Methods and compositions for reversing disruption of the glycocalyx, inflammation, and oxidative damage

Abstract

A composition for treating multiple disease causes including a glycocalyx restoring and maintaining compound. 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. A method of treating cardiovascular disease. A method of restoring the glycocalyx. A method of reversing inflammation. A method of reversing oxidative damage. A method of treating any disease involving a membrane that has a glycocalyx. A method of treating multiple disease causes. A method of restoring the structural and functional integrity of receptors in the glycocalyx. A method of restoring the glycocalyx and receptors therein and potentiating drug response. A composition for treating disease including the glycocalyx restoring and maintaining compound and an antibody. A composition for treating cardiovascular disease including the glycocalyx restoring and maintaining compound and a MAb anti-PCSK9.

Claims

1. A composition comprising a compound or a combination of compounds selected from the group consisting of: ##STR00017## ##STR00018## ##STR00019## ##STR00020## and ##STR00021## or a composition comprising the compound: ##STR00022## and two or more compounds selected from the group consisting of FORMULAS I, III-VI, VII and VIII ##STR00023## ##STR00024## or a composition comprising the compound of FORMULA VII and one or more compounds selected from the group consisting of FORMULAS I-VI and VIII; or a composition comprising the compound of FORMULA VIII and two or more compounds selected from the group consisting of FORMULAS I-VII.

2. The composition of claim 1, wherein said composition is in an oral dosage form.

3. The composition of claim 2, wherein each compound present in said composition is present in an amount from 5 mg to 750 mg.

4. The composition of claim 1, wherein the composition comprises a combination of compounds comprising: ##STR00025##

5. The composition of claim 4, wherein each compound present in said composition is present in an amount from 5 mg to 750 mg.

6. The composition of claim 3, wherein each compound present in said composition is present in an amount of 50 mg.

7. A method of restoring and/or maintaining the integrity of a glycocalyx lining of membrane, the method comprising administering the composition of claim 1 to an individual.

8. A method of restoring and/or maintaining the integrity of a glycocalyx lining of an endothelial vessel wall, the method comprising administering the composition of claim 2 to an individual.

9. The method of claim 7, wherein the composition comprises a combination of compounds comprising: ##STR00026##

10. The composition of claim 1, wherein the composition comprises the compound: ##STR00027##

11. The composition of claim 1, wherein the composition comprises the compound: ##STR00028##

12. The composition of claim 1, wherein the composition comprises the compound: ##STR00029##

13. The composition of claim 1, wherein the composition comprises the compound: ##STR00030##

14. The method of claim 7, wherein the method comprises administering a composition comprising the compound: ##STR00031##

15. The method of claim 7, wherein the method comprises administering a composition comprising the compound: ##STR00032##

16. The method of claim 7, wherein the method comprises administering a composition comprising the compound: ##STR00033##

17. The method of claim 7, wherein the method comprises administering a composition comprising the compound: ##STR00034##

18. The method of claim 9, wherein at least two compounds are administered to produce a synergistic effect in: restoring the glycocalyx of the membrane; reversing inflammation; and/or reversing oxidative damage.

19. The method of claim 9, wherein at least three compounds are administered to produce a synergistic effect in: restoring the glycocalyx of the membrane; reversing inflammation; and/or reversing oxidative damage.

Description

DESCRIPTION OF THE DRAWINGS

(1) Other advantages of the present invention are readily appreciated as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings wherein:

(2) FIG. 1 is a depiction of three enzymes associated with the glycocalyx that regulate blood flow; and

(3) FIG. 2 shows photographs of ‘curative’ and ‘preventive’ histopathology of arterial vessels in compounds B, F, I, and K: Compound B—Preventative (A) and Curative (B); Compound F—Preventative (C) and Curative (D); Compound I—Preventative (E) and Curative (F); Compound K—Preventative (G) and Curative (H).

DETAILED DESCRIPTION OF THE INVENTION

(4) 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.

(5) “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.

(6) “Inflammation” as used herein 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.

(7) “Oxidative damage”, “oxidative stress”, or “oxidation” as used herein 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.

(8) “Antioxidant” as used herein refers to a molecule that inhibits the oxidation of other molecules and is able to neutralize or eliminate ROS.

(9) 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.

