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 PDFInfo
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- US20090248097A1 US20090248097A1 US12/109,334 US10933408A US2009248097A1 US 20090248097 A1 US20090248097 A1 US 20090248097A1 US 10933408 A US10933408 A US 10933408A US 2009248097 A1 US2009248097 A1 US 2009248097A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
- A61N1/36053—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for vagal stimulation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
- A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
- A61N1/36128—Control systems
- A61N1/36146—Control systems specified by the stimulation parameters
- A61N1/36167—Timing, e.g. stimulation onset
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- Y—GENERAL 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- 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.
- 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).
- endotoxin lipopolysaccharide, LPS
- Inflammation and other deleterious conditions 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).
- TNF tumor necrosis factor
- IL-1.alpha. interleukin-1.alpha.
- IL-1.beta. interleukin-1.beta.
- IL-6 interleukin-1.beta.
- MIF macrophage migration inhibitory factor
- HGM-1 high mobility group protein 1
- HGM-1 high mobility group protein 1
- 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.
- 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 granulo
- 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).
- 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).
- 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.
- 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).
- cholinergic agonists can inhibit an inflammatory cytokine cascade, particularly those mediated by macrophages.
- efferent vagus nerve stimulation is effective in inhibiting these cascades.
- 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.
- 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.
- the cell is a macrophage.
- the proinflammatory cytokine is tumor necrosis factor (TNF), interleukin (L)-1.beta., IL-6, IL-18 or HMG-1, most preferably TNF.
- the cholinergic agonist is acetylcholine, nicotine, muscarine, carbachol, galantamine, arecoline, cevimeline, or levamisole.
- 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, eosinophil
- 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.
- the condition is endotoxic shock.
- the cholinergic agonist treatment is effected by stimulating efferent vagus nerve activity sufficient to inhibit the inflammatory cytokine cascade.
- 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.
- 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, vag
- 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.
- the condition is endotoxic shock.
- the cholinergic agonist treatment can be effected by stimulating efferent vagus nerve activity, preferably electrically.
- 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.
- 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.
- 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.
- the cell is a macrophage and the proinflammatory cytokine is TNF.
- 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.
- 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.
- ACh acetylcholine
- nicotine Nic
- Mus muscarine
- 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.
- 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.
- .alpha.-CTX .alpha.-conotoxin
- ATR atropine
- ACh acetylcholine
- FIG. 5 is a graph summarizing experimental results showing that acetylcholine inhibits IL-1.beta. release from human macrophages in a dose-dependent manner.
- FIG. 6 is a graph summarizing experimental results showing that acetylcholine inhibits IL-6 release from human macrophages in a dose-dependent manner.
- FIG. 7 is a graph summarizing experimental results showing that acetylcholine inhibits IL-18 release from human macrophages in a dose-dependent manner.
- FIG. 8 is a graph summarizing experimental results showing that acetylcholine does not inhibit IL-10 release from human macrophages.
- 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.
- STIM vagus nerve stimulation
- VGX vagotomy
- 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.
- STIM vagus nerve stimulation
- VGX vagotomy
- 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.
- STIM vagus nerve stimulation
- VGX vagotomy
- MABP mean arterial blood pressure
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- the proinflammatory cytokine can also cause apoptosis, such as in chronic heart failure, where TNF has been shown to stimulate cardiomyocyte apoptosis (32; 45).
- 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).
- 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.
- the proinflammatory cytokine is TNF.
- 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.
- 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.
- an inflammatory cytokine cascade is inhibited in embodiments of the invention where proinflammatory cytokine release causes a deleterious physiological condition.
- 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.
- the cell is a macrophage.
- 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.
- the use of the terms “inhibit” or “decrease” encompasses at least a small but measurable reduction in proinflammatory cytokine release.
- 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.
- any cholinergic agonist would be expected to inhibit the release of proinflammatory cytokines from mammalian cells.
- the cholinergic agonist is not otherwise toxic to the cell at useful concentrations.
- 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.
- the cholinergic agonist is acetylcholine, nicotine, or muscarine.
- acetylcholine is not preferred because the compound would be expected to be inactivated very quickly due to the widespread occurrence of acetylcholinesterase in tissues.
- 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.
- the cell is in a patient suffering from, or at risk for, a condition mediated by an inflammatory cytokine cascade.
- a patient can be any mammal.
- the patient is a human.
- 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.
- 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.
- 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,
- 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.
- the condition is endotoxic shock.
- 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.
- the cholinergic agonist can be administered orally, parenterally, intranasally, vaginally, rectally, lingually, sublingually, bucally, intrabuccaly and transdermally to the patient.
- 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.
- 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.
- Tablets, pills, capsules, troches and the like may also contain binders, recipients, disintegrating agent, lubricants, sweetening agents, and flavoring agents.
- binders include microcrystalline cellulose, gum tragacanth or gelatin.
- excipients include starch or lactose.
- disintegrating agents include alginic acid, corn starch and the like.
- lubricants include magnesium stearate or potassium stearate.
- An example of a glidant is colloidal silicon dioxide.
- sweetening agents include sucrose, saccharin and the like.
- 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.
- 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.
- 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.
- 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.
- 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.
- the present invention includes nasally administering to the mammal a therapeutically effective amount of the cholinergic agonist.
- nasally administering or nasal administration includes administering the cholinergic agonist to the mucous membranes of the nasal passage or nasal cavity of the patient.
- 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.
- the cholinergic agonist can be administered to the patient in the form of acetylcholine by stimulating efferent vagus nerve fibers.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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.
- 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).
- 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.
- the patient is suffering from, or at risk for, a condition mediated by the inflammatory cytokine cascade.
- 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.
- 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.
- 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.
- the cell can be any cell that can be induced to produce a proinflammatory cytokine.
- the cell is an immune cell, for example macrophages, monocytes, or neutrophils. In the most preferred embodiments, the cell is a macrophage.
- the proinflammatory cytokine to be measured for inhibition can be any proinflammatory cytokine that can be induced to be released from the cell.
- 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).
- 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.
- 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.
- PBS GibcoBRL, Life Technologies, Rockville, Md.
- RNA 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.).
- 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.).
- MCSF macrophage colony stimulating factor
- MCSF macrophage colony stimulating factor
- FIG. 1 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) were added in the concentrations indicated ( 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).
- TNF inhibition was investigated by measuring TNF mRNA levels in an RNase protection assay.
- 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.
- 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.
- Addition of acetylcholine in concentrations (100 nM) that significantly inhibited IL-1.beta. protein release did not significantly alter macrophage IL-1.beta.
- 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).
- 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 ).
- 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).
- Direct electrical stimulation of the peripheral vagus nerve did not stimulate an increase in either the corticosteroid or the IL-10 responses.
- 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.
- 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).
- Acetylcholine is a vasodilator that mediates nitric oxide-dependent relaxation of resistance blood vessels which causes a decrease in blood pressure.
- vagus nerve stimulation 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.
- these observations indicate that stimulation of efferent vagus nerve activity downregulates systemic TNF production and the development of shock during lethal endotoxemia.
- 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.
- 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.
- FIG. 13 shows the heart rate of the experimental animals.
- the heart rate began to increase in rats stimulated with a high dose (5V) of vagus nerve stimulation.
- 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.
- 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.
- 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.
- 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.
- FIG. 15 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.
- 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.
- 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.
- mice 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.
- NASH National Institutes of Health
- 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.
- 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 LD 50 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).
