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近日，第六届东方感染病-肝病会议在上海隆重举行，本次大会邀请到国内外知名的专家学者，通过主题演讲、分组讨论、学术展示和论文交流等形式，深入研讨感染病和肝病的热点问题，分享前沿的科学理念和治疗方案，为感染病和肝病领域的发展贡献智慧和力量。 在本次大会上，来自北京大学第一医院徐小元教授对“肝硬化腹水诊疗指南(2023)解读”进行了详细的分享，本文梳理重点内容，以分享各位同道。 概述 腹水是失代偿期肝硬化患者常见的并发症，也是肝硬化自然病程中疾病进展的重要标志，一旦出现腹水，1年病死率约20%，5年病死率约44%。腹水的防治仍是临床工作中常见的难点问题。 肝硬化腹水 肝硬化腹水的形成机制较复杂，常是几个因素共同作用的结果。门静脉高压是腹水形成的主要原因及始动因素。低蛋白血症、肾素-血管紧张素-醛固酮系统(RAAS)失衡、淋巴液回流受阻及肠道菌群移位等也在腹水的形成中发挥作用。 肝硬化疾病分期模式 我国分期：代偿期、失代偿期、再代偿期和/或肝硬化逆转 国外(5+1期)：代偿期1-2期，5年死亡风险 -Stage1：无胃食管静脉曲张为1.5% -Stage2：有静脉曲张无出血为10% 失代偿期3-5期 -Stage3：仅有静脉曲张出血为20% -Stage4：仅有单一非出血性事件(主要为腹水)为30% -Stage5：≥两个失代偿事件为88% 晚期6期 -Stage6：晚期失代偿：难治性腹水、持续性脑病或黄疸、感染、肾脏和其他器官功能障碍 肝硬化失代偿亚临床形式（但不是失代偿） 轻微肝性脑病（MHE）； B超2cm以下的少量腹水； 肝硬化便潜血试验阳性（排除其他原因）； 临床需重视肝硬化失代偿的亚临床形式，首次失代偿，稳定失代偿及不稳定失代偿。 推荐意见1：肝硬化临床可分为代偿期、失代偿期及再代偿期（B，1）；腹水（排除其他原因）为肝硬化失代偿的常见临床表现。 推荐意见2：对新出现的腹水和2、3级以上腹水患者，应行腹腔穿刺腹水常规检查，包括腹水细胞计数和分类、腹水总蛋白、白蛋白。腹腔穿刺同日检测血清白蛋白，SAAG≥11g/L的腹水提示为门静脉高压性（B，1)。 推荐意见3：疑似腹腔感染时，须在使用抗菌药物前留取标本，使用血培养瓶在床旁行腹水细菌、厌氧菌和/或真菌培养。严格无菌操作，床旁取得腹水立即注入血培养瓶10~20ml，并即刻送检(A，1)。 推荐意见4：顽固型腹水的诊断：①传统利尿药物（螺内酯160mg/d、呋塞米80mg/d）治疗>1周或治疗性间断放腹水(4000~5000mI/次)联合人血白蛋白(20~40g·次-1·d-1)治疗2周，腹水无治疗应答反应；②出现难以控制的利尿药物相关并发症或不良反应；③排除恶性腹水及窦前性门静脉高压症引起的腹水(B,1)。 推荐意见5：复发型腹水：在限盐及应用利尿药物的情况下，1年内腹水复发≥3次。 推荐意见6：乳糜性腹水：外观呈乳白色，腹水的甘油三酯水平>200 mg/dl（11.11mmol/L)，<50 mg/dl 可排除诊断。 推荐意见7：血性腹水：腹水外观血性或腹水红细胞计数>10000个/mm3。 推荐意见8：螺内酯起始剂量40~80mgld，3~5d递增40mg/d，常规剂量上限为100mg/d，最大剂量400mg/d；呋噻米起始剂量20~40mg/d，3~5d递增40mg/d，常规剂量上限80mg/d，最大剂量160mg/d（B，1）。 推荐意见9：托伐普坦是治疗肝硬化腹水，特别是伴低钠血症的有效排水药物，根据血钠水平调整剂量，避免血钠升高过快。起始剂量7.5~15mg/d，最低剂量3.75mg/d，最大剂量60mg/d（A，1）。 顽固型腹水药物治疗（三联药物治疗） 对于顽固型腹水患者，三联药物治疗是一种有效的治疗方案，可以帮助控制腹水，改善患者的生活质量和预后。血管扩张药、多巴胺、前列腺素等对顽固型腹水无效。 推荐意见1：顽固型腹水治疗方案：①利尿药物、人血白蛋白及血管活性药物；②大量放腹水(4000~5000ml·次-1·d-1)联合人血白蛋白(1000ml腹水4g)(B，1)③对治疗效果不佳、门静脉高压起主要作用的顽固型腹水，有条件且无禁忌证时优先TIPS治疗(B，1)。 推荐意见2：对顽固型腹水患者可谨慎长期腹腔放置引流管放腹水(C，1)。肝硬化顽固型腹水患者应列入优先肝移植等待名单(B，2)。 推荐意见3：血压、脉搏正常的肝硬化腹水患者，特别是顽固性腹水伴AKI患者，在食管胃静脉曲张出血级或二级预防时，可谨慎使用NSBBs(D，2)。 推荐意见4：乳糜性腹水可采用高蛋白、低脂肪饮食，特利加压素、生长抑素等，如无效可采用大量放腹水或TIPS(C，2)。 推荐意见5：血性腹水且生命体征不稳定患者需ICU监护，及时检查原因，可应用去甲肾上腺素、特利加压素及生长抑素等(C，2)。 推荐意见6：肝硬化胸水治疗原则同腹水；①顽固性胸水可试用利尿药物、人血白蛋白及血管活性药物；②有明显呼吸困难患者可放胸水联用人血白蛋白(B，1)；③对治疗效果不佳，有条件且无禁忌证时可早期行TIPS治疗等(B，1)。 推荐意见7：积极进行病因治疗，在病因治疗的基础上，可使用中药安络化纤丸、扶正化瘀胶囊和复方鳖甲软肝片等改善肝纤维化和肝硬化，达到肝硬化病情稳定或逆转失代偿期肝硬化为再代偿期(A，1)。 推荐意见8：肝硬化腹水患者可使用利福昔明进行SBP二级预防(B，1)。 推荐意见9：抗菌药物治疗应答差的患者，需考虑耐药菌和/或真菌性腹膜炎，真菌性腹膜炎可选择唑类或棘白菌素类等抗真菌药物(B，1)。 推荐意见10：当血肌酐48h内增加≥0.3mg/dl，或从基线值增加≥50%，应诊断AKI(A，1)。无论肾脏有无器质性损伤(蛋白尿/血尿/超声提示肾脏异常)，eGFR<60ml/min持续3个月以上，可诊断CKD(B，2)。 推荐意见11：HRS-AKI的诊断：(1)肝硬化合并腹水；(2)无休克；(3)符合AKI的诊断标准；(4)停利尿药物补充白蛋白扩充血容量48h无应答；(5)近期无肾毒性药物使用史；(6)无肾实质性损伤(A，1)。 推荐意见12：血管收缩药物治疗无效且满足血液净化治疗标准的HRS，可选择相关血液净化治疗(B，1)。 推荐意见13：对血管收缩药物治疗无应答且伴大量腹水的HRS-NAKI可行TIPS治疗。HRS-AKI应纳入肝移植计划(B，1)。 新概念：有效白蛋白 白蛋白是人体血液中的主要蛋白质。