# US 7,363,076 B2 · Treatment of conditions through modulation of the autonomic nervous system > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 7,363,076 B2 - Document ID: US7363076B2 - Status: Granted - Kind: B2 - Application number: 10/871,366 - Filed: 2004-06-18 - Published: 2005-01-27 - Granted: 2008-04-22 - Earliest claimed: 2003-06-09 - Assignees: Palo Alto Investors - Inventors: Anthony Joonkyoo Yun; Patrick Yuarn-Bor Lee - Web page: https://patentgrep.com/patent/US7363076B2 ## CPC - A61N 1/36017: {with leads or electrodes penetrating the skin} - A61N 1/326: {for promoting growth of cells, e.g. bone cells} - A61N 1/36189: {using modulation techniques} - A61N 1/36021: {for treatment of pain} - A61N 1/36071: {Pain} - A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B) ## Abstract Methods are provided for treating a subject for a condition caused by an abnormality in the subject's autonomic nervous system. In accordance with the subject methods, at least a portion of a subject's autonomic nervous system is modulated to increase the parasympathetic activity/sympathetic activity ratio in a manner that is effective to treat the subject for the condition. Certain embodiments include modulating at least a portion of a subject's autonomic nervous system by inhibiting and/or increasing activity in at least a portion of the subject's autonomic nervous system. The subject methods find use in the treatment of a variety of different conditions, where such conditions include various disease conditions. Also provided are systems and kits for use in practicing the subject methods. ## Claims ### Claim 1 A method of treating a subject for at least one of: hypoxia, hypercapnia, hypercarbia and acidosis, said method comprising: 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 condition, wherein said parasympathetic activity is increased by increasing activity in at least one parasympathetic nerve fiber; and decreasing the sensitivity of a chemoreceptor to said at least one of: hypoxia, hypercapnia, hypercarbia and acidosis. ### Claim 2 (depends on 1) The method of claim 1, wherein said method is a method of treating hypoxia, hypercapnia, hypercarbia and acidosis. ### Claim 3 (depends on 1) The method of claim 1, further comprising determining the presence of at least one of hypoxia, hypercapnia, hypercarbia and acidosis prior to said modulation. ### Claim 4 (depends on 3) The method of claim 3, further comprising determining the cause of at least one of hypoxia, hypercapnia, hypercarbia and acidosis. ### Claim 5 (depends on 3) The method of claim 3, further comprising determining the state of said autonomic nervous system prior to said modulation. ### Claim 6 (depends on 5) The method of claim 5, wherein said method comprises determining the parasympathetic activity/sympathetic activity ratio. ### Claim 7 (depends on 6) The method of claim 6, wherein said method comprises determining the parasympathetic activity/sympathetic activity ratio following said modulation. ### Claim 8 (depends on 6) The method of claim 6, wherein said method further comprises repeating said modulation following said determination. ### Claim 9 (depends on 1) The method of claim 1, wherein said modulation comprises pharmacological modulation. ### Claim 10 (depends on 9) The method of claim 9, wherein said pharmacological modulation comprises administering an effective amount of at least one pharmacological agent to said subject chosen from: beta-blockers; aldosterone antagonists; angiotensin II receptor blockades; angiotensin converting enzyme inhibitors; statins; triglycerides lowering agents; niacin; diabetes agents; immunomodulators; nicotine; sympathomimetics; antihistamines; cholinergics; acetylcholinesterase inhibitors; magnesium and magnesium sulfates; calcium channel blockers; muscarinics; sodium channel blockers; glucocorticoid receptor blockers; peripheral andrenergic inhibitors; blood vessel dilators; central agonists; combined alpha and beta-blockers; alpha blockers; combination diuretics; cyclic nucleotide monophosphodiesterase (“PDE”) inhibitors; alcohols; vasopressin inhibitors; oxytocin inhibitors; glucagons like