JP4832051B2 - Treatment for crescent-forming kidney lesions - Google Patents

Treatment for crescent-forming kidney lesions Download PDF

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JP4832051B2
JP4832051B2 JP2005307018A JP2005307018A JP4832051B2 JP 4832051 B2 JP4832051 B2 JP 4832051B2 JP 2005307018 A JP2005307018 A JP 2005307018A JP 2005307018 A JP2005307018 A JP 2005307018A JP 4832051 B2 JP4832051 B2 JP 4832051B2
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fasudil
glomerular
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輝夫 日高
祐介 鈴木
倫史 山下
康日己 富野
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Juntendo University
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Description

本発明は、腎糸球体の半月体形成性腎病変治療剤に関するものである。   The present invention relates to a therapeutic agent for renal glomerular crescent-forming kidney lesions.

半月体形成性腎病変とは、糸球体疾患の結果、増殖したボーマン嚢上皮細胞がボーマン腔の一部または全部を満たし、半月体様になる病変である。この病態は、急速進行性糸球体腎炎、抗糸球体基底膜抗体型腎炎(グッドパスチャー症候群)、IgA腎症時などに認められる非常に重篤な病態であり、糸球体の炎症性病変の中でも極めて高度な病変であることが知られている。そして、この病態を抑制することは、急速かつ重篤な糸球体障害の伸展を抑制する可能性が高いことから、半月体形成性腎病変の進行を抑制する薬剤が求められている。しかしながら、かかる病変を十分に治療するものは知られていない。   A crescent-forming renal lesion is a lesion in which Bowman's sac epithelial cells that have proliferated as a result of glomerular disease fill part or all of the Bowman's cavity and become crescent-like. This condition is a very serious condition observed in rapidly progressive glomerulonephritis, anti-glomerular basement membrane antibody-type nephritis (Goodpasture syndrome), IgA nephropathy, etc. Among inflammatory lesions of the glomerulus It is known to be an extremely advanced lesion. And since suppression of this disease state has a high possibility of suppressing rapid and severe glomerular damage, there is a need for a drug that suppresses the progression of crescent-forming renal lesions. However, there is no known one that sufficiently treats such lesions.

一方、ファスジル(fasudil)は、Rhoキナーゼ阻害作用などのキナーゼ阻害活性を有し、くも膜下出血術後の脳血管れん縮や、これに伴う脳虚血症状の改善に有用であることが知られており、また、腎間質繊維化を抑制する効果があることが知られている(特許文献1〜3)。しかしながら、ファスジルと半月体形成性腎病変との関係については、一切知られていない。
国際公開98/06433号パンフレット 国際公開01/074391号パンフレット 特開2002−226375号公報
Fasudil, on the other hand, has kinase inhibitory activity such as Rho kinase inhibitory activity, and is known to be useful for cerebral vasospasm after subarachnoid hemorrhage and associated cerebral ischemic symptoms. Moreover, it is known that there is an effect of suppressing renal interstitial fibrosis (Patent Documents 1 to 3). However, nothing is known about the relationship between fasudil and crescent-forming renal lesions.
International Publication No. 98/06433 Pamphlet International Publication No. 01/074391 Pamphlet JP 2002-226375 A

したがって、本発明は、糸球体の半月体形成性腎病変治療剤を提供することを目的とする。   Accordingly, an object of the present invention is to provide a therapeutic agent for glomerular meniscus-forming kidney lesions.

かかる事情のもと、本発明者らは、鋭意検討したところ、意外なことにも、ファスジル、その塩又はそれらの溶媒和物が、糸球体の半月体形成性腎病変の出現を抑制することを見出し、本発明を完成した。   Under such circumstances, the present inventors have intensively studied, and surprisingly, fasudil, a salt thereof, or a solvate thereof suppresses the appearance of glomerular meniscal kidney lesions. The present invention has been completed.

すなわち、本発明は、ファスジル、その塩又はそれらの溶媒和物を有効成分とする糸球体の半月体形成性腎病変治療剤を提供するものである。   That is, the present invention provides a therapeutic agent for glomerular crescent-forming renal lesions containing fasudil, a salt thereof or a solvate thereof as an active ingredient.

