CN111989098A - Compounds and compositions for the treatment of muscle disorders - Google Patents
Compounds and compositions for the treatment of muscle disorders Download PDFInfo
- Publication number
- CN111989098A CN111989098A CN201980026811.XA CN201980026811A CN111989098A CN 111989098 A CN111989098 A CN 111989098A CN 201980026811 A CN201980026811 A CN 201980026811A CN 111989098 A CN111989098 A CN 111989098A
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- epicatechin
- bone
- muscle
- follistatin
- weakening
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Abstract
The present invention relates to compounds and compositions and their use as medicaments for ameliorating bone damage, or weakening of bone, or loss of bone, or preventing bone fractures. Exemplified herein is the administration of a therapeutically effective dose of (+) -epicatechin and/or (-) -epicatechin or an epicatechin derivative to a subject to ameliorate bone damage, or weakening of bone, or loss of bone, or to prevent bone fracture.
Description
Disclosed herein are compounds and compositions and their use as medicaments for the treatment, prevention or reversal of damage to skeletal or cardiac muscle, for the treatment or prevention of diseases associated with structural and functional abnormalities of skeletal or cardiac muscle, and for inducing regeneration or remodeling of skeletal or cardiac muscle, as a means of treating diseases associated with abnormal structural and functional abnormalities of skeletal or cardiac muscle in a human or animal subject. Also disclosed herein are methods for diagnosing skeletal muscle or cardiac muscle damage and for diagnosing the success or failure of therapies designed to treat, prevent, or reverse skeletal muscle or cardiac muscle damage.
The strength and endurance of skeletal muscles are essential for grasping, carrying, walking, running, carrying, or performing many functions of daily life. The strength and endurance of the myocardium are essential for optimal delivery of oxygen and nutrients to all tissues containing the blood vessels and for carrying away waste products of cellular metabolism. Damage to skeletal or cardiac muscle or diseases associated with abnormal structure or function of skeletal or cardiac muscle can make normal activities of daily life difficult or impossible.
In addition, injury or weakness of skeletal muscle often results in loss of bone density in the bone to which the muscle is attached. In the case of systemic muscle weakness, the decrease in bone density can be systemic, which is one of the causes of a bone disease known as osteoporosis. Bone formation or maintenance of healthy bone density is the end result of two opposing cellular processes. Osteoblasts form bone; they are derived from mesenchymal precursor cells. Osteoclasts degrade bone; they are formed from macrophage precursors. Bone disease occurs when the two cellular components of bone remodeling are not balanced. Osteoporosis results from overactivation of osteoclasts or impaired osteoblastogenesis, a state in which bone is highly susceptible to fracture (Raggatt, L et al, 2010, Cellular and molecular mechanisms of bone remodelling, J Biol Chem 285:25103-25108 (journal of biochemistry, Vol. 285, p. 25103-25108)). Another cause of osteoporosis is long-term anti-inflammatory treatment with glucocorticoids, which also weaken the muscle. Corticosteroids induce osteoclast activation and stimulate osteoblast apoptosis, thereby shifting the balance of bone remodeling to a state of increased incidence of pathological fractures. Current treatments are limited in efficacy and consist primarily of bisphosphonates and anabolic agents such as teriparatide. Both classes of drugs have significant side effects and safety risks, resulting in poor patient compliance with these agents. There is a significant need for additional agents that safely and effectively treat osteoporosis.
In addition to glucocorticoids, other factors known to activate osteoclasts include members of the transforming growth factor beta family, including activin a and myostatin. Follistatin is a protein that acts as a naturally occurring inhibitor of myostatin and activin a in stimulating muscle regeneration, thereby preventing or reversing muscle atrophy associated with myostatin and activin a. Follistatin has been shown to inhibit activin A-mediated stimulation of the osteoclastogenesis regulator NFATc1 (Kajita, T et al, 2018, Michansis secreted in enhancement of osteoclastogenesis by activin-A, J Cell Biochem 119:6974-698 (activin A enhances the mechanisms involved in osteoclastogenesis. J. Biochem. J. Cell. Biochem. 119, Vol. 119, p. 6974-698); Kawao, N et al, 2018, Role of follistatin protein and bone alterations induced by change of gravity in mice, J. Cell Physiol. change in mice, J. P. 1191-)).
Damage to skeletal or cardiac muscle may be due to genetic mutations in proteins critical to the structure and function of skeletal or cardiac muscle, insufficient or disrupted blood flow, inactivity due to joint injury or inflammation (as seen in arthritis), overexposure to oxidative damage due to defects in cellular metabolism or insufficient blood flow, exposure to toxic organic or inorganic substances (such as elevated glucose, heavy metals or inflammatory products), trauma due to injury or overactivity, or exposure to certain drugs (such as statins, corticosteroids or chemotherapy, etc.). Examples of inflammatory diseases associated with muscle disorders include polymyositis, polymyalgia rheumatica, and systemic lupus erythematosus.
Injury and subsequent weakness or atrophy of skeletal muscle may occur as a result of damage or disease of neurons that promote muscle function. Proper innervation is essential for skeletal muscle health and function. Neurodegenerative diseases suitable for treatment with agents that stimulate muscle strength and neuromuscular health include Amyotrophic Lateral Sclerosis (ALS), parkinson's disease, huntington's disease, spinal cord injuries or abnormalities, and peripheral and central neuropathy.
Current treatments emphasize prophylaxis, such as the use of stents to improve blood flow through narrowed regions of the vessel. There are general supportive interventions that help muscle repair itself, such as the nutritional supply of muscle protein precursors (such as amino acids or creatine). Current treatments may address the underlying conditions associated with myocardial or skeletal muscle dysfunction without directly treating the muscle cells themselves. The only accepted treatment for the muscle itself is exercise. Regular, moderate activation of myocytes has been shown to improve the structure and function of cardiac and skeletal myocytes. However, this is often insufficient to restore muscle cell health or function.
Complicating potential therapy is the fact that neither skeletal muscle nor cardiac myocytes are able to proliferate sufficiently to replace previously damaged or destroyed myocytes. The ability of stem cells to proliferate may be limited, but this is often insufficient to regenerate functionally significant replacement muscles. Skeletal muscle is known to contain primary satellite cells that can activate, expand and differentiate into skeletal muscle tissue. The role of satellite cells in replacement of cardiomyocytes is currently unknown. Muscle repair is enhanced by myocyte expression of follistatin, which allows muscle precursor cells to activate and differentiate into mature differentiated skeletal muscle cells. Repair of muscle cells or the production of new differentiated muscle cells is inhibited by the expression of a negative regulator known as myostatin.
Disclosed herein are methods of prophylactically and/or therapeutically treating a skeletal or cardiac muscle dysfunction, injury, or disease in a patient by administering epicatechin, an epicatechin derivative, a pharmaceutically acceptable salt or prodrug thereof, or a combination thereof. The methods and compositions described herein can help prevent impaired skeletal and cardiac muscle function, restore skeletal or cardiac muscle health or function, or functionally significantly regenerate skeletal or cardiac muscle cells or function.
In certain embodiments, the invention comprises administering a compound or composition disclosed herein in an amount effective to stimulate the function, recovery, or regeneration of skeletal muscle or cardiac myocytes. Stimulating muscle cell function, recovery, or regeneration may include increasing expression of one or more of the proteins having contraction, regulation, transcription, or attachment functions. Stimulating muscle cell function, recovery or regeneration may include increasing mitochondrial number and function. In certain embodiments, the compound or composition comprises a therapeutically effective amount of epicatechin, the (+) or (-) enantiomer, or a combination of both, an epicatechin derivative, or a pharmaceutically acceptable salt or prodrug thereof.
In additional embodiments, the invention provides methods and compositions for preventing or treating adverse events or diseases associated with impaired skeletal or cardiac myocyte number or function. The method comprises administering to a subject in need thereof one or more compounds or compositions disclosed herein. In additional embodiments, the method reduces a symptom of impaired skeletal muscle or cardiac muscle cell number or function. In certain embodiments, the method comprises administering a composition comprising a therapeutically effective amount of epicatechin, the (+) or (-) enantiomer, or a combination of both, an epicatechin derivative, or a pharmaceutically acceptable salt or prodrug thereof.
In certain embodiments, disclosed herein are methods and compositions for treating diseases associated with loss of skeletal muscle cells or cardiac muscle cells in number, function, or correct, optimally effective internal tissue. In certain embodiments, the method comprises administering a composition comprising a therapeutically effective amount of epicatechin, the (+) or (-) enantiomer, or a combination of both, an epicatechin derivative, or a pharmaceutically acceptable salt or prodrug thereof.
In additional embodiments, disclosed herein are methods and compositions for treating impaired skeletal or cardiac muscle function due to aging, obesity, disuse or inactivity, exposure to potentially toxic nutrients such as fructose, or exposure to insufficient nutrients such as hunger or malnutrition. In certain embodiments, the method comprises administering a composition comprising a therapeutically effective amount of epicatechin, the (+) or (-) enantiomer, or a combination of both, an epicatechin derivative, or a pharmaceutically acceptable salt or prodrug thereof.
In additional embodiments, disclosed herein are methods and compositions for treating muscle-related side effects (including soreness, cramps, weakness, pain, or injury) of athletic training or competition. In certain embodiments, the method comprises administering a composition comprising a therapeutically effective amount of epicatechin, the (+) or (-) enantiomer, or a combination of both, an epicatechin derivative, or a pharmaceutically acceptable salt or prodrug thereof.
In additional embodiments, disclosed herein are methods and compositions for treating skeletal or cardiac muscle diseases associated with ischemia or impaired or insufficient blood flow. Examples of such conditions include, but are not limited to, atherosclerosis, trauma, diabetes, vascular stenosis, peripheral arterial disease, vascular lesions, and vasculitis. In certain embodiments, the method comprises administering a composition comprising a therapeutically effective amount of epicatechin, the (+) or (-) enantiomer, or a combination of both, an epicatechin derivative, or a pharmaceutically acceptable salt or prodrug thereof.
