KR20080041703A - Cytokine modulators and related methods of use - Google Patents

Abstract

A composition for modulating cytokines to regulate an inflammatory or immunomodulatory response. The composition can include at least one of rosehips, blueberry, blackberry, elderberry, cranberry, rosemary, clove, feverfew, nettle root, artichoke, reishi mushroom, olive extract, green tea extract, grape seed extract, resveratrol, viniferin, Aframomum melegueta, boswellia serrata extract, boswellia forte, ipriflavone, tocotrienols, evening primrose oil, INM-176, borage oil, krill oil, at least one type of xanthophyll (e.g., astaxanthin), green coffee extract and ferulic acid. Specifically, a composition of the invention can include: rosehips and at least one of blackberry, blueberry, elderberry, and optionally krill oil; or rosehips, resveratrol and at least one of Aframomum melegueta and astaxanthin. Based on the cytokine modulation and cytokine response inhibition of the composition, it can be used to regulate an immunomodulatory and/or inflammatory response, and subsequently treat diseases and/or abnormal conditions associated with inflammatory response, for example, cardiovascular conditions, arthritis, osteoporosis and Alzheimer's disease.

Description

Cytokine Modulators and Related Methods {CYTOKINE MODULATORS AND RELATED METHODS OF USE}

This application is subject to US patent application Ser. No. 10 / 938,093, filed September 10, 2004, and US Patent Application No. 11, filed August 8, 2005, with partial continuing application to PCT application PCT / IB2004 / 051742, filed September 10, 2004 Partial application of / 200,412 and claims priority to US provisional application 60 / 502,755, filed September 12, 2003 and US provisional application 60 / 710,730, filed August 23, 2005.

Technical Field of the Invention

The present invention relates to inflammation in the body and, more particularly, to limiting inflammation and treating disorders and diseases associated therewith.

Inflammation is associated with various disorders and diseases that affect the body. Inflammation in the joints, for example, is a symptom of arthritis and rheumatoid disease and the symptoms and structural modifications caused by these diseases, such as bursitis, tendonitis, myositis, osteoarthritis and bone and It is known to exacerbate joint destructive diseases such as osteoporosis.

Inflammation is also known to be the cause of insulin resistance associated with various cardiovascular diseases and metabolic disorders such as atherosclerosis, thrombosis, obesity. Atherosclerosis increases the likelihood of stroke and myocardial infarction, and insulin resistance causes diabetes.

Inflammation is also believed to be the cause of the development of neurological disorders such as Alzheimer's disease.

Indeed, one study report linked inflammation to various chronic degenerative diseases. The study report identified specific cell-macrophages that produce pro-inflammatory chemicals, cytokines, that induce signaling cascades that provide inflammatory responses. These cytokines play an important role in inflammatory responses due to the response to foreign and infectious pathogens, traumatic or chronic injury, abnormal chemical or physical stress.

Thus, therapeutic agents have been developed that limit the release of inflammatory cytokines or the signaling of inflammatory cytokines, specifically interleukin-1 (IL-1) cytokines, from macrophages. For example, U.S. Patent 5,635,478 (Vignery) describes the use of calcitonin gene related peptide (CGRP) to treat rheumatoid arthritis by limiting IL-1 release. Although highly specific CGRP is effective in limiting IL-1, its use is expensive and long term doses have not yet been identified for toxic effects.

summary

The above-mentioned problems are overcome by the present invention which provides compositions that limit interleukin cytokines and / or limit the physiological response induced by interleukin cytokines. This restriction is effective in controlling the immune response and / or the inflammatory state. In one aspect, the composition may contain wild rose fruit and at least one of blackberry, blueberry, urinal fruit. In another aspect, the composition may contain at least one of wild rose berries, resveratrol and blackberries, blueberries, elderberry, cranberries. In another aspect, the composition is wild rose fruit; At least one of resveratrol and biniferin; It may contain at least one of blackberries, blueberries, elderberry and cranberries. In another aspect, the composition may contain wild rose fruit and krill oil. In another aspect, the composition may contain wild rose fruit, blackberries, blueberries, elderberry fruit, krill oil. In another aspect, the composition may contain wild rose fruit, resveratrol, Aframomum melegueta . In another aspect, the composition may contain wild rose fruit, at least one of resveratrol and viniferin , Aframomum melegueta . In another aspect, the composition may contain wild rose fruit, resveratrol, astaxanthin. In another aspect, the composition may contain at least one of wild rose fruit, Aframomum melegueta and blackberry, blueberry, urinal fruit, cranberry.

In another aspect, the composition consists of wild rose fruit, blueberry, blackberry, elderberry, cranberry, rosemary, clover, feverfew, nettle root, artichoke, ganoderma, olive extract, green tea extract (epigallocatechin gallate ( epigallocatechin gallate)), grape seed extract, resveratrol, viniferine , guinea ginger ( Aframomum melegueta ), boswellia serrata extract, boswellia forte, pripriflavone, tocotrienol, evening primrose oil, INM-176, borage oil, krill oil And at least one type of santophyll (eg, astaxanthin), green coffee extract (chlorogenic acid), ferulic acid. In a more particular aspect, the composition may contain wild rose fruit, nettle root, olive extract, artichoke. In another particular aspect, the composition may contain wild rose fruit, resveratrol, astaxanthin.

In another aspect, the present invention may provide a method of regulating or controlling an immune response and / or inflammatory condition in an individual, wherein the method comprises an effective amount of a composition of the present invention that modulates or controls an immune response and / or inflammatory condition. Administering to the subject. In certain aspects, the composition may inhibit the function of immunoregulatory cells or pro-inflammatory cells such as macrophages and / or leukocytes. In a more particular aspect, the composition can inhibit the expression of these genes by preventing transcription of the genes that produce interleukin cytokines. In even more specific aspects, the composition may inhibit the interleukin cytokine inflammatory response mechanism. In another particular aspect, the composition can modulate the expression of these immunoregulatory cells or pro-inflammatory cells by, for example, preventing an increase in the expression, secretion and / or synthesis levels of immunoregulatory cells or pro-inflammatory cells. In these aspects, the composition may be a pro-immune response and / or pro-inflammatory response in skeletal mass, joints, muscles, tissues, arteries, veins, capillaries and other organs, systems and / or cells. Can be controlled or controlled.

In another aspect, the present invention may provide a method of limiting and / or controlling the function of immune cells, such as macrophages, white blood cells, lymphocytes, by administering an effective amount of the composition to a subject.

In another aspect, the present invention can provide a method of limiting cytokine release or secretion from cells in an individual by administering to the individual a composition that modulates the synthesis, expression or secretion of a mediator of inflammation.

In another aspect, the present invention can provide a method of inhibiting the response of cells to interleukin cytokines by administering to a subject an effective amount of a composition of the present invention. In certain aspects, such administration may modulate the production of inflammatory biomarkers, such as C reactive proteins, which are biomarkers produced by the liver that indicate excessive inflammation in the body.

In another aspect, the present invention may provide a method of treating a disease or abnormal disorder caused by inflammation by administering a therapeutically effective amount of a composition. In certain aspects, such diseases or abnormal disorders include at least one of cardiovascular diseases or disorders, thrombosis, metabolic disorders associated with insulin resistance and obesity, traumatic injury, arthritis, osteoporosis, Alzheimer's disease. In a more particular aspect, the method includes administering the composition to an individual suffering from an inflammatory disease to relieve or eliminate pain, tenderness, infection, and / or discomfort after traumatic injury, surgery, or other symptoms that cause inflammation. May be included.

The present invention provides compositions and related methods for treating various immunomodulatory- and inflammation-based disorders, symptoms, diseases. Since the ingredients used are readily available and relatively inexpensive, the present invention provides a simple and cost-effective solution for treating a variety of inflammation-induced diseases and disorders. Furthermore, because these components are relatively stable, they can be mixed with other materials and provided as multipurpose supplements or foods.

These objects, advantages, and features of the present invention are more readily appreciated with reference to the drawings and the detailed description of the invention described below.

1 is a sectional view of a blood vessel of an individual in which atherosclerotic plaque developed prior to treatment with the composition of the invention in Example 3;

2 is a second cross-sectional view of a blood vessel and liver of an individual demonstrating the effect of interleukin cytokines in atherosclerotic plaque development in Example 3;

3 is a third cross-sectional view of a blood vessel and liver of an individual demonstrating the effect of the composition on interleukin cytokines in atherosclerotic plaque development in Example 3. FIG.

4 baseline vs. rate across the entire study population. Line graph depicting 12 weeks normalized CRP expression levels. In FIG. 4, "RH" denotes a wild rose fruit, "B" denotes a berry component selected from at least one of blackberries, blueberries, urinal berries and cranberries, and "AM" denotes The guinea ginger ( Aframomum melegueta ) is indicated and "R" represents resveratrol. The results reported in FIG. 4 are based on the daily administration of the following compositions for 12 consecutive weeks: 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 300 mg Aframomum melegueta extract; 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 40 mg resveratrol; 1200 mg wild rose fruit, 40 mg resveratrol, 300 mg Aframomum melegueta ; Or placebo.

5 baseline vs. rate across the entire study population. A graph depicting 12 weeks normalized CRP expression. In Fig. 5, "RH" denotes a wild rose fruit, "B" denotes a berry component selected from at least one of blackberries, blueberries, urinal berries and cranberries, and "AM" denotes The guinea ginger ( Aframomum melegueta ) is indicated and "R" represents resveratrol. The results reported in FIG. 5 are based on the daily administration of the following compositions for 12 consecutive weeks: the first bar was 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 300 mg Aframomum melegueta ) Based on administration of the extract; The second bar is based on the administration of 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 40 mg resveratrol; The third bar is based on the administration of 1200 mg wild rose fruit, 40 mg resveratrol, 300 mg Aframomum melegueta .

