WO2016164534A1 - Procédés et compositions pour l'inversion de la perturbation du glycocalyx, de l'inflammation et de la détérioration oxydative - Google Patents

Procédés et compositions pour l'inversion de la perturbation du glycocalyx, de l'inflammation et de la détérioration oxydative Download PDF

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WO2016164534A1
WO2016164534A1 PCT/US2016/026360 US2016026360W WO2016164534A1 WO 2016164534 A1 WO2016164534 A1 WO 2016164534A1 US 2016026360 W US2016026360 W US 2016026360W WO 2016164534 A1 WO2016164534 A1 WO 2016164534A1
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formula
glycocalyx
restoring
compound
disease
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Josefino B. Tunac
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Kardiatonos Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine

Definitions

  • the present invention relates to methods and compositions for treating diseases involving disruption of the glycocalyx, inflammation, and oxidative damage. More specifically, the present invention relates to methods and compositions for treating cardiovascular disease.
  • glycocalyx a thin layer at the endothelial surface was discovered about 40 years ago (1966. Fed Proc 25:1773-1783). However, the significance of this structure was not recognized, partly because it is destroyed upon conventional tissue fixation and not seen in most light microscopic examinations.
  • the glycocalyx is a protective lining at the surface of the endothelium found in every healthy blood vessel; it is made of proteoglycan, a complex network of protein (glycoprotein) and disaccharide sugar (glycosaminoglycan). This complex network (originating from plasma and vessel wall) forms a dynamic layer between the flowing blood and the endothelium, continuously changing in thickness depending on shear or blood flow pressure.
  • the core protein groups of this layer are syndecans and glypicans promiscuously bound with different glycosaminoglycan including heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, and hyaluronan (or hyaluronic acid).
  • heparan sulfate represents roughly 50-90% of the total amount of proteoglycans followed by chondroitin sulfate with a typical ratio of 4:1, respectively (2007.Pflugers Arch; 454: 345-359).
  • the glycocalyx can also be found on the apical portion of the microvilli within the digestive tract, especially within the small intestine. It creates a meshwork 0.3 micrometers thick and consists of acidic mucopolysaccharides and glycoproteins that project from the apical plasma membrane of epithelial absorptive cells It provides additional surface for adsorption and includes enzymes secreted by the absorptive cells that are essential for the final steps of digestion of proteins and sugars.
  • Each cell is surrounded by a glycocalyx.
  • Cells form a glycocalyx layer of a tissue's surface and form a barrier. Once disrupted, the underlying cell is susceptible to disruption and immune attack by macrophages and the like.
  • the glycocalyx of endothelial cells such as the endometrium, the inner surface of the lungs, the microvilli of the kidney, the pancreas, etc., form a cellular seal that cannot be disrupted.
  • glycocalyx Other generalized functions effected by status of glycocalyx include protection (it cushions the plasma membrane and protects it from chemical injury), immunity to infection (it enables the immune system to recognize and selectively attack foreign organisms), defense against cancer (changes in the glycocalyx of cancerous cells enable the immune system to recognize and destroy them), transplant compatibility (it forms the basis for compatibility of blood transfusions, tissue grafts, and organ transplants), cell adhesion (it binds cells together so that tissues do not fall apart), inflammation regulation (glycocalyx coating on endothelial walls in blood vessels prevents leukocytes from rolling/binding in healthy states), fertilization (it enables sperm to recognize and bind to eggs), and embryonic development (it guides embryonic cells to their destinations).
  • the glycocalyx is recognized as a key structure for maintaining vascular wall integrity and proper function of many organs. Disruptions in the glycocalyx can be due to contact with fluid flow. A thick glycocalyx indicates the absence of plaque, found at straight flow and high shear areas. A thin glycocalyx promotes plaque buildup, especially where there is whirlpool blood flow with low shear in vascular bends. Plaques are essentially patches that cover tiny gaps to maintain osmotic balance of membranes. The tiny gaps in the membrane leak electrolytes both into (Na+CI-, Ca+, HC03) and out (K+, P04-, Mg+) of cells which can lead to a number of conditions. Disruptions can also be caused by the presence of oxidants or debris in adjacent fluid.
  • any disruption or decrease in thickness of the glycocalyx can result in many different conditions, including chronic vascular disease (2010. Cardiovascular Research. Volume 87, Issue 2 pp. 300 - 310).
  • chronic vascular disease 2010. Cardiovascular Research. Volume 87, Issue 2 pp. 300 - 310.
