# US 2017/0281579 A1 · Compositions and methods for treating refractory seizures

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- Number: US 2017/0281579 A1
- Document ID: US20170281579A1
- Status: Published application
- Kind: A1
- Application number: 15/504,141
- Filed: 2015-08-14
- Published: 2017-10-05
- Earliest claimed: 2014-08-15
- Assignees: The Johns Hopkins University; Kennedy Krieger Institute, Inc.
- Applicants: The Johns Hopkins University; Kennedy Krieger Institute, Inc.
- Inventors: Shilpa D. Kadam
- Web page: https://patentgrep.com/patent/US20170281579A1

## CPC

- A61K 31/196: the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
- A61K 31/4015: having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
- A61K 31/4166: having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/515: Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 31/553: having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A01K 2207/20: Animals treated with compounds which are neither proteins nor nucleic acids
- A01K 2207/30: Animals modified by surgical methods
- A01K 2267/0356: Animal model for processes and diseases of the central nervous system, e.g. stress, learning, schizophrenia, pain, epilepsy
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS

## Abstract

The present invention relates to the field of seizures. More specifically, the present invention provides compositions and methods for treating refractory seizures in neonates. In one embodiment, the method comprises the steps of (a) administering to the patient an amount of a KCC2 agonist and/or trkB antagonist effective to restore KCC2 expression to normal physiological levels; and (b) administering to the patient an effective amount of an anti-seizure medication.

## Claims

### Claim 1

A method for treating refractory seizures in a neonatal patient comprising the steps of:
a. administering to the patient an amount of a KCC2 agonist and/or trkB antagonist effective to restore KCC2 expression to normal physiological levels; and
b. administering to the patient an effective amount of an anti-seizure medication.

### Claim 2 (depends on 1)

The method of claim 1, wherein the seizure is an ischemia-related seizure.

### Claim 3 (depends on 1)

The method of claim 1, wherein the KCC2 agonist comprises N-ethylmaleimide (NEM), the chloride channel inhibitor 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), CLP257, or CLP290.

### Claim 4 (depends on 1)

The method of claim 1, wherein the trkB antagonist comprises ANA-12, N-T19, K252a or cyclotraxin-B.

### Claim 5 (depends on 1)

The method of claim 1, wherein the KCC2 agonist is CLP290.

### Claim 6 (depends on 1)

The method of claim 1, wherein the trkB antagonist is ANA-12.

### Claim 7 (depends on 1)

The method of claim 1, wherein the anti-seizure medication is phenobarbital or phenytoin.

### Claim 8

A method for treating refractory seizures in a neonatal patient comprising the steps of:
a. administering to the patient an amount of ANA-12 and/or CLP290 effective to restore KCC2 expression to normal physiological levels; and
b. administering to the patient an effective amount of an anti-seizure medication.

### Claim 9 (depends on 8)

The method of claim 8, wherein the seizure is an ischemia-related seizure.

### Claim 10 (depends on 8)

The method of claim 8, wherein the anti-seizure medication is phenobarbital or phenytoin.

### Claim 11

A method for treating refractory seizures in a neonatal patient comprising the steps of:
a. administering to the patient an amount of ANA-12 and/or CLP290 effective to restore KCC2 expression to normal physiological levels; and
b. administering to the patient an effective amount of phenobarbital.

### Claim 12

A method for treating refractory seizures in a patient comprising the steps of:
a. administering to the patient an effective amount of an agent that increases KCC2 expression back to normal levels, wherein the seizure downregulates KCC2 expression; and
b. administering to the patient an effective amount of an anti-seizure medication.

### Claim 13 (depends on 12)

The method of claim 12, wherein the patient is a neonate.

### Claim 14 (depends on 13)

The method of claim 13, wherein the neonate is administered a transient dose of an anti-seizure medication.

### Claim 15

A method for treating ischemia-related seizures in a neonatal patient comprising the steps of:
a. administering a KCC2 agonist and/or a trkB antagonist in an amount(s) effective to restore KCC2 expression back to normal physiological levels; and
b. administering a transient dose of an anti-seizure medication in an amount effective to stop the seizures.

### Claim 16

A method for making a rodent ischemic seizure model comprising the steps of:
a. anesthetizing the rodent;
b. permanently double ligating the right common carotid artery; and
c. closing the outer skin of the rodent.

### Claim 17 (depends on 16)

The method of claim 16, wherein the rodent is a mouse.

### Claim 18 (depends on 17)

The method of claim 17, wherein the mouse is a CD1 mouse.

### Claim 19 (depends on 16)

The rodent ischemic seizure model produced by the method of claim 16.

### Claim 20 (depends on 5)

The method of claim 5, wherein the effective amount of the anti-seizure medication or phenobarbital is reduced due to anti-seizure activity of CLP290.