Modafinil

文章导读： 继GLP-1药物掀起减肥与代谢疾病治疗革命之后，制药业正在寻找下一个潜在的“超级药物平台”。这一次，目标可能是食欲素（orexin）——一种帮助大脑维持清醒、调节注意力、动机和奖赏的神经递质。 目前，首批食欲素激动剂已经进入临床应用，用于治疗罕见的发作性嗜睡病。更令人期待的是，科学家发现，食欲素的作用远不止“让人保持清醒”：它还可能与缺陷多动障碍、睡眠呼吸暂停、抑郁症和成瘾等疾病有关。 如果说GLP-1药物改变了我们对“饥饿”的控制，那么食欲素药物或许正在尝试改变我们对“清醒”的控制。继减肥药之后，下一场改变制药业的“肽类药物革命”，会不会发生在大脑？ The brain may be about to have its Ozempic moment 大脑药物领域或将迎来属于自己的“司美格鲁肽时刻” Pharma’s newest obsession involves mimicking the system that keeps people awake 制药行业最新的研发风口，是模拟维持人体清醒状态的生理系统 ONE PEPTIDE has recently transformed medicine. Drugs based on glucagon-like peptide-1 (GLP-1), a hormone released by the gut after a meal, began as treatments for diabetes before proving remarkably good at helping people shed weight. They have since shown benefits in the fields of heart disease, kidney disease, sleep apnoea and other ailments. Drugmakers are now betting that others, the orexins, could follow a similar path. 一种肽类物质近来重塑了医药行业格局。胰高糖素样肽-1（GLP-1）是人体进食后肠道分泌的激素；依托该靶点开发的药物最初用于治疗糖尿病，随后人们发现其减重效果十分突出。此后，这类药物又被证实对心脏病、肾病、睡眠呼吸暂停综合征等多种疾病具备疗效。如今各大药企押注另一类肽——食欲素，或将复刻GLP-1的成功之路。 Orexins are a pair of neurotransmitters—chemicals that carry messages between neurons. One of the main jobs of these particular neurotransmitters is to regulate wakefulness. And a new generation of drugs designed to mimic their effects is approaching the market. 食欲素是一对神经递质，也就是在神经元之间传递信号的化学物质。这类神经递质的核心功能之一是调控人的清醒状态。一批旨在模拟食欲素作用的新一代药物，即将登陆市场。 On August 5th America’s drug regulator approved oveporexton, made by Takeda, a Japanese pharmaceutical firm, as the first orexin agonist (ie, molecule that stimulates the same cell-surface receptors) for narcolepsy, a disorder that leaves patients excessively sleepy by day and prone to nod off without warning. Alkermes, an Irish biotech, is developing a competitor. Eli Lilly, whose fortunes GLP-1s have transformed, does not intend to miss another peptide boom: in June it bought Centessa, a biotech with an orexin drug in early trials, in a deal worth up to $7.8bn, depending on the trials’ success. Morgan Stanley, a bank, reckons orexin medicines could generate $16bn a year by 2035 from narcolepsy and related sleep disorders alone. The current crop of narcolepsy drugs, by contrast, have annual sales of $3bn. 8月5日，美国药品监管机构批准日本药企武田制药研发的奥维普雷克斯顿上市。这是全球首款食欲素激动剂（即能够激活细胞表面同源受体的分子），用于治疗发作性睡病。该病患者日间极度嗜睡，常常毫无征兆地骤然入睡。爱尔兰生物科技企业阿尔凯姆斯正在研发同类竞品。依靠GLP-1药物实现业绩腾飞的礼来制药不愿错过新一轮肽类药物热潮：今年6月，礼来收购生物科技公司森泰萨，后者拥有一款处于早期临床试验阶段的食欲素候选药物，这笔交易最高价值可达78亿美元，最终金额取决于临床试验结果。摩根士丹利测算，到2035年，仅发作性睡病及相关睡眠障碍适应症，食欲素类药物年销售额就有望达到160亿美元。与之相比，当前市面上所有发作性睡病药物年销售总额仅30亿美元。 And the excitement is not just about narcolepsy, which is estimated to afflict one person in 2,000 in America. Orexins help co-ordinate sleep, attention, motivation and the brain’s reward system. Drugmakers hope orexin medicines could eventually treat depression, attention deficit hyperactivity disorder (ADHD) and addiction, conditions that burden hundreds of millions of people. 而令制药公司兴奋的远不止发作性睡病。据估算，美国每2000人中就有一人罹患此病。食欲素能够协同调控睡眠、注意力、行动驱动力以及大脑奖赏系统。药企寄望，食欲素类药物未来可用于治疗抑郁症、注意缺陷多动障碍（ADHD）与成瘾性疾病，这些病症困扰着全球数亿人群。 Orexins were discovered nearly three decades ago by two teams working independently. In January 1998 Luis de Lecea and his colleagues at the Scripps Research Institute in La Jolla, California found the peptides and called them hypocretins. Weeks later a group led by Yanagisawa Masashi, of the University of Texas Southwestern Medical Centre in Dallas, reported that injecting the same peptides into rats’ brains made the animals eat more. They named the molecules orexins, from the Greek orexis, meaning appetite. 近三十年前，两支独立科研团队先后发现食欲素。