中外专家怎样面对细菌耐药——挑战与对策

星火

以下来自丁香园的两篇文章,中外专家怎样面对细菌耐药——挑战与对策,有何异同呢?
New Method To Overcome Multiple Drug Resistant Diseases

ScienceDaily (Aug. 19, 2008) — Many drugs once considered Charles Atlases of the pharmaceutical realm have been reduced to the therapeutic equivalent of 97-pound weaklings as the diseases they once dispatched with ease have developed resistance to them.

科学日报2008年8月19日电—很多药物认为，因为耐药，曾经叱诧风云的药物王国中的战斗英雄如今已经风光不再，变成了羸弱的士兵。

The problem is well documented for antibiotics, although not confined to them. Chemotherapy drugs that were once highly effective when first used against a particular cancer now are often rendered near powerless when a patient's cancer resurges.

尽管指的不是抗生素，但在抗生素界这个问题得到了很好的印证。开始用于治疗某种癌时很有效的化疗药物，癌症复发时再用往往就没用了。

Even more devastating, when an organism develops resistance to one drug, it often becomes resistant to other drugs (known as multi-drug resistance), rendering not just one medication but a whole class of therapeutics useless against it.

更糟糕的是，一旦机体对一种药物耐药，常常对其他药物也耐药，即多药耐药。这就使得失效的不只是一种药物，而是一类药物。

But researchers at Stanford University have developed a method to get around one of the most common forms of resistance, thereby opening up some if not many resistant diseases to the reinvigorated fury of the medications that once laid them low. To do it, they took a tip from nature.

不过，斯坦福大学的研究人员已经研究出一种新方法，这种方法能够躲避最常见的耐药，因此打开了一些局面，使曾经将这些疾病打倒的药物重新振作起来。他们从自然界汲取灵感。

"Nature has developed all of this firepower for getting things into cells, and one of the ways is to create entities that are arginine-rich," said Paul Wender, the Bergstrom Professor of Chemistry at Stanford University. Arginine is an amino acid, the building block of proteins, and as such is found in virtually every cell in the human body, as well as other mammalian bodies.

斯坦福大学化学系的Bergstrom 教授Wender说：“自然界在让物质进入细胞方面极尽能事，其中之一就是制造富含精氨酸的东西。精氨酸是一种氨基酸，氨基酸则是构成蛋白质的基本单位，人类的每个细胞都是这样的，其他哺乳动物也是如此。”

Using such a common transporter to ferry a potent medication inside a resistant cell is a bit like recruiting your grandmother to cart a load of switchblade knives through customs. Indeed, Wender said, "Arginine-rich sequences appear to figure in the mechanisms by which many pathogens invade cells." Wender's team used a necklace of eight arginine molecules to surround the medication they worked with.

利用这一常见的载体将有效的药物运送至耐药细胞中，这有点像让你的祖母装一车开关闸刀通过海关。Wender说：“实际上，富含精氨酸的序列也出现在许多病原体侵犯细胞的机制之中。” Wender的研究小组利用一串含有八个精氨酸的分子将目的药物围在其中。

Wender and his colleagues figured out that a particular molecular subunit within arginine, called a guanidinium group, was what nature actually exploits to get foreign substances through cell membranes. Working with Taxol(r), a widely used chemotherapeutic agent, they attached a series of arginines with their associated guanidinium groups and tried it out against Taxol-resistant ovarian cancer cells implanted in mice. It worked.

Wender和同事们发现，在精氨酸中有一个特殊的亚基叫做胍基。自然界中的细胞就是利用这一亚基将外源性物质透过细胞膜的。他们将紫杉醇，一种使用广泛的化疗药物通过胍基接上一串精氨酸，在移植有耐紫杉醇的卵巢癌的荷瘤小鼠身上做实验获得了成功。

"It's an exciting result to be able to take a drug known to work against cancer, but stymied by resistant cells, and restore it to effectiveness using an arginine transporter," Wender said. "This bodes well for use with other drugs that succumb to resistance."

Wender说：“真是令人兴奋，应用精氨酸载体能携带原本对肿瘤有效，但碰到耐药细胞失败的药物，并使它恢复疗效。这预示着其他受困于耐药问题的药物良好的使用前景。”

A paper describing the work is scheduled to be published next week in the online Early Edition of the Proceedings of the National Academy of Sciences. Wender's group collaborated with that of Chris Contag, a professor of pediatrics and of microbiology and immunology at Stanford's School of Medicine, who is a co-author on the paper.

