The tool, with preventive and curative action upon infection with tick-borne encephalitis virus

 

(57) Abstract:

The invention relates to medicine, specifically to pharmacology. The proposed new preventive and therapeutic agent active against the virus of tick-borne encephalitis. The tool is a drug KD, i.e., a mixture of triterpene glycosides from the broth sea cucumbers Cucumaria japonica, and was previously known as immuno - and bio-stimulator, also effective against viruses. The invention expands the Arsenal of the declared destination. 1 PL.

The invention relates to medicine, namely to the experimental Virology, and can be used for the prevention and treatment of viral encephalitis.

The most well-known means of preventing infection with tick-borne encephalitis vaccines are representing inactivated viruses [1]. The disadvantages of the known means are incorporated in the scheme of vaccination: for the first person to be vaccinated requires three injections to be performed at certain intervals during the first year, and then one injection in the next two years or every two years, depending on the type of vaccine. Such extended periods indicate a weak induction of immunity and immunol mova, can't have a reliable protective effect in connection with pronounced heterogeneity of tick-borne encephalitis virus, which currently has about 200 strains. Ill vaccinated when antigenic characterization of strain does not match that of the vaccine strain.

Known seroprotection and serotherapy, where as a remedy against tick-borne encephalitis are immune serum. Serotherapy has a negative impact on active immunogenesis, expressed in a depression of function of b-lymphocytes, reducing the synthesis and accumulation of virus-neutralizing antibodies and antihemagglutinin, persistence of the virus [2]. Serotherapy with focal forms of tick-borne encephalitis shown only in childhood and young age, in patients older than 40 years seroprevelance have a negative effect. When meningeal form of tick-borne encephalitis in the background of specific immunotherapy are often observed deaths.

Known specific human immunoglobulin for the prevention and treatment of tick-borne encephalitis used in medical practice. However, the drug has a poor performance, limited production and is characterized by the absence of encephalitis, as evidenced by the high mortality, persistent residual symptoms, a long rehabilitation period and the need to use non-specific medicines that are complementary to specific treatment (anti-inflammatory, detoxification, dehydrating, antihistaminics, antisense, sedative, tonic, absorbable and other drugs).

The closest in purpose and effect achieved by the claimed means is a chemotherapy drug 4-yodantipirin [4]. In experimental tick-borne encephalitis in the dose of 50 mg/kg of live weight and twice the introduction of its 24 and 1 hour before infection preventive effect reaches 47%. In the medical scheme with the introduction of 50 mg/kg yodanthipirina for 11 days daily protective effect is 60% when introduced through the mouth and 53.4% for parenteral applications. LD50(the dose that causes death in 50% of animals) and the maximum tolerated dose (MTD) of the drug is 1000 mg/kg and 500 mg/kg, respectively. It should be noted that the viral strain Absettarov, with whom he worked in the study known means, characterized by low pathogenicity.

Negotatiate, which is generally typical for the majority of chemicals. So, the current dose of 50 mg/kg 20 times differs from the lethal and upper level 500 mg/kg - only 2 times. In addition, the dose of 50 mg/kg in itself is very large. Per person average weight (60 kg) at one time requires 3 grams of drugs. The use of such large doses increases the likelihood of unwanted side effects and goes against the trends of modern pharmacology, seeking maximum lower doses of drugs due to their high efficiency.

Therefore, the search for effective and low-toxic remedies for the prevention and treatment of viral encephalitis is now an urgent task.

This problem is solved using the product CD as a tool, with preventive and curative action upon infection with tick-borne encephalitis virus.

The product CD or cucumarioside represents the sum of the triterpene glycosides obtained from available natural raw materials, namely, from the broth sea cucumbers Cucumaria japonica [5]. Known drug use KD in veterinary medicine as an immunomodulating and biostimulating tools [6], kachestvenni [8]. It is also known the use of cucumarioside as an agent with activity against viruses, vesicular stomatitis, polio, encephalomyocarditis mice, Coxsackie AND7and B7, herpes, disease, new castle and adenovirus [9].

The use of drugs KD (cucumarioside) as a means for the prevention and treatment of tick-borne encephalitis been discovered for the first time.

A new feature of cucumarioside does not follow clearly from its known properties and composition. Activity cucumarioside in vitro against several of the above viruses does not mean that the drug will possess activity against tick-borne encephalitis virus. The absence of such dependence is confirmed by literature data [10] and our own experiments.