In additional embodiments, disclosed herein are methods and compositions for treating diseases associated with genetic disorders that directly or indirectly affect the number, structure, or function of cardiomyocytes or skeletal muscle cells. Examples of such conditions include, but are not limited to, a group of diseases broadly classified as muscular dystrophy and friedrich's ataxia. In certain embodiments, the method comprises administering a composition comprising a therapeutically effective amount of epicatechin, the (+) or (-) enantiomer, or a combination of both, an epicatechin derivative, or a pharmaceutically acceptable salt or prodrug thereof.
In additional embodiments, disclosed herein are methods and compositions for the therapeutic treatment of diseases associated with impaired neurological control of muscle activity resulting in structural and functional abnormalities of skeletal muscle due to inactivity, abnormal contraction, or contraction states. These diseases include, but are not limited to, conditions associated with loss, reduction, or abnormality of neural activity, including peripheral denervation syndrome, trauma, amyotrophic lateral sclerosis, meningitis, and structural abnormalities of the spine (whether congenital or acquired). In certain embodiments, the method comprises administering a composition comprising a therapeutically effective amount of epicatechin, the (+) or (-) enantiomer, or a combination of both, an epicatechin derivative, or a pharmaceutically acceptable salt or prodrug thereof.
In certain embodiments, disclosed herein are methods and compositions for treating diseases associated with loss of number of skeletal muscle cells or cardiac muscle cells, loss of function, or loss of correct, optimally effective internal tissue. Such diseases can occur in functionally significant states of muscle atrophy, the most obvious form of which is known as sarcopenia. Sarcopenia may be secondary to a variety of disorders including aging, diabetes or other abnormal metabolic disorders, infection, inflammation, autoimmune disease, cardiac dysfunction or the severe disuse syndrome or inactivity associated with arthritis. Examples of such diseases include, but are not limited to, congestive heart failure, aging, myocarditis, myositis, polymyalgia rheumatica, polymyositis, HIV, cancer, and/or side effects of chemotherapy against cancer, malnutrition, aging, inborn errors of metabolism, trauma, stroke, or other types of neurological deficits. In certain embodiments, the method comprises administering a composition comprising a therapeutically effective amount of epicatechin, the (+) or (-) enantiomer, or a combination of both, an epicatechin derivative, or a pharmaceutically acceptable salt or prodrug thereof.
In certain embodiments, disclosed herein are methods and compositions for use in conjunction with exercise or programmed sequence or intensity exercise to optimize methods for prophylactic or therapeutic treatment of diseases or conditions associated with loss of number, function, or proper optimally effective internal tissue of skeletal muscle cells or cardiac muscle cells. In certain embodiments, the method comprises administering a composition comprising a therapeutically effective amount of epicatechin, the (+) or (-) enantiomer, or a combination of both, an epicatechin derivative, or a pharmaceutically acceptable salt or prodrug thereof.
In certain embodiments, disclosed herein are methods and compositions for enhancing athletic performance and endurance, building muscle shape and strength, and promoting recovery from muscle-related side effects of training or competition (such as soreness, weakness, cramps, pain, or injury). In certain embodiments, the method comprises administering a composition comprising a therapeutically effective amount of epicatechin, the (+) or (-) enantiomer, or a combination of both, an epicatechin derivative, or a pharmaceutically acceptable salt or prodrug thereof.
In certain embodiments, disclosed herein are methods and compositions for preventing, ameliorating, or reversing muscle damage, weakness, or pain associated with the administration of certain drugs, including but not limited to corticosteroids such as prednisone, methylprednisolone, or their halogenated derivatives, chemotherapeutic agents such as doxorubicin or methotrexate, and inhibitors of HMG co-reductase, known as statins, which are often associated with muscle disorders or myopathies, including: advicor "' (niacin sustained release/lovastatin), Altoprev" ' (lovastatin sustained release), Caduet "' (amlodipine and atorvastatin), Crestor" ' (rosuvastatin), Juvisync "' (sitagliptin/simvastatin), Lescol" ' (fluvastatin), Lescol XL (fluvastatin sustained release), Lipitor "' (atorvastatin), Compactin (mevastatin),(pitavastatin), Mevacor '"(lovastatin), Pravachol'" (pravastatin), Simcor '"(niacin sustained release/simvastatin), Vytorin'" (ezetimibe/simvastatin), and Zocor "(simvastatin). In certain embodiments, the method comprises administering a composition comprising a therapeutically effective amount of epicatechin, the (+) or (-) enantiomerOr a combination of both, an epicatechin derivative, or a pharmaceutically acceptable salt or prodrug thereof.
In certain embodiments, disclosed herein are methods and compositions for preventing, ameliorating, or reversing muscle damage associated with damage to mitochondria and/or drugs that cause myopathy as a secondary outcome.
In certain embodiments, a subject is selected for treatment with a compound or composition disclosed herein based on the occurrence of one or more physiological manifestations of skeletal or cardiac muscle injury or dysfunction in the subject. Such manifestations include elevation of biomarkers known to be associated with injury to cardiac or skeletal muscle. Examples of such biomarkers include, but are not limited to, elevated plasma levels of cardiac or skeletal myoproteases or proteins, such as myoglobin, troponin, or creatine phosphokinase, lactic acidosis, and elevated serum creatinine.
In certain embodiments, a compound or composition disclosed herein is administered in an amount that stimulates an increase in the number or function of skeletal or contractile muscle cells. Such stimulation of muscle cells may include stimulation of one or more aspects of muscle cell function, including cell division, muscle cell regeneration, activation of muscle satellite cells and their differentiation into adult muscle cells, recovery from injury, increased number or function of mitochondria or processes that exert mitochondrial function, increased expression of proteins that contribute to contractility, modulation of biochemical or translational processes, mitosis, or transduction of mechanical energy via dystrophin or other attachment processes. The methods and compositions described herein can help to prevent the consequences of muscle damage or dysfunction that have not yet occurred, as well as provide an active treatment for muscle damage, dysfunction, or disease that has already occurred.
In certain embodiments, disclosed herein are methods of using muscle proteins whose expression is stimulated by administering a compound or composition disclosed herein as a diagnostic biomarker by which to determine the time and extent of muscle response to the therapeutic methods and compositions disclosed herein. Such biomarkers can be determined by measuring the protein itself or DNA or RNA nucleotides encoding the protein in tissue, plasma, blood or urine. In one embodiment, the reduction of useful muscle proteins in the body, such as dystrophin, or the presence of inhibitory proteins, such as thrombospondin, can be used to diagnose the severity of myocardial structural or functional abnormalities or the probability of response to the therapeutic methods and compositions described herein. In another embodiment, changes in the levels of such biomarkers can be used to assess the success or failure of certain treatment modalities, including those disclosed herein, in order to optimize dosages and decide whether to maintain or alter treatment methods and compositions.
In another embodiment, an increase in plasma concentration of follistatin, or a decrease in myostatin, or an increase in the ratio of plasma follistatin to plasma myostatin can be used as a diagnostic method to diagnose the severity of a muscle disorder or the extent of response to treatment.
In certain embodiments, the methods disclosed herein comprise administering to the cell at least 0.1) lM epicatechin or epicatechin derivatives, at least 0.25) lM epicatechin or epicatechin derivatives, at least 0.5) lM epicatechin or epicatechin derivatives, and at least 1) lM epicatechin or epicatechin derivatives.
In further embodiments, the methods disclosed herein comprise administering a compound of the present disclosure in a total daily dose of about 0.1 mg/kg/dose to about 100 mg/kg/dose, or about 0.3 mg/kg/dose to about 30 mg/kg/dose. In another embodiment, the dosage range is from about 0.5 mg/kg/day to about 10 mg/kg/day. Or from about 0.5 mg/kg/day to about 1 mg/kg/day. Generally, about 25mg to about 1g per day; alternatively, about 25mg to about 200mg may be administered. The dose may conveniently be administered in a plurality of divided doses.
In further embodiments, the methods disclosed herein comprise administering epicatechin, an epicatechin derivative, or a mixture thereof, in a range of about 1mg/kg to about 1000mg/kg, about 1mg/kg to about 50mg/kg, or about 10mg/kg to about 100mg/kg of the subject's body weight.
In further embodiments, the desired concentration is maintained for at least 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, or more. In other embodiments, the desired concentration is achieved at least once during each 12 hour period for at least 24 hours, 48 hours, 72 hours, 1 week, one month, or more; or the desired concentration is reached at least once during each 24 hour period for at least 48 hours, 72 hours, 1 week, one month, or more. To maintain the desired concentration over the desired time, various doses of one or more compounds may be employed. The dosing interval may be determined based on the clearance half-life of each compound of interest from the body.
In certain embodiments, the epicatechin or epicatechin derivative administered in the methods disclosed herein is at least 90% pure relative to other compounds selected from the group consisting of epicatechin, an epicatechin derivative, catechin, or a catechin derivative. For example, if the compound is epicatechin, it contains no more than 10% epicatechin derivatives, catechins, and contamination of catechin derivatives. In further embodiments, the selected epicatechin or epicatechin derivative is at least 95% pure relative to other compounds selected from the group consisting of epicatechin, epicatechin derivatives, catechin, or catechin derivatives. It should be noted that this does not exclude combination with a substantial concentration of additional therapeutic agents.
In a further embodiment, the epicatechin is (-) -epicatechin.
In another embodiment, the epicatechin is (+) -epicatechin.
In other embodiments, the epicatechin is a racemic mixture of (-) -epicatechin and (+) -epicatechin.
