CN101600423A - Be used for improving/compositions of the adverse side effect of prevention of steroid treatment - Google Patents
Be used for improving/compositions of the adverse side effect of prevention of steroid treatment Download PDFInfo
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Abstract
Disclose and be used for improving/compositions of the contingent adverse side effect of prevention of steroid treatment, or be used to suppress the compositions of amyotrophy related gene, described compositions comprises isoleucine, leucine and valine as active component.Contingent adverse side effect in steroid therapy can be improved or prevent to compositions, for example amyotrophy, myalgia, arthralgia, glucose tolerance reduction, bone metabolism reduce, immunity is impaired, anorexia, lose weight and fatigability, and also can prevent the amyotrophy followed with various diseases.Compositions also can be prevented and the relevant amyotrophy of the enhanced expression of amyotrophy related gene, and described enhanced expression is excessive by glucocorticoid, renal failure situation etc. induced.Therefore, compositions is effective for the QOL that improves the patient.
Description
Technical field
The present invention relates to be used for improving or suppressing the side effect of steroid therapy compositions, be used to suppress the compositions of amyotrophy related gene expression, and being used in combination of compositions and steroid medicine.More specifically, the present invention relates to the new purposes of branched-chain amino acid.
Background technology
The symptomatic therapy of the side effect in the steroid therapy comprises that at present (1) infect: the using of antibacterial agent, (2) diabetes: the using of insulin and oral antidiabetic, (3) gastrointestinal symptom: the using of antacid and H2 blocker, (4) osteoporosis: the using of vitamin D and calcium, (5) glaucoma: eye the using and (6) mental disorder and depressive state of hypotensive agent: the using etc. of psychosis.Yet, improving or the inhibition myopathy---the unique method of one of serious side effects is the dosage minimizing of steroid.In addition, when multiple side effect occurs, should take about the symptomatic drugs of every kind of symptom to suppress symptom.In addition, wherein the steroid side effect is also thrown into question by steroid dependence that other steroid suppress etc.
Although have been proposed in the treatment of chronic rheumatoid arthritis the probability (patent document 1) that the steroid dosage by branched-chain amino acid reduces, it does not describe the side effect that branched-chain amino acid self suppresses steroid medicine.For steroid medicine, even dosage can reduce, the life-time service of a small amount of steroid also is considered to cause the side effect with those pars that caused by its high dose.Therefore, think that it is difficult only reducing the side effect that alleviates steroid medicine by dosage.
On the contrary, side effect and use a small amount of steroid medicine possibly can't provide enough therapeutical effect for fear.Its object lesson is to use the pulsed therapy (pulse therapy) of a large amount of steroid medicines.This method needs a large amount of steroid medicines, with quick inhibition symptom, and the symptom that for example fatal symptom, serious organ disease, active disease are interim etc., wherein injudicious dosage reduces and relates to danger.In other words, the minimizing of the dosage of steroid may be life-threatening for the patient.Therefore, there are the needs that do not need the method that dosage reduces about the side effect that can suppress steroid medicine.
One of known side effect of steroid therapy is the amyotrophy effect.Report has in the recent period proved that the effect of this kind amyotrophy is caused by the transcriptional expression that atrogin-1 gene and myostatin gene promote, the transcriptional expression of described promotion is because the transcription activating that the dephosphorylation of these genes by transcription factor Foxo causes, the dephosphorylation of described Foxo results from the activity of Akt1 (protein kinase B) and is subjected to the inhibition (non-patent document 1-3) of steroid (glucocorticoid).Atrogin-1 gene and MuRF-1 gene are the genes of coding ubiquitin ligase, i.e. proteasome degraded induced gene, and it is also referred to as amyotrophy gene (Atrogene).In addition, the myostatin gene belongs to the TGF 'beta ' family, and known be down regulator (non-patent document 4) about muscle growth.In addition, when amyotrophy took place, the FOXO gene was reported to show the expression (non-patent document 5 and 6) that promotes.In addition, KLF15 and the REDD1 gene is known is " metabolic nutrition adjusting related gene ", it relates to and being considered to amyotrophy simultaneously or the metabolism or the malnutrition (non-patent document 7 and 8) that take place in company with amyotrophy.
Exist pathology wherein to increase the weight of the known some diseases (non-patent document 9) of (amyotrophy and cancer cachexia) by the amyotrophy gene expression that except that the side effect of steroid, increases.The example of this kind disease comprises diabetes, cancer, renal failure, heart failure, AIDS, liver cirrhosis, various inflammatory diseases, malnutrition disease etc.Amyotrophy is to reduce the serious problems of patient's QOL.Therefore, there are needs about the medicine of the amyotrophy that can suppress to cause or above-mentioned disease by using of steroid medicine.
Known IGF-1 (insulin like growth factor)/PI3K (phosphoinositide 3-kinase)/AKT/mTOR (mammalian target of rapamycin) approach plays an important role in the amyotrophy expression of gene.When this approach was suppressed owing to some reasons, the amyotrophy expression of gene was considered to increase and cause amyotrophy (non-patent document 10 and 11).It was reported that dexamethasone reduces food intake and body weight for using of rat, cause amyotrophy, and they suppress (non-patent document 12) by IGF-1.On the other hand, it was reported that IGF-1 suppresses in the muscle cell expression (non-patent document 10 and 13) by the atrogin-1 and the MuRF-1 of induced by dexamethasone.In addition, show that amyotrophy gene (atrogin-1 or MuRF-1) knock-out mice does not have amyotrophy (non-patent document 2).
Simultaneously, branched-chain amino acid (isoleucine, leucine and valine) and to the association between the amyotrophic inhibitory action obtained the report ( non-patent document 14 and 15).Yet report is in view of amyotrophy has been discussed in the effect of protein degradation rate and synthetic ratio.On the other hand, some have been described independent branched-chain amino acid and only provide about suppressing the particularly inadequate effect of the protein degradation in the muscle of amyotrophy, and measure the method still unresolved ( non-patent document 15,16,17 and 18) of its efficient and effect.Known branched-chain amino acid comprises that leucine promotes protein synthesis (non-patent document 19) by activating mTOR.Yet it is unknown to the effect of amyotrophy expression of gene.In addition, the gene that its expression in sarcoplast cell line C2C12 changes owing to IGF-1 tends to be subjected to the reverse adjusting of the common existence of mTOR inhibitor rapamycin, and known have MuRF-1, one of amyotrophy gene (non-patent document 20) in them.Yet unknown branched-chain amino acid (for example, leucine etc.) suppresses the expression of amyotrophy gene (atrogin-1 and MuRF-1), and described amyotrophy expression of gene is owing to inducing amyotrophic stimulation to increase.
Patent document 1:WO2005/055997
Non-patent document 1:Proc.Natl.Acad.Sci.U.S.A., 98:14440-14445 (2001)
Non-patent document 2:Science, 294:1704-1708 (2001)
Non-patent document 3:Nature Med., the 10th volume, (6): 584-585 (2004)
Non-patent document 4:Curr Opin Pharmacol., 7 (3): 310-5 (2007)
Non-patent document 5:J.Biol.Chem., the 279th volume, (39): 4114-41123 (2004)
Non-patent document 6:J.Biol.Chem., the 282nd volume, (29): 21176-21186 (2007)
Non-patent document 7:BBRC the 327th volume: 920-926 (2005)
Non-patent document 8:J.Biol.Chem., the 281st volume, (51): 39128-39134 (2006)
Non-patent document 9:FASEB J., 18:39-51 (2004)
Non-patent document 10:Molecular Cell, the 14th volume, 395-403 (2004)
Non-patent document 11:Cell, the 117th volume, 399-412 (2004)
Non-patent document 12:Endocrinology 146:1789-1797 (2005)
Non-patent document 13:Am.J.Physiol.Endocrinol Metab., 287:E591-E601 (2004)
Non-patent document 14:J.Nutr., 136 (1 Suppl): 234S-6S (2006)
Non-patent document 15:J.Nutr., 136 (1 Suppl): 237S-42S (2006)
Non-patent document 16:J.Nutr., 136 (1 Suppl): 264S-68S (2006)
Non-patent document 17:J.Nutr., 136 (1 Suppl): 308S-13S (2006)
Non-patent document 18:J.Nutr.; 136 (1 Suppl): 314S-18S (2006)
Non-patent document 19:J.Nutr., 2006 Jan; 136 (1 Suppl): 269S-73S
Non-patent document 20:J.Biol.Chem., the 280th volume, No.4:2737-2744 (2005)
Summary of the invention
Problem by the present invention's solution
Steroid medicine is to be used for for example very effective drug products of collagenosis etc. of various symptoms.Yet steroid medicine is with high dose or use to cause it may is fatal serious side effects sometimes for a long time.The method that the purpose of this invention is to provide the side effect that improves or suppress to cause by steroid therapy.
