Abstract:
The present invention proposes a cosmetic or pharmaceutical preparation that comprises a mixture of nutritional related co-factors synergistically combined and applied as a topical/transdermal surfactant. Said surfactant formula invokes a precise ordered and sequential synchrony within the treated area initiating the bodies&#39; own natural biological and healing circadia. Said surfactant formula has the ability to regulate an inflammation response and infuse required nutrients for cellular repair at the treated area. The specific ingredients serve as a co-synergist for a clearly defined series of cascading biochemical loops that substantiate the use of each individual ingredient. The concert of regulation of an inflammation response coupled with infused nutritional co-factors and cascading biochemical loops yields a modulation of both chronic and acute inflammation or repair of injured tissue and joints as a result of injury, stress or disease.

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
       [0001]    This application claims the benefit of U.S. Provisional Application No. 61/509,559 titled “A Topical Transdermal Method for Delivering Nutrients through the Skin for Expedited Wound Healing” filed Jul. 19, 2011 at 11:01pm EST. which is hereby incorporated by reference in its entirety. 
     
    
     FIELD OF INVENTION 
       [0002]    This invention relates to the field of nutritional biochemistry for the delivery of nutrients and specific Generally Regarded as Safe compounds involving a precise ordered and sequential synchrony of administration to reset the body&#39;s own natural biological and healing circadian and re-establish pre-injury homeostasis. 
       BACKGROUND OF THE INVENTION 
       [0003]    Current U.S. Class: 514/310; 424/59; 424/61; 424/70.1; 424/400; 424/450; 424/489; 514/159; 514/256 International Class: A61K 031/47 Field of Search: 424/59,61,78,480,489,70,400 514/159,254,310 
         [0004]    This present invention relates to specific and highly selective proteins, amino acids and nucleic acid molecules. This composition has sequences encoding such proteins, nutrient catalyzing cofactors, antibodies and short antisense molecules existing and innate within the various dermal layers of human tissue. Also included are specific functional methods to enable and utilize such polypeptides to modulate healing, apoptosis and curing of wounds. The active ingredients are all “generally regarded as safe” (GRAS) and are factors in the apoptotic cascade and the control and modulation of said bodily processes specifically for the purpose of wound healing and truncation of the tissue insult/injury cycle. The synergy between the components provides for an internal milieu that utilizes the body&#39;s inherent recovery cycle and the antisense technology contained in this invention provides a time-staged transdermal delivery of beneficial nutrients through the medium of a methyl carrier for the purpose of cellular remodeling as well as molecular cleavage by a variety of caspase and other proteases that might otherwise inhibit apoptosis. 
         [0005]    The components of this composition includes but are not limited to tocopherol acetate, b-vitamins; methyl nicotinic acid, glycine, histidine, histamine, beta-alanine, taurine, alpha lipoic acid, hypoxanthine riboside, copper, pyridoxal-5-phosphate, ascorbyl palmitate, vitamin c, glycerol, medium chain triglycerides, poloysorbate 20 or 80, propylene glycol, phosphatidyl choline, ethanol, oleic acid and water. 
         [0006]    The components of this composition are incorporated in combination and within the range of concentrations for which these agents are currently used to treat medical/cosmetic conditions in human patients. Topical/transdermal treatment is preferred for local control of the disease and inflammatory cascade states to insure that disparate and or unwanted side effects are minimized and curtailed. Variations or combinations of this therapy include, through are not strictly limited to the following; a topical spray using a radiant pump dispenser, a topical salve/balm rubbed into the skin, a topical gel w/aloe vera or other cactus derived nutrients, glycerine or other demulcents and vitamin e, a topical wound/burn rinse, a topical roll-on. All of the following nutrients, whether supplied transdermal or recruited to the site, as noted below, play an important role in the accelerated healing which takes place with this unique formulation and delivery system. Though not wanting to be limited by theory, the following account for the likely subcellular events leading to wound healing by this invention. 
         [0007]    Many intracellular signaling pathways lead from cell surface receptors to the nucleus, where they alter gene transcription. The jak-stat signaling pathway provides one of the most direct routes. It was initially discovered in studies of the effects of interferon cytokines secreted by cells in response to viral infection. Interferon&#39;s bind to receptors on non-infected neighboring cells and induce these cells to produce proteins that increase their resistance to viral infection. When activated, interferon receptors activate a novel class of cytoplasmic tyrosine kinases called janus kinases (jaks). The jaks then phosphorylate and activate a set of latent gene regulatory proteins called stats (signal transducers and activators of transcription), which move into the nucleus and stimulate the transcription of specific genes. More than 30 cytokines and hormones activate the jak-stat pathway by binding to cytokine receptors. 
         [0008]    All stats also have an sh2 domain that enables them to dock onto specific phosphotyrosines on some activated receptor tyrosine kinase receptors. These receptors can directly activate the bound stat, independently of jaks. 
