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WO2006001733A1 - Agent de traitement et de prevention de la tuberculose - Google Patents

Agent de traitement et de prevention de la tuberculose Download PDF

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Publication number
WO2006001733A1
WO2006001733A1 PCT/RU2005/000288 RU2005000288W WO2006001733A1 WO 2006001733 A1 WO2006001733 A1 WO 2006001733A1 RU 2005000288 W RU2005000288 W RU 2005000288W WO 2006001733 A1 WO2006001733 A1 WO 2006001733A1
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WO
WIPO (PCT)
Prior art keywords
macrophages
betulin
mycobacteria
drug
tuberculosis
Prior art date
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PCT/RU2005/000288
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English (en)
Russian (ru)
Inventor
Irina Vladimirovna Bocharova
Olga Vladimirovna Demikhova
Vladislav Vsevolodovich Erokhin
Lev Evgenievich Pospelov
Vladimir Vladimirovich Balakshin
Aleksey Nikolaevich Chistyakov
Vladimir Jurievich Mishin
Petr Grigorievich Deriabin
Original Assignee
Obschestvo S Ogranichennoi Otvetstvennostju 'berezovy Mir'
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=35782070&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2006001733(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Obschestvo S Ogranichennoi Otvetstvennostju 'berezovy Mir' filed Critical Obschestvo S Ogranichennoi Otvetstvennostju 'berezovy Mir'
Priority to DE112005001443T priority Critical patent/DE112005001443T5/de
Publication of WO2006001733A1 publication Critical patent/WO2006001733A1/fr
Priority to FI20061130A priority patent/FI20061130L/fi