Another object of the present invention provides the relevant amyotrophic method that takes place and the QOL that the patient reduces is had effect of altitude of progress that can suppress with various diseases.
The method of dealing with problems
The inventor has carried out extensive studies in the trial that solves foregoing problems, and find 3 kinds of branched-chain amino acid isoleucine, leucine and valine (being also referred to as BCAA hereinafter) are effective for improving the side effect that is caused by using of steroid medicine, described side effect is amyotrophy for example, decreased muscle function, myalgia, arthralgia, glucose tolerance reduces, bone metabolism reduces, immunity is impaired, anorexia, fatigability, lose weight etc., the amyotrophy that the expression that promotes for inhibition and amyotrophy related gene is relevant is effective etc., and this causes of the present invention finishing.
Therefore, the invention provides following.
[1] be used for improving or suppressing the compositions of the side effect of steroid therapy, it comprises isoleucine, leucine and valine as active component.
[2] compositions of [1], wherein side effect be selected from following at least a: amyotrophy, decreased muscle function, myalgia, arthralgia, glucose tolerance reduction, anorexia, lose weight, bone metabolism reduces, immunity is impaired and fatigability.
[3] compositions of [2], wherein amyotrophy shows the expression that the amyotrophy related gene promotes.
[4] be used to suppress the compositions of amyotrophy related gene expression, it comprises isoleucine, leucine and valine as active component.
[5] compositions of [4], it suppresses the relevant amyotrophy of expression with the promotion of amyotrophy related gene.
[6] compositions of [5], wherein the expression of Cu Jining is excessive relevant with glucocorticoid.
[7] compositions of [5], wherein the expression of Cu Jining is relevant with renal failure.
[8] any one compositions in [3]-[7], wherein the amyotrophy related gene be selected from following at least a: atrogin-1 gene, MuRF-1 gene, myostatin gene, FOXO1 gene, FOXO3a gene, FOXO4 gene, REDD1 gene and KLF15 gene.
[9] any one compositions in [1]-[8], it comprises in once taking in and is no less than 1g isoleucine, leucine and valine.
[10] any one compositions in [1]-[9], wherein the weight ratio of isoleucine, leucine and valine is 1: 1.5-2.5: 0.8-1.7.
[11] any one compositions in [1]-[10], itself and steroid medicine are used in combination.
[12] any one compositions in [1]-[11], it is a medicine.
[13] any one compositions in [1]-[11], it is a food.
[14] compositions of [13], wherein said food are food or the dietary supplements with health requirements.
[15] compositions of [14], wherein said food with health requirements are to be used for the food of specific health purposes or to have the food that trophic function requires.
[16] any one compositions in [13]-[15], wherein said food are the concentrated liquid diet.
[17] isoleucine, leucine and valine are used for producing the purposes of any one compositions in [1]-[16].
[18] purposes of [17], wherein the weight ratio of isoleucine, leucine and valine is 1: 1.5-2.5: 0.8-1.7.
[19] be used for improving or suppressing the method for the side effect of steroid therapy, it comprises to using isoleucine, leucine and the valine that the experimenter uses effective dose.
[20] method of inhibition amyotrophy gene expression, it comprises to using isoleucine, leucine and the valine that the experimenter uses effective dose.
[21] method of [19] or [20], it comprises in once taking in and is no less than 1g isoleucine, leucine and valine.
[22] any one method in [19]-[21], wherein the weight ratio of isoleucine, leucine and valine is 1: 1.5-2.5: 0.8-1.7.
[23] commercial packing, it comprises any one compositions and written material in [1]-[16], described written material is set forth the side effect that compositions can maybe should be used for improving or suppressing steroid therapy, or the relevant amyotrophy of expression of inhibition and the promotion of amyotrophy related gene.
The invention effect
Comprise 3 kinds of branched-chain amino acid isoleucine, leucine and valines as composition of active components by provided by the invention, be used to improve the side effect that generally speaking causes by steroid therapy.Particularly, compositions of the present invention is effective to improve or suppress the side effect of steroid therapy, and for example amyotrophy, decreased muscle function, myalgia, arthralgia, glucose tolerance reduction, bone metabolism reduce, immunity is impaired, anorexia, fatigability, lose weight etc.
The compositions that is used to suppress the amyotrophy related gene expression of the present invention can directly and effectively be improved the amyotrophy state by suppressing the amyotrophy Expression of Related Genes.Particularly, compositions of the present invention is used to prevent or treat the amyotrophy that it is the side effect of steroid therapy, with the amyotrophy relevant with renal failure, and be used to prevent or amyotrophy that treatment is relevant with various other diseases, described various other diseases are characterised in that the expression that Atrogin-1 and MuRF-1 gene increase.
In addition, the compositions that is used to suppress the amyotrophy related gene expression of the present invention can be used for prevention or treat various chronic or acute illnesss, and its pathology increase the weight of by the amyotrophy that the expression that is promoted by the amyotrophy related gene causes.This kind disease is characterised in that undesirable weight loss, particularly the motor capacity of the minimizing relevant with skeletal muscle atrophy.Use compositions of the present invention, can prevent or treat the motor capacity that the muscle owing to reduction reduces.Therefore, can prevent patient's decline and bedfast patient, and hospitalization phase and treatment phase are shortened in expection.
In addition because medicine of the present invention comprises branched-chain amino acid as active component, so it be high safety and be difficult to cause side effect.Therefore, medicine is used for the treatment of as pharmaceutical product or prevents amyotrophy and the amyotrophy relevant with various other diseases as the side effect of steroid therapy.In addition, because 3 kinds of branched-chain amino acid isoleucine, leucine and valines comprising in compositions of the present invention have definite safety,, and not only can be used for pharmaceutical use and can also be used for food so compositions of the present invention is a high safety.
Description of drawings
Fig. 1 is presented at that BCAA uses group and vehicle is used body weight overview in the group and the change in food intake.
Fig. 2 is presented at BCAA and uses the comparison that group, vehicle are used the muscle weight of gastrocnemius and musculus soleus in group and the contrast (normal group).
Fig. 3 is presented at BCAA and uses the comparison that group, vehicle are used grip measured value in group and the contrast (normal group).Si Shi t check * p＜0.05
Fig. 4 is presented at BCAA and uses the comparison that group, vehicle are used blood sugar level in group and the contrast (normal group).
Fig. 5 is presented at BCAA and uses the comparison that group, vehicle are used plasma insulin level in group and the contrast (normal group).
Fig. 6 is presented at BCAA and uses group and vehicle and use between the group in convalescent period and (recover; When R) the 1st day and the 2nd day, the comparison of the muscle weight of gastrocnemius and musculus soleus.
Fig. 7 is presented at BCAA and uses group and the vehicle comparison of using plasma A LP level between the group.Si Shi t check * p＜0.05
Fig. 8 is presented at the body weight overview in the rat and the change of food intake.
Fig. 9 shows the comparison of the muscle weight of gastrocnemius and musculus soleus.
Figure 10 is presented at the comparison of the expression in atrogin-1 gene, MuRF-1 gene and the Myostatin gene, and wherein the value of each group is with respect to a value as 1 matched group.
