JPS6253922A - Preventive and remedy for nephritis - Google Patents

Abstract

PURPOSE:To provide a preventive and remedy for nephritis, composed of a fat emulsion containing PGE1 or its derivative, capable of significantly suppressing the deposition of fibrin to glomerulus and the production of ascites and useful as a causal treatment agent for nephritis. CONSTITUTION:PGE1 or its derivative is added to a fat emulsion composed mainly of e.g. 5-50W/V% soybean oil, 1-50pts. of phospholipid (based on 100pts. of soybean oil) and a proper amount of water, and the produced PGE1 fat emulsion is used as a preventive and remedy for nephritis. The PGE1 fat emulsion is effective to nephritis, especially to prevent the prolongation, cicatrization and hyalinization of disease including the fibrin deposition to glomerulus. The deposition of fibrin to glomerulus plays an important role on the prolongation of nephritis, and according the agent is effective for the prevention of chronic nephritis. Dose: about 0.1-10mug/kg of PGE1 or its derivative per dose and 1-2 doses daily.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention provides prostaglandin E1 (hereinafter referred to as PGE).
The present invention relates to a nephritis preventive/therapeutic agent comprising a fat emulsion containing a derivative thereof, particularly an agent for preventing fibrin deposition in the glomerulus.

[Prior art]

Nephritis refers to a kidney disease that exhibits symptoms such as edema, oliguria, hematuria, and increased blood pressure, and the &Il structure shows signs of degeneration, inflammation, arteriosclerosis, etc. Factors that cause nephritis include blood VI aggregation, fibrin precipitation, and advanced glomerular basement membrane permeability.

Treatment methods for nephritis include non-steroidal anti-inflammatory drugs, steroids, immunosuppressants, hemostatic agents, anticoagulants, and gamma globulin therapy, but none of them has been clearly positioned as a causal therapy.

PGE is known to have effects on the synaptic transmission mechanism of the central nervous system, cardiac inotropy, vasodilation, and blood pressure lowering effects.

[Problem that the invention seeks to solve]

An object of the present invention is to utilize PCB as a therapeutic agent for the cause of nephritis.

[Means for solving problems]

The present inventors have conducted various studies from this point of view and have found that, based on the results of experimental nephritis in animals, PGE emulsified in fat emulsions and fat emulsions are effective against nephritis when administered to patients with nephritis. The present invention has been made based on the discovery that the present invention can be expected to have a remarkable preventive and therapeutic effect on the glomerular nephropathy, especially the chronicity of glomerular nephropathy including the deposition of fibrin in the glomerulus, scarring, and hyalinization. completed.

The present invention relates to a nephritis preventive/therapeutic agent comprising a PGEr fat emulsion, particularly an agent for preventing fibrin deposition in the glomerulus.

The PGE and fat emulsion used in the present invention are obtained by converting PGE, PGEI or PGEI derivative, which is the main component of the preparation, into a fat emulsion.

The PGEI derivative may be any PGEI derivative as long as it has PGE activity and is soluble in a fat emulsion. Suitably used.

In the present invention, the fat emulsion is, for example, 5 to 50% soybean oil.
(W/V), 1 to 5 phospholipids per 100 parts of soybean oil
0 parts, preferably 5 to 30 parts, and an appropriate amount of water. In addition, if necessary, an emulsification adjuvant [for example, up to 0.3% (W/V) of a fatty acid having 6 to 22 carbon atoms, preferably 12 to 20 carbon atoms, or a physiologically acceptable salt thereof; etc.], stabilizer [e.g. 0.5% (W/
V), preferably in an amount of up to 0.1% (W/V) or 5% (W/V), preferably 1% (
phosphatidic acid, etc.], polymeric substances [e.g., 0.1 to 5 parts by weight, preferably 0.5 to 1 part by weight, albumin, dextran per 1 part by weight of PGEI or PGEI derivative]; , vinyl polymers, nonionic surfactants, gelatin, hydroxyethyl starch, etc.], tonicity agents (e.g., glycerin, glucose, etc.)
etc. can also be added. The content of PGEI and its derivatives in a fat emulsion can be increased or decreased as appropriate depending on the form of the emulsion and its use, but in general, the emulsion contains a trace amount of
For example, it is sufficient to contain 100 to 0.2 pg/@l.

The fat emulsion of the present invention is prepared, for example, by the following method.

namely, soybean oil, phospholipids, and PGE in predetermined amounts.

(derivatives thereof) and other additives mentioned above,
A water-in-oil dispersion is prepared by heating to form a solution and homogenizing it using a commonly used homogenizer (for example, a pressure injection homogenizer, an ultrasonic homogenizer, etc.), and then adding the required amount of water to this. In addition, it can be produced by homogenizing again using the homogenizer to convert it into an oil-in-water emulsion. Depending on the manufacturing convenience, additives such as stabilizers and tonicity agents may be added after the production of the fat emulsion.

The fat emulsion of the present invention is administered intravenously or kinetically.

More preferred is intravenous administration.

The dosage is PGEI or its y,
It is best to administer about 0.1 to 10 pf/kIr body weight once or twice a day, but the dose can be increased as appropriate depending on the symptoms. Administration is preferably carried out continuously for 5 to 10 days.

The timing of administration is preferably within several days after the onset of nephritis.

Targets for administration are patients with nephritis, such as patients with acute nephritis, chronic nephritis, and nephrotic syndrome.

[Action/Effect]

Administration of a fat emulsion containing PGE or its derivative to animals with experimental nephritis significantly prevented fibrin deposition in the glomeruli and suppressed the production of ascites.

Therefore, the fat emulsion containing PGE or its derivative of the present invention can be expected to be highly useful as a therapeutic agent for nephritis patients.

