Two-component formulations, methods and procedures to prevent or reduce trauma-induced neuropathology and neurodegeneration

Abstract

Novel two-component formulations, procedures and methods for use in treating neuropathology incident to trauma are provided. Two-component formulations of the invention comprise biologically active forms of at least one neurosteroid or neuroactive steroid, such as progesterone or synthetic progestin, and at least one anti-epileptic or anticonvulsant, such as gabapentin. The provided formulations are configured or adapted to prevent or reduce the incidence and severity of neurological damage caused by trauma. 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.

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         16 . A method for one or more of preventing, reducing the effects of, or reducing the risk of development of, neuropathology incident to trauma, the method comprising the steps or actions of
 A. providing a formulation adapted for the prevention of the development of neuropathology, wherein the formulation comprises two biologically active compounds in amounts that are pharmaceutically effective for each compound, respectively, when administered in combination with the other biologically active compound, the two compounds respectively comprising a formulation 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 east one form of gabapentin; and   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;   wherein the formulation is in a form 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, and   B. administering the formulation to a mammal in need thereof.   
     
     
         17 . The method of  claim 16 , 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. 
     
     
         18 . The method of  claim 16 , wherein the at least one form of anticonvulsant/antiepileptic is gabapentin, and the at least one form of neurosteroid/neuroactive steroid is at least one form of progesterone or synthetic progestin. 
     
     
         19 . The method of  claim 16 , wherein the formulation is first administered within two hours after the trauma. 
     
     
         20 . The method of  claim 16 , wherein the formulation is first administered within 24 hours after the onset of the trauma. 
     
     
         21 . The method of  claim 16 , wherein the formulation is first administered preventively or prophylactically within 6 hours before the expected onset or the expected end of the trauma. 
     
     
         22 . The method of  claim 16 , wherein the formulation is administered additionally one, or a plurality of, times after the formulation is first administered. 
     
     
         23 . The method of  claim 16 , wherein the formulation is administered one, or a plurality of times as a sustaining dose as needed. 
     
     
         24 . The method of  claim 16 , wherein the at least one form of gabapentin is provided in a dosage range of from about 5.0 mg to about 9,600 mg and wherein the at least one form of progesterone or synthetic progestin is provided in a dosage range of from about 0.05 mg to about 1,200 mg. 
     
     
         25 . The method of  claim 16 , wherein the at least one form of gabapentin is provided in a dosage range of from about 50 mg to about 4,800 mg and wherein the at least one form of progesterone or synthetic progestin is provided in a dosage range of from about 5 mg to about 600 mg. 
     
     
         26 . The method of  claim 16 , wherein the at least one form of gabapentin is provided in a dosage range of from about 100 mg to about 2,400 mg and wherein the at least one form of progesterone or synthetic progestin is provided in a dosage range of from about 50 mg to about 450 mg. 
     
     
         27 . The method of  claim 16 , wherein the at least one form of gabapentin is provided in a dosage range of from about 200 mg to about 600 mg and wherein the at least one form of progesterone or synthetic progestin is provided in a dosage range of from about 100 mg to about 300 mg. 
     
