CN103619405A - 用于治疗慢性炎症的胆碱能抗炎通路的单个脉冲激活 - Google Patents
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Abstract
本文描述了用于施加足以治疗慢性炎症的极低占空比刺激的方法和系统。尤其是，本文描述了足以导致对促炎细胞因子和/或慢性炎症的影响的持久（例如，＞4小时、大于12小时、大于24小时、大于48小时）抑制的电刺激的单个超阈值脉冲。这些方法和设备对治疗炎症性肠病（IBD）尤其感兴趣。
Description
相关申请的交叉引用
本申请要求于2011年5月9日提交的美国临时申请61/484,112的利益，在此通过引用将其整体结合。本专利申请可以涉及下列专利和待决的专利申请中的任一项：于2009年5月1日提交并且题为“VAGUS NERVE STIMULATION ELECTRODES AND METHODSOF USE”的美国申请12/434,462；2009年11月17日提交并且题为“DEVICES AND METHODS FOR OPTIMIZING ELECTRODEPLACEMENT FOR ANTI-INFLAMMATORY STIMULATION”的美国申请12/620,413；2010年9月1日提交并且题为“PRESCRIPTION PADFOR TREATMENT OF INFLAMMATORY DISORDERS”的美国申请12/874,171；2010年11月1日提交并且题为“MODULATION OF THECHOLINERGIC ANTI-INFLAMMATORY PATHWAY TO TREATPAIN OR ADDICTION”的美国申请12/917,197；2010年12月23日提交并且题为“NEURAL STIMULATION DEVICES AND SYSTEMSFOR TREATMENT OF CHRONIC INFLAMMATION”的美国申请12/978,250；以及2010年6月9日提交并且题为“NERVE CUFF WITHPOCKET FOR LEADLESS STIMULATOR”的美国申请12/797,452。
通过引用的结合
本说明书中提及的所有出版物和专利申请通过引用整体结合于此，其程度如同每个单独的出版物或专利申请被特别地和单独地指示为通过引用结合。
技术领域
本发明总体上涉及用于使用极低占空比刺激来治疗包括慢性炎症和炎症性疾病（disorder）在内的疾病的系统和设备。尤其是，本文描述了用于治疗诸如肠道炎症性疾病之类的疾病的系统、设备和方法。本文总体上还描述了适于通过用于调整炎症性反应的极低占空比刺激对迷走神经（vagus nerve）进行电刺激以（经由烟碱性胆碱能抗炎通路（nicotinic cholinergic anti-inflammatory pathway））治疗慢性炎症的方法以及包括可植入微刺激器在内的设备。
背景技术
在文献中已经描述了神经胆碱能抗炎通路（CAP或NCAP）的电刺激，其开始于Kevin Tracey的开创性工作（例如，见Tracey KJ的“Physiology and immunology of the cholinergic antiinflammatorypathway”，The Journal of clinical investigation2007:117(2):289–96），他首次确认了胆碱能抗炎通路并且描述了迷走神经刺激与通过抑制细胞因子的产生的炎症的抑制之间的联系，从那以后，研究继续进行以探索CAP的刺激与炎症性疾病的调整之间的关系。通常的刺激参数已经包括了通过一阵脉冲（例如，在10Hz到1GHz之间持续30秒钟到20分钟）的刺激，具有在较高频率处看的效果的略微提高（例如，见Huston等人的US2009/0143831）。
