A Randomized, Open-label, Active-controlled, Phase 2a Clinical Trial to Evaluate the Efficacy and Safety of TFC-003 in Patients With Primary Open-angle Glaucoma or Ocular Hypertension

The purpose of this study was to explore the efficacy and safety of the weekly intraocular pressure change of the TFC-003 group and the dorzolamid/timolol combination group in patients with primary open-angle glaucoma or ocular hypertension.

开始日期2024-02-01

申办/合作机构

KUKJE PHARMA Co., Ltd.

NCT05697328

/ RecruitingN/AIIT

Pseudoephedrine Prophylaxis for Prevention of Middle Ear Barotrauma in Hyperbaric Oxygen Therapy

The purpose of this research is to study whether the use of pseudoephedrine can help prevent middle ear trauma during HBOT. Pseudoephedrine is an approved drug that is used for temporary relief of nasal or sinus pain and pressure.

开始日期2023-01-31

申办/合作机构

John Muir Health

NCT05692869

/ CompletedN/A

A Study to Investigate Continuous Blood Pressure Monitoring Using Traditional Device (ABPM) Versus Novel Devices (Biobeat and Aktiia)

The main purpose of this study in healthy participants is to find out whether the traditional ambulatory blood pressure monitor (ABPM) and newer wearable devices (EmbracePlus smartwatch device, Biobeat chest patch device, and Aktiia wrist device) will accurately pick up changes in blood pressure caused by 2 different medications (propranolol and pseudoephedrine). The study will last about 29 days excluding the screening period of 28 days.

开始日期2023-01-31

申办/合作机构

Eli Lilly & Co.

100 项与 ADRA2 x β-adrenoceptors 相关的临床结果

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100 项与 ADRA2 x β-adrenoceptors 相关的转化医学

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0 项与 ADRA2 x β-adrenoceptors 相关的专利（医药）

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项与 ADRA2 x β-adrenoceptors 相关的文献（医药）

2025-05-01·Molecular Neurobiology

Selective Noradrenergic Activation of BDNF Translation by Mirtazapine

Article

作者: Santoni, Letizia ; Tongiorgi, Enrico ; Ciraci, Viviana

Antidepressants are known for their neurotrophic effects, particularly through the regulation of brain-derived neurotrophic factor (BDNF) expression. Mirtazapine, a tetracyclic noradrenergic and specific serotonergic antidepressant (NaSSA) has been observed to upregulate BDNF, though its underlying mechanism remains unclear. In this study, we used the human neuroblastoma SH-SY5Y cell line to investigate whether mirtazapine could enhance BDNF translation by modulating serotonin and/or norepinephrine and their receptors. A 1-h stimulation with 1 or 10 µM mirtazapine led to downregulation of serotonergic receptors 5HT1A, while increasing ADRA2A and ADRB2 receptors. Mirtazapine at 10 µM upregulated endogenous BDNF after 3h, but not 1h stimulation. To investigate the translation of major BDNF transcripts, we used chimeric BDNF-luciferase constructs with the untranslated 5'UTR exons I, IIc, IV, or VI, and the long version of the 3'UTR. Luciferase assays and Western blotting revealed that mirtazapine selectively enhanced exon-IIc-BDNF-long3'UTR-Luciferase translation. This increase was associated with norepinephrine release and was inhibited by blocking ADRA2A or ADRB2 adrenoceptors for the exon-IIc-BDNF-long3'UTR-Luciferase, and ADR2B for endogenous BDNF. These findings provide a new perspective on the critical role of the noradrenergic system in mediating mirtazapine's effects on BDNF translation. We propose a novel mechanism of action in which mirtazapine promotes norepinephrine release and noradrenergic responses by upregulating ADRA2A and ADRB2 while downregulating serotonergic receptors.

