Vaccine against hypertension

FIELD: medicine.

SUBSTANCE: vaccine is high molecular weight protein conjugate with angiotensine II taken in high molecular weight protein : angiotensine II proportion of 1:12-55 in % by weight. The conjugate is modified with equilibrium quantity of immunocompetent polyelectrolyte like polyoxydonium.

EFFECT: stable physiological response within prolonged period of 6-12 months.

3 tbl

 

The invention relates to medicine, in particular to pharmacology, and can be used in the treatment of hypertension and prevention of hypertensive crises.

Known antihypertensive agents affecting the renin - angiotensin system is the main regulator of the volume of extracellular fluid and blood pressure. This system is a cascade interconnected enzymatic reactions that result in the synthesis of multifunctional peptide angiotensin II causes increase in blood pressure, vasoconstriction, stimulation and renal reabsorption of sodium; the release of aldosterone, vasopressin, catecholamines and prostaglandins; impact on the release of renin by the principle of negative feedback; the stimulation of thirst and other

Known antihypertensive agents (losartan, enalapril, candesartan, irbesartan, eprosartan, valsartan and others) lead to a decrease in blood pressure.

[see, for example, Russian journal of medicine, that is, nurmuhametova, Olivero Ml. Coffman TM. Angiotensin - II receptors: new targets for antihypertensive therapy. Chin Cardiol 1997; 20:3-6].

Also known antihypertensive drugs propranolol and its analogues, inderal, obzidan and the like, are able to inhibit the release of renin.

Recently appeared a new class of drugs - blocat the ditch angiotensin-converting enzyme (capoten, ramipril and other), not only lower blood pressure but also reduce the degree of left ventricular hypertrophy, vascular lesions, and a positive effect on the course of atherosclerosis. [PPM Mashkovsky, "Drug", so 1,2, M., 2000; Daharki, "Pharmacology", M, 2004].

However, all of the above medications require frequent (1-3 times daily) and long-term use, and do not provide immunological tolerance to angiotensin-II (hypertensin-II).

Known closest to the technical essence and the achieved result to the claimed invention, the vaccine against hypertension (vaccine PMD 3117, Protherics Molecular Design Ltd., UK), which is a conjugate of high molecular weight protein (presumably, tetanus toxin) with angiotensin. And used the analogue of angiotensin-I, consisting of 12 amino acid residues. More detailed information about the composition of the vaccine so far not published. [see Medical news Solvay Pharma, 22.05.2003. Source: Cardiosite.ru].

In clinical studies of the vaccine prototype of its authors set long-term increase in the titer of antibodies to the active components of renioval system, the half-life of the vaccine is 80-90 days, however, any dynamics from blood pressure was not observed even after 3-4 injections, when the fact in some cases it was noted swelling and itching at the injection site.

The present invention is the creation of a harmless vaccine prolonged action (6-12 months), allowing the vaccination of patients of any age and with varying degrees of development of hypertension, including complicated forms of the disease (renal artery stenosis and the like).

The problem is solved in that in the known vaccine against hypertension representing the conjugate high-molecular protein angiotensin, ACCORDING to the INVENTION, the conjugate contains an angiotensin-II in the ratio, wt.%:

high molecular weight protein: angiotensin-II = 1:12÷55,

moreover, the conjugate modified equilibrium number of immunocompetent polyelectrolyte polyoxidonium.

Angiotensin II is a peptide hormone, therefore its properties in the composition of the conjugate change, and polyelectrolyte provides adjuvant properties of vaccines in General. From a regulatory hormone angiotensin II is a full-antigen and can cause the body's immune response by developing antibodies to the abundance of similar molecules.

We offer the vaccine triggers the processes within the immune system: the migration and interaction of the T - and b-lymphocytes, the functioning of NK-cells and macrophages. Under the influence of the vaccine develops antibody synthesis in response to endogenous substances. Phage is city actively capture and digest particles antigen. Within 70 days from the start of the immunization of the inventive vaccine induced the formation of mononuclear cells in the spleen in the body accumulate antibodies capable of binding to the angiotensin-II with the development of persistent hypotensive effect.

The use of the proposed vaccine is also effective in complicated forms of hypertension, such as renal artery stenosis (one of the leading pathogenetic factors of hypertensive disease), cerebral blood flow, obliteration of peripheral vascular hypertrophy of the myocardium.

While the claimed ratio of components in the vaccine hypertension is necessary and sufficient for the development of long-lasting tolerance to hypertensive peptides (angiotensin II) without the use of antihypertensive drug therapy. It allows you to:

to avoid the side effects of pharmacological agents;

to obtain physiological response of the organism in the long term (6-12 months);

to apply vaccination at any age and with varying degrees of development of hypertension.

