WO2007115131A2 - Combinaison de glutathion réduit liposomique et de 1-arginine, avec un ou plusieurs autres ingrédients, pouvant être administrée par plusieurs voies, permettant d'inverser et de prévenir l'obésité et de stimuler la biogenèse mitochondriale - Google Patents

Combinaison de glutathion réduit liposomique et de 1-arginine, avec un ou plusieurs autres ingrédients, pouvant être administrée par plusieurs voies, permettant d'inverser et de prévenir l'obésité et de stimuler la biogenèse mitochondriale Download PDF

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WO2007115131A2
WO2007115131A2 PCT/US2007/065552 US2007065552W WO2007115131A2 WO 2007115131 A2 WO2007115131 A2 WO 2007115131A2 US 2007065552 W US2007065552 W US 2007065552W WO 2007115131 A2 WO2007115131 A2 WO 2007115131A2
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arginine
glutathione
liposomal formulation
composition according
liposomal
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WO2007115131A3 (fr
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F. Timothy Guilford
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Priority claimed from US11/277,845 external-priority patent/US20070077258A1/en
Priority claimed from PCT/US2006/060271 external-priority patent/WO2007053810A2/fr
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Priority to US13/368,689 priority patent/US20120219616A1/en
Priority to US13/396,841 priority patent/US8252325B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • LIPOSOMAL REDUCED GLUTATHIONE AND 1-ARGININE INCLUDING WITH OTHER INGREDIENT(S), CAPABLE OF MULTIPATH ADMINISTRATION FOR REVERSAL AND PREVENTION OF OBESITY AND FOR MITOCHONDRIAL BIOGENESIS
  • This invention proposes the use of glutathione in the reduced state in a liposome alone or in combination with 1-arginine, including in liposomal form, for treatment of inefficiencies in energy metabolism in the mitochondria leading to weight gain.
  • the combination of liposomal glutathione and 1-arginine can be used to manipulate the level of NO to stimulate mitochondrial biogenesis. This method is also useful in the management of some disease states related to mitochondrial dysfunctions as well infectious diseases.
  • the invention enables management of, and the associated method of management of, mammalian disease related to decreased energy production in the mitochondria, the powerhouse of the cell.
  • the invention uses the surprising finding that ingesting the combination of liposomal reduced glutathione and 1-arginine results in weight loss in individuals using the combination for management of high blood pressure.
  • the mechanism of weight loss appears to be related to inefficient production of energy by the respiratory transport chain of mitochondria, the function of which are influenced positively by the availability of antioxidant nitric oxide in a non-oxidized environment.
  • This invention enables weight loss in individuals who's inability to lose weight is related to inefficiency of the biochemical pathways facilitating mitochondrial function and energy production.
  • the pathways related to inability to lose weight are also related to the phenomenon of the inability to metabolize fats, which results in insulin resistance and diabetes.
  • the invention is useful for the management of the metabolic syndrome.
  • the metabolic syndrome is actually a group of metabolic factors associated with an increased risk of vascular disease problems.
  • the invention is also useful for the resolution of fatigue that accompanies both weight gain and illnesses.
  • the biochemical pathways stimulated by this invention can have a beneficial effect in individuals suffering from a variety of infectious diseases.
  • liposomal glutathione with 1-arginine will maintain function of the energy producing mitochondrial system of the body at a rate that will allow fat metabolism to occur and for weight to be lost.
  • the continuous daily ingestion of the invention will provide the combination of adequate antioxidant protection and NO formation that is needed for the mitochondria to utilize fats efficiently and to allow the individual to lose weight.
  • the increase in mitochondrial function enhanced by the mitochondrial biogenesis stimulated by this product will also improve lipid metabolism and diminish the likelihood of developing type 2 diabetes.
  • the continuous daily ingestion of the current invention is proposed as a treatment for those individuals at risk of type 2 diabetes or those who are considered "pre-diabetic" by virtue of increased weight or family history or who are displaying the factors associated with "metabolic syndrome".
  • BACKGROUND The expression of the enzyme endothelial Nitric Oxide synthase or eNOS that produces nitric oxide (NO) appear to be a critical factor in a number of cell functions ranging from arterial relaxation to an increase in the number and function of mitochondria, the sites of energy production in the cell. Factors that diminish the function of eNOS can have a significant impact on the function of cells and thus, the whole system. Human disease dysfunctions that are associated with diminished function of NO include hypertension and atherosclerosis.
  • TNF- ⁇ Tumor Necrosis Factor family and particularly Tumor Necrosis Factor-alpha (TNF- ⁇ ).
  • TNF- ⁇ regulates many biologic functions in the body ranging from organ development to immune homeostasis and disease 3 . Regulation of TNF- ⁇ is important because of the diverse impacts that it can have on different tissues. While on the one hand, TNF- ⁇ is essential for the host defense against infection, while on the other hand, TNF- ⁇ may have detrimental effects on tissues if not regulated properly .
  • TNF- ⁇ is involved with the pathogenesis of multiple diseases including inflammation, obesity and insulin resistance 4 5 ' 6 .
  • a direct correlation between the genetic expression of TNF- ⁇ and insulin resistance has been observed 7 ' 8 .
  • TNF- ⁇ has been found to play a significant role in down-regulating the expression of eNOS, which then leads to a decrease in mitochondrial biogenesis and subsequent obesity 9 .
  • TNF- ⁇ factor is an inflammatory cytokine that causes damage by generation of oxidative stress .
  • TNF- ⁇ has been shown to sensitize cells and mitochondria to injury from peroxide (H 2 O 2 ).
  • Peroxide is an oxidant produced by various cells responding to viral infection including macrophage polymorphonuclear cells, natural killer (NK) cells and T- killer cells. Peroxide is a natural product of mitochondrial respiration but sensitization to H 2 O 2 would be undesirable because of its biological destabilization. During aging there is an increased production OfH 2 O 2 in the liver mitochondria of many animal cells 10 . H 2 O 2 is a product of superoxide radical dismutationthat occurs in the mitochondria and is possibly related to damage of the mitochondria 10 .
  • inflammatory related cells such as macrophages are accumulated in patches in the expanding adipose tissue ⁇ , 12 ' 13 with an increased release of inflammatory mediators, including TNF- ⁇ and iNOS 10 , u .
  • upregulation of iNOS which is induced in inflammatory conditions
  • eNOS 14 downregulation of eNOS 14 .
  • TNF- ⁇ increases iNOS expression in different cells and tissues including fat and muscle 15 .
  • TNF- ⁇ can positively autoregulate its own biosynthesis in adipose tissue, contributing to the maintenance of elevated TNF- ⁇ in obesity 16 .
  • TNF- ⁇ systemic inflammatory marker C-reactive protein
  • CRP systemic inflammatory marker C-reactive protein
  • a variety of stimuli can raise the level of TNF- ⁇ systemically or in specific tissues. These stimuli include bacterial or fungal exposure 9 , as well as hyperglycemia 18 .
  • Environmental factors such as toxins 9 including mercury cadmium, which are known to target mitochondria directly 19 and lead, which lead will increase the amount of TNF- ⁇ that is released by subsequent exposure to lipopolysaccharide (LPS) 20 .
  • LPS lipopolysaccharide
  • TNF- ⁇ even in low concentrations increases the permeability of cells to damage from H 2 O 2 peroxidation 21 .
  • the electron transport chain of mitochondria is the primary producer of the superoxide anion, which is precursor to other highly reactive species such as hydrogen peroxide and the hydroxyl radical 22 23 .
  • Glutathione (GSH) in mitochondria is the only defense available to metabolize hydrogen peroxide 24 .
  • the presence of TNF- ⁇ accelerates the membrane damage from peroxyl radicals and increases the demand and need for protection by glutathione. The amount of reduced glutathione contained in cells has been shown to be decreased in a concentration-dependent fashion upon exposure to TNF- ⁇ 21 .
  • TNF- ⁇ decreases the availability of reduced glutathione, resulting in an increase in local oxidation stress.
  • the formation of the oxidized form of glutathione, GSSG can accumulate when its rate of formation exceeds the cells ability to convert it back to reduced glutathione, GSH.
  • GSH reduced glutathione
  • TNF- ⁇ is overproduced in adipose and muscle tissues of obese individuals 7 8 ⁇ 12 and plays a significant role in the development of obesity by diminishing eNOS expression and thus, decreasing NO production 9 .
  • the presence of TNF- ⁇ markedly decreases both eNOS expression and mitochondrial biogenesis in cultured fat and muscle cells 21 .
