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

• US 20170266448A1
• Filed: 06/07/2017
• Published: 09/21/2017
• 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 9,987,492 B2
• Time in Patent Office: Days
• 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 suffering from a condition mediated by 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 inflammatory cytokines by at least 20% over an untreated state.

2. The method of claim 1, wherein electrically stimulating the patient'"'"'s vagus nerve comprises stimulating for 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-I0 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 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.

10. The method of claim 1, wherein the condition is selected from the group consisting of diseases involving the gastrointestinal tract and associated tissues;

systemic or local inflammatory diseases and conditions;

diseases involving the urogential system and associated tissues;

diseases involving the respiratory system and associated tissues;

diseases arising from infection by various viruses, bacteria, fungi and protozoal and multicellular parasites;

dermatological diseases and conditions of the skin;

diseases involving the cardiovascular system and associated tissues;

diseases involving the central or peripheral nervous system and associated tissues;

diseases of the bones, joints, muscles and connective tissues;

other autoimmune and inflammatory disorders; and

various cancers, tumors and proliferative disorders.

11. The method of claim 10, wherein the group consisting of diseases of the bones, joints, muscles and connective tissues is selected from the group consisting of various arthritides and arthralgias, osteomyelitis, fasciitis, Paget'"'"'s disease, gout, periodontal disease, rheumatoid arthritis, and synovitis.

12. The method of claim 1, wherein the condition is selected from the group consisting of rheumatoid arthritis and Crohn'"'"'s disease.

13. A method for treating a patient suffering from a condition mediated by 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 inflammatory cytokines by at least 20% over an untreated state, wherein electrical stimulation is for less than 20 min.

14. The method of claim 13, 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.

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

16. The method of claim 13, 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.

17. The method of claim 13, wherein electrically stimulating efferent vagus nerve comprises stimulating the vagus nerve with electrical stimulation having a voltage of at least 1 volt.

18. The method of claim 13, wherein the condition is selected from the group consisting of rheumatoid arthritis and Crohn'"'"'s disease.

19. A method for treating a patient suffering from a condition mediated by 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 inflammatory cytokines by at least 20% over an untreated state; and

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