US20090248097A1 - Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation - Google Patents

Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation Download PDF

Info

Publication number
US20090248097A1
US20090248097A1 US12109334 US10933408A US2009248097A1 US 20090248097 A1 US20090248097 A1 US 20090248097A1 US 12109334 US12109334 US 12109334 US 10933408 A US10933408 A US 10933408A US 2009248097 A1 US2009248097 A1 US 2009248097A1
Authority
US
Grant status
Application
Patent type
Prior art keywords
nerve
ganglion
method
nerves
vagus
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12109334
Inventor
Kevin J. Tracey
Jared M. Huston
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
North Shore-Long Island Jewish Research Institute
Original Assignee
North Shore-Long Island Jewish Research Institute
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36128Control systems
    • A61N1/36146Control systems specified by the stimulation parameters
    • A61N1/36167Timing, e.g. stimulation onset
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36053Implantable neurostimulators for stimulating central or peripheral nerve system adapted for vagal stimulation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y02A50/38Medical treatment of vector-borne diseases characterised by the agent
    • Y02A50/381Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a virus
    • Y02A50/384Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a virus of the genus Flavivirus
    • Y02A50/385Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a virus of the genus Flavivirus the disease being Dengue
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y02A50/38Medical treatment of vector-borne diseases characterised by the agent
    • Y02A50/408Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a protozoa
    • Y02A50/411Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a protozoa of the genus Plasmodium, i.e. Malaria

Abstract

A method of inhibiting the release of a proinflammatory cytokine in a cell is disclosed. The method comprises treating the cell with a cholinergic agonist. The method is useful in patients at risk for, or suffering from, a condition mediated by an inflammatory cytokine cascade, for example endotoxic shock. The cholinergic agonist treatment can be effected by stimulation of an efferent vagus nerve fiber, or the entire vagus nerve.

