Development of health food supplements and antioxidants for controlling hyperuricemia and oxidative stress

Abstract

To provide development of health food supplements and antioxidants for controlling hyperuricemia and oxidative stress.SOLUTION: Embodiments of the disclosure include methods and compositions that comprise one or more herb extracts and optionally folic acid and / or one or more of its derivatives. In specific embodiments, the disclosure concerns treatment or prevention of hyperuricemic conditions with combinatorial compositions, such as those including one or more Chinese herbal medicine extracts and optionally folic acid and / or one or more of its derivatives.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application is a direct sequel to U.S. Provisional Patent Application No. 62 / 684,406, filed June 13, 2018. This provisional application claims priority to the same application filed on Dec. 1, 2007, filed on Dec. 1, 2007, the entirety of which is incorporated herein by reference. do.

[0002] Embodiments of the present disclosure encompass at least the fields of cell biology, molecular biology, and medicine. do. [Background technology]

[0003] A 2018 report from the American Heart Association (1 ), the number of deaths due to cardiovascular disease (CVD) in the United States in 2015 was 83. 6,546, which translates to approximately 2,300 Americans dying from CVD every day. This translates to an average of one death every 38 seconds. CVD remains the number one cause of death in the United States. Approximately 92.1 million American adults are living with some form of CVD. In addition to traditional CVD risk factors, new risk factors have recently been recognized and are being further investigated. For example, hyperuricemia was long established as the major etiological factor in gout. In addition to gout, the association between hyperuricemia and CVD was also reported two centuries ago (2). In just a few years, several large clinical studies have identified almost every possible confounding factor. After extensive adjustment for conditions, hyperuricemia was associated with a high risk of CVD, including ischemic heart disease, heart failure, and hypertension. Hyperuricemia has been identified as a significant independent risk factor for atrial fibrillation (3-8). High levels of serum uric acid (SUA) are a concentration-dependent risk factor for cardiovascular disease (9). Each 1 mg / dL increase in SUA increases the overall risk of coronary heart disease and and all-cause mortality increased by 20% and 9%, respectively (3-8). / dl increase in serum cholesterol is associated with a 20 mg / dl increase in serum cholesterol and a 10 mmHg increase in systolic blood pressure. A 1 mg / dL increase in SUA levels resulted in a risk equivalent to that of a 1 mg / dL increase in Hg (10). The risk of hypertension increased by 15% to 23% (11-14). The risk of CKD also increased by 6% for every 1 mg / dL increase (15).

[0004] The prevalence of gout and hyperuricemia in the United States is approximately 4% and 21%, respectively ( 16) The pool of gout and hyperuricemia in mainland China from 2000 to 2014 The prevalence of HIV in some parts of the world was 1.1% and 13-25%, respectively (17, 18). In the region, the prevalence of gout and hyperuricemia is high, up to 11.7% and 41.1%, respectively. % (19). Xanthine oxidase (XO) is the rate-limiting enzyme in purine catabolism. During this chemical reaction, XO produces reactive oxygen species (superoxides) that produce the final product, uric acid. Therefore, hyperuricemia caused by XO Both oxidative stress and metabolic disease contribute significantly to the development of CVD. Uric acid-lowering drugs may play an important role in the prevention and treatment of CVD. In fact, SUA may be a central, rather than an innocent, bystander, player in CVD and several other diseases. Mechanistically, hyperuricemia contributes to oxidative stress, systemic inflammation, and endocrine disruption. This contributes to the progression of CVD through skin dysfunction (20). Treatment with lopurinol has been shown to significantly reduce the risk of myocardial infarction in several clinical trials. reduced total and cardiovascular mortality in high-risk patients and improved endothelial function (2,20-24) However, the clinically available XO inhibitor, allopurinol, due to its potential adverse effects on chronic hyperuricemia-related CVD, and diabetes (26 ), insulin resistance (27), metabolic syndrome (28), chronic kidney disease (29), psoriatic arthritis inflammation (30), microalbuminuria (31), erectile dysfunction (32), preeclampsia (33), cancer ( 34, 35), immune disorders (36), ischemia-reperfusion injury (37), and inflammatory diseases (38, 39) or is not applicable to the clinical management of other diseases, including tumor lysis syndrome.

[0005] Febuxostat is another FDA-approved XO inhibitor; however, However, because of potential side effects, it is recommended to administer it for long periods of time to treat asymptomatic hyperuricemia. This has been avoided.

[0006] In the above clinical trials, the incidence of cerebrovascular disease by preferred term during febuxostat treatment (regardless of dose) was The 10 most common treatment-related adverse events in the LTE study were increased liver enzymes and increased ALT. , abnormal liver function test values, increased AST, hyperlipidemia, increased blood creatinine, nephrolithiasis, arthritis , increased blood urea, and elevated gamma-glutamyltransferase (GGT). (40) Recent reports have shown that febuxostat-induced liver injury can be induced in clinical cases. Febuxostat is not recommended for patients with moderate or severe liver impairment. Not recommended. The most common adverse effects leading to discontinuation of febuxostat were liver function tests In some studies, up to 2-3% of patients had elevated levels three times the upper limit of normal. However, these studies have not shown that febuxo No dose-effect relationship was demonstrated between stats and elevated liver function tests (42).

[0007] The first trial focused on cardiovascular events, particularly thromboembolic events, myocardial infarction, and stroke. One concern was febuxostat treatment (43). This is the first evidence of non-fatal cardiovascular events as a side effect of fluoxetine, and As a result, the FDA required long-term cardiovascular studies as a condition of approving the drug.

[0008] Additionally, early clinical studies have shown that febuxostat reduces skin irritation in approximately 2% of patients. It has been shown that steroid use syndrome (SJS) and anaphylaxis can also result in adverse reactions (44-47). Cases of severe febuxostat hypersensitivity reactions, including shock, have been reported (46, 48 These serious adverse effects of febuxostat may occur especially in patients with renal failure. This may be associated with a history of skin reactions to allopurinol (46, 49, 5 0). One case report also showed that febuxostat induced rhabdomyolysis. (51). Therefore, febuxostat is currently recommended for the treatment of asymptomatic hyperuricemia. It has not been done.

[0009] Currently, the development of new drugs with different pharmacological mechanisms and less toxicity is an active area of ​​research. It is.

[0010] Furthermore, it is a drug that reduces hyperuricemia with little or no adverse effects compared to current XO inhibitors. Development of alternative medicines for long-term management, e.g., functional foods / health supplements and herbal medicines Certain commercially available dietary supplements are being actively researched to lower the body's uric acid levels. Although they may be beneficial in lowering blood pressure, all supplements used for this purpose have a wide range of side effects. It is not backed up by scientific research. Summary of the Invention

[0011] Embodiments of the present disclosure include methods and compositions for the treatment of one or more medical conditions. In certain embodiments, the condition is characterized by inhibition of xanthine oxidase (XO) activity. is therapeutically effective in reducing the presence, severity, or occurrence of at least one symptom of a condition; It is a condition that can be acquired.

[0012] This disclosure relates to the development of alternative medicines, and in the first study, the effectiveness of 72 traditional Chinese herbal medicines was investigated. The XO inhibitory effect was tested. Folic acid is one of the most commonly used dietary supplements. The dynamic effects of folic acid on XO inhibition were investigated. Folic acid and its derivatives exerted XO inhibitory effects. It has been demonstrated that it does (52, 53).

[0013] In certain embodiments, some traditional Chinese herbal medicines have potent XO inhibitory activity. The activity of individual herbs may be influenced by other herbal medicines and / or folic acid and / or one or more of its It may have additive or synergistic effects with folic acid and its derivatives, 5-methyl Tetrahydrofolate (5-MTHF) is an XO inhibitor (52, 53). In a study, folic acid supplements reduced SUA levels and reduced CVD in hypertensive patients. (54-59) Traditional Chinese herbal extracts have been shown to reduce the risk of and / or the use of folic acid and / or one or more of its derivatives. The product / dietary supplement formulation is intended to treat various conditions associated with XO (e.g., asymptomatic hyperuricemia). It offers new opportunities for prevention and / or treatment. The high prevalence of asymptomatic hyperuricemia (approximately 20% in the general population in China and the United States) and there are no safe XO inhibitors. Given this, this novel approach may be useful for the long-term management of asymptomatic hyperuricemia. Asymptomatic hyperuricemia is an independent risk factor for CVD and many other diseases. Considered, the disclosed methods have enormous impact on disease prevention.

[0014] In certain embodiments, the extract is one not found in nature and therefore may contain one or more Compositions containing herbal extracts of are considered non-natural.

[0015] The foregoing has been provided to provide a better understanding of the features and technical aspects of the present disclosure in order that the detailed description that follows may be better understood. The advantages have been outlined quite broadly. Further features and advantages are described hereinafter and are not intended to be limiting. The concepts and specific embodiments disclosed form the subject matter of the claims. can be readily used as a basis for modifying or designing other structures to serve the same purpose. Those skilled in the art will recognize that equivalent constructions may also be used. Those skilled in the art will understand that the present invention does not depart from the spirit and scope of the invention as set forth in the claims. The designs disclosed herein, both in terms of organization and method of operation, should be The novel features believed to be characteristic, together with further objects and advantages, are set forth in the accompanying drawings. The drawings will be better understood from the following description when considered in conjunction with each other. are provided for purposes of illustration and description only and are not intended as a definition of the limits of the disclosure. It should be clearly understood that this is not the case.

[0016] For a more complete understanding of the present disclosure, reference is now made to the following descriptions taken in conjunction with the accompanying drawings, in which: [Brief explanation of the drawings]

[0017] [Figure 1] Figure 1 shows the XO inhibitory effects of 72 traditional Chinese herbal medicines (standard extracts) in a cell-free system. Each extract was tested in both the water-soluble fraction (blue, left side of the pair) and the dimethyl sulfoxide (DMSO)-soluble fraction (red, right side of the pair). The final concentration of each extract was 163 μg / ml. Blue bars: DMSO-soluble fraction of each extract; red bars: water-soluble fraction of each extract.

[0018] [Figure 2A] Figure 2A demonstrates the dose-dependent effects of 14 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 2B] Figure 2B demonstrates the dose-dependent effects of 14 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 2C] Figure 2C demonstrates the dose-dependent effects of 14 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 2D] Figure 2D demonstrates the dose-dependent effects of 14 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 2E] Figure 2E demonstrates the dose-dependent effects of 14 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 2F]Figure 2F demonstrates the dose-dependent effects of 14 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 2G] Figure 2G demonstrates the dose-dependent effects of 14 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 2H] Figure 2H demonstrates the dose-dependent effects of 14 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 2I] Figure 2I demonstrates the dose-dependent effects of 14 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 2J] Figure 2J demonstrates the dose-dependent effects of 14 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 2K] Figure 2K demonstrates the dose-dependent effects of 14 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 2L] Figure 2L demonstrates the dose-dependent effects of 14 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 2M] Figure 2M demonstrates the dose-dependent effects of 14 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 2N] Figure 2N demonstrates the dose-dependent effects of 14 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay.

[0019] [Figure 3]FIG. 3 shows the XO inhibitory effects of folic acid and its two derivatives, dihydrofolic acid and tetrahydrofolic acid, in a cell-free system.

[0020] [Figure 4] Figure 4 provides a comparison of folic acid, allopurinol, and 3,4-dihydroxy-5-nitrobenzaldehyde (DHNB) for XO inhibition in a cell-free system.

[0021] [Figure 5] FIG. 5 illustrates the chemical structures of folic acid, dihydrofolic acid (DHF), tetrahydrofolic acid (THF), 5,10-methylenetetrahydrofolic acid (5,10-MTHFR), 5-methyltetrahydrofolic acid (5-MTHF), 10-formyltetrahydrofolic acid (10-FTHF), and 6-formylpterin.

[0022] [Figure 6] Figure 6 illustrates that folate is an essential vitamin with many important biological functions in the body, including DNA and RNA synthesis, DNA phospholipid and protein methylation for functional control, homocysteine ​​metabolism to reduce homocysteine ​​toxicity and for methionine synthesis for multiple functions: serine hydroxymethyltransferase (SHMT); dihydrofolate reductase (DHFR); thymidylate synthase (TS); methylenetetrahydrofolate reductase (MTHFR); methionine synthase (MS); and S-adenosyl-methionine (SAM).

[0023] [Figure 7] Figure 7 shows the effect of the combination of mint leaf extract and a relatively low concentration of folic acid on XO inhibition assay. The results demonstrate the additive effect of mint leaf extract and folic acid on XO inhibition. Mint leaf extract and folic acid were added separately to the XO reaction system without premixing.

