JP4582561B2 - Inhibitor of vascular lesions caused by transplantation - Google Patents
Inhibitor of vascular lesions caused by transplantation Download PDFInfo
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- JP4582561B2 JP4582561B2 JP2000322141A JP2000322141A JP4582561B2 JP 4582561 B2 JP4582561 B2 JP 4582561B2 JP 2000322141 A JP2000322141 A JP 2000322141A JP 2000322141 A JP2000322141 A JP 2000322141A JP 4582561 B2 JP4582561 B2 JP 4582561B2
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Description
【0001】
【産業上の利用分野】
本発明は、移植による血管病変の発生抑制剤に関する。
【0002】
【従来の技術】
移植には心、腎、肝、肺、小腸、膵等の臓器移植、皮膚、血管等の組織移植が含まれる。血管病変の発生が、移植後の臨床上の大きな問題となっている(現代病理学大系、第6巻p194−209、飯島宗一ら編、中山書店)。
例えば心臓移植は、末期心不全患者の治療に残された唯一の、しかも最も有効な治療法として確立されている。心移植後の生存率は、10年で50%程度である。死亡の深刻な原因の1つとして、移植心冠動脈病変がある。移植心冠動脈病変は、移植後数ヶ月から数年後に出現し、進展する冠動脈狭窄である。これは、中小動脈を中心とした、びまん性病変で、移植心の慢性的虚血をきたす。移植心は除神経心であるため、狭心症などの症状を示さず、また病変はびまん性のため、冠動脈バイパス術や、冠血管形成術は無効なことが多い。また、免疫抑制剤等の投与による進展予防などが検討されているが、満足な結果は得られていない。特異的な治療法が無い現在、救命は再移植しかない(Heart View, Vol. 4, 1999, p55-99)。
【0003】
一方、一般式(I)で示される化合物は、Rhoキナーゼ、ミオシン軽鎖リン酸化酵素、プロテインキナーゼCといったキナーゼ阻害活性を有し、血管平滑筋弛緩作用、血流増加作用、血圧低下作用、脳、心臓保護作用等を示し、血管拡張剤(特に、狭心症治療剤)、脳、心臓保護剤等において有効な物質であることは、既に公知である(例えば特開昭61−152658号公報、特開昭61−227581号公報、特開平2−256617号公報、特開平4−264030号公報、特開平6−056668号公報、特開平6−080569号公報、特開平7−80854号公報、WO98/06433、WO00/03746、Br. J. Pharmacol., 98, 1091 (1989), J. Pharmacol. Exp. Ther., 259, 738 (1991), Circulation, 96, 4357 (1997), Cardiovasc. Res., 43, 1029 (1999))
【0004】
【発明が解決しようとする課題】
従来より、移植による血管病変の発生の抑制を期待し得る新たな医薬の提供が望まれていた。
【0005】
【課題を解決するための手段】
発明者は、このような移植による血管病変の発生に対する抑制効果について、鋭意研究を重ねた結果、驚くべきことに、下記の一般式(I)で示される化合物またはその酸付加塩もしくは水和物が、移植による血管病変の発生の抑制に有効であることを見出し、本発明を完成するに至った。
すなわち、本発明は、下記一般式(I)
【0006】
【化2】
【0007】
(ただし、式中R1は水素原子または水酸基を表す)で示される化合物またはその酸付加塩もしくは水和物を有効成分とする、移植による血管病変の発生抑制剤である。
一般式(I)で示される化合物またはその酸付加塩もしくは水和物は、前述の通り公知であり、血管平滑筋弛緩作用、血流増加作用、血圧低下作用、脳、心臓保護作用等の作用示すことが知られている。しかし、一般式(I)で示される化合物またはその酸付加塩もしくは水和物が移植による血管病変の発生を抑制することは今まで知られていなかった。
