Abstract A42: Comparison between NO-ASA and NONO-ASA as safe anti-inflammatory, analgesic, antipyretic, antioxidant chemopreventive prodrugs
Notice bibliographique
Résumé
Abstract Introduction: Chronic inflammation is widely recognized as an underlying etiological factor in carcinogenesis; there is enough evidence to support the use of non-steroidal anti-inflammatory drugs (NSAIDs), and more importantly, their chemically-modified NO-releasing prodrugs (NO-NSAIDs) as promising chemopreventive agents. Metabolic activation of organic nitrate-containing NO-aspirins may lead to a cytotoxic “activated” linker (a quinone methide), raising safety concerns. Replacement of organic nitrates with N-diazeniumdiolates as a second-generation NONO-NSAIDs allowed us to conduct a head-to-head comparison between NCX-4016 (NO-aspirin), CVM-01 (NONO-aspirin), and aspirin as analgesic, anti-inflammatory, and anti-pyretic agents with no significant gastrointestinal toxicity. Methods: a) Anti-inflammatory: paw edema induced by intraplantar injection of 100 µL of 1% carrageenan, paw volumes measured up to the tibiotarsal joint immediately prior to carrageenan injection and thereafter at 1hr intervals up to 6hrs. Drugs were administered orally 1 hr before carrageenan; b) Anti-pyretic: body core temperature was measured twice at 15 min intervals before administration of lipopolysaccaride (LPS, 50µg/kg, ip) to induce fever. Drugs administered 1hr before LPS; c) analgesic: the time-dependent analgesic effect of prodrugs was evaluated by carrageenan-induced hyperalgesia. Drugs were administered orally 2.5 hours after carrageenan; d) Anti-ulcerogenic: Rats fasted for 48h before drug administration. After 6 hrs animals were euthanized, stomachs removed, cut along the greater curvature, lightly rinsed with water, and observed (with magnifying lenses) to count the numbers and measure the lengths (in mm) of all hemorrhagic lesions (“gastric damage score”) for each stomach. Tissue samples immediately frozen in liquid nitrogen for PGE2, SOD, and MDA determination. Results: NCX-4016 and CVM-01 decreased the carrageenan-induced edema 1h after administration and maintained this anti-inflammatory effect throughout the experiment (up to 7h). Both compounds showed improved anti-inflammatory effect compared to aspirin 3–7h post administration. All test drugs (aspirin, NCX-4016, and CVM-01) were effective anti-pyretics, decreasing the body core temperature starting at 1h post-administration. At the end of the assay (5h) aspirin prodrugs showed slightly improved anti-pyretic effect compared to aspirin. Despite a drastic reduction of PGE2 levels induced by NCX-4016 and CVM-01 in stomach tissue, both prodrugs were devoid of gastric side effects (gastric index < 5) aspirin (GI=48). Lipid peroxidation induced by aspirin (MDA=57 nmol/mg protein) was higher than that observed by the prodrugs NCX-4016 (MDA= 9nmol/mg) and CVM-01 (13 nmol/mg), which resembled control tissue (MDA=12 nmol/mg). Superoxide dismutase (SOD): aspirin (SOD=12 U/mL), NCX-4016 (SOD=21 U/mL), CVM-01 (20 U/mL), control tissue (23 U/mL). Conclusions: The N-diazeniumdiolate containing aspirin prodrug CVM-01 is as effective as NCX-4016 (an organic nitrate-containing aspirin prodrug) in anti-inflammatory, analgesic, and anti-pyretic assays in vivo, and it showed an equivalent safety profile in stomach. These results underscore the use of diazeniumdiolate-containing NSAIDs (NONO-NSAIDs) in future chemopreventive assays. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A42.
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 | 0,004 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
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 ».