[0024] [Figure 8A] Figure 8A shows the effect of combining traditional Chinese herbal medicine extracts with folic acid on XO inhibition. All 14 traditional Chinese herbal medicine extracts were tested. Folic acid (0.167uM) and extracts (13.3ug / ml) were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 8B] Figure 8B shows the effect of combining traditional Chinese herbal medicine extracts with folic acid on XO inhibition. All 14 traditional Chinese herbal medicine extracts were tested. Folic acid (0.167 uM) and extracts (13.3 ug / ml) were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 8C] Figure 8C shows the effect of combining traditional Chinese herbal medicine extracts with folic acid on XO inhibition. All 14 traditional Chinese herbal medicine extracts were tested. Folic acid (0.167uM) and extracts (13.3ug / ml) were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 8D] Figure 8D shows the effect of combining traditional Chinese herbal medicine extracts with folic acid on XO inhibition. All 14 traditional Chinese herbal medicine extracts were tested. Folic acid (0.167uM) and extracts (13.3ug / ml) were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 8E] Figure 8E shows the effect of combining traditional Chinese herbal medicine extracts with folic acid on XO inhibition. All 14 traditional Chinese herbal medicine extracts were tested. Folic acid (0.167 μM) and extracts (13.3 μg / ml) were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 8F] Figure 8F shows the effect of combining traditional Chinese herbal medicine extracts with folic acid on XO inhibition. All 14 traditional Chinese herbal medicine extracts were tested. Folic acid (0.167 μM) and extracts (13.3 μg / ml) were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 8G]Figure 8G shows the effect of combining traditional Chinese herbal medicine extracts with folic acid on XO inhibition. All 14 traditional Chinese herbal medicine extracts were tested. Folic acid (0.167 μM) and extracts (13.3 μg / ml) were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 8H] Figure 8H shows the effect of combining traditional Chinese herbal medicine extracts with folic acid on XO inhibition. All 14 traditional Chinese herbal medicine extracts were tested. Folic acid (0.167 μM) and extracts (13.3 μg / ml) were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 8I] Figure 8I shows the effect of combining traditional Chinese herbal medicine extracts with folic acid on XO inhibition. All 14 traditional Chinese herbal medicine extracts were tested. Folic acid (0.167uM) and extracts (13.3ug / ml) were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 8J] Figure 8J shows the effect of combining traditional Chinese herbal medicine extracts with folic acid on XO inhibition. All 14 traditional Chinese herbal medicine extracts were tested. Folic acid (0.167uM) and extracts (13.3ug / ml) were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 8K] Figure 8K shows the effect of combining traditional Chinese herbal medicine extracts with folic acid on XO inhibition. All 14 traditional Chinese herbal medicine extracts were tested. Folic acid (0.167uM) and extracts (13.3ug / ml) were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 8L] Figure 8L shows the effect of combining traditional Chinese herbal medicine extracts with folic acid on XO inhibition. All 14 traditional Chinese herbal medicine extracts were tested. Folic acid (0.167uM) and extracts (13.3ug / ml) were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 8M]Figure 8M shows the effect of combining traditional Chinese herbal medicine extracts with folic acid on XO inhibition. All 14 traditional Chinese herbal medicine extracts were tested. Folic acid (0.167uM) and extracts (13.3ug / ml) were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 8N] Figure 8N shows the effect of combining traditional Chinese herbal medicine extracts with folic acid on XO inhibition. All 14 traditional Chinese herbal medicine extracts were tested. Folic acid (0.167uM) and extracts (13.3ug / ml) were added separately to the XO reaction system without premixing. XO activity was measured.

[0025] [Figure 9] Figure 9 provides the effect of 5-methyltetrahydrofolic acid (5-MTHF) on XO inhibition. Freshly prepared 5-MTHF inhibited XO activity in a concentration-dependent manner. The IC50 of 5-MTHF is approximately 35.6 μM. However, its effect is weaker than that of folic acid.

[0026] [Figure 10A] Figure 10A demonstrates the effect of combining 5-MTHF with the herbal extract on XO inhibition in vitro. Freshly prepared 5-MTHF (3.3 μM) and the herbal extract (13.3 μg / ml) were added separately to the XO reaction system, and XO activity was recorded. [Figure 10B] Figure 10B demonstrates the effect of combining 5-MTHF with the herbal extract on XO inhibition in vitro. Freshly prepared 5-MTHF (3.3 μM) and the herbal extract (13.3 μg / ml) were added separately to the XO reaction system, and XO activity was recorded. [Figure 10C] Figure 10C demonstrates the effect of combining 5-MTHF with the herbal extract on XO inhibition in vitro. Freshly prepared 5-MTHF (3.3 μM) and the herbal extract (13.3 μg / ml) were added separately to the XO reaction system, and XO activity was recorded. [Figure 10D]Figure 10D demonstrates the effect of combining 5-MTHF with the herbal extract on XO inhibition in vitro. Freshly prepared 5-MTHF (3.3 μM) and the herbal extract (13.3 μg / ml) were added separately to the XO reaction system, and XO activity was recorded. [Figure 10E] Figure 10E demonstrates the effect of combining 5-MTHF with the herbal extract on XO inhibition in vitro. Freshly prepared 5-MTHF (3.3 μM) and the herbal extract (13.3 μg / ml) were added separately to the XO reaction system, and XO activity was recorded. [Figure 10F] Figure 10F demonstrates the effect of combining 5-MTHF with the herbal extract on XO inhibition in vitro. Freshly prepared 5-MTHF (3.3 μM) and the herbal extract (13.3 μg / ml) were added separately to the XO reaction system, and XO activity was recorded. [Figure 10G] Figure 10G demonstrates the effect of combining 5-MTHF with the herbal extract on XO inhibition in vitro. Freshly prepared 5-MTHF (3.3 μM) and the herbal extract (13.3 μg / ml) were added separately to the XO reaction system, and XO activity was recorded. [Figure 10H] Figure 10H demonstrates the effect of combining 5-MTHF with the herbal extract on XO inhibition in vitro. Freshly prepared 5-MTHF (3.3 μM) and the herbal extract (13.3 μg / ml) were added separately to the XO reaction system, and XO activity was recorded. [Figure 10I] Figure 10I demonstrates the effect of combining 5-MTHF with the herbal extract on XO inhibition in vitro. Freshly prepared 5-MTHF (3.3 μM) and the herbal extract (13.3 μg / ml) were added separately to the XO reaction system, and the XO activity was recorded. [Figure 10J] Figure 10J demonstrates the effect of combining 5-MTHF with the herbal extract on XO inhibition in vitro. Freshly prepared 5-MTHF (3.3 μM) and the herbal extract (13.3 μg / ml) were added separately to the XO reaction system, and the XO activity was recorded. [Figure 10K]Figure 10K demonstrates the effect of combining 5-MTHF with the herbal extract on XO inhibition in vitro. Freshly prepared 5-MTHF (3.3 μM) and the herbal extract (13.3 μg / ml) were added separately to the XO reaction system, and XO activity was recorded. [Figure 10L] Figure 10L demonstrates the effect of combining 5-MTHF with the herbal extract on XO inhibition in vitro. Freshly prepared 5-MTHF (3.3 μM) and the herbal extract (13.3 μg / ml) were added separately to the XO reaction system, and XO activity was recorded. [Figure 10M] Figure 10M demonstrates the effect of combining 5-MTHF with the herbal extract on XO inhibition in vitro. Freshly prepared 5-MTHF (3.3 μM) and the herbal extract (13.3 μg / ml) were added separately to the XO reaction system, and XO activity was recorded. [Figure 10N] Figure 10N demonstrates the effect of combining 5-MTHF with the herbal extract on XO inhibition in vitro. Freshly prepared 5-MTHF (3.3 μM) and the herbal extract (13.3 μg / ml) were added separately to the XO reaction system, and XO activity was recorded. 5-MTHF had an additive effect on XO inhibition with 10 of 14 herbal extracts: Pueraria lobata (fruit) extract (Mu Gua, quince); Euryale eriana (seed) extract (Gian Shi); Dianthus japonica (aerial part) extract (Qu Mai, Qu Mai), Honeysuckle (flower bud) extract (Jing Ying Hua), Houttuynia cordata (aerial part) (Yu Xin Cao); Citron (fruit) extract (Xiang Yuan); Lotus seed extract (Lian Zhi); Celery extract (Gao Liang Jiang, Gao Liang Jiang); Euonymus confusum (flower) extract (Ye Ju Hua, Wild chrysanthemum flower); and Mentha orba (Mint leaf) (Figure 10). There was no additive effect with corn bean root (Ci Xiao Dou), adzuki bean extract (Ci Xiao Dou), and unripe wheat extract (Fu Xiao Mei).

[0027] [Figure 11] Figure 11 shows the XO inhibitory effects of 112 herbal extracts in a cell-free system. Each extract was tested in the DMSO-soluble fraction. The final concentration of each extract was 166.7 μg / ml for most extracts, although some extracts were used at lower concentrations due to solubility issues.

[0028] [Figure 12A] Figure 12A demonstrates the dose-dependent effects of 15 standard herbal extracts on XO inhibition in a cell-free system, using the DMSO-soluble fractions of these extracts. [Figure 12B] Figure 12B demonstrates the dose-dependent effects of 15 standard herbal extracts on XO inhibition in a cell-free system, using the DMSO-soluble fractions of these extracts. [Figure 12C] Figure 12C demonstrates the dose-dependent effects of 15 standard herbal extracts on XO inhibition in a cell-free system, using the DMSO-soluble fractions of these extracts. [Figure 12D] Figure 12D demonstrates the dose-dependent effects of 15 standard herbal extracts on XO inhibition in a cell-free system, using the DMSO-soluble fractions of these extracts. [Figure 12E] Figure 12E demonstrates the dose-dependent effects of 15 standard herbal extracts on XO inhibition in a cell-free system, using the DMSO-soluble fractions of these extracts. [Figure 12F] Figure 12F demonstrates the dose-dependent effects of 15 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 12G] Figure 12G demonstrates the dose-dependent effects of 15 standard herbal extracts on XO inhibition in a cell-free system, using the DMSO-soluble fractions of these extracts. [Figure 12H] Figure 12H demonstrates the dose-dependent effects of 15 standard herbal extracts on XO inhibition in a cell-free system, using the DMSO-soluble fractions of these extracts. [Figure 12I] Figure 12I demonstrates the dose-dependent effects of 15 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 12J] Figure 12J demonstrates the dose-dependent effects of 15 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 12K] Figure 12K demonstrates the dose-dependent effects of 15 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 12L] Figure 12L demonstrates the dose-dependent effects of 15 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 12M] Figure 12M demonstrates the dose-dependent effects of 15 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 12N] Figure 12N demonstrates the dose-dependent effects of 15 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay. [Figure 12O] Figure 12O demonstrates the dose-dependent effects of 15 standard herbal extracts on XO inhibition in a cell-free system. The DMSO-soluble fractions of these extracts were used in this assay.

[0029] [Figure 13A]Figure 13A provides the effect of the combination of selected herbal extracts and folic acid on XO inhibition. Eight herbal extracts were selected and tested. Folic acid (0.167 μM) and a specified concentration (μg / ml) of each extract were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 13B] Figure 13B provides the effect of the combination of selected herbal extracts and folic acid on XO inhibition. Eight herbal extracts were selected and tested. Folic acid (0.167 μM) and a specified concentration (μg / ml) of each extract were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 13C] Figure 13C provides the effect of the combination of selected herbal extracts and folic acid on XO inhibition. Eight herbal extracts were selected and tested. Folic acid (0.167 μM) and a specified concentration (μg / ml) of each extract were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 13D] Figure 13D provides the effect of the combination of selected herbal extracts and folic acid on XO inhibition. Eight herbal extracts were selected and tested. Folic acid (0.167 μM) and a specified concentration (μg / ml) of each extract were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 13E] Figure 13E provides the effect of the combination of selected herbal extracts and folic acid on XO inhibition. Eight herbal extracts were selected and tested. Folic acid (0.167 μM) and a specified concentration (μg / ml) of each extract were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 13F] Figure 13F provides the effect of the combination of selected herbal extracts and folic acid on XO inhibition. Eight herbal extracts were selected and tested. Folic acid (0.167 μM) and a specified concentration (μg / ml) of each extract were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 13G]Figure 13G provides the effect of the combination of selected herbal extracts and folic acid on XO inhibition. Eight herbal extracts were selected and tested. Folic acid (0.167 μM) and a specified concentration (μg / ml) of each extract were added separately to the XO reaction system without premixing. XO activity was measured. [Figure 13H] Figure 13H provides the effect of the combination of selected herbal extracts and folic acid on XO inhibition. Eight herbal extracts were selected and tested. Folic acid (0.167 μM) and a specified concentration (μg / ml) of each extract were added separately to the XO reaction system without premixing. XO activity was measured.

[0030] [Figure 14] Figure 14 shows the effect of a rationally designed dietary supplement formula on lowering serum uric acid levels in a mouse model. The formula contains milk thistle extract, grape seed extract, amla fruit extract, pine bark extract, Taiwanese mint extract, and folic acid. The uricase inhibitor, allantoxanamide, was injected intraperitoneally (ip) to induce hyperuricemia in mice. The mice were then given 200-250 ul (for 20-25 g mice) of allopurinol (positive control) or the dietary supplement formula (low and high doses) by oral gavage. Blood was collected from the facial vein 1.5 and 3 hours after treatment. The following day, serum uric acid levels were measured using the phosphotungstic acid method. N = 4 per group. DETAILED DESCRIPTION OF THE INVENTION

[0031] As used herein, "a" or "an" may mean one or more. When used in the claims, the words "a" or "an" in conjunction with the word "comprising" As used herein, "one" or "more than one" can mean one or more than one. When used in conjunction with "another," "another" may mean at least a second or more. In embodiments, the subject aspects may, for example, be directed to one or more of the subject elements or steps " "consisting essentially of" or "consisting of" one or more elements or steps of the subject matter Some embodiments of the subject matter include one or more of the elements, method steps, and / or Any of the methods described herein may consist of, or consist essentially of, any of the methods described herein. or composition is performed in comparison to any other method or composition described herein. It is contemplated that this may be possible.

[0032] Consistent with long-standing patent law practice, the words "a" and "an" refer to the subject matter of this patent, including the claims. In the specification, when used in conjunction with the word "including" it means "one or more." Some embodiments of the present disclosure may comprise one or more elements, method steps, and / or or may consist of or consist essentially of any of the methods described herein. or composition is performed in comparison to any other method or composition described herein. It is contemplated that various embodiments may be combined.