         [0009]    Cytokine receptors are composed to two or more polypeptide chains. Some cytokine receptors chains are specific to a cytokine receptor, while others are shared among several such receptors. All cytokine receptors, however, are associated with one or more jaks. There are four known jaks—jak 1, jak2, jak3 and tyk2- and each is associated with particular cytokine receptors. The receptors for α-interferon, for example, are associated with jak1 and tyk2, whereas the receptors for γ-interferon are associated with jak1 and jak2. 
         [0010]    The trafficking of proteins within eukaryotic cells is achieved by the capture of cargo and targeting molecules into vesicles that bud from a donor membrane and deliver their contents to a receiving compartment. This process is bidirectional and may involve multiple organelles within a cell. Distinct coat proteins mediate each budding event, serving both to shape the transport vesicle and to select, by direct or indirect interaction, the desired set of cargo molecules. Secretion, which has been viewed as a default pathway, may require sorting and packing signals on transported molecules to ensure their rapid delivery to the cell surface. 
         [0011]    The secretory membrane system allows a cell to regulate delivery of newly synthesized proteins, carbohydrates, and lipids to the cell surface, a necessity for growth and homeostasis. The system is made up of distinct organelles, including the endoplasmic reticulum (ER), Golgi complex (apparatus), plasma membrane, and tubulovesicular transport intermediates. These organelles mediate intracellular membrane transport between themselves and the cell surface. Membrane traffic within this system flows along highly organized directional routes. Secretory cargo is synthesized and assembled in the ER and then transported to the Golgi complex for further processing and maturation. Upon arrival at the trans Golgi network (tgn), the cargo is sorted and packaged into Golgi carriers that move through the cytoplasm to fuse with the cell surface. This directional membrane flow is balanced by retrieval pathways that bring membrane and selected proteins back to the compartment of origin. 
         [0012]    Cadherins, selectins, and integrins all depend on extracellular ca2+ (or mg2+ for some integrins) to function in cell adhesion. The molecules responsible for ca2+—independent cell—cell adhesion belong mainly to the large and ancient immunoglobulin (IG) superfamily of proteins. These proteins contain one or more IG-like domains that are characteristic of antibody molecules. One of the best-studied examples is the neural cell adhesion molecule. Some IG-like cell-cell adhesion proteins, however, use a heterophilic mechanism. Intercellular adhesion molecules (icams) on endothelial cells, for example, bind to integrins on blood cells when they migrate out of the bloodstream. 
         [0013]    Methylation is key to the epigenetic perfect expression, peak maintenance and re-assembly of all genes (DNA/RNA). On the skin surface or wound site, methylation can be part of the energy cycle to facilitate the epigenome&#39;s perfect retooling, while the Methyl Nicotinate molecule (MN) is present to affect this reassembly on the skin surface or wound site. This process occurs without any systemic dilution or metabolic transformation that would occur by either an oral or parenteral administration. Methyl Nicotinate molecules are lipophilic in nature and at the cellular level easily traverses the plasma membrane. The methyl group provides energy directly to the site of application on the order of 3 protons (H+) or 12ATP&#39;s for every Methy Nicotinate molecule. Once in the cytosol, it can readily enter the nucleus, delivering the Nicotinate ligand and energy. This Methyl donor energy interacts with the gene (DNA/RNA), via the histone sheath, to expose more of the gene (DNA/RNA), expressing its increased function and or repair, and or gene silencing, or as an activator for apoptosis. The genome (DNA/RNA) is thus rebooted and the epigenetic effects allow more of the phenotypic aspects of the gene (DNA/RNA) to facilitate a renewed, reorganized and enhanced structure within the cell. The repaired gene can now perform with greater efficiency, and the repaired cell containing this gene (DNA) becomes more efficient in its innate cellular functions. There is a special energy balancing synergy to maintain perfect structure and function that requires the delicate pre-programming of the following cellular pathways: CAMP, 1PGC1A, PparG, Foxo1, PARP1a, peroxisomes and proteasomes. These pathways work in concert, aiding and contributing to optimize each individual cellular mechanism. Protons/ATP, seamlessly delivered, assist with the process of cellular respiration and maintain the balance of NAD, NADH, FAD and FADH. 
         [0014]    Whether the gene is carrying out its normal functions or effecting self-repair, it can now do so expediently, due to this delivery of energy via nutrients both transdermal and systemically. Where RNAi or the gene has been silenced, or is malfunctioning, the increased, de novo, energy can retool this nuclear function. If the malfunction is not fixable, this energy can allows Poly(ADP-ribose) polymerase (PARP), induced apoptosis or autophagy via demethylization. When the cell rejuvenates, in turn, the energy and the ligand for the nuclear super family of transcriptional related genes (NSFTRG) will induce the nucleus to engender increased production of mitochondria, proteasome activity, prostaglandin C1a (PGC1a), PparG and PParsA to continue their ever-vigilant maintenance of the gene (DNA). 