FIG. 6 shows baseline vs. score in test subjects with a Pattern 1 genotype. A graph depicting 12 weeks normalized CRP expression levels. In Fig. 6, "RH" denotes a wild rose fruit, "B" denotes a berry component selected from at least one of blackberry, blueberry, urinal fruit and cranberry, and "AM" denotes The guinea ginger ( Aframomum melegueta ) is indicated and "R" represents resveratrol. The results reported in FIG. 6 are based on daily administration of the following compositions for 12 consecutive weeks: 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 300 mg Aframomum melegueta extract; 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 40 mg resveratrol; 1200 mg wild rose fruit, 40 mg resveratrol, 300 mg Aframomum melegueta ; Or placebo.

FIG. 7 shows baseline vs. score in test subjects with a Pattern 1 genotype. A graph depicting 12 weeks normalized CRP expression. In FIG. 7, "RH" denotes a wild rose fruit, "B" denotes a berry component selected from at least one of blackberries, blueberries, urinal berries, and cranberries, and "AM" denotes The guinea ginger ( Aframomum melegueta ) is indicated and "R" represents resveratrol. The results reported in FIG. 7 are based on the daily administration of the following compositions for 12 consecutive weeks: the first bar was 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 300 mg Aframomum melegueta ) Based on administration of the extract; The second bar is based on the administration of 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 40 mg resveratrol; The third bar is based on the administration of 1200 mg wild rose fruit, 40 mg resveratrol, 300 mg Aframomum melegueta .

8 shows baseline vs. rate across the entire study population. Twelve week normalized off-body IL-1 expression is shown. In FIG. 8, "RH" denotes a wild rose fruit, "B" denotes a berry component selected from at least one of blackberries, blueberries, elderberry, cranberries, and "AM" The guinea ginger ( Aframomum melegueta ) is indicated and "R" represents resveratrol. The results reported in FIG. 8 are based on daily dosing of the following compositions for 12 consecutive weeks: the first bar was 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 300 mg Aframomum melegueta ) Based on administration of the extract; The second bar is based on the administration of 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 40 mg resveratrol; The third bar is based on the administration of 1200 mg wild rose fruit, 40 mg resveratrol, 300 mg Aframomum melegueta .

9 shows baseline vs. rate in human subjects having a Pattern 1 genotype. Twelve week normalized off-body IL-1 expression is shown. In Fig. 9, "RH" denotes wild rose fruit, "B" denotes a berry component selected from at least one of blackberry, blueberry, urinal fruit and cranberry, and "AM" denotes The guinea ginger ( Aframomum melegueta ) is indicated and "R" represents resveratrol. The results reported in FIG. 9 are based on the daily administration of the following compositions for 12 consecutive weeks: 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 300 mg Aframomum melegueta extract; 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 40 mg resveratrol; 1200 mg wild rose fruit, 40 mg resveratrol, 300 mg Aframomum melegueta ; Or placebo.

10 shows baseline vs. in human subjects having a Pattern 1 genotype. Twelve week normalized off-body IL-I expression is shown. In FIG. 10, "RH" denotes a wild rose fruit, "B" denotes a berry component selected from at least one of blackberries, blueberries, elderberry, cranberries, and "AM" The guinea ginger ( Aframomum melegueta ) is indicated and "R" represents resveratrol. The results reported in FIG. 10 are based on the daily administration of the following compositions for 12 consecutive weeks: the first bar was 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 300 mg Aframomum melegueta ) Based on administration of the extract; The second bar is based on the administration of 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 40 mg resveratrol; The third bar is based on the administration of 1200 mg wild rose fruit, 40 mg resveratrol, 300 mg Aframomum melegueta .

11 shows baseline vs. rate across the entire study population. 12 weeks normalized IL-1 gene expression is shown. In Fig. 11, "RH" denotes a wild rose fruit, "B" denotes a berry component selected from at least one of blackberries, blueberries, urinal berries and cranberries, and "AM" denotes The guinea ginger ( Aframomum melegueta ) is indicated and "R" represents resveratrol. The results reported in FIG. 11 are based on the daily administration of the following compositions for 12 consecutive weeks: 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 300 mg Aframomum melegueta extract; 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 40 mg resveratrol; 1200 mg wild rose fruit, 40 mg resveratrol, 300 mg Aframomum melegueta ; Or placebo.

12 Baseline vs. scores across the study population. 12 weeks normalized IL-1 gene expression is shown. In Fig. 12, "RH" denotes a wild rose fruit, "B" denotes a berry component selected from at least one of blackberry, blueberry, urinal fruit and cranberry, and "AM" denotes The guinea ginger ( Aframomum melegueta ) is indicated and "R" represents resveratrol. The results reported in FIG. 12 are based on the daily administration of the following compositions for 12 consecutive weeks: the first bar is 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 300 mg Aframomum melegueta ) Based on administration of the extract; The second bar is based on the administration of 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 40 mg resveratrol; The third bar is based on the administration of 1200 mg wild rose fruit, 40 mg resveratrol, 300 mg Aframomum melegueta .

FIG. 13 shows baseline vs. score in test subjects with a Pattern 1 genotype. 12 weeks normalized IL-1 gene expression is shown. In Fig. 13, "RH" denotes a wild rose fruit, "B" denotes a berry component selected from at least one of blackberry, blueberry, urinal fruit and cranberry, and "AM" denotes The guinea ginger ( Aframomum melegueta ) is indicated and "R" represents resveratrol. The results reported in FIG. 13 are based on the daily administration of the following compositions for 12 consecutive weeks: 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 300 mg Aframomum melegueta extract; 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 40 mg resveratrol; 1200 mg wild rose fruit, 40 mg resveratrol, 300 mg Aframomum melegueta ; Or placebo.

FIG. 14 shows baseline vs. score in test subjects with a Pattern 1 genotype. 12 weeks normalized IL-1 gene expression is shown. In Fig. 14, "RH" denotes a wild rose fruit, "B" denotes a berry component selected from at least one of blackberries, blueberries, urinal berries and cranberries, and "AM" denotes The guinea ginger ( Aframomum melegueta ) is indicated and "R" represents resveratrol. The results reported in FIG. 14 are based on the daily administration of the following compositions for 12 consecutive weeks: the first bar was 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 300 mg Aframomum melegueta ) Based on administration of the extract; The second bar is based on the administration of 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 40 mg resveratrol; The third bar is based on the administration of 1200 mg wild rose fruit, 40 mg resveratrol, 300 mg Aframomum melegueta . The results reported in FIG. 14 demonstrate that Composition 2 (second bar) significantly inhibits the expression and / or synthesis of IL-1 in test subjects having a Pattern 1 genotype.

15 shows baseline vs. 12 weeks normalized IL-1 gene expression is shown. In FIG. 15, "RH" denotes a wild rose fruit, "B" denotes a berry component selected from at least one of blackberry, blueberry, urinal fruit and cranberry, and "AM" denotes The guinea ginger ( Aframomum melegueta ) is indicated and "R" represents resveratrol. The results reported in FIG. 15 are based on the daily administration of the following compositions for 12 consecutive weeks: 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 300 mg Aframomum melegueta extract; 1200 mg wild rose fruit, 165 mg blueberry powder extract, 332 mg blackberry powder extract, 40 mg resveratrol; 1200 mg wild rose fruit, 40 mg resveratrol, 300 mg Aframomum melegueta ; Or placebo.

I. Composition

The composition of the present invention is wild rose fruit, blueberry, blackberry, elderberry, cranberry, rosemary, clover, feverfew, nettle root, artichoke, ganoderma, olive extract, green tea extract (epigallocatechin gallate), grape seed extract, resveratrol , Viniferin , Aframomum melegueta , boswellia serrata extract, boswellia forte, ifriflavone, tocotrienol, evening primrose oil, INM-176, borage oil, krill oil, at least one type of santophyll (eg, May contain one or more ingredients selected from astaxanthin), green coffee extract (chlorogenic acid), ferulic acid. Specifically, the composition of the present invention may contain at least one of wild rose fruit and blackberry, blueberry, urinal fruit, krill oil. The composition may also contain wild rose fruit, resveratrol, Aframomum melegueta . Other compositions may contain wild rose fruit, resveratrol, astaxanthin. Furthermore, the composition of the present invention may contain at least one of wild rose fruit, Aframomum melegueta , and beanini and resveratrol. Other compositions of the present invention may contain at least one of wild rose fruit, Aframomum melegueta and blueberries, blackberries, urinal fruits, cranberries. Other compositions may contain at least one of wild rose fruit, resveratrol and blueberries, blackberries, elderberry, cranberries. Other compositions include wild rose fruit; At least one of biniferin and resveratrol; May contain at least one of blueberries, blackberries, elderberry, cranberries. Such compositions inhibit any of the doses mentioned herein to inhibit cytokine expression, production, uptake, secretion and / or release, and also inhibit cytokine responses to reduce or eliminate immunomodulatory and / or inflammatory responses. Can be administered.

Acceptable doses of ingredients effective to modulate cytokines, for example to limit the production, reception, secretion and / or release of typical cytokines such as IL-1 and / or IL-6, are provided in Table I below. Each dose in Table I is the expected effective amount (mg). Furthermore, in Table I all doses are provided in the range of approximately lower limit to approximately upper limit. For example, nettle dose A is designated as "250-2500", which represents a nettle of about 250 to about 2500 mg daily.

Acceptable doses of ingredients that regulate cytokines ingredient Capacity A Capacity B Nettle extract 250-2500 500-1250 Artichoke 150-1500 300-750 Feverfew 50-500 100-250 Sunny place 300-3000 600-1500 Olive extract 300-3000 600-1500 Green tea extract 150-1500 300-750 Grape seed extract 100-1000 200-500 Guinea Ginger ( Aframomum melegueta ) Extract 150-1500 300-750 Boswellia Serrata Extract 350-3500 700-1750 Ifriflavone 100-1000 200-500 Tocotrienol 50-500 100-250 Evening Primrose Oil 500-5000 1000-2500 INM-176 100-1000 200-500 Borage Oil 500-5000 1000-2500 Krill oil 300-3000 600-1500 Green Coffee Extract (chlorogenic acid) 100-1000 200-500 Ferulic acid 100-1000 200-500 Wild rose fruit 50-500 500-5000 Blackberry powder 100-1000 200-500 Blueberry powder 200-2000 300-1500 Cranberry Extract 100-1000 200-500 Rosemary Extract 100-1000 200-500 Clover extract 100-1000 200-500 Resveratrol 100-1000 200-500 Viniferin 100-1000 200-500 Elderberry extract 400-4000 700-2500

The ingredients identified in Table I above are commercially available. Depending on the field of application and / or supplier, the component may be a mixture of extracts, pure ingredients, excipients of a particular potency, and may exist in various physical forms, for example liquids or powders. The ingredient designated INM-176 is a compound of unknown composition available from Scigenic Company, Ltd (Seoul, Korea).

