Beta adrenergic and muscarinic antagonist compositions and methods of use

Abstract

This specification discloses compositions for supporting bladder health and / or treating, ameliorating, preventing, or alleviating overactive bladder or its associated symptoms. The compositions disclosed herein contain a β-adrenergic receptor agonist and at least one muscarinic receptor antagonist. This specification also discloses methods of utilizing the compositions.

Description

[Technical Field]

[0001] Background technology Adrenergic receptors are a type of G protein-coupled receptor, and their biological agonists are catecholamines such as norepinephrine and epinephrine. Agonistic binding of adrenergic receptors stimulates physiological responses related to the sympathetic nervous system. Among adrenergic receptors, β2 and β3 adrenergic receptors are involved in bladder function; when activated by agonists, both mediate signaling cascades that result in relaxation of the detrusor smooth muscle in the bladder wall and an increase in bladder capacity. Agonist activation of β2 / β3 adrenergic receptors triggers a response via G protein stimulation of adenylate cyclase, increasing cyclic adenosine monophosphate (cAMP), and inducing smooth muscle relaxation. In some cases, these signaling pathways can be affected by fluctuations in an individual's hormonal profile. For example, menopause can alter hormonal profiles, which can affect adrenergic receptor signaling pathways and lead to urinary abnormalities such as overactive bladder (OAB). Therefore, researchers in this field have leveraged their knowledge of beta-adrenergic receptors and their signaling pathways to develop agonists that ameliorate symptoms of abnormal bladder function, such as OAB. Two such compounds are mirabegron (MYRBETRIQ®) and vibegron (GEMTESA®), both FDA-approved beta-adrenergic receptor agonists. However, these compounds cause numerous side effects, including hypertension, nasopharyngitis, urinary tract infections, headache, constipation, upper respiratory tract infections, joint pain, diarrhea, tachycardia, abdominal pain, and fatigue.

[0002] Muscarinic acetylcholine receptors (muscarinic receptors) are another type of G protein-coupled receptor involved in bladder function. Muscarinic receptors are activated by acetylcholine, and their binding stimulates physiological responses related to the parasympathetic nervous system. M1, M4, and M5 muscarinic receptors are widely distributed throughout the central nervous system (CNS). Activation of these receptors has been linked to delayed excitatory postsynaptic potentials and mediation of higher cognitive processes (e.g., learning and spatial memory (M1) and motor performance decline (M4)). However, the clinical significance of M5 muscarinic receptors is not fully understood. Of the remaining muscarinic receptors, M2 and M3 muscarinic receptors are activated by acetylcholine and are involved in bladder function. Activation of M3 muscarinic receptors leads to an increase in phospholipase C, which increases intracellular calcium, resulting in an increase in inositol triphosphate, thereby mediating contraction of the detrusor smooth muscle in the bladder wall. As demonstrated in "The role of M2-muscarinic receptors in mediating contraction of the pig urinary bladder in vitro" by Yamanishi et al., activation of M2 muscarinic receptors has been suggested to reduce cAMP and mediate the contractile (recontractile) response to muscarinic agonists (acetylcholine). Therefore, activation of M2 and M3 muscarinic receptors may cause OAB. Conversely, administration of antagonists that block muscarinic receptor activation can reduce contraction of the detrusor smooth muscle in the bladder wall. Therefore, researchers in this field have leveraged their knowledge of muscarinic receptors and their signaling pathways to develop antagonists that ameliorate the symptoms of voiding disorders such as OAB. Tolterodine (Detrol®), oxybutynin (DITROPAN®), trospium (SANCTURA®), darifenacin (ENABLEX®), solifenacin (VESIcare®), and fesoterodine (TOVIAZ™) are FDA-approved medications that are muscarinic antagonists.These medications may improve after about 12 weeks, but are known to have a high incidence of side effects such as dry mouth, constipation, heartburn, blurred vision, increased heart rate (tachycardia), skin flushing, urinary retention, and cognitive side effects (e.g., memory impairment, brain fog, confusion). These side effects arise because antimuscarinic drugs lack binding selectivity for M2 / M3 muscarinic receptors over M1 / M4 muscarinic receptors, and in many cases, these muscarinic agonists are administered to subjects for less than one year, reducing long-term efficacy and reducing subjects' willingness to continue or continue use.

[0003] Based on these results, the inventors recognized a growing need for the development of beta-adrenergic receptor agonists and muscarinic receptor antagonists with fewer undesirable effects. The inventors focused on the relationship between beta-adrenergic receptors and muscarinic receptors, the role their signaling pathways play in bladder health, normal bladder function, and bladder conditions, disorders, or diseases, such as OAB, and the potential for beta-adrenergic receptor agonists and muscarinic receptor antagonists to alleviate, improve, treat, or cure these conditions. It is believed that beta-adrenergic receptor agonists and muscarinic receptor antagonists may provide numerous benefits to subjects, support bladder health, and maintain normal bladder function. The inventors discovered that the combination of a beta-adrenergic receptor agonist and a muscarinic receptor antagonist provides significant and unexpected benefits compared to the use of each agonist / antagonist alone. This discovery is novel. Thus, the combination of beta-adrenergic receptor agonists and muscarinic receptor antagonists as pharmaceuticals and / or dietary supplements can provide therapeutic and nutritional benefits individually, collectively, or in combination with other pharmaceuticals and / or dietary supplements. Summary of the Invention

[0004] Aspects of this disclosure relate to novel beta-adrenergic receptor agonists, muscarinic receptor antagonists, and their use in bladder health and in the amelioration and / or treatment of OAB or symptoms associated therewith.

[0005] These and other features, aspects, and advantages of the present embodiments will become apparent with reference to the following description, claims, and drawings. [Brief explanation of the drawings]

[0006] [Figure 1] FIG. 1 shows the maximum binding rates of 0.05 to 1000 μg of pumpkin seed composition (P), Crataeva nurvala composition (C), Lindera aggregata composition (L), a 1:1 mixture of black (B) and yellow (Y) maca, and a phycocyanin composition to muscarinic receptors M1 (solid), M2 (open), M3 (hatched), M4 (horizontal), and M5 (diagonal grid), evaluated in vitro, according to one or more embodiments of the present disclosure. [Figure 2] FIG. 2 shows in vitro evaluations of 0.05 to 1000 μg of a 2:2:1 mixture of a pumpkin seed composition, a Crataeva nurvala composition, and a Lindera aggregata composition (P+C+L), a 2:2:1:0.5 mixture of a pumpkin seed composition, a Crataeva nurvala composition, a Lindera aggregata composition, and a 1:1 mixture of black (B) maca and yellow (Y) maca (P+C+L+B / Y maca), a 2:2:1:0.5 mixture of a pumpkin seed composition, a Crataeva nurvala composition, a Lindera aggregata composition, and a phycocyanin composition (P+C+L+phycocyanin), and a 2:2:1:0.5 mixture of a pumpkin seed composition, a Crataeva nurvala composition, a Lindera aggregata composition, and a phycocyanin composition (P+C+L+phycocyanin), according to one or more embodiments of the present disclosure. The maximum binding rates of a 2:2:1:0.5 mixture (P+C+L+SAMe+PG) of the Nurbara Composition, the Tendai Uyaku Composition, and a 32:1 mixture of S-adenosyl-L-methionine (SAMe) and propyl gallate (PG) are shown for muscarinic receptors M1 (black), M2 (white), M3 (diagonal lines), M4 (horizontal lines), and M5 (diagonal grid). [Figure 3]Figure 3 shows the relative binding selectivity at maximum binding to M1-M4 muscarinic receptors for 0.05-1000 μg of a pumpkin seed composition (P), a Crataeva nurvala composition (C), a Lindera aggregata composition (L), a 1:1 mixture of black (B) and yellow (Y) maca, and a phycocyanin composition, evaluated in vitro according to one or more embodiments of the present disclosure. The series are M2 / M1 selectivity (solid), M2 / M4 selectivity (diagonal lines), M3 / M1 selectivity (horizontal lines), and M3 / M4 selectivity (open lines). [Figure 4] FIG. 4 shows in vitro evaluations of 0.05 to 1000 μg of a 2:2:1 mixture of a pumpkin seed composition, a Crataeva nurvala composition, and a Lindera aggregata composition (P+C+L), a 2:2:1:0.5 mixture of a pumpkin seed composition, a Crataeva nurvala composition, a Lindera aggregata composition, and a 1:1 mixture of black (B) maca and yellow (Y) maca (P+C+L+B / Y maca), a 2:2:1:0.5 mixture of a pumpkin seed composition, a Crataeva nurvala composition, a Lindera aggregata composition, and a phycocyanin composition (P+C+L+phycocyanin), and a 2:2:1:0.5 mixture of a pumpkin seed composition, a Crataeva nurvala composition, a Lindera aggregata composition, and a phycocyanin composition (P+C+L+phycocyanin), according to one or more embodiments of the present disclosure. The relative binding selectivity at maximum binding to M1-M4 muscarinic receptors for the Nurbala composition, the Tendai Uyaku composition, and a 2:2:1:0.5 mixture of a 32:1 mixture of SAMe and PG (P+C+L+SAMe+PG) is shown. The series are M2 / M1 selectivity (solid), M2 / M4 selectivity (diagonal lines), M3 / M1 selectivity (horizontal lines), and M3 / M4 selectivity (open lines). [Figure 5]FIG. 5 illustrates a pumpkin seed composition (P), (2) a Crataeva nurvala composition (C), (3) a Lindera aggregata composition (L), (4) a 1:1 mixture of black (B) maca and yellow (Y) maca, (5) a phycocyanin composition, (6) a 32:1 mixture of SAMe and PG, (7) a 2:2:1 mixture of a pumpkin seed composition, a Crataeva nurvala composition, and a Lindera aggregata composition (P+C+L), and (8) a pumpkin seed composition and a Crataeva nurvala composition evaluated in vitro at 5-1000 μg / mL as beta-adrenergic receptor agonists, according to one or more embodiments of the present disclosure. EC50 values ​​are shown for a 2:2:1:0.5 mixture of a nutty rose composition, a Tendai yaku composition, and a 1:1 mixture of black (B) maca and yellow (Y) maca (P+C+L+B / Y Maca), (9) a 2:2:1:0.5 mixture of a pumpkin seed composition, a Crataeva nutty rose composition, a Tendai yaku composition, and a phycocyanin composition (P+C+L+Phycocyanin), and (10) a 2:2:1:0.5 mixture of a pumpkin seed composition, a Crataeva nutty rose composition, a Tendai yaku composition, and a 32:1 mixture of SAMe and PG (P+C+L+(SAMe and propyl gallate)). [Figure 6] FIG. 6 shows the change in daytime urination frequency in the group treated with a composition containing 200 mg of SAMe, 360 mg of Crataeva nurvala, and 250 mg of yellow maca, and in the group treated with a composition containing 360 mg of Crataeva nurvala and 250 mg of yellow maca. [Figure 7] FIG. 7 shows the change in nocturnal urination frequency in the group treated with a composition containing 200 mg of SAMe, 360 mg of Crataeva nurvala, and 250 mg of yellow maca, and in the group treated with a composition containing 360 mg of Crataeva nurvala and 250 mg of black and yellow maca. [Figure 8] FIG. 8 shows the change in daytime urgency for the group treated with a composition containing 200 mg of SAMe, 360 mg of Crataeva nurvala, and 250 mg of yellow maca, and the group treated with a composition containing 360 mg of Crataeva nurvala and 250 mg of yellow maca. [Figure 9] FIG. 9 shows the change in nighttime urgency in the group treated with a composition containing 200 mg SAMe, 360 mg Crataeva nurvala, and 250 mg Yellow Maca, and the group treated with a composition containing 360 mg Crataeva nurvala and 250 mg Yellow Maca. [Figure 10] FIG. 10 shows the change in daytime urge urinary incontinence in the group treated with a composition containing 200 mg of SAMe, 360 mg of Crataeva nurvala, and 250 mg of Yellow Maca, and the group treated with a composition containing 360 mg of Crataeva nurvala and 250 mg of Yellow Maca. [Figure 11] FIG. 11 shows the change in overactive bladder screening score (OABSS) for a group treated with a composition containing 200 mg of SAMe, 360 mg of Crataeva nurvala, and 250 mg of yellow maca, and a group treated with a composition containing 360 mg of Crataeva nurvala and 250 mg of yellow maca. [Figure 12] FIG. 12 shows the change in symptom burden score for the group treated with a composition containing 200 mg SAMe, 360 mg Crataeva nurvala, and 250 mg Yellow Maca, and the group treated with a composition containing 360 mg Crataeva nurvala and 250 mg Yellow Maca. [Figure 13] FIG. 13 shows the change in sleep scores for a group treated with a composition containing 200 mg of SAMe, 360 mg of Crataeva nurvala, and 250 mg of yellow maca, and a group treated with a composition containing 360 mg of Crataeva nurvala and 250 mg of yellow maca. [Figure 14] FIG. 14 shows the change in health-related quality of life (HRQL) scores for the group treated with a composition containing 200 mg of SAMe, 360 mg of Crataeva nurvala, and 250 mg of yellow maca, and the group treated with a composition containing 360 mg of Crataeva nurvala and 250 mg of yellow maca. [Figure 15]FIG. 15 shows the change in daytime urination score for the group treated with a composition containing 200 mg of SAMe, 360 mg of Crataeva nurvala, and 250 mg of yellow maca, and the group treated with a composition containing 360 mg of Crataeva nurvala and 250 mg of yellow maca. [Figure 16] FIG. 16 shows the change in nocturnal urination frequency score for the group treated with a composition containing 200 mg of SAMe, 360 mg of Crataeva nurvala, and 250 mg of yellow maca, and the group treated with a composition containing 360 mg of Crataeva nurvala and 250 mg of yellow maca. [Figure 17] FIG. 17 shows the change in urgency score for the group treated with a composition containing 200 mg of SAMe, 360 mg of Crataeva nurvala, and 250 mg of yellow maca, and the group treated with a composition containing 360 mg of Crataeva nurvala and 250 mg of yellow maca. [Figure 18] FIG. 18 shows the change in urge incontinence scores for a group treated with a composition containing 200 mg of SAMe, 360 mg of Crataeva nurvala, and 250 mg of yellow maca, and a group treated with a composition containing 360 mg of Crataeva nurvala and 250 mg of yellow maca. DETAILED DESCRIPTION OF THE INVENTION

[0007] Detailed Description Some embodiments provide a composition containing pumpkin seeds formulated as a pumpkin seed composition.Some pumpkin seed compositions contain pharmaceutically acceptable solvents, carriers or excipients.In some embodiments, the pumpkin seed composition may contain crushed pumpkin seeds, pumpkin seed extracts or combinations thereof.In some embodiments, the amount of these components can be varied.

[0008] In some embodiments, compositions containing Crataeva nurvala are provided, formulated as Crataeva nurvala compositions. Some Crataeva nurvala compositions contain a pharmaceutically acceptable solvent, carrier, or excipient. In some embodiments, the Crataeva nurvala composition may contain ground Crataeva nurvala plant material, an extract of Crataeva nurvala plant material, or a combination thereof. In some embodiments, the amounts of these ingredients may be varied. As used herein, the term "Rosa alba plant material" may refer to the roots, stems, bark, leaves, flowers, fruit, and / or seeds of the Rosa alba plant; the term "ground Rosa alba plant material" may refer to small particles or powder of dried roots, stems, bark, leaves, flowers, fruit, and / or seeds of the Rosa alba plant; and the term "extract of Rosa alba plant material" may refer to substances extracted from the roots, stems, bark, leaves, flowers, fruit, and / or seeds of the Rosa alba plant using an extraction solvent.

[0009] In some embodiments, compositions containing Lindera aggregata are provided, formulated as a Lindera aggregata composition. Some Lindera aggregata compositions contain a pharmaceutically acceptable solvent, carrier, or excipient. In some embodiments, the Lindera aggregata composition may contain ground Lindera aggregata plant material, an extract of Lindera aggregata plant material, or a combination thereof. In some embodiments, these components may be present in varying amounts. As used herein, the term "Lindera aggregata plant material" may refer to the roots, stems, bark, leaves, flowers, fruits, and / or seeds of the Lindera aggregata plant; the term "ground Lindera aggregata plant material" may refer to small particles or powder of dried roots, stems, bark, leaves, flowers, fruits, and / or seeds of the Lindera aggregata plant; and the term "extract of Lindera aggregata plant material" may refer to a substance extracted from the roots, stems, bark, leaves, flowers, fruits, and / or seeds of Lindera aggregata plant material using an extraction solvent.

[0010] In one embodiment, a composition containing yellow Lepidium meyenii (Maca) is provided, formulated as a black maca and / or yellow maca composition. Some black maca and / or yellow maca compositions contain a pharmaceutically acceptable solvent, carrier, or excipient. In one embodiment, the composition may contain ground black maca, ground yellow maca, a mixture of ground black maca and ground yellow maca, an extract thereof, or a combination thereof. In some embodiments, the amounts of these components may be varied. In an embodiment formulated as a mixture of black and yellow maca compositions, the ratio of black maca to yellow maca may be about 1:1, or the ratio of black maca to yellow maca may be about 4:1 to about 1:4.

[0011] In some embodiments, compositions containing phycocyanin are provided, which are formulated as phycocyanin compositions. Some phycocyanin compositions contain a pharmaceutically acceptable solvent, carrier, or excipient. In some embodiments, the compositions may contain phycocyanin, an extract of phycocyanin, or a combination thereof. In some embodiments, the amounts of these components can be varied.

[0012] Some embodiments provide compositions containing S-adenosyl-L-methionine (SAMe) formulated as a SAMe composition. Some SAMe compositions contain a pharmaceutically acceptable solvent, carrier, or excipient. In some embodiments, the amounts of these components can be varied. In some embodiments, the SAMe compositions described herein can further contain a compound that improves their absorption. In some embodiments, the compound that improves absorption is propyl gallate (PG). Some embodiments provide compositions containing SAMe and PG formulated as a SAMe and PG composition. The SAMe and PG composition contains a pharmaceutically acceptable solvent, carrier, or excipient. In some embodiments, the amounts of these components can be varied. In some embodiments, the SAMe and PG composition can be formulated in a SAMe to PG ratio of about 32:1, or a SAMe to PG ratio of about 128:1 to about 8:1.

