WO2009087988A1 - がん化学療法時に起こる酸化ストレス及び/又は副作用の軽減あるいはがん化学療法時の栄養状態を改善するための組成物 - Google Patents
がん化学療法時に起こる酸化ストレス及び/又は副作用の軽減あるいはがん化学療法時の栄養状態を改善するための組成物 Download PDFInfo
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- 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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- A61K31/01—Hydrocarbons
- A61K31/015—Hydrocarbons carbocyclic
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- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/07—Retinol compounds, e.g. vitamin A
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- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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- 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
- A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Definitions
- the present invention relates to a composition for reducing oxidative stress and / or side effects that occur during cancer chemotherapy or improving the nutritional state during cancer chemotherapy.
- Non-patent Document 1 Non-patent Document 1
- cancer chemotherapy a large amount of active oxygen is generated due to biological damage caused by chemotherapy, so that consumption of an antioxidant that captures the active oxygen increases.
- the amount of zinc required for repairing damaged tissue increases due to increased synthesis of DNA and protein, while urinary excretion of zinc increases due to inflammation. Therefore, it is important to supply a sufficient amount of micronutrients such as antioxidant vitamins and zinc.
- micronutrients such as antioxidant vitamins and zinc.
- the main side effects of cancer chemotherapy are loss of appetite, stomatitis, and vomiting, so that sufficient intake cannot be secured, and micronutrient supplementation does not remain with meal alone.
- the lack of micronutrients such as zinc hate taste and olfactory disturbances and delayed wound healing, and has the risk of a vicious cycle. It is important to take preventive measures against these side effects from the viewpoint of quality of life (QOL).
- An object of the present invention is to provide a composition for reducing oxidative stress and / or side effects that occur during cancer chemotherapy or improving the nutritional state during cancer chemotherapy.
- the present inventors have received a composition containing the following components (a) to (f) from patients undergoing cancer chemotherapy and confirmed its usefulness.
- the present inventors have found that the present invention is effective in reducing the oxidative stress and / or side effects that occur, or in improving the nutritional status during cancer chemotherapy.
- (a) Antioxidant (b) At least one component selected from the group consisting of vitamins B 1 , B 2 , B 6 , niacin and pantothenic acid (c) at least one component which folic acid is selected from the group consisting of vitamin B 12 and vitamin A (d) Zinc (e) Selenium (f) Coenzyme Q10
- the gist of the present invention is as follows.
- a composition for reducing oxidative stress and / or side effects occurring during cancer chemotherapy or improving nutritional status during cancer chemotherapy comprising the following components (a) to (f) Said composition.
- (a) Antioxidant (b) At least one component selected from the group consisting of vitamins B 1 , B 2 , B 6 , niacin and pantothenic acid (c) at least one component which folic acid is selected from the group consisting of vitamin B 12 and vitamin A (d) Zinc (e) Selenium (f) Coenzyme Q10
- composition according to (1) wherein the antioxidant is an antioxidant vitamin.
- the antioxidant vitamin is at least one selected from the group consisting of vitamin C, vitamin E, and ⁇ -carotene.
- Vitamin C Vitamin C, vitamin E, ⁇ -carotene, vitamin B 1 , B 2 , B 6 , niacin, pantothenic acid, folic acid, vitamin B 12 , vitamin A, zinc, selenium, coenzyme Q10, vitamin D 3 and iron A composition according to any one of (1) to (4).
- composition Contains 50 ⁇ 10 ⁇ g of biotin, 2 ⁇ 0.4 g of galactooligosaccharide, 90 ⁇ 18 mg of potassium, 70 ⁇ 14 mg of calcium, 3 ⁇ 0.6 mg of magnesium and 30 ⁇ 6 mg of phosphorus per dosage unit (7) Composition.
- the composition according to (9), wherein the liquid is fruit juice.
- the composition according to (9) or (10), wherein the volume per dosage unit is 125 ⁇ 25 mL.
- the following components (a) to (f) are administered to the subject in an amount effective to reduce oxidative stress and / or side effects that occur during cancer chemotherapy or to improve nutritional status during cancer chemotherapy.
- a composition for use in the reduction of oxidative stress and / or side effects that occur during cancer chemotherapy or the improvement of nutritional status during cancer chemotherapy comprising the following (a) to (f): The composition comprising an ingredient.
- composition of the present invention can reduce oxidative stress and / or side effects that occur during cancer chemotherapy or improve the nutritional status during cancer chemotherapy.
- This specification includes the contents described in the specification and / or drawings of Japanese Patent Application No. 2008-001801, which is the basis of the priority of the present application.
- FIG. 1A shows the measurement results of total protein (change rate). The values obtained by averaging the rate of change in each group when the first measurement value is 100% are shown in a graph, with the diamonds ⁇ being the administration group and the squares ⁇ are the non-administration group. The vertical axis represents% and the horizontal axis represents each measurement time. *, **, *** indicate the significant difference from the first value in each group (* p ⁇ 0.05, ** p ⁇ 0.01, *** p ⁇ 0.001). In the non-administration group, the total protein, which is a nutritional index, decreased significantly from the second time to the first time.
- FIG. 1B shows the measurement results of total protein (actually measured values).
- the values obtained by averaging the values in each of the administration group and the square ⁇ mark in the non-administration group are plotted in a graph.
- the vertical axis represents the total protein concentration in blood (g / dl), and the horizontal axis represents each measurement. The measured value showed no significant difference between the two groups.
- FIG. 2A shows the measurement results of albumin (rate of change).
- the values obtained by averaging the rate of change in each group when the first measurement value is 100% are shown in a graph, with the diamonds ⁇ being the administration group and the squares ⁇ are the non-administration group.
- the vertical axis represents%, and the horizontal axis represents the change over time of each measurement.
- FIG. 2B shows the measurement result of albumin (actual value). The values obtained by averaging the values in each of the administration group and the square ⁇ mark in the non-administration group are plotted in a graph. The vertical axis represents blood albumin concentration (g / dl), and the horizontal axis represents each measurement time. The measured values were all within normal values, and no significant difference was observed between the two groups.
- FIG. 3A shows the measurement results of prealbumin (change rate).
