A phase 1, first-in-human, open label, single ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of stabilized isoamyl nitrite nasal spray in healthy adult participants
Bibliographic record
Abstract
Stabilized isoamyl nitrite (SIAN) is a novel small molecule, therapeutic candidate for the treatment of cyanide poisoning. SIAN improves survival and has a demonstrated pharmacodynamic (PD) effect in cyanide challenged nonhuman primates. Here, we report results of phase 1, first-in-human study evaluating the safety, tolerability, pharmacokinetic (PK), and PD of SIAN nasal spray in healthy human subjects (NCT05194358). SIAN was intranasally administered in ascending doses at 2 sites in Texas and Tennessee in the United States. A total of 47 subjects were enrolled across 7 dose cohorts evaluating single doses from 20 to 300 μL. Following the dosing of sentinels in each cohort, safety, PK, and PD data were interpreted by a Safety Monitoring Committee to permit dosing of additional subjects in the cohort or escalation to the next dose level. Isoamyl alcohol peak plasma concentrations were reached within 2 minutes and were highest after a 250 μL dose (125 μL/nostril). This trend was also observed for PD parameters, including a metHB peak at 2 minutes with associated increase in heart rate and systolic and diastolic blood pressure. SIAN was generally well tolerated, no serious or severe drug-related effects were observed, and there were no clinically significant changes in vitals or laboratory parameters. We conclude that SIAN, a potential new treatment for cyanide poisoning, was safe, well tolerated, and showed a relationship between PK and PD parameters at the doses tested. SIGNIFICANCE STATEMENT: This is the first-in-human clinical study to evaluate intranasal stabilized isoamyl nitrite, which was shown to be safe, well tolerated, and to elicit a measurable pharmacokinetic and pharmacodynamic response in healthy human subjects at the doses tested. This study paves the way for investigating stabilized isoamyl nitrite further as a potential emergency treatment for cyanide poisoning.
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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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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".