Method for treating autoimmune diseases

FIELD: medicine.

SUBSTANCE: it is suggested to apply tris-(2-hydroxyethyl)ammonium salt of 1-benzylindolyl-3-thioacetic acid earlier known as a stabilizer of cell membrane as preparation to treat autoimmune diseases. The property of the above-mentioned salt to inhibit T-dependent activation of B-lymphocytes, under conditions of decreased medullary function and body leukopenia should enable to develop new pharmacological preparation for treating autoimmune diseases, such as, for example, systemic lupus, rheumatoid polyarthritis, transplant's detachment at transplanting either organs or bony marrow.

EFFECT: higher efficiency of application.

4 ex, 3 tbl

 

The invention relates to new biologically active agents in their class arylheteroalkanecarboxylic acids and can be used in pharmacology and medicine as the basis for the creation of a medicinal product for the treatment of autoimmune diseases (ulcerative colitis, rheumatoid arthritis, lupus erythematosus, lupus nephritis, chronic hepatitis and others), as well as for the prevention and treatment of graft rejection in organ transplants to suppress the reaction of graft-versus-host had a bone marrow transplant.

Modern immunopharmacology pays close attention to the development of new products, which can effectively reduce symptoms of autoimmune reactions (underlying the pathogenesis of common diseases), since the range of such drugs is very limited.

Currently in practical medicine for the prevention of transplant rejection in transplantation of kidney, heart and other organs, as well as certain autoimmune diseases, used the drug Azathioprine with antitumor and immunosuppressive properties (1). This drug has some serious side effects (inhibits bone marrow function, causing leukopenia and agranulocytosis, which requires Eugene is good monitoring of the peripheral blood; induces the development of toxic hepatitis and allergic reactions, etc).

With the aim of expanding Arsenal of synthetic drugs that suppress the expression of immune responses, it is proposed to use Tris(2-hydroxyethyl)ammonium salt 1-benzimidazolyl-3-teoksessa acid as a new drug for the treatment of autoimmune diseases and to prevent the development of the reaction of transplant rejection in the transplantation of various organs in the recipient.

Derivatives alkenylboronic acids have diverse biological effects. In particular, Tris(2-hydroxyethyl)ammonium salt 1-benzimidazolyl-3-teoksessa acid has properties stabilize cell membranes (“Clinical efficacy and safety of cephalosporin antibiotics produced by LLC “abled”. Sat. works NIIKI, agmu and ICD. Novosibirsk, 2002. - Str; www. abolmed.ru/pages/article33.htm). Know the use of certain drugs, containing salt alkenylboronic acids, as local anti-inflammatory and/or analgesic means (2, 3).

The invention consists in the fact that were investigated immunomodulatory properties of Tris-(2-hydroxyethyl)ammonium salt 1-benzimidazolyl-3-teoksessa acid by the ability of this compound to affect the amount of protein in the urine of the mouse is with immune complex glomerulonephritis, the amount of antibody productive cells (IgM AFC) in vivo (primary humoral immune response).

In this work, we used healthy adult female mice - hybrids (C57BL/6×DBA/2)F1 (B6D2F1)mice hybrids (CBA×C57Bl/6)F1 female mice of the DBA/2, weighing 18-20 g, from nursery ("the Dawn", Tomsk). Before and during the experiment control and experimental animals were kept in a vivarium under the same conditions: standard plastic cages with fine wood shavings (not more than 10 individuals) on a standard diet. All studies were conducted at the same time of day (in the morning).

A model of immune complex glomerulonephritis (autoimmune disease) caused in female B6D2F1 dwukrotnie with a one week interval by the intravenous injection of lymphoid cells from the female parent line DBA/2. The protein content in the urine was determined calorimetrically with dye Kumsai brilliant blue (Loba Feinchemie) Titertec Multiscan, wavelength λ 570 nm. In the experiments used mice with persistent proteinuria and protein content of 3 mg/ml or more (protein in the urine was determined by repeatedly) (4).

The obtained data were analyzed by nonparametric criterion U Wilcoxon-Mann-Whitney.

Example 1. The effect of compounds at a dose of 300 mg/kg at the level of protein in the urine.

In mice with stable proteinuria over 2 months and protein in the urine from 3.0 to 6.5 mg/ml carried out kurso the first introduction of the connection. The course was 5 daily intraperitoneal injection at a dose of 300 mg/kg, 5 days after the last injection of the compounds was measured proteinuria. Found that in 83% of cases (5 mice 6 mice used in the experiment) there is a decrease in proteinuria to 10; 18,5; 30,8; 45,2, and 55.6%, one mouse virtually no effect. The average for the group before the treatment proteinuria was 5.1 mg/ml after treatment with 3.6 mg/ml, which was significantly lower (P<0.05)and the decrease in the group averaged 32.0 per cent.

Example 2. The effect of compounds at a dose of 5 mg/kg at the level of protein in the urine.

Connection at a dose of 5 mg/kg was administered to mice per os daily (once a day), the rate amounted to 10 injections. Similarly and in the same dose (5 mg/kg) to mice injected with a drug comparison of azathioprine. Measurement of proteinuria was performed one day after the last drug injection. Table 1 presents data on the effect of intragastric administration of the compounds at a dose of 5 mg/kg on the amount of protein in urine compared with azathioprine.

td align="center"> Protein in the urine after treatment

(mg/ml)
Table 1.
AzathioprineConnection
Protein in the urine before treatment

(mg/ml)
Protein in the urine after treatment

(mg/ml)
% inhibitionProtein in the urine before treatment

(mg/ml)
% inhibition
5,95,21211,24,858
9,513,6-438,96,428
6,56,6of-1.55,98,1-37
14,65,2646,55,614
7,6the 10.1- 338,13,063

As can be seen from table 1, under the influence of azathioprine reducing protein content in the urine was observed only in 2 of 5 mice (i.e. in 40% of cases), while the connection induced a decrease in proteinuria in 4 of 5 mice (i.e. in 80% of cases). In other words, an investigational compound that is used in a dose of 5 mg/kg, was twice as effective compared to known drug azathioprine. The average percent inhibition for compounds amounted to 41%.