Description

    RELATED APPLICATIONS
  • [0001]
    This application is a continuation of U.S. Ser. No. 10/990,938, filed Nov. 17, 2004, which is a continuation-in-part of U.S. Ser. No. 10/466,625 filed May 28, 2003, now U.S. Pat. No. 6,838,471; which is a continuation of U.S. Ser. No. 09/855,446, filed May 15, 2001, now U.S. Pat. No. 6,610,713; which claims priority to Provisional Application No. 60/206,364 filed May 23, 2000, the disclosures of which are incorporated herein by reference into the present application.
  • BACKGROUND OF THE INVENTION
  • [0002]
    1. Field of the Invention
  • [0003]
    The present invention generally relates to methods of reducing inflammation. More specifically, the invention relates to methods for reducing inflammation caused by proinflammatory cytokines or an inflammatory cytokine cascade.
  • [0004]
    2. Description of the Related Art
  • [0005]
    Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. However, in many disease conditions, this internal homeostasis becomes out of balance. For example, endotoxin (lipopolysaccharide, LPS) produced by all Gram-negative bacteria activates macrophages to release cytokines that are potentially lethal (44; 10; 47; 31).
  • [0006]
    Inflammation and other deleterious conditions (such as septic shock caused by endotoxin exposure) are often induced by proinflammatory cytokines, such as tumor necrosis factor (TNF; also known as TNF.alpha. or cachectin), interleukin (IL)-1.alpha., IL-1.beta., IL-6, IL-8, IL-18, interferony, platelet-activating factor (PAF), macrophage migration inhibitory factor (MIF), and other compounds (42). Certain other compounds, for example high mobility group protein 1 (HGM-1), are induced during various conditions such as sepsis and can also serve as proinflammatory cytokines (57). These proinflammatory cytokines are produced by several different cell types, most importantly immune cells (for example monocytes, macrophages and neutrophils), but also non-immune cells such as fibroblasts, osteoblasts, smooth muscle cells, epithelial cells, and neurons (56). Proinflammatory cytokines contribute to various disorders, notably sepsis, through their release during an inflammatory cytokine cascade.
  • [0007]
    Inflammatory cytokine cascades contribute to deleterious characteristics, including inflammation and apoptosis (32), of numerous disorders. Included are disorders characterized by both localized and systemic reactions, including, without limitation, diseases involving the gastrointestinal tract and associated tissues (such as appendicitis, peptic, gastric and duodenal ulcers, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute and ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, coeliac disease, cholecystitis, hepatitis, Crohn's disease, enteritis, and Whipple's disease); systemic or local inflammatory diseases and conditions (such as asthma, allergy, anaphylactic shock, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, and sarcoidosis); diseases involving the urogential system and associated tissues (such as septic abortion, epididymitis, vaginitis, prostatitis and urethritis); diseases involving the respiratory system and associated tissues (such as bronchitis, emphysema, rhinitis, cystic fibrosis, adult respiratory distress syndrome, pneumonitis, pneumoultramicroscopicsilicovolcanoconiosis, alvealitis, bronchiolitis, pharyngitis, pleurisy, and sinusitis); diseases arising from infection by various viruses (such as influenza, respiratory syncytial virus, HIV, hepatitis B virus, hepatitis C virus and herpes), bacteria (such as disseminated bacteremia, Dengue fever), fungi (such as candidiasis) and protozoal and multicellular parasites (such as malaria, filariasis, amebiasis, and hydatid cysts); dermatological diseases and conditions of the skin (such as burns, dermatitis, dermatomyositis, sunburn, urticaria warts, and wheals); diseases involving the cardiovascular system and associated tissues (such as vasulitis, angiitis, endocarditis, arteritis, atherosclerosis, thrombophlebitis, pericarditis, myocarditis, myocardial ischemia, congestive heart failure, periarteritis nodosa, and rheumatic fever); diseases involving the central or peripheral nervous system and associated tissues (such as Alzheimer's disease, meningitis, encephalitis, multiple sclerosis, cerebral infarction, cerebral embolism, Guillame-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis, and uveitis); diseases of the bones, joints, muscles and connective tissues (such as the various arthritides and arthralgias, osteomyelitis, fasciitis, Paget's disease, gout, periodontal disease, rheumatoid arthritis, and synovitis); other autoimmune and inflammatory disorders (such as myasthenia gravis, thryoiditis, systemic lupus erythematosus, Goodpasture's syndrome, Behcets's syndrome, allograft rejection, graft-versus-host disease, Type I diabetes, ankylosing spondylitis, Berger's disease, Type I diabetes, ankylosing spondylitis, Berger's disease, and Retier's syndrome); as well as various cancers, tumors and proliferative disorders (such as Hodgkins disease); and, in any case the inflammatory or immune host response to any primary disease (13; 55; 30; 20; 33; 25; 18; 27; 48; 24; 7; 9; 4; 3; 12; 8; 19; 15; 23; 22; 49; 34).
  • [0008]
    Mammals respond to inflammation caused by inflammatory cytokine cascades in part though central nervous system regulation. This response has been characterized in detail with respect to systemic humoral response mechanisms during inflammatory responses to endotoxin (2; 54; 21; 28). In one set of responses, afferent vagus nerve fibers are activated by endotoxin or cytokines, stimulating the release of humoral anti-inflammatory responses through glucocorticoid hormone release (51; 41; 39). Previous work elucidated a role for vagus nerve signaling as a critical component in the afferent loop that modulates the adrenocorticotropin and fever responses to systemic endotoxemia and cytokinemia (14; 11; 52; 35). However, comparatively little is known about the role of efferent neural pathways that can modulate inflammation.
  • [0009]
    Efferent vagus nerve signaling has been implicated in facilitating lymphocyte release from thymus via a nicotinic acetylcholine receptor response (1). Clinical studies have also indicated that nicotine administration can be effective for treating some cases of inflammatory bowel disease (17; 36), and that proinflammatory cytokine levels are significantly decreased in the colonic mucosa of smokers with inflammatory bowel disease (40). However, none of these findings would suggest that cholinergic agonists can inhibit an inflammatory cytokine cascade, particularly those mediated by macrophages. Also, there is no suggestion in the literature that efferent vagus nerve stimulation is effective in inhibiting these cascades.
  • SUMMARY OF THE INVENTION
  • [0010]
    Accordingly, the inventor has succeeded in discovering that cholinergic agonists can inhibit the release of proinflammatory cytokines from a mammalian cell, either in vitro or in vivo. This inhibitory effect is useful for inhibiting inflammatory cytokine cascades that mediate many disease conditions. Furthermore, cholinergic agonist treatment in vivo can be effected to inhibit either local or systemic inflammatory cytokine cascades by stimulating efferent vagus nerves.
  • [0011]
    Thus, one embodiment of the present invention is directed to a method of inhibiting the release of a proinflammatory cytokine from a mammalian cell. The method comprises treating the cell with a cholinergic agonist in an amount sufficient to decrease the amount of the proinflammatory cytokine that is released from the cell. In preferred embodiments, the cell is a macrophage. Preferably, the proinflammatory cytokine is tumor necrosis factor (TNF), interleukin (L)-1.beta., IL-6, IL-18 or HMG-1, most preferably TNF. In preferred embodiments, the cholinergic agonist is acetylcholine, nicotine, muscarine, carbachol, galantamine, arecoline, cevimeline, or levamisole. In other preferred embodiments, the cell is in a patient suffering from, or at risk for, a condition mediated by an inflammatory cytokine cascade, preferably appendicitis, peptic, gastric or duodenal ulcers, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute or ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, Crohn's disease, enteritis, Whipple's disease, asthma, allergy, anaphylactic shock, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, cystic fibrosis, pneumonitis, pneumoultramicroscopicsilicovolcanoconiosis, alvealitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus infection, herpes infection, HIV infection, hepatitis B virus infection, hepatitis C virus infection, disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns, dermatitis, dermatomyositis, sunburn, urticaria, warts, wheals, vasulitis, angiitis, endocarditis, arteritis, atherosclerosis, thrombophlebitis, pericarditis, myocarditis, myocardial ischemia, periarteritis nodosa, rheumatic fever, coeliac disease, congestive heart failure, adult respiratory distress syndrome, Alzheimer's disease, meningitis, encephalitis, multiple sclerosis, cerebral infarction, cerebral embolism, Guillame-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritides, arthralgias, osteomyelitis, fasciitis, Paget's disease, gout, periodontal disease, rheumatoid arthritis, synovitis, myasthenia gravis, thryoiditis, systemic lupus erythematosus, Goodpasture's syndrome, Behcets's syndrome, allograft rejection, graft-versus-host disease, Type I diabetes, ankylosing spondylitis, Berger's disease, Type I diabetes, ankylosing spondylitis, Berger's disease, Retier's syndrome, or Hodgkins disease. In more preferred embodiments, the condition is appendicitis, peptic, gastric or duodenal ulcers, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute or ischemic colitis, hepatitis, Crohn's disease, asthma, allergy, anaphylactic shock, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, septic abortion, disseminated bacteremia, burns, Alzheimer's disease, coeliac disease, congestive heart failure, adult respiratory distress syndrome, cerebral infarction, cerebral embolism, spinal cord injury, paralysis, allograft rejection or graft-versus-host disease. In the most preferred embodiments, the condition is endotoxic shock. In some embodiments, the cholinergic agonist treatment is effected by stimulating efferent vagus nerve activity sufficient to inhibit the inflammatory cytokine cascade. Preferably, the efferent vagus nerve activity is stimulated electrically. The efferent vagus nerve can be stimulated without stimulating the afferent vagus nerve. Vagus nerve ganglions or postganglionic neurons can also be stimulated. Additionally, peripheral tissues or organs that are served by the vagus nerve can also be stimulated directly.
  • [0012]
    The present invention is also directed to a method of inhibiting an inflammatory cytokine cascade in a patient. The method comprises treating the patient with a cholinergic agonist in an amount sufficient to inhibit the inflammatory cytokine cascade, wherein the patient is suffering from, or at risk for, a condition mediated by the inflammatory cytokine cascade. The cholinergic agonist is preferably acetylcholine, nicotine, muscarine, carbachol, galantamine, arecoline, cevimeline, or levamisole, and the condition is preferably appendicitis, peptic, gastric or duodenal ulcers, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute or ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, Crohn's disease, enteritis, Whipple's disease, asthma, allergy, anaphylactic shock, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, cystic fibrosis, pneumonitis, pneumoultramicroscopicsilicovolcanoconiosis-, alvealitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus infection, herpes infection, HIV infection, hepatitis B virus infection, hepatitis C virus infection, disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns, dermatitis, dermatomyositis, sunburn, urticaria, warts, wheals, vasulitis, angiitis, endocarditis, arteritis, atherosclerosis, thrombophlebitis, pericarditis, myocarditis, myocardial ischemia, periarteritis nodosa, rheumatic fever, Alzheimer's disease, coeliac disease, congestive heart failure, adult respiratory distress syndrome, meningitis, encephalitis, multiple sclerosis, cerebral infarction, cerebral embolism, Guillame-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritides, arthralgias, osteomyelitis, fasciitis, Paget's disease, gout, periodontal disease, rheumatoid arthritis, synovitis, myasthenia gravis, thryoiditis, systemic lupus erythematosus, Goodpasture's syndrome, Behcets's syndrome, allograft rejection, graft-versus-host disease, Type I diabetes, ankylosing spondylitis, Berger's disease, Type I diabetes, ankylosing spondylitis, Berger's disease, Retier's syndrome, or Hodgkins disease. In more preferred embodiments, the condition is appendicitis, peptic, gastric or duodenal ulcers, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute or ischemic colitis, hepatitis, Crohn's disease, asthma, allergy, anaphylactic shock, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, septic abortion, disseminated bacteremia, burns, Alzheimer's disease, coeliac disease, congestive heart failure, adult respiratory distress syndrome, cerebral infarction, cerebral embolism, spinal cord injury, paralysis, allograft rejection or graft-versus-host disease. In the most preferred embodiments, the condition is endotoxic shock. The cholinergic agonist treatment can be effected by stimulating efferent vagus nerve activity, preferably electrically.
  • [0013]
    In additional embodiments, the present invention is directed to a method for treating a patient suffering from, or at risk for, a condition mediated by an inflammatory cytokine cascade. The method comprises stimulating efferent vagus nerve activity of the patient sufficient to inhibit the inflammatory cytokine cascade. Preferred methods of stimulation and preferred conditions are as with the previously described methods.
  • [0014]
    In still other embodiments, the present invention is directed to a method for attenuation of a systemic inflammatory response to endotoxin in a patient. The method comprises stimulating efferent vagus nerve activity of the patient sufficient to inhibit an inflammatory cytokine cascade.
  • [0015]
    The present invention is additionally directed to a method for determining whether a compound is a cholinergic agonist. The method comprises determining whether the compound inhibits the release of a proinflammatory cytokine from a mammalian cell. In preferred embodiments the cell is a macrophage and the proinflammatory cytokine is TNF.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • [0016]
    FIG. 1 is a graph summarizing experimental results showing that cholinergic agonists inhibit release of TNF from human macrophage cultures in a dose-dependent manner. Acetylcholine (ACh), muscarine, or nicotine was added to human macrophage cultures at the concentrations indicated, followed by LPS addition for 4 hours. TNF concentration was then determined.
  • [0017]
    FIG. 2 shows autoradiographs of TNF or GADPH mRNA from LPS-stimulated human macrophages treated with acetylcholine (ACh), nicotine (Nic) or muscarine (Mus), or no cholinergic agonist, which demonstrate that cholinergic agonists do not reduce LPS-stimulated TNF mRNA levels in macrophages.
  • [0018]
    FIG. 3 shows micrographs of human macrophages stained with TNF antibodies demonstrating the effect of LPS and/or acetylcholine (ACh) treatment on TNF presence in the cells.
  • [0019]
    FIG. 4 is a graph summarizing experimental results showing that .alpha.-conotoxin (.alpha.-CTX), but not atropine (ATR), reverses the inhibitory effect of acetylcholine (ACh)-mediated inhibition of TNF in human macrophages.
  • [0020]
    FIG. 5 is a graph summarizing experimental results showing that acetylcholine inhibits IL-1.beta. release from human macrophages in a dose-dependent manner.
  • [0021]
    FIG. 6 is a graph summarizing experimental results showing that acetylcholine inhibits IL-6 release from human macrophages in a dose-dependent manner.
  • [0022]
    FIG. 7 is a graph summarizing experimental results showing that acetylcholine inhibits IL-18 release from human macrophages in a dose-dependent manner.
  • [0023]
    FIG. 8 is a graph summarizing experimental results showing that acetylcholine does not inhibit IL-10 release from human macrophages.
  • [0024]
    FIG. 9 is a graph summarizing experimental results showing that vagus nerve stimulation (STIM) after vagotomy (VGX) causes a decrease in circulating levels of TNF during endotoxemia induced by LPS.
  • [0025]
    FIG. 10 is a graph summarizing experimental results showing that vagus nerve stimulation (STIM) after vagotomy (VGX) causes a decrease in levels of TNF in the liver during endotoxemia induced by LPS.
  • [0026]
    FIG. 11 is a graph summarizing experimental results showing that vagus nerve stimulation (STIM) after vagotomy (VGX) attenuates the development of hypotension (shock), as measured by mean arterial blood pressure (MABP), in rats exposed to lethal doses of endotoxin.
  • [0027]
    FIG. 12 is a graph summarizing experimental results showing that intact vagus nerve stimulation at 1V and 5V attenuates the development of shock in rats exposed to lethal doses of endotoxin.
  • [0028]
    FIG. 13 is a graph summarizing experimental results showing that intact vagus nerve stimulation at 1V and 5V causes an increase in heart rate in rats exposed to lethal doses of endotoxin.
  • [0029]
    FIG. 14 is a graph summarizing experimental results showing that intact left vagus nerve stimulation at 1V stabilized blood pressure more effectively than intact right vagus nerve stimulation, in rats exposed to lethal doses of endotoxin.
  • [0030]
    FIG. 15 is a western blot and graph of experimental results showing that addition of nicotine to RAW 264.7 macrophage-like cells inhibits the production of HMG-1 by the cells.
  • [0031]
    FIG. 16 is a bar graph showing the percentage of TNF in the serum of mice injected with endotoxin and treated with mechanical stimulation of the vagus nerve compared with untreated controls.
  • [0032]
    FIG. 17 is a dose response curve for TNF suppression in mice injected with enodoxin. The y axis is the percentage of TNF in the serum relative to untreated control; and the x axis is the number of vagus nerve stimulations quantified by frequency and time.
  • DETAILED DESCRIPTION OF THE INVENTION
  • [0033]
    The practice of the present invention will employ, unless otherwise indicated, conventional techniques of cell culture, molecular biology, microbiology, cell biology, and immunology, which are well within the skill of the art. Such techniques are fully explained in the literature. See, e.g., Sambrook et al., 1989, “Molecular Cloning: A Laboratory Manual”, Cold Spring Harbor Laboratory Press; Ausubel et al. (1995), “Short Protocols in Molecular Biology”, John Wiley and Sons; Methods in Enzymology (several volumes); Methods in Cell Biology (several volumes), and Methods in Molecular Biology (several volumes).
  • [0034]
    The present invention is based on the discovery that treatment of a proinflammatory cytokine-producing cell with a cholinergic agonist attenuates the release of proinflammatory cytokines from that cell, and that this attenuation process can be utilized in treatments for disorders mediated by an inflammatory cytokine cascade (5-6). It has further been discovered that stimulation of efferent vagus nerve fibers releases sufficient acetylcholine to stop a systemic inflammatory cytokine cascade, as occurs in endotoxic shock (5), or a localized inflammatory cytokine cascade (6). The efferent vagus nerve stimulation can also inhibit a localized inflammatory cytokine cascade in tissues and organs that are served by efferent vagus nerve fibers.
  • [0035]
    Accordingly, in some embodiments the present invention is directed to methods of inhibiting the release of a proinflammatory cytokine from a mammalian cell. The methods comprise treating the cell with a cholinergic agonist in an amount sufficient to decrease the amount of the proinflammatory cytokine released from the cell.
  • [0036]
    As used herein, a cytokine is a soluble protein or peptide which is naturally produced by mammalian cells and which act in vivo as humoral regulators at micro- to picomolar concentrations. Cytokines can, either under normal or pathological conditions, modulate the functional activities of individual cells and tissues. A proinflammatory cytokine is a cytokine that is capable of causing any of the following physiological reactions associated with inflammation: vasodialation, hyperemia, increased permeability of vessels with associated edema, accumulation of granulocytes and mononuclear phagocytes, or deposition of fibrin. In some cases, the proinflammatory cytokine can also cause apoptosis, such as in chronic heart failure, where TNF has been shown to stimulate cardiomyocyte apoptosis (32; 45). Nonlimiting examples of proinflammatory cytokines are tumor necrosis factor (TNF), interleukin (L)-1.alpha., IL-1.beta., IL-6, IL-8, IL-18, interferon.gamma., HMG-1, platelet-activating factor (PAF), and macrophage migration inhibitory factor (MIF). In preferred embodiments of the invention, the proinflammatory cytokine that is inhibited by cholinergic agonist treatment is TNF, an IL-1, IL-6 or IL-18, because these cytokines are produced by macrophages and mediate deleterious conditions for many important disorders, for example endotoxic shock, asthma, rheumatoid arthritis, inflammatory bile disease, heart failure, and allograft rejection. In most preferred embodiments, the proinflammatory cytokine is TNF.
  • [0037]
    Proinflammatory cytokines are to be distinguished from anti-inflammatory cytokines, such as IL-4, IL-10, and IL-13, which are not mediators of inflammation. In preferred embodiments, release of anti-inflammatory cytokines is not inhibited by cholinergic agonists.
  • [0038]
    In many instances, proinflammatory cytokines are produced in an inflammatory cytokine cascade, defined herein as an in vivo release of at least one proinflammatory cytokine in a mammal, wherein the cytokine release affects a physiological condition of the mammal. Thus, an inflammatory cytokine cascade is inhibited in embodiments of the invention where proinflammatory cytokine release causes a deleterious physiological condition.
  • [0039]
    Any mammalian cell that produces proinflammatory cytokines are useful for the practice of the invention. Nonlimiting examples are monocytes, macrophages, neutrophils, epithelial cells, osteoblasts, fibroblasts, smooth muscle cells, and neurons. In preferred embodiments, the cell is a macrophage.
  • [0040]
    As used herein, a cholinergic agonist is a compound that binds to cells expressing cholinergic receptor activity. The skilled artisan can determine whether any particular compound is a cholinergic agonist by any of several well known methods.
  • [0041]
    When referring to the effect of the cholinergic agonist on release of proinflammatory cytokines or an inflammatory cytokine cascade, or the effect of vagus nerve stimulation on an inflammatory cytokine cascade, the use of the terms “inhibit” or “decrease” encompasses at least a small but measurable reduction in proinflammatory cytokine release. In preferred embodiments, the release of the proinflammatory cytokine is inhibited by at least 20% over non-treated controls; in more preferred embodiments, the inhibition is at least 50%; in still more preferred embodiments, the inhibition is at least 70%, and in the most preferred embodiments, the inhibition is at least 80%. Such reductions in proinflammatory cytokine release are capable of reducing the deleterious effects of an inflammatory cytokine cascade in in vivo embodiments.
  • [0042]
    Any cholinergic agonist, now known or later discovered, would be expected to inhibit the release of proinflammatory cytokines from mammalian cells. In preferred embodiments, the cholinergic agonist is not otherwise toxic to the cell at useful concentrations. In more preferred embodiments, the cholinergic agonist has been used therapeutically in vivo or is naturally produced by mammalian cells. Nonlimiting examples include acetylcholine, nicotine, muscarine, carbachol, galantamine, arecoline, cevimeline, and levamisole. In most preferred in vitro embodiments, the cholinergic agonist is acetylcholine, nicotine, or muscarine. In in vivo embodiments, acetylcholine is not preferred because the compound would be expected to be inactivated very quickly due to the widespread occurrence of acetylcholinesterase in tissues.
  • [0043]
    The present invention is useful for studying cells in culture, for example studying the effect of inflammatory cytokine release on the biology of macrophages, or for testing compounds for cholinergic agonist activity. However, in vivo applications make up many of the preferred embodiments. In those embodiments, the cell is in a patient suffering from, or at risk for, a condition mediated by an inflammatory cytokine cascade. As used herein, a patient can be any mammal. However, in preferred embodiments, the patient is a human.
  • [0044]
    The treatment of any condition mediated by an inflammatory cytokine cascade is within the scope of the invention. In preferred embodiments, the condition is one where the inflammatory cytokine cascade is effected through release of proinflammatory cytokines from a macrophage. The condition can be one where the inflammatory cytokine cascade causes a systemic reaction, such as with septic shock. Alternatively, the condition can be mediated by a localized inflammatory cytokine cascade, as in rheumatoid arthritis. Nonlimiting examples of conditions which can be usefully treated using the present invention include those conditions enumerated in the background section of this specification. Preferably, the condition is appendicitis, peptic, gastric or duodenal ulcers, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute or ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, Crohn's disease, enteritis, Whipple's disease, asthma, allergy, anaphylactic shock, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, cystic fibrosis, pneumonitis, pneumoultramicroscopicsilicovolcanoconiosis-, alvealitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus, herpes, disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns, dermatitis, dermatomyositis, sunburn, urticaria, warts, wheals, vasulitis, angiitis, endocarditis, arteritis, atherosclerosis, thrombophlebitis, pericarditis, myocarditis, myocardial ischemia, periarteritis nodosa, rheumatic fever, Alzheimer's disease, coeliac disease, congestive heart failure, adult respiratory distress syndrome, meningitis, encephalitis, multiple sclerosis, cerebral infarction, cerebral embolism, Guillame-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritides, arthralgias, osteomyelitis, fasciitis, Paget's disease, gout, periodontal disease, rheumatoid arthritis, synovitis, myasthenia gravis, thryoiditis, systemic lupus erythematosus, Goodpasture's syndrome, Behcets's syndrome, allograft rejection, graft-versus-host disease, Type I diabetes, ankylosing spondylitis, Berger's disease, Type I diabetes, ankylosing spondylitis, Berger's disease, Retier's syndrome, or Hodgkins disease. In more preferred embodiments, the condition is appendicitis, peptic, gastric or duodenal ulcers, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute or ischemic colitis, hepatitis, Crohn's disease, asthma, allergy, anaphylactic shock, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, septic abortion, disseminated bacteremia, burns, Alzheimer's disease, coeliac disease, congestive heart failure, adult respiratory distress syndrome, cerebral infarction, cerebral embolism, spinal cord injury, paralysis, allograft rejection or graft-versus-host disease. In the most preferred embodiments, the condition is endotoxic shock.
  • [0045]
    The route of administration of the cholinergic agonist depends on the condition to be treated. For example, intravenous injection may be preferred for treatment of a systemic disorder such as septic shock, and oral administration may be preferred to treat a gastrointestinal disorder such as a gastric ulcer. The route of administration and the dosage of the cholinergic agonist to be administered can be determined by the skilled artisan without undue experimentation in conjunction with standard dose-response studies. Relevant circumstances to be considered in making those determinations include the condition or conditions to be treated, the choice of composition to be administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms. Thus, depending on the condition, the cholinergic agonist can be administered orally, parenterally, intranasally, vaginally, rectally, lingually, sublingually, bucally, intrabuccaly and transdermally to the patient.
  • [0046]
    Accordingly, cholinergic agonist compositions designed for oral, lingual, sublingual, buccal and intrabuccal administration can be made without undue experimentation by means well known in the art, for example with an inert diluent or with an edible carrier. The compositions may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the pharmaceutical compositions of the present invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
  • [0047]
    Tablets, pills, capsules, troches and the like may also contain binders, recipients, disintegrating agent, lubricants, sweetening agents, and flavoring agents. Some examples of binders include microcrystalline cellulose, gum tragacanth or gelatin. Examples of excipients include starch or lactose. Some examples of disintegrating agents include alginic acid, corn starch and the like. Examples of lubricants include magnesium stearate or potassium stearate. An example of a glidant is colloidal silicon dioxide. Some examples of sweetening agents include sucrose, saccharin and the like. Examples of flavoring agents include peppermint, methyl salicylate, orange flavoring and the like. Materials used in preparing these various compositions should be pharmaceutically pure and nontoxic in the amounts used.
  • [0048]
    Cholinergic agonist compositions of the present invention can easily be administered parenterally such as for example, by intravenous, intramuscular, intrathecal or subcutaneous injection. Parenteral administration can be accomplished by incorporating the cholinergic agonist compositions of the present invention into a solution or suspension. Such solutions or suspensions may also include sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents. Parenteral formulations may also include antibacterial agents such as for example, benzyl alcohol or methyl parabens, antioxidants such as for example, ascorbic acid or sodium bisulfite and chelating agents such as EDTA. Buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose may also be added. The parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.
  • [0049]
    Rectal administration includes administering the pharmaceutical compositions into the rectum or large intestine. This can be accomplished using suppositories or enemas. Suppository formulations can easily be made by methods known in the art. For example, suppository formulations can be prepared by heating glycerin to about 120.degree. C., dissolving the cholinergic agonist in the glycerin, mixing the heated glycerin after which purified water may be added, and pouring the hot mixture into a suppository mold.
  • [0050]
    Transdermal administration includes percutaneous absorption of the cholinergic agonist through the skin. Transdermal formulations include patches (such as the well-known nicotine patch), ointments, creams, gels, salves and the like.
  • [0051]
    The present invention includes nasally administering to the mammal a therapeutically effective amount of the cholinergic agonist. As used herein, nasally administering or nasal administration includes administering the cholinergic agonist to the mucous membranes of the nasal passage or nasal cavity of the patient. As used herein, pharmaceutical compositions for nasal administration of a cholinergic agonist include therapeutically effective amounts of the agonist prepared by well-known methods to be administered, for example, as a nasal spray, nasal drop, suspension, gel, ointment, cream or powder. Administration of the cholinergic agonist may also take place using a nasal tampon or nasal sponge.
  • [0052]
    In accordance with the present invention, it has also been discovered that the cholinergic agonist can be administered to the patient in the form of acetylcholine by stimulating efferent vagus nerve fibers. As is well known, efferent vagus nerve fibers secrete acetylcholine upon stimulation. Such stimulation releases sufficient acetylcholine to be effective in inhibiting a systemic inflammatory cytokine cascade as well as a localized inflammatory cytokine cascade in a tissue or organ that is served by efferent branches of the vagus nerve, including the pharynx, the larynx, the esophagus, the heart, the lungs, the stomach, the pancreas, the spleen, the kidneys, the adrenal glands, the small and large intestine, the colon, and the liver.
  • [0053]
    The effect of vagus nerve stimulation on the inhibition of inflammatory cytokine cascades is not necessarily limited to that caused by acetylcholine release. The scope of the invention also encompasses any other mechanism that is partly or wholly responsible for the inhibition of inflammatory cytokine cascades by vagus nerve stimulation. Nonlimiting examples include the release of serotonin agonists or stimulation of other neurotransmitters.
  • [0054]
    As used herein, the vagus nerve is used in its broadest sense, and includes any nerves that branch off from the main vagus nerve, as well as ganglions or postganglionic neurons that are connected to the vagus nerve. The vagus nerve is also known in the art as the parasympathetic nervous system and its branches, and the cholinergic nerve.
  • [0055]
    The efferent vagus nerve fibers can be stimulated by any means. Nonlimiting examples include: mechanical means such as a needle, ultrasound, or vibration. Mechanical stimulation can also be carried out by carotid massage, oculocardiac reflex, dive reflex and valsalva maneuver. Specific examples where an inflammatory response was reduce by mechanical vagal nerve stimulation are provided in Examples 5 and 6. The efferent vagal nerve fibers can also be stimulate by electromagnetic radiation such as infrared, visible or ultraviolet light; heat, or any other energy source. In preferred embodiments, the vagus nerve is stimulated electrically, using for example a commercial vagus nerve stimulator such as the Cyberonics NCP.RTM., or an electric probe. The efferent vagus nerve can be stimulated by stimulating the entire vagus nerve (i.e., both the afferent and efferent nerves), or by isolating efferent nerves and stimulating them directly. The latter method can be accomplished by separating the afferent from the efferent fibers in an area of the nerve where both types of fibers are present. Alternatively, the efferent fiber is stimulated where no afferent fibers are present, for example close to the target organ served by the efferent fibers. The efferent fibers can also be stimulated by stimulating the target organ directly, e.g., electrically, thus stimulating the efferent fibers that serve that organ. In other embodiments, the ganglion or postganglionic neurons of the vagus nerve can be stimulated. The vagus nerve can also be cut and the distal end can be stimulated, thus only stimulating efferent vagus nerve fibers (see, e.g., Example 2).
  • [0056]
    The amount of stimulation useful to inhibit an inflammatory cytokine cascade can be determined by the skilled artisan without undue experimentation for any condition to be treated. To inhibit a systemic inflammatory cytokine cascade, as induced with endotoxin, constant voltage stimuli of 1 to 5 V, at 2 ms and 1 Hz, for 10 min. before exposure and 10 min. after exposure, will inhibit the systemic inflammatory cytokine cascade sufficiently to prevent death of the subject by endotoxic shock (see Examples 2 and 3).
  • [0057]
    In other embodiments, the invention is directed to methods of inhibiting an inflammatory cytokine cascade in a patient. The methods comprise treating the patient with a cholinergic agonist in an amount sufficient to inhibit the inflammatory cytokine cascade. In preferred embodiments, the patient is suffering from, or at risk for, a condition mediated by the inflammatory cytokine cascade.
  • [0058]
    Cholinergic agonists useful for these embodiments have been previously discussed and include acetylcholine, nicotine, muscarine, carbachol, galantamine, arecoline, cevimeline, and levamisole. Also as previously discussed, acetylcholine can be administered by stimulating efferent vagus nerve fibers.
  • [0059]
    In additional embodiments, the present invention is directed to a method for treating a patient suffering from, or at risk for, a condition mediated by an inflammatory cytokine cascade. The method comprises stimulating efferent vagus nerve activity sufficient to inhibit the inflammatory cytokine cascade. Methods for stimulating efferent vagus nerve fibers have been previously discussed.
  • [0060]
    The present invention is also directed to methods for determining whether a compound is a cholinergic agonist. The method comprises determining whether the compound inhibits the release of a proinflammatory cytokine from a mammalian cell.
  • [0061]
    For this method, the cell can be any cell that can be induced to produce a proinflammatory cytokine. In preferred embodiments, the cell is an immune cell, for example macrophages, monocytes, or neutrophils. In the most preferred embodiments, the cell is a macrophage.
