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

• US 8,914,114 B2
• Filed: 11/17/2004
• Issued: 12/16/2014
• Est. Priority Date: 05/23/2000
• Status: Active Grant

• Current Assignee: The Feinstein Institutes For Medical Research
• Original Assignee: The Feinstein Institute for Medical Research (Northwell Health, Inc.)
• Inventors: Tracey, Kevin J., Huston, Jared M.
• Primary Examiner(s): Krass, Frederick
• Assistant Examiner(s): Roney, Celeste A
• Application Number:
  US10/990,938
• Publication Number:
  US 20050125044A1
• Time in Patent Office: 3,681 Days
• Field of Search: None
• US Class Current: 607/45
• 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. A method for providing therapy to a patient suffering from a condition mediated by an inflammatory cytokine cascade, wherein the method comprises:

mechanically stimulating vagus nerve activity by applying mechanical force comprising a plurality of mechanical stimulations in an amount sufficient to inhibit the inflammatory cytokine cascade by at least 20% over the untreated state, and wherein the condition mediated by the inflammatory cytokine cascade is selected from the group consisting of appendicitis, ulcerative colitis, Crohn'"'"'s disease, allergy, organ ischemia, reperfusion injury, sepsis, endotoxic shock, allograft rejection, arthritis, systemic lupus erythematosus, pancreatitis, peritonitis, hepatitis, burns, Behcet'"'"'s syndrome, graft-versus-host disease, multiple sclerosis, atherosclerosis and cachexia; and

monitoring a marker of the patient'"'"'s inflammatory cytokine cascade.

2. The method of claim 1, wherein the method comprises mechanically stimulating efferent vagus nerve activity.

3. The method of claim 1, wherein vagus nerve activity is stimulated using a vagus nerve stimulator.

4. The method of claim 1, wherein the marker comprises TNF level.

5. A method for suppressing the production of TNF, wherein the method comprises:

identifying a patient suffering from a condition that elevates TNF;

monitoring TNF levels in the subject'"'"'s blood; and

mechanically stimulating the patient'"'"'s vagus nerve by applying mechanical force comprising a plurality of mechanical stimulations in an amount sufficient to decrease the amount of TNF in the subject'"'"'s blood by at least 20% over the untreated state.

6. A method for providing therapy to a patient suffering from a condition that causes an inflammatory cytokine cascade, wherein the method comprises:

identifying a patient suffering from a condition that causes inflammation through the inflammatory cytokine cascade; and

evoking a sustained inhibition of the patient'"'"'s inflammatory cytokine cascade by electrically stimulating the patient'"'"'s vagus nerve for a first duration, followed by a second duration during which the patient'"'"'s vagus nerve is not electrically stimulated, wherein the second duration is at least three times longer than the first duration,

wherein at the end of the second duration the levels of inflammatory cytokines are inhibited by at least 20% over the untreated state.

7. The method of claim 6, wherein the first duration is less than about 20 min.

8. The method of claim 6, wherein the second duration is greater than about 30 min.

9. The method of claim 6, wherein the patient'"'"'s vagus nerve is stimulated in an amount sufficient to inhibit the inflammatory cytokine cascade without stimulating humoral anti-inflammatory mediators.

10. The method of claim 9, wherein the electrical stimulation of the patient'"'"'s vagus nerve does not stimulate a corticosteroid or IL-10 response.

11. The method of claim 6, further comprising electrically stimulating the patient'"'"'s entire vagus nerve, including afferent and efferent nerves.

12. The method of claim 6, further comprising electrically stimulating the patient'"'"'s efferent vagus nerve by stimulating close to the target organ served by the efferent fibers or by directly stimulating the target organ.

13. A method for providing therapy to a patient suffering from a condition that causes an inflammatory cytokine cascade, wherein the method comprises:

identifying a patient suffering from a condition that causes inflammation through the inflammatory cytokine cascade; and

mechanically stimulating the patient'"'"'s vagus nerve by applying mechanical force comprising a plurality of mechanical stimulations in an amount sufficient to inhibit the inflammatory cytokine cascade by at least 20% over the untreated state.

14. The method of claim 13, wherein the patient'"'"'s vagus nerve is mechanically stimulated by pressure.

15. The method of claim 13, wherein the patient'"'"'s vagus nerve is mechanically stimulated by vibration.

16. A method of inhibiting an inflammatory cytokine cascade of a patient suffering from a condition that causes an inflammatory cytokine cascade, wherein the method comprises:

identifying a patient suffering from a condition that causes inflammation through the inflammatory cytokine cascade; and

evoking a sustained inhibition of the patient'"'"'s inflammatory cytokine cascade by electrically stimulating the patient'"'"'s vagus nerve for a first duration, followed by a second duration during which the patient'"'"'s vagus nerve is not electrically stimulated, wherein the second duration is at least three times longer than the first duration,

wherein at the end of the second duration the levels of inflammatory cytokines are inhibited by at least 20% over the untreated state.

17. A method of inhibiting an inflammatory cytokine cascade of a patient suffering from a condition that triggers an inflammatory cytokine cascade, wherein the method comprises:

identifying a patient suffering from a condition that causes inflammation through the inflammatory cytokine cascade; and

mechanically stimulating the patient'"'"'s vagus nerve by applying mechanical force comprising a plurality of mechanical stimulations in an amount sufficient to inhibit the inflammatory cytokine cascade by at least 20% over the untreated state.

18. A method of providing therapy to a patient suffering from a condition that causes an inflammatory cytokine cascade, wherein the method comprises:

identifying a patient suffering from a condition that causes inflammation through the inflammatory cytokine cascade;

stimulating vagus nerve activity in an amount sufficient to induce sufficient secretion of a cholinergic agonist to inhibit the inflammatory cytokine cascade by at least 20% over the untreated state; and

monitoring a marker of the patient'"'"'s inflammatory cytokine cascade.

19. The method of claim 18, the stimulating step further comprising stimulating vagus nerve activity in an amount sufficient to induce sufficient secretion of acetylcholine.