(10) For example, the glycocalyx restoring and maintaining compound can be a peptide and homolog of the glycopeptides in the glycocalyx that acts to stimulate glycoprotein synthesis. During 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.

(11) Most preferably, the glycocalyx restoring and maintaining compound can be a combination of the compounds FTX-214, FTX-218, and FTX-219. Alternatively, 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 (and as such they can be used individually in the methods herein), 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.

(12) FTX-214 is an antioxidant and increases the antioxidative capacity to prevent build-up of reactive oxygen species that damage glycocalyx by boosting the antioxidant enzymes GSH, SOD, and CAT. FTX-214 is shown in FORMULA I.

(13) ##STR00001##
The chemical name of FTX-214, according to International Union of Pure and Applied Chemistry (IUPAC) nomenclature rules, and the IUPAC numbering are shown below in Table 1.

(14) FTX-218 is an anti-inflammatory, neutralizes cytokines, and promotes synthesis. FTX-218 (lipoate-choline) is shown in FORMULA II.

(15) ##STR00002##
The IUPAC numbering and chemical name of FTX-218 are shown below in Table 1.

(16) FTX-219 repairs the glycocalyx and restores component building block parts and boosts synthesis of glycocalyx. FTX-219 (lipoate-cysteine-glutamic tripeptide) is shown in FORMULA III.

(17) ##STR00003##
The IUPAC numbering and chemical name of FTX-219 are shown in Table 1.

(18) TABLE-US-00001 TABLE 1 Chemical name and structure (IUPAC) of FTX-218, FTX-219 and FTX-219 Com- pound ID FTX- 218 FTX- 219 FTX- 214

(19) FTX 216-4 has base functionality of 6-N-oxide ribose-phenazinol as exemplified in FORMULA IV.

(20) ##STR00007##
The chemical name of FTX 216-4 is 5-hydroxy-1-((3,4,5-trihydroxytetrahydrofuran-2-yl)methoxy)phenazin-5-ium, according to IUPAC rules, with priority numbering as shown below:

(21) ##STR00008##

(22) The composition in FORMULA IV stimulates chondroitin sulfate synthesis, the second most common glycosaminoglycan (GAG) in the endothelial cell glycocalyx. β-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 inhibit proteoglycan (PG) and glycoprotein synthesis, type of aglycone is critical). The composition is a broad spectrum antimicrobial agent.

(23) FTX 224-2 (FORMULA V) (Di Oxide isothiocyanate indole) was designed to inhibit blood clotting.

(24) ##STR00009##
The chemical name of FTX 224-2 is 5-((3(pyrrolidin-1-yl)propyl)sulfonyl)pentanenitrile, according to IUPAC rules, with priority numbering as shown below:

(25) ##STR00010## Also, the compound of FORMULA V acts as an anti-inflammation agent antiproliferation agent and an antiangiogenesis agent and is known to prevent glutathione depletion in the liver. FTX 226-4 is a piperidine ribose as exemplified in FORMULA VI.

(26) ##STR00011##
The chemical name of FTX 226-4 is 5-((piperidin-3-yloxy)methyl)tetrahydrofuran-2,3,4-triol, according to IUPAC rules, with priority numbering as shown below:

(27) ##STR00012##

(28) The compound of FORMULA VI inhibits production of two important proinflammatory mediators, IL6 and PGE2 (triggers pain) and enhances drug bioavailability by inhibiting drug metabolism or by increasing absorption. This compound can be useful in combination treatments with other drugs by improving therapeutic effect or lowering the dose requirements of other drugs when administrated with disease-modifying antirheumatic drugs (DMARDs) as a therapeutic drug or dietary supplement. The compound is an antihypertensive as it inhibits platelet aggregation, and stabilizes and increases activity of eNOS, which leads to decreased blood pressure. FTX 229 is a nicotinyl choline as exemplified in FORMULA VII.

