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CN101124012B - 通过电刺激迷走神经治疗炎症性疾病的装置 - Google Patents

通过电刺激迷走神经治疗炎症性疾病的装置 Download PDF

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CN101124012B
CN101124012B CN200580048379.2A CN200580048379A CN101124012B CN 101124012 B CN101124012 B CN 101124012B CN 200580048379 A CN200580048379 A CN 200580048379A CN 101124012 B CN101124012 B CN 101124012B
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J·M·休斯顿
K·J·特蕾西
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North Shore Long Island Jewish Research Institute
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    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36053—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for vagal stimulation
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36114—Cardiac control, e.g. by vagal stimulation

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Abstract

本发明提供一种方法和装置，其通过以足以抑制炎性细胞因子级联的量电刺激迷走神经活性，治疗患有由炎性细胞因子级联介导的病症或者具有该病症危险的患者。

Description

通过电刺激迷走神经治疗炎症性疾病的装置
相关申请
本申请要求2004年12月27日提交的美国临时申请No.60/639,332的权利。该申请的所有内容均引入本文作为参考。 
背景技术
脊椎动物在感染或损伤期间通过平衡促炎症和抗炎症通路而达到内稳态。然而在许多疾病情况下，该内稳态的平衡会被打破。例如，所有革兰氏阴性细菌产生的内毒素(脂多糖，LPS)激活巨噬细胞释放可能致死性的细胞因子(Tracey，K.J.等人，Science，234：470-74(1986)；Dinarello，C.A.，FASEB J.，8：1314-25(1994)；Wang，H.，等人，Science，285：248-51(1999)；Nathan，C.F.，J.Clin.Inverst.79：319-26(1987))。 
炎症和其它有害的病症(如接触内毒素引起的脓毒性休克)通常由促炎性细胞因子引发，如肿瘤坏死因子(TNF；也叫作TNFα或恶液质因子)、白介素(IL)-1α、IL-1β、IL-6、IL-8、IL-18、干扰素、血小板活化因子(PAF)、巨噬细胞迁移抑制因子(MIF)以及其它化合物。一些其它化合物如高迁移率族蛋白-1(HMG-1)在诸如脓毒症等多种病症时诱导，它们同样也可发挥促炎性细胞因子的作用。促炎性细胞因子通过在炎症细胞因子级联过程中释放而引起各种紊乱，特别是脓毒症。炎症细胞因子级联可导致许多紊乱的有害特征，包括炎症和细胞凋亡。 
发明内容
本发明为一种治疗细胞因子介导的炎症疾病的方法和装置。 
本发明部分基于通过电刺激迷走神经可治疗受试者的炎症性疾 病的发现。还令人惊讶地发现足以治疗炎症性疾病的电信号参数明显比以前用于治疗其它疾病的参数温和。因此发现炎症性疾病可经电信号治疗，该电信号的电流或电压显著弱于以前治疗其它疾病所采用的电信号。 
在一种实施方式中，本发明为一种治疗患有炎症性疾病或具有患炎症性疾病危险的受试者的方法，它包括用电信号刺激受试者的迷走神经，其中信号电压为0.01伏至1伏，条件是该疾病不是肠梗阻、哮喘或囊性纤维化。 