Figure 11 is presented at the comparison of the expression in FOXO1, FOXO3a and the FOXO4 gene, and wherein the value of each group is with respect to a value as 1 matched group.
Figure 12 shows the comparison of REDD1 expression of gene, and wherein the value of each group is with respect to a value as 1 matched group.
Figure 13 shows the comparison of KLF15 expression of gene, and wherein the value of each group is with respect to a value as 1 matched group.
Figure 14 is presented at convalescent period (recovery; When R) the 1st day and the 2nd day, the comparison of body weight and food intake overview.
Figure 15 is presented at convalescent period (recovery; When R) the 1st day and the 2nd day, the comparison of the muscle weight of gastrocnemius and musculus soleus.
Figure 16 is presented at convalescent period (recovery; When R) the 1st day and the 2nd day, the comparison of atrogin-1 gene and MuRF-1 expression of gene, wherein the value of each group is with respect to a value as 1 matched group.
Figure 17 is presented at the comparison of atrogin-1 gene and MuRF-1 expression of gene in the renal failure rat model, and wherein the value of each group is with respect to a value as 1 matched group.
The specific embodiment
The compositions that is used to improve or suppresses the compositions of side effect and be used to suppress the amyotrophy related gene expression in steroid therapy of the present invention is characterised in that the isoleucine as active component that comprises therein, leucine and valine (being commonly referred to as compositions of the present invention hereinafter sometimes).
Side effect that compositions of the present invention is used to improve or inhibition is relevant with steroid therapy etc.In description of the present invention; " improvement " comprises " prevent, alleviate and treat "; and mean the side effect relevant with steroid therapy; promptly " amyotrophy ", " decreased muscle function ", " myalgia ", " arthralgia ", " glucose tolerance reduction ", " bone metabolism minimizing ", " immunity is impaired ", " anorexia ", " losing weight ", " fatigability " etc. move towards the direction of normalization, and the development that further means side effect is prevented in advance or suppresses.
In severe case, because the side effect of steroid medicine, " development of the side effect relevant with steroid therapy " significantly damages QOL sometimes, even medicine is used for the treatment of disease.In some cases, it is life-threatening.Under the situation of inpatient, for example, symptom may not be improved to the level of leaving hospital of allowing.Under the patient's that needs are nursed or taken care of situation, symptom may enough be improved fully, and with the time that shortens nursing or take care of help, this is patient's nursing or takes care of necessary.Yet compositions of the present invention is all effective for 2 kinds of situations.
The example of the side effect of steroid therapy comprises that (1) infection increases the weight of, induce with symptom latent, immunity is impaired, (2) hypocorticoidism disease, (3) glucose tolerance for example reduces diabetes-induced or increases the weight of, blood glucose level rises is high, (4) gastrointestinal ulceration, gastrointestinal hemorrhage, gastric-intestinal perforation, hemorrhagic pancreatitis, (5) spasm, intracranial hypertension, (6) mental disorder, depressive state, (7) bone metabolism for example reduces osteoporosis (especially, the spinal column compression fracture) etc., (8) aseptic head necrosis (femur, humeral fracture), (9) myopathy (is lost with the muscle strength that amyotrophy is followed, especially, muscle weight reduces and the muscle strength of near-end muscle is lost, decreased muscle function), lose weight, (10) glaucoma, high intraocular pressure, posterior capsular cataract, (11) thrombosis (hypercoagulability), (12) because the rupture of heart of myocardial infarction, (13) asthma attack increases the weight of, (14) because the anaphylaxis of injection, (15) moon-face, buffalo hump, (16) because the hypertension of mineral effect, (17) sodium-hydropexis (edema) weight increase, hypokalemic alkalosis, (18) the growth disease in the childhood period, (19) menoxenia, (20) minimizing in motility of sperm and the number, (21) acne, hirsutism, alopecia, pigmentation, (22) thinning of skin, weak, subcutaneous hyperemia, linear purpura, face red spot, panniculitis, (23) wound healing disease, (24) stimulate (rash) tickle and itch symptom, singultus, (25) glad, insomnia, headache, dizzy, (26) dysidria, excessively urinate, leukocytosis, (27) fatty liver, nitrogen is unbalance, (28) GOT, GPT, ALP increases, (29) hyperlipemia, hypercholesterolemia, cholesterol nephropathy (steroidnephropathy), (30) feel sick, vomiting, stomachache, heartburn, the abdominal distention sense, dry mouth, diarrhoea, bulimia nerovsa, (31) because the retinal disorder or the exophthalmos (eyophthalmos) of central serous chorioretinopathy, (32) myalgia, arthralgia, fever, feeling of fatigue, (33) because muscle, the atrophy in local organization of Intradermal or subcutaneous injection, depressed, lose weight, (34) thrombosis, phlebitis, pain, swelling, tenderness in the intravenous injection process increases the weight of, (35) withdrawal symptom; General symptom: fever, headache, fatigability, general property fatigability, asthenic feeling, shock/digestive organs: apositia, anorexia, nausea and vomiting, diarrhoea/nervous system: headache, anxiety, excitement/spasm, disturbance of consciousness, myalgia, arthralgia etc.The present invention is effective especially for side effect, and described side effect is " amyotrophy ", " decreased muscle function ", " myalgia ", " arthralgia ", " glucose tolerance reduction ", " bone metabolism minimizing ", " immunity is impaired ", " anorexia ", " losing weight ", " fatigability " etc. for example.
The example of the target disease of steroid therapy comprises (1) endocrinopathy: chronic adrenocortical hypofunction (constitutional, Secondary cases, hypophysis, iatrogenic), adrenocortical insufficiency,acute disease (adrenal crisis), A/G syndrome, subacute thyroiditis, thyrotoxicosis [thyroidal (toxicity) crisis], malignant exophthalmos with the thyroidal disease association, unicity ACTH deficiency disease, (2) rheumatism: chronic rheumatoid arthritis, juvenile rheumatoid arthritis (comprising the StillShi disease), rheumatic fever (comprising rheumatic carditis), polymyalgia rheumatica, (3) collagenosis: lupus (general and chronic plate-like erythema), SV (comprises aortitis syndrome, polyarteritis nodosa, polyarteritis, Wegner granulomatosis), polymyositis (dermatomyositis), scleroderma, (4) nephropathy: nephropathy and nephrotic syndrome, (5) heart disease: congestive heart failure, (6) allergic disease: bronchial asthma, asthmatic bronchitis (the asthmatic bronchitis childhood period of comprising), the allergy or the poisoning that are caused by medicine and other chemical substances (comprise drug eruption, the toxic rash), serum sickness (7) severe infections: severe infections (with the chemotherapy combination), (8) hematologic disease: hemolytic anemia (following doubtful immunity or immunologic mechanism), leukemia (acute leukemia, the acute blast cell crisis of chronic granulocytic leukemia, chronic lymphatic leukemia) (comprises leukemia cutis), agranulocytosis (constitutional, Secondary cases), purpura (thrombocytopenic and non-thrombocytopenic), aplastic anemia, because the hemorrhagic diathesis of thrombin disorder, (9) gastrointestinal disease: regional enteritis, ulcerative colitis, (10) serious weak disease: improving of the general situation of serious weak disease (comprises cancer of late stage, sprue), (11) hepatopathy: acute severe hepatitis (comprising clinical serious case), silt gallbladder type acute hepatitis, chronic hepatitis (active type, the recurrent acute type, silt gallbladder type) (is confined to and follow in the liver function the remarkable unusual intractable hepatopathy that continues) to the general treatment no response, liver cirrhosis (active type, follow the situation of refractory ascites, follow cholestatic situation), (12) pneumonopathy: osteitis tuberculosa cystica (except that situation) with independent BHA, diffuse interstitial pneumonia (pulmonary fibrosis) (comprising radiation pneumonia), (13) tuberculosis disease (with the antituberculotics combination), pulmonary tuberculosis (is confined to miliary tuberculosis, serious tuberculosis), tuberculous meningitis, tuberculous pleuritis, tuberculous peritonitis, tuberculous pericarditis, (14) nervous system disease: encephalomyelitis (comprises encephalitis, myelitis) (provide inadequate time spent of doing when observing intracranial hypertension symptom and other drug, short time period is used for the constitutional encephalitis), peripheral neuritis (comprising the Guillain-Barre syndrome), myotonia, myasthenia gravis, multiple sclerosis (comprising a myelitis), chorea minor, facial paralysis, spinal arachnoiditis, (15) malignant tumor: malignant lymphoma (lymphosarcomatosis, reticulosarcoma disease (reticulosarcomatosis), the HodgkinShi disease, the skin eeticulosis, mycosis fungoides) with similar disease (relevant disease), the eosinophilic granuloma, the recurrent of breast carcinoma shifts, (16) other medical conditions: spontaneous hypoglycemia disease, the unknown cause fever, infect (17): SARS etc.In addition, also comprise steroid therapy etc., it is used for suppressing for example purpose of the repulsion of process such as liver transplantation, renal transplantation of organ transplantation.
