U.S. patent application number 14/148709 was filed with the patent office on 2014-07-10 for pharmaceutical formulations for the treatment and prevention of trauma-induced neuropathology and neurodegeneration.
The applicant listed for this patent is James Lorne HENRY. Invention is credited to James Lorne HENRY.
Application Number | 20140193523 14/148709 |
Document ID | / |
Family ID | 51061136 |
Filed Date | 2014-07-10 |
United States Patent
Application |
20140193523 |
Kind Code |
A1 |
HENRY; James Lorne |
July 10, 2014 |
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.
Inventors: |
HENRY; James Lorne;
(Burlington, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
HENRY; James Lorne |
Burlington |
|
CA |
|
|
Family ID: |
51061136 |
Appl. No.: |
14/148709 |
Filed: |
January 6, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61750745 |
Jan 9, 2013 |
|
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|
Current U.S.
Class: |
424/677 ;
424/715; 514/171; 514/236.2; 514/253.13; 514/255.01; 514/561;
514/574 |
Current CPC
Class: |
A61K 31/5377 20130101;
A61K 31/573 20130101; A61K 31/496 20130101; A61K 31/19 20130101;
A61K 33/00 20130101; A61K 31/205 20130101; A61K 33/14 20130101;
A61K 31/197 20130101; A61K 45/06 20130101; A61K 31/495 20130101;
A61P 25/00 20180101; A61K 31/194 20130101; A61K 31/195 20130101;
A61P 25/02 20180101; A61K 31/20 20130101; A61K 31/57 20130101; A61K
33/14 20130101; A61K 2300/00 20130101; A61K 33/00 20130101; A61K
2300/00 20130101; A61K 31/5377 20130101; A61K 2300/00 20130101;
A61K 31/57 20130101; A61K 2300/00 20130101; A61K 31/195 20130101;
A61K 2300/00 20130101; A61K 31/573 20130101; A61K 2300/00 20130101;
A61K 31/20 20130101; A61K 2300/00 20130101; A61K 31/197 20130101;
A61K 2300/00 20130101; A61K 31/19 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
424/677 ;
424/715; 514/171; 514/561; 514/574; 514/236.2; 514/255.01;
514/253.13 |
International
Class: |
A61K 33/14 20060101
A61K033/14; A61K 31/194 20060101 A61K031/194; A61K 31/195 20060101
A61K031/195; A61K 31/496 20060101 A61K031/496; A61K 31/19 20060101
A61K031/19; A61K 31/57 20060101 A61K031/57; A61K 31/5377 20060101
A61K031/5377; A61K 31/495 20060101 A61K031/495; A61K 33/00 20060101
A61K033/00; A61K 31/197 20060101 A61K031/197 |
Claims
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-carboxyl-
ate, 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), 17.alpha.-hydroxypregnenolone,
progesterone, 17.alpha.-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),
3.alpha.,17.beta.-dihydroxy-5.alpha.-androstane,
3.alpha.-hydroxy-5.alpha.-androstan-17-one,
3.alpha.-hydroxy-5.beta.-androstan-17-one,
androst-5-ene-3.beta.,17.beta.-diol,
3.beta.,17.alpha.-dihydroxy-pregn-5-en-20-one
(17.alpha.-hydroxy-pregnenolone),
3.beta.-hydroxy-androst-5-en-17-one (dehydroepiandrosterone, DHEA),
testosterone, androst-4-ene-3,17-dione (androstenedione),
neuroactive estrogens (including but not limited to estradiol,
17.beta.-estradiol (.beta.E2), 17.alpha.-estradiol (.alpha.E2),
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.
Description
RELATED APPLICATION AND PRIORITY
[0001] This Utility Patent Application claims the priority and
benefit of commonly owned U.S. Provisional Patent Application Ser.
No. 61/750,745 of James L. Henry, as filed 9 Jan. 2013, and as
entitled "Formulations, Methods And Procedures For Reducing Or
Preventing The Development Or The Risk Of Development Of
Neuropathology As A Result Of Traumatic Injury," which provisional
patent application is hereby incorporated by reference in its
entirety into the present patent application. Also hereby
incorporated by reference in their entireties are each of the
references cited herein, as well as those cited in Provisional
Patent Application Ser. No. 61/750,745.
