Ultrasound-Induced Mild Hyperthermia as a Novel Approach to Increase Drug Uptake in Brain Microvessel Endothelial Cells

Purpose. Drug delivery to the central nervous system (CNS) is limited by the blood-brain barrier (BBB). Thus, a noninvasive and reversible method to enhance BBB permeation of drugs is highly desirable. In the present work, we studied if ultrasound-induced mild hyperthermia (USHT, 0.4 watts (W)/cm² at 41°C) can enhance drug absorption in BBB endothelial cells, and we elucidated the mechanism of USHT on cellular accumulation. Methods. To accomplish these aims, we studied the effects of hyperthermia (41°C), USHT, P-glycoprotein (P-gp) modulator (PSC 833), and combination of USHT and PSC 833 on accumulation of P-gp substrate (R123) and non-P-gp substrates (sucrose, 2-deoxyglucose, and antipyrine) in monolayers of primary bovine brain microvessel endothelial cells (BBMEC). Results. USHT, through its thermal effect, produces a significant (relative to controls; no USHT) and comparable increase in R123 accumulation with PSC 833. We also demonstrate that USHT increases permeability of hydrophobic (R123 and [¹⁴C]-antipyrine) and not hydrophilic molecules ([¹⁴C]-sucrose and 2-[³H]-deoxy-d-glucose). The enhanced permeability is reversible and size dependent, as USHT produces a much larger effect on cellular accumulation of [¹⁴C]-antitpyrine (molecular weight of 188 D) than that of R123 (molecular weight of 380.8 D). Although USHT increases membrane permeability, it did not affect P-gp activity or the activity of glucose transporters. Conclusions. Our results point to the potential use of USHT as a reversible and noninvasive approach to increase BBB permeation of hydrophobic drugs, including P-gp-recognized substrates.     

P-Glycoprotein Is More Efficient at Limiting Uptake than Inducing Efflux of Colchicine and Vinblastine in HL-60 Cells

Purpose. To investigate the role of the P-glycoprotein (P-gp) drug efflux pump in the intracellular disposition of colchicine and vinblastine. Methods. Uptake and efflux kinetics were studied in vitro in human lymphocytes and in HL-60 cells with or without the P-gp modulator, verapamil. Results. In human lymphocytes, colchicine was slowly taken up (uptake half-life was 18.9 ± 1.1 hr.) and verapamil increased colchicine uptake by 37%, whereas it did not modify colchicine efflux from cells. In HL-60 cells, colchicine uptake was non-linear and slower than that of vinblastine, the colchicine uptake half-life (11.1 ± 0.5 hr.) being 25-fold longer than that of vinblastine at 25 nM. Verapamil did not significantly modify colchicine uptake half-life, but increased its intracellular accumulation by 23% and that of vinblastine by 81%. Immuno-flow cytometry showed that P-gp expression in HL-60 cells increased significantly from 24 hr. following colchicine or vinblastine exposure. The significant increase in colchicine uptake induced by verapamil at 24 hr. was correlated with this enhanced P-gp expression. The drug efflux half-life was 11.5-fold higher for colchicine (23 ± 0.9 hr) than vinblastine, indicating a much slower elimination of colchicine from cells that could be related to its longer dissociation half-life from the tubulin receptor. Verapamil treatment did not modulate either colchicine or vinblastine efflux kinetics, suggesting that the intracellular drugs are not available to the transmembrane P-gp binding sites. Conclusions. P-gp may not be the main reason for the slowness of colchicine uptake. It may be more efficient at controlling entry of colchicine and vinblastine through the plasma membrane than at mediating their efflux from HL-60 cells.     

