关于筛选抗耐药性大肠杆菌的中草药抑菌实验

中草药作为我国特有的中医药理论与实践的产物,对细菌有一定的抑制作用,以其低毒、无药物残留、耐药性发生率低的独特优势,被广泛地应用于临床上,用来治疗各种感染性疾病.因此中草药的抑菌效果研究是目前医学研究的主要方向之一,我们通过筛选有效抑菌实验抑制耐药性大肠杆菌生长,为选择敏感中草药治疗耐药性大肠杆菌引起的疾病奠定基础.     

结直肠癌靶向治疗的研究进展

尽管化学药物治疗在结直肠癌方面取得了比较好的效果,但由于肿瘤细胞的耐药性和药物的毒副作用往往使得很多中晚期的肿瘤患者失去了治疗的机会。近年来靶向治疗的进展给结直肠癌的患者带来了希望。通过对肿瘤生长的关键通路如:表皮生长因子通路、新生血管形成通路等采用小分子化合物阻断其关键酶或采用单克隆抗体与其特异的生长因子或其受体竟争性结合等方式,选择性的阻断肿瘤细胞的生长,取得了非常好的临床效果,尤其是与化疗药物的合用常常可以取得叠加的效果。     

单克隆抗体抗肿瘤药的进展与临床评价

目的:归结于生物工程技术的进步,把对肿瘤细胞攻击锁定于表皮生长因子和血管内皮生长因子等靶位,使药物治疗的切入点由细胞水平向分子水平过度,提高肿瘤联合治疗效果,成为肿瘤综合治疗策略。由此应运而生的单克隆抗体药独树一帜,对其研究和评价日趋活跃,本文总结其作用优势和临床评价。方法:采用国内、外文献综述方法。结果及结论:单克隆抗体药疗效确切、特异性强、不良反应和耐药性小,无疑是药学研究领域中的巨大突破。但抗体药难以穿透肿瘤致密的包裹屏障,且价格昂贵,因此,期盼其根治肿瘤的希望依然渺茫,仍有待于大量循证医学研究结果和时间的推移。     

60例肺结核患者不合理用药的临床观察及分析

<正>结核病是目前全世界由单一致病菌引起且病死率最多的疾病之一。肺结核是临床常见的呼吸道疾病,近年来其发病率趋向于老年化及复发率上升。结核病患者的治疗效果与患者服药情况密切相关。对于初治或复治性结核病都遵循着抗结核药物的应用原则,即早期、规律、全程、适量、联合、然而从前由于种种原因使耐药菌株逐年增加,与抗结核药物的不合理应用,致使部分肺结核患者对多种抗结核药物产生耐药性,造成肺组织的广泛受损,导致病变反     

乳腺癌化疗药物耐药性的机制浅析

恶性肿瘤对化疗药物产生耐药是困扰各种肿瘤治疗的共同难题,同样在乳腺癌的治疗中,这也是导致化疗失败的重要原因。化疗药物耐药性的产生涉及一系列的机制,包括药泵表达增加,βⅢ微管蛋白亚型过度表达,TopoⅡ水平下降,抑癌基因突变,解毒作用增强等。只有充分了解其相关机制,才能指导临床,合理用药,降低耐药的发生率,并有效推动基因组学的广泛应用,研发出不同作用机制的抗肿瘤药物,改善乳腺癌和其他恶性疾病的治疗现状。     

布地奈德雾化吸入联合自拟滋阴利咽饮对慢性咽炎肾阴虚证患者体液免疫功能的影响观察

<正>慢性咽炎为临床常见咽喉部疾病,其主要由于上呼吸道病变、气候环境变化、过敏等因素导致,病因较为复杂。其病程长,易复发,严重影响患者的生活质量。临床上通常使用抗生素对其进行治疗,但抗生素耐药性高,长期使用效果不佳。中医对于慢性疾病治疗优势更明显,因此加入中医治疗十分     

