Agent for treatment of viral hepatitis c

FIELD: medicine, virology, pharmaceutical industry, pharmacy.

SUBSTANCE: invention proposes the preparation used for treatment of viral hepatitis C that comprises birch bark extract with the content of betulin above 70% and a pharmaceutically acceptable carrier. The preparation is administrated to patient by oral route. The preparation promotes to the effective treatment of viral hepatitis C. Invention can be used in treatment of viral hepatitis C.

EFFECT: valuable medicinal properties of agent.

4 cl, 2 tbl

 

The technical field

The present invention relates to the field of medicine and more specifically relates to searching for new, effective treatments for hepatitis C.

The level of technology

Viral hepatitis among the most dangerous and common infectious diseases. Annually in the world from pathologies associated with the disease kills about 2 million people.

Cause of viral hepatitis are at least 5 different viruses enteric viruses a and E and parenteral (b, C, D).

Hepatitis C virus is the most "young", it was opened only in 1989. With his discovery began an intensive study of this type of hepatitis, which is the main reason for the development of chronic diffuse liver diseases and hepatocellular carcinoma.

A distinctive feature of the hepatitis C virus is the ability to long persistence in the body, which causes high levels of chronic infection (50-80% of cases). The stability of the virus due to its ability to replicate with a high level of mutations, resulting in several immunological different options by which the virus evades immune surveillance. Formed virusneutralizing antibodies are highly specific and are unable neitralizovat the newly emerging viral variants.

The extremely high incidence of viral hepatitis, in particular hepatitis C causes the current task to research and create an effective means of treatment of this infection.

Currently in practical medicine officially known two drugs used for the treatment of viral hepatitis C (interferon and ribavirin or virazole), but it does not make the task of searching for new treatments for this disease are irrelevant, particularly because of the side effects that accompany the use of known drugs, such as anemia, neutropenia, leukopenia, dyspepsia.

The invention

The present invention is the finding of a new, highly effective tools for the treatment of hepatitis C.

Another objective of the present invention is to find a highly effective means for treatment of hepatitis C natural origin, since this eliminates a number of problems associated with the use of drugs.

These tasks are solved by the present invention due to the establishment of the authors high antiviral activity against hepatitis C virus in the extract of birch bark (bark) with the content of betulin in the extract above 70%.

Betulin is one of the first natural substances, which for the first time was kind of the Leno from vegetable raw materials in 1778. In 1876 Whayman published the results of elementary analyses betulin (U. Hausmann, Annalen der chemie, 182, R).

The main source of natural betulin is birch. The white part of birch bark in some species of birch (Betula verrucosa, Betula papyfera) contains up to 30% or more of betulin (Hayek, E.W. et al.(1989) A Bicentenmal of Betulin, Phytochemistry, 28(9) R-2242).

Betulin is Pyh triterpenes with the carbon skeleton of a number of Lupan, also called Betulinol, trichotomum, birch camphor and (chastised) retinolum. A characteristic feature of a number of Lupan is a ring of five carbon atoms in the composition Pyh system, which is in position C-19 has α-isopentenyl group. Betulin has a high thermal stability, its melting point is between 250 and 261°and after sublimation of recrystallized product is achieved even higher values. Its molecular weight is 442,7, it is soluble in pyridine and tetrahydrofuran, but little soluble in dichloromethane, chloroform and cold organic solvents, and with increasing temperature the solubility increases significantly. In cold water and petroleum ether betulin is practically insoluble. In addition, kinetic studies showed very low reactivity of the hydroxyl group of betulin.

In 199 year Jailer showed antiseptic properties of betulin, and so it was used to sterilize dressing bandages and plasters (J. Wheeler, (1899), Pharm. J., Die Darstellung des Betulin durch Sublimation, 494, Ref. Chem. Centr. 1900 I, page 353). In naturopathy and traditional medicine have received and do receive still decoction of birch bark, which is used to treat malaria, dropsy, gout and skin diseases, as well as in tincture form of compresses in the treatment of abscesses.

A large number of studies on hepatoprotective activity of betulin. It was found that betulin reduces the activity of alanine aminotransferase, alkaline phosphatase, the content of maleic dialdehyde, prevents the inflammatory process in the liver (Ukiwasiliana and other "Pharmacological properties of triterpenoids of birch bark" Experimental and clinical pharmacology, 1993, t No. 4 pp. 53-55).

However, there is no reliable information about the antiviral activity of betulin, unlike its synthetic derivatives. So, it was reported that 3-substituted Putilova betulin derivatives in vitro have cytotoxicity against lymphocytes, transformed HIV ("Synthesis and anti - HIV activity of betulin derivaties", Bioorg Med Chem Lett. 1998 May 19, 8(10) p.1267-1272).

