蛋白药物聚乙二醇化技术的研究进展

蛋白药物聚乙二醇化技术是指一项利用聚乙二醇衍生物对蛋白药物进行化学修饰的技术。聚乙二醇的代表药物有：腺苷脱氨酶、干扰素α—2b和干扰素α—2a等。它可以改善药物的可溶性和稳定性，减少免疫原性和蛋白水解，显著增加体内循环时间，以及在作用部位提高药物浓度和延长驻留时间从而提高疗效。本文对该技术进行了综述。     

对曾氏推导的药物蛋白结合率公式的修正

对曾氏推导的药物蛋白结合率公式的修正娄建石（天津医科大学药理教研室，天津３０００７０）测定药物蛋白结合率是药物代谢动力学研究中的重要内容之一。曾衍霖教授根据国外文献推导出药物蛋白结合率公式（１），为这方面的研究提供了很好的计算依据。本文作者在计算药物...     

抗生素药物血浆蛋白结合率的定量构动关系

目的 应用人工神经网络方法对61种抗生素进行药物分子结构和药物血浆蛋白结合率的定量结构—药物动力学关系的研究(QSPR)。方法 建立了含一个隐含层的反传神经网络，输出层为实验获得的药物血浆蛋白结合率；输入层为计算获得的药物分子的理化参数，量化参数和分子连接性指数等药物分子结构参数。为了验证网络训练结果，随机挑选51个药物为训练集，进行了1eave—one—out分析。结果 最后利用挑选剩下的10个药物进行预测，其血浆蛋白结合率的预测值能很好地与实验数据相吻合。结论所建立的神经网络模型能够有效地进行药物血浆蛋白结合率与药物分子结构的相关性分析。同时也证明了人工神经网络功能强大，将成为药物QSPR研究的一个有效工具。     

181例次抗癫痫药物血药浓度监测结果分析

癫痫是一种由多种原因引起的脑灰质的偶然、特发、过度、快速和局限性放电而导致的神经系统功能紊乱性疾病，是神经系统的多发病。在我国，癫痫的患病率为0．5％-1．0％。治疗癫痫无论是对原发性癫痫，还是对继发性癫痫，都需要服用抗癫痫药控制发作。由于抗癫痫药物的作用机理目前尚未探明，而有的抗癫痫药具有非线性药动学特征，因而使抗癫痫药在患者体内的代谢差异很大，这为医师制定给药方案带来一定困难。同时，抗癫痫药的应用目的不仅要抑制癫痫发作，而且要尽量减少神经方面的不良反应。因此，血药浓度监测成为药物治疗癫痫的重要措施。     

Sangamo帮助Pfizer生产蛋白

Sangamo BioSciences公司将锌指DNA结合蛋白技术提供给Pfizer公司，由Pfizei评估其在以哺乳动物细胞为基础的蛋白药物生产中的用途。Sangamo将生成细胞系及蛋白生产的载体系统。它说，虽有多种转录因子，但只有锌指DNA结合蛋白能经人工改造而精确地靶向特定的基因或多个基因。这一交易的财务细节没有透露。     

抗癫痫药物监测

癫痫是神经系统的常见疾病。抗癫痫药物(antiepileptic drugs，AEDs)大多治疗窗窄，药动学个体间和个体内差异大，同时癫痫治疗需要长期用药，AEDs须进行治疗药物监测(therapeutic drug monitoring，TDM)和个体化给药。现通过文献查阅和临床实践，对AEDs监测的方法和意义作一综述。     

贯叶金丝桃对健康受试者体内他克莫司药动学的影响[英]／Hebert M F…∥J Clin Pharmacol

他克莫司是一种强免疫抑制剂，是药物代谢酶CYP3A和药物转运蛋白P-糖蛋白(P—gP)的底物，主要用于预防器官移植后的排斥反应。贯叶金丝桃为抗抑郁草药和CYP3A与P—gP诱导剂，曾有1例肾移植患者发生他克莫司和贯叶金丝桃相互作用的报道。     

