A151 STRATEGIES TO ENHANCE THE CLINICAL APPLICATIONS OF A NOVEL PH SENSITIVE ANALGESIC IN A PRECLINICAL MODEL OF COLITIS
Bibliographic record
Abstract
Abstract Background Improved pain management is an identified top five priority for the treatment of patients suffering from inflammatory bowel disease. Although conventional opioids and NSAIDs can provide pain relief, their side effects pose serious health risks. We developed a unique pH-sensitive analgesic, NFEPP, that is only active at sites of injury/inflammation without affecting healthy tissues, e.g. brain and gut. Preclinical studies using parenteral routes(s.c. or i.v.) demonstrate that NFEPP exhibits potency comparable to fentanyl, but without the risks of addiction or severe side effects like respiratory depression. The duration of action of NFEPP is ~2 hrs, which would require continuous infusion or frequent applications to treat a painful disorder. To broaden the potential clinical applications, strategies are needed to increase its half-life and to understand its efficacy compared to conventional treatments. Aims To examine the therapeutic index(TI) of NFEPP and determine if a high index could be exploited to extend its duration of action, and to compare the analgesic efficacy of NFEPP with a standard NSAID, diclofenac. Methods Acute colitis was induced in C57BL/6 mice by administering 2.5% dextran sulfate sodium(DSS) in drinking water for five days. Following s.c. injections of vehicle, NFEPP, fentanyl or diclofenac, visceromotor responses (VMRs) to colorectal distension were measured using telemetric transmitters inserted in the abdominal wall muscles. To assess cardiorespiratory side effects, mice were monitored via pulse oximetry. Results NFEPP(0.4 mg s.c.) and fentanyl(0.4 mg s.c.) exhibited similar analgesic effects on VMR but fentanyl markedly inhibited O2 saturation (~10%; p<0.05), causing hypoxia. NFEPP at 50X’s this analgesic dose(20 mg/kg s.c.) had no effect on O2 saturation, suggesting a very high TI. We therefore examined whether the duration of action of NFEPP could be extended into the range of other oral analgesics by increasing the dose (doubling the dose increases T1/2 by ~<1, 1st order kinetics). NFEPP 0.4 mg/kg s.c. was tested at 2 hrs and 1.6 mg/kg s.c. at 6 hrs. NFEPP (1.6 mg/kg s.c.) caused a 37.8% (p<0.05) reduction in VMR responses after 6 hrs, similar to the effect of NFEPP 0.4 mg/kg at 2 hrs (36.8% reduction in VMR; p<0.01). Comparator studies of the efficacy of NFEPP(0.4 mg/kg s.c.; ~EC75 dose) and diclofenac(30 mg/kg s.c., ~EC100 dose) demonstrated a 54.2% (p<0.001) and 49.7% (p<0.01) reduction in VMR, respectively. Conclusions NFEPP has a very high TI compared to fentanyl, and this property could potentially be exploited to increase its half-life in oral and/or patch formulations by increasing the dose without risk of respiratory depression. NFEPP has similar or greater analgesic efficacy compared to NSAIDs and could potentially be an alternative for some clinical indications. Funding Agencies CIHR
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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) | 0.000 | 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) | 0.003 | 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".