Loperamide-induced severe cardiotoxicity: a toxicokinetic and toxicodynamic analysis derived from a case series and the published literature
Bibliographic record
Abstract
Introduction Chronic loperamide overdose is associated with cardiotoxicity. We describe the toxicokinetics of loperamide and N-desmethyl loperamide, and their concentration–response relationship on cardiotoxicity in newly described and published cases.Materials and methods We obtained serial loperamide and N-desmethyl loperamide concentrations, and corresponding electrocardiographic intervals in three episodes (two patients) of loperamide-related cardiotoxicity. A toxicokinetic and toxicodynamic analysis was undertaken that included data from previous publications to explore the relationship between these variables.Results Patients presented with dizziness, bradycardia, loss of consciousness, and jerking or ventricular tachycardia after taking loperamide 320–400 mg/day for weeks or years. In one patient, ventricular tachycardia occurred on days two and three post-admission. Prolonged electrocardiographic intervals resolved after approximately five days. Admission loperamide concentrations were 5.37–288 μg/L and the terminal elimination half-lives were 21.3–38.7 h. Admission N-desmethyl loperamide concentrations were 87.67–256.34 μg/L and the terminal elimination half-life was 31.9–88.9 h. Overall, there were 42 loperamide and 35 N-desmethyl loperamide concentrations with paired electrocardiographic data, and the concentration–response relationship was derived using a maximum effect (Emax) model. Lower loperamide concentrations were associated with electrocardiographic abnormalities, compared to N-desmethyl loperamide concentrations. The total relative loperamide concentration, which combines both concentrations into a single value using in vitro inhibitory potencies at cardiac ion channels, out-performed either parent or metabolite concentrations alone for predicting cardiotoxicity on receiver operating characteristic curves.Discussion Loperamide and N-desmethyl loperamide have long elimination half-lives causing prolonged cardiotoxicity. Higher loperamide and N-desmethyl loperamide concentrations are associated with prolonged electrocardiographic intervals.Conclusions Patients with chronic loperamide overdose are at risk of cardiotoxicity that persists for days due to persistent loperamide and N-desmethyl loperamide concentrations. We believe patients with loperamide overdose need an admission electrocardiograph and continuous monitoring until electrocardiographic changes resolve.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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".