WO2022167827A1

WO2022167827A1 - Composition for controlling and/or preventing oxidative stress comprising at least s-adenosyl methionine and astragalus sp. polysaccharides

Info

Publication number: WO2022167827A1
Application number: PCT/IB2021/000049
Authority: WO
Inventors: Michel Frey
Original assignee: Idec Therapeutic
Priority date: 2021-02-05
Filing date: 2021-02-05
Publication date: 2022-08-11
Also published as: EP4288063A1

Abstract

Compositions intended for controlling and/or preventing oxidative stress, particularly in a human being, in optimizing GSH/GSSG blood serum ratio. Such a composition comprising at least S-adenosyl methionine and Astragalus sp. polysaccharides, can be used as a food supplement or as a composition for topical application such as a cosmetic and/or dermatological and/or pharmaceutical cream or gel.

Description

Composition for controlling and/or preventing oxidative stress comprising at least S-adenosyl methionine and Astragalus sp. polysaccharides

TECHNICAL FIELD OF THE INVENTION

The invention relates to the field of compositions intended for controlling and/or preventing oxidative stress, particularly in a human being. Such a composition comprising at least S-adenosyl methionine and Astragalus sp. polysaccharides, can be used as a food supplement or as a composition for topical application such as a cosmetic and/or dermatological and/or pharmaceutical cream or gel.

PRIOR ART

[0001] Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species (ROS) and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damages.

Disturbances in the normal “redox state” of cells can cause toxic effects through the production of peroxides and free radicals from mitochondria that damage all components of the cell and tissue, including proteins, lipids, and DNA. Oxidative stress from oxidative metabolism causes basal damage, as well as strand breaks in DNA.

Basal damage is mostly indirect and caused by ROS generated, 02 (superoxide radical), OH (hydroxyl radical) and H2O2 (hydrogen peroxide). Thus, oxidative stress can cause disruptions in normal mechanisms of cellular signaling

[0002] US2015133370 relates to dietary compositions comprising reduced level of methionine, tryptophan, all amino acids, or protein, dietary compositions comprising glycerol as a substitute for monosaccharides, disaccharides, and polysaccharides to protect subjects against chemotherapy, radiotherapy, oxidative stress, or aging.

[0003] Glutathione is a tripeptide (cysteine, glycine, and glutamic acid) found in relatively high concentrations in many bodily tissues. It plays a pivotal role in reducing oxidative stress, maintaining redox balance, enhancing metabolic detoxification, and regulating the immune system and associated functions. Various chronic, age-related diseases such as those related to neurodegenerative disorders, mitochondrial dysfunctions and correlated diseases, and even cancer, have been related to suboptimal/subfunctional or deficient glutathione levels. There is increasing awareness of its utility in mitigating body toxin load through its ability to enhance hepatic conversion and excretion of compounds such as mercury and persistent organic pollutants (POPs). [0004] One usual confounding factor is the complexity of antioxidants or the situation in which antioxidants can possess prooxidant activity causing a hormetic effect enabling the body to bolster its endogenous antioxidant defenses.

Therefore, there is a need to develop a robust and liable method and composition to control and/or balance oxidative stress in human or in animal body.

[0005] The present invention is based on the work done by the inventor to established reference ranges for GSH/GSSG ratio as a biomarker of healthy conditions to limit early subclinical steps of chronic disease risks. Another biomarker deemed clinically useful is serum y-glutamyltransferase (GGT) that is primarily involved in the metabolism of extracellular reduced glutathione, could be also used to follow the redox status of people.

Indeed, the invention is also based on the assumption made by the inventor that the best option to follow the redox status of tissues is the calculation of the ratio between the 2 forms of glutathione i.e. free form to control oxidative (GSSG, after blocking stress redox) and reduced (i.e. free) form (GSH). The ratio between each chemical status shifts the variability known in individuals and provide the functional activity and physiological equilibrium.

With up-reguiated oxidative stress in daily life, aging, subclinical and clinical diseases, malnutrition or increased toxic burden due to exposure to environmental pollutants, there can be even greater need for glutathione functions. While there may be a need to maintain high levels of glutathione, balancing the ratio between GSH and GSSG is required. In cancer, glutathione may need monitoring in patients undergoing chemotherapy due to the potential to support chemoresistance.

[0006] Astragalus Polysacharides (hereafter also APS) showed already antioxidative activities in scavenging models (superoxide anion radical-scavenging activity and hydroxyl radical-scavenging activity (Li Rui et al, 2010, Carbohydrates Polymers) but have been never described to provide activity on glutathione metabolism and GSH/GSSG balance. The present invention shows that a composition comprising at least APS and S- adenosyl methionine (hereafter SAMe) can control and/or prevent oxidative stress in rebalancing the ratio between GSH and GSSG.

