A Phase I, Two-part, Single-center, Open-label, Drug-drug Interaction Study to Assess the Effect of Voriconazole (Part 1) and Quinidine (Part 2) on the Pharmacokinetics of a Single Dose of Repotrectinib (BMS-986472) in Healthy Participants

The purpose of this study is to evaluate the effects of coadministration of voriconazole or quinidine on the pharmacokinetics (PK) of repotrectinib in healthy male and female (individual not of childbearing potential [INOCBP]) participants.

开始日期2024-08-26

申办/合作机构

Bristol Myers Squibb Co.

100 项与 adrenergic receptor x VGSCs 相关的临床结果

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100 项与 adrenergic receptor x VGSCs 相关的转化医学

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0 项与 adrenergic receptor x VGSCs 相关的专利（医药）

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112

项与 adrenergic receptor x VGSCs 相关的文献（医药）

2024-10-01·Cell Reports Medicine

The sympathetic nervous system drives hyperinflammatory responses to Clostridioides difficile infection

Article

作者: Petri, William A ; Naz, Farha ; Leslie, Jhansi L. ; Leslie, Jhansi L ; Thompson, Brandon ; Tyus, David ; Uddin, Md Jashim ; Petri, William A.

Clostridioides difficile infection (CDI) is a leading cause of hospital-acquired infections in the United States, known for triggering severe disease by hyperactivation of the host response. In this study, we determine the impact of the sympathetic nervous system (SNS) on CDI disease severity. Mouse models of CDI are administered inhibitors of SNS activity prior to CDI. Chemical sympathectomy or pharmacological inhibition of norepinephrine synthesis greatly reduces mortality and disease severity in the CDI model. Pharmacological blockade or genetic ablation of the alpha 2 adrenergic receptor ameliorates intestinal inflammation, disease severity, and mortality rate. These results underscore the role of the SNS and the alpha 2 adrenergic receptor in CDI pathogenesis and suggest that targeting neural systems could be a promising approach to therapy in severe disease.

2024-01-20·Biomedical and environmental sciences : BES

Risk Factors of Depression Screened by Two-Sample Mendelian Randomization Analysis: A Systematic Review.

Review

作者: Cui, Bao Qiu ; Liu, Hong ; Xue, Yan Feng ; Shen, Xin Xin ; Wang, Han Lin

ObjectiveThis study explored the potentially modifiable factors for depression and major depressive disorder (MDD) from the MR-Base database and further evaluated the associations between drug targets with MDD.MethodsWe analyzed two-sample of Mendelian randomization (2SMR) using genetic variant depression ( n = 113,154) and MDD ( n = 208,811) from Genome-Wide Association Studies (GWAS). Separate calculations were performed with modifiable risk factors from MR-Base for 1,001 genomes. The MR analysis was performed by screening drug targets with MDD in the DrugBank database to explore the therapeutic targets for MDD. Inverse variance weighted (IVW), fixed-effect inverse variance weighted (FE-IVW), MR-Egger, weighted median, and weighted mode were used for complementary calculation.ResultsThe potential causal relationship between modifiable risk factors and depression contained 459 results for depression and 424 for MDD. Also, the associations between drug targets and MDD showed that SLC6A4, GRIN2A, GRIN2C, SCN10A, and IL1B expression are associated with an increased risk of depression. In contrast, ADRB1, CHRNA3, HTR3A, GSTP1, and GABRG2 genes are candidate protective factors against depression.ConclusionThis study identified the risk factors causally associated with depression and MDD, and estimated 10 drug targets with significant impact on MDD, providing essential information for formulating strategies to prevent and treat depression.

2023-10-01·iScience

Targeting adrenergic receptors to mitigate invariant natural killer T cells-induced acute liver injury

Article

作者: Keller, Alexandre Castro ; Antunes, Maísa Mota ; Freire, Beatriz Marton ; Gonzatti, Michelangelo Bauwelz ; Talbot, Jhimmy ; de Menezes, Gustavo Batista ; Peron, Jean Pierre Schatzmann ; Basso, Alexandre Salgado

Invariant Natural Killer T (iNKT) cell activation by α-galactosylceramide (αGC) potentiates cytotoxic immune responses against tumors. However, αGC-induced liver injury is a limiting factor for iNKT-based immunotherapy. Although adrenergic receptor stimulation is an important immunosuppressive signal that curbs tissue damage induced by inflammation, its effect on the antitumor activity of invariant Natural Killer T (iNKT) cells remains unclear. We use mouse models and pharmacological tools to show that the stimulation of the sympathetic nervous system (SNS) inhibits αGC-induced liver injury without impairing iNKT cells' antitumoral functions. Mechanistically, SNS stimulation prevents the collateral effect of TNF-α production by iNKT cells and neutrophil accumulation in hepatic parenchyma. Our results suggest that the modulation of the adrenergic signaling can be a complementary approach to αGC-based immunotherapy to mitigate iNKT-induced liver injury without compromising its antitumoral activity.

