Oxidative stress is one of the main mechanisms causing harm in severe infection with septic shock, ischemia-reperfusion injury in resuscitated cardiac arrest and ischemic and hemorrhagic stroke.
Melatonin is a potent scavenger of the mediators of oxidative stress, oxygen and nitrogen-reactive species, which directly injure cell structures like walls and DNA and thus cause organ dysfunction.
In a previous study we have observed that high-dose oral bedtime melatonin (OBM) is associated with improved organ function in severe Covid-19 patients

开始日期2025-02-01

申办/合作机构

Hospital San Carlos, Madrid

[+1]

NCT06404086 / Not yet recruiting临床2期IIT

RECOVER-SLEEP: A Platform Protocol for Evaluation of Interventions for Sleep Disturbances in Post-Acute Sequelae of SARS-CoV-2 Infection (PASC)

The platform protocol is designed to be flexible so that it is suitable for a range of study settings and intervention types. Therefore, the platform protocol provides a general protocol structure that can be shared by multiple interventions and allows comparative analysis across the interventions. For example, objectives, measures, and endpoints are generalized in the platform protocol, but intervention-specific features are detailed in separate appendices.
This platform protocol is a prospective, multi-center, multi-arm, randomized controlled platform trial evaluating potential interventions for PASC-mediated sleep disturbances. The hypothesis is that symptoms of sleep and circadian disorders that emerge in patients with PASC can be improved by phenotype-targeted interventions. Specific sleep and circadian disorders addressed in this protocol include sleep-related daytime impairment (referred to as hypersomnia) and complex PASC-related sleep disturbance (reflecting symptoms of insomnia and sleep-wake rhythm disturbance).

开始日期2024-07-01

申办/合作机构

Duke University

100 项与褪黑素相关的临床结果

登录后查看更多信息

100 项与褪黑素相关的转化医学

登录后查看更多信息

100 项与褪黑素相关的专利（医药）

登录后查看更多信息

25,821

项与褪黑素相关的文献（医药）

2024-12-31·Gut Microbes

Gut microbiota regulates host melatonin production through epithelial cell MyD88

Article

作者: Ge, Liangpeng ; Wang, Hao ; Fan, Lijuan ; Ren, Wenkai ; Wang, Youxia ; Liu, Bingnan ; Hung, Ifen ; Yan, Yuqi ; Wei, Hong ; Liu, Chunxue ; Chen, Shuai

Melatonin has various physiological effects, such as the maintenance of circadian rhythms, anti-inflammatory functions, and regulation of intestinal barriers. The regulatory functions of melatonin in gut microbiota remodeling have also been well clarified; however, the role of gut microbiota in regulating host melatonin production remains poorly understood. To address this, we studied the contribution of gut microbiota to host melatonin production using gut microbiota-perturbed models. We demonstrated that antibiotic-treated and germ-free mice possessed diminished melatonin levels in the serum and elevated melatonin levels in the colon. The influence of the intestinal microbiota on host melatonin production was further confirmed by fecal microbiota transplantation. Notably, Lactobacillus reuteri (L. R) and Escherichia coli (E. coli) recapitulated the effects of gut microbiota on host melatonin production. Mechanistically, L. R and E. coli activated the TLR2/4/MyD88/NF-κB signaling pathway to promote expression of arylalkylamine N-acetyltransferase (AANAT, a rate-limiting enzyme for melatonin production), and MyD88 deficiency in colonic epithelial cells abolished the influence of intestinal microbiota on colonic melatonin production. Collectively, we revealed a specific underlying mechanism of gut microbiota to modulate host melatonin production, which might provide novel therapeutic ideas for melatonin-related diseases.

2024-12-31·Gut Microbes

Modulation of chronic obstructive pulmonary disease progression by antioxidant metabolites from Pediococcus pentosaceus : enhancing gut probiotics abundance and the tryptophan-melatonin pathway

Article

作者: Tang, Guiying ; Li, Longjie ; Jin, Fa ; Zhang, Yunlei ; Tu, Qiang ; Yin, Jia ; Liu, Yiting ; Feng, Jing ; Zhang, Xiuwei ; Wan, Bing ; Rodrigues, Lígia R ; Cai, Wei

Chronic obstructive pulmonary disease (COPD), a condition primarily linked to oxidative stress, poses significant health burdens worldwide. Recent evidence has shed light on the association between the dysbiosis of gut microbiota and COPD, and their metabolites have emerged as potential modulators of disease progression through the intricate gut-lung axis. Here, we demonstrate the efficacy of oral administration of the probiotic Pediococcus pentosaceus SMM914 (SMM914) in delaying the progression of COPD by attenuating pulmonary oxidative stress. Specially, SMM914 induces a notable shift in the gut microbiota toward a community structure characterized by an augmented abundance of probiotics producing short-chain fatty acids and antioxidant metabolisms. Concurrently, SMM914 synthesizes L-tryptophanamide, 5-hydroxy-L-tryptophan, and 3-sulfino-L-alanine, thereby enhancing the tryptophan-melatonin pathway and elevating 6-hydroxymelatonin and hypotaurine in the lung environment. This modulation amplifies the secretion of endogenous anti-inflammatory factors, diminishes macrophage polarization toward the M1 phenotype, and ultimately mitigates the oxidative stress in mice with COPD. The demonstrated efficacy of the probiotic intervention, specifically with SMM914, not only highlights the modulation of intestine microbiota but also emphasizes the consequential impact on the intricate interplay between the gastrointestinal system and respiratory health.

