METHODS OF TREATING CONGENITAL ADRENAL HYPERPLASIA
Patients with congenital adrenal hyperplasia (CAH) need adequate care and treatment in order to lead normal lives. Hence, there is a need for new methods of treating CAH. This disclosure provides new compounds, salts, compositions and uses thereof in the treatment of CAH.
1 . A method of treating Congenital Adrenal Hyperplasia (CAH) in a subject, comprising administering to the subject:
a glucocorticoid or a pharmaceutically acceptable salt thereof; and
a pharmaceutical composition comprising:
a corticotropin-releasing factor type-1 (CRF 1 ) antagonist, or a pharmaceutically acceptable salt thereof, wherein the CRF 1 antagonist is SSR125543 or(S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine, or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable excipient,
wherein the glucocorticoid is administered at a reduced dosage compared to a dosage of the glucocorticoid when administered alone, and wherein the reduced dosage is in a 5 mg hydrocortisone equivalent,
wherein the pharmaceutical composition is administered orally twice daily, and
wherein the subject is in a fed state.
2 . The method of claim 1 , wherein the subject has said subject has a level of androstenedione (A4) that is less than two times an upper limit of a reference range of A4 and a level of adrenocorticotropic hormone (ACTH) that is less than two times an upper limit of a reference range of ACTH.
3 . The method of claim 2 , wherein the glucocorticoid is administered at a reduced dosage compared until the subject achieves levels of A4 and ACTH within the normal range for A4 and ACTH.
4 . The method of claim 2 , wherein administering the CRF 1 antagonist reduces a concentration of one or more hormones deoxycorticosterone, 11-deoxycortisol, cortisol, corticosterone, aldosterone, pregnenolone, 17α-hydroxy pregnenolone, progesterone, dehydroepiandrosterone, androstenediol, testosterone, dihydrotestosterone, estrone, estradiol, estriol, or a combination thereof.
5 . The method of claim 1 , wherein the CRF 1 antagonist is SSR125543, or a pharmaceutically acceptable salt thereof.
6 . The method of claim 1 , wherein the CRF 1 antagonist is(S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine.
7 . The method of claim 3 , wherein the CRF 1 antagonist is SSR125543, or a pharmaceutically acceptable salt thereof.
8 . The method of claim 3 , wherein the CRF 1 antagonist is(S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine.
9 . The method of claim 1 , wherein the subject is an adult.
10 . The method of claim 1 , wherein at least one of the twice daily administered doses is administered in the evening.
11 . The method of claim 10 , wherein the CRF 1 antagonist is administered at a dose of about 50 mg/day and about 800 mg/day.
12 . The method of claim 10 , wherein the CRF 1 antagonist is administered at a dose of about 200 mg/day to the subject.
13 . The method of claim 10 , wherein the CRF 1 antagonist is administered at a dose of about 100 mg/day to the subject.
14 . The method of claim 1 , wherein the pharmaceutical composition is formulated as a capsule or a tablet.
15 . The method of claim 14 , wherein the CRF 1 antagonist is present in the pharmaceutical composition in an amount between about 10 mg and about 200 mg.
16 . The method of claim 14 , wherein the pharmaceutically acceptable excipient comprises one or more of an amino acid, monosaccharide, cellulose or derivative thereof, solid lubricant, polyol, emulsifier, wetting agent, diluent, binder, disintegrant, super-disintegrant, glidant, coloring agent, sweetener and flavoring agent, preservative, tonicity adjuster, antioxidant, pH adjuster, cryoprotectant, cationic surfactant, anionic surfactant, non-ionic surfactant, organic material, inorganic material, co-processed diluent, compression aid, anti-tacking agent, or a combination thereof.