Methods and compositions for the treatment of neuropathic pain and neuropsychiatric disorders

• US 20050267103A1
• Filed: 04/07/2005
• Published: 12/01/2005
• Est. Priority Date: 12/23/1998
• Status: Active Grant

• Current Assignee: Neuropro Therapeutics, Inc.
• Original Assignee: Cytoscan Sciences, LLC
• Inventors: Hochman, Daryl W.
• Granted Patent: US 8,722,668 B2
• Time in Patent Office: Days
• US Class Current: 514/223.200
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 31/4166 having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• CPC Class Codes: A61K 31/48 Ergoline derivatives, e.g. lysergic acid, ergotamine
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/549 having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 31/635 having a heterocyclic ring, e.g. sulfadiazine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

The present invention relates to methods and compositions for treating neuropathic pain and neuropsychiatric disorders by administering agents that are effective in reducing the effective amount, inactivating, and/or inhibiting the activity of a Na⁺—K⁺-2Cl⁻ (NKCC) cotransporter. In certain embodiments, the Na⁺—K⁺-2Cl⁻ co-transporter is NKCC1.

Claims

12. A method for treating a neuropsychiatric disorder in a mammalian subject, comprising administering an effective amount of a composition comprising a Na⁺K⁺2Cl co-transporter antagonist to the subject.

1. A method for treating neuropathic pain in a mammalian subject, comprising administering an effective amount of a composition comprising a Na⁺K⁺2Cl co-transporter antagonist to the subject.

2. The method of claim 1, wherein the antagonist reduces or blocks hypersynchronized neuronal population discharges by non-synaptic effects.

3. The method of claim 1, wherein the Na⁺K⁺2Cl co-transporter antagonist is a NKCC1 co-transporter antagonist.

4. The method of claim 1, wherein the antagonist is a loop diuretic.

5. The method of claim 4, wherein the antagonist is selected from the group consisting of:

furosemide;

bumetanide;

ethacrynic acid;

torsemide;

azosemide;

muzolimine;

piretanide;

tripamide; and

functional analogs and derivatives thereof.

6. The method of claim 1, wherein the antagonist is selected from the group consisting of:

thiazide; and

thiazide-like diuretics.

7. The method of claim 6, wherein the antagonist is selected from the group consisting of:

bendroflumethiazide;

benzthiazide;

chlorothiazide;

hydrochlorothiazide;

hydro-flumethiazide;

methylclothiazide;

polythiazide;

trichlormethiazide;

chlorthalidone;

indapamide;

metolazone;

quinethazone; and

functional analogs and derivatives thereof.

8. The method of claim 1, wherein the antagonist modulates extracellular ion composition and chloride gradients in nervous system tissue.

9. The method of claim 1, wherein the composition is delivered orally, sublingually, nasally, transdermally, intravenously or by inhalation.

10. The method of claim 1, wherein the neuropathic pain is selected from the group consisting of:

diabetic neuropathy;

postherpetic neuralgia;

cancer-related pain;

neurotoxicity-induced pain;

spinal cord injury;

causalgia or reflex sympathetic dystrophy;

trigeminal neuralgia;

chronic lower back pain; and

central post-stroke pain.

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

13. The method of claim 12, wherein the antagonist reduces or blocks hypersynchronized neuronal population discharges by non-synaptic effects.

15. The method of claim 12, wherein the antagonist is a loop diuretic.

16. The method of claim 15, wherein the antagonist is selected from the group consisting of:

furosemide;

bumetanide;

ethacrynic acid;

torsemide;

azosemide;

muzolimine;

piretanide;

tripamide; and

functional analogs and derivatives thereof.

17. The method of claim 12, wherein the antagonist is selected from the group consisting of:

thiazide; and

thiazide-like diuretics.

18. The method of claim 17, wherein the antagonist is selected from the group consisting of:

bendroflumethiazide;

benzthiazide;

chlorothiazide;

hydrochlorothiazide;

hydro-flumethiazide;

methylclothiazide;

polythiazide;

trichlormethiazide;

chlorthalidone;

indapamide;

metolazone;

quinethazone; and

functional analogs and derivatives thereof.

19. The method of claim 1, wherein the neuropsychiatric disorder is selected from the group consisting of:

bipolar disorders, anxiety, panic attacks, depression, schizophrenia and post-traumatic stress syndrome

13-1. The method of claim 12, wherein the Na⁺K⁺2Cl co-transporter antagonist is a NKCC1 co-transporter antagonist.