Reduced Infection and Mucositis In Chemotherapy-Treated Animals Following Innate Defense Modulation Using a Novel Drug Candidate.
Notice bibliographique
Résumé
Abstract Abstract 3781 Innate Defense Regulators (IDRs) are a novel class of synthetic peptides with no antimicrobial activity that enhance microbial infection control while suppressing inflammation. IDRs bind to an intracellular scaffold protein, p62 or sequestosome-1, selectively modulating protein-protein complex formation and signaling downstream of receptors such as Toll-like receptors, IL-1 receptor and TNF receptor. Treatment of mice with IDRs enhanced their survival in bacterial infection models. The anti-infective effect of IDRs was maintained in animals depleted of neutrophils, but abolished in animals depleted of macrophages/monocytes, indicating an important role for macrophages in IDR mediated host protection at the site of infection. IDRs have been shown to transiently increase local chemokine levels (CCL5 and CXCL10), enhance macrophage recruitment to the site of infection and improve the resolution of bacterial infection alone or in conjunction with antibiotics. Recently, the enhanced survival benefit conferred by IDR treatment has been shown in clinically-relevant rat models of neutropenic sepsis after cyclophosphamide treatment. In rats pre-treated with cefamandole, made neutropenic with cyclophosphamide and orally colonized with Pseudomonas aeruginosa, administration of IMX942, the lead clinical candidate in the IDR family, once on day 5 (10mg/kg IV) after the development of fever increased survival from 0% (saline group) to 63%. This increased survival was comparable to the antibiotic treated group (75%) and both the antibiotic and IMX942 treated arms demonstrated marked preservation of the mucosal lining in the ileum. Further investigations in an animal model of mucositis, where pathogenesis is linked to the reaction of the innate defense system, have demonstrated that IDRs have significant efficacy in both oral and gut mucositis. In these studies, C3H/HeN mice are administered 5FU (60mg/kg, intraperitoneal injection) on days -4 and -2, and mucositis is induced on day 0 through the application of a chemical burn on the ventral surface of the tongue. Mucositis is then monitored for 14 days, generally peaking on day 2 or 3. Treatment with IMX942 (25mg/kg, IV) on days -1, 2 and 5 or days 0, 2, and 4 resulted in a statistically significant decrease in the duration and severity of oral mucositis (50% reduction) between days 2 and 14, and in the severity of gut mucositis (63% reduction) as measured by clinical endoscopy on day 4. IMX942 has successfully completed Phase 1 clinical studies, and was very well tolerated at single doses up to 8 mg/kg and at multiple doses (7 daily injections) up to 6.5 mg/kg/day. Phase 2 studies evaluating the efficacy of IMX942 in the amelioration of mucositis and infection in cancer patients undergoing radio- or chemo-therapy are currently being planned. Disclosures: Donini: Inimex Pharmaceuticals Inc.: Employment. Watkins:Inimex Pharmaceuticals Inc.: Consultancy. Palardy:Inimex Pharmaceuticals Inc.: Research Funding. Opal:Inimex Pharmaceuticals Inc.: Research Funding. Sonis:Inimex Pharmaceuticals Inc.: Consultancy; Biomodels, LLC: Equity Ownership; SciClione Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Biovitrum: Consultancy; Johnson and Johnson: Consultancy; Clinical Assistance Programs: Consultancy; Pfizer: Consultancy; Merck: Consultancy. Abrams:Inimex Pharmaceuticals Inc.: Employment. North:Inimex Pharmaceuticals Inc.: Employment.
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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 ».