本発明者らが見出したように、ファスジル、その塩又はそれらの溶媒和物は、糸球体の半月体形成性腎病変の出現を抑制するから、これを含む本発明の治療剤は、慢性糸球体腎炎における半月体形成性腎病変の抑制に有用である。また、ファスジルは、臨床において、くも膜下出血罹患後の脳血管れん縮の予防に使用されており、安全性も確認されているものであるから、本発明の半月体形成性腎病変治療剤は、安全性に優れたものである。また、ファスジルの半月体形成性腎病変の抑制は、糸球体上皮細胞の保護作用によっていることから、糸球体上皮細胞障害を有する他の腎炎の病変にも有効である。   As found by the present inventors, fasudil, a salt thereof, or a solvate thereof suppresses the appearance of glomerular meniscus-forming kidney lesions. It is useful for suppressing crescent-forming kidney lesions in spherical nephritis. In addition, since fasudil is clinically used for the prevention of cerebral vasospasm after suffering from subarachnoid hemorrhage, and has been confirmed to be safe, the therapeutic agent for crescent-forming renal lesions of the present invention is , It is excellent in safety. In addition, since fasudil suppresses crescent-forming renal lesions by the protective action of glomerular epithelial cells, it is also effective for other nephritic lesions having glomerular epithelial cell damage.

本発明において用いられるファスジルは、以下の式(1)で表される。   Fasudil used in the present invention is represented by the following formula (1).

ファスジルの塩としては、薬学上許容される非毒性の塩であればよく、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、このうち、塩酸塩が好ましい。また、ファスジル又はその塩は、水和物に代表される溶媒和物の形態であってもよい。本発明で用いられるファスジル、その塩又はそれらの溶媒和物は、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。   The salt of fasudil may be any pharmaceutically acceptable non-toxic salt, for example, inorganic acids 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 salts of organic acids such as fumaric acid, maleic acid and methanesulfonic acid, among which hydrochloride is preferred. Further, fasudil or a salt thereof may be in the form of a solvate represented by a hydrate. Fasudil, a salt thereof, or a solvate thereof used in the present invention may be obtained by a known method, for example, Chem. Pharam. Bull., 40, (3) 770-773 (1992), Japanese Patent Application Laid-Open No. 61-152658. Can be synthesized according to the method described in the above.

後記実施例に示すとおり、ファスジル、その塩又はそれらの溶媒和物は、糸球体の半月体形成性腎病変に対して治療効果を示すものであるから、これを有効量含有するものは、糸球体の半月体形成性腎病変治療剤として用いることができる。より詳細には、半月体形成性腎病変を主病変とする急速進行性糸球体腎炎、抗糸球体基底膜抗体型腎炎(グッドパスチャー症候群)の治療に有効である。また、ファスジルの半月体形成性腎病変の抑制は、糸球体上皮細胞の保護作用によっていることから、糸球体上皮細胞障害を有する他の腎炎の病変にも有効である。さらに、糸球体形成性腎病変における蛋白尿、血尿の抑制、硬化性病変にも有効である。   As shown in the examples below, fasudil, a salt thereof, or a solvate thereof has a therapeutic effect on glomerular meniscus-forming kidney lesions. It can be used as a therapeutic agent for spherical crescent-forming renal lesions. More specifically, it is effective for the treatment of rapidly progressive glomerulonephritis and anti-glomerular basement membrane antibody nephritis (Goodpascher's syndrome) whose main lesions are crescent-forming kidney lesions. In addition, since fasudil suppresses crescent-forming renal lesions by the protective action of glomerular epithelial cells, it is also effective for other nephritic lesions having glomerular epithelial cell damage. Furthermore, it is also effective for suppression of proteinuria and hematuria in glomerular kidney lesions and sclerotic lesions.

