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WO2001093871A1 - Medicaments pour la prevention de la reangiostenose - Google Patents

Medicaments pour la prevention de la reangiostenose Download PDF

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Publication number
WO2001093871A1
WO2001093871A1 PCT/JP2001/001859 JP0101859W WO0193871A1 WO 2001093871 A1 WO2001093871 A1 WO 2001093871A1 JP 0101859 W JP0101859 W JP 0101859W WO 0193871 A1 WO0193871 A1 WO 0193871A1
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WO
WIPO (PCT)
Prior art keywords
dyes
smooth muscle
acridine
vascular smooth
vascular
Prior art date
Application number
PCT/JP2001/001859
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English (en)
Japanese (ja)
Inventor
Yasumi Uchida
Original Assignee
Cardiovascular Institute, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cardiovascular Institute, Ltd. filed Critical Cardiovascular Institute, Ltd.
Publication of WO2001093871A1 publication Critical patent/WO2001093871A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • 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

Definitions

  • the present invention relates to an agent for suppressing vascular smooth muscle growth and an agent for preventing vascular restenosis after angioplasty.
  • PTCA Percutaneous coronary angioplasty
  • stents made of metal or the like has been actively performed.
  • Such restenosis is considered to be mainly caused by intimal hyperplasia and thrombus formation due to migration and proliferation of medial smooth muscle cells into the intima caused by cell proliferative cytokines in the vascular lesions.
  • Drugs such as inhibitors, anticoagulants, and platelet aggregation inhibitors have been studied clinically, but none of them have achieved sufficient effects.
  • an object of the present invention is to provide a medicament that can effectively prevent vascular restenosis after angioplasty such as PTCA or vascular bypass surgery. Disclosure of the invention The present inventors further studied the factors of vascular restenosis after angioplasty, and found that while suppressing the proliferation of vascular smooth muscle cells, endothelial cells were regenerated early to cover the vascular lesion. Can effectively suppress vascular restenosis, and a specific biocompatible dye has an effect of suppressing vascular smooth muscle cell proliferation, and is a vascular smooth muscle growth inhibitor for preventing vascular restenosis.
  • vascular smooth muscle growth inhibitor and indigo carmine which proliferates only endothelial cells, an excellent vascular restenosis preventing effect can be obtained without inhibiting endothelial cell proliferation.
  • the inventors have found that the present invention can be obtained and completed the present invention.
  • the present invention relates to one or more selected from sulfonic acid azo dyes, phthalein dyes, triphenyl methane dyes, phenanthridinium dyes, acridine dyes, xanthene dyes, phenothiazine dyes, and cyanine dyes. It is intended to provide a vascular smooth muscle growth inhibitor and a vascular restenosis inhibitor containing two or more biocompatible dyes.
  • the present invention also provides an agent for preventing vascular restenosis, which comprises the biocompatible dye and indigo carmine.
  • the present invention also provides use of the above biocompatible dye for producing a vascular smooth muscle growth inhibitor or a vascular restenosis inhibitor.
  • the present invention further provides a method for treating a disease caused by vascular smooth muscle proliferation or a method for preventing vascular restenosis, which comprises administering the above-mentioned biocompatible dye.
  • FIG. 1 is a diagram showing the effect of stopping Evans care on the human aortic smooth muscle cell cycle.
  • FIG. 2 is a diagram showing changes in the canine coronary artery stent insertion part ((1) control group, (2) ethidium bromide group, arrows indicate stent parts).
  • FIG. 3 shows the effect of PTCA on the restenosis site due to PTCA by local administration of Evans blue [(1) control group, (2) Evans blue group].
  • FIG. 4 is a graph showing the effect of local administration of Evansbull on restenosis at the stent insertion site in patients with ischemic heart disease.
  • FIG. 5 is a graph showing the effect of one administration of Evanspr to the PTCA site of a patient with ischemic heart disease.
  • FIG. 6 is a diagram showing a chromatogram after mixing Evans blue and batroxobin. BEST MODE FOR CARRYING OUT THE INVENTION
