NEUROACTIVE STEROID COMPOSITIONS AND METHODS OF USE THEREFOR

• US 20090203658A1
• Filed: 03/16/2009
• Published: 08/13/2009
• Est. Priority Date: 01/08/2007
• Status: Abandoned Application

• Current Assignee: Duke University
• Original Assignee: Duke University
• Inventors: Rose, Jed E., Marx, Christine E.
• Application Number:
  US12/404,886
• Publication Number:
  US 20090203658A1
• Time in Patent Office: Days
• US Class Current: 514/171
• CPC Class Codes: A61K 31/5685 having an oxo group in position 17, e.g. androsterone
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: G01N 2800/304 Mood disorders, e.g. bipolar, depression
• CPC Class Codes: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease
• CPC Class Codes: G01N 33/94 involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors

Abstract

Provided are methods for ameliorating a symptom of a neuropsychiatric disorder in a subject. Also provided are methods for ameliorating at least one physical symptom or at least one psychological symptom resulting from tobacco cessation in a subject, methods for ameliorating a symptom of Alzheimer'"'"'s disease or other cognitive disorder in a subject, methods for ameliorating a symptom of schizophrenia, schizoaffective disorder, or other psychotic disorder in a subject, methods for ameliorating a symptom of a depressive disorder in a subject, methods for ameliorating a symptom of bipolar disorder in a subject, methods for ameliorating a symptom of post-traumatic stress disorder or other anxiety disorder in a subject, methods for predicting a predisposition to suicide, suicidal ideation, suicidal behavior, or a combination thereof in a subject, methods for ameliorating a symptom of a pain disorder in a subject, methods for ameliorating a neurodegenerative disorder in a subject, methods for ameliorating a symptom of traumatic brain injury in a subject, methods for ameliorating a sleep disorder in a subject, and methods for improving cognitive functioning in a subject. In some embodiments, the methods include administering to a subject in need thereof an effective amount of a neuroactive steroid composition comprising pregnenolone (PG), allopregnanolone (ALLO), dehydroepiandrosterone (DHEA), progesterone (PROG), precursors thereof, metabolites thereof, pharmaceutically acceptable salts thereof, derivatives thereof, or combinations thereof.

Claims

1. A method for ameliorating a symptom of a neuropsychiatric disorder in a subject, the method comprising administering to the subject an effective amount of a neuroactive steroid composition comprising pregnenolone (PG), precursors thereof, metabolites thereof, pharmaceutically acceptable salts thereof, derivatives thereof, or combinations thereof.

2. The method of claim 1, wherein the neuroactive steroid composition is administered in a sustained release formulation, a controlled release formulation, or a combination thereof.

3. The method of claim 2, wherein the sustained release formulation, the controlled release formulation, or the combination thereof is selected from the group consisting of an oral formulation, a peroral formulation, a buccal formulation, an enteral formulation, a pulmonary formulation, a rectal formulation, a vaginal formulation, a nasal formulation, a lingual formulation, a sublingual formulation, an intravenous formulation, an intraarterial formulation, an intracardial formulation, an intramuscular formulation, an intraperitoneal formulation, a transdermal formulation, an intracranial formulation, an intracutaneous formulation, a subcutaneous formulation, an aerosolized formulation, an ocular formulation, an implantable formulation, a depot injection formulation, and combinations thereof.

4. The method of claim 1, wherein the neuropsychiatric disorder is selected from the group consisting of schizophrenia, schizoaffective disorder, Alzheimer'"'"'s disease, Attention Deficit Disorder/Attention Deficit Hyperactivity Disorder, depression, bipolar disorder, post-traumatic stress disorder (PTSD), a pain disorder, a chronic pain disorder, tobacco dependence, alcohol abuse, alcohol dependence, drug dependence, drug abuse, a sleep disorder, a traumatic brain injury, a concussion disorder, a neurodegenerative disorder, and combinations thereof.

5. The method of claim 4, wherein the neuropsychiatric disorder is a traumatic brain injury, a concussion disorder, or a combination thereof.

6. The method of claim 1, wherein the neuroactive steroid composition further comprises at least one additional active agents selected from the group consisting of allopregnanolone (ALLO), dehydroepiandrosterone (DHEA), progesterone (PROG), precursors thereof, metabolites thereof, pharmaceutically acceptable salts thereof, and derivatives thereof.