  • the present invention has the capacity to reverse this effect by supply reduced glutathione, the critical component for neutralizing the effect of TNF- ⁇ and at the same time supplies also 1-arginine, which is needed to stimulate the availability of NO.
  • glutathione the critical component for neutralizing the effect of TNF- ⁇
  • Supplying arginine alone does not result in an efficient response as the presence of oxidative stress increases the likelihood that peroxynitrites will be formed from the production of nitric oxide in this situation.
  • the combination in the present material provides an efficient mechanism for reversing the effect of TNF- ⁇ on fat and muscle cells.
  • the liposomal reduced glutathione and arginine can be administered at the same time as liposomal glutathione plus oral arginine in capsules as outlined in Example 1 , or as a combination of reduced glutathione and arginine in a liquid drink containing reduced glutathione and arginine in liposomes as in Example 2 or a gel cap containing liposomes with glutathione and arginine as in Example 3.
  • the use of the combination of liposomal reduced glutathione and L-arginine to induce loss of weight has not previously been reported.
  • GSNO vasodilating biochemical S- nitrosylated glutathione
  • GSNO oxidative phosphorylation pathway
  • a study has demonstrates that GSNO reversibly inhibits oxygen utilization by attaching to cytochrome c at the end of the respiratory chain 26 .
  • mitochondria were isolated from rat gastrocnemius muscle and their oxygen utilization measured in support media using a micro oxygen electrode and polarographic analysis of the metabolism of intact, whole mitochondria. 26 .
  • upregulation of GSNO would interfere with weight loss and inhibit mitochondrial respiration 25 .
  • LDL and HDL contain both the enzyme glutathione peroxidase (GPx) and it specific substrate reduced glutathione.
  • GPx glutathione peroxidase
  • the presence of GPx associated with LDL has not previously been reported.
  • the native lipids as obtained from human subjects contain the mechanism to maintain defense against oxidants and to maintain a non-oxidized state.
  • materials known to cause oxidation are added to this system, there is a brief resistance to oxidation, but when the native glutathione is used up oxLDL is created.
  • the surprising finding that leads to this invention is that the addition of even a small amount, 2 ⁇ g/mL, of the liposomal encapsulated reduced glutathione results in a prolonged stabilization of the lipids against the oxidizers.
  • the addition of 2 ⁇ g/mL Liposomal Glutathione to HDL resulted in prolongation of the lag time from 16 minutes in control HDL (incubated with no additions) up to 92 minutes observed for HDL that was incubated in the presence of Liposomal Glutathione.
  • the inventor concluded that the use of his prior invention upregulates GSNO, but contrary to the Cleeter study, in fact determined that his invention beneficially upregulated the GSNO.
  • BMI Body mass index
  • Obesity BMI of 30 or greater Obesity is also associated a group of risk factors of heart disease that have become known as the metabolic syndrome. These risks factors include • The excessive fat tissue in and around the abdomen which is also known as abdominal obesity • Abnormalities of the lipids in the blood including low HDL cholesterol, high LDL cholesterol and high triglycerides that are associated with the formation of atherosclerotic plaque in artery walls • Elevated blood pressure • Insulin resistance or the inability to utilize glucose properly • Pro-inflammatory states, that is the presence of proteins in the blood indicating inflammation in the body and typified by the elevation of C-reactive protein in the blood.
  • Type 2 diabetes is the most common chronic metabolic disease in the elderly, affecting ⁇ 30 million individuals 65 years of age or older in developed countries 32 .
  • the estimated economic burden of diabetes in the United States is -*$ 100 billion per year, of which a substantial proportion can be attributed to persons with type 2 diabetes in the elderly age group 33 .
  • obesity has reached epidemic proportions in developed countries. While most experts view the cause of obesity to be related to overeating and a sedentary life style, the biochemistry of obesity is pointing to changes in the fundamentals of energy metabolism at the most basic levels, the Krebs cycle and the oxidation of fats 27 , both of which occur in the mitochondria of the cell. It appears that the lack of energy and decreased ATP production drives the appetite in a search for energy sources 27 .
  • aconitase diverts metabolism from energy production to energy storage.
  • the readier is referred to the article by Wlodek 21 for a detailed review of this metabolism.
  • the summary is that an inflammatory response leads to TNF- ⁇ release, stimulation of IL-I and oxidation stress. These factors inhibit the Tri-carboxylic acid cycle (Krebs cycle), lowering energy production and increasing fat synthesis.
  • adipose tissue has been shown to be the target of inflammatory cells and there is a increased release of TNF- ⁇ and IL-I 36 8 . This process sets up a repeating cycle leading to obesity.
  • the present invention is a combination that breaks the pattern of the metabolic cycle leading to obesity.
  • the hydroxyl radical is one of a group of radicals that are formed from reactions with oxygen.
  • the oxygen molecule is a stable diradical that can be represented » 0-0 and is a stable molecule with the hyphen representing a single bond and the "dots" representing electrons available for pairing and bonding.
  • the most familiar radical reaction with oxygen is combustion, or burning. Combustion is comprised of a chain reaction of radicals. In the case of oxygen, after enough energy has been entered into the system, the stable radical » 0-0 is converted to singlet oxygen radicals (O- ).
  • Nitric oxide is produced by the vascular endothelium and is responsible for relaxation of both arteries and bronchial tubes, the airways in the lung.
  • Peroxynitrate is a strong oxidant and contributes to damage of cells, especially in the lining of arteries and airways. Excess (ONOO- ) may be produced when cytokines have increased production of both (NO) and (02- ). At physiological pH peroxynitrate causes direct damage to proteins, and decomposes into toxic products that include nitrogen dioxide and hydroxyl radicals.
  • the list of potential radicals from oxygen and nitric oxide include:
  • ROO Peroxyl Radical
  • RO Alkoxyl Radical
  • Alky radicals can also bond together to form compounds called polymers. Lipoproteins can be considered radicals as they are considered polymers of amino acids with a fatty acid end group. These highly reactive radical species of oxygen are also referred to as reactive oxygen species and abbreviated ROS.
  • the highly reactive radical species of nitric oxide are called reactive nitrogen species (RNS). Both Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important mediators of cell and tissue injury (see figs.), and are major players in the process of aging and apoptosis, a mechanism of cell death.
  • oxygen-derived free radicals - superoxide anion, (02- ), hydroxyl radicals OH- or metabolites such as hydrogen peroxide and hypochlorous acid (HOCl) must be regulated.
  • superoxide anions When superoxide anions are formed, they are removed rapidly by interaction with an enzyme called superoxide dismutase. Removal of hydroxyl radicals require interaction with an antioxidant called glutathione (Wu).
  • glutathione the antioxidant molecule glutathione, which is abbreviated GSH, loses the hydrogen atom to OH- , creating HOH and the radical GS " . 2 OH- + 2GSH ⁇ 2 H 2 O + GSSG
  • GSH is the reduced form of glutathione and GSSG is the oxidized form 41 .
  • Non-ionizing radiation Radiation that has enough energy to move atoms in a molecule around or cause them to vibrate, but not enough to remove electrons, is referred to as "non-ionizing radiation.” Examples of this kind of radiation are sound waves, visible light, and microwaves. Radiation that falls within the “ionizing radiation” range has enough energy to remove tightly bound electrons from atoms, thus creating ions. This is the type of radiation that people usually think of as 'radiation.' We take advantage of its properties to generate electric power, to kill cancer cells, and in many manufacturing processes. Higher frequency ultraviolet radiation begins to have enough energy to break chemical bonds.
  • X-ray and gamma ray radiation which are at the upper end of magnetic radiation, have very high frequency —in the range of 100 billion billion Hertz—and very short wavelengths— 1 million millionth of a meter. Radiation in this range has extremely high energy. It has enough energy to strip off electrons or, in the case of very high-energy radiation, break up the nucleus of atoms. Ionization is the process in which a charged portion of a molecule (usually an electron) is given enough energy to break away from the atom. This process results in the formation of two charged particles or ions: the molecule with a net positive charge, and the free electron with a negative charge. Each ionization releases approximately 33 electron volts (eV) of energy.
  • eV electron volts
  • ionizing radiation deposits a large amount of energy into a small area. In fact, the 33 eV from one ionization is more than enough energy to disrupt the chemical bond between two carbon atoms. All ionizing radiation is capable, directly or indirectly, of removing electrons from most molecules.
  • alpha particles which include two protons and two neutrons
  • beta particles which are essentially electrons
  • gamma rays and x-rays which are pure energy (photons). The majority of radiation injury in cells depends on oxidative stress.