  • the biocompatible dye which is an active ingredient of the vascular smooth muscle growth inhibitor and the vascular restenosis inhibitor of the present invention is a dye used as a medical or edible drug such as a drug, a dye for a living body or a biological substance, and a clinical test.
  • a substance that can be administered to mammals including the human body specifically, sulfonic acid-based azo dyes, phthalein-based dyes, triphenylmethane-based dyes, phenanthridine-based dyes, and acridine-based dyes , A xanthene dye, a phenothiazine dye and a cyanine dye.
  • the sulfonic acid-based azo dye refers to an azo dye having a group —S ⁇ 3 _ in the molecule.
  • naphthalenesulfonic acid-based azo dyes such as Evans Blue, Trypan Blue, Trypan Red, and Orange B are used.
  • phthalein dyes for example, phenolphthalein or phenolsul
  • the above dyes have an excellent vascular smooth muscle cell growth inhibitory action as shown in Examples described later, it is needless to say that such action was not known at all.
  • sulfonic acid-based azo dyes particularly naphthylene sulfonic acid-based azo dyes, phenanthridinium-based dyes, acridine-based dyes, and phenothiazine-based dyes
  • Evans blue, ethidium bromide, acridine orange, methylene blue or toluidine blue which have an effect of regenerating endothelial cells at an early stage while suppressing the growth of vascular smooth muscle cells, are particularly preferable.
  • biocompatible pigment of the present invention which has such an excellent vascular smooth muscle cell proliferation inhibitory effect, mononuclear cells that cover a vascular lesion early and cause thrombus formation, site force in, and arteriosclerosis can be obtained. It is possible to prevent the invasion of blood vessels and the like, and effectively prevent restenosis and acute, subacute, and chronic thrombotic occlusion after angioplasty or bypass surgery.
  • vascular smooth muscle growth inhibitor and the vascular restenosis inhibitor of the present invention can be used alone or in combination of two or more.
  • two or more kinds are used in combination, they may be prepared so as to be contained in a single preparation, or each may be prepared as a separate preparation and used in combination.
  • Preferred examples of the combination use of the dye of the present invention include naphthalenesulfonic acid-based azo dyes such as Evans blue, and phenanthridine-based dyes such as ethidium amide and acridine orange from the viewpoint of the effect of preventing vascular restenosis. And the like when used in combination with an acridine dye.
  • indigo carmine is a pigment that is widely used as a renal function test, food coloring and the like, but indigo carmine itself has a vascular smooth muscle growth inhibition referred to in the present invention. Has no effect. However, since it exerts an action of promoting endothelial cell proliferation and regeneration (Example 2), indigo carmine is used as the above dye having an inhibitory action on vascular smooth muscle growth, in particular, a naphthylene sulfonic acid-based azo dye such as Evans blue, ethidizumab.
  • endothelial cells When used in combination with phenanthridinium dyes such as mouth amides or acridine orange dyes such as acridine orange, endothelial cells can be regenerated at an early stage, and damaged areas can be repaired, so more ideal prevention of vascular restenosis The effect can be expected.
  • phenanthridinium dyes such as mouth amides or acridine orange dyes such as acridine orange
  • the anti-restenosis agent of the present invention may contain a conventionally known antiplatelet agent, anticoagulant, thrombolytic agent and Z or a vasodilator.
  • Antiplatelet agents used here include aspirin, sulfinpyrazone, ticlopidine, abciximab, clovidogrel, GPIIb / IIIa inhibitor, tropoxan A2 antagonist, loitcollien antagonist, etc.
  • antithrombin agents such as heparin, argatroban, and batroxobin
  • synthetic anticoagulants such as perfarin.
  • Thrombolytic agents include perokinase and plasminogen activator, and vasodilators.
  • Nitric acid agents such as nitroglycerin and isosorbide dinitrate; nicorandil, trapidil, dipyridamole; calcium antagonists such as diltiazem and dihydropyridin derivatives (such as diphedipine and dicardipine); angiotensin converting enzyme antagonists (such as captopril); and angiotensin Emissions receptor inhibitors, and the like.
  • the pigment component and the above antithrombotic agent are used in combination, the restenosis prevention effect is further enhanced. Therefore, the dose of the conventional antithrombotic agent can be reduced.
  • the compounding ratio of the dye component to the known antithrombotic agent is preferably 1: 10000 to 10000: 1, more preferably 1: 1100 to 100: 1 by weight.