More specifically, the composition may contain one or more wild rose fruit components. Examples of wild rose fruit components include, without limitation, dried wild rose fruit, wild rose oil, wild rose fruit extract. Wild rose fruit components can be obtained from a plurality of plant species belonging to the Rosa family, for example Rosa canina . In addition, wild rose fruit may include the fruit, petals and / or seeds of the Rosa plant.

Any method can be used to prepare the wild rose fruit component. For example, dried wild rose berries can be prepared using conventional harvesting and drying methods. Wild rose oil is produced by standard methods and can be processed into cellulose into tablet or powder compositions. In addition, wild rose berries are commercially available from MB North's America (Torrance, California).

The composition of the present invention may contain one or more wild rose fruit components. For example, dietary supplements may contain dried wild rose fruit and wild rose fruit extract. In addition, the composition may contain any amount of wild rose fruit components. For example, at least 1% of dietary supplements (eg, at least 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, or 90%) is the wild rose fruit component. Can be. Typically, the composition contains approximately 500 mg to 5000 mg, preferably approximately 500 mg to 1500 mg of wild rose fruit component.

More specifically, the composition may contain one or more blackberry components. Examples of the blackberry component include, without limitation, dried blackberry, blackberry powder, blackberry extract. The blackberry component can be obtained from a plurality of plant species belonging to the Robus family, for example Rubus fruticosus .

Any method may be used to prepare the BlackBerry component. For example, blackberry powder can be prepared using conventional harvesting, drying and powdering methods. In addition, blackberries are commercially available from Van Drunen Farms Futureceuticals (Santa Rosa, California).

The composition of the present invention may contain one or more blackberry components. For example, dietary supplements may contain blackberry powder and blackberry extract. In addition, the composition may contain any amount of the BlackBerry component. For example, at least 1% (eg, at least 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, or 90%) of the dietary supplement Can be. Typically, the composition contains approximately 100 mg to 1000 mg of blackberry component.

More specifically, the composition may contain one or more blueberry ingredients. Examples of blueberry ingredients include, without limitation, dried blueberries, blueberry powder, blueberry extracts. The blueberry component may be obtained from a plurality of plant species belonging to the Vaccinium family, for example, Vaccinium corymbosum .

Any method may be used to prepare the blueberry ingredient. By way of example, blueberry powder may be prepared using conventional harvesting, drying and powdering methods. In addition, blueberries are commercially available from Van Drunen Farms Futureceuticals (Santa Rosa, California).

The composition of the present invention may contain one or more blueberry components. For example, dietary supplements may contain blueberry powder and blackberry extract. In addition, the composition may contain the blueberry component in any amount. For example, at least 1% (eg, at least 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, or 90%) of the dietary supplements are blueberry ingredients. Can be. Typically, the composition contains approximately 200 mg to 2000 mg of blueberry component.

More specifically, the composition may contain one or more elderberry components. Examples of elderberry components include, without limitation, dried elderberry fruit, elderberry powder, elderberry extract. Elderberry fruit components can be obtained from a plurality of plant species belonging to the Sambucus family, for example Sambucus canadensis .

Any method may be used to prepare the urinal fruit component. By way of example, horseradish fruit powder can be prepared using conventional extraction techniques. In addition, elderberry is commercially available from Artemis International (Fort Wayne, Indiana).

The composition of the present invention may contain one or more urinal fruit components. For example, dietary supplements may contain elderberry powder and elderberry extract. In addition, the composition may contain an elderberry component in any amount. For example, at least 1% of dietary supplements (eg, at least 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, or 90%) It may be a fruit ingredient. Typically, the composition contains approximately 400 mg to 4000 mg of urinal fruit component.

Furthermore, the composition may contain Aframomum melegueta . Examples of Aframomum melegueta components include, without limitation, ground Aframomum melegueta seeds, Aframomum melegueta powder, and Aframomum melegueta extract.

Any method may be used to prepare Aframomum melegueta ingredients. For example, Aframomum melegueta extract can be prepared using conventional harvesting, drying and extraction methods. In addition, Aframomum melegueta is commercially available from Frontier Natural Products Cooperative (Norway, Iowa).

The composition of the present invention may contain one or more components of Aframomum melegueta . For example, dietary supplements may contain Aframomum melegueta powder and Aframomum melegueta extract. In addition, the composition may contain any amount of the Aframomum melegueta component. For example, at least 1% (eg, at least 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, or 90%) of dietary supplements may contain guinea ginger ( Aframomum melegueta ) may be an ingredient. Typically, the composition contains approximately 500 mg to 1500 mg of Aframomum melegueta component.

The composition of the present invention may contain krill oil. Krill oil can be obtained from any member of the Euphausia strain, for example Eupausia superba . Krill oil can be obtained using conventional oil production techniques. In addition, krill oil is commercially available from Neptune Technologies and Bioresources (Quebec, Canada).

The composition may contain krill oil in any amount. For example, at least 1% of dietary supplements (eg, at least 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, or 90%) may be krill oil. have. Typically, the composition contains approximately 300 mg to 3000 mg krill oil component.

If the composition contains resveratrol, resveratrol can be obtained from grape skins or extracts of other grape components, including grape vines. Resveratrol may be present in the composition in one or more different forms, such as extract form and powder form. Resveratrol can be purchased commercially from Charles Bowman & Co. (Holland, Michigan).

The composition may further contain a resveratrol component comprising resveratrol and / or derivatives thereof. For example, resveratrol is any oligomer of resveratrol, for example ε-viniferin, a dimer of resveratrol. In another example, the resveratrol component may contain resveratrol in combination with a derivative of resveratrol. In one example, the resveratrol component is Resveravine® (BioSerae Laboratoires, S.A., Pare Technologique du Lauragais, Bram, France) containing both resveratrol and ε-viniferin.

The composition may contain any amount of resveratrol component. For example, at least 1% of dietary supplements (eg, at least 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, or 90%) may be resveratrol. have. Typically, the composition contains approximately 100 mg to 1000 mg of resveratrol component.

If the composition contains at least one type of santophyll, the santophyll may be astaxanthin. Astaxanthin can be obtained from natural sources or synthesized. For example, astaxanthin can be obtained from algae, fungi and / or crustacean. One type of astaxanthin can be purchased commercially from Cyanotech Corporation (Kailua-Kona, Hawaii).

The composition may contain the astaxanthin component in any amount. For example, at least 1% of the dietary supplements (eg, at least 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, or 90%) is astaxanthin. Can be. Typically, the composition contains approximately 0.5 mg to 50 mg of astaxanthin component.

The composition may comprise one or more pharmaceutically acceptable excipients such as croscarmellose sodium, maltodextrin, silicified microcrystalline cellulose, silicon dioxide, stearic acid, hydroxyl propyl methyl cellulose (HPMC), lactose, glucose, sucrose, Corn starch, potato starch, cellulose acetate, ethyl cellulose, and the like. Diluents and other additives, such as one or more pharmaceutically acceptable binders, fillers, supporters, thickeners, taste enhancers, colorants, preservatives, proteins, antibacterial agents, chelating agents, inert gases, stabilizers, modifiers, emulsifiers or these Mixtures of are available to suit the type of composition used.

These components of the composition can be processed into forms with various delivery systems. For example, these components can be processed and included in capsules, tablets, gel tabs, lozenges, strips, granules, powders, concentrates, solutions, lotions, creams or suspensions. These ingredients may be administered to the respiratory tract, for example, in asthma, anaphylaxis and / or other acute shock diseases via spray, mist or aerosol. These ingredients may be formulated independently or in combination with other foods to provide pre-adjusted nutritional supplements, supplemental foods such as disposable bars. In one example, the composition may contain one component administered in tablet form and the other component administered in capsule form. More specifically, the compositions can be formulated in a variety of routes of administration, for example intravenous, intramuscular, subcutaneous, nasal, sublingual, intramedullary, topical or intradermal.

The dose of the administered composition can be increased gradually depending on the disease or disorder being treated. For example, in the treatment of arthritis, the composition is administered in multiple continuous doses of about 6 to 12 hours short, about 2 weeks long. Daily doses are administered during periods of achieving symptomatic relief from inflammatory tenderness, edema, and pain. The dose may be adjusted to maintain remission from these symptoms. Treatment can last for weeks or months, or optionally indefinitely in the case of a chronic disease or disorder.

II. Method of Preparation of the Composition

Typical compositions of the present invention containing wild rose fruit, blackberry powder, blueberry powder, elderberry extract can be prepared in tablet form according to the following process. Other dosage media such as gel tabs, capsules, liquids, sustained release formulations and the like can be formulated according to manufacturing techniques well known in the pharmaceutical art.

Wild rose fruit, blackberry powder, blueberry powder are added to silicon dioxide in the amounts listed in Capacity A in Table II above, placed in a polybag and mixed until uniform and homogeneous mixing. The resulting mixture is placed on a Patterson Kelley (P.K.) 100 blender (Patterson-Kelley Co., East Stroudsburg, Pennsylvania). The following components are then described in the order described in P.K. through Sweco Separator (Sweco, Inc., Florence, Kentucky) equipped with a 20-mesh screen. 100 Formulator: Transfer directly to dextrose, croscarmellose sodium, silicified microcrystalline cellulose. The resulting composition was P.K. Mix in 100 blenders.