(29) ##STR00013##
The chemical name of FTX 229 is N,N,N-trimethyl-2-(nicotinoyloxy)ethan-1-aminium, according to IUPAC rules, with priority numbering as shown below:

(30) ##STR00014##

(31) After the discovery of the nicotinic acid receptor GPR109A on adipocytes and immune cells, novel direct immunomodulatory properties of nicotinic acid have been identified, including the release of inflammatory mediators from adipose tissue, direct anti-inflammatory activities of nicotinic acid in other cells previously indicated as key players in atherogenesis (such as hepatocytes and endothelial and vascular cells), nicotinic acid keeps macrophages from entering the atherosclerotic vascular wall by activating its receptor, thereby halting chronic inflammation. On the other hand, choline serves various functions in mammalian bodies: structure of cell membranes, protecting the liver from accumulating fat, as the precursor molecule for the neurotransmitter acetylcholine, and more. Choline via its metabolite, trimethylglycine (betaine), is a major source for methyl groups that participates in the S-adenosylmethionine synthesis pathways, used in treating hepatitis, glaucoma, atherosclerosis, and, possible; neurological disorders.

(32) FTX 230 is an ammonium lipoate, as exemplified in FORMULA VIII.

(33) ##STR00015##

(34) Lipoid acid is reduced to dihydrolipoic acid and serves as an antioxidant. Reduced glutathione (GSH) is the most abundant non-protein thiol in mammalian cells and the preferred substrate for several enzymes in xenobiotic metabolism and antioxidant defense, but direct use of GSH as a therapeutic agent is limited because of its unfavorable biochemical and pharmacokinetic properties.

(35) The chemical name of FTX 230 (IUPAC) is 5-(1,2-dithiolan-3-yl)pentanamide according to IUPAC rules with priority numbering as shown below:

(36) ##STR00016##

(37) It should also be understood that any of the above compounds can be used individually and in any combination to achieve desired effects. Any of these compounds alone or together prevent damage or shedding of existing glycocalyx layers as well as provide any of the functionality described above. The compounds can be administered orally and preferably in a single dosage form. The dose for any of the compounds can 5 mg to 750 mg (per 70 kg average human weight). In the preferred combination, 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 FIGS. 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).

(38) 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) have multiple mechanisms involved in their presentation. For example, the causes of the disease can include glycocalyx disruption, inflammation, and oxidative damage. In order to treat this disease, 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. Previously, 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.

(39) 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. Normal blood flow shear is necessary for a balanced shedding and synthesis of the proteoglycan components of the glycocalyx and maintaining the residency of various enzymes and signaling molecules including the antioxidant superoxide dismutase (SOD), anti-inflammatory antithrombin (AT-III), and proteases (thrombin, plasmin, protease-3, and elastase that are important in blood clotting, immunity, and inflammation). Once the balance of these resident enzymes are disrupted, glycocalyx shedding ensues followed by a cascade of pathological events. Thus, the therapeutic approach of the present invention that improves the glycocalyx structure and function also can prevent the pathological processes connected with vascular inflammation. The composition is able to restore the balance of the enzymes above.

(40) More specifically, 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, restoring the glycocalyx, reversing inflammation, and reversing oxidative damage. 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.

(41) The disease being treated with the glycocalyx restoring and maintaining compound can also be any disease with the indications of disrupted glycocalyx, inflammation, and/or oxidative damage. For example, 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 sclerosis. 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.

(42) Since the glycocalyx restoring and maintaining compound can treat any one of disruption of the glycocalyx, inflammation, and oxidative damage individually or in combination, the present invention also includes the following methods. A method of restoring the glycocalyx is provided by administering the glycocalyx restoring and maintaining compound to an individual and restoring the glycocalyx. A method of reversing inflammation is provided by administering the glycocalyx restoring and maintaining compound to an individual, 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 to an individual, reversing oxidative damage, and restoring the glycocalyx. In other words, by reversing oxidative damage which can be causing disruption and damage of the glycocalyx, the glycocalyx can be restored to normal function.

(43) 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 that has a glycocalyx. The membrane can be, but is not limited to, blood vessels, lungs, endometrial linings, digestive tract linings, epithelium, or any other lining in the body. The glycocalyx restoring and maintaining compound can be any of those described above.