  • Mitochondrial GSH becomes critically important against ROS-mediated damage because it not only functions as a potent antioxidant but is also required for the activities of mitochondrial glutathione peroxidase and mitochondrial phospholipid hydroperoxide glutathione peroxidase 43 which removes mitochondrial peroxides. Because the mechanism of this invention has implications in mitochondrial function, and relates to oxidative stress, the invention has implications for what otherwise might seem to be unrelated fields, those fields being weight loss and radiation or chemotherapy. The common link between these fields is the symptom of fatigue that is related to decreased mitochondrial function.
  • GSH would also protect the local
  • the cell adapts itself by
  • Nitric oxide has been found to have a Janus-faced role in regard to endothelial 1 function in that NO is needed for vasodilation and the prevention of hypertension, but in 2 the presence of oxidative stress NO becomes a source of the cell damaging peroxynitrite 3 radical.
  • Normally functioning mitochondria have several methods for preventing 4 peroxynitrite accumulation, however, if cytochrome c oxidase is not functioning 5 normally, the respiratory chain no longer has the interaction with oxygen available and 6 large amount of superoxide, Oj , can be formed 54 .
  • GSH glutathione reductase
  • the liposomal glutathione component of the current invention has been demonstrated to slow the progression of atherosclerosis in ApoE knockout mice, which are well characterized as the animal model for atherosclerosis, which has been reviewed in Guilford Patent Application # US 60/863,015; PCT ⁇ US06 ⁇ 60271.
  • the application also notes that while lowering oxidized LDL is a beneficial goal of liposomal glutathione additional benefit would accrue from the elevation of HDL and combining the liposomal glutathione with statin drugs was proposed.
  • the liposomal glutathione be combined with one of a class of drugs known as Cholesteryl ester transfer protein (CETP).
  • CETP Cholesteryl ester transfer protein
  • apo-A apoprotein -A
  • VLDL very low density lipoprotein
  • Normally CETP also takes up one TriglycerideG molecule from LDL or VLDL and transfers it to HDL.
  • a CETP inhibitor would thus be expected to raise plasma HDL cholesterol (HDLc) levels, lower LDL cholesterol (LDLc), and provide a potential therapeutic benefit for patients with coronary artery disease (CAD) 62 .
  • CAD coronary artery disease
  • torcetrapib has an increased association with an increase in death and heart problems compared to the control statin group. Additionally there is some elevation of blood pressure with torcetrapib. It is proposed that torcetrapib.be combined with the present invention, liposomal glutathione and 1-arginine to increase the beneficial response to the drug and to decrease the likelihood of side effects. It has been thought that calorie restriction has been the only way to preserve mitochondria and extend life span in rodents 63 . Recent article has confirmed that a 25% caloric deficit either by caloric restriction alone or by a combination of caloric restriction and exercise increased mitochondrial function in overweight, but non-obese humans 64 .
  • Calorie restriction has also been shown to delay the onset of a number of age related diseases including cancer, atherosclerosis and diabetes in rodents and possibly primates and even in humans 65 .
  • Recent evidence that calorie restriction increases the formation of eNOS mediated mitochondrial biogenesis 66 has focused the attention back onto the availability of NO in the mitochondria 67 .
  • Increasing the availability of NO results in a surge of NO that activates synthesis of a broad array of mitochondrial proteins and increases product of mtDNA, respiratory chain function, and ATP levels in a variety of tissues including brain, liver and heart 66 .
  • SIRT 1 the mammalian ortholog of the SIR2 gene, a member of the SIR (silent information regulator) genes that mediates the life-extending effect of calorie restriction in yeast is also up-regulated 66 and may contribute to longevity of organisms through a variety of effects 67 .
  • the purpose of this invention is to facilitate the proper mediation of upregulation ofNO.
  • SIRTl may mediate mitochondrial biogenesis in fat cells by increasing PGC- l ⁇ , which coordinates the genes involved not only with mitochondrial biogenesis, but also oxidation of fatty acids 68 and decreases adipose tissue formation It appears that increased presence of NO stimulates mitochondrial biogenesis with an accompanying set of proteins that not only stimulate mitochondrial reproduction, but also protect and repair mitochondrial DNA. Thus, NO has the ability to reduce fat accumulation by oxidation of fatty acids, lipolysis and inhibition of adipocyte formation by stimulating SIRTl, PGC-l ⁇ and mitochondrial biogenesis 67 Nisoli points out that up to this point in time, this effect has been accomplished only by calorie restriction 67 .
  • This application proposes the use of the invention, liposomal encapsulation of reduced glutathione with liposomal encapsulated 1-arginine or the contemporaneous ingestion of 1-arginine to increase the production of NO for the stimulation of biogenesis of mitochondria and the improved oxidation of fatty acids to result in weight loss.
  • the mechanism appears to be through the pathway described by Valerio in which NO production induces mitochondrial biogenesis, with a concomitant increase of PGC-I ⁇ , NRF-I, and Tfam gene expression, oxygen consumption, and ATP production in adipose and muscle cells 9 .
  • a lack of mitochondrial biogenesis results in visceral and skeletal obesity, increased muscle fat accumulation and metabolic syndrome 9 .
  • Muscle activity is dependent on a steady flow of ATP.
  • ATP allows muscle to get into the position where the elongated myosin is able to contract, shortening the muscle.
  • the "ready to contract” state appears as muscle relaxation.
  • the energy is stored in the biochemical component of actin and myosin.
  • An analogy suggests that ATP provides the energy to pull back the trigger, with this situation storing the energy until the muscle contracts.
  • energy from ATP is required for muscle relaxation 70 .
  • Skeletal muscle has a high reliance on OXPHOS 37 and skeletal muscle becomes the focus of biochemical defects related to glucose metabolism in obesity as abnormal metabolism of fatty acids is found in obesity-related insulin resistance 71
  • the net result of decreased energy production for the individual is the perception that even though they may have recently eaten, they have the perception of needing more energy and thus fell hungry for more food 9 .
  • obese patients feel less energetic and decrease their physical activity in order to conserve energy 27 .
  • the liposomal glutathione provides neutralization for the effect of TNF alpha, and at the same time provides that ability to maintain the NO produced from arginine to be used efficiently either by providing the appropriate antioxidant environment to prevent the oxidation of NO or by binding NO into GSNO.
  • GSNO potentially provides benefit in several ways such as providing a stable carrier of NO or by a direct action that has not been identified in mitochondria, but is well documented in vascular relaxation. The likelihood that GSNO provides a direct action on mitochondria is increased by the observation that it takes ATP to provide muscle relaxation, or stated another way, relaxation (of muscle) takes energy. For GSNO to provide relaxation in arterial vessel smooth muscle respiratory chain activity in the mitochondria must be present to provide the energy.
  • GSNO causes a defect in the respiratory chain function according to one study 26 .
  • liposomal glutathione provides the ability to restore mitochondrial biogenesis and a return to energy production that can result in weight loss as illustrated in case examples 1 and 2.
  • the present invention provides "appetite suppression" by providing the normal mechanism of appetite suppression, namely, the feedback that enough energy is being provided to the system.
  • the present invention is proposed as an appetite suppressant.
  • An additional mechanism for appetite suppression is also presented by the present invention.
  • arginine The metabolism of arginine can follow several pathways. While the production of NO by the interaction of arginine and nitric oxide synthase is well known, a less well known metabolic pathway will convert arginine to the amino acid like biochemical agmatine (l-amino-4-guanidino-butane).
  • Agmatine which falls into the family of molecules known as polyamines such as putrescine, spermine, spermidine, which are formed from ornithine and are essential for the growth, the maintenance and the function of normal cells 72 .
  • Agmatine however, is formed specifically from arginine 72 by the decarboxylation of 1-arginine by an enzyme known as arginine decarboxylase (ADC)
  • ADC arginine decarboxylase
  • Agmatine has subsequently been found to be widely distributed in mammalian tissues and both a hormone like action 73 as well as an action as a neurotransmitter 72 .
  • Agmatine and the ADC enzyme have been found in rat brain, kidney, astrocytes, endothelium and vascular smooth muscle cells 74 .
  • agmatine is synthesized by the decarboxylase enzyme located in the mitochondria 75 of astrocytes and neurons 76 and interacts with receptors such as nicotine, N-methyl-D-aspartate (NMDA) receptor, benzodiazepine and intracellular imidazoline receptors.
  • the molecule is transported into the matrix of mitochondria by an energy-dependent mechanism that seems to be specific for this molecule 77 .