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis

Definitions

  • the invention relates to the field of medicine and veterinary medicine, and more than 5 specifically to the treatment and prevention of tuberculosis. State of the art
  • the treatment of tuberculosis is a lengthy process carried out using 20 (4-5) anti-TB drugs simultaneously.
  • the standard treatment regimen for routine (sensitive) tuberculosis recommended by WHO consists of a six-month daily intake of a standard set of four drugs (rifampicin, isoniazid, pyrazinamide, ethambutol, streptomycin).
  • RF patent Ns 2210379 describes an extract of aspen bark ( ⁇ Guulus tremila).
  • birch bark extract upper, white part of the birch bark
  • FIG. Figure 1 shows a diagram of the effect of betulin on mycobacterium tuberculosis (by selective incorporation of 5,6- [ 3 H] -yracil into living cells).
  • FIG. Figure 2 shows the digram of the effect of betulin on mycobacterium tuberculosis, phagocytosed by macrophages (by selective inclusion of 5, b- [ 3 H] -yracil in living cells)
  • FIG. 3 is a graph showing the percentage of specific lysis of uninfected macrophages (in the presence or absence of betulin in high concentrations) and macrophages that phagocytosed mycobacteria in different ratios (in the presence or absence of betulin in high concentrations).
  • FIG. 4 is a graph of the percentage of specific lysis of uninfected macrophages (in the presence or absence of betulin at low 5 concentrations) and macrophages that phagocytosed mycobacteria in different ratios (in the presence or absence of betulin at low concentrations).
  • FIG. 5 is a diagram showing the specific lysis of uninfected macrophages (in the presence or absence of betulin -2 at low concentrations) and macrophages that phagocytosed mycobacteria in different ratios (in the presence or without betulin-2 at low concentrations).
  • the output of LDH from macrophages into the medium was calculated by the color enzymatic reaction.
  • FIG. 6 is a diagram of the specific lysis of uninfected 15 macrophages (in the presence or absence of betulin in high concentrations) and macrophages that phagocytosed mycobacteria in different ratios (in the presence or without betulin in high concentrations).
  • the output of LDH from macrophages into the medium was calculated by the color enzymatic reaction.
  • the activity of the agents in accordance with the present invention was confirmed not only in 25 ip vitro conditions, but also in ip vivo conditions.
  • Betulin studies were performed ip vivo in a mouse model of active exudation of necrotic tuberculosis and ip vitro in the culture of macrophages infected with MBT (M. tuberusulcis mycobacteria). The following tasks were solved
  • mice 15 vivarium of the Central Research Institute of Tuberculosis of the Russian Academy of Medical Sciences. The weight of the mice is 20 grams. Mice were infected by intravenous administration of M. tubersulosis strain H37Rv from the collection of the Pasteur Institute (France) into the retroorbital sinus of the eye at a dose of 5x10 6 KOE. In preparative amounts, MVTs were obtained in
  • Group 3 infected animals receiving a combination of anti-TB drugs (isoniazid ⁇ rifampicin) - PTP - at a dose of 38 mg / kg-15 pcs.
  • anti-TB drugs isoniazid ⁇ rifampicin
  • Group 5 - infected animals receiving PTP in a standard dose and Betulin at a dose of 50 mg / kg - 15 pcs.
  • the drugs were administered intragastrically, daily, for 2
  • bacterioscopy pieces of the lung, liver, and spleen were subjected to special treatment. From the obtained homogenate of parenchymal organs, smears were prepared, which were stained with luminescent dyes.
  • the number of mycobacteria in the spleen and lungs of infected ⁇ schreib mice was determined 2 months after the start of treatment and 2 months after the end of treatment.
  • Spleens and lungs were homogenized in 2 ml of physiological saline, a series of 10-fold dilutions of the initial suspension in physiological saline was prepared, and 50 ⁇ l of each dilution was placed on a Petri dish coated with Dubot agar.
  • N cel the number of colonies in the spleen
  • the preparation for the study was prepared as follows: the first dilution of the preparation was carried out in 120 ⁇ l of dimethyl sulfoxide (5 mg of birch bark extract was used for each dilution). Then the drugs were diluted in complete RPMI medium
  • the final concentration of the preparations was 160 ⁇ g / ml, 80 ⁇ g / ml, 40 ⁇ g / ml, 2 ⁇ g / ml, 0.2 ⁇ g / ml and 0.02 ⁇ g / ml.
  • Peritoneal macrophages were isolated from mouse peritoneal exudate cells 5-6 days after intraperitoneal injection of 3% peptone. Purification of non-macrophage peritoneal exudate cells was carried out by macrophage adhesion on plastic petri dishes. Attached macrophages were transferred from the monolayer into suspension by Versen's solution. Mycobacteria (MBT) macrophages were infected in flat-bottomed 96-well plates in RPMI medium with 2% FCS.
