COLON-TARGETED CYCLOSPORINE IN THE IL10 KNOCK OUT MODEL OF CROHN'S COLITIS
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».