peptide 1; relaxin hormone; renin inhibitors; estrogen compounds; progesterone inhibitors; testosterone inhibitors; gonadotropin-releasing hormone analogues (GnRH-As); gonadotropin-releasing hormone inhibitors; vesicular monoamine transport (VMAT) inhibitors; dipeptidyl peptidase (DP) IV inhibitors; melatonin; potassium sparing diuretics, adiponectin; phenserine; phospohodiesterase 4 inhibitor; valproate; dehydroepiandrostonedione, and anti-coagulants. ### Claim 11 (depends on 1) The method of claim 1, wherein said modulation comprises electrical modulation. ### Claim 12 (depends on 1) The method of claim 1, wherein said chemoreceptor is a central chemoreceptor. ### Claim 13 (depends on 12) The method of claim 12, wherein said central chemoreceptor is a medulla chemoreceptor. ### Claim 14 (depends on 1) The method of claim 1, wherein said chemoreceptor is a peripheral chemoreceptor. ### Claim 15 (depends on 14) The method of claim 14, wherein said peripheral chemoreceptor is a carotid chemoreceptor. ### Claim 16 (depends on 14) The method of claim 14, wherein said peripheral chemoreceptor is an aortic arch chemoreceptor. ### Claim 17 (depends on 1) The method of claim 1, wherein said method comprises decreasing conduction in an afferent nerve that carries signal from said chemoreceptor. ### Claim 18 (depends on 17) The method of claim 17, wherein said afferent nerve is a nerve that carries signal to sympathetic nerves of said autonomic nervous system. ### Claim 19 (depends on 18) The method of claim 18, wherein said sympathetic nerves participate in stimulating inflammation. ### Claim 20 (depends on 1) The method of claim 1, wherein said method comprises decreasing conduction in an efferent nerve that carries signal from said chemoreceptor. ### Claim 21 (depends on 20) The method of claim 20, wherein said efferent nerve is a nerve that carries signal from sympathetic nerves of said autonomic nervous system. ### Claim 22 (depends on 21) The method of claim 21, wherein said sympathetic nerves participate in stimulating inflammation. ### Claim 23 (depends on 1) The method of claim 1, wherein said method comprises increasing conduction in an afferent nerve that carries signal from said chemoreceptor. ### Claim 24 (depends on 23) The method of claim 23, wherein said afferent nerve is a nerve that carries signal to parasympathetic nerves of said autonomic nervous system. ### Claim 25 (depends on 24) The method of claim 24, wherein said parasympathetic nerves participate in decreasing inflammation. ### Claim 26 (depends on 1) The method of claim 1, wherein said method comprises increasing conduction in an efferent nerve that carries signal from said chemoreceptor. ### Claim 27 (depends on 26) The method of claim 26, wherein said efferent nerve is a nerve that carries signal from parasympathetic nerves of said autonomic nervous system. ### Claim 28 (depends on 27) The method of claim 27, wherein said parasympathetic nerves participate in decreasing inflammation. ### Claim 29 (depends on 1) The method of claim 1, wherein said modulation comprises electrical and pharmacological modulation. ### Claim 30 (depends on 1) The method of claim 1, wherein said modulation treats a condition associated with said at least one of hypoxia, hypercapnia, hypercarbia and acidosis. ### Claim 31 (depends on 30) The method of claim 30, wherein said associated condition is caused by at least one of: hypoxia, hypercapnia, hypercarbia acidosis, and a condition having a manifestation of at least one of hypoxia, hypercapnia, hypercarbia and acidosis at least one of hypoxia, hypercapnia, hypercarbia and acidosis. ### Claim 32 (depends on 31) The method of claim 31, wherein said associated condition is chosen from: aging, cardiovascular conditions, neurodegenerative conditions, neuroinflammatory conditions, orthopedic inflammatory conditions, lymphoproliferative conditions, autoimmune conditions, infections diseases, pulmonary conditions, transplant-related side-effects, gastrointestinal conditions, endocrine conditions, cardiac rhythm conditions, genitourinary conditions, cancer, skin conditions, autonomic instability conditions, sudden death