[0013] As described herein, the compositions of some embodiments may contain at least one of a pumpkin seed composition, a Crataeva nurvala composition, a Lindera aggregata composition, a black maca and / or yellow maca composition, a phycocyanin composition, a SAMe composition, and a SAMe and PG composition.

[0014] In one embodiment, the composition may contain a combination of a pumpkin seed composition, a Crataeva nurvala composition, and a Lindera aggregata composition. The specific ratio of the pumpkin seed composition, the Crataeva nurvala composition, and the Lindera aggregata composition (P+L+C) is not particularly limited. In some embodiments, the ratio is about 1:1:1, 1:1:2, 1:1:3, 1:1:4, 1:1:5, 1:1:6, 1:1:7, 1:1:8, 1:1:9, 1:1:10, 1:2:1, 1:2:2, 1:2:3, 1:2:4, 1:2:5, 1:2:6, 1:2:7, 1:2:8, 1:2:9, 1:2:10, 1:3:1, 1:3:2, 1:3:3, 1:3:4, 1:3:5, 1:3:6, 1:3:7, 1:3:8, 1:3:9, 1:3:10, 1:4:1, 1:4:2, 1:4:3, 1:4:4, 1:4:5, 1:4:6, 1:4:7, 1:4:8, 1:4:9, 1:4:10, 1:5:1, 1:5:2, 1:5:3, 1:5:4, 1:5:5, 1:5:6, 1:5:7, 1:5:8, 1:5:9, 1:5:10, 1:6:1, 1:6:2, 1:6:3, 1:6:4, 1:6:5, 1:6:6, 1:6:7, 1:6:8, 1:6:9, 1:6:10, 1:7:1, 1:7:2, 1:7:3, 1:7:4, 1:7:5, 1:7:6, 1:7: 7, 1:7:8, 1:7:9, 1:7:10, 1:8:1, 1:8:2, 1:8:3, 1:8:4, 1:8:5, 1:8:6, 1:8:7, 1:8:8, 1:8:9, 1:8:10, 1:9:1, 1:9:2, 1:9:3, 1:9:4, 1:9:5, 1:9:6, 1:9:7, 1:9:8, 1:9:9, 1:9:10, 1:10:1, 1:10:2, 1:10:3, 1:10:4, 1:10:5, 1:10:6, 1:10:7, 1:10:8, 1:10:9, 1:10 :10, 2:1:1, 2:1:2, 2:1:3, 2:1:4, 2:1:5, 2:1:6, 2:1:7, 2:1:8, 2:1:9, 2:1:10, 2:2:1, 2:2:2, 2:2:3, 2:2:4, 2:2:5, 2:2:6, 2:2:7, 2:2:8, 2:2:9, 2:2:10, 2:3:1, 2:3:2, 2:3:3, 2:3:4, 2:3:5, 2:3:6, 2:3:7, 2:3:8, 2:3:9, 2:3:10, 2:4:1, 2:4:2, 2:4:3, 2:4:4,2:4:5、2:4:6、2:4:7、2:4:8、2:4:9、2:4:10、2:5:1、2:5:2、2:5:3、2:5:4、2:5:5、2:5:6、2:5:7、2:5:8、2:5:9、2:5:10、2:6:1、2:6:2、2:6:3、2:6:4、2:6:5、2:6:6、2:6:7、2:6:8、2:6:9、2:6:10、2:7:1、2:7:2、2:7:3、2:7:4、2:7:5、2:7:6、2:7:7、2:7:8、2:7:9、2:7:10、2:8:1、2:8:2、2:8:3、2:8:4、2:8:5、2:8:6、2:8:7、2:8:8、2:8:9、2:8:10、2:9:1、2:9:2、2:9:3、2:9:4、2:9:5、2:9:6、2:9:7、2:9:8、2:9:9、2:9:10、2:10:1、2:10:2、2:10:3、2:10:4、2:10:5、2:10:6、2:10:7、2:10:8、2:10:9、2:10:10、3:1:1、3:1:2、3:1:3、3:1:4、3:1:5、3:1:6、3:1:7、3:1:8、3:1:9、3:1:10、3:2:1、3:2:2、3:2:3、3:2:4、3:2:5、3:2:6、3:2:7、3:2:8、3:2:9、3:2:10、3:3:1、3:3:2、3:3:3、3:3:4、3:3:5、3:3:6、3:3:7、3:3:8、3:3:9、3:3:10、3:4:1、3:4:2、3:4:3、3:4:4、3:4:5、3:4:6、3:4:7、3:4:8、3:4:9、3:4:10、3:5:1、3:5:2、3:5:3、3:5:4、3:5:5、3:5:6、3:5:7、3:5:8、3:5:9、3:5:10、3:6:1、3:6:2、3:6:3、3:6:4、3:6:5、3:6:6、3:6:7、3:6:8、3:6:9、3:6:10、3:7:1、3:7:2、3:7:3、3:7:4、3:7:5、3:7:6、3:7:7、3:7:8、3:7:9、3:7:10、3:8:1、3:8:2、3:8:3、3:8:4、3:8:5、3:8:6、3:8:7、3:8:8、3:8:9、3:8:10、3:9:1、3:9:2、3:9:3、3:9:4、3:9:5、3:9:6、3:9:7、3:9:8、3:9:9、3:9:10、3:10:1、3:10:2、3:10:3、3:10:4、3:10:5、3:10:6、3:10:7、3:10:8、3:10:9、3:10:10、4:1:1、4:1:2、4:1:3、4:1:4、4:1:5、4:1:6、4:1:7、4:1:8、4:1:9、4:1:10、4:2:1、4:2:2、4:2:3、4:2:4、4:2:5、4:2:6、4:2:7、4:2:8、4:2:9、4:2:10、4:3:1、4:3:2、4:3:3、4:3:4、4:3:5、4:3:6、4:3:7、4:3:8、4:3:9、4:3:10、4:4:1、4:4:2、4:4:3、4:4:4、4:4:5、4:4:6、4:4:7、4:4:8、4:4:9、4:4:10、4:5:1、4:5:2、4:5:3、4:5:4、4:5:5、4:5:6、4:5:7、4:5:8、4:5:9、4:5:10、4:6:1、4:6:2、4:6:3、4:6:4、4:6:5、4:6:6、4:6:7、4:6:8、4:6:9、4:6:10、4:7:1、4:7:2、4:7:3、4:7:4、4:7:5、4:7:6、4:7:7、4:7:8、4:7:9、4:7:10、4:8:1、4:8:2、4:8:3、4:8:4、4:8:5、4:8:6、4:8:7、4:8:8、4:8:9、4:8:10、4:9:1、4:9:2、4:9:3、4:9:4、4:9:5、4:9:6、4:9:7、4:9:8、4:9:9、4:9:10、4:10:1、4:10:2、4:10:3、4:10:4、4:10:5、4:10:6、4:10:7、4:10:8、4:10:9、4:10:10、5:1:1、5:1:2、5:1:3、5:1:4、5:1:5、5:1:6、5:1:7、5:1:8、5:1:9、5:1:10、5:2:1、5:2:2、5:2:3、5:2:4、5:2:5、5:2:6、5:2:7、5:2:8、5:2:9、5:2:10、5:3:1、5:3:2、5:3:3、5:3:4、5:3:5、5:3:6、5:3:7、5:3:8、5:3:9、5:3:10、5:4:1、5:4:2、5:4:3、5:4:4、5:4:5、5:4:6、5:4:7、5:4:8、5:4:9、5:4:10、5:5:1、5:5:2、5:5:3、5:5:4、5:5:5、5:5:6、5:5:7、5:5:8、5:5:9、5:5:10、5:6:1、5:6:2、5:6:3、5:6:4、5:6:5、5:6:6、5:6:7、5:6:8、5:6:9、5:6:10、5:7:1、5:7:2、5:7:3、5:7:4、5:7:5、5:7:6、5:7:7、5:7:8、5:7:9、5:7:10、5:8:1、5:8:2、5:8:3、5:8:4、5:8:5、5:8:6、5:8:7、5:8:8、5:8:9、5:8:10、5:9:1、5:9:2、5:9:3、5:9:4、5:9:5、5:9:6、5:9:7、5:9:8、5:9:9、5:9:10、5:10:1、5:10:2、5:10:3、5:10:4、5:10:5、5:10:6、5:10:7、5:10:8、5:10:9、5:10:10、6:1:1、6:1:2、6:1:3、6:1:4、6:1:5、6:1:6、6:1:7、6:1:8、6:1:9、6:1:10、6:2:1、6:2:2、6:2:3、6:2:4、6:2:5、6:2:6、6:2:7、6:2:8、6:2:9、6:2:10、6:3:1、6:3:2、6:3:3、6:3:4、6:3:5、6:3:6、6:3:7、6:3:8、6:3:9、6:3:10、6:4:1、6:4:2、6:4:3、6:4:4、6:4:5、6:4:6、6:4:7、6:4:8、6:4:9、6:4:10、6:5:1、6:5:2、6:5:3、6:5:4、6:5:5、6:5:6、6:5:7、6:5:8、6:5:9、6:5:10、6:6:1、6:6:2、6:6:3、6:6:4、6:6:5、6:6:6、6:6:7、6:6:8、6:6:9、6:6:10、6:7:1、6:7:2、6:7:3、6:7:4、6:7:5、6:7:6、6:7:7、6:7:8、6:7:9、6:7:10、6:8:1、6:8:2、6:8:3、6:8:4、6:8:5、6:8:6、6:8:7、6:8:8、6:8:9、6:8:10、6:9:1、6:9:2、6:9:3、6:9:4、6:9:5、6:9:6、6:9:7、6:9:8、6:9:9、6:9:10、6:10:1、6:10:2、6:10:3、6:10:4、6:10:5、6:10:6、6:10:7、6:10:8、6:10:9、6:10:10、7:1:1、7:1:2、7:1:3、7:1:4、7:1:5、7:1:6、7:1:7、7:1:8、7:1:9、7:1:10、7:2:1、7:2:2、7:2:3、7:2:4、7:2:5、7:2:6、7:2:7、7:2:8、7:2:9、7:2:10、7:3:1、7:3:2、7:3:3、7:3:4、7:3:5、7:3:6、7:3:7、7:3:8、7:3:9、7:3:10、7:4:1、7:4:2、7:4:3、7:4:4、7:4:5、7:4:6、7:4:7、7:4:8、7:4:9、7:4:10、7:5:1、7:5:2、7:5:3、7:5:4、7:5:5、7:5:6、7:5:7、7:5:8、7:5:9、7:5:10、7:6:1、7:6:2、7:6:3、7:6:4、7:6:5、7:6:6、7:6:7、7:6:8、7:6:9、7:6:10、7:7:1、7:7:2、7:7:3、7:7:4、7:7:5、7:7:6、7:7:7、7:7:8、7:7:9、7:7:10、7:8:1、7:8:2、7:8:3、7:8:4、7:8:5、7:8:6、7:8:7、7:8:8、7:8:9、7:8:10、7:9:1、7:9:2、7:9:3、7:9:4、7:9:5、7:9:6、7:9:7、7:9:8、7:9:9、7:9:10、7:10:1、7:10:2、7:10:3、7:10:4、7:10:5、7:10:6、7:10:7、7:10:8、7:10:9、7:10:10、8:1:1、8:1:2、8:1:3、8:1:4、8:1:5、8:1:6、8:1:7、8:1:8、8:1:9、8:1:10、8:2:1、8:2:2、8:2:3、8:2:4、8:2:5、8:2:6、8:2:7、8:2:8、8:2:9、8:2:10、8:3:1、8:3:2、8:3:3、8:3:4、8:3:5、8:3:6、8:3:7、8:3:8、8:3:9、8:3:10、8:4:1、8:4:2、8:4:3、8:4:4、8:4:5、8:4:6、8:4:7、8:4:8、8:4:9、8:4:10、8:5:1、8:5:2、8:5:3、8:5:4、8:5:5、8:5:6、8:5:7、8:5:8、8:5:9、8:5:10、8:6:1、8:6:2、8:6:3、8:6:4、8:6:5、8:6:6、8:6:7、8:6:8、8:6:9、8:6:10、8:7:1、8:7:2、8:7:3、8:7:4、8:7:5、8:7:6、8:7:7、8:7:8、8:7:9、8:7:10、8:8:1、8:8:2、8:8:3、8:8:4、8:8:5、8:8:6、8:8:7、8:8:8、8:8:9、8:8:10、8:9:1、8:9:2、8:9:3、8:9:4、8:9:5、8:9:6、8:9:7、8:9:8、8:9:9、8:9:10、8:10:1、8:10:2、8:10:3、8:10:4、8:10:5、8:10:6、8:10:7、8:10:8、8:10:9、8:10:10、9:1:1、9、 :1:2、9:1:3、9:1:4、9:1:5、9:1:6、9:1:7、9:1:8、9:1:9、9:1:10、9:2:1、9:2:2、9:2:3、9:2:4、9:2:5、9:2:6、9:2:7、9:2:8、9:2:9、9:2:10、9:3:1、9:3:2、9:3:3、9:3:4、9:3:5、9:3:6、9:3:7、9:3:8、9:3:9、9:3:10、9:4:1、9:4:2、9:4:3、9:4:4、9:4:5、9:4:6、9:4:7、9:4:8、9:4:9、9:4:10、9:5:1、9:5:2、9:5:3、9:5:4、9:5:5、9:5:6、9:5:7、9:5:8、9:5:9、9:5:10、9:6:1、9:6:2、9:6:3、9:6:4、9:6:5、9:6:6、9:6:7、9:6:8、9:6:9、9:6:10、9:7:1、9:7:2、9:7:3、9:7:4、9:7:5、9:7:6、9:7:7、9:7:8、9:7:9、9:7:10、9:8:1、9:8:2、9:8:3、9:8:4、9:8:5、9:8:6、9:8:7、9:8:8、9:8:9、9:8:10、9:9:1、9:9:2、9:9:3、9:9:4、9:9:5、9:9:6、9:9:7、9:9:8、9:9:9、9:9:10、9:10:1、9:10:2、9:10:3、9:10:4、9:10:5、9:10:6、9:10:7、9:10:8、9:10:9、9:10:10、10:1:1、10:1:2、10:1:3、10:1:4、10:1:5、10:1:6、10:1:7、10:1:8、10:1:9、10:1:10、10:2:1、10:2:2、10:2:3、10:2:4、10:2:5、10:2:6、10:2:7、10:2:8、10:2:9、10:2:10、10:3:1、10:3:2、10:3:3、10:3:4、10:3:5、10:3:6、10:3:7、10:3:8、10:3:9、10:3:10、10:4:1、10:4:2、10:4:3、10:4:4、10:4:5、10:4:6、10:4:7、10:4:8、10:4:9、10:4:10、10:5:1、10:5:2、10:5:3、10:5:4、10:5:5、10:5:6、10:5:7、10:5:8、10:5:9、10:5:10、10:6:1、10:6:2、10:6:3、10:6:4、10:6:5, 10:6:6, 10:6:7, 10:6:8, 10:6:9, 10:6:10, 10:7:1, 10:7:2, 10:7:3, 10:7:4, 10:7:5, 10:7:6, 10:7:7, 10:7:8, 10:7:9, 10:7:10, 10:8:1, 10:8:2, 10:8:3, 10:8:4, 10:8:5, 10:8:6, 10:8:7, 10:8:8, 10:8:9, The P+L+C composition may be 10:8:10, 10:9:1, 10:9:2, 10:9:3, 10:9:4, 10:9:5, 10:9:6, 10:9:7, 10:9:8, 10:9:9, 10:9:10, 10:10:1, 10:10:2, 10:10:3, 10:10:4, 10:10:5, 10:10:6, 10:10:7, 10:10:8, 10:10:9, 10:10:10, or any ratio therebetween. From the results and discussion presented herein, one skilled in the art will understand how to formulate P+L+C compositions to achieve the results described herein.

[0015] In some embodiments, the composition may contain a combination (P+L+C) of a pumpkin seed composition, a Crataeva nurvala composition, a Lindera aggregata composition, and at least one of a black maca and / or yellow maca composition, a phycocyanin composition, a SAMe composition, or a SAMe and PG composition. The specific ratio of the P+L+C composition to the at least one other ingredient is not particularly limited. In some embodiments, the ratio of P+L+C to at least one other ingredient can be about 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, or any ratio therebetween. From the results and discussion presented herein, one of ordinary skill in the art would understand how to formulate a composition containing P+L+C and at least one of a black maca and / or yellow maca composition, a phycocyanin composition, a SAMe composition, or a SAMe and PG composition to achieve the results described herein.

[0016] In some embodiments, the composition may contain at least one of a black maca and / or yellow maca composition, a phycocyanin composition, a SAMe composition, or a SAMe and PG composition in combination with a Crataeva nurvala composition. The specific ratio of the Crataeva nurvala composition to the at least one other ingredient is not particularly limited. In some embodiments, the ratio of the Crataeva nurvala composition to the at least one other ingredient can be about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, or any ratio therebetween. From the results and discussion presented herein, one skilled in the art would understand how to formulate a composition containing at least one of a black maca and / or yellow maca composition, a phycocyanin composition, a SAMe composition, or a SAMe and PG composition, and a Crataeva nulbara composition to achieve the results described herein.