1998年1月，加州拉霍亚斯克里普斯研究所的路易斯·德·莱塞亚团队发现这类肽，并将其命名为“下丘脑分泌素”（hypocretins）。数周后，达拉斯得克萨斯大学西南医学中心的柳泽正史团队发表研究：将同种肽注入大鼠大脑后，大鼠进食量显著上升。研究人员以希腊语中代表“食欲”的orexis为词根，将该物质命名为orexin（食欲素）。 Orexins’ true role emerged the following year. Emmanuel Mignot, of Stanford University, was studying hereditary narcolepsy in Doberman pinschers and Labrador retrievers, breeds of dog prone to sudden collapse mid-play. He showed that a mutation blocked the brain’s ability to respond to them. That same year, Dr Yanagisawa’s laboratory found that mice engineered to lack orexins repeatedly fell asleep and collapsed. Human confirmation followed: narcoleptic patients had lost the neurons that produce orexins. 次年，食欲素真正的生理功能得以揭晓。斯坦福大学的埃马纽埃尔·米尼奥研究杜宾犬与拉布拉多犬的遗传性发作性睡病，这两个品种的犬只经常在玩耍途中突然瘫倒。他证实，基因突变会阻断大脑对食欲素产生应答。同年，柳泽正史团队发现，经过基因改造、体内缺乏食欲素的小鼠会频繁犯困并突然倒下。后续人体研究进一步证实：发作性睡病患者体内合成食欲素的神经元大量丢失。 Orexins are made by a small number of neurons in the hypothalamus, a brain region tucked behind the eyes. Once released, these molecules lock, depending on their nature, onto one of two types of receptors, OXR1 and OXR2, in neighbouring neurons, switching them on. It is OX2R that is important for maintaining wakefulness. Its activation stimulates several wakefulness-promoting systems that rely on other neurotransmitters—norepinephrine, serotonin, dopamine and so on—and keeps them working together, rather like the conductor of an orchestra. OX1R, is more involved with reward and motivation. 食欲素由下丘脑内少量神经元合成，下丘脑是位于双眼后方的脑区。食欲素释放后，会结合邻近神经元上OX1R、OX2R两种受体中的一种并激活靶细胞，具体结合受体类型由自身特性决定。其中OX2R受体对维持清醒状态至关重要。它的激活能够刺激依赖甲肾上腺素、血清素、多巴胺等神经递质的促清醒系统，并统筹协调各个系统协同运转，如同乐队指挥。而OX1R更多参与大脑奖赏机制与动机调控。 You are feeling sleepy... 困意来袭…… Drugmakers first learned how to turn the OX2R conductor off. Orexin antagonists (which block the molecules’ actions rather than mimicking it, and thus promote sleep), have been available since 2014 as treatments for insomnia. They work differently from conventional sleeping pills, which enhance GABA, one of the brain’s main inhibitory neurotransmitters. 药企最先掌握的是“关闭”这位OX2R“指挥官”。食欲素拮抗剂并不模拟食欲素的作用，而是阻断其信号传导，以此诱导睡眠。自2014年起，这类药物已上市用于治疗失眠。它的作用机制和传统安眠药截然不同：传统安眠药主要增强γ-氨基丁酸（GABA）的活性，而GABA是大脑核心抑制性神经递质之一。 Birgitte Kornum, an expert on orexins at the University of Copenhagen, says such pills induce sedation rather than natural sleep and often lose effectiveness with continued use. Orexin antagonists instead turn down the brain’s wakefulness signal, letting its sleep-promoting systems take over. Evidence suggests this produces better sleep, with less risk of dependence and fewer long-term problems. 哥本哈根大学食欲素领域专家比尔吉特·科尔纳姆表示，传统安眠药带来的只是镇静麻醉效果，并非自然睡眠，而且随着持续使用，药效往往会逐渐减弱。与之不同，食欲素拮抗剂能够下调大脑的清醒信号，让促睡眠系统占据主导。现有证据表明，这类药物可以带来更高质量的睡眠，成瘾风险更低，长期不良反应也更少。 The bigger prize lies not in blocking orexin’s signal, but restoring it—for many sleep disorders stem from faulty orexin signalling. The immediate application is for narcolepsy type 1 (NT1), in which excessive daytime sleepiness is accompanied by cataplexy, a sudden loss of muscle control typically triggered by strong emotion. 真正更具价值的目标并不是阻断食欲信号，而是恢复这一信号——大量睡眠障碍都源于食欲素信号传导异常。最先落地的适应症是1型发作性睡病（NT1），患者除日间重度嗜睡外，还会出现猝倒；这类肌肉失控的突发状况，通常由强烈情绪诱发。 NT1 is caused by abnormally low levels of the orexin that binds to OX2R. During REM (rapid eye movement) sleep, the phase when dreams are most intense, the brain paralyses the body to stop it actually acting out movements involved in such dreams. When someone is awake, this paralysis is held in check by norepinephrine and serotonin—two neurotransmitters that orexin sustains. With insufficient orexin, the paralysis circuit may fire even if a person is fully conscious. They might be wide awake, in the middle of a burst of laughter for example, and then lose muscle control and crumple to the floor. 