The tool caramel for treatment of diseases of bacterial origin

 

The invention relates to medicine, in particular to pharmacology, namely the creation of new drugs based on peptides for the treatment and prevention of diseases of bacterial origin, caused by Staphylococcus aureus, Escherichia coli, pneumococcus and other Proposed means includes a linear Hexapeptide structural formula Leu-Val-Cys-Tyr-Pro-Gln and glycine in a ratio of ingredients is 1:1 to 1:2, at a dose of 0.007 mg/kg of weight of the person. The invention allows to create a new medication without side effects and to develop a method for its use for the treatment and prevention of diseases caused by bacterial nature. 7 table.

The invention relates to medicine, in particular for anti-infective pharmacology, namely the creation of new medicines, which have antibacterially action, on the basis of peptides and intended for the treatment and prevention of infectious diseases of bacterial origin, caused by Staphylococcus aureus, Escherichia coli, pneumococcus and other

Known use in antibacterial therapy of different antibiotics. Among them one should mention the drugs group is key aminoglycosides, macrolides and azalides, etc. However, all known antibiotics have a whole range of side effects on the body and, in addition, long-term use, the development of resistance of microorganisms.

In addition to antibiotics, widely in medical practice for the treatment of infectious diseases use of sulfa drugs, which are often used in combination with antibiotics. From side effects of sulfa drugs should be called allergic reactions, nausea, vomiting, dermatitis, neuropathy, disorders of the Central, very often impaired renal function. Introduction in an organism of the patient described drugs in therapeutic doses, can lead to severe side effects, particularly immunodeficiencies. Therefore, it is much preferable to use as antibacterial agents of low molecular weight compounds, especially peptide. They are effective in small doses, does not cause harmful effects.

The prior art connection peptide with antibacterial effect, and tools based on them [1, 2, 3].

The present invention is the creation of a new domestic preparation on the basis of peptide devoid specified is odd, that the proposed means of having high antibacterial activity, containing linear Hexapeptide structural formula: Leu-Val-Cys-Tyr-Pro-GIn and glycine as a filler in the ratio of ingredients is 1:1 to 1:2 and named Seramil.

The Hexapeptide was isolated from culture supernatant of bone marrow cells pigs, sekvenirovan and then synthesized [4].

Stated the vehicle was prepared as follows: linear Hexapeptide mixed with glycine in the stated weight ratios, dissolved in distilled water, poured into ampoules or vials so that each vial contained 0.5 mg Hexapeptide, lyophilized solution, and then sealed ampoules or sterile sealed vials. The tool is a light white powder, soluble in water, physiological solution.

The technical result to be obtained by the use of the invention is the development of new drugs and the development of methods of their use for the treatment and prevention of infectious diseases caused by bacterial nature.

The invention is illustrated by the following examples.

Example 1. The stated means includes ingredients when following their zootoxin and following their ratio of mg: Linear Hexapeptide Leu-Val-Cys-Tyr-Pro-Gln - 1.0 Glycine - 1.0 To Any change in the qualitative or quantitative parameters of the proposed framework does not provide the claimed technical result.

The claimed product is used for injection at a dose of 0.007 mg/kg or 0.5 mg/person as an antibacterial agent. Specific (antibacterial) activity was studied on animal testing of the drug conducted on volunteers with chronic pneumonia.

Impact funds Seramil on the colonization of the internal organs of mice infected with pathogenic microorganisms.

It is known that the intensity of development and the outcome of infection is largely dependent on the residence time of pathogens in the body - terms of their persistence and colonization of internal organs. In a series of experiments investigated the influence of the stated means Seramil on the degree of contamination of the internal organs of infected animals in time. The experiments were conducted on female mice-hybrids (CBAC57Bl/6)F1weighing 18-22 g (20 experimental and 20 control). The day before the intraperitoneal infection of mice to sublethal dose of bacteria cultures they were injected intraperitoneally Seramil at a dose of 0.01 μg/mouse. In experiments were used culture is rangapani, mice - sepsis; - P. Aeruginosa, strain 1677 (Escherichia coli is the causative agent of wound infections; S. aureus, strain 57 (Staphylococcus aureus is the causative agent of purulent and toxic infections.

Control group mice (without prior introduction of Sarmila) were infected simultaneously with experienced. Then at different times (depending on the type of pathogen) were opening five experimental and five control mice with subsequent seeding of the pathogen from the blood, liver, spleen, mesenteric lymph nodes and different parts of the small and large intestine. After 18 hours incubation at 37oFrom the resulting culture were identified by diagnostic sera and calculated the index of contamination (the ratio of the number of positive samples in all investigated organs for all delivered to the samples). The closer the index of contamination to the unit, the greater the contamination of the body of the mouse.

In the study of Kl. pneumoniae strain K-16, the mice were infected intraperitoneally at a dose of 5106microbial cells/mouse. The day before infection were introduced Seramil at a dose of 0.01 μg/mouse. The index of contamination of animals was determined at 1, 2, 3, 6, 7 and 8 days after infection. Table 1 presents data on the effect of MP-3 clearance Klebsiella is Noah and control groups during the first three days did not differ from each other, however, on the fourth day, there was a sharp decline in the number of bacteria in mice of the experimental group compared with the control. 7-8 day has been full clearance culture of Bobadilla pneumonia in experience, whereas in the control of internal organs mice were inseminated by these organisms. Antibodies in the serum of experimental and control groups of mice were not detected.

The index definition contamination after infection of mice P. aeruginosa was carried out on 1, 2, 3 and 5 days after infection, and antibody titers were determined on 7 and 14 day. Dynamics of the index of contamination with animal infections by Escherichia coli are presented in table 2.

