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

• US 9,987,492 B2
• Filed: 06/07/2017
• Issued: 06/05/2018
• Est. Priority Date: 05/23/2000
• Status: Expired due to Term

• 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): Roney, Celeste A
• Application Number:
  US15/616,855
• Publication Number:
  US 20170266448A1
• Time in Patent Office: 363 Days
• Field of Search: None
• 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 a patient by modulating an inflammatory cytokine cascade, wherein the method comprises:

evoking a sustained inhibition of the patient'"'"'s inflammatory cytokine cascade by electrically stimulating the patient'"'"'s vagus nerve to inhibit the level of at least one inflammatory cytokine by at least 20% over an untreated state.

2. The method of claim 1, wherein electrically stimulating the patient'"'"'s vagus nerve comprises delivering an electrical stimulation having a duration of less than about 20 min.

3. The method of claim 2, wherein the patient is not electrically stimulated again for at least about 30 min.

4. The method of claim 1, wherein electrically stimulating the patient'"'"'s vagus nerve comprises stimulating 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-10 response.

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

7. The method of claim 1, wherein electrically stimulating the patient'"'"'s vagus nerve 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.

8. The method of claim 1, wherein electrically stimulating the patient'"'"'s vagus nerve comprises stimulating the vagus nerve with electrical stimulation having a voltage of at least 1 volt.

9. The method of claim 1, wherein the at least one inflammatory cytokine is tumor necrosis factor.

10. The method of claim 1, wherein the patient is suffering from a condition that is selected from the group consisting of endotoxic shock, sepsis, cachexia, rheumatoid arthritis, multiple sclerosis, lupus, colitis, hepatitis, and Crohn'"'"'s disease.

11. A method for treating a patient by modulating an inflammatory cytokine cascade, wherein the method comprises:

evoking a sustained inhibition of the patient'"'"'s inflammatory cytokine cascade by electrically stimulating efferent vagus nerve activity to inhibit the level of at least one inflammatory cytokine by at least 20% over an untreated state, wherein the electrical stimulation is delivered for less than 20 min.

12. The method of claim 11, wherein electrically stimulating efferent vagus nerve activity comprises stimulating the patient'"'"'s vagus nerve in an amount sufficient to inhibit the inflammatory cytokine cascade without stimulating humoral anti-inflammatory mediators.

13. The method of claim 11, wherein electrically stimulating efferent vagus nerve activity does not stimulate a corticosteroid or IL-I0 response.

14. The method of claim 11, wherein electrically stimulating efferent vagus nerve activity comprises stimulating close to the target organ served by the efferent fibers or by directly stimulating the target organ.

15. The method of claim 11, wherein electrically stimulating efferent vagus nerve comprises stimulating the vagus nerve with electrical stimulation having a voltage of at least 1 volt.

16. The method of claim 11, wherein the patient is suffering from a condition that is selected from the group consisting of endotoxic shock, sepsis, cachexia, rheumatoid arthritis, multiple sclerosis, lupus, colitis, hepatitis, and Crohn'"'"'s disease.

17. A method for treating a patient by modulating an inflammatory cytokine cascade, wherein the method comprises:

evoking a sustained inhibition of the patient'"'"'s inflammatory cytokine cascade by electrically stimulating efferent vagus nerve activity to inhibit the level of at least one inflammatory cytokine by at least 20% over an untreated state; and

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