It should be noted that from the literature known synthetic immunogen, consisting of medium - polyoxidonium (N-oxidized derivative polyethyleneimine with high molecular weight) and hapten - molecular compound, the example of the enzyme hyaluronidase, or a mixture of hemagglutinin and neuramidase, or cholera toxin, or titanoboa extract (glycopeptide) cell walls of mycobacteria, BCG, or other

[see, for example, p. the Russian Federation No. 2021816, IPC And 61 To 39/106, Appl. 5.06.91,, publ. 30.10.94,; W. "Immunology", No. 6, special issue, 2002, and others].

Although part of the famous immunogenic polyoxidonium has unique properties (the ability to result in the movement of all factors of protection of the body, the reproducibility of the chemical structure, the lack of ballast impurities, pronounced immunostimulating activity, detoxifying, antioxidant and membrane-stabilizing effects)described the drugs can only be applied for the treatment of acute and chronic bacterial or viral infections due to the presence of specific haptens.

Analysis of the known technical solutions allows us to conclude that the invention is not known from the level of the investigated technique that demonstrates its compliance with the criterion of "novelty".

The essence of the present invention for a specialist not obvious from the prior art, which allows to make a conclusion about its compliance with the criterion of "inventive step".

The possibility of preparation of a vaccine against hypertension of the available industrial-manufactured components is as traditional equipment using known techniques demonstrates compliance invention, the criterion of "industrial applicability".

For preparation of the inventive vaccine hypertension used the following industrially-produced or self-synthesized components shown in table 1.

Table 1.

SubstanceManufacturer
The bovine serum albuminVenture on production of bacterial preparations Bel. Of epidemiology and Microbiology, certificate No. 17 Moscow chemical company, Laverna, packing JSC "Indicator",
Synthetic polypeptides composed of randomly polymerized L - and D-amino acidsIndependent synthesis from amino acids production company "Reanal", Bulgaria
Microbial toxins (diphtheria, tetanus, streptococcal, botulinichesky)Isolated from cultures
Angiotensin-IIICN Biomedicals is now MP Biomedicals
PolyoxidoniumState research center "Institute of immunology"

The preparation of vaccines against hypertension was carried out by known conventional methods.

Methodology 1.

For the synthesis used a high molecular weight protein (bovine serum albumin, synthetic polypeptides, microbial toxins: diphtheria, tetanus, streptococcal, botulinichesky) and ang is otensin - II at a ratio of wt.%:

High molecular weight protein: angiotensin-II = 1:12÷55.

To a solution of 50 mg (0.1 mmol) of 50 wt.% angiotensin - II (or 12 mg - 12 wt.% or 55 mg, 55 wt.%) added glutaric aldehyde 80 mg (0.08 mmol) and a solution of high molecular weight protein is tetanus toxin 120 mg ( 0.001 mmol) of 1 wt.% (or other microbial toxins, or bovine serum albumin or synthetic polypeptides). The resulting mixture was incubated at room temperature for one hour with constant stirring, then spent dialysis during the day, added antibodies and again incubated in the same conditions.

Angiotensin-NH2+O=CH-(CH2)3-CH=O + Tetanus toxin-NH2> Angiotensin-N=CH-(CH2)3-CH=N-Tetanus toxin

For formation of a strong covalent bond between the conjugated peptide - angiotensin II and high molecular weight protein carried out the reaction for reduction of Schiff's base. For that one hour was added sodium borohydride. Then there was dialyzed against phosphate buffer.

Angiotensin-N=CH-(CH2)3-CH=N-Tetanus toxin + NaBH4> Angiotensin-NH-CH2-(CH2)3-CH2-HN - Tetanus toxin

Conjugate modified the equilibrium number of immunocompetent polyelectrolyte polyoxidonium, pre-activated is swetnam by (see, for example, p. No. 1580617, where N is hydroxysuccinimide replaced by p-NITROPHENOL).

Method 2.

Preparing the mixture: 12.5 mg (12 wt.%, or to 41.6 mg - 40 wt.% or 57,3 mg - 55 wt.%) angiotensin-II, 30 mg (1 wt.%) tetanus toxin (or other microbial toxins, or bovine serum albumin or synthetic polypeptides), 12 mg of water-soluble carbodiimide in 5 ml of water.

The reaction mixture was stirred for 10 hours at 4°and the resulting conjugate was isolated by gel chromatography on Sephadex G-25.

Conjugate modified by polyoxidonium in the same way as described in method 1.

The vaccine was administered to experimental animals in the form of a solution intramuscularly in the amount of 0.5 ml of an active immune response was determined by standard methods: RIGA, RTPA, ELISA, RIA.

Preclinical studies.

In a special series of experiments method, a biological sample has been clarified the possibility of using vaccines against hypertension in animals. Group of control animals four unimmunized rabbit and experienced group of four immunized rabbit was injected intravenously at 1 mg angiotensin II in 1 ml of water for injection. It was found that all four of the rabbit of the control group showed an increase in blood pressure to hypertensive indicators (>130/80 mm RT. Art.). Among the immunized rabbits increase hyperte the invasive indicators are not reported in any of the four cases, i.e. there has been a clear immunological protection.