  • a purified suspension of 5 peritoneal macrophages (50,000 per well) was re-adhesion in the wells of the plate, after which different concentrations of M.tibercylosis (ratio of macrophage mycobacteria (MF: MBT) - 1: 2.5; 1 were added to the formed monolayers of macrophages : 5; 1: 10).
  • Infected macrophages were incubated in a COg incubator overnight for phagocytosis of mycobacteria.
  • test preparation was added to the wells at concentrations of 160 ⁇ g / ml, 80 ⁇ g / ml, 40 ⁇ g / ml, 2 ⁇ g / ml, 0.2 ⁇ g / ml and 0.02 ⁇ g / ml.
  • concentrations 160 ⁇ g / ml, 80 ⁇ g / ml, 40 ⁇ g / ml, 2 ⁇ g / ml, 0.2 ⁇ g / ml and 0.02 ⁇ g / ml.
  • M. tubercylosis H37Rv in the amount of 5x10 5 , 2.5 x 10 , 1, 25 x 10 5 CFU / well
  • 96-well plates were placed in complete RPMI 1640 medium with 2% FCS in a 96-well plate (3 wells per dilution). After a 2-hour incubation in a CO2 incubator (atmosphere - 20% oxygen, 5% carbon dioxide, 37 ° C), the drug was added to the wells at concentrations of 2 ⁇ g / ml, 0.2 ⁇ g / ml and 0.02 ⁇ g / ml . After addition of the preparation, 96-well plates were incubated for 48 hours in a COg incubator under the same conditions. 18 hours before the end of the incubation period, a label (5,6- [ 3 H] -yracil diluted in RPMI 1640 medium with 2% FCS) was added to the wells.
  • a label 5,6- [ 3 H] -yracil diluted in RPMI 1640 medium with 2% FCS
  • the number of labels included in live mycobacteria was measured on a liquid scintillator. About activity the studied drugs were judged by the amount of 5,6- [H] - uracil included in live mycobacteria compared to the intact control. All measurements were performed in triplicates.
  • the cytotoxic effect of the drug on macrophages was evaluated by the release of the destroyed macrophages into the environment of the lactate dehydrogenase enzyme (LDH) using the Protega's SutoTokh 96® kit (Protega).
  • LDH lactate dehydrogenase enzyme
  • drug concentrations 160 ⁇ g / ml, 80 ⁇ g / ml, 40 ⁇ g / ml, 2 ⁇ g / ml, 0.2 ⁇ g / ml and 0.02 ⁇ g / ml were taken.
  • the drug in each concentration was added to a pure culture of peritoneal macrophages, as well as to the culture of peritoneal macrophages infected with M.
  • tubersulosis H37Rv in the ratios of macrophage: mycobacteria (MF: MBT) - 1: 2.5; 1: 5 and 1: 10 (table 1).
  • the results of the color reaction were measured on a photocolorimeter (Sigma) at a wavelength of 490 nm. All measurements were performed in triplicates.
  • 5 are the survival time after infection, the ability to control the multiplication of mycobacteria in opganax (that is, the number of mycobacteria, measured in CFU) and the degree of pathological changes in lung tissue.
  • mice of the control group that did not receive any drugs the survival rate after a lethal dose of infection was 31 + 2.07 days.
  • mice The survival rate of mice after intravenous infection with a lethal dose
  • betulin had an inhibitory effect in all concentrations.
  • betulin in high concentrations (40, 80, 160 ⁇ g / ml) reduced the percentage of specific lysis of macrophages that occurs upon infection with tuberculosis mycobacteria.
  • betulin 0.02, 0.2, 2 ⁇ g / ml
  • the lumen of the blood vessels is markedly widened, filled with a dense red blood cell mass.
  • Monocytes, lymphocytes and eosinophilic leukocytes are determined along its periphery.
  • the high vascular permeability of the respiratory department is evidenced by the release of red blood cells into the surrounding tissue, the formation of multiple small hemorrhages.
  • 15 accumulations of mature macrophages of the phagocytic type, mainly erythrophages, are determined.
  • the interalveolar septa are edematous, moderately infiltrated by mononuclear cells; in the loops of the capillary network polynuclear eosinophils are determined.
  • the spleen of most animals of group 3 was characterized by diffuse, rarely local, white and red pulp infiltration mononuclear cells of varying degrees of maturity. In some cases, large multinucleated macrophages with dark cytoplasm were detected.
  • parenchymal 5 organs had the histological structure closest to normal, pneumonic foci were not determined. Small perivascular accumulations of mononuclear cells were observed without detecting neutrophilic leukocytes. Most of the pulmonary parenchyma remained airy. However, the blood vessels were dilated; in their lumen, accumulations of erythrocytes, monocytes, and eosinophils were determined. The same cellular elements, as well as mature macrophages - erythrophages, were located in the intraalveolar space. No features of the histological structure of organs were revealed depending on the applied dose of betulin (25 or 50 mg / kg).
  • BES was administered intragastrically to mice for two weeks in various