在另一实施方式中，本发明为一种治疗患有炎症性疾病或具有患炎症性疾病危险的受试者的方法，它包括用电信号刺激受试者的迷走神经，其中信号电压为0.01伏至1伏，脉冲宽度为0.1ms至5ms；信号频率为0.1Hz至30Hz；信号作用时间(on-time)为1秒至120秒；信号间断时间(off-time)为2小时以上。 
在另一实施方式中，本发明为一种用于治疗患有炎症性疾病或具有患炎症性疾病危险的受试者的电信号发生器及其用途。该电信号发生器包含向受试者迷走神经传送电信号的电极组件和通过限定信号电压为0.01伏至1伏而控制电信号的控制器。 
在另一实施方式中，本发明为一种用于治疗患有炎症性疾病或具有患炎症性疾病危险的受试者的电信号发生器及其用途。该电信号发生器包含向受试者迷走神经传送电信号的电极组件和控制电信号的控制器，该控制器限定信号电压为0.01伏至1伏，脉冲宽度为0.1ms至5ms；信号频率为0.1Hz至30Hz；信号作用时间为1秒至120秒；信号间断时间为2小时以上。 
意外地发现，尽管刺激迷走神经的条件较温和，但是对迷走神经的电刺激仍足以激活胆碱能抗炎症通路，通过小鼠血清TNF水平的测定证明了这一点(实施例1)。电刺激迷走神经引起TNF抑制的有效半衰期为2至3天(实施例2)，表明电刺激的持续作用时间至少与药物干预作用时间一样长。此外，电刺激迷走神经可改善胶原诱导的大鼠关节炎的严重程度(实施例3)。 
附图说明
图1为一种适合实施本发明的可植入式电发生器实施方式的简要框图。 
图2示出了植入患者体内的电信号发生器和电极的一个合适的位置。 
图3为用于说明输出信号的相关参数的信号发生器的理想电输出信号波形示意图。 
图4为通过血清TNF水平减少百分数测定，表示电刺激迷走神经对内毒素血症的作用的柱状图。 
图5显示了用电信号电刺激VNS对受LPS攻击的小鼠中TNF产生的作用。纵轴代表TNF抑制百分数，横轴代表VNS刺激和LPS攻击之间的时间。 
图6显示作为诱导关节炎的胶原免疫后天数(PCID)的函数的大鼠关节炎评分。VNS刺激开始于第13天并持续至第20天。 
发明详述 
本文所述的“受试者”优选是哺乳动物，更优选人类患者，但也可为伴侣动物(如狗或猫)、家畜(如马、牛或绵羊)或实验动物(如大鼠、小鼠或豚鼠)。优选的受试者是人。 
本文所用的术语“迷走神经”为其最宽的含意，包括所有从主迷走神经分支出来的神经，以及与迷走神经相连的神经节或神经节后神经元。在本领域中迷走神经也被称为副交感神经系统及其分支，以及胆碱能神经。迷走神经支配包括咽、喉、食管、心脏、肺、胃、胰腺、脾、肾脏、肾上腺、小肠和大肠、结肠以及肝脏在内的主要器官。电刺激可以直接刺激迷走神经，也可刺激迷走神经支配的器官。 
本申请公开的方法包括刺激全部迷走神经(即传入和传出神经)，或分离传出神经并直接刺激之。后一种方法可在两种纤维均存在的神经区域处将传出神经纤维与传入神经分离。可替代的，在无传入神经纤维处，例如在接近传出神经纤维支配的靶器官处，刺激传出神经纤 维。传出神经纤维还可通过直接刺激靶器官而被激活，例如用电刺激方法，以此刺激支配该器官的传出神经纤维。在另外的实施方式中，可以刺激迷走神经的神经节或神经节后神经元。迷走神经还可被切断后刺激其远端，以此仅刺激传出迷走神经纤维。 
刺激迷走神经的部位可以是颈区(脖子)，也可在颈区周围和远侧的区域，包括横膈膜上或横膈膜下区域。包括支配器官的迷走神经的分支的外周、远侧部位包括但不限于脾、小肠和大肠。迷走神经还可用气管内/食管神经刺激器(如美国专利No.6,735,471所述，在此全文引入作为参考)、透皮神经刺激器(如美国专利No.6,721,603所述，在此全文引入作为参考)或经皮神经刺激器所刺激。在一种实施方式中，迷走神经在颈区被刺激。在另一种实施方式中，迷走神经在外周、远侧部位被刺激。在另一种实施方式中，用装置在脑内刺激迷走神经。 
根据本发明，通过传送由任何适用的迷走神经刺激器产生的电信号来刺激迷走神经。例如，可以使用商品化的迷走神经刺激器，如Cyberonics NCPTM，或是使用电子探针。 
适合的迷走神经刺激器的例子(例如)在美国专利Nos.4,702,254；5,154,172；5,231,988；5,330,507；6,473,644；6,721,603；6,735,471；和美国专利申请公开文本2004/0193231中记载。以上所有出版物的教导在此全文引入作为参考。 
