KCNK1

*仅供医学专业人士阅读参考蔡老师终于带着她的40Hz重回顶刊了，真是好久不见了。前几天编辑们还在讨论，蔡立慧的研究怎么做了3期没有下文了，可别不行了吧。怪不得编辑瞎想，咱们先来简单回顾一下40Hz发迹历程↓2021年2期临床研究初步数据：阿尔茨海默病治疗重大突破！MIT神经科学大牛的无创黑科技2期临床数据公布，6个月治疗显著延缓认知功能下降83% | 临床大发现2016年《自然》关键论文：MIT神经学大牛关于阿尔茨海默病的超级颠覆研究，简直简直简直逆天了丨奇点猛科技2019年《细胞》40Hz声刺激同样有效：《细胞》：膜拜大神！MIT大牛再发阿尔茨海默病颠覆性研究成果，40赫兹的声音可消除AD小鼠大脑β淀粉样蛋白，改善认知丨科学大发现底层机制论文：《细胞》子刊：再拜大牛！MIT蔡教授团队发现40赫兹LED治疗阿尔茨海默病机制，全球首个临床研究已经开展丨科学大发现光看标题都能感觉出来，方法是相当简单，效果是相当好，进展是相当快，前景是相当明朗。但备受瞩目的临床试验至今未有数据发布（新冠疫情耽误了可以理解），去年又出现了一篇论文无法完全复现蔡团队的成果，当时的研究者们提出，40Hz多感官刺激可能并非大脑调控的底层机制，面对个体表现差异化极大的阿尔茨海默病（AD），它可能无法普遍起效。不过今天发布在《自然》杂志上的新成果提供了40Hz刺激疗法的新机制。蔡立慧团队发现，40Hz多感官刺激能够促进AD小鼠脑脊液（CSF）和间质液（ISF）交换，加速淀粉样蛋白的淋巴清除。令人信心倍增的是，《自然》同期发表了来自华盛顿大学团队的另一篇论文，研究者们同样发现了神经元电位活动能够加速CSF-ISF灌注，一定程度上支持了蔡团队的结论。论文题图进入论文之前，我们先来讲讲脑淋巴的故事。大脑中有数以千计的神经元在积极活动，它们通过放电组织人体的运动、思想和行为，这个行为也产生了大量的大脑垃圾。脑淋巴就是清除这些垃圾的重要系统。脑淋巴允许大脑周围的脑脊液进入动脉旁的血管周围空间，在这里脑脊液与神经元周围的间质液进行物质交换，包括各种离子、神经递质和调节分子、还有代谢垃圾，间质液中的废物可以通过静脉血管周围空间排出。这个过程中，星形胶质细胞表达的水通道蛋白-4（AQP-4）是很关键的。星形胶质细胞会与血管形成接触面，在这个接触面上AQP-4充当了水的通道。脑淋巴作用机制曾有研究发现，睡眠和麻醉期间脑脊液流入速率变化，显然不同的大脑节律会影响淋巴转运。如此说来，会影响神经元放电的40Hz刺激，也有可能会改变脑淋巴。研究者在6个月大的5xFAD小鼠中进行实验，40Hz多感官刺激能够显著减少大脑淀粉样蛋白负荷。监测脑脊液动力学结果发现，40Hz刺激后，小鼠脑脊液流入和间质液外排显著增加。当研究者使用小分子抑制剂破坏AQP-4功能，脑脊液流入减少、淀粉样蛋白负荷增加。显然，40Hz刺激真的可以促进淀粉样蛋白的淋巴清除。由于动脉血管运动能够调节脑脊液运动并且会被γ节律影响，研究者在小鼠前额叶皮层处固定了双光子成像，观测小鼠的动脉直径变化。在40Hz多感官刺激1小时后，小鼠动脉搏动显著增加，血管收缩幅度变大、频率也增快了。动脉的加速搏动显然会加速血管周围空间中脑脊液的流动。40Hz刺激后血管搏动增加研究者对刺激后的小鼠脑细胞进行了单核RNA测序，发现星形胶质细胞末端足上与脑脊液运输有关的钾通道Kcnk1表达增加；免疫组化分析也发现，AQP-4极化增加。进一步分析发现，这一过程通过VIP神经元神经肽信号实现。同期发表的另一篇论文则发现，睡眠和麻醉期间出现的神经元同步放电可以加速脑脊液灌注。虽然这项研究并未提及特定神经元活动频率的影响，但也不能排除不同大脑区域具有一个最佳频率的可能。无论如何，脑淋巴如何清除大脑垃圾，是会对包括AD在内多种神经退行性疾病产生影响的问题，如何能够有效利用这个清除系统，可以为治疗疾病带来新的思路。参考资料：[1]https://www-nature-com.libproxy1.nus.edu.sg/articles/s41586-024-07132-6[2]https://www-nature-com.libproxy1.nus.edu.sg/articles/s41586-024-07108-6[3]https://www-nature-com.libproxy1.nus.edu.sg/articles/d41586-024-00422-z本文作者丨代丝雨

New Patents Further Reinforce the FIRDAPSE® (amifampridine) Intellectual Patent PortfolioCORAL GABLES, Fla., Nov. 02, 2023 (GLOBE NEWSWIRE) -- Catalyst Pharmaceuticals, Inc. ("Catalyst" or "Company") (Nasdaq: CPRX), a commercial-stage biopharmaceutical company focused on in-licensing, developing, and commercializing novel medicines for patients living with rare diseases, today announced that the Company has received notification by the United States Patent and Trademark Office ("USPTO") that two additional patents covering FIRDAPSE® (amifampridine) Tablets 10 mg, were allowed and will be granted within the next two months. These new patents are for claims associated with the unique and novel, previously unknown, bioavailability of FIRDAPSE under fasting and fed conditions of dosing. FIRDAPSE is the only approved treatment available in the U.S. for Lambert-Eaton myasthenic syndrome. "We are very pleased to receive these patent notifications from the USPTO. This milestone reaffirms our unwavering dedication to advancing our core objectives, which are crucial in strengthening and maintaining the ongoing commercial success of our flagship product, FIRDAPSE," stated Patrick J. McEnany, Chairman and Chief Executive Officer of Catalyst. "Aligned with our portfolio strategy, we remain committed to advancing our core objectives to reinforce and safeguard the sustained commercial viability of FIRDAPSE, which currently benefits from patent exclusivity protection in the United States until 2037." "These patent allowances strengthen our cumulative understanding of the uniqueness of FIRDAPSE and bolster its strong intellectual property estate offering enhanced patent protection," stated Dr. Steven Miller, Chief Operating Officer and Chief Scientific Officer of Catalyst. "These two new patents, with expiry dates out to mid-2032, cover claims related to the product's novel and unique bioavailability when administered under fasting and fed dosing conditions, further strengthening our NAT2 family of patents. We expect these patents to be granted within two months. Preparations are already in motion to include these additional FIRDAPSE patents in the FDA Orange Book post-grant, bringing the total listed patent count to eight." About FIRDAPSE®FIRDAPSE® (amifampridine) Tablets 10 mg is an oral, nonspecific, voltage-dependent, potassium (K+) channel blocker that causes depolarization of the presynaptic membrane and slows or inhibits repolarization. This