CN102307585A - Dipeptide having antiatherosclerotic action - Google Patents
Dipeptide having antiatherosclerotic action Download PDFInfo
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- CN102307585A CN102307585A CN2010800070659A CN201080007065A CN102307585A CN 102307585 A CN102307585 A CN 102307585A CN 2010800070659 A CN2010800070659 A CN 2010800070659A CN 201080007065 A CN201080007065 A CN 201080007065A CN 102307585 A CN102307585 A CN 102307585A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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Abstract
Disclosed is an antiatherosclerotic agent which can be used, without fear of influencing the heart, for a patient suffering from atherosclerosis in combination with a cardiac disease. Also disclosed is a food inherently having the aforesaid function. Specifically disclosed are an antiatherosclerotic agent which comprises a dipeptide Trp-His and/or a salt thereof as the active ingredient, and a food inherently having the aforesaid function.
Description
Technical field
The present invention relates to the represented dipeptides of Trp-His or its salt as effective ingredient, even and also can use when being accompanied with the heart disease of avoiding with calcium antagonist, atherosclerosis is had prevention or suppresses the compositions of the health food, functional food, pharmaceuticals etc. of the effect of its development.
Background technology
Calcium channel blocker is the medicament with the blood vessel effect of releiving and even vasorelaxation action, and relevant its effect to atherosclerosis also has the document record.For example, in non-patent literature 1,, put down in writing its study of anti-atherogenic effect to the azelnidipine (azelnidipine) that belongs to representational calcium channel blocker.In this smallest effective actuating quantity that can confirm effect of putting down in writing is 3mg/kg/ day, and its actuating quantity 8～16mg/ day required with vasorelaxation action (patient of body weight 60kg) is compared, and is very large value.According to data (" about the data of CALBLOCK (azelnidipine) and CALBLOCK sheet 8mg16mg " Ube Industries, Ltd, (the http://www.info.pmda.go.jp/shinyaku/g030102/ of Sankyo Co., Ltd about azelnidipine; On February 23rd, 2009 obtained from the Internet)); In to the administration of rat experiment, when the administration of 10mg/kg/ day, confirmed to begin to increase such side effect such as cardiac weight.
Calcium channel blocker is because its mechanism of action, and the influence of heart is become problem.Though when calcium channel blocker is used as vasodilation; Its effective action and cause between the amount of the side effect that cardiac weight increases that certain distance is arranged; The doubtful problem that seldom becomes; But when calcium channel blocker is used as antiatherosclerotic; As stated; As the effective action of antiatherosclerotic and cause that the gap between the amount of the side effect that cardiac weight increases only is about 3.3 times; Become problem when therefore, calcium channel blocker being used as antiatherosclerotic.
Technical literature formerly
Non-patent literature
Non-patent literature 1:Atherosclerosis 196 (2008) 172-179
Summary of the invention
Problem to be solved by this invention
The objective of the invention is to, provide less and material with study of anti-atherogenic effect to the influence of heart with the raw material that can obtain with comparalive ease.
Solve the means of problem
The inventor has carried out deep research repeatedly to above-mentioned problem.Thereby find the known dipeptides Trp-His that has vasorelaxation action as Calcilytic; Do not cause and be considered to always so long as the remarkable influence that Calcilytic then will inevitably cause to heart; And demonstrate study of anti-atherogenic effect, and then accomplished the present invention.
That is, the present invention is following:
(1) a kind of prevention of atherosclerosis or improving agent are to be effective ingredient with Trp-His represented dipeptides or its salt, also can not cause the side effect to heart even carry out excessive administration with respect to effective action.
(2) a kind of prevention of atherosclerosis or improving agent, be with the represented dipeptides of Trp-His or its salt as effective ingredient, be used to suffer from the cardiopathic patient who avoids with calcium antagonist.
(3) prevention or the improving agent of (1) or (2) described atherosclerosis, wherein, every day, dosage was, to every 1kg body weight, was 5～100mg.
The invention effect
According to the present invention, utilizing through synthetic grade can represented dipeptides and the salt thereof of synthetic with comparalive ease Trp-His, and the compositions of heart being brought medicament appreciable impact, that have study of anti-atherogenic effect etc. can be provided not.