  • the drugs were administered intragastrically, daily, for 2 weeks, after dissolving them in water with a content of 1% TWIN -
  • mice Two weeks after administration, half of the mice were withdrawn from the experiment by cervical dislocation for histological examination of parenchymal organs. Animals of the 9th group were injected intragastrically with Tween-80 in a dose similar to that used in the other 15 experimental groups. The remaining animals were left to assess survival after infection with a virulent MBT culture.
  • mice The survival rate of mice after intravenous infection with a lethal dose
  • mice that received BAS -1 and BES -2 for two weeks before infection lived significantly longer than mice of the control group.
  • the maximum difference in terms of survival rate was between mice of the control group and mice, receiving BES -2 at a dose of 100 mg / kg (p ⁇ 0.001).
  • the lumen of the blood vessels were dilated, filled with accumulations of red blood cells.
  • red blood cells In some areas of the pulmonary parenchyma, blood formed elements entered the surrounding tissues; small, and sometimes large, hemorrhage zones formed.
  • the prophylactic administration of betulin preparations revealed the activation of immunocompetent cells (macrophages, monocytes and lymphocytes), while the degree of activation of immunocompetent cells with the introduction of BAS -2 at a dose of 100 mg / kg was most significant.
  • the first dilution of the drug (5 mg of each drug was used) was carried out in 120 ⁇ l of dimethyl sulfoxide.
  • the preparations were then diluted in complete RPMI 1640 medium.
  • the final concentration of the preparations was 160 ⁇ g / ml, 80 ⁇ g / ml, 40 ⁇ g / ml, 4 ⁇ g / ml, 0.4
  • MF Peritoneal macrophages
  • MMT Mycobacteria
  • a purified suspension peritoneal macrophages (50,000 per well) were re-adhesion in the wells of the plate, after which different concentrations of M.tibercylosis (ratio of macrophymycobacteria (MF: MBT) - 1: 2.5; 1: 5; 1: 10) were added to the formed monolayers of macrophages. . 5 Infected macrophages were incubated in a CO 2 -incubator overnight for phagocytosis of mycobacteria.
  • the test preparation was added to the wells at concentrations of 160 ⁇ g / ml, 80 ⁇ g / ml, 40 ⁇ g / ml, 4 ⁇ g / ml, 0.4 ⁇ g / ml and 0.04 ⁇ g / ml.
  • concentrations 160 ⁇ g / ml, 80 ⁇ g / ml, 40 ⁇ g / ml, 4 ⁇ g / ml, 0.4 ⁇ g / ml and 0.04 ⁇ g / ml.
  • a label (5,6- [ 3 H] -yracil diluted in RPMl 1640 medium with 2% FCS) was added to the wells.
  • the viability of mycobacteria in a mixed culture with macrophages was evaluated by the selective incorporation of M.tibercylosis 5,6- [ 3 H] -yracil into living cells on a liquid
  • the cytotoxic effect of the drug was evaluated by the release of the destroyed macrophages into the medium of the enzyme lactate dehydrogenase (LDH) using the Protega's SutoTox 96® kit (Protega).
  • LDH lactate dehydrogenase
  • the concentration of the drug was taken 160 ⁇ g / ml, 80 ⁇ g / ml, 40 ⁇ g / ml, 4 ⁇ g / ml, 0.4 ⁇ g / ml and 0.04 ⁇ g / ml .
  • the drug in each concentration was added to a pure culture peritoneal macrophages, as well as to the culture of peritoneal macrophages infected with M.
  • the results of the color reaction were measured on a photocolorimeter (Sigma) at a wavelength of 490 nm. All measurements were performed in triplicates.
  • the drug at a concentration of 40 ⁇ g / ml slightly increased macrophage lysis (up to 5.63%).
  • BES-2 exerted a cytotoxic effect on intact macrophages; the percentage of specific macrophage lysis reached 76.06%.
  • the percentage of growth inhibition of mycobacteria did not differ in both low and high concentrations and at concentrations of MBT 1, 25x10 5 and 2.5x10 5 CFU / well ranged from 42.78% to 52.68%.
  • the exception was the concentration of mycobacteria 5x10 5 CFU / well, at which the percentage of inhibition of MBT growth by the drug was significantly lower than at all other MBT concentrations and ranged from 14.25% to 25.57%.
  • the next stage of the study was a comparison of the cytotoxic effect that mycobacteria exert on macrophages without the drug and in the presence of betulin.
  • both high concentrations of the drug 80 and 160 5 m kg / ml
  • the BEC-2 preparation showed antimycobacterial activity with a direct effect on mycobacteria, and the effect was practically independent of the dose of the drug - inhibition of mycobacterial growth was observed both at low (0.04, 0.4, 4 ⁇ g / ml), and at high doses (40, 80, 160 ⁇ g / ml) BES-2.
  • the percentage of inhibition of growth of zo mycobacteria when exposed to BES-2 was higher (up to 52.68%) than the previously studied drug BES-1 (up to 43.99%).
  • the effect of BES-2 on the macrophage-mycobacteria system inhibitory effects were not observed.
  • BES-2 reduced the destruction of macrophages by mycobacteria only in low doses (0.04, 0.4 and 4 ⁇ g / ml). High doses of BES-2 had no such effect.