[0033] As used herein, the terms "or" and "and / or" refer to multiple constructs. Used to describe components in combination or exclusive of each other. For example, "x, y and / or z" means "x" only, "y" only, "z" only, "x, y and z", "(x and y) or z", "x or (y and z)" or "x or y or z" It is clear that x, y, or z may be specifically excluded from certain embodiments. It is certainly intended.

[0034] Throughout this application, the term "about" means that a value is within the range of the device used to measure that value. Cellular and molecular data are used to indicate that they include the standard deviation of error for the device or method. Used according to its plain and ordinary meaning in the field of biology.

[0035] Throughout this specification, the terms "one embodiment," "an embodiment," and "particular embodiment" are used. "related embodiments," "certain embodiments," "additional embodiments," or "further embodiments" Reference to "any embodiment" or combination thereof means that the invention is described in connection with that embodiment. The particular feature, structure, or characteristic described is included in at least one embodiment of the present invention. Accordingly, the appearance of the foregoing phrases in various places throughout this specification is to be understood as meaning Not all references necessarily refer to the same embodiment. The features may be combined in any suitable manner in one or more embodiments.

[0036] Various aspects of the disclosure may be presented in a range format. Description in range format is merely for convenience. The following statements are for the sake of clarity and brevity and should not be construed as an inflexible limitation on the scope of the present disclosure. It should be understood that the description of ranges does not necessarily imply a limitation on the scope of possible parts. It is as if all the specific ranges and individual values ​​within those ranges are explicitly written out. For example, a description of a range such as 1 to 6 should be deemed to be a clear disclosure of the Partial ranges such as 3, 1-4, 1-5, 2-4, 2-6, 3-6, etc., as well as Individual numbers within a range, e.g., 1, 2, 3, 4, 5, and 6, are considered to be expressly disclosed. This applies regardless of the width of the range. The ranges may include the endpoints of the range.

[0037] The term "subject" as used herein is used interchangeably with the term "individual." The term "subject" generally refers to an individual who has acquired a disease and is in need of treatment. The subject may be a patient, e.g., a mammal, such as a dog, cat, horse, pig, or rodent. For example, having or having a disease or condition related to excess uric acid levels Suspected of having or at risk of having excessive uric acid levels and In the case of a subject having or suspected of having a condition associated with The subject may have or be suspected of having a disease. The subject may be asymptomatic. The subject may be of either gender. The subject , a certain age, for example, at least 30, 35, 40, 45, 50, 55, 60, 6 The person may be 5, 70, 75, 80, 85, 90, 95 or 100 years old or older.

[0038] The compositions of the present disclosure may be suitable for treating diseases in human or animal patients. In one embodiment, the patient is a human, horse, dog, cat, sheep, cow, or primate. In one embodiment, the patient is a human. In this context, a patient is not a human being. An individual may be identified through one or more chemicals via the World Wide Web. You can receive a mixture.

[0039] As used herein, the term "effective amount" refers to the amount sought by, for example, a researcher or clinician. compounds that induce a biological or medical response in a tissue, system, animal or human, Furthermore, the term "therapeutically effective amount" refers to the amount of a drug or pharmaceutical agent administered. Improved treatment, cure, or cure of a disease, disorder, or side effect compared to matched untreated subjects. Any amount that results in a cure, prevention, or amelioration, or a slowing of the rate of progression of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

[0040] As used herein, the term "treatment" refers to a treatment that does not involve administering a pharmaceutical composition of the present disclosure. Preventing or inhibiting symptoms, treating symptoms, delaying the onset of symptoms compared to when reducing the severity of the onset of symptoms and / or the severity of the symptoms the individual is suffering from The term treatment refers to a symptomatic situation. This includes use in

[0041] Embodiments of the present disclosure may comprise one or more herbal extracts and optionally folic acid and / or and one or more compositions containing one or more derivatives of the elements listed herein. Any of these may be combined with any one or more other elements as part of a composition. One or more components in any composition may provide additive or synergistic effects. In particular embodiments, the compositions are used to treat various disease states, including xanthine oxidase (XO) activity. The present invention is used for the treatment or prevention of conditions in which it may be beneficial to reduce the risk of heart disease. Examples of medical conditions include direct or indirect hyperuricemic conditions (e.g., gout, hypertension, atherosclerosis, Atherosclerosis, coronary artery disease, heart failure, left ventricular hypertrophy, atrial fibrillation, peripheral arterial disease, vascular restenosis vascular stenosis, intravascular thrombosis, stroke, diabetes, insulin resistance, metabolic syndrome, chronic kidney disease, psoriasis Arthritis, microalbuminuria, erectile dysfunction, pre-eclampsia, cancer (of any kind), immune disorders or When the condition is cancer, it may be one or more of the following: lung, breast , brain, liver, colon, skin, stomach, prostate, uterus, endometrium, ovaries, testes, bones, spleen, thyroid , cancer of the blood, gallbladder, kidney, etc.

[0042] In some embodiments, Euryale Watermelon (seed) extract; Rumex graminus extract; Wheat ( Unripe fruit extract; Houttuynia cordata (aerial part) extract; Citron (fruit) extract; Lotus (seed) extract Kiss; Taiwan mint extract; Fennel (fruit) extract; Strep thistle (aerial part) ) extract; Fuji bean extract; Abalone shell extract; Bakuga extract; Sterculia (seed) extract Kiss; Haizhou Elsholtzia (aerial parts) extract; Yakuchi (seed) extract; Radish (seed) extract; Lotus (young shoot) extract; Fermented soybean extract Jujube (seed) extract; Nagiikada; Oolong tea (leaf) extract; Senna leaf extract; Yo Himbe bark extract; Thistle extract; Butterbur extract; Caralluma bark ma bark) (wild) extract; Echinacea root extract; Horse chestnut fruit extract; Cola nut extract; Magnolia bark extract; Muira puama bark extract; or combinations thereof In such cases, the composition may be a medicine, a medicinal food, a supplement, or the like. For use in nutritional supplements, foods, supplements, dietary or health supplements, and special dietary products The composition may be formulated as a food or a medical food or a combination thereof.

[0043] Any composition of the present disclosure may comprise: Clove (flower bud) extract; Vietnam Sophora (root) extract; Chaenomeles (fruit) extract; Dianthus campanulata (aerial part) extract; Honeysuckle (flower bud) extract; Alpinia officinarum extract; or cornflower (flower) extract; Fructose Crataegi (burnt) Glycyrrhiza uralensis (root and rhizome) extract; Ginkgo biloba leaf extract; Ebisu Sickle-pod Senna (seed) extract; Bitter Orange (Fruc tus Aurantii (Bitter Orange) Extract; ) (young fruit) extract; Smilax smilax (rhizome) extract; Morus alba (young twig) extract; Morus alba (leaf) extract; lotus (leaf) extract; chrysanthemum (flower) extract; perilla (perilla) (leaf) extract; Job's tears extract; Gosho strawberry extract; or patchouli (aerial parts) extract; Frican mango seed extract; Amla fruit powder; Grape seed extract; Green tea pure extract; Silybum extract; Olive leaf extract; Pine bark; Pomegranate extract; Spearmint leaf extract ;St. John's Wort Extract;Aloe Vera Leaf Extract;Catuaba Bark Extract;Amachi Hawthorn extract; Kudzu root extract; Lemon balm extract; Licorice root extract Moringa extract; Papaya fruit extract; Papaya seed; Red clover (steamed leaf) extract; rosemary extract; or combinations thereof.

[0044] In certain embodiments, the composition comprises: Euryale asiaticus (seed) extract; Rumex graminus extract ;Wheat (immature fruit) extract;Houttuynia cordata (aerial part) extract;Citron (fruit) extract;Lotus (seed) extract; Taiwan mint extract; Nagiikada extract; Oolong tea (leaf) extract; Senna leaf extract; Yohimbe bark extract; Thistle extract; Butterbur extract; Caralluma Bark (wild) extract; Echinacea root extract; Horse chestnut fruit extract; Cola nut extract Kisu; Magnolia bark extract; Muira puama bark extract; or combinations thereof. In some cases, the composition contains Euryale (seed) extract and one or more other compounds. In a specific case, the composition comprises a rice bean extract and one or more other ingredients. In a specific case, the composition comprises a wheat (unripe fruit) extract and In a specific case, the composition contains one or more other compounds. ) extract and one or more other compounds. In a specific case, the composition comprises The extract of torone (fruit) and one or more other compounds. The composition comprises lotus (seed) extract and one or more other compounds. Thus, the composition contains a mint extract and one or more other compounds. In some cases, the composition comprises a thrush extract and one or more other compounds. In some cases, the composition contains oolong tea (leaf) extract and one or more other compounds. In a specific case, the composition comprises a senna leaf extract and one or more other ingredients. In a specific case, the composition comprises a yohimbe bark extract and one other compound. In a specific case, the composition comprises a milk thistle extract and other compounds. In a specific case, the composition comprises one or more compounds of the formula: and one or more other compounds. In a specific case, the composition comprises Caralluma peel. In particular cases, the composition comprises a (wild) extract and one or more other compounds. contains Caralluma bark (wild) extract and one or more other compounds. Thus, the composition comprises Caralluma bark (wild) extract and one or more other compounds. In some cases, the composition contains Echinacea root extract and one or more other compounds. In a specific case, the composition contains a horse chestnut fruit extract and one other In a specific embodiment, the composition comprises a cola nut extract and In a specific case, the composition contains one or more other compounds. and one or more other compounds. In a specific case, the composition comprises Muira Puama bark extract and one or more other compounds.

[0045] In certain embodiments, the composition comprises: Euryale asiaticus (seed) extract; Rumex graminus extract ;Wheat (immature fruit) extract;Houttuynia cordata (aerial part) extract;Citron (fruit) extract;Lotus (seed) extract; Taiwan mint extract; Nagiikada extract; Oolong tea (leaf) extract; Senna leaf extract; Yohimbe bark extract; Thistle extract; Butterbur extract; Caralluma Bark (wild) extract; Echinacea root extract; Horse chestnut fruit extract; Cola nut extract Kisu; Magnolia bark extract; and Muira Puama bark extract 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or all .

[0046] In some embodiments, the composition comprises an extract of Alpinia chinensis (Alpinia chinensis L.). a officinarum), honeysuckle (flower bud) extract, Taiwan mint extract, Contains cinnamon (flower bud) extract, citron (fruit) extract or a combination thereof. In some cases, the composition contains Alpinia officinalis extract (Alpinia officinalis extract). cinarum) and one or more other compounds. The product includes honeysuckle (flower buds) and one or more other compounds. In particular cases, The composition includes an extract of Taiwanese peppermint and one or more other compounds. In the above, the composition comprises clove (flower bud) extract and one or more other compounds. In a specific case, the composition comprises citron (fruit) extract and one or more other compounds. In certain embodiments, the composition comprises a compound containing Aloe barbadensis extract (Alp inia officinarum), honeysuckle (flower bud) extract; Taiwan mint extract One, two, or three of the following: clove (flower bud) extract; and citron (fruit) extract is all-inclusive.

[0047] In a specific embodiment, the composition comprises: Silybum sieboldii extract; Grape seed extract; Ammonium sieboldii extract; Contains: ra extract; pine bark extract; Taiwan mint extract; or a combination thereof In a specific case, the composition contains a milk thistle extract and one or more other compounds. In particular cases, the composition contains grape seed extract and one or more other compounds. In a specific case, the composition comprises an amla extract and one or more other ingredients. In a specific case, the composition comprises a pine bark extract and one other compound. In a specific case, the composition contains the above compounds. and one or more other compounds. In certain embodiments, the composition comprises Silybum sieboldii. Grape seed extract; Amla extract; Pine bark extract; and Mentha occidentalis extract In a specific embodiment, the composition comprises one, two, three, four, or all of: contains at least a syrup extract and a grape seed extract.

[0048] In some embodiments, the one or more compositions comprise folic acid and / or one or more thereof. When using the XO inhibition assay, folic acid and its three derivatives The derivatives dihydrofolic acid, tetrahydrofolic acid and 5-methyltetrahydrofolic acid (5- One or more of the following may be used: folic acid and 5-MTHF. 50 Ha, so The concentrations of dihydrofolic acid and tetrahydrofolic acid are 0.75 uM and 35.6 uM, respectively. , which, at least in some embodiments, is more potent than folic acid. The XO inhibitory effect of the herbal extract in combination with folic acid or 5-MTHF was investigated. Nine of the 14 extracts tested showed additive XO inhibitory effects with folic acid, and 1 of the tested extracts Ten of the four extracts showed an XO inhibitory effect that was additive with 5-MTHF.

[0049] The phase of various combinations of the extract with folic acid or 5-MTHF under various experimental conditions Additive or synergistic effects may be characterized. Several lead combination preparations of herbal extracts can be selected, and each component of the combination In some cases where the dose of the element is relatively low, additive effects on XO inhibition and / or These lead combination formulations can be used in animal models to determine which have potent or synergistic effects. These findings can be characterized in diagnostic tests and ultimately contribute to the severity of cardiovascular disease and many other diseases. Having both symptomatic and asymptomatic hyperuricemic states is a significant independent risk factor These herbal extracts can be characterized for the treatment and / or prevention of patients. Folic acid-based health supplements also have antioxidant properties, reduce oxidative stress, and improve serum hydroxylase activity. It reduces cysteine ​​levels, thereby providing multiple health benefits.

