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André H. Eriksson Manthena V.S. Varma Everett J. Perkins Cheryl L. Zimmerman 《Journal of pharmaceutical sciences》2010,99(3):1574-1581
LY354740 is a potent mGlu2/3 agonist with a limited oral bioavailability. Its alanyl prodrug, LY544344, showed high affinity to the intestinal peptide transporter PEPT1, and improved the oral bioavailability of LY354740 in various animal models. The aim of the present study was to investigate the mechanism of in vivo absorption of the dipeptidic prodrug LY544344. The permeabilities of LY544344 and LY354740 were examined in the rat in situ single‐pass intestinal perfusion model. The intestinal absorptive flux of LY354740 was shown to be very low in comparison with LY544344. The absorptive flux of LY544344 could best be described by a Michaelis–Menten process in parallel with a linear process. The estimated parameters were: Jmax = 26.7 × 10?5 µmol/(cm2‐s), Km = 2.6 mM. The absorptive permeability of LY544344 was reduced to approximately 5% of control in the presence of excess Gly‐Sar, a known PEPT1 substrate. Intracellular accumulation of LY354740 and LY544344, estimated postperfusion, showed high levels of LY354740 over LY544344 at all perfusate concentrations studied. However, there was a decline in the intracellular ratio of LY354740 to LY544344 at higher concentrations, suggesting that the metabolic activation to release LY354740 is saturable. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1574–1581, 2010 相似文献
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Over a period of years the ventilation system of a community hospital progressively deteriorated until it no longer met regulatory guidelines. The hospital, a publicly funded military facility, requested funding to repair the ventilation system, but funds were not forthcoming because of budget austerity. When an increase in infections was documented, high-risk operations were curtailed and funding was expedited. With the new improved ventilation system the operating rooms once again met regulatory guidelines and infections returned to baseline rates. Throughout the period infections remained below recognized national levels. 相似文献
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Skin cancer is the most common malignancy in the United States accounting for more than 840,000 cases and 9,400 deaths annually. It is estimated that 90% of non-melanoma skin cancers and much of melanoma incidence can be attributed to sun exposure. The evidence suggests that regular use of sunscreen (Sun Protective Factor (SPF) of 15 or higher), wearing protective, tightly woven clothing and wide brimmed hats, and avoiding sun exposure when the ultraviolet rays are strongest (between 11:00 a.m. and 3:00 p.m.) can dramatically reduce the risk of skin cancer. Interventions to promote sun-protection behaviors that target children and adults are necessary to reduce the growing incidence rate of skin cancer in the United States.MA during the time of this research 相似文献
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E E Vokes A P Lyss J E Herndon B Cooper M C Perry V Vinciguerra K Mason-Coughlin M R Green 《Annals of oncology》1992,3(9):727-732
This randomized phase II study was designed to evaluate the activity of intravenous 6-thioguanine (6-TG) as a single agent and the combination of cisplatin and 5-fluorouracil (5-Fu) modulated by oral leucovorin (PFL) in patients with advanced non-small cell lung cancer (NSCLC). Eligible patients had measurable or evaluable stage III B or IV NSCLC, had no received prior chemotherapy and had a performance status of 0-2. Patients were randomized to treatment with intravenous 6-TG at 55 mg/m2 administered over 30 minutes for 5 consecutive days and repeated every 35 days, or PFL chemotherapy with cisplatin 100 mg/m2 on day 1, 5-FU 800 mg/m2/day as a continuous intravenous infusion over 5 days and oral leucovorin administered at 100 mg every 4 hours during the entire duration of the cisplatin and 5-FU infusions. PFL was repeated every three weeks. Ninety-five eligible patients were randomized, 46 to 6-TG and 49 to PFL. Response rates were 4% for 6-TG (95% confidence interval 0.5%-14.8%, 1 partial, and 1 complete response) and 29% (16.6%-43.3%) for PFL (all partial). The median time to treatment failure was 2 and 4 months, respectively, and the median survival times were 6 and 10 months, respectively. Toxicities with 6-TG were, generally, mild to moderate but severe or life-threatening granulocytopenia was observed in 21% of patients. With PFL, mucositis was dose-limiting, and 78% of patients had severe or life-threatening mucositis. This led to dose reduction of 5-FU and leucovorin during subsequent cycles or treatment termination in 82% of patients.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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K P Cantor A Blair G Everett S VanLier L Burmeister F R Dick R W Gibson L Schuman 《American journal of public health》1988,78(5):570-571
Data from a population-based case-control study of incident leukemia and non-Hodgkin's lymphoma among adult men in Iowa and Minnesota were used to evaluate risk associated with hair dye use. The relative risk for ever using hair dyes was 1.8 (95% confidence interval [CI] = 1.1-2.7) among leukemia patients, and 2.0 (CI = 1.3-3.0) among cases with non-Hodgkin's lymphoma. There was a suggestion of increased risk with extent of hair dye use. Given the widespread use of hair coloring products, these observations deserve more detailed evaluation in populations where the exposure is relatively common. 相似文献