We also carried out the analysis of blood serum of immunized animals.

Eight rabbits weighing each 2 kg were immunized with a vaccine for hypertension, which was administered intramuscularly in a dose of 30 mg/kg In the serum of animals before immunization and after it was determined the presence of antibodies to drugs: angiotensinogen, angiotensin I (AT-I), angiotensin-II (AT-II), angiotensin III (at-III) and studied their specificity of response inhibition passive haemagglutination by standard methods.

Immunization of rabbits vaccine on the scheme resulted in the serum of high titers of antibodies to immunocomplex vaccine (1:2560). In response inhibition passive haemagglutination assays, it was found that the resulting antibodies bind AT-I, AT-II, AT-III: the titer of antibodies to immunocomplex decreased to 1:320 when using concentrations of 0.001, which indicates the presence of antibodies to these compounds.

Thus, the synthesized vaccine specifically binds to AT-II not only in vitro, but also in the whole organism.

The specificity of antibodies against Angiotensinogen, AT-I, AT-II, AT-III in rabbit immune serum, are presented in table 2.

Table 2

/tr>
NameThe relative specificity of the antibodies, %
Angiotensinogen0,05
AT-I0,06
AT-II100
AT-III100

The data obtained show that binding of AT-II depends on the presence in their molecules of certain amino acid sequences. So, in particular, the high specificity of antibodies to AT-II and AT-III is due to lack of vaccine amino acids present in AT-I and angiotensinogen. Thus, the resulting antibodies have a high specificity to AT-II and AT-III.

Given the experimental results, the authors concluded that AT-II is suitable for synthesis of a vaccine against hypertension. Its chemical structure contains the amino acid sequence for the formation of the immune response and synthesis of high-affinity antibodies to AT-II.

The claimed vaccine hypertension synthesized under conditions of the Department of pharmacology of the Ural medical Academy and repeatedly tested on laboratory animals.

Control efficiency was considered the absence of hypertensive reaction to the introduction angiotenzinamida or synthetic analogue of angiotensin II. In addition, to monitor the effectiveness of vaccination conducted a quantitative content analysis of antibodies in the blood plasma 1 time in 3-12 months. Most of informativni methods are radioimmune analysis (RIA) and enzyme-linked immunosorbent assay (ELISA). By reducing the number of antibodies in the blood is below the required level should be re-vaccinated. No adverse events related to vaccination were observed.

Example 1.

Thirty Mature mongrel rats of both sexes were immunized with a vaccine against hypertension, containing high-molecular protein - bovine serum albumin (1%wt.), angiotensin-II (12 wt.%) and polyoxidonium, at the rate of 50 mg/kg

Entered 1 mg angiotensin II-IV.

Similarly conducted study vaccine against hypertension in examples 2 and 3, which varied used of high molecular weight proteins and the ratio of the components of the conjugate in the claimed range.

The vaccine compositions of hypertension and its pharmacological action in the table.

As can be seen from the examples and table data using the inventive vaccine hypertension compared with opublikovannimi data about known, taken as a prototype vaccine PMD 3117, Protherics Molecular Design Ltd., UK [see Medical news Solvay Pharma, 22.05.2003. Source: Cardiosite.ru]provides the following technical and community benefits:

- lack of side effects of pharmacological agents;

- sustained physiological response of the organism in the long term (6-12 months);

- possibility of use of vaccines is tion at any age and with varying degrees of development of hypertension.

The vaccine compositions of hypertension and its pharmacological effects are presented in table 3.

Table 3
ExamplesThe composition of the vaccine:RatioPharmacological
WascompletelyMacromolecularthe vaccine
proteinprotein:1. No
2. Angiotensin-IIAngiotensin-IIside effects
3. Polyoxidoniumwt.%medication
2. Resistance
physiological
reaction of an organism
RIA 1 ml pmol:
a) after 3 months
b) after 6 months
C) after 12 months
11. Albumin bovine1:121.+
whey2.
2.+a)10500,
3.+b)10300,
in)10200
21. Tetanus1:301.+
toxin2.
2.+a)12500,
3.+b)12400,
in)12250
31. Strep1:551.+
toxin2.
2.+a)13000,
3.+b)12950,
in)12770

Note: when using the vaccine as Vysokomolekulyarnye the th protein synthetic peptides or other microbial toxins (e.g., diphtheria, betweennations etc) or the variation of the ratio (high molecular weight protein: angiotensin-II), the pharmacological effects of the vaccine similarly indicated in the table.

Vaccine against hypertension representing the conjugate high-molecular protein angiotensin, wherein the conjugate contains angiotensin-II in the ratio, wt.%: high molecular weight protein: angiotensin-II = 1:12÷55, and conjugate modified equilibrium number of immunocompetent polyelectrolyte polyoxidonium.



 

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