Pharmaceutical formulations for the treatment and prevention of trauma-induced neuropathology and neurodegeneration

Abstract

Novel multi-component formulations, procedures and methods for use in treating neuropathology and neurodegeneration incident to trauma are provided. Multi-component formulations of the invention comprise biologically active forms of any two, any three, or all four of at least one neurosteroid or neuroactive steroid, such as progesterone or synthetic progestin, at least one anti-epileptic or anticonvulsant, such as gabapentin, pregabalin or valproic acid, at least one NK-1 receptor antagonist, such as aprepitant, casopitant or vestipitant, at least one lithium-containing or lithium-related drug. The provided formulations are configured or adapted to prevent or reduce the incidence and severity of neurological damage caused by trauma, or the risk of such damage. 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 injury or trauma to nerve cells, to neural support cells and to neural support tissues.

What is claimed is: 
     
         1 . A formulation for use in treatment to prevent the development, or the risk of development, of neuropathology and neurodegeneration sequelae associated with or caused by trauma or neurotrauma to a subject in need, or for the amelioration of the effects caused by trauma to a subject in need, the formulation comprising any two or any three or all four biologically active compounds in amounts that are pharmaceutically effective for each compound, respectively, when used in combination with the other biologically active compounds, the compounds being selected from a pharmaceutically effective amount of any two, or any three, or all four of:
 A. at least one biologically active compound selected from the group comprising anticonvulsants and antiepileptics;   B, at least one biologically active compound selected from the group comprising neurosteroids and neuroactive steroids;   C, at least one biologically active compound selected from the group comprising NK-1 receptor antagonists; and   D, at least one biologically active compound selected from the group comprising lithium containing and lithium-related compounds.   
     
     
         2 . The formulation of  claim 1 , wherein the at least one anticonvulsant or antiepileptic agent is one or more from the group consisting of gabapentin, pregabalin, barbiturates (such as phenobarbital, methylphenobarbital, metharbital, barbexaclone and other central nervous system depressants), benzodiazepines (such as clozepam, clonazepam, chlorazepate, diazepam, midazolam, lorazepam, and other hypnotic, anxiolytic, anticonvulsant, amnesic compounds), bromides (such as potassium bromide), carbamates (such as felbamate, fluorofelbamate), carboxamides (such as carbamazepine, oxcarbazepine, eslicarbazepine acetate), fatty acids (such as valproic acid, sodium valproate, divalproex sodium, vigabatrin, progabide, sec-butyl-propylacetamide), fructose derivatives (such as topiramate), hydantoins (such as ethotoin, phenytoin, mephenytoin, fosphentoin), oxazolidinediones (such as paramethadione, trimethadione, ethadione), propionates (such as beclamide), pyrimidinediones (such as primidone), pyrrolidines (such as rivaracetam, levetiracetam, seletracetam), succinimides (such as ethosuximide, phensuximide, mesuximide), sulfonamides (such as acetazolamide, sultiame, methazolamide, zonisamide), triazines (such as lamotrigine), ureas (such as pheneturide, phenacemide) and valproylamides (such as valpromide, valoctamide) and others known and unknown, as well as any homolog or derivative or compound acting on or through a receptor, an enzyme or other mechanism upon which an anticonvulsive/antiepileptic can act, as well as any compound acting on or through mechanisms that would modify or affect in any way pathways or processes affected by one or more anticonvulsant/antiepileptic compounds, as well as any related slow-release compound. 
     
