With the aim of applying mast cell-stabilizing agents as antiulcer agents, N-(1H-tetrazol-5-yl)-2-anilino-5-pyrimidinecarboxamides were synthesized, and initially evaluated pharmacologically for activity in the rat passive cutaneous anaphylaxis test by oral administration. The most active compound 6 was proved to inhibit potently the release of histamine from passively sensitized rat peritoneal mast cells in vitro. When compared with other mast cell-stabilizing agents and an antiulcer agent, compound 6 was found to show excellent gastric mucosal protection and gastric antisecretion activities. Furthermore, compound 6 revealed good activity against acidified aspirin ulcer in rats and water-immersion stress ulcer in rats.
Currently, the only available evidence for the efficacy of once-weekly 17.5 mg risedronate in preventing vertebral fractures was obtained in a 48-week study in Japan. We performed a 156-week prospective, longitudinal, observational study to determine the efficacy of the 17.5 mg risedronate in preventing vertebral fractures. We included Japanese patients with established osteoporosis who were older than 50 years and had radiographically confirmed vertebral fractures. The primary endpoint was the incidence of vertebral fractures every 24 weeks, with the final interval spanning 36 weeks. We also calculated the change in bone mineral density of the lumbar spine (L BMD) and urinary N-telopeptide of type I collagen (u-NTX), and assessed the incidence of adverse drug reactions and the drug adherence rate. Data from 241 patients were available for analysis of vertebral fracture prevention. The incidence rate of vertebral fractures decreased in a time-dependent manner (P = 0.0006; Poisson regression analysis). The risk ratio (fracture incidence per 100 person-years in the final 36 weeks versus that in the first 24 weeks) was 0.21 (95 % confidence interval 0.08-0.55). Compared to baseline values, L BMD increased by 6.41 % at 156 weeks, while u-NTX decreased by 36 % at 24 weeks and was maintained thereafter (P < 0.0001). The incidence rate of adverse drug reactions was 9.18 %. Drug adherence rates assessed every 4 weeks were over 90 %. Our results indicate that 156 weeks of treatment with once-weekly 17.5 mg risedronate effectively reduced the risk of vertebral fracture in Japanese patients with established osteoporosis older than 50 years.
The effect of the Ca(2+)-channel antagonist nicardipine on the basal tone of six segments (duodenum, jejunum, ileum, proximal colon, distal colon and rectum) of the guinea-pig intestine has been investigated in muscle preparations. Nicardipine reduced the basal tone of the proximal and distal colon but not of the duodenum, jejunum, ileum and rectum. Similarly, when each segment was incubated in Ca(2+)-free medium, the basal tone of the proximal and distal colon, but not that of the other four segments, was reduced. The reduced basal tone recovered after cumulative addition of Ca2+ in both colon preparations. The basal tone of the distal colon was partly reduced by tetrodotoxin, atropine and clonidine. Conversely, L-type Ca(2+)-channel antagonists (Cd2+, verapamil and nicardipine), but not the T-type Ca(2+)-channel antagonist Ni2+, completely reduced the basal tone of the distal colon. These results indicate that in the regulation of basal tone there are additional regional differences in the effect of Ca2+ influx into the cells from the extracellular fluid which might involve L-type-like Ca2+ channels and might partly be because of neuronal factors.
A prospective observational study to test the effects of risedronate 17.5 mg/week treatment on quality of life (QOL) of 1,363 Japanese female patients with osteoporosis showed QOL improvement after 12 weeks of administration. Comorbid factors such as ischemic heart disease, hip osteoarthritis, and higher values of FRAX blunted the effects of QOL of the treatment. Few studies have investigated the effect of osteoporosis treatment on QOL in relationship to comorbid factors other than osteoporosis and fracture. Efficacy was determined by changes over time in EQ-5D at baseline, at 12 and 24 weeks, and at the final assessment. Factors affecting changes in EQ-5D were evaluated with a multivariate analysis. Safety was determined by assessing the incident rate of adverse events. The improvement of EQ-5D compared to baseline was observed as significant after 12 weeks of treatment (p < 0.001). The greatest improvement was observed in the dimension of "pain/discomfort" by the multivariate analysis (p < 0.001). Factors affecting QOL improvement were FRAX value without BMD, age, glucocorticoid use, ischemic heart disease, hip osteoarthritis, and pain. The incidence rate of drug-related adverse events was 4.72 % (95 % confidence interval 3.63-6.02 %). Risedronate at 17.5 mg/week improved the QOL in patients with osteoporosis among Japanese women, and comorbidity factors decreased the effects.
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