MICA: Neurokinin 3 Receptor Antagonism as a Novel Treatment for Menopausal Hot Flushes

MICA：神经激肽 3 受体拮抗剂作为治疗更年期潮热的新方法

• 批准号: MR/M024954/1
• 负责人: Waljit Dhillo
• 金额: $ 44.33万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM024954%2F1
• 关键词: MICA; Neurokinin; Receptor; Antagonism; Novel

Hot flushes (or flashes) are transient episodes of sweating and intense heat sensation associated with a chronic decrease in circulating sex steroid levels. Hot flushes are experienced by up to 70% of women during the menopausal transition and postmenopause, and negatively impact on quality of life. Hot flushes are also experienced by many patients undergoing sex steroid deprivation therapy for breast and prostate cancer. Hormone replacement therapy (HRT) is the most effective treatment for menopausal hot flushes. Unfortunately, current recommendations are that HRT be used at the lowest possible dose for the shortest possible duration due to associated risks of breast cancer, stroke, venous thromboembolism and coronary artery disease. Furthermore, HRT is contraindicated in many patients. Hence alternative therapies to HRT are needed for menopausal flushing.Neurokinin B (NKB) is a member of the tachykinin family of peptides. NKB is encoded by the TAC3 gene and binds preferentially to the neurokinin 3 receptor (NK3). Recent human and animal data have demonstrated that NKB signalling is an essential component in mediating menopausal flushing. We performed for the first time a double-blinded, placebo-controlled pilot study which demonstrated that NKB infusion induced hot flush symptoms in women. These data suggest that NK3 receptor antagonists could be a novel and effective therapy for menopausal flushing. The aim of the proposed research is to carry out a study to determine if a Neurokinin 3 Receptor Antagonist is effective in treating hot flushes in menopausal women. AstraZeneca have developed a NK3 receptor antagonist (AZD2624) and shown that it is safe when administered to humans. AstraZeneca have agreed to work with the University researchers by providing their NK3 receptor antagonist (AZD2624) at no cost for this proposed research. The proposed study will determine how effective an NK3 receptor antagonist (AZD2624) is in treating hot flush symptoms in post menopausal women.If the proposed study shows that an NK3 receptor antagonist is an effective new treatment for menopausal flushing then this could provide a new treatment for hot flushes without the potential risks of hormonal administration. This would be beneficial for the following groups of patients:1. The major clinical application would be as a second-line therapy for patients with contraindication to HRT (ischaemic heart disease, cerebrovascular disease, previous thrombosis or high thrombotic risk), or in patient preference for non-hormonal therapy due to previous or anticipated adverse effects. In practice, 25% of women aged 50 or over, cannot take the pill due to a contraindication. Therefore, our solution would benefit an estimated 5 million women per year a third of whom have 'troublesome' flushing symptoms.2. Patients previously treated with HRT for 5 years, who require further treatment for flush symptoms which may persist for a total of 10 years i.e. 5 years beyond the point at which HRT would usually be discontinued. 3. Women with flushes induced by hormonal deprivation therapy for breast cancer.4. Women with a contraindication to HRT due to the diagnosis of previous breast cancer.5. Men with flushes induced by hormonal deprivation therapy for prostate cancer.