选用癫痫药物分六步走

作为城市社区或农村乡镇的基层医生,我们经常会遇到求诊的癫痫患者。从理论上说,近八成的癫痫患者可以通过药物控制或减轻发作强度,然而患者和医生普遍的感觉是癫痫治疗很棘手,找到适用的药物并不容易。其实,癫痫患者的药物治疗从最初的药物选择就需要考虑多种因素,一步一步地进行判断、摸索,最终才能找到最合理的用药方案。     

拉莫三嗪的药动学及其药物相互作用研究进展

拉莫三嗪(lamotrigine,LTG)是一种苯三嗪类的新一代广谱抗癫痫药物,用于治疗儿童和成人多种癫痫发作及癫痫综合征.LTG是一种电压性的钠离子通道阻滞剂,它通过阻断电压依赖性钠离子通道,抑制谷氨酸释放而发挥抗癫痫作用.     

癫痫的药物治疗

癫痫是一种神经系统的常见病，我国目前约有600万癫痫患者。对于癫痫的治疗应着重于三个方面：病因和诱发因素的治疗；对癫痫患者的教育和社会照料；癫痫症状的控制。这三个方面中，控制发作是最主要的目标。癫痫发作的控制有药物治疗和手术治疗，目前药物控制仍是主要的治疗手段。     

Tyrosine kinase inhibitor resistance in cancer: role of ABC multidrug transporters.

Recent antitumor drug research has seen the development of a large variety of tyrosine kinase inhibitors (TKIs) with increasing specificity and selectivity. These are highly promising agents for specific inhibition of malignant cell growth and metastasis. However, their therapeutic potential also depends on access to their intracellular targets, which may be significantly affected by certain ABC membrane transporters. It has been recently shown that several human multidrug transporter ABC proteins interact with specific TKIs, and the ABCG2 transporter has an especially high affinity for some of these kinase inhibitors. These results indicate that multidrug resistance protein modulation by TKIs may be an important factor in the treatment of cancer patients; moreover, the extrusion of TKIs by multidrug transporters may result in tumor cell TKI resistance. Interaction with multidrug resistance ABC transporters may also significantly modify the pharmacokinetics and toxicity of TKIs in patients.     

High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter

Tyrosine kinase inhibitors (TKIs) are promising new agents for specific inhibition of malignant cell growth and metastasis formation. Because most of the TKIs have to reach an intracellular target, specific membrane transporters may significantly modulate their effectiveness. In addition, the hydrophobic TKIs may interact with so-called multidrug transporters and thus alter the cellular distribution of unrelated pharmacological agents. In the present work, we show that certain TKIs, already in the clinical phase of drug development, directly interact with the ABCG2 multidrug transporter protein with a high affinity. We found that in several in vitro assay systems, STI-571 (Gleevec; imatinib mesylate), ZD1839 (Iressa; gefitinib), and N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide (EKI-785) interacted with ABCG2 at submicromolar concentrations, whereas other multidrug transporters, human multidrug resistance protein (P-glycoprotein, ABCB1) and human multidrug resistance protein 1 (ABCC1), showed much lower reactivity toward these agents. Low concentrations of the TKIs examined selectively modulated ABCG2-ATPase activity, inhibited ABCG2-dependent active drug extrusion, and significantly affected drug resistance patterns in cells expressing ABCG2. Our results indicate that multidrug resistance protein modulation by TKIs may be an important factor in the clinical treatment of cancer patients. These data also raise the possibility that an extrusion of TKIs by multidrug transporters, e.g., ABCG2, may be involved in tumor cell TKI resistance.     

