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排序方式: 共有2187条查询结果,搜索用时 15 毫秒
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2.
Peter Chiba Barbara Tell Walter Jger Elisabeth Richter Manuela Hitzlera Gerhard Ecker 《Archiv der Pharmazie》1997,330(11):343-347
A series of 5-hydroxy and 5-benzyloxy analogs of the antiarrhythmic and multidrug resistance (MDR) modulating drug propafenone was synthesized and the MDR-modulating activity of the compounds was evaluated using a daunomycin efflux assay system. The key step of the synthesis is the selective reduction of the double bond in 1 without cleavage of the benzyl group thus leading to the phenol 3 . Alkylation with epichlorohydrine followed by nucleophilic epoxide ring opening gave the benzylated target compounds 5a–d . Subsequent cleavage of the benzyl group gave the 5-hydroxy analogs 6a–d . Structure activity relationship studies showed, that the 5-hydroxy derivates 6a–d fit the log P/log potency correlation line previously established for a series of propafenone analogs. In contrast, all four 5-benzyloxy analogs 5a–d showed almost identical EC50 values, independent of their log P value. 相似文献
3.
Cytochrome P450 3A4 and P-glycoprotein Activity and Assimilation of Tacrolimus in Transplant Patients with Persistent Diarrhea 总被引:2,自引:0,他引:2
Wim Lemahieu Bart Maes Kristin Verbeke Paul Rutgeerts Karel Geboes Yves Vanrenterghem 《American journal of transplantation》2005,5(6):1383-1391
Renal transplant recipients suffering from persistent diarrhea have been repeatedly reported to have increased tacrolimus (Tac) trough levels. This study aimed to explore this phenomenon in detail in 15 renal transplant recipients with diarrhea, whose immunosuppression consisted of corticosteroids, mofetil mycophenolate and Tac. Both hepatic and intestinal CYP3A4 and PGP activity, important determinants of Tac bioavailability, were assessed, together with global CYP activity and investigations for gastrointestinal infection, function and morphology. Global CYP, CYP3A4, PGP and trough/dose levels of Tac were compared with diarrhea-free controls. In addition, a pharmacokinetic study of Tac was performed in 11 patients affected by diarrhea versus 9 controls. As expected, diarrhea was associated with increased Tac trough levels. An even stronger, significant increase of dose-normalized Tac levels was observed between 90 and 360 min after Tac intake. Time to peak concentration and drug half-life, however, were not altered. In addition, a concomitant decrease (+/-50%) of intestinal PGP activity was noticed in patients with diarrhea. For global CYP, CYP3A4 and hepatic PGP activity no such differences were noted. This pattern was not influenced by the specific cause of diarrhea. These data strongly suggest that persistent diarrhea is associated with an increased oral bioavailability of Tac. 相似文献
4.
Hirofumi Nakanishi Akira Myoui Takahiro Ochi Katsuyuki Aozasa 《Journal of cancer research and clinical oncology》1997,123(6):352-356
Multidrug resistance (MDR) is an important problem in chemotheraphy for neoplastic disease. In humans, MDR is mainly mediated by P-glycoprotein (P-gp), a product of theMDR1 gene, which acts as a transmembrane protein pump and eliminates chemotherapeutic agents from the cells. Expression of P-gp was immunohistochemically studied by using two monoclonal antibodies, JSB-1 and C-219, on paraffin-embedded sections from 55 patients with soft-tissue sarcoma. The histological diagnosis of tumors was malignant fibrous histiocytoma in 24 cases, liposarcoma in 9, synovial sarcoma in 7, malignant neurogenic tumors in 6, leiomyosarcoma in 5, others in 4. The histological grade was determined on the basis of criteria previously proposed by us. Out of 55 cases, 34 (62%) were positive for P-gp expression. There was a significant difference in P-gp expression between high-grade (90%) and intermediate and low-grade tumors (46%) (P<0.005). Tumors expressing P-gp had a less favorable prognosis than P-gp-negative tumors in the high- and intermediate-grade tumors. The current study demonstrated that the estimation of P-gp expression could be used to select appropriate therapeutic modalities.Abbreviations
MDR
multidrug resistance
-
P-gp
P-glyco-protein 相似文献
5.
P-glycoprotein (Pgp) is a plasma membrane protein that was first characterised in multidrug resistant cell lines. The occurrence of Pgp in clinical tumors has been widely studied. Recent investigations have begun to focus on the relationship between Pgp detection in tumors and treatment outcome. In several types of tumors, detection of Pgp correlates with poor response to chemotherapy and shorter survival. P-glycoprotein overexpression often occurs upon relapse from chemotherapy but may also occur at the time of diagnosis. Studies of experimental rat liver carcinogenesis have shown that Pgp expression increases in late stages of carcinogenesis, suggesting that Pgp may be involved in tumor progression. While some of the Pgp isoforms are known to transport hydrophobic chemotherapeutic drugs out of tumor cells, the biologic effects of Pgp overexpression in tumor cells are not fully understood, because the spectrum of substrates for Pgp-mediated transport has not been determined. In the rat liver carcinoma model, strong expression of Pgp is associated with a highly vascular stroma, suggesting that Pgp in tumor cells may affect the connective tissue stroma. The regulation of Pgp appears to be complex, and little is known about how it is up-regulated during carcinogenesis. Further studies of the role of Pgp in malignancy may contribute to our understanding of molecular mechanisms which underlie tumor progression. 相似文献
6.