Influence of P-Glycoprotein Modulators on Cardiac Uptake,Metabolism, and Effects of Idarubicin

Purpose. The clinical utility of anthracyclines like idarubicin (IDA) is limited by the occurrence of multidrug resistance and cardiotoxicity. Previous studies have demonstrated that the multidrug transporter P-glycoprotein (P-gp) is present in the heart and have suggested that it exerts a protective function. We sought to determine the influence of P-gp inhibitors verapamil and PSC 833 on myocardial uptake, metabolism, and actions of IDA. Methods. In Langendorff-perfused rat hearts, the outflow concentration-time curve and the residual amount in cardiac tissue of IDA and its active metabolite idarubicinol (IDOL) were measured after 0.5 mg dose of IDA in the absence and presence of the P-gp inhibitors verapamil and PSC 833. Results. During perfusion (80 min), 2% of the IDA dose was converted to IDOL in the heart. Myocardial uptake of IDA was significantly increased by verapamil but not by PSC 833, which increased the recovery of IDA and IDOL. IDA significantly decreased left ventricular developed pressure to approximately 40% and increased coronary vascular resistance to 140% of baseline level, respectively. The vasoconstrictive effect was markedly potentiated by PSC 833. Conclusions. The enhancement of myocardial IDA uptake by verapamil could be due to a decrease in P-gp-mediated efflux. PSC 833 inhibits cardiac metabolism (non-IDOL pathways) and increases the acute cardiotoxicity of IDA.     

Synthesis of 2-Fluoro N10-Substituted Acridones and Their Cytotoxicity Studies in Sensitive and Resistant Cancer Cell Lines and Their DNA Intercalation Studies

A series of 2-fluoro N¹⁰-substituted acridone derivatives with varying alkyl side chain length with propyl, butyl substitution, and a tertiary amine group at the terminal end of the alkyl side chain were synthesized and screened against cancer cell lines SW 1573, SW 1573 2R 160 (P-gp substrate) which are non-small lung cancer cell lines, MCF-7, MCF-7/MR (BCRP substrate) are breast cancer cell lines, 2008 WT, 2008MRP1, 2008MRP2, 2008MRP3 are ovarian cancer cell lines, and human embryo kidney cell lines like HEK293, HEK293 MRP4, and HEK293 MRP5i. The propyl-series compounds showed lipophilicity in the range of 1.93 to 4.40 and the butyl series in the range of 2.37 to 4.78. The compounds 4 , 7 , and 8 showed good cytotoxicity against the 60 human cancer cell line panel of the National Cancer Institute, USA. The compounds 14 and 15 showed a better cytotoxicity in most of the cancer cell lines compared to other compounds tested. The DNA-binding properties of the compounds were evaluated based on their affinity or intercalation with CT-DNA measured with absorption titration. The compound 11 bearing planar tricyclic ring linked with a butyl methylpiperazino side chain showed the highest binding affinity with a binding constant (K_i) of 10.38×10 M^–1. Evaluation of the compounds in cell lines with an overexpression of various multidrug resistance-related protein (MRP), P-glycoprotein (P-gp), or Breast Cancer Resistance Protein (BCRP) showed that all compounds are not substrates for any of these transporters.     

我院2017年多重耐药菌分布特点及耐药性分析

[摘要]目的：探讨我院住院患儿多重耐药菌分布特点及耐药性,为临床合理使用抗菌药物提供依据。方法：回顾性分析我院2017年多重耐药菌感染病例资料,并对结果进行统计分析。结果：我院2017年共检出多重耐药菌368株,检出率32.20%,主要为大肠埃希菌（31.80%）、肺炎克雷伯菌（31.25%）、耐甲氧西林金黄色葡萄球菌（15.49%）、耐甲氧西林凝固酶阴性葡萄球菌（15.76%）;多重耐药菌标本主要为痰液（198例）、血液（102例）、脓液（25例）、中段尿（16例）、分泌物（14例）,主要集中在新生儿内科NICU 136例（36.96%）、重症监护室（PICU）87例(23.64%)、新生儿外科ICU 67例（18.21%）。大肠埃希菌对美罗培南、亚胺培南敏感,肺炎克雷伯菌对美罗培南、亚胺培南敏感性下降,鲍曼不动杆菌对美罗培南、亚胺培南耐药率达到82.34%;革兰阳性多重耐药菌对利奈唑胺和万古霉素敏感。结论：多重耐药菌已成为医院内感染的重要病原菌,应加强多重耐药菌的监管,加强抗菌药物的合理使用,注意手卫生,减少或避免多重耐药菌的发生。     

