Preparation for decreasing and/or blocking adhesion of pathogenic substances and organisms, application of antiadhesive carbohydrates

FIELD: pharmacology.

SUBSTANCE: the present innovation deals with decreasing and/or blocking adhesion of pathogenic substances and organisms upon eucaryotic cells. The preparation suggested contains, at least, one carbohydrate at structural link of uronic acid at one of its ends. About 10 to 100% available terminal structural links of uronic acids of carbohydrates contain, moreover, a double bond which, in particular, is available between C4- and C5-atoms. The innovation broadens the number of antipathogenic means for eucaryotic cells.

EFFECT: higher efficiency.

17 cl, 13 ex, 1 tbl

 

The invention relates to a drug for reducing and/or blocking the adhesion of pathogenic substances and organisms to eukaryotic cells, particularly mammalian cells, which contain at one of its ends at least one antiadhesive carbohydrate with a structural unit of uronic acid, the use of this drug and it contains carbohydrates for these purposes. The drug is a pharmaceutical or dietetic preparation.

Adhesion of pathogenic organisms and cell damaging substances on the surface of mammalian cells is the first step and an undeniable prerequisite for infection or cell damage. The interaction between pathogens and the cells occurs by binding of the ligand-receptor, which is an important factor of virulence or toxicity of the pathogen. Under the pathogens understands at least bacteria, viruses, fungi, unicellular and multicellular parasites, toxins and heavy metal cations. In these relationships, the ligand-receptor play an important role glycosidic structure.

Able to at least reduce or completely prevent the specified binding ligand-receptor is blocking each receptor on the cell surface or on the ligand.

Using a special test system was able to show that R is lichnye carbohydrate mixture reduce or even completely prevent adhesion, for example, microorganisms on the surface of cells, cf: Kunz, S.; Rudloff, S. Acta Paediatr. 1993, 82, 903-912. Here it was assumed that the active carbohydrates have a broad analogy with the structures of the receptors or ligands. In the described studies were included numerous carbohydrates both animal and vegetable origin, as well as the products of hydrolysis of plant polysaccharides.

The composition and structure of naturally occurring carbohydrates and, for example, carbohydrates breast milk is very complex. The same also applies to carbohydrates of vegetable origin, or to the products of hydrolysis of plant carbohydrates. It follows that the installed anti-adhesive effect of carbohydrates on the pathogens to mammalian cells provides the most carbohydrate mixtures, and not the individual purified patterns.

For example, it is known that aqueous extracts, as well as the juices of various herbal products are effective against diseases caused by pathogenic microorganisms in the intestinal and urogenital tracts. In the application PCT/EP 94/03006 (WO 95/07084) is described, which is prepared in a certain way carrot soup, a diuretic tea, coconut milk, etc. significantly reduce the adhesion of pathogens to epithelial cells zheludochno-intestinal and urogenital tracts. For such action must be responsible is found in vegetable products pectins, in regard to the matter of the chains of 1,4-α-glucosinolates galacturonic. Especially active galacturonic must satisfy various criteria, namely the degrees of polymerization and methylation.

The task of the invention is to find ways of using carbohydrates effective to reduce or prevent adhesion of pathogens by interacting with ligands and/or surface structures of eukaryotic cells, particularly mammalian cells.

The problem is solved according to the claims.

The subject of the invention is, therefore, among other things, pharmaceutical or dietetic preparation, which contains at least one antiadhesive carbohydrate with a structural unit of uronic acid at one end. It is known that carbohydrates have at least two ends and may also have three or more ends, if they are extensive. According to the invention, thus, can be applied to linear carbohydrates and branched carbohydrates. On one of these ends is called a structural unit of uronic acid, which has a terminal COOH group, which may be etherification. Preferably however uronic acid or structural units of uronic acid free or atrificial the HN acids: the galacturonic acid, glucuronic acid, guluronic acid, iduronovoy acid, mannurone acid, Rybarikova acid and ultranova acid, of which especially preferred galacturonic and glucuronic acid.

The proposed product contains at least one antiadhesive carbohydrates and, thus, has a certain peculiarity in the form of a link uronic acid at one end. The proposed remedy, however, may contain several antiadhesive carbohydrates with limit structural unit of uronic acid. It is advisable that the proposed remedy contained a mixture of several antiadhesive carbohydrates such.

Under the antiadhesive carbohydrate in the scope of the present invention understand this carbohydrate, which has a terminal structural unit of uronic acid and does not even depend on whether or not the specified structural unit of uronic acid double bond. In other words, the concept of antiadhesive carbohydrates means the amount of carbs with a structural unit of uronic acid, which contains a double bond, and carbohydrates, which although having a structural unit of uronic acid, but does not contain double bonds. An important idea of the invention is that use such antiadhesive carbohydrates, which have an average content of groups of uronic acids with double the ligature.

