WO2022035429A1 - Fullerènes nootropes et leur utilisation - Google Patents

Fullerènes nootropes et leur utilisation Download PDF

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WO2022035429A1
WO2022035429A1 PCT/US2020/046027 US2020046027W WO2022035429A1 WO 2022035429 A1 WO2022035429 A1 WO 2022035429A1 US 2020046027 W US2020046027 W US 2020046027W WO 2022035429 A1 WO2022035429 A1 WO 2022035429A1
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fullerene
functional group
glutathione
phosphate
composition
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PCT/US2020/046027
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Peter Robert BUTZLOFF
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Butzloff Peter Robert
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Priority to PCT/US2020/046027 priority Critical patent/WO2022035429A1/fr
Priority to US17/674,512 priority patent/US20220193257A1/en
Publication of WO2022035429A1 publication Critical patent/WO2022035429A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6923—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B32/00—Carbon; Compounds thereof
    • C01B32/15—Nano-sized carbon materials
    • C01B32/152—Fullerenes
    • C01B32/156—After-treatment

Definitions

  • the present invention is directed in general to a composition of matter to improve biochemical REDOX homeostasis and in particular to improve neural electrochemical REDOX homeostasis using glutathione and adenosine phosphate derivatized fullerene compositions.
  • ASD autism spectrum disorder
  • ASD is genetic and has diverse features that are heritable and complexly distributed over all chromosomes.
  • ASD is characterized by reduced interest in, or apparent inability to learn, effective social communication.
  • the high focus level on task while potentially beneficial in some contexts, is undesirable when a change in task or multi-tasking is needed to address real world demands on time and resources.
  • the origin of inflexibility on task is thought to arise from the need to amplify insufficiently strong neural input, leading to hypersensitivity to noise, light, and too much information.
  • Another equally important aspect of this need to constantly focus attention is the loss of a proper sense of time, as the passing of hours is dismissed as irrelevant information, thereby leading to sleep disorders and poor fatigue recovery.
  • autism is often associated with increased reactive oxygen species in neurons, but separating the origin of these stressors out from a spectrum of genetic changes from the norm, as compared to poor sleep states, has been confounded by the behavior and sleep deprivation that is common in autism.
  • the effects of surface charges in contact with the cell cytosol, proteins, and the lipid membranes of the endoplasmic reticulum become insufficiently engaged in these interactions.
  • This autism related deficit, along with ROS associated in the aging process are thought to contribute to mitochondrial stress.
  • these stressors are related to an imbalance of the reduction-oxidation process (REDOX) of the electron transfer cycle that allows cellular respiration to take place, and the result can be the production of misfolded proteins that are associated with many kinds of mental deficits and neuro-physiological pathologies.
  • REDOX reduction-oxidation process
  • the highest specialization of animals is neural tissue, where neurons have the greatest need for energy, and therefore also obtain the highest concentration of energy harvesting mitochondria in their structures.
  • the brains of higher organisms have evolved strategies to significantly reduce neural size to fit more computational capacity into the same volume.
  • the human brain weight is about 2% of body weight, yet it needs 20% of the total oxygen consumption, and consumes approximately 25% of total body glucose utilized by oxidation to produce energy and release carbon dioxide and water in that process.
  • a delicate chemical balance of reduction and oxidation (REDOX) operates mitochondria and drives cellular function, especially neural function, which is the most energy intensive and therefore the most reliant on mitochondria for energy.
  • Proper brain function can become compromised when genetically encoded or environmentally induced mis-development or evolutionary induced miniaturization of neural structures become compromised by cellular respiration related energy deficits.
  • Autism is impacted by mitochondrial dysfunction in multiple ways.
  • Neural cell migration in the developing brain may have resulted in unusual or poor cortical layer differentiation.
  • the remodeling of dendritic spines is also compromised in autistic brains, and may result in the loss of learning plasticity. It is verified at this point, that the level of neural electrical signals is attenuated in voltage and reduced in signal strength in the brains of autistic people.
  • Impairment of mitochondrial metabolism and defective mitophagy results in age associated neurodegeneration.
  • the fact that neuronal cells are more vulnerable to degeneration in several pathological conditions, including Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth disease, underlines the urgent need for redundant mechanisms to regulate the removal of defective mitochondria, or in the case of autism, to establish conditions leading to a normal immune response that allows proper mitophagy.
  • Autism spectrum disorder is more highly correlated with the dysregulation of the human gene ATP 1 A3 for production of the protein ATPase Na+/K+ Transporting Subunit Alpha 3.
  • This is the active enzyme component to catalyze the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. Especially in neurons, this action creates the electric gradient across the plasma membrane by means of an electrochemical gradient of sodium and potassium ions.
  • This catalytic ATPase enzyme is a protein that provides the energy for active transport of nutrients and is a P-type cation transporter in the subfamily of Na+/K+ -ATPases.
  • the ATP1A3 protein controls the gradients of Na and K ions across the plasma membrane needed for osmoregulation, and sodium coupled transport of organic and inorganic nutrient molecules that are responsible for the electrical excitability of nerve and muscle.
  • This enzyme is composed of two subunits, a large catalytic subunit (alpha) and a smaller glycoprotein subunit (beta).
  • alpha catalytic subunit
  • beta glycoprotein subunit
  • the goal of enhancing autistic and perhaps even neurotypical mental cognition must be to assist this process even when the genetic production of ATP1A3 protein is dysfunctional.
  • a reasonable objective to assist autistic persons is to create a substitute regulatory molecule that performs a similar catalytic task and can restore a more proper electric and electrochemical potential in neurons.
  • Neural plasticity is controlled by epigenetic factors as well as genetic factors. The epigenetic signals of interest arise within the complexities of the cellular respiration cycle. No state of the art exists to assist neural cells to regulate the performance of this more subtle regulatory
  • Such a general treatment for autism spectrum disorders as well as aging related cognitive preservation should include a prophylactic enhancement of nootropic function able to overcome the electrochemical deficits of aging human neural cells. Therefore, to maintain or improve mental function and to restore autistic cognitive facilities, it is believed the present invention can provide such a solution using an artificial yet intelligent biological and electrochemical design to promote and improve the regulation of existing neurological functions.
  • This invention is a small thiol-containing fullerene compound derivatized with both glutathione (GSH) and adenosine phosphates such as adenosine triphosphate (ATP) with enhanced utility to directly inactivate reactive oxygen species (ROS) and prevent ROS initiated reactions.
  • GSH glutathione
  • ATP adenosine triphosphate
  • the invention provides first embodiments of a composition having a fullerene having a cage structure and having at least one first functional group and at least one second functional group.
  • the first functional group includes a glutathione that can accrue negative charge.
  • the at least one second functional group includes at least one phosphate, in which phosphorous has an oxidation state of five (5), and in which biochemical reduction-oxidation (REDOX) reactivity is reversible.
  • the at least one second phosphate functional group includes an adduct of at least one adenosine phosphate functional group, in which phosphorous has an oxidation state of five (5).
  • a mixture of first composition embodiments and second composition embodiments in which the at least one second phosphate functional group includes an adduct of at least one adenosine phosphate functional group, in which phosphorous has an oxidation state of five (5).
  • the fullerene includes C60 fullerene and the first functional group includes a reduced or an oxidized glutathione.
  • the fullerene comprises C70 fullerene and the first functional group comprises a reduced or an oxidized glutathione.
  • the fullerene includes a C60 fullerene or a C70 fullerene or a redox metabolite thereof
  • the first functional group includes a reduced or an oxidized glutathione, in which the redox metabolite adducts up to 6 (six) electrons, and up to 5 (five) protons in any combination.
  • the invention also provides a topical composition, having a fullerene with a cage structure with a hydrophobic region at unreacted carbons regions of the cage structure that is capable of reversibly storing as many as six (6) protons, having at least one first functional group including a glutathione that can accrue negative charge and having at least one second functional group, the at least one second functional group including at least one phosphate, in which phosphorous has an oxidation state of five (5), or the at least one second functional group includes an adduct of at least one adenosine phosphate functional group, in which phosphorous has an oxidation state of five (5), or including an effective mixture thereof.