  • NMDA N-methyl-D-aspartate
  • NMDA N-methyl-D-aspartate
  • Agmatine has been shown to potentiate morphine analgesia, reduced dependence/withdrawal from morphine 80 . and attenuates symptoms of withdrawal from ethanol in a rat model 81 .
  • the exact mechanism of the pain relieving action of agmatine has not been demonstrated, but the interactions with N-methyl-D-aspartate (NMDA) receptors, alpha2-adrenergic receptors, and intracellular cyclic adenosine monophosphate (cAMP) signaling have been proposed as possible explanations 80 .
  • NMDA N-methyl-D-aspartate
  • cAMP intracellular cyclic adenosine monophosphate
  • liposomal glutathione combined with 1-arginine is a combination that raises the level of agmatine both peripherally and centrally.
  • a combination that raises agmatine in the central nervous system offers a real advantage.
  • the increase of agmatine interacts with imidazole receptors and mediates a sympatho-inhibitory action to lower blood pressure via a central nervous system action.
  • agmatine has a peripheral activity related to increasing insulin secretion from beta cells and the ability of increasing lipid metabolism on fat cells. It is proposed that the present invention raises agmatine levels increasing the weight loss components of the invention.
  • Regunathan , et al. in US Patent 5,574,059 references the use of agmatine as an I.sub.2 imidazoline receptor agonist to treat disorders mediated by vascular smooth muscle proliferation by administering a vascular smooth muscle antiproliferative substance.
  • the disorders include atherosclerosis, risk of blockage of artery after coronary angioplasty or blood vessel injury from non-angioplasty cause, and proliferative diabetic retinopathy.
  • I.sub.2 imidazoline receptor agonists include idazoxan, UK 14,304, naphazoline, cirazoline and agmatine.
  • This patent refers to the administration of agmatine and does not reference the combination of liposomal glutathione and 1-arginine to enhance the endogenous production and physiologic utilization of agmatine in the body.
  • Gilad , et al. in US Patent 5,677,349 and 6,114,392 references the use of agmatine or derivatives of agmatine, in the treatment of acute neurotrauma (such as stroke) and degenerative disorders of the central and peripheral nervous system (such as dementia).
  • This patent does not reference the combination of liposomal glutathione and 1-arginine to enhance the endogenous production and physiologic utilization of agmatine in the body.
  • the application referred to pharmaceutical preparations containing of agmatine, congeners, analogs or derivatives thereof for use in preventing or treating epilepsy, seizures and other electroconvulsive disorders are provided.
  • the application referenced embodiments including administering an effective amount of agmatine, an agmatine analog or a pharmaceutically acceptable salt thereof to a human subject in need of treatment or prevention of epilepsy, seizure or other electroconvulsive disorder to treat, reduce, or prevent the disorder in the subject.
  • the application references the use of agmatine to treat epilepsy, but does not reference the combination of liposomal glutathione and 1-arginine to enhance the endogenous production and physiologic utilization of agmatine in the body.
  • the present invention further provides a method of regulating inducible nitric oxide synthase while maintaining constitutive nitric oxide synthase, by administering agmatine or an arginine derivative to a mammal.
  • WO 1998/013037 does not reference the combination of liposomal glutathione and 1-arginine to enhance the endogenous production and physiologic utilization of agmatine in the body.
  • Applicant The Proctor & Gamble Company filed an application entitled the Regulation of Mammalian Hair Growth as WO2005/078157.
  • a topical skin care composition "containing a safe and effective amount of a skin care active comprising agmatine, and its salt; a safe and effective amount of a first additional skin care active selected from the group consisting of BHT or BHA, hexamidine, cetyl pyridinium chloride, green tea catechins, phytosterols, ursolic acid, compounds derived from plant extracts, their salts and derivatives; and a dermato logically acceptable carrier for the agmatine composition.”
  • the present invention also relates to methods of using such agmatine compositions to regulate hair growth and the condition of mammalian skin.
  • the application WO2005/078157 referred to a topical composition containing agmatine, but did not reference 1-glutathione, much less liposomal glutathione in combination with agmatine or arginine.
  • the discussion of hair growth regulation does not relate to the subject of this invention. That application does not reference the combination of liposomal glutathione and arginine as a topical preparation for the stimulating the metabolism of fat under the skin surface.
  • Koide et al, in Patent Application 20060280776 reference the use of an omega-3 polyunsaturated fatty acid (PUFA) or an omega-6 PUFA and at least one of the following L-arginine, L-ornithine, an L-arginine precursor and an L-ornithine precursor, and further includes diacylglycerol, a middle or short chain fatty acid, a phytosterol, a nucleo-base, a nucleoside, a nucleic acid, dextrin, various vitamins, various minerals or a probiotics material.
  • PUFA omega-3 polyunsaturated fatty acid
  • omega-6 PUFA at least one of the following L-arginine, L-ornithine, an L-arginine precursor and an L-ornithine precursor, and further includes diacylglycerol, a middle or short chain fatty acid, a phytosterol, a nucleo-base, a nucleoside, a nucleic
  • Patent Application 20050085498 references a formulation comprised of four active components which are a lipid soluble thiamine, lipoic acid, arginine, alpha. - ketoglutarate, and a creatine derivative for oral administration.
  • active components which are a lipid soluble thiamine, lipoic acid, arginine, alpha. - ketoglutarate, and a creatine derivative for oral administration.
  • liposomal reduced glutathione in combination with arginine to increase cellular metabolism, to increase mitochondrial biogenesis or for weight loss.
  • a search of the literature reveals that there is no article suggesting the combination of liposomal encapsulated glutathione and arginine for the purpose of mitochondrial biogenesis and / or weight loss.
  • Type 2 Diabetes Management of type 2 diabetes generally managed by drugs in the categories known as sulfonylureas, metformin or Thiazolidinediones.
  • Thiazolidinediones such as, rosiglitazone and pioglitazone have become accepted medications for the treatment of type 2 diabetes, and both of these drugs work by increasing insulin sensitivity. It has been demonstrated that the mechanism of action of rosiglitazone and pioglitazone is centered on their ability to activate the peroxisome proliferator-activated receptor PPAR ⁇ , which is abundantly expressed in adipose tissue and is present in vasculature, colonic epithelium, and leukocytes (Wilson-Fritch).
  • PPAR ⁇ Normally fatty acids and eicosanoids bind to PPAR ⁇ , which activates the receptor causing it to migrate to the nucleus and DNA, activating a number of genes. It appears that PPAR ⁇ induces mitochondrial biogenesis in a way that increases fatty acid oxidation and markedly enhances oxygen consumption in these tissues and ultimately in the whole body energy metabolism with a resulting increase in insulin sensitivity (Wilson-Fritch). In spite of the biochemical prediction of benefit, research with pioglitazone teaches away from the expectation of weight loss as it was found that after 26 weeks of usage there was a dose dependent increase in body weight and BMI in the pioglitazone treated individuals of 2.0 to 4.5 Kgs 82 .
  • pioglitazone brand name "Actos” (made under license by Takeda Pharmaceuticals North America, Inc., and Eli Lilly Company of Indianapolis, Indiana), has been found to increase high-density lipoprotein (HDL).
  • the present invention is proposed in combination with pioglitazone as a combination for raising HDL for the treatment of atherosclerosis.
  • the preferred mode of the invention is the combination of pioglitazone 30 to 45 mg/day. and Liposomal glutathione 800 mg (2 teaspoons), and 1-arginine 1.0 to 2.5 gms twice a day.
  • Vitamin D3 exerts a variety of functions in the body related to calcium homeostasis, cell proliferation and cell differentiation. Most of these actions are mediated through the control of target genes stimulated by the action of the vitamin D receptor (VDR). Binding to the vitamin D receptor results in a series of events leading to regulation of target genes and affects a wide variety of tissues including bone, kidney, cardiac and skeletal muscle 83 .
  • PGC- 1- ⁇ acts as a stimulator of the VDR and that both of these receptors are involved in developing skeletal muscle 83 .
  • the present invention is proposed in combination with vitamin D 3 .
  • the increased use of vitamin D is known to increase the number of vitamin D receptors and this will increase the rate of mitochondrial biogenesis progressing.
  • the dose of vitamin D anticipated for function is in the range of 2000 to 50000 IU per day, with monitoring of the blood levels of Vit D(25OH) to be sure that there is both a response to the therapy and that the Vitamin D level does not go excessively high.
  • the normal range of vitamin D in the blood is 20 - 100 ng/ml and a level of 50 to 75 ng/ml is the target level for good vitamin D function.