The example that is used for the steroid medicine of steroid therapy comprises hydrocortin, cortisone, prednisolone, methylprednisolone, omcilon, triamcinolone, paramethasone, dexamethasone, betamethasone, hexestrol, thiamazole, fluocinolone acetonide, fluocinonide, flurandrenolide (fluorometholon), beclomethasone dipropionate, estriol, diflorasone diacetate, nerisona, difluprednate etc.
In the present invention, " amyotrophy related gene " generally means " amyotrophy gene " and " metabolic nutrition adjusting related gene ", and it relates to and being considered to amyotrophy simultaneously or the metabolism or the malnutrition that take place in company with amyotrophy.
" amyotrophy gene " refers to compare with the expression before the atrophy, when amyotrophy, shows different genes of expressing in cell, and comprises gene that shows the expression that promotes and the gene that shows the expression that suppresses.The gene that preferably shows the expression that promotes.Its preferred object lesson comprise known with the excessive relevant amyotrophy process of glucocorticoid in show ubiquitin ligase, particularly atrogin-1 gene, MuRF-1 gene and the myostatin gene of the expression that promotes.In addition, the preferred example that metabolic nutrition is regulated related gene also comprises the FOXO gene, for example FOXO1 gene, FOXO3a gene, FOXO4 gene etc., REDD1 gene and KLF15 gene.
In the present invention, it is excessive that amyotrophic nosetiology is not limited to glucocorticoid, and any reason of inducing the amyotrophy Expression of Related Genes to change all is included in the nosetiology.In addition, glucocorticoid is excessive can be for endogenic or ectogenic.
In the present invention, " inhibition of amyotrophy related gene expression " means when amyotrophy, reduces or increase the gene expression that promotes or suppress respectively.It preferably means the expression of the promotion that reduces the amyotrophy related gene.
Compositions of the present invention preferably suppresses the relevant amyotrophy of expression that promotes with the amyotrophy related gene via amyotrophy Expression of Related Genes inhibitory action.
Be subjected to the amyotrophy related gene of compositions inhibition of the present invention as the expression of its promotion, above-mentioned atrogin-1 gene, MuRF-1 gene, myostatin gene, FOXO1 gene, FOXO3a gene, FOXO4 gene, REDD1 gene, KLF15 gene etc. are preferred, and atrogin-1 gene, MuRF-1 gene, myostatin gene etc. are preferred.
Atrogin-1 gene, MuRF-1 gene, myostatin gene, FOXO1 gene, FOXO3a gene, FOXO4 gene, REDD1 gene and KLF15 are known, and its sequence is disclosed in the ncbi database.For example, at NCBI genetic transcription thing data base UniGene (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? db=unigene) in, the atrogin-1 gene is the gene that its transcript in mice, rat and people can be limited by the IDs of Mm.292042, Rn.72619, Hs.403933 etc. respectively, and particularly in the people, it is defined as the Man at Online Mendelian Inheritance in
TM(OMIM
TM) in * 606604F-BOX ONLY PROTEIN 32; FBXO32.
The MuRF-1 gene is the gene that its transcript in mice, rat and people can be limited by the IDs of the Mm.261690 in UniGene or Mm.331961, Rn.40636, Hs.279709 etc., and particularly in the people, it is defined as at OMIM
TMIn * 606131 RINGFINGER PROTEIN 28; RNF28.
The Myostatin gene is the gene that its transcript in mice, rat and people can be limited by the IDs of the Mm.3514 in UniGene, Rn.44460, Hs.41565 etc., and particularly in the people, it is defined as at OMIM
TMIn * 603936GROWTH/DIFFERENTIATION FACTOR 11; GDF11.
The FOXO1 gene is the gene that its transcript in mice, rat and people can be limited by the IDs of the Mm.29891 in UniGene, Mm.395558, Rn.116108, Hs.370666 etc., and particularly in the people, it is defined as at OMIM
TMIn * 136533FORKHEAD BOX O1A; FOXO1A.The FOXO3a gene is the gene that its transcript in mice, rat and people can be limited by the IDs of the Mm.296425 in UniGene, Rn.24593, Hs.220950 etc., and particularly in the people, it is defined as at OMIM
TMIn * 602681 FORKHEAD BOX O3A; FOXO3A.
The FOXO4 gene is the gene that its transcript in mice, rat and people can be limited by the IDs of the Mm.371606 in UniGene, Rn.19646, Hs.584654 etc., and particularly in the people, it is defined as at OMIM
TMIn * * 300033MYELOID/LYMPHOID OR MIXED LINEAGE LEUKEMIA, TRANSLOCATED TO, 7; MLLT7.The REDD1 gene is the gene that its transcript in mice, rat and people can be limited by the IDs of the Mm.21697 in UniGene, Rn.9775, Hs.523012 etc., and particularly in the people, it is defined as at OMIM
TMIn * 607729 REGULATED IN DEVELOPMENT AND DNA DAMAGERESPONSES 1.
The KLF15 gene is the gene that its transcript in mice, rat and people can be limited by the IDs of the Mm.41389 in UniGene, Rn.22556, Hs.272215 etc., and particularly in the people, it is defined as at OMIM
TMIn * 606465KRUPPEL-LIKEFACTOR 15; KLF15.
In the present invention, " amyotrophy " means the situation that wherein muscle attenuates and muscle strength dies down.
In one embodiment, " amyotrophy " is with relevant with the expression of endogenous or the excessive bonded amyotrophy gene promotion of exogenous glucocorticoid.Particularly, (1) uses the amyotrophic example that causes by steroid medicine, it is the excessive general example of exogenous glucocorticoid, comprises the inductive amyotrophy of using for the purpose of mitigation symptoms by as drug products of steroid medicine, for example various malignant tumor of described symptom, cancer; Respiratory disease is pneumonia, chronic obstructive pulmonary disease, osteitis tuberculosa cystica, pulmonary fibrosis etc. for example; The infection relevant with weak inflammation be AIDS (acquired immune deficiency syndrome (AIDS)), viral hepatitis, influenza etc. for example; The sepsis relevant with infection; Autoimmune disease is chronic rheumatoid arthritis, IBD (inflammatory bowel), collagenosis etc. for example; Diabetes, renal failure, lung failure, liver failure, heart failure etc., (2) the excessive example of endogenous glucocorticoid comprises and following relevant amyotrophy: have the Cushing Cotard that is comprised the distinctive clinical symptoms (the high hydrocortisone mass formed by blood stasis (hypercortisolemia) that for example has adrenal gland's function of promotion) that adrenal gland neoplasms causes by some unknown causes, or the conduct because the inductive high hydrocortisone mass formed by blood stasis of result of the biological response of other chronic inflammatory diseases etc., (3) because excessively stress the waiting of symptom in latter stage generally speaking, with apositia, the muscle quantities that hypercatabolism etc. are relevant reduces or muscle strength reduces; Because the amyotrophy etc. of state or weightless flight can not, be unable to leave the bed in hospitalization, motion.