  • the pigment component used in the present invention and a known antithrombotic agent are easily combined in an aqueous solution to form a force-applying body, which is considered to be effective as such a carohydrate-applied body.
  • a pharmaceutically acceptable carrier It can be formulated as a pharmaceutical composition for parenteral administration, such as rectal, or for oral administration in solid or liquid form.
  • Injectables can be in the form of solutions (sterile water or non-aqueous solutions), emulsions and suspensions.
  • Non-aqueous carriers, diluents, solvents or vehicles used in these injections include, for example, propylene glycol, polyethylene glycol Vegetable oils such as olive oil; and injectable organic acid esters such as ethyl oleate.
  • auxiliary agents such as preservatives, wetting agents, emulsifiers, and dispersants can be appropriately added to the composition.
  • the preparation for oral administration include, for example, solid preparations such as tablets, powders, granules and capsules, solutions, syrups, elixirs, and liquid preparations such as oily or aqueous suspensions.
  • the medicament of the present invention is preferably used as an injection.
  • Intravenous administration, intraarterial administration, local administration in a graft, local administration under pressure using a porous balloon catheter, and the like are more preferable. .
  • the dosage of the medicament of the present invention will depend on the nature of the components to be administered, the route of administration, the desired duration of treatment and other factors, but will generally be from about 0.1 to about 0.1 mg per day as a pigment component; Particularly, about 0.5 to 5 O mg / kg is preferable. If desired, the daily dose can be divided and administered in 2 to 4 times.
  • Ethidium bromide (2,7-diamino-1-10-ethyl-9-phenylphenanthrium bromide) Sterilize the crystals and aseptically dissolve in distilled water for injection to a concentration of 1, 2, 5, 10, 20% by weight. It was melted, sealed in a glass or synthetic resin ampule, and stored at room temperature.
  • 2 ⁇ 10 6 human coronary artery smooth muscle cells (CASMC-2; 28.7PDL) were mixed in a mixed medium of MCDB-104, 10% FBS and EGF 10 Ong / mL supplemented with various concentrations of emissible monohydrate or ethidium disulfide. After 72 hours, the number of cells was counted, and compared with that of the control, the proliferation rate (%) was calculated.
  • 2 ⁇ 10 6 human umbilical cord endothelial cells (HUVEC, KT-T, 8.3PDL) were added to various concentrations of Evans blue or ethidium orbit, MCDB-104, 10% FBS and EGF 10 Ong / mL. The cells were cultured in a mixed medium and counted after 72 hours.
  • the proliferation rate was calculated by dividing the cell number of the group to which Evans blue or ethidium muvide was added by that of the group to which no cell group was added.
  • the proliferation rate of smooth muscle cells was divided by that of endothelial cells to determine the relative selectivity of vascular smooth muscle cell growth inhibition. Methylene blue, toluidine blue, acridine orange, and indigo carmine were similarly examined. Table 1 shows the results.
  • Control group 3_ serum-free medium + 10% 83
  • Figure 1 shows the control and Evans Blue group fluorescence cytometry charts. In the Evans Blue group, S, G 2 ZM phase is hardly seen.
  • a guiding catheter was inserted into the left coronary artery through the right common artery under X-ray fluoroscopy under artificial respiration.
  • a PTCA catheter of 3 diameters was inserted and expanded at 9 atm.
  • a PTCA stent with a diameter of 2.5 mm was inserted, expanded at 9 atm, and placed.
  • mice received ethidium bromide (0.5 mL of a 10% solution) followed by topical administration of Evans blue (0.5 mL of a 10% solution). Similarly, one month later, the coronary artery was removed.
  • the coronary arteries were sliced at intervals of three thighs, stained with Azan, photographed with a microscope, and the area surrounded by the media (A) and the area of the intima that had fibrotic proliferation (B) were measured with a branometer. Each (B / A) XI00 was determined, and the maximum value was defined as the stenosis rate (%). The results are shown in FIG. Table 3
  • n: p 0.01
  • a guide catheter was inserted into the left coronary artery through the right common splenic artery under artificial respiration and X-ray fluoroscopy using a Nembu evening anesthesia beagle dog.
  • a 3 mm diameter PTCA catheter was inserted and expanded at 9 atm.
  • the stenosis rate (%) was measured in the same manner as in Example 3.