尽管该工作已经暗示慢性炎症可以通过可植入刺激器成功地治疗，但是这样的长期地可植入和可用的刺激器的设计和实施已经证明是难懂的，部分地是由于能够真正长期使用的设备将面对的功率要求。
已经针对各种病症和疾病的治疗开发了可植入电刺激设备。例如，可植入心脏复律除颤器（ICD）已经用于治疗各种心脏疾病。脊髓刺激器（SCS）或脊柱刺激器（DCS）已经用于治疗包括背部手术失败综合征、复合性局部疼痛综合征和周围神经病在内的慢性疼痛疾病。周围神经刺激（PNS）系统已经用于治疗慢性疼痛综合征以及其他疾病和疾病。功能电刺激（FES）系统已经被用于在脊髓受伤患者中将某一功能恢复到否则瘫痪的四肢。
最近，已经开发了可植入的迷走神经刺激，包括用于治疗炎症的迷走神经刺激器。这样的植入物通常需要电极和电源。尺寸和用途限制的参数可以通常是功率要求，其要么要求持久的（并且因此通常大的）电池，要么要求充电电路和充电设备所增加的复杂化。
例如，通常的可植入电刺激系统可以包括引线上的一个或多个可编程电极，该可编程电极连接到可植入脉冲发生器（IPG），该可植入脉冲发生器包含电源和刺激电路。甚至相对小的可植入神经刺激器技术（即，具有附接到刺激器的本体的整体电极的微刺激器）可能也有这些缺点中的一些缺点，因为当前开发的无引线设备往往比期望的更大和更重，使得难以稳定地将这些设备相对于神经定位在合适的位置。
本文描述了令人惊讶的结果，即炎症的持久的、稳健的抑制可以通过在施加到迷走神经的单个（或非常少的）超阈值的电脉冲来实现。考虑到尽管施加最小功率却获得格外稳健的效果，该发现尤其令人惊讶，特别是与以高得多的施加的能量显示效果的公布的数据相比。这些发现支持用于治疗慢性炎症的各种极低功率的设备、系统和方法。尤其是，描述了用于治疗包括肠道的炎症性疾病（例如，肠易激症或IBD）在内的炎症性疾病的设备和方法，包括微刺激器以及基于所确认的显著低的功率要求使用微刺激器的方法。
发明内容
本文描述了用于迷走神经的格外低占空比刺激的设备、系统和方法。格外低、极低、超级低或超低占空比一般指的是使用每个时间周期的少数电脉冲和低刺激强度两者来提供刺激以使得占空比的功率要求非常低的占空比。下面是格外低、极低、超级低或超低占空比的各种实施例的示例。在一些实施例中，每4到48小时（以4小时为增量），电脉冲的数目可以介于1和5之间（以1个脉冲为增量）。在一些实施例中，刺激强度可以处于能够通过迷走神经影响所期望的生理反应的超阈值水平。在一些实施例中，超阈值水平介于大约100μA和5000μA之间，或者介于大约100μA和4000μA之间，或者介于大约100μA和3000μA之间，或者介于大约100μA和2000μA之间。在一些实施例中，超阈值水平小于大约2000μA、3000μA、4000μA或5000μA。
在一些实施例中，占空比是每4小时1个超阈值脉冲，且脉冲振幅小于约2000μA。在一些实施例中，占空比是每4小时1个脉冲，且脉冲振幅小于约3000μA。在一些实施例中，占空比是每12小时1个脉冲，且脉冲振幅小于约2000μA。在一些实施例中，占空比是每12小时1个脉冲，且脉冲振幅小于约3000μA。在一些实施例中，占空比是每24小时1个脉冲，且脉冲振幅小于约2000μA。在一些实施例中，占空比是每24小时1个脉冲，且脉冲振幅小于约3000μA。在一些实施例中，占空比是每48小时1个脉冲，且脉冲振幅小于约2000μA。在一些实施例中，占空比是每48小时1个脉冲，且脉冲振幅小于约3000μA。
在一些实施例中，脉冲宽度可以介于大约100到1000μS之间，或者可以是大约或小于大约100、200、300、400、500、600、700、800、900或1000μS。在一些实施例中，频率可以是大约或小于大约10、20、30、40、50、60、70、80、90或100Hz。在一些实施例中，IPI可以是大约或小于大约100、200、300、400、500、600、700、800、900或1000μS。