Description of drawings
Fig. 1 is the sequence of " β-companion's globulin α '-subunit ".
Fig. 2 is the atherosclerotic lesion (white portion) of the aorta (aortic tree) after 9 weeks of raising among comparative example 1 (reference), embodiment 1 (Trp-His dosage 10mg/kg/ day), the embodiment 2 (Trp-His dosage 100mg/kg/ day).The pathological changes that can confirm embodiment 1,2 is littler than comparative example 1 (reference).
Fig. 3 is the numeric value analysis data of the lesion region of Fig. 2.Compare with comparative example 1 (reference), the lesion region of embodiment 1 (Trp-His dosage 10mg/kg/ day), embodiment 2 (Trp-His dosage 100mg/kg/ day) is little.
Fig. 4 is the atherosclerotic lesion of the aortic sinus after 9 weeks of raising among comparative example 1 (reference), embodiment 1 (Trp-His dosage 10mg/kg/ day), the embodiment 2 (Trp-His dosage 100mg/kg/ day).Do not find big difference between comparative example 1, embodiment 1, the embodiment 2.
Fig. 5 is the numeric value analysis data of Fig. 4 lesion region.It is poor significantly not find between comparative example 1, embodiment 1 (Trp-His dosage 10mg/kg/ day), the embodiment 2 (Trp-His dosage 100mg/kg/ day).
The specific embodiment
" study of anti-atherogenic effect " described in the present invention is meant, suppresses the morbidity of atherosclerosis, or suppress the development of the atherosclerosis of interim morbidity.
" effective action " of the present invention is meant, demonstrates the dosage of study of anti-atherogenic effect.And " carrying out excessive administration with respect to effective action " be meant, with respect to thinking few amount of trying one's best in the effective function amount, carries out 10 times of administrations about amount.
In addition; " not causing the side effect to heart " is meant; In view of the medicament that is called as Calcilytic since its mechanism of action ban use of in the present situation that is accompanied with cardiopathic patient, even avoid situation degree, few to the influence of heart that the cardiopathic patient with Calcilytic also can use to being accompanied with.More specifically; Like the embodiment of the invention 2; With respect to the dosage 10mg/kg/ day that can confirm the purpose effect; In the time of also can not bringing the situation of remarkable influence to carry out administration the 100mg/kg/ day that is equivalent to its 10 times of amounts, can be judged as the present invention said " not causing side effect " to heart to cardiac weight.One of characteristic of the present invention is " not causing the side effect to heart ", especially preferably is used in concurrent cardiopathic patient or avoids the patient with Calcilytic.Wherein, avoid heart disease, can enumerate atrioventricular block, cardiogenic shock etc. with Calcilytic.
Tremulous pulse is to be initiated by heart, is that aortic orifice from left ventricle begins up back and shifts to aortic arch with the height of sternal angle or the 2nd costicartilage for the people.Blood vessel footpath on the initial part of aorta ascendens is greater than the tip side, so be called as aortic bulb (bulb of aorta), its inner chamber is called as aortic sinus (sinus of aorta) or Wa Shi hole (sinus of Valsalva).Among the present invention, unconfirmed to effect for aortic sinus.
Bring the tremulous pulse of effect to be designated as aorta (aortic tree) the present invention.(aortic tree) do not comprise aortic sinus at this said aorta.
Dipeptides Trp-His as effective ingredient of the present invention; It is the sequence that also exists in the soybean protein; Can be through soybean protein be decomposed with suitable enzyme; Its fractional distillation purification is obtained for the fraction that contains required peptide; Perhaps since the peptide key length weak point be 2, so also can be through the acquisition of the synthetic method of general peptide.And the sequence of Trp-His is to exist on the 125-126 position in the α ' of soybean protein β-companion's globulin-subunit primary structure.This soya protein amino acid sequence is shown in Fig. 1.If decompose and synthetic Trp-His through enzyme etc. from soybean protein etc., then belong to and derive from the past edible empirical raw material is arranged, have purposes so can be used as the important material of enriching substance, healthy subsidy goods, specific health food.