  • chronic stagnant blood flow common in bifurcated sections of the arteries, triggers glycocalyx shedding and plaque formation.
  • disrupted glycocalyx in the coronaries result in poor blood flow (coronary perfusion); at the arteriolar level, a damaged glycocalyx slows down blood flow and decreases nitric oxide (NO) production creating constrictive vessel; and, at the capillary level, disrupted glycocalyx reduces blood flow to tissues or muscles.
  • NO nitric oxide
  • the glycocalyx harbors a wide array of enzymes that regulate proper blood flow including superoxide dismutase (SOD), an enzyme which neutralizes reactive oxygen species; antithrombin (AT-III), a natural anticoagulant (blood thinner); and, lipoprotein lipase (LPL), an enzyme that releases triglycerides from chylomicrons and very low-density lipoproteins (VLDL) for energy.
  • SOD superoxide dismutase
  • AT-III antithrombin
  • LPL lipoprotein lipase
  • VLDL very low-density lipoproteins
  • glycocalyx dysfunction can lead to blockage of flow in vasculature, the kidneys, the pancreas, and other organs and tissue.
  • Cardiovascular disease is the leading disease killer in the world and because of its complexity and manifested clinical sequelae, it continues to be the main subject in pathology research.
  • members of the CVD family are totally different in clinical presentations, they are basically atherosclerosis related and share a common feature, which is vascular damage, particularly to the endothelial glycocalyx.
  • the thromboembolism cascade ensues.
  • Thromboembolism as a process leading to the formation of thrombus (blood clot); once this thrombus dislodges from its origin, it forms an embolus, which flows downstream in the blood vessel tree as a thromboembolus and clogs up blood flow.
  • a thrombus is a solid mass consisting of platelets, fibrin and blood components.
  • An embolus is a piece of thrombus broken free and carried into the bloodstream.
  • Thromboembolus is a floating embolus that becomes lodged and blocks blood flow, which is the fatal component in CVD.
  • the blood pressure generated by the pumping heart fluctuates and blood flow particularly slows down at arterial forks and bends, notably in the coronary arteries.
  • High fat diet increases blood viscosity and further stagnates blood flow; this stagnation creates low shear and consequently shedding or disruption of the endothelial glycocalyx.
  • Glycocalyx thickness range from 2 to 3 ⁇ in small arteries to 4.5 ⁇ in carotid arteries (2007. J Vase Res 44:87-98) and shedding or damage to this layer decreases protective shield leading to leakage of nutrients (extravasation) and tissue edema, loss of nutritional blood flow, and an increase in coagulability due to platelet and leucocyte clumping (adhesion).
  • therapeutic strategies can be directly aimed at preserving, supporting, or reconstituting the glycocalyx structure or strategies either indirectly by down regulating inflammatory processes or directly by inhibition of glycocalyx degradation with antioxidants (2006. American Journal of Physiology: Heart and Circulatory Physiology, vol. 290, no. 6, pp. H2247-H2256).
  • An example of an anti-inflammatory drug is etanercept (Enbrel), which inhibits TNF-a, and reduces the shedding of glycocalyx constituents, coagulation activation, and functional vessel function in humans (2009. Atherosclerosis, vol. 202, no. 1, pp. 296-303).
  • antithrombin therapy since thrombin is known to cleave the syndecan component of glycocalyx (2009. Circulation Research, vol. 104, no. 11, pp. 1313-1317). Indeed, antithrombin theraqpy protects glycocalyx from TNF-a and ischemia/reperfusion-induced shedding in hearts (2009. Basic Research in Cardiology, vol. 104, no. 1, pp. 78-89; 2010. Shock, vol. 34, no. 2, pp. 133-139), which is accompanied by reduced postischemic leukocyte adhesion in hearts, reduced vascular permeability, reduced coronary leak, and reduced interstitial edema (2009. Basic Research in Cardiology, vol. 104, no. 1, pp. 78-89).
  • CVD includes a family of diseases affecting both arteries and veins: diseases in the arteries include coronary heart disease (CHD), myocardial infarction (Ml), stroke, hypertension, atrial fibrillation, congestive heart failure (CHF), congenital heart condition, and peripheral arterial disease (PAD); diseases in the veins include venous thrombosis, deep venous thrombosis (DVT), and pulmonary embolism (PE).