         [0015]    Through the use of Methyl Nicotinate, the nicotinate molecular capability acts, via the NSFTRG as a ligand, and attracts cytoplasmic organelles into the cytosol for increased mitochondria activity. Within the barrier of the skin where the wound begins, the nicotinate molecule functions as a false analog, creating a false injury (an autocoid response) that is quickly recognized by the body and is quelled more rapidly than a true injury, subsequently stimulating an anti inflammatory response yielding a healing process. 
         [0016]    With the absorption and transfer of the array of accompanying materials for rebuilding cellular tissue (dermis), Methyl Nicotinate causes a phase 1 cell cycle (G-1) stimulation. This coupled with lipolysis through adipose tissue releasing free fatty acids (FFA), including arachidonic acid (AA) recruits both the lipooxigenase, LOX cascades and cyclooxygenase, COX cascades, along with a myriad of other cytokines and chemokines. These enable local inflammation at the cell/wound site. There is also a local transformation of stem cells to mast cells with increased production of histamine and its powerful antioxidant effects at the cell site. 
         [0017]    Arachidonic acid (AA) by-products are legend. The body will transform AA to leukotriene (LTA4) that hydrates to LTB4. Glutathione then helps engender LTC4 from LTB4. Removal of specific amino acids manifests LTD4 and LTE4 from LTC4. The healing cascade is as follows: LTB4 causes adhesion and chemotaxis and Superoxide dismutase (SOD) manufacture and, in general, invites systemic cells to come to this site to assist in a quick/short false inflammatory response. This is followed by a dedicated anti-inflammatory healing response. 
         [0018]    The nutrients delivered to the wound site with Methyl Nicotinate are specific for wound/skin healing. This action truncates and expedites the cellular healing process. The Amino acid L Histidine is a nutrient, whose safety, pharmaceutical evaluation, bioavailability, physiology, metabolism, medical usage and physiologic impact are well documented in the scientific and biomedical literature. Histidine functions as a safe anti-inflammatory and antioxidant. Histidine on its own permeates the skin (integument) to reach the full dermis, down to the keritinocytes, where it renders several restorative functions. Methyl Nicotinate, described above, further enhances tissue penetration and saturation of Histidine while its redox properties allow metal cations, singlet oxygen and hydroxyl groups to be reduced and/or neutralized, thereby rendered non-toxic. 
         [0019]    Free Histidine (HD) is found in all tissue. As HD is decarboxolated to Histamine(HA), Beta-Alanine can combine with HA in the presence of carcine synthetase forming carcinine. Alternately, HD may combine with Beta-Alanine, in the presence of carnosine synthetase, to become carnosine. 
         [0020]    Carnosine (CS) is important in protein manufacturing and diminishing glycosylation and carbonylation. By the modes of actions of HA/HD/CS cells may restore their intrinsic resting electrical potential. This energizing effect further creates, within the epidermal and sub-dermal skin layers, the re-scaffolding needed for new tissue formation. CS along with glycine and imidizole acetic acid (IAA), are needed for collagen and elastin formation. 
         [0021]    While in the re-scaffolding process, reactive oxygen species (ROS) and nitric oxide synthase (NOS) need a suitable blockade, via the HD, HA and CS molecules, to prevent the deterioration and weakening of the newly formed scaffolding. In fact, all the nutrients and molecules being delivered to skin/wound have an increased half life because of these antiox molecules. Quintessentially, HD opens the aquaporine channels (AQP0). Specifically, aquaporine increases the PH within the cell as a signaling mechanism and turns on the calcium channel-signaling pathway that provides cellular hydration directly through aquaglyceroporin channels, as well as a suitable milieu in which to enhance cellular respiration and increase energy manufacturing. Induced Carcinine (CC)—HA derived from HD is can be biochemically changed to CC via HA combining with Beta alanine and P-5-P in the presence of Carnosine synthase. CC is an analog of CS. Although CC is best produced in the central nervous system (CNS) at a rate of 15-fold greater saturation than found in any other tissue, its main mode of action for healing is through the cardiovascular system. This epiphenomenon permits CS and CC to work directly to promote increased blood flow and cardiac output to heal injured tissues. CS presence in muscle and fascia is essential for deep wound healing. CC directly decreases and or reverses skin aging. The transdermal mechanism of this invention allows application to the exact area of injury, a HD, HA, MN, CS, CC, aminoacetic acid (AAA), IAA, glycine, P-5-P, Copper (CU++), and the medium chain triglycerides (MCT) molecules that the integument requires for repair. These restorative nutrient components are either applied to the site of repair, are biochemically or physiologically produced in situ or, alternatively, delivered to the site by the circulation and or neurologic discharge. 
