1. Aldehyde oxidase (AO enzymes)-mediated oxidation predominantly occurs at a carbon atom adjacent to the nitrogen on aromatic azaheterocycles. In the current report, we identified that AO enzymes oxidation took place at both the C-2 and C-4 positions of the methylquinoline moiety of Compound A based on data from mass spectrometric analysis, AO enzymes “litmus” test, and comparison with authentic standards.
2. To assess the potential for inadequate coverage for these two AO enzyme-mediated metabolites in nonclinical safety studies, given concerns due to differences in AO enzymes expression between preclinical species and humans, the human circulating levels of the two AO enzyme-mediated metabolites were predicted prospectively using in vitro and in vivo models. Both formation clearance and elimination clearance of the two metabolites were predicted based on in vitro to in vivo correlation and comparison with in vivo data from rats.
3. The result showed that the 4-OH metabolite of Compound A would account for less than 3% of the total drug-related exposure in human plasma, while the exposure to the 2-oxo metabolite would be relatively high (~70%).
4. The predicted human exposure levels for the two metabolites are in similar ranges as those observed in monkeys. These data taken together support the advancement to clinical development of Compound A. 相似文献
Potential associations of vegetarian diet patterns with fasting insulin (FI) and insulin sensitivity remain unclear. We aimed to investigate whether vegetarian diets were associated with FI and insulin sensitivity in a cross-sectional study in Chinese vegetarians and matched omnivores and then to test whether it is independent of body mass index (BMI).
Methods and results
This study included 279 vegetarians (73 vegans, 206 lacto-ovo-vegetarians) and 279 age- and sex-matched omnivores. Fasting blood glucose (FG) and FI concentrations were measured, and β-cell function (HOMA-β) and insulin resistance index (HOMA-IR) were used to evaluate insulin sensitivity. All blood glucose and insulin sensitivity indices were naturally log-transformed, and multiple-linear regression was used to determine the association between vegetarian diet patterns and insulin sensitivity after adjusting for confounders including BMI, visceral fat area, physical activity, sedentary time, income, alcohol consumption, and daily dietary intakes of macronutrients. Compared to omnivores, both vegan diet [β = ?0.25, 95% CI: (?0.38, ?0.14)] and lacto-ovo-vegetarian diet [β = ?0.10, 95% CI: (?0.18, ?0.01)] were negatively associated with HOMA-IR after adjusting for BMI. Vegan diet remained negatively associated with FI [β = ?0.16, 95% CI: (?0.30, ?0.01)] and HOMA-IR [β = ?0.17, 95% CI: (?0.32, ?0.03)] after adjusting for all confounders.
Conclusion
Vegetarian diet, especially vegan diet, is negatively associated with FI and IR, independent of BMI. 相似文献
Randomized controlled trials, being published in English and investigating the associations of at least 4 weeks intervention of citrus and/or its extracts on weight loss among adults, were searched from PubMed, Web of Science, Scopus, and Cochrane by June 2019 to conduct a meta‐analysis. Thirteen articles, including 921 participants, were selected and evaluated by modified Jadad scale. Pooled results by the random‐effects model showed that citrus and/or its extracts administration significantly reduced 1.280 kg body weight (95% CI: ?1.818 to ?0.741, p = 0.000, I2 = 81.4%), 0.322 kg/m2 BMI (95% CI: ?0.599 to ?0.046, p = 0.022, I2 = 87.0%), 2.185 cm WC (95% CI: ?3.804 to ?0.566, p = 0.008, I2 = 98.3%), and 2.137 cm HC (95% CI: ?3.775 to ?0.500, p = 0.011, I2 = 96.2%), respectively, but no significantly decreased effects on WHR and body fat were observed. Subgroup analysis deduced the different effects of study location, intervention duration on body weight associated indices. No publication bias was observed. Our meta‐analysis supported the beneficial effects of citrus and/or its extracts supplement on body weight control, and future well‐designed studies are required to firmly establish the clinical efficacy of citrus and/or its extracts intervention on body weight. 相似文献