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

• US 6,610,713 B2
• Filed: 05/15/2001
• Issued: 08/26/2003
• Est. Priority Date: 05/23/2000
• Status: Expired due to Term

• Current Assignee: The Feinstein Institutes For Medical Research
• Original Assignee: North Shore-Long Island Jewish Research Institute
• Inventors: Tracey, Kevin J.
• Primary Examiner(s): HENLEY III, RAYMOND J
• Application Number:
  US09/855,446
• Publication Number:
  US 20020016344A1
• Time in Patent Office: 833 Days
• Field of Search: 514/343, 514/472, 514/546, 514/551, 606/32
• US Class Current: 514/343
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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. A method of inhibiting the release of a proinflammatory cytokine from a mammalian cell, the method comprising 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, wherein the cell is a macrophage.

2. The method of claim 1, wherein the proinflammatory cytokine is selected from the group consisting of tumor necrosis factor (TNF), interleukin (IL)-1β

, IL-6, IL-18 and HMG-1.

3. The method of claim 1, wherein the proinflammatory cytokine is TNF.

4. The method of claim 1, wherein the cholinergic agonist is selected from the group consisting of acetylcholine, nicotine, muscarine, carbachol, galantamine, arecoline, cevimeline, and levamisole.

5. The method of claim 1, wherein the cell is in a patient suffering from, or at risk for, a condition mediated by an inflammatory cytokine cascade.

6. The method of claim 5, wherein the condition is selected from the group consisting of appendicitis, peptic, gastric and duodenal ulcers, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute and 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, and Hodgkins disease.

7. The method of claim 6, wherein the condition is selected from the group consisting of appendicitis, peptic, gastric and duodenal ulcers, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute and 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 and graft-versus-host disease.

8. The method of claim 6, wherein the condition is endotoxic shock.

9. The method of claim 6, wherein the treatment with the cholinergic agonist is effected by stimulating efferent vagus nerve activity sufficient to inhibit the inflammatory cytokine cascade.

10. The method of claim 9, wherein efferent vagus nerve activity is stimulated electrically.

11. The method of claim 9, wherein afferent vagus nerve fibers are not stimulated.

12. The method of claim 9, wherein ganglions or postganglionic neurons are stimulated.

13. The method of claim 9, wherein peripheral tissues or organs served by the vagus nerve are stimulated directly.

14. A method of inhibiting an inflammatory cytokine cascade in a patient, comprising 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.

15. The method of claim 14, wherein the cholinergic agonist is selected from the group consisting of acetylcholine, nicotine, muscarine, carbachol, galantamine, arecoline, cevimeline, and levamisole.

16. The method of claim 14, wherein the condition is selected from the group consisting of appendicitis, peptic, gastric and duodenal ulcers, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute and 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, and Hodgkins disease.

17. The method of claim 16, wherein the condition is selected from the group consisting of appendicitis, peptic, gastric and duodenal ulcers, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute and 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 and graft-versus-host disease.

18. The method of claim 17, wherein the condition is endotoxic shock.

19. The method of claim 14, wherein the treatment with the cholinergic agonist is effected by stimulating efferent vagus nerve activity.

20. The method of claim 19, wherein efferent vagus nerve activity is stimulated electrically.

21. The method of claim 19, wherein afferent vagus nerve fibers are not stimulated.

22. The method of claim 19, wherein ganglions or postganglionic neurons are stimulated.

23. The method of claim 19, wherein peripheral tissues or organs served by the vagus nerve are stimulated directly.

36. The method of claim 17, wherein the condition is appendicitis.

37. The method of claim 17, wherein the condition is selected from the group consisting of peptic, gastric and duodenal ulcers.

38. The method of claim 17, wherein the condition is peritonitis.

39. The method of claim 17, wherein the condition is pancreatitis.

40. The method of claim 17, wherein the condition is hepatitis.

41. The method of claim 17, wherein the condition is asthma.

42. The method of claim 17, wherein the condition is allergy.

43. The method of claim 17, wherein the condition is anaphylactic shock.

44. The method of claim 17, wherein the condition is organ ischemia.

45. The method of claim 17, wherein die condition is reperfusion injury.

46. The method of claim 17, wherein the condition is hay fever.

47. The method of claim 17, wherein the condition is sepsis.

48. The method of claim 17, wherein the condition is septicemia.

49. The method of claim 17, wherein the condition is cachexia.

50. The method of claim 17, wherein the condition is septic abortion.

51. The method of claim 17, wherein the condition is disseminated bacteremia.

52. The method of claim 17, wherein the condition is burns.

53. The method of claim 17, wherein the condition is coeliac disease.

54. The method of claim 17, wherein the condition is congestive heart failure.

55. The method of claim 17, wherein the condition is adult respiratory distress syndrome.

56. The method of claim 17, wherein the condition is cerebral infarction.

57. The method of claim 17, wherein the condition is cerebral embolism.

58. The method of claim 17, wherein the condition is spinal cord injury.

59. The method of claim 17, wherein the condition is paralysis.

60. The method of claim 17, wherein the condition is allograft rejection.

61. The method of claim 17, wherein the condition is graft-versus-host disease.

24. A method for treating a patient suffering from, or at risk for, a condition mediated by an inflammatory cytokine cascade, the method comprising stimulating efferent vagus nerve activity of the patient sufficient to inhibit the inflammatory cytokine cascade.

25. The method of claim 24, wherein the vagus nerve activity is stimulated electrically.

26. The method of claim 24, wherein the condition is selected from the group consisting of appendicitis, peptic, gastric and duodenal ulcers, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute and 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, 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, and Hodgkins disease.

27. The method of claim 26, wherein the condition is selected from the group consisting of appendicitis, peptic, gastric and duodenal ulcers, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute and 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 and graft-versus-host disease.

28. The method of claim 26, wherein the condition is endotoxic shock.

29. The method of claim 24, wherein afferent vagus nerves are not stimulated.

30. The method of claim 24, wherein ganglions or postganglionic neurons are stimulated.

31. The method of claim 24, wherein peripheral tissues or organs served by the vagus nerve are stimulated directly.

32. A method for attenuation of a systemic inflammatory response to endotoxin in a patient, comprising stimulating efferent vagus nerve activity of the patient sufficient to inhibit an inflammatory cytokine cascade.

33. A method for determining whether a compound is a cholinergic agonist, the method comprising determining whether the compound inhibits the release of a proinflammatory cytokine from a mammalian cell.

34. The method of claim 33, wherein the cell is a macrophage.

35. The method of claim 33, wherein the proinflammatory cytokine is TNF.