Reduced Heart Exposure of Diclofenac by Its Polymeric Micellar Formulation Normalizes CYP-Mediated Metabolism of Arachidonic Acid Imbalance in An Adjuvant Arthritis Rat Model: Implications in Reduced Cardiovascular Side Effects of Diclofenac by Nanodrug Delivery
Bibliographic record
Abstract
In this study, we tested whether the extent of drug presence in the heart contributes to the elevated cardiovascular risk of nonsteroidal anti-inflammatory drugs (NSAIDs). A fluorescently tagged nanoformulation of an NSAID with high cardiovascular (CV) risk (diclofenac) was developed as diclofenac ethyl ester (DFEE) encapsulated in traceable (cyanine-5.5-labeled) polymeric micelles (DFEE-TM) based on methoxypoly(ethylene oxide)- block -poly(ε-caprolactone)(PEO- b -PCL) (MW, 5000:3500 g/mol). Diclofenac pharmacokinetics and tissue distribution, as well as ex vivo near-infrared images of organs and whole bodies, were compared between healthy rats and rats with adjuvant arthritis (AA) following the administration of a single intravenous (iv) dose of DFEE-TM. Moreover, the biodistribution and antiarthritic activity of DFEE-TM were compared with those of free diclofenac (once-daily intraperitoneal, ip, 10 mg/kg for 7 days). The concentration ratios of cytochrome-P450-mediated cardiotoxic (20-hydroxyeicosatetraenoic acid) over cardioprotective (epoxyeicosatrienoic acids) metabolites of arachidonic acid (ArA) in the heart, kidneys, and plasma were measured as markers of cardiotoxicity. The nanocarrier was found in the joints of AA, but not in those of healthy rats. Both free diclofenac and DFEE-TM comparably controlled AA. Diclofenac delivery via PEO- b -PCL micelles reduced the accumulation of diclofenac in the heart of AA rats. Despite similar antiarthritic activity, the polymeric micellar formulation showed a reduction in the ratio of cardiotoxic-over-cardioprotective eicosanoids of ArA in the heart and plasma of AA rats. The results showed the positive effect of diclofenac prodrug nanodelivery in changing the normal biodistribution of diclofenac away from the heart, leading to lowered diclofenac-induced biomarkers of cardiotoxicity in the heart and plasma of AA rats.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".