单克隆抗体治疗自身免疫性疾病的研究进展

自身免疫性疾病的治疗通常采用的糖皮质激素、免疫抑制剂等,虽然有一定疗效,但长期使用都会产生严重的不良反应,而且都只能减缓病情的发展,并不能根治疾病。近10余年来,单克隆抗体治疗自身免疫性疾病已成为研究热点。这些单克隆抗体通过不同的机制发挥作用,包括结合可溶性细胞因子和生长因子,调节受体和受体信号,以及通过抗体介导的细胞依赖的细胞毒作用、抗体介导的细胞吞噬作用、补体依赖的细胞毒作用耗竭异常的免疫细胞及介导细胞信号等。研制更高效、更安全、给药更方便的抗体药物是未来抗体药物的发展趋势。通过改造IgG的氨基酸序列或者对其蛋白质进行一些修饰,以及以多个不同的信号途径或者致病介质为靶标的双特异性抗体,是新型单克隆抗体药物研究的重要方向。本文就治疗自身免疫性疾病的单克隆抗体研究进展作一综述。     

单克隆抗体药物进展

单克隆抗体药物特异性高、结构与性质均一稳定,其制备技术日益完善,临床应用越来越广泛,已有18种产品上市并用于人类疾病的诊断和治疗,100多种单克隆抗体药物进入临床研究阶段;单克隆抗体药物研究在生物技术药物中占有突出位置。文章综述了其国内外研究开发情况。     

抗体药物时代的来临

抗体作为免疫应答反应的主要产物，构筑了机体抵御感染和疾病的一道重要防线。早在一个多世纪之前，研究者就已开始探索将抗体作为药物治疗疾病。二十世纪七十年代中期，单克隆抗体制备技术的产生和基因工程技术的发展使抗体作为药物成为可能。单克隆抗体因具有特异性、多样性并且能够“量身定做”的特点而被寄予厚望，曾一度被称为疾病治疗的“魔弹”。生物技术制药企业也开始看好抗体药物的商业价值。二十世纪九十年代后期，抗体药物在经历了一段曲折的发展历程之后，又重新焕发出生机和活力。抗体药物的研究和开发迅速成为新世纪生物技术制药领域的一个重要发展方向，抗体药物治疗疾病的时代已经来临。     

中药对P-糖蛋白的影响及机制的研究进展

P-糖蛋白是广泛分布于人体正常组织中的转运蛋白,能将内源性、外源性物质及其代谢物排出细胞。其广泛分布及对药物的逆向转运功能,使其在药物的吸收、分布、代谢和排泄方面都具有重要意义。P-糖蛋白可识别和转运在结构、化学性质和药理学特性等方面均不同的化合物,对P-糖蛋白的抑制或诱导可产生P-糖蛋白介导的药物相互作用,导致底物药物的不良反应增加或治疗不足。抑制P-糖蛋白可减少药物外排,以提高抗肿瘤药物的治疗效果,或增加药物在脑组织中的积累量,提高中枢神经系统疾病的治疗效果。关于中药对P-糖蛋白影响的报道日渐增多,本文根据已有的国内外研究,归纳了各种中药及其成分对P-糖蛋白的影响及作用机制,以系统了解并指导该领域的研究,并为临床合理用药提供参考。     

表皮生长因子受体家族单克隆抗体耐药机制的研究进展

表皮生长因子受体（EGFR）家族广泛存在于体内各种细胞中,其异常活化与多种人类上皮组织肿瘤的发生、发展密切相关,因此已成为肿瘤治疗的重要靶点之一。目前靶向EGFR家族的药物包括小分子酪氨酸激酶抑制剂和单克隆抗体（简称单抗）类药物,特别是单抗类药物近年来在临床上获得了广泛的应用。但是,越来越多的临床资料表明,大量患者对这类药物表现出原发性耐药或获得性耐药。目前靶向EGFR家族单抗类药物产生耐药的原因主要包括：受体结构改变、血管生成、多种受体酪氨酸激酶的活化、EGFR的亚细胞定位、EGFR下游效应分子的持续激活和EGFR家族生长因子表达的上调等。本文就靶向EGFR家族单抗类药物耐药机制的研究进展进行综述。     

Targeted cancer therapies based on antibodies directed against epidermal growth factor receptor： status and perspectives

