Drug−disease interaction: Crohn's disease elevates verapamil plasma concentrations but reduces response to the drug proportional to disease activity
Bibliographic record
Abstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Inflammatory conditions such as Crohn's disease are associated with cardiovascular complications. Inflammation also substantially reduces clearance of some cardiovascular drugs. It has also been shown that in rheumatoid arthritis, an elevation in verapamil concentration does not result in increased response. WHAT THIS STUDY ADDS • A reduced response upon increased verapamil concentration in another inflammatory condition, inflammatory bowel disease, with different aetiology from arthritis was found. Interestingly, however, a mere affliction with the disease is not sufficient to alter pharmacokinetics and pharmacodynamics since we found that the alteration is a function of disease severity. There is a remarkable reverse correlation between the disease severity and response to verapamil. Our observation suggests a complex relationship between pharmacokinetics and pharmacodynamics which may have implications beyond the disease and the drug studied herein. AIMInflammation is involved in the pathogenesis of cardiovascular diseases that includes reduced response to pharmacotherapy due to altered pharmacokinetics and pharmacodynamics. It is not known if these effects exist in general in all inflammatory conditions. It also remains unknown whether in a given population the effect is a function of disease severity. We investigated whether pharmacokinetics and pharmacodynamics of a typical calcium channel inhibitor are influenced by Crohn's disease (CD), a disease for which the disease severity can be readily ranked. METHODSWe administered 80 mg verapamil orally to (i) healthy control subjects (n= 9), (ii) patients with clinically quiescent CD (n= 22) and (iii) patients with clinically active CD (n= 14). Serial analysis of verapamil enantiomers (total and plasma unbound), blood pressure and electrocardiograms were recorded over 8 h post dose. The severity of CD was measured using the Harvey‐Bradshaw Index. RESULTSCD substantially and significantly increased plasma verapamil concentration and in a stereoselective fashion (S, 9‐fold; R, 2‐fold). The elevated verapamil concentration, however, failed to result in an increased verapamil pharmacodynamic effect so that the patients with elevated verapamil concentration demonstrated no significant increase in response measured as PR interval and blood pressure. Instead, the greater the disease severity, the lower was the drug potency to prolong PR interval (r= 0.86,P< 0.0006), CONCLUSIONSCD patients with severe disease may not respond to cardiovascular therapy with calcium channel blockers. Reducing the severity increases response despite reduced drug concentration. This observation may have therapeutic implication beyond the disease and the drug studies herein.
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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 | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.009 | 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".