SUMMARY OF INVENTION

[0007] The present invention regards to a composition for controlling and/or preventing oxidative stress comprising at least: S-Adenosyl-methionine and Astragalus sp. polysaccharides (titred 20%, extract). In a preferred embodiment, the invention is a composition for optimizing GSH/GSSG blood serum ratio, above or equal to 10, preferentially above or equal to 15, comprising at least: S-Adenosyl-methionine and Astragalus sp. polysaccharides (titred 20%, extract). According to another preferred embodiment of the inventio, the composition comprises at least a vitamin chosen from vitamins in the B group. The at least vitamin in the B group is selected from vitamins B6, B9, B12 or a mixture thereof. In said composition, Astragalus sp. is Astragalus membranaceus polysaccharides. Moreover, the composition also comprises a magnesium salt. In a specific embodiment, the said composition also comprises vitamin D. Finally, the composition of the present invention is intended for a daily oral intake and comprises at least:

- between 100 and 750 mg of S-Adenosyl-methionine,

- between 50 and 600 mg by weight of Astragalus sp. polysaccharides (purified or titred extract).

Accordingly, the composition is used as a diet supplement. Hence, the composition is in the form of a solid mixture able to be introduced an oral support such as in a capsule, a pill, a tablet or in the form of a mixture able to be introduced in a liquid form.

[0008] In one aspect, the invention is relating to the composition according to the invention for controlling and/or protecting a human or an animal from oxidative stress. This use of the composition is comprising the steps of:

- Administering the composition to a human or an animal in need thereof,

- Controlling the GSH/GSSG blood serum ratio is above or equal to 10, preferably above or equal to 15, preferentially above 30,

- Determining thus that said human or said animal body cells are controlling oxidative stress and/or protecting against oxidative stress. Accordingly, said composition is intended for a daily intake of 2 or 3 capsules or tablets or pills.

[0009] The invention also provides a method for controlling and/or protecting a human or an animal from oxidative stress comprising:

- Administering a composition as described above, to a human or an animal in need thereof,

- Controlling the GSH/GSSG blood serum ratio is above or equal to 10, preferably above or equal to 15; preferentially above 30.

- Determining thus that after treatment said human or said animal body cells are controlling oxidative stress and/or protecting against oxidative stress.

According to said method, the administration of a composition according to the instant invention is a daily intake of 2 or 3 capsules or tablets or pills as described above.

[00010] In another aspect, the invention provides a composition for topical application such as a cosmetic and/or dermatological and/or pharmaceutical cream or gel.

[00011] In another embodiment the instant invention encompasses a process for diagnosing aging, in particular linked to environmental stress, based on the oxidative stress in a human or in an animal comprising:

- taking a blood sample in a human or in an animal to be diagnosed,

- measuring the GSH/GSSG blood serum ratio,

- optionally, determining whether the GSH/GSSG blood serum ratio is below 30, preferably below 15, preferentially below 10,

- Determining thus that said human or said animal body cells are subject to oxidative stress,

- Optionally, providing a recommendation for rebalancing the GSH/GSSG blood serum ratio and thus controlling and/or preventing said oxidative stress.

DESCRIPTION OF THE FIGURES

Figure 1 :

Figurel depicts the Time-related effects of the treatment, according to the composition claimed herein, on the ratio GSH/GSSG in blood. - Increase of the ratio means higher global ant/oxydative activity (AOX).

- individual profiles by each line.

Figure 2:

This figure 2 shows the Efficacy of a treatment, according to the composition claimed herein, on the ratio GSH/GSSG in blood.

- individuals ’data by circles including sex

- Box-distribution of the ratio GSH/GSSG before and after mix treatment.

- Increase of the ratio means protective AOX activity induced by the mix treatment.

Descriptive statistical analysis by box-plot tool depicts the group of numerical data by each volunteer. This analysis has lines extending from the boxes indicating variability outside the upper and lower quartiles. Box-plot are no parametric, they display variations in samples of a statistical population.

This figure shows the efficacy of a treatment, according to the composition used in example 2, on the ratio GSH/GSSG in blood - global analysis of data in human study -

Figure 3

Figure 3 represents the Sex-dependant analysis of the effects of a mix according to the composition claimed herein, on the ratio GH/GSSG.