     
         3 . The formulation of  claim 1 , wherein the at least one neurosteroid or neuroactive steroid is one or more compounds selected from the group consisting of progesterone, progesterone prodrugs, progesterone derivatives, progesterone analogues, and other progesterone compounds such as but not exclusive to 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, hydroxylprogesterone-3-O-carboxymethyloxime, 21-succinyloxy-6,19-epoxyprogesterone, 6,19-oxidoprogesterone, 17-p-bromophenyl-carbamoyloxypregn-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-(O-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, 21-(phenylseleno)progesterone and others known and unknown, and include other neurosteroids or neuroactive steroids such as, but not exclusive to neuroactive progestagens (including but not limited to pregnenolone (3beta-hydroxypregn-5-en-20-one), 17α-hydroxypregnenolone, progesterone, 17α-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, deoxycorticosterone, 11-deoxycortisol, 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone), 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (allotetrahydroDOC), 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 (including but not limited to estradiol, 17β-estradiol (βE2), 17α-estradiol (αE2), estrone (E1) and estriol (E3), and phytoestrogens), neuroactive glucocorticoids (including but not limited to prednisolone), other neuroactive steroids metabolically downstream from these principal neuroactive steroids including but not limited to allopregnanolone, allotetrahydrodeoxycorticosterone (THDOC), and dehydroepiandrosterone (DHEA), additional neuroactive steroids including other derivatives such as estradiol benzoate, neurosteroids and neuroactive steroids including, but not limited to, prednisolone, methylprednisolone, alphaxalone, alphadolone, hydroxydone, minaxolone, ganaxolone, deoxycorticosterone, 3 alpha-hydroxy-5-alpha-pregnan-one (allopregnanolone), 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (allotetrahydro), as well as metabolites of neurosteroids and neuroactive steroids, and including any corticoid, glucocorticoid, estrogen, estrogen compound, androgen or androgen compound or any such compound acting on or through a progesterone, corticosteroid, glucocorticoid, estrogen, androgen or other neurosteroid or neuroactive steroid receptor or through any other mechanism upon which progesterone, a corticosteroid, a glucocorticoid, an estrogen or other neurosteroid or neuroactive steroid does or can act, as well as any homolog or derivative or compound acting on or through mechanisms that would modify, modulate or affect in any way pathways or processes affected by progesterone, estrogen or any neurosteroid or neuroactive steroid, as well as any related slow-release compound. 
     
     
         4 . The formulation of  claim 1 , wherein the at least one NK-1 receptor antagonist is one or more from the group consisting of aprepitant, fosaprepitant, casopitant, maropitant, vestipitant, CP-99,994, CP-122,721, MK 869, LY 303870, RPR 67580, RPR 100893, L 758298, L 365260, L 733060, GR 205171, CGP 49823, CJ 11974, and others known and unknown, and any compound acting on or through the NK-1 receptor or any other mechanism that involves activation or involvement of the NK-1 receptor or its synthesis, and other chemical entities known and unknown, including any ligand or compound acting on or through an NK-1 receptor or other mechanism upon which substance P, an endogenous ligand for the NK-1 receptor, does or can act, as well as any compound acting on or through mechanisms that would modify or affect in any way pathways or processes affected by substance P or the NK-1 receptor, as well as any related slow-release compound. Further, in view of the evidence that some ligands and compounds can act through or by NK-2 or NK-3 receptors, any ligand or homolog or derivative or compound acting on or through an NK-1 or NK-2 or NK-3 receptor, including receptor isoforms, or related mechanism as well as any ligand that occupies, activates or deactivates these receptors, is included in the presently disclosed technology. 
     
     
         5 . The formulation of  claim 1 , wherein the at least one lithium-containing or lithium-related agent is one or more from the group consisting of lithium carbonate, lithium citrate, lithium chloride, lithium bromatum and others known and unknown, as well as any compound acting on or through a lithium receptor or other mechanism upon which lithium does or can act, as well as any homolog or derivative or compound acting on or through mechanisms that would modify or affect in any way pathways or processes affected by lithium, as well as any related slow-release compound. 
     
     
         6 . The formulation of  claim 1 , wherein the formulation consists of any two or any three or all four of the anticonvulsant or antiepileptic, the neurosteroid or neuroactive steroid, the NK-1 receptor antagonist and the lithium containing or lithium-related compound, and is formulated for first administration within 24 hours after the trauma. 
     