[0017] In some embodiments, the composition may contain a combination of a Crataeva nurvala composition, a black maca and / or yellow maca composition, and a SAMe composition. The specific ratio of the Crataeva nurvala composition to the black maca and / or yellow maca composition and the SAMe composition is not particularly limited. In some embodiments, the Crataeva nurvala composition The ratio of the Nurubara composition to the black maca and / or yellow maca composition to the SAMe composition is about 1:1:1.0, 1:1:1.1, 1:1:1.2, 1:1:1.3, 1:1:1.4, 1:1:1.5, 1:1:1.6, 1:1:1.7, 1:1:1.8, 1:1:1.9, 1:1:2.0, 1:1:2.1, 1:1:2.2, 1:1:2.3, 1:1:2.4, 1:1:2.5, 1:1:2.6, 1:1:2.7, 1:1:2.8, 1:1:2.9, 1:1:3.0, 1:1:3.1 , 1:1:3.2, 1:1:3.3, 1:1:3.4, 1:1:3.5, 1:1:3.6, 1:1:3.7, 1:1:3.8, 1:1:3.9, 1:1:4.0, 1:1:5, 1:1:6, 1:1:7, 1:1:8, 1:1:9, 1:1:10, 1:2:1, 1:2:2, 1:2:3, 1:2:4, 1:2:5, 1:2:6, 1:2:7, 1:2:8, 1:2:9, 1:2:10, 1:3:1, 1:3:2, 1:3:3, 1:3:4, 1:3:5, 1:3:6, 1:3: 7, 1:3:8, 1:3:9, 1:3:10, 1:4:1, 1:4:2, 1:4:3, 1:4:4, 1:4:5, 1:4:6, 1:4:7, 1:4:8, 1:4:9, 1:4:10, 1:5:1, 1:5:2, 1:5:3, 1:5:4, 1:5:5, 1:5:6, 1:5:7, 1:5:8, 1:5:9, 1:5:10, 1:6:1, 1:6:2, 1:6:3, 1:6:4, 1:6:5, 1:6:6, 1:6:7, 1:6:8, 1:6:9, 1:6:10, 1:7:1, 1 :7:2, 1:7:3, 1:7:4, 1:7:5, 1:7:6, 1:7:7, 1:7:8, 1:7:9, 1:7:10, 1:8:1, 1:8:2, 1:8:3, 1:8:4, 1:8:5, 1:8:6, 1:8:7, 1:8:8, 1:8:9, 1:8:10, 1:9:1, 1:9:2, 1:9:3, 1:9:4, 1:9:5, 1:9:6, 1:9:7, 1:9:8, 1:9:9, 1:9:10, 1:10:1, 1:10:2, 1:10:3, 1:10:4, 1:10:5,1:10:6、1:10:7、1:10:8、1:10:9、1:10:10、2:1:1.0、2:1:1.1、2:1:1.2、2:1:1.3、2:1:1.4、2:1:1.5、2:1:1.6、2:1:1.7、2:1:1.8、2:1:1.9、2:1:2.0、2:1:2.1、2:1:2.2、2:1:2.3、2:1:2.4、2:1:2.5、2:1:2.6、2:1:2.7、2:1:2.8、2:1:2.9、2:1:3.0、2:1:3.1、2:1:3.2、2:1:3.3、2:1:3.4、2:1:3.5、2:1:3.6、2:1:3.7、2:1:3.8、2:1:3.9、2:1:4.0、2:1:5、2:1:6、2:1:7、2:1:8、2:1:9、2:1:10、2:2:1.0、2:2:1.1、2:2:1.2、2:2:1.3、2:2:1.4、2:2:1.5、2:2:1.6、2:2:1.7、2:2:1.8、2:2:1.9、2:2:3、2:2:4、2:2:5、2:2:6、2:2:7、2:2:8、2:2:9、2:2:10、2:3:1.0、2:3:1.1、2:3:1.2、2:3:1.3、2:3:1.4、2:3:1.5、2:3:1.6、2:3:1.7、2:3:1.8、2:3:1.9、2:3:2.0、2:3:3、2:3:4、2:3:5、2:3:6、2:3:7、2:3:8、2:3:9、2:3:10、2:3.1:1.0、2:3.1:1.1、2:3.1:1.2、2:3.1:1.25、2:3.125:1.25、2:3.1:1.3、2:3.1:1.4、2:3.1:1.5、2:3.1:1.6、2:3.1:1.7、2:3.1:1.8、2:3.1:1.9、2:3.1:2.0、2:4:1、2:4:2、2:4:3、2:4:4、2:4:5、2:4:6、2:4:7、2:4:8、2:4:9、2:4:10、2:5:1、2:5:2、2:5:3、2:5:4、2:5:5、2:5:6、2:5:7、2:5:8、2:5:9、2:5:10、2:6:1、2:6:2、2:6:3、2:6:4、2:6:5、2:6:6、2:6:7、2:6:8、2:6:9、2:6:10、2:7:1、2:7:2、2:7:3、2:7:4、2:7:5、2:7:6、2:7:7、2:7:8、2:7:9、2:7:10、2:8:1、2:8:2、2:8:3、2:8:4、2:8:5、2:8:6、2:8:7、2:8:8、2:8:9、2:8:10、2:9:1、2:9:2、2:9:3、2:9:4、2:9:5、2:9:6、2:9:7、2:9:8、2:9:9、2:9:10、2:10:1、2:10:2、2:10:3、2:10:4、2:10:5、2:10:6、2:10:7、2:10:8、2:10:9、2:10:10、3:1:1.0、3:1:1.1、3:1:1.2、3:1:1.3、3:1:1.4、3:1:1.5、3:1:1.6、3:1:1.7、3:1:1.8、3:1:1.9、3:1:2.0、3:1:2.1、3:1:2.2、3:1:2.3、3:1:2.4、3:1:2.5、3:1:2.6、3:1:2.7、3:1:2.8、3:1:2.9、3:1:3.0、3:1:3.1、3:1:3.2、3:1:3.3、3:1:3.4、3:1:3.5、3:1:3.6、3:1:3.7、3:1:3.8、3:1:3.9、3:1:4.0、3:1:5、3:1:6、3:1:7、3:1:8、3:1:9、3:1:10、3:2:1、3:2:2、3:2:3、3:2:4、3:2:5、3:2:6、3:2:7、3:2:8、3:2:9、3:2:10、3:3:1、3:3:2、3:3:3、3:3:4、3:3:5、3:3:6、3:3:7、3:3:8、3:3:9、3:3:10、3:4:1、3:4:2、3:4:3、3:4:4、3:4:5、3:4:6、3:4:7、3:4:8、3:4:9、3:4:10、3:5:1、3:5:2、3:5:3、3:5:4、3:5:5、3:5:6、3:5:7、3:5:8、3:5:9、3:5:10、3:6:1、3:6:2、3:6:3、3:6:4、3:6:5、3:6:6、3:6:7、3:6:8、3:6:9、3:6:10、3:7:1、3:7:2、3:7:3、3:7:4、3:7:5、3:7:6、3:7:7、3:7:8、3:7:9、3:7:10、3:8:1、3:8:2、3:8:3、3:8:4、3:8:5、3:8:6、3:8:7、3:8:8、3:8:9、3:8:10、3:9:1、3:9:2、3:9:3、3:9:4、3:9:5、3:9:6、3:9:7、3:9:8、3:9:9、3:9:10、3:10:1、3:10:2、3:10:3、3:10:4、3:10:5、3:10:6、3:10:7、3:10:8、3:10:9、3:10:10、4:1:1.0、4:1:1.1、4:1:1.2、4:1:1.3、4:1:1.4、4:1:1.5、4:1:1.6、4:1:1.7、4:1:1.8、4:1:1.9、4:1:2.0、4:1:2.1、4:1:2.2、4:1:2.3、4:1:2.4、4:1:2.5、4:1:2.6、4:1:2.7、4:1:2.8、4:1:2.9、4:1:3.0、4:1:3.1、4:1:3.2、4:1:3.3、4:1:3.4、4:1:3.5、4:1:3.6、4:1:3.7、4:1:3.8、4:1:3.9、4:1:4.0、4:1:5、4:1:6、4:1:7、4:1:8、4:1:9、4:1:10、4:2:1、4:2:2、4:2:3、4:2:4、4:2:5、4:2:6、4:2:7、4:2:8、4:2:9、4:2:10、4:3:1、4:3:2、4:3:3、4:3:4、4:3:5、4:3:6、4:3:7、4:3:8、4:3:9、4:3:10、4:4:1、4:4:2、4:4:3、4:4:4、4:4:5、4:4:6、4:4:7、4:4:8、4:4:9、4:4:10、4:5:1、4:5:2、4:5:3、4:5:4、4:5:5、4:5:6、4:5:7、4:5:8、4:5:9、4:5:10、4:6:1、4:6:2、4:6:3、4:6:4、4:6:5、4:6:6、4:6:7、4:6:8、4:6:9、4:6:10、4:7:1、4:7:2、4:7:3、4:7:4、4:7:5、4:7:6、4:7:7、4:7:8、4:7:9、4:7:10、4:8:1、4:8:2、4:8:3、4:8:4、4:8:5、4:8:6、4:8:7、4:8:8、4:8:9、4:8:10、4:9:1、4:9:2、4:9:3、4:9:4、4:9:5、4:9:6、4:9:7、4:9:8、4:9:9、4:9:10、4:10:1、4:10:2、4:10:3、4:10:4、4:10:5、4:10:6、4:10:7、4:10:8、4:10:9、4:10:10、5:1:1.0、5:1:1.1、5:1:1.2、5:1:1.3、5:1:1.4、5:1:1.5、5:1:1.6、5:1:1.7、5:1:1.8、5:1:1.9、5:1:2.0、5:1:2.1、5:1:2.2、5:1:2.3、5:1:2.4、5:1:2.5、5:1:2.6、5:1:2.7、5:1:2.8、5:1:2.9、5:1:3.0、5:1:3.1、5:1:3.2、5:1:3.3、5:1:3.4、5:1:3.5、5:1:3.6、5:1:3.7、5:1:3.8、5:1:3.9、5:1:4.0、5:1:5、5:1:6、5:1:7、5:1:8、5:1:9、5:1:10、5:2:1、5:2:2、5:2:3、5:2:4、5:2:5、5:2:6、5:2:7、5:2:8、5:2:9、5:2:10、5:3:1、5:3:2、5:3:3、5:3:4、5:3:5、5:3:6、5:3:7、5:3:8、5:3:9、5:3:10、5:4:1、5:4:2、5:4:3、5:4:4、5:4:5、5:4:6、5:4:7、5:4:8、5:4:9、5:4:10、5:5:1、5:5:2、5:5:3、5:5:4、5:5:5、5:5:6、5:5:7、5:5:8、5:5:9、5:5:10、5:6:1、5:6:2、5:6:3、5:6:4、5:6:5、5:6:6、5:6:7、5:6:8、5:6:9、5:6:10、5:7:1、5:7:2、5:7:3、5:7:4、5:7:5、5:7:6、5:7:7、5:7:8、5:7:9、5:7:10、5:8:1、5:8:2、5:8:3、5:8:4、5:8:5、5:8:6、5:8:7、5:8:8、5:8:9、5:8:10、5:9:1、5:9:2、5:9:3、5:9:4、5:9:5、5:9:6、5:9:7、5:9:8、5:9:9、5:9:10、5:10:1、5:10:2、5:10:3、5:10:4、5:10:5、5:10:6、5:10:7、5:10:8、5:10:9、5:10:10、6:1:1、6:1:2、6:1:3、6:1:4、6:1:5、6:1:6、6:1:7、6:1:8、6:1:9、6:1:10、6:2:1、6:2:2、6:2:3、6:2:4、6:2:5、6:2:6、6:2:7、6:2:8、6:2:9、6:2:10、6:3:1、6:3:2、6:3:3、6:3:4、6:3:5、6:3:6、6:3:7、6:3:8、6:3:9、6:3:10、6:4:1、6:4:2、6:4:3、6:4:4、6:4:5、6:4:6、6:4:7、6:4:8、6:4:9、6:4:10、6:5:1、6:5:2、6:5:3、6:5:4、6:5:5、6:5:6、6:5:7、6:5:8、6:5:9、6:5:10、6:6:1、6:6:2、6:6:3、6:6:4、6:6:5、6:6:6、6:6:7、6:6:8、6:6:9、6:6:10、6:7:1、6:7:2、6:7:3、6:7:4、6:7:5、6:7:6、6:7:7、6:7:8、6:7:9、6:7:10、6:8:1、6:8:2、6、 :8:3、6:8:4、6:8:5、6:8:6、6:8:7、6:8:8、6:8:9、6:8:10、6:9:1、6:9:2、6:9:3、6:9:4、6:9:5、6:9:6、6:9:7、6:9:8、6:9:9、6:9:10、6:10:1、6:10:2、6:10:3、6:10:4、6:10:5、6:10:6、6:10:7、6:10:8、6:10:9、6:10:10、7:1:1、7:1:2、7:1:3、7:1:4、7:1:5、7:1:6、7:1:7、7:1:8、7:1:9、7:1:10、7:2:1、7:2:2、7:2:3、7:2:4、7:2:5、7:2:6、7:2:7、7:2:8、7:2:9、7:2:10、7:3:1、7:3:2、7:3:3、7:3:4、7:3:5、7:3:6、7:3:7、7:3:8、7:3:9、7:3:10、7:4:1、7:4:2、7:4:3、7:4:4、7:4:5、7:4:6、7:4:7、7:4:8、7:4:9、7:4:10、7:5:1、7:5:2、7:5:3、7:5:4、7:5:5、7:5:6、7:5:7、7:5:8、7:5:9、7:5:10、7:6:1、7:6:2、7:6:3、7:6:4、7:6:5、7:6:6、7:6:7、7:6:8、7:6:9、7:6:10、7:7:1、7:7:2、7:7:3、7:7:4、7:7:5、7:7:6、7:7:7、7:7:8、7:7:9、7:7:10、7:8:1、7:8:2、7:8:3、7:8:4、7:8:5、7:8:6、7:8:7、7:8:8、7:8:9、7:8:10、7:9:1、7:9:2、7:9:3、7:9:4、7:9:5、7:9:6、7:9:7、7:9:8、7:9:9、7:9:10、7:10:1、7:10:2、7:10:3、7:10:4、7:10:5、7:10:6、7:10:7、7:10:8、7:10:9、7:10:10、8:1:1、8:1:2、8:1:3、8:1:4、8:1:5、8:1:6、8:1:7、8:1:8、8:1:9、8:1:10、8:2:1、8:2:2、8:2:3、8:2:4、8:2:5、8:2:6、8:2:7、8:2:8、8:2:9、8:2:10、8:3:1、8:3:2、8:3:3、8:3:4、8:3:5、8:3:6、8:3:7、8:3:8、8:3:9、8:3:10、8:4:1、8:4:2、8:4:3、8:4:4、8:4:5、8:4:6、8:4:7、8:4:8、8:4:9、8:4:10、8:5:1、8:5:2、8:5:3、8:5:4、8:5:5、8:5:6、8:5:7、8:5:8、8:5:9、8:5:10、8:6:1、8:6:2、8:6:3、8:6:4、8:6:5、8:6:6、8:6:7、8:6:8、8:6:9、8:6:10、8:7:1、8:7:2、8:7:3、8:7:4、8:7:5、8:7:6、8:7:7、8:7:8、8:7:9、8:7:10、8:8:1、8:8:2、8:8:3、8:8:4、8:8:5、8:8:6、8:8:7、8:8:8、8:8:9、8:8:10、8:9:1、8:9:2、8:9:3、8:9:4、8:9:5、8:9:6、8:9:7、8:9:8、8:9:9、8:9:10、8:10:1、8:10:2、8:10:3、8:10:4、8:10:5、8:10:6、8:10:7、8:10:8、8:10:9、8:10:10、9:1:1、9:1:2、9:1:3、9:1:4、9:1:5、9:1:6、9:1:7、9:1:8、9:1:9、9:1:10、9:2:1、9:2:2、9:2:3、9:2:4、9:2:5、9:2:6、9:2:7、9:2:8、9:2:9、9:2:10、9:3:1、9:3:2、9:3:3、9:3:4、9:3:5、9:3:6、9:3:7、9:3:8、9:3:9、9:3:10、9:4:1、9:4:2、9:4:3、9:4:4、9:4:5、9:4:6、9:4:7、9:4:8、9:4:9、9:4:10、9:5:1、9:5:2、9:5:3、9:5:4、9:5:5、9:5:6、9:5:7、9:5:8、9:5:9、9:5:10、9:6:1、9:6:2、9:6:3、9:6:4、9:6:5、9:6:6、9:6:7、9:6:8、9:6:9、9:6:10、9:7:1、9:7:2、9:7:3、9:7:4、9:7:5、9:7:6、9:7:7、9:7:8、9:7:9、9:7:10、9:8:1、9:8:2、9:8:3、9:8:4、9:8:5、9:8:6、9:8:7、9:8:8、9:8:9、9:8:10、9:9:1、9:9:2、9:9:3、9:9:4、9:9:5、9:9:6、9:9:7、9:9:8、9:9:9、9:9:10、9:10:1、9:10:2、9:10:3、9:10:4、9:10:5, 9:10:6, 9:10:7, 9:10:8, 9:10:9, 9:10:10, 10:1:1, 10:1:2, 10:1:3, 10:1:4, 10:1:5, 10:1:6, 10:1:7, 10:1:8, 10:1:9, 10:1:10, 10:2:1, 10:2:2, 10:2:3, 10:2:4, 10:2:5, 10:2:6, 10:2:7, 10:2:8, 10:2:9, 10:2:10, 10:3:1, 10: 3:2, 10:3:3, 10:3:4, 10:3:5, 10:3:6, 10:3:7, 10:3:8, 10:3:9, 10:3:10, 10:4:1, 10:4:2, 10:4:3, 10:4:4, 10:4:5, 10:4:6, 10:4:7, 10:4:8, 10:4:9, 10:4:10, 10:5:1, 10:5:2, 10:5:3, 10:5:4, 10:5:5, 10:5:6, 10:5:7, 10:5:8, 10:5:9, 10:5:10, 10:6:1, 10:6:2, 10:6:3, 10:6:4, 10:6:5, 10:6:6, 10:6:7, 10:6:8, 10:6:9, 10:6:10, 10:7:1, 10:7:2, 10:7:3, 10:7:4, 10:7:5, 10:7:6, 10:7:7, 10:7:8, 10:7:9, 10:7:10, 10:8:1, 10:8:2, 10:8:3, 10:8:4, 10:8:5, 10:8:6, 10: It can be 8:7, 10:8:8, 10:8:9, 10:8:10, 10:9:1, 10:9:2, 10:9:3, 10:9:4, 10:9:5, 10:9:6, 10:9:7, 10:9:8, 10:9:9, 10:9:10, 10:10:1, 10:10:2, 10:10:3, 10:10:4, 10:10:5, 10:10:6, 10:10:7, 10:10:8, 10:10:9, 10:10:10 or any ratio therebetween. The amount of Crataeva nurbara composition in the combination may be about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, 400 mg, 425 mg, 450 mg,475mg, 500mg, 525mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850m g, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1.25g, 1.5g, 1.75g, 2.0g, 2.25g, 2.5g, 2.75g, 3.0g, 3.25g, The black maca and / or yellow maca compositions in combination may be 3.5g, 3.5g, 3.75g, 4.0g, 4.25g, 4.5g, 4.75g, 5.0g, 5.25g, 5.5g, 5.75g, 6.0g, 6.25g, 6.5g, 6.75g, 7.0g, 7.25g, 7.5g, 7.75g, 8.0g, 8.25g, 8.5g, 8.75g, 9.0g, 8.25g, 9.5g, 9.75g, 10g or more, or any amount therebetween. The amounts are approximately 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 82 5mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1.25g, 1.5g, 1.75g, 2.0g , 2.25g, 2.5g, 2.75g, 3.0g, 3.25g, 3.5g, 3.5g, 3.75g, 4.0g, 4.25g, 4.5g, 4.75g, 5. The amount of SAMe composition in the combination may be about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 725 g, 75 g, 75 g, 80 mg, 825 g, 85 g, 875 g, 90 mg, 95 mg, 96 mg, 975 g, 98 mg, 99 mg, 100 mg, or more, or any amount therebetween.60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425 mg, 450mg, 475mg, 500mg, 525mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950m g, 975 mg, 1000 mg, 1.25 g, 1.5 g, 1.75 g, 2.0 g, 2.25 g, 2.5 g, 2.75 g, 3.0 g, 3.25 g, 3.5 g, 3.5 g, 3.75 g, 4.0 g, 4.25 g, 4.5 g, 4.75 g, 5.0 g, 5.25 g, 5.5 g, 5.75 g, 6.0 g, 6.25 g, 6.5 g, 6.75 g, 7.0 g, 7.25 g, 7.5 g, 7.75 g, 8.0 g, 8.25 g, 8.5 g, 8.75 g, 9.0 g, 8.25 g, 9.5 g, 9.75 g, 10 g or more, or any amount in between. In one embodiment, the composition may contain a combination of 100-500 mg of a Crataeva nurbala composition, 40,000 mg of a black maca and / or yellow maca composition, and 100-500 mg of a SAMe composition. In another embodiment, the composition may contain a combination of 300-400 mg of a Crataeva nurbala composition, 90-500 mg of a black maca and / or yellow maca composition, and 150-200 mg of a SAMe composition. From the results and discussion presented in the specification, those skilled in the art will understand how to formulate a composition containing a Crataeva nurbala composition, a black maca and / or yellow maca composition, and a SAMe composition to achieve the results described in the specification.