(44) 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. Functions of epithelial cells include secretion, selective absorption, protection, transcellular transport and detection of sensation. Cells of epithelial tissue are tightly packed and form a continuous sheet. Epithelial cells line up the cavity of tissues throughout the body and form glands; major layer in mucosal membrane. Most epithelial cells have a fuzz-like coat on the external surface of their plasma membranes called glycocalyx, a glycoprotein-polysaccharide covering that surrounds the cell membranes, including some bacteria. This coating consists of several carbohydrate moieties of membrane glycolipids and glycoproteins, which serve as backbone molecules for support. Generally, the carbohydrate portion of the glycolipids found on the surface of plasma membranes helps these molecules contribute to cell-cell recognition, communication, and intracellular adhesion.

(45) The lining of the mouth, lung alveoli, and kidney tubules all are made of epithelial tissue. The lining of the blood and lymphatic vessels are of a specialized form of epithelium called endothelium. Epithelium lines both the outside (skin) and the inside cavities and lumen of bodies. Epithelial cells in mucosal surfaces are continuously faced with the critical function of forming a protective apical barrier that prevents cellular damage and infection while allowing the exchange of molecules with the extracellular milieu. Loss of barrier function is ascribed to numerous mucosal pathologies, such as dry eye, severe asthma, and inflammatory bowel disease.

(46) The primary functions of epithelial tissues are: (1) to protect the tissues that lie beneath it from radiation, desiccation, toxins, invasion by pathogens, and physical trauma; (2) the regulation and exchange of chemicals between the underlying tissues and a body cavity; (3) the secretion of hormones into the blood vascular system, and/or the secretion of sweat, mucus, enzymes, and other products that are delivered by ducts; and (4) to provide sensation. The glycocalyx restoring and maintaining compound can treat, restore, and maintain any epithelial tissue that has a glycocalyx.

(47) 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, lornoxicam, isoxicam), arylalkanoic acid derivatives (tolmetin); or selective COX-2 inhibitors (celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib). 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. 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.

(48) In other diseases, it can be advantageous to disrupt the glycocalyx. For example, in treating cancer, a glycocalyx disrupting compound 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.

(49) Receptors are imbedded in and pass through the glycocalyx. Transmembrane glycoprotein receptors are an integral part of a membrane bound receptor. Disruption of the glycocalyx, can render dysfunctional and structurally disrupt these membrane bound receptors. The glycocalyx restoring and maintaining compound can restore the glycocalyx and restore structural integrity and function to those receptors. Therefore, the present invention provides for a method of restoring the structural and functional integrity of receptors in the glycocalyx by administering the glycocalyx restoring and maintaining compound to an individual, and restoring structural integrity and function of receptors imbedded in and passing through the glycocalyx.

(50) The receptors in the glycocalyx can be for various antigens and antibodies, both polyclonal and monoclonal. By restoring the receptor integrity, the total systemic effect of the ligand (i.e. antigen or antibody) can be restored to a healthy condition and effectively increased. The activity can be metabolic, immunologic, or any other activity that is receptor-controlled. The response of antibodies can be potentiated with administration of the glycocalyx restoring and maintaining compound because the receptors they bind to are restored.

(51) Therefore, the present invention provides for a method of restoring the glycocalyx and receptors therein and potentiating drug response, by administering the glycocalyx restoring and maintaining compound and an antibody to an individual suffering from disease, restoring the glycocalyx, restoring receptors in the glycocalyx, and potentiating the response of the antibody. The present invention also provides for a composition for treating diseases including the glycocalyx restoring and maintaining compound and an antibody. The components of this combination can be in the same dosage form or in different dosage forms, and can be administered with different or the same release profiles.

(52) The disease being treated can be any disease or condition for which an antibody can be used to treat, such as, but not limited to, autoimmune diseases, cancers, metabolic disorders, or infectious diseases. The receptor being restored can be any receptor that the particular antibody binds to or otherwise interacts with.