潮热（或闪光）是短暂的出汗和强烈的热感觉与循环性类固醇水平的慢性下降。在绝经过渡期和绝经后，高达70%的女性会经历潮热，并对生活质量产生负面影响。许多接受性类固醇剥夺治疗的乳腺癌和前列腺癌患者也会出现潮热。激素替代疗法（HRT）是最有效的治疗更年期潮热。不幸的是，目前的建议是，由于乳腺癌，中风，静脉血栓栓塞和冠状动脉疾病的相关风险，HRT应在尽可能短的时间内以尽可能低的剂量使用。此外，许多患者禁用HRT。神经激肽B（NKB）是速激肽家族的一员。NKB由TAC3基因编码，并优先结合神经激肽3受体（NK3）。最近的人类和动物数据表明，NKB信号转导是介导绝经期潮红的重要组成部分。我们首次进行了一项双盲、安慰剂对照的初步研究，证明NKB输注可诱导女性潮热症状。这些数据表明，NK3受体拮抗剂可能是一种新的和有效的治疗更年期潮红。这项研究的目的是进行一项研究，以确定神经激肽3受体拮抗剂是否能有效治疗更年期妇女的潮热。 阿斯利康开发了一种NK3受体拮抗剂（AZD 2624），并证明其对人体安全。阿斯利康已同意与大学的研究人员合作，免费提供他们的NK3受体拮抗剂（AZD 2624）用于这项拟议的研究。这项研究将确定NK3受体拮抗剂（AZD 2624）治疗绝经后妇女潮热症状的有效性，如果这项研究表明NK3受体拮抗剂是治疗绝经后潮热的有效新疗法，那么这将为潮热提供一种新的治疗方法，而没有激素给药的潜在风险。这将有利于以下患者群体：1。主要的临床应用是作为HRT禁忌症患者（缺血性心脏病、脑血管疾病、既往血栓形成或高血栓形成风险）的二线治疗，或由于既往或预期不良反应而偏好非激素治疗的患者。在实践中，25%的50岁或以上的妇女由于禁忌症而不能服用避孕药。因此，我们的解决方案每年将使大约500万妇女受益，其中三分之一的妇女患有“麻烦的”冲水马桶。既往接受HRT治疗5年，需要进一步治疗潮红症状的患者，潮红症状可能持续总计10年，即超过HRT通常停止的时间点5年。3.乳腺癌激素剥夺治疗引起潮红的女性。妇女与禁忌激素替代疗法由于先前的乳腺癌的诊断。前列腺癌的激素剥夺治疗引起潮红的男性。

项目成果

Neurokinin 3 Receptor Antagonism Rapidly Improves Vasomotor Symptoms With Sustained Duration of Action

神经激肽 3 受体拮抗作用可通过持续作用时间快速改善血管舒缩症状

• DOI: 10.1097/ogx.0000000000000665
• 发表时间: 2019
• 期刊: Obstetrical & Gynecological Survey
• 影响因子: 6.2
• 作者: Prague J

A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial.

• DOI: 10.1093/humrep/dex253
• 发表时间: 2017-09-01
• 期刊: Human reproduction (Oxford, England)
• 作者: Abbara A;Clarke S;Islam R;Prague JK;Comninos AN;Narayanaswamy S;Papadopoulou D;Roberts R;Izzi-Engbeaya C;Ratnasabapathy R;Nesbitt A;Vimalesvaran S;Salim R;Lavery SA;Bloom SR;Huson L;Trew GH;Dhillo WS
• 通讯作者: Dhillo WS

Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial

神经激肽 3 受体拮抗剂作为更年期潮热的新型治疗方法：2 期、随机、双盲、安慰剂对照试验

• DOI: 10.1530/endoabs.49.gp131
• 发表时间: 2017
• 期刊: Endocrine Abstracts
• 作者: Prague J

Neurokinin 3 receptor antagonism for menopausal hot flashes

神经激肽 3 受体拮抗剂治疗更年期潮热

• DOI: 10.1016/j.cell.2023.07.011
• 发表时间: 2023
• 期刊: Cell
• 影响因子: 64.5
• 作者: Comninos A

Neurokinin 3 Receptor Antagonists Do Not Increase FSH or Estradiol Secretion in Menopausal Women

神经激肽 3 受体拮抗剂不会增加更年期女性的 FSH 或雌二醇分泌

• DOI: 10.1210/jendso/bvz009
• 发表时间: 2020
• 期刊: Journal of the Endocrine Society
• 影响因子: 4.1
• 作者: Dhillo W