Antiadhesive carbohydrates can have a certain degree of polymerization, which is shown here to reduce as DP. Usually however, there are antiadhesive gudivada with different DP, and can be used together different antiadhesive carbohydrates with a degree of polymerization or DP. In other words, the proposed remedy includes at least one certain kind of antiadhesive carbohydrate with a structural unit of uronic acid at one of its ends. This type of carbohydrate has, of course, a specific DP. In addition, you can have several different related species together antiadhesive carbohydrates with the same DP. In addition, can be added antiadhesive carbohydrates with different DP, and with every degree of polymerization can be one or several types of antiadhesive carbohydrates.

In the above definition of specific antiadhesive carbohydrates, which at one end containing a structural unit of uronic acid, does not contain information about the types of structural links saccharides or Monomeric links, which is made up of such antiadhesive carbohydrates, i.e. antiadhesive carbohydrate as if consists of a single structural element (degree of polymerization=DP1), namely structural link uronic acid. Since antiage the active carbohydrate has the DP1, it consists solely of the structural link uronic acids such. If antiadhesive carbohydrate characterized DP2 or more, there may be other structural links saccharides associated with a structural unit of uronic acid.

Only from 10 to 100% of the available structural units of uronic acid antiadhesive carbohydrates must have a double bond. Data in % at this point the number of all present units of uronic acids with a double bond at one end of the antiadhesive carbohydrate with such a structural unit of uronic acid in the calculation of the sum of these parts of uronic acids with a double bond and, if necessary, present units of uronic acids without such double bond at the end of the antiadhesive carbohydrate or antiadhesive carbohydrates.

Structural unit of uronic acid at the end of the antiadhesive carbohydrate usually denoted here as of the end structural unit of uronic acid.

According to the invention suitable for use antiadhesive carbohydrate that contains at the end of such a structural unit of uronic acid at the other end (in the case of an unbranched chain) may contain non structural sahariano link or regenerating structural sahariano link. Preferably antiadhesive ug is euodius, containing from 10 to 100% of the limit of structural units of uronic acid, contains at the other end (in the case of a linear chain) or one of the other ends (in the case of branched chain) restorative structural unit of the saccharide such. In other words, from 10 to 100% of the limit of structural units of uronic acid at the non end. Thus, even everyone end structural units of uronic acid can be non the end.

Preferably from 50 to 100% of the double bonds are located between the C4and C5atoms end structural units of uronic acid. In this case, the data in percent refer to the number of double bonds, regardless DP antiadhesive carbohydrates and forming such antiadhesive carbohydrates sharidny structural links. Definition of double bonds and, therefore, limit structural units of uronic acid such double bonds can be carried out by a spectroscope at 235 nm using the molar extinction coefficient 5500 l/mol, cf TR Kravtchenko, I.Arnold, AGJ Vorlagen&W Polnik. Carbohydr. Polymer 1992, 19, 237-242.

Determination of carbohydrates with regenerating end carried by iodometry according to in: Analytical Chemistry of Carbohydrates. H.Scherz, G.Bonn, Herausgeber Thieme Organic Chemistry Monograph Series, Stuttgart, New York, Thieme Verlag 1998, page 32. Plevo the s with exclusively non ends can be determined by conventional methods of analysis, such as osmometry, mass spectrometry (e.g., MALDI-MS (mass spectrometry with ionization by laser desorption from the matrix), ESI-MS (mass spectrometry with electrospray ionization)), chromatography (e.g., GPC (gel permeation chromatography), NRAES (high-performance anion-exchange chromatography), HPLC) and capillary electrophoresis, or by combinations of these methods.

According to the invention suitable for use antiadhesive carbohydrate along with limit structural unit of uronic acid contains non terminal group, while, for example, healing of the end group may be optionally transferred to non end-group. This can be achieved, for example, oxidation, recovery, or also reestablishes connection terminal group with other molecules. Such other molecules include, for example, proteins, lipids and technical polymers, and are formed (neo)glycoconjugates. This additional change of the reducing end of has no effect on the anti-adhesive effect of the proposed suitable for use antiadhesive carbohydrates. These antiadhesive carbohydrates can thus also be immobilized on the well-known media such as the usual media, through the "ex-first" Voss is analysewww end group.