Evidence for Different ABC-Transporters in Caco-2 Cells Modulating Drug Uptake

Purpose. Secretory systems contribute to drug absorption in the gastrointestinal tract. The purpose of this study was the identification of members of the ATP binding cassette superfamily of secretory transport proteins that may potentially modulate drug absorption in Caco-2 cells, which are an important cellular model predicting enteral absorption of drugs. Methods. Kinetic studies as well as PCR- and Western blot studies with confluent epithelial layers of human Caco-2 cells. Results. The study demonstrates functional expression of multidrug resistance related protein (MRP) and P-glycoprotein (P-gp) in Caco-2 cells: 1) Efflux studies with the MRP specific substrate glutathion-methylfluorescein (GS-MF) showed functional activity of MRP in Caco-2 cells preloaded with the metabolic precursor of GS-MF, chloro-methylfluoresceine-diacetate, CMFDA. Excretion of GS-MF was decreased in presence of the MRP-blocker MK-571.2) Transport experiments with cyclosporin A demonstrated the functional activity of P-gp. Cellular accumulation was increased in presence of the P-gp blocking agent SDZ-PSC 833.3) The expression of the 190 kDa protein MRP and the 170 kDa protein P-gp in Caco-2 cells was shown by Western blot analysis with specific monoclonal antibodies. 4) The expression of MRP-mRNA in Caco-2 cells was detected by RT-PCR and compared with the MRP over-expressing cell line H69AR. MRP primers recognize specifically human MRP1 (GenBank accession number L05628), but not all other published sequences of MRP (MRP2-MRP6). P-gp expression on mRNA-level was also confirmed by RT-PCR. Conclusions. The data demonstrate that besides P-gp, multidrug resistance related protein (MRP) is functionally expressed in Caco-2 cells and contributes to the active excretion of substrates in this cell line.     

Inhibition of P-Glycoprotein: Rapid Assessment of Its Implication in Blood-Brain Barrier Integrity and Drug Transport to the Brain by an In Vitro Model of the Blood-Brain Barrier

Purpose. The objective of this work was to assess, in vitro, the passage of P-glycoprotein dependent drugs across brain capillary endothelial cells, when these drugs are associated with a reversing agent. Methods. An in vitro model of the blood-brain barrier consisting of a coculture of brain capillary endothelial cells and astrocytes was used. Results. We demonstrate that P-glycoprotein expression is upregulated by the presence of astrocytes. Uptake in the cells and transport across endothelial cell monolayers of vincristine, cyclosporin A and doxorubicin were studied. Using S9788 or verapamil as reversing agents, we found an increase in vincristine transport across the endothelial cell monolayers. On the other hand, the association of S9788 or verapamil with cyclosporin A failed to increase the transport of this drug. An increase in the transport of doxorubicin from luminal to abluminal compartment was also observed, due to endothelial cell monolayer breakdown. Conclusions. Using this model, it is possible to predict the passage of a P-glycoprotein dependent drug to the brain or its sequestration in brain capillary endothelial cells when this drug is associated with a reversing agent, or its toxicity on the blood-brain barrier integrity.     

P糖蛋白与配体相互作用的结构基础及其肿瘤耐药逆转的研究

P糖蛋白（P-glycoprotein,P-gp）是一种多药外排转运体,对控制各种抗癌药物的生物学活性具有重要意义。P-gp转运体作为生理屏障阻滞药物渗透,从而使药物发挥效应受限。传统的化疗增敏剂通过对转运体的调节可有效改善抗肿瘤药物的药代动力学并逆转多药耐药。本文将简要概述近年来有关P-gp与配体相互作用的结构信息以及肿瘤耐药逆转策略的研究进展。     