- No sex differences observed

- Same level of efficacy between mate and female

DISCLOSURE OF THE INVENTION

[00012] The invention aims to propose a composition able to control and/or preventthe oxidative stress, comprising at least S-Adenosyl-methionine and Astragalus sp. Polysaccharides.

In a preferred embodiment, the instant invention aims to provide a composition for optimizing GSH/GSSG blood serum ratio, above or equal to 10, preferably above or equal to 15, preferentially above 30. Such composition comprising at least: S-Adenosyl- methionine and Astragalus sp. polysaccharides (titred 20%, extract) In a specific embodiment, said composition as describes above comprises in addition a vitamin chosen from vitamins in the B group.

[00013] S-adenosylmethionine (SAMe) is the principai methyl donor and the precursor of aminopropyl groups and of glutathione in the liver; it also regulates the activities of various enzymes. SAMe is formed by activation of dietary methionine by ATP in a reaction catalyzed by methionine adenosyltransferase (EC 2.5.1 .6). SAMe contains a high-energy sulfonium ion, which activates each of the attached carbons toward nucleophilic attack and confers on SAMe the ability to participate in 3 major types of reactions: transmethylation, transsulfuration, and aminopropylation.

[00014] Astragalus membranaceus (essentially roots) is a type of traditional Chinese medicine with a long history of clinical application. It is used in the improvement and treatment of various diseases as medicine and diet to decrease the spleen and improve the qi.

The main component of Astragalus membranaceus, preferably the roots, is the polysaccharide fraction (APS for Astragalus Potysachar/des), which possesses multiple pharmacological properties. Thus, APS known activities are 1 ) immune regulation ie proliferation of immune ceils, release of cytokines, and secretion of immunoglobulin, 2) anti-aging, 3) anti-tumor by enhancing immunity and apoptosis of tumor cells, inhibiting the proliferation and transfer of tumor cells, 4) antiviral effects, 5) regulation of blood glucose such as type I diabetes mellitus, type II diabetes mellitus and diabetic complications, 6) lipid-lowering, 7) anti-fibrosis, 8) antimicrobial activities and antioxidants activities notably.

[00015] The invention relates to a composition inducing an anti-oxidative ratio GSH/GSSG (>=10) which comprises S-Adenosyl-methionine and Astragalus sp. polysaccharides (purified and Hired extracts), preferentially Astragalus membranaceus and a vitamin selected among the B group. A liquid or solid food supplement and a cosmetic or dermatological composition can be characterized in that it comprises the composition described above.

[00016] In a specific embodiment, said composition as describes above comprises in addition a vitamin chosen from vitamins in the B group. “A vitamin chosen in B group” means all the group B vitamins and in particular vitamins: B1 , B2, B3, B5, B6, B8, B9, B12, their respective precursors, or a mixture of vitamins and/or respective precursors. Advantageously, said vitamin is B6, B9 or B12, their respective precursors, alone or a mixture thereof or a mixture of said vitamins and/or respective precursors.

[00017] Vitamin B6 promotes particularly the absorption of magnesium and the synthesis of serotonin (an essential neurotransmitter).

[00018] Vitamin B9 or folic acid has the property of also acting on the metabolism of amino acids and the synthesis of proteins; it participates in the renewal of immune cells, in the formation of red corpuscles and in the supply of oxygen needed by the organism.

[00019] Vitamin B12 is essential to the correct functioning of the central and peripheral nervous systems.

[00020] Optionally, the Vitamin D is added in the composition of the invention alone or mixed with other vitamins.

[00021] Optionnaly, said composition comprises a magnesium salt. “Magnesium salt” means any salt comprising magnesium and being biologically tolerated by the human body. The following can be cited as an example: magnesium chloride, magnesium citrate, magnesium gluconate, magnesium carbonate, magnesium pidolate, magnesium lactate, magnesium aspartate, magnesium sulphate, magnesium hydroxide, magnesium oxide, magnesium bisglycinate and magnesium glycerophosphate. The choice of the type of magnesium salt can be made according to the elementary magnesium content or according to the bioavailability and solubility of the magnesium salt.

[00022] The effect of the magnesium is to reduce inflammation, oxidative stress and endothelial malfunctioning (protective layer in the arteries). It also helps to reduce the formation of blood clots, which give rise to infarcts and certain strokes, and to reduce arterial pressure. Advantageously, said magnesium salt chosen for implementing the invention is magnesium oxide or magnesium glycerophosphate; preferably said magnesium salt is of marine origin. [00023] According to another embodiment, said composition is in the form suitabie for topical administration. Hence, topical composition is in a form of oil in water or water in oil emulsions, an aqueous or oily gel, or any liquid or semi-liquid topical form.

