# US 5,348,729 A · Evaluative means for detecting inflammatory reactivity

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- Number: US 5,348,729 A
- Document ID: US5348729A
- Status: Granted
- Kind: A
- Application number: 07/878,608
- Filed: 1992-05-05
- Granted: 1994-09-20
- Earliest claimed: 1988-11-30
- Assignees: The United States of America as represented by the Department of Health and Human Services
- Inventors: Esther M. Sternberg; Philip W. Gold; Samuel W. Page
- Web page: https://patentgrep.com/patent/US5348729A

## CPC

- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/135: having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)}
- A61K 31/35: having six-membered rings with one oxygen as the only ring hetero atom
- A61K 31/365: Lactones
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 31/565: not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K 31/57: substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K 31/585: containing lactone rings, e.g. oxandrolone, bufalin
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- G01N 33/5091: {for testing the pathological state of an organism}
- G01N 33/564: for pre-existing immune complex or autoimmune disease {, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9}
- G01N 33/74: involving hormones {or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors}
- G01N 33/743: {Steroid hormones}
- G01N 2800/102: Arthritis; Rheumatoid arthritis, i.e. inflammation of peripheral joints
- Y10S 435/975: Kit
- 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)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- Y10S: TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS

## Abstract

The present invention is directed to a method for testing the susceptibility of a mammal to inflammatory diseases which comprises the steps of: administering to a mammal a compound selected from the group consisting of Type 1 mineralocorticoid receptor antagonists, opiate antagonists, estrogen antagonists or mixed estrogen agonists/antagonists, progesterone agonists; or a combination of an estrogen antagonist with one or a combination of a Type I glucocorticoid receptor antagonist, a Type II glucocorticoid agonist or a progesterone agonist which is effective in stimulating the hypothalamic-pituitary-adrenal (HPA) axis; and measuring the level of at least one hormone secreted by the hypothalamus, pituitary or adrenal glands of said mammal. The present invention is also directed to methods of treating inflammatory diseases.

## Claims

### Claim 1

A method for testing the susceptibility of a mammal to inflammatory diseases which comprises the steps of:
administering to a mammal a compound selected from the group consisting of Type 1 mineralocorticoid receptor antagonists, opiate antagonists, estrogen antagonists or mixed estrogen agonists/antagonists, progesterone agonists; or a combination of an estrogen antagonist with one or a combination of a Type I glucocorticoid receptor antagonist, a Type II glucocorticoid agonist or a progesterone agonist which is effective in stimulating the hypothalamic-pituitary-adrenal (HPA) axis; and
measuring the level of at least one hormone secreted by the hypothalamus, pituitary or adrenal glands of said mammal.

### Claim 2 (depends on 1)

The method of claim 1, which comprises the steps of administering to a mammal a compound selected from the group consisting of Type 1 mineralocorticoid receptor antagonists, opiate antagonists, estrogen antagonists or mixed estrogen agonists/antagonists, progesterone agonists; or a combination of an estrogen antagonist with one or a combination of a Type I glucocorticoid receptor antagonist, a Type II glucocorticoid agonist or a progesterone agonist, and measuring the level of glucocorticoids or adrenocorticotropic hormone or corticotropic releasing hormone (CRH) in said mammal.

### Claim 3 (depends on 1)

The method of claim 1, wherein said inflammatory disease is arthritis, uveoretinitis,
pneumonitis, encephalomyelitis, multiple sclerosis or hepatic granulomatas.

### Claim 4 (depends on 1)

The method of claim 1, wherein said compound is mespirenone or tamoxifen; or a pharmaceutically acceptable salt thereof, and said hormone is cortisol, corticosterone, adrenocorticotropic hormone or corticotropic releasing hormone (CRH).

### Claim 5 (depends on 1)

The method of claim 1, wherein the level of said hormones secreted by the hypothalamus, pituitary or adrenal glands are measured 10 minutes to 4 hours after administration of said compound.

### Claim 6

A method for testing the susceptibility of a mammal to arthritis which comprises the steps of:
administering to a mammal an amount of mespirenone or tamoxifen effective to stimulate the hypothalamic-pituitary-adrenal axis; and
measuring the level of CRH adrenocorticotropic hormone or corticosterone in the plasma of said mammal between 10 minutes and 4 hours after administration of said mespirenone or tamoxifen.