1型发作性睡病的成因，是能够结合OX2R受体的食欲素水平异常偏低。快速眼动睡眠（REM）是梦境最鲜活的睡眠阶段，此时大脑会抑制躯体运动，以防止人体在现实中做出梦境里的动作。人清醒时，这套躯体抑制通路会被去甲肾上腺素与血清素限制，而这两种神经递质的分泌依靠食欲素维持。一旦食欲素不足，即便患者意识完全清醒，躯体抑制通路也可能异常启动。比如患者开怀大笑时，意识依旧清晰，却突然丧失肌肉控制力，瘫倒在地。 Turning orexins back on is, however, harder than switching them off. An antagonist need only fit into a receptor to prevent an orexin from binding. An agonist must actually reproduce the effect of a peptide many times the drug’s own size. It must also cross the blood-brain barrier, which keeps potentially harmful molecules out of that organ. 然而，激活食欲素通路远比阻断它更加困难。拮抗剂只需占据受体位点，就能阻止食欲素结合；激动剂却要复刻一种分子量远大于自身的肽类物质的生理效应，同时还必须穿透血脑屏障——这道屏障会阻挡潜在有害物质进入大脑。 Takeda’s first attempt to do this, an agonist called firazorexton, showed early promise, but the firm discontinued it in 2021 after it caused liver damage in several patients. But results published in May 2025 on oveporexton, their follow-up OX2R agonist, created a stir. In its trial, patients sat in a darkened room to see how long they could stay awake—a procedure called the Maintenance of Wakefulness test. Without oveporexton many fell asleep almost instantly. On it, they managed to stay awake 12.5 to 25 minutes longer, depending on the dose, pushing many into the normal range. Cataplexy attacks were roughly a third as frequent in those taking the drug, compared with participants on placebo. Side-effects included insomnia and, in about a third of patients, an uncomfortable need to urinate. 武田制药的首次尝试是一款名为剂菲拉佐雷克斯顿的激动剂，初期数据亮眼，但因多名受试者出现肝损伤，企业在2021年终止研发。而2025年5月公布的二代OX2R激动剂奥维普雷克斯顿临床试验结果引发行业热议。试验中，受试者在昏暗房间内接受维持清醒试验，观测能够保持清醒的时长。未用药时，许多受试者几乎立刻入睡；服药后，根据剂量不同，清醒时长可延长12.5至25分钟，大量受试者指标回归正常区间。相比安慰剂组，用药受试者的猝倒发作频率下降约三分之二。该药不良反应包括失眠，约三分之一受试者会出现尿频不适。 What makes oveporexton different is not just its effect, but how that effect is achieved. Existing treatments, including stimulants such as methylphenidate and wakefulness-promoting agents such as modafinil, manage symptoms rather than the disease itself. They increase the activity of neurotransmitters such as dopamine and norepinephrine in many parts of the brain. That can improve alertness but may also cause anxiety, elevated blood pressure and poor sleep. Some drugs also carry a risk of addiction. 奥维普雷克斯顿的独特之处不只体现在疗效，更在于作用机制。现有治疗方案包括哌甲酯等中枢兴奋剂、莫达非尼等促醒药物，只能缓解症状，无法针对病因治疗。这类药物会在大脑多处区域提升多巴胺、去甲肾上腺素等神经递质活性，虽然能够提升警觉度，却可能引发焦虑、血压升高、夜间睡眠紊乱，部分药物还存在成瘾风险。 Orexins work farther upstream. Rather than stimulating individual parts of the alertness system, they help bring them into line. Dr Yanagisawa says orexin agonists should produce more natural and stable wakefulness, with fewer side-effects and less potential for abuse than stimulants. 食欲素作用点处于更上游。它并非单独刺激警觉系统的各个分支，而是统筹协调整套系统有序运转。柳泽正史认为，相较于中枢兴奋剂，食欲素激动剂能够带来更加自然、平稳的清醒状态，副作用更少，滥用风险也更低。 Drugmakers believe the same molecule could also help with conditions besides NT1. One is narcolepsy type 2 (NT2), which lacks cataplexy. Another is idiopathic hypersomnia, a related type of excessive daytime sleepiness. Lilly’s orexin agonist, acquired through Centessa, is being tested against all three, making it one of the broadest bets in the field. Early data are encouraging. In a small trial the drug improved wakefulness by more than 20 minutes in people with NT1 and by more than ten minutes in those with NT2. 药企认为，这类药物除治疗1型发作性睡病外，还可用于其他病症：一是不伴随猝倒症状的2型发作性睡病；二是特发性嗜睡症，同为日间过度嗜睡相关疾病。礼来通过收购森泰萨获得的食欲素激动剂，正在针对这三类适应症开展临床试验，是该领域布局适应症最广的候选药物之一。早期数据令人振奋：一项小型试验显示，该药让1型发作性睡病患者清醒时长提升20分钟以上，2型患者清醒时长提升超10分钟。 