         [0022]    Additional concentrations of HA and HD pool at injury sites acutely by proximal neural firing. This effects increased HD and HA locally. HA and HD may then be oxidized along with B-alanine to acetic acid, and or imidazol acetic acid (IAA), or they can be methylated. Pain at the NMDA sites may be mitigated by (IAA) by occupying the glycine receptor adjacent to glutamate site. HD is ubiquitous and creates special prostaglandins of the 2 series (PGE2) at the inflammatory sites, which assists in creating accelerated tissue growth. HD and HA, along with their bio-regulatory aminoacetic acid (AAA) are integral in nucleic acid production, essential for new cell growth and replenishment. 
         [0023]    Energy is essential for healing. Methyl Nicotinate, a nicotinic acid (B3), with a methyl group attached for its lipophilicity, transports and transfers local energy. Nicotinate increases the surface temperature of the skin (warming) and causes a significant release of prostaglandins (PGE 2) from the skin. It stimulates histamine release from mast cells in the tissue, thereby initiating the autacoid response of the specific immune system. Methyl Nicotinate, a forerunner of NADPH and NADH keys to glucose metabolism. They are required for the energy 3 production needed for healing. This action is accomplished through the donation of an electron, resulting in increased energy for rapid and repeatable cellular tissue repair. 
         [0024]    Methyl Nicotinate synergizes with Pyridoxal Phosphate (P-5-P) and CU++ to promote scaffolding for the collagen elastin infrastructure and to efficiently reassemble “big” collagen (potential scarring) to normal collagen. The direct infusion of CU++ increases skin growth and matrix molecules for faster keratinocyte growth, thereby yielding faster dermal growth. A nicotinic acid receptor, known as the G-Protein-Coupled Receptor G(1), is highly expressed in adipose tissue. Including both methyl nicotinate and nicotinic acid in this formula, promotes a two-pronged “time released” effect on G(1). 
         [0025]    Pyridoxal-5-Phospate (P-5-P) again assists with energy, in wound/skin methylation by direct application to the site of injury. Again, like Methyl nicotinate it bypasses per oral digestion and systemic dilution, locally empowering this wound/skin site to grow and heal more rapidly than normal. P-5-P directly facilitates copper in the proper redox state to avoid toxicity, thereby increasing the neutralization of reactive oxygen species (ROS, free radicals). Copper also increases the bioavailability of vitamin C important for tissue factors (e.g. Glycosaminoglycan), at the wound site. 
         [0026]    Ceramide manufacture, engendered by niacin, increases skin production, along with signaling molecules for apoptosis, cell growth and/or cell differentiation. Medium Chain Triglycerides (MCT) are structured lipids C-6 through C-12 that are applied topically to the wound to assist in healing, energy and cell wall manufacture. 
         [0027]    Heat Shock Proteins (HSP). The induced local inflammatory site engenders heat shock proteins (HSP) to assist in the chaperoning of specific molecules to their necessary destination of skin and soft tissue remanufacturing sites. Additionally, heat shock factors (HSF1) partner in this process. 
         [0028]    Ribosome switches, or Ribo switches, are now recognized as one of the major metabolite controlling systems and account for about two percent (2%) of genetic regulation in bacteria. They respond to various metabolites, including, co-enzymes, sugars, nucleotide bases, amino acids and cations. With Thiamine, Methyl donor groups, glycine and B-alanine, the ribo switches can be turned on and incrementally speed up the healing of skin/wounds, bypassing part of the molecular networking that could impede this process. 
         [0029]    Sirtuins are necessarily activated by the upstream and downstream energy circuitry that is engendered by multiple networking molecules (CREB, CAMP, FOXO1, FOXO3a, PPARS, and PGC1a). PGC1a becomes a special additional immediate fuel source for SIRTS by its manifold acetylated lysines. This entire energy loop is the source for wound healing. All of the above is engendered in part or all by the methylation process and redox upregulation by Methyl Nicotinate, P-5-P, Cu and the nucleoside, Inosine. Inosine is a commonly found tRNA that impacts on RNA editing and RNAI for maximal cellular integrity. 
         [0030]    To re-emphasize, each of the aforementioned nutrients, and cofactors whether supplied primarily transdermal or secondarily recruited to the site, plays an important role in the accelerated healing that takes place upon application of this unique formulation and delivery system. 
         [0031]    Aquaporins (“AQPs”) constitute a major conduit for movement of water across plasma membranes and as such, constitute an important route for the transdermal movement and diffusion of several components of this invention. AQP0 is expressed in the fiber cells. AQP0 is critical for cell homeostasis. Several cellular functions have been attributed to AQP0. In vitro and ex vivo experiments have confirmed the water permeability function of AQP0. It is our belief that AQP0 performs cell-to-cell adhesion. There is strong support and empirical data validating the possible structural role of AQP0 as a cell-to-cell adhesion protein influencing subdermal ceramides. 
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         Larmi E, Lahti A, Hannuksela M. Effects of infra-red and neodymium yttrium aluminium garnet laser irradiation on non-immunologic immediate contact reactions to benzoic acid and methyl nicotinate. Derm Beruf Umwelt. 1989 November-December; 37(6):210-4. 