迷走神经可通过植入式装置或是患者体外携带型装置来刺激，如美国专利No.5,231,988中描述的Cyberonics NCPTM装置或美国专利No.5,330,507中描述的MedtronicTM装置。这两个专利均描述了采用连续和/或相性电信号刺激右或左迷走神经的装置。 
一种适合实施本发明的典型电信号发生器的示意图见图1。如图1所示，一种典型信号发生器10包括一个电池(或电池组)12，其可以采用任何传统的为医学电子设备提供电能的类型。电池12连接电压调节器14。调节器14稳定电池输出以产生平稳的输出电压，还可根据需要提供电压倍增或分压。 
调节器13为信号控制器16提供电能。信号控制器16可包含微处理器。信号控制器16控制该装置的诸如输出信号的电流或电压、输出信号频率、输出信号脉冲宽度、输出信号作用时间、输出信号间断时间等功能。控制器16可以被编程为控制每天连续或同期性调节迷走神经活性的次数，以及输出信号启始的延迟时间。这种可编程性允许按治疗方案调整输出信号。 
当装置10被植入时，可使用内置天线(未示出)使装置10与体外编程或监测设备(未示出)能够联络。 
信号控制器16控制产生所需电信号的驱动器18。输出信号通过电极20a和20b施加到患者身体上。 
可提供分析器22来处理由检测器24检测到的患者的各种相关生理参数如心率或血压。 
如上所述，装置10可在患者体外携带或是植入体内。图2示出了本发明的一种实施方式，其中信号发生器10被植入由外科医生在患者胸部皮下做成的袋内。适合植入发生器的一个部位是患者胸部，类似于起博器脉冲发生器的植入，同时将电极20a和20b植入患者颈部。 
电极20a和20b可用美国专利No.4,573,481所述类型的双极刺激电极，该专利在此全文引入作为参考。在此实施方式中，电极构成组件，通过手术将该组件植入患者颈部的迷走神经上。两个电极围绕迷走神经，使用美国专利No.4,979,511描述的螺旋锚定索将该组件固定在神经上，该专利在此全文引入作为参考。 
在结构上，电极组件可以包括两根铂丝，分别与环绕迷走神经的两个螺旋环之一相连。每个环均包含硅橡胶。另外还设置一个含硅橡胶的螺旋环将电极组件固定在迷走神经上。螺旋双极电极的内径通常可以是约两毫米(mm)，一个螺旋约七毫米长(沿神经轴测量)。 
除了可将电极组件植入患者颈部，还可将组件植入支配前面所述的任意器官的迷走神经上。电极20a和20b的植入以与植入颈部基本相同的方式进行。 
信号发生器10控制和治疗炎症性疾病的操作将参考图3所示的信号波形和参数来描述。该图为驱动器18发送的输出信号的理想图示。图3用于解释电信号参数的各种术语。这些参数包括信号作用时间、信号间断时间、信号频率、信号脉冲宽度、信号电流和信号电压。对炎症性疾病的治疗可通过向电极20a和20b施加电压并在电极20a和20b之间产生电流来完成。图3显示的脉冲为正电压或电流的输出，而具有负输出的电信号也是可用的。 
信号控制器16通过将输出限定在以上参照图3所述的参数的适当范围从而控制输出信号。每个参数的范围可以独立于任何其他参数来选择。此外，还可以选择任意几个参数的联合范围。下面将提到的有关控制器参数和参数组合的特定数值的优选实例也适用于公开的治疗方法。 
信号控制器可以限定信号电压为约0.01伏至约1伏之间，优选约0.01伏至约0.1伏，更优选约0.01伏至约0.05伏。 
信号控制器可以限定信号电流为约1mA至约100mA之间，优选约1mA至约10mA，更优选约1mA至约5mA。 
在一些实施方式中，信号电压和信号电流均受控制。 
在另一些实施方式中，除了(或者独立于)控制信号电压、信号电流或者共同控制两者，信号控制器还可以控制选自脉冲宽度、作用时间和频率的一个或多个参数。信号控制器可以限定脉冲宽度为约0.1ms至约5ms之间，优选约0.1ms至约1ms，更优选约0.1ms至约0.5ms。信号控制器可以限定信号作用时间为约1秒至约120秒，优选约10秒至约60秒，更优选约20秒至约40秒。信号控制器可以限定信号频率为约0.1Hz至约30Hz之间，优选约1Hz至约30Hz，更优选约10Hz至约30Hz。 
在另一些实施方式中，除了(或者独立于)控制信号电压和/或信号电流以及信号宽度、信号频率和/或信号作用时间，信号控制器还可控制信号间断时间。在一种实施方式中，受试者可采用一个脉冲治疗。在另一些实施方式中，信号控制器可以限定信号间断时间为5分钟以 上，优选2小时以上，更优选4小时以上，甚至更优选8小时以上，再更优选12小时以上。在另一些实施方式中，控制器可以限定信号间断时间为约2小时至约48小时之间，优选约4小时至约36小时，更优选约6小时至约36小时。在另一些优选实施方式中，信号控制器可以限定信号间断时间为选自以下的范围：约6至约36小时，约12至约36小时，约16至约30小时和约20至约28小时。可替代地，信号间断时间还可以不限定，因为本领域技术人员可以很容易地确定两次连续信号之间期望的时间间隔。 
