JP2008063328A - Curative agent for glomerular disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition effective for preventing or treating glomerular diseases, particularly progressive chronic glomerular diseases such as IgA nephropathy, focal glomerulosclerosis, membranous nephropathy, membranoproliferative nephritis, diabetic nephropathy or nephrotic syndrome, through solving such problems that, it has been considered as a critical problem in particular in the progression of nephropathy that, in the glomerular sites in progressive naphropathy, mesangium cell proliferation and mesangium substrate proliferation are seen, and such disorder sites often reach not only glomeruri but also the uriniferous tubules and/or interstitial tissue regions therearound. <P>SOLUTION: The pharmaceutical composition as a prophylactic or curative agent for glomerular diseases comprises pyridoxamine or a salt thereof and dilazep or a salt thereof. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a drug useful for the prevention or treatment of glomerular diseases, particularly progressive chronic glomerular diseases.

  At present, it is said that there are more than 20 million diabetic patients, suspected diabetic patients and pre-diabetes group in Japan. Among complications caused by diabetes, the incidence of diabetic nephropathy has been increasing year by year, already exceeding the incidence of chronic glomerulonephritis.

  The biggest problem when diabetic nephropathy develops is that end-stage renal failure, that is, the rate of transition to dialysis is very high.

  In not only diabetic nephropathy but also chronic glomerulonephritis, the shift to dialysis due to the progress of the pathological condition has become a serious social problem such as an increase in medical costs. Therefore, an inhibitor or a preventive agent related to the development of diabetic nephropathy and chronic glomerulonephritis is strongly desired.

  In the glomerular site of these progressive renal disorders, mesangial cell proliferation and mesangial matrix growth are seen as a particularly serious problem in the progression of the disorder. Furthermore, the damaged part often extends not only to the glomerulus but also to the surrounding tubules and interstitial regions.

In recent years, attention has been focused on the involvement of advanced glycation end products (AGE) as an impairment factor of diabetic nephropathy (Non-patent Document 1). AGE is supposed to be produced mainly by the reaction between sugar and protein, that is, Maillard reaction.
In clinical practice, a large amount of AGE is detected in the plasma of renal dialysis patients not caused by diabetes, and many new AGE generation systems not derived from hyperglycemia have been reported (Non-patent Document 2).

  AGE is known to adversely affect many renal functions such as renal circulation dynamics and glomerular basement membrane filtration mechanism. Furthermore, it is also known that AGE acts on AGE-related receptors (for example, Receptor for AGE: RAGE) that are present in a large number of renal constituent cells such as mesangial cells to produce a disorder factor such as cytokine / growth factor. Yes.

  Therefore, suppression of AGE production is thought to lead to suppression of progression of progressive renal injury, and development of drugs from that aspect is also underway. Among them, pyridoxamine (2-methyl-3-hydroxy-4-aminomethyl-5-hydroxymethylpyridine) and a salt thereof, which is one of vitamin B6, inhibit the AGE formation process and inhibit the production of AGE. It has been reported that it is effective for diabetic nephropathy by suppressing (Patent Document 1).

On the other hand, in diabetic nephropathy and chronic glomerulonephritis, as the disease progresses, not only the systemic blood pressure increases but also the number of nephrons decreases. As a result, the load on the remaining nephron due to the whole body blood pressure increases, and an increase in glomerular capillary internal pressure is induced. As a result, vascular endothelial cells are mechanically damaged, platelet aggregation is induced in the capillaries, and the glomerular degradation progresses. Thus, the number of nephrons is further reduced, the load on the remaining nephrons is further increased, and a vicious circle is formed. In addition, vascular endothelial cell damage changes the permeability of glomerular snare wall (Charge barrier, Size barrier failure), which originally impairs glomerular snare wall that filters and separates other than protein components from plasma. The protein component is also filtered. The protein thus filtered adversely affects various renal constituent organs, including the proximal tubule, the first passage organ after filtration.
Dirazep hydrochloride, which is widely used as a therapeutic agent for IgA nephropathy among chronic glomerulonephritis, has an antiplatelet action and is suggested to have an action to prevent the breakdown of the basement membrane charge barrier in the glomerular snare wall. (Non-patent Document 3).