  • the formula for the composition is C60(glutathione)(phosphate)x, where x includes between about one (1) to about fifteen (15) phosphate groups, having a nominal value of 5 (five) phosphate groups.
  • Some other embodiments of the topical composition include a free- radical scavenging function and an associated anti-oxidant function when dissolved in water and with from about 0% to about 30% by weight glycerol.
  • Yet some other embodiments of the topical composition include an ultraviolet absorbing and sunlight protective function when used to provide redox reaction assisted cellular repairs.
  • the invention also provides a pharmaceutical composition having a C60 fullerene with a carbon cage structure, having at least one adenosine phosphate functional group in which phosphorous has an oxidation state of five (5), and having at least one glutathione functional group.
  • a molecular species has at least one negative charged functional group and at least one neutral or positive charged functional group.
  • a formula for the composition is C60(glutathione)(adenosine phosphate)x, where x comprises between about one (1) to about three (3) adenosine phosphate groups.
  • compositions include physiological metabolites having an allosteric chemical bond to histone signaling effectors of DNA methylation.
  • the formula for the composition includes C60(glutathione))(adenosine phosphate)x where x is between about one (1) to about three (3) phosphate groups and further including a solvating mixture of about 70% glycerol and about 30% propylene glycol that is flash vaporized at about 260 degrees C to create an inhalant aerosol.
  • FIG. 1 is an illustration of molecular structures of glutathione, trisodium phosphate, C60 fullerene, and C70 fullerene, according to the teachings of the present invention
  • FIG. 2 is an illustration of molecular structures of the reversible oxidation of glutathione into dimeric glutathione, according to the teachings of the present invention
  • FIG. 3 is an illustration of molecular structures of the reversible reaction of adenosine triphosphate to adenosine diphosphate at physiological pH, according to the teachings of the present invention
  • FIG. 4 is an illustration of the reaction of adenosine triphosphate with C60 fullerene to form C60 fullerene adenosine triphosphate, according to the teachings of the present invention
  • FIG. 5 is an illustration of molecular structures of glutathione reaction with C60 fullerene to form C60 fullerene glutathione, according to the teachings of the present invention
  • FIG. 6 is an illustration of the molecular structures of one inorganic phosphate reaction with C60 fullerene, according to the teachings of the present invention.
  • FIG. 7 is an illustration of the molecular structure of fullerene glutathione phosphates, and alternative electrical and iconic schematics representing the same, according to the teachings of the present invention.
  • FIG. 8 is an illustration of the molecular structure of C60 fullerene glutathione adenosine diphosphate, an alternative electrical schematic representing it, and dosage to the eye, according to the teachings of the present invention
  • FIG. 9 is an illustration of the molecular structure of a C70 fullerene dimeric glutathione adenosine diphosphate metabolite, and an electrical schematic representing it, according to the teachings of the present invention.
  • FIG. 10 is an illustration of the molecular structure of a C70 fullerene glutathione adenosine ribose diphosphate metabolite, and an electrical schematic representing it, according to the teachings of the present invention
  • FIG. 11 is an illustration of the electrical schematic of a fullerene glutathione phosphate or adenosine phosphate when it is oriented by the cellular electric field, according to the teachings of the present invention
  • FIG. 12 is an illustration of charge coupled REDOX enabled inside a mitochondrion by fullerene glutathione phosphates or glutathione adenosine phosphates of the present invention
  • FIG. 13 is an illustration of cell organelles in proximal abutment with a multiplicity of mitochondria provided with the composition of the present invention
  • FIG. 14 is an illustration of a neuron provided with the composition of the present invention
  • FIG. 15 is an illustration of allosteric portion of sirtuin 1 comparing the location of a phosphate adduct with the same region multiply adducted using the composition of the present invention
  • FIG. 16 is an illustration of the direction of increased DNA binding on chromatin having reversibly silenced genes on treatment with the composition of the present invention
  • FIG. 17 is an illustration to chart a method of Fullerene Glutathione Adenosine Phosphates Synthesis, according to the teachings of the present invention.
  • FIG. 18 is an illustration to chart a method of Fullerene Glutathione Phosphates Synthesis, according to the teachings of the present invention.
  • FIG. 19 is an illustration of the method of thermally aerosolized vapor inhalant selfadministration of the composition of the present invention.
  • FIG. 20 is an illustration of normalized bioenergetic data based on cytochrome c oxidase (COX) concentration in blood plasma with age during a human lifetime, according to the teachings of the present invention
  • FIG. 21 is an illustration of experimental mass spectrograph data for adenosine triphosphate derivatized C60 fullerene, according to the teachings of the present invention.
  • FIG. 22 is an illustration of experimental mass spectrograph data for glutathione derivatized C60 fullerene, according to the teachings of the present invention.
  • FIG. 23 is an illustration of experimental mass spectrograph data for glutathione adenosine triphosphate derivatized C70 fullerene, according to the teachings of the present invention.
  • FIG. 24 is an illustration of experimental mass spectrograph data for glutathione adenosine triphosphate derivatized C60 fullerene, according to the teachings of the present invention.
  • FIG. 25 is an illustration of experimental mass spectrograph data for phosphate derivatized C60 fullerene, according to the teachings of the present invention.
  • CD38 is a multifunctional transmembrane glycoprotein found in humans that can operate as an enzyme, wherein it is responsible for the synthesis of at least two Ca2+ messenger molecules. It also operates as an antigen, wherein it is involved in some aspects of the innate immune inflammatory response, as well as in regulating cell adhesion, differentiation, and proliferation. CD38 is expressed on the surface of activated lymphocytes. The extracellular domain of CD38 is known to have bendable and positively charged extended N terminus residues. [0051] GSH is used to represent glutathione, having CAS registry number 70-18-8.
  • GSSH is used to represent the oxidized disulfide of glutathione, with CAS registry number 27025-41-8.
  • Tumor Necrosis Factor alpha is generally understood to be an inflammatory cytokine produced by macrophages and monocytes during acute inflammation. It can be responsible for a diverse range of signaling events within cells, leading to programmed cell death or apoptosis.
  • NFkB is used to represent nuclear transcription factor kappa B, and is considered a regulator of innate immunity. It regulates the expression of multiple inflammatory and immune genes and is known to be involved with chronic inflammatory diseases.
  • the present invention provides a multiplexed solution for effectively extinguishing the mechanisms leading to reduced membrane potentials related to neurological disorders.
  • a general treatment for autism spectrum disorders as well as aging related cognitive preservation should include a prophylactic enhancement of nootropic function able to overcome the electrochemical deficits of aging human neural cells. Therefore, to maintain or improve mental function and to restore autistic cognitive facilities, it is believed the present invention can provide such a solution using an artificial yet intelligent biological and electrochemical design to promote and improve the regulation of existing neurological functions.
  • Embodiments provide a small thiol-containing fullerene compound derivatized with both glutathione (GSH) and adenosine phosphates such as adenosine triphosphate (ATP) with enhanced utility to directly inactivate reactive oxygen species (ROS) and prevent ROS initiated reactions.
  • GSH glutathione
  • ATP adenosine triphosphate
  • This composition tethers fullerene, well known as a free radical scavenger, to glutathione, the most abundant non-protein thiol providing several vital functions such as direct scavenging of free radicals, detoxification of electrophilic compounds, modulation of cellular redox status and thiol-disulphide modification of proteins.
  • this composition tethers fullerene (C60 or C70) to adenosine phosphates, where such phosphates are essential to the regulation of cell signaling and repair pathways, such as by phosphatizing the sirtuins.
  • This novel and unique composition directs mitochondria and modulates cellular homeostasis by self-adjusting the balance among cellular respiration, protein synthesis (anabolism), protein utilization and recycling (catabolism).
  • Antioxidants of indirect action influenced by this composition include biological phase II detoxifying enzymes, which contribute to biosynthesis, the recycling of thiols, and the excretion of oxidized, reactive secondary metabolites.