Dreaming big 远大前景 Beyond these rarer sleep diseases, drugmakers are studying orexin agonists’ effects on more prevalent conditions. Alkermes is testing one in adults for the treatment of ADHD, based on the observation that an added benefit in narcolepsy patients is sharpened attention, suggesting they might help with ADHD as well. Others are exploring their use for treating sleep apnoea, a far more common disorder. 除上述相对罕见的睡眠疾病外，药企正在研究食欲素激动剂对高发疾病的作用。阿尔凯姆斯正在开展成人ADHD临床试验，研究依据是药物能够改善发作性睡病患者注意力，推测其对多动症同样有效。还有企业探索将其用于治疗患病率更高的睡眠呼吸暂停综合征。 There are more tantalising ideas, too, about the reward-and-motivation role of the other orexin receptor, OX1R—though the science is far less developed. Dr Yanagisawa says blocking OX1R shows promise curbing addictive cravings. Activating the same receptor, rather than blocking it, is a more speculative approach, but he believes boosting the orexin signal into the brain’s reward circuitry could help treat depression and even enhance motivation. 学界对于另一类食欲素受体OX1R在奖赏与动机调控中的作用，还有诸多极具吸引力的猜想，不过相关研究尚处于早期。柳泽正史表示，阻断OX1R受体有望抑制成瘾渴求。与之相反，激活该受体尚属于前沿设想，但他认为，增强大脑奖赏环路的食欲素信号，或许能够帮助治疗抑郁症，甚至提升人的行动动力。 These are hints, not proof, and will need robust tests before any drug reaches the market. Lilly believes the potential is vast. Hunger and sleep, argues Dan Skovronsky, the firm’s chief scientific officer, are both “master homeostasis mechanisms”—systems that keep the body in balance. When they misbehave, illness follows. That, he says, helps explain why incretins, the hormone family behind GLP-1, proved so broadly useful. Hence why orexins could be just as important. ■ 目前这些结论还只是线索，尚未形成定论，相关药物上市前仍需大量严谨试验验证。礼来制药首席科学官丹·斯科夫龙斯基认为，食欲素赛道蕴藏巨大潜力。饥饿调控与睡眠调控同属“核心稳态调节机制”——即维持机体平衡；一旦机制失衡，疾病便会随之而来。这也能够解释，GLP-1所属的肠促胰素家族为何拥有极为广泛的治疗价值，而食欲素很可能拥有同等重要的地位。■ 思维导图 From: The Economist | Science & technology | Wide awake Date：Aug 11th, 2026 ⚠️重要提示：本文节选自英文外刊，译文仅供外语学习交流。文中提及的药物、生理机制、临床试验信息仅为科普资讯，不能替代执业医师的专业诊疗意见，不提供任何用药、治疗指导。请勿仅凭本文内容自行判断病情或购药。 点个关注，回复“原文”，获取原文PDF，扫下方二维码加群，接收最新文章推送，一起读最新外刊、学英语、看世界万象。

The Economist | Aug 11th 2026 继 GLP-1 减重神药席卷全球后，今天的文章深度拆解食欲素这一全新肽类医药靶点。文章梳理食欲素的发现历程、昼夜节律调控原理，对比拮抗剂与激动剂的用药差异，剖析武田、礼来等药企的管线布局，预判其在嗜睡症、抑郁症、多动症等领域的巨大临床潜力，一起学习生物医药下一轮资本角逐方向吧。 标题部分 The brain may be about to have its Ozempic moment Pharma’s newest obsession involves mimicking the system that keeps people awake. 大脑领域或许即将迎来属于它的司美格鲁肽高光时刻 制药行业最新追捧的研发方向，是模拟人体维持清醒的生理调控系统 Ozempic /əʊˈzempɪk/n. 司美格鲁肽（商品名）Ozempic is a blockbuster GLP-1 weight-loss drug. 司美格鲁肽是一款爆款 GLP-1 减重药物。 moment /ˈməʊmənt/n. 高光时刻、爆红节点 The industry had its AI moment five years ago. 这个行业五年前迎来了人工智能爆发期。 pharma /ˈfɑːmə/n. 制药行业（非正式缩写，=pharmaceutical industry）Big pharma is racing to develop orexin agonists. 大型药企竞相研发食欲素激动剂。 obsession /əbˈseʃn/n. 极度热衷、风口焦点 Obesity treatment has become a pharma obsession. 肥胖治疗已成制药界的热门赛道。 mimic /ˈmɪmɪk/v. 模拟、模仿 The drug mimics the function of natural orexin. 该药物模拟天然食欲素的生理功能。 正文部分 ONE peptide has recently transformed medicine. Drugs based on glucagon-like peptide-1 (GLP-1), a hormone released by the gut after a meal, began as treatments for diabetes before proving remarkably good at helping people shed weight. They have since shown benefits in the fields of heart disease, kidney disease, sleep apnoea and other ailments. Drugmakers are now betting that others, the orexins, could follow a similar path. 有一种肽类物质近期革新了医药领域。基于胰高血糖素样肽 - 1（GLP-1）研发的药物由肠道进食后分泌，最初用于糖尿病治疗，后续被证实减脂效果极佳。这类药物还被发现对心脏病、肾病、睡眠呼吸暂停综合征及多种病症有效。制药企业如今押注另一类物质食欲素或将复制这一成功轨迹。 peptide /ˈpeptaɪd/n. 肽，缩氨酸 Proteins are broken down into small peptides in digestion. 蛋白质在消化过程中被分解为小分子肽。 shed weight /ʃed weɪt/phr. 减重，瘦身 Many patients use GLP-1 drugs to shed weight safely. 