However, neither pyridoxamine nor dilazep alone has shown a sufficient effect on progressive kidney disease, and the development of a new drug exhibiting an even better effect is eagerly desired.
WO97 / 09981 pamphlet Am. J. et al. Pathol. 164 (4): 1389-97, 2004. Diabetes Res. Clin. Pract. 61 (3): 145-153, 2003. Am. J. et al. Physiol. , 249: F324, 1985

  An object of the present invention is to provide a pharmaceutical composition effective for the prevention or treatment of glomerular diseases, particularly progressive chronic glomerular diseases. Here, prevention and treatment also mean suppression or improvement of the progression of the disease.

  As a result of intensive studies in view of such circumstances, the present inventors have used pyridoxamine dihydrochloride, which is an AGE production inhibitor, and dilazep hydrochloride, which is an antiplatelet agent, as compared with the case where it is used alone. The present invention has been completed by showing that it has an inhibitory effect on the progression of renal diseases, and that the combined use of these agents is useful as a preventive or therapeutic agent for progressive chronic glomerular disease.

  That is, the present invention provides a prophylactic or therapeutic agent for glomerular diseases containing pyridoxamine or a salt thereof and dilazep or a salt thereof.

  The present invention also provides a method for preventing or treating glomerular diseases, which comprises administering an effective amount of pyridoxamine or a salt thereof and dilazep or a salt thereof.

  Furthermore, the present invention provides use of pyridoxamine or a salt thereof and dilazep or a salt thereof for producing a prophylactic or therapeutic agent for glomerular diseases.

  The prophylactic or therapeutic agent for glomerular disease of the present invention is used for glomerular diseases such as IgA nephropathy, focal glomerulosclerosis, membranous nephropathy, membranoproliferative nephritis, diabetic nephropathy and nephrotic syndrome, especially progression. It is useful as a preventive or therapeutic agent for sexual chronic glomerular kidney disease.

  Pyridoxamine (2-methyl-3-hydroxy-4-aminomethyl-5-hydroxymethylpyridine) or a salt thereof used in the present invention is vitamin B6 having an AGE production inhibitory action. Examples of the salt include acid addition salts such as hydrochloride, nitrate, sulfate, phosphate, oxalate, maleate, succinate, and methanesulfonate, with phosphate and hydrochloride being preferred. Hydrochloride is particularly preferred.

Dirazep or a salt thereof used in the present invention suppresses the antiproteinuria effect by suppressing the decrease in negative charge of the charge base of the glomerular basement membrane, and further suppresses the platelet adhesion ability and the aggregation ability enhanced by the progress of renal injury. In addition, it has an action of improving renal function by inhibiting platelet phospholipase activity and inhibiting platelet release reaction, and can be obtained and used as a medicine (Comerian ^R Kowa Tablet 50, etc.). Examples of the salt include acid addition salts such as hydrochloride, nitrate, sulfate, phosphate, oxalate, maleate, succinate and methanesulfonate, and hydrochloride is preferred.

  Further, pyridoxamine or a salt thereof and dilazep or a salt thereof include a hydrate and a solvate with a pharmaceutically acceptable solvent.

  The agent for preventing or treating glomerular diseases of the present invention can be made into pharmaceutical preparations of various dosage forms according to the usage. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections and the like.

  These preparations include excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers used in pharmacology depending on the dosage form. It can be mixed with a pharmaceutical additive such as a dispersant, a stabilizer, a solubilizing agent, etc., appropriately mixed, diluted or dissolved, and manufactured according to a conventional method.

  For example, in the case of powders, in addition to the essential components, an appropriate excipient, lubricant and the like may be added and mixed as necessary. In the case of a tablet, it may be prepared by adding an appropriate excipient, disintegrant, binder, lubricant, etc. as necessary, and tableting according to a conventional method. Tablets can be coated as necessary to form film-coated tablets, sugar-coated tablets, and the like.

  In the case of an injection, it can be in the form of a solution (sterile water or non-aqueous solution), an emulsion and a suspension. Examples of the non-aqueous carrier, diluent, solvent, or vehicle used for these include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic acid esters such as ethyl oleate. In addition, auxiliary agents such as preservatives, wetting agents, emulsifying agents, and dispersing agents can be appropriately blended in the composition.

  The dose of the agent for preventing or treating glomerular disease of the present invention is appropriately determined depending on the body weight, age, sex, degree of disease, etc. of the patient. As a preferable dose, in the case of oral administration, pyridoxamine or a salt thereof is 50 to 2000 mg per day for an adult, and dirazep or a salt thereof is 100 to 300 mg per day for an adult. Oral administration is preferably administered 3 times a day. The proportion of pyridoxamine or a salt thereof and dilazep or a salt thereof is not particularly limited as long as the doses of both drugs are within the above ranges. Oral administration is preferably administered once or divided into several times a day. Both drugs may be combined together and administered orally or parenterally in one dosage form, or may be administered orally or parenterally in separate dosage forms. When both drugs are administered in separate dosage forms, they can be administered in the same or different dosage forms at the same time, or can be administered with a time difference.

