EP1874354A1 - Composition nutritive comprenant des polyphenols de the vert destinee a traiter l'osteosarcome - Google Patents
Composition nutritive comprenant des polyphenols de the vert destinee a traiter l'osteosarcomeInfo
- Publication number
- EP1874354A1 EP1874354A1 EP05738146A EP05738146A EP1874354A1 EP 1874354 A1 EP1874354 A1 EP 1874354A1 EP 05738146 A EP05738146 A EP 05738146A EP 05738146 A EP05738146 A EP 05738146A EP 1874354 A1 EP1874354 A1 EP 1874354A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- composition
- osteosarcoma
- ascorbate
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 56
- 201000008968 osteosarcoma Diseases 0.000 title claims abstract description 41
- 235000013824 polyphenols Nutrition 0.000 title claims abstract description 14
- 235000015097 nutrients Nutrition 0.000 title description 21
- 244000269722 Thea sinensis Species 0.000 title description 7
- 150000008442 polyphenolic compounds Chemical class 0.000 title description 7
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- -1 ascorbic acid compound Chemical class 0.000 claims abstract description 41
- 235000010323 ascorbic acid Nutrition 0.000 claims abstract description 27
- 239000011668 ascorbic acid Substances 0.000 claims abstract description 27
- 229960005070 ascorbic acid Drugs 0.000 claims abstract description 19
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/32—Manganese; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/34—Copper; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
Definitions
- the present invention relates to the use of a composition comprising an ascorbic acid compound, a L-lysine compound, a L-proline compound, and a polyphenol compound for the preparation of a pharmaceutical composition for treating osteosarcoma. Moreover, the invention further relates to a method of treatment wherein said composition is administered to a subject suffering from osteosarcoma.
- Osteosarcoma a primary malignant tumor of bone or soft parts that arises from bone-forming mesenchymal cells, primarily develops in the distal femur, the proximal tibia, the proximal humerus and the distal radius.
- Classic osteosarcoma demonstrates aggressive, rapid growth with a high risk of local, "skip" metastases and early, pulmonary metastasis. It is the most common bone cancer and the sixth most common cancer in children, and is more frequent in males than females. Most osteosarcomas arise from non-inherited errors in the DNA of growing bone cells. Because these errors occur randomly and unpredictably, there is currently no effective way to prevent this type of cancer [Miller, Dowshen et al.(2002)].
- ECGC is a potent anticancer agent that has been reported to have a growth inhibitory effect against certain human cancer cell lines [Valcic, Timmerman et. al.
- the present invention relates to the use of a composition
- a composition comprising (a) an ascorbic acid compound,
- composition encompasses liquid and solid preparations of the nutritional compounds referred to above as well as gels thereof.
- the solid preparations may be manufactured in a suitable form including tablets, capsules, powders, granules, tea preparations or the like. Its well known in the art how to manufacture said liquid, gel-like and solid preparations referred to herein.
- the composition referred to herein may be provided in accordance with the uses of the invention as mixture of the compounds or by means of a kit including the ingredients separately. The ingredients may be packaged in said kit in separate vials.
- the composition is also suitable for human or animal use. Preferably, said animal is mammal, most preferably a dog, cat or horse.
- amino acids "proline” or “lysine” referred to in accordance with the present invention are preferably the L-amino acids.
- Proline or “Lysine” also encompasses its hydroxyl derivatives hydroxyproline and hydroxylysine as well as salts thereof.
- ascorbic acid preferably refers to ascorbate, ascorbic acid and salts thereof. Sometimes ascorbate compounds may be referred to as vitamin C.
- polyphenol compound refers to a preparation of green tea plants comprising the polyphenols compounds that are present in green tea.
- Polyphenols compounds may be present as up to 30% dry weight in green tea. They include bioflavinoids such as flavanols, flavandiols, flavonoids, and phenolic acids. Flavanols represent the most abundant polyphenols in green tea and are commonly known as catechins. Most preferably, said catechins are EGCG, EG, ECG or EC.
- EGCG refers to (-)-epigallocatechin-3-gallate
- EC refers to epicatechin which refers to (-)-epicatechin
- ECG refers to eipcatechin-3-gallate which refers to (-)-epicatechin-3-gallate
- EGC refers to epigallocatechin which refers to (-)-epigallocatechin. It is well known in the art how such preparations may be obtained.
- polyphenols are to be administered in an amount of 200 mg to 5000 mg per day and subject.