新生儿病区多重耐药菌分布及耐药性分析

目的:通过对2016 年7 月至2017 年7 月河南省妇幼保健院住院患儿多重耐药菌的临床分布及耐药性分析,为临床抗菌药物的合理应用提供理论依据。 方法:应用珠海迪尔 DL-96 系统和手工实验相结合的方法进行细菌鉴定和抗菌药物敏感性试验,部分药敏试验结合 K-B 纸片扩散法。 药敏试验结果参照美国 CLSI 标准判读,将数据录入 WHONET 软件进行细菌分布及耐药性统计分析。 结果:河南省妇幼保健院在 2016 年 7 月至 2017 年 7 月住院的新生儿共检出阳性菌株 1 754 株,检出多重耐药菌 337 株,占 19.21%。 多重耐药菌中,耐碳青霉烯肺炎克雷伯菌(CRKPN)比例最高,占 45.70%;多重耐药菌主要分布在新生儿重症监护病房(NICU),且在新生儿和其他儿童病区中,CRKPN 检出率最高。 NICU 与新生儿普通病区相比,多重耐药菌和CRKPN 阳性率比较差异有统计学意义(P<0.01);新生儿病区与其他儿童病区相比,多重耐药菌和 CRKPN 阳性率比较差异有统计学意义(P<0.01)。 药敏结果显示肺炎克雷伯菌对氨苄西林耐药率 100%,对哌拉西林/他唑巴坦耐药率 80.3%,对碳青霉烯类药物美罗培南、亚胺培南的耐药率高达 65.2%,对复方磺胺甲噁唑的耐药率最低为 28.8%。 结论:我院新生儿病区多重耐药菌检出率较高,以 CRKPN 为主,提示应加强多重耐药菌株监测和抗菌药物监管。     

Star-Shaped Tetraspermine Enhances Cellular Uptake and Cytotoxicity of T-Oligo in Prostate Cancer Cells

Purpose

An oligonucleotide termed ‘T-oligo’ having sequence homology with telomere overhang has shown cytotoxicity in multiple cancers. We have demonstrated that T-oligo can induce apoptosis in androgen independent prostate cancer cell line DU-145. In this report, we evaluate the use of star-shaped tetraspermine (SSTS) for delivery of T-oligo.

Methods

SSTS was synthesized from spermine and its intrinsic cytotoxicity towards DU-145 cells was compared with spermine and branched polyethyleneimine (bPEI). Atomistic molecular dynamic (MD) simulations were conducted to understand binding and complexation of spermine and SSTS with T-oligo. Complexation was also determined using gel electrophoresis and SYBR gold assay. Complexes were characterized for size, cellular uptake and antiproliferative effect.

Results

SSTS exhibited significantly lower toxicity than spermine and bPEI. Its affinity towards T-oligo was significantly higher than spermine as determined by experimental studies and confirmed by MD simulations and it formed stable complexes (TONPs) with T-oligo. TONPs facilitated cellular uptake and nuclear accumulation of T-oligo and their cytotoxic potential was observed at concentration several folds lower than that required for T-oligo alone.

Conclusion

SSTS significantly enhanced therapeutic benefits associated with the use of T-oligo and can be developed as a delivery vehicle for its in-vivo therapeutic applications.

     

美洲大蠊多肽PAE2逆转BEL-7402/5-FU细胞多药耐药性的作用及机制研究

本研究探讨了美洲大蠊多肽PAE2逆转人肝细胞肿瘤耐药细胞株BEL-7402/5-FU的多药耐药性作用及机制.以人肝细胞肿瘤敏感细胞株BEL-7402、人肝细胞肿瘤耐5-氟尿嘧啶(5-FU)细胞株BEL-7402/5-FU和Balb/c-nude小鼠为研究对象,采用噻唑蓝比色分析法检测BEL-7402/5-FU 细胞的多...     