As described in the Examples, puromycin aminonucleoside (PAN) -loaded rats were used as renal disease models, and PAN was administered intravenously at a dose of 50 mg / kg (body weight) at the age of 9 weeks of age. Administration was started, and in the evaluation by repeated administration for 7 days, the combined administration of pyridoxamine dihydrochloride and dilazep hydrochloride of the present invention gave superior results as compared with each single administration. That is, the combined administration group showed a stronger inhibitory effect on the urinary albumin excretion amount, which is one of the major surrogate markers in renal disorders, as compared to the respective single administration groups. This rat has been shown to exhibit high proteinuria among progressive renal injury models (Eup. J. Pharmacol. 236: 337-338, 1993), clinically similar to nephrotic syndrome. It is one of the severe models that present symptoms. In such a severe model, the fact that a strong inhibitory effect on urinary albumin excretion was observed by the combined use of pyridoxamine dihydrochloride and dilazep hydrochloride was useful as a clinically useful utility. It is thought that it is an experimental result.
Therefore, pyridoxamine or a salt thereof and dilazep or a salt thereof used in the present invention are used for glomeruli such as IgA nephropathy, focal glomerulosclerosis, membranous nephropathy, membranoproliferative nephritis, diabetic nephropathy and nephrotic syndrome. It is useful as a preventive or therapeutic agent for diseases, particularly progressive chronic glomerular kidney disease.

  The combination of the present invention prevents the progression of chronic glomerulonephropathy such as IgA nephropathy, focal glomerulosclerosis, membranous nephropathy and membranous proliferative nephritis, including type 1 and type 2 diabetic nephropathy Or it is useful as a therapeutic agent.

  Hereinafter, the present invention will be described in more detail with reference to examples. The present invention is not limited to these examples.

Example 1 Effect on PAN Rat Male Wistar rat (9 weeks old) was fixed with a rat retention device under anesthesia, and 50 mg of PAN (manufactured by Sigma) dissolved in physiological saline from the tail vein. A single dose of / kg was administered to develop renal damage. Immediately after PAN administration, administration of each drug was started according to the group composition shown below, and repeated administration for 7 days was performed. That is, a control group (non-drug administration group, distilled water twice a day, oral administration: N = 8), pyridoxamine dihydrochloride administration group (1 g / L drinking treatment with shading: N = 8), dilazep hydrochloride administration Group (25 mg / kg intraperitoneal administration, twice daily administration: N = 8) and pyridoxamine dihydrochloride (1 g / L drinking treatment under shading) and dilazep hydrochloride (25 mg / kg intraperitoneal administration twice daily) And a total of 4 groups (N = 8).
Pyridoxamine dihydrochloride was dissolved in purified water and allowed to drink freely by rats. Dilazep hydrochloride was dissolved in physiological saline and administered by intraperitoneal administration.
Seven days after the start of administration, urine was collected for 18 hours using a metabolic cage, the urinary albumin concentration was measured by immunoturbidimetry (model name: DCA2000, manufactured by Bayer Medical Co., Ltd.), and urine was obtained from the obtained urine volume. Middle albumin excretion was calculated.

  FIG. 1 shows the effects of pyridoxamine dihydrochloride single administration, dilazep hydrochloride single administration and combination administration thereof on urinary albumin excretion. Compared with the control group (non-drug-administered group), the group administered pyridoxamine dihydrochloride and dilazep hydrochloride together showed a strong inhibitory effect on urinary albumin excretion, compared with the control group. And were found to be statistically significant. As a result, it was experimentally confirmed that the combined use of pyridoxamine dihydrochloride and dilazep hydrochloride strongly inhibits progressive kidney injury.

It is a figure which shows the amount of urinary albumin excretion in a puromycin amino nucleoside (PAN) load renal disorder rat.

Claims (2)

  A prophylactic or therapeutic agent for glomerular disease comprising pyridoxamine or a salt thereof and dilazep or a salt thereof.   The agent for preventing or treating glomerular disease according to claim 1, wherein the glomerular disease is IgA nephropathy, focal glomerulosclerosis, membranous nephropathy, membranoproliferative nephritis, diabetic nephropathy, or nephrotic syndrome. .

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