在一些实施例中，提供用于治疗患者的慢性炎症和/或炎症性疾病的系统。该系统包括可植入微刺激器，被配置为向迷走神经施加低占空比刺激，其中低占空比刺激每4小时仅提供单个超阈值脉冲；以及控制器，被配置为设置用于微刺激器的剂量，其中该剂量包括被至少4小时的关断周期跟随的单个超阈值脉冲。在一些实施例中，关断周期是至少24小时，或者是至少48小时，或者介于大约4到48小时之间，或者介于大约12到48小时之间，或者介于大约24到48小时之间。在一些实施例中，单个超阈值脉冲具有小于5mA、小于3mA或者小于2mA的脉冲振幅。在一些实施例中，单个超阈值脉冲是双相的。在一些实施例中，慢性炎症是肠道炎症。在一些实施例中，慢性炎症是炎症性肠病。在一些实施例中，慢性炎症是克罗恩病（Crohn’sdisease）。
在一些实施例中，提供一种治疗患者的慢性炎症和/或炎症性疾病的方法。该方法包括：植入微刺激器；以及向迷走神经仅施加来自微刺激器的单个超阈值刺激脉冲，该单个超阈值刺激脉冲被至少4小时的关断时间跟随。在一些实施例中，关断时间是至少24小时，至少48小时，或者介于大约4到48小时之间，或者介于大约12到48小时之间，或者介于大约24到48小时之间。在一些实施例中，单个超阈值刺激脉冲具有小于5mA、小于3mA或者小于2mA的脉冲振幅。在一些实施例中，单个超阈值刺激脉冲是双相的。在一些实施例中，慢性炎症是肠道炎症。在一些实施例中，慢性炎症是炎症性肠病。在一些实施例中，慢性炎症是克罗恩病。
如本文所描述的可以被治疗的各种类型的炎症性疾病包括各种疾病状态，包括诸如枯草热、动脉粥样硬化、关节炎(类风湿、滑囊炎、痛风性关节炎、风湿性多肌痛等)、哮喘、自身免疫疾病、慢性炎症、慢性前列腺炎、肾小球肾炎、肾炎、炎症性肠病、盆腔炎性疾病、再灌注损伤、移植排斥、血管炎、心肌炎、结肠炎等疾病。
可以使用本发明治疗的炎症性疾病的非限制性示例包括：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、伪膜性肠炎、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、过敏、过敏性休克、免疫复合物病、器官缺血、再灌注损伤、器官坏死、枯草热、脓毒症、败血症、内毒素性休克、恶病质、高热、嗜酸性肉芽肿、肉芽肿病、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、火山矽肺病（pneumoultramicroscopic silicovolcanoconiosis）、牙槽炎（alvealitis）、支气管炎、咽炎、胸膜炎、鼻窦炎、流感、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、疱疹病毒感染播散菌血症、登革热、念珠菌病、疟疾、丝虫病、变形虫病、包虫囊肿、烧伤、皮炎、皮肌炎、晒伤、荨麻疹、疣、风团、血管炎（vasulitis）、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、阿尔茨海默氏病、腹部疾病、充血性心脏衰竭、成人呼吸窘迫综合征、脑膜炎、脑炎、多发性硬化、脑梗塞、脑栓塞、格林-巴利综合征、神经炎、神经痛、脊髓损伤、瘫痪、葡萄膜炎、关节炎、关节痛、骨髓炎、筋膜炎、佩吉特氏病、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、古德帕斯彻氏综合征、白塞氏综合征、同种异体移植物排斥、移植物抗宿主病、一型糖尿病、二型糖尿病、强直性脊柱炎、伯杰氏病、赖特综合征、何杰金氏病、肠梗阻、高血压、肠易激综合征、心肌梗死、失眠、焦虑以及支架血栓。
附图说明
本发明的新特征与随后的权利要求中的特殊性一起被提出。通过参考下面提出说明性实施例（其中利用了本发明的原理）的详细描述以及附图，将获得本发明的特征和优点的更好的理解，其中：
图1是单个刺激波形的图形；
图2是将来自单个刺激脉冲的对TNF水平的影响与来自多达3000个脉冲的影响进行比较的曲线图；
图3是图示刺激后24小时来自单个刺激脉冲的对TNF水平的影响的曲线图；