     
         28 . A pharmaceutical formulation adapted for the prevention of the development of neuropathology incident to traumatic brain injury, or for the amelioration of the effects caused by traumatic brain injury to a subject,
 the formulation comprising two biologically active compounds in amounts that are pharmaceutically effective for each compound, respectively, when administered in combination with the other biologically active compound, the formulation comprising a pharmaceutically effective amount of:   A) at least one biologically active compound selected from the group consisting of anticonvulsants and antiepileptics,   wherein the at least one anticonvulsants and antiepileptics are one or more compounds selected from the group consisting of gabapentin, pregabalin, barbiturates, benzodiazepines, bromides, carbamates, carboxamides, fatty acids, fructose derivatives, hydantoins, oxazolidinediones, propionates, pyrimidinediones, pyrrolidines, succinimides, sulphonamides, triazines, ureas and valproyamides; and   B) at least one biologically active compound selected from the group consisting of neurosteroids and neuroactive steroids,   wherein the at least one neurosteroids and neuroactive steroids are one or more compounds selected from the group consisting of progesterone, progesterone prodrugs, other progesterone compounds selected from medroxyprogesterone acetate, megestrol acetate, 17alpha-hydroxyprogesterone, 5alpha-dihydroxyprogesterone, 3alpha,5alpha-trihydroxyprogesterone, 14b-hydroxy progesterone, 17alpha-hydroxyprogesterone caproate, 16-methyl-17-benzoyloxypregnen-4-en-3,20-dione, hydroxyprogesterone-3-O-carboxymethyloxime, 21-succinyloxy-6,19-epoxyprogesterone, 6,19-oxidoprogesterone, 17-p-bromophenylcarbamoyloxypregn-4-ene-3,20-dione, 17-phenylcarbamoyl-oxypregn-4-ene-3,20-dione, 4-pregnene-3,20-dione, 6,19-methanoprogesterone, 16,17-cyclohexano-4,5-dihydroprogesterone, nepapakistamine, vaganine D, Crinone, 18-oxo-18-vinylprogesterone, 16,17-cyclopropanoprogesterone, caproxyprogesterone, 21-hydroxy-6,19-oxidoprogesterone, 17-acetoxy-9-fluoro-6-methylprogesterone, ZK 136798, 3,17-dihydroxy-7-(4-methoxyphenyl)-androst-5-ene, 3,17-diacetate, progesterone-11HS-horseradish peroxidase, 21-hydroxy-11,19-oxidopregn-4-ene-3,20-dione, 21-hydroxy-6,19-oxidopregn-4-ene-3,20-dione, 4-cyanoprogesterone, 11,19-oxidoprogesterone, 6-fluoroprogesterone, 2-hydroxy-4-pregnene-3,20-dione, progesterone-3-(0-carboxymethyl oxime)-horseradish peroxidase, progesterone-11-hemisuccinyl-bovine serum albumin, pentarane B, pentarane A, progesterone 6-hemimaleate, progesterone 6-hemisuccinate, 7-(carboxyethylthio)progesterone, progesterone 3-(O-carboxymethyl)oxime-bovine serum albumin, 18-ethynylprogesterone, 18-vinylprogesterone, 6-methylprogesteron-17-pivalate, progesterone-11-bovine serum albumin, allylestriol, progesterone-3-ethanolimine, 3,20-dioxopregn-4-ene-18′-carboxaldehyde cyclic 18′-(1,2-ethandiylmercaptal), 18-ethylenedithioprogesterone, 17-acetoxy-6,16-dimethylene-4-pregnene-3,20-dione, 17-hydroxy-6-dehydroprogesterone, 2′-methyl-16,17-cyclohexaneprogesterone, 21,21-dichloroprogesterone, hydroxyprogesterone hemisuccinate bovine serum albumin tetramethylrhodamine isothiocyanate, 11-progesteryl-2-carboxymethyltyramine-4-(10-methyl)acridinium-9-carboxylate, progesterone 12-succinyltyrosine methyl ester, progesterone 11-succinyltyrosine methyl ester, 11-progesteryl-2-succinoyltyramine-4-(10-methyl)acridinium-9-carboxylate, 2-hydroxymethyleneprogesterone, 2-cyanoprogesterone, 17-(phenylseleno)progesterone and 21-(phenylseleno)progesterone, neuroactive progestagens, neuroactive androgens (including but not limited to androstenedione (the precursor of 3alpha,5alpha-A, or androsterone), androsterone (5alpha-androstan-3alpha-ol-17-one; 3alpha,5alpha-A), 5alpha-dihydrotestosterone (5alpha-DHT) and its metabolite 5alpha-androstane-3alpha,17beta-diol (3alpha,5alpha-Adiol), 3α,17β-dihydroxy-5α-androstane, 3α-hydroxy-5α-androstan-17-one, 3α-hydroxy-5β-androstan-17-one, androst-5-ene-3β,17β-diol, 3β,17α-dihydroxy-pregn-5-en-20-one (17α-hydroxy-pregnenolone), 3β-hydroxy-androst-5-en-17-one (dehydroepiandrosterone, DHEA), testosterone, androst-4-ene-3,17-dione (androstenedione)), neuroactive estrogens, neuroactive glucocorticoids, allopregnanolone, allotetrahydrodeoxycorticosterone (THDOC), and dehydroepiandrosterone (DHEA), estradiol benzoate, methylprednisolone, alphaxalone, alphadolone, hydroxydone, minaxolone, ganaxolone, deoxycorticosterone, 3 alpha-hydroxy-5-alpha-pregnan-one (allopregnanolone), 3 alpha,21-dihydroxy-5 alpha-and pregnan-20-one (allotetrahydro), and   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 incident to traumatic brain injury is reduced, lessened, attenuated or prevented.   
     
     
         29 . The composition of  claim 28 , wherein the at least one anticonvulsants and antiepileptics is at least one benzodiazepine selected from the group consisting clozepam, clonazepam, chlorazepate, diazepam, midazolam and lorazepam. 
     
     
         30 . The composition of  claim 28 , wherein the at least one anticonvulsants and antiepileptics is at least one carboxamide selected from carbamazepine, oxcarbazepeine and eslicarbazepine acetate. 
     
     
         31 . The composition of  claim 28 , wherein the at least one anticonvulsants and antiepileptics is at least one fatty acid selected from valproic acid, sodium valproate, divalproex sodium, vigabatrin, progabide and sec-butyl-propylacetamide. 
     
     
         32 . The composition of  claim 28 , wherein the at least one neurosteroids and neuroactive steroids is at least one neuroactive progestagen selected from pregnenolone, 17α-hydroxypregnenolone, progesterone, 17α-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, deoxycorticosterone, 11-deoxycortisol, allopregnanolone and allotetrahydroDOC. 
     
     
         33 . The composition of  claim 28 , wherein the at least one neurosteroids and neuroactive steroids is the glucocorticoid prednisolone. 
     