7. The method of claim 1, wherein the effective amount is sufficient to raise the level of pregnenolone (PG), allopregnanolone (ALLO), dehydroepiandrosterone (DHEA), progesterone (PROG), or combinations thereof in a source selected from the group consisting of cerebrospinal fluid, serum, plasma, blood, saliva, skin, muscle, olfactory tissue, lacrimal fluid, synovial fluid, nail tissue, hair, feces, urine, in the subject by at least 1.5-fold within 8 weeks from a level in the source in the subject prior to the administering step.

8. The method of claim 1, further comprising administering to the subject at least one additional composition selected from the group consisting of an antidepressant, an anxiolytic, an antipsychotic, an anticonvulsant, and a mood stabilizer, wherein the at least one additional composition is administered to the subject before, after, at the same time as, or a combination thereof the neuroactive steroid composition.

9. A method for ameliorating a symptom of post-traumatic stress disorder or other anxiety disorder in a subject, the method comprising administering to the subject an effective amount of a neuroactive steroid composition comprising pregnenolone (PG), precursors thereof, metabolites thereof, pharmaceutically acceptable salts thereof, derivatives thereof, or combinations thereof.

10. The method of claim 9, wherein the administering is by a route selected from the group consisting of oral, peroral, buccal, enteral, pulmonary, rectal, vaginal, nasal, lingual, sublingual, intravenous, intraarterial, intracardial, intramuscular, intraperitoneal, transdermal, intracranial, intracutaneous, subcutaneous, ocular, via an implant, and via a depot injection.

11. The method of claim 9, wherein the effective amount comprises a daily dose ranging from about 0.005 mg to about 2000 mg of the neuroactive steroid or an equivalent molar amount of the precursor thereof, metabolite thereof, pharmaceutically acceptable salt thereof, derivative thereof, or combination thereof.

12. The method of claim 9, wherein the neuroactive steroid composition further comprises at least one additional active agents selected from the group consisting of allopregnanolone (ALLO), dehydroepiandrosterone (DHEA), progesterone (PROG), precursors thereof, metabolites thereof, pharmaceutically acceptable salts thereof, and derivatives thereof.

13. The method of claim 12, wherein the neuroactive steroid composition comprises each of at least two active agents in a daily dose of at least about 0.005 mg.

14. The method of claim 9, wherein the effective amount is sufficient to improve a cognitive function in the subject.

15. The method of claim 9, wherein the effective amount is sufficient to raise the level of pregnenolone (PG), allopregnanolone (ALLO), dehydroepiandrosterone (DHEA), progesterone (PROG), precursors thereof, metabolites thereof, derivatives thereof, or combinations thereof in a source selected from the group consisting of cerebrospinal fluid, serum, plasma, blood, saliva, skin, muscle, olfactory tissue, lacrimal fluid, synovial fluid, nail tissue, hair, feces, urine, in the subject by at least 1.5-fold within 8 weeks from a level in the source in the subject prior to the administering step.

16. The method of claim 9, further comprising administering to the subject at least one additional composition selected from the group consisting of an antidepressant, an anxiolytic, an antipsychotic, an anticonvulsant, and a mood stabilizer, wherein the at least one additional composition is administered to the subject before, after, at the same time as, or a combination thereof the neuroactive steroid composition.

17. A method for delaying or preventing the onset of, or decreasing the severity of, a symptom associated with traumatic brain injury and/or a concussion disorder in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a neuroactive steroid composition comprising pregnenolone (PG), precursors thereof, metabolites thereof, pharmaceutically acceptable salts thereof, derivatives thereof, or combinations thereof.

18. The method of claim 17, wherein the symptom is selected from the group consisting of depression, irritability, agitation, headache, photophobia, nausea, visual problems, difficulty concentrating, learning and memory problems, tension, speech difficulties, aphasia, apraxia, anger, attentional problems, weakness, stress, psychosis, anxiety, and combinations thereof.

19. The method of claim 17, wherein the neuroactive steroid composition comprises progesterone (PROG), a precursor thereof, a metabolite thereof, a pharmaceutically acceptable salt thereof, a derivative thereof, or a combination thereof.

20. The method of claim 17, further comprising administering to the subject at least one additional composition selected from the group consisting of an antidepressant, an anxiolytic, an antipsychotic, an anticonvulsant, and a mood stabilizer, wherein the at least one additional composition is administered to the subject before, after, at the same time as, or a combination thereof the neuroactive steroid composition.