  • Antioxidants of indirect action influenced by this composition include biological phase II detoxifying enzymes, which contribute to biosynthesis, the recycling of NAD+, and the excretion of oxidized, reactive secondary metabolites.
  • phase II enzymes may include glutathione-S -transferase (GST) isozymes, NADP(H) counterions to quinone oxidoreductase (NQO1), gamma glutamate cysteine ligase (g-GCL), glutathione peroxidase (GPx), glutathione reductase (GR), and stress response proteins such as heme oxygenase (HO)-l and the chains of ferritin.
  • GST glutathione-S -transferase
  • NQO1 quinone oxidoreductase
  • g-GCL gamma glutamate cysteine ligase
  • GPx glutathione peroxidase
  • GR glutathione reductase
  • stress response proteins such as heme oxygenase (HO)-l and the chains of ferritin.
  • Other embodiments include a vapor method of delivery to regenerate neural cell function with age
  • a nanoparticle composition is provided to improve cognitive well-being in both aging related neural decline, and in autism, to remediate reductive and oxidative stresses at mitochondrial lipid membranes by careful design consideration of a molecule having both cholesteric affinity and REDOX capability to confer protective functions to the normal operation of mitochondria and the cellular organelles to which they associate, especially those mitochondria in neural cells and brain tissue.
  • the following fullerene composition is therefore designed to improve cognitive bioenergetics by increasing the electrical potential available for neural function.
  • the composition of derivatized fullerene cores are provided with at least one derivatized adenosine (mono-, di-, tri-) phosphate, and desirably also an equal proportion of derivatized glutathione. Both C60 and C70 fullerenes may be used to construct the specified composition.
  • One aspect of the present invention is to couple either a C60 fullerene adenosine phosphate glutathione or a C70 fullerene adenosine phosphate glutathione with positive charged macrophages of the innate immune system having functional amine groups as part of their inflammatory antigens. Positively charged amines expressed on human protein CD38 at the surface of lymphocytes are part of the innate immune system that can carry the composition of the present invention via negatively charged portions of the fullerene adenosine phosphate functional groups.
  • This aspect serves as one type of plasma delivery system for fullerene GSH-ATP and derivatives fullerene GSH-ADP or fullerene GSH-AMP or fullerene GSH-cyclic AMP.
  • the cellular incorporation of fullerene GSH-ATP of the present invention directly results in an inhibition of the unfolded protein response (UPR) pathways of mitochondria.
  • URR unfolded protein response
  • This aspect is enabled by the antioxidant and free-radical scavenging that is associated with fullerenes.
  • One characteristic of this aspect is the separation of positive and negative charges on functional groups bonded to the core fullerene molecule.
  • the GSH adduct obtains a positive charge, and the adenosine phosphates obtains a negative charge. This space separated charge allows enhanced free radical recombination in aqueous media such as the cytosol.
  • fullerene glutathione phosphates functions substantially in similar manner to glutathione adenosine phosphates.
  • the phosphate functional group can participate in both respiration and enzyme catalyzed reactions.
  • the space separated charges of the fullerene glutathione phosphates allows enhanced free radical recombination in aqueous media such as in the cytosol or inside of mitochondria.
  • fullerene adenosine phosphate glutathione is used to phosphorylate allosteric sites on sirtuins, a type III histone deacetylase. This makes the sirtuin more able to deacetylate histones onto which DNA is wrapped, causing the histones to present primary amines which can then obtain a proton from the nuclear cytosol to from positive charged amine groups.
  • fullerene glutathione adenosine phosphates or fullerene glutathione phosphates may express both positive and negative charges at either of their functional groups
  • This design feature serves to create multiple charge-coupled adducts between the central negative charged phosphate ladder rungs of DNA and the amine positive charge on chromatin on which the DNA loops are bound to further stabilize the silencing of neurological deficit related DNA genes or gene groups from excessive transcriptional expression.
  • the novel coupling agents being functionally bound fullerene serve to confer instant neuroprotection from ineffective catabolism and anabolism, while providing homeostasis of mitochondrial membrane polarization. Defects of lysosomal catabolism influence the function and structural characteristics of the MAMs both in autism and in aging associated neuropathy.
  • the fullerene adenosine phosphate adducts of the present invention are therefore designed to expedite storage of electrons and protons. This expedites neural remodeling both anabolic and catabolic deficits by the interposition between the mitochondrion and the endoplasmic reticulum (ER) as well as between the mitochondrion and other cellular organelles.
  • This neuroprotective feature is of nutritional health maintenance as well as of pharmaceutical interest to help alleviate deficits associated with autism, amyotrophic lateral sclerosis (ALS), and other cognitive dysfunctions.
  • fullerene adduct embodiments are their ability to reside at the membrane-proximal region consistent with the abilities of fullerenes to interact with the hydrophobic tails of lipid rafts, while their hydrophilic adducts associate better to the hydrophilic head of these same lipid rafts, thereby keeping them in proximity to a mitochondrion cell membrane or endoplasmic reticulum.
  • the fullerenes of the present invention express negative charges at the phosphate functional groups to confer the ability to form an adduct with positively charged long side chains of the inflammatory antigen and human proteins such as the human innate immune defense cytokines, and exemplary CD38.
  • This has the immediate effect of temporarily denaturing the positively charged extended N terminus residues of cytokines and CD38, when in proximity to a mitochondrion cell membrane or endoplasmic reticula.
  • the GSH-ATP fullerenes provide protection to NAD+, which is consumed by autoimmune dysregulation.
  • NAD+ is consumed by autoimmune dysregulation.
  • the epigenetic programming of an immune response may be excessive and unable to restore to normal levels.
  • the innate immunity conferred by CD38 consumes NAD+.
  • the electrical nature of the composition allows stabilization of the concentration of NAD+ in cellular respiration for reduction-oxidation pathways that require significant amounts of NAD+. This aspect leads to improved function of mitochondria of neurons in the brain, and therefore provides significantly improved electrical energy output from neural cells.
  • fullerenes are generally known to reduce the inflammatory cytokines such as TNF-alpha and NFkB because they scavenge and terminate the free radicals that are associated with inflammation.
  • the negatively charged adenosine phosphate adduct to fullerene is superior in its ability to attract to and countercharge the positive charged amine groups associated with cytokines and other inflammatory molecules having positive charge.
  • CD38 expression in several cell types is induced by the presence of the inflammatory cytokines. Therefore, the fullerene GSH-ATP of the present invention, together with their metabolites, reduce or eliminate the conditions that give rise to CD38 expression.
  • fullerene GSH-ATP fullerenes are their placement into the gaps between the mitochondrion associated membranes, or MAM. This function is to enable increased catabolism between MAM, for example the catabolism between the Golgi complex and the mitochondrion, or between the endoplasmic reticulum and the mitochondrion.
  • MAM mitochondrion associated membranes
  • What is catabolized, or broken down, are the variety of sugars and proteins required as components to build or to rebuild new cell components.
  • Non-limiting examples of cellular catabolized molecules include glycol- sphingolipidoses, sphingolipids, and carbohydrates.
  • the placement of fullerene GSH-ATP into MAM increases the efficiency of catabolism by storing of electrons and protons.
  • the catabolic restructuring of topical eye cells at the cornea using the composition of this invention is one example of using the energy of sunlight to power the REDOX reaction of mitochondria in the regeneration of clear and transparent tissues at oxidized cataracts without recourse to surgical excision of clouded proteins or the use of foreign tissue transplants to rescue vision from clouded eye tissues.
  • the placement of fullerene GSH-ATP into MAM removes accumulated proteins and detritus that have blocked the ability of the mitochondrion to function with proper electrical potential or bioenergetics, thereby restoring the catabolic function that normally declines with age, and restoring health in favor of senescence.
  • the presence of fullerene GSH-ATP orients in the electric field at the MAM with the positive face of glutathione toward the negative potential, and the negative face of the phosphate ion directed at the positive potential.
  • the binding of cellular hydrogen in physisorption to fullerene derivatives is without dissociating or splitting, and the binding strength is weak and highly localized, limiting storage efficiency and capacity.