图4是图示刺激后3小时和24小时来自单个刺激脉冲的对TNF水平的影响的曲线图；
图5是图示来自单个刺激脉冲的对IBD的大鼠模型中的损伤区域的影响的曲线图；以及
图6是图示来自单个刺激脉冲的对IBD的大鼠模型中的损伤区域的长期影响的曲线图。
具体实施方式
一般而言，本文描述了阐述用于治疗疾病的迷走神经的格外低占空比刺激的系统、方法和设备。尤其是，本文描述了阐述用于在哺乳动物模型中减少或防止炎症和炎症的影响的迷走神经的格外低占空比刺激的系统、方法和设备。格外低、极低、超级低或超低占空比一般指的是使用每个时间周期的少数电脉冲和低刺激强度两者来提供刺激以使得占空比的功率要求非常低的占空比。本文所描述的方法应用可以被用来显著减少炎症和/或炎症的影响的各种刺激方案。可以变化的刺激参数包括脉冲形状（例如，正弦的、方的、双相的、单相的等）、刺激的持续时间、导通时间、关断时间、脉间间隔，等等。本文检查的一个关键因素是超阈值脉冲的数目。如本文所示，即使当与多个刺激比较时，使用甚至单个超阈值刺激的迷走神经的刺激导致显著的和持久的影响。该影响当使用针对IBD的啮齿动物模型进行检查时尤为深刻。
下面是格外低、极低、超级低或超低占空比的各种实施例的示例。在一些实施例中，每4到48小时（以4小时为增量），电脉冲的数目可以介于1和5之间（以1个脉冲为增量）。在一些实施例中，刺激强度可以处于能够通过迷走神经影响所期望的生理反应的超阈值水平。在一些实施例中，超阈值水平介于大约100μA和5000μA之间，或者介于大约100μA和4000μA之间，或者介于大约100μA和3000μA之间，或者介于大约100μA和2000μA之间。在一些实施例中，超阈值水平小于大约2000μA、3000μA、4000μA或5000μA。
在一些实施例中，占空比是每4小时1个超阈值脉冲，且脉冲振幅小于约2000μA。在一些实施例中，占空比是每4小时1个脉冲，且脉冲振幅小于约3000μA。在一些实施例中，占空比是每12小时1个脉冲，且脉冲振幅小于约2000μA。在一些实施例中，占空比是每12小时1个脉冲，且脉冲振幅小于约3000μA。在一些实施例中，占空比是每24小时1个脉冲，且脉冲振幅小于约2000μA。在一些实施例中，占空比是每24小时1个脉冲，且脉冲振幅小于约3000μA。在一些实施例中，占空比是每48小时1个脉冲，且脉冲振幅小于约2000μA。在一些实施例中，占空比是每48小时1个脉冲，且脉冲振幅小于约3000μA。
本文所描述的示例使用被开发以用于驱动迷走神经刺激的刺激器和刺激控制包。在一些示例中，该刺激由软件包控制，该软件包被配置为在微处理器（例如个人计算机）上运行并且控制仿真器/刺激器（其可以称为ITE或集成终端仿真器）的输出。因此，本文所描述的系统可以包括可以是用于控制刺激的施加的软件、固件和/或硬件的逻辑（例如控制逻辑）。例如，在一些变化形式中，控制刺激和数据采集的参数可以包括：（1）包括阴极和阳极的选择的刺激电极对；（2）以1Hz为增量的频率；（3）脉冲宽度（PW）：20-2,000μS（以1μS为增量）；（4）脉冲振幅（PA）：±0-5,000μA（以3μA为增量）；以及（5）波形的A相和B相之间的脉间间隔（IPI）：20-2,000μS（以1μS为增量）。
除了以上提供的示例性参数，在一些实施例中，PW可以介于大约100到1000μS之间，或者可以是大约或小于大约100、200、300、400、500、600、700、800、900或1000μS。在一些实施例中，频率可以是大约或小于大约10、20、30、40、50、60、70、80、90或100Hz。在一些实施例中，IPI可以是大约或小于大约100、200、300、400、500、600、700、800、900或1000μS。