- Non-Invasive External Cervical Massage is Sufficient to Activate the Cholinergic Anti-Inflammatory Pathway
- VNS murine cervical massage in lethal endotoxemia
- 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.
- a dose response curve for TNF suppression was generated from these stimulation groups and is shown in FIG. 17 .
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
- 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.
- 1. Field of the Invention
- 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.
- 2. Description of the Related Art
- 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).
- 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.
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
-
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. -
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. -
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. -
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. -
FIG. 5 is a graph summarizing experimental results showing that acetylcholine inhibits IL-1.beta. release from human macrophages in a dose-dependent manner. -
FIG. 6 is a graph summarizing experimental results showing that acetylcholine inhibits IL-6 release from human macrophages in a dose-dependent manner. -
FIG. 7 is a graph summarizing experimental results showing that acetylcholine inhibits IL-18 release from human macrophages in a dose-dependent manner. -
FIG. 8 is a graph summarizing experimental results showing that acetylcholine does not inhibit IL-10 release from human macrophages. -
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. -
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. -
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. -
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. -
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. -
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. -
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. -
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. -
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. - 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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.
- 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. - 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.).
- 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.).
- 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. - 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). - 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. - 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. - 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. - 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 ). - 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). - 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. - 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. - 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). - 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.
- 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.
- 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 inFIG. 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 rightcarotid 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. - 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). - 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. - 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.
- 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. - 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*
- Data shown are Mean.+−.SEM, n=7 animals per group. *p<0.05 vs. SHAM+LPS.
-
FIG. 11 shows the results of measurement of mean arterial blood pressure (MABP) in the same groups of animals as inFIGS. 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). - 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. - 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.
- 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.
- 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. - 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. -
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. -
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. - 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.
- 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 aCentricon 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. - 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. - 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.
- In view of the above, it will be seen that the several advantages of the invention are achieved and other advantages attained.
- 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.
- 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.
- 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.
- 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).
- 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. - 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.
- 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. -
- 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.
- 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)
1-27. (canceled)
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
50. The method of claim 49 , wherein said at least one nerve fiber is a vagus nerve fiber.
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.
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.
53. The method according to claim 28 , wherein an implanted electrostimulatory device is employed to electrically modulate said subject's autonomic nervous system.
54. The method according to claim 28 , wherein said method further comprises pharmacologically modulating said at least a portion of said autonomic nervous system.
55. The method according to claim 54 , wherein said pharmacological modulation is performed at the same time as said electrical modulation.
56. The method according to claim 54 , wherein said pharmacological modulation is performed before or after said electrical modulation.
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 .
58. A kit comprising: (a) an electrostimulatory device; and (b) instructions for practicing the method of claim 44 .
59. The kit according to claim 58 , wherein said electrostimulatory device is an implantable device.
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.
61. The kit according to claim 58 , further comprising an introducer needle for introducing said electrostimulatory device into the body of a subject.
62. The kit of claim 58 , further comprising a computer-readable medium according to claim 57 .
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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Cited By (52)
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 |
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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 |
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 |
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 |
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 |
US9643008B2 (en) | 2012-11-09 | 2017-05-09 | Cyberonics, Inc. | Implantable neurostimulator-implemented method for enhancing post-exercise recovery 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 |
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 |
US9987492B2 (en) | 2000-05-23 | 2018-06-05 | The Feinstein Institute For Medical Research | Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation |
US9999773B2 (en) | 2013-10-30 | 2018-06-19 | Cyberonics, Inc. | Implantable neurostimulator-implemented method utilizing multi-modal stimulation parameters |
