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

• US 20150100100A1
• Filed: 12/12/2014
• Published: 04/09/2015
• Est. Priority Date: 05/23/2000
• Status: Active Grant

• Current Assignee: The Feinstein Institutes For Medical Research
• Original Assignee: Jared M. Huston, Kevin J. Tracey
• Inventors: TRACEY, Kevin J., HUSTON, Jared M.
• Granted Patent: US 10,166,395 B2
• Time in Patent Office: Days
• US Class Current: 607/2
• 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 treating inflammation by inhibiting an inflammatory cytokine cascade in a patient, wherein the method comprises:

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.

2. The method of claim 1, wherein the first duration is less than about 20 min.

3. The method of claim 1, wherein the second duration is greater than about 30 min.

4. The method of claim 1, wherein the patient'"'"'s vagus nerve is stimulated in an amount sufficient to inhibit the inflammatory cytokine cascade without stimulating humoral anti-inflammatory mediators.

5. The method of claim 1, wherein the electrical stimulation of the patient'"'"'s vagus nerve does not stimulate a corticosteroid or IL-I0 response.

6. The method of claim 1, further comprising electrically stimulating the patient'"'"'s entire vagus nerve, including afferent and efferent nerves.

7. The method of claim 1, 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.

8. A method of inhibiting an inflammatory cytokine cascade of a patient, wherein the method comprises:

evoking a sustained inhibition of the patient'"'"'s inflammatory cytokine cascade by electrically stimulating the patient'"'"'s vagus nerve for a first duration of 20 minutes or less, 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.

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

10. The method of claim 8, wherein the patient'"'"'s vagus nerve is stimulated in an amount sufficient to inhibit the inflammatory cytokine cascade without stimulating humoral anti-inflammatory mediators.

11. The method of claim 8, wherein the electrical stimulation of the patient'"'"'s vagus nerve does not stimulate a corticosteroid or IL-I0 response.

12. The method of claim 8, further comprising electrically stimulating the patient'"'"'s entire vagus nerve, including afferent and efferent nerves.

13. The method of claim 8, 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.

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

electrically 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.

15. The method of claim 14, the stimulating step further comprising stimulating vagus nerve activity in an amount sufficient to induce secretion of acetylcholine.

16. The method of claim 14, wherein the patient'"'"'s vagus nerve is stimulated in an amount sufficient to inhibit the inflammatory cytokine cascade without stimulating humoral anti-inflammatory mediators.

17. The method of claim 14, wherein the electrical stimulation of the patient'"'"'s vagus nerve does not stimulate a corticosteroid or IL-I0 response.

18. The method of claim 14, wherein electrically stimulating vagus nerve activity comprises electrically stimulating electrically stimulating the patient'"'"'s entire vagus nerve, including afferent and efferent nerves.

19. The method of claim 14, wherein electrically stimulating vagus nerve activity comprises 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.