In another embodiment, " amyotrophy " only needs the expression that promotes with the amyotrophy gene relevant, even not straightforward with the excessive causal connection of glucocorticoid.Object lesson comprises and following relevant amyotrophy: various malignant tumor, cancer; Respiratory disease is pneumonia, chronic obstructive pulmonary disease, osteitis tuberculosa cystica, pulmonary fibrosis etc. for example; The infection relevant with weak inflammation be AIDS (acquired immune deficiency syndrome (AIDS)), viral hepatitis, influenza etc. for example; The sepsis relevant with infection; Autoimmune disease is chronic rheumatoid arthritis, IBD (inflammatory bowel), collagenosis etc. for example; Amyotrophy with following disease or disease association: for example diabetes, renal failure, lung failure, liver failure, heart failure etc.; Reduce with the relevant muscle quantities of generally speaking latter stage apositia in the symptom etc., hypercatabolism etc. or muscle strength reduces; Because the amyotrophy etc. of state or weightless flight can not, be unable to leave the bed in hospitalization, motion.
As with the disease except that glucocorticoid is excessive or the amyotrophy of disease association, the amyotrophy relevant with renal failure is effective.
In this manual, amyotrophic " inhibition " comprises " prevention amyotrophy takes place, alleviate or treat " amyotrophy, and means especially by preventing above-mentioned amyotrophy to take place, and alleviates or treat " amyotrophy " muscle to be reached develop the preceding state of amyotrophy.Behind the state before being returned to development amyotrophy by application the present invention, during the muscle undue growth, this kind situation is also contained in the background of the present invention.
Whether the amyotrophy expression of gene obtains promoting and can check by known method itself.For example, can mention and comprise following method: by the cell of results expection expression amyotrophy genes such as biopsy, preferred myocyte's (for example, Skeletal Muscle Cell, smooth muscle cell, myocardial cell etc.), by pcr amplification atrogin-1 gene or MuRF-1 gene, and detect gene.
The example of exogenous glucocorticoid (steroid medicine) comprises hydrocortin, cortisone, prednisolone, methylprednisolone, omcilon, triamcinolone, paramethasone, dexamethasone, betamethasone, hexestrol, thiamazole, fluocinolone acetonide, fluocinonide, flurandrenolide (fluorometholon), Beclomethasone propionic ester, estriol, diflorasone diacetate, nerisona, difluprednate etc.
As mentioned above, reported the dephosphorylation that transcribing of atrogin-1 gene and MuRF-1 gene activation results from transcription factor Foxo, the dephosphorylation of described Foxo is subjected to glucocorticoid to suppress to cause by the activity of Akt1 (protein kinase B).
In the present invention because etiologic " the amyotrophy related gene promote expression " except that glucocorticoid is excessive mean, with following relevant amyotrophy in the expression of above-mentioned " amyotrophy related gene " promotion: various malignant tumor, cancer; Respiratory disease is pneumonia, chronic obstructive pulmonary disease, osteitis tuberculosa cystica, pulmonary fibrosis etc. for example; The infection relevant with weak inflammation be AIDS (acquired immune deficiency syndrome (AIDS)), viral hepatitis, influenza etc. for example; The sepsis relevant with infection; Autoimmune disease is chronic rheumatoid arthritis, IBD (inflammatory bowel), collagenosis etc. for example; Disease or disease be diabetes, renal failure, lung failure, liver failure, heart failure etc. for example; Reduce with the relevant muscle quantities of generally speaking latter stage apositia in the symptom etc., hypercatabolism etc. or muscle strength reduces; Because the amyotrophy etc. of state or weightless flight can not, be unable to leave the bed in hospitalization, motion.
It is isoleucine, leucine and the valine of the active component of compositions of the present invention, when using, can be any form in L type, D type and the DL type separately, preferred L type or DL type, more preferably L type.
In addition, when using, isoleucine in the present invention, leucine and/or valine not only can be free forms separately, can also be salt forms.The isoleucine of this kind salt form, leucine and/or valine are also contained among the present invention.The salt (base addition salts) that the example of salt form comprises the salt (acid-addition salts) that forms with acid, form with alkali etc.The preferred pharmaceutically acceptable salt of selecting.
Example with the acid that forms pharmaceutically-acceptable acid addition in isoleucine to be added, leucine and/or the valine comprises mineral acid, for example hydrogen chloride, hydrogen bromide, sulphuric acid, phosphoric acid etc.; Organic acid is acetic acid, lactic acid, citric acid, tartaric acid, maleic acid, Fumaric acid, monomethyl sulphuric acid etc. for example.
Example with the alkali that forms pharmaceutically acceptable base addition salts in isoleucine to be added, leucine and/or the valine comprises metal hydroxides or metal carbonate, for example sodium, potassium, calcium etc., or inorganic base ammonia etc. for example; Organic base is ethylenediamine, propane diamine, propane diamine, ethanolamine, monoalkyl ethanolamine, dialkyl group ethanolamine, diethanolamine, triethanolamine etc. for example.
The content of 3 kinds of branched-chain amino acid isoleucine, leucine and valines in being applied to people's the present composition is no less than 0.1g altogether for once taking in, preferably is no less than 1g.According to the aspect that is easy to take in, an above-mentioned intake preferably is no more than 100g, more preferably no more than 10g.
In this manual, " intake " is when compositions of the present invention is medicine, the active principle of applied once, and when compositions of the present invention is food, the once active principle of She Ruing.Especially, under the situation of food, food total amount to be taken in is different in individuality, and generally can't easily limit the content of the active component in the compositions.Therefore, recommendation is defined as a intake about active component with this amount.This that is used for once taking in kind of an amount depends on age, body weight, sex, amyotrophy seriousness etc. and becomes.
Compositions of the present invention comprises 3 kinds of branched-chain amino acid isoleucine, leucine and valines as active component.3 seed amino acids with the mixing ratio of weight ratio generally 1: in the scope of 1.5-2.5: 0.8-1.7, preferred especially 1: 1.9-2.2: 1.1-1.3.Outside these scopes, be difficult to reach useful effect and effect.
Compositions of the present invention also can be used in combination with steroid medicine.Herein, " being used in combination " means before steroid therapy, with steroid therapy simultaneously or behind steroid therapy, use, comprise by using, in the admixture of mentioning hereinafter with the alclometasone diproionate polymer blends.
For with being used in combination of steroid medicine, medicine does not have concrete restriction, as long as it generally is used for the target disease, and its object lesson comprises above-described steroid medicine.
Compositions of the present invention is also as medicine, food etc., and the application experimenter comprises mammal (for example, people, mice, rat, hamster, rabbit, cat, dog, cattle, sheep, monkey etc.).For the mammal that is applied to except that the people, the intake of compositions of the present invention can suitably be adjusted according to body weight or the size of animal.
Although compositions of the present invention does not have concrete restriction as the application process of medicine, can adopt for example dosage forms for oral administration of general route of administration, rectal administration, injection is used, infusion etc.
The dosage form of dosage forms for oral administration comprises granule, fine grained, epipasxtic, coated tablet, tablet, suppository, powder, (miniature) capsule, masticatory (chewable), syrup, juice, liquid, suspension, Emulsion etc.As dosage form, can adopt the general dosage form of pharmaceutical preparation, the preparation of for example directly intravenous injection, the release of using, prolonging active substance of instiling etc. by injection.
These medicines are prepared by preparing according to conventional methods.When preparation is essential, can add the various pharmaceutically acceptable material that is used to prepare.Can suitably select according to the dosage form of preparation although be used for the material of preparation, it comprises for example excipient, diluent, additive, disintegrating agent, binding agent, coating materials, lubricant, fluidizer, glazing agent, spice, sweetener, solubilizing agent etc.The object lesson that is used for the material of preparation comprises magnesium carbonate, titanium dioxide, lactose, mannitol and other sugar, Talcum, lactoprotein, gelatin, starch, cellulose and derivant thereof, animal and plant oil, Polyethylene Glycol and solvent, for example sterilized water and unit price or multivalence alcohol (for example glycerol etc.).