2025-05-01·Toxicology and Applied Pharmacology

Adrenergic receptor subtypes differentially influence acrolein-induced ventilatory, vascular leakage, and inflammatory responses

Article

作者: Williams, Wanda C ; Alewel, Devin I ; Evansky, Paul A ; Miller, Colette N ; Rentschler, Katherine M ; Schladweiler, Mette C ; Jackson, Thomas W ; Kodavanti, Urmila P ; Gavett, Stephen H

Adrenergic receptors (AR) are manipulated therapeutically for the treatment of pulmonary and cardiovascular diseases; however, their role in air pollutant-induced respiratory effects is poorly understood. We examined the contribution of AR-subtypes in acrolein-induced respiratory effects through selective receptor inhibition. We pre-treated 12-week-old male Wistar-Kyoto rats intraperitoneally daily for 9-days with subtype-specific AR antagonists prazosin (PRZ, α1-AR antagonist; 2-mg/kg-day), yohimbine (YOH, α2-AR antagonist; 5-mg/kg-day), or propranolol (PROP, β-AR antagonist; 10-mg/kg-day). On day-8 and day-9 of treatment, rats were exposed nose-only to air or acrolein (1.6 or 3.2 ppm), ∼4 h/day. Head-out plethysmography during exposure on Day-9 revealed overall concentration-dependent acrolein-related reduced ventilatory capacity, which was exacerbated in PRZ- and YOH-treated animals. Nasal (NALF) and bronchoalveolar lavage fluid (BALF), and blood samples were collected on day-9. Plasma epinephrine levels did not change; however, corticosterone decreased in YOH- and PROP-treated air-exposed animals. Adrenal and spleen weights were higher in PRZ-treated animals. Acrolein, 3.2-ppm depleted circulating lymphocytes in saline-treated and increased neutrophils in PRZ- and YOH-treated animals. NALF and BALF analysis indicated 3.2-ppm acrolein-induced neutrophilic and lymphocytic inflammation (NALF>BALF), which was exacerbated in lung of PRZ- and YOH-treated rats and slightly dampened in PROP-treated rats. However, acrolein-induced vascular protein leakage and increases in inflammatory cytokines in NALF were reduced by PROP-treatment. In conclusion, this study highlights sympathetically-mediated adrenoreceptor influence on acrolein-indued respiratory health effects, and AR subtype-specific modulation of breathing, hemodynamic, and inflammatory responses. These results have broader translational implications, as those receiving adrenergic agonistic/antagonistic therapies might experience variable air pollution-related respiratory health effects.

2025-01-13·Cancer Discovery

Neuro-Mesenchymal Interaction Mediated by a β2-Adrenergic Nerve Growth Factor Feedforward Loop Promotes Colorectal Cancer Progression

Article

作者: LaBella, Jonathan S. ; Zamechek, Leah B. ; Zheng, Biyun ; White, Ruth A. ; Ochiai, Yosuke ; Malagola, Ermanno ; Zhi, Xiaofei ; Wu, Feijing ; Qian, Jin ; Ogura, Atsushi ; Enomoto, Atsushi ; Wang, Timothy C. ; Iida, Tadashi ; Waterbury, Quin T. ; Worthley, Daniel L. ; Kobayashi, Hiroki ; Tu, Ruhong ; Woods, Susan L.

AbstractCancer-associated fibroblasts (CAF) and nerves, components of the tumor microenvironment, have each been shown to directly promote gastrointestinal cancers. However, it remains unknown whether these cells interact with each other to regulate cancer progression. We found that in colorectal cancer, norepinephrine induces ADRB2 (β2-adrenergic receptor)–dependent nerve growth factor (NGF) secretion from CAFs, which in turn increases intratumor sympathetic innervation and norepinephrine accumulation. Adrenergic stimulation accelerates colorectal cancer growth through ADRA2A/Gi-mediated activation of Yes-associated protein (YAP). NGF from CAFs directly enhances colorectal cancer cell growth via the phosphatidylinositol-3-kinase/AKT pathway. Treatment with a tropomyosin receptor kinase (TRK) inhibitor decreased YAP and AKT activation and colorectal cancer progression in mice. In human colorectal cancer, high NGF expression is associated with mesenchymal-like tumor subtype and poor patient survival. These findings suggest a central role for reciprocal CAF–nerve cross-talk in promoting colorectal cancer progression. Blocking this feedforward loop with a TRK inhibitor may represent a potential therapeutic approach for colorectal cancer.Significance:Our work demonstrates that the bidirectional interplay between sympathetic nerves and NGF-expressing CAFs drives colorectal tumorigenesis. This study also offers novel mechanistic insights into catecholamine action in colorectal cancer. Inhibiting the neuro-mesenchymal interaction by TRK blockade could be a potential strategy for treating colorectal cancer.