【0008】
また移植による血管病変の発生を抑制する作用機序は、血管平滑筋弛緩作用、脳、心臓保護作用等の作用機序と異なると一般に考えられるので、一般式(I)で示される化合物またはその酸付加塩もしくは水和物が、拒絶反応を抑制することは予見することはできなかった。本発明が対象とする臓器もしくは組織は、レシピエント(移植を受けた人間)の本来の臓器もしくは組織ではなく、ドナー(臓器もしくは組織提供者)より移植された臓器もしくは組織で、通常の臓器もしくは組織での疾患とは異なる。
【0009】
また、同一個体間での臓器もしくは組織移植の場合でも、本来の位置から切り離して、本来の生理状態とは異なった環境下での障害であり、通常の疾患とは異なる。例えば、移植心冠動脈病変の発生に対し、免疫抑制薬、さらには狭心症や動脈硬化の治療に用いられている高脂血症のコントロール、血管拡張薬の使用などが試みられているが、満足な結果は得られていない。唯一の有効な治療法は、再心臓移植というのが現状である。このことからも、単に免疫反応を抑えても、血管病変の発生は抑制されず、また狭心症や動脈硬化といった、本来の自分の心臓に生じる血管病変とは異なった病変であることがわかる。一般式(I)で示される化合物またはその酸付加塩もしくは水和物は、移植による血管病変の発生を抑制する。血管病変としては、動脈硬化、血管肥厚、血管狭窄、血管閉塞等を意味する。
【0010】
本発明の一般式(I)で示される化合物は、公知の方法、例えば、Chem. Pharam. Bull., 40, (3) 770-773 (1992)、特開昭61−152658号公報等に記載されている方法に従って合成することができる。また、その酸付加塩は、薬学上許容される非毒性の塩が好ましく、例えば塩酸、臭化水素酸、リン酸、硫酸等の無機酸、および酢酸、クエン酸、酒石酸、乳酸、コハク酸、フマル酸、マレイン酸、メタンスルホン酸等の有機酸の塩を挙げることができる。
【0011】
本発明の、移植による血管病変の発生抑制剤を、投与に適した形の製剤として調整するのに際しては、上述の一般式(I)で示される化合物またはその酸付加塩もしくは水和物と、公知の医薬上許容される担体とを混合すればよい。この担体としては、例えば、ゼラチン;乳糖、グルコース等の糖類;小麦、米、とうもろこし澱粉等の澱粉類;ステアリン酸等の脂肪酸;ステアリン酸カルシウム、ステアリン酸マグネシウム等の脂肪酸塩;タルク;植物油;ステアリンアルコール、ベンジルアルコール等のアルコール;ガム;ポリアルキレングリコール等が挙げられる。
【0012】
また、液状担体としては、一般に水、生理食塩液、デキストロースまたは類似の糖溶液、エチレングリコール、プロピレングリコール、ポリエチレングリコール、ポリプロピレンルリコール等のグルコール類が挙げられる。カプセル剤となす場合には、通常ゼラチンを用いてカプセルを調整することが好ましい。
以上のような担体と一般式(I)で示される化合物またはその酸付加塩もしくは水和物よりなる本発明の移植による血管病変の発生抑制剤中には、通常0.01重量%以上、また80重量%以下、好ましくは60重量%以下の有効成分を含む例が挙げられる。
【0013】
投与方法は、経口投与や非経口投与が挙げられる。経口投与に適した剤形としては、錠剤、カプセル剤、粉剤、顆粒剤、液剤、エリキシル剤等が挙げられ、非経口投与に適した剤形としては、液剤が挙げられる。
非経口的に筋肉内注射、静脈内注射、皮下注射で投与する場合、一般式(I)で示される化合物またはその酸付加塩もしくは水和物を等張にするために、食塩または、グルコース等の他の溶質を添加した無菌溶液として投与される。
【0014】
注射により投与する場合には、滅菌水、塩酸リドカイン溶液(筋肉内注射用)、生理食塩液、ブドウ糖、静脈内注射用溶液、電解質溶液(静脈内注射用)等で溶解することも好ましい。このようにして溶解した場合には、通常0.01重量%以上、また20重量%以下、好ましくは0.1重量%以上、また10重量%以下の有効成分を含むように調整されることがある。経口投与の液剤の場合、0.01-20重量%の有効成分を含む懸濁液またはシロップが好ましい例として挙げられる。この場合における担体としては、香料、シロップ、製剤的ミセル体等の水様賦形剤が挙げられる。