syndromes, atherosclerosis, hypertension, insulin resistance, diabetes, and glaucoma. ### Claim 33 (depends on 31) The method of claim 31, wherein said associated condition is a condition having a manifestation of at least one of hypoxia, hypercapnia, hypercarbia and acidosis. ### Claim 34 (depends on 33) The method of claim 33, wherein said condition is chosen from: sleep apnea, acidemia, hypercapnia, hypoxia ventilation/perfusion, emphysema, chronic obstructive pulmonary disease, primary pulmonary hypertension, secondary pulmonary hypertension, cyctic fibrosis, obesity, obesity hypoventilation syndrome, chronic pulmonary embolism, chronic infection, asthma, inhalational disorders, sarcoid, tuberculosis, pneumoconiosis, coal worker ling, asbestos, left-to-right-shunts, right-to-left shunts, cyanotic lung disease, vascular malformations, atrial septal defects, ventricular septal defects, patent ductus arteriosus, bronchopulmonary dysplasia, granulatomous lung diseases, heart failure, pulmonary edema, usual interstitial pneumonia (UIP), disquamative interstitial pneumonia (DIP), nonspecific interstitial pneumonia (NSIP), lymphocyctic interstitial pneumonia (LIP) acute interstitial pneumonia (AIP), rheumatoid arthritis, wegener's granulomatosis, unilateral pneumonectomy, ARDS, histocytosis, bronchiolitis obliterans organizing pneumonia (BOOP), pleural effusion, cancer, sudden death syndromes, congestive heart failure, pulmonary edema, cardiogenic pulmonary edema, non-cardiogenic pulmonary edema, neurogenic edema, emphysema, pulmonary fibrosis, obesity hypoventilation syndrome, HIV, scleroderma, chronic lung diseases, acute lung injury, acute pulmonary embolism, acute respiratory distress syndrome, asphyxiation, drowning, anemia, sickle cell disease, thalassemia, anion gap, non-anion gap, metabolic acidosis, renal tubular acidosis, drug induced acidosis, renal failure, and uremia. ### Claim 35 (depends on 33) The method of claim 33, wherein said condition is obstructive sleep apnea. ### Claim 36 (depends on 1) The method of claim 1, further comprising observing a physiological aspect or biologic aspect of said subject and adjusting said modulation based on said aspect. ### Claim 37 (depends on 36) The method of claim 36, wherein said adjusting comprises changing a pharmacological modulation protocol. ### Claim 38 (depends on 37) The method of claim 37, wherein the dose of a pharmacological agent is changed. ### Claim 39 (depends on 37) The method of claim 37, wherein the type of pharmacological agent is changed. ### Claim 40 (depends on 36) The method of claim 36, wherein said adjusting comprises changing an electrical energy applying protocol. ### Claim 41 (depends on 40) The method of claim 40, wherein at least one of amplitude, frequency and waveform of applied current. ### Claim 42 (depends on 36) The method of claim 36, wherein said modulation is terminated when a predetermined aspect of said physiological aspect or biologic aspect is observed. ### Claim 43 A method comprising treating a subject for a condition associated with of least one of hypoxia, hypercapnia, hypercarbia and acidosis, said method comprising: 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 condition, wherein said parasympathetic activity is increased by increasing activity in at least one parasympathetic nerve fiber; and decreasing the sensitivity of a chemoreceptor to said at least one of: hypoxia, hypercapnia, hypercarbia and acidosis. ### Claim 44 (depends on 43) The method of claim 43, wherein said associated condition is a condition having a manifestation of least one of hypoxia, hypercapnia, hypercarbia and acidosis. ### Claim 45 (depends on 44) The method of claim 44, wherein said condition is chosen from: sleep apnea, acidemia, hypercapnia, hypoxia ventilation/perfusion, emphysema, chronic obstructive pulmonary disease, primary pulmonary hypertension, secondary pulmonary hypertension, cyctic fibrosis, obesity, obesity hypoventilation syndrome, chronic pulmonary embolism, chronic infection, asthma, inhalational disorders, sarcoid, tuberculosis, pneumoconiosis, coal worker ling, asbestos, left-to-right-shunts, right-to-left