US10188856B1 (en) | 2011-12-07 | 2019-01-29 | Cyberonics, Inc. | Implantable device for providing electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction |
US10314501B2 (en) | 2016-01-20 | 2019-06-11 | Setpoint Medical Corporation | Implantable microstimulators and inductive charging systems |
WO2019204769A1 (en) * | 2018-04-19 | 2019-10-24 | Iota Biosciences, Inc. | Implants using ultrasonic communication for modulating splenic nerve activity |
US10583304B2 (en) | 2016-01-25 | 2020-03-10 | Setpoint Medical Corporation | Implantable neurostimulator having power control and thermal regulation and methods of use |
US10596367B2 (en) | 2016-01-13 | 2020-03-24 | Setpoint Medical Corporation | Systems and methods for establishing a nerve block |
US10695569B2 (en) | 2016-01-20 | 2020-06-30 | Setpoint Medical Corporation | Control of vagal stimulation |
US10912712B2 (en) | 2004-03-25 | 2021-02-09 | The Feinstein Institutes For Medical Research | Treatment of bleeding by non-invasive stimulation |
US11033746B2 (en) | 2018-04-19 | 2021-06-15 | Iota Biosciences, Inc. | Implants using ultrasonic communication for neural sensing and stimulation |
US11051744B2 (en) | 2009-11-17 | 2021-07-06 | Setpoint Medical Corporation | Closed-loop vagus nerve stimulation |
US11173307B2 (en) | 2017-08-14 | 2021-11-16 | Setpoint Medical Corporation | Vagus nerve stimulation pre-screening test |
US11260229B2 (en) | 2018-09-25 | 2022-03-01 | The Feinstein Institutes For Medical Research | Methods and apparatuses for reducing bleeding via coordinated trigeminal and vagal nerve stimulation |
US11311725B2 (en) | 2014-10-24 | 2022-04-26 | Setpoint Medical Corporation | Systems and methods for stimulating and/or monitoring loci in the brain to treat inflammation and to enhance vagus nerve stimulation |
US11406833B2 (en) | 2015-02-03 | 2022-08-09 | Setpoint Medical Corporation | Apparatus and method for reminding, prompting, or alerting a patient with an implanted stimulator |
US11471681B2 (en) | 2016-01-20 | 2022-10-18 | Setpoint Medical Corporation | Batteryless implantable microstimulators |
US11938324B2 (en) | 2020-05-21 | 2024-03-26 | The Feinstein Institutes For Medical Research | Systems and methods for vagus nerve stimulation |
US11964150B2 (en) | 2022-07-27 | 2024-04-23 | Setpoint Medical Corporation | Batteryless implantable microstimulators |
Families Citing this family (66)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7904176B2 (en) * | 2006-09-07 | 2011-03-08 | Bio Control Medical (B.C.M.) Ltd. | Techniques for reducing pain associated with nerve stimulation |
US8571653B2 (en) * | 2001-08-31 | 2013-10-29 | Bio Control Medical (B.C.M.) Ltd. | Nerve stimulation techniques |
EP1487494A2 (en) * | 2002-02-26 | 2004-12-22 | 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 |
US8200331B2 (en) * | 2004-11-04 | 2012-06-12 | Cardiac Pacemakers, Inc. | System and method for filtering neural stimulation |
US8126560B2 (en) | 2003-12-24 | 2012-02-28 | Cardiac Pacemakers, Inc. | Stimulation lead for stimulating the baroreceptors in the pulmonary artery |
JP2007530586A (en) | 2004-03-25 | 2007-11-01 | ザ ファインスタイン インスティテュート フォー メディカル リサーチ | Nervous hemostasis |
US11207518B2 (en) | 2004-12-27 | 2021-12-28 | The Feinstein Institutes For Medical Research | Treating inflammatory disorders by stimulation of the cholinergic anti-inflammatory pathway |
AU2005323463B2 (en) | 2004-12-27 | 2009-11-19 | The Feinstein Institutes For Medical Research | Treating inflammatory disorders by electrical vagus nerve stimulation |
US8041428B2 (en) | 2006-02-10 | 2011-10-18 | Electrocore Llc | Electrical stimulation treatment of hypotension |
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US7630760B2 (en) * | 2005-11-21 | 2009-12-08 | Cardiac Pacemakers, Inc. | Neural stimulation therapy system for atherosclerotic plaques |
EP1984064A4 (en) | 2006-02-10 | 2009-11-11 | Electrocore Inc | 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 | Electrical stimulation treatment for hypotension |
US20100241188A1 (en) * | 2009-03-20 | 2010-09-23 | Electrocore, Inc. | Percutaneous Electrical Treatment Of Tissue |
US20100057178A1 (en) * | 2006-04-18 | 2010-03-04 | Electrocore, Inc. | Methods and apparatus for spinal cord stimulation using expandable electrode |
US8209034B2 (en) * | 2008-12-18 | 2012-06-26 | Electrocore Llc | Methods and apparatus for electrical stimulation treatment using esophageal balloon and electrode |
US8401650B2 (en) | 2008-04-10 | 2013-03-19 | Electrocore Llc | Methods and apparatus for electrical treatment using balloon and electrode |
US20090157138A1 (en) * | 2006-04-18 | 2009-06-18 | Electrocore, Inc. | Methods And Apparatus For Treating Ileus Condition Using Electrical Signals |
US8170668B2 (en) | 2006-07-14 | 2012-05-01 | Cardiac Pacemakers, Inc. | Baroreflex sensitivity monitoring and trending for tachyarrhythmia detection and therapy |
WO2009029614A1 (en) | 2007-08-27 | 2009-03-05 | The Feinstein Institute For Medical Research | Devices and methods for inhibiting granulocyte activation by neural stimulation |
US8989858B2 (en) * | 2007-12-05 | 2015-03-24 | The Invention Science Fund I, Llc | Implant system for chemical modulation of neural activity |
US8233976B2 (en) | 2007-12-05 | 2012-07-31 | The Invention Science Fund I, Llc | System for transdermal chemical modulation of neural activity |
US8483831B1 (en) | 2008-02-15 | 2013-07-09 | Holaira, Inc. | System and method for bronchial dilation |
WO2009146030A1 (en) | 2008-03-31 | 2009-12-03 | The Feinstein Institute For Medical Research | Methods and systems for reducing inflammation by neuromodulation of t-cell activity |
US8543211B2 (en) | 2008-04-10 | 2013-09-24 | ElectroCore, LLC | Methods and apparatus for deep brain stimulation |
US8682449B2 (en) | 2008-04-10 | 2014-03-25 | ElectroCore, LLC | Methods and apparatus for transcranial stimulation |
AU2009244058B2 (en) | 2008-05-09 | 2015-07-02 | Nuvaira, Inc | Systems, assemblies, and methods for treating a bronchial tree |
US10512769B2 (en) | 2009-03-20 | 2019-12-24 | Electrocore, Inc. | Non-invasive magnetic or electrical nerve stimulation to treat or prevent autism spectrum disorders and other disorders of psychological development |
US11229790B2 (en) | 2013-01-15 | 2022-01-25 | Electrocore, Inc. | Mobile phone for treating a patient with seizures |
WO2011056684A2 (en) | 2009-10-27 | 2011-05-12 | Innovative Pulmonary Solutions, Inc. | Delivery devices with coolable energy emitting assemblies |
AU2010319477A1 (en) | 2009-11-11 | 2012-05-24 | Holaira, Inc. | 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 |
US20200086108A1 (en) | 2010-08-19 | 2020-03-19 | Electrocore, Inc. | Vagal nerve stimulation to reduce inflammation associated with an aneurysm |
US11400288B2 (en) | 2010-08-19 | 2022-08-02 | Electrocore, Inc | Devices and methods for electrical stimulation and their use for vagus nerve stimulation on the neck of a patient |
US11511109B2 (en) | 2011-03-10 | 2022-11-29 | Electrocore, Inc. | Non-invasive magnetic or electrical nerve stimulation to treat gastroparesis, functional dyspepsia, and other functional gastrointestinal disorders |
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 |
KR102363552B1 (en) | 2013-05-30 | 2022-02-15 | 그라함 에이치. 크리시 | Topical neurological stimulation |
US11229789B2 (en) | 2013-05-30 | 2022-01-25 | Neurostim Oab, Inc. | Neuro activator with controller |
WO2015127476A1 (en) * | 2014-02-24 | 2015-08-27 | Setpoint Medial Corporation | Vagus nerve stimulation screening test |
CA2977224A1 (en) | 2015-02-20 | 2016-08-25 | The Feinstein Institute For Medical Research | Nerve stimulation for treatment of diseases and disorders |