2024-12-31·Plant Signaling & Behavior

Exogenous melatonin delays leaves senescence and enhances saline and alkaline stress tolerance in grape seedlings

Article

作者: Yang, Zhongyi ; Yang, Xixi ; Wei, Shimei ; Shen, Fengfeng ; Ji, Wei

Saline and alkaline stress is one of the major abiotic stresses facing agricultural production, which severely inhibits the growth and yield of plant. The application of plant growth regulators can effectively prevent crop yield reduction caused by saline and alkaline stress. Exogenous melatonin (MT) can act as a signaling molecule involved in the regulation of a variety of physiological processes in plants, has been found to play a key role in enhancing the improvement of plant tolerance to abiotic stresses. However, the effects of exogenous MT on saline and alkaline tolerance of table grape seedlings and its mechanism have not been clarified. The aim of this study was to investigate the role of exogenous MT on morphological and physiological growth of table grape seedlings (Vitis vinifera L.) under saline and alkaline stress. The results showed that saline and alkaline stress resulted in yellowing and wilting of grape leaves and a decrease in chlorophyll content, whereas the application of exogenous MT alleviated the degradation of chlorophyll in grape seedling leaves caused by saline and alkaline stress and promoted the accumulation of soluble sugars and proline content. In addition, exogenous MT increased the activity of antioxidant enzymes, which resulted in the scavenging of reactive oxygen species (ROS) generated by saline and alkaline stress. In conclusion, exogenous MT was involved in the tolerance of grape seedlings to saline and alkaline stress, and enhanced the saline and alkaline resistance of grape seedlings to promote the growth and development of the grape industry in saline and alkaline areas.