shunts, cyanotic lung disease, vascular malformations, atrial septal defects, ventricular septal defects, patent ductus arteriosus, bronchopulmonary dysplasia, granulatomous lung diseases, heart failure, pulmonary edema, usual interstitial pneumonia (UIP), disquamative interstitial pneumonia (DIP), nonspecific interstitial pneumonia (NSIP), lymphocyctic interstitial pneumonia (LIP) acute interstitial pneumonia (AlP), rheumatoid arthritis, wegener's granulomatosis, unilateral pneumonectomy, ARDS, histocytosis, bronchiolitis obliterans organizing pneumonia (BOOP), pleural effusion, cancer, sudden death syndromes, congestive heart failure, pulmonary edema, cardiogenic pulmonary edema, non-cardiogenic pulmonary edema, neurogenic edema, emphysema, pulmonary fibrosis, obesity hypoventilation syndrome, HIV, scleroderma, chronic lung diseases, acute lung injury, acute pulmonary embolism, acute respiratory distress syndrome, asphyxiation, drowning, anemia, sickle cell disease, thalassemia, anion gap, non-anion gap, metabolic acidosis, renal tubular acidosis, drug induced acidosis, renal failure, and uremia. ### Claim 46 (depends on 45) The method of claim 45, wherein said condition is obstructive sleep apnea. ### Claim 47 (depends on 43) The method of claim 43, wherein said associated condition is caused by at least one of: hypoxia, hypercapnia, hypercarbia, and acidosis, and a condition having a manifestation of at least one of hypoxia, hypercapnia, hypercarbia and acidosis at least one of hypoxia, hypercapnia, hypercarbia and acidosis. ### Claim 48 (depends on 47) The method of claim 47, wherein said associated condition is chosen from: aging, cardiovascular conditions, neurodegenerative conditions, neuroinflammatory conditions, orthopedic inflammatory conditions, lymphoproliferative conditions, autoimmune conditions, infections diseases, pulmonary conditions, transplant-related side-effects, gastrointestinal conditions, endocrine conditions, cardiac rhythm conditions, genitourinary conditions, cancer, skin conditions, autonomic instability conditions, sudden death syndromes, atherosclerosis, hypertension, insulin resistance, diabetes, and glaucoma. ### Claim 49 (depends on 43) The method of claim 43, further comprising determining the presence of at least one of hypoxia, hypercapnia and acidosis prior to said modulation. ### Claim 50 (depends on 49) The method of claim 49, comprising determining at least one of pH, the concentration of oxygen and the concentration of carbon dioxide in bodily fluid of said subject. ### Claim 51 (depends on 43) The method of claim 43, further comprising determining the state of said autonomic nervous system prior to said modulation. ### Claim 52 (depends on 43) The method of claim 43, wherein said method comprises determining the state of at least one of parasympathetic activity and sympathetic activity. ### Claim 53 (depends on 52) The method of claim 52, wherein said method comprises determining the parasympathetic activity/sympathetic activity ratio. ### Claim 54 (depends on 53) The method of claim 53, wherein said method comprises determining the parasympathetic activity/sympathetic activity ratio following said modulation. ### Claim 55 (depends on 53) The method of claim 53, wherein method comprises decreasing conduction in an afferent nerve that carries signal from said chemoreceptor. ### Claim 56 (depends on 55) The method of claim 55, wherein said afferent nerve is one that carries signal to sympathetic nerves of said autonomic nervous system. ### Claim 57 (depends on 56) The method of claim 56, wherein said sympathetic nerves participate in stimulating inflammation. ### Claim 58 (depends on 43) The method of claim 43, wherein said modulation comprises pharmacological modulation. ### Claim 59 (depends on 58) The method of claim 58, wherein said pharmacological modulation comprises administering an effective amount of at least one pharmacological agent to said subject chosen from: beta-blockers; aldosterone antagonists; angiotensin II receptor blockades; angiotensin converting enzyme inhibitors; statins; triglycerides lowering agents; niacin; diabetes