  • CHD coronary heart disease
  • Ml myocardial infarction
  • CHF congestive heart failure
  • PED peripheral arterial disease
  • diseases in the veins include venous thrombosis, deep venous thrombosis (DVT), and pulmonary embolism (PE).
  • Coronary heart disease results from the effects of atherosclerotic plaque formation in coronary arteries.
  • the reduction in blood supply to the heart muscles reduces the heart's efficiency and can cause heart failure.
  • One of the first and major symptoms of this condition is angina (chest pain caused by reduced blood flow to the heart muscle).
  • Myocardial infarction (Ml), commonly known as heart attack, is the irreversible necrosis of heart muscle due to prolonged interruption of blood supply (ischemia).
  • ischemia blood supply
  • the heart requires constant supply of oxygen and nutrients; if one of the arteries or branches becomes blocked suddenly, the heart is starved of oxygen, a condition called “cardiac ischemia.” If cardiac ischemia lasts too long, the starved heart tissue dies, which is called heart attack (myocardial infarction) literally, "death of heart muscle”.
  • Stroke occurs when brain cells die owing to a lack of blood supply, which may be classified as ischemic or hemorrhagic: ischemic stroke involves decreased blood supply to parts of the brain, leading to brain cell death and thus brain dysfunction; hemorrhagic stroke is due to rupture of blood vessels or abnormal vascular structure, causing accumulation of blood in a part of the brain. The majority of strokes (80%) are ischemic in nature.
  • Hypertension or high blood pressure is defined as a condition wherein the pressure of the blood flowing through blood vessels remains high for a prolonged period irrespective of the body's need. An increased blood pressure leads the heart to work harder, which makes the heart and arteries more susceptible to injury. Hypertension further increases the risk of incidents such as heart attack, heart failure, and atherosclerosis.
  • Cardiac arrhythmias are heart rhythm problems, which occur when heartbeats are not well coordinated owing to improper electric impulses. This may cause the heart to beat too fast (tachycardia) or too slowly (bradycardia). Arrhythmias are generally harmless and momentary, but frequent rhythm disturbances increase the risk of stroke and congestive heart failure. Atrial fibrillation is the most common sustained arrhythmia
  • Congestive heart failure is a condition wherein the heart fails to supply blood to the various parts of the body. This can be due to narrowed arteries, myocardial infarction, heart valve disease, high blood pressure, cardiomyopathy, or congenital abnormalities.
  • Peripheral artery disease is a vascular disorder in which the thickening of arteries causes reduction in blood flow to limbs, leading to intermittent leg pain while walking.
  • the disease is an indicator of atherosclerosis. It leads to sores (that do not heal) and gangrenes.
  • Deep Vein Thrombosis is a blood clot that usually forms in the deep veins of the lower leg or arm, which can block the venous return.
  • a DVT may cause leg pain or swelling, but can also present no symptoms.
  • DVT is not usually life threatening, but it can be if the blood clot breaks loose and lodges into the lungs. This is known as a pulmonary embolism (PE).
  • PE pulmonary embolism
  • cardiovascular therapeutic drugs do not, nor are they intended to focus on the cause of CVD, but are focused on developing medicines that target the symptoms of CVD.
  • Strategies currently existing in the marketplace are the development and marketing of symptom- targeted drugs while incidences of cardiovascular disease (CVD) still continue to rise.
  • symptom-targeted drugs currently marketed against cardiovascular disease including cholesterol-lowering drugs such as statins and fibrates for CHD; diuretics, ACE inhibitors, ARBs, calcium inhibitors, and ⁇ -blockers for hypertension; and, anti- clotting drugs such as anti-coagulants (e.g. heparin, rivaroxaban, low molecular weight heparin, dabigatran etexilate mesylate, bivalirudin, Coumadin, abciximab, eprifibatide, tirofiban), antiplatelets (e.g.
  • clopidogrel bisulfate prasugrel, ticagrelor, cilostazol, aspirin, terutroban, dipyridamole
  • fibrinolytics e.g. tissue plasminogen activator (tPA), streptokinase
  • these therapies at best mask and treat the symptoms (hypertension, lipidemia, clotting) of CVD, and not the root causes.
  • the therapies decrease levels of fibrin or platelets but do not bust or dissolve clots, they cause either excessive bleeding at high doses or clotting at low doses, and they can decrease Vitamin K levels leading to poor calcium control and heart calcification and osteoporosis.
  • some drugs such as statins have risk of serious side effects such as liver damage, type 2 diabetes, prostate cancer, memory loss, confusion, and dementia.