action results in the opening of slow voltage-dependent calcium (Ca2+) channels, allowing for a subsequent influx of Ca2+. In turn, it induces the exocytosis of synaptic vesicles containing Acetylcholine (ACh) to release more ACh into the synaptic cleft, enhancing neuromuscular transmission and providing for improved muscle function. About Catalyst PharmaceuticalsWith exceptional patient focus, Catalyst is committed to developing and commercializing innovative first-in-class medicines that address rare neurological and epileptic diseases. Catalyst's flagship U.S. commercial product is FIRDAPSE® (amifampridine) Tablets 10 mg, approved for the treatment of Lambert-Eaton myasthenic syndrome ("LEMS") for adults and for children ages six to seventeen. In January 2023, Catalyst acquired the U.S. commercial rights to FYCOMPA® (perampanel) CIII, a prescription medicine approved in people with epilepsy aged four and older alone or with other medicines to treat partial-onset seizures with or without secondarily generalized seizures and with other medicines to treat primary generalized tonic-clonic seizures for people with epilepsy aged 12 and older. Further, Canada's national healthcare regulatory agency, Health Canada, has approved the use of FIRDAPSE for the treatment of adult patients in Canada with LEMS. Finally, on July 18, 2023, Catalyst acquired an exclusive license for North America for AGAMREE® (vamorolone) oral suspension 40 mg/mL, a novel corticosteroid treatment for Duchenne Muscular Dystrophy. AGAMREE® previously received FDA Orphan Drug and Fast Track designations and was recently approved for commercialization in the U.S. on October 26, 2023. For more information about  Catalyst Pharmaceuticals, Inc., visit the Company's website at www.catalystpharma.com. For Full Prescribing and Safety Information for FIRDAPSE®, visit www.firdapse.com. For Full Prescribing Information, including Boxed WARNING for FYCOMPA®, please visit www.fycompa.com. For Full Prescribing Information for AGAMREE®, please visit www.agamree.com. Forward-Looking StatementsThis press release contains forward-looking statements. Forward-looking statements involve known and unknown risks and uncertainties, which may cause Catalyst's actual results in future periods to differ materially from forecasted results. A number of factors, including (i) whether these new patents will withstand challenge by generic drug companies, (ii) whether Catalyst can successfully protect FIRDAPSE® from generic competitors until the expiration of its patent estate, and (iii) those factors described in Catalyst's Annual Report on Form 10-K for the fiscal year 2022 and its other filings with the U.S. Securities and Exchange Commission ("SEC"), could adversely affect Catalyst. Copies of Catalyst's filings with the SEC are available from the SEC, may be found on Catalyst's website, or may be obtained upon request from Catalyst. Catalyst does not undertake any obligation to update the information contained herein, which speaks only as of this date. Source: Catalyst Pharmaceuticals

CORAL GABLES, Fla., Nov. 02, 2023 (GLOBE NEWSWIRE) -- Catalyst Pharmaceuticals, Inc. ("Catalyst" or "Company") (Nasdaq: CPRX), a commercial-stage biopharmaceutical company focused on in-licensing, developing, and commercializing novel medicines for patients living with rare diseases, today announced that the Company has received notification by the United States Patent and Trademark Office ("USPTO") that two additional patents covering FIRDAPSE® (amifampridine) Tablets 10 mg, were allowed and will be granted within the next two months. These new patents are for claims associated with the unique and novel, previously unknown, bioavailability of FIRDAPSE under fasting and fed conditions of dosing. FIRDAPSE is the only approved treatment available in the U.S. for Lambert-Eaton myasthenic syndrome. "We are very pleased to receive these patent notifications from the USPTO. This milestone reaffirms our unwavering dedication to advancing our core objectives, which are crucial in strengthening and maintaining the ongoing commercial success of our flagship product, FIRDAPSE," stated Patrick J. McEnany, Chairman and Chief Executive Officer of Catalyst. "Aligned with our portfolio strategy, we remain committed to advancing our core objectives to reinforce