Compositions and methods for the treatment of addiction, psychiatric disorders, and neurodegenerative disease
The present invention features, inter alia, pharmaceutically acceptable compositions that include metyrapol as the sole pharmaceutically active agent; compositions that include metyrapol and at least one additional pharmaceutically active agent; compositions in which the agent targeting the HPA axis is, itself, new or modified (e.g., a bi-specific antibody designed to traverse the blood-brain barrier or a known compound redesigned by, for example, conjugation to a substance that traverses the blood-brain barrier); and compositions in which the agent targeting the HPA axis is newly formulated in such a way that it fails to significantly inhibit cortisol production in the adrenal gland. For example, the composition can be formulated to include a dosage that is too low to reduce plasma cortisol levels or formulated to preferentially affect the skin.
1. A pharmaceutical composition for the treatment of a disorder associated with activity in the HPA axis, comprising metyrapol or a pharmaceutically acceptable salt thereof and a second pharmaceutically active agent, wherein said second agent is a benzodiazepine, wherein the composition is formulated for oral or topical administration to a patient, and wherein both the metyrapol and the second agent are present within the composition in an amount that is ineffective to treat said disorder when administered alone.
2. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is in unit dosage form.
3. The pharmaceutical composition of claim 1 , wherein the benzodiazepine is oxazepam or chlordiazepoxide.
4. The pharmaceutical composition of claim 1 , wherein the first agent is present in a unit dosage form in an amount insufficient to reduce plasma levels of cortisol in a patient.
5. The pharmaceutical composition of claim 1 , wherein the first or the second agent is conjugated to a moiety that facilitates movement across the blood-brain barrier.
6. The pharmaceutical composition of claim 1 , further comprising an efflux inhibitor that helps maintain the level of the first agent or the second agent in the brain, or an excipient comprising one or more of: polyethylene glycol, glycerin, or gelatin.
7. A method of treating a patient who is suffering from a disorder associated with aberrant activity in the HPA axis, the method comprising: (a) identifying in a patient in need of treatment; and (b) administering to the patient a therapeutically effective amount of a composition comprising metyrapol or a pharmaceutically acceptable salt thereof and a second pharmaceutically active agent, wherein said second agent is a benzodiazepine,
wherein the composition is formulated for oral or topical administration to a patient, and
wherein both the metyrapol and the second agent are present within the composition in an amount that is ineffective to treat said disorder when administered alone.
8. The method of claim 7 , wherein the disorder is addiction, anxiety, obesity, depression or schizophrenia.
9. A method of treating a patient who is suffering from a neurodegenerative disease, the method comprising: (a) identifying a patient in need of treatment; and (b) administering to the patient a therapeutically effective amount of a composition comprising metyrapol or a pharmaceutically acceptable salt thereof and a second pharmaceutically active agent, wherein said second agent is a benzodiazepine, wherein the composition is formulated for oral or topical administration to a patient, and wherein both the metyrapol and the second agent are present within the composition in an amount that is ineffective to treat said disorder when administered alone.
10. The method of claim 9 , wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, or amytrophic lateral sclerosis.
11. The pharmaceutical composition of claim 1 , further comprising an agent that transiently manipulates the blood-brain barrier.
12. The pharmaceutical composition of claim 11 , wherein the agent that transiently manipulates the blood-brain barrier is mannitol or bradykinin.