agents; immunomodulators; nicotine; sympathomimetics; antihistamines; cholinergics; acetylcholinesterase inhibitors; magnesium and magnesium sulfates; calcium channel blockers; muscarinics; sodium channel blockers; glucocorticoid receptor blockers; peripheral andrenergic inhibitors; blood vessel dilators; central agonists; combined alpha and beta-blockers; alpha blockers; combination diuretics; potassium sparing diuretics, cyclic nucleotide monophosphodiesterase (“PDE”) inhibitors; alcohols; vasopressin inhibitors; oxytocin inhibitors; glucagons like peptide 1; relaxin hormone; renin inhibitors; estrogen compounds; progesterone inhibitors; testosterone inhibitors; gonadotropin-releasing hormone analogues (GnRH-As); gonadotropin-releasing hormone inhibitors; vesicular monoamine transport (VMAT) inhibitors; dipeptidyl peptidase (DP) IV inhibitors; melatonin; adiponectin; phenserine; phospohodiesterase 4inhibitor; valproate; dehydroepiandrostonedione; and anti-coagulants. ### Claim 60 (depends on 43) The method of claim 43, wherein said modulation comprises electrical modulation. ### Claim 61 (depends on 43) The method of claim 43, wherein said chemoreceptor is a central chemoreceptor. ### Claim 62 (depends on 61) The method of claim 61, wherein said central chemoreceptor is a medulla chemoreceptor. ### Claim 63 (depends on 62) The method of claim 62, wherein said chemoreceptor is a peripheral chemoreceptor. ### Claim 64 (depends on 63) The method of claim 63, wherein said peripheral chemoreceptor is a carotid chemoreceptor. ### Claim 65 (depends on 63) The method of claim 63, wherein said peripheral chemoreceptor is an aortic arch chemoreceptor. ### Claim 66 (depends on 43) The method of claim 43, wherein said method comprises decreasing conduction in an efferent nerve that carries signal from said chemoreceptor. ### Claim 67 (depends on 66) The method of claim 66, wherein said efferent nerve is a nerve that carries signal from sympathetic nerves of said autonomic nervous system. ### Claim 68 (depends on 67) The method of claim 67, wherein said sympathetic nerves participate in stimulating inflammation. ### Claim 69 (depends on 43) The method of claim 43, wherein said method comprises increasing conduction in an afferent nerve that carries signal from said chemoreceptor. ### Claim 70 (depends on 69) The method of claim 69, wherein said afferent nerve is a nerve that carries signal to parasympathetic nerves of said autonomic nervous system. ### Claim 71 (depends on 70) The method of claim 70, wherein said parasympathetic nerves participate in decreasing inflammation. ### Claim 72 (depends on 43) The method of claim 43, wherein said method comprises increasing conduction in an efferent nerve that carries signal from said chemoreceptor. ### Claim 73 (depends on 72) The method of claim 72, wherein said efferent nerve is a nerve that carries signal from parasympathetic nerves of said autonomic nervous system. ### Claim 74 (depends on 73) The method of claim 73, wherein said parasympathetic nerves participate in decreasing inflammation. ### Claim 75 (depends on 43) The method of claim 43, wherein said modulation comprises electrical and pharmacological modulation. ### Claim 76 (depends on 43) The method of claim 43, further comprising observing a physiological aspect or biologic aspect of said subject and adjusting said modulation based on said aspect. ### Claim 77 (depends on 76) The method of claim 76, wherein said adjusting comprises changing a pharmacological modulation protocol. ### Claim 78 (depends on 77) The method of claim 77, wherein the dose of a pharmacological agent is changed. ### Claim 79 (depends on 77) The method of claim 77, wherein the type of pharmacological agent is changed. ### Claim 80 (depends on 76) The method of claim 76, wherein said adjusting comprises changing an electrical energy applying protocol. ### Claim 81 (depends on 80) The method of claim 80, wherein at least one of amplitude, frequency and waveform of applied current. ### Claim 82 (depends on 76) The method of claim 76, wherein said modulation is terminated when a predetermined aspect of said physiological aspect or biologic aspect is observed.