# US 8,569,248 B2 · Cardiac glycosides to treat cystic fibrosis and other IL-8 dependent disorders

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- Number: US 8,569,248 B2
- Document ID: US8569248B2
- Status: Granted
- Kind: B2
- Application number: 12/229,399
- Filed: 2009-11-12
- Published: 2010-05-13
- Granted: 2013-10-29
- Earliest claimed: 2002-05-28
- Applicants: Bette Pollard
- Inventors: Bette Pollard
- Web page: https://patentgrep.com/patent/US8569248B2

## CPC

- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 31/7048: having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- 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
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 31/16: for influenza or rhinoviruses
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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

## Abstract

A method of inhibiting the secretion of IL-8 and other pro-inflammatory cytokines from cells secreting elevated levels of these compounds is provided. The method includes contacting the cell with a composition comprising a cardiac glycoside such as oleandrin. The cardiac glycoside can be used to treat cystic fibrosis and other IL-8 dependent disorders by lowering levels of spontaneously secreted IL-8 and other pro-inflammatory cytokines. Oleandrin was found to suppress the secretion of IL-8 from cultured CF lung epithelial cells in the nanomolar concentration range. Structure-activity relationships (SARs) for cardiac glycosides are also elucidated.

## Claims

### Claim 1

A method of treating a patient in need of treatment for a disease condition caused or aggravated by an excessive level of IL-8, comprising administering a cardiac glycoside that lacks an oxygen-containing substituent at both C11 and C12 and has glycosyl moieties at the C3 position, wherein the cardiac glycoside is administered at a concentration of from about 1 nM to about 2 nM, adjusted to the mass of the recipient and the need of the recipient to inhibit or reduce the level of IL-8.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the cardiac glycoside is selected from the group consisting of oleandrin and digitoxin.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the cardiac glycoside is digitoxin.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the cardiac glycoside is oleandrin.

### Claim 5 (depends on 2)

The method according to claim 2, wherein the disease condition is cystic fibrosis, cardiopulmonary bypass surgery, cardiopulmonary arrest, inflammatory bowel disease, lung disorders and lung conditions, traumatic brain injury, stroke, cerebral reperfusion injury, transplant graft rejection, Alzheimer's disease, viral infections, fevers, psoriasis, arthritis, Sjogren's syndrome, Behcet's disease, Parkinson's disease, or glomerulonephritis.

### Claim 6 (depends on 5)

The method according to claim 5, wherein the lung disorders and lung conditions comprise asthma, noneosinophilic asthma, non-specific airway hyper-responsiveness, chronic pulmonary obstructive disease, nosocomial pneumonia, endotoxemia-induced acute respiratory distress syndrome or related conditions.

### Claim 7

A method of treating a mammal in need of treatment for disease conditions characterized by elevated levels of IL-8, comprising administering an effective amount of a cardiac glycoside having glycosyl moieties at the C3 position and lacking an oxygen-containing substituent at both C11 and C12 wherein the effective amount is a concentration of from about 1 nM to about 2 nM, adjusted to the mass of the recipient and the need of the recipient to reduce or inhibit the level of IL-8.

### Claim 8 (depends on 7)

The method according to claim 7, wherein the cardiac glycoside is oleandrin.

### Claim 9 (depends on 7)

The method according to claim 7, wherein the cardiac glycoside is digitoxin.

### Claim 10 (depends on 7)

The method according to claim 7, wherein the disease condition is: cystic fibrosis, cardiopulmonary bypass surgery; cardiopulmonary arrest; inflammatory bowel disease; lung disorders and lung conditions; traumatic brain injury; stroke; cerebral reperfusion injury; transplant graft rejection; Alzheimer's disease; viral infections; fevers; psoriasis; arthritis; Sjogren's syndrome; Behcet's disease; Parkinson's disease; or glomerulonephritis.

### Claim 11 (depends on 7)

The method according to claim 7, wherein the lung disorders and lung conditions comprise asthma, noneosinophilic asthma, non-specific airway hyper-responsiveness, chronic pulmonary obstructive disease, nosocomial pneumonia, endotoxemia-induced acute respiratory distress syndrome or related conditions.

### Claim 12

A method for inhibiting or reducing the secretion of IL-8 from a cell secreting elevated levels of IL-8, comprising administering a cardiac glycoside in a concentration of from about 1 nM to about 2 nM, adjusted to the mass of the recipient and the need of the recipient to reduce or inhibit the level of IL-8, and wherein the cardiac glycoside has glycosyl moieties at the C3 position and lacks an oxygen-containing substituent at both C11 and C12.

### Claim 13 (depends on 12)

The method according to claim 12, wherein the cardiac glycoside is oleandrin.

### Claim 14 (depends on 12)

The method according to claim 12, wherein the cardiac glycoside is digitoxin.

### Claim 15 (depends on 12)

The method according to claim 12, wherein the cardiac glycoside is for use in the treatment of a condition that is: cystic fibrosis, cardiopulmonary bypass surgery; cardiopulmonary arrest; inflammatory bowel disease; lung disorders and lung conditions; traumatic brain injury; stroke; cerebral reperfusion injury; transplant graft rejection; Alzheimer's disease; viral infections; fevers; psoriasis; arthritis; Sjogren's syndrome; Behcet's disease; Parkinson's disease; or glomerulonephritis.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the lung disorders and lung conditions comprise asthma, noneosinophilic asthma, non-specific airway hyper-responsiveness, chronic pulmonary obstructive disease, nosocomial pneumonia, endotoxemia-induced acute respiratory distress syndrome or related conditions.