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

• US 8,722,668 B2
• Filed: 04/07/2005
• Issued: 05/13/2014
• Est. Priority Date: 12/23/1998
• Status: Expired due to Fees

• Current Assignee: Neuropro Therapeutics, Inc.
• Original Assignee: Neuropro Therapeutics, Inc.
• Inventors: Hochman, Daryl W.
• Primary Examiner(s): Sims, Jason
• Assistant Examiner(s): Bori, Ibrahim D
• Application Number:
  US11/101,000
• Publication Number:
  US 20050267103A1
• Time in Patent Office: 3,323 Days
• Field of Search: 514/223.2
• US Class Current: 514/223.2
• 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

1. A method for treating pain or the perception of pain in a mammalian subject in need thereof 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 Na⁺K⁺2Cl⁻

co-transporter antagonist is a NKCC1 co-transporter antagonist.

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

4. The method of claim 3, wherein the antagonist is selected from the group consisting of:

furosemide;

bumetanide;

ethacrynic acid;

torsemide;

azosemide;

muzolimine;

piretanide; and

tripamide.

5. The method of claim 1, wherein the antagonist is selected from the group consisting of thiazide and thiazide-like diuretics.

6. The method of claim 5, wherein the antagonist is selected from the group consisting of bendroflumethiazide;

benzthiazide;

chlorothiazide;

hydrochlorothiazide;

hydroflumethiazide;

methylclothiazide;

polythiazide;

trichlormethiazide;

chlorthalidone;

indapamide;

metolazone; and

quinethazone.

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

8. The method of claim 1, wherein the composition is administered orally, sublingually, nasally, transdermally, intravenously, intracranially, intraperitoneally, subcutaneously, intramuscularly, or by inhalation, spinal tap, direct intrathecal injection, administration into the cerebral spinal fluid via the spinal cord by injection or osmotic pump, or administration in a sustained release formulation.

9. The method of claim 1, wherein the pain is neuropathic pain and said 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.

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

11. The method of claim 1, wherein the pain is neuropathic pain and said neuropathic pain has the following etiologies:

alcohol abuse;

diabetes;

eosinophilia-myalgia syndrome;

Guillain-Barre syndrome;

exposure to arsenic, lead, mercury, and thallium;

HIV/AIDS;

malignant tumors;

amiodarone, aurothioglucose, cisplatinum, dapsone, stavudine, zalcitabine, didanosine, disulfiram, FK506, hydralazine, isoniazid, metronidazole, nitrofurantoin, paclitaxel, phenyloin and vincristine;

monoclonal gammopathies;

multiple sclerosis;

post-stroke central pain, postherpetic neuralgia;

carpal tunnel syndrome, cervical or lumbar radiculopathy, complex regional pain syndrome, spinal cord injury and stump pain;

trigeminal neuralgia;

vasculitis;

vitamin B6 megadosing; and

vitamin B12, B1, B6, or E deficiencies.

12. The method of claim 1, wherein the composition further comprises a component selected from the group consisting of:

phenytoin;

carbamazepine;

barbiturates;

Phenobarbital;

pentobarbital;

mephobarbital;

trimethadione;

mephenytoin;

paramethadione;

phenthenylate;

phenacemide;

metharbital;

benzchlorpropanmide;

phensuximide;

primidone;

methsuximide;

ethotoin;

aminoglutehimide;

diazepam;

clonazepam;

clorazepate;

fosphenytoin;

ethosuximide;

valporate;

felbamate;

gabapentin;

lamotrigine;

topiramate;

vigrabatrin;

tiagabine;

zonisamide;

clobazam;

thiopental;

midazoplam;

propofol;

levetiracetam;

oxcarbazepine;

CCPene;

GYK152466;

sumatriptan;

non-steroidal anti-inflammatory drugs;

neuroleptics;

corticosteroids;

vasoconstrictors;

beta-blockers;

antidepressants;

anticonvulsants;

Depakote;

Ergot alkaloids;

tryptans;

Acetaminophen;

caffeine;

Ibuprofen;

Proproxyphene;

oxycodone;

codeine;

isometheptene;

serotonin receptor agonists;

ergotamine;

dihydroergotamine;

sumatriptan;

propranolol;

metoprolol;

atenolol;

timolol;

nadolol;

nifeddipine;

nimodipine;

verapamil;

aspirin;

ketoprofen;

tofenamic acid;

mefenamic acid;

naproxen;

methysergide;

paracetamol;

clonidine;

lisuride;

iprazochrome;

butalbital;

benzodiazepines;

divalproex sodium, a blood brain barrier permeability enhancer and a hyperosmotic agent.

13. The method of claim 12, wherein said administering comprises simultaneous or sequential administration of one or more agents in the same formulation or unit dosage form or in separate formulations or unit dosage forms.