难治的偏头痛让科学家头痛
Fresh Target In Hunt For A Migraine Cure
来源：华尔街日报    2012-08-21

        The hunt is intensifying for new treatments for migraines, the common and debilitating headaches that have confounded scientists for decades.         
        Of greatest focus for researchers is a brain chemical known as CGRP, which appears to play a role in the transmission of pain, but not in other brain functions, such as cognition or mood. Researchers are trying a variety of experimental drugs to stop CGRP from working by blocking its receptors in the brain. Others are working on artificial antibodies that could soak up the chemical in the bloodstream or brain before it can trigger migraines.        
        Experts say the need for new medicines to treat migraine pain once it begins is great because current drugs only provide some benefit for 50% to 60% of sufferers and can't be used in people with heart disease or who have had a stroke. Also, they aren't a cure, and in many cases, the headaches tend to come back within 24 hours.          
        There also is a separate category of preventive drugs, which tend to be used by a small proportion of people who suffer from more frequent or debilitating migraines.        
        'People need migraine drugs that have a rapid onset of action, that take the pain away and keep it away,' says Richard Lipton, director of the Montefiore Headache Center in New York.
        Headache disorders are among the most common medical conditions world-wide. More than 1 in 10 adults globally are affected by migraines, which can be incapacitating, according to the World Health Organization. International studies have found that 50% to 75% of adults have reported a headache in the past year, with up to 4% of the global population reporting having a headache in half or more of the days each month, WHO says.          
        There isn't such a thing as a 'regular' headache, but rather more than 300 types, says David Dodick, a professor of neurology at the Mayo Clinic's branch in Phoenix and chairman of the American Migraine Foundation. People having migraines usually experience intense pain, sensitivity to light, dizziness and sometimes nausea and visual and sensory symptoms called auras. Two other major types of headaches are caused by tension or medication overuse.         
        Nonsteroidal anti-inflammatory painkillers such as ibuprofen work for some migraine sufferers. But the class of migraine medicines that hit the market in the 1990s called triptans remain the best or only treatment option for many patients. Nevertheless, about half of sufferers don't respond to them or can't take them because of other health reasons.        
        CGRP, which stands for calcitonin gene-related peptide neurotransmitter, has long been thought to play a role in migraines, but for much of that time for the wrong reason. Part of the confusion was because of a misunderstanding of migraines themselves.        
        Why they occur still isn't clear, but specialists say they have recently begun to understand the migraine as a brain disorder and not a vascular disorder. Until about 12 years ago, they were believed to stem from constriction of blood vessels in the brain. The dilation of the vessels to compensate then led to the throbbing pain, so the thinking went.         
        Now, it appears more likely that migraines 'hijack' the brain's normal pain circuitry, says Dr. Dodick. The brain's normal pain-sensory system, in which nerve endings send messages to the brain about a threat, goes awry in migraines.         
        Experts disagree about how a migraine is triggered, but the trigeminal nerve -- an important pathway that carries sensory information about the face -- and its connections to numerous other nerves and the brain appear to be responsible for transmitting the pain.        
        Researchers also have isolated certain genes that might be linked to a predisposition for migraines, Dr. Dodick says.         
        Triptans, which promote blood-vessel constriction and inflammation, block the release of CGRP in the trigeminal nerve. While CGRP does aid the blood-vessel dilation process, its role activating the nerves in the brain appears to be the key when it comes to migraine pain.  
        In the mid-1980s, Peter Goadsby, a neurologist and headache specialist at the University of California San Francisco, and his colleagues found that CGRP is released in migraines and that triptans decreased CGRP action.          
        Several researchers and companies have been trying to develop drugs that bind to the CGRP receptors to prevent the chemical from activating the pain network. But because CGRP has a complex receptor -- the slot where the molecule must bind in order to initiate actions in the body -- it took chemists 15 years to figure out how to block the effects of CGRP, and even longer to develop a compound that could be taken orally, says Dr. Goadsby.       
        Bringing to market CGRP blockers, or antagonists -- the most advanced of the new drugs in development for migraines -- has proved challenging. Several investigational compounds have been shown to be toxic to the liver, a challenge that highlights the difficulty in developing drugs for conditions that affect the brain.        
        CGRP antagonists don't appear to work as well as triptans, but the blockers have an advantage in they don't appear to cause cardiovascular complications, says Stephen Silberstein, a neurology professor and director of Thomas Jefferson University's Headache Center in Philadelphia.           
        'You trade one kind of risk for another,' says Dr. Silberstein, who has served as an investigator on several companies' clinical trials.          
        Merck & Co. had a promising CGRP-receptor antagonist under development but discovered in late-stage clinical-trial testing that some patients experienced liver enzyme changes. In July of last year, the company said it was discontinuing development of the compound, telcagepant, after looking at all its trial data. Germany's Boehringer Ingelheim GmbH was also working on a CGRP antagonist but canceled development. A spokesman declined to comment.          
        Bristol-Myers Squibb Co. is conducting several early stage studies on CGRP antagonists and other companies are testing or may begin development of similar compounds as well.          百时美施贵宝公司（Bristol-Myers Squibb Co.）
        Researchers and companies also are trying to develop artificial antibodies that, when injected, would glom onto CGRP in the bloodstream or brain, before it reaches the receptors in the brain, or by blocking the receptors.          
        Research into these biologic antibody-based approaches is at an earlier stage than the testing of antagonist drugs, but antibodies eventually might be able to block CGRP action regularly so that migraines don't ever begin.          
        'The CGRP story is a story of developing an acute treatment for migraine,' says Dr. Goadsby. 'But the antibody story is testing the larger idea [that] if you blocked continuously CGRP, would you have a preventive treatment.'         