例如，图1上所示的示例性波形是双相的（电荷平衡的）波形100，其包括通过脉间间隔104（IPI）被隔开的两个对称的脉冲宽度102（PW）。脉冲宽度102具有脉冲振幅106（PA），其对于双相刺激的第一相108（A相）和第二相110（B相）也是对称的，且A相中是负脉冲振幅，而B相中是正振幅。可以使用其它脉冲波形。在一些实施例中，脉冲波形可以是非双相的并且/或者可以具有非对称的脉冲宽度和/或非对称的脉冲振幅。
刺激器可以在一对电极上生成脉冲串。这些脉冲可以使用双极电流源来生成，并且可以在两个电极输出上使用＞1μF的陶瓷电容器来容性地隔离，恒流输出电压可以被设置为高达±18.8伏。
本文所描述的不同实验示例显示，迷走神经的合适的NCAP刺激可以用来限制或消除肠道炎症的影响，尤其在结肠炎的大鼠模型和克罗恩病的大鼠模型中。基于该数据，处于上述参数的双相刺激可以成功地治疗肠道炎症。
在一个示例中，小鼠（雄性，BALB/c）被麻醉，并且袖口电极（cuff electrode）（0.3mm ID，0.5mm电极间距离；微探针，Gaithersburg,MD）被置于左颈动脉鞘（包含颈迷走神经）周围且通过缝合来固定。超阈值脉冲（750μA，200μS，10Hz）以各种数目（0，1，10，100，300，600，3000）施加。后来，电极被移除并且关闭钉上的（stapled）伤口。小鼠恢复持续3小时，并且然后使用LPS（5mg/kg；IP）来进行挑战；这些小鼠在LPS之后90分钟牺牲，并且血清TNF通过ELISA测得，以测量对炎症性细胞因子的影响。如图2上所示，甚至单个超阈值刺激导致在治疗之后3小时TNF的显著抑制。因此，影响是持久的，并且来自单个脉冲的3小时处的影响与由多达3000个脉冲产生的影响相当。
进行第二类似实验，以检查单个超阈值脉冲对胆碱能抗炎通路（CAP）的持久影响。小鼠（雄性，BALB/c）被麻醉，并且袖口电极（0.3mm ID，0.5mm电极间距离；微探针，Gaithersburg,MD）被置于左颈动脉鞘（包含颈迷走神经）周围且通过缝合来固定。超阈值脉冲（750μA，200μS，10Hz）以各种数目（0，1，600）施加。后来，电极被移除并且关闭钉上的伤口。小鼠恢复持续24小时，并且然后使用LPS（5mg/kg；IP）来进行挑战；这些小鼠在LPS之后90分钟牺牲，并且血清TNF通过ELISA测得，以测量对炎症性细胞因子的影响。如图3上所示，单个超阈值刺激导致在治疗之后24小时处TNF的显著抑制，其与由600个脉冲产生的影响相当。
图4将以上所描述的两个实验的结果的选择的部分组合，以显示NCAP的单个脉冲刺激以与600个脉冲相同的效力影响刺激后3小时和24小时的可由LPS诱导的TNF的抑制。
在另一示例中，进行实验以确定在针对IBD/克罗恩病的大鼠模型中的损伤区域的单个脉冲抑制的效力。大鼠被麻醉，并且被给予对左颈迷走神经的虚假刺激或者单个超阈值刺激（在750μA、200μS的脉冲宽度、10Hz处的1个脉冲）。IBD通过吲哚美辛（5%碳酸氢钠中的10mg/kg（5mg/mL））的SC注射在刺激后30分钟被诱导。通过使用异氟烷麻醉大鼠并且使用依文思蓝（1%的0.3ml）的四尾部注射来在吲哚美辛注射之后23.5小时完全玷污损伤。大鼠在疾病诱导后24小时经由CO2窒息而牺牲，并且整夜在2%的福尔马林中收割、清洗和固定小肠。对已固定的肠道进行拍照并对照片进行数字化，并且损伤通过盲打分器（blinded scorer）来量化。如图5中图示的，单个超阈值刺激（750μA、200μS的脉冲宽度、10Hz）导致损伤的深刻减少。
考虑到图6中所示的数据，这些结果甚至更为重要，图6图示了在克罗恩病的大鼠模型中迷走神经刺激的“存储器效应”。大鼠被麻醉，并且被给予对左颈迷走神经（1mA、200μS的脉冲宽度、10Hz、60s）的虚假刺激或实际刺激。IBD/克罗恩病通过吲哚美辛（5%碳酸氢钠中的10mg/kg（5mg/mL））的SC注射在刺激之后不同的时间点（见图6）被诱导。通过使用异氟烷麻醉大鼠并且使用依文思蓝（1%的0.3ml）的四尾部注射来在疾病诱导之后23.5小时完全玷污损伤。大鼠在疾病诱导后24小时经由CO2窒息而牺牲，并且整夜在2%的福尔马林中收割、清洗和固定小肠。对已固定的肠道进行拍照并对照片进行数字化，并且损伤通过盲打分器来量化。在该示例中，迷走神经刺激的短暂时期可以导致在减少另外由吲哚美辛的应用所诱导的肠道损伤方面惊人地持久的影响（例如高达48小时）。该数据强烈建议可以极不频繁地提供刺激，具有长的（例如＞48小时）、没有所施加的刺激的“寂静”周期。用于治疗IBD的这样的极低占空比刺激可以在可植入系统中尤其有帮助，允许极长的电池寿命，同时具有出乎意料地稳健的疗效。