### Claim 7 (depends on 6)

The method of claim 6, wherein said mammal is a laboratory animal.

### Claim 8 (depends on 6)

The method of claim 6, wherein said mammal is a human.

### Claim 9

A method for treatment of inflammatory diseases which comprises the step of:
administering to a patient suffering from an inflammatory disease, a compound which stimulates the hypothalamic-pituitary-adrenal axis which is selected from the group consisting of Type 1 mineralocorticoid receptor antagonists, estrogen antagonists, or mixed estrogen agonists/antagonists, progesterone agonists; or a combination of an estrogen antagonist with one or a combination of a Type I glucocorticoid receptor antagonist, a Type II glucocorticoid agonist or a progesterone agonist.

### Claim 10 (depends on 9)

The method of claim 9, wherein said compound is administered to a patient suffering from rheumatoid arthritis.

### Claim 11

A kit comprising:
(a) a HPA axis stimulating agent selected from the group consisting of Type 1 mineralocorticoid receptor antagonists, opiate antagonists, estrogen antagonists, mixed estrogen agonists/antagonists, progesterone agonists; or a combination of an estrogen antagonist with one or a combination of a Type I glucocorticoid receptor antagonist, a Type II glucocorticoid agonist or a progesterone agonist, and measuring the level of glucocorticoids, adrenocorticotropic hormone or CRH; and
(b) reagents for measuring a HPA axis hormone response.

### Claim 12 (depends on 11)

The kit of claim 11 further comprising a tracer.

### Claim 13 (depends on 11)

The kit of claim 11, further comprising antibodies to the HPA axis hormone.

### Claim 14 (depends on 11)

The kit of claim 11, wherein said reagents for measuring the HPA axis hormone response comprise reagents for an ELISA test.

### Claim 15 (depends on 14)

The kit of claim 14 further comprising an ELISA tracer.

### Claim 16 (depends on 13)

The kit of claim 13, further comprising a standardized plasma as a control.

### Claim 17 (depends on 12)

The kit of claim 12, wherein said tracer is I.sup.125.

### Claim 18 (depends on 9)

The method of claim 9, wherein said compound is mespirenone.

### Claim 19 (depends on 2)

The method of claim 2, wherein said compound is an opiate antagonist selected from the group consisting of naloxone and naltrexone.

### Claim 20 (depends on 2)

The method of claim 2, wherein said compound is an estrogen antagonist selected from the group consisting of tamoxifen and triphenylethylene derivatives of tamoxifen, phyto-estrogens and progesterone agonists.

### Claim 21 (depends on 2)

The method of claim 2, wherein said glucocorticoid is selected from the group consisting of cortisol and corticosterone.

### Claim 22 (depends on 2)

The method of claim 2, wherein said measuring of glucocorticoids, adrenocorticotropic hormone or CRH is in blood plasma.

### Claim 23 (depends on 2)

The method of claim 2, wherein said inflammatory disease is arthritis.

### Claim 24 (depends on 9)

The method of claim 9, wherein said compound is a mineralacorticoid receptor antagonist selected from the group consisting of Type 1 mineralocorticoid receptor antagonists, estrogen antagonists, mixed estrogen agonists/antagonists, progesterone agonists; or a combination of an estrogen antagonist with one or a combination of a Type I glucocorticoid receptor antagonist, a Type II glucocorticoid agonist or a progesterone agonist.

### Claim 25 (depends on 9)

The method of claim 9, wherein said compound is an estrogen antagonist or mixed estrogen agonist/antagonist is selected from the group consisting of tamoxifen and triphenylethylene derivatives of tamoxifen, phyto-estrogens and progesterone agonists.

### Claim 26 (depends on 11)

The kit of claim 11, wherein said stimulating agent is an opiate antagonist selected from the group consisting of naloxone and naltrexone.

### Claim 27 (depends on 11)

The kit of claim 11, wherein said stimulating agent is an estrogen antagonist or mixed estrogen agonist/antagonist is selected from the group consisting of tamoxifen and triphenylethylene derivatives of tamoxifen, phyto-estrogens and progesterone agonists.