Although the dosage of medicine of the present invention depends on target patient's age, body weight or pathology, the perhaps dosage form of medicine, application process etc. and become, but it is the isoleucine of 0.005g/kg body weight-5g/kg body weight, the leucine of 0.01g/kg body weight-10g/kg body weight and the valine of 0.005g/kg body weight-5g/kg body weight for adult every day.
For general adult, dosage is preferably for the isoleucine of adult 0.01g/kg every day body weight-1g/kg body weight, the leucine of 0.02g/kg body weight-2g/kg body weight and the valine of 0.01g/kg body weight-1g/kg body weight, and more preferably, the valine of the leucine of the isoleucine of 0.02g/kg body weight-0.2g/kg body weight, 0.04g/kg body weight-0.4g/kg body weight and 0.02g/kg body weight-0.2g/kg body weight.The preferably about 0.01g/kg body weight of amino acid whose total amount-2g/kg body weight/day.Above-mentioned daily dose can once or with several parts be used.The selection of time of using does not have concrete restriction, and can be for example before dining, have meal the back or have meal between.In addition, the administration time section does not have concrete restriction.
When calculating the dosage (amount that is ingested) of branched-chain amino acid, described branched-chain amino acid is the active component of medicine of the present invention, and the active principle that is ready to use in the medicine of purposes such as target treatment of diseases, prevention is in the present invention measured by the aforementioned calculation method.When branched-chain amino acid is ingested or uses when being used for various objectives, for example when satisfying needs in the usual custom of having meal or treatment other diseases, this kind branched-chain amino acid need not to be included in the aforementioned calculation.
For example, amount every day for the treatment of the branched-chain amino acid taken in from usual dining custom need not to get rid of in the calculating of the above-mentioned daily dose of active component from the present invention.
Its isoleucine, leucine and valine for the active component of medicine of the present invention can be included in the preparation separately or with any combination, or all can be included in a kind of preparation.For being processed into using behind the preparation individually, its route of administration and form of administration can be identical or different, and the selection of time of using can simultaneously or be separated.Therefore, dosage form, the selection of time of using, route of administration etc. can carry out suitably determining based on medicament categories of using simultaneously and effect thereof.That is, medicine of the present invention can be the preparation that comprises multiple branched-chain amino acid simultaneously, or the form of the concomitant drugs of taking separately to prepare and being used in combination.Medicine of the present invention comprises all these medicament forms.Particularly, the dosage form that comprises all branched-chain amino acid in single preparation is preferred, because it can be used easily.
In the present invention, " weight ratio " means the weight ratio of dividing other composition in preparation.For example, when dividing other active component isoleucine, leucine and valine to be included in the single preparation, it means the ratio of indivedual content, and when independent active component separately or its any combination when being included in a plurality of preparations, it means the weight ratio of the every kind of active component that comprises in each preparation.
In the present invention, each uses the single dose or the daily dose ratio of every kind of active component of experimenter (that is patient) to actual dose than demonstration.For example, when every kind of active component isoleucine, leucine and valine are included in the single preparation, and be applied to when using the experimenter, weight ratio is corresponding to the dosage ratio.Any combination is included in a plurality of preparations respectively or with it when every kind of active component, and when using, and weight ratio is corresponding to once or the total amount ratio of every kind of active component in every kind of preparation using in one day.
In addition, compositions of the present invention also can with the alclometasone diproionate polymer blends, admixture is used to prevent or treatment is used relevant amyotrophy with steroid medicine to provide.When compositions of the present invention and alclometasone diproionate polymer blends, the mixing ratio of compositions of the present invention and steroid medicine is generally 1: 0.1-1, and in 000,000 the weight ratio scope, preferred especially 1: 1-1,000 weight ratio.
In addition, compositions of the present invention also can be used easily with the food form.When compositions is used as food, can adopt any meals form, as long as it is that the active component that comprises food of the present invention is the general type of branched-chain amino acid.For example, can add suitable spice to produce beverage, for example beverage and powder drink mixture.Particularly, for example compositions can add in juice, breast, confectionery, fruit jelly, Yoghurt, the confection etc., and is used for eating and drinking.
In addition, this kind food also can be used as food or dietary supplement with health requirements provides.Food with health requirements also comprises the food that is used for the specific health purposes, have food that trophic function requires etc.The food that is used for the specific health purposes is such food, and it allows to point out that its expection reaches the specific health purpose, for example suppresses amyotrophy, improvement or the inhibition side effect symptom relevant with steroid therapy etc.Food with trophic function requirement also is such food, and when the nutrition group component that comprises in suitable daily intaking amount satisfied the upper and lower bound of the standard level of being set by Japanese government, it allowed to point out the function of nutrition composition.Dietary supplement comprises the material that is called supplementary, healthy supplement etc.In the present invention, the food that is used for the specific health purposes comprises having the food that it is used to suppress the indication of amyotrophy, improvement or inhibition side effect symptom relevant with steroid therapy etc., further, in packing, be enclosed in and describe written explanation that this food is used for this kind purposes etc. (promptly, inset) food, etc.
In addition, compositions of the present invention can be used as concentrated liquid diet or dietary supplement ingredient use.For the purposes as dietary supplement, for example, it can form tablet, capsule, powder, granule, suspension, masticatory, syrup etc.Except that obtain as food those, the dietary supplement ingredient in this description comprises those that obtain for the purpose that supplements the nutrients, it comprises supplementary, supplement etc.Dietary supplement among the present invention can also comprise the subclass of the food with health requirements.
In this manual, " dietary supplement ingredient " refer to except that as those of food intake, obtains helping those of nutrition, and comprise supplementary, supplement etc.
In the present invention, " concentrated liquid diet " is based on the essential nutritional amt design of every day and is controlled to be total nutriment (aqueous liquid foodstuff) of the concentration of about 1kcal/ml, wherein take into full account the qualitative formation of every kind of nutrition, thereby make the long-term absorption separately of food will not cause the remarkable shortage of nutrition or excessive.
When compositions during as food intake, intake depends on symptom, age or the body weight of taking in the experimenter, perhaps the form of food or absorption method etc. and become.Aequum is for the leucine of the isoleucine of adult 0.005g/kg every day body weight-5g/kg body weight, 0.01g/kg body weight-10g/kg body weight and the valine of 0.005g/kg body weight-5g/kg body weight.
For general adult, amount is preferably for the isoleucine of adult 0.01g/kg every day body weight-1g/kg body weight, the leucine of 0.02g/kg body weight-2g/kg body weight and the valine of 0.01g/kg body weight-1g/kg body weight, and more preferably, 0.02g/kg the valine of the leucine of the isoleucine of body weight-0.2g/kg body weight, 0.04g/kg body weight-0.4g/kg body weight and 0.02g/kg body weight-0.2g/kg body weight, and the preferably about 0.01g/kg body weight of amino acid whose total amount-2g/kg body weight/day.Measure and can once or with several parts take in the above-mentioned every day of food of the present invention.The form of food, absorption method, absorption time period etc. do not have concrete restriction.
Isoleucine, leucine and valine have been widely used in medicine and the food field, and their safety is determined.For example, even when being administered orally in mice, comprise acute toxicity (LD with these amino acid whose pharmaceutical preparatioies of 1: 2: 1.2 weight ratio
50) also be at least 10g/kg.
To be isoleucine, leucine and valine be used for suppressing the compositions of amyotrophy related gene expression or be used for improving or suppress the purposes of compositions of the side effect of steroid therapy of the present invention in production another embodiment of the invention.The preferable range of compositions is with mentioned above those are identical.
Another embodiment is to suppress the method for amyotrophy related gene expression, or improves or suppress the method for the side effect in the steroid therapy, and it comprises to using isoleucine, leucine and the valine that the experimenter uses effective dose.The preferable range of the effective dose of active component etc. are with mentioned above those are identical.
