Abstract:The elimination of leprosy has been possible with the available anti-leprotic drugs. However, the lepra reactions usually occur months or years after multi-drug therapy completion, and continue to be a formidable challenge mainly owing to its role in causing nerve damage and disability. Corticosteroids are commonly used but they lead to systemic complications, and hence require dose reduction and adjunct therapy with a different target. Various drugs with different targets have been identified and are in practice to treat lepra reactions. The newer targets can include genetic and tissue targets in the skin and nerve. Thalidomide treatment reducing pentraxin-3, toll-like receptor antagonists, minocycline, apremilast, immunomodulators, and tenidap can be helpful in lepra reaction. Other modalities to manage lepra reactions include plasma exchange, intravenous immunoglobulins, and immunotherapy. Most of these treatments are based only on the pathological process of the reaction and tend to be incomplete leading to recurrence. Newer multimodal approaches are required based on various biomarkers (genetic, tissue, serological), which can be monitored to prevent the recurrence of reactions. Hence, there is a need for newer targets and drugs to be identified for the management of lepra reactions.

2020-01-01·Indian Dermatology Online Journal

What is new in the pathogenesis and management of erythema nodosum leprosum

Review

作者: Bhat, Ramesh M ; Vaidya, Tanvi P

Erythema nodosum leprosum (ENL) is a manifestation of type II lepra reaction, seen in lepromatous or borderline lepromatous leprosy. Although it is a common reaction encountered in clinical practice, there are an increasingly large number of newer updates in the pathophysiology and management of this condition. The treatment options have expanded far beyond just thalidomide and steroids and now extends to TNF-α inhibitors, thalidomide analogs, tenidap, cyclosporine A, plasma exchange, and even IVIG amongst others. These updates and the current knowledge of ENL are summarized in this review.

2019-12-30·CNS & Neurological Disorders - Drug Targets

Activation of Kir2.3 Channels by Tenidap Suppresses Epileptiform Burst Discharges in Cultured Hippocampal Neurons

Article

作者: Zhang, Lu ; Wang, Guoxiang ; Sun, Wanbing ; Wang, Yun ; Wu, Xunyi ; Zang, Kai ; Chen, Zhiyun ; Zhang, Yuwen

Background & Objective:Tenidap, a selective human inwardly rectifying potassium (Kir) 2.3 channel opener, has been reported to have antiepileptic effect in the pilocarpine temporal lobe epilepsy rat model in our previous study. However, the effect of tenidap on neurons and its relationship with the epileptiform bursting charges in neuron is still required to be explored.Methods:In this study, cyclothiazide (CTZ) induced cultured hippocampal neuron epileptic model was used to study the antiepileptic effect of tenidap and the relationship between Kir2.3 channel and the neuronal epileptiform burst.Results:Patch clamp recording showed that both acute (2h) and chronic (48h) CTZ pre-treatment all significantly induced robust epileptiform burst activities in cultured hippocampal neurons, and tenidap acutely application inhibited this highly synchronized abnormal activities. The effect of tenidap is likely due to increased activity of Kir2.3 channels, since tenidap significantly enhanced kir current recorded from those neurons. In addition, neurons overexpressing Kir2.3 channels, by transfection with Kir2.3 plasmid, showed a significant large increase of the Kir current, prevented CTZ treatment to induce epileptiform burst discharge.Conclusion:Our current study demonstrated that over activation of Kir2.3 channel in hippocampal neurons could positively interference with epileptiform burst activities, and tenidap, as a selective Kir2.3 channel opener, could be a potential candidate for seizure therapy.