项与褪黑素相关的新闻（医药）

2024-04-24

·今日头条

健康枢纽：多文聚焦肠道如何影响全身健康

04月24日的《热心肠日报》，我们解读了 15 篇文献，关注：神经退行性疾病，肠脑轴，性别差异，抑郁，预后标志物，5G，肠骨轴，微塑料，SNIPR Biome，BMS，默沙东，OMNY Health，厌氧生物，长光辰英。该篇日报由R·AI辅助创作生成，人工审核校对。刘志华+黄超兰+曹立等：解析遗传性神经退行性疾病的肠道机制 Protein & Cell——[21.1] ① SCARB2基因缺陷可导致进行性肌阵挛癫痫（一种遗传性神经退行性疾病），清华大学刘志华团队、中国医学科学院北京协和医学院黄超兰团队及上海交通大学附属第六人民医院神经内科曹立团队合作发表研究，揭示了这类疾病中的肠道机制；② Scarb2基因缺失导致小鼠出现年龄依赖性膳食脂质吸收不良，伴随维生素E缺乏；③ Scarb2缺失与肠道菌群失衡和胆汁酸池改变有关，导致肠道FXR过度激活，进而损害肠上皮细胞更新和脂质吸收；④ SCARB2基因突变患者体内维生素E水平严重降低，无法吸收膳食维生素E；⑤ 抑制FXR或补充维生素E可改善Scarb2基因敲除小鼠的神经运动障碍和神经病变；⑥ 本研究表明，通过解决营养缺陷和胃肠道问题，或可改善SCARB2相关神经退行性疾病。【原文信息】 Gut dysbiosis impairs intestinal renewal and lipid absorption in Scarb2 deficiency-associated neurodegeneration 2024-04-18 , doi: 10.1093/procel/pwae016 国内团队：弓形虫感染或通过肠道菌群伤认知 Brain Behavior and Immunity——[15.1] ① 徐州医科大学潘伟、于英华团队联合山东第一医科大学尹昆团队发现肠道菌群改变会导致弓形虫慢性感染引起的认知缺陷；② 弓形虫感染导致小鼠海马突触结构损伤和神经炎症，并伴有肠道菌群失调、屏障完整性受损和炎症；③ 广谱抗生素治疗可减轻弓形虫感染对小鼠认知功能的不良影响，而粪菌移植可将感染小鼠的认知缺陷和海马病理变化转移到健康小鼠；④ 感染小鼠中产丁酸细菌的丰度及血清丁酸盐水平显著降低，而补充丁酸可改善弓形虫感染引起的认知障碍；⑤ 与健康对照相比，丁酸盐水平降低与人类受试者血清中抗弓形虫IgG抗体的水平呈负相关；⑥ 本研究表明肠道菌群是弓形虫引起的认知障碍的关键调节因子。【原文信息】 Alterations in gut microbiota contribute to cognitive deficits induced by chronic infection of Toxoplasma gondii 2024-04-10 , doi: 10.1016/j.bbi.2024.04.008 阿尔茨海默病基因型与小鼠肠道菌群的性别特异性关联 Alzheimer's and Dementia——[14] ① 探究了人源性淀粉样蛋白前体基因敲入（hAβ-KI）小鼠的肠道菌群与阿尔茨海默病（AD）基因型间的性别特异性关联；② 通过宏基因组学和非靶向代谢组学分析，发现18个月大的雌性hAβ-KI小鼠的肠道菌群与野生型小鼠存在显著差异，AD基因型解释了18%的菌群变异；③ 雌性hAβ-KI小鼠的代谢组多样性有所不同，但没有单个代谢物显著差异；④ hAβ-KI小鼠的微生物群落可以与早发型AD模型小鼠区分开，主要由Romboutsia ilealis和Turicibacter属驱动分离；⑤ 笼具分配对菌群和代谢组的变异贡献超过40%，强调了在设计AD小鼠模型研究时考虑菌群的重要性。【原文信息】 Sex-specific associations between AD genotype and the microbiome of human amyloid beta knock-in (hAβ-KI) mice 2024-04-04 , doi: 10.1002/alz.13794 抗生素治疗可减轻癫痫发作？ Brain Behavior and Immunity——[15.1] ① 本研究发现，在癫痫早期使用抗生素利福昔明治疗，可以逆转小鼠肠道变化并减少癫痫发作持续时间，增强了基于肠道的癫痫治疗效果；② 利福昔明在疾病早期阶段（发作后24小时内）给药21天，能显著减少小鼠癫痫发作持续时间，并防止海马体苔藓细胞的损失；③ 与对照饮食的癫痫小鼠相比，利福昔明处理的小鼠肠道结构和细胞变化得到逆转，肠道屏障完整性增强，炎症标志物表达减少；④ 在慢性癫痫（发作后51天）小鼠中给药21天，利福昔明对癫痫发作次数和持续时间无显著影响，且不影响肠道；⑤ 利福昔明在两个疾病阶段均改变了小鼠肠道菌群的α和β多样性，且这些变化与疾病阶段相关，在早期疾病阶段，特定菌群的丰度与小鼠的癫痫持续时间呈正相关。【原文信息】 Early treatment with rifaximin during epileptogenesis reverses gut alterations and reduces seizure duration in a mouse model of acquired epilepsy 2024-04-10 , doi: 10.1016/j.bbi.2024.04.007 肠道MAdCAM-1分子磁共振成像：多发性硬化症预后生物标志物 Brain Behavior and Immunity——[15.1] ① 本研究揭示了肠道炎症与多发性硬化症（MS）之间的相互作用，并提出肠道黏膜地址素细胞黏附分子-1（MAdCAM-1）的分子磁共振成像（MRI）作为MS预后的新生物标志物；② 在两种实验性自身免疫性脑脊髓炎（EAE）模型中，疾病严重程度与MAdCAM-1 MRI信号正相关；③ 在无症状阶段，高MAdCAM-1 MRI信号与进展型EAE疾病发作的延迟及复发性EAE转变为继发进展型的风险降低有关；④ 随着疾病的发展，肠道中CD4+ T细胞和B淋巴细胞的减少与脊髓中这些细胞的增加相一致，即肠道与中枢神经系统之间的双向免疫通信；⑤ 本研究为MS的早期诊断和治疗提供了新的视角和潜在的靶点。【原文信息】 Intestinal MAdCAM-1 imaging as biomarker for prognostic in murine models of multiple sclerosis 2024-04-09 , doi: 10.1016/j.bbi.2024.04.006 压力减少黏蛋白13，改变肠菌促抑郁 Brain Behavior and Immunity——[15.1] ① 通过构建慢性压力模型，探究黏液蛋白13（Muc13）在压力背景下作为微生物组成变化的上游调节因子的作用；② 心理压力暴露后，肠道糖蛋白Muc13的表达显著下降，且Muc13的减少是由Hnf4转录因子家族介导的；③ 靶向敲除Muc13基因足以引起肠道菌群组成的改变和绝望行为，突出了Muc13在维持微生物和行为稳态中的关键作用；④ 本研究揭示了压力诱导微生物变化的机制，并探究了Muc13表达的新调节因子。【原文信息】 Stress-induced mucin 13 reductions drive intestinal microbiome shifts and despair behaviors 2024-04-03 , doi: 10.1016/j.bbi.2024.03.028 国内团队：5G通信频率辐射引发焦虑？或因肠道菌群失调 Science of the Total Environment——[9.8] ① 空军军医大学丁桂荣团队联合山东第二医科大学王春平团队揭示了3.5GHz射频辐射（5G通信常用频率）对小鼠肠道菌群、大脑代谢物以及行为的影响，发现其通过NLRP3炎症体依赖的神经元焦亡介导焦虑样行为；② 连续35天每天1小时的3.5GHz射频辐射诱导小鼠出现焦虑样行为，并伴随海马背部CA3区域的NLRP3依赖性神经元焦亡；③ 3.5GHz射频辐射还导致小鼠肠道菌群组成发生改变；④ 3.5GHz射频辐射还导致小鼠粪便、血清和大脑中代谢物显著改变，且主要富集于甘油磷脂代谢、色氨酸代谢和精氨酸生物合成；⑤ 相关性分析表明肠道菌群失调与差异代谢物有关；⑥ 本研究发现肠道菌群失调及其代谢物可能通过大脑中的神经元焦亡参与射频辐射引发的焦虑样行为，为理解5G射频辐射引起的神经毒性提供了新视角。【原文信息】 Intestinal microbiota via NLRP3 inflammasome dependent neuronal pyroptosis mediates anxiety-like behaviour in mice exposed to 3.5 GHz radiofrequency radiation 2024-04-10 , doi: 10.1016/j.scitotenv.2024.172391 抗炎药物DIZE通过肠-脑-脾轴发挥抗炎作用 Brain Behavior and Immunity——[15.1] ① 本研究发现抗炎药物Diminazene aceturate（DIZE）通过调节肠道菌群-5-HT大脑-脾交感神经轴，以减轻雄性小鼠的全身炎症反应；② 在内毒素血症模型中，DIZE治疗导致小鼠对炎症信号的低反应性，并促进炎症反射激活以减轻炎症；③ 单侧颈部迷走神经切除术不影响DIZE在脾脏和血清中的抗炎效果，而脾神经切除可减少脾脏和血清中肿瘤坏死因子（TNF）的合成；④ LPS调节肠道菌群以诱导肠炎症并降低血清中色氨酸和5-羟色胺（5-HT）的水平，而DIZE可恢复血清色氨酸水平并增加下丘脑5-HT水平；⑤ 5-HT合成抑制剂4-氯-DL-苯丙氨酸（pcpa）可消除DIZE在脾脏中的抗炎效果；⑥ 本研究揭示了DIZE通过肠道菌群调节，增加中枢5-HT水平，并激活炎症反射的交感神经支以控制内毒素血症小鼠脾脏中TNF的产生。