- the composition referred to in accordance with the present invention provides a daily dosage of vitamin C (as ascorbic acid and as Mg, Ca, and palmitate ascorbate) 700 mg; L-lysine 1000 mg; L-proline 750 mg; L-arginine 500 mg; N-acetyl cysteine 200 mg; standardized green tea extract (80% polyphenol) 1000 mg; selenium 30 mg; copper 2 mg; manganese lmg.
- vitamin C as ascorbic acid and as Mg, Ca, and palmitate ascorbate
- the pharmaceutical composition to be administered in accordance with the present invention may include a pharmaceutically acceptable carrier, diluent, or excipient.
- the composition to be used in accordance with the present invention can be prepared by procedures known in the art.
- Respective ingredients may be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, suspensions, powders, and the like, xamples of excipients, diluents, and carriers include: i) fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; ii) binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl-pyrrolidone; iii) moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding dissolution such as paraffin; iv) resorption accelerators such as quaternary ammonium compounds;
- compositions may also be formulated as elixirs or solutions for convenient oral administration or as solutions appropriate for parenteral administration, for example, by intramuscular, subcutaneous or intravenous routes.
- the formulation is in the form of a pill, tablet, capsule, lozenge, liquid or similar dosage form as referred to aove.
- the compositions may well be suited to formulation as sustained release dosage forms and the like.
- treating is used to mean reducing, inhibiting, attenuating or treating the syndromes accompanied with the pathological conditions referred to in accordance with the present invention. Treating becomes apparent for the clinician by monitoring the symptoms accompanied with the said pathological conditions. The symptoms are described in detail in standard text books such as Stedman or Pschyrembel. Treatment preferably refers to significant reduction, inhibition, attenuation or treatment. The significance can be determined by standard methods of statistics, e.g., Student's t-test, chi square test an others.
- ostosarcoma refers to cancer types of the bone.
- the symptoms accompanied with said diseases or disorders are well known in the art and described in detail in medical text books such as Stedman or Pschyrembel. Accordingly, the clinician can determine without further ado whether a patient suffers from osteosarcoma.
- prevention means said the nutritional composition may also be administered in order to avoid the development of osteosarcoma.
- results of the study underlying the present invention demonstrated significant suppression of osteosarcoma tumor growth in immune impaired (athymic) male nude mice by supplementation with 0.5% of the nutrient mixture (which contains ascorbic acid, lysine, proline, and epigallocatechin gallate). Furthermore nutrient supplementation resulted in decreased mitotic index when contrasted with the control mice, see accompanied Examples.
- Current treatment of osteosarcoma is associated with poor prognosis, especially due to the increased risk of developing other cancers with chemotherapy. Therefore, new safe effective treatment strategies are needed.
- NS nutrient mixture
- mice After injection, the mice were randomly divided into two subgroups; group A was fed a regular diet and group B was fed a regular diet supplemented with 0.5% of the nutrient mixture. Four weeks later, the mice were sacrificed, and their tumors were excised, weighed, and processed for histology. Cell proliferation was evaluated by MTT assay, MMP expression by gelatinase zymography, and invasion through Matrigel. Cells were also treated with phorbol 12- myristate 13 -acetate (PMA) to study enhanced MMP expression. Results showed that the nutrient mixture (NS) inhibited the growth and reduced the size of tumors in nude mice. Furthermore, the mitotic index was decreased in the supplemented group (4-5) in contrast to the control group (12-15).
- PMA phorbol 12- myristate 13 -acetate
- osteosarcoma can be treated without harmful side effects of the conventional therapies such as surgery and/or radiation therapy.
- said ascorbic acid compound is selected from the group consisting of ascorbic acid, a pharmaceutically acceptable ascorbate salt, an ascorbate ester, more preferably ascorbyl palmitate, and/or mixtures of the aforementioned compounds. More preferably, said pharmaceutical acceptable ascorbate salt is selected from the group consisting of calcium ascorbate salts and magnesium ascorbate salts. Suitable amounts of the compounds to be used for the preparation of the composition referred to in accordance with the present invention are disclosed in WO 03/057201 A2, which is hereby incorporated by reference, in detail.
- the ascorbic acid compound is ascorbic acid in an amount of 25 mg to 5000 mg and/or calcium ascorbate and/or magnesium ascorbate and/or ascorbyl palmitate in the same amounts. All amounts are calculated per day and subject.