[0018] In some embodiments, the composition may contain a combination of a Crataeva nurvala composition, a black maca and / or yellow maca composition, and a SAMe and PG composition. The specific ratio of the Crataeva nurvala composition to the black maca and / or yellow maca composition and the SAMe and PG composition is not particularly limited. In some embodiments, the Crataeva nurvala composition The ratio of the Nurubara composition to the black maca and / or yellow maca composition to the SAMe and PG composition is about 1:1:1.0, 1:1:1.1, 1:1:1.2, 1:1:1.3, 1:1:1.4, 1:1:1.5, 1:1:1.6, 1:1:1.7, 1:1:1.8, 1:1:1.9, 1:1:2.0, 1:1:2.1, 1:1:2.2, 1:1:2.3, 1:1:2.4, 1:1:2.5, 1:1:2.6, 1:1:2.7, 1:1:2.8, 1:1:2.9, 1:1:3.0, 1:1:3.1, 1:1:3.2, 1:1:3.3, 1:1:3.4, 1:1:3.5, 1:1:3.6, 1:1:3.7, 1:1:3.8, 1:1:3.9, 1:1:4.0, 1:1:5, 1:1:6, 1:1:7, 1:1:8, 1:1:9, 1:1:10, 1:2:1, 1:2:2, 1:2:3, 1:2:4, 1:2:5, 1:2:6, 1:2:7, 1:2:8, 1:2:9, 1:2:10, 1:3:1, 1:3:2, 1:3:3, 1:3:4, 1:3:5, 1 :3:6, 1:3:7, 1:3:8, 1:3:9, 1:3:10, 1:4:1, 1:4:2, 1:4:3, 1:4:4, 1:4:5, 1:4:6, 1:4:7, 1:4:8, 1:4:9, 1:4:10, 1:5:1, 1:5:2, 1:5:3, 1:5:4, 1:5:5, 1:5:6, 1:5:7, 1:5:8, 1:5:9, 1:5:10, 1:6:1, 1:6:2, 1:6:3, 1:6:4, 1:6:5, 1:6:6, 1:6:7, 1:6:8, 1:6:9, 1: 6:10, 1:7:1, 1:7:2, 1:7:3, 1:7:4, 1:7:5, 1:7:6, 1:7:7, 1:7:8, 1:7:9, 1:7:10, 1:8:1, 1:8:2, 1:8:3, 1:8:4, 1:8:5, 1:8:6, 1:8:7, 1:8:8, 1:8:9, 1:8:10, 1:9:1, 1:9:2, 1:9:3, 1:9:4, 1:9:5, 1:9:6, 1:9:7, 1:9:8, 1:9:9, 1:9:10, 1:10:1, 1:10:2, 1:10:3,1:10:4、1:10:5、1:10:6、1:10:7、1:10:8、1:10:9、1:10:10、2:1:1.0、2:1:1.1、2:1:1.2、2:1:1.3、2:1:1.4、2:1:1.5、2:1:1.6、2:1:1.7、2:1:1.8、2:1:1.9、2:1:2.0、2:1:2.1、2:1:2.2、2:1:2.3、2:1:2.4、2:1:2.5、2:1:2.6、2:1:2.7、2:1:2.8、2:1:2.9、2:1:3.0、2:1:3.1、2:1:3.2、2:1:3.3、2:1:3.4、2:1:3.5、2:1:3.6、2:1:3.7、2:1:3.8、2:1:3.9、2:1:4.0、2:1:5、2:1:6、2:1:7、2:1:8、2:1:9、2:1:10、2:2:1.0、2:2:1.1、2:2:1.2、2:2:1.3、2:2:1.4、2:2:1.5、2:2:1.6、2:2:1.7、2:2:1.8、2:2:1.9、2:2:3、2:2:4、2:2:5、2:2:6、2:2:7、2:2:8、2:2:9、2:2:10、2:3:1.0、2:3:1.1、2:3:1.2、2:3:1.3、2:3:1.4、2:3:1.5、2:3:1.6、2:3:1.7、2:3:1.8、2:3:1.9、2:3:2.0、2:3:3、2:3:4、2:3:5、2:3:6、2:3:7、2:3:8、2:3:9、2:3:10、2:3.1:1.0、2:3.1:1.1、2:3.1:1.2、2:3.1:1.25、2:3.125:1.25、2:3.1:1.3、2:3.1:1.4、2:3.1:1.5、2:3.1:1.6、2:3.1:1.7、2:3.1:1.8、2:3.1:1.9、2:3.1:2.0、2:4:1、2:4:2、2:4:3、2:4:4、2:4:5、2:4:6、2:4:7、2:4:8、2:4:9、2:4:10、2:5:1、2:5:2、2:5:3、2:5:4、2:5:5、2:5:6、2:5:7、2:5:8、2:5:9、2:5:10、2:6:1、2:6:2、2:6:3、2:6:4、2:6:5、2:6:6、2:6:7、2:6:8、2:6:9、2:6:10、2:7:1、2:7:2、2:7:3、2:7:4、2:7:5、2:7:6、2:7:7、2:7:8、2:7:9、2:7:10、2:8:1、2:8:2、2:8:3、2:8:4、2:8:5、2:8:6、2:8:7、2:8:8、2:8:9、2:8:10、2:9:1、2:9:2、2:9:3、2:9:4、2:9:5、2:9:6、2:9:7、2:9:8、2:9:9、2:9:10、2:10:1、2:10:2、2:10:3、2:10:4、2:10:5、2:10:6、2:10:7、2:10:8、2:10:9、2:10:10、3:1:1.0、3:1:1.1、3:1:1.2、3:1:1.3、3:1:1.4、3:1:1.5、3:1:1.6、3:1:1.7、3:1:1.8、3:1:1.9、3:1:2.0、3:1:2.1、3:1:2.2、3:1:2.3、3:1:2.4、3:1:2.5、3:1:2.6、3:1:2.7、3:1:2.8、3:1:2.9、3:1:3.0、3:1:3.1、3:1:3.2、3:1:3.3、3:1:3.4、3:1:3.5、3:1:3.6、3:1:3.7、3:1:3.8、3:1:3.9、3:1:4.0、3:1:5、3:1:6、3:1:7、3:1:8、3:1:9、3:1:10、3:2:1、3:2:2、3:2:3、3:2:4、3:2:5、3:2:6、3:2:7、3:2:8、3:2:9、3:2:10、3:3:1、3:3:2、3:3:3、3:3:4、3:3:5、3:3:6、3:3:7、3:3:8、3:3:9、3:3:10、3:4:1、3:4:2、3:4:3、3:4:4、3:4:5、3:4:6、3:4:7、3:4:8、3:4:9、3:4:10、3:5:1、3:5:2、3:5:3、3:5:4、3:5:5、3:5:6、3:5:7、3:5:8、3:5:9、3:5:10、3:6:1、3:6:2、3:6:3、3:6:4、3:6:5、3:6:6、3:6:7、3:6:8、3:6:9、3:6:10、3:7:1、3:7:2、3:7:3、3:7:4、3:7:5、3:7:6、3:7:7、3:7:8、3:7:9、3:7:10、3:8:1、3:8:2、3:8:3、3:8:4、3:8:5、3:8:6、3:8:7、3:8:8、3:8:9、3:8:10、3:9:1、3:9:2、3:9:3、3:9:4、3:9:5、3:9:6、3:9:7、3:9:8、3:9:9、3:9:10、3:10:1、3:10:2、3:10:3、3:10:4、3:10:5、3:10:6、3:10:7、3:10:8、3:10:9、3:10:10、4:1:1.0、4:1:1.1、4:1:1.2、4:1:1.3、4:1:1.4、4:1:1.5、4:1:1.6、4:1:1.7、4:1:1.8、4:1:1.9、4:1:2.0、4:1:2.1、4:1:2.2、4:1:2.3、4:1:2.4、4:1:2.5、4:1:2.6、4:1:2.7、4:1:2.8、4:1:2.9、4:1:3.0、4:1:3.1、4:1:3.2、4:1:3.3、4:1:3.4、4:1:3.5、4:1:3.6、4:1:3.7、4:1:3.8、4:1:3.9、4:1:4.0、4:1:5、4:1:6、4:1:7、4:1:8、4:1:9、4:1:10、4:2:1、4:2:2、4:2:3、4:2:4、4:2:5、4:2:6、4:2:7、4:2:8、4:2:9、4:2:10、4:3:1、4:3:2、4:3:3、4:3:4、4:3:5、4:3:6、4:3:7、4:3:8、4:3:9、4:3:10、4:4:1、4:4:2、4:4:3、4:4:4、4:4:5、4:4:6、4:4:7、4:4:8、4:4:9、4:4:10、4:5:1、4:5:2、4:5:3、4:5:4、4:5:5、4:5:6、4:5:7、4:5:8、4:5:9、4:5:10、4:6:1、4:6:2、4:6:3、4:6:4、4:6:5、4:6:6、4:6:7、4:6:8、4:6:9、4:6:10、4:7:1、4:7:2、4:7:3、4:7:4、4:7:5、4:7:6、4:7:7、4:7:8、4:7:9、4:7:10、4:8:1、4:8:2、4:8:3、4:8:4、4:8:5、4:8:6、4:8:7、4:8:8、4:8:9、4:8:10、4:9:1、4:9:2、4:9:3、4:9:4、4:9:5、4:9:6、4:9:7、4:9:8、4:9:9、4:9:10、4:10:1、4:10:2、4:10:3、4:10:4、4:10:5、4:10:6、4:10:7、4:10:8、4:10:9、4:10:10、5:1:1.0、5:1:1.1、5:1:1.2、5:1:1.3、5:1:1.4、5:1:1.5、5:1:1.6、5:1:1.7、5:1:1.8、5:1:1.9、5:1:2.0、5:1:2.1、5:1:2.2、5:1:2.3、5:1:2.4、5:1:2.5、5:1:2.6、5:1:2.7、5:1:2.8、5:1:2.9、5:1:3.0、5:1:3.1、5:1:3.2、5:1:3.3、5:1:3.4、5:1:3.5、5:1:3.6、5:1:3.7、5:1:3.8、5:1:3.9、5:1:4.0、5:1:5、5:1:6、5:1:7、5:1:8、5:1:9、5:1:10、5:2:1、5:2:2、5:2:3、5:2:4、5:2:5、5:2:6、5:2:7、5:2:8、5:2:9、5:2:10、5:3:1、5:3:2、5:3:3、5:3:4、5:3:5、5:3:6、5:3:7、5:3:8、5:3:9、5:3:10、5:4:1、5:4:2、5:4:3、5:4:4、5:4:5、5:4:6、5:4:7、5:4:8、5:4:9、5:4:10、5:5:1、5:5:2、5:5:3、5:5:4、5:5:5、5:5:6、5:5:7、5:5:8、5:5:9、5:5:10、5:6:1、5:6:2、5:6:3、5:6:4、5:6:5、5:6:6、5:6:7、5:6:8、5:6:9、5:6:10、5:7:1、5:7:2、5:7:3、5:7:4、5:7:5、5:7:6、5:7:7、5:7:8、5:7:9、5:7:10、5:8:1、5:8:2、5:8:3、5:8:4、5:8:5、5:8:6、5:8:7、5:8:8、5:8:9、5:8:10、5:9:1、5:9:2、5:9:3、5:9:4、5:9:5、5:9:6、5:9:7、5:9:8、5:9:9、5:9:10、5:10:1、5:10:2、5:10:3、5:10:4、5:10:5、5:10:6、5:10:7、5:10:8、5:10:9、5:10:10、6:1:1、6:1:2、6:1:3、6:1:4、6:1:5、6:1:6、6:1:7、6:1:8、6:1:9、6:1:10、6:2:1、6:2:2、6:2:3、6:2:4、6:2:5、6:2:6、6:2:7、6:2:8、6:2:9、6:2:10、6:3:1、6:3:2、6:3:3、6:3:4、6:3:5、6:3:6、6:3:7、6:3:8、6:3:9、6:3:10、6:4:1、6:4:2、6:4:3、6:4:4、6:4:5、6:4:6、6:4:7、6:4:8、6:4:9、6:4:10、6:5:1、6:5:2、6:5:3、6:5:4、6:5:5、6:5:6、6:5:7、6:5:8、6:5:9、6:5:10、6:6:1、6:6:2、6:6:3、6:6:4、6:6:5、6:6:6、6:6:7、6:6:8、6:6:9、6:6:10、6:7:1、6:7:2、6:7:3、6:7:4、6:7:5、6:7:6、6:7:7、6:7:8、6:7:9、6:7:10、6:8、 :1、6:8:2、6:8:3、6:8:4、6:8:5、6:8:6、6:8:7、6:8:8、6:8:9、6:8:10、6:9:1、6:9:2、6:9:3、6:9:4、6:9:5、6:9:6、6:9:7、6:9:8、6:9:9、6:9:10、6:10:1、6:10:2、6:10:3、6:10:4、6:10:5、6:10:6、6:10:7、6:10:8、6:10:9、6:10:10、7:1:1、7:1:2、7:1:3、7:1:4、7:1:5、7:1:6、7:1:7、7:1:8、7:1:9、7:1:10、7:2:1、7:2:2、7:2:3、7:2:4、7:2:5、7:2:6、7:2:7、7:2:8、7:2:9、7:2:10、7:3:1、7:3:2、7:3:3、7:3:4、7:3:5、7:3:6、7:3:7、7:3:8、7:3:9、7:3:10、7:4:1、7:4:2、7:4:3、7:4:4、7:4:5、7:4:6、7:4:7、7:4:8、7:4:9、7:4:10、7:5:1、7:5:2、7:5:3、7:5:4、7:5:5、7:5:6、7:5:7、7:5:8、7:5:9、7:5:10、7:6:1、7:6:2、7:6:3、7:6:4、7:6:5、7:6:6、7:6:7、7:6:8、7:6:9、7:6:10、7:7:1、7:7:2、7:7:3、7:7:4、7:7:5、7:7:6、7:7:7、7:7:8、7:7:9、7:7:10、7:8:1、7:8:2、7:8:3、7:8:4、7:8:5、7:8:6、7:8:7、7:8:8、7:8:9、7:8:10、7:9:1、7:9:2、7:9:3、7:9:4、7:9:5、7:9:6、7:9:7、7:9:8、7:9:9、7:9:10、7:10:1、7:10:2、7:10:3、7:10:4、7:10:5、7:10:6、7:10:7、7:10:8、7:10:9、7:10:10、8:1:1、8:1:2、8:1:3、8:1:4、8:1:5、8:1:6、8:1:7、8:1:8、8:1:9、8:1:10、8:2:1、8:2:2、8:2:3、8:2:4、8:2:5、8:2:6、8:2:7、8:2:8、8:2:9、8:2:10、8:3:1、8:3:2、8:3:3、8:3:4、8:3:5、8:3:6、8:3:7、8:3:8、8:3:9、8:3:10、8:4:1、8:4:2、8:4:3、8:4:4、8:4:5、8:4:6、8:4:7、8:4:8、8:4:9、8:4:10、8:5:1、8:5:2、8:5:3、8:5:4、8:5:5、8:5:6、8:5:7、8:5:8、8:5:9、8:5:10、8:6:1、8:6:2、8:6:3、8:6:4、8:6:5、8:6:6、8:6:7、8:6:8、8:6:9、8:6:10、8:7:1、8:7:2、8:7:3、8:7:4、8:7:5、8:7:6、8:7:7、8:7:8、8:7:9、8:7:10、8:8:1、8:8:2、8:8:3、8:8:4、8:8:5、8:8:6、8:8:7、8:8:8、8:8:9、8:8:10、8:9:1、8:9:2、8:9:3、8:9:4、8:9:5、8:9:6、8:9:7、8:9:8、8:9:9、8:9:10、8:10:1、8:10:2、8:10:3、8:10:4、8:10:5、8:10:6、8:10:7、8:10:8、8:10:9、8:10:10、9:1:1、9:1:2、9:1:3、9:1:4、9:1:5、9:1:6、9:1:7、9:1:8、9:1:9、9:1:10、9:2:1、9:2:2、9:2:3、9:2:4、9:2:5、9:2:6、9:2:7、9:2:8、9:2:9、9:2:10、9:3:1、9:3:2、9:3:3、9:3:4、9:3:5、9:3:6、9:3:7、9:3:8、9:3:9、9:3:10、9:4:1、9:4:2、9:4:3、9:4:4、9:4:5、9:4:6、9:4:7、9:4:8、9:4:9、9:4:10、9:5:1、9:5:2、9:5:3、9:5:4、9:5:5、9:5:6、9:5:7、9:5:8、9:5:9、9:5:10、9:6:1、9:6:2、9:6:3、9:6:4、9:6:5、9:6:6、9:6:7、9:6:8、9:6:9、9:6:10、9:7:1、9:7:2、9:7:3、9:7:4、9:7:5、9:7:6、9:7:7、9:7:8、9:7:9、9:7:10、9:8:1、9:8:2、9:8:3、9:8:4、9:8:5、9:8:6、9:8:7、9:8:8、9:8:9、9:8:10、9:9:1、9:9:2、9:9:3、9:9:4、9:9:5、9:9:6、9:9:7、9:9:8、9:9:9、9:9:10、9:10:1、9:10:2、9:10:3、9:10:4, 9:10:5, 9:10:6, 9:10:7, 9:10:8, 9:10:9, 9:10:10, 10:1:1, 10:1:2, 10:1:3, 10:1:4, 10:1:5, 10:1:6, 10:1:7, 10:1:8, 10:1:9, 10:1:10, 10:2:1, 10:2:2, 10:2:3, 10:2:4, 10:2:5, 10:2:6, 10:2:7, 10:2:8, 10:2:9, 10:2:10, 10:3 :1, 10:3:2, 10:3:3, 10:3:4, 10:3:5, 10:3:6, 10:3:7, 10:3:8, 10:3:9, 10:3:10, 10:4:1, 10:4:2, 10:4:3, 10:4:4, 10:4:5, 10:4:6, 10:4:7, 10:4:8, 10:4:9, 10:4:10, 10:5:1, 10:5:2, 10:5:3, 10:5:4, 10:5:5, 10:5:6, 10:5:7, 10:5:8, 10: 5:9, 10:5:10, 10:6:1, 10:6:2, 10:6:3, 10:6:4, 10:6:5, 10:6:6, 10:6:7, 10:6:8, 10:6:9, 10:6:10, 10:7:1, 10:7:2, 10:7:3, 10:7:4, 10:7:5, 10:7:6, 10:7:7, 10:7:8, 10:7:9, 10:7:10, 10:8:1, 10:8:2, 10:8:3, 10:8:4, 10:8:5, 10:8:6, 1 It can be 0:8:7, 10:8:8, 10:8:9, 10:8:10, 10:9:1, 10:9:2, 10:9:3, 10:9:4, 10:9:5, 10:9:6, 10:9:7, 10:9:8, 10:9:9, 10:9:10, 10:10:1, 10:10:2, 10:10:3, 10:10:4, 10:10:5, 10:10:6, 10:10:7, 10:10:8, 10:10:9, 10:10:10 or any ratio therebetween. The amount of Crataeva nurbara composition in the combination may be about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, 400 mg, 425 mg,450mg, 475mg, 500mg, 525mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1.25g, 1.5g, 1.75g, 2.0g, 2.25g, 2.5g, 2.75g, 3.0g, 3.2 It may be 5g, 3.5g, 3.5g, 3.75g, 4.0g, 4.25g, 4.5g, 4.75g, 5.0g, 5.25g, 5.5g, 5.75g, 6.0g, 6.25g, 6.5g, 6.75g, 7.0g, 7.25g, 7.5g, 7.75g, 8.0g, 8.25g, 8.5g, 8.75g, 9.0g, 8.25g, 9.5g, 9.75g, 10g or more, or any amount in between. The amount of black maca and / or yellow maca composition in the combination may be about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, g, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1.25g, 1.5g, 1.7 5g, 2.0g, 2.25g, 2.5g, 2.75g, 3.0g, 3.25g, 3.5g, 3.5g, 3.75g, 4.0g, 4.25g, 4.5g, 4.7 The amount of SAMe and PG in the combination composition may be about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 575 g, 6.0 g, 6.25 g, 6.5 g, 6.75 g, 7.0 g, 7.25 g, 7.5 g, 7.75 g, 8.0 g, 8.25 g, 8.5 g, 8.75 g, 9.0 g, 8.25 g, 9.5 g, 9.75 g, 10 g or more, or any amount therebetween.50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 4 00mg, 425mg, 450mg, 475mg, 500mg, 525mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg , 950mg, 975mg, 1000mg, 1.25g, 1.5g, 1.75g, 2.0g, 2.25g, 2.5g, 2.75g, 3.0g, 3.25g, 3.5g, 3.5g, 3.75g, 4.0g, 4.25g, 4.5g, 4.75g, 5.0g, 5.25g, 5.5g, 5.75g, 6.0g, 6.25g, 6.5g, 6.75g, 7.0g, 7.25g, 7.5g, 7.75g, 8.0g, 8.25g, 8.5g, 8.75g, 9.0g, 8.25g, 9.5g, 9.75g, 10g or more, or any amount therebetween. In one embodiment, the composition may contain a combination of 100-500 mg of a Crataeva nurbala composition, 40-1000 mg of a black maca and / or yellow maca composition, and 100-500 mg of a SAMe and PG composition. In another embodiment, the composition may contain a combination of 300-400 mg of a Crataeva nurbala composition, 90-500 mg of a black maca and / or yellow maca composition, and 150-200 mg of a SAMe and PG composition. From the results and discussion presented in the specification, one skilled in the art would understand how to formulate a composition containing a Crataeva nurbala composition, a black maca and / or yellow maca composition, and a SAMe and PG composition to achieve the results described in the specification.