         Larmi E. PUVA treatment inhibits nonimmunologic immediate contact reactions to benzoic acid and methyl nicotinate. Int J Dermatol. 1989 November; 28(9):609-11. 
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         Fergusson D A. Systemic symptoms associated with a rubefacient. BMJ. 1988 November; 19; 297 (6659):1339. 
         Johansson J, Lahti A. Topical non-steroidal anti-inflammatory drugs inhibit non-immunologic immediate contact reactions. Contact Dermatitis. 1988 September; 19(3): 161-5. 
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         Lahti A. Terfenadine does not inhibit non-immunologic contact urticaria. Contact Dermatitis. 1987 April; 16(4):220-3. 
         Lahti A, Vaananen A, Kokkonen E L, Hannuksela M. Acetyl-salicylic acid inhibits non-immunologic contact urticaria. Contact Dermatitis. 1987 March; 16(3):133-5. 
         Leahy D E, Wait Ark. Solute transport resistance at water-oil interfaces. J Pharm Sci. 1986 December; 75(12):1157-61. 
         Roskos K V, Guy R H, Maibach H I. Percutaneous absorption in the aged. Dermatol Clin. 1986 July; 4(3):455-65. Review. 
         Koch E M, Kohler C O. [Diurnal dependence of skin reactions in the administration of external substances]Z Hautkr. 1986 Mar. 15; 61(6):381-93. German. 
         Lahti A, McDonald D M, Tammi R, Maibach H I. Pharmacological studies on nonimmunologic contact urticaria in guinea pigs. Arch Dermatol Res. 1986; 279(1):44-9. 
         Lahti A, Maibach H I. Long refractory period after one application of nonimmunologic contact urticaria agents to the guinea pig ear. J Am Acad Dermatol. 1985 October; 13(4):585-9. 
         Wilkin J K, Fortner G, Reinhardt L A, Flowers 0 V, Kilpatrick S J, Streeter W C. Prostaglandins and nicotinate-provoked increase in cutaneous blood flow. Clin Pharmacol Ther. 1985 September; 38(3):273-7. 
         Tur E, Maibach H I, Guy R H. Spatial variability of vasodilatation in human forearm skin. Br J Dermatol. 1985 August; 113(2): 197- 203. 
         Lahti A, Maibach H I Species specificity of non-immunologic contact urticaria: guinea pig, rat, and mouse. J Am Acad Dermatol. 1985 July; 13(1):66-9. 
         Guy R H, Tur E, Bjerke S, Maibach H I Are there age and racial differences to methyl nicotinate-induced vasodilatation in human skin? J Am Acad Dermatol. 1985 June; 12(6): 1001-6. 
         Guy R H, Hadgraft J, Maibach H I Percutaneous absorption in man: a kinetic approach. Toxicol Appl Pharmacol. 1985 March; 30; 78(1):123-9. 
         Lahti A, Maibach H I An animal model for non-immunologic contact urticaria. Toxicol Appl Pharmacol. 1984 November; 76(2):219-24. 
         Osamura H, Jimbo Y, Ishihara M. Skin penetration of nicotinic acid, methyl nicotinate, and butyl nicotinate in the guinea pig—comparison of in vivo and excised skin, and the effects of four dermatologic conditions. J Dermatol. 1984 October; 11(5):471-81. 
         Guy R H, Wester R C, Tur E, Maibach H I Noninvasive assessments of the percutaneous absorption of methyl nicotinate in humans. J Pharm Sci. 1983 September; 72(9):1077-9. 
         Tur E, Guy R H, Tur M, Maibach Him Noninvasive assessment of local nicotinate harmacodynamics by photoplethysmography. J Invest Dermatol. 1983 June; 80(6):499-503. 
         Fleming R, Guy RH, Hadgraft J. Kinetics and thermodynamics of interfacial transfer. J Pharm Sci. 1983 February; 72(2): 142-5. 
         Guy R H, Maibach H I. Rapid radial transport of methyl nicotinate in the dermis. Arch Dermatol Res. 1982; 273(1-2):91-5. 
         Matushima I, Osamura H. [Studies on the permeability of human skin to nicotinic acid, methyl nicotinate and butyl nicotinate.—with emphasis on the influence of liquid vehicles and that of water immersion (author&#39;s transl)] Nippon Hifuka Gakkai Zasshi. 1980 July; 90(8):687-99. Japanese. 
         Bunting J W, Laderoute K R, Norris D J The pH dependence of xanthine oxidase catalysis in basic solution. Can J Biochem. 1980 May; 58(5):394-8. 
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         Hadgraft J, Hadgraft J W, Sarkany I. Proceedings: The effect of thermodynamic activity on the percutaneous absorption of methyl nicotinate from water glycerol mixtures. J Pharm Pharmacol. 1973 December; 25:Suppl:122P-123. 
         Hadgraft J, Hadgraft J W, Sarkany I. The effect of glycerol on the percutaneous absorption of methyl nicotinate. Br J Dermatol. 1972 July; 87(1):30-6. 