The plant-based stearic acid powder was then passed through the Sweco separator to P.K. Transfer directly to the 100 blender. The resulting mixture is mixed for an additional 5 minutes. The resulting mixture is placed in a tote or super sack and pressed and tableted into a conventional device. The acceptable weight range of each individual tablet is approximately 250 mg to 500 mg. The amount of wild rose fruit in each tablet is approximately 1200 mg, the amount of blackberries is approximately 165 mg, and the amount of blueberries is approximately 330 mg. Tablets made according to this process can be used for the in vivo testing described herein.

Soft gel capsules of the compositions of the present invention may be prepared to contain krill oil. The capsule can be made using conventional capsule preparation techniques. The amount of krill oil in each capsule is approximately 300 mg. These capsules can be administered alone or in combination with tablets of other components of the composition as part of the in vivo tests described herein.

Other compositions of the present invention containing wild rose fruit and blackberry powder, or wild rose fruit and blueberry powder may be prepared in tablet form according to the tableting process described above. In the wild rose / blackberry tablets the amount of wild rose fruit is approximately 300 mg and the amount of blackberry is approximately 80 mg. In the wild rose / blueberry tablets the amount of wild rose fruit is approximately 300 mg and the amount of blueberries is approximately 40 mg. Tablets prepared according to the above process can be used for the in vivo testing described herein.

Other compositions containing wild rose fruit, resveratrol, Aframomum melegueta can be prepared in tablet form according to the tableting process described above with approximately 300 mg wild rose fruit, 10 mg resveratrol, 75 mg Aframomum melegueta extract. .

Other compositions containing wild rose fruit, resveratrol, astaxanthin may be prepared in tablet form according to the tableting process described above with approximately 300 mg wild rose fruit, 10 mg resveratrol, 1 mg astaxanthin.

Another composition of the present invention containing olive extract, artichoke, nettle root, wild rose fruit can be prepared in tablet form according to the following process. Olive extract, artichoke, nettle root, wild rose fruit are added to silicon dioxide in the amounts listed in dose A of dose A above, placed in a polybag and mixed until uniformly and homogeneously mixed. The resulting mixture is placed on a Patterson Kelley (P.K.) 100 blender (Patterson-Kelley Co., East Stroudsburg, Pennsylvania). The following components are then described in the order described in P.K. through Sweco Separator (Sweco, Inc., Florence, Kentucky) equipped with a 20-mesh screen. 100 Formulator: Transfer directly to dextrose, croscarmellose sodium, silicified microcrystalline cellulose. The resulting composition was P.K. Mix in 100 blenders.

The plant-based stearic acid powder was then passed through the Sweco separator to P.K. Transfer directly to the 100 blender. The resulting mixture is mixed for an additional 5 minutes. The resulting mixture is placed in a tote or super sack and pressed and tableted into a conventional device. The acceptable weight range of each individual tablet is approximately 250 mg to 500 mg.

III. Component Selection of Compositions

The present invention may include an ingredient screening process that selects ingredients that are suitable for a particular health disorder and that can be used in the composition as needed. For example, in the case of nutritional supplements to regulate IL-1, the active ingredient may be selected through a unique screening process. Various factors include biological, commercial, regulatory and descriptive identifiers. Some preferred identifiers and their weights are listed in Table II. Suitably, the identifier is weighted based on a sales or consumer driven object. In Table II, the weight of 3 means that the identifier is very important in the screening process ("factor 3 identifier"); 2 means that the identifier is less but still important than the weight factor of 3 in the screening process (“factor 2 identifier”); 1 means the lowest specific gravity as an identifier ("factor 1 identifier").

Identifiers in Screening of Cytokine Regulatory Components Identifier importance Efficacy in IL-1 screening test (EC <50 μg / ml) 3 Supply possibility 3 Cost per kg of material 3 Raw material name One Plant entity / parent extract One Optional and Secondary Materials and Suppliers 2 Monopoly possibilities 2 Vertical integration possibility 2 Mercury vs. Hydrophobic affinity 2 Known Active Ingredients / Mechanisms of Action 2 Partial Bioavailability * 2 Effective daily dose (mg) based on in vitro EC50 2 Daily effective amount (mg) based on existing literature 2 Estimated raw material costs (monthly costs) based on bioassay EC50 and bioavailability 2 Estimated Raw Material Costs (Monthly Costs) Based on Literary Efficacy 2 Safety / Toxic Status 3 Technical / Administrative Approvals in Market Countries 3 Supply company's products and representation in the overall market 2 Intellectual Property Risk 2

Fractional bioavailability is the ratio (expressed in fractions) of active compounds in orally ingested components that are absorbed into the body and can be used in body tissues throughout the circulation. For example, a partial bioavailability of 0.10 indicates that 10% of the active substance of the orally ingested component is absorbed from the intestine and transported (for a period of time) in the circulation.

In the above example, the primary objective is to find IL-1 modulators that are effective and commercially successful for humans. The selection of the best candidates is accomplished by combining the identifier weights for each candidate and comparing the overall weight scores. Thus, the efficacy of the active ingredients in the regulation of IL-1 is as important as the cost of obtaining certain ingredients and the availability of these ingredients. Other factors important to commercial success are the toxicity and stability of the ingredients and the technical / management approval of the ingredients in the market where the composition is sold. Some components do not meet one Factor 3 identifier, and there are instances where this Factor 3 identifier is different in each component. In these cases, factor 3 identifiers are weighted, and factor 2 identifiers and factor 1 identifiers are also considered in the review process.

In addition to the ingredient screening process described above, the therapeutic composition or ingredient, if possible, undergoes an off-clinical evaluation to confirm biological properties and effects. Specifically, the subject consumes the therapeutic composition or ingredient. Continuous blood samples are taken from the subject before and after consumption for a period of time (approximately 6 hours in most chemicals) where the active ingredient of the ingredient is absorbed and transported to the body's circulatory system. These blood samples are added to an in vitro biopsy system, which has a test readout that is sensitive to changes in the physiological function of the desired system. The results of these tests, called off-body tests, are compared with in vitro clinical results. The closer the results of in vitro and disassembly assessments are, the more likely the therapeutic agent is to have a beneficial effect in the body.

IV. Cytokine Inhibition Potential Assessment

These components of the composition may modulate cytokines through at least two different biological mechanisms. In the first mechanism, these components can inhibit the production, ie synthesis, of interleukin cytokines. In this mechanism, these components are thought to block mRNA transcription of genes encoding the production of interleukin cytokines. As a result, if gene transcription is blocked, cytokines cannot be synthesized in the body. In a second mechanism, these components can inhibit the cascade of chemicals and cells in the body against interleukin cytokines. More specifically, these components can inter alia block the production of acute-phase proteins, such as C reactive proteins (CRP). CRP is synthesized by hepatocytes in the human liver in response to interleukin cytokines such as IL-1 and IL-6 in traumatic and / or inflammatory states. These components can affect the mechanism of the response of cells, such as hepatocytes, to interleukin cytokines such that these cells reduce or stop the production of CRP.

In the examples below, the interleukin cytokine regulatory potentials of the various components listed above in inhibiting the synthesis of cytokines and the responses induced by cytokines were measured, and the results of each exposure were recorded and evaluated.

For this evaluation, white blood cells were injected at various concentrations of these components. Inflammatory stimulants such as lipopolysaccharide (LPS) were then added to the component-cell culture and untreated control samples of leukocytes. By comparing the production of IL-1 cytokines in component-treated and untreated cells, the concentration of these components inducing a 50% change in the concentration of IL-1 produced by these cells was estimated.

These examples are provided to further illustrate and explain the invention, and in no way limit the invention. Unless otherwise specified, all temperature dimensions are expressed in degrees Celsius (° C.).

Example 1

In order to perform the assays that inhibit the interleukin synthesis of this example, human leukocytes, particularly THP-1 cells (ATCC, Manassas, Virginia), were recommended by ATCC in a humidified 37 ° C. incubator fed with 5% carbon dioxide. Growing under conditions. To examine the IL-1 inhibitory potential of various compounds, multiple THP-1 cell populations were plated on 96 well plates. Specifically, 5 × 10 ⁵ THP-1 cells were plated in RPMI 1640 supplemented with 10% fetal bovine serum and antibiotics such as penicillin and streptomycin. These cell samples were injected with chemical solution after smearing.

In chemical dosing, each of these components was injected into THP-1 cells smeared in various quantities, specifically 100 μg / ml, 10 μg / ml, 1 μg / ml, 0 μg / ml. For example, 100 μg / ml of nettle root extract in one cell plate, 10 μg / ml in another cell plate, 1 μg / ml in another cell plate, and nettle root in another cell plate. Did not put. THP-1 cells injected with the desired components were transferred to the incubator and incubated for 4 hours under the same conditions.

A known inflammatory stimulant, lipopolysaccharide (LPS) was then added to each well plate at a final concentration of 100 ng / ml. LPS treated cultures were transferred to the incubator and incubated for an additional 16 hours. Thereafter, the culture was centrifuged at 1000 G for about 5 minutes to obtain a supernatant. The supernatants were labeled and organized for IL-1 detection.

In order to detect IL-1 secreted from differently injected supernatants, and then assess the potential for inhibiting IL-1 secretion of each dose of each component, each supernatant was prepared from a test supplier, Biosource International (Camarillo, California). The presence of IL-1 was investigated according to the conventional IL-1 assay protocol provided by. Specific protocols are provided in the references, Protocol Booklet, Human IL-1, (2001) (Biosource International).

According to the overall coverage of the protocol, 50 μl of each supernatant sample was added to each well of an anti-IL-1 coated plate and these plates were incubated for 2 hours at room temperature. Similarly, a calibration standard designed to establish a known amount of IL-1 was added to designated wells of anti-IL-1 antibody coated plates and incubated for 2 hours at room temperature.