[0019] As disclosed herein, the composition can be formulated as a dietary supplement or a pharmaceutical. The composition of the present disclosure can further comprise a matrix material (e.g., fatty acid, fatty acid ester, triglyceride, oil, lipid solvent). In some embodiments, the composition is a solid composition. In some embodiments, the composition has a sustained-release matrix. In some embodiments, the composition is enteric coated.

[0020] In some embodiments, the composition may contain a beta-adrenergic receptor agonist and a muscarinic receptor antagonist. In some embodiments, the beta-adrenergic receptor agonist comprises a SAMe composition described herein. The SAMe composition may further comprise a compound that improves absorption, such as PG. In some embodiments, the muscarinic receptor antagonist is selected from the group consisting of a pumpkin seed composition described herein, a Crataeva nurvala composition described herein, a Lindera aggregata composition described herein, a black maca and / or yellow maca composition described herein, a phycocyanin composition described herein, and combinations thereof. In some embodiments, the muscarinic receptor antagonist is selected from the group consisting of a Crataeva nurvala composition described herein, a black maca and / or yellow maca composition described herein, and combinations thereof. In some embodiments, the compositions described herein are administered to a subject to support bladder health. In some embodiments, the compositions described herein are administered to a subject to maintain normal bladder function. In some embodiments, the compositions described herein are administered to a subject to maintain healthy levels of bladder activity and urination frequency. In some embodiments, the compositions described herein are administered to a subject to maintain healthy levels of bladder activity and urination frequency. In some embodiments, the compositions described herein are administered to a subject to maintain healthy levels of one or more of urgency, urinary incontinence, urge incontinence, polyuria, nocturia, bladder spasms, and combinations thereof. In some embodiments, the compositions described herein are administered to a subject to treat, ameliorate, prevent, or reduce the effects of overactive bladder or at least one symptom associated therewith, wherein the at least one symptom is selected from the group consisting of urgency, urinary incontinence, urge incontinence, polyuria, nocturia, bladder spasms, and combinations thereof.

[0021] Without being bound by any particular theory, the compositions, dietary supplements, and / or pharmaceuticals disclosed herein are believed to act as beta-adrenergic receptor agonists or muscarinic receptor antagonists, targeting signaling pathways associated with bladder health and normal bladder function. Symptoms of abnormal bladder function (e.g., overactive bladder or associated symptoms) are believed to be caused, in part, by frequent and unexpected contractions of the bladder's detrusor smooth muscle. In the case of beta-adrenergic receptors, overactive bladder or associated symptoms are believed to result from and be characterized by insufficient activation of beta-2 and beta-3 adrenergic receptors. Activation of beta-2 and beta-3 adrenergic receptors stimulates associated G proteins, triggering adenylate cyclase activity and increasing cAMP production, which induces relaxation of the bladder's detrusor smooth muscle. Therefore, providing a β-adrenergic receptor agonist that activates this pathway can minimize and / or prevent unwanted and unexpected contractions of the bladder's detrusor smooth muscle, thereby treating, ameliorating, preventing, or alleviating OAB and its associated symptoms, and maintaining or restoring normal bladder function. In the case of muscarinic receptors, overactive bladder or its symptoms are thought to be caused by and characterized by the activation of M2 and M3 muscarinic receptors by acetylcholine. Activation of M2 muscarinic receptors by acetylcholine reduces cAMP production, which reduces the relaxation of the bladder's detrusor smooth muscle. Meanwhile, activation of M3 muscarinic receptors causes an increase in phospholipase C, which increases inositol triphosphate, which increases intracellular calcium, thereby mediating contraction of the detrusor smooth muscle in the bladder wall. Furthermore, activation of M1 and M4 muscarinic receptors is associated with delayed excitatory postsynaptic potentials and mediation of higher cognitive processes (e.g., learning and spatial memory (M1), motor performance impairment (M4)). Inhibition of M1 and M4 muscarinic receptor activation may be responsible for the side effects associated with this class of muscarinic antagonists (e.g., xerostomia, constipation, heartburn, blurred vision, increased heart rate (tachycardia), skin flushing, urinary retention, and cognitive side effects (memory impairment, brain fog, confusion, etc.)).By providing compounds that specifically target M2 and M3 muscarinic receptors, it is believed that OAB and its associated symptoms can be treated, ameliorated, prevented, or alleviated, and normal bladder function can be maintained or restored, while minimizing or reducing the occurrence of unwanted side effects / adverse events associated with antagonistic interactions with M1 and M4 muscarinic receptors (e.g., xerostomia, constipation, heartburn, blurred vision, increased heart rate (tachycardia), skin flushing, urinary retention, cognitive side effects (memory impairment, brain fog, confusion, etc.)). The compositions and methods described herein are also believed to be useful for supporting bladder health and maintaining healthy bladder function, including avoiding or reducing the severity of consequences associated with OAB, including antagonistic interactions with M1 and M4 muscarinic receptors (e.g., xerostomia, constipation, heartburn, blurred vision, increased heart rate (tachycardia), skin flushing, urinary retention, cognitive side effects (memory impairment, brain fog, confusion, etc.)).

[0022] Unlike the compositions described herein, compounds known in the art do not preferentially bind to M2 and M3 muscarinic receptors over M1 and M4 muscarinic receptors. Therefore, as explained herein, and as one of skill in the art will recognize upon reading this disclosure, compounds known in the art are significantly more likely to cause unwanted effects / adverse events. The embodiments disclosed herein exhibit unexpectedly superior results by selectively binding to M2 and M3 muscarinic receptors over M1 and M4 muscarinic receptors. Accordingly, the embodiments disclosed herein can treat, ameliorate, prevent, or alleviate OAB and its associated symptoms, thereby maintaining and / or restoring normal bladder function while minimizing or reducing the occurrence of unwanted side effects / adverse events, or otherwise being utilized to maintain a healthy level of bladder function associated with OAB.

[0023] In some embodiments, the compositions described herein may contain one or more supplemental ingredients. As used herein, the term supplemental ingredient may refer to essential fatty acids (e.g., linolenic acid, linoleic acid), essential amino acids (e.g., tryptophan, lysine, methionine, phenylalanine, threonine, valine, leucine, isoleucine, arginine, histidine), n-acetylcysteine, nicotinamide riboside, resveratrol, NAD+ precursors, coenzyme Q10, omega-3 fatty acids, cabbage powder, pterostilbene, and / or nicotinamide mononucleotide. Supplement ingredients may also include vitamins such as biotin (vitamin B7, vitamin H), choline (vitamin Bp), folic acids (vitamin M), niacin (vitamin B3), pantothenic acid (vitamin B5), riboflavin (vitamin B2, vitamin G), thiamine (vitamin B1), retinol (vitamin A), pyridoxine, pyridoxamine, or pyridoxal (vitamin B6), cobalamin (vitamin B12), ascorbic acid (vitamin C), tocopherol (vitamin E), and naphthoquinoids (vitamin K). Supplement ingredients may further include dietary minerals, such as, for example, chromium, pharmaceutically acceptable salts, hydrates, solvates, or mixtures thereof, bromine, cobalt, copper, fluorine, germanium, iodine, iron, magnesium, manganese, molybdenum, potassium, selenium, silicon, zinc, calcium, phosphorus, sodium, sulfur, and vanadium. Supplement ingredients may also include cranberry extract, turmeric, royal jelly, acai berry, beetroot, coral calcium, oyster shell, gotu kola, ginkgo biloba, ericaceae mushroom, pomegranate, hibiscus flower, strawberry powder, dandelion root, celery powder, parsley powder, peppermint leaf, cinnamon bark powder, maca root, and combinations thereof. Supplement ingredients may include nitrates such as citrulline nitrate, creatine nitrate, and beta-alanine nitrate, and nitric oxide enhancers. The compositions described herein may contain one or more of the foregoing supplement ingredients, as will be understood by those skilled in the art.

[0024] In some embodiments, the compositions described herein are administered daily, every other day, or multiple times daily. In some embodiments, an ascending dosing protocol can be used, in which a subject is administered increasing amounts of the compositions described herein. For example, a subject can be administered 100 mg of the compositions described herein per day for 7 days, followed by 200 mg for the next 7 days, and then 300 mg for the next 7 days. The dosing protocol can also be a pattern of decreasing dosage over time. For example, a subject can be administered 300 mg of the compositions described herein per day for 7 days, followed by 200 mg for the next 7 days, and then 100 mg for the next 7 days. In some embodiments, the methods described herein are used in combination with a calorie restriction protocol for the subject.

[0025] As used herein, "identifying" refers to detecting or selecting a subject from a population of potential subjects, for example, to confirm that a particular subject possesses a particular property or characteristic. "Identifying" may include, for example, self-identification, self-diagnosis, or diagnosis by a medical professional.

[0026] As used herein, the terms "prophylactic treatment," "prevention," or "preventing" may refer to treatment of a subject who is susceptible to or at risk of developing a particular disease or condition, but who has not yet exhibited symptoms of the disease or condition, such that the treatment reduces the patient's likelihood of developing the disease or condition. A "disorder" is a condition that would benefit from treatment with the compositions described herein.

[0027] As used herein, the terms "prevention," "treatment," "therapy," and the like are used generally to refer to obtaining a desired pharmacological and physiological effect, and may also refer to a nutritional or nutraceutical effect, the scope and meaning of which will be apparent to those skilled in the art based on the context in which these terms are used. The effect may be prophylactic, in that it prevents or partially prevents a disease, symptom, or condition, and / or therapeutic, in that it partially or completely cures the adverse effects caused by the disease, condition, symptom, or disease. The term "treatment," as used herein, encompasses the treatment of disease in mammals, particularly humans, and includes (a) preventing the onset of disease in a subject who may be susceptible to, but has not yet been diagnosed with, the disease; (b) arresting or halting the progression of the disease; or (c) palliating the disease and causing regression of the disease and / or its symptoms, conditions, and co-morbidities. The terms "optimal" or "healthy," etc., may be used to refer to a physiological amount of beta-adrenergic or muscarinic activity in a mammal, and the compositions described herein may be administered to a mammal that may not have a disease or condition associated with beta-adrenergic or muscarinic activity, but may be administered to agonize beta-adrenergic receptors or antagonize muscarinic receptors, along with other physiological effects as described herein. The compositions described herein may be administered to a subject to support normal bladder function. The compositions described herein may be administered to a subject to maintain healthy levels of bladder activity and urination frequency. The compositions described herein may be administered to maintain healthy levels of one or more of urgency, urinary incontinence, urge incontinence, polyuria, nocturia, bladder spasms, and combinations thereof.

[0028] As used herein, the terms "selective binding," "selectively binds," and "selectivity" refer to the binding of a compound to a receptor that has a higher binding affinity for one receptor subtype than another subtype of the same receptor. Examples of "selective binding," "selectively binds," and "selectivity" may be a compound that has a higher binding affinity for the M2 muscarinic receptor than the M1 muscarinic receptor, a compound that has a higher binding affinity for the M3 muscarinic receptor than the M1 muscarinic receptor, a compound that has a higher binding affinity for the M2 muscarinic receptor than the M4 muscarinic receptor, and a compound that has a higher binding affinity for the M3 muscarinic receptor than the M4 muscarinic receptor. In this disclosure, "selective binding," "selectively binds," and "selectivity" may be derived by measuring the binding affinity (e.g., dissociation constant, binding rate compared to a control, etc.) of a receptor subtype, obtaining a ratio between the two receptor subtypes, and determining the value of the ratio. In this disclosure, "selective binding," "selectively binds," and "selectivity" refer to a ratio of at least 1, although "selective" can be used when the ratio is greater than 1, as would be clear to one of skill in the art based on the context in which the term is used.

