Substituted cycloalkanes for managing nephrogenic diabetes insipidus
In certain embodiments, this disclosure relates to methods of treating or preventing nephrogenic diabetes insipidus comprising administering an effective amount of compounds of the class of alkyl carboxylic acids, such as 1,1′-(decane-1,10-diyl)bis(cyclopropane-1-carboxylic acid), pharmaceutical salts or derivatives thereof, and the class of alkyl amides, such as 1,1′-(dodecane-1,12-diyl)bis(cyclopropane-1-carboxamide), pharmaceutical salts or derivatives thereof, as described herein, to a subject in need thereof. In certain embodiments, the subject has been diagnosed with nephrogenic diabetes insipidus.
1. A method for treating nephrogenic diabetes insipidus in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 1,1′-(dodecane-1,12-diyl)bis(cyclopropane-1-carboxylic acid) of the following structure:
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the nephrogenic diabetes insipidus is acquired nephrogenic diabetes insipidus.
3. The method of claim 1 , wherein the nephrogenic diabetes insipidus is congenital nephrogenic diabetes insipidus.
4. The method of claim 1 , wherein the nephrogenic diabetes insipidus is induced by lithium therapy.
5. The method of claim 1 , wherein the subject has at least one symptom of nephrogenic diabetes insipidus selected from the group consisting of a production of large quantities of dilute urine, excessive thirst, and excessive urination, or a combination thereof.
6. The method of claim 1 , wherein the administering to the subject results in a reduction in a volume of urination in the subject to less than 20 L/day.
7. The method of claim 1 , wherein the administering to the subject results in a reduction in a volume of urination in the subject to less than 15 L/day.
8. The method of claim 1 , wherein the administering to the subject results in a reduction in a volume of urination in the subject to less than 10 L/day.
9. The method of claim 1 , wherein the administering to the subject results in a reduction in a volume of urination in the subject to less than 5 L/day.
10. The method of claim 1 , wherein the administering to the subject results in a reduction of a daily volume of urination in the subject by about 50%.
11. The method of claim 1 , wherein the administering to the subject results in a reduction of a daily volume of urination in the subject by about 40%.
12. The method of claim 1 , wherein the administering to the subject results in a reduction of a daily volume of urination in the subject by about 30%.
13. The method of claim 1 , wherein the administering to the subject results in a reduction of a daily volume of urination in the subject by about 20%.
14. The method of claim 1 , wherein the administering to the subject results in a reduction in a daily frequency of urination in the subject by about 50%.
15. The method of claim 1 , wherein the administering to the subject results in a reduction in a daily frequency of urination in the subject by about 40%.
16. The method of claim 1 , wherein the administering to the subject results in a reduction in a daily frequency of urination in the subject by about 30%.
17. The method of claim 1 , wherein the administering to the subject results in a reduction in a daily frequency of urination in the subject by about 20%.
18. The method of claim 1 , wherein the administering to the subject results in an increase in a daily urine osmolality in the subject by about 50%.
19. The method of claim 1 , wherein the administering to the subject results in an increase in a daily urine osmolality in the subject by about 40%.
20. The method of claim 1 , wherein the administering to the subject in need thereof results in an increase in a daily urine osmolality in the subject by about 30%.
21. The method of claim 1 , wherein the administering to the subject results in an increase in a daily urine osmolality in the subject by about 20%.
22. The method of claim 1 , wherein the administering to the subject results in a urine osmolality in the subject greater than 125 mOsm/kg.
23. The method of claim 1 , wherein the administering to the subject results in a urine osmolality in the subject greater than 150 mOsm/kg.
24. The method of claim 1 , wherein the administering to the subject results in a urine osmolality in the subject greater than 200 mOsm/kg.
25. The method of claim 1 , wherein:
(a) the administering to the subject does not alter blood sugar levels in the subject; or
(b) the administering to the subject does not induce hypoglycemia in a fasting condition in the subject.
26. The method of claim 1 , wherein the administering to the subject does not result in gastrointestinal distress in the subject.
27. The method of claim 1 , wherein the subject is an adult.
28. The method of claim 1 , wherein the subject is a child.
29. The method of claim 1 , wherein the pharmaceutical composition is administered to the subject orally.
30. The method of claim 1 , wherein the pharmaceutical composition is a liquid composition.
31. The method of claim 1 , wherein:
(a) the pharmaceutical composition is administered to the subject orally; and
(b) the pharmaceutical composition is a solid composition.
32. The method of claim 1 , wherein the pharmaceutical composition comprises a therapeutically effective amount of 1,1′-(dodecane-1,12-diyl)bis(cyclopropane-1-carboxylic acid) in a range of about 0.1 mg per day to about 3,000 mg per day.
33. The method of claim 1 , wherein the pharmaceutical composition comprises a therapeutically effective amount of 1,1′-(dodecane-1,12-diyl)bis(cyclopropane-1-carboxylic acid) in a range of about 0.1 mg per day to about 250 mg per day.
34. The method of claim 1 , wherein the method further comprises administering to the subject a therapeutically effective amount of a second active agent.