When obtaining dipeptides of the present invention through synthetic method, any kind of biology in the synthesis method that can use synthetic used chemical synthesis (solid phase method, liquid phase method), the enzymatic synthesis method of common peptide and use the DNA recombination method.On the enzyme, there is known the use of a proteolytic enzyme (protease) reverse reaction method (J.Biol.Chem. ,707-720 (1937)), using the heat-resistant amino acid t-RNA synthetase method [refer to Japanese Laid-open Publication No. Sho 59-106298], etc., and recently also discloses that belong to genus Escherichia or Bacillus microorganism producing method (designation of International Publication WO2004/058960).
In addition, can purify with reversed phase high-performance liquid chromatography, the common method of purification that makes spent ion exchange resin or porous height gather the chromatography, affinity chromatography etc. of resin (high porous polymers resin) through the synthetic peptide of the present invention that obtains.And aminoacid is preferably the L type.
The route of administration of medical composition of the present invention, agent shape, those skilled in the art can suit to design.As the example of route of administration per os, oral cavity, injection (Intradermal, subcutaneous, muscle, vein), respiratory tract respiratory apparatus, body opening portion (mucosa) are arranged, powder, granula subtilis, granule, tablet, capsule, pill, liquor, suspending agent, Emulsion, inhalant, spray, aerosol, suppository etc. are arranged as the example of agent shape.Can use the various carriers that allow in the medicine during preparation, for example can use the preparation composition of excipient, bonding agent, crust (covering), disintegrating agent, lubricant, suspending agent, surfactant, seasoning (perfume (or spice)) agent, coloring agent, preservative agent, stabilizing agent etc.This medical composition can oral administration and effective.
In addition, also can be with the form administration of food, the mode that can expect has beverage, sheet type food, bake cake, ice cream, chocolate etc.
And, contain the represented dipeptides of Trp-His or its salt with ormal weight, as long as effect of the present invention etc. is brought under the dysgenic prerequisite, the peptide that mixes other can not become problem with other compositions yet.In addition, " dipeptides or its salt " this record refers to that also dipeptides and its salt mix the state that exists.
For the amount that obtains the necessary Trp-His of study of anti-atherogenic effect is preferably 5～100mg/ day according to every 1kg body weight, more preferably 7～100mg/ day, most preferably be 10～100mg/ day.When the amount of Trp-His is very few, lack study of anti-atherogenic effect, undesirable under most situation.In addition, about surpassing the dosage of 100mg/kg/ day, till the stage on February 23rd, 2009, also do not carry out its checking to the influence of heart.
To put down in writing embodiment below.If do not particularly point out, % representes weight %.
Embodiment
Experiment 1 (embodiment 1～2, comparative example 1)
" study of anti-atherogenic effect of dipeptides Trp-His "
The acquisition of peptide, reagent
Trp-His carries out synthetic through Fmoc solid-phase synthesis (homemade chemical society makes).Other reagent has used the material of SILVER REAGENT.
The animal testing body used by Jackson Laboratory (Bar Harbor, ME, USA) buy and Kyushu University's medical board animal experiment study in the apo-E knock-out mice (male 8～18 ages in week) of raising.It is divided into 3 groups, and the feedstuff shown in the supply schedule 1 raised for 9 weeks.Mice of each group no significant circumferential difference Elderly.(comparative example 1:15.0 ± 0.8, embodiment 1:14.3 ± 1.2, embodiment 2:14.6 ± 1.3).
Table 1: the preparation of feedstuff
The administration of Trp-His is with respect to the body weight of each mice 10 to 100mg/kg Trp-His to be dissolved in the deionized water of 1ml, carries out 1 time on the 1st administration through oral trachea cannula.For as the mice of reference with same method administration deionized water.And, with Trp-His dosage 10mg/kg/ day as embodiment 1, dosage 100mg/kg/ day as the situation of embodiment 2, an administration deionized water as comparative example 1.Mice is under the condition of 22 ℃ of room temperatures, per 12 hours circulation light and shades, to raise.In addition, can freely absorb the feedstuff and the deionized water of table 1.