[0029] In the claims and throughout this disclosure, the term "consisting essentially of" means including all elements listed after the term, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure of the listed elements. Thus, the term "consisting essentially of" indicates that the listed elements are necessary or essential, but that other elements are optional and may or may not be present depending on whether they affect the activity or action of the listed elements. For example, use of a composition "consisting essentially of" to treat a particular disease or disorder or maintain a state of health excludes other ingredients that would materially alter the composition's intended outcome.

[0030] As used herein, a composition that "substantially" contains a compound means that the composition contains more than about 80% by weight of the compound, more preferably more than about 90% by weight, even more preferably more than about 95% by weight, and most preferably more than about 98% by weight.

[0031] The terms "pharmaceutical formulation," "formulation," "composition," and the like may refer to a preparation in a form such that the biological activity of the active ingredient can be effective, and therefore may be administered to a subject for treatment, in addition to use as a dietary supplement and / or nutritional agent. The meaning of these terms will be clear to one of skill in the art based on the context in which they are used.

[0032] As used herein, a "therapeutically effective amount" refers to a non-toxic active compound or a composition containing the same in an amount sufficient to achieve the desired therapeutic effect when used in the manner disclosed herein. Similarly, as used herein, an "effective amount" or "effective amount" refers to a non-toxic active compound or a composition containing the same in an amount sufficient to achieve the desired effect. A "therapeutically effective amount" or "effective amount" includes an amount of a compound that cannot be achieved through a standard diet and requires supplementation and administration as described herein. The exact amount of an active ingredient disclosed herein required will vary from subject to subject, depending on factors such as the species being treated, the subject's age and general condition, the severity of the condition being treated, the drug being administered, the subject's weight, and the method of administration. Therefore, it is not always possible to determine an exact "effective amount." However, in any given case, one of skill in the art will be able to determine an appropriate "effective amount" in light of the disclosure herein. In some aspects, a therapeutically effective amount may be included in a dosing regimen. For example, a therapeutically effective amount may include approximately 100 mg of a composition taken orally daily for 14 days. In some aspects, a therapeutically effective amount may include about 100 mg of the composition taken orally daily for 30 days. The composition may include, for example, 0.1 to 10,000 mg of the composition.

[0033] As used herein, the terms "synergistic," "co-activity," "synergy," and the like generally refer to a therapeutic effect of a composition that is at least equal to the sum of the effects of the individual components of the independently administered composition when administered separately. "Synergistic," "co-activity," "synergy," and the like may also refer to a therapeutic effect of a composition that is greater than the sum of the effects of the individual components of the independently administered composition when administered separately. The scope and meaning of these terms will be apparent to one of skill in the art based on the context in which they are used.

[0034] As used herein, the terms "supporting bladder health" and "maintaining normal bladder function" refer to supporting / maintaining the ability to hold and empty the bladder 4 to 7 times per day.

[0035] Unless otherwise specified, when describing units of mass (e.g., μg, mg, g, kg, etc.) or ratios of units of mass (e.g., ratios, weight ratios, mass ratios, g / g, mg / kg, etc.), the units of mass are on a dry basis. As used herein, the term "dry basis" refers to the mass of a substance from which all solvents have been removed. For example, if a composition contains 100 mg of ground Crataeva nurvala leaves, the composition contains 100 mg of dried ground Crataeva nurvala leaves. In another example, if a composition contains ground Crataeva nurvala leaves and SAMe in a 4:1 ratio, the composition would contain, for example, 400 mg of dried ground Crataeva nurvala leaves and 100 mg of SAMe powder, or 200 mg of dried ground Crataeva nurvala leaves and 50 mg of SAMe powder. In certain embodiments, certain compositions may contain extracts. In such embodiments, the extract may be obtained by aqueous or organic solvent extraction of plant material. The plant material from which the extract is obtained may be obtained from raw or dried plant material. In some embodiments, the extract may be capable of forming a powder. In these embodiments, the dry basis refers to the mass of the dried powder. In other embodiments, the extract may not be capable of forming a powder and may exist as an oil. In these embodiments, the dry basis refers to the mass of the oil without solvent, i.e., the mass of the oil after removal of all solvents used to obtain the extract. As disclosed herein, some embodiments may contain compositions that are beta-adrenergic receptor agonists and / or muscarinic receptor antagonists. These compositions may comprise the composition and its extract. For example, one composition may contain phycocyanin as a muscarinic receptor antagonist, while another composition may contain an extract of phycocyanin as a muscarinic receptor antagonist. Those skilled in the art will understand how to prepare an extract of phycocyanin and how to use this extract as a muscarinic receptor antagonist to achieve the results described herein. In one aspect, an extract of phycocyanin may refer to a composition synthesized or formulated from phycocyanin, where the extract is prepared to have specific compositional characteristics.

[0036] Further, appropriate dosages of the compositions will vary based on, for example, the condition being treated, the severity and course of the condition, the purpose for which the composition is being administered (prophylactic or therapeutic), previous treatments, the patient's medical history and response to the composition, the type of composition used, and the discretion of the attending physician. The compositions may be suitably administered to the patient at one time or over a series of treatments, or may be administered to the patient any time after diagnosis. The compositions may be administered as the sole therapeutic agent or in combination with other agents or therapies useful in treating the condition in question.

[0037] By way of example, a "therapeutically effective amount" and / or an "effective amount" of a compound disclosed herein may be administered in amounts (per subject body weight) of, for example, 0.1 μg / kg, 0.5 μg / kg, 1 μg / kg, 1.5 μg / kg, 2.0 μg / kg, 2.5 μg / kg, 3.0 μg / kg, 3.5 μg / kg, 4.0 μg / kg, 4.5 μg / kg, 5.0 μg / kg, 10 μg / kg, 15 μg / kg, 20 μg / kg, 25 μg / kg, 30 μg / kg, 35 μg / kg, 40 μg / kg, 45 μg / kg, 50 μg / kg, 60 μg / kg, 65 μg / kg, 70 μg / kg, 7 ... / kg, 55μg / kg, 60μg / kg, 65μg / kg, 70μg / kg, 75μg / kg, 80μg / kg, 85μg / kg, 90μg / kg, 95μg / kg, 100μg / kg, 150μg / kg, 200μg / kg, 250μg / kg , 300μg / kg, 350μg / kg, 400μg / kg, 450μg / kg, 500μg / kg, 550μg / kg, 600μg / kg, 650μg / kg, 700μg / kg, 750μg / kg, 80μg / kg0, 850μg / kg, 900 μg / kg, 1mg / kg, 1.5mg.kg, 2.0mg / kg, 2.5mg / kg, 3mg / kg, 3.5mg / kg, 4.0mg / kg, 4.5mg / kg, 5mg / kg, 5.5mg / kg, 6mg / kg, 6.5mg / kg, 7mg / k g, 7.5mg / kg, 8mg / kg, 8.5mg / kg, 9mg / kg, 9.5mg / kg, 10mg / kg10.5mg / kg, 11mg / kg, 11.5mg / kg, 12mg / kg, 12.5mg / kg, 13mg / kg, 13.5mg / k g, 14 mg / kg, 14.5 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg or more, or any integer or decimal point between these two values. An effective amount can include any of the ranges and amounts described herein.

[0038] Thus, in some embodiments, the dosage of the compound in the compositions disclosed herein can preferably be from about 10 μg to about 10 g per day. For example, the amount of the composition can be 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, 525 μg, 575 μg, 600 μg, 62 5μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1000μg, 5mg, 10mg, 15mg, 20 mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225m g, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 7 25mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1.25g, 1.5g, 1.75g, 2.0g, 2.25g, 2.5g, 2.75g, 3 The amount may be 0.0g, 3.25g, 3.5g, 3.5g, 3.75g, 4.0g, 4.25g, 4.5g, 4.75g, 5.0g, 5.25g, 5.5g, 5.75g, 6.0g, 6.25g, 6.5g, 6.75g, 7.0g, 7.25g, 7.5g, 7.75g, 8.0g, 8.25g, 8.5g, 8.75g, 9.0g, 8.25g, 9.5g, 9.75g, 10g or more, or any range or amount between these two values, and other ranges or amounts disclosed herein.The exemplary therapeutically effective amounts above can, in some embodiments, be administered by methods described elsewhere herein, time intervals such as every hour, every 2 hours, every 3 hours, every 4 hours, every 5 hours, every 6 hours, every 7 hours, every 8 hours, every 9 hours, every 10 hours, every 11 hours, every 12 hours, every 13 hours, every 14 hours, every 15 hours, every 16 hours, every 17 hours, every 18 hours, every 19 hours, every 20 hours, every 21 hours, every 22 hours, every 23 hours, or any intervals therebetween, or daily, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, weekly, every 8 days, every 9 days, every 10 days, biweekly, monthly, or at more or less frequent intervals, as needed to achieve the desired therapeutic effect.

[0039] In some embodiments, the compositions, dietary supplements, and / or pharmaceuticals may contain one or more beta-adrenergic receptor agonists, one or more muscarinic receptor antagonists, or a combination thereof, provided in a synergistic ratio. In some embodiments, the beta-adrenergic receptor antagonist is a SAMe composition or a SAMe and PG composition. In some embodiments, the muscarinic receptor antagonist is a pumpkin seed composition, a Crataeva nurvala composition, a Lindera aggregata composition, a black maca and / or yellow maca composition, a phycocyanin composition, or a combination thereof. In some embodiments, the synergistic ratio of pumpkin seed composition: Crataeva nurvala composition: Lindera aggregata composition (P+C+L) may be about 2:2:1. In some embodiments, the synergistic ratio of P+C+L may be about 10:1:1 to about 1:10:1 to about 1:1:10. In some embodiments, the synergistic effect ratio may be about 1:0.5 for P+C+L:black maca and / or yellow maca composition. In some embodiments, the synergistic effect ratio between P+C+L and black maca and / or yellow maca composition may be about 10:1 to about 1:10. In some embodiments, the synergistic effect ratio may be about 1:0.5 for P+C+L:phycocyanin composition. In some embodiments, the synergistic effect ratio between P+C+L and phycocyanin composition may be about 10:1 to about 1:10. In some embodiments, the synergistic effect ratio may be about 1:0.5 for P+C+L:SAMe composition. In some embodiments, the synergistic effect ratio may be about 1:0.5 for P+C+L:SAMe and PG composition. In some embodiments, the synergistic effect ratio between P+C+L and SAMe composition may be about 10:1 to about 1:10. In some embodiments, the synergistic ratio of the P+C+L, SAMe, and PG compositions may be about 10:1 to about 1:10. In some embodiments, the synergistic ratio of the Crataeva nurbana composition: black maca and / or yellow maca composition: SAMe composition may be about 4:1:3.2. In some embodiments, the synergistic ratio of the Crataeva nurbana composition: black maca and / or yellow maca composition: SAMe and PG composition may be about 4:1:3.2.In some embodiments, the synergistic ratio of the Crataeva nurbara composition to the black maca and / or yellow maca composition to the SAMe composition may be about 1.6:2.5:1. In some embodiments, the synergistic ratio of the Crataeva nurbara composition to the black maca and / or yellow maca composition to the SAMe and PG composition may be about 1.6:2.5:1. In some embodiments, the synergistic ratio of the Crataeva nurbara composition to the black maca and / or yellow maca composition to the SAMe and PG composition may be about 4:1:1.5. In some embodiments, the synergistic ratio of the Crataeva nurbara composition to the black maca and / or yellow maca composition to the SAMe and PG composition may be about 4:1:1.5. In some embodiments, the synergistic ratio of the Crataeva nurbara composition to the black maca and / or yellow maca composition to the SAMe and PG composition may be about 2:1:1 to about 1:2:1. In some embodiments, the synergistic effect ratio between the Crataeva syrup composition, the black maca and / or yellow maca composition, and the SAMe and PG composition may be about 2:1:1 to about 1:2:1. In some embodiments, the synergistic effect ratio between the Crataeva syrup composition, the black maca and / or yellow maca composition, and the SAMe and PG composition may be about 4:1:1 to about 4:1:4. In some embodiments, the synergistic effect ratio between the Crataeva syrup composition, the black maca and / or yellow maca composition, and the SAMe and PG composition may be about 4:1:1 to about 4:1:4. In some embodiments, the synergistic effect ratio may be about 1:1 between the Crataeva syrup composition and the SAMe and PG composition. In some embodiments, the synergistic effect ratio may be about 1:1 between the Crataeva syrup composition and the SAMe and PG composition. In some embodiments, the synergistic ratio may be about 2.3:1 Crataeva slimy bara composition: SAMe composition. In some embodiments, the synergistic ratio may be about 2.3:1 Crataeva slimy bara composition: SAMe and PG composition. In some embodiments, the synergistic ratio may be about 2.4:1 Crataeva slimy bara composition: SAMe composition. In some embodiments, the synergistic ratio may be about 2.4:1 Crataeva slimy bara composition: SAMe and PG composition.In some embodiments, the ratio of the synergistic effect between the Crataeva slimy rose composition and the SAMe composition may be about 10:1 to about 1:10. In some embodiments, the ratio of the synergistic effect between the Crataeva slimy rose composition and the SAMe and PG composition may be about 10:1 to about 1:10. In some embodiments, the ratio of the synergistic effect between the Crataeva slimy rose composition and the SAMe and PG composition may be about 2:1 to about 3:1. In some embodiments, the ratio of the synergistic effect between the Crataeva slimy rose composition and the SAMe and PG composition may be about 2:1 to about 3:1.

[0040] This disclosure includes nutritional and therapeutic compositions useful as beta-adrenergic receptor agonists or muscarinic receptor antagonists, and methods of use thereof. Some embodiments provide solid formulations of the compositions disclosed herein. Some embodiments provide aqueous solutions of the compositions disclosed herein. The embodiments described herein, including the compositions disclosed herein as nutritional agents, mean that the compositions disclosed herein exist in a non-natural form, i.e., are provided as a supplement (e.g., tablet, powder) that is different from that found in nature, or that the nutritional agent or dietary supplement provides artificial supplementation that cannot be achieved through diet without consuming the nutritional agent or dietary supplement.

[0041] Some embodiments provide physiologically compatible compositions as disclosed herein, including hydrates, crystals, polymorphs, solids with specific bulk or tapped densities, and solids with specific particle sizes. Some embodiments provide compositions coated with pharmaceutically acceptable materials intended to modify release and / or bioavailability, including, but not limited to, Eudragit®, microcrystalline cellulose, hydroxypropyl methylcellulose phthalate, and the like.

[0042] As used herein, the term "pharmaceutically acceptable solvent" may refer to water, water for injection, a physiologically compatible aqueous buffer, or an aqueous solution containing a physiologically compatible organic solvent. A non-exhaustive list of pharmaceutically acceptable solvents is provided in the U.S. Department of Health & Human Services, Food & Drug Administration, "Guidance for Industry: Q3C Impurities: Residual Solvents," December 1997 or its latest edition.

[0043] As used herein, the term "bioavailability" refers to the amount of a substance that is absorbed in the intestine and ultimately available for biological activity in the tissues and cells of a subject.

[0044] As used herein, the term "increasing bioavailability" and the like refers to the absorption from the intestinal tract or uptake into tissues and cells of a composition after administration to a mammal, resulting in a desired pharmacological and / or physiological effect that does not occur naturally, such as agonizing beta-adrenergic receptors, antagonizing muscarinic receptors, or both. This effect may be preventative in that it prevents or partially prevents the occurrence, risk, or severity of adverse symptoms or conditions caused by or associated with a deficiency of the therapeutic agent.

[0045] As used herein, the term "excipient" refers to a compound that is not an active ingredient, i.e., that has no relevant biological activity, but is a part of the formulation that is added to the formulation to impart certain properties to the formulation, including, for example, protecting the active ingredient from chemical degradation, facilitating removal of the tablet or capsule from manufacturing equipment, etc.

[0046] For purposes of this disclosure, warm-blooded animals include, but are not limited to, mammals and birds. In certain embodiments described herein, mammals include, but are not limited to, horses, dogs, or cats. The most preferred mammal for this application is a human.

[0047] For the sake of simplicity, some quantitative expressions in the specification are not accompanied by the term "about." Regardless of whether the term "about" is explicitly used, all amounts indicated in the specification are intended to refer to the actual indicated value, and also to refer to approximations of the indicated value that can be reasonably estimated based on ordinary knowledge in the art, including approximations based on experimental and / or measurement conditions of the indicated value.

[0048] For oral administration, the compositions disclosed herein can be provided as tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, or beverages. Solid preparations (e.g., tablets, capsules) may be enterically coated. Oral compositions can be prepared by methods known in the art for the manufacture of pharmaceutically acceptable compositions, and such compositions may contain one or more sweeteners, flavorings, colorings, coating agents, and preservatives. Sweeteners and flavorings increase the palatability of the preparation. Tablets containing the complex mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. Pharmaceutically acceptable vehicles, such as excipients, must be compatible (harmless to the patient) with the other ingredients of the formulation. Such excipients include inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate); granulating and disintegrating agents (e.g., corn starch, alginic acid); binding agents (e.g., starch, gelatin, gum arabic); and lubricating agents (e.g., magnesium stearate, stearic acid, talc). Tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material (e.g., glyceryl monostearate or glyceryl distearate alone or with a wax) may be used.

[0049] Oral formulations may be presented as hard gelatin or non-gelatin capsules containing the active ingredient mixed with an inert solid excipient (e.g., calcium carbonate, calcium phosphate, kaolin), or as soft gelatin capsules containing the active ingredient mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, olive oil). Aqueous suspensions may contain the complexes described herein in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients may include a suspending agent, dispersing or wetting agent, one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents (e.g., sucrose, saccharin).

[0050] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil (e.g., arachis oil, olive oil, sesame oil, coconut oil) or a mineral oil (e.g., liquid paraffin). Oily suspensions can contain a thickening agent (e.g., beeswax, hard paraffin, cetyl alcohol). Sweetening and flavoring agents, as described above, can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Additional additives such as sweetening agents, flavorings and colorings can also be present.