Identification of P-Glycoprotein and Transport Mechanism of Paclitaxel in Syncytiotrophoblast Cells

When chemotherapy is administered during pregnancy, it is important to consider the fetus chemotherapy exposure, because it may lead to fetal consequences. Paclitaxel has become widely used in the metastatic and adjuvant settings for woman with cancer including breast and ovarian cancer. Therefore, we attempted to clarify the transport mechanisms of paclitaxel through blood-placenta barrier using rat conditionally immortalized syncytiotrophoblast cell lines (TR-TBTs). The uptake of paclitaxel was time- and temperature-dependent. Paclitaxel was eliminated about 50% from the cells within 30 min. The uptake of paclitaxel was saturable with K_m of 168 μM and 371 μM in TR-TBT 18d-1 and TR-TBT 18d-2, respectively. [³H]Paclitaxel uptake was markedly inhibited by cyclosporine and verapamil, well-known substrates of P-glycoprotein (P-gp) transporter. However, several MRP substrates and organic anions had no effect on [³H]paclitaxel uptake in TR-TBT cells. These results suggest that P-gp may be involved in paclitaxel transport at the placenta. TR-TBT cells expressed mRNA of P-gp. These findings are important for therapy of breast and ovarian cancer of pregnant women, and should be useful data in elucidating teratogenicity of paclitaxel during pregnancy.     

Saturable Absorptive Transport of the Hydrophilic Organic Cation Ranitidine in Caco-2 Cells: Role of pH-Dependent Organic Cation Uptake System and P-Glycoprotein

Purpose The purpose of this work was to investigate the involvement of carrier-mediated apical (AP) uptake and efflux mechanisms in the absorptive intestinal transport of the hydrophilic cationic drug ranitidine in Caco-2 cells. Methods Absorptive transport and AP uptake of ranitidine were determined in Caco-2 cells as a function of concentration. Permeability of ranitidine in the absorptive and secretory directions was assessed in the absence or presence of the P-glycoprotein (P-gp) inhibitor, GW918. Characterization of the uptake mechanism was performed with respect to inhibitor specificity, pH, energy, membrane potential, and Na⁺ dependence. Efflux from preloaded monolayers was evaluated over a range of concentrations and in the absence or presence of high extracellular ranitidine concentrations. Results Saturable absorptive transport and AP uptake of ranitidine were observed with K_m values of 0.27 and 0.45 mM, respectively. The ranitidine absorptive permeability increased and secretory permeability decreased upon inhibition of P-gp. AP ranitidine uptake was inhibited in a concentration-dependent fashion by a diverse set of organic cations including tetraethylammonium, 1-methyl-4-phenylpyridinium, famotidine, and quinidine. AP ranitidine uptake was pH and membrane potential dependent and reduced under conditions that deplete metabolic energy. Efflux of [³H]ranitidine across the basolateral membrane was neither saturable as a function of concentration nor trans stimulated by unlabeled ranitidine. Conclusions Saturable absorptive transport of ranitidine in Caco-2 cells is partially mediated via a pH-dependent uptake transporter for organic cations and is subject to attenuation by P-gp. Inhibition and driving force studies suggest the uptake carrier exhibits similar properties to cloned human organic cation transporters. The results also imply ranitidine transport is not solely restricted to the paracellular space.     

The Effect of Fatty Acids and Analogues upon Intracellular Levels of Doxorubicin in Cells Displaying P-Glycoprotein Mediated Multidrug Resistance

Abstract

Multidrug resistance mediated by overexpression of P-glycoprotein (P-gp) is a major obstacle in the chemotherapeutic management of cancer. The objectives of the current work were to examine if fatty acids affect the intracellular transport and dynamics of doxorubicin in drug-resistant cancer cell lines, and to assess if such effects were mediated through modulation of P-gp efflux pump activity. Among the range of fatty acids tested in this study, eicosapentaenoic acid diester (EPADI) increased doxorubicin accumulation [A] to 137% and retention [R] to 212% in doxorubicin-resistant MCF-7/ADR breast carcinoma cells, and [A] to 147% and [R] to 163% in vinblastine-resistant KBV1 nasopharyngeal carcinoma cells. Consistent with EPADI-induced increases in intracellular doxorubicin concentrations, EPADI (10 μg/ml) sensitized MCF-7/ADR cells to the cytotoxic effects of doxorubicin (1 μg/ml) as assessed by MTT assay (viability < 50% of control), while EPADI itself displayed no cytotoxicity. The combination of EPADI (10 μg/ml) with verapamil (1 μM) resulted in a considerable increase in the [A] and [R] of the model P-gp substrate rhodamine-123 within drug-resistant cells compared to when either agent were used alone. KBV1 cells treated with combination of EPADI (10 μg/ml) and verapamil (1 μM) achieved 160% and 1120% greater [A] and [R] of rhodamine-123, respectively, compared to untreated cells. The P-gp modulatory effects of EPADI either alone, or as part of a combination with more potent inhibitors, should be further investigated.     