  • a strong electric field such as found at MAM
  • the binding of cellular hydrogen in physisorption to fullerene derivatives is without dissociating or splitting, and the binding strength is weak and highly localized, limiting hydrogen storage efficiency and electron charging capacity on the fullerene core molecule.
  • composition of the present invention utilizes a different method.
  • this proximal abutment On interposition within MAM, this proximal abutment generates a high electric field near the surface of the fullerenes to polarize and attract hydrogen molecules or ions with enhanced binding strength that is delocalized with respect to the core fullerene molecule.
  • This aspect is promoted by the spatial orientation of the localized negative charge on the adenosine phosphate and the positive charge on the glutathione functional group in an electric field, and results in enhanced electron exchange capacity on the inner fullerene core molecule that is resistively coupled to these two separated charges.
  • the reversible hydrogen storage effect allows the core fullerene molecule to store hydrogen as well as to charge and discharge electrons while maintaining orientation with respect to opposing charges in the separate spatial regions of this molecular structure for the purpose of enhancing the process of cellular respiration and electron charge transfer in close proximity to mitochondria or the plasma membrane of a cell.
  • the polyphosphorylated fullerene molecules express geometric localization of polyphosphates to one cluster at one face or hemisphere of the substantially spherical carbon molecular cage of the fullerene structure, to enable a hydrophilic face directed at mitigating reactive oxygen species (ROS) at the interface between the endoplasmic reticulum (ER) of the mitochondrial cell membrane and the cytosol or water based fluids abutting the ER, while allowing a hydrophobic region of the fullerene carbon face to reversibly attract to an associated proximal cell lipid membrane, or a microtubule, or an actin filament.
  • ROS reactive oxygen species
  • FIG. 1 illustrates a substantially round chemical cage structure representing 60 aromatic carbon atoms comprising the C60 fullerene molecule 12, and a somewhat elongated chemical cage structure representing 70 aromatic carbon atoms comprising the C70 fullerene molecule 14.
  • the chemical structure representing the sodium salt form of the inorganic triphosphate molecule 19 has three negative charged oxygen atoms to countercharge each sodium ion, where the oxygen sodium ligand 18 is equivalently represented with associated charges 17. It is understood that inorganic phosphate 19 reversibly replaces positive charged sodium ions with positive charged hydrogen protons when sodium phosphates are dissolved in water. Substances 12, 14, 16, 19 are collectively used to create the composition of matter taught herein.
  • FIG. 2 illustrates the reversible biochemical oxidation reaction of glutathione 20.
  • Two of the reduced form of glutathione molecules 22 become oxidized into a dimeric form of glutathione having a characteristic sulfur to sulfur bond 24.
  • the oxidized form of glutathione 24 also known by the abbreviation GSSH
  • GSH two hydrogen protons reversibly into two discrete glutathione molecules 22
  • This reversible biological oxidation and reduction (redox) process will likewise take place in the context of the various derivatives of glutathione specified as a functional operation of the composition of matter herein.
  • FIG. 3 illustrates the reversible biochemical reaction of adenosine phosphates 30.
  • the adenosine triphosphate (ATP) 32 reversibly disassociates into adenosine diphosphate (ADP) 38, with the loss of one free phosphate group 36.
  • ADP 38 and phosphate ion 36 become bonded as illustrated by the region bracketed by 34 on ATP 32.
  • This chemical process is part of the chemical respiration of the cell at physiological pH. It is understood that ADP 38 may also loose yet one more phosphate group 34 to generate adenosine monophosphate (AMP) in a similarly reversible manner, as is well understood in the context of cellular respiration in biological processes.
  • AMP adenosine monophosphate
  • AMP and the related cyclic adenosine monophosphate (cAMP) structures are sufficiently well understood as reversible metabolites of the naturally available adenosine phosphates. It is specified that these variations or metabolites of adenosine phosphates, as well as the extracted inorganic phosphate functional groups are to be included.
  • FIG. 4 illustrates fullerene adenosine triphosphate synthesis 40.
  • the reaction of adenosine triphosphate (ATP) with carbon fullerene may use C60 fullerene 44, or C70 fullerene illustrated in FIG. 1.
  • Hydrogen-bonded nitrogen and hydrogen-bonded hydrogen are shown by the two dotted lines in the region bracketed at 43. These hydrogen bonds become permanent covalent bonds at neutral pH to form fullerene adenosine triphosphate or C60-ATP 46, where the product of this synthesis reaction is shown by the direction of the large black arrow.
  • metabolites of the fullerene adenosine phosphates will be reversibly oxidized and reduced by the gain or loss of phosphate groups in the manner illustrated for adenosine triphosphate (ATP) in FIG. 3 in the context of this and the related adenosine phosphate fullerene compositions herein.
  • ATP adenosine triphosphate
  • FIG. 5 illustrates molecular structures for a fullerene glutathione synthesis 50.
  • the reaction of glutathione (GSH) with carbon fullerene may use C60 fullerene 54, or C70 fullerene illustrated in FIG. 1.
  • Hydrogen bonded Nitrogen and hydrogen bonded Hydrogen are shown by the two dotted lines in the region bracketed at 53. These hydrogen bonds become permanent covalent bonds at neutral pH to form fullerene glutathione or C60-GSH 56.
  • GSSH oxidized glutathione
  • FIG. 6 illustrates molecular structures for a C60 fullerene phosphate synthesis 60.
  • the functional group trisodium phosphate 67 is provided with three negative charged oxygen atoms that have counter-charged sodium anions 63, both of which become attracted by a C60 fullerene molecule 64.
  • Core fullerene 61 may comprise a C60 or a C70 carbon cage molecule, which can accept up to six electrons. It is understood that multiple phosphate groups may react with either C60 fullerene or C70 fullerene to create the desired fullerene phosphates. Phosphorus in the form of inorganic phosphates are widely utilized in the human body.
  • fullerene phosphonates, or like phosphonates, in FIG. 7 is to allow coupling between inorganic phosphorus in the electron transfer chain of cellular respiration, while also providing a hydrophobic and lipophilic carbon cage molecule to anchor these molecular species by van-der- Waals attraction to biological cellular structures between organelles inside cells, as well as to the organic peptides within cellular organelles such as the mitochondria where respiration takes place.
  • the presence of both inorganic and organic functionality improves the cellular respiration process and overcomes some compatibility issues with malformed peptides and neuropeptides that are typically associated with energy production from glucose in some types of cellular neurological deficits.
  • FIG. 7 illustrates a C60 fullerene phosphate glutathione 70 using different schematic formats, where the molecular structures 71a, 73a, 77a are represented by circuit diagram to include 71b, 73b, 77b. Negative charge is represented by source 78.
  • fullerene glutathione phosphates 70 is also represented by an iconic stick figure having a central (black) region to represent a fullerene 71c, and having bent distal ends for glutathione 73c, and phosphate 77c.
  • the core C60 fullerene molecule 71a is covalently bonded to a pendant functional group of glutathione 73a and three pendant functional groups of phosphate 77a.
  • the phosphates 77a may obtain multiple negative charges on oxygen at the loss of hydrogen or sodium cations during ordinary cellular respiration and cellular pH changes that take place during cellular respiration, anabolism, and catabolism processes.
  • Core fullerene 71a may comprise a C60 or a C70 carbon cage molecule, which can accept up to six electrons, or as many as five protons.
  • charge storage by fullerene molecule 71a is represented by the schematic symbol of a capacitance 71b.
  • Glutathione functional group 73a is represented by resistance 73b.
  • the wire to capacitance 71b represents the covalent bond between glutathione functional group 73a and fullerene 71b. Negative charge or charges on phosphates 77a are represented in circuit format by 78 at the end of a resistance 77b.
  • the wire to capacitance 71b represents the covalent bond between phosphate functional groups 77b and the core fullerene 7 lb.
  • Solar irradiation containing ultraviolet light 72 will act to create free radicals in human tissues, especially at the skin.
  • Glutathione functional group 73a, 73b, 73c functions as a free radical scavenger and anti-oxidant, as does the fullerene core molecule 71a, 71b, 71c.