项与 ADRA2 x β-adrenoceptors 相关的新闻（医药）

2024-08-15

·奇点网

好人当了还不到三天，\x0d\x0a又露馅了。

*仅供医学专业人士阅读参考前两天奇点糕才刚说，肿瘤微环境中的成纤维细胞（CAFs）难得干一回好事，帮着搭建了能助力抗肿瘤免疫应答的三级淋巴结构，没想到一转眼的功夫，同样是针对结直肠癌的另一项基础科研里，CAFs又成促癌大反派了，而且这次它还有着明确的犯罪同伙。哥伦比亚大学Timothy C. Wang团队发表在Cancer Discovery期刊上的研究成果显示，结直肠癌微环境中存在由CAFs和去甲肾上腺素能神经通路共同构成的正反馈促癌回路：在去甲肾上腺素的作用下，CAFs可分泌神经生长因子（NGF），促进肿瘤内的交感神经形成和去甲肾上腺素积聚，且肾上腺素能刺激和CAFs分泌的NGF都能直接加快癌细胞的增殖。在这种“神经-间充质”相互作用的影响下，高表达NGF的人体结直肠癌更有可能呈现为间充质样亚型（mesenchymal-like），患者生存预后也相对较差，不过研究者们发现，使用已获批治疗罕见突变患者的原肌球蛋白相关激酶（TRK）抑制剂，可有效减轻“神经-间充质”正反馈相互作用的促癌效应，结直肠癌也有望就此迎来新的精准治疗药物[1]。论文首页截图用研究者们在论文开头的介绍，“我们知道CAFs能促癌，也知道交感神经对癌症发展有重要影响，但确实没想到它们之间还存在关联”，只能说到了肿瘤微环境这个大染缸里，啥坏事都有可能发生。而哥大研究者们一开始追寻的线索，是以NGF为代表的神经营养因子在结直肠癌中的来源，偏偏单细胞测序就显示，特定的CAFs亚群真就是NGF的唯一来源。原位杂交（ISH）分析显示，NGF信号在结直肠癌中水平较正常组织显著升高，且主要位于肿瘤的间质部分，分布也与密度显著升高的肾上腺素能交感神经重合，这就对上了NGF的生理功能；且在结直肠癌模型小鼠身上，肿瘤发生发展期间也存在NGF表达上调和交感神经支配的增加，但这毕竟还是隔着一层，交感神经和CAFs间有没有直接的相互作用呢？肠癌中增多的NGF可增加交感神经支配，且与癌症发展相关哥大研究者们想到在此前的研究中[2]，来自交感神经的去甲肾上腺素能够诱导胰腺癌细胞分泌NGF，就把相同的方法用到了CAFs身上，效果还真是大差不差，CAFs也出现了明显的NGF表达上调，且该效应是β2肾上腺素能受体（ADRB2）依赖性的，ADRB2会激活下游的PKA-CREB和MAPK通路，增加NGF分泌以促进肿瘤内交感神经支配并促癌。但去甲肾上腺素的影响还不止于此，研究者们推测它可能还会直接帮助癌细胞，并借助肿瘤类器官实验证实，去甲肾上腺素处理可另外通过结合α2A肾上腺素能受体（ADRA2A）/Gi蛋白，激活YAP蛋白信号通路的多个下游基因，直接加快癌细胞的增殖速率。相似地，NGF不仅可以促进肿瘤内交感神经支配，增强上述由ADRA2A和YAP蛋白介导的交感神经促癌作用，它本身也可以直接影响癌细胞，影响的主要途径则是TrkA-PI3K/AKT信号通路，而这正是使用TRK抑制剂精准干预的依据。研究者们选用在研的TRKA/TRKC抑制剂selitrectinib，在结直肠癌临床前研究模型中证实，抑制TRK可减少由NGF促进的YAP蛋白激活、AKT磷酸化等调控过程关键环节，从而延缓结直肠癌进展；而在人类结直肠癌患者中，NGF的高表达也确实与不良生存预后及肿瘤呈间充质样亚型（CMS4）[3]相关，因此TRK抑制剂的精准干预应该很有发挥空间。研究揭示的作用机制整体回顾参考文献：[1]Kobayashi H, Iida T, Ochiai Y, et al. Neuro-mesenchymal interaction mediated by a β2 adrenergic-nerve growth factor feedforward loop promotes colorectal cancer progression[J]. Cancer Discovery, 2024.[2]Renz B W, Takahashi R, Tanaka T, et al. β2 adrenergic-neurotrophin feedforward loop promotes pancreatic cancer[J]. Cancer Cell, 2018, 33(1): 75-90. e7.[3]Joanito I, Wirapati P, Zhao N, et al. Single-cell and bulk transcriptome sequencing identifies two epithelial tumor cell states and refines the consensus molecular classification of colorectal cancer[J]. Nature Genetics, 2022, 54(7): 963-975.本文作者丨谭硕