The liquid was then removed from each well and the coated plate washed three times in wash buffer. After the third wash, 100 μl of enzyme (horseradish peroxidase) conjugated anti-IL-1 antibody was added to each well of the coated plate and incubated for 30 minutes at room temperature. Plates were washed again the same as before and 100 μl of substrate solution (TMB) was added to each well to indicate the amount of IL-1 produced by adding LPS inflammatory stimulant in the presence or absence of the aforementioned components. . The reaction was then stopped by adding 100 μl of stop solution, such as hydrochloric acid or sulfuric acid. The reaction of horseradish peroxidase conjugated to the substrate solution (TMB) and the anti-IL-1 antibody yields a colored product having a specific spectral absorbance at a wavelength of 450 nm. As such, the amount of IL-1 present is determined by measuring absorbance values at 450 nm resulting from the amount of bound enzyme conjugated anti-IL-1 antibody that depends on the amount of IL-1 present.

Calibration standard samples were subjected to the same protocol as in supernatant samples to determine the IL-1 present in these calibration samples. The optical density of the calibration standard sample was examined to establish the known absorbance of IL-1 at various levels, such as 1500 to 50, 125, 62.5, 31.2, O picogram / ml in the calibration diluent. The optical density of the calibration standard sample was then entered in the coordinates to determine the normalized IL-1 absorbance calibration curve.

In each sample supernatant examined and optically measured, the absorbance was plotted against the standard IL-1 absorbance calibration curve to determine the amount of IL-1 present in the sample supernatant.

The IL-1 inhibition potential results of various components based on the amount of IL-1 present in the sample supernatant are reported in Table III below. As described herein, these results are reported as EC ₅₀ values, which are commonly accepted effective amount dimensions. In general, EC50 is the concentration of component required to induce a 50% change in IL-1 concentration compared to the control sample.

Results of IL-1 Test in Example 1 ingredient EC50 (μg / mL) (50% effective amount in vitro) Epigallocatechin gallate <1 Grape seed extract <1 Grape seed extract <1 Ifriflavone <1 Nettle Root Extract <1 Wild rose fruit <1 Tocotrienol 1-10 Borage Oil 1-10 Evening Primrose Oil 1-10 Coffee bean extract 1-10 INM-176 1-10 Boswellia serrate <1-10 Boswellia forte 1-10 Nettle Root Extract 1-10 Olive extract 1-10 Krill oil l-10 wisdom 1-10 Guinea Ginger ( Aframomum melegueta ) Extract 1-10 Feverfew 1-10 Artichoke 1-10 Ferulic acid 10

The test results in Table III demonstrate the efficacy of these components to reduce or inhibit the secretion or production of cytokines such as IL-1.

Example 2

This example examines other components that may be included in the compositions of the present invention to assess (a) the efficacy of these components to induce and / or inhibit the secretion or production of cytokines such as IL-1; (b) assessing the interaction of the optimum primary ingredients (wild rose fruit, artichoke extract, olive extract, nettle root) with other ingredients; (c) The effect of other components on interleukin cytokine, eg, IL-1 response, in hepatocytes was assessed by measuring C reactive protein (CRP) secretion by hepatocytes.

Specifically, release of IL-1 from THP-1 cells following pre-treatment with varying amounts of other components, or a combination of these other components and optional primary components, or without exposure to lipopolysaccharide (LPS) By measuring, the effect of other components on monocyte IL-1β secretion was evaluated. The response of hepatocytes to IL-1 expression levels was assessed by measuring CRP in culture supernatants following exposure of hepatocytes to IL-1 and IL-6 with or without varying amounts of other components.

Other components tested were: Blackberry Extract, Blueberry Extract, Cranberry Extract, Rosemary Extract, Clover Extract, Resveratrol. Table IV shows the results of these other components on dose specific inhibition of IL-1α secretion after activation via LPS in the presence or absence of four additional primary components at low doses. The method used to test the inhibition of IL-1α secretion is the same as that performed in Example 1 for these tested components. Among the components tested in Example 2, rosemary extract, blueberry extract, urinal fruit extract, cranberry extract showed an IL-1 modulating effect at a relatively low dose (20-70 ㎍ / ㎖).

The interference of the other components on the IL-1 modulatory effects of the optional primary components listed above may, for example, combine the inhibitory effects of the selective primary component IL-1 secretion shown in Table III with those primary components and the other components listed in Table IV. It was examined by comparing the inhibitory effect of IL-1 secretion. For example, the presence of blackberries did not alter the IL-1 regulatory effect of wild rose fruit, which is evidenced by the absence of characteristic inhibitory activity. None of the other components showed interference with the selective primary components, but rather some had a synergistic effect (the blueberry extracts had a synergistic effect with wild rose and nettle roots, and the elderberry extract with artichoke extract and nettle roots). Synergistic effect). In Table IV, "-" indicates no interference or synergy and "+" indicates interference or synergy.

The IL-1 response effect was assessed in hepatocytes by measuring the secretion of CRP when hepatocytes were exposed to IL-1α and IL-6 with or without various pre-treatments of different components. CRP secretion was chosen because, as mentioned above, CRP is a significant acute-phase protein in humans; Its plasma concentration increases more than 1000-fold during severe trauma and / or inflammation; CRP is expressed in hepatocytes in response to IL-1 and IL-6 in an inflammatory state, for example synthesized or secreted. CRP functions as a biomarker for interleukin cytokines, and it is useful to measure these biomarkers rather than the cytokines themselves because the level of cytokines in the blood does not accurately reflect the actual amount of cytokines in the body. Because it is frequent. Thus, by measuring CRP secreted by hepatocytes, the extent of cellular response to IL-1 and / or IL-6 can be determined.

To perform the evaluation of this example, primary isolated human hepatocytes (In Vitro Technology, Baltimore, Maryland) were restored under conditions recommended by In Vitro Technology in a humidified 37 ° C. incubator fed 5% carbon dioxide. To examine the CRP response potential of various compounds, multiple hepatocyte groups were plated in 96 well plates. Specifically, 1 × 10 ⁴ cells are plated in hepatocyte medium supplemented with 10% fetal calf serum and then various doses, specifically, 100 μg / ml, 10 μg / ml, 1 μg / ml, 0 μg / ml The test ingredient of was exposed. For example, 100 μg / ml of blackberry extract is added to one cell plate, 10 μg / ml to another cell plate, 1 μg / ml to another cell plate, and blackberry to another cell plate. No extract was added. After treating the plated cells with individual components, the hepatocytes injected with the components were transferred to the incubator and incubated for 4 hours under the same conditions.

Then, known CRP inducers such as IL-1 and IL-6 were added to each well plate at a final concentration of 1 ng / ml. IL treated culture was transferred to the incubator and incubated for an additional 16 hours. After incubation, supernatants were labeled and organized for CRP detection.

In order to detect secreted CRP in differently injected supernatants, and then assess the potential for inhibiting CRP secretion at each dose of each component, each supernatant was prepared from a test supplier, Life Diagnostics Inc. (West Chester, Pennsylvania). The presence of CRP was examined according to the conventional CRP assay protocol provided by. Specific protocols are provided in the references, High Sensitivity C-Reactive Protein Enzyme Immunoassay Test Kit, (2003) (Life Diagnostics Inc.).

According to the overall report of the protocol, 10 μl of each supernatant sample was added to the wells of an anti-CRP antibody coated plate, with 100 μl of a second antibody against CRP conjugated to horseradish peroxidase, and these Plates were incubated for 45 minutes at room temperature. Similarly, a calibration standard designed to establish a known amount of CRP, along with the second anti-CRP antibody conjugated to HRP, is added to the designated wells of the anti-CRP antibody coated plate and 45 minutes at room temperature. Incubated.

The liquid was then removed from each well and the coated plate washed three times in wash buffer. After the third wash, 100 μl of substrate solution (TMB) was added to each well to indicate the amount of CRP generated by adding CRP inducers, IL-1 and IL-6 in the presence or absence of the above components. . The reaction was then stopped by adding 100 μl of stop solution, such as hydrochloric acid or sulfuric acid. The reaction of horseradish peroxidase conjugated to the substrate solution (TMB) and anti-CRP antibody yields a colored product having a specific spectral absorbance at a wavelength of 450 nm. As such, the amount of CRP present is determined by measuring absorbance values at 450 nm resulting from the amount of bound enzyme conjugated anti-CRP antibody that depends on the amount of CRP present.

Calibration standard samples were subjected to the same protocol as in supernatant samples to determine the CRP present in these calibration samples. The optical density of the calibration standard sample was examined to establish the known absorbance of the CRP at various levels in the calibration dilution, for example 0, 0.005, 0.01, 0.025, 0.05, 0.1 μg / ml. The optical density of the calibration standard sample was then entered in the coordinates to determine the standardized CRP absorbance calibration curve.

In each sample supernatant examined and optically measured, the absorbance was plotted against the standard CRP absorbance calibration curve to determine the amount of CRP present in the sample supernatant.

The CRP inhibition potential results of various components based on the amount of CRP present in the sample supernatant are reported in Table IV below. As described herein, these results are reported as EC ₅₀ values, which are commonly accepted effective amount dimensions. In general, EC50 is the concentration of component required to induce a 50% change in CRP concentration (reduction in CRP or inhibition of CRP synthesis) compared to the control sample.

When the effect of IL-1 response was evaluated on hepatocytes in the form of CRP secretion, blackberry extract, cranberry extract and resveratrol showed strong activity with an EC50 of 1-10 μg / ml. Thus, these components were particularly effective in modulating the IL-1 / IL-6 response by reducing the synthesis of biomarkers such as CRP. Blueberry powder, rosemary extract and urine fruit powder also showed significant activity in regulating IL-1 / IL-6 response. Additional secreted components were examined for dose specific inhibition of CRP secretion after activation via IL-1 and IL-6 (1 ng / ml, respectively). Among the additional components tested, 10% natural astaxanthin, Aframomum melegueta extract (w / o carrier) and Resveravine® (resveratrol) have strong CRP lowering effects with EC50s of approximately 0.3, 0.6 and 0.8 μg / ml, respectively. (lowering activity). Astaxanthin showed EC50 activity slightly above 1 μg / ml.

