Neural tourniquet

• US 20050282906A1
• Filed: 03/24/2005
• Published: 12/22/2005
• Est. Priority Date: 03/25/2004
• Status: Active Grant

• Current Assignee: The Feinstein Institutes For Medical Research
• Original Assignee: North Shore-Long Island Jewish Research Institute
• Inventors: Amella, Carol Ann, Czura, Christopher, Tracey, Kevin J.
• Granted Patent: US 8,729,129 B2
• Time in Patent Office: Days
• US Class Current: 514/614
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/4747 spiro-condensed
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Abstract

Disclosed is a method of reducing bleed time in a subject by activation of the cholinergic anti-inflammatory pathway in said subject. The cholinergic anti-inflammatory pathway can be activated by direct or indirect stimulation of the vagus nerve. The cholinergic anti-inflammatory pathway can also be activated by administering an effective amount of cholinergic agonist or acetylcholinesterase inhibitor to the subject.

Claims

1. A method of reducing bleed time in a subject in need of such treatment, the method comprising activating the cholinergic anti-inflammatory pathway.

2. The method of claim 1 wherein the subject is a human.

3. The method of claim 1 wherein the cholinergic anti-inflammatory pathway is activated by stimulating the vagus nerve.

4. The method of claim 3 wherein the cholinergic anti-inflammatory pathway is activated by stimulating the vagus nerve in the brain.

5. The method of claim 4 wherein the vagus nerve is indirectly stimulated by administering an effective amount of a muscarinic agonist to the subject.

6. The method of claim 5 wherein the muscarinic agonist is muscarine, McN-A-343, or MT-3.

7. The method of claim 5 wherein the muscarinic agonist is an aromatic amidinohydrazone.

8. The method of claim 7 wherein the muscarinic agonist is N,N′

-bis(3,5-diacetylphenyl) decanediamide tetrakis (amidinohydrazone) tetrahydrochloride (CNI-1493).

9. The method of claim 7 wherein the muscarinic agonist is a compound having the structural formula I:

wherein;

X₂ is NH₂(CNH)—

NH—

N═

CH—

, NH₂(CNH)—

NH—

N═

CCH₃—

or H—

;

X₁, X′

₁ and X′

₂ independently are NH₂(CNH)—

NH—

N═

CH—

or NH₂(CNH)—

NH—

N═

CCH₃—

;

Z is —

NH(CO)NH—

, —

(C₆H₄)—

, —

(C₅H₃)—

or -A-(CH₂)_n-A-;

n is 2-10; and

A independently is —

NH(CO)—

, —

NH(CO)NH—

, —

NH—

or —

O—

;

or

a pharmaceutically acceptable salt thereof.

10. The method of claim 7 wherein the muscarinic agonist is a compound having the structural formula II:

wherein;

X₁, X₂ and X₃ independently are NH₂(CNH)—

NH—

N═

CH—

or NH₂(CNH)—

NH—

N═

CCH₃—

;

X′

₁, X′

₂ and X′

₃ independently are H—

, NH₂(CNH)—

NH—

N═

CH—

or NH₂(CNH)—

NH—

N═

CCH₃—

;

Z is (C₆H₃) and m₁, m₂, and m₃ are 0;

or

Z is N and independently m₁, m₂ and m₃ are 2-6;

A is —

NH(CO)—

, —

NH(CO)NH—

, —

NH—

or —

O—

;

or

a pharmaceutically acceptable salt thereof.

11. The method of claim 5 wherein the muscarinic agonist is administered directly to the brain of the subject.

12. The method of claim 5 wherein the muscarinic agonist can permeate the brain of the subject.

13. The method of claim 1 wherein the cholinergic anti-inflammatory pathway is activated by administering an effective amount of a cholinergic agonist to the subject.

14. The method of claim 13 wherein the cholinergic agonist is acetylcholine, nicotine, muscarine, carbachol, galantamine, arecoline, cevimeline, or levamisole.

15. The method of claim 13 wherein the cholinergic agonist is nicotine.

16. The method of claim 13 wherein the cholinergic agonist is selective for an α

7 nicotinic receptor.

17. The method of claim 16 wherein the α

7 selective nicotinic agonist is a compound of structural formula III;

wherein;

R is hydrogen or methyl; and

n is 0 or 1;

or

a pharmaceutically acceptable salt thereof.

18. The method of claim 17 wherein the α

7 selective nicotinic agonist is (−

)-spiro-[1-azabicyclo[2.2.2]octane-3,5′

-octane-3,5′

oxazolidin-2′

-one.