35. The method of claim 34 , wherein the second active agent is selected from the group consisting of an adenosine monophosphate-activated protein kinase activator, a cyclic guanosine monophosphate-specific phosphodiesterase inhibitor, a diuretic, and a P2Y purinergic receptor antagonist.
36. The method of claim 34 , wherein the second active agent is lithium.
37. A method for treating nephrogenic diabetes insipidus in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 1,1′-(dodecane-1,12-diyl)bis(cyclopropane-1-carboxamide) of the following structure:
or a pharmaceutically acceptable salt thereof.
38. The method of claim 37 , wherein the nephrogenic diabetes insipidus is acquired nephrogenic diabetes insipidus.
39. The method of claim 37 , wherein the nephrogenic diabetes insipidus is congenital nephrogenic diabetes insipidus.
40. The method of claim 37 , wherein the nephrogenic diabetes insipidus is induced by lithium therapy.
41. The method of claim 37 , wherein the subject has at least one symptom of nephrogenic diabetes insipidus selected from the group consisting of a production of large quantities of dilute urine, excessive thirst, and excessive urination, or a combination thereof.
42. The method of claim 37 , wherein the administering to the subject results in a reduction in a volume of urination in the subject to less than 20 L/day.
43. The method of claim 37 , wherein the administering to the subject results in a reduction in a volume of urination in the subject to less than 15 L/day.
44. The method of claim 37 , wherein the administering to the subject results in a reduction in a volume of urination in the subject to less than 10 L/day.
45. The method of claim 37 , wherein the administering to the subject results in a reduction in a volume of urination in the subject to less than 5 L/day.
46. The method of claim 37 , wherein the administering to the subject results in a reduction of a daily volume of urination in the subject by about 50%.
47. The method of claim 37 , wherein the administering to the subject results in a reduction of a daily volume of urination in the subject by about 40%.
48. The method of claim 37 , wherein the administering to the subject results in a reduction of a daily volume of urination in the subject by about 30%.
49. The method of claim 37 , wherein the administering to the subject results in a reduction of a daily volume of urination in the subject by about 20%.
50. The method of claim 37 , wherein the administering to the subject results in a reduction in a daily frequency of urination in the subject by about 50%.
51. The method of claim 37 , wherein the administering to the subject results in a reduction in a daily frequency of urination in the subject by about 40%.
52. The method of claim 37 , wherein the administering to the subject results in a reduction in a daily frequency of urination in the subject by about 30%.
53. The method of claim 37 , wherein the administering to the subject results in a reduction in a daily frequency of urination in the subject by about 20%.
54. The method of claim 37 , wherein the administering to the subject results in an increase in a daily urine osmolality in the subject by about 50%.
55. The method of claim 37 , wherein the administering to the subject results in an increase in a daily urine osmolality in the subject by about 40%.
56. The method of claim 37 , wherein the administering to the subject results in an increase in a daily urine osmolality in the subject by about 30%.
57. The method of claim 37 , wherein the administering to the subject results in an increase in a daily urine osmolality in the subject by about 20%.
58. The method of claim 37 , wherein the administering to the subject results in a urine osmolality in the subject greater than 125 mOsm/kg.
59. The method of claim 37 , wherein the administering to the subject results in a urine osmolality in the subject greater than 150 mOsm/kg.
60. The method of claim 37 , wherein the administering to the subject results in a urine osmolality in the subject greater than 200 mOsm/kg.
61. The method of claim 37 , wherein:
(a) the administering to the subject does not alter blood sugar levels in the subject; or
(b) the administering to the subject does not induce hypoglycemia in a fasting condition in the subject.
62. The method of claim 37 , wherein the administering to the subject does not result in gastrointestinal distress in the subject.
63. The method of claim 37 , wherein the subject is an adult.
64. The method of claim 37 , wherein the subject is a child.
65. The method of claim 37 , wherein the pharmaceutical composition is administered to the subject orally.
66. The method of claim 37 , wherein the pharmaceutical composition is a liquid composition.
67. The method of claim 37 , wherein:
(a) the pharmaceutical composition is administered to the subject orally; and
(b) the pharmaceutical composition is a solid composition.
68. The method of claim 37 , wherein the pharmaceutical composition comprises a therapeutically effective amount of 1,1′-(dodecane-1,12-diyl)bis(cyclopropane-1-carboxamide) in a range of about 0.1 mg per day to about 3000 mg per day.
69. The method of claim 37 , wherein the pharmaceutical composition comprises a therapeutically effective amount of 1,1′-(dodecane-1,12-diyl)bis(cyclopropane-1-carboxamide) in a range of about 0.1 mg per day to about 250 mg per day.
70. The method of claim 37 , wherein the method further comprises administering to the subject a therapeutically effective amount of a second active agent.
71. The method of claim 70 , wherein the second active agent is selected from the group consisting of an adenosine monophosphate-activated protein kinase activator, a cyclic guanosine monophosphate-specific phosphodiesterase inhibitor, a diuretic, and a P2Y purinergic receptor antagonist.
72. The method of claim 70 , wherein the second active agent is lithium.