- said L-lysine compound is selected from the group consisting of L-lysine hydrochloride, L-lysine, and pharmaceutically acceptable L-lysine salts.
- L-lysine compound preferably, may be also a mixture of at least two of the chemicals of the aforementioned group.
- the L- lysine compound is L-lysine in an amount of 50 mg to 5000 mg per day and subject.
- said L-proline compound is selected from the group consisting of L- proline hydrochloride, L- proline, and pharmaceutically acceptable L- proline salts.
- the L-proline compound preferably, may be also a mixture of at least two of the chemicals of the aforementioned group.
- the L- proline compound is L-proline in an amount of 25 mg to 3000 mg per day and subject.
- composition further comprises a trace element selected from the group consisting of selenium, manganese, magnesium, calcium, and copper.
- the composition preferably, comprises at least two, at least three or more of the trace elements of the aforementioned group.
- the trace elements may be used together, separately or in any comination in the following amounts per day and subject: selenium: 1 ⁇ g to 200 ⁇ g; cooper: 20 ⁇ g to 9000 ⁇ g; manganese: 50 ⁇ g to 10000 ⁇ g; calcium: 300 mg to 600 mg; magnesium: 300 mg to 600 mg.
- said composition further comprises an L-arginine compound. More preferably, said L-arginine compound is selected from the group consisting of L- arginine hydrochloride, L- arginine, and pharmaceutically acceptable L- arginine salts.
- Suitable amounts of the compounds to be used for the preparation of the composition referred to in accordance with the present invention are disclosed in WO 03/057201 A2, which is hereby incorporated by reference, in detail.
- the L-arginine compound preferably, may be also a mixture of at least two of the chemicals of the aforementioned group.
- the L- arginine compound is L-arginine in an amount of 50 mg to 3000 mg per day and subject.
- the composition may further comprise N-acetyl cysteine.
- N-acetyl-cysteine as used herein comprises cysteine or cystine (dimer of cysteine) and cysteine salts thereof. Suitable amounts of the compounds to be used for the preparation of the composition referred to in accordance with the present invention are disclosed in WO 03/057201 A2, which is hereby incorporated by reference, in detail. Preferably, the N-acetyl cystein is administered in an amount of 10 mg to 1500 mg per day and subject.
- composition is to be administered in oral, parenteral, subcutaneous, intraarterial, or intravenous form.
- the invention also relates to a method for treating osteosarcoma in a subject comprising the step of administering to a subject suffering from osteosarcoma a composition as defined here- inabove in a therapeutically efficient amount.
- compositions can be administered to a subject.
- Particularly preferred techniques are describe in detail in WO 03/057201 A2 which is hereby incorporated by reference.
- all embodiments of the use of the present invention apply mutatis mutandis for the aforementioned method for treating osteosarcoma.
- said subject is a human.
- composition is administered orally, par- entarally, subcutaneously, intraarterially, or intravenously.
- Figure 1 (A) Effect of NS on total weight of osteosarcoma MNNG xenografts in male nude mice; (B) Histology of tumor tissue in supplemented (Suppl) and contol mice, (C) Photographs of tumors from control and supplemented nude mice.
- Figure 2 Effect of the nutrient mixture (NS) and PMA on human osteosarcoma cells MNNG-HOS proliferation; (B) Effect of exposure to nutrient composition (NS) on MMP-2 expression by human osteosarcoma MNNG HOS cells.
- Figure 3 Effect of the nutrient mixture (NS) on Matrigel invasion and migration by human osteosarcoma cells MNNG-HOS.
- mice Male athymic nude mice (NCr-nu/nu), approximately six weeks of age on arrival, were purchased from Simonsen Laboratories, Gilroy, CA and maintained in microinsulator cages under pathogen-free conditions on a 12-hour light/12-hour dark schedule for a week. All animals were cared for in accordance with institutional guidelines for the care and use of experimental animals. After housing for a week, the mice were inoculated with 3x10 6 human osteosarcoma MNNG-HOS cells in 0.2 ml of PBS and 0.1 ml of Matrigel. After injection, the mice were randomly divided into two groups, A and B. Six mice were allocated to each group.
- the tumors located in the subcutaneous layer, were expansile, with evidence of peripheral invasion.
- the neoplasm was composed of spindle shaped or irregularly round cells with large, irregularly round to oval hyperchromatic nuclei and scant cytoplasm with indistinct borders. Irregular areas of tumor necrosis involved about 70% of the tumor mass.