- the values obtained by averaging the rate of change in each group when the first measurement value is 100% are shown in a graph, with the diamonds ⁇ being the administration group and the squares ⁇ are the non-administration group.
- the vertical axis represents%, and the horizontal axis represents the change over time of each measurement. * Indicates that there was a significant difference from the first value in each group (* p ⁇ 0.05).
- the administration group showed an increasing tendency and the non-administration group showed a decreasing tendency.
- FIG. 3B shows the measurement result of prealbumin (actually measured value).
- the values obtained by averaging the values in each of the administration group and the square ⁇ mark in the non-administration group are plotted in a graph.
- FIG. 4A shows the measurement results of radical generation ability (change rate). The values obtained by averaging the rate of change in each group when the first measurement value is 100% are shown in a graph, with the diamonds ⁇ being the administration group and the squares ⁇ are the non-administration group.
- the vertical axis represents%, and the horizontal axis represents the change over time of each measurement. * And ** indicate the significant difference from the first value in each group (* p ⁇ 0.05, ** p ⁇ 0.01).
- FIG. 4B shows a measurement result of radical generation ability (actual measurement value).
- the values obtained by averaging the values in each of the administration group and the square ⁇ mark in the non-administration group are plotted in a graph.
- the vertical axis represents blood radical production ability (Unit), and the horizontal axis represents the number of measurements.
- the non-administration group showed an increasing trend and the administration group showed a decreasing tendency.
- FIG. 5A shows the measurement results of lipid peroxide (difference).
- the diamond diamonds are the administration group, and the squares ⁇ are the non-administration group, and the values obtained by averaging the differences from the first measurement values in each group were graphed.
- FIG. 5B shows the measurement result of lipid peroxide (actual measurement value). The values obtained by averaging the values in each of the administration group and the square ⁇ mark in the non-administration group are plotted in a graph.
- the vertical axis represents Unit, and the horizontal axis represents measurement times. There was almost no change in the non-administration group, although a decrease trend was seen in the second and third doses, but the fifth dose was almost the same as the first dose.
- FIG. 6A shows the measurement results of vitamin A (change rate). The values obtained by averaging the rate of change in each group when the first measurement value is 100% are shown in a graph, with the diamonds ⁇ being the administration group and the squares ⁇ are the non-administration group. The vertical axis represents%, and the horizontal axis represents the change over time of each measurement. * And ** indicate the significant difference from the first value in each group (* p ⁇ 0.05, ** p ⁇ 0.01). It significantly increased in the administration group and decreased significantly in the non-administration group.
- FIG. 6B shows the measurement result of vitamin A (actual value). The values obtained by averaging the values in each of the administration group and the square ⁇ mark in the non-administration group are plotted in a graph.
- the vertical axis represents blood vitamin A concentration (IU / dl), and the horizontal axis represents each measurement time.
- the non-administration group showed a decreasing trend and the administration group showed an increasing tendency.
- FIG. 7A shows the measurement result of vitamin C (rate of change). The values obtained by averaging the rate of change in each group when the first measurement value is 100% are shown in a graph, with the diamonds ⁇ being the administration group and the squares ⁇ are the non-administration group.
- the vertical axis represents%, and the horizontal axis represents the change over time of each measurement. ** indicates that there was a significant difference from the first value in each group (** 0.01p ⁇ 0.01). Although there was almost no change in the non-administration group, it significantly increased in the administration group.
- FIG. 7A shows the measurement result of vitamin C (rate of change). The values obtained by averaging the rate of change in each group when the first measurement value is 100% are shown in a graph, with the diamonds ⁇ being the administration group and the squares ⁇ are the
- FIG. 7B shows the measurement result of vitamin C (actual value).
- the values obtained by averaging the values in each of the administration group and the square ⁇ mark in the non-administration group are plotted in a graph.
- the vertical axis represents blood vitamin C concentration ( ⁇ g / ml), and the horizontal axis represents each measurement.
- the increase was observed in the administration group, and the increase was significantly greater in the second and fourth times than in the non-administration group.
- ⁇ indicates a significant difference (p ⁇ 0.05) between the two groups.
- FIG. 8A shows the measurement results of vitamin E (rate of change). The values obtained by averaging the rate of change in each group when the first measurement value is 100% are shown in a graph, with the diamonds ⁇ being the administration group and the squares ⁇ are the non-administration group.
- FIG. 8B shows the measurement result of vitamin E (actual value). The values obtained by averaging the values in each of the administration group and the square ⁇ mark in the non-administration group are plotted in a graph.
- the vertical axis represents blood vitamin E concentration (mg / dl), and the horizontal axis represents each measurement. The non-administered group showed a decreasing tendency compared to the first administration, but the administration group showed an increasing tendency.
- FIG. 9A shows the measurement result of Zn (rate of change).
- the values obtained by averaging the rate of change in each group when the first measurement value is 100% are shown in a graph, with the diamonds ⁇ being the administration group and the squares ⁇ are the non-administration group.
- the vertical axis represents%, and the horizontal axis represents the change over time of each measurement. ** indicates that there was a significant difference from the first value in each group (** 0.01p ⁇ 0.01). Although the non-administration group decreased, it increased significantly in the administration group.
- FIG. 9B shows the measurement result of Zn (actual value).
- the values averaged in each group, where the diamond ⁇ is the administration group and the square ⁇ is the non-administration group are graphed.
- the vertical axis represents blood zinc concentration ( ⁇ g / dl), and the horizontal axis represents each measurement.
- FIG. 10A shows the measurement results of the lymphocyte count (change rate). The values obtained by averaging the differences from the first measurement values in the administration group and the square ⁇ in the non-administration group were plotted in each group. *** indicates a significant difference (p ⁇ 0.001) compared to the first time. The vertical axis represents% and the horizontal axis represents each measurement time. Both the administration group and the non-administration group increased at the second time, and then showed a decreasing trend.
- FIG. 10B shows the measurement result of the lymphocyte count (actual value).
- the values obtained by averaging the diamond ⁇ marks in the administration group and the square ⁇ marks in the non-administration group were graphed.
- the vertical axis represents the total lymphocyte count (x100 mm3), and the horizontal axis represents each measurement.