US11077301B2 (en) | 2015-02-21 | 2021-08-03 | NeurostimOAB, Inc. | Topical nerve stimulator and sensor for bladder control |
US20160243358A1 (en) * | 2015-02-24 | 2016-08-25 | Neurostim Solutions LLC | Topical Nerve Stimulator and Sensor for Control of Autonomic Function |
US20170143972A1 (en) | 2015-11-19 | 2017-05-25 | Boston Scientific Neuromodulation Corporation | Neuromodulation for neuroinflammation treatments with parameters controlled using biomarkers |
US10335396B2 (en) | 2016-10-27 | 2019-07-02 | Patrick M. Nemechek | Methods of reversing autonomic nervous system damage |
WO2018195238A1 (en) | 2017-04-20 | 2018-10-25 | The Feinstein Institute For Medical Research | Systems and methods for real-time monitoring of physiological biomarkers through nerve signals and uses thereof |
EP3470111A1 (en) | 2017-10-13 | 2019-04-17 | Setpoint Medical Corporation | Vagus nerve stimulation to treat neurodegenerative disorders |
CN111601636A (en) | 2017-11-07 | 2020-08-28 | Oab神经电疗科技公司 | Non-invasive neural activator with adaptive circuit |
US20200230408A1 (en) * | 2018-12-21 | 2020-07-23 | Electrocore, Inc. | Systems and methods for treating patients with diseases associated with replicating pathogens |
WO2019152686A2 (en) * | 2018-01-31 | 2019-08-08 | Flagship Pioneering Innovations V, Inc. | Methods and compositions for treating inflammatory or autoimmune diseases or conditions using chrna6 activators |
US11660443B2 (en) | 2018-04-20 | 2023-05-30 | The Feinstein Institutes For Medical Research | Methods and apparatuses for reducing bleeding via electrical trigeminal nerve stimulation |
CN113711623A (en) | 2018-09-24 | 2021-11-26 | Nesos公司 | Neural stimulation of the ear for treating a patient's disease, and related systems and methods |
CN113939334A (en) | 2019-04-12 | 2022-01-14 | 赛博恩特医疗器械公司 | Treatment of neurodegenerative disorders by vagal nerve stimulation |
CN114126704A (en) | 2019-06-26 | 2022-03-01 | 神经科学技术有限责任公司 | Non-invasive neural activator with adaptive circuit |
WO2021126921A1 (en) | 2019-12-16 | 2021-06-24 | Neurostim Solutions, Llc | Non-invasive nerve activator with boosted charge delivery |
US11123560B1 (en) | 2020-06-08 | 2021-09-21 | Patrick M. Nemechek | Methods of treating covid-19 induced cytokine storm |
CN112023050A (en) * | 2020-09-10 | 2020-12-04 | 中国科学院深圳先进技术研究院 | Method for regulating polarization state of macrophage |
Citations (96)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
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 |
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 |
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 |
US20060052657A9 (en) * | 2003-12-30 | 2006-03-09 | Jacob Zabara | Systems and methods for therapeutically treating neuro-psychiatric disorders and other illnesses |
US20060052836A1 (en) * | 2004-09-08 | 2006-03-09 | Kim Daniel H | Neurostimulation system |
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 |
US20060064137A1 (en) * | 2003-05-16 | 2006-03-23 | Stone Robert T | Method and system to control respiration by means of simulated action potential signals |
US20060064139A1 (en) * | 2002-06-24 | 2006-03-23 | Jong-Pil Chung | Electric stimilator for alpha-wave derivation |
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 |
US20060074473A1 (en) * | 2004-03-23 | 2006-04-06 | Michael Gertner | Methods and devices for combined gastric restriction and electrical stimulation |
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 |
US7167750B2 (en) * | 2003-02-03 | 2007-01-23 | Enteromedics, Inc. | Obesity treatment with electrically induced vagal down regulation |
US7167751B1 (en) * | 2001-03-01 | 2007-01-23 | Advanced Bionics Corporation | Method of using a fully implantable miniature neurostimulator for vagus nerve stimulation |
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 (334)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB190904133A (en) | 1909-02-19 | 1910-02-21 | Augustus Rosenberg | An Improved Electro-magnetic Vibrator for Local Application to the Person. |
GB191404133A (en) | 1914-02-17 | 1915-01-07 | British Thomson Houston Co Ltd | Improvements in and relating to Protective Devices for Electric Distribution Systems. |
US2164121A (en) | 1938-05-04 | 1939-06-27 | Pescador Hector | Electric hearing apparatus for the deaf |
US3631534A (en) | 1969-09-05 | 1971-12-28 | Matsushita Electric Ind Co Ltd | Variable inductance device |
FR2315274A1 (en) | 1975-06-27 | 1977-01-21 | Parcor | NEW DERIVATIVES OF THIENO (2,3-C) PYRIDINE, THEIR PREPARATION AND THEIR APPLICATIONS |
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 |
US4702254A (en) | 1983-09-14 | 1987-10-27 | Jacob Zabara | Neurocybernetic prosthesis |
US5025807A (en) | 1983-09-14 | 1991-06-25 | Jacob Zabara | Neurocybernetic prosthesis |
US4867164A (en) | 1983-09-14 | 1989-09-19 | 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) PYRIDINE, THEIR USE AS A MEDICAMENT AND METHOD FOR THE PRODUCTION THEREOF |
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 |
US5154172A (en) | 1989-11-13 | 1992-10-13 | Cyberonics, Inc. | Constant current sources with programmable voltage source |
US5235980A (en) | 1989-11-13 | 1993-08-17 | Cyberonics, Inc. | Implanted apparatus disabling switching regulator operation to allow radio frequency signal reception |
US5637459A (en) | 1990-06-11 | 1997-06-10 | Nexstar Pharmaceuticals, Inc. | Systematic evolution of ligands by exponential enrichment: chimeric selex |
US5705337A (en) | 1990-06-11 | 1998-01-06 | Nexstar Pharmaceuticals, Inc. | Systematic evolution of ligands by exponential enrichment: chemi-SELEX |
US5567588A (en) | 1990-06-11 | 1996-10-22 | University Research Corporation | Systematic evolution of ligands by exponential enrichment: Solution SELEX |
US6083696A (en) | 1990-06-11 | 2000-07-04 | Nexstar Pharmaceuticals, Inc. | Systematic evolution of ligands exponential enrichment: blended selex |
US5472841A (en) | 1990-06-11 | 1995-12-05 | Nexstar Pharmaceuticals, Inc. | Methods for identifying nucleic acid ligands of human neutrophil elastase |
US5712375A (en) | 1990-06-11 | 1998-01-27 | Nexstar Pharmaceuticals, Inc. | Systematic evolution of ligands by exponential enrichment: tissue selex |
US5580737A (en) | 1990-06-11 | 1996-12-03 | Nexstar Pharmaceuticals, Inc. | High-affinity nucleic acid ligands that discriminate between theophylline and caffeine |
US6124449A (en) | 1990-06-11 | 2000-09-26 | Nexstar Pharmaceuticals, Inc. | High affinity TGFβ nucleic acid ligands and inhibitors |
US5726017A (en) | 1990-06-11 | 1998-03-10 | Nexstar Pharmaceuticals, Inc. | High affinity HIV-1 gag nucleic acid ligands |
US6140490A (en) | 1996-02-01 | 2000-10-31 | Nexstar Pharmaceuticals, Inc. | High affinity nucleic acid ligands of complement system proteins |
US5654151A (en) | 1990-06-11 | 1997-08-05 | Nexstar Pharmaceuticals, Inc. | High affinity HIV Nucleocapsid nucleic acid ligands |
US6127119A (en) | 1990-06-11 | 2000-10-03 | Nexstar Pharmaceuticals, Inc. | Nucleic acid ligands of tissue target |
DE69128350T2 (en) | 1990-06-11 | 1998-03-26 | Nexstar Pharmaceuticals Inc | NUCLEIC ACID LIGANDS |
US6147204A (en) | 1990-06-11 | 2000-11-14 | Nexstar Pharmaceuticals, Inc. | Nucleic acid ligand complexes |
US5683867A (en) | 1990-06-11 | 1997-11-04 | Nexstar Pharmaceuticals, Inc. | Systematic evolution of ligands by exponential enrichment: blended 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 |
WO1993001862A1 (en) | 1991-07-22 | 1993-02-04 | 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 |