[00024] “Topical administration” means any administration by local method, for example on the skin, an orifice or mucosa. Topical administration, as used here, comprises the cutaneous, auricular, nasal, vaginal, urethral and rectal routes. Preferably the composition is dermatological acceptable composition. “Dermatologically acceptable composition” means all compositions intended to be administered topically and respectful of the physical and chemical integrity of the skin and mucosa, such as so-called cosmetic, dermatological or pharmaceutical compositions.

[00025] For this type of administration, said composition is preferably in the form of a gel or an emulsion, preferably having properties of resistance to oxidation by the incorporation in the composition of antioxidants such as extracts of acai berry, pecan nut, hazelnut, prune, mulberry, pomegranate, strawberry, kiwi fruit, date, fig, garlic, almond, broccoli, beetroot, eggplant or any other known molecule having the property of limiting oxidative stress such as resveratrol, quercetin or any of its derivatives alone or mixed, vitamin E or vitamin C.

[00026] Preferably, and when it is necessary to add an oil, an essential oil will preferably be chosen, for example essential oil of helichrysum italicum to promote microcirculation, essential oil of Aniba parviflora for firming skin tissues, essential oil of Citrus limon, for its blood-fluidising power, essential oil of Wintergreen for its vasodilatory action, essential oil of Lavandula officinalis for its healing and fluidising action, essential oil of Mentha piperita for its antipruritic power, essential oil of ravinsara for its skin energising action, essential oil of Melaleuca alternifolia for its skin antibacterial activity or essential oil of Pelagonium asperum for its “anti-wrinkle” power.

[00027] For administration of the oral type, the composition may be in the form of a liquid such as a syrup or a drinkable suspension, or in the form of a solid such as a tablet, a pill or a capsule. Preferably, the solid form is acid-resistant, in order to ensure disintegration of the constituents for assimilation thereof by the body, at the intestinal and non-gastric level. [00028] Advantageously, said composition according to the invention for ora! administration, comprises at least: between 50 mg and 1000 mg, S-Adenosyl-methionine, between 20 mg and 1000 mg Astragalus sp. polysaccharides, optionally between 1 mg and 50 mg magnesium salt.

[00029] Altogether, the composition according to the invention comprises at least for a daily intake:

- between 100 and 750 mg of S-Adenosyl-methionine,

- between 50 and 600 mg by weight an Astragalus polysaccharides (purified or titred extract).

Preferentially, the daily intake is administrated in 2 or 3 capsules or tablets or pills per day.

[00030] More particularly, when the form of administration is topical, the composition according to the invention may preferably contain at least from 0,5% to 20% by weight S- Adenosyl-methionine, more preferentially at least from 1 % to 10% by weight S- Adenosyl-methionine.

[00031] Another subject matter of the invention is a food supplement for human or animal (preferably domestic pets), liquid or solid, comprising a composition according to the invention.

[00032] A method for, or a process for controlling and/or protecting a human or an animal from oxidative stress comprising:

- Administering a composition as described previously, to a human or an animal in need thereof, preferentially once daily and more preferred for a determined duration. Said duration is at least 2 weeks, better between 3 weeks and several months and even better between 4 weeks (1 month) and 12 weeks (3 months).

- Controlling, preferentially at several time points, that the GSH/GSSG blood serum ratio is above or equal to 10, preferably above or equal to 15, preferentially above 30.

- Determining thus that said human or said animal body cells are controlling oxidative stress and/or protecting against oxidative stress.

Accordingly, it can be decided whether the intake of a composition according to the invention is pursued, modulated or stopped. [00033] Finally, invention encompasses also a process for diagnosing aging in particular linked to environmental stress based on the oxidative stress, in a human or in an animal comprising:

- taking a blood sample in a human or in an animal to be diagnosed,

- measuring the GSH/GSSG blood serum ratio,

- Optionally, providing a recommendation for rebalancing the GSH/GSSG blood serum ratio. The GSH/GSSG blood serum ratio rebalance is the way for controlling and/or preventing said oxidative stress or aging..

Altogether, invention provides a process for diagnosing aging and oxidative stress as well as method (or process) for controlling and/or preventing said oxidative stress in rebalancing GSH/GSSG blood serum ratio.

