INHIBITION OF INFLAMMATORY CYTOKINE PRODUCTION BY CHOLINERGIC AGONISTS AND VAGUS NERVE STIMULATION

• US 20090248097A1
• Filed: 04/24/2008
• Published: 10/01/2009
• Est. Priority Date: 05/23/2000
• Status: Abandoned Application

• Current Assignee: The Feinstein Institute for Medical Research (Northwell Health, Inc.)
• Original Assignee: The Feinstein Institute for Medical Research (Northwell Health, Inc.)
• Inventors: Tracey, Kevin J., Huston, Jared M.
• Application Number:
  US12/109,334
• Publication Number:
  US 20090248097A1
• Time in Patent Office: Days
• US Class Current: 607/3
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61N 1/36053 adapted for vagal stimulation A61N1/36114 takes precedence
• CPC Class Codes: A61N 1/3606 adapted for a particular treatment
• CPC Class Codes: A61N 1/36167 Timing, e.g. stimulation onset
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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.

Claims

1-27. -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.