【原文信息】 Diminazene aceturate attenuates systemic inflammation via microbiota gut-5-HT brain-spleen sympathetic axis in male mice 2024-03-26 , doi: 10.1016/j.bbi.2024.03.037 陆军军医大学：肠道菌群代谢物褪黑素或可用于治疗骨质疏松 Journal of Pineal Research——[10.3] ① 陆军军医大学罗飞、许建中、孙东、Yueqi Chen团队发现，肠道微生物产生的色氨酸代谢产物褪黑激素（MLT）通过调节短链脂肪酸（SCFA）和三甲胺氧化物（TMAO）代谢，有助于改善骨质疏松症（OP）；② OP导致肠道色氨酸紊乱和菌群产生MLT减少，而MLT的补充能够缓解OP相关临床症状并逆转肠道菌群失调，包括提高肠道菌群多样性、增加益生菌（如Allobaculum和Parasutterella）的相对丰度，以及改善肠道菌群的代谢功能，如氨基酸代谢、核苷酸代谢和能量代谢；③ MLT显著增加短链脂肪酸的产量，减少了与TMAO相关的代谢产物；④ MLT能够调节M1/M2巨噬细胞的动态平衡，降低血清中的促炎细胞因子水平，并恢复肠道屏障功能；⑤ 这些发现为MLT作为治疗OP的潜在药物提供了新的见解。【原文信息】 Gut microbially produced tryptophan metabolite melatonin ameliorates osteoporosis via modulating SCFA and TMAO metabolism 2024-04-15 , doi: 10.1111/jpi.12954 吃进肚的微塑料可进入全身不同组织并影响代谢 Environmental Health Perspectives——[10.4] ① 通过经口摄入微塑料小鼠模型模拟微塑料暴露，以研究其在宿主内不同组织的积累情况以及对组织代谢活动的影响；② 对小鼠分别灌胃聚苯乙烯（PS）微球以及PS、聚乙烯（PE）和聚乳酸-羟基乙酸共聚物（PLGA）微球混合组，每周2次，持续四周，随后收集其不同组织进行微球镜检以及代谢组学检测；③ 结果显示微塑料颗粒可透过肠屏障，在小鼠血清、脑、肝脏、肾脏中都有检出，其中肝脏中数量高于脑和血清，肾脏中数量低于脑和血清；④ 微塑料暴露导致结肠、肝脏、脑部组织代谢谱变化，结肠变化最大，而脑部变化最小，其中失调的代谢途径与氨基酸代谢相关；⑤ PS暴露组与混合暴露组对宿主不同组织的代谢谱影响也存在差异，其中结肠中烟酸盐和烟酰胺代谢途径相关代谢物水平差异最为显著。【原文信息】 In Vivo Tissue Distribution of Polystyrene or Mixed Polymer Microspheres and Metabolomic Analysis after Oral Exposure in Mice 2024-04-10 , doi: 10.1289/EHP13435 噬菌体疗法公司SNIPR Biome获得CARB-X 548万美元资金支持 ① 4月22日，SNIPR Biome公司宣布，获得了CARB-X的548万美元（约合人民币3971万元）资助，用于推进管线药物SNIPR001临床开发；② SNIPR001是一款采用了CRISPR基因编辑技术的噬菌体药物，旨在用于预防接受造血干细胞移植患者的大肠杆菌血液感染；③ 1b/2a期临床试验预计今年晚些时候开始，将在欧洲和美国10多家临床机构同步进行，研究口服SNIPR001的安全性、耐受性、药代动力学和药效学特性；④ 在临床前研究中，SNIPR001能够靶向清除抗生素耐药性大肠杆菌株，并且随粪便排出体外。【原文信息】 SNIPR Biome receives funding from CARB-X to support advancement of CRISPRmedicine SNIPR001 into clinical trials in haematological cancer patients 2024-04-22 , SNIPR Biome BMS伊匹木单抗+纳武利尤单抗治疗CRC拟纳入优先审评 ① 4月22日，国家药监局药品审评中心官网显示，百时美施贵宝的伊匹木单抗注射液+纳武利尤单抗注射液联合疗法拟纳入优先审评；② 拟定适应证为：一线治疗不可切除或转移性微卫星高度不稳定性（MSI-H）或错配修复缺陷型（dMMR）结直肠癌（CRC）患者；③ 该联合疗法于2024年3月被纳入突破性治疗品种名单；④ 此前研究结果显示，与化疗相比，该组合疗法能使疾病进展或死亡风险降低79%，其安全性与之前数据一致，且无新的安全性信号。【原文信息】刚刚！BMS伊匹木单抗+纳武利尤单抗拟纳入优先审评 2024-04-23 , Pharma CMC 默沙东K药联合化疗一线治疗G/GEJ获加拿大卫生部门批准 ① 4月19日，默沙东宣布，KEYTRUDA（帕博利珠单抗）联合化疗，一线治疗局部晚期不可切除或转移性、HER2阴性胃或胃食管连接部（G/GEJ）腺癌成人患者，获得加拿大卫生部门批准；② 此次获批是基于3期临床KEYNOTE-859研究结果，与安慰剂组相比，帕博利珠单抗组在总体生存期（OS）、无进展生存期（PFS）和客观响应率（ORR）上有显著改善；③ 主要终点方面，接受帕博利珠单抗联合化疗的患者中位OS为12.9个月，相比于仅接受化疗患者的11.5个月，死亡风险降低22%；④ 次要终点方面，Keytruda组患者的中位PFS和中位DOR分别为6.9和8.0个月，疾病进展或死亡风险降低24%，ORR为51.3%，亦高于安慰剂组。【原文信息】 Health Canada Approves KEYTRUDA® as a first-line treatment for adult patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma in combination with fluoropyrimidine- and platinum-containing chemotherapy 2024-04-19 , Merck OMNY Health推出胃肠病研究真实世界数据解决方案 ① 4月22日，OMNY Health公司宣布与美国顶尖的胃肠病专科机构和综合服务提供商合作，推出新的胃肠病研究真实世界解决方案；② 该合作项目包括5000多家胃肠病服务专研机构，可服务超过1000万患者，合作伙伴包括United Digestive、Borland Groover和OneGI等；③ OMNY Health公司致力于提高真实世界中的患者护理水平，通过提供更具广度和深度的信息帮助解决医疗卫生问题；④ 该合作专项服务内容涵盖药品订购、诊断测试、并发症预测和患者临床评分等，将有利支持胃肠病领域的研究和发展。【原文信息】 OMNY Health launches new GI real-world data solutions in partnership with leading US gastroenterology practices 2024-04-22 , PR Newswire 四川厌氧生物与长光辰英开展战略合作 ① 4月22日，四川厌氧生物与长光辰英两家公司签署战略合作协议；② 双方将在微生态药物研发领域加强合作，共建人体厌氧活菌库，推动微生物筛选分离平台建设，提升微生态药物产业发展；③ 长光辰英专注于光学与生物医学仪器研发，提供生命科学研究一站式解决方案；④ 四川厌氧生物致力于微生态活菌药物创新，建有2000多种人体微生物菌株的资源库。【原文信息】四川厌氧生物与长光辰英达成战略合作，共同推动微生物创新药产业发展！ 2024-04-22 , 厌氧生物感谢本期日报的审核者：圆圈儿，九卿臣，RZN，章台柳，Johnson，Richard 点击阅读过去10天的日报： 0423 | 今日Cell：姜长涛/乔杰/庞艳莉/郑明华/贾彦兴等获胆汁酸重大突破 0422 | 专家声音：Cell子刊两文聚焦菌群与癌症治疗 0421 | 以食为药：10文聚焦疾病中的饮食干预 0420 | Science揭秘：肠道中的噬菌体-病菌"军备竞赛" 0419 | 程功/朱毅斌/王静林等Science突破：巧用共生菌，阻断蚊媒病毒传播 0418 | 聚焦特殊人群：母婴肠道菌群与健康 0417 | 高分Nature子刊：汇集全球玩家力量，助力肠道微生物研究 0416 | 多文聚焦：保卫肠道，免疫细胞和菌群谁都不能少 0415 | Cell重磅综述：系统解析癌症复杂性，菌群作用不容小觑 0414 | 高分Cell子刊综述，一文讲透发酵食品