项与替尼达帕相关的新闻（医药）

2023-08-10

·医药观澜

10余款疗法步入临床，靶向蛋白降解疗法的未来方向是？

▎药明康德内容团队编辑靶向蛋白降解（TPD）是一个快速发展的领域，它有潜力彻底革新我们对疾病的治疗方式。TPD策略是使用小分子来选择性地降解致病蛋白，相比于传统的小分子抑制剂，它展现出了多方面的优势。TPD的概念已经诞生数十年，伴随着化学生物学和药物发现领域研究的不断深入，这一技术近年来得到了广泛关注。近期，《细胞》杂志子刊Cell Chemical Biology发表了一篇综述文章，详细探讨了靶向蛋白降解疗法的进展和未来的方向。什么是靶向蛋白降解？靶向蛋白降解剂是一种新的药物模式，可以彻底消除蛋白质，而不仅仅是抑制它们的活性。TPD的工作原理是利用细胞自身的蛋白质清除机制，即蛋白酶体和溶酶体途径，选择性地降解致病蛋白质。以大热的蛋白降解靶向嵌合体（proteolysis-targeting chimeric molecule，PROTAC）技术为例，它利用PROTAC分子将泛素连接酶招募到目标蛋白附近，给目标蛋白打上泛素标签，使其被蛋白酶体降解。随后，泛素分子和PROTAC分子从目标蛋白上脱离并被循环利用。靶向蛋白降解剂比传统的小分子抑制剂有几个优势，包括能够靶向以前被认为“不可成药”的蛋白质、影响蛋白的非催化功能等。当前，主要的靶向蛋白降解剂形式包括单价和二价小分子降解剂。单价降解剂由能够与特定靶蛋白结合的单个结合配体组成。单价降解剂分子量低，这使得它们很难与传统的抑制剂区分开，但也正因如此，它们可以按照大多数既定的药物开发模式进行优化。从机理上看，单价降解剂可以充当干扰剂，驱动靶蛋白形成一个易被药物干预的构象状态，或者充当“胶水分子”，优先与目标蛋白或细胞内的蛋白降解体系成分（如泛素）结合，修饰其表面，使它们之间产生蛋白-蛋白相互作用。二价降解剂由两个通过接头分子连接在一起的小分子配体组成。每个配体与不同的蛋白质结合，其中一个配体专门与目标蛋白质结合，另一个配体则与引发蛋白降解机制的蛋白分子结合。这种设计使得二价降解剂能够扩大可降解靶点的范围。另一方面，由于二价降解剂比典型的小分子药物具有更大的分子量，它们在药物化学方面面临更多挑战，这些挑战包括如何实现口服给药、确保其在中枢神经系统（CNS）中的有效分布、以及满足制剂和代谢产物相关毒性的要求。TPD领域近年的进展近年来，TPD领域取得了显著进展。其中，新型TPD策略的发展尤为突出，例如PROTAC、分子胶以及溶酶体靶向嵌合体（LYTAC），它们在癌症、神经退行性疾病和病毒感染等多种疾病的临床前研究中展现了巨大的治疗潜力。随着对TPD领域的投资激增，一批以TPD为核心的创新企业和合作伙伴关系相继成立。这种投资推动了TPD技术平台和方法的快速创新和拓展，进一步加速了新型TPD药物的研发进程。▲专注于TPD的部分医药企业及其合作伙伴关系（药明康德内容团队制作，数据来源：参考资料[1]）随着研究的深入，科学家们对蛋白降解机制的了解也逐步加深，这使得多个关键靶点得以被有效降解，解决了以往药物研发中的一些难题。TPD药物在临床应用上已经取得了重大突破，目前，数种TPD药物正在针对乳腺癌、前列腺癌和多发性骨髓瘤等不同类型的癌症进行临床试验，并在早期研究中表现出了积极的治疗效果，为患者提供了更多的治疗选择。值得一提的是，其中三种蛋白降解治疗方法获得了FDA的批准并正式上市。▲已进入临床阶段的TPD疗法（药明康德内容团队制作，数据来源：参考资料[2]，药明康德内容部数据库）经过数年的发展，TPD领域的应用范围逐渐扩大到其他医学领域，如自身免疫性疾病、炎症性疾病等。多家医药企业也与学术界建立了紧密的合作关系，共同推动TPD药物从基础研究到临床应用的转化。预计在未来几年，我们将看到更多的TPD药物进入临床试验阶段，为全球患者带来更多的希望。参考阅读：从被指“业余”到行业翘楚，这家生物技术公司如何花十年完成不凡蜕变？TPD的未来展望总的来说，TPD的未来可期，有望为各种疾病带来更为有效的治疗手段。尽管TPD仍然面临一些挑战有待克服，但该领域的快速发展势头预示着TPD将在未来数年内持续成为药物研发的焦点。近年来，TPD的一个发展趋势是与其他学科，如合成生物学、蛋白工程和核酸调控的深度融合，从而让TPD分子的形式变得更为多样化。例如，为了特异性地降解目标蛋白，研究者们正在设计类似于抗体偶联药物（ADC）的新型结构“抗体-PROTAC”偶联物。这种结构由定向E3连接酶的降解剂分子与抗体连接子结合而成，当抗体-PROTAC进入细胞后，连接子会被水解，从而释放活性的PROTAC，并进一步诱导目标蛋白的降解。此外，双特异性抗体降解剂被证实能够有效地驱动与细胞膜结合的E3泛素连接酶RNF和ZNRF3，从而导致诸如PD-L1、EGFR和IGF1R等跨膜蛋白的降解。另一发展趋势是基于蛋白质的生物降解剂（biodegraders），这种生物降解剂以细胞内一种嵌合蛋白为中心，该嵌合蛋白由一个高亲和力目标结合域和一个工程化的E3泛素连接酶适配器融合而成。在向细胞递送编码生物降解剂蛋白的mRNA后，它可以针对如增殖细胞核抗原（PCNA）这类重要的癌症蛋白进行作用。另一方面，为了扩大可降解基因组的范围，寡核苷酸已开始被用来针对那些缺乏明确的可供配体结合口袋结构的RNA和DNA结合蛋白。除了通过诱导蛋白泛素化的方法外，我们预见新的邻近性诱导调控策略也会引导其它的转录后修饰（PTM），例如去泛素化、去磷酸化、磷酸化和乙酰化，进而实现目标蛋白的稳定、失活、激活和定位等多种功能。这些创新性的研究进一步推动了TPD领域的发展，为其带来更多转化应用的机会。通过结合传统的药物研发方法和新兴技术，研究人员正在不断拓展TPD策略的应用边界。这些进展不仅凸显了跨学科合作的重要性，还突出了科学研究、技术创新和药物开发之间的紧密结合。随着更多的药物靶点和治疗方法得到开发和验证，我们期待在未来看到更多的靶向蛋白降解疗法进入临床阶段，为患者带来实际的治疗益处。参考资料：[1] Teng, Mingxing, and Nathanael S Gray. “The rise of degrader drugs.” Cell chemical biology, S2451-9456(23)00198-8. 6 Jul. 2023, doi:10.1016/j.chembiol.2023.06.020[2] Chirnomas, Deborah et al. “Protein degraders enter the clinic - a new approach to cancer therapy.” Nature reviews. Clinical oncology vol. 20,4 (2023): 265-278. doi:10.1038/s41571-023-00736-3[3] Maneiro, Marı A et al. “Antibody-PROTAC Conjugates Enable HER2-Dependent Targeted Protein Degradation of BRD4.” ACS chemical biology vol. 15,6 (2020): 1306-1312. doi:10.1021/acschembio.0c00285本文来由药明康德内容团队根据公开资料整理编辑，欢迎个人转发至朋友圈。转发授权请在「药明康德」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

