JPH0262891A - Improver for albuminuria - Google Patents

Abstract

PURPOSE:To obtain the subject improver, containing 2'-deoxycoformycin as an active ingredient and capable of suppressing transudation of blood serum protein into urine. CONSTITUTION:A microorganism belonging to the genus Aspergillus, Streptomyces or Emericella is cultured and 2'-deoxycoformycin is then obtained from the resultant culture. For example, in use as an injection, a pH adjuster, buffering agent, stabilizer, etc., are added to the 2'-deoxycoformycin to afford the objective improver. Furthermore, the daily dose of the 2'-deoxycoformycin is preferably 1-50mg for an adult.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to an agent for improving proteinuria found in nephrotic syndrome.

[Conventional technology]

Nephrotic syndrome is a general term for a syndrome whose basic conditions include proteinuria and hypoproteinemia (also known as hypoalbuminemia) caused by high-level protein leakage, as well as accompanying edema and hyperlipidemia. be.

Proteinuria seen in nephrotic syndrome is caused by increased protein permeability in the renal glomerular capillaries.

It is caused by large amounts of serum proteins leaking into the urine. Although the mechanism of advanced protein permeability in the renal glomerulus has not been elucidated in detail, the pores of the glomerular basement membrane (Par
e) Molecular sieves (Molecular s
It is believed that this is due to an abnormality in the glomerular basement membrane (ieving) and a weakening of the negative charge on the glomerular basement membrane.

As an experimental model for the leakage of serum proteins into the urine in nephrotic syndrome, puromycin aminonucleoside was administered to rats.
Experimental nephrosis (also referred to as PAN nephrosis) created by administering aminonucleoside (abbreviated as PAN) is used. Recently, some new findings regarding the leakage of serum proteins into the urine in this model have been reported.

That is, Wood et al.
amole) suppressed the leakage of serum proteins into the urine in experimental nephrosis (J, Tox
icol, Sci, 4, 1 (1979))
, J.R. Diamond et al. also reported that allopurinol and superoxide dismutase suppressed the urinary leakage of serum proteins in experimental nephrosis.
e), indicating that active oxygen produced by xanthine oxidase plays an important role in serum protein leakage in experimental nephrosis (Kidney Int, 29.478
(1986)). Furthermore, as a result of investigating the distribution of xanthine oxidase and guanase in the kidney, Endo et al.
It is predicted that purine metabolism in AN is dominated by the adenosine-5'-monophosphate, adenosine, and inosine pathways, and this prediction is based on the aforementioned allopurinol (xanthine oxidase inhibitor), superoxide dismutase, and dipridamole (adenosine potency inhibitor). (M. et al.) reported that it is consistent with suppressing serum protein leakage in experimental nephrosis (M. et al.).
Olecular Nephrology Bioche
Mical Aspects of KidneyFu
tion, 347-352 (1987)).

[Problem to be solved by the invention]

As mentioned above, dipyridamole, allopurinol, and superoxide dismutase have been reported as drugs that inhibit the leakage of serum and proteins into the urine in experimental nephrosis. cannot be completely suppressed,
It did not necessarily have a satisfactory effect.

Therefore, an object of the present invention is to provide a drug that can completely suppress the leakage of serum proteins into the urine that occurs in nephrotic syndrome.

[Means to solve the problem]

As a result of repeated research to discover a compound that can suppress the leakage of serum proteins into the urine in experimental nephrosis, the present inventors discovered 2'-deoxycoformycin (2'-deoxycoformycin, hereafter DC).
It is abbreviated as F. ) was found to completely suppress the leakage of serum proteins into the urine.

DCF is a strong adenosine deaminase inhibitor (adenosine potentiator) discovered in 1976 in a culture of a microorganism belonging to the genus Streptomyces.
It is a known compound with activity. However, it was not known at all whether CF has the activity of suppressing the leakage of serum proteins into the urine.

That is, the present invention relates to a proteinuria improving agent containing DCF as an active ingredient.

Note that the term "proteinuria improving agent" as used herein is a general term for both prophylactic and therapeutic agents for proteinuria.

Hereinafter, the drug of the present invention will be explained in detail.

