CYP2D6 genotype and concomitant potent CYP2D6 inhibitors are highly associated with endoxifen plasma concentration and may have an impact on the response to tamoxifen therapy. These iterative approaches may be valuable in the study of other complex genotype-phenotype relationships.

Background Accurate assessment of CYP2D6 phenotypes from genotype is inadequate in patients taking CYP2D6 substrate together with CYP2D6 inhibitors. We propose a novel CYP2D6 scoring systems that incorporates the impact of concomitant medications with the genotype in calculating the CYP2D6 activity score. Method Training (n=159) and validation (n=81) data sets were obtained from a prospective cohort tamoxifen pharmacogenetics registry. Two inhibitor factors were defined: one genotype-independent and one genotype-based. Three CYP2D6 gene score systems, and their combination with the inhibitor factors, were compared. These three scores were based on Zineh, Zanger, and Gaedigk's approaches. Endoxifen/NDM-Tam plasma ratio was used as the phenotype. Results The overall performance of the three gene score systems without consideration of CYP2D6 inhibiting medications in predicting CYP2D6 phenotype was poor both in the training (R2=0.24, 0.22 and 0.18) and the validation set, (R2=0.30, 0.24 and 0.15). Once the CYP2D6 genotype-independent inhibitor factor was integrated into the score calculation, the R2 values in the training and validation data sets are nearly twice as high as the genotype only scoring model: (0.44, 0.43, 0.38) and (0.53, 0.50, 0.41) respectively. Conclusion The integration of the inhibitory effect of concomitant medications with the CYP2D6 genotype into the composite CYP2D6 Activity Score doubled our ability to predict the CYP2D6 phenotype. However, endoxifen phenotypes still varied substantially, even with incorporation of CYD2D6 genotype and inhibiting factors, suggesting that other, yet unidentified, factors must be involved in tamoxifen activation.

Antidepressant maintenance trials have a high rate of success, indicating a benefit of continuing drug treatment after initial response to an antidepressant. This benefit appears to result mainly from a decreased rate of recurrent depression rather than from an effect of drug withdrawal in the placebo groups.

The HFD caused neuronal loss in the myenteric plexus, and nitrergic neurons were more resilient. The changes were more pronounced in the distal colon after 17 weeks.

ABSTRACT:Dextromethorphan urinary metabolic ratio is widely used to determine the CYP2D6 phenotype, but its utility to reflect subtle differences in catalytic activity is unclear. We evaluated the capability of dextromethorphan urinary metabolic ratio to predict dextromethorphan oral clearance as a measure of CYP2D6 activity. Data from 10 healthy extensive metabolizers of CYP2D6 were given 30 mg of dextromethorphan hydrobromide orally on two occasions. Blood and urine samples were collected for 72 h. Dextromethorphan and dextrorphan were determined in urine by high-performance liquid chromatography with fluorescence detection and in serum by liquid chromatography-mass spectrometry. The urinary metabolic ratio was very weakly correlated with dextromethorphan oral clearance (r ‫؍‬ 0.24; p ‫؍‬ 0.04). In contrast, the dextromethorphan oral clearance was highly correlated with the dextromethorphan to dextrorphan area under the concentration-time curve ratio (r ‫؍‬ 0.84; p ‫؍‬ 0.005) and the 3-h (r ‫؍‬ 0.60; p ‫؍‬ 0.003), 4-h (r ‫؍‬ 0.72, p < 0.001), 6-h (r ‫؍‬ 0.67; p < 0.001), and 8-h (r ‫؍‬ 0.74; p < 0.001) dextromethorphan to dextrorphan serum ratios. Assuming an effect size of 30%, the number of volunteers required for crossover and cross-sectional studies using the urinary metabolic ratio as the CYP2D6 index was calculated to be 56 and 524, respectively, whereas 14 and 60 subjects are needed if oral clearance is used. Considering the required sample size and the low correlation with oral clearance, urinary metabolic ratio is not recommended as the primary outcome variable in studies requiring the detection of modest changes in CYP2D6 activity.

This study analyzes 131 chagasic patients from different endemic areas that came to the Chagas' disease laboratory at the Maringa State University. The subjects discovered they were infected principally because they presented symptoms (58%) or donated blood (29.4%). During etiologic treatment for Trypanosoma cruzi, 45.2% of benznidazole users complained of side effects. Based on these data, the ACHEI program (Chagas' Disease Awareness through Comprehensive Education) was developed, which is a multiprofessional/interdisciplinary extension project. Monthly meetings are held that are divided into two parts: The first half of the meetings provide specific information, including the distribution of brochures explaining Chagas' disease transmission, symptoms and treatment. The second half of the meetings focuses on psycho-social assistance and includes topics such as self-esteem and personal responsibility. The meetings provide an environment for chagasic patients to share their concerns regarding post-diagnosis quality of life, fear, anxiety, stigma and family and social group relationships. In short, the meetings offer an opportunity for patients to reflect on their situation and to discover ways to deal with their disease.

No abstract

The gastrointestinal tract is extremely sensitive to ischemia and reperfusion (I/R). Studies have reported that resveratrol (RSV) is able to combat damage caused by intestinal I/R. Because of its effectiveness in increasing the permanence and bioavailability of resveratrol in the intestinal epithelium, we investigated whether the effect of resveratrol-loaded in poly(anhydride) nanoparticles reduce oxidative stress and promote myenteric neuroprotection in the ileum of rats subjected to I/R. Physicochemical evaluations were performed on nanoparticles. The animals were divided into nine groups (n = 6/group) and treated every 48 h. Treatments with resveratrol (7 mg/kg of body weight) were applied 5 days before surgery and continued for 7 days after surgery (reperfusion period). The superior mesenteric artery was occluded to cause I/R injury. Oxidative stress, myeloperoxidase, nitrite, aspartate aminotransferase, alanine aminotransferase, immunolabeling of myenteric neurons and glial cells, and gastrointestinal transit was evaluated. Both nanoparticle formulations presented negative charge with homogeneous distribution, and the payload, showed an encapsulation efficiency of 60%. Resveratrol administered in free form prevented alterations that were caused by I/R. The results of the groups treated with RSV-loaded nanoparticles presented similar results to the group treated with free resveratrol. Treatment with empty nanoparticles showed that poly(anhydride) is not an ideal nanocarrier for application in in vivo models of intestinal I/R injury, because of hepatotoxicity that may be caused by epithelial barrier dysfunction that triggers the translocation of nanoparticles.