许多患者借助 GLP-1 药物安全减重。 Orexins are a pair of neurotransmitters—chemicals that carry messages between neurons. One of the main jobs of these particular neurotransmitters is to regulate wakefulness. And a new generation of drugs designed to mimic their effects is approaching the market. 食欲素是一对神经递质，即在神经元之间传递信息的化学物质。这类神经递质核心作用之一是调节清醒状态，新一代模拟其作用的药物即将上市。 neurotransmitter /ˌnjʊərəʊtrænzˈmɪtə(r)/n. 神经递质 Dopamine is an important neurotransmitter in the brain. 多巴胺是大脑中重要的神经递质。 On August 5th America’s drug regulator approved oveporexton, made by Takeda, a Japanese pharmaceutical firm, as the first orexin agonist(ie, molecule that stimulates the same cell-surface receptors) for narcolepsy, a disorder that leaves patients excessively sleepy by day and prone to nod off without warning. Alkermes, an Irish biotech, is developing a competitor. Eli Lilly, whose fortunes GLP-1s have transformed, does not intend to miss another peptide boom: in June it bought Centessa, a biotech with an orexin drug in early trials, in a deal worth up to $7.8bn, depending on the trials’ success. Morgan Stanley, a bank, reckons orexin medicines could generate $16bn a year by 2035 from narcolepsy and related sleep disorders alone. The current crop of narcolepsy drugs, by contrast, have annual sales of $3bn. 8 月 5 日美国药监局批准日本武田制药的奥维普雷克斯通上市，这是首款用于发作性睡病的食欲素激动剂，该病症患者日间过度嗜睡，会毫无征兆突然入睡。爱尔兰药企 Alkermes 正在研发竞品。靠 GLP-1 药物崛起的礼来不愿错失新一轮肽类药物风口，6 月斥资最高 78 亿美元收购拥有在研食欲素药物的 Centessa 公司。摩根士丹利预测，到 2035 年仅发作性睡病及相关睡眠障碍领域，食欲素药物年销售额可达 160 亿美元，现有同类药物年销售额仅 30 亿美元。 agonist /ˈæɡənɪst/n. 激动剂 The agonist can activate specific protein receptors on cells. 激动剂可以激活细胞上特定的蛋白受体。 And the excitement is not just about narcolepsy, which is estimated to afflict one person in 2,000 in America. Orexins help co-ordinate sleep, attention, motivation and the brain’s reward system. Drugmakers hope orexin medicines could eventually treat depression, attention deficit hyperactivity disorder (ADHD) and addiction, conditions that burden hundreds of millions of people. 行业热度不止局限于发作性睡病，美国约每 2000 人中就有一人患病。食欲素可协同调控睡眠、专注力、行动力与大脑奖赏系统，药企期望这类药物未来能治疗抑郁症、多动症以及成瘾问题，惠及数亿受困扰人群。 afflict /əˈflɪkt/v. 折磨，使受病痛困扰 Chronic insomnia afflicts a large number of adults. 慢性失眠困扰着大量成年人。 Orexins were discovered nearly three decades ago by two teams working independently. In January 1998 Luis de Lecea and his colleagues at the Scripps Research Institute in La Jolla, California found the peptides and called them hypocretins. Weeks later a group led by Yanagisawa Masashi, of the University of Texas Southwestern Medical Centre in Dallas, reported that injecting the same peptides into rats’ brains made the animals eat more. They named the molecules orexins, from the Greek orexis, meaning appetite. 食欲素由两支独立科研团队在近 30 年前发现。1998 年 1 月加州斯克里普斯研究所团队发现该肽并命名为分泌素；数周后达拉斯得州大学西南医学中心柳泽正史团队发现，向大鼠脑部注射该物质会提升进食量，并以希腊语 “食欲” 一词将其命名为 orexin。 independently /ˌɪndɪˈpendəntli/adv. 独立地，各自地 The two scientists finished the research independently. 两位科学家各自独立完成了这项研究。 Orexins’ true role emerged the following year. Emmanuel Mignot, of Stanford University, was studying hereditary narcolepsy in Doberman pinschers and Labrador retrievers, breeds of dog prone to sudden collapse mid-play. He showed that a mutation blocked the brain’s ability to respond to them. That same year, Dr Yanagisawa’s laboratory found that mice engineered to lack orexins repeatedly fell asleep and collapsed. Human confirmation followed: narcoleptic patients had lost the neurons that produce orexins. 次年食欲素的核心功能被揭开。斯坦福大学学者研究杜宾犬、拉布拉多犬的遗传性发作性睡病时发现，基因突变会阻断大脑对食欲素的应答。同年柳泽团队敲除食欲素基因的实验小鼠会频繁倒地昏睡。后续人体研究证实：发作性睡病患者体内分泌食欲素的神经元已经凋亡。 