  • Figure 3 shows an example of the Evansbull single administration group, and Table 4 shows the restenosis rate.
  • a guide catheter was inserted into the left coronary artery via the right common carotid artery under artificial respiration and X-ray fluoroscopy using a Nembutal anesthetized beagle dog. Then, a three-band PTCA parkin catheter was inserted into the left anterior descending branch and expanded at 9 atm. Next, a balloon was inserted into the circumflex branch and expanded in the same manner. A 2.5-thigh stent was introduced and expanded at 9 atm.
  • Intravenous injection group immediately after Evans Blue. 6 heads. Immediately after, intravenous Evansbull 20% 1 OmL was injected, and three months later, the coronary artery was removed.
  • the coronary artery removed was cut into slices at intervals of three thighs, and Azan staining was performed.
  • the area of the fibrotic tissue inside the media (A) and the area surrounding the media (B) were measured with a branometer. Calculate A / BX 100 and calculate the maximum value in each coronary artery was used as the restenosis rate and compared between groups. Table 5 shows the results.
  • PTCA control group 30 cases. Normal PTCA was performed. Six months later, coronary angiography was performed to examine changes in the treatment site.
  • Stent control group 20 cases. Six months after normal stent placement, coronary angiography was performed.
  • Example 8 Certification of Evans Blue and Batroxobin Adduct and Preparation of Injection Formulation
  • Sephadex G-15 manufactured by Pharmacia
  • % Solution % Solution
  • batroxobin (20 BU units, ZmL) were mixed at 1: 1 and fractionated by 3 mL with a fraction collector.
  • the absorbance of each fraction was measured at wavelengths of 28 Onm and 62 Onm.
  • the bovine fibrinogen solution was put into the reactor, and after keeping the temperature at 37 ° C, each fraction was put therein, and the coagulation time was measured. As a result, as shown in FIG.
  • Such an adduct is formed as soon as the Evansable solution and the batroxobin solution (both in ampoules) are placed in an injection bowl and mixed, so that the adducts may be used by mixing them at the time of use.
  • a guide catheter was inserted into the left coronary artery through the right common carotid artery under artificial respiration and X-ray fluoroscopy using a Nembutal anesthetized beagle dog. Then, a balloon catheter for 3 mm PTCA was inserted into the left anterior descending branch and expanded at 9 atm. Nineteen animals were placed in the PTCA group, and the other 19 animals were inserted with a stent to form a stent group. The PTCA group and the stent group were grouped as follows and examined. That is,
  • the extracted coronary arteries were cut into slices at 3 mm intervals and stained with Azan.
  • the area of fibrotic tissue inside the media (S) and the area surrounding the media (B) are measured with a planimeter, AZBX100 is calculated, and the maximum value in each coronary artery is restenosis. Rates and were compared between groups. Table 6 shows the results.
  • the vascular smooth muscle growth inhibitor and vascular restenosis inhibitor of the present invention have an effect of regenerating endothelial cells early while suppressing the growth of vascular smooth muscle cells, and include coronary arteries, cerebral arteries, peripheral arteries and the like. It is useful as a medicament for the prevention and treatment of diseases caused by vascular smooth muscle proliferation such as vascular restenosis after angioplasty or bypass surgery in patients.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des inhibiteurs de prolifération de muscle vasculaire lisse, des médicaments de prévention de la réangiosténose, etc. contenant au moins un pigment biocompatible sélectionné dans le groupe constitué par des pigments azoïques sous forme acide sulfonique, des pigments de phtaléine, des pigments de triphénylméthane, des pigments de phénanthridinium, des pigments d'acridine, des pigments de xanthène, des pigments de phénothiazine, et de pigments de cyanine. Les inhibiteurs de prolifération de muscle vasculaire lisse et les médicaments de prévention de la réangiosténose, qui ont un effet de régénération de cellules endothéliales à un stade précoce tout en inhibant la prolifération de muscle vasculaire lisse, sont utilisés comme médicaments pour prévenir et traiter des maladies induites par la prolifération de cellules de muscle vasculaire lisse après une angioplastie, la réangiosténose après dérivation, etc.
PCT/JP2001/001859 2000-06-07 2001-03-09 Medicaments pour la prevention de la reangiostenose WO2001093871A1 (fr)