Also disclosed herein is a novel class of compounds, which are the only known agents that, when administered, induce the production of circulating follistatin in animals and humans. Follistatin and its closely homologous (80% sequence homology) family of follistatin-like proteins are produced in vivo by a variety of cell types, including myocytes and osteocytes. Follistatin is known to induce muscle regeneration in various disease states. It has recently been shown that follistatin-like protein 3 stimulates bone regeneration and increases the mechanical strength of bone during exercise. See J Nam et al, Follistatin-like 3is a mediator of existance-drive bone formation and stretch hening. bone 201578: 62-70 (Follistatin-like 3is a mediator of exercise-driven bone formation and reinforcement, bone 2015, Vol. 78, pp. 62-70), doi:10.1016/J. bone 2015.04.038. Strengthening muscle and bone exercise induces increased plasma levels of follistatin and its related follistatin-like protein. See Hansen J et al, where exposure enzymes a marked increase in plasma follistatin a concentration-induced hepatokinase.2011Endocrinology 152: 164. sup. 171 (Exercise induced significant increase in plasma follistatin: evidence that follistatin is a contractile induced liver factor, 2011. Endocrinology 152, pp. 164. sup. D. 21068158). Animals lacking follistatin exhibit weak bone formation and severe muscle weakness. See Matzuk, MM et al, Mulltule defects and pernal defects in mice in follistatin Nature 1995374:360-3 (Nature 1995, Vol.374, p.360-. The production of extracellular matrix and its mineralization are essential components of new bone formation by osteoblasts. Follistatin stimulates two activities in human osteoblast cultures. See Eijken et al, The activin A-follistatin system: patent regulator of human extracellular matrix mineralization Faeb J200721: 2949-60 (activin A-follistatin system: effective modulators of human extracellular matrix mineralization, J.Federation of Experimental biologies, 2007, Vol.21, p.2949-2960). During fracture healing, the expression of follistatin and its receptors in the periosteum near the ends of the fracture is strongly increased, indicating that follistatin contributes to bone formation and remodeling during fracture healing. See, Nagame T et al, Immunochemical detection of activin A, follistatin, and activin receptors in the rat J ortho Res 199816: 314-21 (Immunochemical detection of activin A, follistatin and activin receptors during fracture healing in rats, J.orthopedics. 1998, Vol.16, p.314-. Thus, any agent that stimulates production of follistatin should be therapeutic in the context of a number of diseases, disorders, drug side effects and genetic defects that contribute to the development of osteoporosis and its attendant increased risk of fracture.
Some embodiments relate to the following methods: inducing an increase in cellular or muscle or body production of follistatin and follistatin-like protein so as to reverse or ameliorate bone damage, weakening or loss of bone, or prevent bone fracture in a subject in need thereof, the method comprising administering to the subject a therapeutically effective dose of (+) -epicatechin and/or (-) -epicatechin or an epicatechin derivative of any of (+) -epicatechin or (-) -epicatechin. In further embodiments, (+) -epicatechin and/or (-) -epicatechin or an epicatechin derivative is administered orally or intravenously or intramuscularly at 5mg to 2g per day in single or divided doses. In other embodiments, (+) -epicatechin and/or (-) -epicatechin or an epicatechin derivative is administered orally or intravenously or intramuscularly in a single or divided dose between 0.1mg/kg body weight/day and 10mg/kg body weight/day. In still other embodiments, the method induces new or additional bone formation or stronger bone formation or bone regeneration in order to prevent the fracture.
Additional embodiments disclosed herein relate to the following methods: inducing an increase in cellular or muscle or body production of follistatin and follistatin-like proteins so as to reverse or improve weakening of the bone, thereby preventing bone fractures caused by administration of compounds known to induce weakening of bone or damage to bone, impaired osteogenesis or impaired bone growth, including but not limited to corticosteroids such as prednisone or deflazacort, anticonvulsants such as phenytoin and phenobarbital, chemotherapeutic agents such as aromatase inhibitors and progestins. Further method aspects relate to the following method: inducing an increase in cellular or muscle or body production of follistatin or follistatin-like protein so as to reverse or improve weakening of bone strength, thereby preventing fractures associated with genetic predisposition, aging, inactive lifestyle, or low estrogen status such as post-menopausal or ovariectomy; the method comprises the following steps: inducing an increase in cellular or muscle or body production of follistatin or follistatin-like protein so as to reverse or ameliorate weakening of bone caused by medical conditions known to be associated with weakening of bone or damage to bone, impaired osteogenesis or impaired bone growth (such as celiac disease, kidney or liver disease, and inflammatory diseases such as systemic lupus erythematosus and rheumatoid arthritis); the method comprises the following steps: inducing an increase in cellular or muscle or body production of follistatin or follistatin-like protein so as to reverse or ameliorate bone weakening, in combination with the administration of other agents (including calcium, vitamin D and calcitonin) for the treatment of osteoporosis so as to prevent bone fractures; the method comprises the following steps: inducing an increase in the production of cells or muscles or the body of follistatin or follistatin-like protein as a therapeutic agent that accelerates healing of bone fractures, such as those experienced in accidents, sports or combat, or increases the extent of fracture recovery; and the following method: the induction of an increase in cellular or muscular or bodily production of follistatin or follistatin-like protein in order to prevent the systemic loss of bone density and thus subsequent fracture is known to result in decreased bone density and muscle weakness following orthopedic surgery or during recovery periods following the onset of diseases or conditions requiring long periods of bed rest or physical inactivity.
In any of the preceding method embodiments, it is contemplated that (+) -epicatechin and/or (-) -epicatechin or an epicatechin derivative may optionally be administered orally or intravenously or intramuscularly at 5mg to 2g per day, and/or in single or divided doses.
Detailed Description
Thus, provided herein are methods of treating, preventing, or reversing skeletal or cardiac muscle damage, comprising administering to a patient in need thereof a therapeutically effective amount of epicatechin ((+) or (-) either of the enantiomers or a combination of both), an epicatechin derivative, a pharmaceutically acceptable salt or prodrug thereof, or a combination thereof. Also provided are compositions for treating, preventing, or reversing skeletal or cardiac muscle damage, the compositions comprising administering to a patient in need thereof a therapeutically effective amount of epicatechin ((+) or (-) either of the enantiomers or a combination of both), an epicatechin derivative, a pharmaceutically acceptable salt or prodrug thereof, or a combination thereof.
Also provided are methods of treating diseases associated with impaired skeletal or myocardial structure or impaired skeletal or myocardial function comprising administering to a patient in need thereof a therapeutically effective amount of epicatechin ((+) or (-) either or a combination of both enantiomers), an epicatechin derivative, a pharmaceutically acceptable salt or prodrug thereof, or a combination thereof. Also provided are compositions for treating, preventing, or reversing skeletal or cardiac muscle damage comprising a therapeutically effective amount of epicatechin ((+) or (-) either of the enantiomers or a combination of the two), epicatechin derivatives, pharmaceutically acceptable salts or prodrugs thereof, or combinations thereof, in a patient in need thereof.
In certain embodiments, the damage is due to aging, obesity, disuse or inactivity, exposure to potentially toxic nutrients such as fructose, or exposure to insufficient nutrients such as hunger or malnutrition.
Also provided herein are methods of inducing skeletal or cardiac muscle regeneration or remodeling comprising administering to a patient in need thereof a therapeutically effective amount of epicatechin ((+) or (-) either of the enantiomers or a combination of both), an epicatechin derivative, a pharmaceutically acceptable salt or prodrug thereof, or a combination thereof. Also provided are compositions for inducing skeletal or cardiac muscle regeneration or remodeling comprising a therapeutically effective amount of epicatechin ((+) or (-) either of the enantiomers or a combination of the two), an epicatechin derivative, a pharmaceutically acceptable salt or prodrug thereof, or a combination thereof, in a patient in need thereof.
Also provided herein are methods of diagnosing skeletal muscle or cardiac muscle damage and for diagnosing the success or failure of a therapy designed to treat, prevent or reverse skeletal muscle or cardiac muscle damage, the method comprising:
a. observing one or more physiological manifestations of skeletal or cardiac muscle injury or dysfunction in a subject;
b. administering to a patient in need thereof a therapeutically effective amount of epicatechin ((+) or (-) either of the enantiomers or a combination of both), an epicatechin derivative, a pharmaceutically acceptable salt or prodrug thereof, or a combination thereof; and
c. the change or absence is observed in said physiological manifestation of skeletal or cardiac muscle damage or dysfunction.
Also provided herein are methods of improving muscle cell function, recovery, or regeneration, comprising administering to a patient in need thereof a therapeutically effective amount of epicatechin ((+) or (-) either of the enantiomers or a combination of both), an epicatechin derivative, a pharmaceutically acceptable salt or prodrug thereof, or a combination thereof. Also provided are compositions for improving muscle cell function, recovery or regeneration, comprising a therapeutically effective amount of epicatechin ((+) or (-) either of the enantiomers or a combination of both), an epicatechin derivative, a pharmaceutically acceptable salt or prodrug thereof, or a combination thereof, in a patient in need thereof.
In certain embodiments, improving muscle cell function, recovery, or regeneration comprises increasing mitochondrial number and function.
Also provided herein are methods of treating muscle-related side effects of exercise training or competition, including soreness, cramps, weakness, pain, or injury, comprising administering to a patient in need thereof a therapeutically effective amount of epicatechin ((+) or (-) either or a combination of the two enantiomers), an epicatechin derivative, a pharmaceutically acceptable salt or prodrug thereof, or a combination thereof. Also provided are compositions for treating muscle-related side effects of exercise training or competition, including soreness, cramps, weakness, pain, or injury, comprising a therapeutically effective amount of epicatechin ((+) or (-) either or a combination of the two enantiomers), epicatechin derivatives, pharmaceutically acceptable salts or prodrugs thereof, or combinations thereof, in a patient in need thereof.
Also provided herein are methods of treating skeletal or cardiac muscle diseases associated with ischemia or impaired or insufficient blood flow, comprising administering to a patient in need thereof a therapeutically effective amount of epicatechin ((+) or (-) either or a combination of both enantiomers), an epicatechin derivative, a pharmaceutically acceptable salt or prodrug thereof, or a combination thereof. Also provided are compositions for treating skeletal or cardiac muscle diseases associated with ischemia or impaired or inadequate blood flow, comprising a therapeutically effective amount of epicatechin ((+) or (-) enantiomer, either or a combination of both), epicatechin derivatives, pharmaceutically acceptable salts or prodrugs thereof, or combinations thereof, in a patient in need thereof.
In certain embodiments, the disease is selected from the group consisting of: atherosclerosis, trauma, diabetes, vascular stenosis, peripheral arterial disease, vasculopathy and vasculitis.
Also provided herein are methods of treating a disease associated with a genetic disorder that directly or indirectly affects the number, structure, or function of cardiomyocytes or skeletal muscle cells, the method comprising administering to a patient in need thereof a therapeutically effective amount of epicatechin ((+) or (-) either or a combination of both enantiomers), an epicatechin derivative, a pharmaceutically acceptable salt or prodrug thereof, or a combination thereof. Also provided are compositions for treating a disease associated with a genetic disorder that directly or indirectly affects the number, structure, or function of cardiomyocytes or skeletal muscle cells, the composition comprising a therapeutically effective amount of epicatechin ((+) or (-) either or a combination of both enantiomers), an epicatechin derivative, a pharmaceutically acceptable salt or prodrug thereof, or a combination thereof, in a patient in need thereof.