【0015】
本発明の移植による血管病変の発生抑制剤の投与量は、被投与者の年齢、健康状態、体重、症状の程度、同時処置があるならばその種類、処置頻度、所望の効果の性質、あるいは投与経路や投与計画などによって異なるが、一般には、非経口投与で0.01-20mg/kg・日、経口投与で0.02-40mg/kg・日が挙げられる。
【0016】
【発明の実施の形態】
以下に実施例及び参考例を挙げ、この発明をさらに具体的に説明するが、本発明はこれらに限定されるものではない。
【0017】
【実施例1】
AKR/N系雌性マウス(donor)を麻酔、開胸し、下行大静脈から氷冷した心筋保護液を投与した。下行大静脈、左右肺動静脈、左右上行大静脈、左総頚動脈を結さつし、心臓を摘出した。C3H/He系雌系マウス(recipient)を麻酔し、頚部を切開した。recipientの頚動脈とdonorの心臓の湾頭動脈をカフを介して繋いだ。recipientの頚静脈とdonor心臓の主肺動脈をカフを介して繋いだ。
【0018】
移植4週間後、マウスを麻酔し、心臓を10%ホルマリン溶液で灌流固定した。心臓の病理標本を作成し、HE染色およびMasson's trichrome染色を行い、冠動脈の閉塞率を画像解析により測定した。
被験液(一般式(I)式中R1は水素原子)は生理食塩液に溶解し、10mg/kg/dayの割合で、移植前日より4週間経口投与した。被験液(一般式(I)式中R1は水酸基)は、生理食塩液に溶解し、移植前日より4週間1日2回、5mg/kgの用量で、腹腔内に投与した。
【0019】
さらに、被験薬と免疫抑制剤との併用による効果を検討した。被験液(一般式(I)式中R1は水素原子)は、10mg/kg/dayの割合で、移植前日より4週間経口投与した。サイクロスポリンを10mg/kg/dayの割合で、移植後より4週間1日1回腹腔内投与した。
その結果を表1に示す。
【0020】
【表1】
一般式(I)(式中R1は水素原子および水酸基)は、マウス心臓移植後の冠動脈内腔狭窄を改善した。
【0021】
サイクロスポリンは、マウス心臓移植後の冠動脈内腔狭窄を改善しなかった。一般式(I)(式中R1は水素原子)による、マウス心臓移植後の冠動脈内腔狭窄改善作用を、サイクロスポリンは増強した。
【0022】
【実施例2】
本発明の化合物の急性毒性試験を、ラット(Jcl:Wistar,5週齢)およびマウス(Slc:ddY,5週齢)を用いて実施した結果、低毒性であることが確認された。
その結果を表2に示す。
【0023】
【表2】
【0024】
【実施例3】
製剤例(無菌注射剤)
下記表3の成分を注射用蒸留水に溶解し、その後、注射用蒸留水を添加し、必要な最終重量とし、この溶液2mlをアンプルに密封し、加熱滅菌した。
【0025】
【表3】
【0026】
【実施例4】
製剤例(錠剤)
下記表4の成分を含む錠剤を常法により調整した。
【0027】
【表4】
【0028】
【発明の効果】
本発明によれば、移植による血管病変の発生抑制剤が提供できる。[0001]
[Industrial application fields]
The present invention relates to an agent for suppressing the occurrence of vascular lesions caused by transplantation.
[0002]
[Prior art]
The transplant includes organ transplants such as heart, kidney, liver, lung, small intestine, pancreas, and tissue transplants such as skin and blood vessels. The occurrence of vascular lesions is a major clinical problem after transplantation (Modern Pathology, Vol. 6, p194-209, edited by Souichi Iijima et al., Nakayama Shoten).
