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

Description

  The present invention relates to a therapeutic agent for renal glomerular crescent-forming kidney lesions.

  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.

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

  Accordingly, an object of the present invention is to provide a therapeutic agent for glomerular meniscus-forming kidney lesions.

  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.

  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.

  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.

  Fasudil used in the present invention is represented by the following formula (1).

  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.

  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.

  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.

  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.

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.

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.

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. 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). 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). 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). 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)

  A therapeutic agent for glomerular crescent-forming kidney lesions comprising fasudil, a salt thereof or a solvate thereof as an active ingredient.   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.