hereditary /həˈredɪtri/adj. 遗传的，遗传性的 Hereditary diseases can be passed down from parents to children. 遗传病可以由父母遗传给子女。 mutation /mjuˈteɪʃn/n. 基因突变 Gene mutation is the root cause of many congenital illnesses. 基因突变是许多先天性疾病的根源。 Orexins are made by a small number of neurons in the hypothalamus, a brain region tucked behind the eyes. Once released, these molecules lock, depending on their nature, onto one of two types of receptors, OXR1 and OXR2, in neighbouring neurons, switching them on. It is OX2R that is important for maintaining wakefulness. Its activation stimulates several wakefulness-promoting systems that rely on other neurotransmitters—norepinephrine, serotonin, dopamine and so on—and keeps them working together, rather like the conductor of an orchestra. OX1R, is more involved with reward and motivation. 食欲素由双眼后方下丘脑的少量神经元合成。释放后会根据自身特性绑定邻近神经元的 OX1R、OX2R 两类受体并激活细胞。其中 OX2R 受体主导清醒状态维持，激活后协同去甲肾上腺素、血清素、多巴胺等多种促清醒递质，如同乐队指挥统筹整套系统；OX1R 更多参与大脑奖赏与动力调控。 hypothalamus /ˌhaɪpəʊˈθæləməs/n. 下丘脑 The hypothalamus regulates human sleep and appetite. 下丘脑调控人体睡眠与食欲。 conductor /kənˈdʌktə(r)/n. 指挥；引导者 The receptor acts as the conductor of the wakefulness system. 该受体充当着清醒系统的总指挥。 You are feeling sleepy... Drugmakers first learned how to turn the OX2R conductor off. Orexin antagonists (which block the molecules’ actions rather than mimicking it, and thus promote sleep), have been available since 2014 as treatments for insomnia. They work differently from conventional sleeping pills, which enhance GABA, one of the main inhibitory neurotransmitters. 你感到昏昏欲睡…… 药企最先研发出关闭 OX2R 通路的方法。食欲素拮抗剂通过阻断食欲素起效来诱导睡眠，2014 年起用于失眠治疗。它作用机制区别于传统安眠药，后者仅增强抑制性神经递质GABA 的活性。 antagonist /ænˈtæɡənɪst/n. 拮抗剂，阻断剂 Orexin antagonists are widely used for chronic insomnia. 食欲素拮抗剂被广泛用于慢性失眠治疗。 inhibitory /ɪnˈhɪbɪtri/adj. 抑制性的 GABA is a key inhibitory neurotransmitter in the brain. γ- 氨基丁酸是大脑关键的抑制性神经递质。 Birgitte Kornum, an expert on orexins at the University of Copenhagen, says such pills induce sedation rather than natural sleep and often lose effectiveness with continued use. Orexin antagonists instead turn down the brain’s wakefulness signal, letting its sleep-promoting systems take over. Evidence suggests this produces better sleep, with less risk of dependence and fewer long-term problems. 哥本哈根大学食欲素研究专家表示，传统安眠药只是强制镇静而非自然睡眠，长期服用极易耐药。而食欲素拮抗剂下调大脑清醒信号，让自身睡眠机制主导休息，睡眠质量更佳，成瘾风险与长期副作用更低。 sedation /sɪˈdeɪʃn/n. 镇静，麻醉状态 High-dose pills will lead to strong sedation. 大剂量药片会产生强烈的镇静效果。 dependence /dɪˈpendəns/n. 药物依赖 Long-term sleeping pill use may cause drug dependence. 长期服用安眠药可能造成药物依赖。 The bigger prize lies not in blocking orexin’s signal, but restoring it—for many sleep disorders stem from faulty orexin signalling. The immediate application is for narcolepsy type 1 (NT1), in which excessive daytime sleepiness is accompanied by cataplexy, a sudden loss of muscle control typically triggered by strong emotion. 更大的研发价值不在于阻断食欲素信号，而是修复该通路，多数睡眠障碍都源于食欲素传导异常。首要应用场景是 1 型发作性睡病，患者日间嗜睡伴随猝倒症，受剧烈情绪刺激会瞬间丧失肌肉控制力。 stem from /stem frəm/phr. 源于，由…… 造成 Most sleep problems stem from irregular work and rest. 大部分睡眠问题源于作息不规律。 cataplexy /ˈkætəpleksi/n. 猝倒症 Cataplexy is a typical symptom of type 1 narcolepsy. 猝倒是 1 型发作性睡病的典型症状。 NT1 is caused by abnormally low levels of the orexin that binds to OX2R. During REM (rapid eye movement) sleep, the phase when dreams are most intense, the brain paralyses the body to stop it actually acting out movements involved in such dreams. When someone is awake, this paralysis is held in check by norepinephrine and serotonin—two neurotransmitters that orexin sustains. With insufficient orexin, the paralysis circuit may fire even if a person is fully conscious. They might be wide awake, in the middle of a burst of laughter for example, and then lose muscle control and crumple to the floor. 