- the non-administration group showed a significant increase (* p ⁇ 0.05), but then decreased.
- the administration group showed a slight decreasing trend.
- FIG. 11 shows the results of anorexia.
- the black column is the administration group and the shaded column is the non-administration group.
- the vertical axis represents the average product of anorexia grade and frequency, and the horizontal axis represents the period between measurements.
- FIG. 12 shows the results of nausea / vomiting.
- the black column is the administration group and the shaded column is the non-administration group.
- the vertical axis shows the average product of nausea / vomiting grade and frequency, and the horizontal axis shows the period between measurements. Nausea and vomiting were significantly more in the treated group in the first and second times, and in the non-treated group in the second and third times.
- FIG. 13 shows the result of fatigue.
- the black column is the administration group and the shaded column is the non-administration group.
- the vertical axis represents the average product of fatigue grade and frequency, and the horizontal axis represents the period between measurements.
- the present invention is a composition for reducing oxidative stress and / or side effects that occur during cancer chemotherapy or improving the nutritional state during cancer chemotherapy, comprising the following components (a) to (f):
- the composition comprising is provided.
- (a) Antioxidant (b) at least one component selected from the group consisting of vitamins B 1 , B 2 , B 6 , niacin and pantothenic acid (c) at least one component which folic acid is selected from the group consisting of vitamin B 12 and vitamin A (d) Zinc (e) Selenium (f) Coenzyme Q10
- composition containing vitamins and trace elements such as zinc and selenium, coenzyme Q10, etc. induces in vivo functions such as metabolism promotion and anti-inflammatory action, and also reinforces the antioxidant action.
- oxidative stress and / or side effects that occur during cancer chemotherapy can be reduced, and the nutritional state during cancer chemotherapy can be improved.
- the composition of the present invention broadly includes a group of components involved in the removal of active oxygen, a metabolic cofactor, and a cell growth promoting factor.
- Antioxidants, zinc, selenium and coenzyme Q10 are a group of components involved in the removal of active oxygen.
- Antioxidants have a strong reducing action against oxidative stress caused by biological damage caused by chemotherapy.
- antioxidants include antioxidant vitamins such as vitamin C, vitamin E, and ⁇ -carotene.
- Antioxidant vitamins such as vitamin E and vitamin C have a reduced type and an oxidized type, and receive a free radical of active oxygen, thereby oxidizing themselves and removing active oxygen. Since these antioxidant vitamins act at different stages, it is preferable to use these antioxidant vitamins simultaneously rather than using them alone.
- the intake of the vitamin group depends on the content of the meal, and tends to be deficient particularly in patients who need dietary restrictions. Therefore, it is desirable that the composition of the present invention contains a combination of a plurality of antioxidant vitamins.
- Vitamin C one of the antioxidant vitamins, not only acts as an antioxidant, but is directly involved in cAMP enhancement and lipid solubilization, as well as collagen formation, xenobiotic detoxification, and induction of interferon production. Since it has various actions such as antihistaminic action, immune function enhancement, antiviral and antibacterial, it is preferable to include at least vitamin C as an antioxidant vitamin.
- the antioxidant vitamin agent is shown as a preferred embodiment, but the antioxidant is not limited to the antioxidant vitamin agent, instead of or supplementing the antioxidant vitamin agent, polyphenol, Antioxidant substances contained in foods such as catechins can be used.
- Selenium is a constituent of glutathione peroxidase, an antioxidant enzyme, and zinc is a constituent of superoxide dismutase, an antioxidant enzyme. Since coenzyme Q10 has a strong antioxidant effect, it can be expected to prevent or prevent diseases caused by oxidative stress. In addition, since it is a component involved in ATP production, supplementation can also be expected to have an effect of smooth metabolism of nutrients.
- an antioxidant vitamin is used as the antioxidant, the amount added to the composition is suitably 100 mg to 2000 mg, preferably 300 mg to 1000 mg as vitamin C content, preferably 300 mg to 1000 mg. 3 mg to 600 mg is suitable, 5 mg to 300 mg is preferred, and ⁇ -carotene is suitably 2.0 mg to 10.0 mg, preferably 5.0 mg to 7.0 mg.
- the amount of addition to the composition of the present invention is, for example, as the content per dosage unit, for example, zinc is suitably 1.2-30 mg, preferably 9-12 mg, and selenium is suitably 10-250 ⁇ g, 30-60 ⁇ g is preferred.
- the content of coenzyme Q10 is suitably 1.0 to 1,000 mg, preferably 2 to 100 mg per dosage unit.
- any or all of vitamins B 1 , B 2 , B 6 , B 12 , niacin, pantothenic acid, and folic acid can be added.
- vitamins that support metabolism have a role as coenzymes for the metabolism of carbohydrates, lipids, and amino acids, and are important components for life activities.
- vitamin B 1 represents a TPP (thiamine pyrophosphate)
- vitamin B 2 are as FMN (flavin mononucleotide), FAD (flavin adenine dinucleotide), glycolytic pathway, TCA cycle, involved in the regulation of ⁇ -oxidation.
- Vitamin B 6 is involved in amino acid metabolism as such pyridoxal phosphate.
- Niacin is involved in glycolysis and lipid metabolism as NAD and NADP. Moreover, pantothenic acid is involved in the TCA cycle, amino acid metabolism, and lipid metabolism as CoA. Folic acid is involved in amino acid metabolism and nucleic acid metabolism as FH4. Vitamin B 12 is as C0B12, involved in amino acid metabolism.
- these vitamin groups are components constituting different coenzymes, it is preferable to use all of the above-mentioned vitamin groups as the metabolic cofactors.
- the intake of these vitamin groups depends on the amount of energy and protein intake, and patients with low food intake, such as patients during cancer chemotherapy, or patients with low absorption and utilization rates. Tend to run out overall. Therefore, in these patients, in order to efficiently supply intracellular energy necessary for wound healing, it is preferable to add all of the above vitamin groups to the composition.
- Vitamin B 1 is suitably added in an amount of 0.5-10 mg, preferably 1.0-5.0 mg, and vitamin B 2 is added in an amount of 0.5-20 mg as a content per dosage unit.