[0051] Syrups and elixirs may be formulated with sweetening agents, for example, glycerin, sorbitol or sucrose. Such preparations may also contain a demulcent, a preservative, a flavoring or a coloring agent.

[0052] Compositions for parenteral administration can be in the form of sterile injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions). These suspensions can be formulated using dispersing or wetting agents and suspending agents according to methods well known in the art. The sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable excipients or solvents (e.g., 1,3-butanediol solution). Suitable excipients include, for example, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils can conventionally be used as solvents or suspending media. For this purpose, bland, fixed oils, including synthetic mono- or diglycerides, can be used. Furthermore, fatty acids such as oleic acid can also be used in the preparation of injectable preparations.

[0053] It will be appreciated that the compounds may be mixed with carrier materials to prepare a single dosage form, which will vary depending upon the host to be treated and the mode of administration.

[0054] In some embodiments, the compositions described herein can be administered in supplements or dosage forms designed for veterinary use. For veterinary applications, the compounds or compositions can be added to or included in pet treats or biscuits (e.g., dog biscuits, cat treats).

[0055] Aqueous suspensions may contain the compounds disclosed herein in admixture with excipients suitable for the manufacture of aqueous suspensions, such as suspending agents, dispersing or wetting agents, one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents (e.g., sucrose, saccharin).

[0056] In view of the disclosure herein, the use of controlled-release vehicles will be readily apparent to those skilled in the art of pharmacy, and these aspects are applicable to nutritional and dietary supplements. Technology and products in this field are referred to by various names, including controlled-release, sustained-release, sustained-action, depot, reservoir, delayed-action, extended-release, and timed-release; as used herein, the term "controlled-release" is intended to encompass each of these technologies.

[0057] A number of controlled-release vehicles can be used, including biodegradable or bioelutable polymers such as polylactic acid, polyglycolic acid, regenerated collagen, etc. Controlled-release drug delivery devices may include creams, lotions, tablets, capsules, gels, microspheres, liposomes, intraocular inserts, minipumps, and other infusion devices (e.g., pumps, syringes). Implantable or injectable polymer matrices and transdermal formulations that slowly release the active ingredient can be used in the disclosed methods.

[0058] Controlled-release preparations can be achieved by using polymers to complex or absorb the composition. Controlled delivery is achieved by selecting appropriate polymers (e.g., polyesters, polyamino acids, polyvinylpyrrolidone, ethylene vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate), and the concentration and method of incorporation of these polymers are selected to control the release of the active complex.

[0059] Controlled release of an active complex refers to sustained release formulations as known in the art or as described herein. The following terms may be considered to be substantially the same as controlled release in this disclosure: continuous release, controlled release, delayed release, depot, staged release, extended release, programmed release, sustained release, programmed release, time-proportional release, deferred release, depot, prolonged, slow release, interval release, sustained release, time-coat, time release, delayed action, prolonged action, layered time action, prolonged action, sustained action medication and extended release, release based on intestinal pH, molecular degradation and absorption and bioavailability.

[0060] Hydrogels, in which the compositions disclosed herein dissolve in an aqueous medium and are gradually released over time, can be prepared by copolymerization of hydrophilic monoolefin monomers (e.g., ethylene glycol methacrylate). Matrix devices can be used in which the compositions are dispersed in a matrix of a carrier material. The carrier can be porous, non-porous, solid, semi-solid, permeable, or impermeable. Alternatively, devices with a central reservoir of the compositions disclosed herein surrounded by a rate-controlling membrane can be used to control the release of the conjugate. Rate-controlling membranes include ethylene vinyl acetate copolymer or butylene terephthalate / polytetramethylene ether terephthalate. The use of silicone rubber or ethylene-vinyl alcohol depots has also been contemplated.

[0061] The embodiments described herein may also use controlled-release oral formulations. In some embodiments, the compositions described herein are incorporated into a soluble or dissolvable matrix (e.g., pill, lozenge). In another example, the oral formulation may be a liquid for sublingual administration. These liquid compositions may be in the form of a gel or paste. Hydrophilic gums such as hydroxymethylcellulose are commonly used. Lubricants (e.g., magnesium stearate, stearic acid, calcium stearate) may be used to aid in the tableting process.

[0062] The compositions described herein may be administered once, twice, or three times daily. In some embodiments, the compositions are administered four times daily. For example, the compositions may be administered before or after meals, or during meals. Oral administration may be once daily, once every two days, once within 72 hours of the first administration, or in a regimen requiring multiple daily administrations. The active agents that make up the therapeutic agent may be administered simultaneously in a combined formulation or in separate formulations for substantially simultaneous oral administration. The active agents that make up the therapeutic agent may also be administered separately in a regimen requiring the ingestion of either active ingredient in two steps. Thus, the regimen may be sequential administration of the active agents, with each active agent being taken at an interval. The interval between doses may be from a few minutes to up to about 72 hours, depending on the characteristics of each active agent (e.g., their potency, solubility, bioavailability, plasma half-life, and kinetic profile) and the age and condition of the patient. The therapeutic active agents may be in a regimen calling for one active agent to be administered orally and another active agent to be administered intravenously, regardless of whether the administration is simultaneous, substantially simultaneous, or sequential. In certain aspects, the embodiments described herein may achieve heretofore unrecognized or unattainable benefits in therapeutic and / or nutritional support, thus achieving unexpected and surprising improvements in the ability to use the compositions. In some embodiments, the compositions are formulated for intravenous administration, due to the ability to produce highly concentrated solutions. Whether the therapeutic active agents are administered orally or intravenously, separately or together, each active agent is included in a suitable pharmaceutical formulation of pharmaceutically acceptable additives, excipients, or other formulation ingredients.

[0063] The active ingredients (i.e., the compositions disclosed herein, optionally in combination with other pharmaceutical or adjunct ingredients that may be present) can be administered orally in solid formulations (e.g., tablets, capsules, powders) or liquid formulations (e.g., elixirs, syrups, suspensions). Each active ingredient can be administered parenterally in a liquid formulation. The compositions can be manufactured as dosage units containing a specific amount of each active ingredient. An example of an oral formulation of the compositions of the present application is a powder mixture packaged in a sachet. Because the compositions of the present application are non-hygroscopic and have no unpleasant taste or odor, powder mixtures containing the compositions of the present application can be sprinkled on food or mixed into beverages, improving ease of use and supporting a high level of compliance with daily medication.

[0064] In general, formulations of the compositions disclosed herein can be prepared using techniques described in Remington's Pharmaceutical Sciences (Gennaro AR, Ed. Remington: The Science and Practice of Pharmacy. 20th Edition. Baltimore: Lippincott, Williams & Williams, 2000), a reference text in this field. For therapeutic purposes, the active ingredients of the combination therapy can be combined with one or more adjuvants appropriate for the route of administration. These ingredients may be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol and tableted or encapsulated for convenient administration in amounts ascertainable by one of ordinary skill in the art. Such capsules or tablets may also contain controlled-release formulations, such as those provided in hydroxypropylmethylcellulose dispersions of the active compound. Solid formulations can be prepared as sustained-release products, providing continuous release of the drug over several hours. Compressed tablets can be sugar-coated or film-coated to mask unpleasant tastes and protect the tablet from the atmosphere, or enteric-coated for selective disintegration in the gastrointestinal tract. Solid and liquid oral formulations can be formulated with coloring and flavoring agents to enhance patient acceptance. Other adjuvants and modes of administration can also be used, and these aspects are applicable to the nutritional or dietary supplement products described herein. [Example]

[0065] Example 1 The muscarinic receptor antagonist activity of the compositions disclosed herein was determined by a G-coupled protein receptor (GPCR) arrestin assay, commercially available as the PathHunter® β-arrestin assay.

[0066] Cell lines were grown from frozen stocks according to standard procedures. A total volume of 20 μL of cells was then seeded into 384-well white-walled microplates and incubated at 37°C for the appropriate time before testing. Cells were preincubated with antagonists and then incubated with EC 80 Cells were stimulated with agonists at concentrations of 0.05-1000 mg / ml. Stock solutions of muscarinic receptor antagonists were prepared at concentrations of 0.05-1000 mg / ml. Sample stocks were intermediately diluted with assay buffer to prepare 5x samples. 5 μL of 5x sample was added to the cells and incubated at 37°C or room temperature for 30 minutes. The solvent concentration was 1%. 6xEC in assay buffer 80 Five μL of agonist was added to the cells and incubated at 37° C. or room temperature for 90 or 180 minutes. Assay signal was developed by adding 12.5 or 15 μL (50% v / v) of detection reagent cocktail once and incubating at room temperature for 1 hour. Microplate chemiluminescent signals were read on a PerkinElmer Envision® instrument. Compound activity was analyzed with the CBIS data analysis suite (ChemInnovation, CA). Percent inhibition was calculated using the following formula: Inhibition rate = 100% × (1 − (mean RLU of test sample − mean RLU of solvent control) / (EC 80 Mean RLU of control - Mean RLU of solvent control

[0067] The results are shown in Figure 1 as the maximum binding rates of muscarinic receptors M1 (solid), M2 (open), M3 (hatched), M4 (horizontal), and M5 (diagonal grid) when 0.05 to 1000 μg of pumpkin seed composition (P), Crataeva nurvala composition (C), Lindera aggregata composition (L), a 1:1 mixture of black (B) and yellow (Y) maca, and phycocyanin composition were administered in vitro. ...

[0068] Figure 1 shows the excellent and unexpected M2 and M3 muscarinic receptor antagonism, expressed as % receptor binding, achieved by administration of various compositions, including the Crataeva nulbara composition (C), the Tendai Uyaku composition (L), a 1:1 mixture of black (B) and yellow (Y) maca, and the phycocyanin composition: 45.6%, 21.9%, 35.4%, and 16.1%, respectively, for M2, and 24.2%, 0.3%, 16.0%, and 1.3%, respectively, for M3.

[0069] The results in Figure 1 were converted to binding selectivities for muscarinic receptor antagonists and are shown in Figure 3. The maximum binding selectivities of M2 / M1 (solid), M2 / M4 (diagonal lines), M3 / M1 (horizontal lines), and M3 / M4 (open lines) were obtained for the pumpkin seed composition (P), the Crataeva nurbreta composition (C), the Tendai Uyaku composition (L), the 1:1 mixture of black (B) and yellow (Y) maca, and the phycocyanin composition.

[0070] Figure 3 shows the remarkable and unexpected selective binding to M2 and M3 muscarinic receptors over M1 and M4 muscarinic receptors achieved by administration of various compounds; both the Crataeva nulbara composition (C) and a 1:1 mixture of black (B) and yellow (Y) maca specifically exhibited high selectivity (>1) for M2 and M3 muscarinic receptors over M1 and M4 muscarinic receptors, and the phycocyanin composition exhibited high selectivity for M2 muscarinic receptors over M4 muscarinic receptors.

[0071] Example 2 The experimental procedures for Example 2 were the same as those and analyses described in Example 1. In Example 2, the treatments were adjusted to include a 2:2:1 mixture of pumpkin seed composition, Crataeva nurvala composition, and Lindera aggregata composition (P+C+L), a 2:2:1:0.5 mixture of pumpkin seed composition, Crataeva nurvala composition, Lindera aggregata composition, and a 1:1 mixture of black (B) maca and yellow (Y) maca (P+C+L+B / Y maca), a 2:2:1:0.5 mixture of pumpkin seed composition, Crataeva nurvala composition, Lindera aggregata composition, and a phycocyanin composition (P+C+L+phycocyanin), and a 2:2:1:0.5 mixture of pumpkin seed composition, Crataeva nurvala composition, Lindera aggregata composition, and a phycocyanin composition (P+C+L+phycocyanin). A 2:2:1:0.5 mixture of the Nurbara and Tendai Uyaku compositions and a 32:1 mixture of SAMe and PG (P+C+L+SAMe+PG) was evaluated at doses ranging from 0.05 to 1000 μg. The results in Figure 2 show the maximum binding rates for the aforementioned compositions to muscarinic receptors: M1 (solid), M2 (open), M3 (hatched), M4 (horizontal), and M5 (diagonal grid).

[0072] Figure 2 shows the superior and unexpected M2 and M3 muscarinic receptor antagonism, expressed as % receptor binding, achieved by administration of various compounds, including a mixture of pumpkin seed, Crataebacterium nurbresum, and Tendai Uyaku compositions (P+C+L), a mixture of P+C+L and a 1:1 mixture of black (B) maca and yellow (Y) maca (P+C+L+B / Y maca), a mixture of P+C+L and a phycocyanin composition (P+C+L+phycocyanin), and a mixture of P+C+L with SAMe and PG (P+C+L+SAMe+PG), compared to prior art formulations: 38.6%, 55.1%, 52.4%, and 54.2%, respectively, for M2, and 4.5%, 24.6%, 15.9%, and 19.2%, respectively, for M3.

[0073] The results in Figure 2 were converted to binding selectivities for muscarinic receptor antagonists, as disclosed herein, and are shown in Figure 4. The maximum binding selectivities of M2 / M1 (solid black), M2 / M4 (diagonal lines), M3 / M1 (horizontal lines), and M3 / M4 (open white) were compared for a 2:2:1 mixture of the pumpkin seed composition, the Kurapa ulmarica composition, and the Tendai Uyaku composition (P+C+L), a 2:2:1:0.5 mixture of the pumpkin seed composition, the Kurapa ulmarica composition, the Tendai Uyaku composition, and a 1:1 mixture of black (B) maca and yellow (Y) maca (P+C+L+B / Y maca), a 2:2:1:0.5 mixture of the pumpkin seed composition, the Kurapa ulmarica composition, the Tendai Uyaku composition, and a phycocyanin composition (P+C+L+phycocyanin), and a 2:2:1:0.5 mixture of the pumpkin seed composition, the Kurapa ulmarica composition, the Tendai Uyaku composition, and a phycocyanin composition (P+C+L+phycocyanin). A 2:2:1:0.5 mixture (P+C+L+SAMe+PG) of the Nurbara composition, the Tendai Uyaku composition, and a 32:1 mixture of SAMe and PG was obtained.

[0074] Figure 4 shows the superior and unexpected selective binding to M2 and M3 muscarinic receptors over M1 and M4 muscarinic receptors achieved by administration of various compounds, representing a novel improvement over the prior art; in the case of M2, all combinations specifically showed unexpectedly high selectivity (>1) compared to M1 and M4, and in the case of M3, P+C+L+B / Y Maca, P+C+L+Phycocyanin, and P+C+L+SAMe+PG showed unexpectedly high selectivity (>1) compared to M4.

[0075] Example 3 The beta adrenergic activity of the compositions disclosed herein was evaluated using a cAMP assay commercially available as the HitHunter® cAMP assay.

[0076] Cell lines were grown from frozen stocks according to standard procedures. Cells were then seeded in a total volume of 20 μL into 384-well white-walled microplates and incubated at 37°C for the appropriate time before testing. Cells were treated with 5 μL of 3× agonist solution prepared from the stock solution. β-adrenergic agonist stock solutions were prepared at concentrations ranging from 5 to 1000 μg / ml. 3× samples were prepared by intermediate dilutions of sample stocks in assay buffer. Cells were then incubated at 37°C or room temperature for 90 or 180 minutes. Assay signal was developed by adding 12.5 or 15 μL (50% v / v) of detection reagent cocktail once and incubating at room temperature for 1 hour. 20 μL of cAMP solution was then added, and the cells were incubated at room temperature for 180 minutes. The chemiluminescent signal of the microplate was read using a PerkinElmer Envision® instrument. EC values ​​were calculated by reference to an agonist reference curve using known methods. 50 It was decided that:

[0077] The results are shown for 5-1000 μg / ml of (1) pumpkin seed composition (P), (2) Crataeva nurvala composition (C), (3) Lindera aggregata composition (L), (4) a 1:1 mixture of black (B) maca and yellow (Y) maca, (5) a phycocyanin composition, (6) a 32:1 mixture of SAMe and PG, (7) a 2:2:1 mixture of pumpkin seed composition, Crataeva nurvala composition, and Lindera aggregata composition (P+C+L), (8) a 2:2:1:0.5 mixture of pumpkin seed composition, Crataeva nurvala composition, Lindera aggregata composition, and a 1:1 mixture of black (B) maca and yellow (Y) maca (P+C+L+B / Y Maca), and (9) a 2:2:1:0.5 mixture of pumpkin seed composition, Crataeva nurvala composition, Lindera aggregata composition, and a 1:1 mixture of black (B) maca and yellow (Y) maca (P+C+L+B / Y Maca). The EC2 activity of the beta-adrenergic receptors when administered a 2:2:1:0.5 mixture of the safflower composition, the celery extract composition, and the phycocyanin composition (P+C+L+phycocyanin), and (10) a 2:2:1:0.5 mixture of the pumpkin seed composition, the safflower composition, the celery extract composition, and a 32:1 mixture of SAMe and PG (P+C+L+SAMe+PG). 50 The EC values ​​(μg / ml) are shown in Figure 5.50 Values ​​were obtained only for the 32:1 mixture of SAMe and PG and the 2:2:1:0.5 mixture of pumpkin seed composition, Kutara nurbara composition, Tendai Uyaku composition, and the 32:1 mixture of SAMe and PG, which were 119.5 μg / ml and 273.4 μg / ml, respectively.

[0078] Example 4 An open-label, 12-week clinical trial was conducted to determine the efficacy of a composition described herein, i.e., a combination of a beta-adrenergic agonist and a muscarinic antagonist, for treating overactive bladder symptoms in women, compared to a composition containing a muscarinic antagonist but no beta-adrenergic agonist. A representative composition described herein ("Composition 1") containing 200 mg of SAMe, 360 mg of dried Crataeva nurvala bark powder, and 250 mg of dried yellow maca root powder was used (labeled "SAMe" in Figures 6-18). A composition containing 360 mg of dried Crataeva nurvala bark powder and 250 mg of dried yellow maca root powder ("Composition 2," labeled "No SAMe" in Figures 6-18) was used for comparison.