微生物疗法临床研究

2024-04-09

·BioPharmaDive

PureTech launches Seaport, hoping to create Karuna 2.0

Hoping to repeat a recent success story, the biotechnology startup creator PureTech Health has launched a new company aimed at developing psychiatric medicines.Seaport Therapeutics officially debuted Tuesday with $100 million from a Series A financing round that received more investor interest than expected. High-profile biotech backers like ARCH Venture Partners, Sofinnova Investments and Third Rock Ventures participated in the round, which Seaport will use to support the rapid advancement of its experimental therapies.PureTech operates through a hub-and-spoke model, wherein it discovers, develops or acquires promising drug programs, then spins them out into individual startups that are kept at arms reach.The most well-known of these startups, Karuna Therapeutics, recently sold to Bristol Myers Squibb for $14 billion.Its KarXT medicine could receive Food and Drug Administration approval before the end of September as a treatment for schizophrenia, which some Wall Street analysts believe, at its peak,could generate billions of dollars each year.That deal with Bristol Myers has already generated around $1.1 billion in gross proceeds for PureTech, which initially put in less than $19 million to get Karuna off the ground, and could result in upwards of $400 million more if certain regulatory and commercial milestones are hit.At Seaport, scientists have created a technology designed to help oral drugs bypass the liver, where theyre often metabolized and their effects diminished. Seaports Glyph platform attaches drugs to dietary fat molecules, rerouting them to the lymphatic system to keep more of them circulating through the body while also reducing side effects.The companys most advanced candidate is a prodrug of allopregnanolone, a steroid that is found in the brain, regulates neuron excitability and is the active ingredient in Sage Therapeutics postpartum depression therapy Zulresso. Seaport, though, is developing the prodrug for anxious depression. A mid-stage clinical trial of healthy volunteers showed it acted as researchers had suspected, according to the startup.Additionally, Seaport is working on a novel prodrug of agomelatine, a compound very similar to melatonin, for the treatment of generalized anxiety disorder. PureTech has said this program should enter human testing in the first half of 2025.Farther behind, Seaport has multiple discovery and preclinical programs underway, including one built around a prodrug of a non-hallucinogenic compound believed to help the brain function and adapt. That program targets mood and other psychiatric disorders.PureTech sees immense opportunity in Seaport, so much so that its pursuing a leadership reshuffle. Founding CEO Daphne Zohar is stepping down from the companys board of directors to fill the top spot at Seaport. She will continue to advise the board, however.PureTech has now reached both financial independence and the important inflection point of returning capital, Zohar said in a statement. I will continue to work on behalf of PureTech shareholders by advancing the exciting Seaport programs through a structure that can help unlock their value for PureTech.PureTech senior executive Bharatt Chowrira took over as CEO on Tuesday.Eric Elenko, who co-founded the company and currently serves as chief innovation officer, has been promoted to president.Steven Paul, the former CEO and Chair of Karuna, also founded Seaport. He will now helm the startups board of directors, which will include Elenko and Chowrira as well as Robert Nelsen, managing partner and co-founder of ARCH, and James Healy, managing partner of Sofinnova.Courtney Wallace, a venture partner at Third Rock, will join, too, but as a board observer.At Seaport Therapeutics, PureTech has brought together the proven team that helped build Karuna and some of the investors that backed Karunas initial funding rounds, Chowrira said. I am confident that following our well charted strategy of starting with validated mechanisms and applying our proprietary Glyph technology to solve previous limitations will enable Seaport to provide important new options for patients with depression, anxiety and other neuropsychiatric conditions. '