Example 3. The effect of compounds at a dose of 10 mg/kg on the level of protein in the urine.

Connection at a dose of 10 mg/kg was administered to mice per os daily (once a day). The course was 10 introductions. Similarly injected drug comparison azathioprine (at a dose of 10 mg/kg). Measurement of proteinuria conducted che is ez day after the last drug injection.

Table 2 presents data on the effect of intragastric administration of the compounds at a dose of 10 mg/kg on the content of protein in the urine compared with azathioprine.

Table 2.
AzathioprineConnection
Protein in the urine before treatment (mg/ml)Protein in the urine after treatment (mg/ml)% inhibitionProtein in the urine before treatment (mg/ml)Protein in the urine after treatment

(mg/ml)
% inhibition
2,70,7843,01,860
1,95,6-2904.05,0-25
3.91,8542,41,921
4,63,524a 3.92,731
4,12,1492,31.057
a 3.91,562   

As can be seen from table 2, under the influence of azathioprine in 5 out of 6 mice (83%) saw a decrease of proteinuria (average with irenie was 55%). Under the influence of the connection from 4 mice of 5 (80% of cases) there is a decrease in proteinuria (average reduction of 42%).

After analyzing the data it can be concluded that the connection used in doses of 5 and 10 mg/kg in 80% of cases leads to a decrease of protein in the urine. The connection is used in smaller doses (5 and 10 mg/kg) is more effective than high dose (300 mg/kg). Doses of 5 and 10 mg/kg reduced proteinuria by 41% and 42%, respectively, whereas the dose of 300 mg/kg of 32%. In General, the data obtained suggest that the connection used in the dose of 5 and 10 mg/kg in efficiency is not inferior widely used in clinical practice the drug azathioprine (5 mg/kg is more effective than 2 times). However, when comparing compounds and of azathioprine on the parameters of toxicity may be noted that the connection (LD50=500 mg/kg) twenty times less toxic compared with azathioprine (LD50=25 mg/kg). According to the literature azathioprine already at a dose of 10 mg/kg inhibits the function of bone marrow, causes leukopenia and agranulocytosis (1).

We used a murine model of glomerulonephritis, immunological substrate, triggering a cascade of disturbances in the kidney, is a T-dependent polyclonal activation of b-cells, accompanied by increased synthesis of anti-DNA antibodies, formation of immune complexes, which leads to the system immunolo the complex inflammatory process in the kidneys the nephritis and proteinuria. This type of kidney damage compare morphologically and functionally with severe human disease - systemic lupus erythematosus (5). Confirmation of the immunomodulating effect of the connection, i.e. its ability to suppress T-dependent activation of b-cells, are the data presented in example 4.

Example 4. The effect of compounds on the synthesis of IgM antibodies in vivo by activation of b-cells by T-dependent antigen sheep erythrocytes.

Animals were immunized intravenously with sheep erythrocytes (EB) at a dose of 0.5×107/mouse. From the day of immunization was administered the compound intraperitoneally or per os daily for 4 days, once a day) at a dose of 5 and 10 mg/kg Number of IgM AFC in the spleen of mice was evaluated 4 days after immunization by the number of local hemolysis in semi-solid medium by the modified method of Cunningham (1968). The results were expressed in absolute number of IgM AFC in the spleen. Data on the effect of compounds on the number of antibody productive cells (AFC) are presented in table 3.

Table 3.
GroupThe number of AFC/ spleen
The method of introduction connections
IntragastricIntraperitoneally
Control 4023 (n=15)6227 (n=12)
Compound dose: 5 mg/kg

10 mg/kg
730* (n=16)

585* (n=15)
1129* (n=14)

752* (n=15)

* significantly, P<0,05; n - number of animals

As can be seen from table 3, the connection, regardless of the method of administration, in large decreases in the spleen, the number of IgM antibody productive cells, i.e. effectively suppresses T-dependent activation of b-lymphocytes.

Thus, our studies suggest that Tris(2-hydroxyethyl)ammonium salt 1-benzimidazolyl-3-teoksessa acid, with a strong ability to inhibit T-dependent activation of b-lymphocytes (i.e. to inhibit the main pathogenetic link of the mechanism of formation and development of the autoimmune process, for example, glomerulonephritis), is perspektivnym chemical compound to create new drugs for the effective treatment of autoimmune diseases.

Literature

1. Mashkovsky PPM //Medicines.-2001.-S-200.

2. Patent of great Britain No. 2093693.

3. U.S. patent No. 4551475.

4. Kimura M., Gleichmann E. Depressed antibody responses to exogenous antigens in mice with lupus-like graft-versus-host diseases. //Clin. Immunol. and Immunopathol.-1987.-V.43.-N.1.-P.97-109.

5. Appleby P., Webber D.G., Bowen J.G. Murine chronic graft-versus-host disease as a model of systemic lupus lupus.: Effect of immunosuppressive drugs on disease development.//Clin. and Exp. Immunol.-199.-V.78.-N3.-P.449-453.

The use of Tris(2-hydroxyethyl)ammonium salt 1-benzimidazolyl-3-teoksessa acid as a treatment for autoimmune diseases.



 

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