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author:("araic, Amparo")
1.  Role of nuclear factor-κB and heme oxygenase-1 in the mechanism of action of an anti-inflammatory chalcone derivative in RAW 264.7 cells 
British Journal of Pharmacology  2004;142(7):1191-1199.
The synthetic chalcone 3′,4′,5′,3,4,5-hexamethoxy-chalcone (CH) is an anti-inflammatory compound able to reduce nitric oxide (NO) production by inhibition of inducible NO synthase protein synthesis. In this work, we have studied the mechanisms of action of this compound.CH (10–30 μM) prevents the overproduction of NO in RAW 264.7 macrophages stimulated with lipopolysaccharide (1 μg ml−1) due to the inhibition of nuclear factor κB (NF-κB) activation.We have shown that treatment of cells with CH results in diminished degradation of the NF-κB–IκB complex leading to inhibition of NF-κB translocation into the nucleus, DNA binding and transcriptional activity.We also demonstrate the ability of this compound to activate NfE2-related factor (Nrf2) and induce heme oxygenase-1 (HO-1).Our results indicate that CH determines a rapid but nontoxic increase of intracellular oxidative species, which could be responsible for Nrf2 activation and HO-1 induction by this chalcone derivative. This novel anti-inflammatory agent simultaneously induces a cytoprotective response (HO-1) and downregulates an inflammatory pathway (NF-κB) with a mechanism of action different from antioxidant chalcones.
PMCID: PMC1575177  PMID: 15249426
3′,4′,5′,3,4,5-Hexamethoxy-chalcone; nuclear factor-κB; heme oxygenase; NfE2-related factor; nitric oxide
2.  Pharmacokinetics of the time-dependent elimination of all-trans-retinoic acid in rats 
AAPS PharmSci  2004;6(1):1-9.
The time-dependent elimination kinetics of all-transretinoic acid (ATRA) has been associated with autoinduction of its metabolism and has led to the hypothesis that rapid development of acquired clinical resistance to ATRA may be prevented by coadministration of metabolic inhibitors. This study in rats was performed to investigate the pharmacokinetics and onset of timedependent elimination of ATRA, with the purpose of establishing an animal model suitable for in vivo preclinical studies of compounds capable of inhibiting ATRA metabolism. After the intravenous (IV) bolus administration of single doses of ATRA (1.60 mg kg−1 and 0.40 mg kg−1), the plasma concentration-time curves showed an accelerated decline at 180 minutes after dosing. The plasma clearance (Cl) of ATRA, determined after IV administration of a second dose (1.60 mg kg−1), at 180 minutes was greater than Cl after a single dose, thus indicating the existence of a time-dependent elimination process detectable 180 minutes after administration of the first dose. Such time-dependent elimination was confirmed by means of an IV constant-rate infusion of 0.48 mg h−1 kg−1 of ATRA during 10 hours. Peak plasma ATRA concentration was achieved at 180 minutes, after which the plasma concentration decreased to reach a much lower apparent steady-state drug concentration at 420 minutes. The area under the plasma concentration-time curve (AUC) obtained after oral administration of a second ATRA dose (1.60 mg kg−1) was ∼8% of the AUC obtained after a single oral dose; consistent with a time-dependent increase in the elimination of ATRA, as was observed after IV administration.
PMCID: PMC2750936  PMID: 18465253
all-trans-retinoic acid; time-dependent elimination; pharmacokinetic model; rat; intravenous administration; oral administration

Results 1-2 (2)