         Fountain R B, Baker B S, Hadgraft J W, Sarkany I. The rate of absorption and duration of action of four different solutions of methyl nicotinate. Br J Dermatol. 1969 March; 81(3):202-6. 
         van der Wegen P A. [Crystal reactions in methyl nicotinate]Pharm Weekbl. 1966 Jan. 14; 101(2):33-6. Dutch. 
         Tonder J E, Olesen P H. Agonists at the alpha4beta2 nicotinic acetylcholine receptors: structure-activity relationships and molecular modelling. Curr Med Chem. 2001 May; 8(6):651-74. 
         Narahashi T, Fenster C P, Quick M W, Lester R A, Marszalec W, Aistrup G L, Sattelle D B, Martin B R, Levin E D. Symposium overview: mechanism of action of nicotine on neuronal acetylcholine receptors, from molecule to behavior. Toxicol Sci. 2000 October; 57(2):193-202. 
         Yamamoto I, Tomizawa M, Saito T, Miyamoto T, Walcott E C, Sumikawa K. Structural factors contributing to insecticidal and selective actions of neonicotinoids. Arch Insect Biochem Physiol. 1998; 37(1):24-32. 
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       SUMMARY OF INVENTION 
       [0144]    This present invention relates to specific and highly selective proteins, amino acids and nucleic acid molecules. This formula has sequences encoding protiens, nutrient catalyzing cofactors, antibodies and short antisense molecules existing and innate within the various dermal layers of human tissue. Also included are specific functional methods to enable and utilized such polypeptides to module healing, apoptosis, Riboswitch activation and curation of wounds. 
     
    
     DETAILED DESCRIPTION 
       [0145]    Methyl nicotinate is present for its ability to easily and consistently pass through the epidermis and as such carry with it nutrients to the target area, there-by by passing the G. I. tract and liver. This eliminates the usual degradation and metabolism associated with oral ingestion. Nicotinate increases the surface temperature of the skin (warming) and causes a significant release of prostaglandins (PGE 2) from the skin, as well as stimulating histamine release from the of the mast of the cells in the tissue thereby initiating the autacoid response of the specific immune system. This facilitates blood circulation to and then away from the site of an injury. Increased circulation facilitates the repair process by supplying needed molecules and removing deleterious ones. Methyl nicotinate also interacts with other members of the nicotinoid super-family and produces a catalyzing effect on the absorption of nutrients and expeditious transport of nutrients to deep soft tissues and joints. 
         [0146]    Nicotinic acid is used as a complement to methyl nicotinate. Nicotinic acid is used topically to act as an additional electron donor from which to draw upon for heightened tissue repair. Nicotinate forms its own biochemical loop interacting with the epidermis and creating a “skin-flush”, as well as, co-synergizing with P-5-P, methyl nicotinate, and copper. 
         [0147]    Nicotinic acid receptors know as the G-Protein-Coupled Receptor G(1) are highly expressed in adipose tissue. By including both methyl nicotinate and nicotinic acid in this formula there is a 2 pronged “time released” effect on G(1). This serves to stimulate the release of fatty acids from the adipose tissue. Adipose tissue contains (stores) various fatty acids—one of which is arachadonic acid (AA). AA is the main constituent of the autacoid—prostaglandins, part of the specific immune system which initiates the repair process. The combination of these nicotinoids provides the formulation with the beginning of a healing loop to undo the internal oxidative insult due to injury or atrophy. 
         [0148]    Pyridoxol-5-Phosphate is a potent and active form of Vitamin B-6. P-5-P is a vital cofactor—necessary in the methylation process, which is endemic in the biochemical process called “Life”. By directly introducing P-5-P, where it is needed—through a trans-dermal system we have eliminated the associated degradation resulting from oral ingestion and the concomitant pass through the GI tract and liver. P-5-P can work as a catalyst with the requisite enzymes, amino acids and other nutrients/vitamins to produce a reaction(s). 
         [0149]    P-5-P is required for the absorption and movement (transport) into the bloodstream and tissue of amino acids—as such it is a conduit provider. P-5-P forms its own facilitator loop allowing for greater biochemical uptake of copper, as well as, the amino acids beta alanine and L-histidine. Of other importance, P-5-P (as an anti-oxidant) minimizes “free” copper from oxidizing HDL cholesterol more effectively than vitamin E. It helps to ensure copper&#39;s utility in the formulation and increases its transport and bio-availability. Thus, P-5-P forms a conduit loop, an antioxidant loop, a methylation loop while catalyzing histidine into histamine and further into carcinine. 
         [0150]    Alpha-Lipoic Acid—ALA is a universal antioxidant, which interacts with other water and fat-soluble antioxidants. ALA potentiates them and increases their respective bio-absorbability by serving to re-cycle these anti-oxidants. forms an exceptionally strong antioxidant loop while interacting with -5-P, copper, histidine, beta alanine, methyl nicotinate and nicotinic acid substantiating the respective antioxidant benefits of those nutrients and acting as a biochemical overseer for anti-oxidation and free radical quenching. 