and safeguard the sustained commercial viability of FIRDAPSE, which currently benefits from patent exclusivity protection in the United States until 2037." "These patent allowances strengthen our cumulative understanding of the uniqueness of FIRDAPSE and bolster its strong intellectual property estate offering enhanced patent protection," stated Dr. Steven Miller, Chief Operating Officer and Chief Scientific Officer of Catalyst. "These two new patents, with expiry dates out to mid-2032, cover claims related to the product's novel and unique bioavailability when administered under fasting and fed dosing conditions, further strengthening our NAT2 family of patents. We expect these patents to be granted within two months. Preparations are already in motion to include these additional FIRDAPSE patents in the FDA Orange Book post-grant, bringing the total listed patent count to eight." About FIRDAPSE® FIRDAPSE® (amifampridine) Tablets 10 mg is an oral, nonspecific, voltage-dependent, potassium (K+) channel blocker that causes depolarization of the presynaptic membrane and slows or inhibits repolarization. This action results in the opening of slow voltage-dependent calcium (Ca2+) channels, allowing for a subsequent influx of Ca2+. In turn, it induces the exocytosis of synaptic vesicles containing Acetylcholine (ACh) to release more ACh into the synaptic cleft, enhancing neuromuscular transmission and providing for improved muscle function. About Catalyst Pharmaceuticals With exceptional patient focus, Catalyst is committed to developing and commercializing innovative first-in-class medicines that address rare neurological and epileptic diseases. Catalyst's flagship U.S. commercial product is FIRDAPSE® (amifampridine) Tablets 10 mg, approved for the treatment of Lambert-Eaton myasthenic syndrome ("LEMS") for adults and for children ages six to seventeen. In January 2023, Catalyst acquired the U.S. commercial rights to FYCOMPA® (perampanel) CIII, a prescription medicine approved in people with epilepsy aged four and older alone or with other medicines to treat partial-onset seizures with or without secondarily generalized seizures and with other medicines to treat primary generalized tonic-clonic seizures for people with epilepsy aged 12 and older. Further, Canada's national healthcare regulatory agency, Health Canada, has approved the use of FIRDAPSE for the treatment of adult patients in Canada with LEMS. Finally, on July 18, 2023, Catalyst acquired an exclusive license for North America for AGAMREE® (vamorolone) oral suspension 40 mg/mL, a novel corticosteroid treatment for Duchenne Muscular Dystrophy. AGAMREE® previously received FDA Orphan Drug and Fast Track designations and was recently approved for commercialization in the U.S. on October 26, 2023. For more information about Catalyst Pharmaceuticals, Inc., visit the Company's website at . For Full Prescribing and Safety Information for FIRDAPSE®, visit . For Full Prescribing Information, including Boxed WARNING for FYCOMPA®, please visit . For Full Prescribing Information for AGAMREE®, please visit Forward-Looking Statements This press release contains forward-looking statements. Forward-looking statements involve known and unknown risks and uncertainties, which may cause Catalyst's actual results in future periods to differ materially from forecasted results. A number of factors, including (i) whether these new patents will withstand challenge by generic drug companies, (ii) whether Catalyst can successfully protect FIRDAPSE® from generic competitors until the expiration of its patent estate, and (iii) those factors described in Catalyst's Annual Report on Form 10-K for the fiscal year 2022 and its other filings with the U.S. Securities and Exchange Commission ("SEC"), could adversely affect Catalyst. Copies of Catalyst's filings with the SEC are available from the SEC, may be found on Catalyst's website, or may be obtained upon request from Catalyst. Catalyst does not undertake any obligation to update the information contained herein, which speaks only as of this date. Source: Catalyst Pharmaceuticals Investor Relations Contact: Mary Coleman, Catalyst Pharmaceuticals (305) 420-3200 mcoleman@catalystpharma.com Media Contact: David Schull, Russo Partners (858) 717-2310 david.schull@russopartnersllc.com