  • nitroglycerin is administered for angina symptoms such as chest pain in order to open blood vessels and improve blood flow. It is not administered to treat the underlying cause of why the blood vessels are constricted in the first place.
  • Anti-inflammatories such as aspirin, ibuprofen, and naproxen (NSAIDS - non-steroidal antiinflammatory drugs) are administered in order to reduce inflammation or swelling in the body and relieve pain. They are not administered to treat the underlying cause of why the inflammation is present.
  • Analgesics especially narcotic analgesics (morphine, codeine, oxycodone, and other opiates), are administered to relieve the symptom of pain or severe pain. They are not administered to treat the underlying cause of the pain.
  • One of the few existing therapeutics that treats an underlying cause is antibiotics, which are administered to kill or inhibit the growth of bacteria in the body. The bacteria themselves can present a whole range of symptoms including pain, irritation, and inflammation that go away once the source is eliminated.
  • the present invention provides for a composition for treating multiple disease causes including a glycocalyx restoring and maintaining compound.
  • the present invention provides for a method of treating multiple disease causes, by administering a glycocalyx restoring and maintaining compound to an individual, restoring the glycocalyx, reversing inflammation, and reversing oxidative damage.
  • the present invention provides for a method of treating cardiovascular disease (CVD), by administering a glycocalyx restoring and maintaining compound to an individual suffering from CVD, restoring the glycocalyx, reversing inflammation, and reversing oxidative damage.
  • CVD cardiovascular disease
  • the present invention provides for a method of restoring the glycocalyx by administering the glycocalyx restoring and maintaining compound to an individual and restoring the glycocalyx.
  • the present invention provides for a method of reversing inflammation by administering the glycocalyx restoring and maintaining compound to an individual, reversing inflammation, and restoring the glycocalyx.
  • the present invention provides for a method of reversing oxidative damage by administering the glycocalyx restoring and maintaining compound to an individual, reversing oxidative damage, and restoring the glycocalyx.
  • the present invention also provides for a method of treating any disease involving a membrane that has a glycocalyx, by administering the glycocalyx restoring and maintaining compound to an individual, restoring the glycocalyx of the membrane, reversing inflammation, and reversing oxidative damage.
  • the present invention provides for a method of disrupting the glycocalyx by administering a glycocalyx disrupting compound to a n individual, and loosening and disrupting the glycocalyx in order to administer a therapeutic.
  • the present invention further provides for a method of treating multiple disease causes, by administering a combination therapeutic to an individual, and targeting multiple causes of a disease.
  • FIGURE 1 is a depiction of three enzymes associated with the glycocalyx that regulate blood flow.
  • FIGURES 2A-2H are photographs of 'curative' and 'preventive' histopathology of arterial vessels in compounds B, F, I, and K;
  • the present invention is generally directed to methods and compositions that restore the glycocalyx. Disruption of the glycocalyx is at the root of many diseases, especially CVD.
  • the compositions of the present invention maintain the integrity of glycocalyx in many different membranes.
  • Disrupting or “disruption of” the glycocalyx as used herein refers to any process or disease state that affects the glycocalyx such that it is not functioning normally. Disruption can be caused by inflammation or oxidation in the body. Disruption can cause the glycocalyx to thin and lose its component proteoglycans.
  • Inflammation refers to a protective response of tissue to injury or destruction in order to eliminate or cordon off any injurious agent and the injured tissue and initiate tissue repair. Inflammation can cause pain, heat, redness, swelling, and loss of function. Inflammatory mediators (cytokines and chemoattractants) can cause shedding of the glycocalyx. Inflammation can also cause leukocytes to degranulate enzymes that can degrade the glycocalyx.
  • Oxidative damage refers to an imbalance of reactive oxygen species (ROS) and the body's ability to detoxify reactive intermediates and repair damage caused by ROS. Inflammation can cause the release of ROS. The presence of ROS can cause significant damage to cell structures, including the glycocalyx.
  • ROS reactive oxygen species
  • Antioxidant refers to a molecule that inhibits the oxidation of other molecules and is able to neutralize or eliminate ROS.
  • the present invention provides for a composition for treating multiple disease causes of a glycocalyx restoring and maintaining compound.
  • the composition preferably treats disruption of the glycocalyx, inflammation, and oxidative damage.
  • the composition can also treat any one of these causes individually.
  • the glycocalyx restoring and maintaining compound can be any suitable compound that is able to perform these functions in the body.
