Newer approaches and novel drugs for inhalational therapy for pulmonary arterial hypertension

ABSTRACT

Introduction: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by remodeling of small pulmonary arteries leading to increased pulmonary arterial pressure. Existing treatments acts to normalize vascular tone via three signaling pathways: the prostacyclin, the endothelin-1, and the nitric oxide. Although over the past 20 years, there has been considerable progress in terms of treatments for PAH, the disease still remains incurable with a disappointing prognosis.

Areas covered: This review summarizes the pathophysiology of PAH, the advantages and disadvantages of the inhalation route, and assess the relative advantages various inhaled therapies for PAH. The recent studies concerning the development of controlled-release drug delivery systems loaded with available anti-PAH drugs have also been summarized.

Expert opinion: The main obstacles of current pharmacotherapies of PAH are their short half-life, stability, and formulations, resulting in reducing the efficacy and increasing systemic side effects and unknown pathogenesis of PAH. The pulmonary route has been proposed for delivering anti-PAH drugs to overcome the shortcomings. However, the application of approved inhaled anti-PAH drugs is limited. Inhalational delivery of controlled-release nanoformulations can overcome these restrictions. Extensive studies are required to develop safe and effective drug delivery systems for PAH patients.

KEYWORDS:

• Pulmonary arterial hypertension
• inhaled route
• targeted drug delivery

Article highlights

• Current PAH therapies have been focused on reestablishing the right balance between vasoconstriction and vasodilatation in pulmonary arteries, while some of them have anti-proliferative effects that tackle the abnormal proliferation of pulmonary arterial cells via augmenting the prostacyclin pathway, enhancing the NO pathway, or inhibiting the endothelin pathway.

• While current pharmacotherapies have improved the quality of life of the patients, PAH drugs suffer from limitations in the form of instability, poor organ specificity, short-term pharmacokinetics, and formulation limitations, resulting in deleterious side effects and inadequate efficacy.

• Inhalational delivery offers several advantages in the PAH treatment including, local drug delivery, higher concentration of therapeutics on the site of action, avoidance of systemic adverse effects, the lower total dose of medication with less frequent administrations, rapid drug absorption and fast onset of effect, and avoidance of the first-pass metabolism.

• Polymeric carriers have been extensively studied as carriers for inhalable, controlled-release formulations of therapeutics because this approach has tremendous potential for producing prolonged, localized delivery of anti-PAH agents, including, sildenafil, prostaglandin E1, rosiglitazone, and pitavastatin.

• Liposomes have been applied as carriers for inhaled, controlled, targeted drug delivery of various PAH treatments such as iloprost, NO, NO donors, and fasudil.

• Inhalational delivery of controlled-release nanoparticles containing targeting moiety represents an attractive strategy for mainly targeting pulmonary tissues and has several advantages, including selective short- and long-term vasodilation of the pulmonary arteries, reduced dose and dosing frequency, enhanced patient compliance, higher bioavailability as well as avoiding the clearance mechanisms of the lung and the risk of being exhaled.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported in part by two NIH grants [R01HL114677 and R01HL144590]; and the Cardiovascular Medical Research and Education Fund (CMREF) grant awarded to F Ahsan.