In certain embodiments, the disease is selected from the group consisting of muscular dystrophy and friedrich's ataxia.
Also provided herein are methods of treating a disease associated with impaired neurological control of muscle activity resulting in abnormal structure and function of skeletal muscle due to inactivity, abnormal contraction or contraction states, comprising administering to a patient in need thereof a therapeutically effective amount of epicatechin ((+) or (-) either or a combination of the two enantiomers), an epicatechin derivative, a pharmaceutically acceptable salt or prodrug thereof, or a combination thereof. Also provided are compositions for treating diseases associated with impaired neurological control of muscle activity resulting in abnormal structure and function of skeletal muscle due to inactivity, abnormal contraction or contraction states, comprising a therapeutically effective amount of epicatechin ((+) or (-) either or a combination of both enantiomers), an epicatechin derivative, a pharmaceutically acceptable salt or prodrug thereof, or a combination thereof, in a patient in need thereof.
In certain embodiments, the disease is selected from the group consisting of: peripheral denervation syndrome, trauma, amyotrophic lateral sclerosis, meningitis and structural abnormalities of the spine.
Also provided herein are methods of treating a disease associated with loss of number, loss of function, or loss of correct, optimally effective internal tissue of skeletal or cardiac myocytes, the method comprising administering to a patient in need thereof a therapeutically effective amount of epicatechin ((+) or (-) either or a combination of the two enantiomers), an epicatechin derivative, a pharmaceutically acceptable salt or prodrug thereof, or a combination thereof. Also provided are compositions for treating diseases associated with loss of number, loss of function, or loss of correct optimally effective internal tissue of skeletal muscle cells or cardiac muscle cells, the compositions comprising a therapeutically effective amount of epicatechin ((+) or (-) either or a combination of both enantiomers), an epicatechin derivative, a pharmaceutically acceptable salt or prodrug thereof, or a combination thereof, in a patient in need thereof.
In certain embodiments, the disease is muscle atrophy.
In certain embodiments, the disease is sarcopenia.
In certain embodiments, the sarcopenia is associated with aging, diabetes, an abnormal metabolic disorder, an infection, inflammation, an autoimmune disease, cardiac dysfunction, arthritis, congestive heart failure, aging, myocarditis, myositis, polymyalgia rheumatica, polymyositis, HIV, cancer, a side effect of chemotherapy, malnutrition, aging, inborn errors of metabolism, trauma, stroke, and impaired neurological function.
In certain embodiments, the method of treating a disease associated with loss of number of skeletal muscle cells or cardiac muscle cells, loss of function, or loss of correct, optimally effective internal tissue further comprises exercise or exercise of a programmed sequence or intensity.
Also provided herein are methods of enhancing athletic performance, endurance, building muscle shape or strength, or promoting recovery from the effects of training or competition, comprising administering to a patient in need thereof a therapeutically effective amount of epicatechin ((+) or (-) either or a combination of both enantiomers), an epicatechin derivative, a pharmaceutically acceptable salt or prodrug thereof, or a combination thereof. Also provided are compositions for enhancing athletic performance, endurance, building muscle shape or strength, or promoting recovery from the effects of training or competition, comprising a therapeutically effective amount of epicatechin ((+) or (-) either or a combination of both enantiomers), epicatechin derivatives, pharmaceutically acceptable salts or prodrugs thereof, or combinations thereof, to a patient in need thereof.
Also provided herein are methods of treating muscle damage, weakness, or pain associated with administration of a drug, the methods comprising administering to a patient in need thereof a therapeutically effective amount of epicatechin ((+) or (-) either or a combination of both enantiomers), an epicatechin derivative, a pharmaceutically acceptable salt or prodrug thereof, or a combination thereof. Also provided are compositions for treating muscle damage, weakness, or pain associated with administration of a drug, the compositions comprising a therapeutically effective amount of epicatechin ((+) or (-) either or a combination of the two enantiomers), epicatechin derivatives, pharmaceutically acceptable salts or prodrugs thereof, or combinations thereof, in a patient in need thereof.
In certain embodiments, the drug is selected from the group consisting of: corticosteroids such as prednisone, methylprednisolone, or their halogenated derivatives, chemotherapeutic agents such as doxorubicinOr methotrexate, and inhibitors of HMG co-reductase, known as statins, which are often associated with muscle disorders or myopathies, including: advicor "' (niacin sustained release/lovastatin), Altoprev" ' (lovastatin sustained release), Caduet "' (amlodipine and atorvastatin), Crestor" ' (rosuvastatin), Juvisync "' (sitagliptin/simvastatin),(fluvastatin), Lescol XL (fluvastatin sustained release), Lipitor' ″ (atorvastatin), Compactin (mevastatin),(pitavastatin), Mevacor '"(lovastatin), Pravachol'" (pravastatin), Simcor '"(niacin sustained release/simvastatin), Vytorin'" (ezetimibe/simvastatin), and(simvastatin).
In certain embodiments of any of the embodiments disclosed above, the epicatechin is substantially (-) -epicatechin.
In certain embodiments of any of the embodiments disclosed above, the epicatechin is substantially (+) -epicatechin.
In certain embodiments of any of the embodiments disclosed above, the epicatechin is a racemic mixture of (-) -epicatechin and (+) -epicatechin.
In certain embodiments of any of the embodiments disclosed above, the patient is selected for treatment based on the presence of one or more physiological manifestations of skeletal or cardiac muscle injury or dysfunction in the subject.
In further embodiments, the manifestation is an increase in a biomarker selected from the group consisting of: myoglobin, troponin or creatine phosphokinase, lactic acidosis and elevated plasma levels of creatinine.
In certain embodiments of any of the embodiments disclosed above, the diagnostic biomarker is used to determine the time and extent of a muscle response.
In additional embodiments, the diagnostic biomarker is dystrophin or thrombospondin.
In certain embodiments of any of the embodiments disclosed above, the epicatechin is administered.
In certain embodiments of any of the embodiments disclosed above, the epicatechin derivative is administered.
In additional embodiments, the epicatechin, epicatechin derivatives, pharmaceutically acceptable salts and prodrugs thereof, or combinations thereof are administered orally.
In other embodiments, the epicatechin, epicatechin derivatives, pharmaceutically acceptable salts and prodrugs thereof, or combinations thereof are administered parenterally.
In other embodiments, the epicatechin, epicatechin derivatives, pharmaceutically acceptable salts and prodrugs thereof, or combinations thereof are administered as a neutraceutical.
In additional embodiments, epicatechin derivatives, pharmaceutically acceptable salts and prodrugs thereof, or combinations thereof are administered in combination with an additional therapeutic agent. The additional therapeutic agent is selected from the group consisting of: hormones that stimulate myocyte growth, y-aminobutyric acid or derivatives thereof, dietary protein supplements, anabolic steroids, biological factors known to enhance skeletal or cardiac muscle growth, strength, endurance or metabolism or to restore skeletal or cardiac muscle from injury or weakness, compounds known to be associated with increased nitric oxide production by promoting blood flow through muscle, extracts of natural products known to promote muscle strength or endurance, inhibitors of myostatin, and stimulators of follistatin expression.
Also provided herein is a method of diagnosing the severity of a muscle disorder, the method comprising the step of measuring the plasma level of follistatin, myostatin, or the ratio of follistatin to myostatin.
Also provided herein is a method of determining the extent of response to treatment of a muscle disorder, the method comprising the steps of:
a) measuring a pre-treatment plasma level of follistatin, myostatin, or a ratio of follistatin to myostatin;
b) measuring post-treatment plasma levels of follistatin, myostatin, or a ratio of follistatin to myostatin; and
c) comparing pre-and post-treatment levels of follistatin, myostatin, or a ratio of follistatin to myostatin.
Also provided herein is a method of treating a muscle disorder, the method comprising the steps of:
a) measuring for the first time the plasma levels of follistatin, myostatin, or the ratio of follistatin to myostatin;
b) administering a first amount of epicatechin ((+) or (-) enantiomer or a combination of both), an epicatechin derivative, or a pharmaceutically acceptable salt or prodrug thereof;
c) measuring post-treatment plasma levels of follistatin, myostatin, or a ratio of follistatin to myostatin;
d) comparing pre-and post-treatment levels of follistatin, myostatin, or a ratio of follistatin to myostatin; and
e) any one of the following:
i) increasing the dose of epicatechin ((+) or (-) enantiomer or a combination of both), epicatechin derivative or a pharmaceutically acceptable salt or prodrug thereof administered in step b when the measured concentration of follistatin in the subject is increased, when the measured concentration of myostatin in the subject is decreased, or when the ratio of plasma follistatin to plasma myostatin is increased; or
ii) reducing or maintaining the dose of epicatechin ((+) or (-) enantiomer or a combination of both), epicatechin derivative or a pharmaceutically acceptable salt or prodrug thereof administered in step b when the measured concentration of follistatin in the subject is reduced, when the measured concentration of myostatin in the subject is increased, or when the ratio of plasma follistatin to plasma myostatin is reduced.
In certain embodiments of any of the embodiments disclosed above, the epicatechin is a racemic mixture of greater than 50% (-) -epicatechin and less than 50% (+) -epicatechin.
In certain embodiments of any of the embodiments disclosed above, the racemic mixture is greater than 75% (-) -epicatechin.
In certain embodiments of any of the embodiments disclosed above, the racemic mixture is greater than 90% (-) -epicatechin.
In certain embodiments of any of the embodiments disclosed above, the racemic mixture is greater than 75% (+) -epicatechin.
In certain embodiments of any of the embodiments disclosed above, the racemic mixture is greater than 90% (+) -epicatechin.
Also provided herein is the use of epicatechin, (+) -epicatechin, (-) -epicatechin, (+) -epicatechin and (-) -epicatechin, an epicatechin derivative, a pharmaceutically acceptable salt or prodrug of any of the foregoing, or a combination of any of the foregoing, for the manufacture of a medicament for the treatment of any disease or for achieving any therapeutic or functional endpoint, as disclosed herein.