JP3034953B2 (en) | 1992-08-31 | 2000-04-17 | ユニバーシティー オブ フロリダ リサーチ ファンデーション,インコーポレーテッド | Anabaseine derivatives useful for 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 |
DE59410125D1 (en) * | 1993-02-10 | 2002-07-04 | Siemens Ag | DEVICE FOR PAIN THERAPY AND / OR INFLUENCING THE VEGETATIVE NERVOUS SYSTEM |
US5344438A (en) | 1993-04-16 | 1994-09-06 | Medtronic, Inc. | Cuff electrode |
AU698101B2 (en) | 1993-06-01 | 1998-10-22 | Cortex Pharmaceuticals, Inc. | 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 drug |
ES2157326T3 (en) | 1994-04-22 | 2001-08-16 | Sanquin Bloedvoorziening | SYSTEM FOR THE TREATMENT OF ANOMALIES IN THE CASCADA DE COAGULACION SANGUINEA. |
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 |
KR100366331B1 (en) | 1994-08-24 | 2003-04-10 | 아스트라제네카 악티에볼라그 | Spiro-azabicyclic Compounds Useful for Treatment |
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 |
US5607459A (en) | 1995-10-27 | 1997-03-04 | Intermedics, Inc. | Implantable cardiac stimulation device with time-of-day selectable warning system |
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 |
SE9600683D0 (en) | 1996-02-23 | 1996-02-23 | Astra Ab | Azabicyclic esters of carbamic acids useful in therapy |
EP0796634B1 (en) | 1996-03-21 | 2005-11-16 | BIOTRONIK Mess- und Therapiegeräte GmbH & Co Ingenieurbüro Berlin | 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 |
US6166048A (en) | 1999-04-20 | 2000-12-26 | Targacept, Inc. | Pharmaceutical compositions for inhibition of cytokine production and secretion |
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 |
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 |
US7269457B2 (en) | 1996-04-30 | 2007-09-11 | Medtronic, Inc. | Method and system for vagal nerve stimulation with multi-site cardiac pacing |
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 |
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 |
US20050191661A1 (en) | 1996-11-06 | 2005-09-01 | Tetsuya Gatanaga | Treatment of inflammatory disease by cleaving TNF receptors |
CA2271693C (en) | 1996-11-15 | 2009-01-20 | 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 |
US6208894B1 (en) | 1997-02-26 | 2001-03-27 | Alfred E. Mann Foundation For Scientific Research And Advanced Bionics | 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 |
AR013184A1 (en) | 1997-07-18 | 2000-12-13 | Astrazeneca Ab | SPYROZOBICYCLIC HETERO CYCLIC AMINES, PHARMACEUTICAL COMPOSITION, USE OF SUCH AMINES TO PREPARE MEDICINES AND METHOD OF TREATMENT OR PROPHYLAXIS |
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 |
US7231254B2 (en) | 1998-08-05 | 2007-06-12 | Bioneuronics Corporation | Closed-loop feedback-driven neuromodulation |
US7242984B2 (en) | 1998-08-05 | 2007-07-10 | Neurovista Corporation | Apparatus and method for closed-loop intracranial stimulation for optimal control of neurological disease |
US8762065B2 (en) | 1998-08-05 | 2014-06-24 | Cyberonics, Inc. | Closed-loop feedback-driven neuromodulation |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 | NONANE 1,4-DIAZABICYCLO [3.2.2.] DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
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 |
CA2376903A1 (en) | 1999-06-25 | 2001-01-04 | Emory University | 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 |
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 |
US6587724B2 (en) | 1999-12-17 | 2003-07-01 | Advanced Bionics Corporation | Magnitude programming for implantable electrical stimulator |
FR2803186B1 (en) | 2000-01-05 | 2002-08-09 | Guy Charvin | METHOD AND APPARATUS FOR COLLECTING HEARING MESSAGE POTENTIALS |
US6447443B1 (en) | 2001-01-13 | 2002-09-10 | Medtronic, Inc. | Method for organ positioning and stabilization |
US20060085046A1 (en) | 2000-01-20 | 2006-04-20 | Ali Rezai | Methods of treating medical conditions by transvascular neuromodulation of the autonomic nervous system |
US6826428B1 (en) | 2000-04-11 | 2004-11-30 | The Board Of Regents Of The University Of Texas System | Gastrointestinal electrical stimulation |
JP2003530169A (en) | 2000-04-11 | 2003-10-14 | ザ・ボード・オブ・リージェンツ・オブ・ザ・ユニバーシティ・オブ・テキサス・システム | Electrical stimulation of the gastrointestinal tract |
US8914114B2 (en) | 2000-05-23 | 2014-12-16 | The Feinstein Institute For Medical Research | Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation |
EP1324709B1 (en) | 2000-09-26 | 2006-07-12 | Medtronic, Inc. | Medical device for directing blood flow |
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 |
JP2004514722A (en) | 2000-12-01 | 2004-05-20 | ニューロサーチ、アクティーゼルスカブ | 3-Substituted quinuclidine and methods of using same as nicotine antagonists |
US20020086871A1 (en) | 2000-12-29 | 2002-07-04 | O'neill Brian Thomas | Pharmaceutical composition for the treatment of CNS and other disorders |
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 |
US8060208B2 (en) | 2001-02-20 | 2011-11-15 | Case Western Reserve University | Action potential conduction prevention |
CA2438541A1 (en) | 2001-02-20 | 2002-08-29 | Case Western Reserve University | Systems and methods for reversibly blocking nerve activity |
US7069082B2 (en) | 2001-04-05 | 2006-06-27 | Med-El Elektromedizinische Gerate Gmbh | 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 |
US6901294B1 (en) | 2001-05-25 | 2005-05-31 | Advanced Bionics Corporation | Methods and systems for direct electrical current stimulation as a therapy for prostatic hypertrophy |
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 |
US20060116736A1 (en) | 2001-07-23 | 2006-06-01 | Dilorenzo Daniel J | Method, apparatus, and surgical technique for autonomic neuromodulation for the treatment of obesity |
US20060167498A1 (en) | 2001-07-23 | 2006-07-27 | Dilorenzo Daniel J | Method, apparatus, and surgical technique for autonomic neuromodulation for the treatment of disease |
US6622047B2 (en) | 2001-07-28 | 2003-09-16 | Cyberonics, Inc. | Treatment of neuropsychiatric disorders by near-diaphragmatic nerve stimulation |
US6622038B2 (en) | 2001-07-28 | 2003-09-16 | Cyberonics, Inc. | Treatment of movement disorders by near-diaphragmatic nerve stimulation |
US20040193230A1 (en) | 2001-08-17 | 2004-09-30 | Overstreet Edward H. | Gradual recruitment of muscle/neural excitable tissue using high-rate electrical stimulation parameters |
US6622041B2 (en) | 2001-08-21 | 2003-09-16 | Cyberonics, Inc. | Treatment of congestive heart failure and autonomic cardiovascular drive disorders |
US6600956B2 (en) | 2001-08-21 | 2003-07-29 | Cyberonics, Inc. | Circumneural electrode assembly |
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 |
US20140046407A1 (en) | 2001-08-31 | 2014-02-13 | Bio Control Medical (B.C.M.) Ltd. | Nerve stimulation techniques |
US7734355B2 (en) | 2001-08-31 | 2010-06-08 | Bio Control Medical (B.C.M.) Ltd. | Treatment of disorders by unidirectional nerve stimulation |
US7778711B2 (en) | 2001-08-31 | 2010-08-17 | Bio Control Medical (B.C.M.) Ltd. | Reduction of heart rate variability by parasympathetic stimulation |
US8571653B2 (en) | 2001-08-31 | 2013-10-29 | Bio Control Medical (B.C.M.) Ltd. | Nerve stimulation techniques |
US7974693B2 (en) | 2001-08-31 | 2011-07-05 | Bio Control Medical (B.C.M.) Ltd. | Techniques for applying, configuring, and coordinating nerve fiber stimulation |
US7885709B2 (en) | 2001-08-31 | 2011-02-08 | Bio Control Medical (B.C.M.) Ltd. | Nerve stimulation for treating disorders |
US20040002546A1 (en) | 2001-09-15 | 2004-01-01 | Eric Altschuler | Methods for treating crohn's and other TNF associated diseases |
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 |
EP1487494A2 (en) | 2002-02-26 | 2004-12-22 | North Shore-Long Island Jewish Research Institute | Inhibition of inflammatory cytokine production by stimulation of brain muscarinic receptors |