     
         34 . The composition of  claim 28 , comprising a single dosage unit. 
     
     
         35 . The composition of  claim 28 , wherein the anticonvulsant or antiepileptic is gabapentin provided in a dosage range of from about 5.0 mg to about 9,600 mg. 
     
     
         36 . The composition of  claim 28 , wherein the anticonvulsant or antiepileptic is pregabalin provided in a dosage range of from about 0.5 mg to about 2,400 mg. 
     
     
         37 . The composition of  claim 28 , wherein the anticonvulsant or antiepileptic is valproic acid provided in a dosage range of from about 25 mg to about 8,400 mg. 
     
     
         38 . The composition of  claim 28 , wherein the neurosteroid or neuroactive steroid is progesterone and is provided in a dosage range of from about 0.05 mg to about 1,200 mg. 
     
     
         39 . The composition of  claim 28 , wherein the neurosteroid or neuroactive steroid is methyl-prednisolone and is provided in a dosage range of from about 0.02 mg to about 500 mg. 
     
     
         40 . The composition of  claim 28 , wherein the neurosteroid or neuroactive steroid is medroxy-progesterone and is provided in a dosage range of from about 0.005 mg to about 400 mg. 
     
     
         41 . The composition of  claim 28 , 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, analogues, homologues, 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. 
     
     
         42 . The composition of  claim 28 , wherein one or more of the compounds are provided in a controlled release form. 
     
     
         43 . The composition of  claim 28 , wherein the anticonvulsant or antiepileptic is gabapentin, and is provided in a dosage range of from 5 to 9,600 mg; and the neurosteroid or neuroactive steroid is progesterone, and is provided in a dosage range of from about 0.05 to about 1,200 mg. 
     
     
         44 . The composition of  claim 28 , wherein the anticonvulsant or antiepileptic is pregabalin, and is provided in a dosage range of from 0.5 to 2,400 mg; and the neurosteroid or neuroactive steroid is progesterone, and is provided in a dosage range of from about 0.05 to 1,200 mg. 
     
     
         45 . The composition of  claim 28 , wherein the anticonvulsant or antiepileptic is valproic acid, and is provided in a dosage range of from about 25 to about 8,400 mg; and the neurosteroid or neuroactive steroid is progesterone, and is provided in a dosage range of from about 0.05 to about 1,200 mg. 
     
     
         46 . The composition of  claim 28 , wherein the anticonvulsant or antiepileptic is gabapentin, and is provided in a dosage range of from about 5 to about 9,600 mg; and the neurosteroid or neuroactive steroid is methylprednisolone, and is provided in a dosage range of from about 0.02 to about 500 mg. 
     
     
         47 . The composition of  claim 28 , wherein the anticonvulsant or antiepileptic is pregabalin, and is provided in a dosage range of from 0.5 to 2,400 mg; and the neurosteroid or neuroactive steroid is methylprednisolone, and is provided in a dosage range of from about 0.02 to about 500 mg. 
     
     
         48 . The composition of  claim 28 , wherein the anticonvulsant or antiepileptic is valproic acid, and is provided in a dosage range of from 25 to 8,400 mg; and the neurosteroid or neuroactive steroid is methylprednisolone, and is provided in a dosage range of from about 0.02 to about 500 mg. 
     
     
         49 . The composition of  claim 28 , wherein the anticonvulsant or antiepileptic is gabapentin, and is provided in a dosage range of from 5 to 9,600 mg; and the neurosteroid or neuroactive steroid is medroxyprogesterone and is provided in a dosage range of from about 0.005 mg to about 400 mg. 
     
     
         50 . The composition of  claim 28 , wherein the anticonvulsant or antiepileptic is pregabalin, and is provided in a dosage range of from about 0.5 to about 2,400 mg; and the neurosteroid or neuroactive steroid is medroxyprogesterone and is provided in a dosage range of from about 0.005 mg to about 400 mg. 
     
     
         51 . The composition of  claim 28 , wherein the anticonvulsant or antiepileptic is valproic acid, and is provided in a dosage range of from about 25 to about 8,400 mg; and the neurosteroid or neuroactive steroid is medroxyprogesterone and is provided in a dosage range of from about 0.005 mg to about 400 mg. 
     
     
         52 . A method for reducing the effects of, for treating, or for reducing the risk of development of, neuropathology incident to a trauma, the method comprising the step of
 A) providing an effective amount of the composition of  claim 28  to a mammal in need thereof.   
     
     
         53 . The method of  claim 52 , wherein the composition is formulated for use during one or more temporal periods, wherein the periods consist of i) before the onset of the trauma, ii) in anticipation of the trauma, 
       iii) during the trauma, iv) during a period after the trauma, and v) during a period of recovery from the trauma. 
     
     
         54 . The method of  claim 52 , wherein the composition is formulated for use within 24 hours of the trauma. 
     
     
         55 . The method of  claim 52 , wherein the composition is formulated for use within one week of the trauma.