[Experiment example/Example]

Experimental examples, manufacturing examples, and clinical examples of the fat emulsion of the present invention are shown below, but the present invention is not limited thereto.

Experimental Example 1 LD5. The values were 200 m1/kg body weight or more for a 10% fat emulsion, and 150 m1/kg body weight or more for a 20% fat emulsion, and no hemolysis was observed when instilled at a normal rate.

Experimental Example 2 1. Method for producing rabbit anti-rat glomerular basement membrane antibody Rat kidney (
The glomerular basement membrane was purified from glomerular basement membrane (200 cells), and then treated with complete Freund's adjuvant (co++plete Freund'5).
An emulsion was prepared with an adjuvant) and immunization needles were administered to four rabbits, first in the paw region and then every other week in the back region.

On the 7th day of the final immunization, whole blood was collected, and after separating the serum, the presence of antibodies against the rat glomerular basement membrane in the serum was confirmed by indirect fluorescent antibody using frozen sections of the kidney. In addition, we intravenously injected this serum into rats, and confirmed that severe glomerulonephritis (Masugi nephritis) caused by anti-basement membrane antibodies occurred in rats with approximately the same titer of serum from four domestic rabbits. Feather rabbit antisera were pooled, dispensed into 5 cc portions, and stored frozen (-20°C). In addition, in order to examine the appropriate amount of antiserum for the onset of Umasugi nephritis, 1 ml of antiserum, 0.5 ml, and 0.1 ml were each diluted with physiological saline so that the dosage was 1), and 3 rats were administered to each group. The drug was administered intravenously through the Jakkatsu vein.

In the 1 ml administration group, severe pulmonary and renal hemorrhage occurred, and the patient died within 30 minutes of administration. 0.5ml, 0.1
The o+1 administration group developed severe hematuria and proteinuria, but no deaths were observed during the one-week observation period.

Based on the above experiment, it was decided to administer antiserum 0.501) containing a rabbit anti-rat glomerular basement membrane antibody in the following experiment.

2. Effect of PGE and fat emulsion on Masugi nephritis PGE,
The fat emulsion was administered at the same time as 0.5 ml of the antiserum, and readministered the next day.

The dosage of PGE and fat emulsion was 1+ml(5q), 0.
The volume was 1 ml (0.5q), and physiological saline was used as a control drug. Note that there were 6 animals in each group.

One week later, the amount of protein in the urine was measured, and the average for each group was 200.
~400 mg, and also exhibited nephrotic symptoms.

Two weeks later, ascites was observed in all the animals in the physiological saline administration group, but ascites was not observed in most of the animals in the PGF, 1-fat emulsion 5Pg, o, sq administration group. Two weeks later, unilateral nephrectomy was performed, and the patient was examined using light microscopy and fluorescent antibody techniques.

Findings by fluorescent antibody method showed that rabbit and rough) IgG
Strong linear deposits along the glomerular loop were observed in all cases. In line with this, a slight amount of rat C3 deposition was also observed. Regarding rat fibrin, very strong deposition was observed throughout the gold glomeruli in all animals in the physiological saline administration group, but no fibrin deposition was observed in most of the glomeruli in the 5H and 0.5 pg administration groups.

Regarding clinical symptoms, no significant difference was observed in urine protein, but a therapeutic effect was observed in ascites.

Regarding glomerular lesions, light microscopic findings revealed crescent formation in the glomeruli, chronic glomerular basement membrane thickening, occlusion of the capillary lumen, and slight proliferation in the group administered only with anti-glomerular basement membrane antibodies.

On the other hand, in the PGEI fat emulsion administration group, although diffuse thickening of the glomerular basement membrane was observed, crescent formation and capillary lumen occlusion were slight, and almost no proliferation of glomerular cells was observed.

On the other hand, regarding changes in the renal interstitium, degeneration of renal tubules, round cell infiltration into the renal interstitium, and nitrified casts within the renal tubular lumen were observed in many rat kidneys in the group administered only with antiglomerular antibody. Although the above-mentioned changes were observed in the fat emulsion administration group, they were generally minor compared to the untreated group.

Although no significant difference was observed in the deposition of IgG (rabbit and rough) using the fluorescent antibody method, it was confirmed that the method had the effect of significantly reducing fibrin deposition. Fibrin deposition plays an important role in the chronicity of nephritis, and the ability of this substance to reduce the deposition of deposited substances can be said to be a finding suggesting that PGE and fat emulsions are effective in preventing chronic nephritis.

Example 1 30g of refined soybean oil, 3.6g of egg yolk lecithin, PGE19
00q, 0.15 g of sodium palmitate, and 0.15 g of phosphatidic acid were added and dissolved by heating at 40 to 75°C. Add 200a+1 of distilled water to this, then add 7.5g of glycerin in the Japanese Pharmacopoeia,
The total volume was made up to 300 ml with distilled water for injection at ℃, and coarse emulsification was performed using a homomixer.

Using a Manton-Gallin type homogenizer,
Stage 120kg/c+J, total pressure 500kg/c+J
It was emulsified by passing it 10 times under the pressure of . As a result, a homogenized extremely fine fat emulsion containing PGE1 was obtained. The average grain size of this emulsion is 0.2 to 0.4μ,
It did not contain particles larger than 1μ.

Continuation of the hand (1 post by Hosei) October 9, 1985

Claims (2)

[Claims] (1) A prophylactic/therapeutic agent for nephritis comprising a fat emulsion containing prostaglandin E_1 or its derivative. (2) The nephritis preventive/therapeutic agent according to claim (1), wherein the nephritis preventive/therapeutic agent is an agent for preventing fibrin deposition in the glomerulus.