For example, heart transplantation has been established as the only and most effective treatment left in the treatment of patients with end-stage heart failure. The survival rate after heart transplantation is about 50% in 10 years. One serious cause of death is transplanted coronary artery lesions. Transplanted coronary artery lesions are coronary stenosis that develops and progresses months to years after transplantation. This is a diffuse lesion centering on the small and medium arteries and causes chronic ischemia of the transplanted heart. Since the transplanted heart is a denervated heart, it does not show symptoms such as angina pectoris, and because the lesion is diffuse, coronary artery bypass surgery and coronary angioplasty are often ineffective. In addition, progress prevention by administration of immunosuppressants and the like has been studied, but satisfactory results have not been obtained. Currently, there is no specific treatment, and lifesaving can only be reimplanted (Heart View, Vol. 4, 1999, p55-99).
[0003]
On the other hand, the compound represented by the general formula (I) has kinase inhibitory activities such as Rho kinase, myosin light chain phosphorylase, protein kinase C, vascular smooth muscle relaxing action, blood flow increasing action, blood pressure reducing action, brain It is already known that it is a substance that exhibits cardioprotective action and the like and is effective in vasodilators (especially angina pectoris), brain, cardioprotective agents and the like (for example, JP-A-61-152658). JP-A-61-227581, JP-A-2-256617, JP-A-4-264030, JP-A-6-056686, JP-A-6-080569, JP-A-7-80854, WO 98/06433, WO 00/03746, Br. J. Pharmacol., 98, 1091 (1989), J. Pharmacol. Exp. Ther., 259, 738 (1991), Circulation, 96, 4357 (1997), Cardiovasc. Res ., 43, 1029 (1999))
[0004]
[Problems to be solved by the invention]
Conventionally, it has been desired to provide a new medicine that can be expected to suppress the occurrence of vascular lesions by transplantation.
[0005]
[Means for Solving the Problems]
As a result of extensive research on the inhibitory effect on the occurrence of vascular lesions caused by such transplantation, the inventors have surprisingly found that the compound represented by the following general formula (I) or an acid addition salt or hydrate thereof: Has been found to be effective in suppressing the occurrence of vascular lesions caused by transplantation, and the present invention has been completed.
That is, the present invention provides the following general formula (I)
[0006]
[Chemical 2]
[0007]
(Wherein R1 represents a hydrogen atom or a hydroxyl group) or an acid addition salt or hydrate thereof as an active ingredient.
The compound represented by the general formula (I) or an acid addition salt or hydrate thereof is known as described above, and has effects such as vascular smooth muscle relaxing action, blood flow increasing action, blood pressure lowering action, brain, cardioprotective action and the like. It is known to show. However, it has not been known so far that a compound represented by the general formula (I) or an acid addition salt or hydrate thereof suppresses the occurrence of vascular lesions caused by transplantation.
[0008]
In addition, since the mechanism of action that suppresses the occurrence of vascular lesions due to transplantation is generally considered to be different from the mechanism of action such as vascular smooth muscle relaxation, brain, and cardioprotection, the compound represented by general formula (I) or its It could not be foreseen that acid addition salts or hydrates would suppress rejection. An organ or tissue targeted by the present invention is not an original organ or tissue of a recipient (human transplanted), but an organ or tissue transplanted from a donor (organ or tissue provider). It is different from diseases in tissues.
[0009]
Further, even in the case of organ or tissue transplantation between the same individuals, it is a disorder under an environment that is separated from the original position and different from the original physiological state, and is different from a normal disease. For example, for the occurrence of transplanted coronary artery lesions, immunosuppressive drugs, as well as the control of hyperlipidemia used for the treatment of angina and arteriosclerosis, the use of vasodilators, etc. Satisfactory results have not been obtained. The only effective treatment is re-heart transplantation. From this, it can be seen that even if the immune response is simply suppressed, the occurrence of vascular lesions is not suppressed, and the lesions are different from those of the original vascular lesions such as angina pectoris and arteriosclerosis. . The compound represented by the general formula (I) or an acid addition salt or hydrate thereof suppresses the occurrence of vascular lesions due to transplantation. The vascular lesion means arteriosclerosis, vascular thickening, vascular stenosis, vascular occlusion and the like.
