Interaction of Ethanol and Oral ANS‐6637, a Selective ALDH2 Inhibitor in Males: A Randomized, Double‐Blind, Placebo‐Controlled, Single‐Ascending Dose Cohort Study
Bibliographic record
Abstract
BACKGROUND: ANS-6637, an orally bioavailable selective and reversible aldehyde dehydrogenase-2 (ALDH2) inhibitor, is under development for drug and alcohol use disorders. During the elimination of alcohol, ALDH2 metabolizes acetaldehyde to acetate; inhibiting this enzyme can lead to aversive reactions due to the accumulation of acetaldehyde. Thus, understanding the safety and tolerability of ANS-6637 in combination with alcohol is essential. TRIAL DESIGN AND METHODS: Forty eight healthy males participated in a randomized, double-blind, placebo-controlled, single-ascending dose cohort study of oral ANS-6637. Eligible participants were randomized to ANS-6637 (n = 36) or placebo (n = 12) in a 3:1 fashion in each of 6 dose cohorts (8 per cohort; ANS-6637 dose levels were 25, 50, 100, 200, 400, and 600 mg). Two hours after receiving study drug, participants drank up to 5 standard drinks, 1 every 30 minutes. Safety assessments, pharmacodynamic measures, and pharmacokinetic blood samples were obtained. RESULTS: drink). No participant met HR or systolic blood pressure criteria for stopping ethanol administration. There were no clinically significant QTc interval prolongations. Individuals receiving ANS-6637 reported lower ratings of liking, alcohol effects, and feeling drunk. CONCLUSIONS: A single oral dose of ANS-6637 with up to 5 standards drinks over 2.5 hours was generally well tolerated in healthy males. The most common pharmacological response was flushing and an increase in HR, which are known effects of acetaldehyde accumulation and consistent with inhibition of ALDH2 with oral ANS-6637 in combination with alcohol. The results of this alcohol interaction study support further testing of ANS-6637 in individuals who consume alcohol heavily.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.006 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".