高管变更

2024-03-23

·药融圈

【药融咨询】掘金中国失眠创新药蓝海，谁领风骚？

▲5月30-31日第八届广州生物医药创新者峰会扫码立即报名注：本文不构成任何投资意见和建议，以官方/公司公告为准；本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及），不代表平台立场。任何文章转载需得到授权。3月21日是世界睡眠日，人的生命约有1/3是在睡眠中度过的，睡眠与健康密切相关。睡眠障碍已经成为影响全球人类健康的一个突出问题，失眠症是最常见的睡眠障碍，流行病学研究显示，中国有45.4%的被调查者在过去1个月中曾经历过不同程度的失眠。长期失眠影响个体的正常生活和工作，增加罹患各种健康问题的风险。严重的睡眠缺失将降低患者的工作效率和警觉水平，甚至有可能引发恶性意外事故，造成巨大损失。目前催眠镇静剂市场规模超48亿，临床仍有较大的未满足需求失眠的治疗方法主要包括心理治疗和药物治疗。心理治疗是首选的治疗方法，但因难以获得和成本高昂等原因应用不广。药物治疗主要包括苯二氮卓类受体激动剂（benzodiazepine receptor agonists，BZRAs）、褪黑素受体激动剂、食欲素受体拮抗剂和具有催眠效应的抗抑郁药物。据药融云数据显示，2022年失眠化药在全国院内市场销售额超48亿元。目前国内失眠化药多为老品种(地达西尼上市前我国失眠行业近16年没有新药获批)，多家仿制药上市，价格偏低，导致国内市场规模始终保持较低水平。2018-2023年全国院内镇静催眠药物市场规模（数据截至2023Q3）截图来源：药融云全国院内销售数据库BZRAs：分为苯二氮卓类药物和非苯二氮卓类药物。BZDs于20世纪60年代开始使用，可非选择性激动γ-氨基丁酸受体A上不同的α1亚基，具有镇静、催眠、抗焦虑、肌肉松弛和抗惊厥的药理作用。20世纪80年代以来，以唑吡坦（zolpidem）和右佐匹克隆（eszopiclone）为代表的non-BZDs先后应用于失眠的临床治疗，它们对γ-氨基丁酸受体A上的α1亚基选择性激动，主要发挥催眠作用，不良反应较BZDs轻，已经逐步成为治疗失眠的临床常用药物。褪黑素和褪黑素受体激动剂：褪黑素参与调节睡眠觉醒周期，可以改善时差变化所致睡眠觉醒障碍、睡眠觉醒时相延迟障碍等昼夜节律失调性睡眠觉醒障碍，但使用普通褪黑素治疗失眠尚无一致性结论，故不推荐将普通褪黑素作为催眠药物使用。食欲素受体激动剂：食欲素又称下丘脑分泌素，具有促醒作用。针对食欲素双受体发挥抑制作用的拮抗剂苏沃雷生（suvorexant），已获得美国食品药品监督管理局批准用于治疗成人失眠（入睡困难和睡眠维持障碍）。其发挥催眠作用的靶点不同于其他催眠药，现有研究数据显示其具有较好的临床疗效和耐受性。抗抑郁药物：部分抗抑郁药具有镇静作用，在失眠伴随抑郁、焦虑心境时应用较为有效。临床上常用具有镇静催眠作用的药物中国失眠创新药一片蓝海，空间巨大自2007年江苏天士力帝益药业的右佐匹克隆上市以来，中国创新失眠药领域一直面临长期空白，直到2023年浙江京新药业的地达西尼上市后，才打破国内16年来没有治疗失眠障碍创新药上市的局面。2010年以来中国上市失眠创新药Dimdazenil（地达西尼）地达西尼是治疗失眠的1类小分子新药，为为γ-氨基丁酸A型（GABAA）受体的部分正向别构调节剂，通过部分激活GABAA受体，产生促进睡眠的作用。与传统失眠药物相比具有GABAA受体部分激动，避免过度抑制，日间损害和不良反应更小；1h达峰，快速诱导睡眠；半衰期4h，有效维持生理睡眠；主要通过FMO代谢，显著降低药物相互作用风险的特点。截图来源：药融云全球药物研发数据库地达西尼最早由Roche研发，随后德国公司Evotec获得全球独占权并将其开发用于治疗失眠症，于2008年在国外完成I、II期临床。2010年京新药业与Evotec签署协议，获得地达西尼在中国的独家专利许可和开发权。地达西尼在中国的获批上市是基于JX202001-EVT201-III一项评价EVT201胶囊对比安慰剂在失眠障碍患者中疗效和安全性的多中心、随机、双盲III期临床试验。基于统计分析模型，以第13/14晚PSG监测的平均TST值为反应变量，基线TST、年龄为协变量，组别为自变量计算，EVT201胶囊组相对于安慰剂组的优效性成立，EVT201胶囊可快速起效、提高睡眠效率，同时改善次日嗜睡等残留效应。食欲素是一种由下丘脑自然产生的神经肽，食欲素和其受体共同构成的食欲素系统能够刺激唤醒中枢神经系统的目标神经元，然后释放几种促进清醒的化学物质。近年来食欲素及其拮抗剂的研究越来越受到重视，已发现食欲素拮抗剂对失眠具有治疗作用。目前中国在研失眠新药中就是主要以食欲素受体（OX1R、OX2R）为主。中国在研失眠创新药Lemborexant（莱博雷生）Lemborexant是卫材研发的一款双重食欲素拮抗小分子药物，通过竞争性结合OX1R、OX2R，抑制食欲素神经传递，调节睡眠-觉醒节律。双食欲素神经肽信号系统在觉醒中有重要作用，作为一种竞争性拮抗剂，莱博雷生对OX2R具有更强的抑制作用，可抑制REM和非REM睡眠驱动，从而为患者提供更快的睡眠开始、更好的睡眠维持。截图来源：药融云全球药物研发数据库一项为期12个月的全球多中心、随机双盲、平行组的III期临床实验结果显示，莱博雷生与安慰剂相比，对于所有睡眠参数都观察到了显著的益处。与唑吡坦相比，莱博雷生疗法显著改善了睡眠的维持时间，并缩短了下半夜的觉醒时间。同时，相比苯二氮卓类药物的戒断反应，莱博雷生没有出现相关的戒断反应，这表明服药达一年不会产生躯体依赖。Fazamorexant（YZJ-1139）Fazamorexant是扬子江药业子公司上海海雁医药的一款双重食欲素抗体拮抗药物，通过抑制食欲素受体从而改善睡眠，包括加快睡眠速度和延长睡眠时间。同时，fazamorexant拥有吸收快速和半衰期适中的优势，可以达到快速起效和次日残留效应低的效果。截图来源：药融云全球药物研发数据库2021年5月举办的亚洲睡眠医学会第三届睡眠大会（ASSM 2021）公布的该药的Ⅱ期临床试验结果显示，YZJ-1139可剂量相关地改善睡眠效率，各剂量组均可以改善受试者睡眠效率至健康水平。同时，与安慰剂组相比，YZJ-1139未出现明显的中枢神经系统副作用，第二日残留效应低。YZJ-1139 Ⅱ期临床试验的积极结果，为Ⅲ期临床试验提供了有力依据。Daridorexant hydrochloride（达利雷生）Daridorexant是由Idorsia研发的双重食欲素拮抗药。Daridorexant是通过阻断食欲素受体与促觉醒神经肽食欲素的结合，抑制过度活跃的不眠状态。2022年11月先声药业与Idorsia签订独家授权协议，先声药业获得大中华地区开发和商业化独家权益。截图来源：药融云全球药物研发数据库发表于《柳叶刀神经病学》的海外III期临床数据显示，在接受1个月、3个月治疗后，达利雷生较安慰剂显著改善了患者入睡、睡眠维持及自我报告的总睡眠时间，不改变睡眠结构，且未发现依赖性、反跳性失眠、戒断症状和药物滥用证据，显著区分于传统镇静催眠药苯二氮卓类药物。版权声明：本文转自药融云，如不希望被转载的媒体或个人可与我们联系，我们将立即删除活动推荐 8月 • 第六届CMC-China博览会关键词：生物药、小分子创新药、药学CMC&创新&CXO、原辅包（点击下方图片查看详情）▼【关于药融圈】药融圈PRHub旨在帮助生物医药科技型企业进行品牌推广及商务拓展服务，针对客户的真实需求制定系统化解决方案，通过“翻译-降维-场景化”将客户的品牌信息以直白易懂的方式被公众知悉，同时在流量渠道覆盖100万+垂直用户基础上实现合作目的，帮助合作伙伴完成从品牌开始到商务为终的闭环营销服务。我们已经完成了数十场线下1000人规模的生物医药研发类会议，涵盖小分子新药，大分子新药，改良型新药，BD跨境交易等多个领域，服务了百余家上市/独角兽/生物技术/制药企业。