[0050] I. Pharmaceuticals and Other Compositions

[0051] According to the present disclosure, the term "composition" or "pharmaceutical composition" refers to a composition for administration to an individual. In certain embodiments, the pharmaceutical or other composition relates to a composition, e.g., a non- Compositions for oral, transdermal, intracavitary, intraarterial, intrathecal or intravenous administration It is specifically contemplated that the pharmaceutical composition is administered orally to an individual. The composition can be administered in various ways, for example, orally, intravenously, subcutaneously, intraperitoneally, Intramuscular, topical, intradermal, infusion, injection, or rectal (e.g., using a suppository) This can be done by (including use).

[0052] Pharmaceutical or other compositions of the disclosure may be administered in an acceptable carrier, e.g., a pharmaceutically acceptable carrier. Examples of suitable carriers are well known in the art. These include phosphate buffered saline solutions, water, emulsions (e.g., oil / water emulsions), These include various types of wetting agents, sterile solutions, etc. Compositions containing the a can be formulated by well-known conventional methods. The compound may be administered to a subject in a suitable dose.

[0053] The dosage regimen will be determined by the attending physician and clinical factors. As is known, the dosage for any one patient will vary depending on the patient's size, body surface area, age, The specific compound being administered, gender, time and route of administration, general health, and It depends on many factors, including other drugs being administered concomitantly. The dosage is 0.24 μg to 48 mg per kilogram of body weight per day, preferably 0 0.24 μg to 24 mg, more preferably 0.24 μg to 2.4 mg, even more preferably Preferably, the dose ranges from 0.24 μg to 1.2 mg, and most preferably from 0.24 μg to 240 mg. Progress can be monitored by periodic evaluation.

[0054] The compositions of the present disclosure can be administered locally or systemically. Administration is generally parenteral. The DNA can be delivered directly to the target site, e.g., by biolistic delivery. The drug may be administered to an internal or external target site by a catheter or to an arterial site. In certain embodiments, the pharmaceutical composition is administered subcutaneously, and in an even more preferred embodiment In the case of parenteral administration, the drug is administered intravenously. Preparations for parenteral administration include sterile aqueous solutions or non-steroidal anti-inflammatory drugs. Examples of non-aqueous solvents include aqueous solutions, suspensions, and emulsions. polyethylene glycol, vegetable oils such as olive oil, and ethyl oleate It is an injectable organic ester. Aqueous carriers include water, alcoholic / aqueous solutions, Emulsions or suspensions, including saline and buffered media. Examples of solutions include sodium chloride solution, Ringer's dextrose, dextrose and chloride Intravenous vehicles include sodium chloride, lactated Ringer's solution, or fixed oils. and fluid and nutrient replenishes , electrolyte replenishers (e.g., those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents and inert gases. Furthermore, the pharmaceutical compositions of the present disclosure preferably contain or proteinaceous substances of human origin, such as serum albumin or immunoglobulins The pharmaceutical compositions of the present disclosure may comprise a proteinaceous, bispecific single chain antibody construct. construct, or a nucleic acid molecule or vector encoding same (as described in this disclosure) In addition to the above, biologically active agents may be added depending on the intended use of the composition. It is expected that the following may be included:

[0055] In some embodiments, any of the compositions encompassed herein may be administered by an individual. It may be consumed once or more than once or may be used in other ways. When something is consumed or otherwise used more than once, the duration between doses The period can be approximately 1-24 hours, 1-7 days, 1-4 weeks, or 1-12 months or longer. The individual may, after a diagnosis indicating that the individual is in need of these compositions, These compositions may or may not be consumed or used. In the present study, individuals have excessive uric acid levels, e.g., compared to the general population or controls. The individual is diagnosed with the disease and then the composition is subsequently consumed or used. The compositions may be obtained through commercial sources, including the World Wide Web.

[0056] More than one element listed herein may be present in the compositions as encompassed herein. When elements (e.g., extract type) are included, those elements are For example, in some cases, the compositions may or may not be present in the same ratio. Two different elements are arranged in a 1:1 ratio, a 1:2 ratio, a 1:5 ratio, a 1:10 ratio, a 1 :25 ratio, 1:50 ratio, 1:100 ratio, 1:500 ratio, 1:1000 ratio, 1: The composition may be formulated to be present in a ratio of 10,000 to 10,000. If two elements (e.g., extract type) are included, the ratio is 1:1:1, 1 :2:1 ratio, 1:5:1 ratio, 1:10:1 ratio, 1:50:1 ratio, 1:100:1 Ratio of 1:500:1, Ratio of 1:1000:1, Ratio of 1:1:2, Ratio of 1:1:5, 1:1:10 ratio, 1:1:50 ratio, 1:1:100 ratio, 1:1:500 ratio, 1: 1:1000 ratio, 2:1:1 ratio, 5:1:1 ratio, 10:1:1 ratio, 50:1:1 ratio, 100:1:1 ratio, 500:1:1 ratio, 1000:1:1 ratio, etc. .

[0057] In some embodiments, one or more specific elements (e.g., type of extract) The concentration of the extracts may be within a range. For example, one or more extracts may be present in the composition at a concentration of 0.1 to 1.0%. In a specific embodiment, one or more enzymes may be present in a concentration range of 100 mg / kg. Kiss, for example, in the composition: 0.1 to 100 mg / kg; 0.1 to 75 mg / kg; 0.1~50mg / kg;0.1~25mg / kg;0.1~10mg / kg / 0.1~ 5mg / kg;0.1~1mg / kg;0.1~0.75mg / kg / 0.1~0.5m g / kg;0.5~100mg / kg;0.5~75mg / kg;0.5~50mg / k g;0.5~25mg / kg;0.5~10mg / kg;0.5~5mg / kg;0.5 ~1mg / kg;1~100mg / kg;1~75mg / kg;1~50mg / kg;1 ~25mg / kg;1~10mg / kg;1~5mg / kg;5~100mg / kg;5 ~75mg / kg;5~50mg / kg;5~25mg / kg;5~10mg / kg;1 0~100mg / kg / 10~75mg / kg;10~50mg / kg / 10~25mg / kg;25~100mg / kg;25~75mg / kg;25~50mg / kg;50 ~100mg / kg; 50-75mg / kg; or 75-100mg / kg concentration range It can exist within

[0058] Any of the compositions described herein can be included in a kit. In the method, one or more components of the composition and / or reagents for extracting the herbal medicine are included in the kit. The components of the kit are provided in suitable container means.

[0059] Some components of the kits may be packaged in aqueous media or in lyophilized form. The container means of the kits may include, preferably, suitably aliquoted, at least one vial, test tube, flask, bottle, syringe or other container Container means will generally include. Where there is more than one component in the kit, the kit The container generally includes a second, third, or other additional container into which additional components may be separately disposed. However, various combinations of components may be contained in a single vial. A kit typically contains components in close confinement for commercial sale. Such containers may include injection molded or other suitable containers that hold the desired vials. Examples include blow-molded plastic containers.

[0060] When the components of the kit are provided in one and / or more liquid solutions, The liquid solution is an aqueous solution, with sterile aqueous solutions being particularly useful. The vessel means itself may be a syringe, pipette and / or other such device, From there, the formulation can be applied to the infected area of ​​the body, injected into an animal, and / or administered to a kit. The composition may be applied to and / or mixed with other components of the composition.

[0061] However, the components of the kit may also be provided as dry powders. Alternatively, when the components are provided as dry powders, the powders may be mixed with a suitable solvent. The solvent may also be provided in another container means. It is envisioned that the kit may contain sterile, pharmaceutically acceptable buffers and / or A second container means for containing another diluent may also be included.

[0062] In certain embodiments, the compositions are provided as kits, and in some cases, The composition is essentially the only component of the kit. The kit contains the desired extract or composition. In certain embodiments, the kit may include reagents and materials for producing the composition. The device includes one or more devices suitable for extracting one or more samples from an individual. The device may be a syringe, a scalpel, or the like.

[0063] In some cases, the kit may include, in addition to the disclosed embodiments, a second treatment (e.g., For example, one or more uricosuric agents other than those described in this disclosure and / or one or more Also contains xanthine oxidase inhibitors.

[0064] II. Dietary Supplements or Health Food Supplements

[0065] Any herbal and non-herbal ingredients of the present disclosure may be used in dietary or health food supplements. In the form of a tablet or as a pharmaceutical formulation, for example, a solid formulation comprising a composition of the present disclosure as an active ingredient They can be used in a semi-solid or liquid form, which, at least in some cases, are suitable for topical use. , an organic or inorganic carrier or excipient suitable for enteral or parenteral application The active ingredient may be, for example, in a form suitable for use as a tablet, pellet, capsule, or the like. Ordinary non-toxic medicines for tablets, suppositories, solutions, emulsions, suspensions and any other forms The formulations of the present disclosure may be formulated with a carrier, e.g. , water, glucose, lactose, gum arabic, gelatin, mannitol, starch sucrose, magnesium trisilicate, cornstarch, keratin, colloidal silica, potato Starch, urea, and other substances used in the manufacture of the preparations, in solid, semi-solid or liquid form. The present invention also encompasses formulations containing the exemplified carriers, including other carriers suitable for use in the preparation of pharmaceutical compositions containing the invention, and further includes ... Auxiliaries, stabilizing, thickening and coloring agents and flavoring agents may be used.

[0066] When preparing solid compositions such as tablets or capsules, the main active ingredient is preferably a carrier ( For example, conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, Thor, talc, stearic acid, magnesium stearate, dicalcium phosphate or rubbers) and other diluents (e.g., water) to form one or more compositions of the present disclosure or A solid preformulation composition comprising a substantially homogeneous mixture of pharmaceutically acceptable non-toxic salts thereof. When a preformulation composition is referred to as being substantially homogeneous, it means that the active ingredient is are evenly dispersed throughout the composition, and the composition is distributed in an equally effective unit dosage form (e.g., tablet form). This means that the solid can be easily further divided into smaller pieces (pills, capsules, etc.). The preformulation composition is a unit of the type described above containing 0.4 mg of the composition of the present disclosure. The tablets or pills of the novel composition may be further divided into dosage forms, such as capsules. In some cases, they may be coated to provide a dosage form that offers the advantage of prolonged action. For example, a tablet or pill may contain an inner dosage component, an outer dosage component, or other compounding methods. In some cases, the dosage form may contain a second dosage component, the latter being in the form of an envelope for the former. These ingredients help resist disintegration in the stomach, keeping the inner ingredients intact. Separated by an enteric layer, which allows passage through the intestine or delayed release A variety of materials can be used for such enteric layers or coatings, including Such materials include some polymeric acids, as well as shellac, cetyl alcohol, and and mixtures of polymeric acids with materials such as cellulose acetate.

[0067] The liquid forms into which the novel compositions of the present disclosure can be incorporated for oral or injectable administration are When used, their liquid forms include, for example, aqueous solutions, suitably flavored syrups, and the like. Ingredients include: water-based or oily suspensions, and edible oils (e.g., cottonseed oil, sesame oil, coconut oil, or raisin oil). Flavored emulsions and elixirs and similar pharmaceutical vehicles containing citric acid (flower oil) Suitable dispersing or suspending agents for aqueous suspensions include synthetic natural gums, , e.g., tragacanth, acacia, alginate, dextran, carboxymethylcellulose Examples of suitable cellulose acetates include sodium cellulose, methylcellulose, polyvinylpyrrolidone, and gelatin. do.

[0068] In one embodiment, the composition is a powder that is mixed with a liquid such as a drink or broth. It is formulated as

[0069] Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions. and is provided as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain pharmaceutically acceptable excipients, such as suspending agents (e.g., sorbitol syrup, methylcellulose or edible hydrogenated fats); emulsifiers (e.g. , lecithin, or acacia); non-aqueous vehicle (e.g., almond oil, oily emulsion, or ethyl alcohol); preservatives (e.g., methyl p-hydroxybenzoate or p-hydroxybenzoic acid propyl or sorbic acid); and artificial colors or natural prepared by conventional means, together with coloring and / or artificial or natural sweeteners It can be manufactured.

[0070] For buccal administration, the compositions take the form of tablets or lozenges formulated in conventional manner. It is possible.

[0071] The active compounds may be administered parenterally by injection, including using conventional catheterization or infusion. Formulations for injection may be formulated in unit dosage form, e.g., in ampoules or in multi-dose infusions. The composition may be provided in an oily vehicle or in a container for dissolving the composition (with a preservative added). It may take such forms as suspensions, solutions or emulsions in aqueous vehicles, and may contain suspending agents, stabilizing agents, Alternatively, the active ingredient may be dissolved in water prior to use. , in powder form for reconstitution with a suitable vehicle, e.g., sterile, pyrogen-free water. It could be.

[0072] III. Methods of Preventing or Treating Medical Conditions

[0073] In certain embodiments, one or more compositions of the present disclosure are used to prevent or treat a condition. The medical condition may be of any type, and the medical condition may be treated with Eastern or Western medicine. They may or may not have been diagnosed by any type of medical professional, including a healthcare professional. In particular embodiments, the condition is one directly or indirectly associated with oxidative stress. The condition is caused by excessive uric acid levels in an individual, such as when compared to the norm or general population. The compositions and methods of the present disclosure may inhibit the condition entirely or may slow the onset of the condition. The present invention may be used to treat or reduce the severity of one or more symptoms of a medical condition. Hypertension, atherosclerosis, coronary artery disease, heart failure, left ventricular hypertrophy, atrial fibrillation, peripheral arterial disease Disease, vascular restenosis, intravascular thrombosis, stroke, diabetes, insulin resistance, metabolic syndrome, chronic kidney disease Disease, psoriatic arthritis, microalbuminuria, erectile dysfunction, pre-eclampsia, cancer, immune disorders or inflammation It may be an infectious disease.