(53) The antibody can generally be any suitable monoclonal or polyclonal antibody, such as, but not limited to, 3F8, 8H9, abagovomab, abciximad, abrilumab, actoxumab, adalimumab, adecatumumab, aducanumab, afelimomab, afutuzumab, alacizumab pegol, ALD518, alemtuzumab, alirocumab, altumomab pentetate, amatuximab, anatumomab mafenatox, anifrolumab, anrukinzumab, apolizumab, arcitumomab, aselizumab, atinumab, atlizumab, atorolumumab, bapineuzumab, basiliximab, bavituximab, bectumomab, belimumab, benralizumab, bertilimumab, besilesomab, bevacizumab, beziotoxumab, biciromab, bimagrumab, bivatuzumab mertansine, blinatumomab, blosozumab, brentuximab vedotin, briakinumab, brodalumab, canakinumab, cantuzumab mertansine, cantuzumab ravtansine, caplacizumab, capromab pendetide, carlumab, catumaxomab, cBR96-doxorubicin immunoconjugate, CC49, cedelizumab, certolizumab pegol, cetuximab, Ch.14.18, citatuzumab bogatox, cixutumumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, cnatumumab, concizumab, CR6261, crenezumab, dacetuzumab, daclizumab, dalotuzumab, daratumumab, demcizumab, denosumab, detumomab, dinutuximab, diridavumab, dorlimomab aritox, drozitumab, duligotumab, dupilumab, durvalumab, dusigitumab, ecromeximab, eculizumab, edobacomab, edrecolomab, efalizumab, efungumab, eldelumab, elotuzumab, elsilimomab, emibetuzumab, enavatuzumab, enfortumab vedotin, enlimomab pegol, enokizumab, enoticumab, ensituximab, epitumomab cituxetan, epratuzumab, erlizumab, ertumaxomab, etaracizumab, etrolizumab, evinacumab, evolocumab, exbivirumab, fanolesomab, faralimomab, farletuzumab, fasinumab, FBTA05, felvizumab, fezakinumab, ficlatuzumab, figitumumab, flanvotumab, fletikumab, fontolizumab, foralumab, forvirumab, fresolimumab, fluranumab, futuximab, galiximab, ganitumab, gantenerumab, gavilimomab, gemtuzumab ozogamicin, gevokizumab, girentuximab, glembatumumab vedotin, golimumab, gomiliximab, guselkumab, ibalizumab, ibritumomab tiuxetan, icrucumab, igovomab, IMAB362, imciromab, imgatuzumab, inclacumab, indatuximab ravtansine, infliximab, inolimomab, inotuzumab ozogamicin, intetumumab, ipilimumab, iratumumab, itolizumab, ixekizumab, keliximab, labetuzumab, lambrolizumab, lampalizumab, lebrikizumab, lemalesomab, lerdelimumab, lexatumumab, libivirumab, lifastuzumab vedotin, ligelizumab, lintuzumab, lirilumab, lodelcizumab, lorvotuzumab, lorvotuzumab mertansine, lucatumumab, lulizumab pegol, lumiliximab, mapatumumab, margetuximab, maslimomab, matuzumab, mavrilimumab, mepolizumab, metelimumab, milatuzumab, minretumomam, mitumomab, mogamulizumab, morolimumab, motavizumab, moxetumomab pasudotox, muromonab-CD3, nacolomab tafenatox, namilumab, naptumomab estafenatox, narnatumab, natalizumab, nebacumab, necitumumab, nerelimomab, nesvacumab, nimotuzumab, nivolumab, nofetumomab merpentan, obiltoxaximab, ocaratuzumab, ocrelizumab, odulimomab, ofatumumab, olaratumab, olokizumab, omalizumab, onartuzumab, ontuxizumab, oportuzumab monatox, oregovomab, orticumab, otelixizumab, otlertuzumab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, palivizumab, panitumumab, pankomab, panobacumab, parsatuzumab, pascolizumab, pateclizumab, patritumab, pembrolizumab, pemtumomab, perakizumab, pertuzumab, pexelizumab, pidilizumab, pinatuzumab vedotin, pintumomab, placulumab, polatuzumab vedotin, ponezumab, priliximab, pritoxaximab, pritumumab, PRO 140, quilizumab, racotumomab, radretumab, rafivirumab, ramucirumab, ranibizumab, raxibacumab, regavirumab, reslizumab, rilotumumab, rituximab, robatumumab, roledumab, romosozumab, rontalizumab, rovelizumab, ruplizumab, samilizumab, sarilumab, satumomab pendetide, secukinumab, seribantumab, setoxaximab, sevirumab, SGN-CD19A, SGN-CD33A, sibrotuzumab, sifalimumab, siltuximab, simtuzumab, siplizumab, sirukumab, sofitzumab vedotin, solanezumab, solitomab, sonepcizumab, sontuzumab, stamulumab, sulesomab, suvizumab, tabalumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tanezumab, taplitumomab paptox, tarextumab, tefibazumab, telimomab aritox, tenatumomab, teneliximab, teplizumab, teprotumumab, TGN1412, ticilimumab, tigatuzumab, tildrakizumab, TNX-650, tocilizumab, toralizumab, tositumomab, tovetumab, tralokinumab, trastuzumab, TRBS07, tregalizumab, tremelimumab, tucotuzumab celmoleukin, tuvirumab, ublituximab, urelumab, urtoxazumab, ustekinumab, vantictumab, vapaliximab, varlilumab, vatelizumab, vedolizumab, veltuzumab, vepalimomab, vesencumab, volociximab, vorsetuzumab mafodotin, votumumab, zalutumumab, zanolimumab, zatuximab, ziralimumab, or zolimimab aritox.