如上所述，各种参数均可被单独或组合地限定在特定范围之内。在一个实施例中，信号控制器可如下限定参数的组合：信号电压为约0.01伏至约1伏；脉冲宽度为约0.1ms至约5ms；信号频率为约0.1Hz至约30Hz；信号作用时间为约1秒至约120秒。信号间断时间可不限定。可替代的，也可限定信号间断时间为约5分钟以上。在另一些优选实施方式中，信号控制器可将信号间断时间限定为选自以下的范围：约6至约36小时，约12至约36小时，约16至约30小时和约20至约28小时。 
在另一个实施例中，信号控制器可如下限定参数的组合：信号电流为约1mA至约100mA；脉冲宽度为约0.1ms至约5ms；信号频率为约0.1Hz至约30Hz；信号作用时间为约1秒至约120秒。信号间断时间可不限定。可替代的，也可限定信号间断时间为约5分钟以上。在另一些优选实施方式中，信号控制器可将信号间断时间限定为选自以下的范围：约6至约36小时，约12至约36小时，约16至约30小时和约20至约28小时。 
在一个优选实施方式中，信号控制器可如下限定参数的组合：信号电压为约0.01伏至约0.1伏；脉冲宽度约0.1ms至约1ms；信号频率约1Hz至约30Hz；信号作用时间约10秒至约60秒；信号间断时间为2小时以上。或者可以不限定信号间断时间。在另一些优选实施方式中，信号控制器可以将信号间断时间限定为选自以下的范围：约6至约36小时，约12至约36小时，约16至约30小时和约20至 约28小时。 
可替代的，信号控制器可如下限定参数的组合：信号电流为约1mA至约10mA；脉冲宽度为约0.1ms至约1ms；信号频率为约1Hz至约30Hz；信号作用时间为约10秒至约60秒；信号间断时间为2小时以上。或者可以不限定信号间断时间。在另一些优选实施方式中，信号控制器可以将信号间断时间限定为选自下列的范围：约6至约36小时，约12至约36小时，约16至约30小时和约20至约28小时。 
更优选的是，信号控制器可如下限定参数的组合：信号电压为约0.01伏至约0.05伏；脉冲宽度为约0.1ms至约0.5ms；信号频率为约10Hz至约30Hz；信号作用时间为约20秒至约40秒；信号间断时间为约2小时至约24小时。或者可以不限定信号间断时间。在另一些优选实施方式中，信号控制器可以将信号间断时间限定为选自下列的范围：约6至约36小时，约12至约36小时，约16至约30小时和约20至约28小时。在另一些优选实施方式中，信号控制器可从以下范围中选择限定信号间隔时间范围：约从6至36小时，约从12至36小时，约从16至30小时和约从20至28小时。 
可替代的，信号控制器可如下限定参数的组合：信号电流为约1mA至约5mA；脉冲宽度为约0.1ms至约0.5ms；信号频率为约10Hz至约30Hz；信号作用时间为约20秒至约40秒；信号间断时间为约2小时至约24小时。或者可以不限定信号间断时间。在另一些优选实施方式中，信号控制器可将信号间断时间限定为选自下列的范围：约6至约36小时，约12至约36小时，约16至约30小时和约20至约28小时。 
本文使用的“治疗”包括预防性的和治疗性的治疗。“预防性治疗”是指在炎症病症发作之前预防、抑制或减少其发生。治疗性治疗是指治疗已经患有炎症性疾病的受试者。 
“炎症性疾病”通常是由炎性细胞因子级联介导的，炎性细胞因子级联在本文定义为受试者体内从细胞释放至少一种促炎性细胞因子，其中该细胞因子的释放会影响受试者的生理状态。产生促炎性细胞因 子的细胞的非限定例子包括单核细胞、巨噬细胞、嗜中性粒细胞、上皮细胞、成骨细胞、成纤维细胞、平滑肌细胞和神经元。 
本文使用的“细胞因子”是一种可溶性蛋白质或多肽，它由哺乳细胞天然产生，在微摩尔到皮摩尔的浓度下作为体液调节因子在体内发挥作用。细胞因子可在正常或病理状况下调节细胞和组织的功能活性。促炎性细胞因子是一类能够引起以下任意与炎症有关的生理反应的细胞因子：血管舒张、充血、伴有水肿的血管渗透性增加、粒细胞和单核吞噬细胞聚集或纤维蛋白沉积。在一些情况下，促炎性细胞因子还可引起细胞凋亡，如在慢性心力衰竭中，已经证明在该情况下TNF能刺激心肌细胞凋亡。促炎性细胞因子的非限定例子包括肿瘤坏死因子(TNF)、白介素(IL)-1α、IL-1β、IL-6、IL-8、IL-18、干扰素γ、HMG-1、血小板活化因子(PAF)和巨噬细胞迁移抑制因子(MIF)。在本发明的优选实施方式中，通过胆碱能激动剂治疗而抑制的促炎性细胞因子包括TNF、IL-1、IL-6或IL-18，因为以上细胞因子均为巨噬细胞产生的，并且介导多种重要疾病的有害病症，例如内毒素休克、哮喘、类风湿性关节炎、炎症性胆汁病、心力衰竭和异体移植排斥。在最优选的实施方式中，促炎性细胞因子为TNF。 