[0010]
The compound represented by the general formula (I) of the present invention is described in a known method such as Chem. Pharam. Bull., 40, (3) 770-773 (1992), JP-A 61-152658. Can be synthesized according to the methods described. The acid addition salt is preferably a pharmaceutically acceptable non-toxic salt, for example, an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and acetic acid, citric acid, tartaric acid, lactic acid, succinic acid, Mention may be made of organic acid salts such as fumaric acid, maleic acid and methanesulfonic acid.
[0011]
In preparing the vascular lesion development inhibitor by transplantation of the present invention as a preparation suitable for administration, the compound represented by the above general formula (I) or an acid addition salt or hydrate thereof, A known pharmaceutically acceptable carrier may be mixed. Examples of the carrier include gelatin; sugars such as lactose and glucose; starches such as wheat, rice and corn starch; fatty acids such as stearic acid; fatty acid salts such as calcium stearate and magnesium stearate; talc; vegetable oil; stearic alcohol And alcohol such as benzyl alcohol; gum; polyalkylene glycol and the like.
[0012]
Examples of the liquid carrier generally include water, physiological saline, dextrose or a similar sugar solution, and glycols such as ethylene glycol, propylene glycol, polyethylene glycol, and polypropylene glycol. When preparing capsules, it is usually preferable to prepare capsules using gelatin.
In the agent for suppressing the occurrence of vascular lesions by transplantation according to the present invention comprising the above carrier and the compound represented by the general formula (I) or an acid addition salt or hydrate thereof, usually 0.01% by weight or more, and 80% by weight. % Or less, preferably 60% by weight or less of the active ingredient is included.
[0013]
Examples of the administration method include oral administration and parenteral administration. Examples of dosage forms suitable for oral administration include tablets, capsules, powders, granules, liquids, elixirs, and the like, and dosage forms suitable for parenteral administration include liquids.
When administered parenterally by intramuscular injection, intravenous injection, or subcutaneous injection, sodium chloride, glucose or the like is used to make the compound represented by the general formula (I) or an acid addition salt or hydrate thereof isotonic. It is administered as a sterile solution with the addition of other solutes.
[0014]
When administering by injection, it is also preferable to dissolve in sterile water, lidocaine hydrochloride solution (for intramuscular injection), physiological saline, glucose, intravenous injection solution, electrolyte solution (for intravenous injection) and the like. When dissolved in this manner, it may be adjusted so as to contain an active ingredient of usually 0.01% by weight or more and 20% by weight or less, preferably 0.1% by weight or more and 10% by weight or less. In the case of a solution for oral administration, a preferred example is a suspension or syrup containing 0.01 to 20% by weight of the active ingredient. Examples of the carrier in this case include aqueous excipients such as fragrances, syrups, and pharmaceutical micelles.
[0015]
The dose of the vascular lesion development inhibitor by transplantation of the present invention is the age, health status, body weight, degree of symptom of the recipient, type of treatment if simultaneous treatment, frequency of treatment, nature of desired effect, or Generally, 0.01-20 mg / kg / day for parenteral administration and 0.02-40 mg / kg / day for oral administration are mentioned, although it varies depending on the administration route and administration schedule.
[0016]
DETAILED DESCRIPTION OF THE INVENTION
EXAMPLES The present invention will be described more specifically with reference to examples and reference examples below, but the present invention is not limited thereto.
[0017]
[Example 1]
An AKR / N female mouse (donor) was anesthetized and thoracotomized, and an ice-cold myocardial protective solution was administered from the descending vena cava. The descending vena cava, left and right pulmonary arteriovenous, left and right ascending vena cava, and the left common carotid artery were connected, and the heart was removed. C3H / He female mice (recipient) were anesthetized and the neck was incised. The recipient's carotid artery and donor's heart gulf artery were connected via a cuff. The recipient's jugular vein and the main pulmonary artery of the donor heart were connected via a cuff.
[0018]
Four weeks after transplantation, the mice were anesthetized and the heart was fixed by perfusion with 10% formalin solution. A pathological specimen of the heart was prepared, HE staining and Masson's trichrome staining were performed, and the occlusion rate of the coronary artery was measured by image analysis.
