Abstract 4136839: HBI-3000: Pharmacological Conversion of Atrial Fibrillation With Unique Defense Against Excessive QT Interval Prolongation
Bibliographic record
Abstract
Background: HBI-3000 (Sulcardine sulfate) is a new antiarrhythmic drug (AAD) that inhibits multiple cardiac ion channels (INa-peak, INa-late, ICa,L and IKr (hERG)) with uniquely similar potencies. A major AAD limitation is malignant proarrhythmia due to excessive hERG-mediated delay in repolarization, manifested by QT prolongation with proportional J to T peak [JTp] prolongation. While sulcardine inhibits hERG, it also possesses an intrinsic protective mechanism, inhibiting inward INa-late and ICa,L early repolarization currents. In Phase 1 volunteers in sinus rhythm (SR) therapeutic levels of sulcardine not only reduced but reversed the lengthening of the rate-corrected JTp (JTpc), reducing the extent of hERG-related QT prolongation. We investigated this protective JTpc effect in atrial fibrillation (AF) patients at the anticipated clinical dose, and examined the relationships between plasma concentration, QT prolongation, and the JTPc reduction. Methods: Ten patients received 350 mg HBI-3000 IV over 30 min in a Phase 2 open-label study of patients with acute AF. Sulcardine plasma concentrations and ECG intervals (from 5-min summary ECGs) were obtained at baseline and several time points. Mean baseline-subtracted, heart rate-corrected QTcF (dQTcF) and JTp (dJTpc; Johannesen’s method) were calculated at each time point. AF patient data were compared to those of volunteers in SR. Results: In AF patients, dQTcF prolonged with a linear relationship to plasma concentration as expected (Fig 1A, blue). HBI-3000 IV produced a large linear reduction in JTpc contribution to the QT interval (Fig 1A, red). This is consistent with findings in SR (Fig 1B [350 mg dose] and 1C [360 mg dose]) and unique among AADs that inhibit IKr along with INa-late and/or ICa,L. Calculated dQTcF changes without the JTpc effect were greater than the observed dQTcF (Fig 1A, green) by 27%-76% at Cmax in the three studies. Conclusions: HBI-3000 (Sulcardine) exhibits dQTcF prolongation protection in both AF and SR due to a unique pattern of channel fluxes that shortens early repolarization. This shorter dJTp interval acts as a mechanism for effectively limiting excessive QT prolongation and reducing proarrhythmic risk. [Registration: NCT04680026]
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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) | 0.004 | 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".