　　人类正在加紧寻求治疗偏头痛的方法，这种让人身体虚弱的常见头痛病已经困扰了科学家数十年。 

　　研究人员关注最多的是一种名为降钙素基因相关口（CGRP）的大脑化学物质，这种物质似乎与痛感传递有关，但是在认知或情绪等大脑的其它功能方面并没有造成影响。研究人员尝试使用各种实验药物，通过屏蔽大脑里感应CGRP的部分来阻止CGRP发生作用。还有一些人正致力于人工抗体的研制，使其在CGRP引发偏头痛之前将血液或大脑中的这种化学物质吸收。 

　　专家说，治疗偏头痛的新药一旦面世就会有巨大需求，因为目前的药物只对大约50%-60%的患者有一定疗效，并且心脏病患者和有中风病史的人都不能服用。而且这些药物并不能治本，在很多病例中，患者在24小时内又会出现头痛。

　　还有一种单独类型的预防性药物，使用者一般是一小部分偏头痛发生频率较高或发作起来更难受的人。 
“人们需要立竿见影的偏头痛药，能够止痛并让它不再复发，”纽约蒙特菲奥里头痛研究中心（Montefiore Headache Center）的主任理查德•利普顿（Richard Lipton）说。

　　头痛症是全世界最常见的医学病症之一。根据世界卫生组织（World Health Organization）的数据，在全球范围内，每10名成年人中就有1人以上身受可能让人无法正常行动的偏头痛之苦。世卫组织说，国际研究发现，在过去的一年里，有50%-75%的成年人声称发生过头痛。全球人口中有4%的人每月有一半或者一半以上的日子里会发生头痛。
　　美国梅约诊所（Mayo Clinic）凤凰城分所神经学教授、美国偏头痛基金会（American Migraine Foundation）主席大卫•多迪克（David Dodick）说，头痛没有一种“常规”病症，而是有300多种类型他也是。患偏头痛的人通常会感受到剧痛、对光线敏感、头晕，有时会感到恶心，还会有一些被称为先兆的视觉和知觉症状。另外两大类头痛的成因是紧张或药物使用过度。

　　像布洛芬这样的非类固醇抗炎镇痛药对某些偏头痛患者有效。但是上世纪90年代面市的曲坦类偏头痛药对很多患者来说仍然是最好或唯一的药物选择。然而，大约一半的患者要么服用这类药后没有效果，要么由于其他健康原因不能服用此类药物。 