The technical result is achieved due to the prolonged action of the drug KD for prophylactic use and with extremely low doses of the drug required to achieve comparable with prototype effects, due to its exceptionally high activity. So in experiments on mice with the introduction of cucumarioside at a dose of 3.5×10-3g/kg for 7 days before infection index C is P CLASS="ptx2">LD50for mice with intraperitoneal injection is 29 mg/kg Cytogenetic evaluation of the mutagenic action showed that in a micro-kernel test polychromatophilic bone marrow erythrocytes of mice, the average number of mn did not differ from control; when taking into account structural changes of chromosomes in the cells of bone marrow metaphases with structural aberrations of chromosomes do not differ from the control. It should be noted that all work was carried out with strain Nikolaenko, isolated in 1978 from brain dead against tick-borne encephalitis and highly cerebral and peripheral activities during infection of mice. Therefore, working with a highly virulent strain Nikolaenko, highlighted in the Primorsky region, is of great importance in connection with the peculiarities of clinical manifestations of tick-borne encephalitis in the region include severe infection and high mortality (in some years 25-30%.

The invention expands the Arsenal of the declared destination.

Example. Determination of the antiviral activity of the drug KD was carried out on nonlinear white mice weighing 14 g according to the standard technique [11]. Mice were infected by intraperitoneal injection of the virus of tick encephal the h-2 Ig LD50/0,2 ml

Cucumarioside was administered subcutaneously 1 once a day at doses of 3.5×10-4, 3,5×10-3, 3,5×10-2and 3.5×10-1g/kg in 0.2 ml of saline. For each definition was taken in 20 mice.

Conducted 3 trials of antiviral activity: in the first series investigated the prophylactic use of the proposed drug - cucumarioside entered once for 7 days before infection of mice with tick-borne encephalitis virus. In the second series was performed simultaneous introduction of cucumarioside and virus. In the third series did a study of therapeutic effect of cucumarioside, performing a single injection of cucumarioside 24 hours after infection and twice the introduction of the drug after 24 and 48 hours after infection.

All series of experiments was accompanied by a control group of uninfected mice, which was introduced cucumarioside, and the group infected with tick-borne encephalitis virus of mice, which did not undergo therapeutic or preventive effect of the test drug).

The observation period for all animals 21 days.

The drug efficacy KD characterized by the index of protection (FROM), which was calculated by the formula:

The experiments chosen the most effective dose KD - 3,5×10-3ug/kg showed a significant reduction in mortality of mice infected with highly virulent strain Nikolaenko, when applying cucumarioside on preventive and curative two schemes. So with the introduction of 7 days before infection at a dose of 3.5×10-3mg/kg cucumarioside gives a protection factor of 57%. With the introduction of cucumarioside twice after 24 and 48 hours after exposure to the same dose index protection is 44%. Concurrent with infection using cucumarioside no significant protective effect (20%), and the implementation of this scheme is practically impossible in the real world.

Thus, the inventive tool in the prevention scheme is superior to the prototype as the duration of effect, and magnitude (57% 7 days before infection for the proposed drug and 47% for the day before infection for the prototype), and quite active in the medical scheme. The big advantage of the drug KD is its extremely low toxicity at the doses employed (different from LD50106times), as well as prolonged preventive action against tick-borne encephalitis virus,then

1. Leonov, N. Tick-borne encephalitis in Primorsky Krai. -Vladivostok - 1997. - S. 165-179.

2. Perekhodova S. K., Brinova B. N., Shmatko Century, and others in the book. Natural focal diseases (issues in laboratory diagnosis, epidemiology and prevention). - Omsk, 1982. - S. 56-62.

3. EN 2158606 C1, a 61 K 39/395, And 61 R 31/0027, 10.11.2000.

4. EN 2025126 C1, a 61 K 31/41, 30.12.1994.

5. EN 2110522 C1, C 07 H 3/06, 10.05.1998.

6. THE 9388-018-02698170-94 on the product CD (cucumarioside). Registered Seaside center for standardization and Metrology No. 035/001357 from 05.05.1994.

7. EN 2036654 C1, a 61 K 35/78, 09.06.1990.

8. EN 2141833 C1 And 61 To 35/56, 27.11.1999.

9. EN 2184556 C1 And 61 To 35/56, a 61 P 31/12, 10.07.2002.

10. R. Pompei, O. Flore, M. A. Marccialis, A. Pani, B. Loddo.//Nature/ - 1979 - Vol.281. - P. 689

11. Evaluation of the specific action of anti-viral compounds in experimental viral encephalitis. - Bel. Research Institute of epidemiology and Microbiology of the Ministry of health of the BSSR. - 1986.

Drug use KD as a means, with preventive and curative action upon infection with tick-borne encephalitis virus.



 

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