蛋白降解靶向嵌合体

2023-07-31

·药明康德

WuXi AppTec Announced Strong Results of the Q2 and H1 of 2023

Management CommentDr. Ge Li, Chairman and CEO of WuXi AppTec, said, “We continued to achieve steady growth of revenue, net profit, and free cash flow in the first half of 2023. Our revenue increased 6.3% year-over-year to RMB18.87 billion, or 27.9% if excluding COVID-19 commercial projects. Our adjusted non-IFRS net profit attributable to owners of the Company increased 18.5% year-over-year, outpacing the revenue growth rate, and our free cash flow achieved RMB2.93 billion, as a result of the Company’s pursuit of operational excellence and productivity.”“The Company’s performance in the first half of 2023 demonstrated that WuXi AppTec’s unique CRDMO and CTDMO business models can effectively meet the growing demands from customers worldwide and continue to drive solid growth for the Company. In 2023, we aim to deliver a 5-7% revenue growth, increase adjusted non-IFRS gross profit by 13-14%, and expand free cash flow by 750-850%. We remain committed to prioritizing our customers’ needs and enhancing our capacity and capabilities as we support our customers’ efforts to bring groundbreaking therapies to patients around the world. Together, we can realize our vision that ‘every drug can be made and every disease can be treated’.”About WuXi AppTecAs a global company with operations across Asia, Europe, and North America, WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable the global pharmaceutical and healthcare industry to advance discoveries and deliver groundbreaking treatments to patients. Through its unique business models, WuXi AppTec’s integrated, end-to-end services include chemistry drug CRDMO (Contract Research, Development and Manufacturing Organization), biology discovery, preclinical testing and clinical research services, cell and gene therapies CTDMO (Contract Testing, Development and Manufacturing Organization), helping customers improve the productivity of advancing healthcare products through cost-effective and efficient solutions. WuXi AppTec received an AA ESG rating from MSCI in 2022 and its open-access platform is enabling more than 6,000 customers from over 30 countries to improve the health of those in need – and to realize the vision that "every drug can be made and every disease can be treated." Please visit: http://www.wuxiapptec.comForward-Looking StatementsThis press release may contain certain “forward-looking statements” which are not historical facts, but instead are predictions about future events based on our beliefs as well as assumptions made by and information currently available to our management. Although we believe that our predictions are reasonable, future events are inherently uncertain and our forward-looking statements may turn out to be incorrect. Our forward-looking statements are subject to risks relating to, among other things, the ability of our service offerings to compete effectively, our ability to meet timelines for the expansion of our service offerings, our ability to protect our customers’ intellectual property, unforeseeable international tension, competition, the impact of emergencies and other force majeure. Our forward-looking statements in this press release speak only as of the date on which they are made, and we assume no obligation to update any forward-looking statements except as required by applicable law or listing rules. Accordingly, you are strongly cautioned that reliance on any forward-looking statements involves known and unknown risks and uncertainties. All forward-looking statements contained herein are qualified by reference to the cautionary statements set forth in this section. All information provided in this press release is as of the date of this press release and are based on assumptions that we believe to be reasonable as of this date, and we do not undertake any obligation to update any forward-looking statement, except as required under applicable law. Use of Non-IFRS and Adjusted Non-IFRS Financial MeasuresWe provide non-IFRS gross profit and non-IFRS net profit attributable to owners of the Company, which exclude share-based compensation expenses, issuance expenses of convertible bonds, fair value gain or loss from derivative component of convertible bonds, foreign exchange-related gains or losses, amortization of intangible assets acquired in business combinations, non-financial assets impairment, etc. We also provide adjusted non-IFRS net profit attributable to owners of the Company and earnings per share, which further exclude realized and unrealized gains or losses from our venture capital investments and joint ventures. Neither is required by, or presented in accordance with IFRS. We believe that the adjusted financial measures used in this press release are useful for understanding and assessing our core business performance and operating trends, and we believe that management and investors may benefit from referring to these adjusted financial measures in assessing our financial performance by eliminating the impact of certain unusual, non-recurring, non-cash and non-operating items that we do not consider indicative of the performance of our core business. Such adjusted non-IFRS net profit attributable to owners of the Company, the management of the Company believes, is widely accepted and adopted in the industry the Company is operating in. However, the presentation of these adjusted non-IFRS financial measures is not intended to be considered in isolation or as a substitute for the financial information prepared and presented in accordance with IFRS. You should not view adjusted results on a stand-alone basis or as a substitute for results under IFRS, or as being comparable to results reported or forecasted by other companies. This release provides a summary of the results and is not intended to be a comprehensive report. For additional information, please refer to the 2023 Interim Report and other relevant announcements published on the websites of the Shanghai Stock Exchange (www.sse.com.cn) and the Stock Exchange of Hong Kong (www.hkexnews.hk), and the designated media for dissemination of the relevant information. Investors are advised to exercise caution and be aware of the investment risks in trading Company shares.All financial information disclosed in this press release is prepared based on International Financial Reporting Standards (IFRS), in currency of RMB.The 2023 Interim Report of the Company has not been audited.