  • phosphate groups 77a, 77b, 77c serve to anchor this composition at the phospholipids of the outside membrane of cells. This molecular composition also confers free radical protection from reactive oxygen species when it diffuses into the interior or inside regions of any cell.
  • adenosine functionality in addition to phosphates 77a, 77b, 77c as illustrated in FIG. 7 will extend the chemical functionality of free radical scavenging into the citric acid portion of the cellular respiration cycle to enable the pharmaceutical cell signal embodiment.
  • FIG. 8 illustrates a C60 fullerene glutathione adenosine triphosphate 80.
  • the functional group of glutathione (GSH) 83a provided with a positive charge proton 85a hydrogen bonded to the core fullerene molecule 81a.
  • the functional group adenosine triphosphate (ATP) 87a is provided with at least one negative charge under physiological pH.
  • Pendant functional groups 83a and 87a are covalently bonded to a core C60 fullerene 81a. A multiplicity of negative charges can arise at the adenosine phosphate groups 87a as part of the cell respiration process of the citric acid cycle.
  • Phosphate group negative charges 87a are sufficiently removed from the core fullerene 81a that these do not influence the ability to store positive charged proton 85a being represented by positive charge 85a.
  • This unique feature overcomes past limitations using homogeneous exohederal doping or functionalization using charge transfer complexes that have been unable to achieve water soluble and reversibly charged fullerene anions and cations.
  • the molecular structures are also represented as a circuit schematic diagram to clarify their roles as localized charges that serve to stabilize and insulate the core fullerene molecule 81a, such that 81b is represented as a capacitance having the ability to be more stable in anionic or cationic charge storage under biological conditions.
  • Glutathione 83a has the role of an insulating resistance 83b.
  • Hydrogen proton 85a has a role as cationic stored charge 85b.
  • Adenosine 89a has a role as an insulating resistance 89b.
  • Pendant multiple negative phosphate charges 87a have expression as a negative potential at 87b.
  • reactive oxygen species and free radicals are formed in the eye 84.
  • the fullerene glutathione adenosine triphosphate is introduced into the human eye as a topical eyedrop having pharmaceutical properties as this material becomes an internalized at the cornea in the presence of sunlight.
  • the presence of multiple hydrogen protons 85a reduces the aged and crosslinked corneal tissues 88 to restore cataract transparency by the REDOX reaction.
  • Core fullerene 81a, 81b may comprise a C60 or a C70 carbon cage molecule, which can accept up to six electrons, or as many as five protons.
  • the fullerene composition of the present invention also functions to strengthen chemical bonds to allosteric sites of enzymes as effectors of DNA expression.
  • hydrogen 85a, 85b promotes cell flexibility to quickly and reversibly transition histone deacetylation processes needed to switch from citric acid cycle respiration to glycolysis energy use during hypoxic or low oxygen conditions.
  • the C60 fullerene glutathione adenosine triphosphate molecule is also represented in electric circuit format such that the capacitance 81b represents core fullerene 81a that can store electrons as negative charges or hydrogen protons 85a as positive charge 85b.
  • Covalent bonds with glutathione 83a are resistive in nature and are represented as resistance 83b.
  • Covalent bonds with adenosine triphosphate pendant functional group 89a are resistive in nature and are represented as resistance 89b having negative charge.
  • FIG. 9 illustrates a C70 fullerene dimerized glutathione adenosine diphosphate 90.
  • the pendant functional group of dimerized glutathione (GSSH) 95a is comprised of two glutathione molecules 92a that have been oxidized to each other by the bridging sulfur to sulfur bond 93a and represents one of many possible metabolites of the present invention.
  • the functional group of adenosine diphosphate (ADP) 97a is pendant from the core carbon cage molecule of C70 carbon fullerene 91a.
  • the carbon fullerene of molecular structure 90 may alternatively use a C60 fullerene as the core carbon cage molecule.
  • a positive charge on glutathione 95a can arise from the acquisition of a hydrogen proton onto the primary amine functional group.
  • a multiplicity of negative charge can arise at the adenosine phosphate groups 97a.
  • Both adenosine phosphate group 97a and glutathione 95a are localized charges that are far away from, and does not influence, the delocalized charge stored at the core fullerene 91a.
  • This unique feature overcomes past limitations using homogeneous exohederal doping or functionalization with charge transfer complexes that have been unable to achieve reproducible and reversible fullerene anions and cations, because the appearance of localized charges and the orientation of these localized charges serve to stabilize and insulate the core fullerene molecule 91a, thereby providing the ability of molecule 91a to be more stable in anionic or cationic charge storage under biological conditions.
  • Charge storage by fullerene molecule 91b is represented by the schematic symbol of a capacitance 92b.
  • Positive charge on GSSH 95a is represented by charge 95b, where the glutathione functional group is represented by resistance 92b.
  • the wire to capacitance 9 lb represents the covalent bond between functional group GSSH 92b and capacitance 91b.
  • Negative charge on ADP 97a is represented by 97b, where the adenosine diphosphate functional group is represented by resistance 93b.
  • the wire 93b to capacitance 91b represents the covalent bond between functional group ADP 97a and the core fullerene 91a.
  • FIG. 10 illustrates a phospho-ribose metabolite of C60 fullerene glutathione adenosine diphosphate 1000.
  • Functional group of glutathione (GSH) 1030a is pendant from the core molecule of C60 fullerene 1010a.
  • a second functional group, adenosine diphosphate 1020a has been metabolized during the cellular respiration cycle to append one phosphate group 1050a to a ribose, and represents one of many possible metabolites of the present invention that still maintains the utility of the composition of the present invention.
  • the carbon fullerene 1010a may alternatively substitute a C70 fullerene as the core carbon cage molecule in this structure without deviating from the utility and function of the composition of the present invention.
  • the fullerene glutathione adenosine phosphate molecule is schematically represented for the purpose of introducing a simplified fullerene with generic features having two distal ends 1090.
  • End 1030b corresponds with glutathione group 1030a
  • the core fullerene molecule is represented by 1010b corresponding to a fullerene, which may be either a C60 or a C70 core molecule
  • the adenosine diphosphate or related metabolite 1020a is provided with at least one negative charge, that corresponds with 1020b.
  • FIG. 11 illustrates an electric schematic diagram used to clarify the equivalent molecular device physics of the molecular composition of the present invention when utilized in an electric field between cell organelles 1100.
  • Organelle membrane 1110 is supplied with a net negative charge
  • organelle membrane 1190 is supplied by a net positive charge. These differences in potential are generally understood to function as control signals for internal cell processes.
  • a composition of the present invention operates to modify cell signal voltage as follows.
  • the positive charge on membrane 1190 may arise from a histone acetyltransferase as found in a cell nucleus in chromatin, or by means of some redox reaction associated with a mitochondrion represented by the symbol for battery B.
  • the negative charge on membrane 1110 may arise from the phosphate bridges associated with proximal deoxyribonucleic acid loops in the cell nucleus, or the release of a source of electrons which can arise because of some redox reaction associated with a biological process being contained by membrane 1110 such as by a cell membrane.
  • Capacitance 1150 represents the charge storage ability of the core fullerene molecule
  • resistance 1170 represents the adenosine phosphate resistance wired to capacitance 1150 by means of a covalent chemical bond
  • resistance 1130 represents the glutathione molecule wired to capacitance 1150 by means of a covalent chemical bond.
  • Positive charge 1120 can be expressed on the glutathione molecule represented by resistance 1130.
  • Positive charge 1120 can reside on the sulfur atom of glutathione equivalent 1130 provided that one electron has been removed from the sulfur atom to leave an exposed proton of plus one charge.
  • Negative charge 1180 can be expressed on the adenosine phosphate molecule represented by resistance 1170. Depending on the number of oxygen groups having an unpaired oxygen atom with no pendant hydrogen, negative charge 1180 represents a multiplicity of negative charges residing on oxygen atoms. Both negative charge 1180 and positive charge 1120 may have charge neutrality, in which case the number of charges can equal zero at negative charge 1180 or at positive charge 1120.