As used herein, the following terms have the indicated meanings.
When a range of values is disclosed and the symbol "from n.. to n" or "between n.,. and n" is used, where n and n2 are numbers, the symbol is intended to include the numbers themselves and ranges therebetween unless otherwise indicated. The range can be whole or continuous between and including the endpoints. By way of example, a range of "2 to 6 carbons" is intended to include two, three, four, five, and six carbons, as carbons are present in integer units. By way of example, comparing the range "1 uM to 3uM (micromolar)" with any number of significant figures (e.g., 1.255uM, 2.1uM, 2.9999uM, etc.), the range is intended to include 1uM, 3uM, and all values therebetween.
As used herein, the term "about" is intended to quantify the modification to it, thereby expressing such values as variables within a margin of error. When a specific error range is not set forth (such as the standard deviation from the mean value given in a data sheet or data table), the term "about" should be understood to mean that the range for the value set forth will be covered and that the range for which the effective figure is also considered to be encompassed by rounding to that number.
As used herein, the term "disease" is intended to be generally synonymous with and used interchangeably with the terms "disorder", "syndrome" and "condition" (as in medical conditions), as all of these reflect an abnormal condition of one of the human or animal bodies or parts thereof that impairs normal function, usually manifested as distinguishing signs and symptoms, and results in a reduction in the time to live or quality of life of the human or animal.
The term "muscle disease" refers to a disease associated with an impaired number or function of skeletal or cardiac myocytes.
The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule with a fixed ratio of active ingredients or in multiple separate capsules for each active ingredient. Moreover, such administration also encompasses the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide a beneficial effect of the drug combination in treating the conditions or disorders described herein. In certain embodiments, the combination of compounds is administered such that the clearance half-lives of each compound from the body at least partially overlap with each other. For example, a first drug has a clearance half-life of 1 hour and is administered at time O, and a second drug has a clearance half-life of 1 hour and is administered at time 45 minutes.
The phrase "therapeutically effective" is intended to quantify the amount of active ingredient used to treat a disease or disorder or to affect a clinical endpoint.
The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) that are suitable for use in contact with the tissues of a patient without excessive toxicity, irritation, and allergic response, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
As used herein, reference to "treatment" of a patient is intended to include prophylaxis. Treatment may also be antecedent in nature, i.e., it may include prevention of disease. Prevention of a disease may involve complete prevention of the disease, for example in the case of prevention of infection by a pathogen, or may involve prevention of disease progression. For example, preventing a disease may not mean completely eliminating any effect associated with the disease at any level, but may mean preventing the symptoms of the disease to a clinically significant or detectable level. Preventing a disease may also mean preventing the disease from progressing to a later stage of the disease.
The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.
As used herein, the term "epicatechin" refers to (+) -epicatechin (2R-3R), (-) -epicatechin (2S-3S), or a mixture thereof. In certain embodiments, "epicatechin" refers to (+) -epicatechin. In other embodiments, "epicatechin" refers to (-) -epicatechin. In other embodiments, "epicatechin" refers to a racemic mixture of (+) -epicatechin and (-) -epicatechin.
As used herein, the term "epicatechin derivative" refers to any compound that retains the ring structure and stereochemistry of epicatechin itself, but contains one or more substituents relative to epicatechin. Certain naturally occurring epicatechin derivatives are known, such as (-) -Epigallocatechin (EGC), (-) -epicatechin-3-gallate (ECG), (-) -epigallocatechin-3-gallate (EGCG), (+) -Epigallocatechin (EGC), (+) -epicatechin-3-gallate (ECG), and (+) -epigallocatechin-3-gallate (EGCG). The term also includes combination molecules or prodrugs that release epicatechin or a derivative thereof when administered to a subject. Such a combination molecule may include, for example, epicatechin and an agent linked through a hydrolyzable linker group.
Epicatechin and its derivatives can be prepared synthetically or can be isolated from natural sources containing these compounds, such as chocolate, tea, and nuts. As used herein, the term "chocolate" refers to a solid or semi-plastic food and is intended to refer to all chocolate or chocolate-like compositions that comprise a dispersion of solids within a fat phase. The term is intended to include compositions that meet the U.S. food characteristic provisions (SOI), the CODEX Alimentarius, and/or other international standards as well as compositions that do not meet the U.S. food characteristic provisions or other international standards. The term "chocolate" encompasses sweet chocolate, bitter or semi-sweet chocolate, milk chocolate, buttermilk chocolate, skim milk chocolate, mixed dairy product chocolate, sweet cocoa and vegetable fat coatings, sweet chocolate and vegetable fat coatings, milk chocolate and vegetable fat coatings, vegetable fat based coatings, pastes including white chocolate or coatings made from cocoa butter or vegetable fat or combinations thereof, nutritionally modified chocolate-like compositions (chocolate or coatings made with low calorie ingredients), and low fat chocolate, unless specifically indicated otherwise. See, for example, U.S. patent 6,312,753, which is hereby incorporated by reference. By way of example, epicatechin and its derivatives can be delivered by administering tea extract, cocoa components, partially and fully defatted cocoa solids, cocoa nibs and fractions derived therefrom, cocoa polyphenol extract, cocoa butter, chocolate liquor, and mixtures thereof.
The term "prodrug" refers to a compound that becomes more active in vivo. Certain compounds disclosed herein may also exist as prodrugs, as described in the following documents: hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M.Wiley-VHCA, Zurich, Switzerland 2003) (Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry and Enzymology, Testa, Bernard and Mayer, Joachim M., Wiley-VHCA Press, Su. Switzerland, 2003). Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide structurally modified forms of the compounds. In addition, prodrugs can be converted to compounds by chemical or biochemical methods in an in vitro environment. For example, a prodrug may be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical agent. Prodrugs are often useful because, in some cases, they may be easier to administer than the compound or the parent drug. They may be bioavailable, for example by oral administration, whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug. A variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. A non-limiting example of a prodrug would be a compound that is administered as an ester ("prodrug"), but is subsequently metabolically hydrolyzed to the carboxylic acid (active entity). Additional examples include peptidyl derivatives of the compounds.
The compounds disclosed herein may exist as therapeutically acceptable salts. The invention includes the compounds listed above in salt form, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts are generally pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be used in the preparation and purification of the contemplated compounds. Base addition salts may also be formed and are pharmaceutically acceptable. For a more complete discussion of salt preparation and Selection, see Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P.Heinrich.Wiley-VCHA, Zurich, Switzerland,2002) (Pharmaceutical Salts: Properties, Selection, and uses, Stahl, P.Heinrich.Wiley-VHCA Press, Zuis, Inc., 2002).
As used herein, the term "therapeutically acceptable salt" means a salt or zwitterionic form of a compound disclosed herein, which is water or oil soluble or dispersible and is therapeutically acceptable as defined herein. Salts may be prepared during the final isolation and purification of the compound or separately by reacting the appropriate compound in free base form with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonic acid (benzenesulfonate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-isethionate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphonate, picrate, etc, Pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonic acid (p-toluenesulfonic acid salt), and undecanoate. Additionally, the basic groups in the compounds disclosed herein can be quaternized with: methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; decyl, lauryl, myristyl and sterol chlorides, bromides and iodides; and benzyl and phenethyl bromides. Examples of acids that can be used to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. Salts may also be formed by coordination of the compound with an alkali or alkaline earth metal ion. Accordingly, the present invention encompasses sodium, potassium, magnesium, and calcium salts, and the like, of the compounds disclosed herein.
Base addition salts can be prepared during the final isolation and purification of the compounds by reacting the carboxyl group with a suitable base such as the hydroxide, carbonate or bicarbonate of a metal cation or with ammonia or an organic primary, secondary or tertiary amine. Cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary ammonium cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N-dibenzylphenethylamine, 1-diphenylmethylamine, and N, N-dibenzylethylenediamine. Other representative organic amines useful for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
Salts of the compounds may be prepared by reacting the appropriate compound in free base form with the appropriate acid.
While the compounds of the subject invention may be administered as raw chemicals, they may also be presented as pharmaceutical formulations. Accordingly, provided herein are pharmaceutical formulations comprising one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. A carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The appropriate formulation depends on the chosen route of administration. Any of the well known techniques, carriers and excipients may be used as suitable techniques, carriers and excipients and as understood in the art; for example, in Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences). The pharmaceutical compositions disclosed herein can be manufactured in any manner known in the art, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compressing methods.
Formulations include those suitable for oral administration, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary) administration, intraperitoneal administration, transmucosal administration, transdermal administration, rectal and topical (including dermal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Generally, these methods comprise the step of bringing into association a compound of the subject invention, or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof ("active ingredient"), with the carrier which constitutes one or more accessory ingredients. Generally, the formulation is prepared by: the active ingredient is uniformly and intimately associated with a liquid carrier or a finely divided solid carrier or both, and the product is then, if necessary, shaped into the desired formulation.
Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in a water-soluble or non-water-soluble liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
Pharmaceutical preparations which can be used orally include tablets, push-fit capsules made of gelatin, and sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, inert diluent or lubricant, surfactant or dispersant. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. Push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. To this end, concentrated sugar solutions may be used, which may optionally comprise gum arabic, talc, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings to identify or characterize different combinations of active compound doses.
Specific sustained release formulations of the compounds disclosed herein are described in U.S. patent 6,410,052, which is hereby incorporated by reference.
The compounds may be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Ready-to-use injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.
Pharmaceutical formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
In addition to the foregoing formulations, the compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.
For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, troches or gels formulated in a conventional manner. Such compositions may comprise the active ingredient in a flavor base such as sucrose and gum arabic or tragacanth.
The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycols or other glycerides.
Certain compounds disclosed herein may be administered locally, i.e., not systemically. This includes applying the compounds disclosed herein outside the epidermis or buccal cavity, and instilling such compounds into the ear, eye and nose so that the compounds do not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.
Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetrating the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may comprise, for example, 0.001% w/w to 10% w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise up to 10% w/w. In other embodiments, it may comprise less than 5% w/w. In certain embodiments, the active ingredient may be present in an amount of 2% w/w to 5% w/w. In other embodiments, it may comprise from 0.1% w/w to 1% w/w of the formulation.
