EFFECTS AND MECHANISMS OF CHRONIC ELECTROACUPUNCTURE FOR EMESIS

描述(申请人提供)：癌症是一组疾病，其特征是异常细胞的不受控制的生长和扩散。每年有100多万人罹患癌症。大约每两名美国男性中就有一名，每三名美国女性中就有一名会在一生中的某个时候患上某种癌症。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，对患者来说可能比未来对预期寿命的担忧更令人痛苦。事实上，由于顺铂引起的严重恶心和呕吐，一些患者选择停止潜在的根治疗法。止吐药物是治疗癌症患者化疗引起的恶心和呕吐的最常见的干预措施。止吐治疗的基础是呕吐的神经化学控制。然而，目前尚无满意的治疗方法来治疗化疗所致的呕吐，尤其是迟发性呕吐。针灸或电针(EA)已被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，当与止吐药物联合应用时，通过插入的针对穴位进行电刺激在减少急性呕吐方面是有效的。该项目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。在这个项目中，我们提出了一种创新的方法，通过在穴位长期植入电极和放置在腹部皮肤下的植入式脉冲发生器来传递慢性电针。有了这种新的方法，电针可以按需方便地由患者或连续给药。本项目将进行系统的研究，以优化电针的方法学(最佳电针位置和最佳刺激参数)。慢性电针在治疗化疗引起的呕吐方面有效的假设将在啮齿动物模型中进行测试，该模型使用PICA(粘土消费)。还将进行机制研究，以检验电针通过迷走神经通路介导并涉及中枢神经递质、多巴胺和5-羟色胺的假说。此外，还将研究慢性电针控制长期顺铂引起的急性和迟发性呕吐的可行性、安全性和有效性。成立了一支由中医药、胃肠电刺激、中枢神经系统生理学和医疗器械方面的专家组成的竞争团队。 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，超过90%的使用某些药物的病例会发生呕吐，如顺铂。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，迟发性呕吐仍然是一个巨大的挑战。本课题提出了一种利用植入式电极和刺激器进行慢性电针治疗化疗所致呕吐的新方法。初步数据支持了这一新概念，并设计了实验来验证该方法的可行性。

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.