  • liposomal glutathione alone or in the form of the present invention is proposed to manage the oxidation stress increase mitochondrial biogenesis and increase the availability of ATP for management of the fatigue that accompanies decreased ATP production 27 , from sources such as increased TNF- ⁇ , environmental toxins, and post radiation or chemotherapy for individuals who have undergone these therapies for cancer. 90 . All the changes caused by ionizing radiation are compatible with mitochondrial failure, encompassing reduced production of ATP, generation of ROS, and accumulation of rhodamine 123 which reflect mitochondrial swelling or changes in the mitochondrial inner membrane 91 . Chemotherapeutic agents used in treating various cancers have been demonstrated to increase oxidation stress of the proteins and lipids in the brain.
  • chemobrain 89 and is characterized by forgetfulness, lack of concentration, dizziness and fatigue to the point of sleeping. It is proposed that either liposomal reduced glutathione alone or in the form of the present invention as a treatment for the symptoms of "chemobrain". These symptoms are associated with decreased glutathione levels in brain tissue.
  • the invention may be used between episodes of the administration of the chemotherapy agent or at the conclusion of the therapy. As the formation of ROS and Peroxynitrite occurs during radiation therapy 92 , strategies of mitigating or correcting damage to mitochondria have advantages in rehabilitating the individual and their tissues after radiation or chemotherapy will have advantages.
  • Chemotherapy agents with which the present invention is intended include, but is not limited to: • Alkalating agents such as cisplatin, carboplatin, oxaliplatin, Busulfan, Cyclophoshamide and Melphalan • Antimetabolites such as azathioprine, mercaptopurine, pyrimdine, 5- Fluorouracil, Methotrexate and Fludarabine • Vinca alkaloids such as Vincristine, Vinblastine, Vinorelbine, Vindesine
  • Antitumor Antibiotics such as Bleomycin, Doxorubicin and Idarubicin • Mitotic Inhibitors including Taxanes such as paclitaxel, Docetaxel, Etoposide and Vinorelbine • Cyclophosphamide (Cytoxan, Neosar)
  • An embodiment of the present invention for use in individuals undergoing radionuclide exposure for either diagnostic purposes or as a therapy using radioactively tagged tumor specific modalities.
  • These materials in general consist of a tumor targeting agent such as an antibody that targets tumor tissue to which a radioactive component has been attached.
  • Liposomes tagged with radionuclide agents have been used for tumor imaging to stage cancers, image repeatedly and for the delivery of therapeutic doses of radionuclide such as technicium 99' Liposomes have been shown to be useful in carrying 99m Tc to tumor targets.
  • 99m Tc is a preferred material for imaging compared to 111 In and 67 Ga based on aspects of availability, cost and better imaging characteristics.
  • liposomes use energy provided as heat, sonication, extrusion, or homogenization for their formation, which gives them a high energy state. Since every high-energy state tries to lower its free energy, many liposome formulations can experience problems with aggregation, fusion, sedimentation and leakage of liposome associated material. A thermodynamically stable liposome formulation which could avoid these problems is a technological advance in liposome construction.
  • the additional advantage that the Qusome self-forming liposome is self forming at room temperature means that this is a true "mix and go" liposome that can be formed by mixing the lipid and an aqueous of lipid containing solution, without the worry that the contents will be altered, preserving the immunogenicity of the antigen and modulators.
  • the resulting liposome is in a low free energy state so it remains stable and reproducible. This means that the QuSome self- forming liposome can be readily translated from bench top to large scale production without problem.
  • the formulation of this embodiment is reviewed in example 4.
  • the QuSome self- forming liposome uses polyethyleneglycol (PEG) as a steric stabilizer and the resulting liposome is of a moderate size, 150nm - 250 nm.
  • PEG polyethyleneglycol
  • the combination of 150nm - 250 nm size and the PEG component is known to create long circulating liposomes.
  • the size of the QuSome self- forming liposome allows them to be sterile filtered.
  • the QuSome liposome encapsulating a radionuclide useful for targeting tumors with either diagnostic radionuclides or therapeutic radionuclides.
  • the QuSome self- forming liposome is of such as size and the presence of the steric stability with PEG results in long circulation and an increased accumulation in the fine trabecular mesh of blood vessels supplying growing tumors. This characteristic will allow for improved diagnostics as more radionuclide accumulates around the tumor improving the image of scans. This characteristic of accumulating in the trabecular mesh of blood vessels leading to tumors will also leads to an improved therapeutic.
  • liposomal glutathione in liposomes derived from lecithin that are more "fast acting” in terms or releasing their contents into the system can be administered to decrease the damage that radiation has on the surrounding tissues. It is proposed that the present invention be used to ameliorate the effects of chemotherapy and / or radiation that affect mitochondrial function resulting in tissue damage. This application applies to whether these exposures come from controlled exposures such as medical therapies or uncontrolled exposures as is seen with chemical toxicities or radiation exposure from industrial, accidental or intentional situations such as poisonings or bombs .
  • OBJECTIVES OF THE INVENTION It is an objective of the invention to enable weight loss and reduce of oxidative stress and well as positively influencing mitochondrial biogenesis. It is an objective of the invention to enable the prevention and treatment of insulin resistance and particularly insulin resistance in the elderly. Insulin resistance has been shown to occur in the elderly population associated with an increase in fat accumulation in muscle and liver and with a 40% decrease in mitochondrial oxidative phosphorylation (OXPHOS) 93 . As these findings are consistent with an age related decline in mitochondrial function as previously discussed, the invention is useful in treating insulin resistance.
  • vitamin D in addition to increase the number of receptor sites utilized by PGC- 1- ⁇ in order to increase the stimulation for and the rate of mitochondrial biogenesis, which is an increase in the number and function of mitochondria 67 .
  • It is an objective of the invention to be used for the treatment of chronic fatigue syndrome. It is an objective of the invention to treat the fatigue that accompanies therapies utilizing chemotherapy or radiation for the treatment of various disease states such as cancer. It is an objective of the invention to treat malaria and other intracellular diseases such as lyme disease.
  • Alternative biochemicals may be substituted for arginine in the formation of nitric oxide. The amino acid lysine has been demonstrated to form nitric oxide when added to the diet or supplemented in animal studies 94 . Citrulline will also become incorporated in the pathways forming arginine and may be considered a substitute for arginine 41 Agmatine is another substitute.
  • the combination of Liposomal glutathione 2500 mg per ounce with 1-arginine 3000 mg per ounce designed to be ingested orally is the preferred mode of the present invention.
  • the liposome for this mode is described in the Example numbers 1 and 2 uses the material derived from lecithin for the liposome.
  • the preferred mode of the present invention is in the liposome composed of material derived from lecithin for oral use
  • a second preferred mode is the combination of liposomal reduced glutathione and 1-arginine encapsulated in the Qusome for topical use for application to areas of excess fat.
  • the Qusome is composed of fatty material that is readily absorbed through the skin and into fat tissue under the skin.
  • the amount of materials is 2500 mg glutathione plus 1-arginine 3000 mg per ounce in a cream for topical application. It is proposed that the topical Qusome encapsulating reduced glutathione and 1-arginine will be used for topical application either alone or in conjunction with the oral ingestion of the present invention to increase the mitochondrial metabolism of cells such as adipocytes, which are fat cells.
  • the combination of oral ingestion of the invention and the topical application of the invention in the Qusome may speed the resolution of fatty deposits in specific sites as well as an aid in wound healing by increasing local tissue mitochondrial biogenesis to support healing as well as increasing local blood flow by dilating the local vessels.
  • Additional components of the topical may include forskolin, aminophyllin or yohimbe as supplemental materials to stimulate increased lypolysis of fat cells.
  • forskolin a labdane diterene that is produced from the plant Plectranthus barbatus and is known to raise levels of cyclic Adenosine Monophospate (cAMP).
  • cAMP is a signal carrying molecule that is necessary for responses in cells.
  • cAMP is the signaling molecule that is triggered by nitric oxide that goes on to cause muscle relaxation. While important in regulating cell functions, too much cAMP in cells will cause problems such as the development of insulin resistance.
  • Stimulants to cell metabolism such as catecholamines (epinephrine) or glutathione or an enzyme that prevents the breakdown of cAMP called cAMP- phosphodiesterase inhibitor, will increase cAMP and result in insulin resistance and slowing of fat metabolism in cells 95 .
  • Aminophyllin is a methylxanthines, a group that also includes caffeine and theophylline, that is known to cause smooth muscle relaxation and also increase production of enzymes in cells and can inhibit macrophage inflammation and phagocytosis 96 .