- 1 to 10 mg is preferred
- vitamin B 6 is suitably 1.6 to 60.0 mg
- 3.0 to 8.0 mg is preferred
- vitamin B 12 is suitably 1.1 to 50.0 ⁇ g
- 5.0 to 15.0 ⁇ g 1 to 100 mg is suitable for niacin
- 5 to 50 mg is preferred
- 200 to 1.1 mg is suitable for folic acid
- 600 to 1,000 ⁇ g is preferred
- 1 to 100 mg is suitable for pantothenic acid 5 to 50 mg is preferable.
- cell growth promoting factors contained in the composition are factors that can encourage cell differentiation, proliferation, as the cell growth promoting factors, for example, folic acid, any or all of such vitamin B 12 or vitamin A Can be used.
- Folic acid and vitamin B 12 not only function as a metabolic cofactor in the living body but also have a function of promoting cell differentiation and proliferation.
- Vitamin A has a function of promoting cell differentiation and proliferation in addition to the function as an antioxidant vitamin.
- vitamin A retinol equivalent
- iron deficiency occurs, so iron can be added to the composition. Since iron is also a constituent of hemoglobin, deficiency can lead to anemia. By adding iron, prevention, prevention and improvement of anemia can be expected.
- calcium, vitamin D (for example, vitamin D 3 ) for promoting absorption of calcium, and the like can be added.
- an intestinal regulating substance such as raffinose can be added.
- the iron content per dosage unit of the composition of the present invention is suitably 0.5-50 mg, preferably 1.0-30 mg, and the vitamin D 3 content is suitably 1.0 ⁇ g-10.0 ⁇ g, 2.0 ⁇ g ⁇ 8.0 ⁇ g is preferred.
- vitamin C vitamin C
- vitamin E ⁇ -carotene
- vitamin B 1 , B 2 , B 6 niacin
- pantothenic acid folic acid
- vitamin B 12 vitamin A
- coenzyme Q10 is a composition comprising a vitamin D 3 and iron.
- This composition contains 10 ⁇ 2 mg, selenium 50 ⁇ 10 ⁇ g, coenzyme Q10 15 ⁇ 3 mg, vitamin D 3 3.7 ⁇ 0.74 ⁇ g and iron 5 ⁇ 1 mg, and has an energy of 80 ⁇ 16 kcal.
- composition of the present invention may further contain ⁇ -lipoic acid and / or chromium.
- ⁇ -Lipoic acid is involved in the promotion of sugar metabolism. It is thought to stimulate the mobilization of glucose transporter (GLUT-4) present in the cell to the cell membrane, and to significantly increase glucose uptake by insulin in muscles and muscle cells.
- the content of ⁇ -lipoic acid is, for example, suitably 20 to 1,000 mg, preferably 25 to 100 mg per dosage unit.
- Chromium increases insulin receptor binding ability and increases insulin sensitivity by increasing insulin receptor number and insulin receptor kinase activity.
- the chromium content is, for example, suitably 5 to 50 ⁇ g, preferably 10 to 40 ⁇ g per dosage unit.
- composition of this invention can contain another component other than said component.
- biotin, galactooligosaccharide, potassium, calcium, magnesium, phosphorus and the like may be contained. By containing these, it is possible to prevent deficient components in diets that are restricted such as sick meals.
- the biotin content per dosage unit is suitably 1 to 200 ⁇ g, preferably 10 to 100 ⁇ g, and the galactooligosaccharide content is suitably 0.1 to 20 g.
- the potassium content is suitably 10 to 1,000 mg, 15 to 500 mg is preferred, the calcium content is suitably 1 to 2,300 mg, and 10 to 600 mg is preferred, magnesium
- the content of is suitably 0.1 to 10 mg, preferably 1 to 5 mg, and the content of phosphorus is suitably 1 to 3500 mg, preferably 5 to 1050 mg.
- composition of the present invention is biotin 50 ⁇ 10 ⁇ g, galactooligosaccharide 2 ⁇ 0.4 g, potassium 90 ⁇ 18 mg, calcium 70 ⁇ 14 mg, magnesium 3 ⁇ 0.6 mg and phosphorus per dosage unit. Contains 30 ⁇ 6 mg.
- the amount of energy of the composition of the present invention is suitably 5 to 200 kcal per dosage unit, and preferably 20 to 150 kcal.
- the protein content is about 0.4 ⁇ 0.08 g or 0.7 ⁇ 0.14 g
- carbohydrate content is about 11.1 ⁇ 2.22 g or 21.2 ⁇ 4.24 g
- sodium The content should be about 30 ⁇ 6mg.
- compositions of the present invention can be prepared by methods well known to those skilled in the art.
- each of the above components can be mixed and prepared in a dosage form such as powder, granule, tablet, or liquid.
- a liquid is a more preferable dosage form because it can be administered by tube to a patient who is difficult to take orally.
- the liquid in which the composition is dispersed or dissolved is not particularly limited as long as it is a liquid that is usually taken and does not diminish the action of each component on the living body.
- Physiological saline or the like can be used.
- fruit juice may be used. Examples of fruit juices include blueberry juice, grape juice, grapefruit juice, lemon juice, tangerine juice, carrot juice, apple juice, and pineapple juice, and can relieve the acidity and odor of vitamin C and vitamin B groups. Therefore, carrot juice, blueberry juice and grape juice are preferred.
- the volume per dosage unit is suitably 10 to 250 ml, preferably 50 to 200 ml, and more preferably 125 ⁇ 25 ml.
- the water content in the case of a liquid preparation can be, for example, about 116 ⁇ 23.2 g or about 110 ⁇ 22 g per dosage unit.
- composition of the present invention is shown in Table 1 below.
- Table 1 An example of a component table (in 125 ⁇ 25 mL) of the composition of the present invention is shown in Table 1 below.
- the composition prepared as described above is effective in reducing oxidative stress and / or side effects that occur during cancer chemotherapy or improving nutritional status during cancer chemotherapy.
- the reference values in blood are 4.4 to 5.4 million red blood cells / mm3 (male), 3.8 million to 4.6 million cells / mm3 (female), 4000 to 8000 leukocytes / ⁇ l, leukocyte fraction (neutrophils), respectively.
