Use of glucocorticoid receptor antagonists in combination with glucocorticoids to treat adrenal insufficiency
This invention provides for a method of treating secondary adrenal insufficiency by co-administrating therapeutically effective amounts of a glucocorticoid and a glucocorticoid receptor antagonist to the patient in need thereof. In some embodiments, the method includes the proviso that the patient not be otherwise in need of treatment with a glucocorticoid and a glucocorticoid receptor antagonist. The treatment method can increase the patient's morning or basal cortisol level to at least about 12 μg/dL or a standard control level, and in turn, expedite significantly the recovery of the HPA axis. The method provided herein can improve health outcomes and life-threatening complications associated with secondary adrenal insufficiency.
1 . A method of treating secondary adrenal insufficiency, the method comprising co-administering a therapeutically effective amount of a glucocorticoid (GC) and a non-steroidal glucocorticoid receptor antagonist (GRA), wherein the glucocorticoid receptor antagonist backbone is a fused azadecalin, to a patient in need thereof, wherein administering said non-steroidal GRA comprises administering initial low dose amounts of the non-steroidal GRA once per day along with initial high dose amounts of said GC administration for at least a week, wherein said once-daily initial low dose amount said non-steroidal GRA is between 100 milligrams (mg) and 150 mg of the non-steroidal GRA, and wherein said initial high dose amount of said GC is between 15 and 30 mg of the GC, and then continuing to administer the GC and continuing to administer the non-steroidal GRA once per day, wherein said continued once per day non-steroidal GRA administration is at a non-steroidal GRA dose amount that is greater than said initial GRA low dose amount, and wherein said continued GC administration is at a GC dose amount that is less than said initial GC high dose amount, effective to increase the patient's morning plasma levels of cortisol to at least about 12 μg/dL, whereby said secondary adrenal insufficiency is treated, wherein the glucocorticoid receptor antagonist backbone is a fused azadecalin.
2 . The method of claim 1 , wherein the fused azadecalin is a compound having the following formula:
wherein
L 1 and L 2 are members independently selected from a bond and unsubstituted alkylene;
R 1 is a member selected from unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl, —OR 1A N 1C R 1D , —C(O)NR 1C R 1D and —C(O)OR 1A , wherein
R 1A is a member selected from hydrogen, unsubstituted alkyl and unsubstituted heteroalkyl,
R 1C and R 1D are members independently selected from unsubstituted alkyl and unsubstituted heteroalkyl,
wherein R 1C and R 1D are optionally joined to form an unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises an additional ring nitrogen;
R 2 has the formula:
wherein
R 2G is a member selected from hydrogen, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, —CN, and —CF 3 ;
J is phenyl;
t is an integer from 0 to 5;
X is —S(O 2 )—; and
R 5 is phenyl optionally substituted with 1-5 R 5A groups, wherein
R 5A is a member selected from hydrogen, halogen, —OR 5A1 , S(O 2 )NR 5A2 R 5A3 , —CN, and unsubstituted alkyl, wherein
R 5A1 is a member selected from hydrogen and unsubstituted alkyl, and
R 5A2 and R 5A3 are members independently selected from hydrogen and unsubstituted alkyl,
or salts and thereof.
3 . The method of claim 1 , wherein the patient has secondary adrenal insufficiency after successful surgery for endogenous Cushing's syndrome.
4 . The method of claim 1 , wherein the patient has secondary adrenal insufficiency after successful surgery of a pituitary ACTH-secreting tumor, an extra-adrenal cortisol secreting tumor, a unilateral hyperplastic adrenal gland associated with autonomous cortisol secretion, an ectopic ACTH secreting non-pituitary tumor, or a unilateral adrenocortical cortisol secreting tumor.
5 . The method of claim 1 , wherein the patient has not received glucocorticoid and glucocorticoid receptor antagonist treatment.
6 . The method of claim 5 , wherein the patient has not been treated for a disorder or condition selected from the group consisting of glaucoma, inflammatory diseases, rheumatoid arthritis, asthma and rhinitis, chronic pulmonary disease, allergies, and autoimmune diseases.
7 . The method of claim 5 , wherein the patient has not been treated to reduce a side effect of glucocorticoid treatment.
8 . The method of claim 7 , wherein the side effect is selected from the group consisting of weight gain, glaucoma, fluid retention, increased blood pressure, mood swings, cataracts, high blood sugar, diabetes, infection, loss of calcium from bones, osteoporosis, menstrual irregularities, fat redistribution, growth retardation, and cushingoid appearance.
9 . The method of claim 1 , wherein the glucocorticoid is selected from the group consisting of hydroxycortisone, prednisone and dexamethasone.