上市批准

100 项与褪黑素相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
D08170	褪黑素	N05CH01	DB01065

研发状态

批准上市

10 条最早获批的记录,

后查看更多信息

适应症	国家/地区	公司	日期
自闭症谱系障碍	列支敦士登	RAD Neurim Pharmaceuticals EEC SARL	2018-09-20
自闭症谱系障碍	挪威	RAD Neurim Pharmaceuticals EEC SARL	2018-09-20
自闭症谱系障碍	欧盟	RAD Neurim Pharmaceuticals EEC SARL	2018-09-20
自闭症谱系障碍	冰岛	RAD Neurim Pharmaceuticals EEC SARL	2018-09-20
Smith-Magenis综合征	列支敦士登	RAD Neurim Pharmaceuticals EEC SARL	2018-09-20
Smith-Magenis综合征	挪威	RAD Neurim Pharmaceuticals EEC SARL	2018-09-20
Smith-Magenis综合征	冰岛	RAD Neurim Pharmaceuticals EEC SARL	2018-09-20
Smith-Magenis综合征	欧盟	RAD Neurim Pharmaceuticals EEC SARL	2018-09-20
入睡和睡眠障碍	列支敦士登	RAD Neurim Pharmaceuticals EEC SARL	2007-06-29
入睡和睡眠障碍	欧盟	RAD Neurim Pharmaceuticals EEC SARL	2007-06-29
入睡和睡眠障碍	挪威	RAD Neurim Pharmaceuticals EEC SARL	2007-06-29
入睡和睡眠障碍	冰岛	RAD Neurim Pharmaceuticals EEC SARL	2007-06-29