[0074] In certain embodiments, the composition is administered to an individual in need thereof in one or more doses. When more than one dose is given, the duration between doses can be any duration. ,e.g., 1-60 minutes, 24, days, 1-4 weeks, or 1-12 months or longer. The dosages used in multiple administrations may or may not be the same. . [Example]

[0075] The following examples are presented in order to more fully illustrate the preferred embodiments of the present disclosure. They should in no way, however, be construed as limiting the broad scope of the present disclosure. Example 1 Examples of Materials and Methods

[0076] The inventors carefully selected and ordered standard extracts from 72 traditional Chinese herbal medicines. (Table 1).

[0077] All 72 herbal extracts (100g) are in powder form. Each was dissolved in DMSO with vigorous vortexing to a stock concentration of 50 mg / ml. The solution was kept at room temperature for 30 minutes and then centrifuged at 14 krpm. was used to assay XO inhibitory activity. spectrophotometric rate measurements method (60) was used to measure XO activity. The reaction mixture was diluted with 67 mM phosphate buffer (pH 7 4) xanthines in the extract solution and 20 nM XO with an activity of 5 uU / mL. The extract (0-10 ul) was incubated with XO at 25°C with or without extract solution. After pre-incubation for 1 minute, 50 μM xanthine was added to induce the formation of uric acid. The increase in uric acid absorbance at 295 nm was monitored dynamically. The initial rate of XO activity was recorded. When 0 to 10 μl of DMSO was assayed, it was found to have no inhibitory effect on XO activity. For the first screening of herbal extracts, The final concentration of the inhibitor was 163 μg / ml. Calculate the percentage of inhibition: Percentage = (1 - test OD / blank OD) x 100

[0078] Folic acid, dihydrofolic acid, and tetrahydrofolic acid are available from Alfa Aesar (Tewksb 5-Methyltetrahydrofolate (5-MTHF) was purchased from Sigma-Aldrich. a-Aldrich (St. Louis, Missouri) and 6-formyl Lupterin is available from Cayman Chemical (Ann Arbor, Michigan). The XO inhibition assay for folate-related molecules was performed in the same manner as that for herbal extracts. Folic acid was dissolved in DMSO. The dose-dependence and photodegradation effects of folic acid were investigated. The FDA-approved OX inhibitor allopurinol and the small molecule XO inhibitor DH NB was included as a positive control. Example 2 Health Food Supplements / Antioxidants for Controlling Hyperuricemia and Oxidative Stress development

[0079] 72 kinds of traditional Chinese herbal medicines (single dose experiment: 163ug / ml in two factions) The xanthine oxidase (XO) inhibition assay for the standard extract of 14 kinds of herbal extracts have strong OX inhibitory effects (water-soluble fraction or DMSO-soluble fraction). The 27 herbal extracts showed 20% to 40% in either the soluble fraction or the soluble fraction. The remaining 31 herbal extracts have a weak XO inhibitory effect (<20%). A preliminary literature search revealed that 7 of 14 extracts (>40% XO inhibition) However, this has not been reported so far, and 12 of the 27 extracts (20-40% OXI) The DMSO-soluble fraction of these extracts was significantly higher than the water-soluble fraction. The inventors have investigated the effects of these 14 extracts (DMSO-soluble fractions) on XO activity. A dose-dependent study of XO inhibition was carried out for each of the 14 extracts. A dose-dependent XO inhibition curve was observed. IC 50 is required to achieve 50% inhibition of the enzyme The IC is an operating parameter defined as the effective inhibitor concentration. 50 The lower the value, the greater the inhibition. The agent is powerful. IC of each extract 50 The top five potent XO inhibitors are Al pinia officinarum (Kora Kyo, IC 50 28.5ug / ml), Kazura (IC 50 33.5ug / ml), Taiwan Mint (Mint Leaf, IC 50 34u g / ml), clove (flower bud), IC 50 63ug / ml) and citron fruit (I C 50 71ug / ml).

[0080] 1. Data on 72 standard herbal extracts

[0081] in both the water-soluble and DSMO-soluble fractions at a final concentration of 163ug / ml Standard extracts of 72 kinds of traditional Chinese herbal medicines were mixed with 20nM XO, and the reaction system The initial rate of uric acid formation in the test sample was recorded, and the XO inhibition rate of each herbal extract was calculated. The data are shown in Table 1. Fourteen herbal extracts showed strong XO inhibitory effects (water-soluble fraction or DMSO The 27 herbal extracts showed >40% of the soluble fraction. The remaining 31 herbal extracts have a weak XO inhibitory effect (<20%). )

[0082] 72 items:

[0083] 14 extracts: >40% XO inhibition (according to our preliminary keyword search, 7 / 14 not previously reported)

[0084] 27 extracts: 20-40% XO inhibition (based on our preliminary keyword search) and 12 of the 27 species have never been described before.

[0085] 31 extracts: <20% XO inhibition

[0086] [Table 1] JPEG2025178470000002.jpg198131JPEG2025178470000003.jpg193132JPEG2025178470000004.jpg97132

[0087] NA means that the extract has not been previously reported for XO inhibition. .

[0088] The blank spaces indicate that the extract, when tested, does not have XO inhibition and that a literature search has revealed that It means that it wasn't done.

[0089] 1 DMSO fraction of the extract

[0090] 2 Water fraction of the extract

[0091] Generally, the DMSO-soluble fractions of most herbal extracts are stronger than the water-soluble fractions. These data show that, in specific embodiments, potent XO inhibitors This suggests that the compound is hydrophobic.

[0092] 2. Dose-response data of 14 standard herbal extracts

[0093] XO inhibition of standard extracts of 72 traditional Chinese herbal medicines at a single dose (163ug / ml) From the initial screening of adverse effects, 14 extracts were found to have greater than 40% inhibition of XO activity. The DMSO-soluble fractions of these extracts were more potent XO inhibitors than the water-soluble fractions. (Figure 1). Furthermore, the inventors investigated the effects of each of these 14 extracts (DMSO-soluble fractions). Dose-dependent XO inhibition assay was performed on each compound. The concentration range of each extract (8-10 doses were tested). All 14 extracts showed good A dose-dependent XO inhibition curve was shown (Fig. 2). IC 50 was used to achieve 50% inhibition of the enzyme. IC is an operating parameter defined as the concentration of inhibitor required to 50 The lower the The inhibitors are strong. IC of each extract 50 Calculate the top five most powerful X (Table 2). O inhibitors are Alpinia officinarum (Chinese ginger, IC 50 28.5u g / ml), honeysuckle (IC 50 33.5ug / ml), Taiwan Mint (Mint Leaf, I C 50 34ug / ml), clove, IC 5063ug / ml) and Cyto Long Fruit (IC 50 These data indicate the efficacy of these extracts. It is useful to understand the power of each extract and the combination of folic acid and 5-MTHF (for example) Assay or combination assay of multiple extracts with folate and 5-MTHF (for example) Provides a rational design for

[0094] [Table 2]

[0095] NA means that the extract has not been previously reported for XO inhibition. .

[0096] The blank spaces indicate that the extract, when tested, does not have XO inhibition and that a literature search has revealed that It means that it wasn't done.

[0097] Data on folic acid and its derivatives

[0098] Folic acid and its two derivatives, dihydrofolic acid and tetrahydrofolic acid, inhibit XO. 20 nM XO was used in the assay to compare folic acid, dihydrofolic acid, and tetrahydrofolic acid. The initial rate of uric acid formation was measured using the negative control. The effect of folic acid on the XO activity was concentration-dependently reduced compared to that of folic acid, which reflected the reduction in XO activity (Fig. 3). Dihydrofolic acid and tetrahydrofolic acid significantly inhibited XO activity within the dose range of 2 μM. The potency of XO inhibition is shown as dihydrofolate > tetrahydrofolate > folic acid. When compared with allopurinol and DHNB, folic acid had a stronger X-ray activity than allopurinol and DHNB. The half-maximal inhibitory concentrations of folic acid, allopurinol, and DNHB were 0.01 and 0.02, respectively (Figure 4). (I C 50 ) are 0.75uM, 1.8uM and 3.0uM, respectively.

[0099] Significance of Certain Embodiments (Folic Acid is an XO Inhibitor)

[0100] Folate and folic acid are water-soluble forms of vitamin B. They help to make DNA, RNA, and They metabolize amino acids necessary for cell division and many physiological functions. Humans cannot produce folic acid, so they need folic acid. Folate is an essential vitamin that must be obtained from the diet. Leafy greens, beans, eggs, citrus fruits, avocado, and beef liver. Folate is the most common form of vitamin B9, present in many natural foods, including: Synthetic versions of vitamin B9 added to processed foods and used in supplements Folic acid is the oxidized form of folate, which is the most commonly used version of vitamin B9. It has a molecular structure almost identical to that of folate (salt form). Since 1998, folic acid has been used in foods containing folic acid as required by federal law in the United States. cereals, flour, bread, pasta, bakery items, cookies and crackers. Over 50 countries do this. The target is a common birth defect that has shown some association with maternal vitamin B9 intake. It is an attempt to reduce the prevalence of certain neural tube defects (NTDs). Folate deficiency can lead to growth retardation, megaloblastic anemia, weight loss, digestive problems, leukopenia, Thrombocytopenia, cracked / red tongue / mouth, diarrhea, liver disease, cancer, cardiovascular disease, depression, and others This can lead to many health problems, including behavioral changes (93-96). Supplements have been shown to improve and improve human health, including the prevention and treatment of many diseases. This has a huge impact on maintenance.

[0101] Before the body can use folic acid, it is first converted into dihydrofolate (DHF) and then into tetrahydrofolate (TF). THF must undergo two transformations to become trihydrofolic acid (THF). 10-Methylenetetrahydrofolic acid (5,10-MTHFR) and 10-formyltetrahydrofolic acid Hydrofolate (10-FTHF), as well as folate, which the body needs for many important functions. The final form of folate is 5-methyltetrahydrofolate (5-MTHF, levomefolic acid). One of the most important folate-dependent reactions is the conversion of folate to ATP in the formation of DNA (Figure 5). The methylation of deoxyuridylate to thymidylate, which is required for proper cell division, Impairment of this response can lead to megaloblastic anemia, one of the hallmarks of folate deficiency. Another folate-dependent reaction is the synthesis of S-adenosyl-methionine. The conversion of homocysteine ​​to methionine in the synthesis of cy) is toxic and a well-known risk factor for cardiovascular disease and many other diseases (97) The chemical reactions required for the breakdown of Hcy occur in the presence of folic acid, vitamins B6, and B12. Folic acid is essential for the regulation of DNA, phospholipid and protein function. These are also important for methylation, as well as serotonin, epinephrine, and dopamine. It is also important for the synthesis of several important neurotransmitters (Figure 6). Both direct and indirect antioxidant effects (e.g., free radical scavenging) There is evidence that this approach is effective (98).

[0102] Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme that regulates this conversion process. However, up to 60% of Americans do not convert 5-methyl-5-methyl-2-hydroxybenzoate (5-MTH) from folic acid by itself. It is believed that this gene has a genetic variation that reduces its ability to transform F. In individuals with genetic variations, folic acid supplementation may result in varying amounts of 5-MTHF converted forms. This can result in the body retaining less than it needs. Furthermore, this allows the body to store that form of folic acid. For people who may not get enough, 5-MTHF supplementation may be superior to folic acid use. This is why THF is only active in its (unstable) reduced form. In general, supplementation with recommended amounts of folic acid and 5-MTHF is not suitable for oral supplementation. Folate is a water-soluble vitamin that is passed regularly through the urine. The risk of toxicity from folic acid is low because it is eliminated from the body as a result of steroid use (99). Folate below the established acceptable upper intake level (UL) of 1000 μg / day Intake has not been associated with any health outcomes (100). However, excessive Folate intake may be associated with significant health risks, including cancer (101-103). This risk is under debate and has not yet been confirmed. In fact, folate deficiency: By causing genomic instability and altered methylation patterns in the genome. This enhances carcinogenesis and alters the expression of oncogenes and tumor suppressor genes (100).

[0103] The effect of folic acid on XO inhibition was first reported in 1948 (104), and subsequently In 1950, the same research team discovered that this inhibition was due to the photodegradation product of folic acid, pterin-6. -aldehyde (2-NH,-4-OH-pteridine-6-aldehyde) (105) This debate continued into the 1980s (106, 107). 198 By 1999, further experiments using various methods had shown that uric acid and its derivatives were indeed potent XO inhibitory effects of THF and DHF The effect of 5-MTHF on the in vivo It has been shown to be able to effectively inhibit XO activity in vitro and in vivo ( 110 ). Folic acid is known to be sensitive to ultraviolet (UV) radiation (111-116 ), folic acid, when exposed to ultraviolet radiation, converts to p-aminobenzoyl-L-glutamic acid and When the irradiation is continued, the 6-formylpterin is cleaved into pterin. 6-Formylpterin is degraded to terin-6-carboxylic acid (117). pterin-6-carboxylic acid is a highly potent XO inhibitor in (117)

[0104] Like humans, birds such as chickens and quails lack the uricase enzyme, Blood uric acid levels are normally measured by those who have the uricase enzyme, which metabolizes uric acid to 5-hydroxyisouric acid. The incidence of gout in chickens is higher than that in mice or rats (118). This is a common condition in birds with uric acid levels of 5-7 mg / dL compared to normal birds. Dietary folic acid supplementation can increase liver XO in chicks. Recent studies have shown that dietary folic acid supplementation significantly inhibits the activity of folic acid. It has been shown that folic acid significantly reduces serum uric acid in older laying hens (121). Intraperitoneal administration of allopurinol (12.5–50 mg / kg) was shown to be effective in mouse models. Daily oral folic acid supplementation significantly inhibited radiation-induced XO activation (122). This significantly increased serum uric acid levels and associated renal pathology in a rat model. Furthermore, folic acid supplementation significantly reduced cardiovascular disease (123) in animal models. 24-126) and kidney disease (127), inhibit tumor formation (128), and It can enhance the effectiveness of tumor chemotherapy ( 129 ).