  • the glycocalyx restoring and maintaining compound can be a peptide and homolog of the glycopeptides in the glycocalyx that act to stimulate glycoprotein synthesis.
  • the peptide portion of the molecule is synthesized first, then the sugar moieties are incorporated. Attachment of the peptide portion to the surface appears to be by association between a region of repeated amino acids and components of the glycocalyx.
  • the glycocalyx restoring and maintaining compound can be any of the compounds FTX-214, FTX-218, FTX-219, FTX-226-4, FTX-224-2, or FTX-216-4, alone or in combination.
  • Each compound can be effective on its own for the indications described below and for restoring the glycocalyx, but in combination they can synergistically be used to restore and maintain the glycocalyx as well as provide the other functions described below.
  • FTX-214 is an antioxidant and increases the antioxidative capacity to prevent buildup of reactive oxygen species that damage glycocalyx by boosting the antioxidant enzymes GSH, SOD, and CAT.
  • FTX-214 (melatonin 6, ⁇ - ⁇ xyloside) is shown in FORMULA I.
  • FTX-218 is an anti-inflammatory, neutralizes cytokines, and promotes glycocalyx synthesis.
  • FTX-218 lipoate-choline is shown in FORMULA II.
  • FTX-219 repairs the glycocalyx, restores component building block parts, and boosts synthesis of glycocalyx as it is a glycocalyx peptidoglycan precursor.
  • FTX-219 lipoate-cysteine- glutamic tripeptide is shown in FORMULA III.
  • FTX-226-4 (piperidine ribose, shown in FORMULA IV) is an anti-TG/obesity compound that inhibits production of two important proinflammatory mediators, IL6 and PGE2 (triggers pain) and enhances drug bioavailability by inhibiting drug metabolism or by increasing absorption.
  • FTX-226-4 can be useful in combination treatments with other drugs by improving therapeutic effect or lower the dose requirements of other drugs when administrated with DMARDs as a therapeutic drug or dietary supplement. It is an antihypertensive and inhibits platelet aggregation and stabilizes and increases activity of eNOS that leads to decreased blood pressure.
  • FTX-224-2 (Di Oxide isothiocyanate indole, shown in FORMULA V) is an antithromt designed to inhibit blood clotting. It also provides anti-inflammatory, antiproliferation, a antiangiogenesis effects and is known to prevent glutathione depletion in the liver.
  • FTX-216-4 (6-N-oxide ribose-phenazinol, shown in FORMULA VI) is a glycocalyx stabilizer.
  • ⁇ -D-Xylosides act as primers for GAG chain initiation and compete with the xylosilated core protein, which adds galactose to a xylose residue on the core protein.
  • Xyloside activity varies with the aglycone (since primers compete with endogenous substrates and inhibits proteoglycan (PG) and glycoprotein synthesis, type of aglycone is critical).
  • FTX-216-4 reduces inflammatory cytokines and is a broad spectrum antimicrobial agent.
  • the glycocalyx restoring and maintaining compound can be a combination of the compounds FTX-214, FTX-218, and FTX-219.
  • Each compound can be effective on its own for the indications described below and for restoring the glycocalyx, but in combination they can synergistically be used to restore and maintain the glycocalyx, and reverse inflammation and oxidative damage that can be damaging and disrupting the glycocalyx.
  • any combination of the above compounds can be administered orally and preferably in a single dosage form, i.e. each compound can be contained together within a single oral dosage form.
  • the dose for any of the compounds can be from 5 mg to 750 mg (per 70 kg average human weight).
  • the dose can be 50 mg FTX-214, 50 mg FTX-218, and 50 mg FTX-219 (effective dose) up to 750 mg FTX-214, 750 mg FTX-218, and 750 mg FTX-219 (maximum tolerated dose).
  • a 50 mg dose proved to prevent or reverse the disruption of the glycocalyx as evidenced by plaque formation of reversion, as shown in FIGURES 2A-2H (B; FTX-226-4 + FTX-229 + FTX-214; F: FTX-224-2 + FTX-216 + FTX-214; I : FTX-216 + FTX-214 + FTX-218; and K: FTX-214 + FTX-218 + FTX-219).
  • the present invention generally provides for a method of treating multiple disease causes, by administering a combination therapeutic to an individual, and targeting multiple causes of a disease.
  • the combination therapeutic has multiple components necessary to target each underlying cause of a disease.