Raise 9 all backs, went on a hunger strike 6 hours, take a blood sample from heart afterwards.And win film, subcutaneous part, pars epididymica between the white adipose tissue, intestinal of liver, posterior peritoneum, cool off with liquid nitrogen.Likewise win aorta and heart, fix with formalin.
Triglyceride in the blood plasma, T-CHOL, HDL-cholesterol are to carry out through enzymic measuring reagent box (Triglyceride E test from Wako Pure Chemicals, T-CHO kainos from Kainos).The concentration determination of blood plasma MCP-1 (person monocytic cell's chemotactic protein) is that (Mouse MCP-1ELISA kit from Invitrogen, California USA) carries out through the ELISA test kit.The lipid of liver is with CHCl3-CH3OH mixed liquor extraction, and the method for being put down in writing with " Bt J Nutr.94,896-901 (2005) " is measured.
The quantitative analysis of atherosclerosis pathological changes is to carry out with the method that " J Nurt 128,1884-1889 (1998) " put down in writing.The result is with standard error (SEM) expression of meansigma methods and meansigma methods.In addition, according to the multiple comparisons of Tukey-Kramer, estimate with one way analysis of variance.P (probability)＜0.05 is judged as significantly.Parsing is that (Stat View J5.0 (SAS Institute, Cary, NC, USA)) carries out with software.
The result:
Body weight and give feed efficiency
After raising for 9 weeks, for body weight, organ weights, feedstuff intake, give feed efficiency, in 3 groups, do not find differences by (table 2).Body fat content (comparative example 1 reference: average 8.9 (SEM1.2) %, n8; Embodiment 110mg/kg Trp-His: average 7.1 (SEM0.7) %, n7; Embodiment 2100mg/kg Trp-His: average 7.5 (SEM0.6) %, n8), identical with the fat mass of film, spermary, hypodermis between intestinal, between each group, do not find differences.
Table 2: raise the state after 9 weeks
Lipid in the blood
In the analysis of blood,, in 3 groups, do not find differences by (table 3) for the amount of T-CHOL, HDL-cholesterol, MCP-1.Though plasma cholesterol amount high relatively (＞1000mg/ day) thinks that this is owing to hypercholesterolemia food causes.
Table 3: raise cholesterol amount after 9 weeks etc.
After 9 weeks of dipeptides Trp-His administration, on aorta (aortic tree), the atherosclerotic lesion of Trp-His administration group (dosage 10mg/kg (embodiment 1), 100mg/kg (embodiment 2) both) less than reference group (comparative example 1) (Fig. 2).The numerical value aspect, as shown in Figure 3, the ratio of the lesion region of Trp-His administration group (10mg/kg: average 9.5 (SEM 1.3) %, n7,100mg/kg: average 8.1 (SEM1.6) %, n8, P＜0.05) be significantly less than reference group (average 13.0 (SEM 1.0) %, n8).This shows that dipeptides Trp-His suppresses the development of arteriosclerotic lesion.Do not find to exist with ... the marked difference of dosage between the Trp-His administration group.This shows as long as the dosage of Trp-His is 10mg/kg/ day, just can cause enough effects.
In the numeric value analysis data (Fig. 5) of atherosclerotic lesion of aortic sinus (Fig. 4) and lesion region, do not find difference (P＞0.05) three groups.
Analyze:
Like above-mentioned result, for the dipeptides Trp-His administration 9 apo-E knock-out mice in week, the lesion region of the atherosclerosis of aorta (aortic tree) is less than the situation of administration dipeptides not.This shows that dipeptides Trp-His has the effect of development of the atherosclerosis of inhibition aorta (aortic tree).And think for aorta (aortic tree) basic structure similarly other blood vessel, especially tremulous pulse is had same effect.And, occur because the difference of the dosage of the per unit body weight of Trp-His does not cause the significance difference of effect, so think just can display effect with the dosage of 5～100mg/kg/ day.
In addition, in this experiment, with respect to the dosage 10mg/kg/ day that can confirm effect of sufficient, even the dosage of the 100mg/kg/ day of its 10 times of amounts, the significant variation to cardiac weight also unconfirmed.This situation is former complete the unknown, and can infer dipeptides Trp-His of the present invention is to demonstrate study of anti-atherogenic effect through the mechanism of action beyond the known calcium retardation.