If from 10 to 100% present limit of structural units of uronic acids have a double bond, this means, of course, that from 0 to 90% present end links uronic acids do not have such a double bond. Preferably from 10 to 50% of the attendees end links uronic acid antiadhesive carbohydrate or antiadhesive carbohydrates have a dual relationship.

Unexpectedly, it was found that in contrast to the previously mentioned application WO 95/07084 neither the degree of polymerization or the degree of methylation is not responsible for the pronounced anti-adhesive function, even if in case you need some of the carbohydrates can have this kind of function. Expressed anti-adhesive function rather refers to carbohydrates with integral structural suenami uronic acids with a double bond. This kind of antiadhesive carbohydrates, in particular, such a structural unit of uronic acid containing a double bond between C4- and5atoms, however, are not described in the application WO 95/0784 that below will be specified more in detail.

If according to the invention it is about the antiadhesive carbohydrate with a given degree of polymerization, it may also be only separate the antiadhesive carbohydrate. But it can also go on several different built anti-Christ. designig carbohydrates, common symptoms of which are, on the one hand, the desired degree of polymerization and, on the other hand, the end structural unit of uronic acid.

Preferably the proposed product contains not only one or more of the antiadhesive carbohydrates with a given DP, but also several antiadhesive carbohydrates with different degree of polymerization. Suitable for use antiadhesive carbohydrates have preferably a degree of polymerization from DP2 to the DP40 and, in particular, from DP2 to DP10 and maximum DP100. Preferably used a mixture of antiadhesive carbohydrates with different chain length. In this case also we can talk about how the antiadhesive carbohydrate with a certain chain length or a specified degree of polymerization as the only form of carbohydrate or several, or any large number of antiadhesive carbohydrates.

Antiadhesive carbohydrates with limit structural unit of uronic acid, in particular in non end groups and containing a double bond, have increased anti-adhesive effect. These antiadhesive carbohydrates in the scope of the present invention have also been identified as unsaturated carbohydrates.

According to the invention used antiadhesive carbohydrates and thus also unsaturated antiadhesive carbohydrates can be half the ENES, for example, the splitting of the net carbohydrate and preferably carbohydrate containing uronic acid by enzymes or chemical means so that the received particular content of the structural units of uronic acids with a double bond. As the preferred source of carbohydrates can be used: pectin, pectate, alginate, chondroitin, hyaluronic acid, heparin, heparan, bacterial carbohydrates and other carbohydrates containing uronic acid. Preferred raw materials are plants and/or plant parts (such as carrots, citrus fruits, beets and apples, compare .Rolin, BU Nielsen, & RE Glahn in Polysaccarides (ed. S.Dimitru), Marcel Dekker, New York, 1998. May also find application algae, animal tissues and bacterial products.

If unsaturated antiadhesive carbohydrates get chemical cleavage, it is done so that the double bond was introduced by β-elimination, splitting, for example, the pectin in a neutral or weakly basic conditions, cf MJH Keijbets&W.Pilnik. Carbohydr. Res. 1974, 33, 359-362.

Enzymatic cleavage is carried out, in particular, by using LiAZ (such as pectinase or Pentacles) and enzyme preparations containing liasu.

In the case of chemical cleavage operate in conditions from neutral to alkaline, in order to obtain desire the th content of double bonds. With an appropriate choice of other parameters, such as temperature, pH and concentration of buffer solution, can also affect the degree of esterification of carboxyl and/or hydroxyl groups. When a higher degree of esterification used parent compounds (e.g., pectin) used according to the invention antiadhesive carbohydrates and thereby unsaturated antiadhesive carbohydrates equally can be obtained by splitting carried out in weakly acidic conditions.

On the anti-adhesive activity of unsaturated antiadhesive carbohydrates is also influenced by the presence of the methyl esters of carboxylic groups, as well as acetylenic esters, such as p-2 and/or 3 atoms of uronic acids. This applies in particular to galacturonic acids, pectin. The degree of methylation or acetylation is preferably from 20 to 75%, in particular from 20 to 50%.

As already mentioned, important in the case of a proposed preferred to use mixtures of antiadhesive carbohydrates have, in particular, a double bond, in particular, in the structural units of uronic acid at the non terminal group. For other structural units of uronic acid containing a double bond or does not contain such double bonds and related sharedname structural units, it can be the t to go about extremely acid structural units of carbohydrates, about the only neutral structural units of carbohydrates and a mixture of acidic and neutral structural units of carbohydrates. Thus, the anti-adhesive activity of unsaturated antiadhesive carbohydrates is also influenced by neutral structural units of carbohydrates. We are basically talking about the rhamnose, arabinose, galactose, xylose, glucose, fucose and apiose, which on its part can be connected with perolini residues and phenolic substances. This applies in particular to the pectin. The share of neutral carbohydrate structural units is thus a maximum of 50%, in particular from 0 to 30%.

