EFFECTS AND MECHANISMS OF CHRONIC ELECTROACUPUNCTURE FOR EMESIS

描述（由申请人提供）：癌症是一组以异常细胞的不受控制的生长和扩散为特征的疾病。每年有超过一百万人患癌症。大约每两个美国男性中就有一个，每三个美国女性中就有一个在他们一生中的某个时候会患上某种类型的癌症。顺铂是癌症化疗中最常用的药物之一。然而，化疗引起的严重不良事件，主要是恶心和呕吐，可能比预期寿命的未来担忧更令患者痛苦。事实上，一些患者由于严重的顺铂诱导的恶心和呕吐而选择停止潜在的治愈性治疗。止吐药是治疗癌症患者化疗引起的恶心和呕吐的最常见干预措施。止吐治疗的基础是呕吐的神经化学控制。然而，目前对于化疗引起的呕吐，尤其是迟发性呕吐，尚无满意的治疗方法。针灸或电针（EA）已被应用于治疗化疗引起的恶心和呕吐。最近的一项荟萃分析表明，通过插入针头对穴位进行电刺激，当与止吐药物联合使用时，可有效减少急性呕吐。本研究的长期目标是开发一种有效的电针方法来治疗化疗引起的恶心和呕吐患者。在这个项目中，我们提出了一种创新的方法，通过长期植入电极在穴位和植入式脉冲发生器放置在腹部皮肤下的慢性EA。通过这种新方法，可以方便地按需或连续地递送EA。本研究将对电针的最佳位置和最佳刺激参数进行系统的研究。将在使用异食癖（消耗粘土）的啮齿动物模型中测试慢性EA在治疗化疗诱导的呕吐中有效的假设。机制研究也将进行测试的假设，EA是通过迷走神经元通路介导的，涉及中枢神经递质，多巴胺和血清素。本研究亦将探讨慢性电针控制长期顺铂所致急性及迟发性呕吐的可行性、安全性及有效性。拥有一支由中医、胃肠电刺激、中枢神经系统生理学、医疗器械等方面专家组成的高素质团队。 公共卫生相关性：化疗引起的呕吐是癌症患者治疗中的主要问题之一，并且在使用某些药物（例如顺铂）的情况下超过90%的病例中发生。随着最近止吐药物的进步，急性呕吐得到了更好的控制;然而，延迟呕吐仍然是一个很大的挑战。本研究提出一种利用植入式电极及刺激器进行慢性电针治疗化疗所致呕吐的新方法。初步的数据支持这一新的概念和实验设计，以测试所提出的方法的可行性。

DESCRIPTION (provided by applicant): Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells. Over one million people get cancer each year. Approximately one out of every two American men and one out of every three American women will have some type of cancer at some point during their lifetime. Cisplatin is one of the most commonly used drugs in chemotherapy for cancers. However, severe adverse events resulting from chemotherapies, mainly nausea and vomiting may be much more distressing to a patient than future concerns of life expectancy. In fact, some patients choose to discontinue potentially curative therapy because of severe Cisplatin-induced nausea and vomiting. Antiemetic agents are the most common intervention in the management of chemotherapy-induced nausea and vomiting in cancer patients. The basis for antiemetic therapy is the neurochemical control of vomiting. However, currently, there are no satisfactory therapies for treating chemotherapy-induced emesis, especially delayed emesis. Acupuncture or electroacupuncture (EA) has been applied for treating chemotherapy-induced nausea and vomiting. A recent meta-analysis has indicated that electrical stimulation of the acupoint via inserted needles is effective in reducing acute vomiting when applied in combination with the anti-emetic medications. The long-term aim of this project is to develop an effective EA method to treat patients with chemotherapy-induced nausea and vomiting. In this project, we propose an innovative method of chronic EA delivered via chronically implanted electrodes at acupoints and an implantable pulse generator placed underneath the abdominal skin. With this new method, EA can be delivered on-demand conveniently by the patient or continuously. Systematic studies will be performed in this project to optimize the methodology of EA (best EA locations and optimal stimulation parameters). The hypothesis that chronic EA is effective in treating chemotherapy-induced emesis will be tested in a rodent model using pica (consumption of clay). Mechanistic studies will also be performed to test the hypotheses that EA is mediated via the vagal neuronal pathway and involves central neurotransmitters, dopamine and serotonin. The feasibility, safety and efficacy of chronic EA in controlling acute and delayed emesis induced by long-term cisplatin will also be investigated. A competitive team has been established, including experts in Traditional Chinese Medicine, gastrointestinal electrical stimulation, physiology of the central nervous system and medical device. PUBLIC HEALTH RELEVANCE: Chemotherapy-induced emesis is one of major problems in the treatment of patients with cancer and occurs in more than 90% of cases with certain medications, such as Cisplatin. With the recent advancement of anti-emetic medications, acute emesis is better controlled; however, delayed emesis remains a big challenge. A novel method of chronic electroacupuncture using implantable electrodes and stimulator is proposed in this project for the treatment of chemotherapy-induced emesis. Preliminary data supports this novel concept and experiments are designed to test the feasibility of the proposed method.