申请上市临床1期

2023-07-13

·生物谷

Nature：老药新用，朱晶晶团队发现降压药α2-AR激动剂能够强效抗肿瘤

该研究表明，之前用于治疗高血压的药物α-2肾上腺素受体（α2-AR）激动剂能够通过调节肿瘤相关巨噬细胞和CD4+T细胞功能，帮助免疫系统更好地对抗肿瘤，而且对于对标准免疫疗法有抵抗力的癌症模型同样有效朱晶晶博士于2013年毕业于比利时荷语鲁汶大学。博士毕业后，加入了比利时杜弗研究所（由1974年诺奖得主Christiaan de Duve 所创办）／路德维格癌症研究所布鲁塞尔分所，致力于抗肿瘤免疫治疗靶点的开发和方法的优化。肾上腺素受体（Adrenergic Receptors，AR），是一类G蛋白偶联受体（GPCR），其可分为两种类型——α-AR和β-AR，α-AR主要分为α1-AR和α2-AR两个亚型，而β-AR主要分为β1-AR、β2-AR和β3-AR三个亚型。其中，α2-AR通过Gi抑制腺苷酸环化酶，降低环磷腺苷（cAMP）水平和蛋白激酶A（PKA）活性。AR在交感神经系统中的作用已经被很好地阐释，但AR也在其他组织中表达，其在神经系统外的功能还不清楚，尤其是α2-AR。在这项最新研究中，朱晶晶等发现，α2-AR激动剂作为单一疗法时就足以在多种免疫活性肿瘤模型（包括免疫检查点抑制剂耐药模型）中发挥很强的抗肿瘤作用，显著延长肿瘤小鼠模型的生存期，而在免疫缺陷小鼠模型中则没有这种作用。该研究还观察到，α2-AR激动剂对人源化淋巴细胞重组小鼠模型植入的人类肿瘤异种移植物具有显著的治疗效果。 α2-AR激动剂的抗肿瘤作用可被α2-AR拮抗剂逆转，并且在Adra2a基因敲除小鼠（不表达α2a-AR）中则不存在这些作用，这表明α2-AR激动剂的抗肿瘤效果是作用于宿主细胞，而不是肿瘤细胞。之前有研究显示，β-AR在某些情况下可能具有刺激肿瘤生长的作用，而该研究显示，α2-AR则具有抗肿瘤作用，朱晶晶博士表示，虽然同样作为肾上腺素受体（AR），但α-AR和β-AR在细胞表面具有不同的分布和功能。α-AR和β-AR在肿瘤生长方面的截然相反效果，可以归因于它们对细胞信号转导途径的不同影响。α2-AR的激活通常会导致细胞内cAMP水平的下降，从而抑制腺苷酸环化酶的活性。相反，β-AR的激活通常会导致cAMP水平的上升，从而激活腺苷酸环化酶。α-AR和β-AR在肿瘤生长方面的作用是复杂的，并受到多种因素的影响，包括肿瘤类型、细胞类型、组织微环境等。因此，对于不同类型的肿瘤和特定的情况，它们的作用可能会有所不同。 α2-AR激动剂的抗肿瘤活性示意图近年来，基于巨噬细胞的CAR-M细胞疗法开始进入临床试验。朱晶晶博士表示，这项研究提示我们，α2-AR激动剂可能通过调节巨噬细胞的活性来增强CAR-M治疗的抗肿瘤效果。肿瘤微环境对于CAR-M治疗的效果至关重要。α2-AR激动剂可能通过调节肿瘤微环境中的免疫细胞活性、血管生成和肿瘤相关因子的产生等方面，对肿瘤微环境进行调节。这可能有助于改善CAR-M治疗的效果和持久性。值得一提的是，α2-AR激动剂已经作为降压、镇痛和麻醉药物上市。而这项研究提示我们，α2-AR激动剂还可以直接刺激巨噬细胞发挥“哨兵”作用，使T细胞更活跃，从而更有效地对抗癌细胞，而且对于对标准免疫疗法有抵抗力的癌症模型同样有效。这些发现为开发可能与免疫疗法联合使用以提高其疗效的新分子提供了理论依据。