90%以上健康成人血清白蛋白在4-5g/dl，也是体内液体分布的主要调节分子。 白蛋白还具有许多非胶体渗透压相关的生物功能。这些功能与白蛋白特殊结构密切相关。在失代偿期肝硬化中，促氧化和促炎状态导致白蛋白的结构发生显著改变。由于白蛋白的分子结构破坏，白蛋白的功能也因此发生障碍。白蛋白结构和功能的改变与肝硬化的严重程度相平行。 待解决的问题 1、敏感性和特异性高的腹水病原微生物快速检测方法的研究；肝硬化腹水患者AKI早期诊断生物标志物的研究。 2、大量放腹水与人血白蛋白不同剂量或疗程的有效性、安全性研究。 3、肝硬化腹水SBP一级预防、真菌性腹膜炎早期诊治的临床研究。 4、螺内酯、呋塞米与托伐普坦的优化配伍新方案研究。 5、益生菌、血管活性药物、干细胞等非肝硬化病因治疗方案及效果研究。 6、利用互联网医院等信息化技术对肝硬化腹水患者进行长期随访、专业护理及健康指导的研究。 来源 | 梅斯医学官网 编辑 | Swagpp ● 警惕！千万别把酒和这种饮品混合喝！最新研究：酒精+它，长期改变大脑，影响认知功能 ● 痛心！近期报道两起患者院内死亡！要么判为一级甲等医疗事故；要么索赔200万，连告两家医院！为何医生越来越难当了？带来哪些教训？ ● 持续热议！医务人员投诉三甲医院：压榨新人，月薪仅1700，院领导每月工资却有几万！劳务派遣饱受诟病，多少医护恨得牙痒痒 版权说明：梅斯医学（MedSci）是国内领先的医学科研与学术服务平台，致力于医疗质量的改进，为临床实践提供智慧、精准的决策支持，让医生与患者受益。欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。 点击下方「阅读原文」 立刻下载梅斯医学APP！

- Transaction Includes JNT-517, a Potential First-In-Class Oral Treatment for Phenylketonuria (PKU) - - Expands Specialty and Autoimmune Portfolios and Drug Discovery Technologies - TOKYO and BOSTON, Aug. 01, 2024 (GLOBE NEWSWIRE) -- Otsuka Pharmaceutical Co., Ltd. (Otsuka) and Jnana Therapeutics Inc. (Jnana) today announced that they have entered into a definitive merger agreement pursuant to which Otsuka will acquire Jnana, making it a wholly owned subsidiary through Otsuka’s 100-percent owned subsidiary, Otsuka America, Inc. (OAI). The acquisition is expected to be completed in the third quarter of fiscal 2024, subject to customary closing conditions. Based on the terms of the agreement, Otsuka will pay USD $800 million to the shareholders of Jnana upon completion of the acquisition, as well as up to an additional USD $325 million in development and regulatory milestones. 1．Reasons for the acquisition Jnana’s novel approach to drug discovery is enabled by RAPID – the company’s next-generation chemoproteomics platform designed to discover medicines for highly validated but challenging-to-drug targets. The platform leverages a high-throughput, binding-based screening approach that is inherently flexible, enabling the discovery of binding sites across the surface of a target protein and the identification of small molecules that elicit diverse pharmacologies. Jnana has used RAPID to successfully identify first-in-class compounds and address a range of historically challenging-to-drug target classes, including solute carriers, transcription factors, and signaling scaffold proteins. Jnana pursues drug discovery based on concepts that are complementary to those of Astex Pharmaceuticals, a subsidiary of Otsuka based in Cambridge, UK. While Jnana's RAPID platform is not limited to any specific therapeutic area, the company has built a unique competitive position by concentrating on PKU, a rare inherited metabolic disorder in which phenylalanine