     
         7 . The formulation of  claim 1 , wherein the formulation consists of any two or any three or all four of the anticonvulsant or antiepileptic, the neurosteroid or neuroactive steroid, the NK-1 receptor antagonist and the lithium containing or lithium-related agent, and is formulated for administration within 90 minutes before an expected or potential trauma or before a possible trauma, and wherein the formulation consisting of any two or any three or all four of the anticonvulsant or antiepileptic, the neurosteroid or neuroactive steroid, the NK-1 receptor antagonist and the lithium containing or lithium-related agent is formulated for administration within 24 hours of the trauma. 
     
     
         8 . The formulation of  claim 1 , formulated for administration of as a tablet, a capsule, a pill, or an injectable solution. 
     
     
         9 . The formulation of  claim 1 , formulated for administration via an oral, buccal, mucosal, parenteral, rectal, sub-cutaneous, transdermal, intravenous, intrathecal, intravaginal, nasal, nasal inhalation, pulmonary inhalation, iontophoresis through the skin, iontophoresis through mucosal or buccal membranes, dermal patch, epidural, intracranial, intrapharyngeal, sublingual, intra-articular, intramuscular or a subcutaneous route. 
     
     
         10 . 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, 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 or formulations of the invention and wherein the formulation is in such a form that it can be safely administered to, given to, or taken by, a subject, and may include other ingredients or substances such as excipients, buffers, penetration enhancers, stabilizers, absorption enhancers and carriers. 
     
     
         11 . The formulation of  claim 1 , wherein the at least one anticonvulsant is gabapentin, pregabalin or valproic acid, in a form adapted and arranged for administration to a mammal in need thereof, wherein the gabapentin is provided in a dosage range of from 5.0 to 9.600 mg, the pregabalin is provided in a dosage range of from 0.5 to 2,400 mg and the valproic acid is provided in a dosage range of from 25 to 4,800 mg. 
     
     
         12 . The formulation of  claim 1 , wherein the at least one neurosteroid is progesterone, methylprednisolone, or medroxyprogesterone acetate, in a form adapted and arranged for administration to a mammal in need thereof, wherein the progesterone, is provided in a dosage range of from 0.05 to 1,200 mg, the methylprednisolone, is provided in a dosage range of from 0.02 to 500 mg and the medroxyprogesterone acetate, is provided in a dosage range of from 0.001 to 400 mg. 
     
     
         13 . The formulation of  claim 1 , wherein the at least one NK-1 receptor antagonist is aprepitant, casopitant or vestipitant, in a form adapted and arranged for administration to a mammal in need thereof, wherein the aprepitant, is provided in a dosage range of from 0.05 to 750 mg, the vestipitant, is provided in a dosage range of from 0.001 to 200 mg and the casopitant, is provided in a dosage range of from 0.005 to 1,000 mg. 
     
     
         14 . The formulation of  claim 1 , wherein the at least one lithium-containing compound is lithium carbonate, lithium citrate or lithium chloride, in a form adapted and arranged for administration to a mammal in need thereof, wherein the lithium carbonate, is provided in a dosage range of from 0.5 to 3,600 mg, the lithium citrate, is provided in a dosage range of from 0.01 to 2,400 mg and the lithium chloride, is provided in a dosage range of from 3.0 to 3,600 mg. 
     
     
         15 . The formulation of  claim 1 , adapted and arranged to treat one or more changes in cellular or tissue structure, function or health, occurring in one or more of the central nervous system, including the brain, the brainstem, the cerebellum and the spinal cord, and the periphery, including the enteric nervous system and the peripheral nervous system, wherein the changes include neuropathy, neuropathology, neurodegeneration and the effects of trauma, and can be due to one or more neurotrophic and neuroprotective and neurodegenerative mechanisms, the changes resulting short-, medium- or long-term from trauma, including Alzheimer's disease, Parkinson's disease and other degenerative disorders where trauma is a risk factor. 
     