[0105] A study of folic acid supplements for patients with hyperuricemia and / or gout was reported. Case-control studies have shown that high folate intake can prevent gout. (130) In adult hypertensive patients, a daily dose of 10 mg of enalapril was administered 0. When administered in combination with 8 mg of folic acid, patients with high UA concentrations or baseline hyperuricemia This treatment has a higher effect on serum UA levels than 10 mg enalapril alone in patients with (54, 55) Furthermore, folic acid supplementation has been shown to improve circulating blood cholesterol levels in clinical trials. It can reduce the risk of cardiovascular disease and chronic kidney disease (56-59,131 ).

[0106] The effectiveness of folic acid or 5-MTHF in controlling hyperuricemia can be confirmed, and specific implementation is needed. In this form, it is used as an example of a dietary supplement for the long-term management of hyperuricemia. It can be included in one or more combination formulations with traditional Chinese medicines or other botanical ingredients. In certain embodiments, folic acid is one of the components of any of the compositions encompassed herein. In a specific embodiment, folic acid enhances the therapeutic effect of the combination therapy.

[0107] 4. Data on the combination of a single herbal extract with folic acid

[0108] Based on the results of dose-dependent XO inhibition experiments with herbal extracts and folic acid, relatively low concentrations Each extract (a total of 14 extracts) and folic acid were used in the combined assay. Therefore, Taiwanese peppermint leaf extract (6.67ug / ml) and folic acid (0.167uM) and inhibited XO activity by 25.85% and 16.49%, respectively. The combination of mint leaf extract and folic acid showed 34.4% XO inhibition (Figure 7). The combination of Taiwanese peppermint leaf extract and folic acid showed an additive effect on XO inhibition. One of the key benefits of such combination supplements is that each component By lowering the dose of The advantage is that it can reduce the XO-inhibiting effect of the supplement while enhancing its XO-inhibiting function.

[0109] Plus, folic acid and all 14 traditional Chinese herbal extracts, including Mentha orba extract. A combination essay was conducted for each of the following: folic acid (0.167uM) and extract (13. The XO activity was measured. Extracts from nine of the species showed an XO inhibitory effect that was additive with folic acid (Figure 8). Extracts include Taiwan Mentha Extract (Mint Leaf); Clove (Flower Bud) Extract (Ding Vietnamese Sophora (Root) Extract (San Dou Geng Mountain Bean Extract) root); Mu Gua (fruit) extract; Honeysuckle (flower bud) extract g Ying Hua); Houttuynia cordata (aerial parts) extract (Yu Xin Cao); Citronellol Xiang Yuan (fruit) extract; Gao Liang extract ng Jiang Gaoliang); and Bokong Aesthetic Flower Extract (Ye Ju Hua (Chrysanthemum).

[0110] 5. Combination of herbal extract and 5-methyltetrahydrofolic acid (5-MTHF) Data

[0111] 5-Methyltetrahydrofolate (5-MTHF) is considered a superior form of folic acid supplementation. Studies have shown that 5-MTHF inhibits XO activity in vitro and in vivo. (90) We have demonstrated that 5-MTHF can effectively inhibit the in vivo We confirmed that 5-HT100 effectively inhibited XO activity in a concentration-dependent manner in vitro (Figure 9). -MTHF IC 50 However, the XO inhibitory activity of 5-MTHF is approximately 35.6 μM. The harmful effect is due to folic acid (IC 50 The present inventors also found that 5-MTH The combination of F with various traditional Chinese herbal extracts was investigated to determine their effects on XO activity. The effects of 5-MTHF on the hydroxylase activity of 14 herbal extracts were examined in vitro (Figure 10). 10 of these: Mu Gua (Fruit) Extract; Euryale (Seed) Extract ( Gian Shi); Dianthus campestris (aerial parts) extract (Qu Mai, Qu Mai), watermelon Extract of Houttuynia cordata (flower buds) (Jing Ying Hua), Houttuynia cordata (aerial parts) (Yu Xi n Cao); Citron (fruit) extract (Xiang Yuan); Lotus (seed) extract (Lian Zhi);Cornflower Extract (Gao Liang Jiang, Gao Good ginger); Bok choy (flower) extract (Ye Ju Hua (wild chrysanthemum flower); and Taiwan hyacinth Bo He Yie (peppermint leaf) had an additive effect on XO inhibition (Fig. 10). Clove (flower bud) extract (Ding xiang); Vietnamese sophora (root) extract Mountain bean root (San Dou Geng); Rice bean extract (Ci Xiao Dou Red adzuki bean); and wheat (immature fruit) extract (Fu Xiao Mei) It had no additive effect on O inhibition.

[0112] In some embodiments, folic acid or 5-methyltetrahydrofolic acid and the individual extracts Premixing with folic acid is used for XO inhibition. Studies of the combination of a single extract with folic acid have not been completed. After completion, the combination of multiple herbal extracts and folic acid can be further characterized. Combination of multiple herbal extracts without acid and / or 5-methyltetrahydrofolic acid can also be characterized for XO inhibition.

[0113] The XO activity assay can be expanded to more Chinese herbal extracts and other plant components. These effects were assessed with and without folic acid and / or 5-methyltetrahydrofolate. Additive or synergistic effects between substances can be investigated. for the purpose of del study and ultimately for the treatment of both symptomatic and asymptomatic hyperuricemia (cardiovascular Treatment and management of patients with cerebrospinal fluid (a major independent risk factor for cerebrospinal fluid disorders and many other diseases) Several herbal extracts with or without folic acid or 5-MTHF for the prevention of cancer Lead combination formulations can be screened and characterized. Example 3 Specific Uses of Dietary Supplements / Antioxidants to Control Hyperuricemia and Oxidative Stress embodiment

[0114] Embodiments of the present disclosure may be used to, for example, lower blood uric acid and reduce oxidative stress. and / or a composition capable of reducing the risk of gout and cardiovascular disease ( For example, health food supplements or functional foods). , especially for long-term use to prevent and treat gout and hyperuricemia-induced cardiovascular disease A new and safe health food supplement for controlling hyperuricemia and oxidative stress in humans For the purpose of developing functional foods or functional foods, certain Chinese herbal extracts and / or ordinary Foods and vitamins, minerals and nutrients are selected, characterized, optimized and For example, cell-free systems and XO enzyme activity assays have been performed. and mouse models can be used for this embodiment.

[0115] In vitro screening of effective ingredients for dietary supplement products has been used to identify xanthines More effective formulations / prescriptions for inhibiting oxidase (XO) activity and oxidative stress are needed. Can be developed (various substrates and combinations, additive and synergistic effects). Animal studies have been used to evaluate the efficacy and safety of dietary supplement formulations / prescriptions for controlling hyperuricemia. Chronic (relatively long-term) animal studies can also be used to characterize the effects and toxicity of Also characterize the efficacy and toxicity of dietary supplement formulations / prescriptions for controlling hyperuricemia. It is possible.

[0116] In specific embodiments, some traditional Chinese herbal medicines have potent XO inhibitory activity, such as The activity of individual herbs may be influenced by other herbal medicines and / or by the presence of e.g. Folic acid and / or one or more of its derivatives (folic acid and its derivatives are XO inhibitors ( 52, 53)) may have an additive or synergistic effect with conventional Chinese herbal extracts and (optionally) folic acid and / or one or more of its derivatives The functional food / health supplement formulation of the present disclosure, which contains provides methods and / or treatments and is used as a prophylactic and / or treatment. In some cases, the compositions of the present disclosure may be used to treat asymptomatic hyperuricemia, which is an independent risk factor for CVD. provides long-term management of the disease and therefore has implications for the prevention of CVD.

[0117] Specific embodiments of the present disclosure relate to the efficacy of folic acid or 5-MTHF for controlling hyperuricemia. It provides confirmation of efficacy and has been used as a dietary supplement for the long-term management of hyperuricemia, for example. It may be included with Chinese herbal medicines and / or other botanical ingredients. Folic acid is one of the components This may enhance the therapeutic effect of the combination therapy.

[0118] Examples of herbal extracts that may be included in the composition include one or more of the following:

[0119] [Table 3] JPEG2025178470000007.jpg217165

[0120] Additionally, one or more of the following compositions may be used in any of the compositions of the present disclosure: These vitamins may be useful in treating, for example, hyperuricemia, oxidative stress, and / or hypervitaminosis. Controlling cysteinemia (which is a risk factor for cardiovascular disease and many other diseases) These compounds may have additive or synergistic effects with the compositions of the present disclosure, such as for controlling the Any of the compositions of the present disclosure may be used as a prophylactic composition, including compositions using: obtain.

[0121] [Table 4]

[0122] The following items in Table 5 may be used in any of the compositions of the present disclosure.

[0123] [Table 5] JPEG2025178470000010.jpg76131

[0124] An example of an experimental design is as follows: First, individual extracts are tested for their XO inhibitory and anti-XO effects. Any suitable method can be used to screen for oxidative effects, These include at least the following:

[0125] Method (1):

[0126] Xanthine oxidase (XO) inhibition assay (one or more groups for screening) (These methods are described in detail in a previous publication (132).

[0127] Method (2):

[0128] DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging assay ( (Use one substrate concentration for screening.) If the compound being tested is DPPH radical, The ability of the compound to scavenge fluorine was assessed by monitoring the decrease in absorbance at 429 nm. The antioxidant activity of these compounds was measured optically using the method described above. The detailed method is described in our previous publication (132). There are.

[0129] Based on the effective health supplement ingredients selected, valid prescriptions / prescriptions will be searched and and can be developed (various substrates and combinations, additive and synergistic effects can be achieved). Initial screening results from raw materials identified a group of extracts that inhibit XO activity. If so, use an effective standard extract for further characterization studies. It is possible to extend the concentration range of these selected materials and mix them with other materials. In the case of The effects of various combinations with other herbal extracts were tested in in vitro assays. Any additive or synergistic effects of these combinations may be characterized. In at least some cases, additive or synergistic effects of the components may exist. Reduce the potential side effects of each component while maintaining drug tolerance for long-term management of hyperuricemia. To achieve maximum therapeutic benefit while reducing the potential risks of such components, can be used in combination formulations (e.g., in which a small amount of each (using components).

[0130] Characterize the efficacy and toxicity of dietary supplement formulations / prescriptions for controlling hyperuricemia Use of acute (short-term) animal experiments to

[0131] Research materials:

[0132] In light of the results of in vitro experiments, the combination with or without folic acid / 5-MTHF The effective formulation / prescription of the herbal extract is characterized in animal tests. Each formulation contains 3-5 individual extracts or natural compounds / vitamin supplements. Before testing the individual components as a combined formulation in animal studies, Each component may or may not be tested in animal studies. , the formulation / prescription alone is characterized in animal studies as a whole.

[0133] Example study designs:

[0134] A. Formulation and Characterization of Selected Combination Formulations for Animal Studies

[0135] Based on the initial study, the DMSO-soluble fraction of the herbal extract was found to be more soluble than the water-soluble fraction. DMSO also had a strong XO inhibitory effect. DMSO is effective in bringing a wide range of compounds into solution. Each selected herbal extract is further extracted into DMSO and freeze-dried (lyophilized). The XO inhibitory effect and antioxidant capacity of each DMSO extract were evaluated by increasing the in vitro XO activity. This is confirmed by the scavenging assay and DPPH scavenging assay. (oral gavage), one or more oils (e.g., one or more cooking oils (e.g., oleic acid, Acid, isopropyl myristate, medium chain triglycerides, olive oil, castor oil, peanut oil , corn oil, sesame oil, soybean oil, almond oil, linseed oil, rapeseed oil, sunflower oil, Coconut oil, peanut oil and / or palm oil)) to mix these extracts can be selected.

[0136] B. Acute Model of Hyperuricemia and Toxicity in Mice

[0137] The uric acid-lowering effect of the formulation can be measured in allantoxanamide-treated mice. Intraperitoneal (ip) injection of allantoxanamide, a uricase inhibitor, Therefore, the conversion of uric acid to 5-hydroxyisouric acid is effectively blocked, and The present invention provides an animal model of hyperuricemia by significantly increasing serum uric acid levels in rats. The urate-lowering effects of selected formulations were determined in well-characterized mouse models. The selected formulations were administered to the mice by oral gavage. Detailed methods are described in a previous publication (132).

[0138] [Table 6]

[0139] Toxicity in mice. Potential toxicity of selected formulations was assessed at low and high doses (oral administration). ) can be investigated in mice. and allopurinol control. Formulated dietary supplements may be administered orally. Mice can be administered once daily by gavage for 15 days. Primary endpoints include: General health status and weight, blood counts, blood chemistry and enzymes (liver function, cardiac function and renal function) functional panel), as well as histological examination of organs (Table 7).