  • Many diseases such as CVD, cancer, diabetes, or any other disease described below
  • the causes of the disease can include glycocalyx disruption, inflammation, and oxidative damage.
  • the combination therapeutic can include a component that can target glycocalyx disruption, a component that can target inflammation, and a component that can target oxidative damage.
  • the multiple components can be in a single poly pill.
  • One example of the combination therapeutic is the glycocalyx restoring and maintaining compound of the combination of FTX-214, FTX-218, and FTX-219 described above.
  • diseases were treated just by their symptoms and not their underlying causes, or a single composition was given to treat the underlying cause (as with antibiotics).
  • the present invention allows for multiple components to be administered (preferably within a single pill) that each target a different cause of disease, making it easier for a patient to take their medicine as well as targeting the root causes of their disease.
  • the present invention provides for a method of treating multiple disease causes, by administering a glycocalyx restoring and maintaining compound to an individual, restoring the glycocalyx, reversing inflammation, and reversing oxidative damage.
  • the glycocalyx restoring and maintaining compound treats the root cause of a disease, restores the glycocalyx, and maintains the glycocalyx.
  • the glycocalyx restoring and maintaining compound can be any of those described above.
  • the disease being treated can be any cardiovascular disease (CVD), as CVD involves disruption of the glycocalyx, inflammation, and oxidative damage resulting in eventual clot formation and travel of the clot to small vessels, resulting in flow disruption (i.e. stroke, etc.). Therefore, the present invention provides for a method of treating CVD, by administering a glycocalyx restoring and maintaining compound to an individual suffering from CVD, restoring the glycocalyx, reversing inflammation, and reversing oxidative damage.
  • CVD cardiovascular disease
  • the CVD being treated can be, but is not limited to, coronary heart disease, myocardial infarction, stroke, hypertension, atrial fibrillation, congestive heart failure, congenital heart condition, peripheral arterial disease, venous thrombosis, deep venous thrombosis, and pulmonary embolism.
  • the disease being treated with the glycocalyx restoring and maintaining compound can also be any disease or condition with the indications of disrupted glycocalyx, inflammation, and/or oxidative damage.
  • a disrupted glycocalyx can be indicated in damage to the body (as it cushions the plasma membrane and protects it from chemical injury), impaired immunity to infection (as it enables the immune system to recognize and selectively attack foreign organisms), cancer (changes in the glycocalyx of cancerous cells enable the immune system to recognize and destroy them), transplant rejection (it forms the basis for compatibility of blood transfusions, tissue grafts, and organ transplants), cell adhesion issues (it binds cells together so that tissues do not fall apart), inflammation regulation diseases (glycocalyx coating on endothelial walls in blood vessels prevents leukocytes from rolling/binding in healthy states), fertilization issues (as it enables sperm to recognize and bind to eggs), embryonic development issues (as it guides embryonic cells to their destinations), and diabetes.
  • Inflammation can be indicated in plasma cell leukemia, rheumatoid arthritis, multiple myeloma, Lennert syndrome, Castleman's disease, cardiac myxomas, liver cirrhosis, chronic polyarthritis, bacterial and viral meningitis, graft-versus-host reactions, intra-amniotic infections, inflammatory intestinal disease, many cancers and advanced cancers (including pancreatic cancer), encephalitis, decreased gene expression, schizophrenia, depression, bacterial, viral, fungal, parasitic infections, microbial toxins, tissue necrosis, foreign bodies present, immune reaction, acne vulgaris, asthma, autoimmune diseases, celiac disease, chronic prostatitis, glomerulonephritis, hypersensitivities, inflammatory bowel diseases, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, vasculitis, interstitial cystitis, atherosclerosis, allergies, myopathies, leukocyte defects, endometriosis, and multiple
  • Oxidative damage can be indicated in cancer, Parkinson's disease, Alzheimer's disease, atherosclerosis, heart failure, myocardial infarction, fragile X syndrome, sickle cell disease, lichen planus, vitiligo, autism, infection, and chronic fatigue syndrome. It should be understood that the glycocalyx restoring and maintaining compound can not only reverse the diseases listed above but also prevent their occurrence.
  • the present invention also includes the following methods.
  • a method of restoring the glycocalyx is provided by administering the glycocalyx restoring and maintaining compound and restoring the glycocalyx.
  • a method of reversing inflammation is provided by administering the glycocalyx restoring and maintaining compound, reversing inflammation, and restoring the glycocalyx. In other words, by reversing inflammation which can be causing disruption and damage of the glycocalyx, the glycocalyx can be restored to normal function.