尽管以上提供的示例描述了用于在大鼠模型中治疗炎症性疾病的方法、系统和设备，但是本文所描述的所有方法、系统和设备可以用于和/或适用于在其他哺乳动物（例如人类）中使用。例如，一种用于使用单个超阈值脉冲和/或格外低占空比刺激方案治疗人类的炎症性疾病的系统和方法可以包括电极（诸如袖口电极），该电极被配置为围绕迷走神经植入并且将电刺激传递到患者的迷走神经。该系统可以进一步包括处理器、用于存储指令的存储器、和/或控制器，该控制器可以包括编程以将包括单个超阈值脉冲方案在内的低占空比刺激方案经由袖口电极传递到迷走神经。可以提供电池来为系统提供功率，并且因为低占空比刺激方案消耗很少的能量，所以电池寿命可以大大延长，允许在电池需要更换或再充电之前系统被完整地植入患者体内很长一段时间。对于植入系统，这提供大的益处，因为其可以减少外科手术的频率，该外科手术可以被要求更换电池。
在该系统中使用的刺激参数可以与以上公开的参数相同或相似。例如，脉冲振幅可以小于大约5、4、3或2mA。另外，低占空比刺激方案可以在介于大约4到48小时之间或者至少4、12、24或48小时的关断时间之间传递单个超阈值脉冲。在一些实施例中，脉冲宽度可以介于大约100到1000μS之间，或者可以是大约或小于大约100、200、300、400、500、600、700、800、900或1000μS。在一些实施例中，频率可以是大约或小于大约10、20、30、40、50、60、70、80、90或100Hz。在一些实施例中，IPI可以是大约或小于大约100、200、300、400、500、600、700、800、900或1000μS。
一般而言，这些结果暗示，迷走神经的甚至单个短暂超阈值刺激的应用可以可能通过抑制炎症性细胞因子（诸如TNF）而导致炎症影响的大量减少。这些结果既令人惊讶（考虑到刺激持续长得多的时间的现有技术趋势），又对于设计今后的设备和方法是重要的。尤其是，迷走神经（或炎症性反应的其他部分）的刺激可以被配置为施加极低占空比刺激。如简要地提到的，这将考虑到更小、更轻和更有效率的可植入刺激系统。
如本文所描述的可以被治疗的各种类型的炎症性疾病包括各种疾病状态，包括诸如枯草热、动脉粥样硬化、关节炎(类风湿、滑囊炎、痛风性关节炎、风湿性多肌痛等)、哮喘、自身免疫疾病、慢性炎症、慢性前列腺炎、肾小球肾炎、肾炎、炎症性肠病、盆腔炎性疾病、再灌注损伤、移植排斥、血管炎、心肌炎、结肠炎等疾病。
可以使用本发明治疗的炎症性疾病的非限制性示例包括：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、伪膜性肠炎、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、过敏、过敏性休克、免疫复合物病、器官缺血、再灌注损伤、器官坏死、枯草热、脓毒症、败血症、内毒素性休克、恶病质、高热、嗜酸性肉芽肿、肉芽肿病、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、火山矽肺病、牙槽炎、支气管炎、咽炎、胸膜炎、鼻窦炎、流感、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、疱疹病毒感染播散菌血症、登革热、念珠菌病、疟疾、丝虫病、变形虫病、包虫囊肿、烧伤、皮炎、皮肌炎、晒伤、荨麻疹、疣、风团、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