  • the case of non-zero charges on either 1180 or 1120 may be necessary and sufficient to orient the glutathione fullerene adenosine phosphate molecule represented by resistance 1130, capacitance 1150, and resistance 1170 with respect to the opposing charges on proximal abutting membranes 1110, 1190.
  • the electric field represented by “E” is a vector pointing in the direction indicated by the two large white arrows and represents the origin at positively charged membrane 1190 and a destination at negatively charged membrane 1110.
  • Fullerene core molecule 1150 may store as many as about six electrons and as many as about five protons in the configuration expressed by resistance 1130, capacitance 1150, and resistance 1170. If for some biological process of catabolism, the adenosine phosphate adduct 1170 becomes removed, then the exposed fullerene 1150 illustrated by the structure of FIG. 5 can still act as a capacitance to store positive or negative charge.
  • the glutathione adducts 1130 becomes removed, then the exposed fullerene 1150 illustrated by the structure of FIG. 4 can still act as a capacitance to store positive or negative charge.
  • the presence of at least one of resistance 1130, 1170 assures a preferred orientation of the composition of the present invention with respect to the electric field and at least one proximal and charged region 1110 or 1190.
  • FIG. 12 illustrates the influence of charge coupled REDOX enabled by fullerene glutathione adenosine phosphates 1200.
  • Mitochondrial oxidative phosphorylation includes the process of electron transfer through the mitochondrial respiratory chain, trans-inner mitochondrial membrane ATPase proton pump, and generates the mitochondrial membrane potential, arriving at the final ATP generation.
  • the mitochondria produce energy in the form of ATP by oxidizing carbohydrates, and by the release of hydrogen from fatty acids.
  • Electrons derived from NADH 1280 are passed sequentially through the electron transfer chain (ETC) complexes 1240, 1245 and the released energy is used to pump protons into the mitochondria intermembrane space 1250 from outside of the region bounded by membrane 1290 to create a mitochondrial membrane potential, or voltage, which is coupled to ATP synthesis.
  • ETC electron transfer chain
  • ROS 1230 reactive oxygen species
  • ROS 1230 can be quenched by proximal fullerene glutathione adenosine phosphates 1210, 1212 by attracting and recombining multiple ROS free radicals.
  • This free radical quenching process takes place conventionally in well-known ambient cellular respiration reactions, but it is especially and highly catalyzed by the charge attraction of the central fullerene core molecule of each representative fullerene glutathione adenosine phosphate 1210, 1212.
  • Additional free radical quenching is provided by the glutathione group on one side and adenosine phosphates on the other side of the fullerene adduct 1210 or 1212, while simultaneously and unconventionally providing a novel delocalized site on to which to proximally store as many as six (6) negative electron charges that were leaked from the ETC complexes 1240, 1245.
  • fullerene glutathione adenosine phosphate 1212 allows it to phosphorylate at the allosteric site of any available sirtuin enzyme (a protein catalyst, of which there are seven representative types) 1260 which allows such a sirtuin enzyme 1260 to change its shape or conformation and therefore tune its chemical reactivity in a way that is illustrated for SIRT1 in FIG. 15. Any of a multiplicity of exiting phosphorylated sirtuin enzyme molecules 1260 may then leave mitochondria membrane 1290 to enter a cell nucleus, where these may then operate to alter the function or chemical expression of histones, such as by performing a deacetylation reaction, as illustrated in FIG. 16. [0088] FIG.
  • FIG. 13 illustrates organelles of mitochondrial associated membranes (MAM) 1300, where the distance between proximal abutting mitochondria 1301, 1302, 1303, 1304, 1305 and organelle structures is about 90 nanometers during the cellular process of catabolism or anabolism.
  • Expanded inset 1321 contains the stick-figure symbol representing fullerene adenosine phosphate glutathione or any of their metabolites as non-limiting embodiments of the composition of the present invention.
  • One or more of such molecules are interposed in the gap region between mitochondrion 1301 and the endoplasmic reticulum (ER) 1350 structure to which it proximally abuts.
  • the illustrated portion of neural or somatic cell 1390 includes the endoplasmic reticulum 1320, 1350 and those membranes 1360, 1370 associated with the cell nucleus, the Golgi complex 1310, lysosome 1330, 1380 which are organelles that can at any time come into similar proximal abutting contact with one or more mitochondria such as 1301, 1302, 1303, 1304, 1305 for the purpose of exchanging signaling molecules and performing exchange of energy by hydrogen and electron transfer which enables cellular respiration.
  • composition of the present invention is to expedite such signaling and therefore regulate mitophagy, restore calcium ion homeostasis, reduce mitochondrial oxidative stress, improve efficiency of the generation of adenosine triphosphate (ATP) by the electron transfer cycle (ETC), and reduce mitochondrial nitric oxide synthase expression by acting as a nanoparticulate enzyme having the functional role of facilitating and therefore helping to regulate these natural processes.
  • ETC electron transfer cycle
  • adenosine phosphate glutathione fullerenes One purpose of the adenosine phosphate glutathione fullerenes is to provide charged and insulative neuroprotection between organelles to scavenge free radicals and to limit damage from ineffective catabolism and anabolism, while providing a reservoir of stored electrons at the core C60 or C70 fullerene molecule. This storage of charges helps to regulate charge distribution and thereby improve the state of homeostasis of mitochondrial membrane polarization. Defects of lysosomal catabolism in lysosomes 1330, 1380 may influence the function and structural characteristics of the MAMs both in autism and in aging associated neuropathy.
  • the present invention functions to expedite storage of electrons and protons to overcome these defects by the interposition of the composition of the present invention between the mitochondrion and the endoplasmic reticulum (ER) as well as between the mitochondrion and other cellular organelles such as organelles 1310, 1320, 1350, 1360.
  • This interposition will better orient, reinforce, and distribute the existing natural lipids of cellular MAMs.
  • every MAM between 1301, 1302, 1303, 1304, 1305 may incorporate or interpose fullerene GSH-ATP, or fullerene GSH- ADP, or fullerene GSH-AMP, or fullerene GSH-cAMP at a multiplicity of MAMs in any combination without limit, where the fullerene adduct serves to transfer hydrogen protons and also in the transfer of electrons as needed for catabolism and anabolism, as well as to promote mitochondrial homeostasis.
  • FIG. 14 illustrates neuronal cell 1400.
  • Dendrite 1426 is illustrated by circled expanded inset view 1421.
  • the expanded view illustrates endoplasmic reticulum (ER) 1424 extending throughout the cell cytosol 1445 where it is bounded by the cell plasma membrane (PM) 1440.
  • ER 1424 is in physical proximity with the plasma membrane (PM) 1420, 1440 at a multiplicity of neuronal dendrites 1420, 1426, 1428.
  • ER-PM contacts expedite lipid transfer, Ca2+ ion homeostasis, and synaptic plasticity.
  • Vesicles originate at multiple Golgi apparatus 1430, 1432, 1434, 1436 to transport lipids, calcium ions, hydrogen protons, electrons, and cellular signaling molecules (not shown) to the plasma membrane 1420, 1440.
  • Golgi apparatus 1430, 1432, 1434, 1436 to transport lipids, calcium ions, hydrogen protons, electrons, and cellular signaling molecules (not shown) to the plasma membrane 1420, 1440.
  • effective transport of critical cellular materials from the cell nucleus 1460 and the Golgi apparatus 1430, 1432, 1434, 1436 via the ER 1424 to the plasma membrane 1420, 1440 can become compromised.
  • composition embodiment of the present invention fullerene glutathione adenosine phosphates 1422, inset expanded view 1410, can facilitate the transport of such cellular materials including electrons and protons between the ER 1424 and the plasma membrane 1420, 1440 to restore and remediate functional neuronal processes in neurons.
  • FIG. 15 illustrates an allosteric portion of enzyme sirtuin-1, 1500.
  • the allosteric region 1525 is a location on a section of the molecule of enzyme sirtuin-1 where amino acid locations 517 to 528 are numbered by the reference line with tick marks bracketed by 1510.
  • Histone deacetylase type III sirtuin-1 location 522 is a tyrosine amino acid 1525 which has undergone phosphorylation, as indicated by phosphorylation symbol 1520.