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 |
US20080213331A1 (en) | 2002-04-08 | 2008-09-04 | Ardian, Inc. | Methods and devices for renal nerve blocking |
US20030191404A1 (en) | 2002-04-08 | 2003-10-09 | Klein George J. | Method and apparatus for providing arrhythmia discrimination |
US6990372B2 (en) | 2002-04-11 | 2006-01-24 | Alfred E. Mann Foundation For Scientific Research | Programmable signal analysis device for detecting neurological signals in an implantable device |
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 |
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) |
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) |
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) |
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 |
US7321793B2 (en) | 2003-06-13 | 2008-01-22 | Biocontrol Medical Ltd. | Vagal stimulation for atrial fibrillation therapy |
US20060116739A1 (en) | 2002-05-23 | 2006-06-01 | Nir Betser | Electrode assembly for nerve control |
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 |
WO2004110550A2 (en) | 2003-06-13 | 2004-12-23 | Biocontrol Medical Ltd. | Vagal stimulation for anti-embolic therapy |
US7277761B2 (en) | 2002-06-12 | 2007-10-02 | Pacesetter, Inc. | Vagal stimulation for improving cardiac function in heart failure or CHF patients |
US7203548B2 (en) | 2002-06-20 | 2007-04-10 | Advanced Bionics Corporation | Cavernous 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 |
US7292890B2 (en) | 2002-06-20 | 2007-11-06 | Advanced Bionics Corporation | Vagus nerve stimulation via unidirectional propagation of action potentials |
US20040049240A1 (en) | 2002-09-06 | 2004-03-11 | Martin Gerber | Electrical and/or magnetic stimulation therapy for the treatment of prostatitis and prostatodynia |
EP1629341A4 (en) | 2002-10-15 | 2008-10-15 | 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 |
US7079977B2 (en) | 2002-10-15 | 2006-07-18 | Medtronic, Inc. | Synchronization and calibration of clocks for a medical device and calibrated clock |
EP1558131A4 (en) | 2002-10-15 | 2008-05-28 | Medtronic Inc | Timed delay for redelivery of treatment therapy for a medical device system |
EP1558130A4 (en) | 2002-10-15 | 2009-01-28 | Medtronic Inc | Screening techniques for management of a nervous system disorder |
WO2004037204A2 (en) | 2002-10-25 | 2004-05-06 | University Of South Florida | 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 |
ES2293086T3 (en) | 2002-12-06 | 2008-03-16 | The Feinstein Institute For Medical Research | INFLAMMATION INHIBITION USING COLINERGIC AGONISTS FROM UNION TO ALFA RECEIVER 7. |
US20040111139A1 (en) | 2002-12-10 | 2004-06-10 | Mccreery Douglas B. | Apparatus and methods for differential stimulation of nerve fibers |
TR200202651A2 (en) | 2002-12-12 | 2004-07-21 | Met�N�Tulgar | the vücutádışındanádirekátedaviásinyaliátransferliáábeyinápil |
JP2004201901A (en) | 2002-12-25 | 2004-07-22 | Yoshimi Kurokawa | Stomach electrostimulator |
WO2004064918A1 (en) | 2003-01-14 | 2004-08-05 | Department Of Veterans Affairs, Office Of General Counsel | Cervical wagal stimulation induced weight loss |
WO2004064729A2 (en) | 2003-01-15 | 2004-08-05 | Alfred E. Mann Institute For Biomedical Engineering At The University Of Southern California | Treatments for snoring using injectable neuromuscular stimulators |
US20050143781A1 (en) | 2003-01-31 | 2005-06-30 | Rafael Carbunaru | Methods and systems for patient adjustment of parameters for an implanted stimulator |
US20040172084A1 (en) | 2003-02-03 | 2004-09-02 | Knudson Mark B. | Method and apparatus for treatment of gastro-esophageal reflux disease (GERD) |
US7269455B2 (en) | 2003-02-26 | 2007-09-11 | Pineda Jaime A | Method and system for predicting and preventing seizures |
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 |
US6814418B2 (en) | 2003-03-14 | 2004-11-09 | D'orso Ronald | Locker organizer |
US7430449B2 (en) | 2003-03-14 | 2008-09-30 | Endovx, Inc. | Methods and apparatus for testing disruption of a vagal nerve |
US7155279B2 (en) | 2003-03-28 | 2006-12-26 | Advanced Bionics Corporation | Treatment of movement disorders with drug therapy |
US7228167B2 (en) | 2003-04-10 | 2007-06-05 | Mayo Foundation For Medical Education | Method and apparatus for detecting vagus nerve stimulation |
US7187979B2 (en) | 2003-04-25 | 2007-03-06 | Medtronic, Inc. | Medical device synchronization |
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 | Attaching a hearing aid or earmold in the ear |
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) |
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) |
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) |
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 |
US20060111755A1 (en) | 2003-05-16 | 2006-05-25 | Stone Robert T | Method and system to control respiration by means of neuro-electrical coded signals |
AU2004240663A1 (en) | 2003-05-16 | 2004-12-02 | Neurosignal Technologies, Inc. | Respiratory control 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 |
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 |
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 |
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 |
DE10328816A1 (en) | 2003-06-21 | 2005-01-05 | Biotronik Meß- und Therapiegeräte GmbH & Co. Ingenieurbüro Berlin | Implantable stimulation electrode with a coating to increase tissue compatibility |
JP2007530417A (en) | 2003-07-01 | 2007-11-01 | プレジデント・アンド・フェロウズ・オブ・ハーバード・カレッジ | Composition for manipulating the longevity and stress response of cells and organisms |
WO2005007223A2 (en) | 2003-07-16 | 2005-01-27 | Sasha John | Programmable medical drug delivery systems and methods for delivery of multiple fluids and concentrations |
WO2005007120A2 (en) | 2003-07-18 | 2005-01-27 | 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 |
US7797058B2 (en) | 2004-08-04 | 2010-09-14 | Ndi Medical, Llc | Devices, systems, and methods employing a molded nerve cuff electrode |
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 |
US20050095246A1 (en) | 2003-10-24 | 2005-05-05 | Medtronic, Inc. | Techniques to treat neurological disorders by attenuating the production of pro-inflammatory mediators |
KR20050039445A (en) | 2003-10-25 | 2005-04-29 | 대한민국(경북대학교 총장) | Wireless power transmission equipment for totally middle ear implant |
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 |
US7317941B2 (en) | 2003-11-13 | 2008-01-08 | Medtronic, Inc. | Time syncrhonization of data |
CA2536242A1 (en) | 2003-11-20 | 2005-06-09 | Angiotech International Ag | Implantable sensors and implantable pumps and anti-scarring agents |
US20090312817A1 (en) | 2003-11-26 | 2009-12-17 | Wicab, Inc. | Systems and methods for altering brain and body functions and for treating conditions and diseases of the same |
US20050137645A1 (en) | 2003-12-05 | 2005-06-23 | Juha Voipio | Novel method for the adjustment of human and animal vagus nerve stimulation |
US7769461B2 (en) | 2003-12-19 | 2010-08-03 | Boston Scientific Neuromodulation Corporation | Skull-mounted electrical stimulation system and method for treating patients |
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 |
US20050149129A1 (en) | 2003-12-24 | 2005-07-07 | Imad Libbus | Baropacing and cardiac pacing to control output |
US8147561B2 (en) | 2004-02-26 | 2012-04-03 | Endosphere, Inc. | Methods and devices to curb appetite and/or reduce food intake |
WO2005089646A1 (en) | 2004-03-16 | 2005-09-29 | Medtronic, Inc. | Sensitivity analysis for selecting therapy parameter sets |