促炎性细胞因子区别于抗炎性细胞因子如IL-4、IL-10和IL-13，后者不是炎症的介质。在优选实施方式中，抗炎性细胞因子的释放不被胆碱能激动剂所抑制。 
在提到迷走神经刺激对炎症性疾病的影响时，使用的术语“治疗”、“抑制”、“减少”或“减轻”表示所治疗疾病的相关症状至少有很小但可测量的减轻。 
本发明涉及对由炎性细胞因子级联介导的炎症疾病或炎症病症的治疗。在一个方面，该疾病不是肠梗阻、哮喘或囊性纤维化。 
在另一方面，本发明为任何上述装置在制造用于治疗受试者炎症性疾病的治疗性设备中的用途，其中该该装置在操作中直接刺激迷走神经以治疗炎症性疾病。术语“操作”表示在受试者身体上、向受试者或接近受试者使用或施用装置时，直接刺激迷走神经以治疗炎症性疾 病。 
在另一方面，本发明涉及装置在制造用于治疗受试者炎症性疾病的治疗性设备中的用途，其中单独地使用该装置刺激迷走神经以治疗炎症性疾病。术语“单独地”包括使用装置选择性地治疗炎症性疾病，其中其他疾病或病症也可能通过刺激迷走神经而治疗。 
优选的是，使用装置直接刺激迷走神经不能治疗除了炎症性疾病以外的其他病症。在一种实施方式中，可以特定地改变该装置，以通过直接刺激迷走神经仅治疗炎症性疾病。 
病症可以是炎性细胞因子级联引起系统性反应的病症，如脓毒性休克。可替代的，病症可以是由局部炎性细胞因子级联介导的，如类风湿性关节炎。 
可应用本发明治疗的病症的非限定例子包括阑尾炎、消化性溃疡、胃溃疡、十二指肠溃疡、腹膜炎、胰腺炎、溃疡性结肠炎、假膜性结肠炎、急性结肠炎、缺血性结肠炎、憩室炎、会厌炎、失弛缓症、胆管炎、胆囊炎、肝炎、克罗恩病、肠炎、惠普尔病、变态反应、过敏性休克、免疫复合物病、器官缺血、再灌注损伤、器官坏死、花粉热、脓毒症、败血病、内毒素休克、恶病质、高烧、嗜酸性肉芽肿、肉芽肿、结节病、脓毒性流产、附睾炎、阴道炎、前列腺炎、尿道炎、支气管炎、肺气肿、鼻炎、肺炎、肺尘病、肺泡炎(alvealitis)、细支气管炎、咽炎、胸膜炎、窦炎、流行性感冒、呼吸道合胞病毒感染、HIV感染、乙型肝炎病毒感染、丙型肝炎病毒感染、疱疹病毒感染、播散性菌血症、登革热、念珠菌病、疟疾、丝虫病、阿米巴病、水泡囊、烧伤、皮炎、皮肌炎、晒伤、荨麻疹、疣、水疱、血管炎、脉管炎、心内膜炎、动脉炎、动脉粥样硬化、血栓性静脉炎、心包炎、心肌炎、心肌缺血、结节性动脉周炎、风湿热、阿尔茨海默病、乳糜泄、充血性心力衰竭、成人呼吸窘迫综合症、脑膜炎、脑炎、多发性硬化症、脑梗死、脑栓塞、格林-巴利综合征、神经炎、神经痛、脊髓损伤、麻痹、葡萄膜炎、关节炎性皮疹、关节痛、骨髓炎、筋膜炎、佩吉特病、痛风、牙周病、类风湿性关节炎、滑膜炎、重症肌无力、甲 状腺炎、系统性红斑狼疮、古德帕斯彻综合征、贝切特综合征、异体移植排斥、移植物抗宿主病、I型糖尿病、强直性脊柱炎、贝格尔病、莱特尔综合征和何杰金病。 
在更优选的实施方式中，病症是阑尾炎、消化性、胃或十二指肠溃疡、腹膜炎、胰腺炎、溃疡性、假膜性、急性或缺血性结肠炎、肝炎、克罗恩病、哮喘、变态反应、过敏性休克、器官缺血、再灌注损伤、器官坏死、花粉热、脓毒症、败血病、内毒素休克、恶病质、脓毒性流产、播散性菌血症、烧伤、阿尔茨海默病、乳糜泄、充血性心力衰竭、成人呼吸窘迫综合症、脑梗死、脑栓塞、脊髓损伤、麻痹、异体移植排斥或移植物抗宿主病。在最优选的实施方式中，病症为内毒素休克。 
在另一些优选实施方式中，病症是脓毒症、内毒素休克、异体移植排斥、类风湿性关节炎、成人呼吸窘迫综合症、哮喘、系统性红斑狼疮、胰腺炎、腹膜炎、烧伤、心肌缺血、异体移植排斥、移植物抗宿主病、充血性心力衰竭、器官缺血、再灌注损伤、恶病质和囊性纤维化。 
在另一些优选实施方式中，病症是阑尾炎、溃疡性结肠炎、克罗恩病、变态反应、再灌注损伤、系统性红斑狼疮、肝炎、贝切特综合征、多发性硬化症和动脉粥样硬化。 
在另一些优选实施方式中，病症是内毒素休克和脓毒症。 
本发明通过下列非限定性实施例进行说明。 
实施例