[0140] [Table 7]

[0141] Testing the efficacy and toxicity of dietary supplement formulas / prescriptions for controlling hyperuricemia Use of chronic (relatively long-term) animal experiments for

[0142] Study design:

[0143] A chronic model of hyperuricemia in uricase knockout mice: a novel approach to the treatment of hyperuricemia in mice and other animals In most mammals, uric acid is further oxidized to allantoin by uricase. The normal blood concentration of uric acid is relatively low (1-2 mg / dL) (Chen, Lu, et In humans and higher primates, the decline in uricase has occurred over approximately 15 million years. This results in relatively higher serum uric acid (SUA) levels than in these lower animals. To establish an animal model of chronic hyperuricemia, scientists have developed a model of severe hyperuricemia and We generated uricase (Uox) gene knockout mice that exhibit urate nephropathy (133 Under allopurinol maintenance, adult uricase − / − mice exhibited relatively low S However, once allopurinol was discontinued, However, uricase − / − mice showed high SUA levels (6–10 mg / dL) after 1 week. By using uricase knockout mice, the selected product The long-term hypouricemia effect of the selected formulation can be measured by oral gavage. Administer once daily for two weeks or via drinking water for two months. Uric acid levels will be tested every two days or once a week. During the study, general health, including weight, will be monitored. Health status will be monitored. Once the mice are sacrificed, blood counts, blood chemistries and enzymes (liver function, cardiac function) will be monitored. Examine the blood and kidney function panels and perform histological examination of organs (Table 6). It is estimated that 1 g of each ingredient will be required for this experiment. The extracts were further extracted into DMSO and freeze-dried. The fruit and antioxidant capacities were evaluated using in vitro XO activity assay and DPPH scavenging assay, respectively. For administration to animals (oral gavage), one or more Oil (e.g., one or more cooking oils (e.g., oleic acid, isopropyl myristate, High chain triglycerides, olive oil, castor oil, peanut oil, corn oil, sesame oil, soybean oil oil, almond oil, linseed oil, rapeseed oil, sunflower oil, palm oil, peanut oil and / or Palm oil may be selected for mixing these extracts.

[0144] [Table 8]

[0145] All publications mentioned in this specification are intended to instill in those skilled in the art to which this disclosure pertains the level of All publications are specifically and individually indicated to be incorporated by reference. and the like, all of which are incorporated herein by reference to the same extent as if fully set forth herein.

[0146] 1~3, 1~3, 100,000

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[0278] 132. Lu JM, Yao Q, Chen C. 3,4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a pote nt inhibitor of xanthine oxidase: a potential therapeutic agent for treatment of hyperuricemia and gout. Biochem Pharmacol. 2013 Nov 1;86(9):1328-37.

[0279] 133. Wu X, Wakamiya M, Vaishnav S, Geske R, Montgomery C Jr, Jones P, Bradley A, Caskey CT. Hyperuricemia and urate nephropathy in urate oxidase-deficient mice . Proc Natl Acad Sci US A. 1994 Jan 18;91(2):742-6. Example 4 Health Food Supplements / Antioxidants for Controlling Hyperuricemia and Oxidative Stress development

[0280] As described herein, the inventors have developed Bulk Supplements. com(111) and Trustworthy Herbs Inc(1). The xanthine oxidase (XO) inhibitory effects of 112 standard herbal extracts were investigated. A final concentration of 166.7 μg / ml ( DSMO solubility in most extracts (except for some extracts at lower concentrations due to solubility issues) All extracts in the fractions were used in this assay. The 19 herbal extracts showed a high XO inhibitory effect (>40%) of 20% to 40%. The remaining 78 herbal extracts had weak XO inhibitory effects (<20%). Five of the 15 extracts (>40% XO inhibition) have not been reported before, and 19 Seven of the extracts (20-40% OXI) have not been reported before. Dose-dependent XO inhibition assays were performed on each of these 15 extracts and 6 extracts. They found that a single dose (166.7ug / ml) reduced the risk of 20-40% The XO inhibitory effect was observed in the range of 0-250 or 333 μg / ml of each extract. (8-10 doses were tested). All 21 extracts showed good dose-dependent XO inhibition curves. IC 50 is defined as the concentration of inhibitor required to achieve 50% inhibition of the enzyme. It is an operating parameter defined by IC 50 The lower the value, the more potent the inhibitor. IC 50 The top 10 potent XO inhibitors are Milk Thistle (IC 50 3.3ug / ml), Chillies extract (IC 50 3.8ug / ml), Amla fruit ( Yu Amoko, IC 50 5.6ug / ml), grape seeds (IC 50 8ug / ml), Zak (40% ellagic acid, pomegranate, IC 50 10ug / ml), green tea (50% EGCG, IC 50 11.5ug / ml), pine bark (IC 5012ug / ml), St. John's wort Resou (IC 50 14ug / ml), African mango seeds (non-Israeli mango, IC 50 35ug / ml) and raft (IC 50 82ug / ml). Eight herbal extracts with relatively low concentrations and folic acid were selected for the combined assay. Acid (0.167uM) and extracts at specified concentrations (ug / ml) were tested. Three of the ingredients (grape seed, milk thistle, and milk thistle extract) act synergistically with folic acid. Three of the eight extracts (amla fruit, green tea, and pine bark) showed O inhibitory effects. It showed an additive XO inhibitory effect with folic acid.

[0281] For animal testing, the inventors used five herbal extracts (Silybum sieboldii extract, Grape seed extract, Kiss extract, Amla extract, Pine bark extract, Taiwan mint extract) and folic acid A dietary supplement containing allopurinol in a reasonable dose was designed. Each mouse was given an IP injection of allatoxanamide, which was then used as a control. These mice were given allopurinol or the extract formula by oral gavage, respectively. Blood was collected from the facial vein 1.5 and 3 hours after treatment. Serum uric acid levels Treatment with uricase inhibitor, allatoxanamide (IP injection) showed 1. It significantly increased serum uric acid levels at 5 and 3 hours. Ipopurinol significantly reduced the oxidative stress in allantoxanamide-treated mice at both 1.5 and 3 hours. The clinically relevant dose of the dietary supplement significantly reduced serum uric acid levels in Although less potent than lopurinol, it was effective in allantoxanamide-treated mice for 1.5 hours. The serum uric acid level was significantly reduced both at 1 and 3 hours after administration. This effect was dose-dependent. It showed an existential style.

[0282] 1.Data on 112 standard herbal extracts

[0283] Standardized herbal extract (111) from Bulk Supplements.com One herbal extract was obtained from Trustworthy Herbs Inc. Bulk Supplements Inc. is located in Henderson, Nevada. According to the company's website, 1) the company is an FDA-registered cGM P manufacturing and distribution facility; 2) the company diligently adheres to all health standards and government regulations 3) Each supplement is tested in our in-house laboratory before distribution, and all products are guaranteed to be safe for consumption. g) was in powder form and was packaged sealed in an alumina bag. The pack provides a daily dose of each extract.

[0284] All extracts were obtained at a final concentration of 166.7 μg / ml (due to solubility issues). DSMO was present in the soluble fraction in most extracts (except for some extracts with lower concentrations), and these were The initial rate of uric acid formation in the reaction system was recorded, and the XO content of each herbal extract was The O inhibition rate was calculated. All data are shown in Table 9 and Figure 11 (on the x-axis in Figure 11). (The numbering corresponds to the order of the compounds listed in Table 9.) 15 herbal extracts The extracts of 19 herbal medicines showed a strong XO inhibitory effect (>40%). The remaining 78 herbal extracts have a weak XO inhibitory effect (<20%). Had.

[0285] The inventors searched both Medline and Google scholar search engines. A preliminary literature search (herbal medicine name, xanthine oxidase, English and Chinese) was conducted on As a result, the following was discovered:

[0286] Of the 15 extracts (>40% XO inhibition), five have not been reported before: Ikada extract (64% XOI), Oolong tea (60% XOI), Senna leaf (45% XOI) ), Yohimbe bark (62% XOI) and Milk Thistle extract (at 33.3ug / ml The XO inhibitory effects of the other 10 extracts have been previously reported: Mango seeds (non-Shukan mango, 78% XOI) (1, 2), Amla fruit (Yasushi, 10 0%XOI) (5), Grape Seed (78%XOI) (7, 8, 9), Green Tea (50%EGC) G, 77% XOI (10, 11, 12), milk thistle (8 at 33.3 ug / ml) 7% XOI) (19), olive leaf (65%) (21, 22), pine bark (87% XOI) )(25), pomegranate (40% ellagic acid, pomegranate, 90% XOI)(26,27,28), Pearmint (63.6%) (15, 32) and St. John's wort (87% X OI)(33).

[0287] Seven of the 19 extracts (20-40% OXI) have not been reported before: Butterbur (20% XOI), Caralluma bark (30% XOI), Echinacea root (pine chrysanthemum, 2 1%XOI), Horse Chestnut Fruit (23.5%XOI), Cola Nut (20%XOI) I), Magnolia bark (22% XOI) and Muirapuama bark (31.6% XOI).

[0288] 112 items (111 and 112 items obtained from Bulk Supplements.com) and Trustworthy Herbs Inc.): Single dose (166.7ug / ml, DMSO fraction):

[0289] 15 extracts: >40% XO inhibition (according to our preliminary keyword search, Five of the 15 species have never been described before.

[0290] 19 extracts: 20-40% XO inhibition (based on our preliminary keyword search) and 7 of the 19 species have never been described before.

[0291] 78 extracts: <20% XO inhibition [Table 9] JPEG2025178470000025.jpg196133JPEG2025178470000026.jpg161131

[0292] NA means that the extract has not been previously reported for XO inhibition. .

[0293] The blank spaces indicate that the extract, when tested, does not have XO inhibition and that a literature search has revealed that It means that it wasn't done. 2. Dose-response data of 21 standard herbal extracts

[0294] The maximum XO inhibitory effect of 112 herbal extracts using a single dose (166.7 μg / ml) From the initial screening, 15 extracts were found to have an XO activity inhibition of over 40%. Furthermore, a dose-dependent XO inhibition assay was performed on each of these 15 extracts. Furthermore, the inventors also conducted dose-dependent studies on six extracts, which showed A single dose (166.7 μg / ml) showed 20-40% XO inhibitory effect. A range of concentrations (8-10 doses) of each extract was tested, ranging from 250 to 333 μg / ml. All 21 extracts showed good dose-dependent XO inhibition curves. IC 50 is an enzyme is an operating parameter defined as the concentration of inhibitor required to achieve 50% inhibition of IC 50 The lower the IC of each extract, the more potent the inhibitor. 50 Calculate (Table 10, Figure 12). The top 10 potent XO inhibitors were Milk Thistle (IC 50 3.3u g / ml), Milk thistle extract (IC50 3.8ug / ml), Amla fruit (sweetener, I C 50 5.6ug / ml), grape seeds (IC 50 8ug / ml), pomegranate (40 % Ellagic acid, pomegranate, IC 50 10ug / ml), green tea (50% EGCG, IC 50 1 1.5ug / ml), pine bark (IC 50 12ug / ml), St. John's wort ( I C 50 14ug / ml), African mango seeds (non-Israeli mango, IC 50 35ug / ml) and rafts (IC 50 82ug / ml). These data are This will be useful in understanding the efficacy of these extracts and the combination of each extract with folic acid and 5-MTHF. For combined assays or combined assays of multiple extracts with folic acid and 5-MTHF Provides a rational design. [Table 10]

[0295] NA means that the extract has not been previously reported for XO inhibition. .

[0296] 3. Data on the combination of a single herbal extract with folic acid

[0297] Based on the results of the dose-dependent XO inhibition experiments of herbal extracts and folic acid, a relatively low concentration of 8 Each herbal extract of the species and folic acid were selected for the combination assay. One of the key benefits of combined supplements is that they can be used for a longer period by reducing the dose of each component. Reduce the potential side effects of the supplement during early use while The O inhibitory function can be enhanced by folic acid (0.167uM) and the specified concentration (ug / m The extracts (1) were added separately to the XO reaction system without premixing. XO activity was measured (Figure 13). Of the eight extracts, three (grape seed, milk thistle, and field thistle extract) contain folic acid. Three of the eight extracts (amla fruit, green tea, and maca) showed synergistic XO inhibitory effects. The bark of the tree showed an additive XO inhibitory effect with folic acid; two of the eight extracts (African mango and pomegranate) did not show any additive or synergistic XO inhibitory effect with folic acid. It was.

[0298] 4. Uric acid-lowering effect of one dietary supplement formula in allantoxanamide-treated mice Data

[0299] Design of dietary supplement formula (combination). Combination of several herbal extracts and folic acid. One of the key advantages of the combination is that it allows for lower doses of each component, making it more suitable for long-term use. The supplement's XO inhibitory function can be enhanced while reducing the potential side effects of the supplement. The selected herbal extracts showed strong XO inhibitory effects in vitro. It should have an additive or synergistic effect with folic acid. Untreated herbal extracts are used in specific embodiments. Therefore, the inventors have designed an exemplary formulation containing five herbal extracts and folic acid. (Table 11). [Table 11]

[0300] Design, method and results of the mouse experiment. The extract combination sample was 4.2 mg of milk thistle extract, 3.3mg of grape seed extract, 13.3mg of amla extract, 4 Weigh out 0.2mg of pine bark extract and 16.7mg of Taiwanese peppermint extract and mixed them with 10 ml of 1% PEG400 to give a total of 41.7 mg / 10 ml The folic acid solution was prepared by dissolving 2.6 mg of folic acid in 1 ml of 0.1 M potassium phosphate buffer. FA solution was prepared separately by dissolving in buffer solution, and then 6 ul of this FA solution was added to the 10 As a positive control, a clinical XO inhibitor, Allopurinol was used at 13.3 mg / kg for mouse experiments. The human dose is approximately 800 mg per day.