Applications Claiming Priority (4)

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JP2000-0170515 2000-06-07
JP2000170515 2000-06-07
JP2001-014509 2001-01-23
JP2001014509 2001-01-23

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PCT/JP2001/001859 WO2001093871A1 (fr) 2000-06-07 2001-03-09 Medicaments pour la prevention de la reangiostenose

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004108129A1 (fr) * 2003-06-09 2004-12-16 Cardiovascular Institute, Ltd. Inhibiteur de l'invasion des cellules souches
JP2005533604A (ja) * 2002-07-25 2005-11-10 アバンテック バスキュラー コーポレーション 治療薬を送達する装置とこれに関する方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4243850A4 (fr) * 2020-11-13 2024-05-01 Mayo Foundation for Medical Education and Research Hydrogels de fibrine

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WO1989004166A1 (fr) * 1987-10-30 1989-05-18 Bmrt, Ltd. Procede de prevention et de traitement de la thrombose
EP0354714A2 (fr) * 1988-08-12 1990-02-14 Hadassah Medical Organization Compositions pharmaceutiques renfermant des composés polyaromatiques
WO1991003226A2 (fr) * 1989-08-14 1991-03-21 Rorer International (Holdings), Inc. Compositions pharmaceutiques contenant des polymeres aromatiques et procedes therapeutiques les employant

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Publication number Priority date Publication date Assignee Title
WO1989004166A1 (fr) * 1987-10-30 1989-05-18 Bmrt, Ltd. Procede de prevention et de traitement de la thrombose
EP0354714A2 (fr) * 1988-08-12 1990-02-14 Hadassah Medical Organization Compositions pharmaceutiques renfermant des composés polyaromatiques
WO1991003226A2 (fr) * 1989-08-14 1991-03-21 Rorer International (Holdings), Inc. Compositions pharmaceutiques contenant des polymeres aromatiques et procedes therapeutiques les employant

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CHEMICAL ABSTRACTS, vol. 76, Columbus, Ohio, US; abstract no. 94482 *
CHEMICAL ABSTRACTS, vol. 80, Columbus, Ohio, US; abstract no. 10415 *
CHEMICAL ABSTRACTS, vol. 84, Columbus, Ohio, US; abstract no. 116379 *
CHEMICAL ABSTRACTS, vol. 87, Columbus, Ohio, US; abstract no. 194034 *
CHEMICAL ABSTRACTS, vol. 94, Columbus, Ohio, US; abstract no. 60116 *
GIG. TR. PROF. ZABOL., vol. 10, 1989, pages 54 - 56 *
JPN. J. TOXICOL. ENVIRON. HEALTH, vol. 40, no. 5, 1994, pages 448 - 453 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005533604A (ja) * 2002-07-25 2005-11-10 アバンテック バスキュラー コーポレーション 治療薬を送達する装置とこれに関する方法
WO2004108129A1 (fr) * 2003-06-09 2004-12-16 Cardiovascular Institute, Ltd. Inhibiteur de l'invasion des cellules souches

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