Another one embodiment of the present invention is the commercial packing that comprises written material, and described written material is set forth and comprised 3 kinds of branched-chain amino acid isoleucine, leucine and valines and can or be applied to suppress amyotrophy as composition of active components or improve or suppress side effect in the steroid therapy.
Any publication of quoting in this description comprises that disclosed content is incorporated herein by reference in this integral body in patent and the patent application, and its degree discloses identical with them in this article.
The present invention makes an explanation in more detail by mentioning following embodiment, and described embodiment only provides illustration of the present invention and do not limit the scope of the invention.
[embodiment]
The amyotrophy preventive effect of (embodiment 1) BCAA in the rat that dexamethasone is used
Dexamethasone (600 μ g/kg) intraperitoneal is applied to rat (SD; 10-11 week is big), carried out continuous 5 days.Isoleucine, leucine and valine (weight ratio 1: 2: 1.2) admixture (BCAA) is used group and is carried out dosage forms for oral administration simultaneously with the above-mentioned BCAA of 0.75g/kg, carries out continuous 5 days.The vehicle group is carried out dosage forms for oral administration continuously with distilled water in the same manner.
In the time of the 5th day, rat carries out obduction, and analyzes with regard to muscle strength functional assessment, blood sugar level and plasma insulin level, wherein uses food intake, body weight overview, muscle weight, grip measuring device.
Organize in contrast, use the normal rat of pair fed.
By with the vehicle group relatively, BCAA use group show lose weight and food intake in the inhibition (Fig. 1) of minimizing.Minimizing in the muscle weight also be inhibited (Fig. 2).In addition, it obviously is high in the group that grip is used at BCAA, and observes improve (Fig. 3) of muscle function.Increase blood sugar level and insulin level although dexamethasone is used, increase obtains proofreading and correct (Figure 4 and 5) by using of BCAA.
The amyotrophy therapeutic effect of (embodiment 2) BCAA in the rat that dexamethasone is used
Dexamethasone (600 μ g/kg) intraperitoneal is applied to rat (SD; 10-11 week is big), carried out continuous 5 days, to induce amyotrophy.Use the 6th day and the 7th day of end at the distance dexamethasone, BCAA (0.75g/kg) carries out dosage forms for oral administration, and checks amyotrophic therapeutic effect.The vehicle group is carried out dosage forms for oral administration continuously with distilled water in the same manner.
At the 6th day and the 7th day, rat carried out obduction, and analyzes with regard to muscle weight.R1 and R2 (recover convalescent period; R) the 1st day and the 2nd day, and use the 6th day and the 7th day of end corresponding to the distance dexamethasone.
By comparing with the vehicle group, BCAA uses the early recovery (Fig. 6) that group shows muscle weight.
The osteoporosis preventive effect of (embodiment 3) BCAA in the rat that dexamethasone is used
Dexamethasone (600 μ g/kg) intraperitoneal is applied to rat (SD; 10-11 week is big), carried out continuous 1.5 months.Isoleucine, leucine and valine (weight ratio 9: 7: 6) admixture (BCAA) is used group and is carried out dosage forms for oral administration simultaneously with the above-mentioned BCAA of 0.75g/kg, carries out continuous 1.5 months.The vehicle group is carried out dosage forms for oral administration continuously with distilled water in the same manner.
In the time of 1.5 months, rat carries out obduction, and analyzes with regard to plasma A LP level.Knownly have enough to meet the need when high when bone metabolism, plasma A LP shows high value.
By comparing with the vehicle group, BCAA uses group and shows low plasma A LP value (Fig. 7).
The amyotrophy preventive effect of (embodiment 4) branched-chain amino acid in the rat that dexamethasone is used
Dexamethasone (600 μ g/kg) intraperitoneal is applied to rat (SD; 10-11 week is big), carried out continuous 5 days, to induce amyotrophy.Isoleucine, leucine and valine (weight ratio 1: 2: 1.2) admixture (BCAA) use group (point out as BCAA in the drawings and hereinafter as BCAA use the group point out) carry out dosage forms for oral administration simultaneously with the above-mentioned BCAA of 0.75g/kg, carried out continuous 5 days.The vehicle group is carried out dosage forms for oral administration continuously with distilled water in the same manner.At the 5th day, rat carried out obduction, and measured with regard to food intake, body weight overview and muscle weight, and amyotrophy expression of gene amount is analyzed by known method own.
For special, cDNA uses the RNA that extracts from skeletal muscle to synthesize as template, wherein uses ISOGEN (NIPPON GENE) and SuperScript III (Invitrogen).Primer (seeing table 1) and the powder cyber green (Applied Biosystems) of cDNA (2.5ng), Atrogin-1 and MuRF-1 are mixed, and by the real-time RT-PCR method relatively and the expression of the amyotrophy related gene (Atrogin-1, MuRF-1, Myostatin, FOXO1, FOXO3a, FOXO4, REDD1 and KLF15) that exists in the test of quantitative analysis sample, the use matched group is the sort of as 1.
Organize in contrast, use the normal rat of pair fed.
[table 1]
| The gene title | 5 '-primer | 3 '-primer |
| atrogin-1 | AGCGCTTCTTGGATGAGAAA (SEQ?ID?NO：1) | TCTTGGCTGCAACATCGTAG (SEQ?ID?NO：2) |
| MuRF-1 | CCAGGTGAAGGAGGAACTGA (SEQ?ID?NO：3) | CTCCTGCTCCTGAGTGATCC (SEQ?ID?NO：4) |
| Myostatin | ACGCTACCACGGAAACAATC (SEQ?ID?NO：5) | GGAGTCTTGACGGCTCTCAG (SEQ?ID?NO：6) |
| Foxo?1 | CGGCCAATCCAGCATGAGCCC (SEQ?ID?NO：7) | GTGGGGAGGAGAGTCAGAAGTC (SEQ?ID?NO：8) |
| Foxo?3a | GCTCCACCACCAGCACCAAACC (SEQ?ID?NO：9) | CGAGAGGGTTTGCATAGACTGGC (SEQ?ID?NO：10) |
| Foxo?4 | GCCATGACAGAATGCCTCAGGATC (SEQ?ID?NO：11) | GGCTCAAAGTTGAAGTCCAGTCCC (SEQ?ID?NO：12) |
| REDD1 | TAGTGCCCACCTTTCAGTTG (SEQ?ID?NO：13) | GTCAGGGACTGGCTGTAACC (SEQ?ID?NO：14) |
| KLF15 | CTGCAGCAAGATGTACACCAA (SEQ?ID?NO：15) | TCATCTGAGCGTGAAAACCTC (SEQ?ID?NO：16) |
Known dexamethasone is applied to rat and reduces body weight and food intake, and it is induced with development amyotrophy for atrogin-1, the MuRF-1 of proteasome degraded induced gene and the expression of Myostatin, this reduces muscle quantities (referring to Endocrinology 146:1789-1797 (2005), Am.J.Physiol.Endocrinol.Metab.287:E591-E601 (2004)).
In the vehicle group, observe the minimizing in body weight and the food intake.Yet be inhibited (Fig. 8) used in the group in this kind minimizing at BCAA.Use in the group at BCAA, compare, the minimizing in the muscle weight be inhibited (Fig. 9) with the vehicle group.In addition, use in the group at BCAA, the negative somatomedin of amyotrophy related gene atrogin-1 and MuRF-1 and Myostatin---muscle, with and be FOXO1, FOXO3a, FOXO4, REDD1 and the KLF15 expression of gene of atrophy related gene also be inhibited (Figure 10-13).
