moinuddin SM;Isbatan A;Chen J;Mann D;Ahsan F
这项研究检验了使用法舒地尔（一种 Rho 激酶抑制剂）和 DETA NONOate (DN)（一种一氧化氮供体）联合疗法的治疗潜力，该联合疗法以用称为 CAR（CAR-脂质混合物）的环状归巢肽修饰的脂质混合物形式提供，用于治疗肺动脉高压（PAH）。 CAR-脂质混合物最初通过薄膜水合方法制备，然后与法舒地尔、DN 或两者的混合物组合。通过测量 RV 收缩压 (RVSP)、平均肺动脉压 (mPAP)、富尔顿指数、评估右心室 (RV) 功能以及评估肺血管形态，在 Sugen/缺氧 (Su/Hx) 大鼠 PAH 模型中评估这种载药脂质混合物的治疗效果。未接受治疗的大鼠表现出 RVSP、mPAP、富尔顿指数的增加和 RV 功能参数的变化。然而，与盐水治疗的大鼠相比，用含有法舒地尔或 DN 或两者组合的 CAR-脂质混合物治疗导致 mPAP、RVSP 和 Fulton 指数下降。同样，接受这些治疗的大鼠显示出各种超声心动图参数的同时改善，例如肺加速时间（PAT）、三尖瓣环平面收缩期偏移（TAPSE）和心室游离壁厚度（RVFWT）。联合治疗观察到大于 100 µm 的肺动脉壁厚度显着减少。研究结果表明，法舒地尔、DN 及其在 CAR 修饰脂质混合物中的组合可改善肺血流动力学、右心室功能和肺脉管系统的病理改变。这项研究强调了联合疗法和靶向药物递送在 PAH 治疗中的潜力，为未来研究这些疗法的优化、其长期安全性和有效性以及拟议疗法的潜在作用机制奠定了基础。
This study examined the therapeutic potential of a combination therapy using fasudil, a Rho-kinase inhibitor, and DETA NONOate (DN), a nitric oxide donor, delivered as a lipid admixture modified with a cyclic homing peptide known as CAR (CAR-lipid mixture) for the treatment of pulmonary arterial hypertension (PAH). CAR-lipid mixtures were initially prepared via a thin-film hydration method and then combined with fasudil, DN, or a mixture of both. The therapeutic efficacy of this drug-laden lipid mixture was evaluated in a Sugen/Hypoxia (Su/Hx) rat model of PAH by measuring RV systolic pressure (RVSP), mean pulmonary arterial pressure (mPAP), Fulton indices, and assessing right ventricular (RV) functions, as well as evaluating pulmonary vascular morphology. Rats that received no treatment exhibited increases in RVSP, mPAP, Fulton indices, and changes in RV functional parameters. However, the treatment with the CAR-lipid mixture containing either fasudil or DN or a combination of both led to a decline in mPAP, RVSP, and Fulton indices compared to saline-treated rats. Similarly, rats that received these treatments showed concurrent improvement in various echocardiographic parameters such as pulmonary acceleration time (PAT), tricuspid annular plane systolic excursion (TAPSE), and ventricular free wall thickness (RVFWT). A significant decrease in the wall thickness of pulmonary arteries larger than 100 µm was observed with the combination therapy. The findings reveal that fasudil, DN, and their combination in a CAR-modified lipid mixture improved pulmonary hemodynamics, RV functions, and pathological alterations in the pulmonary vasculature. This study underscores the potential of combination therapy and targeted drug delivery in PAH treatment, laying the groundwork for future investigations into the optimization of these treatments, their long-term safety and efficacy, and the underlying mechanism of action of the proposed therapy.
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DOI：
10.1615/critrevtherdrugcarriersyst.v26.i6.10
发表时间：
2009
影响因子：
2.7
作者：
Puri A;Loomis K;Smith B;Lee JH;Yavlovich A;Heldman E;Blumenthal R
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影响因子：
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8.3
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