  • [0062]
    The proinflammatory cytokine to be measured for inhibition can be any proinflammatory cytokine that can be induced to be released from the cell. In preferred embodiments, the cytokine is TNF. Evaluation of the inhibition of cytokine production can be by any means known, including quantitation of the cytokine (e.g., with ELISA), or by bioassay, (e.g. determining whether proinflammatory cytokine activity is reduced).
  • [0063]
    Preferred embodiments of the invention are described in the following examples. Other embodiments within the scope of the claims herein will be apparent to one skilled in the art from consideration of the specification or practice of the invention as disclosed herein. It is intended that the specification, together with the examples, be considered exemplary only, with the scope and spirit of the invention being indicated by the claims which follow the examples.
  • Example 1 Cholinergic Agonists Inhibit Release of Proinflammatory Cytokines from Macrophages 1. Materials and Methods
  • [0064]
    Human macrophage cultures were prepared as follows. Buffy coats were collected from the blood of healthy individual donors to the Long Island Blood Bank Services (Melville, N.Y.). Primary blood mononuclear cells were isolated by density-gradient centrifugation through Ficoll/Hypaque (Pharmacia, N.J.), suspended (8.times.10.sup.6 cells/ml) in RPMI 1640 medium supplemented with 10% heat inactivated human serum (Gemini Bio-Products, Inc., Calabasas, Calif.), and seeded in flasks (PRIMARIA; Beckton and Dickinson Labware, Franklin Lakes, N.J.). After incubation for 2 hours at 37.degree. C., adherent cells were washed extensively, treated briefly with 10 mM EDTA, detached, resuspended (10.sup.6 cells/ml) in RPMI medium (10% human serum), supplemented with human macrophage colony stimulating factor (MCSF; Sigma Chemical Co., St. Louis, Mo.; 2 ng/ml), and seeded onto 24-well tissue culture plates (PRIMARIA; Falcon) (10.sup.6 cells/well). Cells were allowed to differentiate for 7 days in the presence of MCSF. On day 7 the cells were washed 3 times with 1.times. Dulbecco's phosphate buffered saline (PBS, GibcoBRL, Life Technologies, Rockville, Md.), fresh medium devoid of MCSF was added, and experiments performed as indicated.
  • [0065]
    RNase protection assays were performed as follows. Total RNA was isolated from cultured cells by using TRIzol reagent (GIBCO BRL, Rockville, Md.) following the manufacturer's instructions, and electrophoresed on 1.2% agarose/17% formaldehyde gel for verification of the integrity of the RNA samples. The RNase protection assay was conducted using a kit obtained from PharMingen (San Diego, Calif.). The anti-sense RNA probe set (hck-3) was labeled with [a-.sup.32P] UTP (Sp. Act. 800 Ci/mmol, Amersham, Arlington Heights, Ill.) using T7 RNA polymerase. Molecular weight markers were prepared by using pBR-322 plasmid DNA digested with MSP I (New England Bio Labs, Beverly, Mass.) and end-labeled using [a-.sup.32P] dCTP (Sp. Act. 800 Ci/mmol, Amersham, Arlington Heights, Ill.) with Klenow enzyme (Strategene, La Jolla, Calif.).
  • [0066]
    TNF immunohistochemistry was performed as follows. Human macrophages were differentiated as described above, and grown on glass chamber slides (Nunc, Naperville, Ill.). Slides were incubated in a blocking solution (1% BSA, 5% normal goat serum, 0.3% Triton X-100 in PBS) for 1 hour at room temperature and then incubated for 24 hours at 4.degree. C. with a primary mouse anti-human TNF monoclonal antibody (Genzyme, Cambridge, Mass.) diluted 1:100 in PBS containing 0.3% Triton X-100, 0.1% BSA, and 3% normal goat serum. Washed sections were incubated for 2 hours with secondary biotinylated anti-mouse IgG (1:200, Vector Laboratories, Inc., Burlingame, Calif.). The reaction product was visualized with 0.003% hydrogen peroxide and 0.05% 3,3′-diaminobenzidine tetrahydrochloride as a chromogen. Negative controls were incubated in the absence of primary antibodies (not shown). Slides were analyzed on a light microscope (Olympus BX60, Japan) using a MetaMorth Imaging System (Universal Imaging Co., West Chester, Pa.).
  • 2. Results
  • [0067]
    Primary human macrophage cultures were established by incubating human peripheral blood mononuclear cells in the presence of macrophage colony stimulating factor (MCSF; Sigma Chemical Co., St. Louis, Mo.). These cells were used in experiments to determine the effects of cholinergic agonists on TNF levels in macrophage cultures conditioned by exposure to LPS for 4 hours (FIG. 1). In those experiments, acetylcholine chloride (ACh; Sigma Chemical Co., St. Louis, Mo.) was added to human macrophage cultures at the indicated concentrations (squares) in the presence of the acetylcholinesterase inhibitor pyridostigmine bromide (1 mM, Sigma Chemical Co., St. Louis, Mo.). Muscarine (triangles) and nicotine (circles) (Sigma Chemical Co., St. Louis, Mo.) were added in the concentrations indicated (FIG. 1). LPS was added five minutes later (100 ng/ml), and conditioned supernatants collected after 4 hours of stimulation for subsequent analysis by TNF enzyme-linked immunosorbent assay (ELISA). All the experimental conditions were performed in triplicate. Data from nine separate macrophage preparations are shown as Mean.+−.SEM; n=9.
  • [0068]
    As shown in FIG. 1, acetylcholine, nicotine, and muscarine all inhibited TNF release in a dose dependent manner. Comparable inhibition of TNF release by acetylcholine was observed in macrophage culture media conditioned by exposure to LPS for 20 hours (not shown), indicating that the inhibitory effect of acetylcholine on TNF did not merely delay the onset of the TNF response. Inhibition of TNF was also observed in macrophage cultures treated with carbachol, a chemically distinct cholinergic agonist (not shown).
  • [0069]
    The molecular mechanism of TNF inhibition was investigated by measuring TNF mRNA levels in an RNase protection assay. In those experiments (FIG. 2), macrophages were incubated in the presence of ACh (100 .mu.M), muscarine (Mus, 100 .mu.M), nicotine (Nic, 100 .mu.M) or medium alone for 5 minutes followed by 2 hour exposure to LPS (100 ng/ml). ACh was added with pyridostigmine bromide (1 mM). Control wells were incubated with medium alone for 2 hours. Expression of the GAPDH gene product was measured to control for mRNA loading.
  • [0070]
    TNF mRNA levels in acetylcholine-treated, LPS-stimulated macrophages did not decrease as compared to vehicle-treated, LPS-stimulated macrophages, even when acetylcholine was added in concentrations that inhibited TNF protein release (FIG. 2). This indicates that acetylcholine suppresses TNF release through a post-transcriptional mechanism.
  • [0071]
    To determine whether acetylcholine inhibited macrophage TNF synthesis or macrophage TNF release, monoclonal anti-TNF antibodies were used to label cell-associated TNF in human macrophage cultures. In those experiments (FIG. 3), cells were exposed to either ACh (100 .mu.M), either alone or in the presence of pyridostigmine bromide (1 mM), five minutes before LPS (100 ng/ml) treatment. Two hours later the cells were fixed in buffered 10% formalin and subjected to immunocytochemical analysis using primary mouse anti-hTNF monoclonal antibodies as described in Materials and Methods.
  • [0072]
    Those experiments established that acetylcholine significantly attenuated the appearance of LPS-stimulated TNF immunoreactivity in macrophages (FIG. 3). Considered together, these results indicate that the inhibitory effect of acetylcholine on human macrophage TNF production occurs through the post-transcriptional suppression of TNF protein synthesis, or possibly through an increased rate of degradation of intracellular TNF (FIG. 3).
  • [0073]
    Previous work indicated that peripheral blood mononuclear cells express nicotinic and muscarinic acetylcholine receptors (37-38; 53). To define pharmacologically the type of macrophage cholinergic receptor activities involved in modulating the TNF response, the results in FIG. 1 were further analyzed. Nicotine significantly inhibited TNF release in a dose-dependent manner; the effective concentration of nicotine that inhibited 50% of the TNF response (E.C.sub.50) was estimated to be 8.3.+−.7.1 nM (n=9). This E.C.sub.50 for nicotine compared favorably with the E.C.sub.50 for acetylcholine-mediated inhibition of TNF (acetylcholine E.C.sub.50=20.2.+−.8.7 nM, n=9). Muscarine also significantly inhibited TNF release, although it was a much less effective inhibitor of macrophage TNF as compared to either acetylcholine or nicotine (muscarine E.C.sub.50=42.4.+−18.6 mM, n=9; P<0.01 vs. nicotine or acetylcholine).
  • [0074]
    To establish whether acetylcholine inhibited TNF primarily through the activity of nicotinic or muscarinic acetylcholine receptors, the specific muscarinic antagonist, atropine, was added to LPS-stimulated macrophage cultures that were co-treated with acetylcholine (FIG. 4). I also addressed whether the nicotinic acetylcholine receptor activity that mediated inhibition of TNF was a-bungarotoxin-sensitive or a-bungarotoxin-insensitive (FIG. 4). Conditions for macrophage culture and TNF assays were as previously described. Atropine (striped bars) (1 mM; Sigma Chemical Co., St. Louis, Mo.) or .alpha.-conotoxin (black bars) (0.1, 0.01 mM; Oncogene Research Products, Cambridge, Mass.) were added to macrophage cultures 5 minutes prior to acetylcholine (10 .mu.M) and LPS (100 ng/ml). Data shown are Mean.+−.SEM of 3 separate experiments using different macrophages prepared from separate donors.
  • [0075]
    Addition of atropine, even in concentrations as high as 1 mM, failed to restore TNF release in acetylcholine-treated macrophage cultures (FIG. 4). Note that Acetylcholine inhibited TNF release by 80%, but this was not reversed by atropine. However, addition of .alpha.-conotoxin to acetylcholine-treated LPS-stimulated macrophage cultures significantly reversed the inhibitory effect of acetylcholine in a dose dependent manner (FIG. 4). (**P<0.005 vs. ACh; *P<0.05 vs. ACh). Neither atropine nor .alpha.-conotoxin altered TNF production in vehicle-treated cultures (not shown). Considered together, these data provide evidence that the inhibitory effect of acetylcholine on the LPS-induced TNF response in human macrophage cultures is mediated primarily by .alpha.-bungarotoxin-sensitive, nicotinic acetylcholine receptors. Acetylcholine levels in mammalian tissues can reach the millimolar range (50); however so, it is possible that both the nicotinic and muscarinic macrophage acetylcholine receptor activities described here participate in the inhibition of macrophage TNF synthesis in vivo.
  • [0076]
    To assess specificity, the release of other macrophage-derived cytokines was measured in LPS-stimulated macrophage cultures treated with acetylcholine. In those experiments, human macrophage cultures were incubated with ACh at the indicated concentrations in the presence of pyridostigmine bromide (1 mM) and LPS (100 ng/ml) for 20 hours. IL-1.beta. (FIG. 5), IL-6 (FIG. 6) and IL-10 (FIG. 8) levels were measured in media using commercially available ELISA kits (R&D Systems Inc., Minneapolis, Minn.). IL-18 (FIG. 7) levels were determined by specific ELISA (Medical & Biological Laboratories Co., Ltd., Nagoya, Japan). Each sample was analyzed in triplicate. Data are expressed as Mean.+−.SEM from 4 separate experiments using macrophages prepared from 4 separate healthy donors. These experiments established that acetylcholine dose-dependently inhibits the release of other LPS-inducible cytokines (IL-1.beta., IL-6 and IL-18, FIGS. 5, 6, and 7, respectively), but does not prevent the constitutive release of the anti-inflammatory cytokine IL-10 (FIG. 8). Thus, acetylcholine specifically inhibits release of pro-inflammatory cytokines (FIGS. 5-7) by LPS-stimulated human macrophage cultures, but does not suppress release of the anti-inflammatory cytokine IL-10 (FIG. 8). Staining with tetrazolium salt MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, Sigma Chemical Co., St. Louis, Mo.), and Trypan blue exclusion of macrophage cultures treated with LPS and acetylcholine indicated that specific LPS-inducible cytokine inhibition was not due to cytotoxicity (not shown).
  • [0077]
    The molecular mechanism of acetylcholine inhibition of IL-1.beta. and IL-6 was investigated further by measuring gene-specific mRNA levels with biotin-labeled capture oligonucleotide probes in a calorimetric microplate assay (Quantikine mRNA, R&D Systems, Inc., Minneapolis, Minn.). Stimulation of human macrophage cultures with LPS for 2 hours significantly increased the mRNA levels of L-1.beta. as compared to vehicle-treated controls (vehicle-treated IL-1.beta. mRNA=120.+−.54 attomole/ml vs. LPS-stimulated IL-1.beta. mRNA=1974.+−.179 attomole/ml; n=3; P<0.01). Addition of acetylcholine in concentrations (100 nM) that significantly inhibited IL-1.beta. protein release did not significantly alter macrophage IL-1.beta. mRNA levels (acetylcholine-treated LPS-stimulated IL-1.beta. mRNA=2128.+−.65 attomole/ml; n=3). Similarly, LPS-stimulated IL-6 mRNA levels in macrophages were not significantly altered by acetylcholine concentrations that significantly inhibited IL-6 protein (LPS-stimulated IL-6 mRNA=1716.+−.157 attomole/ml vs. acetylcholine-treated LPS-stimulated IL-6 mRNA=1872.+−.91 attomole/ml; n=3). Together, these observations give evidence that acetylcholine post-transcriptionally inhibits the LPS-stimulated release of TNF, IL-1.beta. and IL-6 in macrophages.
  • [0078]
    The present results indicate that differentiated human macrophage cultures are extremely sensitive to acetylcholine and nicotine. Previous reports of cholinergic receptor activity in human peripheral blood mononuclear cells that were not differentiated into macrophages (53; 29; 46) suggested that maximal cholinergic responses required micromolar concentrations of cholinergic agonists. Our own studies establish that significantly higher concentrations of acetylcholine are required to suppress cytokine synthesis in differentiated human macrophages (acetylcholine E.C.sub.50 for inhibiting TNF=0.8.+−.0.2 mM, n=3). The pharmacological results now implicate an .alpha.-bungarotoxin-sensitive, nicotinic acetylcholine receptor activity that can modulate the macrophage cytokine response. This type of cholinergic receptor activity is similar to that previously described in peripheral blood mononuclear cells (53), except that macrophages are significantly more sensitive to cholinergic agonists as compared to peripheral blood mononuclear cells. The skilled artisan would not necessarily have expected macrophages to be so sensitive to cholinergic agonists, or even have any sensitivity at all, given what was previously known with mononuclear cells. Indeed, recent evidence in our lab has revealed nicotinic receptor subunit expression patterns in macrophages that are distinct from monocytes. Therefore, the skilled artisan would understand that molecular differences underlie the greater sensitivity to cholinergic agonists of macrophages over monocytes.
  • Example 2 Inhibition of Endotoxic Shock by Stimulation of Efferent Vagus Nerve Fibers
  • [0079]
    To determine whether direct stimulation of efferent vagus nerve activity might suppress the systemic inflammatory response to endotoxin, adult male Lewis rats were subjected to bilateral cervical vagotomy, or a comparable sham surgical procedure in which the vagus nerve was isolated but not transected. Efferent vagus nerve activity was stimulated in vagotomized rats by application of constant voltage stimuli to the distal end of the divided vagus nerve 10 min before and again 10 min after the administration of a lethal LPS dose (15 mg/kg, i.v.). An animal model of endotoxic shock was utilized in these experiments. Adult male Lewis rats (280-300 g, Charles River Laboratories, Wilmington, Mass.) were housed at 22.degree. C. on a 12 h light/dark cycle. All animal experiments were performed in accordance with the National Institute of Health Guidelines under the protocols approved by the Institutional Animal Care and Use Committee of North Shore University Hospital/New York University School of Medicine. Rats were anesthetized with urethane (1 g/kg, intraperitoneally), and the trachea, the common carotid artery, and the jugular vein were cannulated with polyethylene tubing (Clay Adams, Parsippany, N.J.). The catheter implanted into the right common carotid artery was connected to a blood pressure transducer and an Acquisition System (MP100, BIOPAC Systems, Inc., Santa Barbara, Calif.) for continuous registration of mean arterial blood pressure (MABP in FIG. 9). Animals were subjected to bilateral cervical vagotomy (VGX, n=7) alone or with electrical stimulation (VGX+STIM, n=7) or sham surgery (SHAM, n=7). In vagotomized animals, following a ventral cervical midline incision, both vagus trunks were exposed, ligated with a 4-0 silk suture, and divided. In sham-operated animals both vagal trunks were exposed and isolated from the surrounding tissue but not transected. Electrical stimulation of the vagus nerve was performed in animals previously subjected to vagotomy. In these groups, the distal end of right vagus nerve trunk was placed across bipolar platinum electrodes (Plastics One Inc., Roanoke, Va.) connected to a stimulation module (STM100A, Harvard Apparatus, Inc., Holliston, Miss.) as controlled by an Acquisition System (MP100, BIOPAC Systems, Inc., Santa Barbara, Calif.). Constant voltage stimuli (5 V, 2 ms, 1 Hz) were applied to the nerve for 20 min (10 min before LPS administration and 10 min after). Lipopolysaccharide (Escherichia coli 0111::B4; Sigma Chemical Co, St. Louis, Mo.; 10 mg/ml in saline) was sonicated for 30 minutes, and administered at a lethal dose (15 mg/kg, iv.). Blood was collected from the right carotid artery 1 hour after LPS administration. Serum TNF levels were quantified by the L929 bioactivity assay. To determine liver TNF levels, animals were euthanized and livers rapidly excised, rinsed of blood, homogenized by polytron (Brinkman, Westbury, N.Y.) in homogenization buffer (PBS, containing 0.05% sodium azide, 0.5% Triton X-100 and a protease inhibitor cocktail (2 tablets/10 ml PBS, Boehringer Mannheim, Germany); pH 7.2; 4.degree. C.), and then sonicated for 10 minutes. Homogenates were centrifuged at 12,000 g for 10 minutes, and TNF levels in supernatants determined by ELISA (Biosource International, Camarillo, Calif.). Protein concentrations in the supernatants were measured by the Bio-Rad protein assay (Bio-Rad Lab., Hercules, Calif.), and liver TNF content normalized by the amount of protein in the sample. Blood samples were collected 1 hour after LPS and TNF was measured by L929 assay.-P<0.05, **-P<0.005 vs. SHAM+LPS, #-P<0.05 vs. VGX+LPS.
  • [0080]
    As shown in FIG. 9, the results establish that electrical stimulation of the efferent vagus nerve significantly attenuates peak serum TNF levels; vagotomy without electrical stimulation significantly increased peak serum TNF levels as compared to sham-operated controls (P<0.05).
  • [0081]
    TNF levels in liver homogenates were measured next, because liver is a principle source of peak serum TNF during endotoxemia (26; 16). Electrical stimulation of the distal vagus nerve significantly attenuated hepatic TNF synthesis as compared to sham-operated controls (FIG. 10). In that figure, *-P<0.05 vs. SHAM+LPS, #-P<0.05 vs. VGX+LPS. These data directly implicate efferent vagus nerve signaling in the regulation of TNF production in vivo.
  • [0082]
    It was theoretically possible that electrical stimulation of the vagus nerve induced the release of humoral anti-inflammatory hormones or cytokines that inhibit TNF production. Measurements of corticosterone and IL-10 levels in sham-operated controls were performed (Table 1) to determine this.
  • [0083]
    In those studies, animals were subjected to either sham surgery (SHAM), vagotomy (VGX), or electrical stimulation with vagotomy (VGX+STIM) 30 minutes before systemic administration of LPS (15 mg/kg). Blood samples were collected 1 hour after administration of LPS or vehicle. Serum corticosterone was measured by radioimmunoassay (ICN Biomedicals, Costa Mesa, Calif.) and IL-10 was determined by ELISA (BioSource International, Camarillo, Calif.). All assays were performed in triplicate. The results are shown in Table 1, which indicates that endotoxemia was associated with increases in corticosterone and IL-10 levels. In agreement with previous studies, vagotomy significantly reduced corticosterone levels, in part because it eliminated the afferent vagus nerve signals to the brain that are required for a subsequent activation of the hypothalamic-pituitary-adrenal axis (14; 11). This decreased corticosteroid response and likely contributed to the increased levels of TNF observed in the serum and liver of vagotomized animals (FIGS. 9 and 10), because corticosteroids normally down-regulate TNF production (41; 39). Direct electrical stimulation of the peripheral vagus nerve did not stimulate an increase in either the corticosteroid or the IL-10 responses. Thus, suppressed TNF synthesis in the serum and liver after vagus nerve stimulation could not be attributed to the activity of these humoral anti-inflammatory mediators.
  • [0000]
    TABLE 1 Effects of vagotomy and vagus nerve stimulation on serum IL-10 and corticosteroid levels during lethal endotoxemia. Group of animals IL-10 (ng/ml) Corticosterone (ng/ml) SHAM+vehicle N.D. 160.+−.20 SHAM+LPS 8.+−.0.3 850.+−.50 Vagotomy+LPS 9.+−.0.4 570.+−.34* Vagotomy+LPS+Stimulation 9.+−.0.5 560.+−.43*
  • [0084]
    Data shown are Mean.+−.SEM, n=7 animals per group. *p<0.05 vs. SHAM+LPS.
  • [0085]
    FIG. 11 shows the results of measurement of mean arterial blood pressure (MABP) in the same groups of animals as in FIGS. 9 and 10 (as described in methods). Circles—sham-operated rats (SHAM), triangles—vagotomized rats (VGX), squares—animals with electrical stimulation of the vagus nerve and vagotomy (VGX+STIM. LPS (15 mg/kg, i.v.) was injected at time=0. All data are expressed as % of MABP [MABP/MABP (at time=0).times.100%], Mean.+−.SEM; n=7. Sham-surgery, vagotomy and electrical stimulation with vagotomy did not significantly affect MABP in vehicle-treated controls (not shown).
  • [0086]
    Peripheral vagus nerve stimulation significantly attenuated the development of LPS-induced hypotension (shock) in rats exposed to lethal doses of endotoxin (FIG. 11). This observation was not unexpected, because TNF is a principle early mediator of acute endotoxin-induced shock (43-44). Vagotomy alone (without electrical stimulation) significantly shortened the time to development of shock as compared to sham-operated controls (sham time to 50% drop in mean arterial blood pressure 30.+−.3 minutes versus vagotomy time to 50% drop in mean arterial blood pressure=15.+−.2 minutes; P<0.05). This amplified development of shock following vagotomy alone corresponded to the decreased corticosteroid response and the increased TNF response.
  • [0087]
    Acetylcholine is a vasodilator that mediates nitric oxide-dependent relaxation of resistance blood vessels which causes a decrease in blood pressure. Thus, we wished to exclude the possibility that stimulation of the efferent vagus might have mediated a paradoxical hypertensive response. Hypertension was not observed following vagus nerve stimulation of controls given saline instead of endotoxin (not shown), indicating that protection against endotoxic shock by vagus nerve stimulation is specific. Considered together, these observations indicate that stimulation of efferent vagus nerve activity downregulates systemic TNF production and the development of shock during lethal endotoxemia.
  • Example 3 Stimulation of Intact Vagus Nerve Attenuates Endotoxic Shock
  • [0088]
    Experiments were conducted to determine whether the inhibition of inflammatory cytokine cascades by efferent vagus nerve stimulation is effective by stimulation of an intact vagus nerve. Stimulation of left and right vagus nerves were also compared.
  • [0089]
    The vagus nerves of anesthetized rats were exposed, and the left common iliac arteries were cannulated to monitor blood pressure and heart rate. Endotoxin (E. coli 0111:B4; Sigma) was administered at a lethal dose (60 mg/kg). In treated animals, either the left or the right intact vagus nerve was stimulated with constant voltage (5V or 1V, 2 ms, 1 Hz) for a total of 20 min., beginning 10 min. before and continuing 10 min. after LPS injection. Blood pressure and heart rate were through the use of a Bio-Pac M100 computer-assisted acquisition system. FIGS. 12-14 show the results of these experiments.
  • [0090]
    As shown in FIG. 12, within minutes after LPS injection, the blood pressure began to decline in both unstimulated rats and rats treated with a low dose (1V) of vagus nerve stimulation, while rats treated with a high dose (5V) of stimulation maintained more stable blood pressures. Between 30 and 40 min. post-LPS, the blood pressure stabilized in animals treated with a low dose of voltage.
  • [0091]
    FIG. 13 shows the heart rate of the experimental animals. Within minutes after LPS injection, the heart rate began to increase in rats stimulated with a high dose (5V) of vagus nerve stimulation. On the other hand, the heart rates of both unstimulated rats and rats stimulated with a low dose (1V) of voltage remained stable for approximately 60 min. post-LPS. After one hour, the heart rates of the rats treated with a low dose of stimulation began to increase, and reached levels comparable to those rats receiving a high dose of vagus nerve stimulation.
  • [0092]
    FIG. 14 compares left vs. right vagus nerve stimulation. Endotoxic animals were treated with 1V stimulation in either the left or the right vagus nerve. Within minutes after LPS injection, the blood pressure began to decline in all three sets of animals (unstimulated, left stimulation, right stimulation). Though both sets of stimulated animals recovered blood pressure, those animals receiving stimulation in the left vagus nerve maintained more stable blood pressures for the duration of the experiment. However, the difference in results between left and right vagus nerve stimulation was not statistically significant, and would not be expected to have any practical difference.
  • [0093]
    This set of experiments confirms that stimulation of an intact vagus nerve can effectively inhibit an inflammatory cytokine cascade sufficiently to alleviate conditions caused by the cascade.
  • Example 4 Inhibition of HMG-1 Release from Macrophages by Nicotine
  • [0094]
    Experiments were performed to determine whether the inhibitory effect of cholinergic agonists on proinflammatory cytokines applied to HMG-1. Murine RAW 264.7 macrophage-like cells (American Type Culture Collection, Rockville, Md., USA) were grown in culture under DMEM supplemented with 10% fetal bovine serum and 1% glutamine. When the cells were 70-80% confluent, the medium was replaced by serum-free OPTI-MEM 1 medium. Nicotine (Sigma) was then added at 0, 0.1, 1, 10 or 100 .mu.M. Five minutes after adding the nicotine, the cultures were treated with LPS (500 ng/ml). Culture medium was collected after 20 hr. The culture medium was concentrated with a Centricon T 10 filter, then analyzed by western blot, using an anti-HMG-1 polyclonal antisera (WO 00/47104) and standard methods. Band densities were determined using a Bio-Rad Imaging densitometer.
  • [0095]
    The results are shown in FIG. 15. The HMG-1 bands are shown along the top, with the corresponding nicotine and LPS concentrations, and the densities of the bands shown are graphed in the graph below. FIG. 15 clearly shows that nicotine inhibited HMG-1 production in a dose-dependent manner. This demonstrates that HMG-1 behaves as a proinflammatory cytokine in that its production can be inhibited by a cholinergic agonist.
  • [0096]
    The neural-immune interaction described here, which we term the “cholinergic anti-inflammatory pathway,” can directly modulate the systemic response to pathogenic invasion. The observation that parasympathetic nervous system activity influences circulating TNF levels and the shock response to endotoxemia has widespread implications, because it represents a previously unrecognized, direct, and rapid endogenous mechanism that can be activated to suppress the lethal effects of biological toxins. The cholinergic anti-inflammatory pathway is positioned to function under much shorter response times as compared to the previously described humoral anti-inflammatory pathways. Moreover, activation of parasympathetic efferents during systemic stress, or the “flight or fight” response, confers an additional protective advantage to the host by restraining the magnitude of a potentially lethal peripheral immune response.
  • [0097]
    In view of the above, it will be seen that the several advantages of the invention are achieved and other advantages attained.
  • [0098]
    As various changes could be made in the above methods and compositions without departing from the scope of the invention, it is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.
  • Example 5 Mechanical Vagus Nerve Stimulation is Sufficient to Inhibit Inflammatory Cytokine Release
  • [0099]
    To determine the activation sensitivity of the cholinergic anti-inflammatory via VNS, the ability of mechanical nerve stimulation to activate the cholinergic anti-inflammatory pathway was examined. Male 8- to 12-week-old BALB/c mice (25-30 g Taconic) were housed at 25° C. on a 12 h light/dark cycle. Animals were allowed to acclimate to the facility for at least 7 days prior to experimental manipulation. Standard mouse chow and water were freely available. All animal experiments were performed in accordance with the National Institutes of Health (NIH) Guidelines under protocols approved by the Institutional Animal Care and Use Committee of the North Shore-Long Island Jewish Research Institute.
  • [0100]
    Mice were anesthetized with isoflurane (1.5-2.0%) and placed supine on the operating table. A ventral cervical midline incision was used to expose and isolate the left cervical vagus nerve. The left vagus nerve was exposed via a midline cervical incision. After isolating the nerve from the surrounding structures, the surgery was terminated, without subsequent electrode placement. LPS administration preceded surgery by 5 min. Sham operated mechanical VNS mice underwent cervical incision followed by dissection of the underlying submandibular salivary glands only. The vagus nerve was neither exposed nor isolated.
  • [0101]
    Mice were injected with endotoxin (Escherichia coli LPS 0111:B4; Sigma) that was dissolved in sterile, pyrogen-free saline at stock concentrations of 1 mg/ml. LPS solutions were sonicated for 30 min immediately before use for each experiment. Mice received an LD50 dose of LPS (7.5 mg/kg, i.p.). Blood was collected 2 h after LPS administration, allowed to clot for 2 h at room temperature, and then centrifuged for 15 min at 2,000×g. Serum samples were stored at −20° C. before analysis. TNF concentrations in mouse serum were measured by ELISA (R & D Systems).
  • [0102]
    Mechanical VNS significantly reduced TNF production during lethal endotoxemia (FIG. 16). Compared with the control group, the mechanical VNS group had a 75.8% suppression in TNF production (control=1819±181 pg/ml vs. mechanical VNS=440±64 pg/ml, p=0.00003). These results indicate that mechanical nerve stimulation is sufficient to inhibit cytokine release.
  • Example 6 Non-Invasive External Cervical Massage is Sufficient to Activate the Cholinergic Anti-Inflammatory Pathway
  • [0103]
    To determine whether mechanical VNS could be utilized in a non-invasive, transcutaneous manner to elicit anti-inflammatory effects, a model of murine cervical massage in lethal endotoxemia was developed. Mice were anesthetized and positioned as described above. Following the midline cervical incision, a unilateral left total submandibular sialoadenectomy was performed. No further dissection was performed, and the underlying vagus nerve was not exposed. Following closure of the incision, animals received external vagus nerve cervical massage using a cotton-tip applicator. Cervical massage was performed using alternating direct pressure applied antero-posteriorly adjacent to the left lateral border of the trachea. Each pressure application was defined as one stimulation. The number of stimulations was quantified by frequency and time. The lowest dose cervical massage group underwent 40 sec stimulation at 0.5 stimulations s−1. The middle dose cervical massage group underwent 2 min stimulation at 1 stimulations s−1. The highest dose cervical massage group underwent 5 min stimulation at 2 stimulations s−1. Sham operated cervical massage mice underwent unilateral left submandibular sialoadenectomy only.
  • [0104]
    A dose response curve for TNF suppression was generated from these stimulation groups and is shown in FIG. 17. The 40 sec (0.5 Hz) group had a 29.2% suppression of TNF (control=1879±298 pg/ml vs. massage=1331±503 pg/ml, p=0.38). The 2 min (1 Hz) group had a 36.8% suppression of TNF (control=1909±204 pg/ml vs. massage=1206±204 pg/ml, p=0.04). The 5 min (2 Hz) group had a 50.7% suppression of TNF (control=2749±394 pg/ml vs. massage=1355±152 pg/ml, p=0.02). These data indicate that a non-invasive, easily performed, low risk, accepted clinical therapeutic maneuver could be utilized to significantly reduce systemic inflammation.
  • REFERENCES CITED
  • [0000]
    • 1. Antonica, A., et al., J. Auton. Nerv. Syst., 48:187-97, 1994.
    • 2. Besedovsky, H., et al., Science, 233:652-54, 1986.
    • 3. Blackwell, T. S., and Christman, J. W., Br. J. Anaesth., 77: 110-17, 1996.
    • 4. Blum, A. and Miller, H., Am. Heart J., 135:181-86, 1998.
    • 5. Borovikova, L. V., et al., Nature, 405: 458-62, 2000a.
    • 6. Borovikova, L. V., et al., Auton. Neurosci., 20:141-47, 2000b.
    • 7. Bumgardner, G. L., and Orosz, C. G., Semin. Liver Dis., 19: 189-204, 1999.
    • 8. Carteron, N. L., Mol. Med. Today, 6:315-23, 2000.
    • 9. Dibbs, Z., et al., Proc. Assoc. Am. Physicians, 111:423-28, 1999.
    • 10. Dinarello, C. A., FASEB J., 8:1314-25, 1994.
    • 11. Fleshner, M., et al., J. Neuroimmunol., 86:134-41, 1998.
    • 12. Fox, D. A., Arch. Intern. Med., 28:437-444, 2000.
    • 13. Gattorno, M., et al., J. Rheumatol., 27:2251-2255, 2000.
    • 14. Gaykema, R. P., et al., Endocrinology, 136:4717-4720, 1995.
    • 15. Gracie, J. A., et al., J. Clin. Invest., 104:1393-1401, 1999.
    • 16. Gregory, S. H. and Wing, E. J., Immunology Today, 19:507-10, 1998.
    • 17. Guslandi, M., Br. J. Clin. Pharmacol., 48:481-84, 1999.
    • 18. Hirano, T., J. Surg. Res., 81:224-29, 1999.
    • 19. Hommes, D. W. and van Deventer, S. J., Curr. Opin. Clin. Nutr. Metab. Care, 3:191-95, 2000.
    • 20. Hsu, H. Y., et al., J. Pediatr. Gastroenterol., 29:540-45, 1999.
    • 21. Hu, X. X., et al., J. Neuroimmunol., 31:35-42, 1991.
    • 22. Jander, S. and Stoll, G., J. Neuroimmunol., 114:253-58, 2001.
    • 23. Kanai, T. et al., Digestion, 63 Suppl. 1:37-42, 2001.
    • 24. Katagiri, M., et al., J. Clin, Gastroenterol., 25 Suppl. 1: S211-14, 1997.
    • 25. Kimmings, A. N., et al., Eur. J. Surg., 166:700-05, 2000.
    • 26. Kumins, N. H., et al., SHOCK, 5:385-88, 1996.
    • 27. Lee, H. G., et al., Clin. Exp. Immunol., 100:139-44, 1995.
    • 28. Lipton, J. M. and Catania, A., Immunol. Today, 18:140-45, 1997.
    • 29. Madretsma, G. S., et al., Immunopharmacology, 35:47-51, 1996.
    • 30. McGuinness, P. H., et al., Gut, 46:260-69, 2000.
    • 31. Nathan, C. F., J. Clin. Invest., 79:319-26, 1987.
    • 32. Pulkki, K. J., Ann. Med., 29:339-43, 1997.
    • 33. Prystowsky, J. B. and Rege, R. V., J. Surg. Res., 71; 123-26 1997.
    • 34. Rayner, S. A. et al., Clin. Exp. Immunol., 122:109-16, 2000.
    • 35. Romanovsky, A. A., et al., Am. J. Physiol., 273:R407-13, 1997.
    • 36. Sandborn W. J., et al., Ann. Intern. Med, 126:364-71, 1997.
    • 37. Sato, E., et al., Am. J. Physiol., 274:L970-79, 1998.
    • 38. Sato, K. Z., et al., Neurosci. Lett., 266:17-20, 1999.
    • 39. Scheinman, R. I., et al., Science, 270:283-86, 1995.
    • 40. Sher, M. E., et al., Inflamm. Bowel Dis., 5:73-78, 1999.
    • 41. Sternberg, B. M., J. Clin. Invest., 100:2641-47, 1997.
    • 42. Thompson, A., Ed. The Cytokine Handbook, 3.sup.rd ed., Academic Press, 1998.
    • 43. Tracey, K. J. et al., Nature, 330:662-64, 1987.
    • 44. Tracey, K. J. et al., Science, 234:470-74, 1986.
    • 45. Tsutsui, H., et al., Immunol. Rev., 174:192-209, 2000.
    • 46. van Dijk, A. P., et al., Eur. J. Clin. Invest., 28:664-71, 1998.
    • 47. Wang, H., et al., Science, 285:248-51, 1999.
    • 48. Waserman, S., et al., Can. Respir. J., 7:229-37, 2000.
    • 49. Watanabe, H. et al., J. Reconstr. Microsurg., 13:193-97, 1997.
    • 50. Wathey, J. C., et al., Biophys. J., 27:145-64, 1979.
    • 51. Watkins, L. R. and Maier, S. F., Proc. Natl. Acad. Sci. U.S.A., 96:7710-13, 1999.
    • 52. Watkins L. R., et al., Neurosci. Lett. 183:27-31, 1995.
    • 53. Whaley, K., et al., Nature, 293:580-83, 1981.
    • 54. Woiciechowsky, C., et al., Nat. Med., 4: 808-13, 19981.
    • 55. Yeh, S. S., and Schuster, M. W., Am. J. Clin. Nutr., 70, 183-97, 1999.
    • 56. Zhang and Tracey, in The Cytokine Handbook, 3.sup.rd ed., Ed. Thompson, Academic Press, 515-47, 1998.
    • 57. PCT patent publication WO 00/47104.
    • 58. Sambrook, et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 1989.
  • [0163]
    All references cited in this specification are hereby incorporated by reference. The discussion of the references herein is intended merely to summarize the assertions made by the authors and no admission is made that any reference constitutes prior art. Applicants reserve the right to challenge the accuracy and pertinence of the cited references.