         [0151]    ALA also works along with the nicotinates to seamlessly pass through the skin barrier and protect and buffer any and all metabolic by-products deposited beyond the plasma membrane; in this way it serves both as an antioxidant loop coordinator and becomes a vital part of the intra-epidermal transport loop. ALA serves as a prosthetic group, a scaffold of the H-protein of the glycine cleavage system and the dihydrolipoamide acyltransferases (E2) of the pyruvate, alpha ketoglutarate and branched-chain alpha-keto acid dehydrogenase complexes. ALA and its reduced form, di-hydrolipoic acid scavenges ROS (reactive oxygen species). ALA has proven beneficial clinical effects on oxidative stress models by blocking the reuptake/reactivation of the neuro-toxic glutamate metabolites. 
         [0152]    Copper—A ubiquitous mineral, copper, is utilized by the body in a variety of ways. When added to this present composition copper provides an analgesic-like effect to the structures deep within the joint and soft tissues. Copper provides the biochemical infrastructure and scaffolding for the universal anti-oxidant, one of the body&#39;s principal free radical scavengers, superoxide dismutase (Cu SOD). 
         [0153]    Copper is an element necessary for oxidation and absorption of iron and vitamin C (ascorbic acid) in digestion. Copper also acts as a catalyst in the formation of hemoglobin, the oxygen-carrying blood component, and a condition similar to iron-deficiency (anemia) has been produced experimentally in cases of copper deficiency. Thus, copper serves as an antioxidant loop, part of the overall healing loop and a part of the pain diminishment loop. Working in synergy with P-5-P free copper is made safe, non-toxic and bioavailable to become SOD—countering oxidative tissue and joint insult. 
         [0154]    L-Histidine forms its own loop with respect to entry. As a potent anti-oxidant histidine is also a pro-stimulator of circulation when topically applied. But, much more as a co-synergist with several other substrates to form a histidine -histamine-carcinine-carnosine loop, protecting tissues from further oxidative stress/damage while providing a readily available scaffold for neural-transmission and pain mitigation. Histidine acts as a neuro-modulator, secondary neurotransmitter, neuro-protectant against hydroxyl radicals, a cellular homeostasis regulator and anti-inflammatory agent. 
         [0155]    The carnosine loop elucidated is such. Histidine in the presence of beta alanine, ATP, and carnosine synthetase is metabolized to yield carnosine. Carnosine is a biologically super-active peptide, with a multitude of functions. Carnosine synthetase is found in tissue both slow twitch and fast twitch. This is where carnosine is synthesized. 
         [0156]    This is also where carnosine effects are most required. This method of transdermal, local introduction into tissue cells—histidine and beta alanine—tissue that contains carnosine synthetase, for the expressed, expedited purpose of synthesizing carnosine—where it is most needed—is indeed novel. 
         [0157]    The metabolism of carnosine loop elucidated is such. Carnosine, a peptide is metabolized by carnosinase in the plasma. Yielding histidine and beta alanine which may then again be synthesized back into carnosine, however carnosine synthetase is needed, this enzyme is an enzyme that is under-abundant and unstable. This fact is expressed to limit the availability and quantity of carnosine. 
         [0158]    An alternative metabolic process for histidine is into histamine. Histidine in the presence of histidine decarboxylase—with the required cofactor P-5-P is metabolized into histamine. Histamine, in its own right is a super-potent anti oxidant, anti-inflammatory, neuro modulator, neuro-protectant, neuro-transmitter amino acid. Like its sister molecule histidine, histamine has a multitude of biological functions. When histamine is present it is able to exert its activity as histamine, or it can be metabolized into carcinine 
         [0159]    Carcinine is synthesized in the presence of carcinine synthetase, histamine, beta alanine, ATP and the required co-factor P-5-P. Carcinine a potent anti oxidant is primarily active in the CNS (central nervous system). It has been shown that carcinine synthetase enzyme levels are 15 times higher in the CNS than elsewhere. The seat of carcinine synthesis and activity is the CNS. 
         [0160]    After carcinine has exerted its activity as an anti oxidant in the CNS it is transported away in the plasma resulting in a smooth-muscle relaxatory effect, which lowers blood pressure. Additionally, carcinine as an anti oxidant accumulates in the heart expressing its activity there. Carcinine can be metabolized back into histamine and beta alanine, also by carnosinase, however, it is relatively resistant to its effects. Histamine and beta alanine are both oxidized into acetic acid. Additionally histamine could remain as histamine retaken up in the carcinine loop, or methylated into 3 methylhistamine. 
         [0161]    The vast majority of histamine is methylated then oxidized to imidazole acetic acid, a molecule that can occupy the glycine receptor—preventing glutamate activity. Glutamate, an excitatory amino acid responsible for the “Pain Signal” cannot send the pain signal unless glycine occupies its receptor at the same time. 