本発明におけるファスジル、その塩又はそれらの溶媒和物は、そのままあるいは慣用の製剤担体と共に動物又は人に投与して糸球体の半月体形成性腎病変治療剤として用いることができ、投与形態としては特に限定がなく、必要に応じて適宜選択して使用される。例えば、生理食塩水等に溶解して注射剤の形態にして静脈、動脈、皮下、筋肉内等に投与することができる。またファスジル、その塩又はそれらの溶媒和物は、カオリン、タルク、乳酸、デンプン、結晶セルロースなどの担体と混合し、錠剤、散剤、顆粒剤、カプセル剤等の経口投与剤として投与することもできる。投与量は、ファスジル、その塩又はそれらの溶媒和物として成人あたり20mg〜500mgであり、これを1日1回ないし数回に分けて投与するのが好ましい。   Fasudil, a salt thereof, or a solvate thereof according to the present invention can be used as a therapeutic agent for glomerular meniscus-forming kidney lesions as it is or by being administered to an animal or a human together with a conventional pharmaceutical carrier. There is no limitation in particular and it selects and uses suitably as needed. For example, it can be dissolved in physiological saline or the like and administered into veins, arteries, subcutaneous, intramuscular or the like in the form of injections. Fasudil, a salt thereof, or a solvate thereof can be mixed with a carrier such as kaolin, talc, lactic acid, starch, crystalline cellulose, and administered as an oral administration agent such as a tablet, powder, granule, capsule or the like. . The dosage is 20 mg to 500 mg per adult as fasudil, a salt thereof or a solvate thereof, and it is preferable to administer this once a day or several times a day.

以下に実施例を示し、本発明をさらに詳しく説明するが、本発明はこれら実施例に制限されるものではない。   EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

実施例1 腎炎動物の作製
異種性抗基底膜抗体を感作させることにより、馬杉腎炎と呼ばれる腎炎を発症した実験腎炎動物を作製することができることが知られている。通常、野生型マウスにおいて馬杉腎炎を発症させた場合、急性期に発現するFcR(免疫グロブリンのFc(定常部)に接合する受容体)依存的な多型核白血球の浸潤と、FcR非依存的でアンギオテンシンII依存性の腎炎が混在し、病態が複雑になるという問題がある。一方、FcR欠失マウスにマスギ腎炎を惹起させると、アンギオテンシンII依存性のメサンギウム増殖性糸球体腎炎のみが特異的に誘導されることが知られている(Suzuki Y et.al Kidney Int 1998; 54: 1166)。本実施例においては、FcR欠失マウス(FcRKO)に対して馬杉腎炎を発症させた。
具体的には、以下のように行った。すなわち、20-25週令のFcRKOマウスに対して異種性免疫グロブリン0.25mg/20g(約一匹のマウス体重あたり)静注することによって5日前に前感作を行い、0日目に異種性抗基底膜抗体血清200μlを静注した。
14日間の経過を観察し、その間、体重、血圧、蛋白尿、潜血について検査した。そして、14日目に屠殺し、血清、腎組織を採取した。
その経過中、蛋白尿、血尿を観察した。
また、その腎組織をパラフィンで固定した検体に対して、抗WT-1抗体を使用して免疫組織化学染色を行ったところ、WT-1陽性細胞である糸球体上皮細胞の減少が観察された。糸球体上皮細胞は、糸球体の中での血液濾過に必要な糸球体基底膜の産生や形態学的な濾過構造の維持などに大きな役割を担っている細胞である。
さらに、抗BrdU抗体を使用して免疫組織化学染色を行ったところ、BrdU陽性細胞の増加が観察された。このことは、糸球体既存細胞と糸球体浸潤白血球(主にマクロファージ)が増殖していることを意味し、炎症反応に伴う増殖性変化が起こっていることを示す。
また、これら腎組織中の糸球体においては、半月体形成性腎病変、硬化性病変が観察された。硬化性病変とは、炎症の進行に伴って糸球体が線維化し器質化する、糸球体の末期病変である。
以上のように、半月体形成性糸球体腎炎を発症したマウスを作製することができた。
Example 1 Production of Nephritic Animal It is known that an experimental nephritic animal that has developed nephritis called Masugi nephritis can be produced by sensitizing a heterologous anti-basement membrane antibody. In general, when Masugi nephritis develops in wild-type mice, FcR (receptor conjugated to immunoglobulin Fc (constant region))-dependent polymorphonuclear leukocyte infiltration in the acute phase and FcR-independent However, there is a problem that angiotensin II-dependent nephritis is mixed and the pathological condition becomes complicated. On the other hand, it is known that when masagi nephritis is induced in FcR-deficient mice, only angiotensin II-dependent mesangial proliferative glomerulonephritis is specifically induced (Suzuki Y et.al Kidney Int 1998; 54 : 1166). In this example, Masugi nephritis was developed in FcR-deficient mice (FcRKO).
Specifically, it was performed as follows. In other words, 20-25 weeks old FcRKO mice were presensitized 5 days ago by injecting heterologous immunoglobulin 0.25mg / 20g (per body weight of one mouse), and heterogeneous on day 0. 200 μl of anti-basement membrane antibody serum was intravenously injected.
The course of 14 days was observed, during which body weight, blood pressure, proteinuria, and occult blood were examined. On the 14th day, the mice were sacrificed, and serum and kidney tissues were collected.
During the course, proteinuria and hematuria were observed.
In addition, when immunohistochemical staining was performed on a specimen in which the kidney tissue was fixed with paraffin using an anti-WT-1 antibody, a decrease in glomerular epithelial cells, which are WT-1 positive cells, was observed. . Glomerular epithelial cells are cells that play a major role in the production of glomerular basement membrane necessary for blood filtration in the glomeruli and the maintenance of the morphological filtration structure.
Furthermore, when immunohistochemical staining was performed using an anti-BrdU antibody, an increase in BrdU positive cells was observed. This means that glomerular preexisting cells and glomerularly infiltrating leukocytes (mainly macrophages) are proliferating, indicating that a proliferative change accompanying an inflammatory reaction has occurred.
Moreover, in the glomeruli in these kidney tissues, crescent-forming kidney lesions and sclerotic lesions were observed. A sclerotic lesion is a glomerular end-stage lesion in which the glomerulus becomes fibrotic and organized as inflammation progresses.
As described above, it was possible to produce a mouse that developed crescent-forming glomerulonephritis.