Example 2 results, including optional primary components, LPS-promoted IL-1 secretion, IL-1 / IL-6 promoted CRP secretion, or EC50 of other components that inhibit synergistic or antagonistic effects ingredient IL-1 EC50 (μg / mL) (50% effective amount in vitro) CRP EC50 (μg / ml) (50% effective amount in vitro) Synergy +/- Interference +/- Blackberry powder N / A 1-10 Wild rose fruit - Wild rose fruit - Artichoke - Artichoke - Nettle root - Nettle root - Olive extract - Olive extract - Blueberry powder 30-40 10-20 Wild rose fruit + Wild rose fruit - Artichoke - Artichoke - Nettle root + Nettle root - Olive extract - Olive extract - Cranberry Extract > 100 1-10 Wild rose fruit - Wild rose fruit - Artichoke - Artichoke - Nettle root - Nettle root - Olive extract - Olive extract - Rosemary Extract 20-30 30-40 Wild rose fruit - Wild rose fruit - Artichoke - Artichoke - Nettle root - Nettle root - Olive extract - Olive extract - Clover extract N / A N / A Wild rose fruit - Wild rose fruit - Artichoke - Artichoke - Nettle root - Nettle root - Olive extract - Olive extract - Resveratrol N / A 1-10 Wild rose fruit - Wild rose fruit - Artichoke - Artichoke - Nettle root - Nettle root - Olive extract - Olive extract - Elderberry extract 60-70 30-40 Wild rose fruit - Wild rose fruit - Artichoke + Artichoke - Nettle root + Nettle root - Olive extract - Olive extract -

Example 3

In vivo testing is performed in approximately 150-200 human subjects by administering a composition of the present invention at a daily dose for 20 weeks. More specifically, the compositions of the present invention (a) assess inhibition of IL-1 synthesis in Pattern 1 subjects, and (b) measure CRP levels in Pattern 2 subjects with CRP levels above 3 mg CRP / L blood. Investigate to assess the inhibition of the IL-1 response.

In this example, the Pattern 1 subject is a human with an IL-1 genotype that is known to exhibit a "normal" or "hypemic" IL-1 gene expression response. Exaggerated IL-1 gene expression genotype is defined as the presence of at least one copy of allele 2 at the +3954 locus of the IL-1α gene, or two copies of allele 2 at the +4845 locus of the IL-1α gene. In this example, Pattern 2 subjects are humans with elevated blood levels of inflammatory biomarkers, eg, CRP levels of approximately 3-10 mg / L or more. In this range of CRPs, it is more likely that a noticeable improvement, ie a decrease in CRP levels, is observed. In other words, it is likely that a gentle decrease in CRP is detected in Pattern 2 subjects.

One composition of the present invention administered to 50 test subjects in a daily tablet form contains a daily amount of wild rose fruit, blackberry and blueberry: 1200 mg wild rose fruit, 165 mg blackberry, 330 mg blueberry .

Another composition of the present invention administered to 50 test subjects contains a daily amount of wild rose fruit, blackberry, blueberry, Aframomum melegueta : 1200 mg wild rose fruit, 165 mg blackberry, 330 Mg blueberry, 300 mg guinea ginger ( Aframomum melegueta ). These components are provided in tablet form.

Another composition of the present invention administered to 50 test subjects comprises daily doses of wild rose fruit, Aframomum melegueta , and resveratrol (e.g., resveratrol products commercially available from Resveravine®, Bio Serae (Bram, France)) Contains: 1200 mg wild rose fruit, 150 mg Aframomum melegueta , 40 mg resveratrol. These components are provided in tablet form.

Placebos containing no ingredients of the present invention are administered to 50 subjects in the form of daily tablets.

The first 12 weeks of administering the composition and placebo to individual subjects is a double blind phase of the test. During this step, the dose is a loading dose. After 12 weeks, a single blind phase of the test begins. During this step, the above dose is changed to the maintenance dosage estimated from the dripping step data.

In the in vivo test of this example, blood samples are taken from the subject to measure IL-1 and CRP. However, such blood sampling is controlled to quantify and minimize intra-individual variability. For example, inflammatory biomarkers such as CRP and gene expression results such as transcription and subsequent synthesis of IL-1 are measured in a plurality of fasting blood samples; Samples from female subjects are obtained in the same week as the subject's monthly menstrual cycle. This is because high fat diets and menstrual cycles have been found to substantially increase inflammatory biomarkers. Furthermore, this CRP monitoring protocol suggests multiple sampling at close dates.

After administration, the efficacy of the placebo, the first composition, and the second composition may be characterized by inhibition of off body IL-1 production (see method above); IL-1 gene expression in vivo; Inflammatory biomarkers such as IL-6, TNF, IL-10, IL-12, serum amyloid A, fibrinogen, ICAM-1, C reactive proteins, and the like are evaluated. In vivo IL-1 gene expression is assessed by measuring the amount of IL-1 mRNA in subject leukocytes by rtPCR. Evidence of effective interventions for limiting the inflammatory process include inhibition of off-body IL-1 production, inhibition of IL-1 gene expression in vivo, and reduced levels of one or more of the inflammatory biomarkers listed above.

The results of the in vivo test of this example are expected to demonstrate that the composition of the present invention exhibits the effect of inhibiting interleukin cytokines by inhibiting the synthesis of interleukin cytokines in the subject and inhibiting the cascade response induced by interleukin cytokines. Specific examples of this benefit are described in conjunction with subjects in which atherosclerotic plaques have developed that are exacerbated by inflammation, with reference to FIGS. 1-3.

1 shows how inflammation and interleukin cytokines contribute to the development of atherosclerotic plaques. Specifically, monocyte leukocytes 10 enter arterial wall tissue 100 to suck up oxidative lipids, recruit additional leukocytes 14 with inflammatory cytokines such as IL-1, and plaque through growth factors. Stimulates growth 30 to cause stenosis. Cytokines 20 released by leukocytes in plaques can cause plaque destabilization and ultimately rupture and thrombosis.

2 shows IL-1 synthesis 200 and IL-1 reaction 300. Specifically, leukocytes 10 synthesize cytokines 20, which promote liver 500 production of acute-phase proteins, such as CPR.

3 shows that the composition of the present invention inhibits the production of cytokine 200 by leukocytes 10. Certain components 500, such as wild rose fruit, blueberry, urinal fruit, may specifically perform this function. The compositions of the present invention may also inhibit the reaction 300 of cells and / or liver 50 to cytokines by reducing or eliminating the synthesis of CRP. Certain components 600, such as blackberry, resveratrol, Aframomum melegueta and / or astaxanthin, may specifically perform this function.

Example 4

The in vivo effect of daily administration of three different compositions of the invention was assessed periodically in 120 human subjects for 12 weeks using a double blind, placebo-controlled test. In particular, for recognized markers of inflammation such as plasma levels of C-reactive protein (CRP) and other markers of inflammation such as exogenous IL-1 production and in vivo IL-1 synthesis and / or expression The effect of the composition of the present invention was evaluated. All human subjects who participated in the study were 18 years of age or older, judged to be generally healthy based on interviews and abbreviated physical exams, and were willing to maintain their normal diet and exercise habits during the test, at least 1 It was non-smoker for years and showed mean CRP levels between 2 mg / l and 10 mg / l.

All human subjects analyzed in this study were classified into two groups: (1) subjects with IL-1 pattern 1 genotype and (2) subjects with IL-1 non-pattern 1 genotype. As described above, human subjects carrying the IL-1 Pattern 1 genotype are generally known to possess an "hypemic" IL-1 gene expression response. The IL-1 Pattern 1 genotype is at least one copy of allele 2 at the +3954 locus of the IL-1β gene [IL-1α (4845) = 1.2 and IL-1β (+3954) = 1.2 or 2.2], or IL- It is defined as the presence of two copies of allele 2 [IL-1α (+4845) = 2.2] at the +4845 locus of the 1α gene. Subjects having an IL-1 non-pattern 1 genotype may have genotypes other than Pattern 1 as defined herein.

All subjects were randomly assigned to one of four groups. Group 1 consisted of 10 subjects of pattern 1 genotype and 22 subjects of non-pattern 1 genotype. Group 1 was administered Composition 1, as described in Table V below. Group 2 consisted of 9 subjects of pattern 1 genotype and 22 subjects of non-pattern 1 genotype. Group 2 was administered Composition 2, as described in Table V below. Group 3 consisted of 10 subjects of pattern 1 genotype and 20 subjects of non-pattern 1 genotype. Group 3 was administered Composition 3, as described in Table V below. Group 4 consisted of 12 subjects of pattern 1 genotype and 15 subjects of non-pattern 1 genotype. Group 4 received placebo.

Table V lists the components of each composition of the invention tested in this test and the dosage regimen for each of them.

Tablet compositions administered according to Example 4 and their dosage regimens Tablet Compositions Administered Daily dose (taken once in the morning) Composition 1: 300 mg wild rose fruit powder extract + 41 mg blueberry powder extract + 83 mg blackberry powder extract + 75 mg Aframomum melegueta extract 4 active tablets Composition 2: 300 mg wild rose fruit powder extract + 41 mg blueberry powder extract + 83 mg blackberry powder extract + 10 mg resveratrol (eg, resveratrol product commercially available from Resveravine®, Bio Serae (Bram, France)) 4 active tablets Composition 3: 300 mg wild rose fruit powder extract + 10 mg resveratrol (such as resveratrol product commercially available from Resveravine®, Bio Serae (Bram, France)) + 75 mg Aframomum melegueta extract 4 active tablets Placebo 4 placebo tablets

Regardless of group assignment, subjects were instructed to take the same number of tablets once daily, as described in Table V. All tablets and all placebo tablets comprising the compositions of the present invention (compositions 1-3) were identical in appearance. Inert excipients such as microcrystalline cellulose, corn starch, dicalcium phosphate and modified cellulose gum, magnesium stearate, silicon dioxide Processing aids such as dioxide) have been added to tablets comprising the compositions of the present invention to enable processing of these compositions into tablets.

