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THERAPEUTIC AGENT FOR INJURY IN EPITHELIUM AND ENDOTHELIUM meetings

Foreign code F130007767
Posted date Dec 10, 2013
Country WIPO
International application number 2013JP062989
International publication number WO 2013162078
Date of international filing Apr 30, 2013
Date of international publication Oct 31, 2013
Priority data
  • P2012-102910 (Apr 27, 2012) JP
Title THERAPEUTIC AGENT FOR INJURY IN EPITHELIUM AND ENDOTHELIUM meetings
Abstract The present invention provides: a therapeutic agent for injury in an epithelium and an endothelium, particularly minute injury in an epithelium and an endothelium; and others. The therapeutic agent according to the present invention is characterized by comprising, for example, a peptide (a) or (b) as mentioned below, a derivative of the peptide, or a salt of the peptide or the derivative: (a) a peptide comprising an amino acid sequence represented by any one of SEQ ID NOs: 10, 4, 12 and 6; and (b) a peptide comprising an amino acid sequence represented by any one of SEQ ID NOs: 16, 18, 20 and 22.
Outline of related art and contending technology BACKGROUND ART
9 Hemostatic clotting factors that are involved in the coagulation of the long-known (F9) is an essential and blood coagulation factors, protein known as the cause of hemophilia. F9 Is, in the course of the blood coagulation reaction, coagulation factor 11 and coagulation factors 7 (F11), present between the light and heavy chains of an intermediate portion (Activation peptide (F9-AP) ) is cut off, is activated. After cutting the light and heavy chains is also connected by a disulfide bond and, as a single molecule of 1, to promote blood coagulation reaction (non-patent document 1: Textbook of Medical Physiology,10e.Arthur C. Guyton MD). However, the function of the intermediate part F9-AP hardly reported. However, epithelial cells which is one type of vascular endothelial cells, in the normal state, platelet function and coagulation line controls the fibrinolytic system, and thrombus formation within the vessel so as not functioning. In addition, the components of the blood vessel does not leak out to the outside of the inner surface of the vessel by means of a covering responsiveness. Fails by vascular endothelial cells of various acute diseases (non-patent document 2: Harrison's Principles of Internal Medicine, 18e.Dan Longo). For example, acute coronary syndrome (ACS) such as myocardial infarction, blood coagulation is the bleed site to occur only in the blood vessels occurs randomly systemic disseminated intravascular coagulation syndrome (DIC), systemic inflammatory response syndrome caused by bacteria of sepsis, the most violent and allergic disease of severe symptoms of anaphylaxis and the like. Endothelial cell damage in these diseases is very small, coagulation abnormality within the blood vessel or blood component of any leakage to the outside of the vessel and for the occurrence of severe and acute, rapid administration of the therapeutic agent and an appropriate action is required. Treatment of the acute phase of the disease, conventional, anti-hypertensive agents and anti-histamine, steroid, such as administration of anti-coagulant such as bypass surgery or invasive procedure being performed. Are different from each of the above but the pathogenesis of the disease, or vascular endothelial cell dysfunction, interstitial of plasma components caused thereby is leaking to, influences the prognosis of these diseases is turning. Therefore, more rapid repair of the epithelial and endothelial injury and improving the function of the therapeutic agents that can be required in the clinical field. However, the therapeutic agents of the conventional epithelial and endothelial damage, any therapeutic effect is obtained quickly and did not.