実施例2 ファスジル投与による糸球体病変の抑制
ファスジル投与による影響を検討した。すなわち、20-25週令のFcRKOマウスに対して異種性免疫グロブリン0.25mg/20g(約一匹のマウス体重あたり)静注することによって5日前に前感作を行い、4日前からファスジル(比較対照群は生理食塩水)を10mg/Kg/dayにて腹腔内投与を開始した(連日)。0日目に異種性抗基底膜抗体血清200μlを静注し、馬杉腎炎を発症させた。比較対照群としては、ファスジルの代わりに生理食塩水を使用した群を用いた。
14日間の経過を観察し、その間、体重、血圧、蛋白尿、潜血について検査した。そして、14日目に屠殺し、血清、腎組織を採取した。
その結果、ファスジル投与群においては、ファスジル非投与群に比して、蛋白尿の抑制(p<0.01;図2)、血尿の抑制(p<0.01;図3)、糸球体に占める糸球体上皮細胞数の減少の抑制(p<0.05)、糸球体に占めるBrdU陽性細胞細胞の減少(p<0.3)、硬化性病変の出現の抑制(p<0.01;図4)が認められた。
さらに、PAS(Periodic acid Schiff)染色した組織を用いて切片中に含まれる単位面積あたりの半月体を示す糸球体病変の数を計測した。切片のパラフィン固定PAS染色による写真を図1に示す。その結果、ファスジル非投与群においては、腎組織切片あたりの全糸球体のうち半月体形成性腎病変を呈していたのは10.6%であったのに対し、ファスジル投与群においては、0.4%であった(図5)。このことから、ファスジルを投与することによって、糸球体における半月体形成性腎病変の出現を抑制することができることが明らかになった。
Example 2 Inhibition of glomerular lesions by fasudil administration The effect of fasudil administration was examined. In other words, 20-25 weeks old FcRKO mice were presensitized 5 days ago by intravenous injection of xenogeneic immunoglobulin 0.25mg / 20g (about 1 mouse body weight). In the control group, physiological saline was administered intraperitoneally at 10 mg / Kg / day (every day). On day 0, 200 μl of heterologous anti-basement membrane antibody serum was intravenously injected to develop Masugi nephritis. As a comparative control group, a group using physiological saline instead of fasudil was used.
The course of 14 days was observed, during which body weight, blood pressure, proteinuria, and occult blood were examined. On the 14th day, the mice were sacrificed, and serum and kidney tissues were collected.
As a result, in the fasudil-administered group, proteinuria suppression (p <0.01; FIG. 2), hematuria suppression (p <0.01; FIG. 3), and glomerular epithelium occupying the glomeruli, compared with the fasudil non-administration group. Suppression of cell number reduction (p <0.05), reduction of BrdU positive cell cells in glomeruli (p <0.3), and suppression of appearance of sclerotic lesions (p <0.01; FIG. 4) were observed.
Furthermore, the number of glomerular lesions showing the meniscus per unit area contained in the section was counted using a tissue stained with PAS (Periodic acid Schiff). A photograph of the section by PAS staining with paraffin is shown in FIG. As a result, in the fasudil non-administered group, 10.6% of all glomeruli per kidney tissue section had a crescent-forming kidney lesion, compared with 0.4% in the fasudil-administered group. (FIG. 5). From this, it became clear that administration of fasudil can suppress the appearance of a meniscus-forming renal lesion in the glomerulus.