实施例1采用减少的刺激强度和持续时间进行迷走神经电刺激足以活化胆碱能抗炎症通路。 
为确定减弱的刺激参数是否可达到抗炎效果，在致死性内毒素血症的状况下，采用逐渐降低的刺激强度和持续时间对完整迷走神经进行电刺激。雄性8-12周BALB/c小鼠(20-30g；Taconic)在25℃12小时明/暗循环的环境中饲养。动物在进行实验操作前至少适应环境7 天。随意摄取标准小鼠饲料和饮水。所有动物实验均按照国立卫生研究院(NIH)指南，以北岸-长岛犹太研究院的实验动物管理与使用委员会(the Institutional Animal Care and Use Committee of the NorthShore-Long Island Jewish Research Institute)批准的实验方案进行。 
小鼠采用异氟烷(1.5-2.0％)麻醉并仰卧置于操作台上。沿颈部腹侧中线切开，暴露并分离左颈迷走神经。为进行电刺激，将完整的迷走神经置于与刺激模块(STM100C，Biopac Systems)相连并受采集系统(MP150，Biopac Systems)控制的双极铂电极(Plastics One)之间。电刺激参数采用AcqKnowledge软件(Biopac Systems)编程。刺激参数包括(100mA，2ms，5Hz)20min(LPS给予前后各10min)，(100mA，2ms，5Hz)2min(LPS给予前后各1min)，(100mA，2ms，5Hz)30sec(LPS给予5min后)，(1mA，0.5ms，30Hz)30sec((LPS给予5min后)。假手术的电VNS小鼠在颈部切开后仅切开颌下唾液腺。既不被暴露也不被分离迷走神经。 
内毒素(大肠杆菌LPS 0111：B4；Sigma)以1mg/ml的贮存浓度溶于无菌无热原盐水，注射小鼠。紧接每次实验之前LPS溶液均超声处理30min。小鼠按LD50剂量注射LPS(7.5mg/kg，腹膜内)。LPS注射后2h收集血液，室温凝结2h后，然后以2,000×g离心15min。血清样本在分析前于-20℃保存。小鼠血清TNF浓度采用ELISA(R&D Systems)检测。 
如图5所示，全部四种刺激参数均足以抑制TNF。注射LPS然后进行假VNS的对照组小鼠的血清TNF平均水平为2755±424pg/ml。电VNS组小鼠的血清TNF水平分别为：20min(712±128pg/ml，为对照的25.8％，p＝0.02)，2min(688±114pg/ml，为对照的25.0％，p＝0.02)，100mA作用30sec(821±378pg/ml，为对照的29.8％，p＝0.46)，1mA作用30sec(767±144g/ml，为对照的27.8％，p＝0.03)。1mA作用30sec组对应于获准用于临床的刺激方案(REF)。 
以上结果表明生理、临床上良好耐受的电刺激参数可激活胆碱能 抗炎症通路。并且，施加超过生理剂量的电流或延长刺激时间对减少促炎性细胞因子的产生无任何额外的益处。 
实施例2电刺激迷走神经介导的TNF抑制的有效半衰期为2至3天。 
为确定刺激完成后迷走神经刺激产生的抗炎作用的持续时间，小鼠经电刺激30sec(1mA，0.5ms，30Hz)，并在给予LPS之前使其恢复一定时间。对照小鼠在0时间点进行假手术，并在与刺激组小鼠相同的时间进行LPS攻击。四个实验组的结果显示于图5中。VNS与随后给予脂多糖(LPS)之间间隔2小时导致TNF被抑制71％(对照＝1606±326pg/ml，与之相比VNS＝474±157pg/ml，p＝0.01)。VNS与给予LPS之间间隔1天导致TNF被抑制72％(对照＝2813±503pg/ml，与之相比VNS＝783±87pg/ml，p＝0.004)。VNS与给予LPS之间间隔2天导致TNF被抑制44％(对照＝1590±351pg/ml，与之相比VNS＝892±85pg/ml，p＝0.09)。最后，间隔3天未导致TNF抑制(对照＝1253±202pg/ml，与之相比VNS＝1393±263pg/ml，p＝0.7)。动物在给予LPS两小时后施以安乐死。 
以上结果显示胆碱能抗炎通路的作用持续时间非常长，在刺激后至少可持续2天。并且，在LPS攻击之前延迟2小时与延迟1天相比，其抗炎作用无显著差异。最后，结果表明在刺激三天后迷走神经刺激产生的抗炎作用即消失。 
实施例3电刺激迷走神经可改善胶原诱导关节炎大鼠模型的关节炎严重程度 