FIELD OF THE INVENTION
[0002] The presently disclosed invention and many particular
invention embodiments relate to multiple-component formulations,
the use of such formulations, and to methods, procedures and
combinations thereof to prevent or reduce, or to reduce the risk
of, the damage that can otherwise lead to numerous types of
neuropathology as a result of trauma.
SUMMARY OF THE INVENTION
[0003] Anticonvulsant/antiepileptic compounds suitable for use as
components of invention embodiments include, but not exclusively,
one or more from the group comprising 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,
oxcarbazepeine, 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 valproyamides (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.
[0004] Neurosteroid/neuroactive steroid compounds suitable for use
as components of invention embodiments include, but not
exclusively, one or more from the group comprising progesterone,
progesterone prodrugs, progesterone derivatives, progesterone
analogs, and other progesterone compounds such as but not exclusive
to medroxyprogesterone acetate, megestrol acetate,
17a-hydroxyprogesterone, 5a-dihydroxyprogesterone,
3a,5a-trihydroxyprogesterone, 14b-hydroxy progesterone,
17a-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-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-carboxyl-
ate, 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 prednisolone,
methylprednisolone, alphaxolone, 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 compound or any
such compound acting on or through a progesterone, corticosteroid,
glucocorticoid, estrogen or other neurosteroid receptor or through
any other mechanism upon which progesterone, a corticosteroid, a
glucocorticoid, an estrogen or other neurosteroid 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, as well as any related slow-release compound.
[0005] NK-1 receptor antagonist compounds suitable for use as
components of invention embodiments include, but not exclusively,
any biologically active compound of one or more from the group
comprising 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.
[0006] Lithium-related/lithium-containing compounds suitable for
use as components of invention embodiments include, but not
exclusively, any biologically active compound of one or more from
the group comprising lithium citrate, lithium carbonate, 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.
[0007] Numerous compounds can be administered to a subject in any
combination or permutation of these classes of compound to practice
this invention aimed to reduce or prevent the development or the
risk of development of neuropathology as a result of traumatic
injury to a subject by administering to a subject in need thereof a
multiplicity of compounds by such combinations of any two, any
three or any four compounds from the classes of compounds
comprising anticonvulsants/antiepileptics,
neurosteroids/neuroactive steroids, NK-1 receptor antagonists and
lithium-related/lithium-containing compounds. These combinations of
above said compounds can be given by various routes of
administration to treat any injury or damage that has resulted,
will result or may result from trauma, and that injury or damage
can be to any nerve cell or nerve cells, to any neural support cell
as described herein, or to any neural support tissue as described
herein. Injury or damage can be to the brain, the brain stem, the
cerebellum, the spinal cord, the enteric nervous system and the
peripheral nervous system or any other nerve cell. A subject in
need of invention embodiments can be an individual who is at risk
of injury or damage, an individual who is about to experience an
event that has the potential to cause traumatic damage or injury,
or an individual who has experienced a trauma as described
herein.
[0008] The presently disclosed technology includes formulations,
methods and procedures aimed at reducing or preventing the
development, or the risk of development, of neuropathology as a
result of traumatic injury. Embodiments of the invention address
unmet or unsolved medical needs including brain injury, central
nervous system ischemia, spinal cord injury, enteric nervous system
injury, peripheral nerve injury and any other injury that can
include or affect nerve cells, neural support cells or neural
support tissues. These unmet or unsolved medical needs share the
commonness of the potential for life-long adverse health conditions
or disability. They also share the commonness of the void in
current medical interventions to reduce or prevent these adverse
health conditions or disability.
[0009] These conditions also share similar, common or overlapping
mechanisms of the secondary injury that develops following a
primary injury or trauma, common mechanisms that trigger or lead to
this secondary injury and common possible therapeutic targets for
inhibiting or promoting the cascades of mechanisms triggered by a
primary injury. As such mechanisms are triggered immediately by
trauma while others downstream in the cascades of biochemical and
metabolic pathways are engaged at different times following trauma,
it is necessary to administer components of the formulation through
the hours, days and in some cases the weeks following trauma, with
immediate initiation of treatment of paramount importance for the
preventive measures to arrest the degenerative cascades and to
promote the restorative cascades, as well as continuation of
practice according to need.