  • Such phosphorylation alters the conformation or shape of sirtuin-1 to enable a significant improvement in the catalytic deacetylase function of this enzyme.
  • Phosphorylation by inorganic phosphate group 1520 is only one type of a phosphate adduct that may bind with tyrosine at location 522 on sirtuin-1.
  • Fullerene adenosine phosphate glutathione 1540 is illustrated to have phosphorylated tyrosine at location 522 of a sirtuin-1 at 1552, wherein this allosteric site phosphorylation is accompanied by a multiplicity of hydrogen bonds 1541, 1542, 1543 that enable far greater conformational change in sirtuin-1 shown by the bent conformation of regions 1550, 1555 than is possible by native cellular phosphates.
  • This action serves to stabilize the enhancement of deacetylase enzymatic activity, which then proceeds through a cascade of signaling molecules to deacetylate chromatin histones at the cell nucleus, illustrated in FIG. 16.
  • the utility of the artificial phosphorylation molecule fullerene adenosine phosphate glutathione is designed to improve histone deacetylase enzyme catalytic function, especially in the sirtuins as indicated herein.
  • FIG. 16 illustrates the direction of increased DNA packing and binding on chromatin 1600.
  • the direction of cooperative shrinkage facilitated by mutual molecular associations is illustrated by multiple black arrows pointed to central histones 1620, around which is wrapped the double stranded helix of deoxyribonucleic acid (DNA) 1610 having multiple silenced genes on treatment with multiple fullerene glutathione adenosine phosphates (FGAP) represented by the enlarged inset view of symbol 1640.
  • DNA deoxyribonucleic acid
  • FGAP fullerene glutathione adenosine phosphates
  • Multiple FGAP 1640 can have both positive and negative charged ends, where the positive end is attracted to form counter-ionic bonds with the negatively charged phosphate bridges of the central ladder regions of DNA 1610, and the negative end of FGAP 1640 can be attracted to the exposed amine functional groups of deacetylated histones in the chromatin molecular spool 1620 located within the cell nucleus. It is noted that chromatin spool 1620 has become deacetylated by histone type III deacetylases or sirtuins where a section of this class of enzyme can be illustrated in FIG. 15.
  • Multiple hydrogen bonds are formed between abutting structures in DNA 1610 and the deacetylated positively charged chromatin histones 1620 by the interposition of a multiplicity of FGAP 1640 to stabilize the silencing of a multiplicity of genes from transcriptional expression within and among DNA 1610, thereby collectively stabilizing the genome of the affected individual.
  • FIG. 17 illustrates a flow chart of fullerene glutathione adenosine phosphates synthesis S1700.
  • step S1710 a sufficient amount of carbon fullerenes, being either the C60 or the C70 type, is combined with about a molar ratio of reduced glutathione (GSH).
  • step S1720 mill, or perform any suitable high shearing process to, this mixture for about 15 minutes, taking care not to let this mixture exceed about 55°C to avoid glutathione oxidation or decomposition.
  • step S1730 add about two or more molar ratios of adenosine phosphates to this mixture by fullerene basis weight.
  • the preferred additive is adenosine tri-phosphate (ATP), however the local price and availability of other adenosine phosphates is allowed, because the cellular metabolism will facilitate the metabolic interconversion of adenosine phosphates by the addition or loss of a phosphate group, as illustrated in FIG. 3.
  • step S1740 perform a high shear mixing or milling process to the combined mixture for about 15 minutes, taking care not to let this mixture exceed about 55°C to avoid functional group decomposition.
  • step S1750 transfer the chemical reaction product of fullerene glutathione adenosine phosphates to dissolve into water containing at least about 10% glycerol to create an oral solution, or a topical solution that can be applied to the skin.
  • step S1760 transfer the chemical reaction product of fullerene glutathione adenosine phosphates to dissolve into a solution of 70% glycerol and 30% propylene glycol for e-vapor fluid dispensing.
  • a solution of 70% glycerol and 30% propylene glycol for e-vapor fluid dispensing.
  • FIG. 18 illustrates a flow chart of fullerene glutathione phosphates synthesis S 1800.
  • a sufficient amount of carbon fullerenes being either the C60 or the C70 type, can be combined with about a molar ratio of reduced glutathione (GSH).
  • GSH reduced glutathione
  • step SI 820 mill or perform any suitable high shearing process to this mixture for about 15 minutes, taking care not to let this mixture exceed about 55 °C to avoid significant glutathione group oxidation or decomposition.
  • step S183O add about two or more molar ratios of sodium phosphates to this mixture by fullerene basis weight.
  • step S1840 perform a high shear mixing or milling process to the combined mixture for about 15 minutes, taking care not to let this mixture exceed about 55°C to avoid functional group decomposition.
  • step S1850 transfer the chemical reaction product of fullerene glutathione phosphates to dissolve into water containing at least about 10% glycerol to create an oral solution, or a topical solution that can be applied to the skin.
  • step S1860 transfer the chemical reaction product of fullerene glutathione phosphates to dissolve into a solution of about 70% glycerol and about 30% propylene glycol for e-vapor fluid dispensing.
  • a solution of about 70% glycerol and about 30% propylene glycol for e-vapor fluid dispensing.
  • FIG. 19 illustrates exemplary methods of use of an embodiment 1900 of a composition of the present invention.
  • Exemplary adenosine phosphate glutathione fullerenes 1910, 1912, 1914 are charged into a solution for electronic inhalation at the electronic vapor generating device 1920.
  • Large white arrow 1960a indicates fullerenes 1910, 1912, 1914 as being aspirated or breathed in by patient or user 1950 into the airways and lungs.
  • large black downward arrow 1960b serves to indicate the oral administration of the nanoparticulate composition of the present invention as an ingestible solution as it travels in the direction of the esophagus to the region of the stomach and into the digestive system.
  • a third method of use protection from damaging free radicals arising from the energetic ultra-violet rays of solar irradiation 1970, is conferred by the application of any of the phosphate nanoparticulate variations or metabolites of the present invention when used as a topical skin protective film shown by iconic symbol within a starburst pattern 1955 on the forehead skin surface.
  • symbol 1955 can be separately understood to represent the cognitive effect of a composition of the present invention on the brain resulting from the administration of the adenosine containing phosphates pharmaceutical composition of FIG. 8 or its metabolites as one method or embodiment of use.
  • Eye exposure to the composition of the present invention is enabled by the physical application of an oral aqueous solution of about 10% glycerol to be used as eyedrops to treat the onset of cataracts of the eye 1959, using the REDOX reaction as electrically enabled by the presence of fullerene storage and donation of both protons and electrons in a pharmaceutical formulation.
  • the action of sunlight to enable the restorative function to the tissues of the eye is fundamentally equivalent to the topical REDOX described at starburst pattern 1955 for the restoration of skin cells.
  • any of the fullerene glutathione adenosine phosphate variations or their metabolites, with or without stored protons, or any of the fullerene glutathione adenosine phosphate variations or their metabolites, fullerene glutathione phosphates, or mixtures thereof may comprise the methods of use of the nanoparticulate composition embodiments of the present invention, as an electronic vapor inhalant, or as a topical cream, or as an orally ingested solution, or as an eyedrop medication.
  • the redox utility and biological electrochemical functions operate with substantially the same cellular effects and metabolic design intent in these applications.
  • either C60 or C70 may be used as the core capacitance molecule to expedite proton or electron charge storage and REDOX reaction among these structures, when aspirated in the form of a heated aerosol and used in accordance with the inhalant method embodiments of the present invention.
  • FIG. 20 illustrates a normalized data graph of typical cytochrome c oxidase concentration, where this protein is also known as ‘Complex IV’ or COX, 2000.
  • COX is associated with bioenergetics effectiveness because it is the last enzyme in the respiratory electron transport chain (ETC) of mitochondria in cells.
  • ETC respiratory electron transport chain
  • COX is located within the cell membrane, where it functions to convert molecular oxygen to two molecules of water by the transfer of 4 electrons combined with four protons from the cell cytosol or inner aqueous phase to make two water molecules.
