Treatment of disease with esters of selective RXR agonists
The present specification provides methods of treating disease with an ester of an RXR agonist or a combination of an ester of an RXR agonist and a thyroid hormone. The esters of an RXR agonist can be useful in the treatment of cancer, nervous system, autoimmune, and muscular disorders.
1. A method of providing IRX4204 to a patient in need thereof, comprising administering to the patient an ethyl ester of IRX4204, wherein IRX4204 has the structure
wherein an effective dose of the IRX4204 ethyl ester is lower than a corresponding effective dose of IRX4204 in treating a nervous system disorder, wherein the nervous system disorder is selected from Parkinson's disease, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, and aging-related neurodegeneration.
2. A method of providing IRX4204 to a patient in need thereof, comprising administering to the patient an ethyl ester of IRX4204, wherein the dose of the IRX4204 ethyl ester is greater than a toxicity producing dose of IRX4204 in treating a nervous system disorder, wherein the nervous system disorder is selected from Parkinson's disease, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, and aging-related neurodegeneration.
3. A method of providing IRX4204 to a patient in need thereof, comprising administering to the patient an ethyl ester of IRX4204, wherein Cmax of the active species is less than would result from administration of a same dose of IRX4204 in treating a nervous system disorder, wherein the nervous system disorder is selected from Parkinson's disease, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, and aging-related neurodegeneration.
4. A method of providing IRX4204 to a patient in need thereof, comprising administering an ethyl ester of IRX4204 to the patient, wherein Tmax of the active species is greater than would result from administration of a same dose of IRX4204 in treating a nervous system disorder, wherein the nervous system disorder is selected from Parkinson's disease, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, and aging-related neurodegeneration.
5. The method of claim 4 , wherein Tmax is determined in the plasma.
6. The method according to claim 1 , wherein target tissue penetration by the ester is greater than by a same dose of IRX4204.
7. The method according to claim 1 , wherein the doses of IRX4204 and the IRX4204 ethyl ester are compared on a mass basis.
8. The method according to claim 1 , wherein the doses of IRX4204 and the IRX4204 ethyl ester are compared on a molar basis.
9. The method of claim 1 , wherein the IRX4204 ethyl ester is administered at a dosage that produces a systemic concentration of IRX4204≥50 pM.
10. The method of claim 1 , wherein the IRX4204 ethyl ester is administered at a dosage that produces a systemic concentration of IRX4204≥0.1 nM.
11. The method of claim 1 , wherein the IRX4204 ethyl ester is administered at a dosage that produces a systemic concentration of IRX4204≥1 nM.
12. The method of claim 1 , wherein the IRX4204 ethyl ester is administered at a dosage that produces a concentration of IRX4204≥50 pM in a target tissue.
13. The method of claim 1 , wherein the IRX4204 ethyl ester is administered at a dosage that produces a concentration of IRX4204≥0.1 nM in a target tissue.
14. The method of claim 1 , wherein the IRX4204 ethyl ester is administered at a dosage that produces a concentration of IRX4204≥1 nM in a target tissue.
15. The method of claim 1 , wherein the IRX4204 ethyl ester is administered at a dosage that produces a systemic concentration of IRX4204 that does not exceed 200 nM.
16. The method of claim 15 , wherein the IRX4204 ethyl ester is administered nasally.
17. The method of claim 15 , wherein the IRX4204 ethyl ester is administered orally.
18. The method of claim 17 , wherein the dosage is up to 24, 40, 60, 80, 100, or 120 mg/m 2 /day.
19. The method of claim 18 , wherein the dosage exceeds 20 mg/m 2 /day.
20. The method according to claim 1 , further comprising administration of a neurotrophic factor or a mimetic thereof.
21. The method of claim 20 , wherein the neurotrophic factor is brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), basic fibroblast growth factor (bFGF), ciliary neurotrophic factor (CNTF), neurotrophic factors-4/5 (NT-4/5), insulin-like growth factor (IGF), or insulin, or a mimetic thereof.
22. The method according to claim 1 , further comprising administration of a therapeutically effective amount of thyroid hormone.
23. The method according to claim 21 , further comprising administration of a therapeutically effective amount of thyroid hormone.