  • Additional applications that will benefit from the application of the present invention are the treatment of disease such as malaria, which is associated with both a decrease in arginine systemically and nitric oxide in the brain during acute malaria (Lopansri 2006).
  • the present invention offers advantages that would not accompany the single administration of arginine to these individuals.
  • PCT ⁇ US06 ⁇ 60271 increasing the level of nitric oxide without providing liposomal encapsulated glutathione would not result in the formation of GSNO, which has been shown to be an inhibitor of a critical enzyme needed for the malaria parasite to infect red blood cells 97 ' 98 ).
  • the present invention is proposed as a method of directly or as an adjunct with chloroquine and aminoisoquino lines pharmacologies in the management and prevention and malaria. Additionally, the present invention is proposed in combination with a liposomal encapsulation of an extract of Artemisia, such as artesuate, which has been found useful in the management and prevention of malaria ".
  • Simultaneously liposomal glutathione 1200 mg + 1-arginine 1000 mg is given every 4 hours for the first 48 hours and then ever ⁇ ' 6 hours in addition to Primaquine 15 mg once a day for fourteen days for 14 days.
  • An additional embodiment of the invention proposes the combination of Liposomal glutathione and 1-arginine with colloidal silver.
  • the preferred embodiment of this combination is Liposomal glutathione 1200 mg + arginine 1500 mg plus colloidal silver 32 ppm of silver nano particles 10 cc to be used three times a day for the treatment of acute malarial disease.
  • agonist or "agonist of eNOS or cNOS” refers to an agent that stimulates the bio-transformation of a substrate such as, for example, L- arginine to NO.
  • An agonist of eNOS or cNOS includes, for example, an HMG-CoA reductase inhibitor.
  • HMG-CoA reductase (3-hydroxy-3-methylglutaryl-coenzyme A) is the microsomal enzyme that catalyzes the rate limiting reaction in cholesterol biosynthesis.
  • HMG-CoA reductase inhibitor inhibits HMG-CoA reductase.
  • HMG- CoA reductase inhibitors are also referred to as "statins.”
  • the composition may further include a number of non-active compounds, such as effervescent combinations, diluents, buffers, preservatives, desiccants, thickeners, fillers, flavorings, sweeteners, colorings and any other excipients or non-active ingredients known in the art.
  • the composition maybe in the form of a powder, liquid, capsule, tablet or chewing gum and/or may be formed as part of a food product.
  • the composition is a powder that may be solubilized in a liquid for ingestion.
  • Alternative biochemicals may be substituted for arginine in the formation of nitric oxide.
  • the amino acid lysine has been demonstrated to form nitric oxide when added to the diet or supplemented in animal studies 94 .
  • Citrulline will also become incorporated in the pathways forming arginine and may be considered a substitute for arginine 41 .
  • Case Example 1 MR, a 60 year old woman, with diabetes requiring insulin therapy also has a long history of elevated blood pressure and increased weight. MR also has a long history of type 2 diabetes requiring insulin therapy on a twice daily basis. In spite of numerous attempts to lose weight the patient had been unable to lose weight and at the start of the usage of the present invention she was 5 feet 4.5 inches and weighed 230 pounds, which calculates to a Body Mass Index of 39.5.
  • Example 1 1-Arginine 1000 mg to 3000 mg is ingested orally followed by the liposomal glutathione drink 420 mg per teaspoon, which is constructed in the following manner. Liposomal glutathione Drink or Spray 2500 mg per ounce
  • Glutathione reduced 8.25w/w% is 82.5 mg per ml.
  • a lipid mixture having components lecithin, and glycerin were commingled in a large volume flask and set aside for compounding.
  • a water mixture having water, glycerin, glutathione were mixed and heated to 50. degree. C.
  • the water mixture was added to the lipid mixture while vigorously mixing with a high speed, high shear homogenizing mixer at 750-1500 rpm for 30 minutes.
  • the homogenizer was stopped and the solution was placed on a magnetic stirring plate, covered with paraf ⁇ lm and mixed with a magnetic stir bar until cooled to room temperature.
  • a spoilage retardant such as potassium sorbate or BHT would be added.
  • the solution would be placed in appropriate dispenser for ingestion as a liquid or administration as a spray.
  • Analysis of the preparation under an optical light microscope with polarized light at 400 X magnification confirmed presence of both multilamellar lipid vesicles (MLV) and unilamellar lipid vesicles.
  • MLV multilamellar lipid vesicles
  • the preferred embodiment includes the variations of the amount of glutathione to create less concentrated amounts of glutathione.
  • the methods of manufacture described in Keller et al, U.S. Pat. No. # 5,891,465, April 6, 1999, are incorporated into this description.
  • the preferred liposomal glutathione is available from Your Energy Systems, Inc. of Palo Alto, California.
  • Example 2 Liposomal glutathione Drink or Spray 2500 mg per ounce with 1-arginine 3000 mg per ounce.
  • a lipid mixture having components lecithin, and glycerin were commingled in a large volume flask and set aside for compounding.
  • a water mixture having water, glycerin, glutathione were mixed and heated to 50. degree. C.
  • the water mixture was added to the lipid mixture while vigorously mixing with a high speed, high shear homogenizing mixer at 750-1500 rpm for 30 minutes.
  • the homogenizer was stopped and the solution was placed on a magnetic stirring plate, covered with paraf ⁇ lm and mixed with a magnetic stir bar until cooled to room temperature.
  • a spoilage retardant such as potassium sorbate or BHT would be added.
  • the solution would be placed in appropriate dispenser for ingestion as a liquid or administration as a spray.
  • Analysis of the preparation under an optical light microscope with polarized light at 400 X magnification confirmed presence of both multilamellar lipid vesicles (MLV) and unilamellar lipid vesicles.
  • the preferred embodiment includes the variations of the amount of glutathione to create less concentrated amounts of glutathione. The methods of manufacture described in Keller et al, U.S. Pat. No. # 5,891,465, April 6, 1999, are incorporated into this description.
  • liposomes Components are commingled and liposomes are made using the injection method (Lasic, D., Liposomes, Elsevier, 88-90, 1993).
  • liposome mixture cooled down 0.7 ml was drawn into a 1 ml insulin syringe and injected into the open-end of a soft gelatin capsule then sealed with tweezers.
  • the resulting one gram capsule contains 450 mg reduced glutathione and 450 mg 1-arginine.
  • Large scale manufacturing methods for filling gel caps, such as the rotary die process, are the preferred method for commercial applications.
  • the liposomal glutathione for this invention is and was made by Biozone Laboratories, Inc. of Pittsburg, California and sold by Your Energy Systems, Inc. of Palo Alto, California.
  • Embodiment number three of the present invention includes the creation of liposome suspension using a self-forming, thermodynamically stable liposomes formed upon the adding of a diacylglycerol-PEG lipid to an aqueous solution when the lipid has appropriate packing parameters and the adding occurs above the melting temperature of the lipid.
  • the method described by Keller et al, U.S. Pat. No. 6,610,322 is incorporated into this description.
  • Most, if not all, known liposome suspensions are not thermodynamically stable. Instead, the liposomes in known suspensions are kinetically trapped into higher energy states by the energy used in their formation. Energy may be provided as heat, sonication, extrusion, or homogenization. Since every high-energy state tries to lower its free energy, known liposome formulations experience problems with aggregation, fusion, sedimentation and leakage of liposome associated material. A thermodynamically stable liposome formulation which could avoid some of these problems is therefore desirable.
  • the present embodiment teaches liposome suspensions which are thermodynamically stable at the temperature of formation.
  • the formulation of such suspensions is achieved by employing a composition of lipids having several fundamental properties.
  • the lipid composition must have packing parameters which allow the formation of liposomes.
  • the lipid should include polyethyleneglycol (PEG) or any polymer of similar properties which sterically stabilizes the liposomes in suspension.
  • PEG polyethyleneglycol
  • the lipid must have a melting temperature which allows it to be in liquid form when mixed with an aqueous solution.
  • the invention includes a method of preparing liposomes.
  • the method comprises providing an aqueous solution; providing a lipid solution, where the solution has a packing parameter measurement of P a (P a references the surface packing parameter) between about 0.84 and 0.88, a P v (P v references the volume packing parameter) between about 0.88 and 0.93, (See, D. D. Lasic, Liposomes, From Physics to Applications, Elsevier, p. 51 1993), and where at least one lipid in the solution includes a polyethyleneglycol (PEG) chain; and combining the lipid solution and the aqueous solution.
  • PEG chain preferably has a molecular weight between about 300 Daltons and 5000 Daltons.