Claims (60)

  1. 1-27. (canceled)
  2. 28. A method of treating a subject for a condition caused by an abnormality in said subject's autonomic nervous system, said method comprising: electrically modulating at least a portion of said subject's autonomic nervous system to increase the parasympathetic activity/sympathetic activity ratio to a ratio analogous to that observed in a health subject in a manner effective to treat said subject for said condition, wherein said parasympathetic activity/to sympathetic activity ratio is increased by increasing activity in at least one parasympathetic nerve fiber and inhibiting activity in at least one sympathetic nerve fiber, wherein said at least one sympathetic nerve fiber is a cardiac nerve fiber, wherein said condition is chosen from neurodegenerative diseases, neuroinflammatory diseases, orthopedic diseases, lymphoproliferative diseases, inflammatory diseases, infectious diseases, gastrointestinal disorders, endocrine disorders, genitourinary disorders, skin disorders, conditions that cause hypoxia, conditions that cause hypercarbia, conditions that cause acidosis and Th-2 dominant conditions, wherein said condition is treated by applying electrical energy to at least one of the vagus nerve, cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, sympathetic nerve, sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, cardiac and pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, coccygeal ganglia, greater splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion, lumber splanchnic nerves, and lesser splanchnic nerves.
  3. 29. The method according to claim 28, wherein said abnormality is an abnormally low parasympathetic activity in at least a portion of said subject's autonomic nervous system.
  4. 30. The method according to claim 28, wherein said abnormality is an abnormally high parasympathetic activity in at least a portion of said subject's autonomic nervous system.
  5. 31. The method according to claim 28, wherein said abnormality is an abnormally high sympathetic activity in at least a portion of said subject's autonomic nervous system.
  6. 32. The method according to claim 31, wherein said parasympathetic activity in at least a portion of said subject's autonomic nervous system is normal.
  7. 33. The method according to claim 31, wherein said parasympathetic activity in at least a portion of said subject's autonomic nervous system is abnormally low.
  8. 34. The method according to claim 31, wherein said parasympathetic activity in at least a portion of said subject's autonomic nervous system is abnormally high.
  9. 35. The method of claim 28, wherein said method is employed to treat a neurodegenerative condition by applying electrical energy to at least one of the vagus nerve, cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, sympathetic nerve and sympathetic ganglia.
  10. 36. The method of claim 28, wherein said method is employed to treat orthopedic conditions by applying electrical energy to at least one of the vagus nerve, spinal nerves, postganglionic fibers to spinal nerves and sympathetic chain ganglia.
  11. 37. The method of claim 28, wherein said method is employed to treat neuroinflammatory conditions by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac and pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  12. 38. The method of claim 28, wherein said method is employed to treat lymphoproliferative conditions by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac and pulmonary plexus, celiac plexus, hypogastric plexus, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  13. 39. The method of claim 28, wherein said method is employed to treat inflammatory conditions by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac and pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  14. 40. The method of claim 28, wherein said method is employed to treat infectious diseases by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac and pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  15. 41. The method of claim 28, wherein said method is a method of treating gastrointestinal conditions by applying electrical energy to at least one of the vagus nerve, celiac plexus, hypogastric plexus, pelvic nerves, sympathetic chain ganglia, coccygeal ganglia, cardiac plexus, pulmonary plexus, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  16. 42. The method of claim 28, wherein said method is a method of treating endocrine disorders by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac plexus, pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  17. 43. The method of claim 28, wherein said method is a method of treating genitourinary conditions by applying electrical energy to at least one of the vagus nerve, cardiac plexus, pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  18. 44. The method of claim 28, wherein said method is a method of treating skin conditions by applying electrical energy to at least one of the vagus nerve, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia and coccygeal ganglia.
  19. 45. The method of claim 28, wherein said method is a method of treating Th-2 dominant conditions by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac plexus, pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  20. 46. The method of claim 28, wherein said method is a method of treating conditions that cause hypoxia, by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac plexus, pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  21. 47. The method of claim 28, wherein said method is a method of treating conditions that cause hypercarbia, by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac plexus, pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  22. 48. The method of claim 28, wherein said method is a method of treating conditions that cause acidosis by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac plexus, pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  23. 49. The method according to claim 28, wherein said parasympathetic activity/to sympathetic activity ratio is increased by increasing activity in at least one parasympathetic nerve fiber.
  24. 50. The method of claim 49, wherein said at least one nerve fiber is a vagus nerve fiber.
  25. 51. The method according to claim 28, wherein increasing said activity in at least one parasympathetic nerve fiber is performed at the same time as inhibiting activity in at least one sympathetic nerve fiber.
  26. 52. The method according to claim 51, wherein increasing said activity in at least one parasympathetic nerve fiber is performed before or after inhibiting activity in at least one sympathetic nerve fiber.
  27. 53. The method according to claim 28, wherein an implanted electrostimulatory device is employed to electrically modulate said subject's autonomic nervous system.
  28. 54. The method according to claim 28, wherein said method further comprises pharmacologically modulating said at least a portion of said autonomic nervous system.
  29. 55. The method according to claim 54, wherein said pharmacological modulation is performed at the same time as said electrical modulation.
  30. 56. The method according to claim 54, wherein said pharmacological modulation is performed before or after said electrical modulation.
  31. 57. A computer-readable medium comprising programming for electrically modulating at least a portion of a subject's autonomic nervous system according to claim 44.
  32. 58. A kit comprising: (a) an electrostimulatory device; and (b) instructions for practicing the method of claim 44.
  33. 59. The kit according to claim 58, wherein said electrostimulatory device is an implantable device.
  34. 60. The kit according to claim 58, wherein said kit further comprises at least one pharmacological agent for modulating at least a portion of said autonomic nervous system.
  35. 61. The kit according to claim 58, further comprising an introducer needle for introducing said electrostimulatory device into the body of a subject.
  36. 62. The kit of claim 58, further comprising a computer-readable medium according to claim 57.
  37. 63. A method of treating a subject for a condition caused by an abnormality in said subject's autonomic nervous system, said method comprising: electrically modulating at least a portion of said subject's autonomic nervous system to increase the parasympathetic activity/sympathetic activity ratio in a manner effective to treat said subject for said condition, wherein said method is employed to treat a neurodegenerative condition by applying electrical energy to at least one of the vagus nerve, cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, sympathetic nerve and sympathetic ganglia.
  38. 64. A method of treating a subject for a condition caused by an abnormality in said subjects autonomic nervous system, said method comprising: electrically modulating at least a portion of said subject's autonomic nervous system to increase the parasympathetic activity/sympathetic activity ratio in a manner effective to treat said subject for said condition, wherein said method is employed to treat orthopedic conditions by applying electrical energy to at least one of the vagus nerve, spinal nerves, postganglionic fibers to spinal nerves and sympathetic chain ganglia.
  39. 65. A method of treating a subject for a condition caused by an abnormality in said subject's autonomic nervous system, said method comprising; electrically modulating at least a portion of said subject's autonomic nervous system to increase the parasympathetic activity/sympathetic activity ratio in a manner effective to treat said subject for said condition, wherein said method is employed to treat neuroinflammatory conditions by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac and pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, cardiac and pulmonary plexus, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  40. 66. A method of treating a subject for a condition caused by an abnormality in said subject's autonomic nervous system, said method comprising: electrically modulating at least a portion of said subject's autonomic nervous system to increase the parasympathetic activity/sympathetic activity ratio in a manner effective to treat said subject for said condition, wherein said method is employed to treat lymphoproliferative conditions by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac and pulmonary plexus, celiac plexus, hypogastric plexus, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, cardiac and pulmonary plexus, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  41. 67. A method of treating a subject for a condition caused by an abnormality in said subject's autonomic nervous system, said method comprising: electrically modulating at least a portion of said subject's autonomic nervous system to increase the parasympathetic activity/sympathetic activity ratio in a manner effective to treat said subject for said condition, wherein said method is employed to treat inflammatory conditions by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac and pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, cardiac and pulmonary plexus, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  42. 68. A method of treating a subject for a condition caused by an abnormality in said subject's autonomic nervous system, said method comprising: electrically modulating at least a portion of said subject's autonomic nervous system to increase the parasympathetic activity/sympathetic activity ratio in a manner effective to treat said subject for said condition, wherein said method is employed to treat infectious diseases by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac and pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, cardiac and pulmonary plexus, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  43. 69. A method of treating a subject for a condition caused by an abnormality in said subject's autonomic nervous system, said method comprising: electrically modulating at least a portion of said subject's autonomic nervous system to increase the parasympathetic activity/sympathetic activity ratio in a manner effective to treat said subject for said condition, wherein said method is a method of treating Th-2 dominant conditions by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac plexus, pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  44. 70. A method of treating a subject for a condition caused by an abnormality in said subject's autonomic nervous system, said method comprising: electrically modulating at least a portion of said subject's autonomic nervous system to increase the parasympathetic activity/sympathetic activity ratio in a manner effective to treat said subject for said condition, wherein said method is a method of treating conditions that cause hypoxia, by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac plexus, pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  45. 71. A method of treating a subject for a condition caused by an abnormality in said subject's autonomic nervous system, said method comprising: electrically modulating at least a portion of said subject's autonomic nervous system to increase the parasympathetic activity/sympathetic activity ratio in a manner effective to treat said subject for said condition, wherein said method is a method of treating conditions that cause hypercarbia, by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac plexus, pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  46. 72. A method of treating a subject for a condition caused by an abnormality in said subject's autonomic nervous system, said method comprising: electrically modulating at least a portion of said subject's autonomic nervous system to increase the parasympathetic activity/sympathetic activity ratio in a manner effective to treat said subject for said condition, wherein said method is a method of treating conditions that cause acidosis by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac plexus, pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  47. 73. A method of treating a subject for a condition caused by an abnormality in said subject's autonomic nervous system, said method comprising: electrically modulating at least a portion of said subject's autonomic nervous system to increase the parasympathetic activity/sympathetic activity ratio to a ratio analogous to that observed in a health subject in a manner effective to treat said subject for said condition, wherein said parasympathetic activity/to sympathetic activity ratio is increased by increasing activity in at least one parasympathetic nerve fiber and inhibiting activity in at least one sympathetic nerve fiber, wherein said condition is chosen from cardiovascular diseases, neurodegenerative diseases, neuroinflammatory diseases, orthopedic diseases, lymphoproliferative diseases, inflammatory diseases, infectious diseases, gastrointestinal disorders, endocrine disorders, genitourinary disorders, skin disorders, conditions that cause hypoxia, conditions that cause hypercarbia, conditions that cause acidosis, Th-2 dominant conditions, wherein said method is employed to treat a neurodegenerative condition by applying electrical energy to at least one of the vagus nerve, cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, sympathetic nerve and sympathetic ganglia wherein said method is further employed to treat a second condition by applying electrical energy to at least one of the vagus nerve, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, cardiac plexus and pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  48. 74. The method of claim 73, wherein said method is further employed to treat orthopedic conditions by applying electrical energy to at least one of the vagus nerve, spinal nerves, postganglionic fibers to spinal nerves and sympathetic chain ganglia.
  49. 75. The method of claim 73, wherein said method is further employed to treat neuroinflammatory conditions by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac and pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  50. 76. The method of claim 73, wherein said method is further employed to treat lymphoproliferative conditions by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac and pulmonary plexus, celiac plexus, hypogastric plexus, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  51. 77. The method of claim 73, wherein said method is further employed to treat inflammatory conditions by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac and pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  52. 78. The method of claim 73, wherein said method is further employed to treat infectious diseases by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac and pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  53. 79. The method of claim 73, wherein said method is a method of treating gastrointestinal conditions by applying electrical energy to at least one of the vagus nerve, celiac plexus, hypogastric plexus, pelvic nerves, sympathetic chain ganglia, coccygeal ganglia, cardiac plexus, pulmonary plexus, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  54. 80. The method of claim 73, wherein said method is a method of treating endocrine disorders by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac plexus, pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  55. 81. The method of claim 73, wherein said method is a method of treating genitourinary conditions by applying electrical energy to at least one of the vagus nerve, cardiac plexus, pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  56. 82. The method of claim 73, wherein said method is a method of treating skin conditions by applying electrical energy to at least one of the vagus nerve, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia and coccygeal ganglia.
  57. 83. The method of claim 73, wherein said method is a method of treating Th-2 dominant conditions by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac plexus, pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  58. 84. The method of claim 73, wherein said method is a method of treating conditions that cause hypoxia, by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac plexus, pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  59. 85. The method of claim 73, wherein said method is a method of treating conditions that cause hypercarbia, by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac plexus, pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
  60. 86. The method of claim 73, wherein said method is a method of treating conditions that cause acidosis by applying electrical energy to at least one of the cranial nerve III, cranial nerve VII, cranial nerve IX, sphenopalatine ganglion, ciliary ganglion, submandibular ganglion, otic ganglion, vagus nerve, cardiac plexus, pulmonary plexus, celiac plexus, hypogastric plexus, pelvic nerves, cervical sympathetic ganglia, spinal nerves, postganglionic fibers to spinal nerves, sympathetic chain ganglia, coccygeal ganglia, greater splanchnic nerve, lesser splanchnic nerve, inferior mesenteric ganglion, celiac ganglion, superior mesenteric ganglion and lumber splanchnic nerves.
US12109334 2000-05-23 2008-04-24 Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation Abandoned US20090248097A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US20636400 true 2000-05-23 2000-05-23
US09855446 US6610713B2 (en) 2000-05-23 2001-05-15 Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation
US10446625 US6838471B2 (en) 2000-05-23 2003-05-28 Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation
US10990938 US8914114B2 (en) 2000-05-23 2004-11-17 Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation
US12109334 US20090248097A1 (en) 2000-05-23 2008-04-24 Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US12109334 US20090248097A1 (en) 2000-05-23 2008-04-24 Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10990938 Continuation US8914114B2 (en) 2000-05-23 2004-11-17 Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation

Publications (1)

Publication Number Publication Date
US20090248097A1 true true US20090248097A1 (en) 2009-10-01

Family

ID=46303330

Family Applications (4)

Application Number Title Priority Date Filing Date
US10990938 Active 2023-07-29 US8914114B2 (en) 2000-05-23 2004-11-17 Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation
US12109334 Abandoned US20090248097A1 (en) 2000-05-23 2008-04-24 Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation
US14569504 Pending US20150100100A1 (en) 2000-05-23 2014-12-12 Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation
US15616855 Pending US20170266448A1 (en) 2000-05-23 2017-06-07 Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US10990938 Active 2023-07-29 US8914114B2 (en) 2000-05-23 2004-11-17 Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation

Family Applications After (2)

Application Number Title Priority Date Filing Date
US14569504 Pending US20150100100A1 (en) 2000-05-23 2014-12-12 Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation
US15616855 Pending US20170266448A1 (en) 2000-05-23 2017-06-07 Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation

Country Status (1)

Country Link
US (4) US8914114B2 (en)

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011025524A1 (en) * 2009-08-26 2011-03-03 The Feinstein Institute For Medical Research Methods for treating conditions mediated by the inflammatory cytokine cascade using gapdh inhibitors
US20110152967A1 (en) * 2009-03-20 2011-06-23 ElectroCore, LLC. Non-invasive treatment of neurodegenerative diseases
US8412338B2 (en) 2008-11-18 2013-04-02 Setpoint Medical Corporation Devices and methods for optimizing electrode placement for anti-inflamatory stimulation
US8571654B2 (en) 2012-01-17 2013-10-29 Cyberonics, Inc. Vagus nerve neurostimulator with multiple patient-selectable modes for treating chronic cardiac dysfunction
US8577458B1 (en) 2011-12-07 2013-11-05 Cyberonics, Inc. Implantable device for providing electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction with leadless heart rate monitoring
US8600505B2 (en) 2011-12-07 2013-12-03 Cyberonics, Inc. Implantable device for facilitating control of electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction
US8612002B2 (en) 2009-12-23 2013-12-17 Setpoint Medical Corporation Neural stimulation devices and systems for treatment of chronic inflammation
US8630709B2 (en) 2011-12-07 2014-01-14 Cyberonics, Inc. Computer-implemented system and method for selecting therapy profiles of electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction
US8688212B2 (en) 2012-07-20 2014-04-01 Cyberonics, Inc. Implantable neurostimulator-implemented method for managing bradycardia through vagus nerve stimulation
US8700150B2 (en) 2012-01-17 2014-04-15 Cyberonics, Inc. Implantable neurostimulator for providing electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction with bounded titration
US8788034B2 (en) 2011-05-09 2014-07-22 Setpoint Medical Corporation Single-pulse activation of the cholinergic anti-inflammatory pathway to treat chronic inflammation
US8886339B2 (en) 2009-06-09 2014-11-11 Setpoint Medical Corporation Nerve cuff with pocket for leadless stimulator
US8918191B2 (en) 2011-12-07 2014-12-23 Cyberonics, Inc. Implantable device for providing electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction with bounded titration
US8918190B2 (en) 2011-12-07 2014-12-23 Cyberonics, Inc. Implantable device for evaluating autonomic cardiovascular drive in a patient suffering from chronic cardiac dysfunction
US8923964B2 (en) 2012-11-09 2014-12-30 Cyberonics, Inc. Implantable neurostimulator-implemented method for enhancing heart failure patient awakening through vagus nerve stimulation
US8996116B2 (en) 2009-10-30 2015-03-31 Setpoint Medical Corporation Modulation of the cholinergic anti-inflammatory pathway to treat pain or addiction
US9211410B2 (en) 2009-05-01 2015-12-15 Setpoint Medical Corporation Extremely low duty-cycle activation of the cholinergic anti-inflammatory pathway to treat chronic inflammation
US9272143B2 (en) 2014-05-07 2016-03-01 Cyberonics, Inc. Responsive neurostimulation for the treatment of chronic cardiac dysfunction
US9409024B2 (en) 2014-03-25 2016-08-09 Cyberonics, Inc. Neurostimulation in a neural fulcrum zone for the treatment of chronic cardiac dysfunction
US9415224B2 (en) 2014-04-25 2016-08-16 Cyberonics, Inc. Neurostimulation and recording of physiological response for the treatment of chronic cardiac dysfunction
WO2016137926A1 (en) * 2015-02-24 2016-09-01 Creasey Graham H Topical nerve stimulator and sensor for control of autonomic function
US9452290B2 (en) 2012-11-09 2016-09-27 Cyberonics, Inc. Implantable neurostimulator-implemented method for managing tachyarrhythmia through vagus nerve stimulation
US9504832B2 (en) 2014-11-12 2016-11-29 Cyberonics, Inc. Neurostimulation titration process via adaptive parametric modification
US9511228B2 (en) 2014-01-14 2016-12-06 Cyberonics, Inc. Implantable neurostimulator-implemented method for managing hypertension through renal denervation and vagus nerve stimulation
US9533153B2 (en) 2014-08-12 2017-01-03 Cyberonics, Inc. Neurostimulation titration process
US9572983B2 (en) 2012-03-26 2017-02-21 Setpoint Medical Corporation Devices and methods for modulation of bone erosion
US9643011B2 (en) 2013-03-14 2017-05-09 Cyberonics, Inc. Implantable neurostimulator-implemented method for managing tachyarrhythmic risk during sleep through vagus nerve stimulation
US9643008B2 (en) 2012-11-09 2017-05-09 Cyberonics, Inc. Implantable neurostimulator-implemented method for enhancing post-exercise recovery through vagus nerve stimulation
US9662490B2 (en) 2008-03-31 2017-05-30 The Feinstein Institute For Medical Research Methods and systems for reducing inflammation by neuromodulation and administration of an anti-inflammatory drug
US9713719B2 (en) 2014-04-17 2017-07-25 Cyberonics, Inc. Fine resolution identification of a neural fulcrum for the treatment of chronic cardiac dysfunction
US9737716B2 (en) 2014-08-12 2017-08-22 Cyberonics, Inc. Vagus nerve and carotid baroreceptor stimulation system
US9770599B2 (en) 2014-08-12 2017-09-26 Cyberonics, Inc. Vagus nerve stimulation and subcutaneous defibrillation system
US9833621B2 (en) 2011-09-23 2017-12-05 Setpoint Medical Corporation Modulation of sirtuins by vagus nerve stimulation
US9950169B2 (en) 2014-04-25 2018-04-24 Cyberonics, Inc. Dynamic stimulation adjustment for identification of a neural fulcrum