DETAILED DESCRIPTION OF THE INVENTION
[0010] In accordance with some of the objects of the invention,
formulations for use in one or more treatments, procedures and
methods 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,
are provided.
[0011] In one advantageous aspect, the present technology presents
many embodiments of formulations comprising, or consisting
essentially of, 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.
[0012] As one of skill in the art will appreciate, many embodiments
of the present formulations suitable for use in methods or
procedures for treatment of such neuropathology and
neurodegeneration sequelae associated with or caused by trauma or
neurotrauma are within the scope and spirit of the present
technology. Such formulations include, as examples, 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 valproyamides (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.
[0013] In a similar advantageous combinatorial aspect, the present
technology provides many embodiments of formulations 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, 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,
hydroxyprogesterone-3-O-carboxymethyloxime,
21-succinyloxy-6,19-epoxyprogesterone, 6,19-oxidoprogesterone,
17-p-bromophenyl-carbamoyloxy-pregn-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-carboxy-methyl)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-carboxyl-
ate, 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), 17.alpha.-hydroxypregnenolone,
progesterone, 17.alpha.-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),
3.alpha.,17.beta.-dihydroxy-5.alpha.-androstane,
3.alpha.-hydroxy-5.alpha.-androstan-17-one,
3.alpha.-hydroxy-5.beta.-androstan-17-one,
androst-5-ene-3.beta.,17.beta.-diol,
3.beta.,17.alpha.-dihydroxy-pregn-5-en-20-one
(17.alpha.-hydroxy-pregnenolone),
3.beta.-hydroxy-androst-5-en-17-one (dehydroepiandrosterone, DHEA),
testosterone, androst-4-ene-3,17-dione (androstenedione),
neuroactive estrogens (including but not limited to estradiol,
17.beta.-estradiol (.beta.E2), 17.alpha.-estradiol (.alpha.E2),
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.
[0014] In yet another advantageous combinatorial aspect, the
present technology also provides many embodiments of formulations
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, 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.
[0015] In yet an additional advantageous and combinatorial aspect,
the many embodiments of the present technology include many
embodiments of formulations 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,
wherein the at least one lithium-containing/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.
[0016] Examples of the many embodiments of formulations, methods
and procedures of the present technology are many. These include
wherein the formulation consists of any two, or any three, or all
four, of the anticonvulsants or antiepileptics, the neurosteroids
or neuroactive steroids, the NK-1 receptor antagonists and the
lithium-containing or lithium-related compounds, and wherein the
formulation is formulated, or adapted and arranged, for
administration within 12 hours after the trauma.
[0017] Such examples also include wherein the formulation consists
essentially of any two, or any three, or all four, of the
anticonvulsants or antiepileptics, the neurosteroids or neuroactive
steroids, the NK-1 receptor antagonists and the lithium-containing
or lithium-related compounds, and wherein the formulation is
formulated, or adapted and arranged, to be first administered to a
mammal in need thereof, within 24 hours after the trauma.
[0018] In a similar aspect, the present technology includes
formulations consisting essentially of any two, or any three, or
all four, of the anticonvulsants or antiepileptics, the
neurosteroids or neuroactive steroids, the NK-1 receptor
antagonists and the lithium-containing or lithium-related agents,
and is formulated, or adapted and arranged, to be first
administered as a prophylactic measure within 90 minutes before an
expected or potential trauma, and wherein the formulation consists
essentially 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 are formulated, or adapted and arranged, for
administration within 24 hours of the trauma.
[0019] The present technology also includes formulations consisting
essentially of combinations wherein the anticonvulsants or
antiepileptics, the neurosteroids or neuroactive steroids and the
NK-1 receptor antagonists are formulated for administration as a
preventive measure within 90 minutes before a possible trauma.
[0020] Moreover, embodiments of the present technology include
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 as a precautionary measure within 90 minutes before
a possible trauma.