Compelling experimental and clinical evidence suggests that epidermal growth factor receptor （EGFR） plays an important role in the pathogenesis of a variety of human cancers; thus, providing a strong rationale for the development of receptor antagonists as effective and specific therapeutic strategies for the treatment of EGFR-expressing cancers. Monoclonal antibodies （mAb）, owing to their high specificity towards a given target, represent a unique class of novel cancer therapeutics. A number of anti-EGFR mAb are currently being developed in our clinic, including two that have been approved by the United States Food and Drug Administration for the treatment of refractory metastatic colorectal cancer （mCRC） and squamous cell carcinomas of the head and neck （SCCHN）. Cetuximab （Erbitux, IMC-C225）, an IgG 1 mAb, has demonstrated significant antitumor activity, both as a single agent and in combination with chemotherapeutics and radiation, in patients with refractory mCRC and SCCHN, respectively. Panitumumab （Vectibix）, an IgG2 mAb, has been approved as a single agent for the treatment of patients with refractory mCRC. These mAb, via blocking ligand/receptor interactions, exert their biological activity via multiple mechanisms, including inhibition of cell cycle progression, potentiation of cell apoptosis, inhibition of DNA repair, inhibition of angiogenesis, tumor cell invasion and metastasis and, potentially, induction of immunological effector mechanisms. Anti-EGFR antibodies have demonstrated good safety profiles and potent anticancer activity in our clinic and may prove to be efficacious agents in the treatment of a variety of human malignancies.     

Modifications of DNA by platinum complexes. Relation to resistance of tumors to platinum antitumor drugs.

The importance of platinum drugs in cancer chemotherapy is underscored by the clinical success of cisplatin [cis-diamminedichloroplatinum(II)] and its analogues and by clinical trials of other, less toxic platinum complexes that are active against resistant tumors. The antitumor effect of platinum complexes is believed to result from their ability to form various types of adducts with DNA. Nevertheless, drug resistance can occur by several ways: increased drug efflux, drug inactivation, alterations in drug target, processing of drug-induced damage, and evasion of apoptosis. This review focuses on mechanisms of resistance and sensitivity of tumors to conventional cisplatin associated with DNA modifications. We also discuss molecular mechanisms underlying resistance and sensitivity of tumors to the new platinum compounds synthesized with the goal to overcome resistance of tumors to established platinum drugs. Importantly, a number of new platinum compounds were designed to test the hypothesis that there is a correlation between the extent of resistance of tumors to these agents and their ability to induce a certain kind of damage or conformational change in DNA. Hence, information on DNA-binding modes, as well as recognition and repair of DNA damage is discussed, since this information may be exploited for improved structure-activity relationships.     

Looking at drug resistance mechanisms for microtubule interacting drugs: does TUBB3 work?

Vinca alkaloids and taxanes represent the mainstay of medical treatment of hematological and solid tumors. Unfortunately, a major clinical problem with these agents is drug resistance. Although a plethora of mechanisms of drug resistance have been described, only a few of them have been validated in clinical trials. Among these, the one involving the protein TUBB3 seems to represent a promising target for studying drug resistance. In fact, it seems that this protein is a factor promoting cell survival and represents an endogenous element of an inherent drug-resistance program built into cells to counteract the activity of microtubule-interacting drugs. Its pivotal role has been ascertained in clinical trials in lung, breast, and ovarian cancer, three diseases that can be successfully treated with microtubule-interacting drugs. Although TUBB3 is probably not a unique factor in drug resistance, the hope is that direct targeting of this protein will increase the response to microtubule-interacting drugs, thereby overcoming an important element in the growth of drug resistance.     

Targeting polyamine metabolism: a viable therapeutic/preventative solution for cancer?

The polyamine pathway has been identified as a target for the design of new antiproliferative drugs, due to the strong positive relationship between intracellular polyamine content and cell, particularly cancer cell growth. A number of single enzyme inhibitors have been synthesised against the two key biosynthetic enzymes, ornithine decarboxylase and S-adenosylmethionine decarboxylase, but their success in the clinic has been limited due to incomplete polyamine depletion and induction of compensatory mechanisms that counteract the effects of enzyme inhibition. Overall, clinical trials of these agents as chemotherapeutic drugs have proved disappointing, with either little clinical efficacy or unacceptable toxicity. The polyamine analogues provide an alternative strategy that shows promise, particularly against diseases other than cancer. Combination of the polyamine inhibitors with classic cytotoxic agents may be an alternative strategy that is showing some promise, at least in vitro. An avenue that is, however, presently more promising is the use of polyamine inhibitors or analogues as chemopreventative agents against a range of human cancers. It seems likely that the future use of these drugs will be in disease prevention rather than treatment. With regard to the newer agents with restricted conformation that are now undergoing clinical trials, it is too early to say whether they will be chemotherapeutic and/or chemopreventative. This article focuses on the clinical use and responses to inhibitors of polyamine metabolism.     

