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

• US 6,838,471 B2
• Filed: 05/28/2003
• Issued: 01/04/2005
• Est. Priority Date: 05/23/2000
• Status: Active Grant

• 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:
  US10/446,625
• Publication Number:
  US 20040038857A1
• Time in Patent Office: 587 Days
• Field of Search: 514/343, 514/472, 514/546, 514/551
• 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 proinflamniatory cytokine from a mammalian cell in need thereof, the method comprising treating the cell with an agonist selective for the α

-bungarotoxin-sensitive nicotinic acetylcholine receptor in an amount sufficient to decrease the amount of 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)-1B, 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 proinflammatory cytokine is HMG-1.

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 ulcer, gastric ulcer, duodenal ulcer, peritonitis, pancreatitis, ulcerative colitis, pseudoniembranous colitis, acute colitis, ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitits, 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, pneumonitits, pneumotransmicroscopicsilicovolcanoconiosis, alvealitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus 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, thyroiditis, systemic lupus erythematosis, Goodpasture'"'"'s syndrome, Behcet'"'"'s syndrome, allograft rejection, graft-versus-host disease, Type I diabetes, ankylosing spondylitis, Berger'"'"'s disease, Reiter'"'"'s syndrome and Hodgkin'"'"'s disease.

7. The method of claim 6, wherein the condition is selected from the group consisting of appendicitis, peptic ulcer, gastric ulcer, duodenal ulcer, peritonitis, pancreatitis, ulcerative colitis, pseudomembranous colitis, acute colitis, 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, graft-versus-host-disease, rheumatoid arthritis, systemic lupus erythematosis, burns, myocardial ischemia, cachexia and cystic fibrosis.

8. The method of claim 7, wherein the condition is selected from the group consisting of sepsis, endotoxic shock, allograft rejection, rheumatoid arthritis, adult respiratory distress syndrome, asthma, systemic lupus erythematosis, pancreatitis, peritonitis, burns, myocardial ischemia, allograft rejection, graft-versus-host disease, congestive heart failure, organ ischemia, reperfusion injury, cachexia and cystic fibrosis.

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

10. The method of claim 8, wherein the condition is sepsis.

11. A method of inhibiting an inflammatory cytokine cascade in a patient suffering from, or at risk for, a condition mediated by the inflammatory cytokine cascade, comprising treating the patient with an agonist that is selective for an α

-bungarotoxin-sensitive, nicotinic acetylcholine receptor in an amount sufficient to inhibit the inflammatory cytokine cascade.

12. The method of claim 11, wherein the condition is selected from the group consisting of appendicitis, peptic ulcer, gastric ulcer, duodenal ulcer, peritonitis, pancreatitis, ulcerative colitis, pseudomembranous colitis, acute colitis, ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitits, 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, pneumonitits, pneumotransmicroscopicsilicovolcanoconiosis, alvealitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus 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, thyroiditis, systemic lupus erythematosis, Goodpasture'"'"'s syndrome, Behcet'"'"'s syndrome, allograft rejection, graft-versus-host disease, Type I diabetes, ankylosing spondylitis, Berger'"'"'s disease, Reiter'"'"'s syndrome and Hodgkin'"'"'s disease.

13. The method of claim 12, wherein the condition is selected from the group consisting of appendicitis, peptic ulcer, gastric ulcer and duodenal ulcers, peritonitis, pancreatitis, ulcerative colitis, pseudomembranous colitis, acute colitis, 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, graft-versus-host-disease, rheumatoid arthritis, systemic lupus erythematosis, burns, myocardial ischemia, cachexia and cystic fibrosis.

14. The method of claim 13, wherein the condition is selected from the group consisting of sepsis, endotoxic shock, allograft rejection, rheumatoid arthritis, adult respiratory distress syndrome, asthma, systemic lupus erythematosis, pancreatitis, peritonitis, burns, myocardial ischemia, allograft rejection, graft-versus-host disease, congestive heart failure, organ ischemia, reperfusion injury, cachexia and cystic fibrosis.

15. The method of claim 14, wherein the condition is sepsis.

16. The method of claim 14, wherein the condition is endotoxic shock.

17. The method of claim 14, wherein the condition is allograft rejection.

18. The method of claim 14, wherein the condition is rheumatoid arthritis.

19. The method of claim 14, wherein the condition is adult respiratory distress syndrome.

20. The method of claim 14, wherein the condition is asthma.

21. The method of claim 14, wherein the condition is systemic lupus erythematosis.

22. The method of claim 14, wherein the condition is pancreatitis.

23. The method of claim 14, wherein the condition is peritonitis.

24. The method of claim 14, wherein the condition is burns.

25. The method of claim 14, wherein the condition is myocardial ischemia.

26. The method of claim 14, wherein the condition is allograft rejection.

27. The method of claim 14, wherein the condition is graft-versus-host disease.

28. The method of claim 14, wherein the condition is congestive heart failure.

29. The method of claim 14, wherein the condition is organ ischemia.

30. The method of claim 14, wherein the condition is reperfusion injury.

31. The method of claim 14, wherein the condition is cachexia.

32. The method of claim 14, wherein the condition is cystic fibrosis.