Placebo tablets matched tablets of compositions 1, 2, and 3 in size and appearance. These placebo tablets included a combination of inert excipients. For example, these placebo tablets include microcrystalline cellulose, corn starch, dicalcium phosphate and modified cellulose gum, magnesium stearate, silicon dioxide It contains one or more processing aids, such as silicon dioxide.

During the course of the trial, each subject underwent 11 periodic (approximately weekly) analyzes as outlined below. Each analysis included an informal physical examination of the test subject, including measurement of the vital sign, weight, assessment of concurrent medical use, assessment of dose compliance of the tablets prescribed during the trial, and investigation of adverse events. Additionally, approximately once every other periodic analysis (approximately every two weeks), CRP, glucose, creatinine, uric acid, SGOT, SGPT, total bilirubin, albumin, sodium chloride various molecules including sodium chloride, BUN, calcium, LDH, alkaline phosphatase, total protein, potassium, CO ₂ , GGT, phosphorus, magnesium, CPK Serum levels were analyzed. Subjects with abnormal serum levels were reviewed approximately 1 week later. In addition, cytokine inflammatory biomarkers, including IL-1β, TNF-α, IL-6, IL-8, IL-10, IL-12, were analyzed in each subject approximately every two weeks. Furthermore, blood and urine samples were taken from each individual for approximately seventh and eleventh weeks, with each blood sample measuring hemoglobin, hematocrit, blood count, and urine samples Color, specific gravity, pH, protein, glucose, ketone, bilirubin, nitrite, leukocyte esterase, urobilinogen, leukocyte cells, epithelial cells, and bacteria were analyzed.

In this example, blood sampling was controlled to quantify and minimize intra-individual variability. For example, as outlined above, inflammatory biomarkers such as CRP and gene expression results, such as transcription and subsequent synthesis of IL-1, were measured in a plurality of fasting blood samples; Blood samples from female subjects were obtained in the same week as the subject's monthly menstrual cycle. These blood sampling methods are designed to control substantially increased expression of inflammatory biomarkers that frequently occur during the menstrual cycle in response to high fat meals.

Periodically, for example, at 4, 8, 12 weeks post-dose, the efficacy of placebo, Composition 1, Composition 2, Composition 3 is determined by (a) inhibition of IL-1 synthesis and / or expression in the test subject. Off body analysis (see method above); (b) analysis of IL-1 gene expression in vivo (rtPCR was used to measure IL-1 mRNA levels in samples obtained from test subjects); (c) serum and / or cell synthesis and expression levels of inflammatory biomarkers such as IL-6, TNF, IL-10, IL-12, serum amyloid A, fibrinogen, ICAM-1, C reactive proteins, etc. Evaluated by analysis.

The results of these evaluations are reported in Figures 4-15. The graphs shown in FIGS. 4-15 are normalized to baseline values and are expressed as fractions or folds (percentage of base divided by 100) of baseline values.

5 shows that after 12 weeks of administration of Compositions 1, 2, 3 to the entire study population, there is a decrease in CRP synthesis and / or expression compared to administration of placebo.

As shown in FIG. 7, when the CRP response in a pattern 1 subject was analyzed separately from the response in a non-pattern 1 test subject, all active treatments vs. There was a marked difference between baseline and placebo. In particular, Composition 2 (wild rose + berry + Resveravine® ((Resveravine® is a product of resveratrol commercially available from Bio Serae (Bram, France))) (P = 0.0113)) is approximately 50% of the ratio. Inhibited CRP synthesis and / or expression.

FIG. 8 shows that after 12 weeks of administration of Compositions 1, 2, and 3 the off-body IL-1 synthesis is slightly reduced compared to placebo and baseline levels. No significant difference was observed between compositions 1, 2 and 3.

FIG. 10 shows that in test subjects having a Pattern 1 genotype, there is a significant deviation of the response between the composition of the present invention and the placebo composition. In particular, after 12 weeks, IL-1 production was reduced by approximately 20% -30% compared to baseline in Group 1, Group 2 and Group 3 (P = 0.0068).

As shown in FIG. 12, criteria vs. Analysis of the 12-week data demonstrates that IL-1 gene expression is significantly decreased after administration of Compositions 1, 2, and 3, with the most prominent result associated with administration of Composition 2 (P = 0.0047).

As shown in FIG. 14, independently evaluating data for test subjects carrying a Pattern 1 genotype reduced IL-1 gene expression by approximately 80% relative to baseline. This reduction is in group 2 administered Composition 2 (Composition 2 contains wild rose fruit, berry and Resveravine® (Resveravine® is a product of resveratrol commercially available from Bio Serae (Bram, France)). Especially remarkable (P = 0.0158).

4, 6, 9, 11, 13, and 15 show that test subjects who received placebo experienced a sharp increase in CRP expression levels, IL-1 exogenous expression levels, and IL-1 gene expression levels after 4 weeks of administration. Without being bound to any theory, it is believed that this sharp increase is due to changes in the dietary subject's dietary habits. This change in dietary habits is likely due to the simultaneous occurrence of certain holidays and clinical trials.

Significantly, each of FIG. 4, 6, 9, 11, 13, 15 also shows that the test subjects to whom compositions 1, 2, or 3 were administered were at some point during the clinical trial, CRP expression levels, exogenous expression levels of IL-1, Or does not show a sharp increase in IL-1 gene expression levels. Rather, these subjects maintained a sustained or reduced state of expression of CRP and IL-1. Thus, although compositions 1, 2, and 3 do not always reduce CRP expression levels, off-body expression levels of IL-1, or IL-1 gene expression levels, compositions 1, 2, 3 each express CRP and IL-1 expression. The immune response was regulated by preventing a sharp increase in levels. One example of this regulatory effect can be observed at the 4 week marker in FIGS. 4, 6, 9, 11, 13, 15.

The results shown in FIGS. 4-15 show that Composition 2 comprises Pattern 1 genotype containing wild rose fruit + berry + Resveravine® (Resveravine® is a product of resveratrol commercially available from Bio Serae (Bram, France)). Demonstrating that the subjects selectively down-regulate IL-1 gene activity, including synthesis and expression. The magnitude and time patterns of IL-1 gene expression, IL-1 production, CRP expression, and / or synthesis observed in this Example illustrate the inflammatory environment amplified in subjects with exaggerated IL-1 gene responses having a Pattern 1 genotype. Is consistent with the current paradigm.

In contrast to the results in pattern 1 subjects, the anti-inflammatory effect observed in non-pattern 1 subjects was much unknown. This genotypic (IL-1 haplotype) differential response is characterized by composition 2 (ie, wild rose + berry + Resveravine® (Resveravine® is a product of resveratrol commercially available from Bio Serae (Bram, France)). Pattern 1 subjects selectively down-regulate the inflammatory pathway at the level of IL-1 gene activity and imply a clinically significant reduction in established downstream markers of inflammation, eg, CRP.

V. How to use

Based on the test results of the components that may be included in the composition according to the present invention as illustrated by Examples 1-4 above, when a composition containing these components is administered to a subject, a mediator of inflammation, eg interleukin, It is clear that inflammatory responses can be controlled by controlling cytokines. More specifically, it is clear that the compositions of the present invention can be used to specifically inhibit the synthesis of interleukin cytokines such as interleukin-1 (IL-1), for example by inhibiting mRNA transcription of IL-1. In addition, as evidenced by the results reported herein, the compositions of the present invention can be used to specifically inhibit the expression / secretion of interleukin cytokines such as IL-1. Furthermore, it is clear that the compositions of the present invention can modulate the inflammatory response by reducing the synthesis and / or expression / secretion of inflammatory biomarkers such as CRP. Reduction in the synthesis and / or expression / secretion of CRP inhibits the response of CRP to interleukin cytokines in the subject's body. In addition, it is clear that the compositions of the present invention can modulate the immune response by preventing an increase in expression, synthesis and / or secretion levels of mediators of inflammation such as CRP and IL-1.

The results described herein demonstrate that daily administration of three different compositions of the invention achieves a reduction in IL-synthesis and expression and a reduction in CRP synthesis and / or expression / secretion in the entire subject population. However, the most striking evidence of the ability to modulate the inflammatory response using the compositions of the present invention was observed in a population of subjects with a pattern 1 genotype. For example, daily administration of composition 2 (eg, wild rose fruit + berry + Resveravine® (Resveravine® is a product of resveratrol commercially available from Bio Serae (Bram, France)) at the doses described above is pattern 1 After two weeks in the subject population with genotype, a reduction of approximately 80% (relative to baseline) in IL-1 gene expression and a reduction of approximately 50% in expression of inflammatory biomarker CRP were achieved.

These results are significant because inflammation is a major component of various diseases, including cardiovascular disease. Indeed, given that inflammatory cytokines such as IL-1 and IL-6 are key mediators of the inflammatory response in the body, the compositions of the present invention can be used to modulate inflammatory responses associated with diseases and / or abnormal disorders. Note that there is. For example, the compositions of the present invention may be used for arthritis, cardiovascular disease, osteoporosis, Alzheimer's disease, inflammatory responses to trauma, or other abnormal disorders or diseases associated with inflammation or immunomodulatory responses, such as pain and stiffness associated with inflammation. It is used to control the inflammatory response in afflicted individuals.

In another example, osteoporosis is associated with abnormally high IL-1 release levels. For this reason, a method of treating osteoporosis by controlling IL-1 synthesis and expression through administration of a therapeutically effective amount of a composition of the invention is envisioned in the present invention.