The emergence of resistance to targeted cancer therapeutics

Drug resistance has always been a concern in cancer treatment, often blamed on the genetic complexity and instability of tumor cells. While studies of cancer cell lines have implicated an array of potential mechanisms, it has been difficult to translate these insights into clinically meaningful improvements in cancer treatment. The successful deployment of molecularly targeted therapeutics in some cancers has led to widespread optimism that this approach will become broadly applicable. Despite their early promise in the clinic, the novel therapeutics are often plagued with the age old problem of acquired drug resistance. Progress in understanding why certain patients respond and why some develop resistance can be made rapidly through studies of the drug target in tumor tissue from patient. One important lesson is that many cancers, even in the most advanced stages, continue to rely on a limited number of critical oncogenic signals for maintenance of the malignant phenotype. This article reviews the mechanisms of drug resistance to a variety of cancer therapeutics and provides an approach for how measures of drug target activity can be incorporated into clinical trial design.     

Understanding resistance to combination chemotherapy

The current clinical application of combination chemotherapy is guided by a historically successful set of practices that were developed by basic and clinical researchers 50–60 years ago. Thus, in order to understand how emerging approaches to drug development might aid the creation of new therapeutic combinations, it is critical to understand the defining principles underlying classic combination therapy and the original experimental rationales behind them. One such principle is that the use of combination therapies with independent mechanisms of action can minimize the evolution of drug resistance. Another is that in order to kill sufficient cancer cells to cure a patient, multiple drugs must be delivered at their maximum tolerated dose – a condition that allows for enhanced cancer cell killing with manageable toxicity. In light of these models, we aim to explore recent genomic evidence underlying the mechanisms of resistance to the combination regimens constructed on these principles. Interestingly, we find that emerging genomic evidence contradicts some of the rationales of early practitioners in developing commonly used drug regimens. However, we also find that the addition of recent targeted therapies has yet to change the current principles underlying the construction of anti-cancer combinatorial regimens, nor have they made substantial inroads into the treatment of most cancers. We suggest that emerging systems/network biology approaches have an immense opportunity to impact the rational development of successful drug regimens. Specifically, by examining drug combinations in multivariate ways, next generation combination therapies can be constructed with a clear understanding of how mechanisms of resistance to multi-drug regimens differ from single agent resistance.     

Overcoming resistance to molecularly targeted anticancer therapies: Rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies

Accumulating evidence suggests that cancer can be envisioned as a “signaling disease”, in which alterations in the cellular genome affect the expression and/or function of oncogenes and tumour suppressor genes. This ultimately disrupts the physiologic transmission of biochemical signals that normally regulate cell growth, differentiation and programmed cell death (apoptosis). From a clinical standpoint, signal transduction inhibition as a therapeutic strategy for human malignancies has recently achieved remarkable success. However, as additional drugs move forward into the clinical arena, intrinsic and acquired resistance to “targeted” agents becomes an issue for their clinical utility. One way to overcome resistance to targeted agents is to identify genetic and epigenetic aberrations underlying sensitivity/resistance, thus enabling the selection of patients that will most likely benefit from a specific therapy. Since resistance often ensues as a result of the concomitant activation of multiple, often overlapping, signaling pathways, another possibility is to interfere with multiple, cross-talking pathways involved in growth and survival control in a rational, mechanism-based, fashion. These concepts may be usefully applied, among others, to agents that target two major signal transduction pathways: the one initiated by epidermal growth factor receptor (EGFR) signaling and the one converging on mitogen-activated protein kinase (MAPK) activation. Here, we review the molecular mechanisms of sensitivity/resistance to EGFR inhibitors, as well as the rationale for combining them with other targeted agents, in an attempt to overcome resistance. In the second part of the paper, we review MAPK-targeted agents, focusing on their therapeutic potential in haematologic malignancies, and examine the prospects for combinations of MAPK inhibitors with cytotoxic agents or other signal transduction-targeted agents to obtain synergistic anti-tumour effects.