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Abstract

Cette invention porte sur la possibilité d'utiliser la bétuline et de l'extrait d'écorce de bouleau la contenant pour traiter et prévenir la tuberculose.
PCT/RU2005/000288 2004-06-21 2005-05-27 Agent de traitement et de prevention de la tuberculose WO2006001733A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DE112005001443T DE112005001443T5 (de) 2004-06-21 2005-05-27 Mittel gegen Tuberkulose zur Behandlung und Prophylaxe
FI20061130A FI20061130L (fi) 2004-06-21 2006-12-18 Tuberkuloosia hoitava ja ehkäisevä aine

Applications Claiming Priority (2)

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RU2004118625 2004-06-21
RU2004118625/15A RU2262349C1 (ru) 2004-06-21 2004-06-21 Средство для лечения и профилактики туберкулеза

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KR (1) KR20070072852A (fr)
CN (1) CN101010089A (fr)
DE (1) DE112005001443T5 (fr)
FI (1) FI20061130L (fr)
RU (1) RU2262349C1 (fr)
WO (1) WO2006001733A1 (fr)

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KR100827072B1 (ko) * 2007-01-29 2008-05-02 에스케이건설 주식회사 자작나무 수피로부터 고순도 베츌린를 효율적으로 추출하는방법
RU2385159C2 (ru) * 2007-09-05 2010-03-27 Общество с ограниченной ответственностью "Биотех" Способ получения препарата ягель-м, обладающего противотуберкулезным действием
CN106962893B (zh) * 2017-03-21 2020-10-09 舟山昌国食品有限公司 一种冷冻虾仁品质改良剂

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WO1998034603A1 (fr) * 1997-02-11 1998-08-13 Regents Of The University Of Minnesota Utilisation de la betuline et d'analogues dans le traitement de l'infection par herpesvirus
RU2183965C1 (ru) * 2001-06-27 2002-06-27 Сироткин Геннадий Владимирович Способ профилактики и лечения алкогольной интоксикации
CN1393243A (zh) * 2001-06-28 2003-01-29 郭连英 一种治疗结核病的中药
RU2203081C1 (ru) * 2001-12-13 2003-04-27 Санкт-Петербургская Государственная Химико-Фармацевтическая Академия Препарат ислацет для профилактики и лечения туберкулеза и способ его получения
RU2206572C1 (ru) * 2002-03-12 2003-06-20 Общество с ограниченной ответственностью Химико-биологическое объединение при РАН "Фирма Вита" Способ выделения бетулинола
RU2211035C1 (ru) * 2002-03-18 2003-08-27 Государственное федеральное учреждение Уральский научно-исследовательский институт фтизиопульмонологии Противотуберкулезный препарат

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RU2050855C1 (ru) * 1992-02-04 1995-12-27 Стрелис Айвар Карлович Способ патогенетического лечения больных инфильтративным туберкулезом легких
RU2122424C1 (ru) * 1998-03-18 1998-11-27 Мухина Валентина Афанасьевна Лекарственное средство "савитам", обладающее общеукрепляющим действием
RU2174982C2 (ru) * 1999-11-05 2001-10-20 Институт органической химии Уфимского научного центра РАН 3,28-ди-о-никотинат бетулина, проявляющий гепатопротекторную и анти-вич активность
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WO1998034603A1 (fr) * 1997-02-11 1998-08-13 Regents Of The University Of Minnesota Utilisation de la betuline et d'analogues dans le traitement de l'infection par herpesvirus
RU2183965C1 (ru) * 2001-06-27 2002-06-27 Сироткин Геннадий Владимирович Способ профилактики и лечения алкогольной интоксикации
CN1393243A (zh) * 2001-06-28 2003-01-29 郭连英 一种治疗结核病的中药
RU2203081C1 (ru) * 2001-12-13 2003-04-27 Санкт-Петербургская Государственная Химико-Фармацевтическая Академия Препарат ислацет для профилактики и лечения туберкулеза и способ его получения
RU2206572C1 (ru) * 2002-03-12 2003-06-20 Общество с ограниченной ответственностью Химико-биологическое объединение при РАН "Фирма Вита" Способ выделения бетулинола
RU2211035C1 (ru) * 2002-03-18 2003-08-27 Государственное федеральное учреждение Уральский научно-исследовательский институт фтизиопульмонологии Противотуберкулезный препарат

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VASILENKO J.K. ET AL: "Farmalogicheskie svoystva triterpenoidov kory berezy", EXPERIMENTALNAYA I KLINICHESKAYA FARMAKOLOGYA, vol. 56, no. 4, 1993, pages 53 - 55 *

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FI20061130L (fi) 2006-12-18
RU2262349C1 (ru) 2005-10-20
KR20070072852A (ko) 2007-07-06
CN101010089A (zh) 2007-08-01
DE112005001443T5 (de) 2007-05-16

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