In such a situation, the treatment of epithelial and endothelial damage, especially epithelial and endothelial micro rapid and effective treatment of injuries to carry out the development of therapeutic agents has been desired. The present invention is, in consideration of the above circumstances with an object, shown below, epithelial and endothelial injury therapeutic agent, to enhance epithelial and endothelial cells of extension of the agent, the therapeutic agent or a pharmaceutical composition comprising a hyper-extension agent (for example, epithelial and endothelial damage and diseases associated with pharmaceutical composition for the treatment of disease states or conditions) system according to the invention and the like. (1) - (F) the following (a) the peptide either, its derivatives or a salt thereof. (a) Of SEQ ID NO:10, 4, 12 and 6 comprising an amino acid sequence shown in any of. (b) And 22 of the sequence shown in any of 16, 18, 20 comprising an amino acid sequence. (c) And 6 of SEQ ID NO:10, 4, 12 in amino acid sequence shown in any of 1 or an amino acid deletion, substitution or addition of the amino acid sequence, and, or epithelial and endothelial damage repair activity enhancing epithelial and endothelial cells of extension of the peptide having the activity. (d) And 22 of SEQ ID NO:16, 18, 20 in amino acid sequence shown in any of 1 or an amino acid deletion, substitution or addition of the amino acid sequence, and, epithelial and endothelial damage repair activity enhancing epithelial and endothelial cells of stretch or a peptide having the activity. (e) And SEQ ID NO:10, 4, 12 to the amino acid sequence shown in any of the 6, 80% amino acid sequence having a homology of at least, and, epithelial and endothelial damage repair activity or enhance epithelial and endothelial cells of extension of the peptide having the activity. (f) And 22 of the sequence shown in any of 16, 18, 20 to the amino acid sequence, 80% amino acid sequence having a homology of at least, and, epithelial and endothelial damage repair activity or enhance epithelial and endothelial cells of extension of the peptide having the activity. The (1) peptide, its derivatives or a salt thereof in, epithelial and endothelial damage may include, for example micro-damage and the like. (2) - (F) the following (a) the peptide either, its derivatives or salts thereof and, the therapeutic agent of the epithelial and endothelial injury. (a) Of SEQ ID NO:10, 4, 12 and 6 comprising an amino acid sequence shown in any of. (b) And 22 of the sequence shown in any of 16, 18, 20 comprising an amino acid sequence. (c) And 6 of SEQ ID NO:10, 4, 12 in amino acid sequence shown in any of 1 or an amino acid deletion, substitution or addition of the amino acid sequence, and, a peptide having the activity of the epithelial and endothelial injury repair. (d) And 22 of SEQ ID NO:16, 18, 20 in amino acid sequence shown in any of 1 or an amino acid deletion, substitution or addition of the amino acid sequence, and, a peptide having the activity of the epithelial and endothelial injury repair. (e) And SEQ ID NO:10, 4, 12 to the amino acid sequence shown in any of the 6, 80% amino acid sequence having a homology of at least, and, a peptide having the activity of the epithelial and endothelial injury repair. (f) And 22 of the sequence shown in any of 16, 18, 20 to the amino acid sequence, 80% amino acid sequence having a homology of at least, and, a peptide having the activity of the epithelial and endothelial injury repair. In the above-described (2) therapeutic agent, epithelial and endothelial damage may include, for example, and micro-damage. (3) - (F) the following (a) the peptide either, its derivatives or salts thereof characterized in that, the extension of the epithelial and endothelial cells enhance agent. (a) Of SEQ ID NO:10, 4, 12 and 6 comprising an amino acid sequence shown in any of. (b) And 22 of the sequence shown in any of 