Neuronal MDR-1 gene expression and persistent low levels of anticonvulsants in a child with refractory epilepsy

SUMMARY: It is estimated that 20-25% of epileptic patients fail to achieve good control with antiepileptic drug (AED) treatment; thus, refractory epilepsy (RE) has been described in patients who have adequate therapeutic levels of AEDs without control of seizures. Multidrug resistance genes have been reported to be highly expressed in brain of patients with RE. Persistent low plasma levels of AEDs and high brain expression of the multidrug resistance product P-glycoprotein (P-gp) have been previously communicated in a case report of RE secondary to tuberous sclerosis. Here, the authors report a case of an 8-year-old boy diagnosed with partial RE with focal seizures who was admitted to hospital for a severe episode of subintrant crisis. The patient received polytherapy with carbamazepine (CBZ), phenytoin (PHT), and valproic acid (VA); however, habitual doses of these AEDs failed to control the patient's symptoms. AED blood levels were monitored for 25 consecutive days and showed low values in 8/25 (33%) for CBZ, 10/25 (40%) for PHT, and 25/25 (100%) for VA of samples studied. Because the patient developed focal status epilepticus, surgical treatment by callosotomy was done, resulting in a significant improvement in epileptic symptoms. The immunostaining of brain specimens showed significantly increased expression of P-gp not only in vascular endothelial cells and related astrocytes but also in neurons. Overexpression of P-gp in the brain does not explain the low blood levels of AEDs described in these cases. Different mechanisms such as drug-drug interactions and drug transporters can be involved in the results observed. The P-gp overexpression and/or its pharmacologic induction should be considered as a potential mechanism responsible for drug resistance to epilepsy treatment and highly suspected in patients with persistent subtherapeutic AEDs plasma levels.     

介导肿瘤多药耐药的ATP结合盒转运体的研究进展

多药耐药（MDR）是阻碍肿瘤化疗成功的一大障碍,其机制之一就是耐药的肿瘤细胞高表达三磷酸腺苷（ATP）结合盒（ABC）转运体。依据此机制提出克服肿瘤细胞耐药的策略即开发外排转运体抑制剂,以期逆转MDR。最近的研究发现肿瘤干细胞也可能是通过表达外排转运体天然耐药,这就提供了一个新的抗癌药物作用靶点。对介导肿瘤细胞多药耐药的ABC转运体及其抑制剂的开发作一综述。     

Nanoparticle delivery of anticancer drugs overcomes multidrug resistance in breast cancer

Breast cancer is a serious threat to women's health, because multidrug resistance (MDR) has hampered treatment and prognosis. Nanodelivery of anticancer agents is a new technology to be exploited in the treatment of patients, because it bypasses multispecific drug efflux transporters such as P-glycoprotein (ABCB1), multidrug resistance protein-1 (MRP1, ABCC1) and breast cancer resistance protein (BCRP, ABCG2). Drugs can be delivered to tumor tissue by passive and active tumor targeting strategies, which may reduce or reverse drug resistance. This review will mainly focus on MDR-associated proteins, as well as various nanoparticle formulations developed to overcome MDR in breast cancer.     

Structural understanding of efflux-mediated drug resistance: potential routes to efflux inhibition

The active efflux of cytotoxic drugs mediated by multidrug transporters is the basis of multidrug resistance in prokaryotic and eukaryotic cells. Individual multidrug transporters can be extremely versatile, often exhibiting a staggering range of substrate specificity that can negate the effects of clinically relevant therapies. The effective treatment of bacterial, fungal and protozoan infections, along with certain cancer treatments, has been compromised by the presence of multidrug transporters. Traditionally, advances in the understanding of multidrug transporters have been made through biochemical analyses; more recently, however, fundamental advances have been made with the elucidation of several three dimensional structures of representative multidrug pumps. Biochemical and structural analysis of multidrug pumps could lead to the development of novel 'anti-efflux' therapies.     

