Crohn's disease is a chronic inflammatory bowel disease characterized by inflammation of both the small and large intestines. Methotrexate (MTX), a classical dihydrofolate reductase (DHFR) inhibitor, has been used as a therapeutic agent in the treatment of patients with Crohn's disease in recent years. We sought to develop antifolates similar in structure to MTX that would be effective in reducing inflammation in a mouse disease model of colitis. Four classical DHFR inhibitors encompassing ester bridges in the central parts of the molecules were synthesized. These antifolates were efficient inhibitors of the DHFR enzyme derived from rat. They were also tested in vitro for their ability to inhibit induced proliferation of lymphocytes from mouse spleen. Inhibition of cell proliferation was achieved only in the micromolar range, whereas MTX was effective at low nanomolar concentrations. One of the DHFR inhibitors (1), with an IC(50) value for rlDHFR approximately 8 times higher than that of methotrexate, was selected for in vivo experiments in an experimental colitis model in mice. This compound demonstrated a clear antiinflammatory effect after topical administration, comparable to the effect achieved with the glucocorticoid budesonide. Three parameters were evaluated in this model: myeloperoxidase activity, colon weight, and inflammation scoring. A favorable in vivo effect of compound 1 (15 mg/(kg.day)) was observed in all three inflammatory parameters. However, the results cannot be explained fully by DHFR inhibition or by inhibition of lymphocyte cell proliferation, suggesting that other yet unidentified mechanisms enable reduction of inflammation in the colitis model. The mechanism of action of methotrexate analogues encompassing a bridging ester group is not well understood in vivo but seems to lend itself well to further development of similar compounds.
The Metro Vancouver region of southwestern British Columbia, Canada, is exposed to significant earthquake risk. Earthquake hazard has yet to be mapped to an effective scale in Metro Vancouver and so it is critical to generate comprehensive seismic hazard maps for the region. The Metro Vancouver Seismic Microzonation Project is tasked with the assessment and mapping of earthquake shaking hazard and liquefaction and landslide susceptibility hazards at a 1:25,000 scale. The detailed hazard information and data collected as part of this project, like most traditional hazard studies, is highly technical and unsuitable for the needs of intermediate users (e.g. regional planners and emergency managers). In this study we evaluate metrics and delivery format used to communicate seismic hazard information to intermediate users so it may be applied effectively in regional planning and emergency management strategies. Our methodology to evaluate effective communication of the seismic hazard products (GIS shapefiles and maps) involves a stakeholder workshop and online questionnaire survey. Existing microzonation maps for other regions in Canada are referenced throughout this consultation process and feedback is used as a benchmark to develop upon. A sequence of iterative discussion and consultation is necessary to determine the comprehensible metrics, desired interaction level and stylistic preferences to be used in final mapped products. Responses reiterate that the use of technical metrics is not effective in communicating hazard to intermediate users; separate map products are required for primary and intermediate users. Additionally, participants express importance of visual simplicity, open access to background data and interactive capabilities (e.g. GIS shapefiles). Feedback indicates that a lack of standardization leads to misinterpretation when comparing seismic microzonation maps of different regions; thus, results of this consultation process are integrated into a set of preliminary recommendations for producing seismic microzonation maps in a move towards standardization.
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