、阿尔茨海默氏病、腹部疾病、充血性心脏衰竭、成人呼吸窘迫综合征、脑膜炎、脑炎、多发性硬化、脑梗塞、脑栓塞、格林-巴利综合征、神经炎、神经痛、脊髓损伤、瘫痪、葡萄膜炎、关节炎、关节痛、骨髓炎、筋膜炎、佩吉特氏病、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、古德帕斯彻氏综合征、白塞氏综合征、同种异体移植物排斥、移植物抗宿主病、一型糖尿病、二型糖尿病、强直性脊柱炎、伯杰氏病、赖特综合征、何杰金氏病、肠梗阻、高血压、肠易激综合征、心肌梗死、失眠、焦虑以及支架血栓。
这些疾病中的任何一种疾病（例如炎症性疾病）可以例如通过在迷走神经周围植入袖口电极并且使用如本文所述的用于治疗的格外低占空比刺激方案来治疗。用于存储指令和/或编程的处理器以及存储器可以用来控制刺激方案。在该系统和方法中使用的刺激参数可以与以上公开的参数相同或相似。例如，单个超阈值脉冲的脉冲振幅可以小于大约5、4、3或2mA。另外，低占空比刺激方案可以在介于大约4到48小时之间或者至少4、12、24或48小时的关断时间之间传递单个超阈值脉冲。这些方法中的任何一种方法可以包括确定治疗功效的步骤。例如，这些方法中的任何一种方法可以包括在治疗前和/或期间监视患者的步骤。例如，在治疗炎症性疾病中，可以监视用于炎症的生物标志物，例如细胞因子或其他标志物。在一些变化形式中，监视患者可以包括可视化地评估患者（例如，针对肿胀、体温等）。在一些变化形式中，本文所描述的系统可以包括用于监视患者和/或使用该系统的治疗效果的传感器和/或数据处理子系统。
尽管以上示例和描述主要集中在炎症性疾病上，但是在某一实施例中，本文所描述的系统、设备和方法可以用于治疗非炎症性病症或疾病。例如，本文所描述的系统、设备和方法可以用来通过迷走神经的格外低占空比刺激激活、调节和/或调整去乙酰化酶（sirtuin）的水平。通过迷走神经刺激的去乙酰化酶的调整还在2011年12月27日提交并且题为“MODULATION OF SIRTUINS BY VAGUS NERVESTIMULATION”的美国申请13/338,185中进行了讨论，该申请出于所有目的通过引用全文结合于此。如上，袖口电极可以围绕迷走神经植入，并且用于存储指令和/或编程的处理器和存储器可以用来控制刺激方案。在该系统和方法中使用的刺激参数可以与以上公开的参数相同或相似。例如，单个超阈值脉冲的脉冲振幅可以小于大约5、4、3或2mA。另外，低占空比刺激方案可以在介于大约4到48小时之间或者至少4、12、24或48小时的关断时间之间传递单个超阈值脉冲。在一些实施例中，脉冲宽度可以介于大约100到1000μS之间，或者可以是大约或小于大约100、200、300、400、500、600、700、800、900或1000μS。在一些实施例中，频率可以是大约或小于大约10、20、30、40、50、60、70、80、90或100Hz。在一些实施例中，IPI可以是大约或小于大约100、200、300、400、500、600、700、800、900或1000μS。
如上所述，在一些实施例中，系统、设备和/或方法包括监测刺激对正在治疗的疾病的影响。例如，炎症指示器或疾病指示器或其他指示器可以被监测以评价治疗方案的功效，允许基于该评价调节刺激方案。可以基于该评价调整本文所述参数中的任何一个参数。例如，可以增加或减少脉冲振幅和/或关断时间以优化疗效。可以被监测的指示器的示例包括TNF水平、损伤尺寸、炎症的程度或水平，细胞因子水平、疼痛水平、去乙酰化酶水平，等等。
本文公开的设备和方法的变化和修改对于本领域技术人员而言将很容易是显而易见的。同样地，应当理解的是，前述详细描述和附图是出于清晰和理解的目的而做出，并且并非旨在限制本发明的范围，本发明的范围由附于其的权利要求来限定。在本文所述任何一个实施例中所描述的任何特征可以与其它实施例中的任何实施例的任何其他特征组合而不论是否是优选的。
