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

潮热(或潮热)是一过性出汗和强烈的热感，与循环性类固醇水平的慢性下降有关。高达70%的女性在绝经过渡期和绝经后会经历潮热，并对生活质量产生负面影响。许多接受性激素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)是治疗更年期潮热最有效的方法。不幸的是，目前的建议是，由于乳腺癌、中风、静脉血栓栓塞症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，HRT在许多患者中是禁忌的。因此，更年期需要替代激素替代疗法。神经激动素B(NKB)是速激肽家族的一员。NKB由TAC3基因编码，优先与神经激肽3受体(NK3)结合。最近的人类和动物数据表明，NKB信号是调节更年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输注会导致女性出现潮热症状。这些数据表明，NK3受体拮抗剂可能是治疗更年期潮红的一种新的有效方法。这项拟议研究的目的是进行一项研究，以确定神经激肽3受体拮抗剂是否有效治疗更年期妇女的潮热。阿斯利康已经开发出一种NK3受体拮抗剂(AZD2624)，并表明它在人类使用时是安全的。阿斯利康已同意与大学研究人员合作，为这项拟议的研究免费提供他们的NK3受体拮抗剂(AZD2624)。这项拟议的研究将确定NK3受体拮抗剂(AZD2624)在治疗绝经后妇女潮热症状方面的有效性。如果拟议的研究表明NK3受体拮抗剂是治疗更年期潮热的有效新方法，那么这将为治疗潮热提供一种新的治疗方法，而不存在激素治疗的潜在风险。这将对以下患者群体有利：1.主要的临床应用将作为HRT禁忌症(缺血性心脏病、脑血管疾病、既往血栓形成或高血栓风险)患者的二线治疗，或由于既往或预期的不良反应而倾向于非激素治疗的患者。在实践中，25%的50岁或50岁以上的女性由于禁忌症而不能服用该药。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有“麻烦的”脸红症状。曾接受激素替代治疗5年的患者，他们的潮红症状可能会持续总共10年，即在通常停止激素替代治疗的时间点之后5年。3.乳腺癌激素剥夺治疗所致面色发红的女性。因既往乳腺癌诊断为激素替代治疗禁忌症的女性。前列腺癌激素剥夺治疗引起面色发红的男性。

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.