Novel therapeutic approaches for pulmonary arterial hypertension: Unique molecular targets to site-specific drug delivery

Vaidya, Bhuvaneshwar; Gupta, Vivek

doi:10.1016/j.jconrel.2015.05.287

Cited by 36 publications

(32 citation statements)

References 151 publications

(179 reference statements)

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“…This profile indicates a moderate lung retention, which could be compatible with a once-a-day administration frequency and a sustained drug release profile over a 24 h period. Therapeutic applications for such a pharmacokinetic-modulating formulation include the treatment of pulmonary hypertension with inhaled iloprost (Ventavis®), which due to the short half-life of iloprost in the lung requires administration frequencies of 6-9 doses per day [35].…”

Section: Discussionmentioning

confidence: 99%

Lung inflammation does not affect the clearance kinetics of lipid nanocapsules following pulmonary administration

Patel

Woods

Riffo‐Vasquez

et al. 2016

Journal of Controlled Release

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Lipid nanocapsules (LNCs) are semi-rigid spherical capsules with a triglyceride core that present a promising formulation option for the pulmonary delivery of drugs with poor aqueous solubility. Whilst the biodistribution of LNCs of different size has been studied following intravenous administration, the fate of LNCs following pulmonary delivery has not been reported. We investigated quantitatively whether lung inflammation affects the clearance of 50 nm lipid nanocapsules, or is exacerbated by their pulmonary administration. Studies were conducted in mice with lipopolysaccharide-induced lung inflammation compared to healthy controls. Particle deposition and nanocapsule clearance kinetics were measured by single photon emission computed tomography/computed tomography (SPECT/CT) imaging over 48 h. A significantly lower lung dose of 111 In-LNC50 was achieved in the lipopolysaccharide (LPS)-treated animals compared with healthy controls (p < 0.001). When normalised to the delivered lung dose, the clearance kinetics of 111 In-LNC50 from the lungs fit a first order model with an elimination half-life of 10.5 ± 0.9 h (R 2 = 0.995) and 10.6 ± 0.3 h (R 2 = 1.000) for healthy and inflamed lungs respectively (n = 3). In contrast, 111 In-diethylene triamine pentaacetic acid (DTPA), a small hydrophilic molecule, was cleared rapidly from the lungs with the majority of the dose absorbed within 20 min of administration. Biodistribution to lungs, stomach-intestine, liver, trachea-throat and blood at the end of the imaging period was unaltered by lung inflammation. This study demonstrated that lung clearance and whole body distribution of lipid nanocapsules were unaffected by the presence of acute lung inflammation.

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Section: Discussionmentioning

confidence: 99%

Lung inflammation does not affect the clearance kinetics of lipid nanocapsules following pulmonary administration

Patel

Woods

Riffo‐Vasquez

et al. 2016

Journal of Controlled Release

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“…The exact cause of PAH is still unknown, but the progress in the understanding of its pathophysiology enabled the development of new therapies based on the treatment of endothelial dysfunction. Although PAH is treatable, the cure for this chronic disease, affecting both children and adults between 20 and 50 years of age, is still not known (2,3).…”

Section: Introductionmentioning

confidence: 99%

“…PAH can be treated by intravenous, subcutaneous, inhaled or oral route, according to medical standards (3). Phosphodiesterase-5 inhibitors (PDE-5i), such as sildenafil citrate (SIL) and tadalafil (TA) as well as endothelin-1 receptor antagonists, i.e.…”

Section: Introductionmentioning

confidence: 99%

Physicochemical Properties of Bosentan and Selected PDE-5 Inhibitors in the Design of Drugs for Rare Diseases

et al. 2016

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Abstract.The study provides the physicochemical characteristic of bosentan (BOS) in comparison to tadalafil (TA) and sildenafil citrate (SIL). Despite some reports dealing with thermal characteristic of SIL and TA, physicochemical properties of BOS have not been investigated so far. Recent clinical reports have indicated that the combination of bosentan and PDE-5 inhibitor can improve the effectiveness of pharmacotherapy of pulmonary arterial hypertension (PAH). However, in order to design personalized medicines for therapy of chronic rare diseases, detailed information on the thermal behaviour and solubility of each drug is indispensable. Thus, XRD, DSC and TGA-QMS analyses were applied to compare the properties of the drugs, their thermal stability as well as to identify the products of thermal degradation. The dehydration of BOS started at 70°C and was followed by the chemical degradation with the onset at 290°C. The highest thermal stability was stated for TA, which decomposed at ca. 320°C, whereas the lowest onset of the thermal decomposition process was stated for SIL, i.e. 190°C. The products of the drug decomposition were identified. FT-FIR was applied to study intra-and intermolecular interactions between the drug molecules. FT-MIR and Raman spectroscopy were used to examine the chemical structure of the drugs. Chemoinformatic tools were used to predict the polar surface area, pKa, or logP of the drugs. Their results were in line with solubility and dissolution studies.

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“…(20)(21)(22) NPs are taken up by the target organ because of their small size and permeability and their retention effect. Drug release from NPs is controlled according to the NP composition.…”

Section: Nanoparticle-mediated Drug Delivery System (Nano-dds)mentioning

confidence: 99%

Nanoparticle-Mediated Drug Delivery System for Pulmonary Arterial Hypertension

Nakamura

Matsubara

Akagi

et al. 2017

Preprint

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Nanoparticles have been used as a novel drug delivery system. Drug-incorporated nanoparticles for local delivery might optimize the efficacy and minimize the side effects of drugs. The efficacy and safety of intratracheal administration of prostacyclin analog (beraprost)-incorporated nanoparticles and imatinib, a PDGF-receptor tyrosine kinase inhibitor, -incorporated nanoparticles in Sugen-hypoxia-normoxia or monocrotaline rat models of PAH and in human PAH-pulmonary arterial smooth muscle cells have been reported. The use of inhaled drug-incorporated nanoparticles might be a novel approach for treatment of PAH.

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Novel therapeutic approaches for pulmonary arterial hypertension: Unique molecular targets to site-specific drug delivery

Cited by 36 publications

References 151 publications

Lung inflammation does not affect the clearance kinetics of lipid nanocapsules following pulmonary administration

Lung inflammation does not affect the clearance kinetics of lipid nanocapsules following pulmonary administration

Physicochemical Properties of Bosentan and Selected PDE-5 Inhibitors in the Design of Drugs for Rare Diseases

Nanoparticle-Mediated Drug Delivery System for Pulmonary Arterial Hypertension

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