Families Citing this family (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8571653B2 (en) * 2001-08-31 2013-10-29 Bio Control Medical (B.C.M.) Ltd. Nerve stimulation techniques
US20040048795A1 (en) * 2002-02-26 2004-03-11 North Shore-Long Island Jewish Research Institute Inhibition of inflammatory cytokine production by stimulation of brain muscarinic receptors
US7238715B2 (en) * 2002-12-06 2007-07-03 The Feinstein Institute For Medical Research Treatment of pancreatitis using alpha 7 receptor-binding cholinergic agonists
US20040226556A1 (en) 2003-05-13 2004-11-18 Deem Mark E. Apparatus for treating asthma using neurotoxin
US8024050B2 (en) 2003-12-24 2011-09-20 Cardiac Pacemakers, Inc. Lead for stimulating the baroreceptors in the pulmonary artery
US7869881B2 (en) 2003-12-24 2011-01-11 Cardiac Pacemakers, Inc. Baroreflex stimulator with integrated pressure sensor
US8126560B2 (en) 2003-12-24 2012-02-28 Cardiac Pacemakers, Inc. Stimulation lead for stimulating the baroreceptors in the pulmonary artery
US8729129B2 (en) 2004-03-25 2014-05-20 The Feinstein Institute For Medical Research Neural tourniquet
US8200331B2 (en) * 2004-11-04 2012-06-12 Cardiac Pacemakers, Inc. System and method for filtering neural stimulation
US8812112B2 (en) * 2005-11-10 2014-08-19 ElectroCore, LLC Electrical treatment of bronchial constriction
US9037247B2 (en) 2005-11-10 2015-05-19 ElectroCore, LLC Non-invasive treatment of bronchial constriction
US20100241188A1 (en) * 2009-03-20 2010-09-23 Electrocore, Inc. Percutaneous Electrical Treatment Of Tissue
CN101674862A (en) * 2005-11-10 2010-03-17 电子核心公司 Electrical stimulation treatment of bronchial constriction
US20070106337A1 (en) * 2005-11-10 2007-05-10 Electrocore, Inc. Methods And Apparatus For Treating Disorders Through Neurological And/Or Muscular Intervention
US20090234417A1 (en) * 2005-11-10 2009-09-17 Electrocore, Inc. Methods And Apparatus For The Treatment Of Metabolic Disorders
US7630760B2 (en) * 2005-11-21 2009-12-08 Cardiac Pacemakers, Inc. Neural stimulation therapy system for atherosclerotic plaques
CN101400403A (en) 2006-02-10 2009-04-01 电子核心公司 Methods and apparatus for treating anaphylaxis using electrical modulation
JP2009525806A (en) 2006-02-10 2009-07-16 エレクトロコア、インコーポレイテッド Low blood pressure electrical stimulation therapy
US8041428B2 (en) 2006-02-10 2011-10-18 Electrocore Llc Electrical stimulation treatment of hypotension
US20090157138A1 (en) * 2006-04-18 2009-06-18 Electrocore, Inc. Methods And Apparatus For Treating Ileus Condition Using Electrical Signals
US20100057178A1 (en) * 2006-04-18 2010-03-04 Electrocore, Inc. Methods and apparatus for spinal cord stimulation using expandable electrode
US8170668B2 (en) 2006-07-14 2012-05-01 Cardiac Pacemakers, Inc. Baroreflex sensitivity monitoring and trending for tachyarrhythmia detection and therapy
US7904176B2 (en) * 2006-09-07 2011-03-08 Bio Control Medical (B.C.M.) Ltd. Techniques for reducing pain associated with nerve stimulation
US8391970B2 (en) 2007-08-27 2013-03-05 The Feinstein Institute For Medical Research Devices and methods for inhibiting granulocyte activation by neural stimulation
US8160695B2 (en) * 2007-12-05 2012-04-17 The Invention Science Fund I, Llc System for chemical modulation of neural activity
US8180447B2 (en) 2007-12-05 2012-05-15 The Invention Science Fund I, Llc Method for reversible chemical modulation of neural activity
US8483831B1 (en) 2008-02-15 2013-07-09 Holaira, Inc. System and method for bronchial dilation
US9211409B2 (en) 2008-03-31 2015-12-15 The Feinstein Institute For Medical Research Methods and systems for reducing inflammation by neuromodulation of T-cell activity
US8682449B2 (en) 2008-04-10 2014-03-25 ElectroCore, LLC Methods and apparatus for transcranial stimulation
US8401650B2 (en) * 2008-04-10 2013-03-19 Electrocore Llc Methods and apparatus for electrical treatment using balloon and electrode
US8543211B2 (en) 2008-04-10 2013-09-24 ElectroCore, LLC Methods and apparatus for deep brain stimulation
ES2398052T3 (en) 2008-05-09 2013-03-13 Innovative Pulmonary Solutions, Inc. Systems for treating bronchial tree
US8209034B2 (en) * 2008-12-18 2012-06-26 Electrocore Llc Methods and apparatus for electrical stimulation treatment using esophageal balloon and electrode
CA2779135A1 (en) 2009-10-27 2011-05-12 Innovative Pulmonary Solutions, Inc. Delivery devices with coolable energy emitting assemblies
CN106618731A (en) 2009-11-11 2017-05-10 赫莱拉公司 Systems, apparatuses, and methods for treating tissue and controlling stenosis
US8911439B2 (en) 2009-11-11 2014-12-16 Holaira, Inc. Non-invasive and minimally invasive denervation methods and systems for performing the same
US8865641B2 (en) 2011-06-16 2014-10-21 The Feinstein Institute For Medical Research Methods of treatment of fatty liver disease by pharmacological activation of cholinergic pathways
US9398933B2 (en) 2012-12-27 2016-07-26 Holaira, Inc. Methods for improving drug efficacy including a combination of drug administration and nerve modulation
US20160243358A1 (en) * 2015-02-24 2016-08-25 Neurostim Solutions LLC Topical Nerve Stimulator and Sensor for Control of Autonomic Function

Citations (97)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6168778A (en) *
US3363623A (en) * 1965-07-28 1968-01-16 Charles F. Atwell Hand-held double-acting nerve reflex massager
US4073296A (en) * 1976-01-02 1978-02-14 Mccall Francis J Apparatus for acupressure treatment
US4503863A (en) * 1979-06-29 1985-03-12 Katims Jefferson J Method and apparatus for transcutaneous electrical stimulation
US4573481A (en) * 1984-06-25 1986-03-04 Huntington Institute Of Applied Research Implantable electrode array
US4590946A (en) * 1984-06-14 1986-05-27 Biomed Concepts, Inc. Surgically implantable electrode for nerve bundles
US4649936A (en) * 1984-10-11 1987-03-17 Case Western Reserve University Asymmetric single electrode cuff for generation of unidirectionally propagating action potentials for collision blocking
US4929734A (en) * 1987-03-31 1990-05-29 Warner-Lambert Company Tetrahydropyridine oxime compounds
US4991578A (en) * 1989-04-04 1991-02-12 Siemens-Pacesetter, Inc. Method and system for implanting self-anchoring epicardial defibrillation electrodes
US5019648A (en) * 1987-07-06 1991-05-28 Dana-Farber Cancer Institute Monoclonal antibody specific for the adhesion function domain of a phagocyte cell surface protein
US5106853A (en) * 1989-05-15 1992-04-21 Merck Sharp & Dohme, Ltd. Oxadiazole and its salts, their use in treating dementia
US5111815A (en) * 1990-10-15 1992-05-12 Cardiac Pacemakers, Inc. Method and apparatus for cardioverter/pacer utilizing neurosensing
US5179950A (en) * 1989-11-13 1993-01-19 Cyberonics, Inc. Implanted apparatus having micro processor controlled current and voltage sources with reduced voltage levels when not providing stimulation
US5186170A (en) * 1989-11-13 1993-02-16 Cyberonics, Inc. Simultaneous radio frequency and magnetic field microprocessor reset circuit
US5188104A (en) * 1991-02-01 1993-02-23 Cyberonics, Inc. Treatment of eating disorders by nerve stimulation
US5203326A (en) * 1991-12-18 1993-04-20 Telectronics Pacing Systems, Inc. Antiarrhythmia pacer using antiarrhythmia pacing and autonomic nerve stimulation therapy
US5205285A (en) * 1991-06-14 1993-04-27 Cyberonics, Inc. Voice suppression of vagal stimulation
US5299569A (en) * 1991-05-03 1994-04-05 Cyberonics, Inc. Treatment of neuropsychiatric disorders by nerve stimulation
US5403845A (en) * 1991-08-27 1995-04-04 University Of Toledo Muscarinic agonists
US5487756A (en) * 1994-12-23 1996-01-30 Simon Fraser University Implantable cuff having improved closure
US5496938A (en) * 1990-06-11 1996-03-05 Nexstar Pharmaceuticals, Inc. Nucleic acid ligands to HIV-RT and HIV-1 rev
US5503978A (en) * 1990-06-11 1996-04-02 University Research Corporation Method for identification of high affinity DNA ligands of HIV-1 reverse transcriptase
US5604231A (en) * 1995-01-06 1997-02-18 Smith; Carr J. Pharmaceutical compositions for prevention and treatment of ulcerative colitis
US5611350A (en) * 1996-02-08 1997-03-18 John; Michael S. Method and apparatus for facilitating recovery of patients in deep coma
US5618818A (en) * 1996-03-20 1997-04-08 The University Of Toledo Muscarinic agonist compounds
US6017891A (en) * 1994-05-06 2000-01-25 Baxter Aktiengesellschaft Stable preparation for the treatment of blood coagulation disorders
US6028186A (en) * 1991-06-10 2000-02-22 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands of cytokines
US6051017A (en) * 1996-02-20 2000-04-18 Advanced Bionics Corporation Implantable microstimulator and systems employing the same
US6168778B1 (en) * 1990-06-11 2001-01-02 Nexstar Pharmaceuticals, Inc. Vascular endothelial growth factor (VEGF) Nucleic Acid Ligand Complexes
US6171795B1 (en) * 1999-07-29 2001-01-09 Nexstar Pharmaceuticals, Inc. Nucleic acid ligands to CD40ligand
US6205359B1 (en) * 1998-10-26 2001-03-20 Birinder Bob Boveja Apparatus and method for adjunct (add-on) therapy of partial complex epilepsy, generalized epilepsy and involuntary movement disorders utilizing an external stimulator
US6208902B1 (en) * 1998-10-26 2001-03-27 Birinder Bob Boveja Apparatus and method for adjunct (add-on) therapy for pain syndromes utilizing an implantable lead and an external stimulator
US6210321B1 (en) * 1999-07-29 2001-04-03 Adm Tronics Unlimited, Inc. Electronic stimulation system for treating tinnitus disorders
US6224862B1 (en) * 1996-03-20 2001-05-01 Baxter Aktiengesellschaft Pharmaceutical preparation for treating blood coagulation disorders
US6233488B1 (en) * 1999-06-25 2001-05-15 Carl A. Hess Spinal cord stimulation as a treatment for addiction to nicotine and other chemical substances
US20010002441A1 (en) * 1998-10-26 2001-05-31 Boveja Birinder R. Electrical stimulation adjunct (add-on) therapy for urinary incontinence and urological disorders using an external stimulator
US6337997B1 (en) * 1998-04-30 2002-01-08 Medtronic, Inc. Implantable seizure warning system
US6339725B1 (en) * 1996-05-31 2002-01-15 The Board Of Trustees Of Southern Illinois University Methods of modulating aspects of brain neural plasticity by vagus nerve stimulation
US6341236B1 (en) * 1999-04-30 2002-01-22 Ivan Osorio Vagal nerve stimulation techniques for treatment of epileptic seizures
US20020026141A1 (en) * 1999-11-04 2002-02-28 Medtronic, Inc. System for pancreatic stimulation and glucose measurement
US6356787B1 (en) * 2000-02-24 2002-03-12 Electro Core Techniques, Llc Method of treating facial blushing by electrical stimulation of the sympathetic nerve chain
US6356788B2 (en) * 1998-10-26 2002-03-12 Birinder Bob Boveja Apparatus and method for adjunct (add-on) therapy for depression, migraine, neuropsychiatric disorders, partial complex epilepsy, generalized epilepsy and involuntary movement disorders utilizing an external stimulator
US20020040035A1 (en) * 2000-08-18 2002-04-04 Myers Jason K. Quinuclidine-substituted aryl compounds for treatment of disease
US6381499B1 (en) * 1996-02-20 2002-04-30 Cardiothoracic Systems, Inc. Method and apparatus for using vagus nerve stimulation in surgery
US20030018367A1 (en) * 2001-07-23 2003-01-23 Dilorenzo Daniel John Method and apparatus for neuromodulation and phsyiologic modulation for the treatment of metabolic and neuropsychiatric disease
US6511500B1 (en) * 2000-06-06 2003-01-28 Marc Mounir Rahme Use of autonomic nervous system neurotransmitters inhibition and atrial parasympathetic fibers ablation for the treatment of atrial arrhythmias and to preserve drug effects
US6528529B1 (en) * 1998-03-31 2003-03-04 Acadia Pharmaceuticals Inc. Compounds with activity on muscarinic receptors
US20030045909A1 (en) * 2001-08-31 2003-03-06 Biocontrol Medical Ltd. Selective nerve fiber stimulation for treating heart conditions
US6532388B1 (en) * 1996-04-30 2003-03-11 Medtronic, Inc. Method and system for endotracheal/esophageal stimulation prior to and during a medical procedure
US6542774B2 (en) * 1996-04-30 2003-04-01 Medtronic, Inc. Method and device for electronically controlling the beating of a heart
US20030088301A1 (en) * 2001-11-07 2003-05-08 King Gary William Electrical tissue stimulation apparatus and method
US20040015202A1 (en) * 2002-06-14 2004-01-22 Chandler Gilbert S. Combination epidural infusion/stimulation method and system
US6684105B2 (en) * 2001-08-31 2004-01-27 Biocontrol Medical, Ltd. Treatment of disorders by unidirectional nerve stimulation
US20040024422A1 (en) * 2000-09-26 2004-02-05 Hill Michael R.S. Method and system for sensing cardiac contractions during a medical procedure
US20040024439A1 (en) * 2000-10-11 2004-02-05 Riso Ronald R. Nerve cuff electrode
US6690973B2 (en) * 2000-09-26 2004-02-10 Medtronic, Inc. Method and system for spinal cord stimulation prior to and during a medical procedure
US20040039427A1 (en) * 2001-01-02 2004-02-26 Cyberonics, Inc. Treatment of obesity by sub-diaphragmatic nerve stimulation
US20040049121A1 (en) * 2002-09-06 2004-03-11 Uri Yaron Positioning system for neurological procedures in the brain
US6718208B2 (en) * 1996-04-30 2004-04-06 Medtronic, Inc. Method and system for nerve stimulation prior to and during a medical procedure
US6721603B2 (en) * 2002-01-25 2004-04-13 Cyberonics, Inc. Nerve stimulation as a treatment for pain
US6838471B2 (en) * 2000-05-23 2005-01-04 North Shore-Long Island Jewish Research Institute Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation
US20050021092A1 (en) * 2003-06-09 2005-01-27 Yun Anthony Joonkyoo Treatment of conditions through modulation of the autonomic nervous system
US20050027328A1 (en) * 2000-09-26 2005-02-03 Transneuronix, Inc. Minimally invasive surgery placement of stimulation leads in mediastinal structures
USRE38705E1 (en) * 1996-04-30 2005-02-22 Medtronic, Inc. Method and device for electronically controlling the beating of a heart using venous electrical stimulation of nerve fibers
US20050043774A1 (en) * 2003-05-06 2005-02-24 Aspect Medical Systems, Inc System and method of assessment of the efficacy of treatment of neurological disorders using the electroencephalogram
US20050049655A1 (en) * 2003-08-27 2005-03-03 Boveja Birinder R. System and method for providing electrical pulses to the vagus nerve(s) to provide therapy for obesity, eating disorders, neurological and neuropsychiatric disorders with a stimulator, comprising bi-directional communication and network capabilities
US20050065553A1 (en) * 2003-06-13 2005-03-24 Omry Ben Ezra Applications of vagal stimulation
US20050065575A1 (en) * 2002-09-13 2005-03-24 Dobak John D. Dynamic nerve stimulation for treatment of disorders
US20050070970A1 (en) * 2003-09-29 2005-03-31 Knudson Mark B. Movement disorder stimulation with neural block
US20050070974A1 (en) * 2003-09-29 2005-03-31 Knudson Mark B. Obesity and eating disorder stimulation treatment with neural block
US20050075702A1 (en) * 2003-10-01 2005-04-07 Medtronic, Inc. Device and method for inhibiting release of pro-inflammatory mediator
US20050075701A1 (en) * 2003-10-01 2005-04-07 Medtronic, Inc. Device and method for attenuating an immune response
US6879859B1 (en) * 1998-10-26 2005-04-12 Birinder R. Boveja External pulse generator for adjunct (add-on) treatment of obesity, eating disorders, neurological, neuropsychiatric, and urological disorders
US6885888B2 (en) * 2000-01-20 2005-04-26 The Cleveland Clinic Foundation Electrical stimulation of the sympathetic nerve chain
US20060009815A1 (en) * 2002-05-09 2006-01-12 Boveja Birinder R Method and system to provide therapy or alleviate symptoms of involuntary movement disorders by providing complex and/or rectangular electrical pulses to vagus nerve(s)
US20060015151A1 (en) * 2003-03-14 2006-01-19 Aldrich William N Method of using endoscopic truncal vagoscopy with gastric bypass, gastric banding and other procedures
US20060025828A1 (en) * 2004-07-28 2006-02-02 Armstrong Randolph K Impedance measurement for an implantable device
US20060036293A1 (en) * 2004-08-16 2006-02-16 Whitehurst Todd K Methods for treating gastrointestinal disorders
US20060052831A1 (en) * 2003-03-24 2006-03-09 Terumo Corporation Heart treatment equipment and heart treatment method
US20060052836A1 (en) * 2004-09-08 2006-03-09 Kim Daniel H Neurostimulation system
US20060052657A9 (en) * 2003-12-30 2006-03-09 Jacob Zabara Systems and methods for therapeutically treating neuro-psychiatric disorders and other illnesses
US7011638B2 (en) * 2000-11-14 2006-03-14 Science Medicus, Inc. Device and procedure to treat cardiac atrial arrhythmias
US20060058851A1 (en) * 2004-07-07 2006-03-16 Valerio Cigaina Treatment of the autonomic nervous system
US20060064139A1 (en) * 2002-06-24 2006-03-23 Jong-Pil Chung Electric stimilator for alpha-wave derivation
US20060064137A1 (en) * 2003-05-16 2006-03-23 Stone Robert T Method and system to control respiration by means of simulated action potential signals
US20060074473A1 (en) * 2004-03-23 2006-04-06 Michael Gertner Methods and devices for combined gastric restriction and electrical stimulation
US20060074450A1 (en) * 2003-05-11 2006-04-06 Boveja Birinder R System for providing electrical pulses to nerve and/or muscle using an implanted stimulator
US20060079936A1 (en) * 2003-05-11 2006-04-13 Boveja Birinder R Method and system for altering regional cerebral blood flow (rCBF) by providing complex and/or rectangular electrical pulses to vagus nerve(s), to provide therapy for depression and other medical disorders
US7167751B1 (en) * 2001-03-01 2007-01-23 Advanced Bionics Corporation Method of using a fully implantable miniature neurostimulator for vagus nerve stimulation
US7167750B2 (en) * 2003-02-03 2007-01-23 Enteromedics, Inc. Obesity treatment with electrically induced vagal down regulation
US20070055324A1 (en) * 2003-11-26 2007-03-08 Thompson David L Multi-mode coordinator for medical device function
US7191012B2 (en) * 2003-05-11 2007-03-13 Boveja Birinder R Method and system for providing pulsed electrical stimulation to a craniel nerve of a patient to provide therapy for neurological and neuropsychiatric disorders
US20070067004A1 (en) * 2002-05-09 2007-03-22 Boveja Birinder R Methods and systems for modulating the vagus nerve (10th cranial nerve) to provide therapy for neurological, and neuropsychiatric disorders
US7204815B2 (en) * 2004-08-11 2007-04-17 Georgia K. Connor Mastoid ear cuff and system
US7209787B2 (en) * 1998-08-05 2007-04-24 Bioneuronics Corporation Apparatus and method for closed-loop intracranial stimulation for optimal control of neurological disease
US20070093434A1 (en) * 2003-02-13 2007-04-26 Luciano Rossetti Regulation of food intake and glucose production by modulation of long-chain fatty acyl-coa levels in the hypothalamus
US20110054569A1 (en) * 2009-09-01 2011-03-03 Zitnik Ralph J Prescription pad for treatment of inflammatory disorders