A large number of publications devoted to the obtaining of a number of derivatives of Betulinol acid as a potential means of AIDS (see, for example, "Synthesis and anti - HIV activity of betulinic cid and dihidrobetulinic acid derivaties", Bioorg Med Chem lett, 1997, Dec 5(12) p.2133-2143).

The possibility of using betulin derivatives were also studied in relation to hepatitis models of hepatitis are not of viral origin, caused by Cll4, tetracycline and acetone. (Oberlehrer "Synthesis of esters of triterpenoids group Lupan and their hepatoprotective activity", Bioorganic chemistry, 2000, vol 26, No. 3, pp. 215-223).

Disclosure of inventions

The authors of the present invention it has been unexpectedly discovered that the extract of birch bark has anti-viral properties. This effect was discovered in the model of experimental infection caused by the hepatitis C virus human in mice.

Although the antiviral activity of betulin derivatives was shown by a number of authors to model HIV infection in vitro, the surprise of this result is due not only to the fact that previous studies betulin did not find him and its derivatives antiviral activity against hepatitis C, but also the fact that the authors of the invention in the study of extract of birch bark in cell cultures (in vitro) not to have found this activity. It is manifest only in vivo.

The implementation of the invention

The following describes the results of studies of the effect of the extract of birch bark on the reproduction of the hepatitis C virus (further reducing the NGOs HCV) in the organism of laboratory animals.

Material and methods:

Virus: used cytopathogenic variant of HCV isolated from the serum of chronically infected HCV patient. According to genotyping isolated variant HCV belongs to the most widespread in Russia genotype 1b HCV. The studies used infectious doses of HCV equal 10,0 TCD 50.

Antiviral drug. In this work, we used the extract containing betulin, determined by HPLC - 72%. In the experiment used different breeding from 50 to 150 mg per 1 kg of body weight, which was administered to animals by oral way daily for 4 days.

Animals. To study the antiviral activity of betulin used outbred adult mice weighing 18-20 g

Methods. Material containing HCV, animals were injected intraperitoneal way. Part of the animal was left of the control. On the 9th day after infection, mice were fed” (administered orally) with a solution of betulin (saline, 10% Tween-80) (hereinafter the company refers to the above-described preparation) in a volume of 50 µl, containing 50, 100 and 150 mg of betulin. Betulin was given to mice 1 time a day for 4 days. In the experiment used 10 animals for each version of the experiment. After 2 days, and 10 days after the last injection of the drug, 50% of the animals were dissected, removed Iceni, the brain was taken away by the blood. Samples of blood serum, supernatant, obtained after centrifugation at 3000 rpm for 15 min homogenates of liver tissue and brain used to determine HCV antigens and infectious activity of hepatitis C. this purpose vaccinated samples were titrated in cultures of human kidney cells of the embryo pig spew. The HCV antigen in the samples studied in the reaction of hemagglutination using the classical method described by Clarke and Casals (1968).

Cell culture. Were used highly sensitive to cytopathogenic action HCV culture transplantable kidney cell embryo pig (SPM)obtained from the company “Narvak”, Moscow. They were used in the form of one-day monolayer cells grown in 24-hole plastic panels. Cell culture SPM were grown in medium 199 with 10% serum embryo calves, with added glutamine and antibiotics (100 U/ml). For the titration of residual infectious virus activity used the same cell line kidney fetal pigs (SPM).

Infectious HCV activity contained in samples of organs and tissues of infected mice, took into account the results of the titration, usually 6-7 days after infection, when developed maximum cytopathogenic action of the virus, using the formula of reed and turns into a hissing drone for the couple titer hepatitis C.

Results.