  • Kinetic energy such as shaking or vortexing
  • the lipid solution may comprise a single lipid.
  • the lipid may comprise dioleolylglycerol-PEG-12, either alone or as one of the lipids in a mixture.
  • the method may further comprise providing an active compound, in this case glutathione (reduced) and combining the active compound with the lipid solution and the aqueous solution.
  • an active compound in this case glutathione (reduced)
  • the self forming liposome (“QuSome" by Biozone Laboratories, Inc. of Pittsburg, California, is used to create a radiopharmaceutical
  • the radionuclide will first be created with the ligand selected to target a particular tissue.
  • the active substance radiopharmaceutical would be combined with the self- forming lipid solution and any desired the aqueous solution.
  • the selected dose would be selected by a dosimeter, and administered. Because the liposomes will pass into the digestive tract, the dose may be given orally, but also intravenously, or for certain types of cancers, by injection. Additional variations of accomplishing this embodiment are described in Keller et al U.S. Pat.No. 6,610,322.
  • the accumulation of QuSome self-forming liposomes in the blood vessel supply to tumors increases the radiation dosing to this area, creating damage to the tumor blood vessels creating an anti-angiogenic effect as well, resulting in a decreased supply of blood to the tumor and leading to death of tumor cells.
  • the tumor is selectively preferred as the target at the same time as normal cells are better protected.
  • Some preferred applications include stabilization of radiolabeled peptides, [18 F] deoxyglucose, radiolabeled annexin, 99 mTc-annexin, radiolabeled monocyte chemoattractant protein, i.e.
  • radiolabeled Dopamine transporter agents (S)-N-(I -ethylpyrrolidin-2-ylmethyl)-2-hydro- xy-3-iodo- 6-methoxybenzamide (3-IBZM)(More generally "BZM,), (S)-N-(I -ethylpyrrolidin-2- ylmethyl)-2-hydroxy-5-iodo-6-methoxybenzamide (5-IBZM), I-123-2-beta- carbomethoxy-3-beta(4-iodophenyl) N-(3-fluro propyl) nortropane ("CIT” or "beta-CIT”) and various tropane derivatives, 1-123 fatty acids, particularly for cardiovascular imaging, radiolabeled octreotide or radiolabeled depreotide, HEDP (diagnostic skeletal imaging or treatment of metastatic bone pain), radiolabeled antibodies, both
  • Preferred ligands are 1 -hydroxy ethylidene diphosphonate, methylene diphosphonate, (dimethylamino)methyl diphosphonate, methanehydroxydiphosphonate, and imidodiphosphonate (for bone-scanning and alleviation of pain); strontium 89 ethylene diamine tetramethylene phosphate, samarium 153-ethylene diamine tetramethylene phosphate, radiolabeled monoclonal antibodies, 99m-Tc HMPAO (hexamethylproplyene amine oxime), yttrium 90-labeled ibritumomab tiuxetan (Zevalin.RTM.
  • Ethylene diamine tetramethylene phosphate and ethylene diamine tetramethylene phosphoric acid and the pharmaceutically related mono-, di- and polyphosphoric acids and their pharmaceutically-acceptable salts including polyphosphates, pyrophosphates, phosphonates, diphosphonates and imidophosphonates are collectively called EDTMP.
  • radionuclides which are well-known to those skilled in the art include radioisotopes of copper, technetium-99m, rhenium-186, rhenium-188, antimony-127, lutetium-177, lanthanum- 140, samarium-153, radioisotopes of iodine, indium-111, gallium-67 and -68, chromium-51, strontium-89, radon-222, radium-224, actinium-225, californium-246 and bismuth-210.
  • radionuclides include F-18, C-I l, Y-90, Co-55, Zn-62, Fe-52, Br-77, Sr-89, Zr-89, Sm-153, Ho-166, and TI-201.
  • RECOMMENDED USE in conjunction with radiation therapy or chemotherapy in the dose of radiopharmaceutical selected by a person reasonably skilled in the art is: (1 ounce is 5.56 teaspoons.) 1 teaspoon of oral liposomal glutathione reduced +l-arginine contains approximately 440mg GSH + 500 mg L-arginine. Suggested dose depends on body weight. Recommended amounts are for daily use. ADULT DOSING Recommended dose for adult is two teaspoons twice a day for a 70 Kg person. For adults of 100 Kg the dose is 2 teaspoons three times a day. For adults of 150 Kg the dose is 2 teaspoons four times a day.
  • the invention proposes utilizing a self- forming liposome in solution, reconstituting the radiopharmaceutical with the solution with the self- forming liposome, and administering the radiopharmaceutical, now in the self- forming liposome, to the patient.
  • Liposomal glutathione may be added to the solution prior to administration.
  • Example 5 Diabetes Management
  • the present invention is proposed in combination with pioglitazone as a combination for raising HDL for the treatment of atherosclerosis.
  • the preferred mode of the invention is the combination of pioglitazone 30 to 45 mg/day. and Liposomal glutathione 800 mg (2 teaspoons), and 1-arginine 1.0 to 2.5 gms twice a day.
  • Management of malaria The present invention is proposed as a method of directly or as an adjunct with chloroquine and aminoisoquinolines pharmacologies in the management and prevention and malaria. Additionally, the present invention is proposed in combination with a liposomal encapsulation of an extract of Artemisia, such as artesuate, which has been found useful in the management and prevention of malaria ".
  • Simultaneously liposomal glutathione 1200 mg + 1-arginine 1000 mg is given every 4 hours for the first 48 hours and then every 6 hours in addition to Primaquine 15 mg once a day for fourteen days for 14 days.
  • An additional embodiment of the invention proposes the combination of Liposomal glutathione and 1-arginine with colloidal silver.
  • the preferred embodiment of this combination is Liposomal glutathione 800 mg + arginine 1500 mg plus colloidal silver 32 ppm of silver nano particles 10 cc to be used three times a day for the treatment of acute malarial disease.
  • Lyme disease Individuals with chronic and active lyme disease often have fatigue accompanying their symptoms and have been shown to have decreased function of the enzyme glutathione peroxidase and increased markers of oxidative stress 10 ° and have also been demonstrated to have increased levels of TNF- ⁇ 101 . It is proposed that a similar combination of liposomal glutathione 800 mg + arginine 1500 mg plus colloidal silver 32 ppm of silver nano particles 10 cc to be used three times a day for the treatment of acute and chronic lyme disease.
  • the colloidal silver described in this embodiment may be obtained from American Biotech Laboratories of Alpine, Utah, USA.
  • Menshikova EV Ritov VB, Fairfull L, Ferrell RE, Kelley DE, Goodpaster BH.
  • Kern PA Saghizadeh M
  • Ong JM Bosch RJ
  • Deem R Simsolo RB.
  • the expression of tumor necrosis factor in human adipose tissue Regulation by obesity, weight loss, and relationship to lipoprotein lipase. The Journal of clinical investigation. 1995;95(5):2111-2119.
  • Buckley BJ Whorton AR. Adaptive responses to peroxynitrite: increased glutathione levels and cystine uptake in vascular cells.
  • Brito PM Mariano A, Almeida LM, Dinis TC. Resveratrol affords protection against peroxynitrite-mediated endothelial cell death: A role for intracellular glutathione. Chemico-biological interactions. 2006;164(3):157-166. 57. Knight TR, Ho YS, Farhood A, Jaeschke H. Peroxynitrite is a critical mediator of acetaminophen hepatotoxicity in murine livers: protection by glutathione.
  • CETP Oral cholesteryl ester transfer protein
  • Nisoli E Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L, Falcone S, Valerio A, Cantoni O, Clementi E, Moncada S, Carruba MO. Calorie Restriction Promotes Mitochondrial Biogenesis by Inducing the Expression of eNOS. Science. 2005;310(5746):314-317. 67.
  • Nisoli E Carruba MO. Nitric oxide and mitochondrial biogenesis. Journal of cell science. 2006;119(14):2855-2862. 68. Lin S-J, Ford E, Haigis M, Liszt G, Guarente L. Calorie restriction extends yeast life span by lowering the level of NADH. Genes Dev.
  • Agmatine an endogenous ligand at imidazoline receptors is a novel neurotransmitter. Annals of the New York Academy of Sciences. 1999;881 :65-80. 73. Li G, Regunathan S, Barrow CJ, Eshraghi J, Cooper R, Reis DJ. Agmatine: an endogenous clonidine-displacing substance in the brain. Science. 1994;263(5149):966-969. 74. Sastre M, Galea E, Feinstein D, Reis DJ, Regunathan S. Metabolism of agmatine in macrophages: modulation by lipopolysaccharide and inhibitory cytokines. The Biochemical journal.