[0301] C57BL / 6 adult mice (approximately 20 g body weight) were used. Four groups of mice were divided into Each group (n=4) was assigned to a different treatment or control (Table 12). Intraperitoneal (ip) injection of the antidote allantoxanamide converts uric acid to 5-hydroxybenzoates. It effectively blocks the conversion of uric acid to isouriceous acid, significantly increasing serum uric acid levels in mice. This provides an animal model of hyperuricemia (34). Toxanamide was injected ip at a dose of 200 mg / kg, and the mice were then 00µl to 250µl (for a 20-25g mouse) of allopurinol or extract The solutions were given by oral gavage, respectively. Blood was measured 1.5 and 3 hours after treatment. The serum uric acid level was measured by the phosphotungstic acid method. Treatment with the enzyme inhibitor allantoxanamide (IP injection) resulted in a 1.5-h and significantly increased serum uric acid levels 3 hours after administration. These data are consistent with previous publications. As a positive control, a clinically relevant dose was used. Allopurinol was significantly lower than allantoxanamide treatment at both 1.5 and 3 hours. Significantly reduced serum uric acid levels in mice. Clinically relevant doses of dietary supplements The formulation was less potent than allopurinol but not in allantoxanamide-treated mice. This significantly reduced serum uric acid levels at both 1.5 and 3 hours after administration. showed a dose-dependent manner (Figure 14). [Table 12]

[0302] References for Example 4

[0303] TIFF2025178470000030.tif19170

[0304] TIFF2025178470000031.tif19170

[0305] TIFF2025178470000032.tif17170

[0306] 4. Taukoorah U, Mahomoodally MF. Crude Aloe vera Gel Shows Antioxidant Propensit ies and Inhibits Pancreatic Lipase and Glucose Movement In Vitro. Adv Pharmacol Sci. 2016;2016:3720850. doi: 10.1155 / 2016 / 3720850. Epub 2016 Jan 3.

[0307] 5. Sarvaiya VN, Sadariya KA, Pancha PG, Thaker AM, Patel AC, Prajapati AS. Evalu ation of antigout activity of Phyllanthus emblica fruit extracts on potassium ox onate- induced gout rat model. Vet World. 2015 Oct;8(10):1230- 6. doi: 10.14 202 / vetworld.2015.1230- 1236. Epub 2015 Oct 23.

[0308] 6. Bernardo J, Ferreres F, Gil- Izquierdo A, Videira RA, Valentao P, Veiga F, Andrade PB. In vitro multimodal- effect of Trichilia catigua A. Juss. (Meliace ae) bark aqueous extract in CNS targets. J Ethnopharmacol. 2018 Jan 30;211:247- 255. doi: 10.1016 / j.jep.2017.09.039. Epub 2017 Sep 29.

[0309] 7. Belviranli M, Gokbel H, Okudan N, Buyukbas S. Effects of grape seed extract o n oxidative stress and antioxidant defense markers in streptozotocin- induced diabetic rats. Turk J Med Sci. 2015;45(3):489- 95.

[0310] 8. Wang Y, Zhu JX, Kong LD, Yang C, Cheng CH, Zhang X. Administration of procyan idins from grape seeds reduces serum uric acid levels and decreases hepatic xant hine dehydrogenase / oxidase activities in oxonate- treated mice. Basic Clin Pha rmacol Toxicol. 2004 May;94(5):232- 7.

[0311] TIFF2025178470000033.tif26170

[0312] 10. Zhu C, Xu Y, Liu ZH, Wan XC, Li DX, Tai LL. The anti- hyperuricemic effect of epigallocatechin- 3- gallate (EGCG) on hyperuricemic mice. Biomed Pharma cother. 2018 Jan;97:168- 173. doi: 10.1016 / j.biopha.2017.10.013. Epub 2017 Nov 6.

[0313] 11. Zhu C, Tai LL, Wan XC, Li DX, Zhao YQ, Xu Y. Comparative effects of green an d black tea extracts on lowering serum uric acid in hyperuricemic mice. Pharm Bi ol. 2017 Dec;55(1):2123- 2128. doi: 10.1080 / 13880209.2017.1377736.

[0314] 12. Chen G, Tan ML, Li KK, Leung PC, Ko CH. Green tea polyphenols decreases uric acid level through xanthine oxidase and renal urate transporters in hyperuricem ic mice. J Ethnopharmacol. 2015 Dec 4;175:14- 20. doi: 10.1016 / j.jep.2015.08.0 43. Epub 2015 Sep 3.

[0315] 13. Pang M, Fang Y, Chen S, Zhu X, Shan C, Su J, Yu J, Li B, Yang Y, Chen B, Lia ng K, Hu H, Lv G. Gypenosides Inhibits Xanthine Oxidoreductase and Ameliorates U rate Excretion in Hyperuricemic Rats Induced by High Cholesterol and High Fat Fo od (Lipid Emulsion). Med Sci Monit. 2017 Mar 4;23:1129- 1140.

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[0317] TIFF2025178470000035.tif20170

[0318] TIFF2025178470000036.tif17170

[0319] TIFF2025178470000037.tif17170

[0320] 18. Hatano T, Yasuhara T, Fukuda T, Noro T, Okuda T. Phenolic constituents of li corice. II. Structures of licopyranocoumarin, licoarylcoumarin and glisoflavone, and inhibitory effects of licorice phenolics on xanthine oxidase. Chem Pharm Bu ll (Tokyo). 1989 Nov;37(11):3005- 9.

[0321] 19. Zarrelli A, Romanucci V, Tuccillo C, Federico A, Loguerccio C, Gravante R, Di Fabio G. New silibinin glyco- conjugates: synthesis and evaluation of antioxidants dant properties. Bioorg Med Chem Lett. 2014 Nov 15;24(22):5147-9 6 / j.bmcl.2014.10.023. Epub 2014 Oct 14 .

[0322] TIFF2025178470000038.tif17170

[0323] 21. De Marino S, Festa C, Zollo F, Nini A, Antenucci L, Raimo G, Iorizzi M. Anti oxidant activity and chemical components as potential anticancer agents in the o live leaf (Olea europaea L. cv Leccino.) decoction. Anticancer Agents With Chem. 2014;14(10):1376-85.

[0324] [ PubMed ] 22. Flemmig J, Kuchta K, Arnhold J, Rauwald HW. Olea europaea leaf (Ph.Eur.) ext ract as well as several of its isolated phenolics inhibit the gout- related and zyme xanthine oxidase. Phytomedicine. 2011 May 15;18(7):561- 6. doi: 10.1016 / j .phymed.2010.10.021. Epub 2010 Dec 8.

[0325] 23.Azmi SMN, Jamal P, Amid A. Xanthine oxidase inhibitory activity from potentia l Malaysian medicinal plant as remedies for gout. International Food Research Jo urnal, 2012;19(1), 159- 65.

[0326] TIFF2025178470000039.tif16170

[0327] 25. Moini H, Guo Q, Packer L. Enzyme inhibition and protein- binding action of the procyanidin- rich french maritime pine bark extract, pycnogenol: effect o n xanthine oxidase. J Agric Food Chem. 2000 Nov;48(11):5630-9.

[0328] 26. Les F, Prieto JM, Arbones- Mainar JM, Valero MS, Lopez V. Bioactive proper ties of commercialised pomegranate (Punica granatum) juice: antioxidant, antipro liferative and enzyme inhibiting activities. Food Funct. 2015 Jun;6(6):2049-5 7. doi: 10.1039 / c5fo00426h.

[0329] [ PMC free article ] [ PubMed ] 27. Sestili P, Martinelli C, Ricci D, Fraternale D, Bucchini A, Giamperi L, Curc io R, Piccoli G, Stocchi V. Cytoprotective effect of preparations from various p arts of Punica granatum L. fruits in oxidatively injured mammalian cells in comp arison with their antioxidant capacity in cell-free systems. Pharmacol Res. 2007 Jul;56(1):18- 26. Epub 2007 Feb 20.

[0330] [ PubMed ] 28. Rummun N, Somanah J, Ramsaha S, Bahorun T, Neergheen- Bhujun VS. Bioactivity ty of Nonedible Parts of Punica granatum L.: A Potential Source of Functional In gradients. Int J Food Sci. 2013;2013:602312. doi: 10.1155 / 2013 / 602312. Epub 2013 Jul 8th.

[0331] 29. Namuslu M, Kocaoglu H, Celik HT, Avci A, Devrim E, Genc Y, Gocmen E, Erguder IB, Durak I. Effects of aqueous soybean, mistletoe and red clover extracts on a ctivities of adenosine deaminase and xanthine oxidase enzyme. Bratisl Lek Listy. 2014;115(6):367- 71.

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[0333] TIFF2025178470000040.tif16170

[0334] TIFF2025178470000041.tif17170

[0335] 33. Havlik J, Gonzalez de la Huebra R, Hejtmankova K, Fernandez J, Simonova J, M elich M, Rada V. Xanthine oxidase inhibitory properties of Czech medicinal plant s. J Ethnopharmacol. 2010 Nov 11;132(2):461- 5. doi: 10.1016 / j.jep.2010.08.044 .Epub 2010 Aug 26.

[0336] 34.Lu JM, Yao Q, Chen C. 3,4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a potent inhibitor of xanthine oxidase: a potential therapeutic agent for treatment of h yperuricemia and gout. Biochem Pharmacol. 2013 Nov 1;86(9):1328-37.

[0337] Although the present disclosure and its advantages have been described in detail, the design defined by the appended claims is not intended to be limiting. Various changes, substitutions and alterations may be made without departing from the spirit and scope of the It should be understood that the scope of the present application is not limited to the scope of the invention as described herein. Any such disclosure is limited to certain embodiments of the process, machine, manufacture, composition of matter, means, methods and steps. As one skilled in the art will readily appreciate from this disclosure, the inventions described herein are not intended to be limiting. perform substantially the same function or achieve substantially the same result as the corresponding embodiment to be described. Any now existing or later developed process, apparatus, manufacture, composition of matter, means, method, Any method or process may be used in accordance with the present disclosure. Accordingly, the appended claims are directed to such It is intended to include within their scope any process, machine, manufacture, composition of matter, means, methods, or steps It has been done.

Claims

1. one or more of: milk thistle extract, Chinese mint extract, amla extract, milk thistle extract, Rhodiola rosea linn extract, and / or vitamin D3; and Folic acid or its functionally active derivatives 10. A composition comprising:

2. 2. The composition of claim 1, wherein the functionally active derivative is dihydrofolic acid, tetrahydrofolic acid, 5-methyltetrahydrofolic acid (5-MTHF), or a combination thereof.

3. The composition of claim 1 or 2, further comprising grape seed extract.

4. The composition according to any one of claims 1 to 3, further comprising a pine bark extract.

5. The composition according to any one of claims 1 to 4, comprising an extract of Chinese mint.

6. The composition according to any one of claims 1 to 5, further comprising: Euryale (seed) extract; Rice bean extract; Wheat (immature fruit) extract; Houttuynia cordata (aerial part) extract; Citron (fruit) extract; Lotus (seed) extract; Fennel (fruit) extract; Strep thistle (aerial part) extract; Lavender bean extract; Abalone shell extract; Bakuga extract; Sterculia (seed) extract; Lanceolata ulmoides (aerial part) extract; Yakuchi (seed) extract; Radish (seed) extract; Lotus (juvenile sprout) extract; Fermented Soybean extract; Jujube (seed) extract; Butterbur extract; Oolong tea (leaf) extract; Senna leaf extract; Yohimbe bark extract; Butterbur extract; Caralluma bark (wild) extract; Echinacea root extract; Horse chestnut fruit extract; Cola nut extract; Magnolia bark extract; Muira puama bark extract; Clove (flower bud) extract; Sophora violacea (root) extract; Chaenomeles japonica (fruit) extract; Dianthus campestris (aerial part) extract; Honeysuckle (flower bud) extract; Alpinia japonica extract officinarum); or Bougainvillea (flower) extract; Fructose Crataegus (charred) extract; Glycyrrhiza uralensis (root and rhizome) extract; Ginkgo biloba leaf extract; Senna serrata (seed) extract; Bitter orange processed extract; Bitter orange (young fruit) extract; Sarmiento barbadensis (rhizome) extract; Morus alba (young twig) extract; Morus alba (leaf) extract; Lotus (leaf) extract; Chrysanthemum (flower) extract; Perilla frutescens (leaf) extract; Job's tears extract; Strawberry extract; Patchouli (aerial parts) extract; African A composition comprising one or more of the following: mango seed extract; green tea pure extract; milk thistle extract; olive leaf extract; pomegranate extract; spearmint leaf extract; St. John's wort extract; aloe vera leaf extract; catuaba bark extract; gynostemma pentaphyllum extract; hawthorn leaf extract; kudzu root extract; lemon balm extract; licorice root extract; moringa extract; papaya fruit extract; papaya seed; red clover (steam leaf) extract; rosemary extract; Siberian ginseng extract; rosehip (flower bud) extract, or Rhodiola rosea linn extract.

7. 7. The composition of claim 1, further comprising one or more components selected from vitamin D3, vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, nicotinic acid (B3), biotin (B7), choline, vitamin C, vitamin K, pantothenic acid, and vitamin E.

8. 8. The composition of any one of claims 1 to 7, wherein the composition is formulated as a medicine, medicated food, supplement, food, supplemental food, dietary supplement, health supplement, food for use in special diets, medical food, powder for dissolution in a drink or broth, foodstuff, beverage, food ingredient, health food supplement, nutraceutical, drug formulation or combinations thereof.

9. 9. The composition of any one of claims 1 to 8, wherein the composition is used in a method for inhibiting xanthine oxidase in an individual with hyperuricemia, gout, cardiovascular disease, systemic inflammation, endothelial dysfunction, myocardial infarction, diabetes, insulin resistance, metabolic syndrome, chronic kidney disease, psoriatic arthritis, microalbuminuria, erectile dysfunction, pre-eclampsia, cancer, an immune disorder, ischemia-reperfusion injury, hyperhomocysteinemia, and / or tumor lysis syndrome.

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