Control of Oxidant-Stress and Inflammation by Iron Chelators Deferasirox (ICL670) or Deferoxamine in β-Thalassemia: An Ancillary Study of the Novartis CICL670A0107 Trial.
Notice bibliographique
Résumé
Abstract Objective: We examined whether oxidant-stress and inflammation in β-thalassemia can be controlled by deferasirox as effectively as by deferoxamine (DFO) through analysis of body iron burden and biomarkers of lipid peroxidation and inflammation. Methods: Thalassemia Clinical Research Network patients participating in the Novartis CICL670A0107 trial (a randomized comparison of deferasirox, an oral iron chelator, vs. DFO) were eligible and 44 (25 male, 21.8±11.1 yrs) were enrolled in the study. Blood samples were obtained fasting after a 5-day washout of DFO prior to commencing treatment with study drug, and 24 hours post-chelator and antioxidant supplementation at 1, 6, and 12 months on study. Thirty healthy untreated controls matched for age, sex, and race (15 male, 24.5±9 yrs) were also studied. Plasma levels of malondialdehyde (MDA), a marker of lipid peroxidation, were determined by GC-MS; vitamin C by spectrophotometry; α-tocopherol by HPLC; and high-sensitivity C-reactive protein (hsCRP), a marker of inflammation, by nephelometry. In patients with thal, liver iron concentration (LIC) was analyzed by atomic absorption spectrometry and ferritin by immuno-assay. MDA, α-tocopherol, and hsCRP were log-transformed prior to analysis. Back-transformed means are reported. Results: Mean MDA concentrations (nmol/L) at 0, 1, 6, and 12 months were as follows: deferasirox: 78, 77, 46, 48; DFO: 40, 44, 37, 33. Mean MDA concentration in control subjects was 19 nmol/L (range 2–76 nmol/L). MDA was elevated in both treatment groups as compared to controls (p<.05). Mean MDA was highest prior to commencing study treatment and after 1 mo of study treatment with a significant decrease noted in both treatment groups over the course of treatment (deferasirox −27 nmol/L, DFO −12 nmol/L, p<.001 for average decline, p=.34 for difference in rate of decline). This parallels significant declines in both groups in LIC (mean 2.0 mg/g dry/yr, p=.01) and ferritin (mean 444 ng/mL/yr, p<.001). In cross-sectional analysis, MDA was positively correlated with ferritin (r2=.21, p=.06) and LIC (r2=.42, p<.001) and negatively correlated with Vitamin C (r2= −.37, p<.001) and α-tocopherol (r2= −.38, p<.001). Mean hsCRP (mg/L) at months 0, 1, 6, and 12 were as follows: deferasirox: 1.4, 2.1, 0.9, 0.6; DFO: 0.8, 1.1, 0.9, 1.2. Mean hsCRP concentration in control subjects was 0.66 mg/L (range 0.2–5.1 mg/L). In contrast with MDA trajectories, hsCRP showed significant decrease only in the group receiving deferasirox (deferasirox −1.0 mg/L, DFO +0.37 mg/L, p<.001). Conclusions: These results demonstrated a correlation of iron burden with elevated biomarkers of oxidant-stress and inflammation. Iron chelation therapy with DFO or with deferasirox showed equal effectiveness in decreasing MDA. In contrast, only therapy with deferasirox produced a significant decline in hsCRP.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,002 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 source (Gemma direct ou Codex distillé), 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 ».