Family Cites Families (289)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2164121A (en) 1938-05-04 1939-06-27 Pescador Hector Electric hearing apparatus for the deaf
FR2315274B1 (en) 1975-06-27 1979-08-10 Parcor
US4098277A (en) 1977-01-28 1978-07-04 Sherwin Mendell Fitted, integrally molded device for stimulating auricular acupuncture points and method of making the device
US4305402A (en) 1979-06-29 1981-12-15 Katims Jefferson J Method for transcutaneous electrical stimulation
US4867164A (en) 1983-09-14 1989-09-19 Jacob Zabara Neurocybernetic prosthesis
US4702254A (en) 1983-09-14 1987-10-27 Jacob Zabara Neurocybernetic prosthesis
US5025807A (en) 1983-09-14 1991-06-25 Jacob Zabara Neurocybernetic prosthesis
US4632095A (en) 1984-11-05 1986-12-30 Tamiko Inc. Pressure-point attachment for use with electrical hand-held massagers
US4930516B1 (en) 1985-11-13 1998-08-04 Laser Diagnostic Instr Inc Method for detecting cancerous tissue using visible native luminescence
US4935234A (en) 1987-06-11 1990-06-19 Dana-Farber Cancer Institute Method of reducing tissue damage at an inflammatory site using a monoclonal antibody
US4840793A (en) 1987-06-11 1989-06-20 Dana-Farber Cancer Institute Method of reducing tissue damage at an inflammatory site using a monoclonal antibody
DE3736664A1 (en) 1987-10-29 1989-05-11 Boehringer Ingelheim Kg Tetrahydro-furo and thieno (2,3-c) pyridines, their use as medicaments and processes for their preparation
US5038781A (en) 1988-01-21 1991-08-13 Hassan Hamedi Multi-electrode neurological stimulation apparatus
US5049659A (en) 1988-02-09 1991-09-17 Dana Farber Cancer Institute Proteins which induce immunological effector cell activation and chemattraction
US4920979A (en) 1988-10-12 1990-05-01 Huntington Medical Research Institute Bidirectional helical electrode for nerve stimulation
US4979511A (en) 1989-11-03 1990-12-25 Cyberonics, Inc. Strain relief tether for implantable electrode
US5235980A (en) 1989-11-13 1993-08-17 Cyberonics, Inc. Implanted apparatus disabling switching regulator operation to allow radio frequency signal reception
US5154172A (en) 1989-11-13 1992-10-13 Cyberonics, Inc. Constant current sources with programmable voltage source
US6083696A (en) 1990-06-11 2000-07-04 Nexstar Pharmaceuticals, Inc. Systematic evolution of ligands exponential enrichment: blended selex
US5683867A (en) 1990-06-11 1997-11-04 Nexstar Pharmaceuticals, Inc. Systematic evolution of ligands by exponential enrichment: blended SELEX
US6124449A (en) 1990-06-11 2000-09-26 Nexstar Pharmaceuticals, Inc. High affinity TGFβ nucleic acid ligands and inhibitors
US5705337A (en) 1990-06-11 1998-01-06 Nexstar Pharmaceuticals, Inc. Systematic evolution of ligands by exponential enrichment: chemi-SELEX
US5472841A (en) 1990-06-11 1995-12-05 Nexstar Pharmaceuticals, Inc. Methods for identifying nucleic acid ligands of human neutrophil elastase
US5654151A (en) 1990-06-11 1997-08-05 Nexstar Pharmaceuticals, Inc. High affinity HIV Nucleocapsid nucleic acid ligands
US6147204A (en) 1990-06-11 2000-11-14 Nexstar Pharmaceuticals, Inc. Nucleic acid ligand complexes
US5637459A (en) 1990-06-11 1997-06-10 Nexstar Pharmaceuticals, Inc. Systematic evolution of ligands by exponential enrichment: chimeric selex
DE69133513D1 (en) 1990-06-11 2006-04-27 Gilead Sciences Inc A process for Vervendung of nucleic acid ligands
US5567588A (en) 1990-06-11 1996-10-22 University Research Corporation Systematic evolution of ligands by exponential enrichment: Solution SELEX
US5726017A (en) 1990-06-11 1998-03-10 Nexstar Pharmaceuticals, Inc. High affinity HIV-1 gag nucleic acid ligands
US6127119A (en) 1990-06-11 2000-10-03 Nexstar Pharmaceuticals, Inc. Nucleic acid ligands of tissue target
US5580737A (en) 1990-06-11 1996-12-03 Nexstar Pharmaceuticals, Inc. High-affinity nucleic acid ligands that discriminate between theophylline and caffeine
US5712375A (en) 1990-06-11 1998-01-27 Nexstar Pharmaceuticals, Inc. Systematic evolution of ligands by exponential enrichment: tissue selex
US5073560A (en) 1990-07-20 1991-12-17 Fisons Corporation Spiro-isoxazolidine derivatives as cholinergic agents
US5263480A (en) 1991-02-01 1993-11-23 Cyberonics, Inc. Treatment of eating disorders by nerve stimulation
US5269303A (en) 1991-02-22 1993-12-14 Cyberonics, Inc. Treatment of dementia by nerve stimulation
US5251634A (en) 1991-05-03 1993-10-12 Cyberonics, Inc. Helical nerve electrode
US5215086A (en) 1991-05-03 1993-06-01 Cyberonics, Inc. Therapeutic treatment of migraine symptoms by stimulation
US5335657A (en) 1991-05-03 1994-08-09 Cyberonics, Inc. Therapeutic treatment of sleep disorder by nerve stimulation
EP0600916A4 (en) 1991-07-22 1995-11-02 Cyberonics Inc Treatment of respiratory disorders by nerve stimulation.
US5222494A (en) 1991-07-31 1993-06-29 Cyberonics, Inc. Implantable tissue stimulator output stabilization system
US5231988A (en) 1991-08-09 1993-08-03 Cyberonics, Inc. Treatment of endocrine disorders by nerve stimulation
US5582981A (en) 1991-08-14 1996-12-10 Gilead Sciences, Inc. Method for identifying an oligonucleotide aptamer specific for a target
US5215089A (en) 1991-10-21 1993-06-01 Cyberonics, Inc. Electrode assembly for nerve stimulation
US5304206A (en) 1991-11-18 1994-04-19 Cyberonics, Inc. Activation techniques for implantable medical device
US5237991A (en) 1991-11-19 1993-08-24 Cyberonics, Inc. Implantable medical device with dummy load for pre-implant testing in sterile package and facilitating electrical lead connection
US5330507A (en) 1992-04-24 1994-07-19 Medtronic, Inc. Implantable electrical vagal stimulation for prevention or interruption of life threatening arrhythmias
US5330515A (en) 1992-06-17 1994-07-19 Cyberonics, Inc. Treatment of pain by vagal afferent stimulation
WO1994005288A1 (en) 1992-08-31 1994-03-17 University Of Florida Anabaseine derivatives useful in the treatment of degenerative diseases of the nervous system
US5977144A (en) 1992-08-31 1999-11-02 University Of Florida Methods of use and compositions for benzylidene- and cinnamylidene-anabaseines
DE4447855B4 (en) * 1993-02-10 2008-10-16 Siemens Ag Use of a source of pulse-like waves, namely for the treatment of pain conditions and apparatus for such use
US5344438A (en) 1993-04-16 1994-09-06 Medtronic, Inc. Cuff electrode
CA2163966A1 (en) 1993-06-01 1994-12-08 Judith A. Kelleher Alkaline and acid phosphatase inhibitors in treatment of neurological disorders
US5594106A (en) * 1993-08-23 1997-01-14 Immunex Corporation Inhibitors of TNF-α secretion
US5599984A (en) 1994-01-21 1997-02-04 The Picower Institute For Medical Research Guanylhydrazones and their use to treat inflammatory conditions
JP3269125B2 (en) 1994-01-28 2002-03-25 東レ株式会社 Atopic dermatitis treatment
DE69520569T2 (en) 1994-04-22 2001-10-04 Sanquin Bloedvoorziening agent for the treatment of disorders of the blood coagulation process
US5458625A (en) 1994-05-04 1995-10-17 Kendall; Donald E. Transcutaneous nerve stimulation device and method for using same
US6405732B1 (en) 1994-06-24 2002-06-18 Curon Medical, Inc. Method to treat gastric reflux via the detection and ablation of gastro-esophageal nerves and receptors
DK0777671T3 (en) 1994-08-24 2000-07-24 Astrazeneca Ab Spiro-azabicyclic compounds
US5531778A (en) 1994-09-20 1996-07-02 Cyberonics, Inc. Circumneural electrode assembly
US5540734A (en) 1994-09-28 1996-07-30 Zabara; Jacob Cranial nerve stimulation treatments using neurocybernetic prosthesis
US5571150A (en) 1994-12-19 1996-11-05 Cyberonics, Inc. Treatment of patients in coma by nerve stimulation
US5540730A (en) 1995-06-06 1996-07-30 Cyberonics, Inc. Treatment of motility disorders by nerve stimulation
US5707400A (en) 1995-09-19 1998-01-13 Cyberonics, Inc. Treating refractory hypertension by nerve stimulation
US5700282A (en) 1995-10-13 1997-12-23 Zabara; Jacob Heart rhythm stabilization using a neurocybernetic prosthesis
WO1997014473A1 (en) 1995-10-18 1997-04-24 Novartis Ag Thermopile powered transdermal drug delivery device
US6140490A (en) 1996-02-01 2000-10-31 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands of complement system proteins
US6096728A (en) 1996-02-09 2000-08-01 Amgen Inc. Composition and method for treating inflammatory diseases
US5651378A (en) 1996-02-20 1997-07-29 Cardiothoracic Systems, Inc. Method of using vagal nerve stimulation in surgery
EP0885221B1 (en) 1996-02-23 2002-06-12 AstraZeneca AB Azabicyclic esters of carbamic acids useful in therapy
DE59712479D1 (en) 1996-03-21 2005-12-22 Biotronik Gmbh & Co Kg The implantable stimulation electrode
US5690681A (en) 1996-03-29 1997-11-25 Purdue Research Foundation Method and apparatus using vagal stimulation for control of ventricular rate during atrial fibrillation
US5726179A (en) 1996-04-01 1998-03-10 The University Of Toledo Muscarinic agonists
US7269457B2 (en) 1996-04-30 2007-09-11 Medtronic, Inc. Method and system for vagal nerve stimulation with multi-site cardiac pacing
US7225019B2 (en) 1996-04-30 2007-05-29 Medtronic, Inc. Method and system for nerve stimulation and cardiac sensing prior to and during a medical procedure
US6735471B2 (en) 1996-04-30 2004-05-11 Medtronic, Inc. Method and system for endotracheal/esophageal stimulation prior to and during a medical procedure
US5853005A (en) 1996-05-02 1998-12-29 The United States Of America As Represented By The Secretary Of The Army Acoustic monitoring system
US5792210A (en) 1996-06-10 1998-08-11 Environmental Behavior Modification Inc. Electrical tongue stimulator and method for addiction treatment
JPH1094613A (en) 1996-08-02 1998-04-14 Mieko Sato Appetite adjusting implement
US5718912A (en) 1996-10-28 1998-02-17 Merck & Co., Inc. Muscarine agonists
WO1998020868A1 (en) 1996-11-15 1998-05-22 The Picower Institute For Medical Research Guanylhydrazones useful for treating diseases associated with t cell activation
US6164284A (en) 1997-02-26 2000-12-26 Schulman; Joseph H. System of implantable devices for monitoring and/or affecting body parameters
US5788656A (en) 1997-02-28 1998-08-04 Mino; Alfonso Di Electronic stimulation system for treating tinnitus disorders
US5919216A (en) 1997-06-16 1999-07-06 Medtronic, Inc. System and method for enhancement of glucose production by stimulation of pancreatic beta cells
CA2296031C (en) 1997-07-18 2008-01-08 Astra Aktiebolag Novel spiroazabicyclic heterocyclic compounds
US5824027A (en) 1997-08-14 1998-10-20 Simon Fraser University Nerve cuff having one or more isolated chambers
US6479523B1 (en) 1997-08-26 2002-11-12 Emory University Pharmacologic drug combination in vagal-induced asystole
US6011005A (en) 1997-09-18 2000-01-04 The Picower Institute For Medical Research Prevention of pregnancy miscarriages
US6141590A (en) 1997-09-25 2000-10-31 Medtronic, Inc. System and method for respiration-modulated pacing
US5928272A (en) 1998-05-02 1999-07-27 Cyberonics, Inc. Automatic activation of a neurostimulator device using a detection algorithm based on cardiac activity
US6002964A (en) 1998-07-15 1999-12-14 Feler; Claudio A. Epidural nerve root stimulation
US7242984B2 (en) 1998-08-05 2007-07-10 Neurovista Corporation Apparatus and method for closed-loop intracranial stimulation for optimal control of neurological disease
US20060116736A1 (en) 2001-07-23 2006-06-01 Dilorenzo Daniel J Method, apparatus, and surgical technique for autonomic neuromodulation for the treatment of obesity
US8762065B2 (en) 1998-08-05 2014-06-24 Cyberonics, Inc. Closed-loop feedback-driven neuromodulation
US20060167498A1 (en) 2001-07-23 2006-07-27 Dilorenzo Daniel J Method, apparatus, and surgical technique for autonomic neuromodulation for the treatment of disease
US6668191B1 (en) 1998-10-26 2003-12-23 Birinder R. Boveja Apparatus and method for electrical stimulation adjunct (add-on) therapy of atrial fibrillation, inappropriate sinus tachycardia, and refractory hypertension with an external stimulator
US6269270B1 (en) 1998-10-26 2001-07-31 Birinder Bob Boveja Apparatus and method for adjunct (add-on) therapy of Dementia and Alzheimer's disease utilizing an implantable lead and external stimulator
US6615081B1 (en) 1998-10-26 2003-09-02 Birinder R. Boveja Apparatus and method for adjunct (add-on) treatment of diabetes by neuromodulation with an external stimulator
US6564102B1 (en) 1998-10-26 2003-05-13 Birinder R. Boveja Apparatus and method for adjunct (add-on) treatment of coma and traumatic brain injury with neuromodulation using an external stimulator
US20050137644A1 (en) 1998-10-26 2005-06-23 Boveja Birinder R. Method and system for vagal blocking and/or vagal stimulation to provide therapy for obesity and other gastrointestinal disorders
US6611715B1 (en) 1998-10-26 2003-08-26 Birinder R. Boveja Apparatus and method for neuromodulation therapy for obesity and compulsive eating disorders using an implantable lead-receiver and an external stimulator
US5994330A (en) 1998-11-09 1999-11-30 El Khoury; Georges F. Topical application of muscarinic agents such as neostigmine for treatment of acne and other inflammatory conditions
FR2786770B1 (en) 1998-12-04 2001-01-19 Synthelabo Derivatives of 1,4-diazabicyclo [3.2.2.] Nonane, their preparation and their application in therapeutic
US6376675B2 (en) 1999-01-22 2002-04-23 The University Of Toledo Muscarinic receptor agonists
US6303321B1 (en) 1999-02-11 2001-10-16 North Shore-Long Island Jewish Research Institute Methods for diagnosing sepsis
US6166048A (en) 1999-04-20 2000-12-26 Targacept, Inc. Pharmaceutical compositions for inhibition of cytokine production and secretion
EP1198271A4 (en) 1999-06-25 2009-01-21 Univ Emory Devices and methods for vagus nerve stimulation
US6587719B1 (en) 1999-07-01 2003-07-01 Cyberonics, Inc. Treatment of obesity by bilateral vagus nerve stimulation
US6804558B2 (en) 1999-07-07 2004-10-12 Medtronic, Inc. System and method of communicating between an implantable medical device and a remote computer system or health care provider
US20050143781A1 (en) 2003-01-31 2005-06-30 Rafael Carbunaru Methods and systems for patient adjustment of parameters for an implanted stimulator
US6304775B1 (en) 1999-09-22 2001-10-16 Leonidas D. Iasemidis Seizure warning and prediction
US6636767B1 (en) 1999-09-29 2003-10-21 Restore Medical, Inc. Implanatable stimulation device for snoring treatment
US6473644B1 (en) 1999-10-13 2002-10-29 Cyberonics, Inc. Method to enhance cardiac capillary growth in heart failure patients
FR2803186B1 (en) 2000-01-05 2002-08-09 Guy Charvin Method and auditory evoked potentials collection device
US20060085046A1 (en) 2000-01-20 2006-04-20 Ali Rezai Methods of treating medical conditions by transvascular neuromodulation of the autonomic nervous system
EP1272250A4 (en) 2000-04-11 2003-07-09 Univ Texas Gastrointestinal electrical stimulation
US6826428B1 (en) 2000-04-11 2004-11-30 The Board Of Regents Of The University Of Texas System Gastrointestinal electrical stimulation
WO2002026140A1 (en) 2000-09-26 2002-04-04 Medtronic, Inc. Medical method and system for directing blood flow
US6904318B2 (en) 2000-09-26 2005-06-07 Medtronic, Inc. Method and system for monitoring and controlling systemic and pulmonary circulation during a medical procedure
US20060173508A1 (en) 2003-05-16 2006-08-03 Stone Robert T Method and system for treatment of eating disorders by means of neuro-electrical coded signals
US6832114B1 (en) 2000-11-21 2004-12-14 Advanced Bionics Corporation Systems and methods for modulation of pancreatic endocrine secretion and treatment of diabetes
US6633779B1 (en) 2000-11-27 2003-10-14 Science Medicus, Inc. Treatment of asthma and respiratory disease by means of electrical neuro-receptive waveforms
DE60132710D1 (en) 2000-12-01 2008-03-20 Neurosearch As 3-substituted quinuclidine derivatives and their use as nicotinic agonists
US20020086871A1 (en) 2000-12-29 2002-07-04 O'neill Brian Thomas Pharmaceutical composition for the treatment of CNS and other disorders
US6447443B1 (en) 2001-01-13 2002-09-10 Medtronic, Inc. Method for organ positioning and stabilization
US7519421B2 (en) 2001-01-16 2009-04-14 Kenergy, Inc. Vagal nerve stimulation using vascular implanted devices for treatment of atrial fibrillation
WO2002057275A1 (en) 2001-01-17 2002-07-25 University Of Kentucky Research Foundation Boron-containing nicotine analogs for use in the treatment of cns pathologies
US6735475B1 (en) 2001-01-30 2004-05-11 Advanced Bionics Corporation Fully implantable miniature neurostimulator for stimulation as a therapy for headache and/or facial pain
CA2441669C (en) 2001-04-05 2013-01-08 Med-El Elektromedizinische Gerate Ges.M.B.H. Pacemaker for bilateral vocal cord autoparalysis
US7369897B2 (en) 2001-04-19 2008-05-06 Neuro And Cardiac Technologies, Llc Method and system of remotely controlling electrical pulses provided to nerve tissue(s) by an implanted stimulator system for neuromodulation therapies
US20050240229A1 (en) 2001-04-26 2005-10-27 Whitehurst Tood K Methods and systems for stimulation as a therapy for erectile dysfunction
US6928320B2 (en) 2001-05-17 2005-08-09 Medtronic, Inc. Apparatus for blocking activation of tissue or conduction of action potentials while other tissue is being therapeutically activated
US6947782B2 (en) 2001-06-18 2005-09-20 Alfred E. Mann Foundation For Scientific Research Miniature implantable connectors
US7054692B1 (en) 2001-06-22 2006-05-30 Advanced Bionics Corporation Fixation device for implantable microdevices
US6622038B2 (en) 2001-07-28 2003-09-16 Cyberonics, Inc. Treatment of movement disorders by near-diaphragmatic nerve stimulation
US6622047B2 (en) 2001-07-28 2003-09-16 Cyberonics, Inc. Treatment of neuropsychiatric disorders by near-diaphragmatic nerve stimulation
US6600956B2 (en) 2001-08-21 2003-07-29 Cyberonics, Inc. Circumneural electrode assembly
US6622041B2 (en) 2001-08-21 2003-09-16 Cyberonics, Inc. Treatment of congestive heart failure and autonomic cardiovascular drive disorders
US6760626B1 (en) 2001-08-29 2004-07-06 Birinder R. Boveja Apparatus and method for treatment of neurological and neuropsychiatric disorders using programmerless implantable pulse generator system
US7054686B2 (en) 2001-08-30 2006-05-30 Biophan Technologies, Inc. Pulsewidth electrical stimulation
US7974693B2 (en) 2001-08-31 2011-07-05 Bio Control Medical (B.C.M.) Ltd. Techniques for applying, configuring, and coordinating nerve fiber stimulation
US7778711B2 (en) 2001-08-31 2010-08-17 Bio Control Medical (B.C.M.) Ltd. Reduction of heart rate variability by parasympathetic stimulation
US7885709B2 (en) 2001-08-31 2011-02-08 Bio Control Medical (B.C.M.) Ltd. Nerve stimulation for treating disorders
US7734355B2 (en) 2001-08-31 2010-06-08 Bio Control Medical (B.C.M.) Ltd. Treatment of disorders by unidirectional nerve stimulation
US6934583B2 (en) 2001-10-22 2005-08-23 Pacesetter, Inc. Implantable lead and method for stimulating the vagus nerve
US7155284B1 (en) 2002-01-24 2006-12-26 Advanced Bionics Corporation Treatment of hypertension
US20040048795A1 (en) 2002-02-26 2004-03-11 North Shore-Long Island Jewish Research Institute Inhibition of inflammatory cytokine production by stimulation of brain muscarinic receptors
US7269455B2 (en) 2003-02-26 2007-09-11 Pineda Jaime A Method and system for predicting and preventing seizures
US7937145B2 (en) 2002-03-22 2011-05-03 Advanced Neuromodulation Systems, Inc. Dynamic nerve stimulation employing frequency modulation
US7465555B2 (en) 2002-04-02 2008-12-16 Becton, Dickinson And Company Early detection of sepsis
US6978787B1 (en) 2002-04-03 2005-12-27 Michael Broniatowski Method and system for dynamic vocal fold closure with neuro-electrical stimulation
US20030191404A1 (en) 2002-04-08 2003-10-09 Klein George J. Method and apparatus for providing arrhythmia discrimination
WO2003092796A1 (en) 2002-05-03 2003-11-13 Musc Foundation For Research Development Method, apparatus and system for determining effects and optimizing parameters of vagus nerve stimulation
US20050154426A1 (en) 2002-05-09 2005-07-14 Boveja Birinder R. Method and system for providing therapy for neuropsychiatric and neurological disorders utilizing transcranical magnetic stimulation and pulsed electrical vagus nerve(s) stimulation
US20050165458A1 (en) 2002-05-09 2005-07-28 Boveja Birinder R. Method and system to provide therapy for depression using electroconvulsive therapy(ECT) and pulsed electrical stimulation to vagus nerve(s)
US20050216070A1 (en) 2002-05-09 2005-09-29 Boveja Birinder R Method and system for providing therapy for migraine/chronic headache by providing electrical pulses to vagus nerve(s)
US20030212440A1 (en) 2002-05-09 2003-11-13 Boveja Birinder R. Method and system for modulating the vagus nerve (10th cranial nerve) using modulated electrical pulses with an inductively coupled stimulation system
US7076307B2 (en) 2002-05-09 2006-07-11 Boveja Birinder R Method and system for modulating the vagus nerve (10th cranial nerve) with electrical pulses using implanted and external components, to provide therapy neurological and neuropsychiatric disorders
US20050209654A1 (en) 2002-05-09 2005-09-22 Boveja Birinder R Method and system for providing adjunct (add-on) therapy for depression, anxiety and obsessive-compulsive disorders by providing electrical pulses to vagus nerve(s)
US20060116739A1 (en) 2002-05-23 2006-06-01 Nir Betser Electrode assembly for nerve control
US7277761B2 (en) 2002-06-12 2007-10-02 Pacesetter, Inc. Vagal stimulation for improving cardiac function in heart failure or CHF patients
US7292890B2 (en) 2002-06-20 2007-11-06 Advanced Bionics Corporation Vagus nerve stimulation via unidirectional propagation of action potentials
US20040015205A1 (en) 2002-06-20 2004-01-22 Whitehurst Todd K. Implantable microstimulators with programmable multielectrode configuration and uses thereof
US7203548B2 (en) 2002-06-20 2007-04-10 Advanced Bionics Corporation Cavernous nerve stimulation via unidirectional propagation of action potentials
US8579786B2 (en) 2002-10-15 2013-11-12 Medtronic, Inc. Screening techniques for management of a nervous system disorder
WO2004034880A3 (en) 2002-10-15 2004-07-22 Medtronic Inc Timed delay for redelivery of treatment therapy for a medical device system
US8594798B2 (en) 2002-10-15 2013-11-26 Medtronic, Inc. Multi-modal operation of a medical device system
US20040138518A1 (en) 2002-10-15 2004-07-15 Medtronic, Inc. Medical device system with relaying module for treatment of nervous system disorders
US20040146949A1 (en) 2002-10-25 2004-07-29 Jun Tan Methods and compounds for disruption of CD40R/CD40L signaling in the treatment of alzheimer's disease
US20030229380A1 (en) 2002-10-31 2003-12-11 Adams John M. Heart failure therapy device and method
US7305265B2 (en) 2002-11-25 2007-12-04 Terumo Kabushiki Kaisha Heart treatment equipment for treating heart failure
EP1426078A1 (en) 2002-12-04 2004-06-09 Terumo Kabushiki Kaisha Heart treatment equipment for preventing fatal arrhythmia
US7238715B2 (en) 2002-12-06 2007-07-03 The Feinstein Institute For Medical Research Treatment of pancreatitis using alpha 7 receptor-binding cholinergic agonists
DE60317564T2 (en) 2002-12-06 2008-10-23 The Feinstein Institute For Medical Research Inhibition of inflammation using alpha-7 receptor-binding cholinergic agonists
US20040111139A1 (en) 2002-12-10 2004-06-10 Mccreery Douglas B. Apparatus and methods for differential stimulation of nerve fibers
WO2004052450A1 (en) 2002-12-12 2004-06-24 Metin Tulgar Externally activated neuro-implant which directly transmits therapeutic signals
JP2004201901A (en) 2002-12-25 2004-07-22 Yoshimi Kurokawa Stomach electrostimulator
US8064994B2 (en) 2003-01-14 2011-11-22 The United States Of America As Represented By The Department Of Veterans Affairs Cervical vagal stimulation induced weight loss
EP1596805A2 (en) 2003-01-15 2005-11-23 Alfred E. Mann Institute for Biomedical Engineering at the University of Southern California Treatments for snoring using injectable neuromuscular stimulators
US20040172084A1 (en) 2003-02-03 2004-09-02 Knudson Mark B. Method and apparatus for treatment of gastro-esophageal reflux disease (GERD)
US7783358B2 (en) 2003-03-14 2010-08-24 Endovx, Inc. Methods and apparatus for treatment of obesity with an ultrasound device movable in two or three axes
US7430449B2 (en) 2003-03-14 2008-09-30 Endovx, Inc. Methods and apparatus for testing disruption of a vagal nerve
US6814418B2 (en) 2003-03-14 2004-11-09 D'orso Ronald Locker organizer
US7155279B2 (en) 2003-03-28 2006-12-26 Advanced Bionics Corporation Treatment of movement disorders with drug therapy
US20040199209A1 (en) 2003-04-07 2004-10-07 Hill Michael R.S. Method and system for delivery of vasoactive drugs to the heart prior to and during a medical procedure
US7228167B2 (en) 2003-04-10 2007-06-05 Mayo Foundation For Medical Education Method and apparatus for detecting vagus nerve stimulation
US7065412B2 (en) 2003-04-25 2006-06-20 Medtronic, Inc. Implantable trial neurostimulation device
US7706871B2 (en) 2003-05-06 2010-04-27 Nellcor Puritan Bennett Llc System and method of prediction of response to neurological treatment using the electroencephalogram
DE10320863B3 (en) 2003-05-09 2004-11-11 Siemens Audiologische Technik Gmbh Fixing of a hearing aid or an ear mold in the ear
US20050187590A1 (en) 2003-05-11 2005-08-25 Boveja Birinder R. Method and system for providing therapy for autism by providing electrical pulses to the vagus nerve(s)
US20050197678A1 (en) 2003-05-11 2005-09-08 Boveja Birinder R. Method and system for providing therapy for Alzheimer's disease and dementia by providing electrical pulses to vagus nerve(s)
US7444184B2 (en) 2003-05-11 2008-10-28 Neuro And Cardial Technologies, Llc Method and system for providing therapy for bulimia/eating disorders by providing electrical pulses to vagus nerve(s)
EP1628707A4 (en) 2003-05-16 2008-04-09 Neurosignal Technologies Inc Respiratory control by means of neuro-electrical coded signals
US20060111755A1 (en) 2003-05-16 2006-05-25 Stone Robert T Method and system to control respiration by means of neuro-electrical coded signals
US20060287679A1 (en) 2003-05-16 2006-12-21 Stone Robert T Method and system to control respiration by means of confounding neuro-electrical signals
US7620454B2 (en) 2003-05-19 2009-11-17 Medtronic, Inc. Gastro-electric stimulation for reducing the acidity of gastric secretions or reducing the amounts thereof
US7742818B2 (en) 2003-05-19 2010-06-22 Medtronic, Inc. Gastro-electric stimulation for increasing the acidity of gastric secretions or increasing the amounts thereof
JP4213522B2 (en) 2003-05-30 2009-01-21 テルモ株式会社 Heart treatment equipment
US7738952B2 (en) 2003-06-09 2010-06-15 Palo Alto Investors Treatment of conditions through modulation of the autonomic nervous system
US7321793B2 (en) 2003-06-13 2008-01-22 Biocontrol Medical Ltd. Vagal stimulation for atrial fibrillation therapy
EP1648560A4 (en) 2003-06-13 2015-10-28 Biocontrol Medical Ltd Vagal stimulation for anti-embolic therapy
US8036745B2 (en) 2004-06-10 2011-10-11 Bio Control Medical (B.C.M.) Ltd. Parasympathetic pacing therapy during and following a medical procedure, clinical trauma or pathology
DE10328816A1 (en) 2003-06-21 2005-01-05 Biotronik Meß- und Therapiegeräte GmbH & Co. Ingenieurbüro Berlin The implantable stimulation electrode having a coating to increase the tissue compatibility
US20050096256A1 (en) 2003-07-01 2005-05-05 President And Fellows Of Harvard College Compositions for manipulating the lifespan and stress response of cells and organisms
US20080208266A1 (en) 2003-07-18 2008-08-28 The Johns Hopkins University System and Method for Treating Nausea and Vomiting by Vagus Nerve Stimulation
US7174218B1 (en) 2003-08-12 2007-02-06 Advanced Bionics Corporation Lead extension system for use with a microstimulator
JP4439215B2 (en) 2003-08-26 2010-03-24 テルモ株式会社 Heart treatment equipment
US20050153885A1 (en) 2003-10-08 2005-07-14 Yun Anthony J. Treatment of conditions through modulation of the autonomic nervous system
US7062320B2 (en) 2003-10-14 2006-06-13 Ehlinger Jr Philip Charles Device for the treatment of hiccups
US20050180974A1 (en) 2003-10-24 2005-08-18 Medtronic, Inc. Extracellular TNF inhibitors for treating CNS disorders
DE20316509U1 (en) 2003-10-27 2004-03-11 Lukl, Alfred Ear acupressure and massage unit covers whole ear and applies sprung pins from commercial massage unit
US20050131467A1 (en) 2003-11-02 2005-06-16 Boveja Birinder R. Method and apparatus for electrical stimulation therapy for at least one of atrial fibrillation, congestive heart failure, inappropriate sinus tachycardia, and refractory hypertension
WO2005051232A3 (en) 2003-11-20 2005-12-08 Angiotech Int Ag Soft tissue implants and anti-scarring agents
US20050137645A1 (en) 2003-12-05 2005-06-23 Juha Voipio Novel method for the adjustment of human and animal vagus nerve stimulation
WO2005062829A3 (en) 2003-12-19 2005-10-06 Advanced Bionics Corp Skull-mounted electrical stimulation system and method for treating patients
US20050149129A1 (en) 2003-12-24 2005-07-07 Imad Libbus Baropacing and cardiac pacing to control output
US7486991B2 (en) 2003-12-24 2009-02-03 Cardiac Pacemakers, Inc. Baroreflex modulation to gradually decrease blood pressure
US7460906B2 (en) 2003-12-24 2008-12-02 Cardiac Pacemakers, Inc. Baroreflex stimulation to treat acute myocardial infarction
US8147561B2 (en) 2004-02-26 2012-04-03 Endosphere, Inc. Methods and devices to curb appetite and/or reduce food intake
US7542803B2 (en) 2004-03-16 2009-06-02 Medtronic, Inc. Sensitivity analysis for selecting therapy parameter sets
US8729129B2 (en) 2004-03-25 2014-05-20 The Feinstein Institute For Medical Research Neural tourniquet
EP1750799A2 (en) 2004-05-04 2007-02-14 The Cleveland Clinic Foundation Methods of treating medical conditions by neuromodulation of the sympathetic nervous system
US20060111644A1 (en) 2004-05-27 2006-05-25 Children's Medical Center Corporation Patient-specific seizure onset detection system
EP3006040B1 (en) 2004-06-04 2017-11-22 Washington University Methods and compositions for treating neuropathies
US7565197B2 (en) 2004-06-18 2009-07-21 Medtronic, Inc. Conditional requirements for remote medical device programming
US7711432B2 (en) 2004-07-26 2010-05-04 Advanced Neuromodulation Systems, Inc. Stimulation system and method for treating a neurological disorder
WO2006017634A3 (en) 2004-08-04 2006-11-23 James Coburn Devices, systems, and methods employing a molded nerve cuff electrode
US20050154425A1 (en) 2004-08-19 2005-07-14 Boveja Birinder R. Method and system to provide therapy for neuropsychiatric disorders and cognitive impairments using gradient magnetic pulses to the brain and pulsed electrical stimulation to vagus nerve(s)
US20060161216A1 (en) 2004-10-18 2006-07-20 John Constance M Device for neuromuscular peripheral body stimulation and electrical stimulation (ES) for wound healing using RF energy harvesting
WO2006047264A1 (en) 2004-10-21 2006-05-04 Advanced Neuromodulation Systems, Inc. Peripheral nerve stimulation to treat auditory dysfunction
US7672733B2 (en) 2004-10-29 2010-03-02 Medtronic, Inc. Methods and apparatus for sensing cardiac activity via neurological stimulation therapy system or medical electrical lead
US7818342B2 (en) 2004-11-12 2010-10-19 Sap Ag Tracking usage of data elements in electronic business communications
US8332047B2 (en) 2004-11-18 2012-12-11 Cardiac Pacemakers, Inc. System and method for closed-loop neural stimulation
US9089691B2 (en) 2004-12-07 2015-07-28 Cardiac Pacemakers, Inc. Stimulator for auricular branch of vagus nerve
US7366571B2 (en) 2004-12-10 2008-04-29 Cyberonics, Inc. Neurostimulator with activation based on changes in body temperature
US20060161217A1 (en) 2004-12-21 2006-07-20 Jaax Kristen N Methods and systems for treating obesity
CA2593079C (en) 2004-12-27 2014-08-19 North Shore-Long Island Jewish Research Institute Treating inflammatory disorders by electrical vagus nerve stimulation
US8788044B2 (en) 2005-01-21 2014-07-22 Michael Sasha John Systems and methods for tissue stimulation in medical treatment
US8825166B2 (en) 2005-01-21 2014-09-02 John Sasha John Multiple-symptom medical treatment with roving-based neurostimulation
US8609082B2 (en) 2005-01-25 2013-12-17 Bio Control Medical Ltd. Administering bone marrow progenitor cells or myoblasts followed by application of an electrical current for cardiac repair, increasing blood supply or enhancing angiogenesis
US8600521B2 (en) 2005-01-27 2013-12-03 Cyberonics, Inc. Implantable medical device having multiple electrode/sensor capability and stimulation based on sensed intrinsic activity
US20060173493A1 (en) 2005-01-28 2006-08-03 Cyberonics, Inc. Multi-phasic signal for stimulation by an implantable device
US7548780B2 (en) 2005-02-22 2009-06-16 Cardiac Pacemakers, Inc. Cell therapy and neural stimulation for cardiac repair
US20060200219A1 (en) 2005-03-01 2006-09-07 Ndi Medical, Llc Systems and methods for differentiating and/or identifying tissue regions innervated by targeted nerves for diagnostic and/or therapeutic purposes
US8700163B2 (en) 2005-03-04 2014-04-15 Cyberonics, Inc. Cranial nerve stimulation for treatment of substance addiction
US7613511B2 (en) 2005-03-09 2009-11-03 Cardiac Pacemakers, Inc. Implantable vagal stimulator for treating cardiac ischemia
US7499748B2 (en) 2005-04-11 2009-03-03 Cardiac Pacemakers, Inc. Transvascular neural stimulation device
US20060229681A1 (en) 2005-04-11 2006-10-12 Fischell Robert E Implantable system for the treatment of atrial fibrillation
US7881782B2 (en) 2005-04-20 2011-02-01 Cardiac Pacemakers, Inc. Neural stimulation system to prevent simultaneous energy discharges
US20060282121A1 (en) 2005-04-25 2006-12-14 Payne Bryan R Vagus nerve stimulation for chronic intractable hiccups
US7310557B2 (en) 2005-04-29 2007-12-18 Maschino Steven E Identification of electrodes for nerve stimulation in the treatment of eating disorders
US7899540B2 (en) 2005-04-29 2011-03-01 Cyberonics, Inc. Noninvasively adjustable gastric band
US7835796B2 (en) 2005-04-29 2010-11-16 Cyberonics, Inc. Weight loss method and device
US7734348B2 (en) 2005-05-10 2010-06-08 Cardiac Pacemakers, Inc. System with left/right pulmonary artery electrodes
US7765000B2 (en) 2005-05-10 2010-07-27 Cardiac Pacemakers, Inc. Neural stimulation system with pulmonary artery lead
US7617003B2 (en) 2005-05-16 2009-11-10 Cardiac Pacemakers, Inc. System for selective activation of a nerve trunk using a transvascular reshaping lead
US7584004B2 (en) 2005-06-13 2009-09-01 Cardiac Pacemakers, Inc. Vascularly stabilized peripheral nerve cuff assembly
US8036750B2 (en) 2005-06-13 2011-10-11 Cardiac Pacemakers, Inc. System for neural control of respiration
US20060293721A1 (en) 2005-06-28 2006-12-28 Cyberonics, Inc. Vagus nerve stimulation for treatment of depression with therapeutically beneficial parameter settings
US20070016262A1 (en) 2005-07-13 2007-01-18 Betastim, Ltd. Gi and pancreatic device for treating obesity and diabetes
US7711419B2 (en) 2005-07-13 2010-05-04 Cyberonics, Inc. Neurostimulator with reduced size
US8165693B2 (en) 2005-07-21 2012-04-24 Cyberonics, Inc. Safe-mode implantable medical devices
US20070021786A1 (en) 2005-07-25 2007-01-25 Cyberonics, Inc. Selective nerve stimulation for the treatment of angina pectoris
US20070027497A1 (en) 2005-07-27 2007-02-01 Cyberonics, Inc. Nerve stimulation for treatment of syncope
US20070027504A1 (en) 2005-07-27 2007-02-01 Cyberonics, Inc. Cranial nerve stimulation to treat a hearing disorder
US7840280B2 (en) 2005-07-27 2010-11-23 Cyberonics, Inc. Cranial nerve stimulation to treat a vocal cord disorder
US7706874B2 (en) 2005-07-28 2010-04-27 Cyberonics, Inc. Stimulating cranial nerve to treat disorders associated with the thyroid gland
US8660647B2 (en) 2005-07-28 2014-02-25 Cyberonics, Inc. Stimulating cranial nerve to treat pulmonary disorder
US20070027484A1 (en) 2005-07-28 2007-02-01 Cyberonics, Inc. Autonomic nerve stimulation to treat a pancreatic disorder
US7856273B2 (en) 2005-07-28 2010-12-21 Cyberonics, Inc. Autonomic nerve stimulation to treat a gastrointestinal disorder
US20070027499A1 (en) 2005-07-29 2007-02-01 Cyberonics, Inc. Neurostimulation device for treating mood disorders
US7499752B2 (en) 2005-07-29 2009-03-03 Cyberonics, Inc. Selective nerve stimulation for the treatment of eating disorders
US7532935B2 (en) 2005-07-29 2009-05-12 Cyberonics, Inc. Selective neurostimulation for treating mood disorders
US20070027486A1 (en) 2005-07-29 2007-02-01 Cyberonics, Inc. Medical devices for enhancing intrinsic neural activity
US7860566B2 (en) 2005-10-06 2010-12-28 The Cleveland Clinic Foundation System and method for achieving regular slow ventricular rhythm in response to atrial fibrillation
US7616990B2 (en) 2005-10-24 2009-11-10 Cardiac Pacemakers, Inc. Implantable and rechargeable neural stimulator
US7620455B2 (en) 2005-10-25 2009-11-17 Cyberonics, Inc. Cranial nerve stimulation to treat eating disorders
US7957796B2 (en) 2005-10-28 2011-06-07 Cyberonics, Inc. Using physiological sensor data with an implantable medical device
US7555344B2 (en) 2005-10-28 2009-06-30 Cyberonics, Inc. Selective neurostimulation for treating epilepsy
CN101674862A (en) 2005-11-10 2010-03-17 电子核心公司 Electrical stimulation treatment of bronchial constriction
US7630760B2 (en) 2005-11-21 2009-12-08 Cardiac Pacemakers, Inc. Neural stimulation therapy system for atherosclerotic plaques
US7596414B2 (en) 2005-12-05 2009-09-29 Boston Scientific Neuromodulation Corporation Cuff electrode arrangement for nerve stimulation and methods of treating disorders
US7570999B2 (en) 2005-12-20 2009-08-04 Cardiac Pacemakers, Inc. Implantable device for treating epilepsy and cardiac rhythm disorders
US7672728B2 (en) 2005-12-28 2010-03-02 Cardiac Pacemakers, Inc. Neural stimulator to treat sleep disordered breathing
US9566447B2 (en) 2005-12-28 2017-02-14 Cardiac Pacemakers, Inc. Neural stimulation system for reducing atrial proarrhythmia
CA2680477A1 (en) 2007-03-13 2008-09-18 The Feinstein Institute For Medical Research Treatment of inflammation by non-invasive stimulation
EP2355893B1 (en) 2008-11-18 2013-12-25 Setpoint Medical Corporation Devices for optimizing electrode placement for anti-inflamatory stimulation
WO2011079309A3 (en) 2009-12-23 2011-11-24 Setpoint Medical Corporation Neural stimulation devices and systems for treatment of chronic inflammation
EP2707094B1 (en) 2011-05-09 2016-02-03 Setpoint Medical Corporation Single-pulse activation of the cholinergic anti-inflammatory pathway to treat chronic inflammation