- the measured value is within the range of these reference values, the oxidative stress that occurs during cancer chemotherapy is reduced, or cancer chemotherapy It can be said that the nutritional status of the time has improved.
- composition of the present invention can be used to reduce oxidative stress and / or side effects that occur during cancer chemotherapy or to improve the nutritional state during cancer chemotherapy.
- the composition of the present invention may be administered to patients undergoing cancer chemotherapy at a dose per dosage unit per day. Administration may be performed orally or by tube.
- This composition contains vitamin A (retinol equivalent) 300 ⁇ g, ⁇ -carotene 6.6mg, vitamin B1 3mg, vitamin B2 3mg, vitamin B6 5mg, vitamin B12 10 ⁇ g, vitamin C 500mg, niacin 15mg, folic acid 800 ⁇ g , Vitamin D3 3.7 ⁇ g, Vitamin E 20mg, Biotin 50 ⁇ g, Pantothenic acid 10mg, Iron 5mg, Zinc 10mg, Copper 0.01mg, Selenium 50 ⁇ g, Potassium 90mg, Calcium 70mg, Magnesium 3mg, Phosphorus 30mg, Sodium 30mg, Coenzyme Q10 15mg, Galactooligo Contains 2.0g of sugar.
- vitamin A retinol equivalent
- composition prepared in Preparation Example 1
- a composition which is a vitamin and trace element supplement drink, is administered to a blood tumor patient undergoing cancer chemotherapy, and occurs during chemotherapy
- Subject of research method Products for patients with hematological malignancies scheduled to undergo consented cancer chemotherapy: Composition prepared in Preparation Example 1 (125 mL / tube)
- Administration method Fresh blood tumor patients with cancer chemotherapy scheduled and consented are registered, and ingestion group (administration group) and non-intake group (non-administration group) of the composition prepared in Preparation Example 1 by the envelope method Group).
- the administration group one (125 ml) / day of the composition prepared in Preparation Example 1 is administered in addition to a normal meal from the start date of cancer chemotherapy (the start date of the first course) to the end date of the second cool.
- the non-administration group is only a normal meal.
- the start of cancer chemotherapy (the day before the start of administration of the composition prepared in Preparation Example 1) is set to 1 day, and the 1st, 10th, and 22nd days (end of the first course), 32 5 points on the first day (10th day of the second course) and the 43rd day (end date of the second course).
- meals consumed in addition to school lunch should be listed in the “Food Diary” and intake of supplements such as vitamins and trace elements should be avoided. Number of cases: 6 administration groups, 6 non-administration groups (12 cases in total)
- Evaluation items before and after administration 1) Blood test Red blood cell count, white blood cell count, white blood cell fraction, lymphocyte count, platelet count, total protein, albumin, blood glucose level, total cholesterol, triglyceride, total bilirubin, direct bilirubin, AST, ALT, Al-p, BUN, Creatinine, Na, K, Cl, CRP, Hb 2) Special inspection Prealbumin, radical generating ability, lipid peroxide, antioxidant vitamins (VA, VC, VE), Zn 3) General examination of urine Protein (qualitative), sugar (qualitative), urobilinogen (qualitative) 4) QOL evaluation by questionnaire Presence / absence of stomatitis, appetite loss, nausea / vomiting, fatigue, presence of diarrhea, incidence of side effects
- Lipid peroxide decreased in the 2nd and 3rd doses in the administration group, but increased after the 4th dose, and was almost the same as the 1st value in the 5th dose.