为确定迷走神经刺激是否可减轻胶原诱导关节炎大鼠模型中关节炎的严重程度，大鼠在胶原免疫后，通过植入的电极接受几天的反复迷走神经刺激，并对关节炎严重程度进行评分。 
纯化的大鼠II型胶原(CII)(Chondrex，Redmond，WA，USA)溶于0.01M醋酸。等体积的胶原溶液和不完全弗氏佐剂(IFA；DifcoLaboratories，Detroit，MI)在4℃乳化，使200μl乳液中含有150μg大 鼠CII( 
Figure G05848379220070817D000141
等人，Clinical&Experimental Immunology 1999115：32-41；Kokkola R等人，Arthritis Rheum.200348：2052-8.)。按每只大鼠200μl的体积在鼠尾皮内注射进行免疫。发展为慢性破坏性关节炎，开始发作的平均时间为免疫后14天。 
采用以前描述的关节炎临床评分系统(Kokkola R等人，ArthritisRheum 2003.48(7)：2052-2058)。该评分系统已经证明对于治疗性研究是可靠的和高度辨别性的( 
Figure G05848379220070817D000142
等人，Clin Exp Immunol 1999，115：32-41)。每天观察大鼠关节炎的临床指征，包括关节的红斑和肿胀。趾骨间关节、前爪的掌指关节及腕关节、后爪的跖趾关节及踝关节各自被看作为一类关节。每只爪按以下标准评为0-4分：0＝无累及，1＝累及1型关节，2＝累及2型关节，3＝累及3型关节，4＝累及3型关节并且有最严重的红斑和肿胀。计算每只大鼠的关节炎指数，表示为全部爪的累加得分，可能的最高分为16分。两位观察人员独立进行全部的关节炎评价。并且观察人员不知道动物的身份。 
电刺激迷走神经在胶原免疫后(PCID)第13天开始。VNS大鼠每天一次刺激10min(5V，1-2mA；0.5msec脉冲；30Hz；交替“开”30sec“关”300sec作用10min)，连续刺激20天(第16天跳过)。使用均来自Biopac Systems，Inc.的STMISOC刺激适配器、STM100C刺激模块和MP150数据采集系统产生刺激。在指明时，所有动物均采用异氟烷吸入气体(2-4％)麻醉。在手术过程中，通过面罩输送系统使动物置于维持麻醉剂量下。异氟烷麻醉起效后，将动物仰卧放置，在下颚与胸骨之间沿颈部腹侧中线切开2cm。切开皮下组织向侧面迁拉。钝性分离颚唾液腺并向侧面迁拉。在胸锁乳突肌与胸骨舌骨肌之间分离左迷走神经，并清除临近的颈动脉，用4-0号丝缝线控制。使用围绕迷走神经的多个360度环形包绕，将直径为0.003英寸的Teflon包被的银电极设置在迷走神经上。仅在线末端剥去Teflon以使对周围颈部肌肉的电刺激最小化。银线末端然后绕左颈在皮下穿行至背侧颈部中线。在此部位从皮肤中引出，并与穿过索装置的刺激电线相连。 
如图6所示，与对照组和假手术组动物相比，反复电刺激迷走神经可减轻关节炎的临床指征(根据关节红斑和肿胀确定)(被刺激的大鼠：N＝4；假手术：N＝5；对照：N＝3)。在第16天，接受迷走神经刺激的大鼠的关节炎评分显著低于对照和假手术组动物(p＜0.05)。在第19天，接受迷走神经刺激的大鼠的关节炎评分显著低于假手术组动物(p＜0.05)。以上结果表明反复刺激迷走神经可有效缓解胶原诱导的关节炎模型的关节炎严重程度。 
虽然参照优选实施方式具体列举并描述了本发明，但是本领域技术人员应了解，在不背离附加权利要求书包括的发明范围的情况下，可对其形式和细节进行各种改变。 

Claims (23)

1.一种用于治疗患有炎症性疾病或具有患炎症性疾病危险的受试者的电信号发生器，包括：
电极组件，用于传送电信号至受试者的迷走神经；和
控制器，通过将信号电压限定在0.01伏至1伏之间，限定脉冲宽度为0.1ms至5ms，限定信号频率为0.1Hz至30Hz，限定信号作用时间为1秒至120秒，限定信号间断时间为2小时以上，从而控制电信号。
2.根据权利要求1所述的信号发生器，其中信号电压限定为0.01伏至0.05伏。
3.根据权利要求1所述的信号发生器，所述控制器限定信号电压为0.01伏至0.05伏；脉冲宽度为0.1ms至0.5ms；信号频率为10Hz至30Hz；信号作用时间为20秒至40秒。
4.一种用于治疗患有炎症性疾病或具有患炎症性疾病危险的受试者的电信号发生器，包括：
电极组件，用于传送电信号至受试者的迷走神经；和
控制器，通过限定信号电流为1mA至5mA，脉冲宽度为0.1ms至5ms；信号频率为0.1Hz至30Hz；信号作用时间为1秒至120秒；信号间断时间为2小时以上，从而控制电信号。