[0021] Formulations of the present invention include also wherein
the formulation comprises a single dosage unit, wherein the
formulation is adapted and arranged for administration a plurality
of times, such as in some type or types of sequences. These include
wherein the formulation is adapted and arranged for administration
in one or more dosage units per day, and wherein they are
formulated for administration as one or more of tablets, capsules,
pills, lozenges or as one or more ingestible or injectable
solutions.
[0022] Consonant with the numerous embodiments of the invention are
formulations adapted and arranged, or provided, as examples, 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.
Preferable subjects of the present technology include animals such
as mammals, and more preferably humans.
[0023] As yet another advantage, the present formulations can be
provided in one or more such forms adapted and arranged to be
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.
[0024] Also consonant with the present formulations are those
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.
[0025] As one of skill in the art will comprehend, the present
technology includes numerous combinations, variations and
permutations of the many formulations provided within the spirit
and scope of the present description. Examples of embodiments of
the present formulations include wherein the at least one
anticonvulsant is gabapentin, in a form adapted and arranged for
administration to a mammal in need thereof, wherein the at least
one anticonvulsant is pregabalin, in a form adapted and arranged
for administration to a mammal in need thereof, and wherein the at
least one anticonvulsant is valproic acid, in a form adapted and
arranged for administration to a mammal in need thereof.
[0026] Exemplary formulation dosage ranges of the present
technology include, as examples, wherein the gabapentin is provided
in a range of from 5.0 to 9,600 mg, wherein the pregabalin is
provided in a range of from 0.5 to 2,400 mg, wherein the valproic
acid is provided in a range of from 25 to 4,800 mg.
[0027] Examples of embodiments of the present formulations include
also wherein the at least one neurosteroid is progesterone, in a
form adapted and arranged for administration to a mammal in need
thereof, wherein the at least one neurosteroid is
methylprednisolone, in a form adapted and arranged for
administration to a mammal in need thereof, and wherein the at
least one neurosteroid is medroxyprogesterone acetate, in a form
adapted and arranged for administration to a mammal in need
thereof.
[0028] Exemplary formulation dosage ranges of the present
technology include wherein the progesterone is provided in a range
of from 0.05 to 1,200 mg, the methylprednisolone, is provided in a
range of from 0.02 to 500 mg, wherein the medroxyprogesterone
acetate, is provided in a range of from 0.001 to 400 mg. Examples
of embodiments of the present formulations include also wherein the
at least one NK-1 receptor antagonist is aprepitant, in a form
adapted and arranged for administration to a mammal in need
thereof, wherein the at least one NK-1 receptor antagonist is
vestipitant, in a form adapted and arranged for administration to a
mammal in need thereof; wherein the at least one NK-1 receptor
antagonist is casopitant, in a form adapted and arranged for
administration to a mammal in need thereof.
[0029] Dosage ranges of the individual two, or three or four
components of the present formulations include any which are
effective, and especially wherein the aprepitant, is provided in a
range of from 0.05 to 750 mg, wherein the vestipitant, is provided
in a range of from 0.001 to 200 mg, and wherein the casopitant, is
provided in a range of from 0.005 to 1,000 mg.
[0030] With respect to lithium-containing variations of the present
invention, the present formulations include wherein the at least
one lithium-containing compound is lithium carbonate, in a form
adapted and arranged for administration to a mammal in need
thereof; wherein the at least one lithium-containing compound is
lithium citrate, in a form adapted and arranged for administration
to a mammal in need thereof, and wherein the at least one
lithium-containing compound is lithium chloride, in a form adapted
and arranged for administration to a mammal in need thereof.
[0031] With respect to exemplary dosage ranges, embodiments of the
present technology include also wherein the lithium carbonate, is
provided in a range of from 0.5 to 3,600 mg, wherein the lithium
citrate, is provided in a range of from 0.01 to 2,400 mg, and
wherein the lithium chloride, is provided in a range of from 3.0 to
3,600 mg.
[0032] The present technology includes also wherein embodiments of
the present formulations are 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, and also wherein they are adapted and
arranged to treat one or more selected from the group comprising
neuropathy, neuropathology, neurodegeneration and the effects of
trauma, and those governed by a balance of
neurotrophic/neuroprotective and neurodegenerative mechanisms.
