Three-component formulations, methods and procedures, and combinations thereof, for reducing or preventing the development, or the risk of development, of neuropathology resulting from trauma

Abstract

Novel three-component formulations, procedures and methods for use in treating neuropathology incident to trauma are provided. Three-component formulations of the invention comprise biologically active forms of at least one neurosteroid, at least one anti-epileptic or anticonvulsant, and at least one lithium-containing or lithium-related compound. The provided formulations are configured or adapted to prevent or reduce the incidence and severity of neurological damage caused by neurotrauma. Formulations, procedures and methods of the invention advantageously effect both neuroprotective actions to prevent or reduce secondary injuries, and neurotrophic actions to repair and restore cells and tissues affected by the trauma, and are especially useful in treating neurological trauma, such as those caused by sports injuries, chemical weapons, vehicle collisions and improvised explosive devices in combat.

1 . A formulation adapted for the prevention of the development of neuropathology, or for the amelioration of the effects caused by trauma to a subject, the formulation comprising three biologically active compounds in amounts that are pharmaceutically effective for each compound, respectively, when administered in combination with the other two biologically active compounds, the formulation comprising a pharmaceutically effective amount of:
 A. at least one biologically active compound from the group comprising anticonvulsants and antiepileptics, wherein the anticonvulsant or antiepileptic is at least one form of gabapentin;   B. at least one biologically active compound from the group comprising neurosteroids and neuroactive steroids, wherein the neurosteroid or neuroactive steroid is at least one form of progesterone or synthetic progestin;   C. at least one biologically active compound from the group comprising lithium—containing and lithium-related compounds, wherein the lithium-containing or lithium-related com-pound is at least one form of lithium carbonate;
 wherein the formulation is in a form and a dosage with respect to each of its components such that it is adapted and arranged for administration to a mammal in need thereof, such that the development, or the risk of development, of neuropathology is reduced, lessened, attenuated or prevented. 
   
     
     
         2 . The formulation of  claim 1 , wherein the gabapentin is provided in a dosage range of from about 5.0 mg to about 9,600 mg, wherein the progesterone or synthetic progestin is provided in a dosage range of from about 0.05 mg to about 1,200 mg, and wherein the lithium carbonate is provided in a dosage range of from about 0.5 mg to about 3,600 mg. 
     
     
         3 . The formulation of  claim 1 , wherein the gabapentin is provided in a dosage range of from about 50 mg to about 4,800 mg, wherein the progesterone or synthetic progestin is provided in a dosage range of from about 5 mg to about 600 mg, and wherein the lithium carbonate is provided in a dosage range of from about 30 mg to about 1,800 mg. 
     
     
         4 . The formulation of  claim 1 , wherein the gabapentin is provided in a dosage range of from about 100 mg to about 2,400 mg, wherein the progesterone or synthetic progestin is provided in a dosage range of from about 50 mg to about 450 mg, and wherein the lithium carbonate is provided in a dosage range of from about 100 mg to about 900 mg. 
     
     
         5 . The formulation of  claim 1 , wherein the gabapentin is provided in a dosage range of from about 200 mg to about 600 mg, wherein the progesterone or synthetic progestin is provided in a dosage range of from about 100 mg to about 300 mg, and wherein the lithium carbonate is provided in a dosage range of from about 200 mg to about 600 mg. 
     
     
         6 . The formulation of  claim 1 , wherein the formulation comprises a single dosage unit. 
     
     
         7 . The formulation of  claim 1 , wherein the formulation is adapted and arranged to be administered a plurality of times in a sequence. 
     
     
         8 . The formulation of  claim 6 , wherein an effective treatment level for the prevention or treatment of neuropathological sequelae associated with trauma to a subject comprises an administration of one or more dosage units per day. 
     
     
         9 . The formulation of  claim 1 , wherein the subject for which the treatment is effective is human. 
     
     
         10 . The formulation of  claim 1 , wherein the gabapentin is provided in a dosage range of from about 5.0 mg to about 9,600 mg. 
     
     
         11 . The formulation of  claim 1 , wherein the progesterone or synthetic progestin is provided in a dosage range of from about 0.05 mg to about 1,200 mg. 
     
     
         12 . The formulation of  claim 1 , wherein the lithium carbonate is provided in a dosage range of from about 0.05 mg to about 3,600 mg. 
     