描述这一工作的报道将登在下周国家科学院年报网络版。Wender小组的合作者，同时也是这篇报道的合著者，包括：斯坦福医学院的儿科学教授Chris Contag领导的小组，一位微生物学教授和一位免疫学教授。

"Overcoming Taxol resistance is big. It's huge," said Nelson Teng, professor of obstetrics and gynecology at the Medical School. "In essence, the technology can be used to overcome one of the most challenging types of problems of drug resistance."

医学院妇产科教授尼尔森Teng说：“攻克紫杉醇的耐药性是重大的发现，是特大的发现。实质上，这种技术可以用来攻克最具挑战性的耐药问题。”

The type of drug resistance that Wender's work has overcome develops when pumps located in the membrane that encloses a cell become sensitized to a medication. It is one of the most common ways in which resistance manifests. The pumps, which normally capture and eject foreign material from a cell, are produced at higher levels in certain resistant cells and, because of their increased number, become more effective at tossing the drug molecules out.

位于细胞膜的泵对药物敏感的时候，Wender的工作已经克服的耐药类型发生了。这是耐药产生的最常见的方式。这些泵通常是将外来物质捕获，并泵出细胞。耐药细胞会产生很多泵，由于数量很多，泵出药物分子格外有效。

"It is kind of like a bouncer," Wender said. "If you're not recognized as being part of the club, then you're kicked out." Resistant cells also create a lot more of the pumps than a normal cell would have.

Wender说：“它的作用有点和保镖类似。如果它认为你不是俱乐部的成员，就会把你踢出去。”耐药细胞的泵较正常细胞多得多。

Some researchers have tried dealing with this situation by adding another molecule to the mix to inhibit the pump, keeping it busy so the medication can slip in while the pumps are occupied with the decoy molecule. But if any of the molecules make their way into healthy cells, they can gum up the proper functioning of the pumps in those cells, too, adding to the litany of undesirable side effects that generally accompany chemotherapy.

有人想办法解决这一问题，加入另一种分子抑制泵，泵忙着泵出诱饵分子，药物乘机溜进去。但是如果这些药物进入正常细胞中，就会扰乱这些细胞中泵功能的正常发挥，这加剧了化疗药物治疗本来就有的副作用。

Wender's group decided to see if they could take drugs to which diseases had become resistant and, by combining them with what they call "molecular transporters," get them in around the pump.

Wender的研究小组决定看看，它们能不能把药物带入耐药的细胞中；将它们与他们所谓的“分子载体”结合以后，它们能不能使药物避开泵的外排。

"If we think of the pump as being a bouncer for the cellular club, then effectively what we're doing is disguising one of these therapeutic agents to get it in through the back door or the side door," Wender said. "We're not even going to deal with the bouncer."

Wender说：“如果我们把泵比作是细胞俱乐部的保镖，那么我们所要做的就是把治疗药物乔装打扮，从后门或侧门混进去。我们甚至不需要搭理保镖。”

Therein lies what may be the greatest value of the work. The basic approach of bonding a medication to an arginine-rich transporter to slip it past the cellular sentries could, in theory, be used to get any of a host of medications into any cell that has developed the type of resistance involving increased numbers of export pumps.

这项工作的最大价值就在于：其基本思想，即将药物结合到一个富含精氨酸的载体上，穿过细胞膜，理论上，可以将之用于把任何药物带入任何因为外排泵增加产生耐药的细胞。

"This could potentially be used with any drug which is effective but has a delivery problem," Teng said. "Not just Taxol."

“这可能适用于任何有效，但无法到达用药部位的药物。不只是紫杉醇。”Teng说。


That could include medications for diseases caused by antibiotic resistant bacteria, such as multi-drug resistant tuberculosis, or by drug resistant parasites such as malaria, as well as other types of cancer.

那可能包括耐药菌导致的疾病，比如多药耐药的结核；耐药的寄生虫性疾病，比如疟疾；还有其他肿瘤。

The arginine transporter manages to avoid ejection by slipping through the membrane of the cell in between the pumps. The key is the ability of arginine to form weak, temporary bonds with some of the molecules that reside in the membrane.

精氨酸载体通过泵之间的膜进入细胞，从而避开泵外排。关键是精氨酸与存在于膜内的其他分子形成弱的、暂时性的键的能力。

"As the transporter, with all these arginine guanidinium groups, approaches the cell, it basically does a handshake using hydrogen bonds with cell surface constituents that are in the membrane," Wender said. "In essence, it changes its physical properties by shaking hands with all these cell membrane components."

Wender说：“作为载体，它利用这些精氨酸胍基接近细胞，常常通过氢键与细胞表面的成分握手。实质上，它通过与膜上所有的成分握手，改变了自身的物理性质。”

That change in physical properties effectively cloaks the arginine-Taxol complex, allowing it to slip past the sentries and into the cell. As it passes into the cell, the weak bonds it formed with the membrane components break and the transporter, with its therapeutic load, is free to roam inside the cell.