The amyotrophy therapeutic effect of (embodiment 5) BCAA in the rat that dexamethasone is used
Dexamethasone (600 μ g/kg) intraperitoneal is applied to rat (SD; 10-11 week is big), carried out continuous 5 days, to induce amyotrophy.Use the 6th day and the 7th day of end at the distance dexamethasone, isoleucine, leucine and valine (weight ratio 1: 2: 1.2) admixture (0.75g/kg) carries out dosage forms for oral administration, and checks amyotrophic therapeutic effect.The vehicle group is carried out dosage forms for oral administration continuously with distilled water in the same manner.At the 6th day and the 7th day, rat carried out obduction, and analyzed with regard to food intake, body weight, muscle weight, amyotrophy gene expression amount.R1 and R2 (recover convalescent period; R) the 1st day and the 2nd day, and use the 6th day and the 7th day of end corresponding to the distance dexamethasone.
By with the vehicle group relatively, although BCAA use group show lose weight and food intake in the low recovery level (Figure 14) of minimizing, its shows that the height of muscle weight recovers level (Figure 15).In addition, amyotrophy expression of gene amount is carried out quantitative analysis by above-mentioned real-time PCR method.As a result, BCAA uses the expression (Figure 16) that group also significantly suppresses amyotrophy gene atrogin-1 and MuRF-1.
According to The above results, illustrated recovery that muscle weight uses via BCAA and be attributable to and result from the amyotrophic inhibition of inhibition of amyotrophy gene expression rather than the increase in the food intake.
(embodiment 6) BCAA suppresses amyotrophy gene expression in 5/6 nephrectomy rat
To rat (WKY; 7-9 week is big) implement 5/6 nephrectomy, with preparation renal failure rat model.The amyotrophy expression of gene is analyzed in 3 groups of above-mentioned rat model by above-mentioned real-time PCR method: have that BCAA uses or do not have group that BCAA uses and the group (vacation) with independent sham-operation.In not containing the renal failure rat model group that BCAA uses, to compare with the vacation group, the expression of amyotrophy gene atrogin-1 and MuRF-1 increases.By contrast, BCAA uses the almost extremely false level of organizing (Figure 17) of expression that group suppresses atrogin-1 and MuRF-1.In Figure 17, the relative value's of each group meansigma methods is drawn as 1.0 with the value of a case in the false group.
According to The above results, though illustrated BCAA to since the amyotrophy gene expression of renal failure in increase also inhibited.
Although embodiments more of the present invention are described in detail above obtaining, yet, those of ordinary skills can basically without departing the teaching of the invention with the situation of advantage under to shown in specific embodiments carry out various modifications and change.This kind modified and changed in the spirit and scope of the present invention that are included in described in accessory claim.
The application is based on the number of patent application 2006-335057 and the 2006-335059 that submit in Japan, and the content of described patent application all is incorporated herein by reference.
Sequence table
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＜223〉5 '-primer of Foxo 4
<400>11
gccatgacag?aatgcctcag?gatc 24
<210>12
<211>24
<212>DNA
＜213〉artificial
<220>
＜223〉3 '-primer of Foxo 4
<400>12
ggctcaaagt?tgaagtccag?tccc 24
<210>13
<211>20
<212>DNA
＜213〉artificial
<220>
＜223〉5 ' of REDD1-primer
<400>13
tagtgcccac?ctttcagttg 20
<210>14
<211>20
<212>DNA
＜213〉artificial
<220>
＜223〉3 ' of REDD1-primer
<400>14
gtcagggact?ggctgtaacc 20
<210>15
<211>21
<212>DNA
＜213〉artificial
<220>
＜223〉5 ' of KLF15-primer
<400>15
ctgcagcaag?atgtacacca?a 21
<210>16
<211>21
<212>DNA
＜213〉artificial
<220>
＜223〉3 ' of KLF15-primer
<400>16
tcatctgagc?gtgaaaacct?c 21
Claims (23)
1. compositions that is used for improving or suppressing the side effect of steroid therapy, it comprises isoleucine, leucine and valine as active component.
2. the compositions of claim 1, wherein said side effect be selected from following at least a: amyotrophy, decreased muscle function, myalgia, arthralgia, glucose tolerance reduction, anorexia, lose weight, bone metabolism reduces, immunity is impaired and fatigability.
3. the compositions of claim 2, the wherein expression of amyotrophy demonstration amyotrophy related gene promotion.
4. compositions that is used to suppress the amyotrophy related gene expression, it comprises isoleucine, leucine and valine as active component.
5. the compositions of claim 4, it suppresses the relevant amyotrophy of expression with the promotion of amyotrophy related gene.
6. the compositions of claim 5, the expression of wherein said promotion is excessive relevant with glucocorticoid.
7. the compositions of claim 5, the expression of wherein said promotion is relevant with renal failure.
8. each compositions among the claim 3-7, wherein said amyotrophy related gene be selected from following at least a: atrogin-1 gene, MuRF-1 gene, myostatin gene, FOXO1 gene, FOXO3a gene, FOXO4 gene, REDD1 gene and KLF15 gene.
9. each compositions among the claim 1-8, it comprises in once taking in and is no less than 1g isoleucine, leucine and valine.
10. each compositions among the claim 1-9, wherein the weight ratio of isoleucine, leucine and valine is 1: 1.5-2.5: 0.8-1.7.
11. each compositions among the claim 1-10, itself and steroid medicine are used in combination.
12. each compositions among the claim 1-11, it is a medicine.
13. each compositions among the claim 1-11, it is a food.
14. the compositions of claim 13, wherein said food are food or the dietary supplements with health requirements.
15. the compositions of claim 14, wherein said food with health requirements are to be used for the food of specific health purposes or to have the food that trophic function requires.
16. each compositions among the claim 13-15, wherein said food are the concentrated liquid diet.
17. isoleucine, leucine and valine are used for each the purposes of compositions of production claim 1-16.
18. the purposes of claim 17, wherein the weight ratio of isoleucine, leucine and valine is 1: 1.5-2.5: 0.8-1.7.
19. a method that is used for improving or suppressing the side effect of steroid therapy, it comprises to using isoleucine, leucine and the valine that the experimenter uses effective dose.
20. a method that suppresses amyotrophy gene expression, it comprises to using isoleucine, leucine and the valine that the experimenter uses effective dose.
21. the method for claim 19 or 20, it comprises in once taking in and is no less than 1g isoleucine, leucine and valine.
22. each method among the claim 19-21, wherein the weight ratio of isoleucine, leucine and valine is 1: 1.5-2.5: 0.8-1.7.
23. commercial packing, it comprises among the claim 1-16 each compositions and written material, described written material is set forth the side effect that described compositions can maybe should be used for improving or suppressing steroid therapy, or the relevant amyotrophy of expression that promotes of inhibition and amyotrophy related gene.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310021017.0A CN103120655B (en) | 2006-12-12 | 2007-12-12 | For improving/prevention of steroid treat in the composition of adverse side effect |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP335057/2006 | 2006-12-12 | ||
| JP2006335057 | 2006-12-12 | ||
| JP335059/2006 | 2006-12-12 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310021017.0A Division CN103120655B (en) | 2006-12-12 | 2007-12-12 | For improving/prevention of steroid treat in the composition of adverse side effect |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101600423A true CN101600423A (en) | 2009-12-09 |
Family
ID=41421501
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800511359A Pending CN101600423A (en) | 2006-12-12 | 2007-12-12 | Be used for improving/compositions of the adverse side effect of prevention of steroid treatment |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101600423A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112839528A (en) * | 2018-04-18 | 2021-05-25 | 独创成分有限合伙公司 | Compositions for promoting muscle growth and function and methods of use |
| CN114025781A (en) * | 2019-06-28 | 2022-02-08 | 导博药物公司 | Composition for treating muscle decline |
-
2007
- 2007-12-12 CN CNA2007800511359A patent/CN101600423A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112839528A (en) * | 2018-04-18 | 2021-05-25 | 独创成分有限合伙公司 | Compositions for promoting muscle growth and function and methods of use |
| CN114025781A (en) * | 2019-06-28 | 2022-02-08 | 导博药物公司 | Composition for treating muscle decline |
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Application publication date: 20091209 |