- Stock solution of the nutrient mixture (total weight 4.4 Gm) for the experiments was composed of the following: vitamin C (as ascorbic acid and as Mg, Ca, and palmitate ascorbate) 700 mg; L-lysine 1000 mg; L-proline 750 mg; L-arginine 500 mg; N-acetyl cysteine 200 mg; standardized green tea extract (80% polyphenol) 1000 mg; selenium 30 mg; copper 2 mg; manganese lmg.
- vitamin C as ascorbic acid and as Mg, Ca, and palmitate ascorbate
- Example 2 Effects of the nutrient composition on isolated MNNG-HOS cells from nude mice in culture
- mice Male athymic nude mice (NCr-nu/nu), approximately six weeks of age on arrival, were purchased from Simonsen Laboratories, Gilroy, CA and maintained in microinsulator cages under pathogen- free conditions on a 12-hour light/12-hour dark schedule for a week. All animals were cared for in accordance with institutional guidelines for the care and use of experimental animals. After housing for a week, the mice were inoculated with 3x10 6 human osteosarcoma MNNG-HOS cells in 0.2 ml of PBS and 0.1 ml of Matrigel. After injection, the mice were randomly divided into two groups, A and B. Six mice were allocated to each group.
- mice from Group A were fed a regular diet and those in Group B were fed a regular diet supplemented with 0.5% NS.
- mice were sacrificed, tumors were excised, weighed, fixed in 10% (v/v) buffered formalin and processed for histology- Human osteosarcoma cells were grown in MEM in 24-well tissue culture plates (Costar, Cambridge, MA). Cell cultures were supplemented with 10% fetal bovine serum, penicillin (100 U/ml) and streptomycin (100 mg/ml). Cells were incubated with 1 ml of media at 37° C in a tissue culture incubator equilibrated with 95% air and 5% CO 2 .
- the cells were treated with the nutrient mixture (NS) dissolved in media and tested at 0, 10, 100, 500, and 1000 ⁇ g/ml in triplicate at each dose. A group of cells were also treated with PMA 200 ng/ml. The plates were then returned to the incubator. Cell proliferation was evaluated 24 hrs following incubation with test reagents.
- NS nutrient mixture
- MTT assay is a colorimetric assay based on the ability of viable cells to reduce a soluble yellow tetrazolium salt [3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide] (MTT) to a blue formazan crystal by mitochondrial succinate dehydrogenase activity of viable cells.
- MTT addition 0.5mg/ml
- the plates were covered and returned to the 37 C incubator for 2 hours, the optimal time for formazan product formation.
- MMP expression in condition media was determined by gelatinase zymography. Gelatinase zymography was performed in 10% polyacrylamide precast Novex gel (Invitrogen Corporation) in the presence of 0.1% gelatin. Culture media (20 ⁇ l) was loaded and SDS-PAGE was performed with a tris-glycine SDS buffer.
- the gels were washed with 5% Triton X-100 for 30 minutes. The gels were then incubated for 24 hours at 37 0 C in the presence of 5OmM Tris-HCl, 5mM CaCl 2 , 5 ⁇ M ZnCl 2 , PH 7.5 and stained with Coomassie Blue R 0.5% for 30 minutes and destained. Protein standards were run concurrently and approximate molecular weights were determined.
- the cells that had penetrated the Matrigel membrane and migrated onto the lower surface of the Matrigel were stained with Hematoxylin and Eosin and visually counted under the microscope.
- Stock solution of the nutrient mixture was as described above. The results were expressed as means + SD for the groups. Data were analyzed by independent sample "t" test.
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Abstract
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JP2016519092A (ja) * | 2013-03-18 | 2016-06-30 | デンタルメッド ファーム ホールディング リミテッド | 組成物におけるn−アセチルシステイン誘導体とクランベリーポリフェノールとの組み合わせ、並びに歯周疾患及びインプラント周囲炎を予防及び処置するための方法 |
WO2022124386A1 (fr) * | 2020-12-07 | 2022-06-16 | L' Oreal | Composition comprenant de l'acide ascorbique et un acide aminé cyclique |
CN115836666B (zh) * | 2021-09-20 | 2024-11-01 | 上海中医药大学附属龙华医院 | 原位骨肉瘤和肺转移瘤小鼠模型及其制法和应用 |
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