         [0162]    Histidine as you can understand, is therefore involved in its own neuro-hormonal loop, a synergized breakdown—conversion loop and an anti-inflammatory loop. Together with P-5-P and the nicotinoids, histidine forms a powerful inflammatory cascade and resulting/subsequent anti-inflammatory loop. By engendering the formation of site specific prostaglandins—tissue and joint insult is rapidly mitigated and systemic healing/replacement is permitted to occur at a much more rapid rate. 
         [0163]    Beta alanine—the predominate branch amino acid in mammals and also the only naturally occurring branch amino acid is part of its own loop, the regenerating keratin loop—a constituent of the major molecular ingredient of human skin—keratin. Additionally, it is known to stimulate collagen (constituent of cartilage and platelets) and nucleic acid synthesis. 
         [0164]    Beta alanine is an essential co-factor for the carcinine-carnosine loop—efficacious as an anti-oxidant and for the cellular regulation/repair process. Beta alanine together with histidine/histamine forms the carnosine-carcinine covalent bond. Beta alanine is a key molecule necessary for production of carcinine—found almost exclusively in the central nervous system (CNS) and acts as an arbiter and anti-inflammation regulator, antioxidant and neuro-modulation agent. 
         [0165]    Beta alanine is also a key molecule necessary for production of carnosine, a vital part of this multi-clustered loop. Carnosine acts as a very powerful wound-healing agent, exhibiting anti-senescent effect at the cellular level. As well as, a potent time-dependent regulator of the intracellular “biological-clock” cascade, also serving as an autoimmune function protector. 
         [0166]    Beta alanine additionally is a necessary component for the synthesis (non-vertebrates) of pantothenic acid (B 5 ), which is a cofactor needed for the synthesis of Co A. Co A, a very interesting enzyme, initiates the Krebs cycle. The Krebs cycle is the system in the body that produces ATP (adenosine tri phosphate) energy. This cycle of energy is the most basic molecular production of energy in all cells of the body. Interestingly, injury and exercise deplete cells of ATP. ATP depleted cells, “pre-loaded” with beta alanine stimulates the uptake of beta alanine, and thus the “Krebs Cycle” and repair process. 
         [0167]    Beta alanine, completely desensitizes the glycine receptor and then metabolizes into acetic acid—a molecule which is also able to occupy the glycine receptor. This receptor occupation prevents the neuron from sending a glutamate-induced signal a signal that results in feeling pain. With the glycine receptor occupied by acetic acid, the metabolite of beta alanine, a concomitant cessation of glutamate excitation is prevented. This prevention minimizes NMDA neuro-toxicity, a metabolite of glutamate excitation, allowing for a quick, utilizable uptake of the formulation substrates. 
         [0168]    Leukotrienes B4 are the predominant pro-inflammatory molecule in the body. Leukotrienes B4, metabolites of arachadonic acid are rapidly, potently suppressed by beta alanine Hence, this method of delivery of beta alanine and its ability to suppress leukotriene initiated inflammation is an example of gene silencing. 
         [0169]    Medium Chain Triglycerides—are involved in the surface absorption of the formulation and play a vital role in the ability of this formulation to pass thorough the skin&#39;s plasma membrane and also act as a carrier, bringing nutrients to injured joints and tissues. They improve and enhance the trans-dermal delivery of nutrients and as such are involved in the transport loop of the formulation. 
         [0170]    Propylene Glycol and Polysorbate 80—are both non-ionic solvents, which serve as coupling agents in the formulation. They are both used principally in the transport loop. Both provide for the marriage and transport of water, nutrients and oils (MCT&#39;s) by acting as a bridge and conduit between the glycerol backbone of the MCT&#39;s and the water. Thus, permitting the oil, water, and nutrient mixture to restructure its molecular makeup and become one, while passing through the epidermis and dermis into the tissue, joint, cells, ultimately into the plasma. While allowing the nutrients as well as the metabolites to be become systemic, thereby allowing the required environment to be created for the desired healing/repairing processes. 
         [0171]    Glycerol is hydroscopic and acts as a moisturizing agent, more directly as a method to open this solutions&#39; molecules, enabling better, more complete uptake through the pores of the skin, which allows better reception of the formulations substrates. Thus, glycerol is part of the transport and initial delivery loop. It provides the first entry into the skin barrier where propylene glycol and polysorbate-80, as well as, MCT&#39;s take over to provide a secondary transport and delivery system. 
         [0172]    A transdermal healing composition has been described with reference to a particular embodiment. For one skilled in the art, other modifications and enhancements can be made without departing from the spirit and scope of the aforementioned claims. 
         [0173]    While endeavoring in the foregoing specification to draw attention to those features of the invention believed to be of particular importance it should be understood that the Applicant claims protection in respect of any patentable feature hereinbefore referred to whether or not particular emphasis has been placed thereon.