  • Pancewicz SA Hermanowska-Szpakowicz T, Makarewicz-Plonska M, Witek A, Farbiszewski R, Zajkowska J, Michalska B. [Decreased antioxidant-de fence mechanisms in cerebrospinal fluid (CSF) in patients with tick-borne encephalitis (TBE)].
  • Kisand KE Prukk T, Kisand KV, Luus SM, Kalbe I, Uibo R. Propensity to excessive proinflammatory response in chronic Lyme borreliosis. Apmis. 2007;115(2):134-141.

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Abstract

L'invention concerne le traitement chez un mammifère d'une maladie associée à une baisse de production d'énergie dans la mitochondrie, la centrale énergétique de la cellule. L'invention concerne plus précisément une combinaison de glutathion réduit liposomique et de 1-arginine permettant d'augmenter la capacité de perte de poids chez des individus présentant une surcharge pondérale. Le mécanisme de perte de poids est associé à une amélioration de la production de la chaîne respiratoire de la mitochondrie dont la fonction est influencée positivement par la disponibilité de l'oxyde d'azote antioxydant dans un environnement non oxydé. La présente invention permet d'obtenir une perte de poids chez un individu dont l'incapacité à perdre du poids est liée à l'inefficacité des voies biochimiques associées à la fonction mitochondriale et à la production d'énergie. Les voies liées à l'incapacité de perdre du poids sont également liées à l'incapacité de métaboliser les graisses, ce qui donne lieu à une résistance à l'insuline et au diabète. L'invention permet de traiter le syndrome métabolique. Le syndrome métabolique est en fait un groupe de facteurs métaboliques associés à un risque accru d'affections vasculaires. L'invention permet également de réduire la fatigue qui accompagne à la fois la prise de poids et les maladies. La capacité de l'invention à augmenter la production d'agmatine biochimique dans le système nerveux central et globalement dans le corps résulte de la combinaison de glutathion réduit liposomique et de 1-arginine. De plus, les voies biochimiques stimulées par la présente invention peuvent avoir un effet bénéfique sur des individus souffrant de diverses maladies infectieuses.
PCT/US2007/065552 2004-11-07 2007-03-29 Combinaison de glutathion réduit liposomique et de 1-arginine, avec un ou plusieurs autres ingrédients, pouvant être administrée par plusieurs voies, permettant d'inverser et de prévenir l'obésité et de stimuler la biogenèse mitochondriale Ceased WO2007115131A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US12/281,066 US20090047340A1 (en) 2006-03-29 2007-03-29 Liposomal reduced glutathione and 1-arginine, including with other ingredient(s), capable of multipath administration for reversal and prevention of obesity and for mitochondrial biogenesis
US13/368,689 US20120219616A1 (en) 2006-03-29 2012-02-08 LIPOSOMAL REDUCED GLUTATHIONE AND l-ARGININE, INCLUDING WITH OTHER INGREDIENT(S), CAPABLE OF MULTIPATH ADMINISTRATION FOR REVERSAL AND PREVENTION OF OBESITY AND FOR MITOCHONDRIAL BIOGENESIS
US13/396,841 US8252325B2 (en) 2004-11-07 2012-02-15 Liposome-encapsulated glutathione for oral administration

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US11/277,845 2006-03-29
USPCT/US2006/011397 2006-03-29
US11/277,845 US20070077258A1 (en) 2005-03-29 2006-03-29 ADMINISTRATION OF GLUTATHIONE (REDUCED) VIA INTRAVENOUS OR ENCAPSULATED IN LIPOSOME FOR THE AMELIORATION OF TNF-alpha EFFECTS AND FLU-LIKE VIRAL SYMPTOMS AND TREATMENT AND PREVENTION OF VIRUS
PCT/US2006/011397 WO2006105155A2 (fr) 2005-03-29 2006-03-29 Administration de glutathion (reduit) par intraveineuse ou encapsule dans des liposomes pour le traitement des effets du tnf-$g(a) et des symptomes viraux pseudogrippaux
US86301506P 2006-10-26 2006-10-26
US60/863,015 2006-10-26
PCT/US2006/060271 WO2007053810A2 (fr) 2005-11-06 2006-10-26 Glutathion reduit encapsule dans des liposomes, comprenant une autre preparation pharmacologique, concu sous forme de preparation pour administration orale, topique, intra-orale ou transmucosale permettant d'inverser ou de prevenir une oxydation de cholesterol et de lipoproteine a faible densite
USPCT/US2006/060271 2006-10-26

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/368,689 Continuation US20120219616A1 (en) 2006-03-29 2012-02-08 LIPOSOMAL REDUCED GLUTATHIONE AND l-ARGININE, INCLUDING WITH OTHER INGREDIENT(S), CAPABLE OF MULTIPATH ADMINISTRATION FOR REVERSAL AND PREVENTION OF OBESITY AND FOR MITOCHONDRIAL BIOGENESIS

Publications (2)

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WO2007115131A2 true WO2007115131A2 (fr) 2007-10-11
WO2007115131A3 WO2007115131A3 (fr) 2008-11-20

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Family Applications (2)

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PCT/US2007/065553 Ceased WO2007115132A2 (fr) 2006-03-29 2007-03-29 Produit radiopharmaceutique utilisé dans une préparation liposomale auto-formante pouvant être administrée par diverses voies, contenant d'autres ingrédients
PCT/US2007/065552 Ceased WO2007115131A2 (fr) 2004-11-07 2007-03-29 Combinaison de glutathion réduit liposomique et de 1-arginine, avec un ou plusieurs autres ingrédients, pouvant être administrée par plusieurs voies, permettant d'inverser et de prévenir l'obésité et de stimuler la biogenèse mitochondriale

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PCT/US2007/065553 Ceased WO2007115132A2 (fr) 2006-03-29 2007-03-29 Produit radiopharmaceutique utilisé dans une préparation liposomale auto-formante pouvant être administrée par diverses voies, contenant d'autres ingrédients

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US20140234397A1 (en) * 2013-02-15 2014-08-21 Lou Ann Brown Treatment of klebsiella pneumoniae with liposomally formulated glutathione
US20150216925A1 (en) * 2012-02-15 2015-08-06 Kyowa Hakko Bio Co., Ltd. Agent for preventing or ameliorating vascular endothelial malfunction
WO2016053899A1 (fr) * 2014-09-29 2016-04-07 Your Energy Systems, LLC Procédé de traitement utilisant du glutathion réduit formulé dans des liposomes pour coopérer avec l'interleukine 10 (il-10) afin de moduler une réponse inflammatoire déclenchée chez des patients diabétiques séropositifs et immuno-compromis par la tuberculose
US20160296586A1 (en) * 2012-02-15 2016-10-13 Kyowa Hakko Bio Co., Ltd. Agent for preventing or ameliorating vascular endothelial malfunction
EP2956153A4 (fr) * 2013-02-15 2017-03-22 Your Energy Systems, LLC Traitement de maladies de résistance bactérienne évolutive comprenant klebsiella pneumoniae avec du glutathion formulé dans des liposomes

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US20150216925A1 (en) * 2012-02-15 2015-08-06 Kyowa Hakko Bio Co., Ltd. Agent for preventing or ameliorating vascular endothelial malfunction
US20160296586A1 (en) * 2012-02-15 2016-10-13 Kyowa Hakko Bio Co., Ltd. Agent for preventing or ameliorating vascular endothelial malfunction
US20140023696A1 (en) * 2012-07-20 2014-01-23 Frederick Timothy Guilford Treatment for idiopathic pulmonary fibrosis
US20140234397A1 (en) * 2013-02-15 2014-08-21 Lou Ann Brown Treatment of klebsiella pneumoniae with liposomally formulated glutathione
EP2956153A4 (fr) * 2013-02-15 2017-03-22 Your Energy Systems, LLC Traitement de maladies de résistance bactérienne évolutive comprenant klebsiella pneumoniae avec du glutathion formulé dans des liposomes
WO2016053899A1 (fr) * 2014-09-29 2016-04-07 Your Energy Systems, LLC Procédé de traitement utilisant du glutathion réduit formulé dans des liposomes pour coopérer avec l'interleukine 10 (il-10) afin de moduler une réponse inflammatoire déclenchée chez des patients diabétiques séropositifs et immuno-compromis par la tuberculose

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WO2007115132A3 (fr) 2008-10-30
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