未上市

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
自闭症谱系障碍	临床3期	-	Nobelpharma Co., Ltd.	2016-06-16
睡眠-觉醒节律障碍	临床3期	芬兰	Neurim Pharmaceuticals Ltd.	2013-10-01
入睡和睡眠障碍	临床3期	英国	Neurim Pharmaceuticals Ltd.	2006-10-01
入睡和睡眠障碍	临床3期	英国	Neurim Pharmaceuticals Ltd.	2006-10-01
神经发育障碍	临床前	-	Nobelpharma Co., Ltd.	2016-06-21
内因性睡眠障碍	临床前	-	Nobelpharma Co., Ltd.	2016-06-21
自闭症谱系障碍	临床前	-	Nobelpharma Co., Ltd.	2016-06-16
睡眠-觉醒节律障碍	临床前	荷兰	Neurim Pharmaceuticals Ltd.	2013-10-01

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00972075 (Pubmed \| Nat Sci Sleep) 人工标引	临床2期	入睡和睡眠障碍	13	Circadin	(蓋壓餘鑰願鹹餘艱鏇齋) = 積鬱糧鹹鏇衊淵獵夢鹽獵鑰衊鹽壓遞糧齋製選 (選憲廠鹽夢獵鹽鬱鬱膚 )	积极	2015-01-29
				Placebo	(蓋壓餘鑰願鹹餘艱鏇齋) = 願壓鏇襯淵鏇遞繭鹹襯獵鑰衊鹽壓遞糧齋製選 (選憲廠鹽夢獵鹽鬱鬱膚 )
WSC2023	N/A	发作性睡病	-	Dextroamphetamine-amphetamine	顧積窪鏇鹽鏇廠壓齋襯(構襯鏇願膚鏇鹽鏇鏇積) = 衊鑰選積簾窪鬱築醖積夢築醖構範窪齋窪鹽選 (鏇鑰積觸衊廠醖壓獵艱 ) 更多	-	2023-10-23
				Modafinil	顧積窪鏇鹽鏇廠壓齋襯(構襯鏇願膚鏇鹽鏇鏇積) = 窪願願製獵觸鏇糧鏇遞夢築醖構範窪齋窪鹽選 (鏇鑰積觸衊廠醖壓獵艱 ) 更多
Pubmed 人工标引	N/A	新型冠状病毒感染辅助	67	melatonin	築夢蓋製築遞艱憲壓鹹(壓餘鏇鹽鑰遞築淵壓淵) = No significant differences 鹽蓋醖襯積積觸壓鏇壓 (願廠憲觸遞齋憲廠襯艱 ) 更多	积极	2022-06-01
				Placebo
WSC2023	N/A	-	-	melatonin	築範範鑰簾網艱鏇膚簾(齋鹹獵餘製顧獵範觸憲) = 廠簾壓夢淵餘簾壓膚繭繭醖鬱醖築齋範憲範網 (製遞範廠製餘製膚築淵 )	-	2023-10-23
				melatonin	築範範鑰簾網艱鏇膚簾(齋鹹獵餘製顧獵範觸憲) = 遞獵製淵蓋膚齋範艱餘繭醖鬱醖築齋範憲範網 (製遞範廠製餘製膚築淵 )
WSC2023	N/A	-	-	Melatonin-enriched milk	(鑰壓遞窪鬱蓋膚膚顧艱) = 選衊鏇齋鑰鹹淵鏇繭鑰淵構衊廠簾積夢繭襯繭 (鏇艱窪齋範遞鬱顧憲獵 )	-	2023-10-24
				melatonin-rich milk	(鑰壓遞窪鬱蓋膚膚顧艱) = 憲顧襯夢鏇憲窪網網顧淵構衊廠簾積夢繭襯繭 (鏇艱窪齋範遞鬱顧憲獵 )
NCT04353128 (Pubmed) 人工标引	临床2/3期	新型冠状病毒感染	308	melatonin	構積壓淵艱齋艱壓襯獵(憲鏇夢醖積壓膚繭窪願) = 繭顧廠網壓鏇積選積憲鹽鹽築膚醖壓繭範膚鹽 (願憲築網醖鬱顧觸廠衊 ) 更多	不佳	2022-02-21
				Placebo	構積壓淵艱齋艱壓襯獵(憲鏇夢醖積壓膚繭窪願) = 艱製鹽糧鬱鏇網膚鬱獵鹽鹽築膚醖壓繭範膚鹽 (願憲築網醖鬱顧觸廠衊 ) 更多
WSC2023	N/A	自闭症谱系障碍 melatonin decrease	49	Cognitive Behavioral Therapy + Melatonin	艱壓範積夢膚鹽夢齋艱(窪積製壓鏇廠糧積積觸) = better social abilities 網夢顧夢憲鏇膚膚衊夢 (積齋繭淵選艱選夢齋廠 ) 更多	积极	2023-10-24
ANA2023	N/A	发作性睡病	110	Dextroamphetamine-amphetamine	窪夢壓選鏇糧鬱餘簾鏇(範獵醖遞選壓餘獵廠糧) = 選鑰遞繭選餘廠鏇餘鹹獵選餘獵簾選餘遞鹹醖 (齋簾齋構範製鑰鏇窪憲 )	-	2023-09-01
				Modafinil	窪夢壓選鏇糧鬱餘簾鏇(範獵醖遞選壓餘獵廠糧) = 構醖窪範蓋鹽築蓋衊願獵選餘獵簾選餘遞鹹醖 (齋簾齋構範製鑰鏇窪憲 )