For administration by inhalation, the compounds may be conveniently delivered from an insufflator, nebulizer pressurized pack, or other convenient means of delivering an aerosol spray. The pressurized pack may contain a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder compositions may be presented in unit dosage form in, for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered by means of an inhaler or insufflator.
Preferred unit dose formulations are those containing an effective dose of the active ingredient or an appropriate fraction thereof as described hereinafter.
It will be appreciated that in addition to the ingredients particularly mentioned above, the formulations described above may contain other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
The compounds may be administered orally or by injection at a dose of 0.1mg/kg to 500mg/kg per day. The dosage range for adults is usually 5mg to 2g per day. The presentation in tablet or other form provided in discrete units may conveniently contain an amount of one or more compounds effective at such a dose or a multiple of the same dose, for example a unit containing from 5mg to 500mg, typically from about 10mg to 200 mg.
The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration.
The compounds may be administered in various modes, for example, orally, topically or by injection. The precise amount of the compound administered to the patient will be the responsibility of the attending physician. The specific dosage level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, the exact disorder being treated and the severity of the indication or condition being treated. In addition, the route of administration may vary depending on the condition and its severity.
In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by the patient while receiving one of the compounds herein is hypertension, then administration of an antihypertensive agent in combination with the initial therapeutic agent may be appropriate. Alternatively, by way of example only, the therapeutic effect of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., administration of the adjuvant alone may have only minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, by way of example only, the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a treatment regimen) that also has therapeutic benefit. By way of example only, in the treatment of diabetes involving administration of one of the compounds described herein, increased therapeutic benefit may also result from providing the patient with another therapeutic agent for diabetes. In any case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may simply be the sum of the two therapeutic agents, or the patient may experience a synergistic benefit.
Specific non-limiting examples of possible combination therapies include the use of certain compounds of the present invention with agents that allow or enhance improvement in the number, structure or function of skeletal or cardiac myocytes.
In additional embodiments, such agents include hormones that stimulate muscle cell growth, butyric acid or derivatives thereof, dietary protein supplements, anabolic steroids, biological factors known to enhance skeletal or cardiac muscle growth, strength, endurance or metabolism or to restore skeletal or cardiac muscle from injury or weakness, compounds known to be associated with increased nitric oxide production by promoting blood flow through muscle, extracts of natural products known to promote muscle strength or endurance, inhibitors of myostatin, and stimulators of follistatin expression.
In additional embodiments, the hormone that stimulates muscle cell growth includes, but is not limited to, growth hormone analogs, growth hormone releasing peptide or analogs thereof, growth hormone secretagogues or other hormones, such as somatotropin or mechano growth factor.
In additional embodiments, butyric acid derivatives include neurotransmitters that are beneficial to muscle by modulating the pituitary gland.
In further embodiments, the dietary protein supplement includes, but is not limited to, proteins having known attributes for enhancing muscle growth such as casein, amino acid precursors or derivatives thereof, such as leucine, valine, isovaline, beta-alanine, glutamine dipeptide, or guanidinoacetic acid.
In additional embodiments, anabolic steroids include, but are not limited to, testosterone or related steroid compounds with muscle growth inducing properties, such as cyclosterozole or methadone enol, prohormone or derivatives thereof, estrogen modulators, and Selective Androgen Receptor Modulators (SARMS).
In additional embodiments, biological factors known to enhance growth, strength, endurance or metabolism of skeletal or cardiac muscle, or recovery of skeletal or cardiac muscle from injury or weakness include, but are not limited to, alpha-lipoic acid, taurine, caffeine, magnesium, nicotinic acid, folic acid, ornithine, vitamin B6, B12 or D, aspartic acid, creatine, and various salts thereof, such as creatine monohydrate, betaine, N-acetyl cysteine, beta-hydroxybutyrate methyl ester, lecithin, choline, phospholipid mixtures, phosphatidylserine, carnitine, L-carnitine, and glycinoyl-L-carnitine.
In additional embodiments, compounds known to be associated with increased nitric oxide production through muscle promoting blood flow include, but are not limited to, arginine and citrulline.
In additional embodiments, extracts of natural products known to promote muscle strength or endurance include, but are not limited to, guarana, houttuynia cordata, Cirsium allophylum, bauhinia, yohimbe, bacopa monnieri, beet powder, rhodiola rosea, or tea extracts.
In additional embodiments, the myostatin inhibitor is a protein, antibody, peptide, or small molecule.
In further embodiments, the stimulator of follistatin expression or function is a protein, peptide, or small molecule.
In any case, the multiple therapeutic agents (wherein at least one of the therapeutic agents is a compound disclosed herein) can be administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents may be provided in a single unified form or in multiple forms (by way of example only, as a single pill or as two separate pills). One of the therapeutic agents may be provided in multiple doses, or both may be provided in multiple doses. The timing between multiple doses may be of any duration ranging from a few minutes to four weeks, if not simultaneous.
Thus, in another aspect, certain embodiments provide a method for treating a muscle disease in a human or animal subject in need of such treatment, the method comprising administering to the subject an amount of a compound disclosed herein effective to reduce or prevent the disorder in the subject, in combination with at least one additional agent known in the art for treating the disorder. In a related aspect, certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein, in combination with one or more additional agents for treating muscle disorders.
The compositions of the present invention may also be formulated as neutraceutical compositions. As used herein, the term "neutraceutical composition" refers to a food product, dietary supplement, nutritional supplement, or supplement composition for a food product or food product comprising exogenously added catechins and/or epicatechins. Details regarding The formulation and application techniques of such compositions can be found in Remington, The Science and Practice of Pharmacy 21st Edition (Mack Publishing Co., Easton, Pa.) (Remington: Pharmaceutical Science and Practice, 21st Edition, Mack Publishing company, Iston, Pa.) and Nielloud and Marti-Mestres, Pharmaceutical Emulsions and separations: 2nd Edition (Marcel Dekker, Inc., New York) ("Pharmaceutical Emulsions and Suspensions", 2nd Edition, New York Dekker, Inc.).
As used herein, the term food product refers to any food or feed suitable for consumption by a human or animal. The food product can be a prepared and packaged food (e.g., mayonnaise, salad dressing, bread, cereal bar, beverage, etc.) or animal feed (e.g., extruded and pelleted animal feed, coarse mixed feed, or pet food composition). As used herein, the term food product refers to any substance suitable for human or animal consumption.
Food products or foodstuffs are, for example, beverages such as non-alcoholic beverages such as soft drinks, sports drinks, fruit juices such as orange juice, apple juice and grapefruit juice, and liquid preparations to be added to drinking water and liquid foods; catalpa lemongshui, tea, near water beverages and milk and other dairy beverages (such as yoghurt beverages) and diet beverages. In another embodiment, food product or foodstuff refers to a solid or semi-solid food comprising the composition according to the invention. These forms may include, but are not limited to, baked goods such as cakes and cookies, puddings, dairy products, confections, snack foods, or frozen confections or novelty products (e.g., ice cream, milkshakes), prepared frozen meals, candies, snack products (e.g., potato chips), liquid foods such as soups, spreads, sauces, salad dressings, prepared meat products, cheeses, yogurt, and any other fat or oil containing food, and food ingredients (e.g., wheat flour).
Animal feeds comprising pet food compositions advantageously include foods intended to provide the necessary dietary requirements, as well as treats (e.g., dog biscuits) or other food supplements. The animal feed comprising the composition according to the invention may be in the form of a dry composition (e.g. kibble), a semi-moist composition, a wet composition, or any mixture thereof. Alternatively or in addition, the animal feed is a supplement, such as a gravy, drinking water, yogurt, powder, suspension, chew, treat (e.g., biscuit), or any other delivery form.
The term "dietary supplement" refers to a small amount of a compound packaged in a single dose unit or in multiple dose units for supplementing the diet of a human or animal.
Dietary supplements do not typically provide significant amounts of calories, but may include other micronutrients (e.g., vitamins or minerals). The term food product or foodstuff also includes functional foods and prepared food products prepackaged for human consumption.
The term nutritional supplement refers to a composition comprising a dietary supplement in combination with a source of calories. In some embodiments, the nutritional supplement is a meal replacement or supplement (e.g., a nutrient or energy bar or nutritional beverage or concentrate).
The dietary supplement of the present invention may be delivered in any suitable form. In certain embodiments, the dietary supplement is formulated for oral delivery. The ingredients of the dietary supplement of the present invention are contained in acceptable excipients and/or carriers for oral consumption. The actual form of the carrier, and hence the dietary supplement itself, is not critical. The carrier can be a liquid, gel, caplet, capsule, powder, solid tablet (coated or uncoated), tea, or the like.
In certain embodiments, the dietary supplement is in the form of a tablet or capsule, and in further embodiments in the form of a hard (shell) capsule. Suitable excipients and/or carriers include maltodextrin, calcium carbonate, dicalcium phosphate, tricalcium phosphate, microcrystalline cellulose, dextrose, rice flour, magnesium stearate, stearic acid, croscarmellose sodium, sodium starch glycolate, crospovidone, sucrose, vegetable gums, lactose, methylcellulose, povidone, carboxymethylcellulose, corn starch, and the like (including mixtures thereof). In certain embodiments, the carrier comprises calcium carbonate, magnesium stearate, maltodextrin, and mixtures thereof. The various ingredients are mixed with excipients and/or carriers and formed into the desired form using conventional techniques. The tablets or capsules of the invention may be coated with an enteric coating that dissolves at a pH of about 6.0 to 7.0. A suitable enteric coating that dissolves in the small intestine but not in the stomach is cellulose acetate phthalate.
In other embodiments, the dietary supplement is provided as a powder or liquid suitable for addition by the consumer to a food or beverage. For example, in some embodiments, the dietary supplement may be administered to an individual in powder form, for example, by mixing into a beverage, or by stirring into a semi-solid food such as a pudding, topping, sauce, puree, cooked cereal or salad dressing, or by otherwise adding to the food or dietary supplement (e.g., enclosed in a lid of a food or beverage container for immediate release prior to consumption). The dietary supplement may comprise one or more inert ingredients, particularly if it is desired to limit the number of calories the dietary supplement adds to the diet. For example, the dietary supplement of the present invention may further comprise optional ingredients including, for example, herbs, vitamins, minerals, enhancers, colors, sweeteners, flavors, inert ingredients, and the like.