馬杉腎炎発症マウスの14日目の腎組織切片のPAS染色像を示した図である。It is the figure which showed the PAS dyeing | staining image of the kidney tissue section | slice of the 14th day of a mouse | mouth cedar nephritis developing mouse. 馬杉腎炎発症マウスの尿中の蛋白量の推移を、ファスジル投与群(fasudil)及びファスジル非投与群(control)について示したグラフである。It is the graph which showed transition of the protein amount in the urine of the masugine nephritis crisis mouse | mouth about a fasudil administration group (fasudil) and a fasudil non-administration group (control). 馬杉腎炎発症マウスの尿潜血の半定量化と推移を、ファスジル投与群(fasudil)及びファスジル非投与群(control)について示したグラフである。It is the graph which showed the semi-quantification and transition of urine occult blood of Masugi nephritis crisis mouse about the fasudil administration group (fasudil) and the fasudil non-administration group (control). 馬杉腎炎発症マウスの14日目の硬化性病変の全糸球体における平均数を、ファスジル投与群(fasudil)とファスジル非投与群(control)について示したグラフである。It is the graph which showed the average number in the whole glomerulus of the sclerotic lesion | pathology of the 14th day of a masugine nephritis onset mouse | mouth about a fasudil administration group (fasudil) and a non-fasudil administration group (control). マスギ腎炎発症マウスの14日目の半月体形成性腎病変の全糸球体における平均数を、ファスジル投与群(fasudil)とファスジル非投与群(control)について示したグラフである。It is the graph which showed the average number in the whole glomerulus of the meniscus formation renal lesion of the 14th day of a cedar nephritis onset mouse | mouth about a fasudil administration group (fasudil) and a fasudil non-administration group (control).

Claims (2)

ファスジル、その塩又はそれらの溶媒和物を有効成分とする糸球体の半月体形成性腎病変治療剤。   A therapeutic agent for glomerular crescent-forming kidney lesions comprising fasudil, a salt thereof or a solvate thereof as an active ingredient. 糸球体の半月体形成性腎病変が、糸球体の半月体形成性腎病変を主病変とする急速進行性糸球体腎炎又は抗糸球体基底膜抗体型腎炎(グッドパスチャー症候群)である請求項1記載の治療剤。   The glomerular meniscus-forming renal lesion is rapidly progressive glomerulonephritis or anti-glomerular basement membrane antibody-type nephritis (Goodpascher's syndrome) whose main lesion is a glomerular meniscal kidney lesion. The therapeutic agent described.
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