     
         13 . The formulation of  claim 1 , wherein one or more of the compounds is in the form of one or more of salts, prodrugs, hydrates, derivatives or metabolites of the compound itself, analogs, homologs, compounds acting on or through mechanisms that compounds can act on or through or compounds that modify, modulate or affect in any way pathways or processes affected by compounds or formulations of the invention. 
     
     
         14 . The formulation of  claim 1 , wherein one or more of the biologically active compounds are provided in a controlled release form. 
     
     
         15 . The formulation of  claim 1 , adapted and arranged to be administered as one or more sustaining doses. 
     
     
         16 . The formulation of  claim 1 , adapted and arranged to be administered before, during or after a traumatic event or a possible traumatic event. 
     
     
         17 . A method for the prevention of the development of neuropathology, or for the amelioration of the effects caused by trauma to a subject, the formulation comprising three biologically active compounds in amounts that are pharmaceutically effective for each compound, respectively, when administered in combination with the other two biologically active compounds, the formulation comprising a pharmaceutically effective amount of the three biologically active compounds, the method comprising the steps or actions of
 A. providing a formulation adapted for the prevention of the development of neuro-pathology, wherein the formulation comprises three biologically active compounds in amounts that are pharmaceutically effective for each compound, respectively, when administered in combination with the other two biologically active compounds, the three compounds respectively comprising a pharmaceutically effective amount of:   i. at least one biologically active compound from the group comprising anticonvulsants and antiepileptic drugs; wherein the anticonvulsant or antiepileptic is at least one form of gabapentin;   ii. at least one biologically active compound from the group comprising neurosteroids and neuroactive steroids; wherein the neurosteroid or neuroactive steroid is at least one form of progesterone or synthetic progestin:   iii. at least one biologically active compound from the group comprising lithium-containing and lithium-related compounds; wherein the lithium-containing or lithium-related compound is at least one form of lithium carbonate:   wherein the formulation is in a form and a dosage with respect to each of its components, such that the development, or the risk of development, of neuropathology is reduced, lessened, attenuated or prevented, and   B. administering the formulation to a mammal in need thereof.   
     
     
         18 . The method of  claim 17 , wherein Step B is effected with respect to time in relation to one or more of i.) the onset of the trauma, ii.) in anticipation of a possible or potential trauma, iii.) during the trauma, and iv.) during a period of recovery from the trauma. 
     
     
         19 . The method of  claim 17 , wherein the at least one anticonvulsant/antiepileptic is gabapentin, the at least one neurosteroid/neuroactive steroid is progesterone or synthetic progestin, and the at least one biologically lithium-containing/lithium-related compound is lithium carbonate. 
     
     
         20 . The method of  claim 18 , wherein the formulation is first administered within two hours after the trauma. 
     
     
         21 . The method of  claim 18 , wherein the formulation is first administered within 24 hours after the onset of the trauma. 
     
     
         22 . The method of  claim 18 , wherein the formulation is first administered preventively or prophylactically within 6 hours before the expected onset or the expected end of the trauma. 
     
     
         23 . The method of  claim 18 , wherein the formulation is administered additionally one, or a plurality of, times after the formulation is first administered. 
     
     
         24 . The method of  claim 18 , wherein the formulation is administered one, or a plurality of times as a sustaining dose as needed. 
     
     
         25 . The method of  claim 17 , wherein the gabapentin is provided in a dosage range of from about 5.0 mg to about 9,600 mg, wherein the progesterone or synthetic progestin is provided in a dosage range of from about 0.05 mg to about 1,200 mg, and wherein the lithium carbonate is provided in a dosage range of from about 0.5 to about 3,600 mg. 
     
     
         26 . The method of  claim 17 , wherein the gabapentin is provided in a dosage range of from about 50 mg to about 4,800 mg, wherein the progesterone or synthetic progestin is provided in a dosage range of from about 5 mg to about 600 mg, and wherein the lithium carbonate is provided in a dosage range of from about 30 mg to about 1,800 mg. 
     
     
         27 . The method of  claim 17 , wherein the gabapentin is provided in a dosage range of from about 100 mg to about 2,400 mg, wherein the progesterone or synthetic progestin is provided in a dosage range of from about 50 mg to about 450 mg, and wherein the lithium carbonate is provided in a dosage range of from about 100 mg to about 900 mg. 
     
     
         28 . The method of  claim 17 , wherein the gabapentin is provided in a dosage range of from about 200 mg to about 600 mg, wherein the progesterone or synthetic progestin is provided in a dosage range of from about 100 mg to about 300 mg, and wherein the lithium carbonate is provided in a dosage range of from about 200 mg to about 600 mg.