  • Neurons rely on oxidative phosphorylation by COX for energy and to produce their electrical potentials.
  • Dotted line 2010 represents the percentage decline of COX in human beings from birth over the span of a typical human lifetime.
  • the objective of the fullerene glutathione adenosine phosphates of the present invention is to restore as much as possible of the bioenergetic capability of a newborn to the adult human being using a cascade of signaling molecules via enzyme activation, as indicated by the upward direction of the large black arrow pointing toward dashed line 2020.
  • FIG. 21 illustrates negative mode MALDI-TOF mass spectrograph data of adenosine triphosphate (ATP) derivatized fullerene (C60), where the largest molecular peak at 720 mass-to-charge ratio represents the core molecule of C60 after all of the functional groups have been ablated away.
  • the grouping of peaks at mass-to-charge ratio of 1414 represents the molecular fragments associated with one adenosine triphosphate group functionalized to one fullerene molecule as the primary reaction product.
  • the grouping of peaks at mass-to-charge ratio of 2132 represents the minor amounts of molecular fragments associated with two adenosine triphosphate groups functionalized to one fullerene molecule.
  • the grouping of peaks at mass-to-charge ratio of 2823 represents the trace amounts of molecular fragments associated with three adenosine triphosphate groups functionalized to one fullerene molecule.
  • FIG. 22 illustrates experimental data for negative mode MAEDI-TOF mass spectrograph, of glutathione (GSH) derivatized fullerene (C60), where the largest molecular peak at 720 mass-to-charge ratio represents the core molecule of C60 after all of the functional groups have been ablated away.
  • GSH glutathione
  • C60 fullerene having some residual spallation fragment typically associated with a glutathione remnant is observed at mass-to-charge of 770.
  • the grouping of peaks at mass-to-charge ratio of 1415 represents the molecular fragments associated with one glutathione group functionalized to one fullerene molecule as the primary reaction product.
  • the grouping of peaks at mass-to-charge ratio of 2060 represents the minor amounts of molecular fragments associated with two glutathione groups functionalized to one fullerene molecule.
  • the grouping of peaks at mass-to-charge ratio of 2802 represents the trace amounts of molecular fragments associated with three glutathione groups functionalized to one fullerene molecule.
  • FIG. 23 illustrates experimental mass spectrograph data for negative mode MALDI- TOF glutathione and adenosine triphosphate derivatized fullerene (C70), where the largest molecular peak at 840 mass-to-charge ratio represents the core molecule of C70 after all of the functional groups have been ablated away.
  • the trace peak at 985 mass-to-charge ratio indicates a partial glutathione fragment on the core fullerene molecule peak.
  • the grouping of peaks at mass- to-charge ratio of 1658 represents the molecular fragments associated with one adenosine triphosphate group functionalized to one fullerene molecule, or one glutathione group functionalized to one fullerene, with significant overlap of spallation products for each functional moiety.
  • the grouping of peaks at mass-to-charge ratio of 2449 represents the molecular fragments associated with one glutathione functional group and one adenosine triphosphate group where both functional groups chemically adduct to one fullerene molecule.
  • the grouping of peaks at mass-to- charge ratio of 3291 represents the trace amounts of molecular fragments associated with three functional groups selected from one or two adenosine triphosphate groups with either two or one functionalized glutathione group, respectively, as reacted to one C70 fullerene molecule.
  • FIG. 24 illustrates experimental mass spectrograph data for negative mode MALDI- TOF glutathione and adenosine triphosphate derivatized fullerene (C60), where the largest molecular peak at 720 mass-to-charge ratio represents the core molecule of C60 after all of the functional groups have been ablated away.
  • the trace peak at 770 mass-to-charge ratio indicates a partial glutathione fragment on the core fullerene molecule peak.
  • the grouping of peaks at mass- to-charge ratio of 1414 represents the molecular fragments associated with one adenosine triphosphate group functionalized to one fullerene molecule, or one glutathione group functionalized to one fullerene, with significant overlap of spallation products for each functional moiety.
  • the grouping of peaks at mass-to-charge ratio of 2012 represents the molecular fragments associated with one glutathione functional group and one adenosine triphosphate group where both functional groups chemically adduct to one fullerene molecule.
  • the grouping of peaks at mass-to- charge ratio of 2658 represents the trace amounts of molecular fragments associated with three functional groups selected from one or two adenosine triphosphate groups with either two or one functionalized glutathione group, respectively, as reacted to one C60 fullerene molecule.
  • FIG. 25 illustrates experimental mass spectrograph data for negative mode MALDI- TOF phosphate derivatized fullerene (C60), as the reaction product of trisodium phosphate with C60 fullerene.
  • the largest molecular peak at 719 atomic mass-to-charge ratio represents the core fullerene molecule cage structure.
  • the cluster of peaks at 1390 represents five (5) functional groups of disodium phosphate at mass 134 each, where the third sodium ion of each functional group has been lost in the process of bonding inorganic sodium phosphate to the core fullerene molecule in the synthesis process, and one extra sodium atom has also been removed.
  • the cluster of peaks at 1989 represents 10 disodium phosphate functional groups added to the fullerene C60 with a loss of two sodium atoms.
  • the cluster of peaks at 2637 represents 15 disodium phosphate functional groups added to the fullerene C60 molecule with a loss of three sodium ions.
  • the cluster of peaks at about 3307 is a trace quantity of 20 disodium phosphate functional groups with a loss of three sodium ions.
  • the C60 fullerene disodium phosphates mixture is determined in this analysis to indicate the molecular structure of phosphate groups were added as clusters of 5, to obtain C60 fullerene (NaPO4) of 5 (five), 10 (ten), 15 (fifteen), and 20 (twenty) phosphate groups.

Abstract

L'invention concerne une composition contenant un fullerène avec une structure de cage, un premier groupe fonctionnel et un second groupe fonctionnel. Le premier groupe fonctionnel comprend du glutathion qui peut accumuler une charge négative. Le second groupe fonctionnel comprend du phosphate, le phosphore présentant un état d'oxydation de 5. Le premier et le second groupe fonctionnel subissent indépendamment une réactivité biochimique réversible d'oxydoréduction. Le second groupe fonctionnel phosphate comprend un adduit d'un groupe fonctionnel adénosine. Un second groupe fonctionnel phosphate comprend un adduit d'un groupe fonctionnel phosphate d'adénosine, le phosphore présentant un état d'oxydation de 5. Certains fullerènes comprennent le fullerène C60 ou C70. Certaines compositions comprennent un métabolite redox des phosphates d'adénosine de glutathion-fullerène, comme dans le cas où le premier groupe fonctionnel comprend un glutathion dimère ou oxydé. La composition ou ses métabolites redox peuvent stocker jusqu'à six (6) électrons, et jusqu'à cinq (5) protons dans n'importe quelle combinaison. L'invention concerne également une composition topique et une composition pharmaceutique.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022187061A1 (fr) * 2021-03-01 2022-09-09 Peter Butzloff Traitement de la maladie d'alzheimer et méthodes
WO2023107144A1 (fr) * 2021-12-10 2023-06-15 Peter Butzloff Oxyde nitrique c60-gsh-atp et son utilisation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190053991A1 (en) * 2016-02-04 2019-02-21 The Cleveland Clinic Foundation Polyhydroxy fullerene sunscreen active agents and compositions
WO2019117986A1 (fr) * 2017-12-14 2019-06-20 Butzloff Peter Robert Compositions de nanoparticules anisotropes et procédés

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190053991A1 (en) * 2016-02-04 2019-02-21 The Cleveland Clinic Foundation Polyhydroxy fullerene sunscreen active agents and compositions
WO2019117986A1 (fr) * 2017-12-14 2019-06-20 Butzloff Peter Robert Compositions de nanoparticules anisotropes et procédés

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022187061A1 (fr) * 2021-03-01 2022-09-09 Peter Butzloff Traitement de la maladie d'alzheimer et méthodes
WO2023107144A1 (fr) * 2021-12-10 2023-06-15 Peter Butzloff Oxyde nitrique c60-gsh-atp et son utilisation

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