免疫疗法细胞疗法

2023-06-11

·医药地理

2022年获批进口药品分析（精神障碍、呼吸系统、骨骼与肌肉、泌尿系统）

本文数据来自于CPM新药研发监测数据库（cpm.pharmadl.com）。精神障碍用药2022年NMPA批准的进口消化系统用药，共计24个（按照注册证号分类），获批品种较多的企业有H Lundbeck A/S（8个）、Aurobindo Pharma Ltd（4个）；涉及靶点排名前三的是5-HTT（11个）、ADRA2A（4个）、DRD2（4个）。在政策相关度方面，2022年获批的进口消化系统用药中，2022国家医保目录品种共有19个，带量采购招标品种有1个。呼吸系统用药2022年NMPA批准的进口呼吸系统用药，共计22个（按照注册证号分类），获批品种最多的企业是Organon Pharma (UK) Ltd（6个）。涉及较多的靶点是ADRB2（6个）、CYSLTR1（6个）。在政策相关度方面，2022年获批的进口血液和造血系统用药中，2022国家医保目录品种共有21个，没有带量采购招标品种。骨骼与肌肉用药2022年NMPA批准的进口内分泌及代谢调节用药，共计23个（按照注册证号分类），获批品种最多的企业是Organon Pharma (UK) Ltd（8个）。涉及靶点排名前三的是COX-2（12个）、IL6（4个）。在政策相关度方面，2022年获批的进口内分泌及代谢调节用药中，2022国家医保目录品种共有22个，没有带量采购招标品种。泌尿系统用药2022年NMPA批准的进口内分泌及代谢调节用药，共计10个（按照注册证号分类），获批品种最多的三家企业分别是Astellas Pharma Europe BV（8个）、Genzyme Europe BV（3个）、Meda Pharma Gmbh & Co Kg（2个）。涉及最多的靶点是ADRB3（4个）。在政策相关度方面，2022年获批的进口内分泌及代谢调节用药中，2022国家医保目录品种共有7个，没有带量采购招标品种。年度发布2023年《全球药研新动态》《中国医院市场用药格局》（2023版）2023年《数图药讯》权威发布2021年度中国医药工业百强榜单解读中国仿制药发展报告（2022版）医药行业专项报告中国医药中间体和原料药行业调研报告中国非甾体抗炎类原料药市场调研报告中国祛痰类原料药市场调研报告中国钙拮抗剂类原料药市场调研报告中国血管紧张素Ⅱ受体拮抗剂类原料药市场调研报告中国口服血糖调节类原料药市场调研报告中国中枢兴奋类原料药市场调研报告中国抗痛风类原料药市场调研报告中国脑血管病类原料药市场调研报告END如需获取更多数据洞察信息或公众号内容合作，请联系医药地理小助手微信号：pharmadl001

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