[0033] The present technology includes also wherein embodiments of
the present formulations are adapted and arranged to treat one or
more changes governed by neurotrophic and regenerative mechanisms
that repair or regenerate nerve cells, neural support cells or
neural support tissues. In a similar manner, the present technology
includes also wherein embodiments of the present formulations are
adapted and arranged to treat one or more changes governed by
neurodegenerative mechanisms that lead to secondary injury,
neuropathology and neurodegeneration, and cell death.
[0034] The presently disclosed technology also includes wherein
embodiments of the present formulations are adapted and arranged to
treat neuroprotective mechanisms to prevent or ameliorate
neuropathology and neurodegeneration caused by or resulting from
trauma.
[0035] In accordance with the broad applicability of the present
formulations, methods and procedures, the present formulations can
also be adapted and arranged to treat one or more selected from the
group comprising physical trauma, 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, and can
also be adapted and arranged to treat one or more from the group
comprising brain changes resulting short-, medium- or long-term
from trauma, including Alzheimer's disease, Parkinson's disease and
other disorders where brain trauma is a risk factor.
[0036] Similarly, formulations of the invention can be adapted and
arranged to treat spinal cord trauma comprising one or more from
the group comprising 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.
[0037] Also, formulations of the invention also can be adapted and
arranged to treat brain, brainstem and cerebellum trauma including
one or more from the group comprising brain injury, ischemia of the
central nervous system, physical trauma, chemical trauma, metabolic
trauma, trauma from surgical or medical intervention or procedure
and other trauma.
[0038] As one of skill in the art will appreciate, formulations of
the invention can be adapted and arranged to treat enteric nervous
system trauma including injury to 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.
[0039] Similarly, formulations of the invention can be adapted and
arranged to treat peripheral nerve trauma including 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. Other targets for the present formulations
include those 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 and neurodegeneration or the risk of development of
neuropathology and neurodegeneration 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 to prevent secondary injury,
neuropathology and neurodegeneration 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.
[0040] The present formulations, methods and procedures can also be
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 treatment for trauma is
different from pre- and post-surgical care, where steps are taken
to ensure the patient's comfort and rapid recovery from the
immediate condition.
[0041] Also advantageously, the present formulations, methods and
procedures can also be adapted and arranged to anticipatorily treat
before as a precaution 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.
[0042] In a similar manner, the present formulations can be 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, as well as to
treat 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.
[0043] In addition, the present technology can be adapted and
arranged to treat 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.
[0044] Thus, the many embodiments of the invention are adaptable
and arrangeable to treat metabolic trauma including, as examples,
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.
[0045] Other exemplary applications of the present technology
include those adapted and arranged to treat 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.
[0046] 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, as well as to treat 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, and to treat any damage or
injury to a cell that 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, to treat any damage or injury to a tissue that
supports 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, and to
treat 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.
Scope of the Invention
[0047] The foregoing description sets forth various embodiments of
formulations, methods, procedures and practices for reducing or
preventing the development, or the risk of development, of
neuropathology as a result of traumatic injury. Insofar as such
formulations, methods, procedures and practices contain one or more
functions or operations, it will be understood by those within the
art that each formulation, method, procedure and practice can be
implemented, individually or collectively, within a wide range of
many combinations without undue experimentation.
[0048] A person having ordinary skill in the art will recognize
that, in one significant aspect, the herein described formulations
(e.g., any combination of any two, any three or all four of
gabapentin, progesterone, aprepitant and lithium), methods, and
procedures and practices, and the discussion accompanying them, are
used as examples for the sake of conceptual clarity and that
various methods, procedures and practices are within the skill of
those in the art. Consequently, as used herein, the specific
exemplars set forth and the accompanying discussion are intended to
be representative of their more general classes. In general, use of
any specific exemplar herein is also intended to be representative
of its class, and the non-inclusion of such specific formulation
components (e.g., gabapentin, progesterone, aprepitant and
lithium), methods, and procedures and practices herein should not
be taken as indicating that limitation is desired.