- Antioxidant vitamin A, vitamin C, vitamin E and zinc decreased in the non-administered group and increased significantly (P ⁇ 0.01) in the treated group.
- the number of lymphocytes which is an index of immunity, showed a slight increase in the administration group, but almost no change.In the non-administration group, an increase of about 2000 mm 3 was observed at the second measurement, but 3 It decreased after the second measurement.
- composition of the present invention was particularly effective in improving oxidative stress and increasing antioxidant capacity that occur during cancer chemotherapy, and was considered effective in improving nutritional status. All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety.
- composition of the present invention can be used as a trace element-supplemented food or drink for patients undergoing cancer chemotherapy, which reduces oxidative stress and / or side effects that occur during cancer chemotherapy or nutrition during cancer chemotherapy. Useful to improve the condition.
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Abstract
Description
がん化学療法施行時には、化学療法による生体損傷に起因した活性酸素が大量に発生するため、その活性酸素を捕捉する抗酸化物質の消耗が亢進する。
しかし、がん化学療法の主たる副作用が食欲不振や口内炎、嘔吐であるため十分な摂取量を確保できず、食事だけでは微量栄養素の補給はままならない。さらに、亜鉛などの微量栄養素の欠乏は味覚・嗅覚障害、創傷治癒遅延を憎悪し、悪循環に陥る危険性を持つ。Quality of life (QOL)の観点からもそれらの副作用の予防対策を講じることが重要である。
(a)抗酸化剤
(b)ビタミンB1、B2、B6、ナイアシン及びパントテン酸からなる群より選択される少なくとも1つの成分
(c)葉酸、ビタミンB12及びビタミンAからなる群より選択される少なくとも1つの成分
(d)亜鉛
(e)セレン
(f)コエンザイムQ10
本発明の要旨は以下の通りである。
(a)抗酸化剤
(b)ビタミンB1、B2、B6、ナイアシン及びパントテン酸からなる群より選択される少なくとも1つの成分
(c)葉酸、ビタミンB12及びビタミンAからなる群より選択される少なくとも1つの成分
(d)亜鉛
(e)セレン
(f)コエンザイムQ10
(3)抗酸化ビタミンがビタミンC,ビタミンE及びβ-カロテンからなる群より選択される少なくとも1つである(2)記載の組成物。
(4)さらに、ビタミンD3及び/又は鉄を含む(1)~(3)のいずれかに記載の組成物。
(6)一投与単位あたり、ビタミンC 500±100 mg,ビタミンE 20±4 mg、β-カロテン6.6±1.32 mg、ビタミンB1 3±0.6 mg、ビタミンB2 3±0.6 mg、ビタミンB6 5±1 mg、ナイアシン15±3 mg、パントテン酸10±2 mg、葉酸800±160 μg、ビタミンB12 10±2 μg、ビタミンA(レチノール当量)550±110μg、亜鉛10±2 mg、セレン50±10 μg、コエンザイムQ10 15±3mg、ビタミンD3 3.7±0.74 μg及び鉄5±1 mgを含み、エネルギーが80±16 kcalである(5)記載の組成物。
(7)さらに、ビオチン、ガラクトオリゴ糖、カリウム、カルシウム、マグネシウム及びリンを含む(1)~(6)のいずれかに記載の組成物。
(9)服用可能な液体に分散されている(1)~(8)のいずれかに記載の組成物。
(10)前記液体が果汁である(9)記載の組成物。
(11)一投与単位あたりの容量が125±25 mLである(9)又は(10)記載の組成物。
(12)がん化学療法時に起こる酸化ストレス及び/又は副作用の軽減、あるいはがん化学療法時の栄養状態の改善に有効な量で下記の(a)~(f)の成分を被験者に投与することを含む、がん化学療法時に起こる酸化ストレス及び/又は副作用の軽減、あるいはがん化学療法時の栄養状態の改善方法。
(a)抗酸化剤
(b)ビタミンB1、B2、B6、ナイアシン及びパントテン酸からなる群より選択される少なくとも1つの成分
(c)葉酸、ビタミンB12及びビタミンAからなる群より選択される少なくとも1つの成分
(d)亜鉛
(e)セレン
(f)コエンザイムQ10
(13)がん化学療法時に起こる酸化ストレス及び/又は副作用の軽減、あるいはがん化学療法時の栄養状態を改善するための組成物を製造するための下記の(a)~(f)の成分の使用。
(a)抗酸化剤
(b)ビタミンB1、B2、B6、ナイアシン及びパントテン酸からなる群より選択される少なくとも1つの成分
(c)葉酸、ビタミンB12及びビタミンAからなる群より選択される少なくとも1つの成分
(d)亜鉛
(e)セレン
(f)コエンザイムQ10
(14)がん化学療法時に起こる酸化ストレス及び/又は副作用の軽減、あるいはがん化学療法時の栄養状態の改善に使用するための組成物であって、下記の(a)~(f)の成分を含む前記組成物。
(a)抗酸化剤
(b)ビタミンB1、B2、B6、ナイアシン及びパントテン酸からなる群より選択される少なくとも1つの成分
(c)葉酸、ビタミンB12及びビタミンAからなる群より選択される少なくとも1つの成分
(d)亜鉛
(e)セレン
(f)コエンザイムQ10
本明細書は、本願の優先権の基礎である日本国特許出願、特願2008‐001801の明細書および/または図面に記載される内容を包含する。
本発明は、がん化学療法時に起こる酸化ストレス及び/又は副作用の軽減あるいはがん化学療法時の栄養状態を改善するための組成物であって、下記の(a)~(f)の成分を含む前記組成物を提供する。
(a)抗酸化剤
(b)ビタミンB1、B2、B6、ナイアシン及びパントテン酸からなる群より選択される少なくとも1つの成分
(c)葉酸、ビタミンB12及びビタミンAからなる群より選択される少なくとも1つの成分
(d)亜鉛
(e)セレン
(f)コエンザイムQ10
抗酸化剤、亜鉛、セレン及びコエンザイムQ10は、活性酸素除去に関与する成分群である。がん化学療法施行時には、化学療法による生体損傷に起因した活性酸素が大量に発生するため、その活性酸素を捕捉する抗酸化物質の消耗が亢進する。活性酸素除去に関与する上記成分は、抗酸化物質の消耗の改善に重要な役割を果たす。
コエンザイムQ10は、強い抗酸化作用を有するため、酸化ストレスに起因する疾患の予防、防止効果が期待できる。また、ATP産生に関与する成分であるため、補充することで栄養素の代謝が円滑に行われる効果も期待できる。