JP2007530586A (en) | 2004-03-25 | 2007-11-01 | ザ ファインスタイン インスティテュート フォー メディカル リサーチ | Nervous hemostasis |
US20160250097A9 (en) | 2004-03-25 | 2016-09-01 | The Feinstein Institute For Medical Research | Treatment of inflammation by non-invasive stimulation |
US10912712B2 (en) | 2004-03-25 | 2021-02-09 | The Feinstein Institutes For Medical Research | Treatment of bleeding by non-invasive stimulation |
WO2006007048A2 (en) | 2004-05-04 | 2006-01-19 | 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 |
WO2006001982A2 (en) | 2004-06-04 | 2006-01-05 | 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 |
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) |
WO2006045054A2 (en) | 2004-10-18 | 2006-04-27 | E-Soc | Device for neuromusclar, 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 |
AU2005323463B2 (en) | 2004-12-27 | 2009-11-19 | The Feinstein Institutes For Medical Research | Treating inflammatory disorders by electrical vagus nerve stimulation |
US11207518B2 (en) | 2004-12-27 | 2021-12-28 | The Feinstein Institutes For Medical Research | Treating inflammatory disorders by stimulation of the cholinergic anti-inflammatory pathway |
US8825166B2 (en) | 2005-01-21 | 2014-09-02 | John Sasha John | Multiple-symptom medical treatment with roving-based neurostimulation |
US8788044B2 (en) | 2005-01-21 | 2014-07-22 | Michael Sasha John | Systems and methods for tissue stimulation in medical treatment |
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 |
US20060229681A1 (en) | 2005-04-11 | 2006-10-12 | Fischell Robert E | Implantable system for the treatment of atrial fibrillation |
US7499748B2 (en) | 2005-04-11 | 2009-03-03 | Cardiac Pacemakers, Inc. | Transvascular neural stimulation device |
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 |
US7899540B2 (en) | 2005-04-29 | 2011-03-01 | Cyberonics, Inc. | Noninvasively adjustable gastric band |
US7310557B2 (en) | 2005-04-29 | 2007-12-18 | Maschino Steven E | Identification of electrodes for nerve stimulation in the treatment of eating disorders |
US7835796B2 (en) | 2005-04-29 | 2010-11-16 | Cyberonics, Inc. | Weight loss method and device |
US7765000B2 (en) | 2005-05-10 | 2010-07-27 | Cardiac Pacemakers, Inc. | Neural stimulation system with pulmonary artery lead |
US7734348B2 (en) | 2005-05-10 | 2010-06-08 | Cardiac Pacemakers, Inc. | System with left/right pulmonary artery electrodes |
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 |
US7499752B2 (en) * | 2005-07-29 | 2009-03-03 | Cyberonics, Inc. | Selective nerve stimulation for the treatment of eating disorders |
US20070027499A1 (en) * | 2005-07-29 | 2007-02-01 | Cyberonics, Inc. | Neurostimulation device for treating mood 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 |
US7555344B2 (en) | 2005-10-28 | 2009-06-30 | Cyberonics, Inc. | Selective neurostimulation for treating epilepsy |
US7957796B2 (en) | 2005-10-28 | 2011-06-07 | Cyberonics, Inc. | Using physiological sensor data with an implantable medical device |
US7747324B2 (en) | 2005-11-10 | 2010-06-29 | Electrocore Llc | 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 |
US9566447B2 (en) | 2005-12-28 | 2017-02-14 | Cardiac Pacemakers, Inc. | Neural stimulation system for reducing atrial proarrhythmia |
US7672728B2 (en) | 2005-12-28 | 2010-03-02 | Cardiac Pacemakers, Inc. | Neural stimulator to treat sleep disordered breathing |
WO2009029614A1 (en) | 2007-08-27 | 2009-03-05 | The Feinstein Institute For Medical Research | Devices and methods for inhibiting granulocyte activation by neural 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 |
WO2009146030A1 (en) | 2008-03-31 | 2009-12-03 | The Feinstein Institute For Medical Research | Methods and systems for reducing inflammation by neuromodulation of t-cell activity |
US20090275997A1 (en) | 2008-05-01 | 2009-11-05 | Michael Allen Faltys | Vagus nerve stimulation electrodes and methods of use |
CN102215909B (en) | 2008-11-18 | 2014-09-10 | 赛博恩特医疗器械公司 | Devices and methods for optimizing electrode placement for anti-inflamatory stimulation |
US8612002B2 (en) | 2009-12-23 | 2013-12-17 | Setpoint Medical Corporation | Neural stimulation devices and systems for treatment of chronic inflammation |
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 |
AU2010258792B2 (en) | 2009-06-09 | 2015-07-02 | Setpoint Medical Corporation | Nerve cuff with pocket for leadless stimulator |
US20160331952A1 (en) | 2009-11-17 | 2016-11-17 | Michael A. Faltys | External programmer |
US9833621B2 (en) | 2011-09-23 | 2017-12-05 | Setpoint Medical Corporation | Modulation of sirtuins by vagus nerve stimulation |
WO2014169145A1 (en) | 2013-04-10 | 2014-10-16 | Setpoint Medical Corporation | Closed-loop vagus nerve stimulation |
CN103619405B (en) | 2011-05-09 | 2015-11-25 | 赛博恩特医疗器械公司 | The individual pulse being used for the treatment of the cholinergic anti-inflammatory pathway of chronic inflammatory disease activates |
US9572983B2 (en) | 2012-03-26 | 2017-02-21 | Setpoint Medical Corporation | Devices and methods for modulation of bone erosion |
WO2015127476A1 (en) | 2014-02-24 | 2015-08-27 | Setpoint Medial Corporation | Vagus nerve stimulation screening test |
US11311725B2 (en) | 2014-10-24 | 2022-04-26 | Setpoint Medical Corporation | Systems and methods for stimulating and/or monitoring loci in the brain to treat inflammation and to enhance vagus nerve stimulation |
US11406833B2 (en) | 2015-02-03 | 2022-08-09 | Setpoint Medical Corporation | Apparatus and method for reminding, prompting, or alerting a patient with an implanted stimulator |
US10596367B2 (en) | 2016-01-13 | 2020-03-24 | Setpoint Medical Corporation | Systems and methods for establishing a nerve block |
EP3405255A4 (en) | 2016-01-20 | 2019-10-16 | Setpoint Medical Corporation | Implantable microstimulators and inductive charging systems |
US10695569B2 (en) | 2016-01-20 | 2020-06-30 | Setpoint Medical Corporation | Control of vagal stimulation |
US10583304B2 (en) | 2016-01-25 | 2020-03-10 | Setpoint Medical Corporation | Implantable neurostimulator having power control and thermal regulation and methods of use |
-
2004
- 2004-11-17 US US10/990,938 patent/US8914114B2/en not_active Expired - Lifetime
-
2008
- 2008-04-24 US US12/109,334 patent/US20090248097A1/en not_active Abandoned
-
2014
- 2014-12-12 US US14/569,504 patent/US10166395B2/en not_active Expired - Fee Related
-
2017
- 2017-06-07 US US15/616,855 patent/US9987492B2/en not_active Expired - Fee Related
-
2018
- 2018-12-23 US US16/231,581 patent/US10561846B2/en not_active Expired - Fee Related
Patent Citations (100)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
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 |
US5496938A (en) * | 1990-06-11 | 1996-03-05 | Nexstar Pharmaceuticals, Inc. | Nucleic acid ligands to HIV-RT and HIV-1 rev |
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 |
US6381499B1 (en) * | 1996-02-20 | 2002-04-30 | Cardiothoracic Systems, Inc. | Method and apparatus for using vagus nerve stimulation in surgery |
US6051017A (en) * | 1996-02-20 | 2000-04-18 | Advanced Bionics Corporation | Implantable microstimulator and systems employing the same |
US5618818A (en) * | 1996-03-20 | 1997-04-08 | The University Of Toledo | Muscarinic agonist compounds |
US6224862B1 (en) * | 1996-03-20 | 2001-05-01 | Baxter Aktiengesellschaft | Pharmaceutical preparation for treating blood coagulation disorders |
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 |
US6542774B2 (en) * | 1996-04-30 | 2003-04-01 | Medtronic, Inc. | Method and device for electronically controlling the beating of a heart |