Examples:

[00034] Example 1 : example of compositions in the scope of invention

Compositions according to preferred embodiment of the invention have the following composition in weight:

- SAMe: from about 250 mg to 500mg

- Astragalus membranaceus polysaccharides (20% extract): from about 100mg to 500mg

- Magnesium/marine salt: from about 50mg to 300mg, preferably between 100mg and 200 mg

- Zinc Citrate: from about 10 to 50mg

- Magnesium stearate: from about 5 to 30mg

- Selenomethionine (0,5%): from about 0,1 mg to 5mg, preferably between 1 mg and 3mg

- Vit B6 (Piridoxine chlor. 82%): from about 0,1 mg to 5mg preferably between 1 mg and 3mg

- Vit B12 (Mecobalamine): from about 1 pg to 5 pg According to a preferred embodiment, compositions as described above are included in vegetal caps HPMC

[00035] Example 2: clinical trial in human volunteers after 2 months treatment This example is clinical results in human volunteers after 2 months treatment with a mix of SAMe (500 mg per day) and Astragalus membranaceus polysaccharides (20% titred extract (400mg per day)) Table 1 :

This example provides individual data as depicted in Figure 1 and shows the benefits of a composition according to the invention regarding the prevention of oxidative stress. It shows particularly that after treatment according to example 1 , the balance ratio is favorably in favor of GSH rate. These results show that after treatment, GSH/GSSG blood serum ratio is at least above or equal to 10 and preferentially above or equal to 15, preferentially above 30.

[00036] Example 3: Efficacy of a treatment

This example demonstrates the efficacy of a treatment, according to the composition used in example 2, on the ratio GSH/GSSG in blood. The data of example 2 have been compiled and provide now a global analysis of data in human study as depicted in Figure 2 and 3.

- individuals ’data by circles

- Box-distribution of the ratio GSH/GSSG before and after mix treatment.

According to the Figure 2, it is clearly showed that a treatment according to the invention provides an Increase of the ratio means protective AOX activity induced by the mix treatment.

According to Figure 3, it appears that no difference has been registered between the two sexes. The same results on the ratio GSH/GSSG in blood have been obtain independently of sex.

Claims

1.Composition for controlling and/or preventing oxidative stress comprising at least: S- Adenosyl-methionine and Astragalus sp. polysaccharides (titred 20%, extract)

2.Composition according to claim 1 for optimizing GSH/GSSG blood serum ratio, above or equal to 10 comprising at least: S-Adenosyl-methionine and Astragalus sp. polysaccharides (titred 20%, extract).

3. Composition according to claim 1 for optimizing GSH/GSSG blood serum ratio, above or equal to 15, preferentially above 30, comprising at least: S-Adenosyl-methionine and Astragalus sp. Polysaccharides (titred 20%, extract)

4.Composition according to claim 1 , which further comprises at least one vitamin chosen from vitamins in the B group

5. Composition according to claim 4, wherein the vitamin in the B group is selected from vitamins B6, B9, B12 or a mixture thereof.

6.Composition according to claim 1 , wherein said Astragalus sp. is Astragalus membranaceus.

7.Composition according to claim 6, wherein said Astragalus sp. is Astragalus membranaceus extract contains above or equal to 20% of polysacharrides.

8. Composition according to claims 4 or 6, wherein said composition also comprises magnesium salts.

9. Composition according to claims 4 or 6, wherein said composition also comprises Vitamin D.

10. Composition according to claim the preceding claims is a diet supplement.

11. Composition according to claim 10, is in the form of a solid mixture able to be introduced in oral support such as in a capsule, a pill or a tablet.

12. Composition according to claim 10, wherein it comprises at least daily intake:

- between 100 and 750 mg of S-Adenosyl-methionine,

- between 50 and 600 mg by weight of Astragalus polysaccharides (purified or titred extract at 20%).

13. Composition according to claim 1 , wherein it is in the form of a mixture able to be introduced in a liquid form.

14. Composition according to claim 1 , for topical application such as a cosmetic and/or dermatological and/or pharmaceutical cream or gel.

15. A method of controlling and/or protecting a human or an animal from oxidative stress comprising:

- Administering a composition according to claims 1 to 13, to a human or an animal in need thereof,

- Controlling the GSH/GSSG blood serum ratio is above or equal to 10, preferably above or equal to 15, preferentially above 30.

16. Method according to claim 15, wherein administering a composition according to claim 1 is a daily intake of 2 or 3 capsules or tablets or pills per day according to claim 11 .

17. Process for diagnosing aging, in particular linked to environmental stress, based on the oxidative stress in a human or in an animal comprising:

- taking a blood sample in a human or in an animal to be diagnosed,

- measuring the GSH/GSSG blood serum ratio,

- Determining thus that said human or said animal tissues are subject to an excessive oxidative stress,