这种物理性质的改变有效地遮蔽了精氨酸－紫杉醇复合体，允许它绕过岗哨，溜进细胞。进入细胞后，它与膜组分之间形成的这种弱键断裂，载体与它带进来的治疗药物自由地徜徉在细胞内。

But after getting into the cell, the arginine-Taxol complex still has to break apart for the Taxol to do its job against the cancer cell. Wender's group achieved this by taking advantage of the presence of a molecule called glutathione, which is generally abundant inside cells and which in cancer cells tends to be present in higher levels than usual.

但是，进入细胞后，精氨酸－紫杉醇复合体还要释放出紫杉醇，紫杉醇才能发挥抗肿瘤作用。Wender的研究小组利用谷胱甘肽分子的存在实现了这一目标。谷胱甘肽通常在细胞内很多，而且，肿瘤细胞内谷胱甘肽的含量比正常细胞中多。

Glutathione is predisposed to attacking sulphur-sulphur bonds, so that is the bond the researchers used to hold the arginine and Taxol together. Once the arginine-Taxol complex is inside the cell, the glutathione can get to work hacking away at the sulphur bonds, and in the process, unwittingly release the compound that will spell its doom.

谷胱甘肽容易攻击二硫键，二硫键正是研究人员用来将紫杉醇和药物连接起来的键。一旦精氨酸－紫杉醇复合体进入细胞内，谷胱甘肽就会打断二硫键，从而解离了精氨酸－紫杉醇复合体，复合体也完成了它的使命。

Because glutathione is relatively scarce outside of cells, the arginine transporter is effectively inert in that environment, so there are no side effects from having the arginine-Taxol complex moving through the patient's body. This is in stark contrast to the present situation, as many patients are extremely sensitive to the molecular vehicle that is currently used to administer ferried Taxol to the cancer cells.

因为谷胱甘肽在细胞外相对而言比较稀少，精氨酸载体在那样的环境中实际上是没有活性的，所以病人体内有精氨酸－紫杉醇复合体没有任何副作用。这和现今的情况形成了鲜明的对比，很多病人对一些用来将紫杉醇运到癌细胞的载体分子异常敏感。

The researchers achieved another breakthrough by tinkering with the form of the arginine used in their transporter. By altering certain aspects of the arginine, the researchers were able to control the rate at which glutathione slices and dices the arginine-Taxol complex.

研究人员在精氨酸的形式方面取得另一突破。通过改变精氨酸的某些性质，研究人员能够控制谷胱甘肽切割精氨酸－紫杉醇复合体的速率。

This gives them an unprecedented ability to regulate the amount of medication that is active inside the patient at any point in time. To date, doctors have had to be content with injecting as high a dose of medication as patients can tolerate and then waiting as the effective amount in the patients slowly dwindled until they could safely inject more. This approach results in a repeated pattern of rapid spikes in the amount of medication in the system, followed by slow declines until the next spike. Ideally, doctors would like the patient to be continually experiencing the maximum tolerable dosage to keep the pressure on the cancer cells, killing them off as quickly and as thoroughly as possible. The arginine transporter makes this possible.

这一突破使他们在任何时间点控制病人体内有活性的药物的量方面拥有了空前的能力。迄今为止，医生不得不满足于给病人一剂能够耐受的最高剂量，等待病人将药物缓慢排出，才开始注射下一剂量。这种方法导致病人体内的药物出现一个快速上升的峰，然后是缓慢的下降，直到下一个峰出现。理想的情况是，医生希望病人体内有持续的可耐受的最大浓度的药物剂量，以便压制肿瘤细胞，尽可能在最短时间内彻底地杀死肿瘤细胞。精氨酸载体使这一夙愿成为可能。

Ovarian cancer was chosen as the subject cancer for this study in part because it commonly develops resistance to Taxol, but also because of a low long-term success rate in treating it. The American Cancer Society estimates that in the United States alone there will be 21,650 diagnoses of ovarian cancer this year and 15,500 deaths from it.

之所以选择卵巢癌作为研究主题，除了卵巢癌常常对紫杉醇耐药以外，更重要的是因为治疗卵巢癌长期成功率很低。据美国癌症学会估计，今年美国就有21650人被诊断为卵巢癌，15,500人死于卵巢癌。

"Ovarian cancer has a drug [Taxol] that works pretty well in the beginning. Seventy or eighty percent of the patients have a response," Teng said. "But it fails at the end because drug resistance develops."