[0049] It is generally contemplated that the formulations according
to the inventive subject matter will be formulated for
administration to a mammal, and especially to a human, having a
condition that is responsive to the administration of such a
formulation. Therefore, where contemplated formulation compounds
are administered in a pharmacological composition, it is understood
that contemplated compounds can be formulated in admixture with
pharmaceutically acceptable carriers. As an example but not
exclusively, contemplated compounds can be administered orally as
pharmacologically acceptable salts, or intravenously in a
physiological saline solution (e.g., buffered to a pH of about 7.2
to 7.5). Conventional buffers such as phosphates, bicarbonates or
citrates can be used for this purpose. Of course, one of ordinary
skill in the art may modify the formulations within the teachings
of the present disclosure to provide numerous formulations for a
particular route of administration.
[0050] In particular, contemplated compounds may be modified to
render them more soluble in water or other vehicle that, for
example, may be easily accomplished with minor modifications (e.g.
salt formulation, esterification, etc.) that are well within the
ordinary skill in the art. It is also well within the ordinary
skill of the art to modify the route of administration and dosage
regimen of a particular compound or formulation in order to manage
the pharmacokinetics of the present compounds for maximum
beneficial effect in a patient or subject.
[0051] Also in particular, contemplated compounds may be prepared
for delivery in tablet, capsule, pill or solution form, including
any form that can deliver a controlled release of these
compounds.
[0052] Similarly, it should be appreciated that while some claims
recite components of formulations of invention embodiments, one of
skill in the art will comprehend that other constituents, while
pharmacologically inactive or inert in the context of the presently
disclosed technology, might be a part of the formulation. Such
inactive constituents include, as examples, excipients, binders,
coatings, absorption enhancers, penetration enhancers, transport
enhancers, stabilizers, chelators, buffers, carriers, clearance
modifiers, emulsifying agents, antioxidants, preservatives, sugars,
salts, cellulose, dyes, flavoring agents and any other inactive
ingredients that are considered generally recognized as safe.
[0053] In certain pharmaceutical dosage forms, prodrug and
derivative forms of contemplated compounds may be formed for
various purposes, including reduction of toxicity, increasing the
organ or target cell specificity, etc. Among various prodrug and
derivative forms, acylated (acetylated or other) derivatives,
pyridine esters and various salt forms of the present compounds may
be advantageous. One of ordinary skill in the art will recognize
how to readily modify the present compounds to prodrug and other
forms to facilitate delivery of active compounds to a target site
within the host organism or patient. One of ordinary skill in the
art will also take advantage of favorable pharmacokinetic
parameters of the prodrug and other forms, where applicable, in
delivering the present compounds to a targeted site within the host
organism, subject or patient to maximize the intended effect of the
formulation.
[0054] Similarly, it should be appreciated that contemplated
compounds may also be metabolized to their biologically active form
(e.g., via hydroxylation, glycolsylation, oxidation etc.), and all
metabolites of the compounds herein are therefore specifically
contemplated. In addition, contemplated compounds (and combinations
thereof) may be administered in combination with yet further
antiviral and/or antibacterial agents. Suitable additional drugs
therefore include but are not limited to various antibiotics (e.g.,
beta-lactam antibiotics, tetracycline antibiotics, oxazine
antibiotics, etc.), various antiviral compounds (e.g., polymerase
inhibitors), and/or compounds that stimulate the immune system.
[0055] With the presently disclosed technology described in detail
herein, it is to be understood that the invention is not limited to
the particular embodiments described, as such may, of course, vary.
It is also to be understood that the terminology used herein is for
the purpose of describing particular embodiments, and is not
intended to be limiting, since the scope of the presently disclosed
technology will be limited only by the appended claims or by a fair
reading of the application as a whole.
[0056] Where a range of values is provided, it is understood that
each intervening value, to the tenth of the unit of the lower limit
unless the context clearly dictates otherwise, between the upper
and lower limit of that range and any other stated or intervening
value in that stated range is encompassed within embodiments of the
invention. The upper and lower limits of these smaller ranges may
independently be included in the smaller ranges is also encompassed
within embodiments of the invention, subject to any specifically
excluded limit in the stated range. Where the stated range includes
one or both of the limits, ranges excluding either or both of those
included limits are also included in embodiments of the
invention.