目的:研究肺癌放射导向手术中肿瘤及正常组织P糖蛋白(P-gp)、Ki-67抗原表达与放射性核素摄取比(T/NT)的关系.方法:采用免疫组化方法和显微图像分析技术,测定32例接受放射导向手术的肺癌病人P-gp和Ki-67抗原表达,分析P-gp和Ki-67的标记指数(LI)与T/NT之间的相关性.结果:P-gp和Ki-67的LI和肺癌病人T/NT之间均有相关性(r=-0.61,P=0.0002; r=0.75,P=0.0001).结论:Ki-67的LI越高(肿瘤增殖越旺盛),T/NT值越高;P-gp阳性的肿瘤,T/NT值较低. 相似文献
7.
JUDITH VAN ASPEREN OLAF H. VAN TELLINGEN JOS H. BEIJNEN 《Pharmacological research》1998,37(6):429-435
P-glycoprotein, a membrane-associated transport protein, has recently been recognised as an important element of the intestinal epithelium. This paper summarises thein vivodata on the pharmacological role of intestinal P-glycoprotein. These data show that P-glycoprotein contributes to the elimination of many drugs by mediating their direct secretion from the blood into the intestinal lumen. In addition, there is also evidence that this protein can limit oral drug absorption. Hence, inhibition of intestinal P-glycoprotein, e.g. by a reversal agent like cyclosporin A, may be a promising strategy for improving the oral bioavailability of P-glycoprotein substrate drugs. Indeed, several preclinical and clinical studies have shown that coadministration of drugs with a reversal agent can substantially increase oral drug absorption. 相似文献
8.
Vera S. Donnenberg Gilbert J. Burckart Albert D. Donnenberg 《Clinical and Applied Immunology Reviews》2003,4(1):15-30
P-glycoprotein (P-gp), a member of the adenosine triphosphate (ATP)-binding cassette (ABC) family of transporter molecules, is responsible for maintaining low intracellular concentrations of a variety of extracellular compounds and xenobiotics, and for transport of various intracellular molecules. Many drugs are P-gp substrates and intracellular concentrations of these agents may be critical for drug action. Experience in oncology indicates that repeated exposure to P-gp substrate cytotoxic drugs leads to the selection of drug-resistant tumor cells that overexpress P-gp. Since immunosuppressive agents such as cyclosporine, tacrolimus, sirolimus and corticosteroids are substrates for P-gp and since T-cells also express P-gp, it is conceivable that an analogous mechanism exits for therapy-resistant graft rejection. As will be discussed in this article, P-gp may interfere with the response to immunosuppressive therapy through several distinct mechanisms, and as such may represent an attractive therapeutic target. 相似文献
9.
目的探索性应用苯妥英钠(PHT)、苯巴比妥钠(PB)诱导建立难治性癫痫动物模型,并研究其多药耐药机制。方法将60只大鼠随机分为实验组50只和对照组10只;实验组给予亚抽搐剂量戊四氮腹腔注射,其中45只大鼠确定点燃.将其随机分为给药组35只和未给药组10只。给药组应用较大剂量PHT、PB腹腔注射,其间注射小剂量戊四氮.根据Racine行为分级以及脑电图改变,从中筛选出耐PHT和PB的难治性癫痫动物模型。应用免疫组化法观察比较P糖蛋白(Pgp)在各组脑组织中的表达。结果12只大鼠制成难治性癫痫动物模型(耐药组),11只为药物有效组,12只死亡。耐药组大鼠脑组织Pgp表达较对照组、未给药组和药物有效组增强,差异有高度统计学意义(P〈0.01)。结论应用较大剂量PHT和PB诱导点燃大鼠制作难治性癫痫的动物模型.方法可行。该模型可以用于研究难治性癫痫脑内PgP的表达。PgP的高表达与难治性癫痫发生密切相关。 相似文献
10.
卵巢癌中蛋白激酶C的表达及其临床意义 总被引:2,自引:0,他引:2
目的 探讨上皮性卵巢癌组织蛋白激酶C (proteinkinaseC ,PKC)的表达和化疗耐药的关系 ,以及与P -糖蛋白 (P -gp)的相关性。方法 用免疫组化S -P法检测 35例卵巢上皮性肿瘤组织、 2 0例卵巢良性肿瘤组织和 2 0例正常卵巢组织中PKC和P -gp的表达 ,并进行相关临床因素分析。结果 ①PKC、P -gp在卵巢恶性肿瘤中的表达明显高于在良性及正常组织中的表达 ;并且PKC和P -gp的表达有相关性 (P <0 0 5 ) ;②卵巢癌PKC的表达与临床病理因素无直接关系 ;③恶性肿瘤中 ,初治和复发的PKC表达阳性率分别为 34 8%和 75 % ;④化疗对PKC表达阳性和阴性卵巢癌患者的有效率分别为 2 3 5 %、 6 6 7% (P <0 0 5 ) ;⑤PKC表达阴性患者的预后优于阳性者 (P =0 0 39)。结论 PKC表达与卵巢癌组织化疗耐药明显相关 ,可能在P -gp介导的卵巢癌多药耐药中起重要作用。 相似文献