In some embodiments, the dietary supplement further comprises vitamins and minerals including, but not limited to, calcium tribasic phosphate or acetate, potassium dibasic phosphate, magnesium sulfate or oxide, salts (sodium chloride), potassium chloride or acetate, ascorbic acid, iron orthophosphate, niacinamide, zinc sulfate or oxide, calcium pantothenate, copper gluconate, riboflavin, beta-carotene, pyridoxine hydrochloride, thiamine mononitrate, folic acid, biotin, chromium chloride or picolinic acid, potassium iodide, sodium selenate, sodium molybdate, phylloquinone, vitamin D3, cyanocobalamin, sodium selenite, copper sulfate, vitamin a, vitamin C, inositol, potassium iodide. Suitable dosages of vitamins and minerals may be obtained, for example, by consulting the U.S. RDA guidelines.
In other embodiments, the invention provides a nutritional supplement (e.g., an energy bar or meal replacement bar or beverage) comprising a composition according to the invention. Nutritional supplements can be used as meal or snack substitutes, and typically provide nutritional calories. In certain embodiments, the nutritional supplement provides carbohydrate, protein, and fat in balanced amounts. The nutritional supplement may further comprise carbohydrates, simple medium chain lengths, or polysaccharides, or combinations thereof. Simple sugars can be selected for desired organoleptic properties. Uncooked corn starch is one example of a complex carbohydrate. If it is desired that it should retain its high molecular weight structure, it should only be included in the uncooked or heat-treated food preparation or portion thereof, as the heat will decompose the complex carbohydrate into simple carbohydrates, wherein the simple carbohydrates are mono-or di-saccharides. In one embodiment, the nutritional supplement comprises a combination of three levels of carbohydrate sources of chain length (simple, medium and complex, e.g., sucrose, maltodextrin and uncooked corn starch).
The protein source to be incorporated into the nutritional supplement of the present invention may be any suitable protein for use in nutritional formulations, and may include whey protein, whey protein concentrate, whey powder, egg, soy flour, soy milk soy protein, soy protein isolate, caseinates (e.g., sodium caseinate, sodium calcium caseinate, potassium caseinate), animal and plant proteins, and hydrolysates or mixtures thereof. When selecting the protein source, the biological value of the protein should first be considered, with the highest biological value being present in caseinate, whey, lactalbumin, ovalbumin and whole egg protein. In an embodiment, the protein is a combination of whey protein concentrate and calcium caseinate. These proteins have high biological value; that is, they have a high proportion of essential amino acids. See model Nutrition in Health and Disease,8th ed., Lea & Febiger,1986 (Modern Nutrition for Health and Disease,8th edition, Lea & Febiger Press, 1986), especially Vol.1, pp.30-32.
The nutritional supplement may also include other ingredients, such as one or a combination of other vitamins, minerals, antioxidants, fiber, and other dietary supplements (e.g., protein, amino acids, choline, lecithin). The choice of one or several of these ingredients is a matter of formulation, design, consumer preference, and end user. The amounts of these ingredients added to the dietary supplement of the present invention are readily known to the skilled artisan. Guidance for such amounts may be provided by U.S. RDA dosages for children and adults. Additional vitamins and minerals that may be added include, but are not limited to, calcium tribasic phosphate or acetate, potassium dibasic phosphate, magnesium sulfate or oxide, salts (sodium chloride), potassium chloride or acetate, ascorbic acid, iron orthophosphate, nicotinamide, zinc sulfate or oxide, calcium pantothenate, copper gluconate, riboflavin, beta-carotene, pyridoxine hydrochloride, thiamine mononitrate, folic acid, biotin, chromium chloride or picolinic acid, potassium iodide, sodium selenate, sodium molybdate, phylloquinone, vitamin D3, cyanocobalamin, sodium selenite, copper sulfate, vitamin a, vitamin C, inositol, potassium iodide.
Nutritional supplements may be provided in a variety of forms, and may be provided by a variety of manufacturing methods. In embodiments, to make a food bar, the liquid ingredients are cooked; adding the dry ingredients to the mixer together with the liquid ingredients and mixing until a dough phase is reached; putting the dough into an extruder and extruding; cutting the extruded dough into suitable lengths; and the product is cooled. In addition to the ingredients specifically listed herein, the bar may also contain other nutrients and fillers to enhance taste.
It will be understood by those skilled in the art that other ingredients may be added to those described herein, such as fillers, emulsifiers, preservatives, and the like, for processing or manufacturing of the nutritional supplement.
Additionally, flavors, colors, spices, nuts, and the like may be incorporated into the nutraceutical compositions. The flavoring agent may be in the form of a flavor extract, a volatile oil, a chocolate flavoring agent, a peanut butter flavoring agent, a cookie crumb, crisp rice, vanilla or any commercially available flavoring agent. Examples of useful flavoring agents include, but are not limited to, pure anise extract, imitation banana extract, imitation cherry extract, chocolate extract, pure lemon extract, pure orange extract, pure peppermint extract, imitation pineapple extract, imitation rum extract, imitation strawberry extract, or pure vanilla extract; or a volatile oil such as a balsam, bay oil, bergamot oil, cedar oil, walnut oil, cherry oil, cinnamon oil, clove oil, or peppermint oil; peanut butter, chocolate flavoring, vanilla cookie pieces, creamy candy, or toffee. In one embodiment, the dietary supplement comprises cocoa or chocolate.
For stability of the nutraceutical composition, emulsifiers may be added. Examples of suitable emulsifiers include, but are not limited to, lecithin (e.g., from egg or soy), and/or mono-and diglycerides. Other emulsifiers will be apparent to the skilled artisan and the selection of a suitable emulsifier will depend in part on the formulation and the final product. Preservatives may also be added to the nutritional supplement to extend the shelf life of the product. In certain embodiments, preservatives such as potassium sorbate, sodium sorbate, potassium benzoate, sodium benzoate, or calcium disodium EDTA are used.
In addition to the carbohydrates described above, the nutraceutical compositions may contain natural or artificial (preferably low calorie) sweeteners such as sugars, cyclamates, aspartates, aspartame, acesulfame k and/or sorbitol. Such artificial sweeteners are desirable if the nutritional supplement is intended to be consumed by an overweight or obese individual or an individual with type II diabetes who is prone to hyperglycemia.
In addition, multivitamin and mineral supplements may be added to the neutraceutical composition of the present invention to obtain sufficient amounts of essential nutrients, which are missing in some diets. Multi-vitamin and mineral supplements may also be used to prevent disease and to prevent loss and deficiency of nutrients due to lifestyle patterns.
The dosages and ratios of catechins and/or epicatechins and additional components administered by the neutraceuticals will vary depending on known factors, such as the pharmaceutical characteristics of the particular composition and its mode and route of administration; age, health, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent therapy; the frequency of treatment; as well as the desired effect, which may be determined by the expert in the field by normal experimentation or by the usual considerations regarding the formulation of neutraceutical compositions.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have been previously administered; and the severity of the particular disease being treated, as is well known to those skilled in the art.
Specific diseases to be treated by the compounds, compositions and methods disclosed herein include: impaired skeletal muscle and cardiac muscle function, restoration of skeletal muscle or cardiac muscle health or function, significant regeneration of skeletal muscle or cardiac muscle cell or function, and any other disease disclosed herein.
In addition to being useful for human therapy, certain compounds and formulations disclosed herein may also be useful for veterinary therapy of companion, exotic, and farm animals (including mammals, rodents, and the like). More preferred animals include horses, dogs, and cats.
Biological activity assay
Western blot assay:
Cell or skeletal muscle tissue samples were lysed in 50ul of lysis buffer (1% triton X-100, 20mmol/L Tris, 140mmol/L NaCI, 2mmol/L EDTA and 0.1% SDS) with 1mmol/L PMSF, 2mmol/L Na supplemented3V04And 1mmol/L NaP of protease and phosphatase inhibitor mixture. The homogenate was passed five times through an insulin syringe, sonicated at 4DC for 30 min and centrifuged (12,000X g) for 10 min. The total protein content in the supernatant was measured. A total of 40) lg protein was loaded on 5% or 10% SDS-PAGE, electrotransferred, and added to blocking solution (5% skim milk powder in TBS plus 0.1% Tween 20[ TBS-T ]]) Incubated for 1 hour at room temperature followed by 3 hours at room temperature or incubated overnight with a temperature resistant at 4 DC. Primary antibodies are usually diluted 1:1000 or 1:2000 in TBS-T plus 5% bovine serum albumin. Membranes were washed in TBS-T (3X, 5 min) and incubated in the presence of HRP-conjugated secondary antibody at 1:10,000 dilution in blocking solution for 1 hour at room temperature.The membrane was washed again 3 times in TBS-T and the immunoblots were developed using an enhanced chemiluminescence detection kit. The tape strength was quantified digitally. All primary antibodies are commercially available.
Mouse myoblast assay
Epicatechin induces follistatin expression, inhibits myostatin expression, and accelerates differentiation of cultured mouse myoblasts into myotubes. These phenomena are associated with increased expression of biomarkers of muscle differentiation, such as myogenin and myoD. The mouse myoblast cell line C2C12 was grown to semi-confluence in 6-well tissue culture plates and then exposed to epicatechin (100nM) for three days using a literature standardized differentiation induction medium (DMEM supplemented with 2% horse serum). The proteins were extracted, separated by conventional gel electrophoresis, and stained as western blots by reaction with commercially available antibodies specific for markers of muscle cell growth and differentiation. In experiments to examine the comparative effect of (-) and (+) epicatechin enantiomers on myocytes, cells were grown to half confluence in 6-well plates, placed in literature-standardized differentiation media containing horse serum, and then stimulated with (-) or (+) epicatechin enantiomers at concentrations ranging from 10nM to 1000nM for 24 hours. Cells were then harvested as above and western blots were prepared using commercially available specific primary antibodies to determine the relative expression of PGCla and follistatin.
Treatment of diabetic patients with epicatechin-rich cocoa products
Five patients with type 2 diabetes and heart failure were provided epicatechin-rich cocoa products (about 100mg epicatechin provided per day) daily for three months.