项与 adrenergic receptor x VGSCs 相关的新闻（医药）

2023-05-11

·药明康德

前沿 | 降低三阴性乳腺癌复发转移率！这类组合疗法有望成为潜在临床治疗选项

▎药明康德内容团队编辑乳腺癌是最为常见的癌症类型，2020年的一项最新统计显示，当年全球约新增230万名乳腺癌患者，死亡人数高达68.5万名患者。其中，三阴性乳腺癌（TNBC）是乳腺癌最具侵袭性的分子亚型之一，占所有乳腺癌病例的10%-15%，其特征是缺乏雌激素和孕酮受体（ER/PR）以及缺乏人表皮生长因子受体-2（HER2）。与其他乳腺癌亚型相比，TNBC患者往往更易出现复发和转移，导致预后不良。同时，由于ER、PR和HER2的表达水平较低，这类患者对于内分泌治疗和常用的靶向疗法都不敏感，而即使进行了标准化疗方案的治疗，TNBC患者的生存率依然较低，亟待开发更多的治疗靶点。TNBC过去被发现受神经支配并往往表达β2-肾上腺素能受体（β2AR）。临床前研究表明，TNBC细胞中β2AR信号的激活会促进肿瘤细胞的转移，而以治疗为目的阻滞β2AR有潜力提高TNBC患者的预后。来自澳大利亚莫纳什大学莫纳什药学院的团队对1135名非转移性TNBC女性进行回顾性研究后发现，使用β受体阻滞剂可以降低接受蒽环类化疗方案治疗的患者的复发转移风险。为了验证该发现，该研究小组又使用了另一组样本进行了类似的分析。在获得确认的结果后，他们又使用临床前模型和临床样本对β受体阻滞剂影响蒽环类药物疗效的机制进行了探索。该研究的成果于近期被发表在《科学》杂志子刊Science Translational Medicine上。在首个回顾性研究中，报告有使用过β受体阻滞剂的TNBC患者约占11%（126例）。多因素分析结果显示，使用β受体阻滞剂联用化疗组患者的局部淋巴结和远处器官转移风险较单用化疗组患者显著降低，这意味着这部分患者的生存获益可能会增加。为了验证这些发现，研究人员又在907名接受化疗的TNBC患者中进行了类似的多因素分析。结果与先前的发现一致，使用β受体阻滞剂的患者死于乳腺癌的风险也有明显的降低。为了探索这种联用β受体阻滞剂带来的生存益处是否与使用蒽环类化疗药物相关，研究人员将使用蒽环类化疗的患者与接受非蒽环类化疗药物的患者再次分组进行分析。结果显示，只有在使用蒽环类药物的TNBC患者中，β受体阻滞剂的使用与癌症转移风险降低有关。更进一步的分析发现，使用β受体阻滞剂在缩小原发性肿瘤方面没有显著的影响。也就是说，β受体阻滞剂可能增强蒽环类化疗对TNBC患者的治疗效果，对复发转移性肿瘤的影响最为显著，但对原发性肿瘤可能影响不大。图片来源：123RF为了更好地了解β受体阻滞剂是通过何种机制增强蒽环类化疗的作用的，研究人员利用TNBC小鼠异种移植模型对其进行了探索。结果显示，对TNBC小鼠异种移植模型给予非选择性β受体阻滞剂普萘洛尔（propranolol）与蒽环类药物阿霉素治疗时，成功延缓了小鼠中肿瘤自发性转移的发生，并减少了已发生的远处转移的进展。在体外试验中，尽管阿霉素抑制了肿瘤细胞的增殖，但这种作用并未因添加了普萘洛尔而发生改变。随着进一步的探索，研究人员在TNBC小鼠模型中发现，交感神经系统（SNS）的激活会增加肿瘤转移，β受体阻滞剂能够阻止这种作用。而在没有蒽环类药物的情况下，单用β受体阻滞剂对肿瘤转移或进展没有影响。这再次支持了研究人员先前的假设——β受体阻滞剂可以提高蒽环类化疗的疗效，以减少肿瘤的转移和复发。由于β受体阻滞剂会通过β-肾上腺素能受体（βAR）阻断SNS的神经递质信号传导，研究人员接着探索了蒽环类化疗是否会影响肿瘤中SNS的活性。结果显示，不论是阿霉素还是另一种蒽环类化疗药物表阿霉素，都能增加TNBC小鼠模型中肿瘤外周儿茶酚胺能SNS神经的密度，从而使肿瘤中的去甲肾上腺素浓度增加。而其他非蒽环类化疗药物（例如紫杉醇和环磷酰胺）都不具有这种作用。图片来源：123RF那么蒽环类药物为什么能增加肿瘤中的SNS神经呢？研究人员通过对一系列能够调节SNS生长的细胞因子进行量化后发现，阿霉素治疗能够增加肿瘤中神经生长因子（NGF）的转录。在后续的细胞实验中，研究人员证实阿霉素能够直接调节肿瘤细胞中NGF的表达，并且肿瘤细胞表达的NGF能够促进PC12细胞的轴突生长。这些研究结果表明，阿霉素能够诱导肿瘤细胞分泌功能性的NGF。随后，在异种移植小鼠模型中，研究人员分别通过使用6-羟基多巴胺、敲除肿瘤细胞中表达NGF或β2AR的基因来抑制乳腺肿瘤中的SNS信号传导，阻止了阿霉素升高肿瘤中的去甲肾上腺素水平，通过减少转移增强了蒽环类化疗的治疗效果。总结来看，这些发现揭示了蒽环类化疗具有神经调节作用，这种作用会破坏其潜在的治疗作用。不过，通过抑制肿瘤微环境中的β2-肾上腺素能信号可以克服这种作用。也就是说，使用β2-肾上腺素能拮抗剂补充蒽环类化疗有望成为加强TNBC临床管理的一种潜在治疗策略。近年来，已有两项2期临床试验证了普萘洛尔能够降低接受肿瘤切除手术的乳腺癌患者的转移相关转录生物标志物。尽管这些试验并没有考察患者长期的生存结果，但是它们为评估转移复发风险提供了一个重要的基础。此外，一项研究发现将普萘洛尔与化疗药物联合使用是安全的，且患者对治疗方案的依从性很高。加上研究人员此次发现的结果，将为后续设计将β受体阻滞剂纳入TNBC治疗的3期临床试验奠定基础。期待更多临床上的好消息的传来，为广大TNBC患者扩大有限的治疗选择。药明康德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，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。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Chang A, Botteri E, Gillis RD, et al. Beta-blockade enhances anthracycline control of metastasis in triple-negative breast cancer. Sci Transl Med. 2023;15(693):eadf1147. doi:10.1126/scitranslmed.adf1147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。版权说明：本文来自药明康德内容团队，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。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