[0057] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which embodiments of this invention
belongs. Although any methods and materials similar or equivalent
to those described herein can also be used in the practice or
testing of the presently disclosed technology, a limited number of
the exemplary methods and materials are described herein.
[0058] All publications mentioned herein are hereby incorporated by
reference to disclose and describe the methods and/or materials in
connection with which the publications are cited, as well as the
general background for the inventive subject matter disclosed
herein. The publications discussed herein are provided solely for
their disclosure prior to the filing date of the present
application. Nothing herein is to be construed as an admission that
the presently disclosed technology is not entitled to antedate such
publication by virtue of prior invention. Further, the dates of
publication provided might be different from the actual publication
dates, which may need to be independently confirmed.
[0059] The inventive technology described herein sometimes
illustrates different components contained within, or connected
with, different other components. It is to be understood that such
descriptions or subject matter are merely exemplary, and that in
fact many other descriptions, examples, methods, procedures and
practices can be implemented which achieve the same functionality.
In a conceptual sense, any arrangement of components to achieve the
same functionality is effectively "associated" or "coupled" such
that the desired functionality is achieved. Hence, any two or more
methods, procedures or practices herein combined to achieve a
particular functionality can be seen as "associated with" each
other such that the desired functionality is achieved, irrespective
of condition, event, injury, damage or pathology components.
Likewise, any two or more components so associated can also be
viewed as being "operably connected", or "operably coupled", to
each other to achieve the desired functionality, and any two or
more components capable of being so associated can also be viewed
as being "operably couplable", to each other to achieve the desired
functionality. Specific examples of operably couplable include but
are not limited to, practices of embodiments of the invention
required under different conditions, practices of embodiments of
invention requiring different routes or methods of administration,
practices of embodiments of invention requiring repeated
administration for varying periods of time or logically interacting
or logically interactable components to achieve the desired
functionality.
[0060] In a general sense, those skilled in the art will recognize
that the various aspects described herein which could be
implemented, individually or collectively, by a wide range of
methods, procedures or practices, or any combination thereof, can
be viewed as being composed of various types of "formulation."
Consequently, as used herein "formulation" includes, but is not
limited to, two compounds selected from gabapentin, progesterone,
aprepitant and lithium, three compounds selected from gabapentin,
progesterone, aprepitant and lithium or all four compounds selected
from gabapentin, progesterone, aprepitant and lithium. Those having
skill in the art will recognize that the subject matter described
herein may be implemented in a method, procedure or practice as
described herein, or some combination thereof.
[0061] As examples, the formulations, methods, procedures or
practices of certain embodiments of the invention include many
combinations and permutations thereof with respect to the nature of
the individual formulations, and their relative methods, procedures
or practices, can vary in operation by the relative methods,
procedures or practices.
[0062] While particular aspects of the present subject matter
described herein have been shown and described, it will be apparent
to those skilled in the art that, based upon the embodiments
herein, changes and modifications may be made without departing
from the subject matter described herein and its broader aspects
and, therefore, the appended claims are to encompass within their
scope all such changes and modifications as are within the true
spirit and scope of the subject matter described herein.
[0063] Those skilled in the art will recognize that it is common
within the art to describe methods, procedures or practices in the
fashion set forth herein, and thereafter use standard practices to
integrate such described methods, processes or procedures to reduce
or prevent the development or the risk of development of
neuropathology as a result of traumatic injury. That is, at least a
portion of the methods, procedures or practices described herein
can be integrated into reducing or preventing the development or
the risk of development of neuropathology as a result of traumatic
injury via a reasonable amount of experimentation. Those having
skill in the art will recognize that typical methods, procedures or
practices generally include those described herein. A typical
method, procedure or practice may be implemented utilizing any
suitable commercially available instrument, tool or device, such as
any typically found in a medical facility or health delivery
context or venue, and available to those typically familiar with
methods, procedures or practices generally applied by those skilled
in the art.
[0064] With respect to the use of substantially any plural or
singular terms herein, those having skill in the art can translate
from the plural to the singular or from the singular to the plural
as is appropriate to the context or application. The various
singular/plural permutations are not expressly set forth herein for
sake of clarity.
