Abstract
There are three critical pathways for the pathogenesis and progression of pulmonary arterial hypertension (PAH): the prostacyclin (prostaglandin I2) (PGI2), nitric oxide (NO), and endothelin pathways. The current approved drugs targeting these three pathways, including prostacyclin (PGI2), phosphodiesterase type-5 (PDE5) inhibitors, and endothelin receptor antagonists (ERAs), have been shown to be effective, however, PAH remains a severe clinical condition and the long-term survival of patients with PAH is still suboptimal. The full therapeutic abilities of available drugs are reduced by medication, patient non-compliance, and side effects. Nanoparticles are expected to address these problems by providing a novel drug delivery approach for the treatment of PAH. Drug-loaded nanoparticles for local delivery can optimize the efficacy and minimize the adverse effects of drugs. Prostacyclin (PGI2) analogue, PDE5 inhibitors, ERA, pitavastatin, imatinib, rapamycin, fasudil, and oligonucleotides-loaded nanoparticles have been reported to be effective in animal PAH models and in vitro studies. However, the efficacy and safety of nanoparticle mediated-drug delivery systems for PAH treatment in humans are unknown and further clinical studies are required to clarify these points.
Highlights
Pulmonary arterial hypertension (PAH) is a progressive disease caused by vasoconstriction and remodeling of the pulmonary vasculature [1,2,3]
In an randomized clinical trials (RCTs) (SERAPHIN trial) adopting clinical aggravation as the composite primary endpoint, which consists of a first event related to pulmonary arterial hypertension (PAH) or death from any cause, the macitentan 10 mg treatment group showed significant improvement compared with the placebo group [16]
The AMBITION study showed that using the upfront combination therapy with ambrisentan and tadalafil reduced the risk of the primary endpoint of the first event of clinical failure by
Summary
Pulmonary arterial hypertension (PAH) is a progressive disease caused by vasoconstriction and remodeling of the pulmonary vasculature [1,2,3]. Drugs targeting the three pathways, including prostacyclin (PGI2 ), endothelin receptor antagonists (ERAs), phosphodiesterase type-5. B receptor; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; GTP guanosine triphosphate; cGMP, cyclic guanosine monophosphate; PDE5, phosphodiesterase type triphosphate; Prostacyclin Activated adenylate prostaglandin I2 2receptor (IP) in pulmonary artery smooth muscle cells (PASMCs). Nitric oxide (NO) released from vascular endothelium activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation in pulmonary arteries. In an RCT (SERAPHIN trial) adopting clinical aggravation as the composite primary endpoint, which consists of a first event related to PAH or death from any cause, the macitentan 10 mg treatment group showed significant improvement compared with the placebo group [16]
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