The data presented show that with the introduction of funds Pseudomonas aeruginosa derived from mice already on the second day after infection, whereas in the control of bacteria persist until the 5th day. The process is accompanied by an increase in antibody titer in the serum of both groups equally, despite the absence of the pathogen in the experimental group at the end of the observation period (table 3).

Infection of mice with S. aureus strain 57 index of contamination, as well as antibody titer in the serum was performed at 1, 2, 3 and 6 days. Dinamic data shows, that Staphylococcus aureus in mice that received vehicle Seramil, is present in smaller amount in comparison with the control. On the 6th day experimental mice were completely free of the pathogen, while in the control was still a minor infection. Differences in antibody titers were insignificant (table 5).

Impact funds Seramil on the colonization of the internal organs of mice infected with different pathogenic microorganisms was evaluated in a series of experiments upon its introduction in already infected organism. Experimental and control groups of mice were infected intraperitoneally sublethal (pre-titrated) dose of bacteria cultures. In experiments were used to culture the causative agents of the following bacterial infections:
- Kl. Pneumoniae, strain K-16;
- P. Aeruginosa, strain 1677.

2, 3 and day 4 after infection, the mice of the experimental group was injected subcutaneously substance of Sarmila at a dose of 0.01 μg/mouse. Then at different times made the opening five mice experimental and control groups with subsequent seeding of the blood, liver, spleen, mesenteric lymph nodes and different parts of the small and large intestine. After 18 hours incubation at 37oWith dedicated to the Ah to study the effects of Sarmila on the colonization of the internal organs of mice, infected Kl. Pneumoniae, the observations were carried out for 1 to 9 days. Seramil was injected three times at 2, 3 and 4 days after infection. The results of these studies are presented in table 6.

As can be seen from the data presented, the introduction Ceramic during infection of mice with Klebsiella pneumonia significantly reduces the colonization of organs of mice on day 7 there is a complete disappearance of the pathogen from the body, while the control mice pathogen is detected and on the 9th day from the moment of infection.

When studying the effect of the declared funds Seramil on the colonization of the internal organs of mice infected with P. Aeruginosa, the observations were carried out at 1-7 days after infection. The results of the experiments are presented in table 7.

As can be seen from the presented data, after double injection substance of Sarmila the colonization of the internal organs of mice dramatically falls to 5 days there is a complete cleansing of the organs of mice against the pathogen in the experimental group, while of the organs of control mice pathogen were inoculated to 7 days.

The data on the clearance of the organs of infected animals from pathogens of various bacterial infections allow to conclude that Caramel significantly SN the sludge, proposed for use as antimicrobial drugs. The program Toxicological research involved the study of the toxicity of the substance of tools in a single laboratory animals, the study of the toxicity of the substance of tools and finished dosage forms in chronic experiments on rats and dogs. In addition, a study was made irritant action of finished dosage form tools, research potential mutagenic, embryotoxic, teratogenic and allergenic properties, tools, and investigated its influence on the reproductive function of animals.

It is shown that the substance of sarmila is low-toxic substance; not set the death of BALB/C mice and WISTAR rats with a single intraperitoneal and subcutaneous possible for technical reasons doses (the limit of solubility of the drug) 925-950 mg/kg the dose more than 130 000 times the daily therapeutic dose (0.5 mg/person or 0.007 mg/kg).

Studied at subcutaneous doses of 0.14 and 0.35 mg/kg in 3-month chronic experiment on rats substance and a 3-month chronic experiment on sobaku dose of 0.14 mg/kg, in excess of 20 and 50 times the daily therapeutic dose for humans, well tolerated by the animals and do not cause toxic lesions. The finished dosage form of sarmila does not have irritant properties.

In the tested doses and concentrations Seramil does not show mutagenicity in the Ames test, does not cause chromosomal aberrations in bone marrow cells of mammals, dominant lethal mutations in germ cells of mice, has no DNA-damaging effect in the SOS chromotest, indicating the absence of the drug have the potential carcinogenic hazard.

In the tested dose of 0.14 mg/kg Seramil does not show embryotoxic and teratogenic properties, and does not affect the reproductive function of animals.

In the range of tested doses and schemes sensitization Seramil has no properties.

Antibacterial action funds was studied on a group of volunteers with chronic pneumonia. The patients ' age from 35 to 60 years, the number of patients in the group of 10 people. Before the study, all patients were treated with conventional drugs: antibiotics, sulfonamides according to the standard scheme, however, signs hronicheskogo during exercise, periodic fever, pain in the chest. Radiographically, all 10 people identified pockets of pneumonic infiltration, inflammation and deformation of the bronchi, increased ESR, increased C-reactive protein. The treatment claimed by the tool: 5 injections of Sarmila 0.5 mg/person a day, if necessary, a second course in 2-3 weeks. Upon completion of the course of treatment, the total state of the patient improved significantly: " there was a cough, body temperature remained within normal limits, stopped torturing pain in the chest. Radiographically in all patients decreased foci of infiltration, 6 people foci of infiltration is not found, the inflammation of the bronchi mentioned by only 1 person, erythrocyte sedimentation rate and C-reactive protein within the physiological norm.

Thus, on the basis of the conducted research it can be concluded that the proposed tool has a high antibacterial activity, non-toxic, does not show mutagenicity, has no allergenic and irritant properties, does not show embryotoxic and teratogenic properties.

References
1. EN 2183643 C1, 20.06.2002.

2. EN 2141483 C1, 20.11.1999.

3. EP 0979831,16.02.2000 - the prototype.

4. R. C. Smith and others the treatment of diseases of bacterial origin, containing peptide, characterized in that it comprises a linear Hexapeptide structural formula Leu - Val - Cys - Tyr - Pro - Gln and glycine in a ratio of components 1: 1 to 1: 2, and the dose means is 0.007 mg/kg of weight of the person.

 

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