1 型发作性睡病病因是结合 OX2R 受体的食欲素分泌严重不足。快速眼动睡眠阶段大脑会麻痹躯体避免梦境动作外化；清醒时食欲素维持的去甲肾上腺素、血清素会抑制麻痹通路。一旦食欲素匮乏，人在完全清醒时也会触发麻痹，比如开怀大笑瞬间浑身脱力瘫倒在地。 paralyse /ˈpærəlaɪz/v. 使瘫痪，麻痹 The nerve signal will paralyse voluntary muscle movement. 该神经信号会麻痹自主肌肉活动。 crumple /ˈkrʌmpl/v. 瘫倒，垮掉 He crumpled to the ground after the sudden muscle loss. 肌肉突然失控后他瘫倒在了地上。 Turning orexins back on is, however, harder than switching them off. An antagonist need only fit into a receptor to prevent an orexin from binding. An agonist must actually reproduce the effect of a peptide many times the drug’s own size. It must also cross the blood-brain barrier, which keeps potentially harmful molecules out of that organ. 但激活食欲素远比阻断它难度更高。拮抗剂只需占位堵住受体即可；激动剂要复刻大分子肽的生理活性，还必须穿透血脑屏障，隔绝有害物质侵入脑组织。 barrier /ˈbæriə(r)/n. 屏障，壁垒 The blood-brain barrier protects the central nervous system. 血脑屏障保护中枢神经系统不受侵害。 Takeda’s first attempt to do this, an agonist called firazorexton, showed early promise, but the firm discontinued it in 2021 after it caused liver damage in several patients. But results published in May 2025 on oveporexton, their follow-up OX2R agonist, created a stir. In its trial, patients sat in a darkened room to see how long they could stay awake—a procedure called the Maintenance of Wakefulness test. Without oveporexton many fell asleep almost instantly. On it, they managed to stay awake 12.5 to 25 minutes longer, depending on the dose, pushing many into the normal range. Cataplexy attacks were roughly a third as frequent in those taking the drug, compared with participants on placebo. Side-effects included insomnia and, in about a third of patients, an uncomfortable need to urinate. 武田初代激动剂 firazorexton 早期数据亮眼，但因多名受试者肝损伤在 2021 年终止研发。2025 年 5月二代 OX2R 激动剂 oveporexton 临床试验结果引发行业震动。在清醒维持测试中，未服药患者在暗室几乎立刻入睡；服药后可延长 12.5 至 25 分钟清醒时长，多数回归正常水平，猝倒发作频次降至安慰剂组的三分之一，副作用为失眠和约三分之一受试者尿频。 discontinue /ˌdɪskənˈtɪnjuː/v. 终止，停止研发 The company decided to discontinue the unsafe experimental drug. 公司决定终止这款存在安全隐患的试验药物。 placebo /pləˈsiːbəʊ/n. 安慰剂 The control group only received inert placebo pills. 对照组仅服用无药效的安慰剂药片。 create a stir /kriˈeɪt ə stɜː(r)/phr. 引发轰动，掀起热议 The breakthrough clinical data created a stir in the pharmaceutical circle. 突破性临床数据在医药圈掀起热议。 What makes oveporexton different is not just its effect, but how that effect is achieved. Existing treatments, including stimulants such as methylphenidate and wakefulness-promoting agents such as modafinil, manage symptoms rather than the disease itself. They increase the activity of neurotransmitters such as dopamine and norepinephrine in many parts of the brain. That can improve alertness but may also cause anxiety, elevated blood pressure and poor sleep. Some drugs also carry a risk of addiction. Oveporexton 的核心优势不止疗效，更是作用逻辑的革新。现有哌甲酯、莫达非尼等促清醒药物只对症缓解，大范围刺激多巴胺、去甲肾上腺素，虽提升警觉度，却易引发焦虑、高血压、夜间失眠甚至药物成瘾。 stimulant /ˈstɪmjələnt/n. 中枢兴奋剂 Strong stimulants will impose a heavy burden on the cardiovascular system. 强效兴奋剂会给心血管系统带来巨大负担。 alertness /əˈlɜːtnəs/n. 警觉度，清醒状态 Caffeine temporarily boosts mental alertness. 咖啡因会短暂提升大脑清醒度。 Orexins work farther upstream. Rather than stimulating individual parts of the alertness system, they help bring into line. Dr Yanagisawa says orexin agonists should produce more natural and stable wakefulness, with fewer side-effects and less potential for abuse than stimulants. 食欲素作用于上游调控通路，并非零散刺激单个神经节点，而是统筹整套清醒系统。柳泽博士称，食欲素激动剂带来的清醒状态更自然平稳，副作用与滥用风险远低于中枢兴奋剂。 upstream /ˌʌpˈstriːm/adv. 