  • a method of reversing oxidative damage is provided by administering the glycocalyx restoring and maintaining compound, reversing oxidative damage, and restoring the glycocalyx.
  • the glycocalyx can be restored to normal function.
  • the present invention also provides more generally for a method of treating any disease involving a membrane that has a glycocalyx, by administering a glycocalyx restoring and maintaining compound to an individual, restoring the glycocalyx of the membrane, reversing inflammation, and reversing oxidative damage.
  • the glycocalyx restoring and maintaining compound can treat, restore, and maintain any membrane.
  • the glycocalyx is a carbohydrate-rich, extrinsic cell surface coat that forms a layer along the apical epithelium of cells. Glycocalyx components are key elements in eukaryotic cell, tissue, and organ homeostasis.
  • Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body. Many glands are made up of epithelial cells. The lining of the mouth, lung alveoli, kidney tubules, and ocular surface are all made of epithelial tissue. The lining of the blood and lymphatic vessels are of a specialized form of epithelium called endothelium. Epithelial cells line up the cavity of tissues throughout the body and form glands, a major layer in mucosal membrane. Endometrium consists of a single layer of columnar epithelium resting on the stroma, a layer of connective tissue that varies in thickness according to hormonal influences.
  • the functional layer which is adjacent to the uterine cavity, is completely shed during menstruation. It is adapted to provide an optimum environment for the implantation and growth of the embryo.
  • the basal layer which is adjacent to the myometrium and below the functional layer, is not shed at any time during the menstrual cycle, and from it the functional layer develops.
  • the membrane can be epithelial linings in general or more specifically glands, mouth linings, lung alveoli, kidney tubules, ocular surfaces, blood vessels, lungs, endometrial linings, digestive tract linings, or any other lining in the body.
  • the glycocalyx restoring and maintaining compound can be any of those described above.
  • the glycocalyx restoring and maintaining compound can also be administered in combination with other therapeutic agents to treat specific diseases and conditions.
  • the therapeutic agents can include, but are not limited to, non-steroidal anti-inflammatory drugs (NSAIDS) such as, but not limited to, acetaminophen, salicylates (aspirin, diflunisal, salsalate), acetic acid derivatives (indomethacin, ketorolac, sulindac etodolac, diclofenac, nabumetone), propionic acid derivatives (ibuprofen, naproxen, flurbiprofen, ketoprofen, oxaprozin, fenoprofen, loxoprofen), fenamic acid derivatives (meclofenamic acid, mefenamic acid, flufenamic acid, tolfenamic acid), oxicam (enolic acid) derivatives (piroxicam, meloxicam, tenoxicam, droxicam
  • the therapeutic agent can also be generally from the classes antihistamines, anti-infective agents, antineoplastic agents, autonomic drugs, blood derivatives, blood formation agents, coagulation agents, thrombosis agents, cardiovascular drugs, cellular therapy, central nervous system agents, contraceptives, dental agents, diagnostic agents, disinfectants, electrolytic, caloric, and water balance, enzymes, respiratory tract agents, eye, ear, nose, and throat preparations, gold compounds, heavy metal antagonists, hormones and synthetic substitutes, oxytocics, radioactive agents, serums, toxoids, and vaccines, skin and mucous membrane agents, smooth muscle relaxants, and vitamins. Any combination of therapeutic agents can be administered. These therapeutic agents can be administered at the same time, before, or after the glycocalyx restoring and maintaining compound, they can be in separate or the same dosage form, and they can have different or the same release profiles.
  • a glycocalyx disrupting compound in treating cancer, can be administered with an immune potentiator in order to disrupt the glycocalyx and allow for an immune attack by the body (potentiated by the immune potentiator especially in immune deficient individuals) to reduce and destroy any cancer cells. It can be difficult to deliver therapeutics to the brain or eyes because of the special barriers that protect them.
  • the brain has a blood-brain barrier property due to specially tight and thick endothelium junctions.
  • the eye also has a protective endothelium.
  • Pretreatment with the glycocalyx disrupting compound can loosen up the endothelium in order to deliver therapeutics past the protective barrier. Therefore, the present invention provides for a method of disrupting the glycocalyx by administering a glycocalyx disrupting compound to an individual, and loosening and disrupting the glycocalyx in order to administer a therapeutic.
  • the compound of the present invention is administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, patient age, sex, body weight and other factors known to medical practitioners.