US6532388B1 (en) * | 1996-04-30 | 2003-03-11 | Medtronic, Inc. | Method and system for endotracheal/esophageal stimulation prior to and during a medical procedure |
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 |
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 |
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 |
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 |
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 |
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 |
US20050027328A1 (en) * | 2000-09-26 | 2005-02-03 | Transneuronix, Inc. | Minimally invasive surgery placement of stimulation leads in mediastinal structures |
US7184828B2 (en) * | 2000-09-26 | 2007-02-27 | Medtronic, Inc. | Method and system for spinal cord stimulation prior to and during a medical procedure |
US6690973B2 (en) * | 2000-09-26 | 2004-02-10 | Medtronic, Inc. | Method and system for spinal cord stimulation prior to and during a medical procedure |
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 |
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 |
US20030045909A1 (en) * | 2001-08-31 | 2003-03-06 | Biocontrol Medical Ltd. | Selective nerve fiber stimulation for treating heart conditions |
US6684105B2 (en) * | 2001-08-31 | 2004-01-27 | Biocontrol Medical, Ltd. | Treatment of disorders by unidirectional nerve stimulation |
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 |
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) |
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 |
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 |
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US10166395B2 (en) | 2000-05-23 | 2019-01-01 | The Feinstein Institute For Medical Research | Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation |
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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 |
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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 |
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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 |
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 |
US11878159B2 (en) | 2011-12-07 | 2024-01-23 | Livanova Usa, Inc. | Implantable device for providing electrical stimulation of cervical vagus nerves for treatment of 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 |
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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 |
US8571654B2 (en) | 2012-01-17 | 2013-10-29 | Cyberonics, Inc. | Vagus nerve neurostimulator with multiple patient-selectable modes for treating chronic cardiac dysfunction |
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US8688212B2 (en) | 2012-07-20 | 2014-04-01 | Cyberonics, Inc. | Implantable neurostimulator-implemented method for managing bradycardia through vagus nerve stimulation |
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US10384065B2 (en) | 2012-11-09 | 2019-08-20 | Livanova Usa, Inc. | Implantable neurostimulator—implemented method for enhancing post-exercise recovery through vagus nerve stimulation |
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US11097106B2 (en) | 2012-11-09 | 2021-08-24 | LivaNovaUSA, Inc. | Implantable neurostimulator-implemented method for managing tachyarrhythmia 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 |
US9643008B2 (en) | 2012-11-09 | 2017-05-09 | Cyberonics, Inc. | Implantable neurostimulator-implemented method for enhancing post-exercise recovery through vagus nerve stimulation |
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US10195437B2 (en) | 2012-11-09 | 2019-02-05 | Cyberonics, Inc. | Implantable neurostimulator-implemented method for managing techyarrhythmia through vagus nerve stimulation |
US10004903B2 (en) | 2012-11-09 | 2018-06-26 | Cyberonics, Inc. | Implantable neurostimulator-implemented method for enhancing heart failure patient awakening through vagus nerve stimulation |
US10413732B2 (en) | 2012-11-09 | 2019-09-17 | Livanova Usa, Inc. | Implantable neurostimulator-implemented method for enhancing heart failure patient awakening through vagus nerve stimulation |
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US11738199B2 (en) | 2014-03-25 | 2023-08-29 | Livanova Usa, Inc. | Neurostimulation in a neural fulcrum zone for the treatment of chronic cardiac dysfunction |
US10300284B2 (en) | 2014-03-25 | 2019-05-28 | Livanova Usa, Inc. | Neurostimulation in a neural fulcrum zone for the treatment of chronic cardiac dysfunction |
US11077304B2 (en) | 2014-03-25 | 2021-08-03 | Livanova Usa, 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 |
US10463859B2 (en) | 2014-04-17 | 2019-11-05 | Livanova Usa, Inc. | Fine resolution identification of a neural fulcrum for the treatment of chronic cardiac dysfunction |
US10426961B2 (en) | 2014-04-25 | 2019-10-01 | Livanova Usa, Inc. | Dynamic stimulation adjustment for identification of a neural fulcrum |
US10195438B2 (en) | 2014-04-25 | 2019-02-05 | Cyberonics, Inc. | Neurostimulation and recording of physiological response 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 |
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US10166391B2 (en) | 2014-05-07 | 2019-01-01 | Cybertronics, Inc. | Responsive neurostimulation for the treatment of chronic cardiac dysfunction |
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US9737716B2 (en) | 2014-08-12 | 2017-08-22 | Cyberonics, Inc. | Vagus nerve and carotid baroreceptor stimulation system |
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US11185698B2 (en) | 2014-08-12 | 2021-11-30 | Livanova Usa, Inc. | Neurostimulation titration process |
US10646716B2 (en) | 2014-08-12 | 2020-05-12 | Livanova Usa, 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 |
US11918812B2 (en) | 2014-08-12 | 2024-03-05 | Livanova Usa, Inc. | Vagus nerve and carotid baroreceptor stimulation system |
US10220212B2 (en) | 2014-08-12 | 2019-03-05 | Livanova Usa, Inc. | Neurostimulation titration process |
US11311725B2 (en) | 2014-10-24 | 2022-04-26 | Setpoint Medical Corporation | Systems and methods for stimulating and/or monitoring loci in the brain to treat inflammation and to enhance vagus nerve stimulation |
US9504832B2 (en) | 2014-11-12 | 2016-11-29 | Cyberonics, Inc. | Neurostimulation titration process via adaptive parametric modification |
US10500398B2 (en) | 2014-11-12 | 2019-12-10 | Livanova Usa, Inc. | Neurostimulation titration process via adaptive parametric modification |
US10099055B2 (en) | 2014-11-12 | 2018-10-16 | Cyberonics, Inc. | Neurostimulation titration utilizing T-wave alternans |
US11865344B2 (en) | 2014-11-12 | 2024-01-09 | Livanova Usa, Inc. | Neurostimulation titration process via adaptive parametric modification |
US10870005B2 (en) | 2014-11-12 | 2020-12-22 | Livanova Usa, Inc. | Neurostimulation titration utilizing T-wave alternans |
US11406833B2 (en) | 2015-02-03 | 2022-08-09 | Setpoint Medical Corporation | Apparatus and method for reminding, prompting, or alerting a patient with an implanted stimulator |
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US11964150B2 (en) | 2022-07-27 | 2024-04-23 | Setpoint Medical Corporation | Batteryless implantable microstimulators |
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US20150100100A1 (en) | 2015-04-09 |
US20050125044A1 (en) | 2005-06-09 |
US10166395B2 (en) | 2019-01-01 |
US20190117979A1 (en) | 2019-04-25 |
US8914114B2 (en) | 2014-12-16 |
US10561846B2 (en) | 2020-02-18 |
US9987492B2 (en) | 2018-06-05 |
US20170266448A1 (en) | 2017-09-21 |
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