Influence of Surface Chemistry on Cytotoxicity and Cellular Uptake of Nanocapsules in Breast Cancer and Phagocytic Cells

The present work tests the hypothesis that stabilizers have a critical role on nanocarrier stealthiness and anticancer drug efficacy. Two different types of docetaxel (Doc)-loaded nanocapsules (NCs) stabilized with polysorbate 80 (NC_T80) and polyvinyl alcohol (NC_PVA) were synthesized using the emulsion solvent diffusion method. These NCs were characterized for particle mean diameter (PMD), drug content, morphology, surface composition, and degree of crystallinity. Furthermore, the cytotoxicity and cellular uptake of the NCs were investigated in MDA-MB 231 cells, THP-1 monocytes, and THP-1-derived macrophages. The optimized spherical NC_T80 had 123.02 ± 14.6 nm, 0.27 ± 0.1, and 101 ± 37.0% for PMD, polydispersity index, and drug encapsulation efficiency, respectively. Doc release kinetics from NC_T80 and NC_PVA mostly provided better fit to zero-order and Higuchi models, respectively. Powder X-ray diffraction (PXRD) and X-ray photoelectron spectroscopy (XPS) results revealed the presence of amorphous stabilizers on the surface of the NCs. At high drug concentration, the cytotoxicity of NC_T80 was substantially improved (1.3–1.6-fold) compared with that of NC_PVA in MDA-MB 231 cells. The uptake of both NCs was inhibited by latrunculin A and dynasore, indicating an actin- and dynamin-dependent endocytosis in MDA-MB 231 cells. This occurred via a multifaceted mechanism involving clathrin, caveolin, cytoskeleton, and macropinocytosis. Interestingly, the uptake of NC_PVA was 2.7-fold greater than that of NC_T80 and occurred through phagocytosis in monocytes and macrophages. This study demonstrates the potential impact of the surface chemistry on the cytotoxicity and phagocytic clearance of nanocarriers for a subsequent improvement of the efficacy of Doc intended for breast cancer chemotherapy.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9572-0) contains supplementary material, which is available to authorized users.KEY WORDS: cancer chemotherapy, cytotoxicity, nanocapsules, phagocytosis, surface chemistry     

Pharmacological Modulation of Cytotoxicity and Cellular Uptake of Anti-cancer Drugs by PDE5 Inhibitors in Lung Cancer Cells

Purpose

Previous research has led to the recognition of a cGMP signaling pathway governing drug transport. This study is to investigate whether inhibitors of phosphodiesterase type 5 (PDE5), which increase intracellular cGMP levels, modulate the cytotoxicity and uptake of anti-cancer drugs in cancer cells.

Methods

The experiments were conducted with and without PDE5 inhibitors: dipyridamole, vardenafil, and/or sildenafil. The cytotoxicity of doxorubicin, cisplatin and oxaliplatin was determined in multiple cancer cell lines derived from different tissues. The cellular uptake of structurally diverse compounds was further examined in lung cancer cells with and without various endocytotic inhibitors. The tumor accumulation and the anti-tumor effect of trastuzumab were examined in a lung cancer xenograft mouse model.

Results

Dipyridamole could modulate the cytotoxicity of doxorubicin, cisplatin, and oxaliplatin in cancer cells. Particularly, PDE5 inhibitors increased cellular uptake of structurally diverse compounds into lung cancer cells both in vitro and in vivo. The effect of vardenafil on drug uptake could be blocked by endocytotic inhibitors. The growth of lung cancer xenograft in nude mice was significantly suppressed by addition of vardenafil to trastuzumab treatment.

