FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3131958712> ?p ?o ?g. }

• W3131958712 endingPage "102002" @default.
• W3131958712 startingPage "102002" @default.
• W3131958712 abstract "Treprostinil (TRE) is a prostanoid analog pulmonary vasodilator drug marketed with subcutaneous, intravenous (i.v.), oral, and inhaled routes of administration for the treatment of pulmonary arterial hypertension (PAH). Due to its short half-life, TRE requires either continuous infusion or multiple dosing, which exacerbates its side effects. Therefore, a long-acting prostanoid analog that maintains the positive attributes of TRE but has fewer TRE-related side effects could be of clinical benefit. In this report, we describe the discovery, preclinical development, and biology of the TRE ester prodrug, treprostinil palmitil (TP), which is formulated in a lipid nanoparticle (LNP) for administration as a nebulized inhaled suspension (TPIS). In screening assays focused on the conversion of prodrug to TRE, TP (16 carbon alkyl chain) had the slowest rate of conversion compared with short–alkyl chain TRE prodrugs (i.e., 2–8 carbon alkyl chain). Furthermore, TP is a pure prodrug and possesses no inherent binding to G-protein coupled receptors including prostanoid receptors. Pharmacokinetic studies in rats and dogs demonstrated that TPIS maintained relatively high concentrations of TP in the lungs yet had a low maximum plasma concentrations (Cmax) of both TP and, more importantly, the active product, TRE. Efficacy studies in rats and dogs demonstrated inhibition of pulmonary vasoconstriction induced by exposure to hypoxic air or i.v.-infused U46619 (thromboxane mimetic) over 24 h with TPIS. Cough was not observed with TPIS at an equivalent dose at which TRE caused cough in guinea pigs and dogs, and there was no evidence of desensitization to the inhibition of pulmonary vasoconstriction in rats with repeat inhaled dosing. TPIS was also more efficacious than i.v.-infused TRE in a sugen/hypoxia rat model of PAH to inhibit pulmonary vascular remodeling, an effect likely driven by local activities of TRE within the lungs. TPIS also demonstrated antifibrotic and anti-inflammatory activity in the lungs in rodent models of pulmonary fibrosis and asthma. In a phase 1 study in healthy human participants, TPIS (referred to as INS1009) had a lower plasma TRE Cmax and fewer respiratory-related side effects at equimolar doses compared with inhaled TRE. We have now formulated TP as an aerosol powder for delivery by a dry powder inhaler (referred to as treprostinil palmitil inhalation powder-TPIP), and as an aerosol solution in a fluorohydrocarbon solvent for delivery by a metered dose inhaler. These options may reduce drug administration time and involve less device maintenance compared with delivery by nebulization." @default.
• W3131958712 created "2021-03-01" @default.
• W3131958712 creator A5024460960 @default.
• W3131958712 creator A5032971644 @default.
• W3131958712 creator A5046870824 @default.
• W3131958712 creator A5054893065 @default.
• W3131958712 creator A5064542031 @default.
• W3131958712 creator A5089080826 @default.
• W3131958712 creator A5091642462 @default.
• W3131958712 date "2020-12-01" @default.
• W3131958712 modified "2023-10-16" @default.
• W3131958712 title "An overview of the biology of a long-acting inhaled treprostinil prodrug" @default.
• W3131958712 cites W1037787398 @default.
• W3131958712 cites W1840736932 @default.
• W3131958712 cites W1975351849 @default.
• W3131958712 cites W1977368405 @default.
• W3131958712 cites W1980682121 @default.
• W3131958712 cites W1982891071 @default.
• W3131958712 cites W1985442159 @default.
• W3131958712 cites W1987942129 @default.
• W3131958712 cites W1990796256 @default.
• W3131958712 cites W1992912127 @default.
• W3131958712 cites W2005845306 @default.
• W3131958712 cites W2006259818 @default.
• W3131958712 cites W2012675069 @default.
• W3131958712 cites W2013426785 @default.
• W3131958712 cites W2015018206 @default.
• W3131958712 cites W2020990243 @default.
• W3131958712 cites W2025126892 @default.
• W3131958712 cites W2029325214 @default.
• W3131958712 cites W2061667034 @default.
• W3131958712 cites W2072132671 @default.
• W3131958712 cites W2076810386 @default.
• W3131958712 cites W2081327751 @default.
• W3131958712 cites W2082293728 @default.
• W3131958712 cites W2083977896 @default.
• W3131958712 cites W2085750668 @default.
• W3131958712 cites W2087055962 @default.
• W3131958712 cites W2088282211 @default.
• W3131958712 cites W2092188218 @default.
• W3131958712 cites W2101960743 @default.
• W3131958712 cites W2118695925 @default.
• W3131958712 cites W2118734145 @default.
• W3131958712 cites W2121464855 @default.
• W3131958712 cites W2133645194 @default.
• W3131958712 cites W2134780421 @default.
• W3131958712 cites W2136978968 @default.
• W3131958712 cites W2144678486 @default.
• W3131958712 cites W2145732660 @default.
• W3131958712 cites W2146403616 @default.
• W3131958712 cites W2148965526 @default.
• W3131958712 cites W2154863191 @default.
• W3131958712 cites W2155720896 @default.
• W3131958712 cites W2158255274 @default.
• W3131958712 cites W2163323710 @default.
• W3131958712 cites W2166719339 @default.
• W3131958712 cites W2183644045 @default.
• W3131958712 cites W2199432351 @default.
• W3131958712 cites W2290741181 @default.
• W3131958712 cites W2318095272 @default.
• W3131958712 cites W2515029578 @default.
• W3131958712 cites W2532369118 @default.
• W3131958712 cites W2558563023 @default.
• W3131958712 cites W2607217884 @default.
• W3131958712 cites W2611852258 @default.
• W3131958712 cites W2752655957 @default.
• W3131958712 cites W2755800927 @default.
• W3131958712 cites W2792301413 @default.
• W3131958712 cites W2793807241 @default.
• W3131958712 cites W2804342246 @default.
• W3131958712 cites W2805592280 @default.
• W3131958712 cites W2810131842 @default.
• W3131958712 cites W2886383171 @default.
• W3131958712 cites W2887053618 @default.
• W3131958712 cites W2899003343 @default.
• W3131958712 cites W2902543379 @default.
• W3131958712 cites W2903654157 @default.
• W3131958712 cites W2904280618 @default.
• W3131958712 cites W2934343946 @default.
• W3131958712 cites W2976822390 @default.
• W3131958712 cites W3090470109 @default.
• W3131958712 cites W3113013830 @default.
• W3131958712 cites W3119793303 @default.
• W3131958712 cites W3119984225 @default.
• W3131958712 cites W2054405861 @default.
• W3131958712 doi "https://doi.org/10.1016/j.pupt.2021.102002" @default.
• W3131958712 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/33596473" @default.
• W3131958712 hasPublicationYear "2020" @default.
• W3131958712 type Work @default.
• W3131958712 sameAs 3131958712 @default.
• W3131958712 citedByCount "10" @default.
• W3131958712 countsByYear W31319587122021 @default.
• W3131958712 countsByYear W31319587122022 @default.
• W3131958712 countsByYear W31319587122023 @default.
• W3131958712 crossrefType "journal-article" @default.
• W3131958712 hasAuthorship W3131958712A5024460960 @default.
• W3131958712 hasAuthorship W3131958712A5032971644 @default.
• W3131958712 hasAuthorship W3131958712A5046870824 @default.

• next