  • the pharmaceutically "effective amount" for purposes herein is thus determined by such considerations as are known in the art. The amount must be effective to achieve improvement including but not limited to improved survival rate or more rapid recovery, or improvement or elimination of symptoms and other indicators as are selected as appropriate measures by those skilled in the art.
  • the compound of the present invention can be administered in various ways. It should be noted that it can be administered as the compound and can be administered alone or as an active ingredient in combination with pharmaceutically acceptable carriers, diluents, adjuvants and vehicles.
  • the compounds can be administered orally, subcutaneously or parenterally including intravenous, intraarterial, intramuscular, intraperitoneally, intratonsillar, and intranasal administration as well as intrathecal and infusion techniques. Implants of the compounds are also useful.
  • the patient being treated is a warmblooded animal and, in particular, mammals including man.
  • the pharmaceutically acceptable carriers, diluents, adjuvants and vehicles as well as implant carriers generally refer to inert, nontoxic solid or liquid fillers, diluents or encapsulating material not reacting with the active ingredients of the invention.
  • the doses can be single doses or multiple doses over a period of several days.
  • the treatment generally has a length proportional to the length of the disease process and drug effectiveness and the patient species being treated.
  • the pharmaceutical formulations suitable for injection include sterile aqueous solutions or dispersions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • the carrier can be a solvent or dispersing medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Nonaqueous vehicles such as cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil, or peanut oil and esters, such as isopropyl myristate, may also be used as solvent systems for compound compositions.
  • various additives which enhance the stability, sterility, and isotonicity of the compositions including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added.
  • antibacterial and antifungal agents for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • isotonic agents for example, sugars, sodium chloride, and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. According to the present invention, however, any vehicle, diluent, or additive used would have to be compatible with the compounds.
  • Sterile injectable solutions can be prepared by incorporating the compounds utilized in practicing the present invention in the required amount of the appropriate solvent with various other ingredients, as desired.
  • a pharmacological formulation of the present invention can be administered to the patient in an injectable formulation containing any compatible carrier, such as various vehicle, adjuvants, additives, and diluents; or the compounds utilized in the present invention can be administered parenterally to the patient in the form of slow-release subcutaneous implants or targeted delivery systems such as monoclonal antibodies, vectored delivery, iontophoretic, polymer matrices, liposomes, and microspheres.
  • any compatible carrier such as various vehicle, adjuvants, additives, and diluents
  • the compounds utilized in the present invention can be administered parenterally to the patient in the form of slow-release subcutaneous implants or targeted delivery systems such as monoclonal antibodies, vectored delivery, iontophoretic, polymer matrices, liposomes, and microspheres.
  • Examples of delivery systems useful in the present invention include: 5,225,182; 5,169,383; 5,167,616; 4,959,217; 4,925,678; 4,487,603; 4,486,194; 4,447,233; 4,447,224; 4,439,196; and 4,475,196. Many other such implants, delivery systems, and modules are well known to those skilled in the art.

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Abstract

L'invention concerne une composition de traitement de causes de multiples maladies contenant un composé de restauration et d'entretien du glycocalyx. L'invention concerne un procédé de traitement de causes de multiples maladies, en administrant un composé de restauration et d'entretien du glycocalyx à un individu, en restaurant le glycocalyx, en inversant l'inflammation, et en inversant la détérioration oxydative. L'invention concerne un procédé de traitement de maladies cardiovasculaires (CVD) en administrant un composé de restauration et d'entretien du glycocalyx à un individu souffrant de CVD, en restaurant le glycocalyx, en inversant l'inflammation, et en inversant la détérioration oxydative. L'invention concerne un procédé de restauration du glycocalyx en administrant le composé de restauration et d'entretien du glycocalyx à un individu et en restaurant le glycocalyx. L'invention concerne des procédés d'inversion de l'inflammation et d'inversion de la détérioration oxydative en administrant le composé de restauration et d'entretien du glycocalyx à un individu. L'invention concerne un procédé de traitement de toute maladie impliquant une membrane comportant un glycocalyx. L'invention concerne un procédé de perturbation du glycocalyx. L'invention concerne un procédé de traitement de causes de multiples maladies.
PCT/US2016/026360 2015-04-09 2016-04-07 Procédés et compositions pour l'inversion de la perturbation du glycocalyx, de l'inflammation et de la détérioration oxydative Ceased WO2016164534A1 (fr)

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