Epicatechin-rich cocoa increases protein levels of skeletal muscle growth stimulators (follistatin), muscle differentiation markers (myogenin, myoD), and inhibits expression of arrestin (myostatin) in biopsy samples of human skeletal muscle after three months of treatment. The patient biopsies his quadriceps before and after completing the treatment. The biopsy material was analyzed by western blot to analyze muscle protein content.
Electron micrographs of quadriceps biopsy samples taken before and after three months of treatment showed severe destruction and distortion of sarcomere ultrastructures in human skeletal muscle in diabetic patients with heart failure, consistent with sarcopenia. Treatment significantly restored sarcomere supertissues of skeletal muscle to near normal. This phenomenon was confirmed in all five patients, as the mean histological score improved significantly.
Epicatechin treatment induces increased expression of the activated form (deacetylation) of PGC 1a (a transcriptional regulator of muscle repair and regeneration and mitochondrial biogenesis) in the quadriceps of patients. Treatment also increased the expression of elements of the myosin family (including dystrophin, dysferlin and utrophin), consistent with the observed improvement in sarcomere morphology. Treatment also increased mitochondrial biogenesis as evidenced by increased electron transport complex protein per mg of quadriceps tissue.
Baseline skeletal muscle thiol levels (by using the glutathione assay kit of Cayman inc.) in diabetic patients with heart failure showed a significant reduction, indicating significant oxidative stress of the tissue compared to normal muscle. Treatment with epicatechin-rich cocoa restored total thiol levels, indicating normalization of tissue oxidative stress levels. Epicatechin treatment also increases quadriceps expression of superoxide dismutase and catalase, which are important enzymes for preventing oxidative muscle damage.
In vivo study of wild mice and mouse muscular dystrophy model
Wild type (i.e., normal) and myosaccharide (8-SG) null mice that developed muscular dystrophy were treated by oral gavage with epicatechin from Sigma Aldrich (Sigma-Aldrich) at 1mg/kg twice daily or with water alone (control) for 30 days. Quadriceps protein samples were analyzed by western blot to assess changes in protein levels of the mitochondrial protein porin, mitochondrial inner membrane protein antibodies, complex v (cv), superoxide dismutase 2(SOD2), and catalase. Epicatechin treatment was increased in wild-type mice, and mitochondrial protein loss was prevented in 8-SG null mice. In dystrophic mice, epicatechin increases protein expression in both heart and quadriceps of both catalase and superoxide dismutase 2, which are important enzymes that counteract the damaging effects of oxidative damage by reducing the severity of oxidative damage.
Myoglucose (8-SG) dystrophic mice show reduced glutathione content in the quadriceps (GSH, by using the glutathione assay kit from Cayman inc.) confirming increased oxidative stress of the tissue. Epicatechin treatment significantly increased muscle GSH levels in both wild-type and inositol knockout mice.
After treatment with oral epicatechin 1mg/kg (twice daily for 4 weeks), the myoglucose knockout dystrophic mice showed a significant increase in PGC 1a (a transcription factor that regulates muscle repair and regeneration and regulates mitochondrial biogenesis) in skeletal muscle.
In one experiment, aged, muscle-impaired aged wild-type mice (26 months) were treated with epicatechin 1mg/kg (twice daily for two weeks) for 2 weeks. They also showed a significant increase in PGC1u in skeletal muscle, and a related increase in mitochondrial protein expression.
In one experiment, mdx mice, characterized by the same dystrophin mutation as seen in duchenne muscular dystrophy, were treated by oral administration of epicatechin 1mg/kg (twice daily for 4 weeks). They showed increased muscle strength compared to water treated controls as determined by standard timed hang-up tests.
In the mouse myocyte line, C2C12((-) and (+) epicatechin enantiomer) stimulated the expression of PGC1u and follistatin within 24 hours, consistent with activation of the transcriptional pathway regulating muscle regeneration and expression of muscle trophic hormone (follistatin).
Biomarkers
Induction of follistatin (muscle growth hormone) and inhibition of myostatin (muscle growth inhibitor) by epicatechin in vitro and in vivo suggest that these proteins may be useful biomarkers for monitoring the effects of epicatechin in vivo. In diabetic patients with heart failure, the ratio of follistatin to myostatin was measured and calculated before and after treatment with epicatechin-rich cocoa. There was a statistically significant increase in the follistatin/myostatin ratio associated with treatment, indicating an increase in follistatin and a decrease in its natural antagonist (myostatin).
Influence on body growth
SD rats having a body weight of 50g to 60g and an age of 3 weeks to 4 weeks were divided into 4 groups. Group a animals were part of the vehicle control group, group B animals were administered dexamethasone daily; group C animals were dosed with epicatechin 3mg/kg followed by dexamethasone; group D animals were dosed with 10mg/kg epicatechin, followed by dexamethasone. All administrations were performed by Subcutaneous (SC) mode of administration. The animals were dosed for 36 days. Body weight was measured every other day and total length was measured weekly. The animals were photographed periodically to further support the data. Feed intake, overall health and movement were routinely assessed. On day 37, animals were sacrificed and femoral and tibial lengths were measured using vernier calipers. Blood was collected and stored.
Follistatin has been shown to have beneficial ameliorating effects on the reduction in body growth associated with inhibition of bone formation secondary to corticosteroid toxicity, as shown in table 1 below.
Tables 1 to 3
Bone length (mm)
Claims (22)
1. A method of reversing or ameliorating bone injury, weakening or loss of bone, or preventing bone fracture in a subject in need thereof, the method comprising administering to the subject a therapeutically effective dose of (+) -epicatechin and/or (-) -epicatechin or a epicatechin derivative.
2. The method of claim 1, wherein the (+) -epicatechin and/or (-) -epicatechin or an epicatechin derivative is administered orally or intravenously or intramuscularly at 5mg to 2g per day in single or divided doses.
3. The method of claim 1, wherein the (+) -epicatechin and/or the (-) -epicatechin or epicatechin derivative is administered orally or intravenously or intramuscularly in single or divided doses at a dose between 0.1mg/kg body weight/day and 10mg/kg body weight/day.
4. The method of claim 1, wherein the method induces new bone formation or additional bone formation or stronger bone formation or bone regeneration so as to prevent a fracture.
5. The method of claim 1, wherein the method reverses or ameliorates weakening of bone, thereby preventing a bone fracture caused by administration of a compound known to induce weakening of bone or damage to bone, impaired osteogenesis or impaired bone growth, wherein the compound is selected from the group consisting of corticosteroids, anticonvulsants, chemotherapeutic agents.
6. The method of claim 1, wherein the weakening of bone is caused by a medical condition known to be associated with weakening of bone or damage to bone, impaired osteogenesis or impaired bone growth.
7. The method of claim 1, wherein the (+) -epicatechin and/or (-) -epicatechin is co-administered with calcium, vitamin D, or calcitonin.
8. The method of claim 4, wherein the (+) -epicatechin and/or (-) -epicatechin or an epicatechin derivative is administered orally or intravenously or intramuscularly at 5mg to 2g per day in single or divided doses.
9. The method of claim 5, wherein the (+) -epicatechin and/or (-) -epicatechin or an epicatechin derivative is administered orally or intravenously or intramuscularly at 5mg to 2g per day in single or divided doses.
10. The method of claim 6, wherein the (+) -epicatechin and/or (-) -epicatechin or an epicatechin derivative is administered orally or intravenously or intramuscularly at 5mg to 2g per day in single or divided doses.
11. The method of claim 7, wherein the (+) -epicatechin and/or (-) -epicatechin or an epicatechin derivative is administered orally or intravenously or intramuscularly at 5mg to 2g per day in single or divided doses.
12. A composition comprising or consisting of: (+) -epicatechin, (-) -epicatechin, or a mixture of both, or a pharmaceutically acceptable salt or prodrug thereof, for use as a medicament for:
(a) reversing or ameliorating bone damage, weakening or loss of bone, or preventing fracture, and/or
(b) Preventing, treating or curing osteoporosis.
13. The composition according to claim 12, characterized in that (+) -epicatechin, (-) -epicatechin, or a mixture of both, or a pharmaceutically acceptable salt or prodrug thereof, is administered orally or intravenously or intramuscularly.
14. Composition according to claims 12 and/or 13, characterized in that (+) -epicatechin, (-) -epicatechin, or a mixture of both, or a pharmaceutically acceptable salt or prodrug thereof, is administered in a single or divided dose from 5mg to 2g per day.
15. Composition according to any one of the preceding claims 12 to 14, characterized in that the (+) -epicatechin, (-) -epicatechin, or a mixture of both, or a pharmaceutically acceptable salt or prodrug thereof, is administered orally or intravenously or intramuscularly in a single or divided dose between 0.1mg/kg body weight/day and 10mg/kg body weight/day.
16. Composition according to any of the preceding claims 12 to 15, characterized in that it induces new bone formation or additional bone formation or stronger bone formation or bone regeneration in order to prevent bone fractures.
17. The composition according to any of the preceding claims 12 to 16, characterized in that said weakening of bone or loss of bone is caused by administration of a compound known to induce weakening of bone or damage of bone, impaired osteogenesis or impaired bone growth, wherein said compound is selected from the group consisting of corticosteroids, anticonvulsants and chemotherapeutic agents or mixtures thereof.
18. Composition according to any one of the preceding claims 12 to 17, characterized in that said weakening of bone is caused by a medical condition known to be associated with weakening of bone or damage of bone, impaired osteogenesis or impaired bone growth.
19. Composition according to any one of the preceding claims 12 to 18, characterized in that it further comprises calcium, vitamin D, or calcitonin, or a mixture thereof.
20. Composition according to any one of the preceding claims 12 to 19, characterized in that it further comprises a corticosteroid, an anticonvulsant agent, a chemotherapeutic agent or a mixture thereof.
21. A composition according to any of the preceding claims 12 to 20, characterized in that the composition increases cellular or muscle or body production of follistatin and follistatin-like protein.
22. The method of claim 1, wherein the therapeutic dose increases cellular or muscle or body production of follistatin and follistatin-like protein.
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WO2017221269A1 (en) | 2016-06-21 | 2017-12-28 | Sphaera Pharma Pvt. Ltd., | Utility of (+) epicatechin and their analogs |
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