16, 18, 20 comprising an amino acid sequence. (c) And 6 of SEQ ID NO:10, 4, 12 in amino acid sequence shown in any of 1 or an amino acid deletion, substitution or addition of the amino acid sequence, and, epithelial and endothelial cells to enhance the extension of a peptide having the activity. (d) And 16, 18, 20 SEQ ID NO:22 in the amino acid sequence shown in any of the 1 or an amino acid deletion, substitution or addition of the amino acid sequence, and, epithelial and endothelial cells to enhance the extension of a peptide having the activity. (e) And SEQ ID NO:10, 4, 12 to the amino acid sequence shown in any of the 6, 80% amino acid sequence having a homology of at least, and, epithelial and endothelial cells to enhance the extension of a peptide having the activity. (f) And 22 of the sequence shown in any of 16, 18, 20 to the amino acid sequence, 80% amino acid sequence having a homology of at least, and, epithelial and endothelial cells to enhance the extension of a peptide having the activity. (4) Animals enhancing agent as defined above (3) comprising administering to the extension, the extension of the epithelial and endothelial cells to enhance the method. (5) Extension of the enhancing agent mentioned (2) above (3) or, the pharmaceutical composition. The pharmaceutical compositions described above (5) is, for example, diseases associated with epithelial and endothelial injury and the like used in the treatment of disease states or conditions. Here, the epithelial and endothelial damage may include, for example, and micro-damage, as the disease or condition, for example, sepsis, arteriosclerosis, acute myocardial infarction, angina pectoris, arteriovenous thrombosis, bronchial asthma as well as cerebral edema after cerebral infarction and vascular hyperpermeability state at least one selected from the group consisting of 1 species. (6) Animals as defined above (5) comprising administering a pharmaceutical composition, the disease or condition associated with epithelial and endothelial injury treatment. In the above method (6), epithelial and endothelial damage may include, for example, and micro-damage, as the disease or condition, for example, sepsis, arteriosclerosis, acute myocardial infarction, angina pectoris, arteriovenous thrombosis, bronchial asthma as well as cerebral edema after cerebral infarction and vascular hyperpermeability state at least one selected from the group consisting of 1 species. According to the present invention, the therapeutic agent of the epithelial and endothelial damage, especially epithelial and endothelial micro damage therapeutic agent can be provided. In addition, the extension of the epithelial and endothelial cells enhance agent can also be provided. The therapeutic agent or enhancing agent is extended, epithelial and endothelial injury (particularly minute damage) associated with the disease or condition used in the treatment of various types can be achieved, to be very useful. In addition, the therapeutic agent and extension enhancing agent is, in view the effects, and cell gap between the intercellular adhesion enhancing agents can be used as the shrinkage agent. This is, for example, 4 and 8 will be described later as the result of the embodiment of the present can be understood.
Scope of claims (In Japanese)請求の範囲 [請求項1]
以下の(a)~(f)のいずれかのペプチド、その誘導体あるいはこれらの塩。
(a)配列番号10、4、12及び6のいずれかに示されるアミノ酸配列を含むペプチド。
(b)配列番号16、18、20及び22のいずれかに示されるアミノ酸配列を含むペプチド。
(c)配列番号10、4、12及び6のいずれかに示されるアミノ酸配列において1若しくは数個のアミノ酸が欠失、置換若しくは付加されたアミノ酸配列を含み、かつ、上皮及び内皮損傷の修復活性あるいは上皮及び内皮細胞の伸展亢進活性を有するペプチド。
(d)配列番号16、18、20及び22のいずれかに示されるアミノ酸配列において1若しくは数個のアミノ酸が欠失、置換若しくは付加されたアミノ酸配列を含み、かつ、上皮及び内皮損傷の修復活性あるいは上皮及び内皮細胞の伸展亢進活性を有するペプチド。
(e)配列番号10、4、12及び6のいずれかに示されるアミノ酸配列に対して、80%以上の相同性を有するアミノ酸配列を有し、かつ、上皮及び内皮損傷の修復活性あるいは上皮及び内皮細胞の伸展亢進活性を有するペプチド。
(f)配列番号16、18、20及び22のいずれかに示されるアミノ酸配列に対して、80%以上の相同性を有するアミノ酸配列を有し、かつ、上皮及び内皮損傷の修復活性あるいは上皮及び内皮細胞の伸展亢進活性を有するペプチド。