[0065] Furthermore, it is to be understood that the invention is
defined by the appended claims, and by the many claims that could
be supported by the present specification. It will be understood by
those within the art that, in general, terms used herein, and
especially in the appended claims (e.g., bodies of the appended
claims) are generally intended as "open" terms (e.g., the term
"including" should be interpreted as "including but not limited
to," the term "having" should be interpreted as "having at least,"
the term "includes" should be interpreted as "includes but is not
limited to," etc.). It will be further understood by those within
the art that if a specific number of an introduced claim recitation
is intended, such an intent will be explicitly recited in the
claim, and in the absence of such recitation no such intent is
present. For example, as an aid to understanding, the appended
claims may contain usage of the introductory phrases "at least one"
and "one or more" to introduce claim recitations. However, the use
of such phrases should not be construed to imply that the
introduction of a claim recitation by the indefinite articles "a"
or "an" limits any particular claim containing such introduced
claim recitation to inventions containing only one such recitation,
even when the same claim includes the introductory phrases "one or
more" or "at least one" and indefinite articles such as "a" or "an"
(e.g., "a" or "an" should typically be interpreted to mean "at
least one" or "one or more"); the same holds true for the use of
definite articles used to introduce claim recitations.
[0066] It will be further understood by those within the art that
virtually any disjunctive word or phrase presenting two or more
alternative terms, whether in the description, claims, or
practices, should be understood to contemplate the possibilities of
including one of the terms, either of the terms, or both terms. It
is also to be understood that the terminology employed in the
Detailed Description sections of this application is for the
purpose of describing particular embodiments. It is also
contemplated that any optional feature of the inventive variations
described herein may be set forth and claimed independently, or in
combination with any one or more of the features described herein.
Moreover, in interpreting the disclosure, all terms should be
interpreted in the broadest possible manner consistent with the
context of the disclosed technology. In particular, the terms
"comprises" and "comprising" should be interpreted as referring to
elements, components, or steps in a non-exclusive manner,
indicating that the referenced elements, components, or steps may
be present, or utilized, or combined with other elements,
components, or steps that are not expressly referenced.
[0067] Thus, many specific compositions, procedures and methods of
the present "Pharmaceutical Formulations For The Treatment And
Prevention Of Trauma-Induced Neuropathology And Neurodegeneration"
have been disclosed and exemplified. It should be apparent,
however, to those skilled in the art that many more modifications
besides those already described are possible without departing from
the inventive concepts herein, or from the spirit of the invention.
The inventive subject matter, therefore, is not to be restricted
except in the spirit of the disclosure.
[0068] To assist in understanding the numerous embodiments of the
invention, Table 1 provides some examples of dose ranges of drug
categories for some particular embodiments of the invention. As
such, Table 1 illustrates both the components of the 2-component,
3-component, and 4-component formulation of the invention, and the
numerous unspecified formulations, which also fall within the
spirit and scope of the invention.
TABLE-US-00001 TABLE 1 Dose Ranges of Drug Categories For Some
Particular Embodiments of The Invention More Most Drug Exemplary
Acceptable Preferable Preferable Preferable category Compound Range
(mg) Range (mg) Range (mg) Range (mg) A/A Gabapentin 5-9,600
50-4,800 100-2,400 200-600 A/A Pregabalin 0.5-2,400 15-1,200 25-600
50-150 A/A Valproic acid 25-8,400 250-4,200 750-3,750 1,000-3,000
N/N Progesterone 0.05-1,200 5-600 40-450 100-305 N/N Methyl-
0.02-500 2-250 10-80 15-45 prednisolone sodium succinate N/N
Medroxy- 0.001-400 0.5-200 1-50 2.5-7.5 progesterone acetate N/K
Aprepitant 0.05-750 5-375 20-250 40-120 N/K Vestipitant 0.001-200
1-100 1-60 5-15 N/K Casopitant 0.005-1,000 0.5-500 10-300 50-150
L/L Lithium 0.5-3,600 30-1,800 100-900 200-600 carbonate L/L
Lithium citrate 0.01-2,400 10-1,200 50-900 200-600 L/L Lithium
chloride 3-3,600 30-1,800 100-900 20600
* * * * *