Patent Citations (101)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6168778A (en) *
US3363623A (en) * 1965-07-28 1968-01-16 Charles F. Atwell Hand-held double-acting nerve reflex massager
US4073296A (en) * 1976-01-02 1978-02-14 Mccall Francis J Apparatus for acupressure treatment
US4073296B1 (en) * 1976-01-02 1983-07-19
US4503863A (en) * 1979-06-29 1985-03-12 Katims Jefferson J Method and apparatus for transcutaneous electrical stimulation
US4590946A (en) * 1984-06-14 1986-05-27 Biomed Concepts, Inc. Surgically implantable electrode for nerve bundles
US4573481A (en) * 1984-06-25 1986-03-04 Huntington Institute Of Applied Research Implantable electrode array
US4649936A (en) * 1984-10-11 1987-03-17 Case Western Reserve University Asymmetric single electrode cuff for generation of unidirectionally propagating action potentials for collision blocking
US4929734A (en) * 1987-03-31 1990-05-29 Warner-Lambert Company Tetrahydropyridine oxime compounds
US5019648A (en) * 1987-07-06 1991-05-28 Dana-Farber Cancer Institute Monoclonal antibody specific for the adhesion function domain of a phagocyte cell surface protein
US4991578A (en) * 1989-04-04 1991-02-12 Siemens-Pacesetter, Inc. Method and system for implanting self-anchoring epicardial defibrillation electrodes
US5106853A (en) * 1989-05-15 1992-04-21 Merck Sharp & Dohme, Ltd. Oxadiazole and its salts, their use in treating dementia
US5186170A (en) * 1989-11-13 1993-02-16 Cyberonics, Inc. Simultaneous radio frequency and magnetic field microprocessor reset circuit
US5179950A (en) * 1989-11-13 1993-01-19 Cyberonics, Inc. Implanted apparatus having micro processor controlled current and voltage sources with reduced voltage levels when not providing stimulation
US5496938A (en) * 1990-06-11 1996-03-05 Nexstar Pharmaceuticals, Inc. Nucleic acid ligands to HIV-RT and HIV-1 rev
US5503978A (en) * 1990-06-11 1996-04-02 University Research Corporation Method for identification of high affinity DNA ligands of HIV-1 reverse transcriptase
US6168778B1 (en) * 1990-06-11 2001-01-02 Nexstar Pharmaceuticals, Inc. Vascular endothelial growth factor (VEGF) Nucleic Acid Ligand Complexes
US5111815A (en) * 1990-10-15 1992-05-12 Cardiac Pacemakers, Inc. Method and apparatus for cardioverter/pacer utilizing neurosensing
US5188104A (en) * 1991-02-01 1993-02-23 Cyberonics, Inc. Treatment of eating disorders by nerve stimulation
US5299569A (en) * 1991-05-03 1994-04-05 Cyberonics, Inc. Treatment of neuropsychiatric disorders by nerve stimulation
US6028186A (en) * 1991-06-10 2000-02-22 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands of cytokines
US5205285A (en) * 1991-06-14 1993-04-27 Cyberonics, Inc. Voice suppression of vagal stimulation
US5403845A (en) * 1991-08-27 1995-04-04 University Of Toledo Muscarinic agonists
US5203326A (en) * 1991-12-18 1993-04-20 Telectronics Pacing Systems, Inc. Antiarrhythmia pacer using antiarrhythmia pacing and autonomic nerve stimulation therapy
US6017891A (en) * 1994-05-06 2000-01-25 Baxter Aktiengesellschaft Stable preparation for the treatment of blood coagulation disorders
US5487756A (en) * 1994-12-23 1996-01-30 Simon Fraser University Implantable cuff having improved closure
US5604231A (en) * 1995-01-06 1997-02-18 Smith; Carr J. Pharmaceutical compositions for prevention and treatment of ulcerative colitis
US5611350A (en) * 1996-02-08 1997-03-18 John; Michael S. Method and apparatus for facilitating recovery of patients in deep coma
US6051017A (en) * 1996-02-20 2000-04-18 Advanced Bionics Corporation Implantable microstimulator and systems employing the same
US6381499B1 (en) * 1996-02-20 2002-04-30 Cardiothoracic Systems, Inc. Method and apparatus for using vagus nerve stimulation in surgery
US6224862B1 (en) * 1996-03-20 2001-05-01 Baxter Aktiengesellschaft Pharmaceutical preparation for treating blood coagulation disorders
US5618818A (en) * 1996-03-20 1997-04-08 The University Of Toledo Muscarinic agonist compounds
US7184829B2 (en) * 1996-04-30 2007-02-27 Medtronic, Inc. Method and system for nerve stimulation prior to and during a medical procedure
USRE38705E1 (en) * 1996-04-30 2005-02-22 Medtronic, Inc. Method and device for electronically controlling the beating of a heart using venous electrical stimulation of nerve fibers
US6718208B2 (en) * 1996-04-30 2004-04-06 Medtronic, Inc. Method and system for nerve stimulation prior to and during a medical procedure
US6532388B1 (en) * 1996-04-30 2003-03-11 Medtronic, Inc. Method and system for endotracheal/esophageal stimulation prior to and during a medical procedure
US6542774B2 (en) * 1996-04-30 2003-04-01 Medtronic, Inc. Method and device for electronically controlling the beating of a heart
US6556868B2 (en) * 1996-05-31 2003-04-29 The Board Of Trustees Of Southern Illinois University Methods for improving learning or memory by vagus nerve stimulation
US6339725B1 (en) * 1996-05-31 2002-01-15 The Board Of Trustees Of Southern Illinois University Methods of modulating aspects of brain neural plasticity by vagus nerve stimulation
US6528529B1 (en) * 1998-03-31 2003-03-04 Acadia Pharmaceuticals Inc. Compounds with activity on muscarinic receptors
US6337997B1 (en) * 1998-04-30 2002-01-08 Medtronic, Inc. Implantable seizure warning system
US7209787B2 (en) * 1998-08-05 2007-04-24 Bioneuronics Corporation Apparatus and method for closed-loop intracranial stimulation for optimal control of neurological disease
US6879859B1 (en) * 1998-10-26 2005-04-12 Birinder R. Boveja External pulse generator for adjunct (add-on) treatment of obesity, eating disorders, neurological, neuropsychiatric, and urological disorders
US20010002441A1 (en) * 1998-10-26 2001-05-31 Boveja Birinder R. Electrical stimulation adjunct (add-on) therapy for urinary incontinence and urological disorders using an external stimulator
US6205359B1 (en) * 1998-10-26 2001-03-20 Birinder Bob Boveja Apparatus and method for adjunct (add-on) therapy of partial complex epilepsy, generalized epilepsy and involuntary movement disorders utilizing an external stimulator
US6356788B2 (en) * 1998-10-26 2002-03-12 Birinder Bob Boveja Apparatus and method for adjunct (add-on) therapy for depression, migraine, neuropsychiatric disorders, partial complex epilepsy, generalized epilepsy and involuntary movement disorders utilizing an external stimulator
US6208902B1 (en) * 1998-10-26 2001-03-27 Birinder Bob Boveja Apparatus and method for adjunct (add-on) therapy for pain syndromes utilizing an implantable lead and an external stimulator
US6341236B1 (en) * 1999-04-30 2002-01-22 Ivan Osorio Vagal nerve stimulation techniques for treatment of epileptic seizures
US6233488B1 (en) * 1999-06-25 2001-05-15 Carl A. Hess Spinal cord stimulation as a treatment for addiction to nicotine and other chemical substances
US6171795B1 (en) * 1999-07-29 2001-01-09 Nexstar Pharmaceuticals, Inc. Nucleic acid ligands to CD40ligand
US6210321B1 (en) * 1999-07-29 2001-04-03 Adm Tronics Unlimited, Inc. Electronic stimulation system for treating tinnitus disorders
US20020026141A1 (en) * 1999-11-04 2002-02-28 Medtronic, Inc. System for pancreatic stimulation and glucose measurement
US6885888B2 (en) * 2000-01-20 2005-04-26 The Cleveland Clinic Foundation Electrical stimulation of the sympathetic nerve chain
US6356787B1 (en) * 2000-02-24 2002-03-12 Electro Core Techniques, Llc Method of treating facial blushing by electrical stimulation of the sympathetic nerve chain
US6838471B2 (en) * 2000-05-23 2005-01-04 North Shore-Long Island Jewish Research Institute Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation
US6511500B1 (en) * 2000-06-06 2003-01-28 Marc Mounir Rahme Use of autonomic nervous system neurotransmitters inhibition and atrial parasympathetic fibers ablation for the treatment of atrial arrhythmias and to preserve drug effects
US20020040035A1 (en) * 2000-08-18 2002-04-04 Myers Jason K. Quinuclidine-substituted aryl compounds for treatment of disease
US6690973B2 (en) * 2000-09-26 2004-02-10 Medtronic, Inc. Method and system for spinal cord stimulation prior to and during a medical procedure
US20050027328A1 (en) * 2000-09-26 2005-02-03 Transneuronix, Inc. Minimally invasive surgery placement of stimulation leads in mediastinal structures
US20040024422A1 (en) * 2000-09-26 2004-02-05 Hill Michael R.S. Method and system for sensing cardiac contractions during a medical procedure
US7184828B2 (en) * 2000-09-26 2007-02-27 Medtronic, Inc. Method and system for spinal cord stimulation prior to and during a medical procedure
US20040024439A1 (en) * 2000-10-11 2004-02-05 Riso Ronald R. Nerve cuff electrode
US7011638B2 (en) * 2000-11-14 2006-03-14 Science Medicus, Inc. Device and procedure to treat cardiac atrial arrhythmias
US20040039427A1 (en) * 2001-01-02 2004-02-26 Cyberonics, Inc. Treatment of obesity by sub-diaphragmatic nerve stimulation
US7167751B1 (en) * 2001-03-01 2007-01-23 Advanced Bionics Corporation Method of using a fully implantable miniature neurostimulator for vagus nerve stimulation
US20030018367A1 (en) * 2001-07-23 2003-01-23 Dilorenzo Daniel John Method and apparatus for neuromodulation and phsyiologic modulation for the treatment of metabolic and neuropsychiatric disease
US6684105B2 (en) * 2001-08-31 2004-01-27 Biocontrol Medical, Ltd. Treatment of disorders by unidirectional nerve stimulation
US20030045909A1 (en) * 2001-08-31 2003-03-06 Biocontrol Medical Ltd. Selective nerve fiber stimulation for treating heart conditions
US20030088301A1 (en) * 2001-11-07 2003-05-08 King Gary William Electrical tissue stimulation apparatus and method
US6721603B2 (en) * 2002-01-25 2004-04-13 Cyberonics, Inc. Nerve stimulation as a treatment for pain
US20070067004A1 (en) * 2002-05-09 2007-03-22 Boveja Birinder R Methods and systems for modulating the vagus nerve (10th cranial nerve) to provide therapy for neurological, and neuropsychiatric disorders
US20060009815A1 (en) * 2002-05-09 2006-01-12 Boveja Birinder R Method and system to provide therapy or alleviate symptoms of involuntary movement disorders by providing complex and/or rectangular electrical pulses to vagus nerve(s)
US20040015202A1 (en) * 2002-06-14 2004-01-22 Chandler Gilbert S. Combination epidural infusion/stimulation method and system
US20060064139A1 (en) * 2002-06-24 2006-03-23 Jong-Pil Chung Electric stimilator for alpha-wave derivation
US20040049121A1 (en) * 2002-09-06 2004-03-11 Uri Yaron Positioning system for neurological procedures in the brain
US20050065575A1 (en) * 2002-09-13 2005-03-24 Dobak John D. Dynamic nerve stimulation for treatment of disorders
US7167750B2 (en) * 2003-02-03 2007-01-23 Enteromedics, Inc. Obesity treatment with electrically induced vagal down regulation
US20070093434A1 (en) * 2003-02-13 2007-04-26 Luciano Rossetti Regulation of food intake and glucose production by modulation of long-chain fatty acyl-coa levels in the hypothalamus
US20060015151A1 (en) * 2003-03-14 2006-01-19 Aldrich William N Method of using endoscopic truncal vagoscopy with gastric bypass, gastric banding and other procedures
US20060052831A1 (en) * 2003-03-24 2006-03-09 Terumo Corporation Heart treatment equipment and heart treatment method
US20050043774A1 (en) * 2003-05-06 2005-02-24 Aspect Medical Systems, Inc System and method of assessment of the efficacy of treatment of neurological disorders using the electroencephalogram
US20060079936A1 (en) * 2003-05-11 2006-04-13 Boveja Birinder R Method and system for altering regional cerebral blood flow (rCBF) by providing complex and/or rectangular electrical pulses to vagus nerve(s), to provide therapy for depression and other medical disorders
US7191012B2 (en) * 2003-05-11 2007-03-13 Boveja Birinder R Method and system for providing pulsed electrical stimulation to a craniel nerve of a patient to provide therapy for neurological and neuropsychiatric disorders
US20060074450A1 (en) * 2003-05-11 2006-04-06 Boveja Birinder R System for providing electrical pulses to nerve and/or muscle using an implanted stimulator
US20060064137A1 (en) * 2003-05-16 2006-03-23 Stone Robert T Method and system to control respiration by means of simulated action potential signals
US20050021092A1 (en) * 2003-06-09 2005-01-27 Yun Anthony Joonkyoo Treatment of conditions through modulation of the autonomic nervous system
US20050065553A1 (en) * 2003-06-13 2005-03-24 Omry Ben Ezra Applications of vagal stimulation
US20050049655A1 (en) * 2003-08-27 2005-03-03 Boveja Birinder R. System and method for providing electrical pulses to the vagus nerve(s) to provide therapy for obesity, eating disorders, neurological and neuropsychiatric disorders with a stimulator, comprising bi-directional communication and network capabilities
US20050070974A1 (en) * 2003-09-29 2005-03-31 Knudson Mark B. Obesity and eating disorder stimulation treatment with neural block
US20050070970A1 (en) * 2003-09-29 2005-03-31 Knudson Mark B. Movement disorder stimulation with neural block
US20050075701A1 (en) * 2003-10-01 2005-04-07 Medtronic, Inc. Device and method for attenuating an immune response
US20050075702A1 (en) * 2003-10-01 2005-04-07 Medtronic, Inc. Device and method for inhibiting release of pro-inflammatory mediator
US20070055324A1 (en) * 2003-11-26 2007-03-08 Thompson David L Multi-mode coordinator for medical device function
US20060052657A9 (en) * 2003-12-30 2006-03-09 Jacob Zabara Systems and methods for therapeutically treating neuro-psychiatric disorders and other illnesses
US20060074473A1 (en) * 2004-03-23 2006-04-06 Michael Gertner Methods and devices for combined gastric restriction and electrical stimulation
US20060058851A1 (en) * 2004-07-07 2006-03-16 Valerio Cigaina Treatment of the autonomic nervous system
US20060025828A1 (en) * 2004-07-28 2006-02-02 Armstrong Randolph K Impedance measurement for an implantable device
US7204815B2 (en) * 2004-08-11 2007-04-17 Georgia K. Connor Mastoid ear cuff and system
US20060036293A1 (en) * 2004-08-16 2006-02-16 Whitehurst Todd K Methods for treating gastrointestinal disorders
US20060052836A1 (en) * 2004-09-08 2006-03-09 Kim Daniel H Neurostimulation system
US20110054569A1 (en) * 2009-09-01 2011-03-03 Zitnik Ralph J Prescription pad for treatment of inflammatory disorders