理解的是，本文所述示例和实施例仅仅是出于说明的目的，并且根据其的各种修改或改变将被建议给本领域技术人员，并且将被包括在本申请的精神和权限以及所附权利要求的范围以内。本文所引用的所有出版物、专利和专利申请出于所有目的通过引用被结合于此。
Claims (20)
1.一种用于治疗患者的慢性炎症的系统，所述系统包括：
可植入微刺激器，被配置为向迷走神经施加低占空比刺激，其中所述低占空比刺激每4小时仅提供单个超阈值脉冲；以及
控制器，被配置为设置用于所述微刺激器的剂量，其中所述剂量包括被至少4小时的关断周期跟随的所述单个超阈值脉冲。
2.根据权利要求1所述的系统，其中所述关断周期是至少24小时。
3.根据权利要求1所述的系统，其中所述关断周期是至少48小时。
4.根据权利要求1所述的系统，其中所述单个超阈值脉冲具有小于5mA的脉冲振幅。
5.根据权利要求1所述的系统，其中所述单个超阈值脉冲具有小于3mA的脉冲振幅。
6.根据权利要求1所述的系统，其中所述单个超阈值脉冲具有小于2mA的脉冲振幅。
7.根据权利要求1所述的系统，其中所述单个超阈值脉冲是双相的。
8.根据权利要求1所述的系统，其中所述慢性炎症是肠道炎症。
9.根据权利要求1所述的系统，其中所述慢性炎症是炎症性肠病。
10.根据权利要求1所述的系统，其中所述慢性炎症是克罗恩病。
11.一种治疗患者的慢性炎症的方法，所述方法包括：
植入微刺激器；以及
向迷走神经仅施加来自所述微刺激器的单个超阈值刺激脉冲，所述单个超阈值刺激脉冲被至少4小时的关断时间跟随。
12.根据权利要求11所述的方法，其中所述关断时间是至少24小时。
13.根据权利要求11所述的方法，其中所述关断时间是至少48小时。
14.根据权利要求11所述的方法，其中所述单个超阈值刺激脉冲具有小于5mA的脉冲振幅。
15.根据权利要求11所述的方法，其中所述单个超阈值刺激脉冲具有小于3mA的脉冲振幅。
16.根据权利要求11所述的方法，其中所述单个超阈值刺激脉冲具有小于2mA的脉冲振幅。
17.根据权利要求11所述的方法，其中所述单个超阈值刺激脉冲是双相的。
18.根据权利要求11所述的方法，其中所述慢性炎症是肠道炎症。
19.根据权利要求11所述的方法，其中所述慢性炎症是炎症性肠病。
20.根据权利要求11所述的方法，其中所述慢性炎症是克罗恩病。
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| CN109069824A (zh) * | 2016-02-02 | 2018-12-21 | 阿莱瓦神经治疗股份有限公司 | 使用深部脑刺激治疗自身免疫疾病 |
| US11266830B2 (en) | 2018-03-02 | 2022-03-08 | Aleva Neurotherapeutics | Neurostimulation device |
| US11738192B2 (en) | 2018-03-02 | 2023-08-29 | Aleva Neurotherapeutics | Neurostimulation device |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2707094A2 (en) | 2014-03-19 |
| EP2707094B1 (en) | 2016-02-03 |
| US20120290035A1 (en) | 2012-11-15 |
| US8788034B2 (en) | 2014-07-22 |
| WO2012154865A3 (en) | 2013-01-31 |
| WO2012154865A2 (en) | 2012-11-15 |
| CN103619405B (zh) | 2015-11-25 |
| EP2707094A4 (en) | 2014-11-26 |
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