Prolonged activity of inhaled treprostinil prodrug nanoparticles in a rat model of pulmonary arterial hypertension
Bibliographic record
Abstract
Introduction : Inhaled treprostinil (Tyvaso™) for pulmonary arterial hypertension (PAH) is dosed 4 times daily. In an effort to reduce dosing frequency, the effects of inhaled treprostinil ester prodrugs (TPD) formulated in lipid nanoparticles (LNP) were studied in a rat model of acute hypoxia-induced hypertension. Methods : TPDs were synthetized by addition of alkyl chains to the carboxyl group, and their conversion to TRE was assessed in vitro in aqueous media and in homogenized lung tissue. For in vivo studies, anesthetized-ventilated rats were monitored for pulmonary arterial pressure (PAP), systemic blood pressure (BP) and heart rate (HR) under hypoxic conditions (FIO 2 ∼0.10, SaO 2 ∼50 %) before and after nebulization of the drugs. Drug concentration in blood samples and lungs excised at the end of the study were measured using LC/MS/MS analysis. Results : TPDs improved retention of TRE in LNP. The conversion of TPD to active TRE was slow and chain-length dependent. In rats, nebulized TPD (15 nmole/kg), unlike TRE, had significant reductions in PAP that persisted well beyond 2h. The long-chain TPD formulations (alkyl chains of lengths C12, C14, and C16) exhibited greater bioactivity at relatively low levels of TRE in the blood and high concentrations of TPDs in the lungs. Conclusions : In a rat model of acute hypoxia-induced hypertension, inhaled LNP formulations of treprostinil prodrug demonstrate an extended duration of activity compared to the free form of TRE. The longer chain prodrugs of treprostinil (C12, C14, and C16) exhibit the greater duration in activity and are the focus of additional investigations to assess longer term PK.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".