DCF, which is the active ingredient of the drug of the present invention, can be prepared by a known method. Namely, Aspergillus spp.
DCF may be collected from the culture by culturing microorganisms belonging to the genus Emericella or Streptomyces (
For details, see Japanese Patent Publication No. 53-44559, etc.).

The dose of DCF depends on the patient's severity, tolerance to the drug,
The dosage varies depending on the route of administration, etc., and cannot be definitively limited, and the final decision should be made by the doctor's judgment, but the usual dosage for adults is 1.11 g to 50 mg per day, either once or in divided doses. It can be administered by

The administration method can be any method suitable for the administration route, such as oral administration or parenteral administration such as injection administration, and various formulations can be prepared depending on the administration route.

For example, when preparing a composition formulation for injection administration, 1
If necessary, a pH adjuster, a buffer, a stabilizer, a preservative, a solubilizing agent, etc. are added to DCF, which is the active ingredient of the drug of the present invention, and a subcutaneous, intramuscular, or intravenous injection is prepared by a conventional method.

The acute toxicity of DCF is >100/- (intravenous administration in mice) (The Journal of Antibiotics).
biotics.

18.1008-1015 (1985)).

Hereinafter, the present invention will be specifically explained by showing formulation examples and DCF test examples.

〔Example〕

Example 1 Injection DCF 1g Mannitol 5g Total amount
After dissolving 6g in water using the usual method, 10ml
Aseptically divide the solution into 1 aliquot into 2 ampoules and lyophilize.

Contains DCFIO■ in one ampoule. When used, when physiological saline solution 5- is dissolved in each ampoule, 1 ml of injection solution 1-
Contains 2■ DCF in Q.

Test Example 1 (Preventive effect of DCF on the onset of PAN nephrosis) Five male SD rats (150 to 180 g) were each treated with PA
Group receiving only N (100 μg/kg subcutaneous injection once) (target drug administration group), DCF 6 hours before administration of PAN
A group in which 5■/kg was intraperitoneally administered once (single administration group);
A group in which DCFI/kg was administered intraperitoneally 6 hours before administration of PAN, and then the same amount of DCF was administered 4 times daily (
The subjects were divided into four groups: a continuous administration group) and a group receiving only physiological saline (control group).

Each rat was placed in a metabolic cage capable of collecting urine, and protein in the urine was quantified by the trichloroacetic acid-Lory method (TCA-Lo%iry method).

Figure 1 shows the changes in urinary protein. As is clear from FIG. 1, DCF completely suppressed the leakage of serum proteins into the urine in PAN nephrosis.

Test Example 2 (Treatment effect of DCF on PAN nephrosis) Five male SD rats (150-180 g) were each treated with PAN.
A group in which 100 μ/kg was subcutaneously injected once (target drug administration group) and a group in which DCF 5 μ/kg was administered intraperitoneally once on the 7th day after PAN administration (single administration group) Whitening and 7 days after PAN administration After the first day, take 1 dose of DCF in your daily diet for 5 days.
The mice were divided into 3 groups: 1/kg intraperitoneally administered group (continuous administration group).

Each rat was placed in a metabolic gauge, urine was collected in the same manner as in Test Example 1, and the amount of protein in the urine was determined.

The results are shown in FIG. As is clear from Figure 2, D
Administration of CF significantly reduced leakage of serum proteins into the urine.

〔Effect of the invention〕

As is clear from the above test examples, the drug of the present invention can prevent (prevent) and suppress the leakage of serum proteins into the urine, thereby reducing proteinuria and hypoproteinemia seen in nephrotic syndrome. It is useful for improvement.

Previously, it has been reported that dipyridamole, which has adenosine potentiator activity similar to DCF, suppresses the leakage of serum proteins into the urine, but the degree of suppression is not as good as that of DCF, and the present invention This provided the first useful drug.

[Brief explanation of the drawing]

FIG. 1 shows the effect of DCF on preventing the onset of PAN nephrosis. FIG. 2 shows the therapeutic effect of DCF on PAN nephrosis. Fue 2/fJ Patent applicant Tsuyoshi Takahashi

Claims (1)

[Claims] 1) Proteinuria improving agent containing 2'-deoxycoformycin as an active ingredient.