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排序方式: 共有235条查询结果,搜索用时 62 毫秒
121.
Walker DK Beaumont KC Comby P Evans KM Gedge JI Halliday RC Roffey SJ Wright PA 《Xenobiotica; the fate of foreign compounds in biological systems》2001,31(8-9):651-664
1. UK-343,664 is a novel potent and selective PDE5 inhibitor. Plasma clearances in the male and female rat were high (120 and 54 ml min(-1) kg(-1)), giving rise to short elimination half-lives (0.2 and 0.3h respectively). Lower clearance in dog (14 ml min(-1) kg(-1)) was the primary factor resulting in a longer elimination half-life (3.7 h). The higher clearance in rat than dog was in agreement with in vitro metabolism rates in hepatic microsomes. 2. The volume of distribution was lower in rat (1.3-2.11 kg(-1)) compared with dog (4.61 kg(-1)) probably due to increased plasma protein binding in rat (96 versus 81% in dog). 3. Oral bioavailabilities were 2, 12 and 70% in the male and female rat and dog respectively. Tmax < or = 0.5 h in all animals. 4. In multiple oral dose studies, increased systemic exposure was seen with increasing dose up to doses of 200 mg kg(-1) in rat and 150 mg kg(-1) in dog. A marked super-proportional increase in the male rat indicated a capacity-limited clearance at high doses. 5. At the maximal dose of 200 mg kg(-1) in the female rat, no clinical signs were observed after 14 days of treatment. Only minimal signs were recorded in the male rat and dog at the highest dose levels investigated. 6. After single oral or intravenous doses of [14C]-UK-343,664, the majority of radioactivity was excreted in the faeces of both species. 7. UK-343,664 was extensively metabolized in both rat and dog. The major primary pathways in dog involved piperazine N-deethylation and loss of a two carbon fragment from the piperazine ring (N,N'-de-ethylation). More extensive metabolism in the rat included additional notable metalbolites arising from hydroxylation and lactamization of the piperazine ring, which were only minor metabolites in the dog. 相似文献
122.
Computerized radiologic reporting with voice data-entry 总被引:2,自引:0,他引:2
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126.
目的 探讨肿瘤坏死因子 -α(TNF -α)与 2型糖尿病胰岛素的关系。方法 用homa -R法选取有胰岛素抵抗 (IR组 )和无胰岛素抵抗 (NIR组 )的 2型糖尿病患者各 2 0例。另以 2 0名年龄及体重指数相匹配的人群的作为对照组 ,分别检测其空腹血糖、胰岛素 ,计算Homa -R值 ,用ELISA法检测TNF -α。结果 IR组的TNF -α与NIR组及对照组相比较明显增高 ,有统计学意义(P <0 0 5 ) ,IR组的空腹胰岛素水平及胰岛素抵抗指标Homa -R也显著高于NIR组及对照组 (P值为 <0 0 1) ,而三组间年龄、BMI、血脂、脂蛋白、血压均无显著性差异 (P >0 0 5 )。结论 血浆TNF -α水平与胰岛素抵抗呈密切相关 ,在 2型DM中有重要病理意义 ,可作为评估有无胰岛素抵抗的一项重要参考指标 相似文献
127.
S J Roffey S Cole P Comby D Gibson S G Jezequel A N R Nedderman D A Smith D K Walker N Wood 《Drug metabolism and disposition》2003,31(6):731-741
Voriconazole is a new triazole antifungal agent with potent, wide-spectrum activity. Its pharmacokinetics and metabolism have been studied in mouse, rat, rabbit, dog, guinea pig, and humans after single and multiple administration by both oral and intravenous routes. Absorption of voriconazole is essentially complete in all species. The elimination of voriconazole is characterized by non-linear pharmacokinetics in all species. Consequently, pharmacokinetic parameters are dependent upon dose, and a superproportional increase in area under the curve is seen with increasing dose in rat and dog toxicology studies. Following multiple administration, there is a decrease in systemic exposure. This is most pronounced in mouse and rat, less so in dog, and not observed in guinea pig or rabbit. Repeat-dose toxicology studies in mouse, rat, and dog have demonstrated that induction of cytochrome P450 by voriconazole (autoinduction of metabolism) is responsible for the decreased exposure in these species. Autoinduction of metabolism is not observed in humans, and plasma steady-state concentrations remain constant with time. Voriconazole is extensively metabolized in all species. The major pathways in humans involve fluoropyrimidine N-oxidation, fluoropyrimidine hydroxylation, and methyl hydroxylation. Also, N-oxidation facilitates cleavage of the molecule, resulting in loss of the fluoropyrimidine moiety and subsequent conjugation with glucuronic acid. Major pathways are represented in animal species. The major circulating metabolite in rat, dog, and human is the N-oxide of voriconazole. It is not thought to contribute to efficacy since it is at least 100-fold less potent than voriconazole against fungal pathogens in vitro. 相似文献
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129.
Sivaraman L; Stephens LC; Markaverich BM; Clark JA; Krnacik S; Conneely OM; O'Malley BW; Medina D 《Carcinogenesis》1998,19(9):1573-1581
One of the most consistent results in the epidemiology of human breast
cancer is the inverse relationship of risk and early full-term parity. The
goal of this study was to investigate the molecular mechanisms through
which early full-term pregnancy protects the breast from cancer
development. We used Wistar-Furth (WF) rats as our experimental system and
mimicked pregnancy using estrogen and progesterone (E/P). Sexually mature
female rats were treated with steroid hormones for 21 days and after 28
days of gland involution, the rats were administered MNU. Rats that
received a high dose of 20 microg E and 20 mg P exhibited an 82% reduction
in the incidence of mammary adenocarcinomas as compared to the rats
receiving only blank pellets. Decreasing doses of E/P were partially
protective suggesting that complete differentiation of the gland was not
required for refractoriness. We measured the RNA expression levels of
several target genes involved in the regulation of mammary cell
proliferation and/or differentiation including estrogen receptor (ER) and
progesterone receptor (PR), cyclins D1 and D2, the cell cycle inhibitors
p16, p21 and p27, and the tumor suppressor p53. At the time of MNU
treatment we found no significant differences in the expression of these
genes, with the possible exception of p21, indicating that hormone
treatment did not result in constitutive changes in expression levels. The
numbers of apoptotic cells were low and comparable in the hormone exposed
and age-matched virgin gland (AMV) at the time of carcinogen challenge and
remained low for 8 days after MNU treatment. The number of BrdU-labeled
cells at the time of carcinogen challenge were also low in both the AMV
(1.8%) and hormone exposed (0.8%) animals. In contrast, cell proliferation
in the AMV (5.7%) was significantly different from both the parous
involuted (1.2%) and the E/P-treated involuted (1.5%) animals 8 days after
MNU treatment. We interpret these data to indicate that hormone treatment
results in mammary epithelial cells that have persistent alterations in
intracellular pathways governing proliferation responses to carcinogens.
相似文献
130.
Austin CB; Young JW; Park HJ; Needleman BW; Handwerger BS; Rosenbaum RC 《Radiology》1987,164(3):787-789
Adult T-cell leukemia/lymphoma is a relatively uncommon disease, most often found in Japan, the Caribbean, the southeastern United States, and South America. To date there have been few reports of its skeletal manifestations. A case is reported in a 44-year-old man in which a short history of swelling of the hands and feet and painful motion in the fingers was followed by the rapid development of severe acroosteolysis. 相似文献