上游地，根源层面 The drug intervenes upstream of the neural regulatory pathway. 该药物在神经调控通路的上游进行干预。 bring into line /brɪŋˈɪntə laɪn/phr. 统筹协调，使步调一致 The receptor brings multiple nerve pathways into line. 该受体统筹多条神经通路协同运作。 Drugmakers believe the same molecule could also help with conditions besides NT1. One is narcolepsy type 2 (NT2), which lacks cataplexy. Another is idiopathic hypersomnia, a related type of excessive daytime sleepiness. Lilly’s orexin agonist, acquired through Centessa, is being tested against all three, making it one of the broadest bets in the field. Early data are encouraging. In a small trial the drug improved wakefulness by more than 20 minutes in people with NT1 and by more than ten minutes in those with NT2. 药企认为该靶点可拓展至更多病症：无猝倒症状的 2 型发作性睡病、特发性嗜睡症。礼来收购管线中的激动剂同时针对三种疾病开展试验，早期数据喜人，小样本试验中分别为 1 型、2 型患者延长 20 分钟、10 分钟以上清醒时长。 idiopathic /ˌɪdiəˈpæθɪk/adj. 特发性的，病因不明的 Idiopathic hypersomnia cannot be traced to clear organic lesions. 特发性嗜睡症无法找到明确的器质性病变诱因。 encouraging /ɪnˈkʌrɪdʒɪŋ/adj. 令人鼓舞的 The preliminary clinical results are highly encouraging. 初步临床结果十分振奋人心。 Dreaming big Beyond these rarer sleep diseases, drugmakers are studying orexin agonists’ effects on more prevalent conditions. Alkermes is testing one in adults for the treatment of ADHD, based on the observation that an added benefit in narcolepsy patients is sharpened attention, suggesting they might help with ADHD as well. Others are exploring their use for treating sleep apnoea, a far more common disorder. 宏大研发蓝图 除罕见睡眠疾病外，药企探索食欲素激动剂在高发疾病的潜力。Alkermes 开展成人多动症临床试验，源于药物可提升发作性睡病患者专注力的临床观察；还有团队研究其在高发的睡眠呼吸暂停综合征中的应用。 prevalent /ˈprevələnt/adj. 普遍的，高发的 Sleep apnoea is highly prevalent among middle-aged overweight groups. 睡眠呼吸暂停综合征在超重中年人群中发病率很高。 sharpen /ˈʃɑːpn/v. 提升，增强 The medicine can sharpen focus and reaction speed. 这款药物能够提升专注力与反应速度。 There are more tantalising ideas, too, about the reward-and-motivation role of the other orexin receptor, OX1R—though the science is far less developed. Dr Yanagisawa says blocking OX1R shows promise curbing addictive cravings. Activating the same receptor, rather than blocking it, is a more speculative approach, but he believes boosting the orexin signal into the brain’s reward circuitry could help treat depression and even enhance motivation. 针对 OX1R 受体调控奖赏与行动力的研究设想更具吸引力，只是基础研究尚不成熟。柳泽团队表示阻断 OX1R 可抑制成瘾渴求；激活该受体属于前瞻性探索，有望通过激活大脑奖赏环路治疗抑郁症、提升内在驱动力。 tantalising /ˈtæntəlaɪzɪŋ/adj. 极具诱惑力的，令人向往的 The therapeutic prospect of the target is tantalising. 该靶点的治疗前景极具吸引力。 speculative /ˈspekjələtɪv/adj. 推测性的，尚在设想中的 This treatment plan is still speculative without sufficient data support. 缺乏充足数据支撑，这套治疗方案仍停留在设想阶段。 circuitry /ˈsɜːkɪtri/n. 神经环路 The brain’s reward circuitry controls pleasure and motivation. 大脑奖赏神经环路管控愉悦感与行动力。 These are hints, not proof, and will need robust tests before any drug reaches the market. Lilly believes the potential is vast. Hunger and sleep, argues Dan Skovronsky, the firm’s chief scientific officer, are both “master homeostasis mechanisms”—systems that keep the body in balance. When they misbehave, illness follows. That, he says, helps explain why incretins, the hormone family behind GLP-1, proved so broadly useful. Hence why orexins could be just as important. 目前这些都只是初步线索，仍需大量严谨临床试验才能落地上市。礼来首席科学官指出，食欲与睡眠都是维持人体稳态的核心底层机制，机制失衡便会诱发各类疾病，这也解释了 GLP-1 所在肠促胰素家族为何适应症广泛，食欲素靶点未来或将拥有同等巨大的医药价值。 robust /rəʊˈbʌst/adj. 严谨的，充分的 We need robust clinical trials to verify drug safety. 我们需要严谨的临床试验验证药物安全性。 homeostasis /ˌhəʊmiəʊˈsteɪsɪs/n. 体内稳态 Sleep and metabolism jointly maintain bodily homeostasis. 睡眠与新陈代谢共同维持机体稳态。 | 推荐阅读 | 2026 年 GLP-1 药物新浪潮：口服、长效与多靶点的革新突破 | 经济学人双语学习笔记