(54) One particular receptor whose integrity can be restored by the glycocalyx restoring and maintaining compound is the LDL receptor, which mediates LDL endocytosis in the liver, the major route of LDL clearance from circulation. It is desired to reduce LDL levels in individuals with high cholesterol and atherosclerosis and other cardiovascular diseases. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in cholesterol metabolism by controlling the levels of LDL particles that circulate in the bloodstream. PCSK9 increases plasma LDL cholesterol by promoting degradation of the LDL receptor. Monoclonal antibody (MAb) anti-PCSK9 (U.S. Pat. No. 8,062,640 to Sleeman, et al., U.S. Pat. Nos. 8,030,457, 8,168,762, U.S. Patent Application Publication Nos. 2011/0027287, 2012/0020975, 2012/0027765, 2012/0213797, and 2012/0251544 to Jackson, et al., WO2011/027257 to Champion, et al. describe various MAb anti-PCSK9's) is used to bind with PCSK9, or a portion(s) thereof, in order to block its mechanism of action. However, the effectiveness of MAb anti-PCSK9 is diminished when there has been disruption of the glycocalyx and in turn disruption of the receptors therein, including the LDL receptor. By administering the glycocalyx restoring and maintaining compound and restoring the glycocalyx, the LDL receptor can be restored as well, increasing receptor binding, and thereby increasing the efficacy of MAb anti-PCSK9 in a patient suffering from cardiovascular disease and lowering LDL levels.

(55) Therefore, the present invention provides for a method of restoring the glycocalyx and receptors therein and potentiating drug response, by administering the glycocalyx restoring and maintaining compound and MAb anti-PCSK9 to an individual suffering from cardiovascular disease, restoring the glycocalyx, restoring LDL receptors in the glycocalyx, and potentiating the response of the MAb anti-PCSK9. The MAb anti-PCSK9 can be any of those described above, as well as bococizumab (Pfizer RN316, described in U.S. Pat. No. 8,080,243 to Liang, et al.). The present invention also provides for a composition for treating cardiovascular diseases including the glycocalyx restoring and maintaining compound and a MAb anti-PCSK9. The components of this combination can be in the same dosage form or in different dosage forms, and can be administered with different or the same release profiles.

(56) 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.

(57) In the method of the present invention, 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, intra-arterial, 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 warm-blooded animal and, in particular, mammals including man. The pharmaceutically acceptable carriers, diluents, adjuvants and vehicles as well as implant carriers generally refer to inert, non-toxic solid or liquid fillers, diluents or encapsulating material not reacting with the active ingredients of the invention.

(58) 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.

(59) When administering the compound of the present invention parenterally, it will generally be formulated in a unit dosage injectable form (solution, suspension, emulsion). 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.

(60) 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 a 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. Additionally, various additives which enhance the stability, sterility, and isotonicity of the compositions, including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. In many cases, it will be desirable to include 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.

(61) 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 of the other ingredients, as desired.

(62) 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. Examples of delivery systems useful in the present invention include: U.S. Pat. Nos. 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.

(63) Throughout this application, various publications, including United States patents, are referenced by author and year and patents by number. Full citations for the publications are listed below. The disclosures of these publications and patents in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

(64) The invention has been described in an illustrative manner, and it is to be understood that the terminology, which has been used is intended to be in the nature of words of description rather than of limitation.

(65) Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention can be practiced otherwise than as specifically described.