Among the present invention, unconfirmed to the study of anti-atherogenic effect that causes by dipeptides Trp-His on aortic sinus.Consider very unusual from the mechanism of action of thinking in the past.Promptly; If it is only show study of anti-atherogenic effect,, same with the tremulous pulse beyond it then for aortic sinus through previously known calcium antagonism; Ought to demonstrate study of anti-atherogenic effect, therefore prove the mechanism of action that exists beyond the calcium antagonism from the side.And, near aortic sinus existence and the heart, play the probability of unknown in the past specific effect for heart so hinted dipeptides Tpr-His.
And because Trp-His finds above-mentioned effect, so those skilled in the art can infer that fully its salt also can find same effect.In addition, though this experiment is carried out to mice, those skilled in the art can infer and can expect same effect to general mammals fully.
Utilize probability on the industry
According to the present invention,,, also the antiatherosclerotic that can take can be provided even worried in the past patient that the influence of heart is failed to take calcium antagonist even to concurrent cardiopathic atherosclerosis patient.
Claims (3)
1. the prevention of an atherosclerosis or improving agent as effective ingredient, do not cause side effect to heart even carry out excessive administration with respect to effective action with the represented dipeptides of Trp-His or its salt yet.
2. the prevention of an atherosclerosis or improving agent as effective ingredient, are used to suffer from the cardiopathic patient who avoids with calcium antagonist with the represented dipeptides of Trp-His or its salt.
3. the prevention of atherosclerosis as claimed in claim 1 or 2 or improving agent, its, dosage was to every 1kg body weight, to be 5～100mg every day.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2009-060978 | 2009-03-13 | ||
| JP2009060978 | 2009-03-13 | ||
| PCT/JP2010/000008 WO2010103708A1 (en) | 2009-03-13 | 2010-01-05 | Dipeptide having antiatherosclerotic action |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102307585A true CN102307585A (en) | 2012-01-04 |
Family
ID=42728009
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010800070659A Pending CN102307585A (en) | 2009-03-13 | 2010-01-05 | Dipeptide having antiatherosclerotic action |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP5627568B2 (en) |
| KR (1) | KR20110130397A (en) |
| CN (1) | CN102307585A (en) |
| WO (1) | WO2010103708A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1658893A (en) * | 2002-04-05 | 2005-08-24 | 加利福尼亚大学董事会 | G-type peptides to ameliorate atherosclerosis |
| CN101018564A (en) * | 2004-09-13 | 2007-08-15 | 阿法里斯研发有限责任公司 | Treatment of atherosclerosis |
-
2010
- 2010-01-05 KR KR1020117018268A patent/KR20110130397A/en not_active Application Discontinuation
- 2010-01-05 WO PCT/JP2010/000008 patent/WO2010103708A1/en active Application Filing
- 2010-01-05 CN CN2010800070659A patent/CN102307585A/en active Pending
- 2010-01-05 JP JP2011503658A patent/JP5627568B2/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1658893A (en) * | 2002-04-05 | 2005-08-24 | 加利福尼亚大学董事会 | G-type peptides to ameliorate atherosclerosis |
| CN101018564A (en) * | 2004-09-13 | 2007-08-15 | 阿法里斯研发有限责任公司 | Treatment of atherosclerosis |
Non-Patent Citations (3)
| Title |
|---|
| TANAKA M: ""Endothelium-independent vasodilation effect of di- and tri-peptides in thoracic aorta of Sprague-Dawley rats."", 《LIFE SCI.》 * |
| 孟军: ""钙通道阻滞剂在动脉粥样硬化中的抗氧化作用"", 《中国动脉硬化杂质》 * |
| 肖华: ""钙通道阻滞剂抗动脉粥样硬化作用的研究进展"", 《心血管病学进展》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20110130397A (en) | 2011-12-05 |
| JPWO2010103708A1 (en) | 2012-09-13 |
| JP5627568B2 (en) | 2014-11-19 |
| WO2010103708A1 (en) | 2010-09-16 |
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Application publication date: 20120104 |