Abstract 10715: Therapeutic Efficacy of Drpitor1a, a Novel Dynamin-Related Protein 1 (DRP1) Inhibitor, in Preclinical Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Introduction: Dynamin-related protein 1 (DRP1) is a large GTPase that mediates mitotic fission (the division of mitochondria which is coordinated with mitosis, ensuring equitable distribution of mitochondria to daughter cells). In pulmonary arterial hypertension (PAH) pulmonary artery smooth muscle cells (PASMC), mitotic fission, and DRP1 activity are increased, contributing to its hyperproliferative phenotype. We investigated the therapeutic efficacy of Drpitor1a, a novel, small molecule, Drp1 GTPase inhibitor, in a rat PAH model. Methods: A single dose of monocrotaline (MCT, 60mg/kg, SC) or PBS was injected to female Sprague-Dawley rats on day 0 (n=20 for MCT and n=15 for PBS). On day 14, the development of PAH was confirmed by echocardiography and the rats were randomized for treatments. An indwelling catheter was implanted through the left jugular vein on day 15. Drpitor1a (1mg/kg) or normal saline (NS) was administered by IV every 48 hours from day 17 to day 27. Right ventricular (RV) structure and function were assessed on day 28 with echocardiography. Pulmonary hemodynamics was evaluated on day 29 using right heart catheterization (RHC). Results: MCT rats developed PAH with RV dysfunction on day 14. There was no statistical difference between the Drpitor1a and NS groups at randomization. At the endpoint, MCT+Drpitor1a rats, vs. MCT+NS rats, had a significantly reduced severity of pulmonary hypertension evident as longer pulmonary artery acceleration time (PAAT) and lower pulmonary vascular resistance index. Drpitor1a also improved RV function, evident as greater RV free wall thickening (RVFWT%), increased tricuspid annular plane systolic excursion (TAPSE), and increased cardiac index (CI). Drpitor1a regressed pulmonary artery medial thickening and inhibited RV hypertrophy without hepatological, renal or hepatic toxicities. Conclusion: Drpitor1a is a safe and effective treatment for preclinical PAH.
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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) | 0.001 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".