Abstract 13094: Pharmacokinetics and Therapeutic Efficacy of Drpitor1a, a Novel Dynamin-Related Protein 1 Inhibitor, in a Preclinical Model of Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Introduction: Increased dynamin-related protein 1 (Drp1)-mediated mitochondrial fission contributes to the pathogenesis of pulmonary arterial hypertension (PAH). We investigated the pharmacokinetic characteristics of Drpitor1a, a novel, small molecule, ellipticine Drp1 inhibitor (prepared in-house), and tested its therapeutic efficacy in a pilot study using the rat monocrotaline (MCT)-PAH model. Methods: A single dose of Drpitor1a (5mg/kg) was administered IV or PO to male and female rats (n=3/sex). Blood was collected at 0, 5 and 30 minutes, and at 1, 2, 4, 6, 8 and 24 hours post drug administration. Plasma, lung and right ventricle (RV) were collected and tissue concentration of Drpitor1a was measured using HPLC coupled with mass spectrometry. The effects of Drpitor1a on mitochondrial fission and cell proliferation were assessed in human PAH pulmonary artery smooth muscle cells (PASMC). In an MCT-PAH model, a catheter was implanted in the left jugular vein on day 14 post-MCT injection. Drpitor1a (1mg/kg) was administered by IV every 48 hours from day 17 to day 27. On day 28, RV function and pulmonary hemodynamics were assessed. Results: Drpitor1a’s half-life varies by sex (9.9±5.3 hours and 24.3±21.4 hours in male and female rats respectively). Oral bioavailability of Drpitor1a was similar in males (21.1%) and females (19.7%). Lung concentration of Drpitor1a was similar between males and females (0.441±0.015 nM/mg and 0.444±0.581 nM/mg, respectively). In the RV, Drpitor1a level was higher in females (0.102±0.053 nM/mg) than males (0.055±0.015 nM/mg). Drpitor1a inhibited mitochondrial fission and cell proliferation in human PAH PASMC. In addition, Drpitor1a regressed pulmonary artery medial thickening (25.5% vs 34.9%), inhibited RV hypertrophy (Fulton index: 0.33 vs 0.39) and improved RV function (TAPSE: 2.2mm vs 1.8mm) in female MCT-PAH rats. Conclusion: Drpitor1a is a potential therapeutic agent for preclinical PAH and may be more effective in females.
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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) | 0.001 | 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) | 0.002 | 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".