accumulates to abnormally high levels in the blood, and autoimmune diseases, where small molecule drug discovery has been challenging. Jnana’s technology successfully generated JNT-517, an allosteric small molecule inhibitor of SLC6A19, an SLC (solute carrier) that regulates amino acid reabsorption in the kidney. JNT-517 has the potential to become a first-in-class oral treatment for PKU, as it has been shown to be effective, well-tolerated, and safe in a Phase 1b/2 study. A majority of the PKU population is not effectively treated with existing therapies, and JNT-517 is an approach that could address individuals of all ages across the spectrum of mild to severe disease. In the autoimmune disease field, the company is pursuing small molecule drug discovery for highly validated, but challenging-to-drug, targets such as interferon regulatory factor 3 (IRF3), a master transcription factor for the production of interferon. Otsuka has advanced contributions to patients with a wide range of rare diseases, not only in the renal area with JINARC (approved for autosomal dominant polycystic kidney disease), sibeprenlimab (IgA nephropathy), and voclosporin (lupus nephritis), but also by adding new specialty drugs such as donidalorsen (hereditary angioedema). Additionally, through Visterra, a Boston-based company that Otsuka acquired in 2018, Otsuka is advancing research and development in the autoimmune field using antibody drug technology, while also expanding its drug discovery platform. Makoto Inoue, president and representative director of Otsuka Pharmaceutical commented, "I am gratified that Otsuka has entered into an agreement with Jnana. The addition of Jnana's drug discovery technology and small molecule pipeline in PKU and autoimmune diseases will strengthen our R&D in the Boston area of the U.S., one of the most important bioclusters in the world, and in a combined form will have a synergistic effect on Otsuka Pharmaceutical's global expansion.” Joanne Kotz, Ph.D., CEO and co-founder of Jnana, commented, "This transaction recognizes the Jnana team’s accomplishments since the founding of the company, which include creating RAPID – a world-class small molecule drug discovery platform. Leveraging our platform, the team discovered JNT-517, a potential first-in-class oral medicine for the treatment of PKU, and has demonstrated positive clinical proof of concept for JNT-517 in individuals with PKU. We are excited to join Otsuka with our shared goal of developing transformative therapies for patients and look forward to advancing JNT-517 into a registrational study in 2025 and continuing to progress our pipeline of innovative oral medicines for autoimmune diseases." 2．