Teng说：“其实一开始，有一种药物（紫杉醇）可以很好地控制卵巢癌，大约百分之七、八十的病人对治疗有反应。但是，最终由于耐药治疗失败了。”

Further studies need to be done to demonstrate the safety of arginine transporters before they can be used in this application in humans, Wender and Teng said. But the researchers already have positive safety data from tests of arginine-transporter technology in another application, one that does not involve drug resistance, so they are optimistic. The discovery of effective arginine transporters could be the key to treating ovarian cancer, as well as other diseases that develop drug resistance, more effectively.

还需要更多的实验证实精氨酸载体的安全性后，才能将它用于人体。但是，研究人员已经从别的实验中（不是耐药性实验）获得了精氨酸载体的安全性数据，所以他们对此持乐观态度。有效的精氨酸载体的发现可能是更有效地治疗卵巢癌以及其他耐药性疾病的钥匙。

Other co-authors of the paper in PNAS are Elena Dubikovskaya, a graduate student at the time this work was done and now a postdoctoral fellow at University of California-Berkeley; Steve Thorne, a postdoctoral fellow at the time this work was done and now on a faculty member at the University of Pittsburgh; and Thomas Pillow, a graduate student in chemistry.

该报道的其他合著者为：Elena Dubikovskaya，完成这个工作时是研究生，现在是加州大学伯克利分校的博士后研究员；Steve Thorne，完成这项工作时是博士后研究员，现在是匹兹堡大学的教师；Thomas Pillow，化学系的研究生。

Teng is working with Wender on other projects stemming from the work with Taxol but was not involved in the research described in this paper.

Teng在紫杉醇项目衍生的其他项目上，也在和Wender合作，其具体的研究内容本文未涉及。

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heyuhuan

谢谢,老师的敬业精神值得学习

海内知己

不错的东东,谢谢啦!!!:ok

星火

英国禁止医生随意开抗生素的启示
来自医药经济报   作者：沈峰
　　
　　英国国家医疗服务系统所属“全国卫生与临床学会”出台新规。根据新规，英国医生不得给患有轻微耳道感染、咽喉痛、扁桃体炎、感冒、咳嗽、鼻窦炎、支气管炎的病人开具抗生素类药品处方，取而代之的是建议患者回家休息或服用止痛片。今年年初，英国卫生大臣艾伦•约翰逊曾在全国范围内组织宣传活动，呼吁民众不要在咳嗽或感冒时服用抗生素，因为它对这两种病几乎无效。
　　对于感冒、咳嗽、喉痛等病症，英国规定医生不得开抗生素，这对我国具有极强的启示。世界卫生组织调查显示，中国住院患者抗生素药物使用率高达80%，其中联合使用两种以上抗生素的占58%，远高于30%的国际水平。据统计，我国每年有8万人直接或间接死于滥用抗生素，滥用抗生素使我们战胜疾病的代价越来越高。
　　造成国内抗生素滥用的原因，一是目前不够完善的医疗体系、以药养医的机制。笔者就有亲身经历，在过去的几年中，笔者带孩子在当地的三甲医院儿科看病（只有专家号），每次费用都不下200元，孩子不管是感冒，还是咳嗽，医生总是开出一大堆抗生素。难道那些享受国家津贴的老专家，不知道滥用抗生素的危害？看一个小病，医生为什么要让患者大掏荷包呢？
　　其次，少数医生随意地开具抗生素处方，患者在少数药店可以不凭处方买到抗生素。很多患者对抗生素的认识不够，盲目相信它的功效。很多人对抗生素的认识仍然停留在可以消炎的水平上。
　　另外，一些医疗广告也在诱导人们滥用抗生素。从这个意义上说，英国禁止医生给患者滥开抗生素值得我们效仿，这样做可以从源头上降低滥用抗生素对人们健康的危害。目前我国有80%以上的药品是通过医院卖给消费者的，和医院出售的抗生素相比，药店的销量占很少的比例，所以抗生素滥用的问题主要出在医院。
　　前不久笔者看了一部韩国电视剧，剧中的女儿因嗓子痛让做医生的父亲开些药，父亲说，这种小病还要吃药吗？回家多喝白开水就可以了。笔者以为，我国医院的大夫，也应“深怀爱民之心”，多些民生情怀，不可在利益诱惑下对患者随意开抗生素。绝大部分患者会听从医生的建议，医生做到不随意开抗生素，患者滥用抗生素的几率就会下降。当然，最根本的措施还是要像英国那样，通过制度建设让国民认识到滥用抗生素的危害，并禁止医生给患者滥开抗生素。

潇湘雨

滥用抗生素的例子比比皆是，甚至达到触目惊心的程度。
星版的建议很中肯，遏制抗生素滥用关键是医生的责任心，同时也要有相应的制度来约束。

Yubl

谢谢专家，我学习了，多谢！