Given the relationship between inflammation and cardiovascular disease, such as atherosclerosis, thrombosis, aortic stenosis, etc., such cardiovascular disease may be administered by administering a therapeutically effective amount of a composition containing at least one Methods of treatment are also contemplated herein. Indeed, inflammation in cardiovascular disease is associated with increased synthesis and expression levels of IL-1. Expression of IL-1 induces the synthesis, expression, and secretion of CRP, which is thought to further promote IL-1 synthesis and / or expression. For this reason, the compositions of the present invention, for example, Composition 2, which have been shown to reduce CRP levels by approximately 50% and reduce levels of IL-1 gene activity by approximately 80%, are useful for modulating inflammatory responses and for treating cardiovascular disease. .

In addition, the IL-1 restriction compositions of the present invention can be used to limit or control inflammatory reactions resulting from surgery, trauma and allergic reactions involving the skin, lungs, eyes, ears, nose, neck, digestive tract, nervous system, and the like. .

Furthermore, it has been observed that nervous system cells and tissues secrete significant amounts of IL-1 when stressed under inflammation, and for this reason, the compositions of the present invention can cause mental problems, headaches, earaches and degenerative neurological diseases, such as It can also be used to treat Alzheimer's disease.

The above description is a preferred embodiment of the present invention. Various modifications may be made without departing from the spirit and broader aspects of the invention as defined in the appended claims (interpreted in accordance with the principles of patent law, including equivalents). By way of example, any citation of a component in the singular form is not to be construed as limiting the component to the singular.

Claims (56)

In a method of controlling the inflammatory response in a subject, rosehip and blackberry, blueberry, resveratrol or a derivative thereof, viniferin, Aframomum melegueta extract A composition comprising at least one of the foregoing, wherein administration of the composition reduces the synthesis of at least one mediator of inflammation. The composition of claim 1, wherein the composition is wild rose fruit; At least one of resveratrol and biniferin; Blackberry, blueberry, Ginger ( Aframomum melegueta ) extract characterized in that it contains at least one. The method of claim 1, wherein at least one mediator of inflammation is interleukin-1. The method of claim 3, wherein reducing the synthesis of mediators of inflammation further comprises blocking transcription of Interleukin-1. The method of claim 1, wherein the mediator of inflammation is a C reactive protein. The method of claim 3, further comprising reducing the synthesis of a second mediator of inflammation. The method of claim 6, wherein the second mediator of inflammation is a C reactive protein. The method of claim 1, wherein the subject has an IL-1 Pattern 1 genotype. The method of claim 1, wherein the composition contains 800-1500 mg wild rose fruit, 200-500 mg blackberry powder, 50-300 mg blueberry powder, 20-150 mg resveratrol or a derivative thereof. . The method of claim 2, wherein the composition contains approximately 1200 mg wild rose fruit, approximately 330 mg blackberry powder, approximately 165 mg blueberry powder, approximately 40 mg resveratrol or a derivative thereof. The method of claim 1, wherein the composition contains 800-1500 mg wild rose fruit, 20-150 mg resveratrol or a derivative thereof, 150-500 mg Aframomum melegueta extract. The method of claim 2, wherein the composition contains approximately 1200 mg wild rose fruit, approximately 40 mg resveratrol or a derivative thereof, approximately 300 mg of Aframomum melegueta extract. In a method of modulating an inflammatory response in an individual, there is provided a composition comprising at least one of wild rose fruit and blackberry, blueberry, resveratrol or derivatives thereof, viniferin , Aframomum melegueta extract, wherein the composition of the composition Administration reduces the expression of at least one mediator of inflammation. The composition of claim 13, wherein the composition is wild rose fruit; At least one of resveratrol and biniferin; Blackberry, blueberry, Ginger ( Aframomum melegueta ) extract characterized in that it contains at least one. The method of claim 13, wherein at least one mediator of inflammation is interleukin-1. The method of claim 13, wherein the mediator of inflammation is a C reactive protein. The method of claim 13, further comprising reducing the synthesis of a second mediator of inflammation. The method of claim 17, wherein the second mediator of inflammation is a C reactive protein. The method of claim 13, wherein the subject has an IL-1 Pattern 1 genotype. The method of claim 13, wherein reducing the expression of the mediator of inflammation further comprises reducing the level of interleukin-1 in the serum of the individual. The method of claim 13, wherein the composition contains 800-1500 mg wild rose fruit, 200-500 mg blackberry powder, 50-300 mg blueberry powder, 20-150 mg resveratrol or a derivative thereof. . The method of claim 13, wherein the composition contains approximately 1200 mg wild rose fruit, approximately 330 mg blackberry powder, approximately 165 mg blueberry powder, approximately 40 mg resveratrol or a derivative thereof. The method of claim 13, wherein the composition contains 800-1500 mg wild rose fruit, 20-150 mg resveratrol or a derivative thereof, 150-500 mg Aframomum melegueta extract. The method of claim 13, wherein the composition contains approximately 1200 mg wild rose fruit, approximately 40 mg resveratrol or derivative thereof, approximately 300 mg of Aframomum melegueta extract. The composition of claim 13, wherein the composition contains approximately 1200 mg wild rose fruit, approximately 330 mg blackberry powder, approximately 165 mg blueberry powder, approximately 40 mg resveratrol or a derivative thereof, wherein the individual has IL-1 pattern 1 Retaining genotypes. The composition of claim 13, wherein the composition contains approximately 1200 mg wild rose fruit, approximately 40 mg resveratrol or derivative thereof, approximately 300 mg of Aframomum melegueta extract, wherein the individual has an IL-1 Pattern 1 genotype Characterized in that the method. In dietary supplements containing wild rose fruit and at least one of blueberry, blackberry, resveratrol or derivatives thereof, viniferin , Aframomum melegueta extract and for regulating the immune response in an individual, Dietary supplement, characterized in that the effective. The fruit of claim 27, wherein the wild rose fruit; At least one of resveratrol and biniferin; A dietary supplement characterized in that it contains at least one of blackberry, blueberry, and Aframomum melegueta extracts. The dietary supplement of claim 27, wherein the inflammatory cytokine is interleukin-1. The dietary supplement of claim 27, further comprising 800-1500 mg wild rose fruit, 200-500 mg blackberry powder, 50-300 mg blueberry powder, 20-150 mg resveratrol or a derivative thereof. . The dietary supplement of claim 27, which contains 800-1500 mg of wild rose fruit, 20-150 mg of resveratrol or a derivative thereof, and 150-500 mg of Aframomum melegueta extract. Wild rose fruit; At least one of resveratrol and biniferin; A dietary supplement containing at least one of blueberry, blackberry and Aframomum melegueta extracts and effective for reducing the expression of inflammatory cytokines in a dietary supplement for modulating an immune response in a subject. The dietary supplement of claim 32, wherein the inflammatory cytokine is interleukin-1. 33. The dietary supplement of claim 32, further comprising 800-1500 mg wild rose fruit, 200-500 mg blackberry powder, 50-300 mg blueberry powder, 20-150 mg resveratrol or viniperin. . The dietary supplement of claim 32, further comprising 800-1500 mg of wild rose fruit, 20-150 mg of resveratrol or viperin, 150-500 mg of Aframomum melegueta extract. In a method of modulating an inflammatory response in an individual, there is provided a composition comprising at least one of wild rose fruit and blackberry, blueberry, resveratrol or derivatives thereof, viniferin , Aframomum melegueta extract, wherein Administering prevents an increase in the synthesis of at least one mediator of inflammation. The composition of claim 36, wherein the composition is wild rose fruit; At least one of resveratrol and biniferin; Blackberry, blueberry, Ginger ( Aframomum melegueta ) extract characterized in that it contains at least one. The method of claim 36, wherein at least one mediator of inflammation is interleukin-1. The method of claim 36, wherein the mediator of inflammation is a C reactive protein. The method of claim 38, further comprising reducing the synthesis of a second mediator of inflammation. The method of claim 40, wherein the second mediator of inflammation is a C reactive protein. The method of claim 36, wherein the subject has an IL-1 Pattern 1 genotype. The method of claim 36, wherein the composition contains 800-1500 mg wild rose fruit, 200-500 mg blackberry powder, 50-300 mg blueberry powder, 20-150 mg resveratrol or a derivative thereof. . The method of claim 37, wherein the composition contains approximately 1200 mg wild rose fruit, approximately 330 mg blackberry powder, approximately 165 mg blueberry powder, approximately 40 mg resveratrol or a derivative thereof. The method of claim 36, wherein the composition contains 800-1500 mg wild rose fruit, 20-150 mg resveratrol or a derivative thereof, 150-500 mg Aframomum melegueta extract. The method of claim 37, wherein the composition contains approximately 1200 mg wild rose fruit, approximately 40 mg resveratrol, approximately 300 mg Aframomum melegueta extract. In a method of modulating an inflammatory response in an individual, there is provided a composition containing at least one of wild rose fruit and blackberry, blueberry, resveratrol or derivatives thereof, viniferin , Aframomum melegueta extract, wherein the composition Administration of prevents an increase in the expression of at least one mediator of inflammation. The composition of claim 47, wherein the composition is wild rose fruit; At least one of resveratrol and biniferin; Blackberry, blueberry, Ginger ( Aframomum melegueta ) extract characterized in that it contains at least one. The method of claim 48, wherein the at least one mediator of inflammation is interleukin-1. The method of claim 47, wherein the mediator of inflammation is a C reactive protein. The method of claim 49, further comprising reducing the synthesis of a second mediator of inflammation. The method of claim 51, wherein the second mediator of inflammation is a C reactive protein. The method of claim 47, wherein the subject has an IL-1 Pattern 1 genotype. The method of claim 47, wherein the composition contains 800-1500 mg wild rose fruit, 200-500 mg blackberry powder, 50-300 mg blueberry powder, 20-150 mg resveratrol or a derivative thereof. . The method of claim 47, wherein the composition contains 800-1500 mg wild rose fruit, 20-150 mg resveratrol or a derivative thereof, 150-500 mg Aframomum melegueta extract. The composition of claim 47, wherein the composition contains approximately 1200 mg wild rose fruit, approximately 330 mg blackberry powder, approximately 165 mg blueberry powder, approximately 40 mg resveratrol or a derivative thereof, wherein the subject has IL-1 pattern 1 Retaining genotypes.

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