     
         16 . The formulation of  claim 1 , adapted and arranged to treat one or more selected from the group comprising physical trauma including vehicle accidents, workplace accidents, sports accidents, falls, burns, radiation, battlefield injuries, concussive injuries, blast injuries, injuries from landmines, injuries from improvised explosive devices, penetrating injuries, non-penetrating injuries or the result of any traumatic event that can injure, damage, modify, kill or otherwise change the phenotype, gene expression function of a nerve cell, a neural support cell or a neural support tissue, chemical trauma, metabolic trauma, medically-related trauma and other trauma, where injury or damage is to at least one nerve, at least one nerve cell, at least one neural support cell or at least one neural support tissue, whether in the central nervous system or in the periphery, comprising chemical trauma including alcohol overdose, drug abuse, stimulant drugs, carbon dioxide poisoning, lead poisoning, copper poisoning, acrylamide and related chemicals, overexposure to certain environmental chemicals such as copper or natural hazards such as insect and other animal venom toxins, herbicides, insecticides, industrial toxic chemicals, bioterrorism chemicals and other chemicals that can injure, damage, modify, kill or otherwise change the phenotype, gene expression function of a nerve cell, a neural support cell or a neural support tissue, comprising metabolic trauma including hypoxia, ischemia, hypoxia, multiple sclerosis, shingles, diabetes, stroke, epileptic or other seizure, post-polio syndrome, HIV/AIDS peripheral neuropathy, subacute posttraumatic myelopathy, and other effects, syndromes and conditions following a type of trauma to the body that can injure, damage, modify, kill or otherwise change the phenotype, gene expression function of a nerve cell, a neural support cell or a neural support tissue, comprising trauma resulting from medical treatment or medical procedure trauma including injections, surgery, amputation, implantation, laparoscopy, chemotherapy (for example but not exclusively with methotrexate, cisplatin, cytosine arabinose, carmustine, thiotepa among others), radiation therapy, immunosuppressants (for example tacrolimus) and the like, or during a medical procedure that can reduce or impede the blood supply for any period of time and the like, where trauma from surgery includes, as examples, laparoscopy, amputation, mastectomy, cesarean section, cardiac surgery, hernia repair, cholecystectomy, joint replacement, thoracotomy, reparative surgery or any case, condition or situation where there is or might be detectable or undetectable cut, wound, injury or damage to nerves, nerve cells, neural support cells or neural support tissues that can injure, damage, modify, kill or otherwise change the phenotype, gene expression function of a nerve cell, a neural support cell or a neural support tissue, and comprising trauma including radiation, burns, hypoxia, cold, heat or other trauma that can injure, damage, modify, kill or otherwise change the phenotype, gene expression function of a nerve cell, a neural support cell or a neural support tissue. 
     
     
         17 . The formulation of  claim 1 , adapted and arranged to treat brain, brainstem and cerebellum trauma comprising one or more from the group comprising brain injury, ischemia of the central nervous system, spinal cord trauma comprising one or more of compression, vertebral collapse, cutting wounds, puncture wounds, crush wounds, surgical or medical intervention, and ischemia resulting from loss of blood, insufficient circulation from stoppage or slowing of the heart, or surgical interruption of the blood supply to the spinal cord, enteric nervous system trauma comprising one or more from the group comprising neurons, progenitor cells, glial cells and interstitial cells of Cajal, cells of Auerbach's myenteric plexus and Meissner's submucosal plexus, as well as neural support cells and neural support tissues, including luminal, lamina propria and muscularis mucosal cells, as well as endothelial cells of the vasculature, peripheral nerve trauma comprising one or more from the group comprising sensory nerves, motor nerves, autonomic nerves, nerve cells, neural support cells, such as Schwann cells, myelin cells, satellite cells, as well as neural support tissues such as the vasculature. 
     
     
         18 . The formulation of  claim 1 , adapted and arranged to treat following trauma as an emergency treatment of trauma as would be in the case of unanticipated or accident-related trauma, taken as soon after trauma as possible that may prevent the development of neuropathology or the risk of development of neuropathology including such conditions as motor vehicle accidents, battlefield injuries, sports injuries, toxic chemical spill and the like, where evidence informs that there is a risk of damage to brain, spinal cord or peripheral nerve. Emergency treatment of neurotrauma is different from emergency treatment of trauma, where immediate steps are taken to prevent further injury, to stop bleeding, to stabilize the victim and to take life-saving steps. 
     