抗酸化剤として、抗酸化ビタミンを用いる場合、組成物への添加量としては、一投与単位あたりの含有量として、ビタミンCは、100mg~2000mgが適当であり、300mg~1000mgが好ましく、ビタミンEは、3mg~600mgが適当であり、5mg~300mgが好ましく、β-カロテンは、2.0mg~10.0mgが適当であり、5.0mg~7.0mgが好ましい。
コエンザイムQ10の含有量は、一投与単位あたり、1.0~1,000mgが適当であり、2~100mgが好ましい。
各成分の組成物への添加量は、一投与単位あたりの含有量として、葉酸、ビタミンB12は上述の通りであり、ビタミンA(レチノール当量)は、10μg~3,000μgが適当であり、100μg~550μgが好ましい。
α-リポ酸は、糖代謝の促進に関与している。細胞内に存在するグルコーストランスポーター(GLUT-4)の細胞膜への動員を刺激し、筋や筋細胞におけるインスリンによる糖の取り込みを大幅に増加させると考えられている。
α-リポ酸の含有量は、例えば、一投与単位あたり、20~1,000mgが適当であり、25~100mgが好ましい。
クロムは、インスリンレセプター結合能を高め、インスリンレセプター数、インスリンレセプターキナーゼ活性を高めることでインスリン感受性を増加させる。
クロムの含有量は、例えば、一投与単位あたり、5~50μgが適当であり、10~40μgが好ましい。
また、本発明の組成物において、例えば、一投与単位当たり、ビオチンの含有量は、1~200μgが適当であり、10~100μgが好ましく、ガラクトオリゴ糖の含有量は、0.1~20gが適当であり、1~10gが好ましく、カリウムの含有量は、10~1,000mgが適当であり、15~500mgが好ましく、カルシウムの含有量は、1~2,300mgが適当であり、10~600mgが好ましく、マグネシウムの含有量は、0.1~10mgが適当であり、1~5mgが好ましく、リンの含有量は、1~3500mgが適当であり、5~1050mgが好ましい。
本発明の組成物のエネルギー量は、一投与単位あたり、5~200kcalが適当であり、20~150kcalが好ましい。また、一般成分については、例えば、一投与単位当たり、たんぱく質の含有量は0.4±0.08g程度又は0.7±0.14g程度、炭水化物の含有量は11.1±2.22g程度又は21.2±4.24g程度、ナトリウムの含有量は30±6mg程度とするとよい。
本発明の組成物は、当業者にとって周知の方法で調製することができる。例えば、上記各成分を混合し、粉末、顆粒、錠剤、液剤等の剤形で調製することができる。液剤は、経口摂取が困難な患者に対し、経管投与が可能であるため、より好ましい剤形である。
〔調製例1〕組成物の調製
組成物として、キャロット抽出液を含む果汁液に各種成分が含まれる組成物を調整した。該組成物1本(125ml)には、ビタミンA(レチノール当量)300μg、β-カロテン 6.6mg、ビタミンB1 3mg、ビタミンB2 3mg、ビタミンB6 5mg、ビタミンB12 10μg、ビタミンC 500mg、ナイアシン 15mg、葉酸 800μg、ビタミンD3 3.7μg、ビタミンE 20mg、ビオチン 50μg、パントテン酸10mg、鉄 5mg、亜鉛 10mg、銅 0.01mg、セレン 50μg、カリウム 90mg、カルシウム 70mg、マグネシウム 3mg、リン 30mg、ナトリウム 30mg、コエンザイムQ10 15mg、ガラクトオリゴ糖 2.0g が含まれる。
目的:がん化学療法を施行する血液腫瘍患者に対し、ビタミン、微量元素補給飲料である組成物(調製例1で調製)を投与し、化学療法時に起こる酸化ストレス及び副作用の軽減、栄養状態の改善や患者のQOLへの影響に対する有効性を検討した。
研究方法
対 象 :同意の得られた癌化学療法を施行する予定の血液腫瘍患者
対象製品:調製例1で調製した組成物(125 mL/本)
投与方法:癌化学療法が予定され、同意の得られたFreshな血液腫瘍患者を登録し、封筒法により、調製例1で調製した組成物の摂取群(投与群)、非摂取群(非投与群)に割り付ける。投与群については癌化学療法開始日(第一クール開始日)から第二クール終了日まで通常の食事に加え調製例1で調製した組成物を1本(125ml)/日を投与する。非投与群は通常の食事のみとする。
血液検査については、癌化学療法開始(調製例1で調製した組成物の投与開始前日)を1日と設定し、1日目、10日目、22日目(第一クール終了日)、32日目(第二クール10日目)、43日目(第二クール終了日)の5ポイントとする。
なお、給食以外に摂取した食事については「食べ物日記」に記載し、ビタミン・微量元素などのサプリメントの摂取は避けることとする。
症例数:投与群6症例、非投与群6症例(合計12症例)
1)血液検査
赤血球数、白血球量、白血球分画、リンパ球数、血小板数、総蛋白、アルブミン、血糖値、総コレステロール、トリグリセリド、総ビリルビン、直接ビリルビン、AST、ALT、Al-p、BUN、クレアチニン、Na、K、Cl、CRP、Hb
2)特別検査
プレアルブミン、ラジカル生成能、過酸化脂質、抗酸化ビタミン(VA、VC、VE)、Zn
3)尿一般検査
蛋白(定性)、糖(定性)、ウロビリノーゲン(定性)
4)アンケートによるQOL評価
口内炎の有無、食欲不振の有無、嘔気・嘔吐の有無、倦怠感の有無、下痢の有無、副作用の発現頻度
栄養状態の指標であるアルブミンについては、化学療法開始時点に比べ、投与群では有意に(p<0.01)増加し、非投与群では有意に(p<0.001)減少した。ただし、実測値ではいずれも正常値内での変動であった。プレアルブミンは、非投与群では変化は見られなかったものの、投与群で有意に(p<0.05)増加した。総蛋白は両群で減少傾向がみられ、非投与群では有意に(p<0.001)減少した。また、活性酸素量の指標であるラジカル生成能は、非投与群では若干上昇傾向が見られた一方、投与群では有意に(p<0.01)減少した。過酸化脂質は、投与群で2回目、3回目で減少したものの、4回目以降では増加し、5回目では1回目の値とほぼ同値であった。抗酸化作用のあるビタミンA,ビタミンC、ビタミンEおよび亜鉛については、非投与群では減少し、投与群では有意に(P<0.01)増加した。免疫能の指標であるリンパ球数は、投与群は若干の増加はみられたもののほとんど変化はなく、また非投与群では、2回目測定時で約2000mm3の増加はみられたものの、3回目測定以降で減少した。
考察:
本発明の組成物は、がん化学療法時に起こる酸化ストレス改善および抗酸化力増加に特に有効であり、栄養状態の改善に有効であると考えられた。
本明細書で引用した全ての刊行物、特許および特許出願をそのまま参考として本明細書にとり入れるものとする。
Claims (14)
- がん化学療法時に起こる酸化ストレス及び/又は副作用の軽減、あるいはがん化学療法時の栄養状態を改善するための組成物であって、下記の(a)~(f)の成分を含む前記組成物。
(a)抗酸化剤
(b)ビタミンB1、B2、B6、ナイアシン及びパントテン酸からなる群より選択される少なくとも1つの成分
(c)葉酸、ビタミンB12及びビタミンAからなる群より選択される少なくとも1つの成分
(d)亜鉛
(e)セレン
(f)コエンザイムQ10 - 抗酸化剤が抗酸化ビタミンである請求項1記載の組成物。
- 抗酸化ビタミンがビタミンC,ビタミンE及びβ-カロテンからなる群より選択される少なくとも1つである請求項2記載の組成物。
- さらに、ビタミンD3及び/又は鉄を含む請求項1~3のいずれかに記載の組成物。
- ビタミンC,ビタミンE、β―カロテン、ビタミンB1、B2、B6、ナイアシン、パントテン酸、葉酸、ビタミンB12、ビタミンA、亜鉛、セレン、コエンザイムQ10、ビタミンD3及び鉄を含む請求項1~4のいずれかに記載の組成物。
- 一投与単位あたり、ビタミンC 500±100 mg,ビタミンE 20±4 mg、β-カロテン6.6±1.32 mg、ビタミンB1 3±0.6 mg、ビタミンB2 3±0.6 mg、ビタミンB6 5±1 mg、ナイアシン15±3 mg、パントテン酸10±2 mg、葉酸800±160 μg、ビタミンB12 10±2 μg、ビタミンA(レチノール当量)550±110μg、亜鉛10±2 mg、セレン50±10 μg、コエンザイムQ10 15±3mg、ビタミンD3 3.7±0.74 μg及び鉄5±1 mgを含み、エネルギーが80±16 kcalである請求項5記載の組成物。
