COLON-TARGETED CYCLOSPORINE IN THE IL10 KNOCK OUT MODEL OF CROHN'S COLITIS
Bibliographic record
Abstract
Introduction Cyclosporine A (CyA) is a powerful immunosuppressive agent and has been used off label for steroid-dependent or steroid-refractory ulcerative colitis. However, systemic exposure results in a number of side effects. A novel advanced oral drug delivery system, SmPill ® , has been developed to permit targeted release of CyA directly into the colon tissue with limited systemic exposure. Aims/Background The objective was to compare SmPill ® -CyA activity in the IL10 knock-out mouse model of Crohn's colitis against the marketed Neoral ® (po) and Sandimmun ® (ip). Method Mice were treated for 42 days, received the equivalent of 15 mg/kg/day CyA as well as untreated and SmPill ® placebo. A secondary objective was to measure systemic pro-inflammatory cytokine activity in isolated spleen cells. Results General Mouse Health: The SmPill ® -CyA group were significantly heavier than mice in all other groups on Day 42. The SmPill ® -CyA group had the lowest Disease Activity Index scores relative to the other groups. Colon Tissue Inflammatory Biomarkers: The untreated mice had the highest Serum Amyloid A levels (SAA), with the lowest levels seen with those treated with SmPill ® -CyA (p<0.001) followed by Sandimmun ® (i.p) (p<0.01) treated mice. Sandimmun (i.p) and SmPill ® -CyA groups had significantly lower (P<0.01) histology scores relative to Neoral ® . Neoral ® (po) had the greatest relative score. The highest levels of Myeloperoxidase (MPO) activity were seen in the untreated and placebo mice. There was statistically lower MPO activity in both the SmPill ® -CyA and Sandimmune ® (i.p.) groups relative to untreated mice (p<0.05). Similarly to a reduction in MPO activity, the SmPill ® -CyA groups also had reduced IL-1α, IL-17 and TNFα pro-inflammatory cytokine levels (p<0.05) in colon tissue at Day 42. Systemic Tissue Inflammatory Biomarkers: In a measure of systemic CyA activity, the activity of a number of pro-inflammatory cytokines in activated isolated spleen cells was measured. The Sandimmune ® (i.p) treated mice had significantly reduced production of TNF-α (p<0.01) and IL-17 (p<0.05) relative to cells from the untreated and placebo treated mice. In mice treated with SmPill ® -CyA the reduction in TNF-α and IL-17 release by cells was non-significant. The pro-inflammatory cytokine expression levels for Neoral ® was between that of Sandimmune ® and SmPill ® -CyA. Conclusion The above study demonstrated that SmPill ® -CyA conferred preferential local colonic efficacy with limited systemic activity, in effect, harnessing the local efficacy of CyA and reducing systemic side effect risks. A SmPill ® -CyA formulation, CyCol ® , has progressed through human Phase I (PK) study in Canada and Phase IIb study in Ireland and the UK. A multi-centre Phase IIb study is being planned.
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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 | 0.000 | 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 | 0.000 | 0.000 |
| 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".