5.根据权利要求4所述的信号发生器，所述控制器限定信号间断时间为2小时至24小时。
6.电信号发生器在构造医疗装置中的用途，该医疗装置用于治疗患有炎症性疾病或具有患炎症性疾病危险的受试者，包括：
电极组件，用于传送电信号至受试者的迷走神经；和
控制器，通过限定信号电流为1mA至5mA，脉冲宽度为0.1ms至5ms，限定信号频率为0.1Hz至30Hz，限定信号作用时间为1秒至120秒，限定信号间断时间为2小时以上，从而控制电信号，
条件是所述病症不是肠梗阻、哮喘或囊性纤维化。
7.根据权利要求6所述的信号发生器的用途，所述控制器限定信号电压为0.01伏至0.05伏。
8.根据权利要求6所述的信号发生器的用途，所述控制器限定脉冲宽度为0.1ms至5ms；信号频率为0.1Hz至30Hz；信号作用时间为1秒至120秒。
9.根据权利要求6所述的信号发生器的用途，所述控制器限定信号电压为0.01伏至0.05伏；脉冲宽度为0.1ms至0.5ms；信号频率为10Hz至30Hz；信号作用时间为20秒至40秒。
10.根据权利要求6所述的电信号发生器的用途，其中由炎性细胞因子级联介导的病症选自阑尾炎、消化性溃疡、胃溃疡、十二指肠溃疡、腹膜炎、胰腺炎、溃疡性结肠炎、假膜性结肠炎、急性结肠炎、缺血性结肠炎、憩室炎、会厌炎、失弛缓症、胆管炎、胆囊炎、肝炎、克罗恩病、肠炎、惠普尔病、变态反应、过敏性休克、免疫复合物病、器官缺血、再灌注损伤、器官坏死、花粉热、脓毒症、败血病、内毒素休克、恶病质、高烧、嗜酸性肉芽肿、肉芽肿、结节病、脓毒性流产、附睾炎、阴道炎、前列腺炎、尿道炎、支气管炎、肺气肿、鼻炎、肺炎、肺尘病、肺泡炎、细支气管炎、咽炎、胸膜炎、窦炎、流行性感冒、呼吸道合胞病毒感染、HIV感染、乙型肝炎病毒感染、丙型肝炎病毒感染、播散性菌血症、登革热、念珠菌病、疟疾、丝虫病、阿米巴病、水泡囊、烧伤、皮炎、皮肌炎、晒伤、荨麻疹、疣、水疱、血管炎、脉管炎、心内膜炎、动脉炎、动脉粥样硬化、血栓性静脉炎、心包炎、心肌炎、心肌缺血、结节性动脉周炎、风湿热、阿尔茨海默病、乳糜泄、充血性心力衰竭、成人呼吸窘迫综合症、脑膜炎、脑炎、多发性硬化症、脑梗死、脑栓塞、格林-巴利综合征、神经炎、神经痛、脊髓损伤、麻痹、葡萄膜炎、关节炎性皮疹、关节痛、骨髓炎、筋膜炎、佩吉特病、痛风、牙周病、类风湿性关节炎、滑膜炎、重症肌无力、甲状腺炎、系统性红斑狼疮、古德帕斯彻综合征、贝切特综合征、异体移植排斥、移植物抗宿主病、I型糖尿病、强直性脊柱炎、贝格尔病、莱特尔综合征和何杰金病。
11.根据权利要求6所述的电信号发生器的用途，其中受试者为人。
12.根据权利要求6所述的电信号发生器的用途，其中在外周远侧位置处刺激所述迷走神经活性。
13.根据权利要求6所述的电信号发生器的用途，其中在颈区刺激所述迷走神经活性。
14.根据权利要求6所述的电信号发生器的用途，其中刺激神经节或神经节后神经元。
15.根据权利要求6所述的电信号发生器的用途，其中在脑内刺激迷走神经。
16.根据权利要求6所述的电信号发生器的用途，其中刺激传出迷走神经。
17.根据权利要求6所述的电信号发生器的用途，其中刺激传入迷走神经。
18.根据权利要求6所述的电信号发生器在制造用于治疗受试者炎症性疾病的治疗性装置中的用途，其中该装置在操作中直接刺激迷走神经以治疗炎症性疾病。
19.根据权利要求6所述的电信号发生器在制造用于治疗受试者炎症性疾病的治疗性装置中的用途，其中单独地使用该装置刺激迷走神经以治疗炎症性疾病。
20.电信号发生器在构造医疗装置中的用途，该医疗装置用于治疗患有炎症性疾病或具有患炎症性疾病危险的受试者，包括：
控制器，通过限定信号电压为0.01伏至1伏，限定脉冲宽度为0.1ms至5ms；限定信号频率为0.1Hz至30Hz；限定信号作用时间为1秒至120秒；限定信号间断时间为2小时以上，从而控制电信号。
21.根据权利要求20所述的用途，所述控制器限定信号间断时间为2小时至24小时。
22.根据权利要求20所述的电信号发生器在制造用于治疗受试者炎症性疾病的治疗性装置中的用途，其中该装置在操作中直接刺激迷走神经以治疗炎症性疾病。
23.根据权利要求20所述的电信号发生器在制造用于治疗受试者炎症性疾病的治疗性装置中的用途，其中单独地使用该装置刺激迷走神经以治疗炎症性疾病。
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