- さらに、ビオチン、ガラクトオリゴ糖、カリウム、カルシウム、マグネシウム及びリンを含む請求項1~6のいずれかに記載の組成物。
- 一投与単位あたり、ビオチン50±10 μg、ガラクトオリゴ糖2±0.4 g、カリウム90±18 mg、カルシウム70±14 mg、マグネシウム3±0.6 mg及びリン30±6 mgを含む請求項7記載の組成物。
- 服用可能な液体に分散されている請求項1~8のいずれかに記載の組成物。
- 前記液体が果汁である請求項9記載の組成物。
- 一投与単位あたりの容量が125±25 mLである請求項9又は10記載の組成物。
- がん化学療法時に起こる酸化ストレス及び/又は副作用の軽減、あるいはがん化学療法時の栄養状態の改善に有効な量で下記の(a)~(f)の成分を被験者に投与することを含む、がん化学療法時に起こる酸化ストレス及び/又は副作用の軽減、あるいはがん化学療法時の栄養状態の改善方法。
(a)抗酸化剤
(b)ビタミンB1、B2、B6、ナイアシン及びパントテン酸からなる群より選択される少なくとも1つの成分
(c)葉酸、ビタミンB12及びビタミンAからなる群より選択される少なくとも1つの成分
(d)亜鉛
(e)セレン
(f)コエンザイムQ10 - がん化学療法時に起こる酸化ストレス及び/又は副作用の軽減、あるいはがん化学療法時の栄養状態を改善するための組成物を製造するための下記の(a)~(f)の成分の使用。
(a)抗酸化剤
(b)ビタミンB1、B2、B6、ナイアシン及びパントテン酸からなる群より選択される少なくとも1つの成分
(c)葉酸、ビタミンB12及びビタミンAからなる群より選択される少なくとも1つの成分
(d)亜鉛
(e)セレン
(f)コエンザイムQ10 - がん化学療法時に起こる酸化ストレス及び/又は副作用の軽減、あるいはがん化学療法時の栄養状態の改善に使用するための組成物であって、下記の(a)~(f)の成分を含む前記組成物。
(a)抗酸化剤
(b)ビタミンB1、B2、B6、ナイアシン及びパントテン酸からなる群より選択される少なくとも1つの成分
(c)葉酸、ビタミンB12及びビタミンAからなる群より選択される少なくとも1つの成分
(d)亜鉛
(e)セレン
(f)コエンザイムQ10
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CN2009801017990A CN101909639B (zh) | 2008-01-09 | 2009-01-06 | 用于减轻在癌化学疗法中引起的氧化应激和/或副作用、或者改善癌化学疗法中的营养状态的组合物 |
US12/811,682 US9511141B2 (en) | 2008-01-09 | 2009-01-06 | Composition for reducing oxidative stress and/or side effects occurring during cancer chemotherapy or improving nutritional status during cancer chemotherapy |
JP2009548912A JP5931324B2 (ja) | 2008-01-09 | 2009-01-06 | がん化学療法時に起こる酸化ストレス及び/又は副作用の軽減あるいはがん化学療法時の栄養状態を改善するための組成物 |
CA2711611A CA2711611C (en) | 2008-01-09 | 2009-01-06 | Composition for reducing oxidative stress and/or side effects occurring during cancer chemotherapy or improving nutritional status during cancer chemotherapy |
KR1020107015209A KR101243406B1 (ko) | 2008-01-09 | 2009-01-06 | 암 화학 요법시에 일어나는 산화 스트레스 및/또는 부작용의 경감 혹은 암 화학 요법시의 영양 상태를 개선하기 위한 조성물 |
EP09700277.8A EP2236146B1 (en) | 2008-01-09 | 2009-01-06 | Composition for reducing oxidative stress and/or side effects occurring during cancer chemotherapy or improving nutritional status during cancer chemotherapy |
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CN103099211A (zh) * | 2012-12-21 | 2013-05-15 | 洪万雄 | 一种融合辅酶q10的广谱性一氧化氮保健品 |
JP2013170156A (ja) * | 2012-02-22 | 2013-09-02 | Terumo Corp | 固形組成物 |
JP2019532098A (ja) * | 2016-08-26 | 2019-11-07 | ダブドゥブ, アティフDABDOUB, Atif | 腎臓透析を受けている患者のための食餌性多量/微量栄養補給剤 |
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WO2014159684A1 (en) * | 2013-03-13 | 2014-10-02 | The Trustees Of The University Of Pennsylvania | Compositions and methods for treating or preventing insulin resistance or abnormal levels of circulating lipids in a mammal |
US11761949B2 (en) | 2016-10-10 | 2023-09-19 | Lankenau Institute For Medical Research | Methods and compositions for assessing and treating emetogenic drug-related nausea |
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JP2019532098A (ja) * | 2016-08-26 | 2019-11-07 | ダブドゥブ, アティフDABDOUB, Atif | 腎臓透析を受けている患者のための食餌性多量/微量栄養補給剤 |
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US9511141B2 (en) | 2016-12-06 |
CN101909639A (zh) | 2010-12-08 |
EP2236146A1 (en) | 2010-10-06 |
EP2236146A4 (en) | 2013-05-29 |
US20100291057A1 (en) | 2010-11-18 |
JP5931324B2 (ja) | 2016-06-08 |
CN101909639B (zh) | 2013-09-11 |
KR20100099273A (ko) | 2010-09-10 |
CA2711611A1 (en) | 2009-07-16 |
JPWO2009087988A1 (ja) | 2011-05-26 |
KR101243406B1 (ko) | 2013-03-13 |
EP2236146B1 (en) | 2014-07-16 |
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