Regulation of drug transporter expression by oncostatin M in human hepatocytes

The cytokine oncostatin M (OSM) is a member of the interleukin (IL)-6 family, known to down-regulate expression of drug metabolizing cytochromes P-450 in human hepatocytes. The present study was designed to determine whether OSM may also impair expression of sinusoidal and canalicular drug transporters, which constitute important determinants of drug hepatic clearance. Exposure of primary human hepatocytes to OSM down-regulated mRNA levels of major sinusoidal solute carrier (SLC) influx transporters, including sodium-taurocholate co-transporting polypeptide (NTCP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, OATP2B1, organic cation transporter 1 and organic anion transporter 2. OSM also repressed mRNA expressions of ATP binding cassette (ABC) efflux transporters such as multidrug resistance protein (MRP) 2/ABCC2 and breast cancer resistance protein/ABCG2, without however impairing those of multidrug resistance gene 1/P-glycoprotein/ABCB1, MRP3/ABCC3, MRP4/ABCC4 and bile salt export pump/ABCB11. The cytokine concomitantly reduced NTCP, OATP1B1, OATP2B1 and ABCG2 protein expression and NTCP and OATP transport activities. OSM effects towards transporters were found to be dose-dependent and highly correlated with those of IL-6, but not with those of other inflammatory cytokines such as tumor necrosis factor-α or interferon-γ. In addition, OSM-mediated repression of some transporters such as NTCP, OATP1B1 and OATP2B1, was counteracted by knocking-down expression of the type II OSM receptor subunits through siRNA transfection. This OSM-mediated down-regulation of drug SLC transporters and ABCG2 in human hepatocytes may contribute to alterations of pharmacokinetics in patients suffering from diseases associated with increased production of OSM.     

Cerebral expression of drug transporters in epilepsy

Over-expression of drug efflux transporters at the level of the blood-brain barrier (BBB) has been proposed as a mechanism responsible for multidrug resistance. Drug transporters in epileptogenic tissue are not only expressed in endothelial cells at the BBB, but also in other brain parenchymal cells, such as astrocytes, microglia and neurons, suggesting a complex cell type-specific regulation under pathological conditions associated with epilepsy. This review focuses on the cerebral expression patterns of several classes of well-known membrane drug transporters such as P-glycoprotein (Pgp), and multidrug resistance-associated proteins (MRPs) in the epileptogenic brain. Both experimental and clinical evidence of epilepsy-associated cerebral drug transporter regulation and the possible mechanisms underlying drug transporter regulation are discussed. Knowledge of the cerebral expression patterns of drug transporters in normal and epileptogenic brain will provide relevant information to guide strategies attempting to overcome drug resistance by targeting specific transporters.     

孕烷X受体介导的代谢酶和转运体转录调控及其在化疗药物耐药中的作用

孕烷X受体(PXR,NR1I2)是生物体内药物代谢酶和转运体基因表达的主要调控因子之一.近来研究发现,PXR介导的药物代谢酶和转运体的过表达,与化疗药物多药耐药的产生密切相关.鉴于PXR在药物代谢酶和转运体调控中的重要性和PXR转录调控的多样性,有必要对其导致的多药耐药形成机制进行更深入的研究.本文综述了PXR介导的代谢酶和转运体基因表达调控机制,及其引起化疗药物多药耐药的相关研究进展,为提高化疗药物敏感性、逆转化疗药物的多药耐药提供有效的治疗策略.     

Design, synthesis and structure-activity relationships of novel taxane-based multidrug resistance reversal agents

A series of novel taxane-based multidrug resistance (MDR) reversal agents (TRAs) has been designed and synthesized. Structure-activity relationship (SAR) study clearly indicates that modification of the C-7 position with hydrophobic arenecarbonylcinnamoyl groups brings about high potency against drug efflux mediated by P-glycoprotein (P-gp). Six TRAs exhibit ability to modulate a wide range of ATP-binding cassette (ABC) transporters, such as P-gp, multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP), which may serve as novel broad-spectrum modulators of ABC transporters.