The test solution (R1 in formula (I) is a hydrogen atom) was dissolved in physiological saline and orally administered at a rate of 10 mg / kg / day for 4 weeks from the day before transplantation. The test solution (R1 in formula (I) is a hydroxyl group) was dissolved in physiological saline and administered intraperitoneally at a dose of 5 mg / kg twice a day for 4 weeks from the day before transplantation.
[0019]
Furthermore, the effect of the combined use of the test drug and the immunosuppressant was examined. The test solution (R1 in formula (I) is a hydrogen atom) was orally administered at a rate of 10 mg / kg / day for 4 weeks from the day before transplantation. Cyclosporine was intraperitoneally administered once a day for 4 weeks after transplantation at a rate of 10 mg / kg / day.
The results are shown in Table 1.
[0020]
[Table 1]
General formula (I) (wherein R1 is a hydrogen atom and a hydroxyl group) improved coronary lumen stenosis after mouse heart transplantation.
[0021]
Cyclosporine did not improve coronary lumen stenosis after mouse heart transplantation. Cyclosporine enhanced the effect of improving coronary artery lumen stenosis after mouse heart transplantation by general formula (I) (wherein R1 is a hydrogen atom).
[0022]
[Example 2]
An acute toxicity test of the compound of the present invention was carried out using rats (Jcl: Wistar, 5 weeks old) and mice (Slc: ddY, 5 weeks old), and as a result, it was confirmed that the compounds had low toxicity.
The results are shown in Table 2.
[0023]
[Table 2]
[0024]
[Example 3]
Formulation example (sterile injection)
The components in Table 3 below were dissolved in distilled water for injection, and then distilled water for injection was added to the required final weight, and 2 ml of this solution was sealed in an ampoule and sterilized by heating.
[0025]
[Table 3]
[0026]
[Example 4]
Formulation example (tablet)
Tablets containing the components shown in Table 4 below were prepared by a conventional method.
[0027]
[Table 4]
[0028]
【The invention's effect】
According to the present invention, an agent for suppressing the occurrence of vascular lesions caused by transplantation can be provided.
Claims (6)
Priority Applications (1)
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JP2000322141A JP4582561B2 (en) | 2000-10-23 | 2000-10-23 | Inhibitor of vascular lesions caused by transplantation |
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JP2000322141A JP4582561B2 (en) | 2000-10-23 | 2000-10-23 | Inhibitor of vascular lesions caused by transplantation |
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JP2002128676A JP2002128676A (en) | 2002-05-09 |
JP4582561B2 true JP4582561B2 (en) | 2010-11-17 |
Family
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JP2000322141A Expired - Lifetime JP4582561B2 (en) | 2000-10-23 | 2000-10-23 | Inhibitor of vascular lesions caused by transplantation |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61227581A (en) * | 1985-04-02 | 1986-10-09 | Asahi Chem Ind Co Ltd | Isoquinoline derivative bearing sulfone group |
JPH0656668A (en) * | 1992-08-10 | 1994-03-01 | Asahi Chem Ind Co Ltd | Heart-protecting agent |
WO1998006433A1 (en) * | 1996-08-12 | 1998-02-19 | Yoshitomi Pharmaceutical Industries, Ltd. | MEDICINES COMPRISING Rho KINASE INHIBITOR |
WO2000064477A1 (en) * | 1999-04-22 | 2000-11-02 | Mitsubishi Pharma Corporation | Preventives/remedies for angiostenosis |
-
2000
- 2000-10-23 JP JP2000322141A patent/JP4582561B2/en not_active Expired - Lifetime
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61227581A (en) * | 1985-04-02 | 1986-10-09 | Asahi Chem Ind Co Ltd | Isoquinoline derivative bearing sulfone group |
JPH0656668A (en) * | 1992-08-10 | 1994-03-01 | Asahi Chem Ind Co Ltd | Heart-protecting agent |
WO1998006433A1 (en) * | 1996-08-12 | 1998-02-19 | Yoshitomi Pharmaceutical Industries, Ltd. | MEDICINES COMPRISING Rho KINASE INHIBITOR |
WO2000064477A1 (en) * | 1999-04-22 | 2000-11-02 | Mitsubishi Pharma Corporation | Preventives/remedies for angiostenosis |
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