Outline of the acquisition Upon completion of the acquisition, Jnana will operate as a wholly owned subsidiary of Otsuka in Boston and will continue its research and development. The acquisition will be implemented by merging a special purpose company, established under OAI for this acquisition, into Jnana Therapeutics, with Jnana remaining as the surviving company. Existing shareholders of Jnana will be paid cash as consideration for this merger. Although the Boards of Directors of both Otsuka and Jnana have approved this acquisition, the execution of this acquisition may require the approval of Jnana's shareholders and the fulfillment of conditions under U.S. antitrust laws. After completion of necessary procedures, we aim to complete the acquisition during the third quarter of 2024. 3．Additional information about Otsuka (https://www.otsuka.co.jp/en/) Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: Otsuka–people creating new products for better health worldwide. Otsuka researches, develops, manufactures, and markets innovative products, with a focus on pharmaceutical products to meet unmet medical needs and nutraceutical products for the maintenance of everyday health.In pharmaceuticals, Otsuka is a leader in the challenging areas of mental, renal, and cardiovascular health and has additional research programs in oncology and on several under-addressed diseases including tuberculosis, a significant global public health issue. These commitments illustrate how Otsuka is a “big venture” company at heart, applying a youthful spirit of creativity in everything it does. 4．Additional information about Jnana (https://www.jnanatx.com/) Jnana Therapeutics is a clinical-stage biotechnology company leveraging its next-generation RAPID chemoproteomics platform to discover medicines for highly validated, challenging-to-drug targets to treat diseases with high unmet needs. Jnana is focused on developing first- and best-in-class therapies to treat a wide range of diseases, including rare diseases and immune-mediated diseases. Jnana’s lead program, JNT-517, which targets an allosteric site on the phenylalanine transporter SLC6A19, is a potential first-in-class oral approach for the treatment of PKU, a rare genetic metabolic disease. Located in Boston, Jnana brings together scientific leaders in small molecule drug discovery and development, a highly experienced management team, and the backing of leading life science investors Bain Capital Life Sciences, RA Capital Management, Polaris Partners, Versant Ventures, Avalon Ventures, Pfizer Ventures, and AbbVie Ventures. 5．Advisors Centerview Partners LLC acted as financial advisor to Jnana and Latham & Watkins LLP acted as its legal advisor.