Survey data are shown in tables 1 and 2. As can be seen from the data table. 1A, all samples of blood sera obtained from HCV infected mice belonging to the various groups contain both antigenic and infectious HCV activity. Moreover, the maximum expression of these indicators detected in the control group of HCV infected animals not treated betulin. In animals treated with the drug at a dose of 50 mg per 1 kg of body weight in 50 μl, was marked by a noticeable trend of decreasing titers of hemagglutinin HCV, and infectious titers of HCV in the serum fell by 2.6 lg (average data). A significant reduction in antigenic and infectious activities HCV in serum were observed in the group of animals treated with daily medication betulin” in a dose of 100 mg/kg In this case, the titers of infectious HCV activity fell by 3.4 lg, and more than 2 times decreased antigenic activity of HCV in serum samples of mice. To a lesser extent, the drug was active in the case of using it in a dose of 150 mg/kg Decreased antigenic activity of the virus titers of infectious activity declined slightly under the influence of the drug (1.8, lg). Similar results, demonstrating the effectiveness of the drug “betulin were obtained from the study of liver tissues from all groups of animals (TBLB). In particular, it was shown that h is about the maximum reduction in HCV antigens and infectious activity was observed in the case of using the drug in a dose of 50 and 100 mg per 1 kg of body weight at 4-fold drug. From the data of table 1B shows that the antigenic activity of HCV was decreased in 2 times or more and up to 2 lg noted a decrease in the infectious activity of HCV in liver tissues. Reduced, and the size of the liver HCV infected mice under the influence of therapeutic effect of the drug Most HCV titers (up to 7.0 lg TCD50/20 ál) was observed in brain tissue HCV infected mice (table 1). However, in this case of mice treated with the drug, “betulin in doses of 50 and 100 mg kg-1 was observed reduced titers of infectious HCV activity by 2.0-2.5 lg, respectively. The decline of HCV antigen was noted in all groups of animals treated with the drug. In the group of mice treated with betulin at a dose of 150 mg per 1 kg, there was a trend to increase in the titres of infectious HCV activity in the brain.

Thus, the data obtained in the study of organs and tissues of mice on day 17 after infection with HCV and day 3 after 4 times of use of the drug “the company”, show high antiviral activity of the drug against infections caused by HCV in animals.

In this regard, it was revealed the duration of the positive changes in the body HCV infected mice after withdrawal of the drug. Therefore, the 2nd group of HCV infected animals was examined at 28 days after infection and on the 11th day after discontinuation of treatment agents is om “the company”.

The results are shown in tables 2A, b, C. a Study of the antigenic activity of HCV in organs and tissues of mice during this period of time has allowed to establish that treatment with the drug, “betulin in doses of 50 mg and 100 mg per 1 kg, as a rule, led to a significant decrease in the content of hemagglutinin HCV in the serum samples of blood, liver and brain HCV infected animals (at a dose of 100 mg per 1 kg up to 4 times in the liver of mice in 2 and more times in serum and brain of animals). The dose of 150 mg per 1 kg, generally resulted in a slight decrease in the content of HCV antigen in organs and tissues of animals infected with HCV.

The study of infectious HCV activity in organs and tissues of HCV infected mice showed that in the long term after completion of treatment antiviral effect of the drug was maintained for more than 10 days. However, the analysis of the obtained data allowed us to detect different patterns in the parameters of HCV infection in these terms. In particular, it is shown that the titers of HCV contained in the serum and in the liver of the control group animals were significantly higher than these values, identified in the early stages after infection of mice (1.5 lg - serum, 2.4 lg in the liver). At the same time, on the 28th day after infection in the brain virus titres the hoist to fall noticeably.

Antiviral effect of the drug, “company” in these terms after the drug was somewhat reduced, however, the greatest effect was observed in the period when the treatment is used the dose of 50 mg per 1 kg of body weight. In this case, in the serum of animals the titres decreased on average by 1.9 lg, liver - 2.9 lg, brain - 2.4 lg. 4-fold drug “the company” in a dose of 100 mg kg-1 resulted in less significant changes in the titer of HCV downward (see tablica, b, C).

Thus, the positive effect of the drug “betulin” on reducing rates of infection caused by HCV in mice and 10 days after its cancellation.

Obtained by the authors of the invention results suggest that the extract of birch bark has high antiviral activity against infections caused by hepatitis C virus, which allows us to offer it as a treatment for this type of hepatitis.

There is no reason to assert that the content of betulin in the extractive not less than 70% is critical and restrict their scope of the invention. Practically meaningful results can be obtained for smaller values of the content of betulin. The establishment of these boundary values can be made JV is by employees in the normal course of routine work, in particular, based on the above description of the present invention.

The preferred form of application of the extract of birch bark are solid dosage forms: tablets, pills, capsules, powders. This may be normal for this type of pharmaceutically acceptable carriers. The drug can include one or more fillers, such as microcrystalline cellulose, lactose, sugar, starch, mannitol, sorbitol and other polyols, calcium carbonate, calcium phosphate, calcium sulfate, glycols, etc.

The drug may also include surfactants and other conventional components for solid pharmaceutical preparations such as dyes, flavoring agents, adsorbents.

In the manufacture of the drug in the form of coated tablets, the latter can be obtained from such film-forming substances such as hydroxypropylcellulose, plasticizer, such as polyethylene glycols, and other auxiliary additives such as pigments.

1. The use of birch bark extract as a treatment for hepatitis C.

2. Drug for the treatment of viral hepatitis C, including birch bark extract with a content of betulin 70%, and a pharmaceutically acceptable carrier.

3. The method of treatment of viral hepatitis C is characterized by the fact that the patient is the orally administered preparation according to claim 2.



 

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