临床结果

2023-04-23

·SYNAPSE

New five-year data on disability outcomes and safety of Ofatumumab in patients with relapsing multiple sclerosis presented by novartis

PatSnap Synapse, a novel, AI Powered Drug Competitive Intelligence database. Access to drugs, clinical trials, patents, literature and news in one search. Novartis AG, a Swiss-based multinational pharmaceutical company, has recently presented new 5-year data on the safety and disability outcomes of its monoclonal antibody drug, Ofatumumab, for people living with relapsing multiple sclerosis (RMS). The drug targets CD20, which is found on the surface of B-lymphocytes, and works by inhibiting CD20, leading to complement-dependent cytotoxicity (CDC) effects and antibody-dependent cellular cytotoxicity (ADCC) against B-cells. The 5-year data presented by Novartis AG showed that patients treated earlier and continuously with Kesimpta® (ofatumumab) had fewer disability worsening events and low brain volume change versus those who started on teriflunomide and were later switched to Kesimpta. A separate analysis showed that treatment with Kesimpta for up to five years was well-tolerated, with no new or increased safety risks identified. Ofatumumab is a monoclonal antibody drug that targets CD20, a protein found on the surface of B-lymphocytes. The drug works by inhibiting CD20, leading to complement-dependent cytotoxicity (CDC) effects and antibody-dependent cellular cytotoxicity (ADCC) against B-cells. Ofatumumab is used to treat multiple sclerosis, both relapsing-remitting and lymphoid leukemia. It has been approved for use in the United States since October 2009 for the treatment of B-cell chronic lymphocytic leukemia. Ofatumumab has also been tested for the treatment of diffuse large B-cell lymphoma, follicular lymphoma, and mantle-cell lymphoma, but did not show significant benefits for these indications. The therapeutic areas for Ofatumumab include neoplasms, immune system diseases, and nervous system diseases. The drug was originally developed by Genmab A/S and is now actively developed and marketed by Novartis AG. Novartis AG is focused on developing drugs for neoplasms, nervous system diseases, immune system diseases, endocrinology and metabolic disease, infectious diseases, and hemic and lymphatic diseases. The company's drug development technologies include small molecule drugs, monoclonal antibodies, diagnostic radiopharmaceuticals, and prophylactic vaccines. Some of the most frequently developed targets by Novartis AG include GR, PSMA, c-Kit, SCNA, and the β2-adrenergic receptor. In conclusion, the new 5-year data presented by Novartis AG on the safety and disability outcomes of Ofatumumab for RMS patients is promising. As Novartis AG continues to focus on developing innovative drugs for a variety of therapeutic areas, Ofatumumab remains a valuable treatment option for patients living with RMS.