19. The method of claim 16 wherein the α

7 selective nicotinic agonist is a compound of structural formula IV;

wherein;

m is 1 or 2;

n is 0 or 1;

Y is CH, N, or NO;

X is oxygen or sulfur;

W is oxygen, H₂, or F₂;

A is N or C(R²);

G is N or C(R³);

D is N or C(R⁴);

with the proviso that no more than one of A, G, and D is nitrogen but at least one of Y, A, G, and D is nitrogen or NO;

R¹ is hydrogen or C, to C₄ alkyl;

R², R³, and R⁴ are independently hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, aryl, heteroaryl, OH, OC, —

C₄ alkyl, CO₂R¹, —

CN, —

NO₂, —

NR⁵R⁶, —

CF₃ or —

OSO₂CF₃;

or

R² and R³, or R³ and R⁴, respectively, may together form another six membered aromatic or heteroaromatic ring sharing A and G, or G and D, respectively, containing between zero and two nitrogen atoms, and substituted with one to two of the following substitutents;

independently hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, aryl, heteroaryl, OH, OC₁-C₄ alkyl, CO₂R¹, —

CN, —

NO₂, —

NR⁵R⁶, —

CF₃ or —

OSO₂CF₃;

R⁵ and R⁶ are independently hydrogen, C₁-C₄ alkyl, C(O)R⁷, C(O)NHR⁸, C(O)OR⁹, SO₂R¹⁰ or may together be (CH₂)_jQ(CH₂)_k;

where

Q is O, S, NR¹¹, or a bond;

j is 2 to 7;

k is 0 to 2; and

R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are independently C₁-C₄, alkyl, aryl, or heteroaryl;

an enantiomer thereof;

or

a pharmaceutically acceptable salt thereof.

20. The method of claim 19 wherein the α

7 selective nicotinic agonist is (R)-(−

)-5′

-phenylspiro[1-azabicyclo[2.2.2]octane-3,2′

octane-3,2′

(3′

H)-furo[2,3-b]pyridine].

21. The method of claim 16 wherein the α

7 selective nicotinic agonist is a compound of structural formula V;

wherein;

R¹ is hydrogen or C₁-C₄ alkyl;

R⁶ and R⁷ are independently absent, hydrogen or C₁-C₄ alkyl; and

R² is;

wherein;

R³, R⁴ and R⁵ are independently hydrogen, C₁-C₄ alkyl optionally substituted with N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, C₁-C₆ alkoxy optionally substituted with N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, carboalkoxy having 1 to 4 carbons in the alkoxy, amino, amido having 1 to 4 carbons in the acyl, cyano, and N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, halo, hydroxyl, or nitro.

22. The method of claim 21 wherein the α

7 selective nicotinic agonist is trans-3-cinnamylidene anabaseine, trans-3-(2-methoxy-cinnamylidene)anabaseine or trans-3-(4-methoxycinnamylidene anabaseine, 3-(4-hydroxy-2-methoxybenzylidene)anabaseine or 3-(2,4-dimethoxybenzyldine)anabaseine (GTS-21).

23. The method of claim 16 wherein the α

7 selective nicotinic agonist is a compound of structural formula VI;

wherein;

X is O or S;

R is H, OR¹, NHC(O)R¹, or a halogen; and

R¹ is a C₁-C₄ alkyl;

or

a pharmaceutically acceptable salt thereof.

24. The method of claim 16 wherein the α

7 selective nicotinic agonist is (1-aza-bicyclo [2.2.2]oct-3-yl)-carbamic acid 1-(2-fluorophenyl)-ethyl ester.

25. The method of claim 16 wherein the α

7 selective nicotinic agonist is cocaine methiodide.

26. The method of claim 16 wherein the α

7 selective nicotinic agonist is choline.

27. The method of claim 3 wherein the vagus nerve is indirectly stimulated.

28. The method of claim 27 wherein the vagus nerve is indirectly stimulated with a transdermal or trans-esophogeal device.

29. The method of claim 3 wherein the vagus nerve is directly stimulated.

30. The method of claim 29 wherein the vagus nerve is stimulated electrically.

31. The method of claim 29 wherein the efferent vagus nerve is stimulated.

32. The method of claim 31 wherein the efferent vagus nerve is stimulated electrically.

33. The method of claim 29 wherein the vagus nerve is directly stimulated with an implanted device.

34. The method of claim 1 wherein the cholinergic anti-inflammatory pathway is activated by administering an acetylcholinesterase inhibitor to the subject.

35. The method of claim 1 wherein the subject suffers from a condition of hemophilia.

36. The method of claim 1 wherein the subject is suffering from a clotting disorder other than hemophilia.

37. The method of claim 1 wherein the subject is suffering bleeding caused by a wound.

38. The method of claim 1 wherein the subject is undergoing surgery.

39. The method of claim 1 wherein the cholinergic anti-inflammatory pathway is stimulated prior to surgery.