　　CGRP是降钙素基因相关口神经递质的缩写，长久以来它被认为在偏头痛中发挥了作用，不过很长一段时间里这种看法的依据都是错误的。出现混乱的原因是对偏头痛本身产生了误解。 

　　偏头痛发生的原因尚不清楚，但是专家们说他们最近开始把偏头痛当作一种大脑病症而非血管病症。直到大约12年前，偏头痛都被认为是由于大脑血管收缩引起的。血管的补偿性扩张就导致了搏动痛，当时的人们就是这么想的。 
　　多迪克说，现在看来，更有可能是偏头痛“拦截”了大脑的正常疼痛回路。在大脑正常的疼痛感知系统里，神经末梢会将威胁信息发送给大脑，偏头痛发生时这个系统就会出错。 
　　偏头痛是如何引发的？专家们对此意见不一，但是三叉神经（传递面部周围感官信息的重要途径）以及它与其它各种神经和大脑的连接神经似乎是传递疼痛的介质。

　　多迪克医生说，研究人员已经把某些与易患偏头痛体质相关的基因分离出来。 

　　引起血管收缩和发炎的曲坦类药物可以阻止三叉神经中CGRP的释放。虽然CGRP的确促进了血管的扩张进程，但在偏头痛问题上，它对激活大脑神经所起的作用似乎才是最关键的。

　　20世纪80年代中期，加州大学旧金山分校（University of California San Francisco）的神经病学家和头痛治疗专家彼得•戈德比（Peter Goadsby）和他的同事发现，CGRP在偏头痛发生时被释放出来，而曲坦类药物减少了CGRP的活动。

　　好几家研究机构和公司一直在努力研发可以作用于CGRP感应器官的药物，从而阻止这种化学物质激活疼痛网络。但是戈德比医生说，由于CGRP的感应器官非常复杂──药物分子必须作用于这种感应器官才能激发身体的行动──药物学家用了15年时间来研究如何阻止CGRP起效，而研制可以口服的药物还要更长时间。 
　　事实证明，面向市场推出CGRP阻滞药物或者拮抗物──最先进的偏头痛治疗新药──难度很大。好几种正在研制中的药物都被发现对肝脏有毒害作用，这项挑战突显了针对可影响大脑的病症开发药物的难度有多大。 
　　费城托马斯•杰斐逊大学头痛病研究中心（Thomas Jefferson University's Headache Center）的神经病学教授兼主任史蒂芬•西尔伯斯坦（Stephen Silberstein）说，CGRP拮抗药物的疗效似乎不如曲坦类药物，但是阻滞类药物的优点是它们似乎不会引起心血管并发症。

　　“你是以一种风险来替代了另一种风险，”西尔伯斯坦医生说。他担任了好几家公司产品临床试验的调研员。
　　默克公司（Merck & Co.）曾经研制了一种让人看好的CGRP感受器官拮抗药，但是在后期的临床测试中发现，有些患者出现了肝脏 改变的情况。去年7月，该公司称，在查看了所有试验数据之后，公司不再继续研制这种名为telcagepant的化学药物。德国的勃林格殷格翰制药公司（Boehringer Ingelheim GmbH）也曾研制过一种CGRP拮抗药，但后来终止了该产品的开发。一名发言人拒绝置评。
　　正在进行几种CGRP拮抗药的早期研究，其它公司也在对类似药物进行测试或者准备开始进行开发。 
　　研究人员和企业也在努力开发人工抗体，注射进人体后，人工抗体会在CGRP抵达感应器官之前拦截血液或大脑中的CGRP，或者屏蔽感应器官。
　　对于这类基于生物抗体的方法的研究处于早期，还未达到拮抗药物的测试阶段，但是抗体也许最终能够规律性地阻止CGRP的活动，使偏头痛无从发作。
　　“CGRP之说涉及到偏头痛紧急治疗方法的开发，”戈德比医生说，“但是对抗体的研究实际上是就更重要的理念展开测试，即如果不断阻止CGRP，就会是一种预防性的治疗手段。”