[請求項2]
上皮及び内皮損傷が微小損傷である、請求項1記載のペプチド、その誘導体あるいはこれらの塩。

[請求項3]
以下の(a)~(f)のいずれかのペプチド、その誘導体あるいはこれらの塩を含むことを特徴とする、上皮及び内皮損傷の治療剤。
(a)配列番号10、4、12及び6のいずれかに示されるアミノ酸配列を含むペプチド。
(b)配列番号16、18、20及び22のいずれかに示されるアミノ酸配列を含むペプチド。
(c)配列番号10、4、12及び6のいずれかに示されるアミノ酸配列において1若しくは数個のアミノ酸が欠失、置換若しくは付加されたアミノ酸配列を含み、かつ、上皮及び内皮損傷の修復活性を有するペプチド。
(d)配列番号16、18、20及び22のいずれかに示されるアミノ酸配列において1若しくは数個のアミノ酸が欠失、置換若しくは付加されたアミノ酸配列を含み、かつ、上皮及び内皮損傷の修復活性を有するペプチド。
(e)配列番号10、4、12及び6のいずれかに示されるアミノ酸配列に対して、80%以上の相同性を有するアミノ酸配列を有し、かつ、上皮及び内皮損傷の修復活性を有するペプチド。
(f)配列番号16、18、20及び22のいずれかに示されるアミノ酸配列に対して、80%以上の相同性を有するアミノ酸配列を有し、かつ、上皮及び内皮損傷の修復活性を有するペプチド。

[請求項4]
上皮及び内皮損傷が微小損傷である、請求項3記載の治療剤。

[請求項5]
以下の(a)~(f)のいずれかのペプチド、その誘導体あるいはこれらの塩を含むことを特徴とする、上皮及び内皮細胞の伸展亢進剤。
(a)配列番号10、4、12及び6のいずれかに示されるアミノ酸配列を含むペプチド。
(b)配列番号16、18、20及び22のいずれかに示されるアミノ酸配列を含むペプチド。
(c)配列番号10、4、12及び6のいずれかに示されるアミノ酸配列において1若しくは数個のアミノ酸が欠失、置換若しくは付加されたアミノ酸配列を含み、かつ、上皮及び内皮細胞の伸展亢進活性を有するペプチド。
(d)配列番号16、18、20及び22のいずれかに示されるアミノ酸配列において1若しくは数個のアミノ酸が欠失、置換若しくは付加されたアミノ酸配列を含み、かつ、上皮及び内皮細胞の伸展亢進活性を有するペプチド。
(e)配列番号10、4、12及び6のいずれかに示されるアミノ酸配列に対して、80%以上の相同性を有するアミノ酸配列を有し、かつ、上皮及び内皮細胞の伸展亢進活性を有するペプチド。
(f)配列番号16、18、20及び22のいずれかに示されるアミノ酸配列に対して、80%以上の相同性を有するアミノ酸配列を有し、かつ、上皮及び内皮細胞の伸展亢進活性を有するペプチド。

[請求項6]
被験動物に請求項5記載の伸展亢進剤を投与することを含む、上皮及び内皮細胞の伸展亢進方法。

[請求項7]
請求項3若しくは4記載の治療剤又は請求項5記載の伸展亢進剤を含む、医薬組成物。

[請求項8]
上皮及び内皮損傷に伴う疾患又は病態の治療に用いるものである、請求項7記載の医薬組成物。

[請求項9]
上皮及び内皮損傷が微小損傷である、請求項8記載の医薬組成物。

[請求項10]
前記疾患又は病態が、敗血症、動脈硬化症、急性心筋梗塞、狭心症、動静脈血栓症、脳梗塞後脳浮腫及び気管支喘息並びに血管透過性亢進状態からなる群より選ばれる少なくとも1種である、請求項8又は9記載の医薬組成物。

[請求項11]
被験動物に請求項8記載の医薬組成物を投与することを含む、上皮及び内皮損傷に伴う疾患又は病態の治療方法。

[請求項12]
上皮及び内皮損傷が微小損傷である、請求項11記載の方法。

[請求項13]
前記疾患又は病態が、敗血症、動脈硬化症、急性心筋梗塞、狭心症、動静脈血栓症、脳梗塞後脳浮腫及び気管支喘息並びに血管透過性亢進状態からなる群より選ばれる少なくとも1種である、請求項11又は12記載の方法。

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • NIHON UNIVERSITY
  • Inventor
  • HIDAI, Chiaki
  • KITANO, Hisataka
  • MAMIYA, Atsushi
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG
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