     
         19 . The formulation of  claim 1 , adapted and arranged to treat before trauma as a precautionary treatment in case of an unanticipated or accident-related trauma that may occur, as a pre-exposure precautionary measure taken to reduce the risk of neuropathology in individuals who are about to enter into a situation or condition where there is a great likelihood of trauma, including such conditions as a dangerous military or law enforcement operation or situation, an impending or underway bioterrorism or other attack where neurotoxic chemicals or other agents have been or may have been released. 
     
     
         20 . The formulation of  claim 1 , adapted and arranged to treat before trauma as would be in the case of anticipated, potential or purposeful trauma, taken as a pre-exposure prophylaxis measure to reduce the risk of neuropathology in individuals who are about to undergo procedures where there is a risk of trauma, including such conditions as surgery, chemotherapy, radiation therapy and the like, where evidence informs that there is a risk of damage to brain, brain stem, cerebellum, spinal cord, peripheral nerve and/or enteric nerve cells, and wherein prophylaxis of neurotrauma is different from pre- and post-surgical care, where steps are taken 
     
     
         21 . The formulation of  claim 1 , adapted and arranged to treat any damage, wound, insult, cut, laceration, concussion, lesion, abrasion, contusion, shock, strain, abrupt acceleration, abrupt deceleration, explosion, percussion, metabolic event that causes, results in, brings about, triggers or leads to or can trigger or can lead to secondary injury or damage or change in structure or change in phenotype or change in gene expression or loss of function or altered function or cell death of a nerve cell, a neural support cell or a neural support tissue, wherein the formulation is required for or promotes or facilitates the normal function, health, survival, phenotype, gene expression and function of nerve cells including glial cells, microglia, myelin cells, satellite cells, astroglia, oligodendrocytes, Schwann cells, satellite cells, interstitial cells of Cajal and vascular endothelial cells or is required for or promotes or facilitates the normal function, health, survival, phenotype, gene expression, survival or function of nerve cells and neural support cells and includes the vasculature and microvasculature to nerve cells and neural support cells in the central nervous system and in the periphery. 
     
     
         22 . The formulation of  claim 1 , adapted and arranged to treat by promoting or facilitating any neurotrophic mechanism or neurotrophic effect or neurotrophic action that encompass therapeutic strategies intended to promote, facilitate or augment survival, health, function, recovery, proliferation, differentiation, growth, or regeneration of one or more cells or tissues, and includes any biochemical, cellular, tissue or metabolic process that is activated by the traumatic event or by the direct tissue damage from that event and that leads to or can lead to restoration, recovery or repair of nerves, nerve cells, neural support cells or neural support tissue or that protects or restores health of nerves, nerve cells, neural support cells or neural support tissues. 
     
     
         23 . The formulation of  claim 1 , adapted and arranged to treat by inhibiting or slowing degenerative mechanisms involved in the progression of secondary injury or damage, apoptosis, necrosis, excitotoxicity, atrophy or cell death of one or more cells or tissues following the onset of insult or trauma and includes any biochemical, cellular, tissue or metabolic process that is activated by the traumatic event or by the direct tissue damage from that event and that leads to or can lead to loss of cell integrity, structure, phenotype, gene expression, function or survival, or cell death. Such processes can or do lead to further damage or injury to such cells and tissues, as a secondary injury or damage. 
     
     
         24 . The formulation of  claim 1 , adapted and arranged to treat any damage, injury, harm, loss, change in structure, change in phenotype, change in gene expression or change in function or survival of nerves, nerve cells, neural support cells or neural support tissue that occurs after a traumatic event and develops over the seconds, minutes, hours, days, weeks or months following such an event. Secondary injury or secondary damage is usually considered to result from biochemical cascades of cellular and metabolic processes that are activated or triggered by the trauma-induced direct tissue damage. Secondary injury or secondary damage is usually considered to involve endogenous processes or biosynthetic pathways that govern, regulate or influence the structure, health, function or survival of nerves or nerve cells, or cells upon which nerves or nerve cells depend to maintain health and function, such as neural support cells and neural support tissues.