Conclusion

PDE5 inhibitors may increase the efficacy of anti-cancer drugs by increasing endocytosis-mediated cellular drug uptake, and thus serve as adjuvant therapy for certain cancers such as lung cancer.     

Quantitative Evaluation of the Function of Small Intestinal P-Glycoprotein: Comparative Studies Between in Situ and in Vitro

Purpose. The extent of intestinal absorption of MDR1 P-glycoprotein (P-gp) substrate drugs may be affected by interindividual differences in the expression level of P-gp, and/or by simultaneously administered P-gp substrates/inhibitors. The purpose of the present study is to examine whether the extent to which the intestinal absorption is affected by P-gp can be predicted from in vitro experiments. Methods. The in situ intestinal perfusion experiments were performed for 12 compounds in mdr1a/1b (–/–) and normal mice to determine the permeability-surface area (PS) product. Thus determined intestinal P-gp function was compared with the in vitro P-gp function, which was determined by comparing the transcellular transport across human P-gp expressing and parental LLC-PK1 monolayers. Results. In situ experimental results revealed that the extent to which the intestinal absorption is affected by P-gp was in the following order; quinidine > ritonavir > loperamide, verapamil, daunomycin > digoxin, cyclosporin A > dexamethasone, and vinblastine. A significant correlation was observed between P-gp function determined in the intestinal perfusion and that in LLC-PK1 monolayers. Conclusion. The in vitro transcellular transport across P-gp expressing monolayers may be used to predict the extent to which the intestinal absorption is affected by P-gp.     

医院感染多重耐药鲍曼不动杆菌临床特征及耐药性分析

目的：分析医院感染多重耐药鲍曼不动杆菌临床特征及耐药情况,为临床合理使用抗菌药物提供依据。方法分离的358株鲍曼不动杆菌采用法国生物梅里埃公司ATB自动细菌鉴定分析系统进行细菌鉴定,K-B纸片扩散法进行药敏试验,对所得数据用WHONET5．4软件进行分析。结果临床分离出鲍曼不动杆菌358株,91．62％分离自痰与咽拭子的标本,52．23％来自重症监护病房（ ICU）;多重耐药鲍曼不动杆菌217株占总数的60．61％。多重耐药鲍曼不动杆菌对多黏菌素B耐药率最低（0．0％）,其次为米诺环素（5.1％）、头孢哌酮/舒巴坦（9．8％）、奈替米星（21．1％）和美洛培南（41．5％）。结论 ICU病区的多重耐药鲍曼不动杆菌的比例明显高于其他病区,应根据药敏结果合理使用抗菌药物,减少和控制医院感染的发生。     

Epothilones and new analogues of the microtubule modulators in taxane-resistant disease

Background: Microtubule-stabilising agents typified by the epothilone class of drug have demonstrated promising activity in Phase II and III clinical trials. Objective: Data supporting the efficacy of these agents are reviewed and their potential use in taxane-refractory disease assessed. Methods: Preclinical evidence assessing the role of the spindle assembly checkpoint in determining the cellular response to microtubule stabilization are presented together with clinical data documenting the efficacy of non-taxane microtubule modulators. Results/conclusions: Evidence suggests that microtubule-stabilising agents prolong activation of the spindle assembly checkpoint which may promote cancer cell death in mitosis or following mitotic exit. A weakened spindle assembly checkpoint is associated with altered sensitivity to agents targeting the microtubule and therefore pathways of drug resistance may be shared by these cytotoxic therapies. Preliminary clinical trial data do suggest modest activity of epothilones in truly taxane-resistant patient cohorts, indicating the potential niche for these agents in a molecularly undefined patient group, potentially implicating the role of P-glycoprotein in the acquisition of taxane-resistant disease. Trial data of these antimitotic agents will be presented together with their potential role in taxane-resistant disease and the implications for future clinical trial design.