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
Polybrominated diphenyl ethers (PBDEs) are major brominated flame retardant (BFR) chemicals with endocrine-disrupting properties. One small-scale study on humans has suggested that prenatal exposure to PBDEs is adversely related to anogenital distance (AGD) a sensitive marker for prenatal androgen exposure. The aim of the present study was to examine the associations between prenatal exposure to PBDEs and AGD among boys 0–4 years of age in a cohort study.
Methods
In the Shanghai-Minhang Birth Cohort Study (S-MBCS), nine PBDE congeners were measured in cord plasma of 192 male infants. We measured anopenile distance (AGDAP) and anoscrotal distance (AGDAS) at birth, 6 months, 12 months, and 48 months of age. A total of 190 boys with neonatal concentrations of PBDEs (ng/g lipid) who had at-least one AGD measurement were included in our study. Information on potential confounding variables were collected through in-person interviews. Multiple linear regression models and generalized estimating equation (GEE) models were used to evaluate the associations between prenatal PBDEs concentrations and AGD.
Results
Among the nine congeners, BDE-47 had the highest detection rate (83.68%) and the highest median concentration (0.18?ng/g lipid). Boys who had neonatal concentration of BDE-47 or Σ4PBDEs (sum of BDE-47, BDE-99, BDE-100, and BDE-153) in the higher quartile generally had shorter AGDAP and AGDAS than those in the first quartile. Significant inverse associations were found between AGDAS and fourth quartile BDE-47 levels among boys 12 months and 48 months of age (β?=??5.57, 95% confidence interval (CI): ?9.89, ?1.25 for 12 month of age; β?=??4.32, 95% CI: ?8.18, ?0.46 for 48 month of age). Inverse associations were also observed between AGDAS and fourth quartile Σ4PBDEs levels among boys 12 months of age (β?=??5.13, 95% CI: ?9.89, ?1.25). In GEE models, similar patterns of association were also observed between BDE-47 and AGDAS.
Conclusions
Our findings provide preliminary evidence that prenatal exposure to BDE-47 and Σ4PBDEs, even at low environmental levels, may be associated with shorter AGD in boys. This data suggest that prenatal exposure to PBDEs may have adverse effects on male reproductive development. Further studies should be conducted to validate these results. 相似文献
The protozoan pathogen Cryptosporidium is an important cause of diarrhoeal disease, but in many contexts its burden remains uncertain. The Global Waterborne Pathogen model for Cryptosporidium (GloWPa-Crypto) predicts oocyst concentrations in surface water at 0.5 by 0.5° (longitude by latitude) resolution, allowing us to assess the burden specifically associated with the consumption of contaminated surface water at a large scale. In this study, data produced by the GloWPa-Crypto model were used in a quantitative microbial risk assessment (QMRA) for sub-Saharan Africa, one of the regions most severely affected by diarrhoeal disease. We first estimated the number of people consuming surface water in this region and assessed both direct consumption and consumption from a piped (treated) supply. The disease burden was expressed in disability adjusted life years (DALYs). We estimate an annual number of 4.3 × 107 (95% uncertainty interval [UI] 7.4 × 106–5.4 × 107) cases which represent 1.6 × 106 (95% UI 3.2 × 105–2.3 × 106) DALYs. Relative disease burden (DALYs per 100,000 persons) varies widely, ranging between 1.3 (95% UI 0.1–5.7) for Senegal and 1.0 × 103 (95% UI 4.2 × 102–1.4 × 103) for Eswatini. Countries that carry the highest relative disease burden are primarily located in south and south-east sub-Saharan Africa and are characterised by a relatively high HIV/AIDS prevalence. Direct surface water consumption accounts for the vast majority of cases, but the results also point towards the importance of stable drinking water treatment performance. This is, to our knowledge, the first study to utilise modelled data on pathogen concentrations in a large scale QMRA. It demonstrates the potential value of such data in epidemiological research, particularly regarding disease aetiology. 相似文献
Health systems guidance (HSG) documents contain systematically developed statements or recommendations intended to address a health system challenge. The concept of HSG is fairly new and considerable effort has been undertaken to build tools to support the contextualization of recommendations. One example is the Appraisal of Guidelines for REsearch and Evaluation - Health Systems (AGREE-HS), created by international stakeholders and researchers, to assist in the development, reporting and evaluation of HSG. Here, we present the quality appraisal of 85 HSG documents published from 2012 to 2017 using the AGREE-HS. The AGREE-HS consists of five items (Topic, Participants, Methods, Recommendations, and Implementability), which are scored on a 7-point response scale (1=lowest quality; 7=highest quality). Overall, AGREE-HS item scores were highest for the 'Topic' and 'Recommendations' items (means above the mid-point of 4), while the 'Participants', 'Methods', and 'Implementability' items received lower scores. Documents without a specific health focus and those authored by the National Institute for Health and Care Excellence group, achieved higher AGREE-HS overall scores than their comparators. No statistically significant changes in overall scores were observed over time. This is the first time that the AGREE-HS has been applied, providing a current quality status report of HSG and identifying where improvements in HSG development and reporting can be made. 相似文献
A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o.) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents. 相似文献