Cited By (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9662490B2 (en) 2008-03-31 2017-05-30 The Feinstein Institute For Medical Research Methods and systems for reducing inflammation by neuromodulation and administration of an anti-inflammatory drug
US8412338B2 (en) 2008-11-18 2013-04-02 Setpoint Medical Corporation Devices and methods for optimizing electrode placement for anti-inflamatory stimulation
US8868177B2 (en) 2009-03-20 2014-10-21 ElectroCore, LLC Non-invasive treatment of neurodegenerative diseases
US20110152967A1 (en) * 2009-03-20 2011-06-23 ElectroCore, LLC. Non-invasive treatment of neurodegenerative diseases
US9211410B2 (en) 2009-05-01 2015-12-15 Setpoint Medical Corporation Extremely low duty-cycle activation of the cholinergic anti-inflammatory pathway to treat chronic inflammation
US9849286B2 (en) 2009-05-01 2017-12-26 Setpoint Medical Corporation Extremely low duty-cycle activation of the cholinergic anti-inflammatory pathway to treat chronic inflammation
US8886339B2 (en) 2009-06-09 2014-11-11 Setpoint Medical Corporation Nerve cuff with pocket for leadless stimulator
US9174041B2 (en) 2009-06-09 2015-11-03 Setpoint Medical Corporation Nerve cuff with pocket for leadless stimulator
US9700716B2 (en) 2009-06-09 2017-07-11 Setpoint Medical Corporation Nerve cuff with pocket for leadless stimulator
US8715658B2 (en) 2009-08-26 2014-05-06 The Feinstein Institute For Medical Research Methods for treating conditions mediated by the inflammatory cytokine cascade using GAPDH inhibitors
WO2011025524A1 (en) * 2009-08-26 2011-03-03 The Feinstein Institute For Medical Research Methods for treating conditions mediated by the inflammatory cytokine cascade using gapdh inhibitors
US8996116B2 (en) 2009-10-30 2015-03-31 Setpoint Medical Corporation Modulation of the cholinergic anti-inflammatory pathway to treat pain or addiction
US9162064B2 (en) 2009-12-23 2015-10-20 Setpoint Medical Corporation Neural stimulation devices and systems for treatment of chronic inflammation
US8855767B2 (en) 2009-12-23 2014-10-07 Setpoint Medical Corporation Neural stimulation devices and systems for treatment of chronic inflammation
US8612002B2 (en) 2009-12-23 2013-12-17 Setpoint Medical Corporation Neural stimulation devices and systems for treatment of chronic inflammation
US8788034B2 (en) 2011-05-09 2014-07-22 Setpoint Medical Corporation Single-pulse activation of the cholinergic anti-inflammatory pathway to treat chronic inflammation
US9833621B2 (en) 2011-09-23 2017-12-05 Setpoint Medical Corporation Modulation of sirtuins by vagus nerve stimulation
US8918191B2 (en) 2011-12-07 2014-12-23 Cyberonics, Inc. Implantable device for providing electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction with bounded titration
US8600505B2 (en) 2011-12-07 2013-12-03 Cyberonics, Inc. Implantable device for facilitating control of electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction
US8923990B2 (en) 2011-12-07 2014-12-30 Cyberonics, Inc. Implantable device for providing electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction with leadless heart rate monitoring
US8577458B1 (en) 2011-12-07 2013-11-05 Cyberonics, Inc. Implantable device for providing electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction with leadless heart rate monitoring
US9114262B2 (en) 2011-12-07 2015-08-25 Cyberonics, Inc. Implantable device for evaluating autonomic cardiovascular drive in a patient suffering from chronic cardiac dysfunction
US8630709B2 (en) 2011-12-07 2014-01-14 Cyberonics, Inc. Computer-implemented system and method for selecting therapy profiles of electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction
US8918190B2 (en) 2011-12-07 2014-12-23 Cyberonics, Inc. Implantable device for evaluating autonomic cardiovascular drive in a patient suffering from chronic cardiac dysfunction
US8700150B2 (en) 2012-01-17 2014-04-15 Cyberonics, Inc. Implantable neurostimulator for providing electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction with bounded titration
US8571654B2 (en) 2012-01-17 2013-10-29 Cyberonics, Inc. Vagus nerve neurostimulator with multiple patient-selectable modes for treating chronic cardiac dysfunction
US8965522B2 (en) 2012-01-17 2015-02-24 Cyberonics, Inc. Implantable neurostimulator for providing electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction with bounded titration
US9526898B2 (en) 2012-01-17 2016-12-27 Cyberonics, Inc. Implantable neurostimulator for providing electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction with bounded titration
US9572983B2 (en) 2012-03-26 2017-02-21 Setpoint Medical Corporation Devices and methods for modulation of bone erosion
US8688212B2 (en) 2012-07-20 2014-04-01 Cyberonics, Inc. Implantable neurostimulator-implemented method for managing bradycardia through vagus nerve stimulation
US9919157B2 (en) 2012-07-20 2018-03-20 Cyberonics, Inc. Implantable neurostimulator-implemented method for managing bradycardia through vagus nerve stimulation
US8923964B2 (en) 2012-11-09 2014-12-30 Cyberonics, Inc. Implantable neurostimulator-implemented method for enhancing heart failure patient awakening through vagus nerve stimulation
US9764138B2 (en) 2012-11-09 2017-09-19 Cyberonics, Inc. Implantable neurostimulator-implemented method for managing tachyarrhythmia through vagus nerve stimulation
US9452290B2 (en) 2012-11-09 2016-09-27 Cyberonics, Inc. Implantable neurostimulator-implemented method for managing tachyarrhythmia through vagus nerve stimulation
US9643008B2 (en) 2012-11-09 2017-05-09 Cyberonics, Inc. Implantable neurostimulator-implemented method for enhancing post-exercise recovery through vagus nerve stimulation
US9393419B2 (en) 2012-11-09 2016-07-19 Cyberonics, Inc. Implantable neurostimulator-implemented method for enhancing heart failure patient awakening through vagus nerve stimulation
US9643011B2 (en) 2013-03-14 2017-05-09 Cyberonics, Inc. Implantable neurostimulator-implemented method for managing tachyarrhythmic risk during sleep through vagus nerve stimulation
US9511228B2 (en) 2014-01-14 2016-12-06 Cyberonics, Inc. Implantable neurostimulator-implemented method for managing hypertension through renal denervation and vagus nerve stimulation
US9669220B2 (en) 2014-03-25 2017-06-06 Cyberonics, Inc. Neurostimulation in a neural fulcrum zone for the treatment of chronic cardiac dysfunction
US9409024B2 (en) 2014-03-25 2016-08-09 Cyberonics, Inc. Neurostimulation in a neural fulcrum zone for the treatment of chronic cardiac dysfunction
US9713719B2 (en) 2014-04-17 2017-07-25 Cyberonics, Inc. Fine resolution identification of a neural fulcrum for the treatment of chronic cardiac dysfunction
US9789316B2 (en) 2014-04-25 2017-10-17 Cyberonics, Inc. Neurostimulation and recording of physiological response for the treatment of chronic cardiac dysfunction
US9415224B2 (en) 2014-04-25 2016-08-16 Cyberonics, Inc. Neurostimulation and recording of physiological response for the treatment of chronic cardiac dysfunction
US9950169B2 (en) 2014-04-25 2018-04-24 Cyberonics, Inc. Dynamic stimulation adjustment for identification of a neural fulcrum
US9272143B2 (en) 2014-05-07 2016-03-01 Cyberonics, Inc. Responsive neurostimulation for the treatment of chronic cardiac dysfunction
US9808626B2 (en) 2014-05-07 2017-11-07 Cyberonics, Inc. Responsive neurostimulation for the treatment of chronic cardiac dysfunction
US9446237B2 (en) 2014-05-07 2016-09-20 Cyberonics, Inc. Responsive neurostimulation for the treatment of chronic cardiac dysfunction
US9737716B2 (en) 2014-08-12 2017-08-22 Cyberonics, Inc. Vagus nerve and carotid baroreceptor stimulation system
US9770599B2 (en) 2014-08-12 2017-09-26 Cyberonics, Inc. Vagus nerve stimulation and subcutaneous defibrillation system
US9533153B2 (en) 2014-08-12 2017-01-03 Cyberonics, Inc. Neurostimulation titration process
US9504832B2 (en) 2014-11-12 2016-11-29 Cyberonics, Inc. Neurostimulation titration process via adaptive parametric modification
WO2016137926A1 (en) * 2015-02-24 2016-09-01 Creasey Graham H Topical nerve stimulator and sensor for control of autonomic function

Also Published As

Publication number Publication date Type
US20150100100A1 (en) 2015-04-09 application
US20170266448A1 (en) 2017-09-21 application
US8914114B2 (en) 2014-12-16 grant
US20050125044A1 (en) 2005-06-09 application

Similar Documents

Publication Publication Date Title
US6518245B1 (en) Treatment of arrhythmias via inhibition of a multifunctional calcium/calmodulin-dependent protein kinase
Laird et al. Opposing roles for reactive astrocytes following traumatic brain injury
US7053087B1 (en) Aminocycloalkyl cinnamide compounds for arrhythmia and analgesics and anesthetics
Chen et al. Angiotensin II and angiotensin II receptor blocker modulate the arrhythmogenic activity of pulmonary veins
Bevan et al. Capsazepine: a competitive antagonist of the sensory neurone excitant capsaicin
US5874420A (en) Process for regulating vagal tone
Khanna et al. Anti–tumor necrosis factor α therapy and heart failure: What have we learned and where do we go from here?
US6919366B2 (en) Benzimidazole derivatives as modulators of IgE
US7238715B2 (en) Treatment of pancreatitis using alpha 7 receptor-binding cholinergic agonists
US20040204355A1 (en) Inhibition of inflammation using alpha 7 receptor-binding cholinergic agonists
Mazayev et al. Valsartan in heart failure patients previously untreated with an ACE inhibitor
US20030055077A1 (en) Method and compositions for the treatment of allergic conditions using pgd2 receptor antagonists
Marcus et al. Carotid body denervation improves autonomic and cardiac function and attenuates disordered breathing in congestive heart failure
US20050148587A1 (en) Thiazolidinone, oxazolidinone, and imidazolone derivatives for treating lower urinary tract and related disorders
Hahn et al. Antihypertensive activity of LY141865, a selective presynaptic dopamine receptor agonist.
Conlon et al. Neuronal nitric oxide facilitates vagal chronotropic and dromotropic actions on the heart
WO1997029739A2 (en) Use of 5ht4 receptor antagonists for overcoming gastrointestinal effects of serotonin reuptake inhibitors
US20060293309A1 (en) Method of treating disorders and conditions using peripherally-restricted antagonists and inhibitors
US20100247517A1 (en) Use of mnk inhibitors for the treatment of alzheimer&#39;s disease
Fischer Histamine in the treatment of vertigo
WO2004067006A1 (en) Combination of a pde iv inhibitor and a tnf-alpha antagonist
US20040048795A1 (en) Inhibition of inflammatory cytokine production by stimulation of brain muscarinic receptors
US20040198775A1 (en) Methods for treating lower urinary tract disorders and the related disorders vulvodynia and vulvar vestibulitis using Cav2.2 subunit calcium channel modulators
Lee et al. Selective muscarinic receptor antagonists for airway diseases
Paton et al. Properties of solitary tract neurons receiving inputs from the sub-diaphragmatic vagus nerve

Legal Events

Date Code Title Description
AS Assignment

Owner name: THE FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH, NEW

Free format text: CHANGE OF NAME;ASSIGNOR:NORTH SHORE-LONG ISLAND JEWISH RESEARCH INSTITUTE;REEL/FRAME:023424/0491

Effective date: 20050707

Owner name: NORTH SHORE-LONG ISLAND JEWISH RESEARCH INSTITUTE,

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:TRACEY, KEVIN J.;HUSTON, JARED M.;REEL/FRAME:023424/0479;SIGNING DATES FROM 20050104 TO 20051011