Lead Chemical (Japan)

Resistance to azacitidine is a major issue in the treatments of myelodysplastic syndrome and acute myeloid leukemia, and previous studies suggest that changes in drug metabolism are involved in the resistance. Therefore, drugs with mechanisms resistant or alternative to such metabolic changes have been desired for the treatment of resistant disease. We generated azacitidine‐resistant cells derived from SKM‐1 and MOLM‐13 leukemia cell lines in vitro, analyzed the mechanisms, and examined the impact on the efficacy of other antimetabolic drugs. It appeared that the cell growth‐inhibitory effect of azacitidine, expression levels of uridine–cytidine kinase 2, and the concentrations of azacitidine triphosphate were remarkably decreased in the resistant cells compared with those in parent cells. These results were consistent with previous observations that azacitidine resistance is derived from metabolic changes. Cross‐resistance of greater than 10‐fold (shift in IC50 value) was observed in azacitidine‐resistant cells for decitabine and for cytarabine, but not for gemcitabine or the inosine‐5′‐monophosphate dehydrogenase (IMPDH) inhibitors FF‐10501 and mycophenolate mofetil (cross‐resistance to 5‐fluorouracil was cell line dependent). The IMPDH inhibitors maintained their cell growth‐inhibitory activities in the azacitidine‐resistant cell lines, in which the levels of adenine phosphoribosyltransferase (which converts FF‐10501 to its active form, FF‐10501 ribosylmonophosphate [FF‐10501RMP]), FF‐10501RMP, and the target enzyme, IMPDH, were equivalent to those in the parent cell lines. These results suggest that an IMPDH inhibitor such as FF‐10501 could be an alternative therapeutic treatment for leukemia patients with acquired resistance to azacitidine.

High serum concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for coronary heart disease. The efficacy of pantethine treatment on cardiovascular risk markers was investigated in a randomized, triple-blinded, placebo-controlled study, in a low to moderate cardiovascular disease (CVD) risk North American population eligible for statin therapy, using the National Cholesterol Education Program (NCEP) guidelines. A total of 32 subjects were randomized to pantethine (600 mg/day from weeks 1 to 8 and 900 mg/day from weeks 9 to16) or placebo. Compared with placebo, the participants on pantethine showed a significant decrease in total cholesterol at 16 weeks (P=0.040) and LDL-C at 8 and 16 weeks (P=0.020 and P=0.006, respectively), and decreasing trends in non-high-density lipoprotein cholesterol at week 8 and week 12 (P=0.102 and P=0.145, respectively) that reached significance by week 16 (P=0.042). An 11% decrease in LDL-C from baseline was seen in participants on pantethine, at weeks 4, 8, 12, and 16, while participants on placebo showed a 3% increase at week 16. This decrease was significant between groups at weeks 8 (P=0.027) and 16 (P=0.010). The homocysteine levels for both groups did not change significantly from baseline to week 16. Coenzyme Q10 significantly increased from baseline to week 4 and remained elevated until week 16, in both the pantethine and placebo groups. After 16 weeks, the participants on placebo did not show significant improvement in any CVD risk end points. This study confirms that pantethine lowers cardiovascular risk markers in low to moderate CVD risk participants eligible for statins according to NCEP guidelines.

This study proposes the method of quantitative analysis on discussion in workshop for proper operation of discussion. It also shows the characteristics and the roles of discussion in workshop in planning process. There is a perception gap about policy issues of the region between planners who set up a workshop, and participants. The objectives of this study are to make clear its gap quantitatively, and to establish a management solution for minimizing them. This study provides quantitative analysis of a content of discussion to make participant's concern clear. The efficacy of this method is also discussed.