2023-07-23

·药明康德

倒计时7天，药明康德2023年中期业绩交流电话会 | Bilingual

尊敬的投资者，我们诚挚邀请您参加药明康德2023年中期业绩交流电话会，出席会议请拨打下图电话号码。中文会议将于北京时间2023年8月1日上午8:00-8:55召开英文会议将于北京时间2023年8月1日上午9:00-10:00召开*非白名单用户请通过海报内的链接预先注册参会。Dear Investors,WuXi AppTec is pleased to invite you to our 1H23 Results Webcast. We thank you for your interest and we sincerely hope you will join us.English Webcast at 9:00-10:00 a.m., August 1, China time (9:00-10:00 p.m., July 31, EST.)Chinese Webcast at 8:00-8:55 a.m., August 1, China time*Please sign up in advance for the English webcast through the link on the poster.关于药明康德药明康德（股票代码：603259.SH/2359.HK）为全球生物医药行业提供一体化、端到端的新药研发和生产服务，在亚洲、欧洲、北美等地均设有运营基地。药明康德通过独特的“CRDMO”和“CTDMO”业务模式，不断降低研发门槛，助力客户提升研发效率，为患者带来更多突破性的治疗方案，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。2022年，药明康德被MSCI评为ESG（环境、社会及管治）AA级。目前，公司的赋能平台正承载着来自全球30多个国家的6000多家合作伙伴的研发创新项目，致力于将更多新药、好药带给全球病患，早日实现“让天下没有难做的药，难治的病”的愿景。About WuXi AppTecAs a global company with operations across Asia, Europe, and North America, WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable global pharmaceutical and healthcare industry to advance discoveries and deliver groundbreaking treatments to patients. Through its unique business models, WuXi AppTec’s integrated, end-to-end services include chemistry drug CRDMO (Contract Research, Development and Manufacturing Organization), biology discovery, preclinical testing and clinical research services, cell and gene therapies CTDMO (Contract Testing, Development and Manufacturing Organization), helping customers improve the productivity of advancing healthcare products through cost-effective and efficient solutions. WuXi AppTec received AA ESG rating from MSCI in 2022 and its open-access platform is enabling more than 6,000 collaborators from over 30 countries to improve the health of those in need – and to realize the vision that "every drug can be made and every disease can be treated."

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