[0079] Six peri-menopausal and 19 postmenopausal women with an average age of 55.6 years and an average weight of 153 pounds, all suffering from overactive bladder symptoms, were randomly assigned to two groups: one group of 13 participants received Composition 1, and the other group of 12 participants received Composition 2, administered orally twice daily with 8 ounces of water, once immediately upon waking and once 30 minutes before lunch.

[0080] Prior to oral administration of Composition 1 and Composition 2, participants were assessed for five overactive bladder symptoms, namely, daytime urinary frequency, nocturnal urinary frequency, daytime urgency, nocturnal urgency, and daytime urge incontinence, and these were used as baseline data. Over the 12-week treatment period, participants recorded their overactive bladder symptoms online daily. Changes from baseline in the five overactive bladder symptoms were calculated. The results are shown in Figures 6-10. Additionally, scores for overactive bladder symptoms (OABS; range 0–15 points, where 0–2 points indicate no OAB symptoms, 3–5 points indicate mild OAB symptoms, 6–11 points indicate moderate OAB symptoms, and 12–15 points indicate severe OAB symptoms (Homma et al., 2006); the score is the sum of the scores, as shown in Table 1), symptom bother, sleep, health-related quality of life (HRQL), daytime voiding, nocturnal frequency, urgency, and urge incontinence were determined before treatment (baseline) and during the 12-week treatment period. Percent change in scores from baseline was calculated and is shown in Figures 11–18. OABS scores are shown in Table 2.

[0081] [Table 1]

[0082] Figure 6 shows that daytime urination frequency in the Composition 1 treatment group decreased by 27% at week 4, and such a decrease continued at week 12. In contrast, the Composition 2 treatment group increased slightly by 7% at week 4 and decreased by only 13% at week 8.

[0083] Figure 7 shows that nocturnal urination was reduced by 41% at week 4 in the Composition 1 treatment group, compared to only a 25% reduction at week 4 in the Composition 2 treatment group.

[0084] FIG. 8 shows that the Composition 1 treatment group experienced a 71% reduction in daytime urgency at week 4, while the Composition 2 treatment group experienced only a 38% reduction at week 4.

[0085] Figure 9 shows that the Composition 1 treatment group experienced a 91% reduction in nighttime urgency at week 4, while the Composition 2 treatment group experienced only a 66% reduction at week 4.

[0086] FIG. 10 shows that daytime urge incontinence was reduced by 100% in the Composition 1 treatment group compared to a 39% reduction at week 4 in the Composition 2 treatment group.

[0087] FIG. 11 shows that the OABS scores for the Composition 1 treatment group decreased by 38%, 48%, and 63% at weeks 4, 8, and 12, respectively, while the scores for the Composition 2 treatment group decreased by 6%, 26%, and 31% at weeks 4, 8, and 12, respectively.

[0088] Figure 12 shows that the symptom burden scores for the Composition 1 treatment group decreased by 39%, 48%, and 51% at weeks 4, 8, and 12, respectively, while the scores for the Composition 2 treatment group increased by 1% at week 4 and decreased by 18% and 27% at weeks 8 and 12, respectively.

[0089] FIG. 13 shows that the sleep scores of the Composition 1 treatment group decreased by 36%, 47%, and 51% at weeks 4, 8, and 12, respectively, while the scores of the Composition 2 treatment group increased by 1% at week 4 and decreased by 19% and 32% at weeks 8 and 12, respectively.

[0090] FIG. 14 shows that the HRQL scores for the Composition 1 treatment group decreased by 39%, 47%, and 49% at weeks 4, 8, and 12, respectively, while the scores for the Composition 2 treatment group decreased by 2%, 19%, and 28% at weeks 4, 8, and 12, respectively.

[0091] FIG. 15 shows that the daytime voiding scores for the Composition 1 treatment group decreased by 31%, 43%, and 51% at weeks 4, 8, and 12, respectively, while the scores for the Composition 2 treatment group increased by 2% at week 4 and decreased by 26% and 21% at weeks 8 and 12, respectively.

[0092] Figure 16 shows that the nocturnal urination scores for the Composition 1 treatment group decreased by 31%, 45%, and 47% at weeks 4, 8, and 12, respectively, while the scores for the Composition 2 treatment group remained unchanged during the first 4 weeks of treatment and decreased by 11% and 24%, respectively, at weeks 8 and 12.

[0093] Figure 17 shows that the urgency scores for the Composition 1 treatment group decreased by 32%, 39%, and 50% at weeks 4, 8, and 12, respectively, while the scores for the Composition 2 treatment group increased by 3% at week 4 and decreased by 16% and 16% at weeks 8 and 12, respectively.

[0094] Figure 18 shows that the urge incontinence scores for the Composition 1 treatment group decreased by 11%, 34%, and 48% at weeks 4, 8, and 12, respectively, while the scores for the Composition 2 treatment group decreased by 18%, 13%, and 5% at weeks 4, 8, and 12, respectively.

[0095] Figures 6-18 all demonstrate that the compositions described herein containing a combination of a beta-adrenergic agonist and a muscarinic antagonist are unexpectedly effective in treating and / or ameliorating overactive bladder symptoms compared to compositions containing a muscarinic antagonist but no beta-adrenergic agonist, which is consistent with the results shown in Table 2.

[0096] [Table 2]

[0097] Table 2 shows that during the 12-week administration of Composition 1, participants experienced moderate to almost no OAB symptoms, and in contrast, during the 12-week administration of Composition 2, participants experienced moderate to mild OAB symptoms.

[0098] At the end of week 12, participants were administered Composition 1 and completed a consumer experience survey. The results are shown in Table 3.

[0099] [Table 3]

[0100] The side effects of these compositions were also evaluated. No dry mouth or constipation was observed in any of the groups. Both Composition 1 and Composition 2 showed a lower incidence of side effects and adverse events than those frequently reported with prior art pharmaceutical OAB compositions.

[0101] Example 5 A randomized, double-blind, placebo-controlled, parallel clinical trial is conducted to determine the effectiveness of the compositions described herein for treating overactive bladder symptoms in women.

[0102] Ninety-six generally healthy women (aged 40-65 years) participated in a 3-day online home bladder monitoring diary screening (adapted from the International Consultation on Incontinence Questionnaire bladder diary (Bright, Cotterill, Drake, & Abrams, 2014)) to determine whether they had four lower urinary tract symptoms: (i) 8 or more urinations per day (daytime and nighttime), (ii) 2 or more nocturnal urination episodes per day, (iii) 3 or more urgency episodes per day, and (iv) less than 1 leakage episode per day. 80 women who met all four symptoms were selected to participate in the study.

[0103] Eighty participants will be randomly and equally divided into two groups (placebo and active treatment). 24-48 hours before the study, participants will answer five online questions: (i) The Overactive Bladder Questionnaire (OAB-Q), which includes an 8-item symptom burden scale and a 25-item health-related quality of life (HRQoL) scale. The HRQoL scale is divided into three subscales: coping (8 items), interest (7 items), sleep (5 items), and social interaction (5 items). The HRQoL total score is calculated by summing the individual HRQoL subscale scores; (ii) OABS score; (iii) Patient Perception of Bladder Status (PPBC), which measures participants' own perception of urinary (bladder) problems ( Coyne, Matza, Kopp, & Abrams, 2006 ; Matza et al., 2005 ); (iv) the Healthy Everyday Core Module (HRQOL-4) used by the Centers for Disease Control and Prevention for various surveys, including the National Health and Nutrition Examination Survey, to assess health-related quality of life; (v) the Sexual Quality of Life Questionnaire-Women (SQoL-F), an 18-item questionnaire that specifically assesses the relationship between sexual dysfunction and quality of life in women ( Symonds, Boolell, & Quirk, 2005 ); and (vi) PROMIS Sleep Disorders Short Form 8B, which assesses the pure domain of sleep disturbances ( Yu et al., 2011 ).

[0104] During the study, the placebo group will be orally administered a placebo composition containing sodium starch glycolate, magnesium stearate, microcrystalline cellulose, and triethyl citrate, while the active treatment group will be orally administered a representative composition containing 360 mg of Crataeva nurvala bark dry powder, 45 mg of black maca dry powder, 45 mg of yellow maca dry powder, 150 mg of SAMe, and 9 mg of propyl gallate, and a placebo composition. The compositions will be administered twice daily, once immediately after waking and once at least 30 minutes before lunch, with 8 ounces of water, for 84 consecutive days. Participants (a) completed a 3-day home bladder monitoring diary on days 5-7, 12-14, 19-21, 26-28, 54-56, and 82-84; (b) completed online questions (i)-(iv) and (vi) on days 28, 56, and 84; and (c) answered question (v) on day 84.

[0105] Changes from baseline in the number of urinations and urgency episodes without leakage per day (daytime and nighttime) will be calculated based on the data in (a) above. For purposes of this specification, a urination event is defined as a daytime or nighttime urine loss. For purposes of this specification, an urgency episode is defined as an occurrence of urgency without leakage, as obtained from the home bladder monitoring diary. A day (daytime and nighttime) is defined as the time from when the subject wakes up until the participant wakes up the next day. During the intervention, the numbers of urinations and urgency episodes collected for all collection periods (i.e., days 5-7, 12-14, 19-21, 26-28, 54-56, and 82-84) will be summed and divided by 3 to obtain the number of urinations / day (daytime and nighttime) and the number of urgency episodes / day (daytime and nighttime), respectively.

[0106] Additionally, the change from baseline in data (b) and (c) is also determined.

[0107] The OAB Product Experience Questionnaire will also be administered on day 84.

[0108] Monitor for adverse side effects such as xerostomia and constipation.

[0109] Although the invention has been described in some detail for purposes of clarity and understanding, those skilled in the art will recognize that various changes in form and detail may be made therein without departing from the true scope of the invention.

Claims

1. A composition for supporting bladder health and / or treating overactive bladder or at least one symptom associated therewith, the composition comprising a beta-adrenergic receptor agonist and at least one muscarinic receptor antagonist.

2. 2. The composition of claim 1, wherein the beta-adrenergic receptor agonist comprises S-adenosyl-L-methionine (SAMe) and the at least one muscarinic receptor antagonist is selected from the group consisting of pumpkin seeds, Crataeva nurvala plant material or an extract thereof, Lindera aggregata plant material or an extract thereof, black maca, yellow maca, phycocyanin or an extract thereof, and combinations thereof.

3. 3. The composition of claim 2, wherein the at least one muscarinic receptor antagonist is a mixture of Crataeva nurvala plant material or an extract thereof and black maca and yellow maca, wherein the ratio of black maca to yellow maca in the mixture of black maca and yellow maca is from about 4:1 to about 1:

4.

4. 4. The composition of claim 3, wherein the ratio of the Crataeva nurvala plant material or extract thereof, the blend of black maca and yellow maca, and the SAMe is from about 4:1:1 to about 4:1:

4.

5. 3. The composition of claim 2, wherein the beta-adrenergic receptor agonist further comprises propyl gallate (PG), and SAMe and PG are in a mixture in a ratio of about 8:1 to about 128:

1.

6. 6. The composition of claim 5, wherein the at least one muscarinic receptor antagonist is Crataeva nurvala plant material or an extract thereof and a mixture of black maca and yellow maca, wherein the ratio of black maca to yellow maca in the mixture of black maca and yellow maca is from about 4:1 to about 1:

4.

7. 7. The composition of claim 6, wherein the ratio of the Crataeva nurvala plant material or extract thereof, the blend of black maca and yellow maca, and the blend of SAMe and PG is from about 4:1:1 to about 4:1:

4.

8. 3. The composition of claim 2, wherein the at least one muscarinic receptor antagonist is Crataeva nurvala plant material or an extract thereof.

9. The composition of claim 8 , wherein the beta-adrenergic receptor agonist further comprises PG.

10. 3. The composition of claim 2, wherein the beta-adrenergic receptor agonist further comprises PG, and the at least one muscarinic receptor antagonist consists of pumpkin seeds, Crataeva nurvala plant material or an extract thereof, and Lindera aggregata plant material or an extract thereof.

11. 2. The composition of claim 1, wherein the at least one muscarinic receptor antagonist has at least one selected from the group consisting of a higher binding affinity to the M2 muscarinic receptor than the M1 muscarinic receptor, a higher binding affinity to the M3 muscarinic receptor than the M1 muscarinic receptor, a higher binding affinity to the M2 muscarinic receptor than the M4 muscarinic receptor, a higher binding affinity to the M3 muscarinic receptor than the M4 muscarinic receptor, and combinations thereof.

12. A dietary supplement containing a beta-adrenergic receptor agonist and a muscarinic receptor antagonist.

13. 13. The dietary supplement of claim 12, wherein the beta-adrenergic receptor agonist comprises S-adenosyl-L-methionine (SAMe) and the at least one muscarinic receptor antagonist is selected from the group consisting of pumpkin seeds, Crataeva nurvala plant material or an extract thereof, Lindera aggregata plant material or an extract thereof, black maca, yellow maca, phycocyanin or an extract thereof, and combinations thereof.

14. 14. The dietary supplement of claim 13, wherein the at least one muscarinic receptor antagonist is Crataeva nurvala plant material or an extract thereof and the mixture of black maca and yellow maca, wherein the ratio of black maca to yellow maca in the mixture of black maca and yellow maca is from about 4:1 to about 1:

4.

15. 15. The dietary supplement of claim 14, wherein the ratio of the Crataeva nurvala plant material or extract thereof, the blend of black maca and yellow maca, and the SAMe is from about 4:1:1 to about 4:1:

4.

16. 14. The dietary supplement of claim 13, wherein the beta-adrenergic receptor agonist further comprises propyl gallate (PG), wherein SAMe and PG are in a mixture in a ratio of about 8:1 to about 128:

1.

17. 17. The dietary supplement of claim 16, wherein the at least one muscarinic receptor antagonist is Crataeva nurvala plant material or an extract thereof and the mixture of black maca and yellow maca, wherein the ratio of black maca to yellow maca in the mixture of black maca and yellow maca is from about 4:1 to about 1:

4.

18. 18. The dietary supplement of claim 17, wherein the ratio of said Crataeva nurvala plant material or extract thereof, said blend of black maca and yellow maca, and said blend of SAMe and PG is from about 4:1:1 to about 4:1:

4.

19. 13. The dietary supplement of claim 12, wherein the dietary supplement is administered to a subject, and administration of the dietary supplement treats, ameliorates, prevents, or alleviates overactive bladder or at least one symptom associated therewith, wherein the at least one symptom is selected from the group consisting of urgency, urinary incontinence, urge incontinence, polyuria, nocturia, bladder spasms, and combinations thereof.

20. 13. The dietary supplement of claim 12, wherein the at least one muscarinic receptor antagonist has at least one selected from the group consisting of a higher binding affinity to the M2 muscarinic receptor than the M1 muscarinic receptor, a higher binding affinity to the M3 muscarinic receptor than the M1 muscarinic receptor, a higher binding affinity to the M2 muscarinic receptor than the M4 muscarinic receptor, a higher binding affinity to the M3 muscarinic receptor than the M4 muscarinic receptor, and combinations thereof.

21. 14. The dietary supplement of claim 13, wherein said at least one muscarinic receptor antagonist is Crataeva nurvala plant material or an extract thereof.

22. 22. The dietary supplement of claim 21, wherein the beta adrenergic receptor agonist further comprises PG.

23. 14. The dietary supplement of claim 13, wherein the beta-adrenergic receptor agonist further comprises PG and the at least one muscarinic receptor antagonist consists of pumpkin seeds, Crataeva nurvala plant material or extract thereof, and Lindera aggregata plant material or extract thereof.

24. 13. The dietary supplement of claim 12, wherein said dietary supplement is administered to maintain healthy levels of bladder activity and urination frequency.

25. 13. The dietary supplement of claim 12, wherein the dietary supplement is administered to maintain healthy levels of one or more of urinary urgency, urinary incontinence, urge incontinence, polyuria, nocturia, bladder spasms, and combinations thereof.

26. 13. The dietary supplement of claim 12, wherein the dietary supplement is administered to support bladder health.

27. A method for supporting bladder health comprising administering to a subject a composition comprising a beta-adrenergic receptor agonist and at least one muscarinic receptor antagonist.

28. 28. The method of claim 27, wherein the beta-adrenergic receptor agonist comprises S-adenosyl-L-methionine (SAMe) and the at least one muscarinic receptor antagonist is selected from the group consisting of pumpkin seeds, Crataeva nurvala plant material or an extract thereof, Lindera aggregata plant material or an extract thereof, black maca, yellow maca, phycocyanin or an extract thereof, and combinations thereof.

29. 29. The method of claim 28, wherein the beta-adrenergic receptor agonist further comprises PG.

30. 28. The method of claim 27, wherein the at least one muscarinic receptor antagonist is the Crataeva nurvala plant material or extract thereof and a mixture of black maca and yellow maca, wherein the ratio of black maca to yellow maca in the mixture of black maca and yellow maca is from about 4:1 to about 1:

4.

31. 1. A method for treating, ameliorating, preventing, or alleviating overactive bladder or at least one symptom associated therewith, comprising: Identifying a subject who is suffering from or may be suffering from overactive bladder or at least one symptom associated therewith; and administering to said subject a composition comprising a beta adrenergic receptor agonist and at least one muscarinic receptor antagonist; A method comprising:

32. 32. The method of claim 31, wherein the beta-adrenergic receptor agonist comprises S-adenosyl-L-methionine (SAMe) and the at least one muscarinic receptor antagonist is selected from the group consisting of pumpkin seeds, Crataeva nurvala plant material or an extract thereof, Lindera aggregata plant material or an extract thereof, black maca, yellow maca, phycocyanin or an extract thereof, and combinations thereof.

33. 32. The method of claim 31, wherein the at least one muscarinic receptor antagonist has at least one selected from the group consisting of a higher binding affinity to the M2 muscarinic receptor than the M1 muscarinic receptor, a higher binding affinity to the M3 muscarinic receptor than the M1 muscarinic receptor, a higher binding affinity to the M2 muscarinic receptor than the M4 muscarinic receptor, a higher binding affinity to the M3 muscarinic receptor than the M4 muscarinic receptor, and combinations thereof.

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