Antiadhesive action suitable for use antiadhesive carbohydrates or mixtures antiadhesive carbohydrates depends not only on the concentration in the final product, but also on the quantity entered. Thus, the proposed remedy may consist solely of one antiadhesive carbohydrate or mixture of antiadhesive carbohydrates. In addition, the drug is manufactured, for example, in the form of tablets or in the form of dietary supplements. Needless to say that in the case of a pharmaceutical product can be conventional pharmaceutically acceptable carriers, diluents and/or excipients. These antiadhesive carbohydrates can also be attached to any foods or f is rmaceuticals drugs, that contain other ingredients. In the case of food it can go about fats, proteins, mineral substances, trace elements, vitamins, and other substances that are applicable to obtain food. In addition, you can make proposed for use according to the invention antiadhesive carbohydrates, along with other carbohydrates of any kind.

According to a preferred form of execution in the case of other carbohydrates talking about prebiotic mixture of carbohydrates according to the description of WO 00/08948 international registration number PCT/ER/05878, and it is the prebiotic mixture of carbohydrates from two different, mainly soluble carbohydrate components a and b, which remain undigested in the gastrointestinal tract and not rezorbiruetsa until the large intestine; and the carbohydrate component And constructed of at least one monosaccharide or at least one oligosaccharide (from disaccharide to hexasaccharide) or from a mixture of two or more of these saccharides; and the carbohydrate component In built of polysaccharide (from Gateshead) or of a mixture of two or more polysaccharides; and constitute the carbohydrate component a= 5 to 95 wt.% and the carbohydrate component B= 5 to 95 wt.% from the amount of carbohydrate components a+b (=100 wt%); and at least 80 wt.% carbohydrates/saccharides of the carbohydrate comp the components a and b are prebiotics. For the purposes of the present invention, of course, can only use carbohydrates that are not antiadhesive carbohydrates containing uronic acid, and which correspond to the carbohydrate component and a carbohydrate component C. Thus, the components a and b do not belong to the antiadhesive carbohydrates. These carbohydrates, which correspond to the carbohydrate components a and carbohydrate components, because of their easy availability, denoted hereinafter as prebiotic carbohydrates, although only a portion of these carbohydrates really are prebiotics.

At least 80% carbohydrates or saccharides called prebiotic, from the amount of the carbohydrate components a and b are prebiotics. Preferably prebiotics are at least 80 wt.% called prebiotic carbohydrates related to carbohydrate components a and at least 80 wt.%, related to carbohydrate components Century. Otherwise, preferably at least 80 wt.% called prebiotic carbohydrates or saccharides of the carbohydrate components a and b must be neperevershenymy (and thus preserveratio in the small intestine) and should reach the large intestine. In other words, these carbohydrates or saccharides of the carbohydrate components a and b in the gastrointestinal tract is not rezorbiruetsa no Gelo the ke, neither in the small intestine and enter as such into the large intestine.

Under soluble carbohydrates understand these carbohydrate components a and b, which form in water in a concentration of at least 1 g/l at room temperature homogeneous in the physical sense, the solution (for example, according Roumpps Chemie Lexikon).

Number not applicable prebiotics carbohydrates or sugars in the carbohydrate components a and b is thus a maximum of 20 wt.%. In the case of such carbohydrates or saccharides we are talking about carbohydrates, which although they are soluble, but can stand out undigested. These carbohydrates can have a physical effect, for example, increasing the volume of stool or linking water.

Preferably prebiotic carbohydrates/sugars, which are carbohydrate components And have a different structure than prebiotic carbohydrates/sugars, which predstavlyaet a carbohydrate components Century. Additionally preferred at least 80 wt.% prebiotic carbohydrates/saccharides of the carbohydrate components a and b, which promotirovat and/or are bifidogenic to lactic acid bacteria. Weight fraction of the carbohydrate component And preferably greater than the weight fraction of the carbohydrate component C. the Carbohydrate component a is preferably from 95 to 60 wt.% and, in particular,about 90 wt.%, while the carbohydrate component is preferably from 5 to 40 wt.% and, in particular, about 10 wt.%, and a+b=100 wt.%. Prebiotic gudivada/saccharides of the carbohydrate components a and b, in particular, do not contain glucose structural elements in the α1-4 and/or α1-6-ties. Prebiotic carbohydrates/saccharides of the carbohydrate component In this preferably constructed of a maximum of 100 monosaccharide structural elements.

Further preferably at least 60 wt.% and, particularly, from 80 to 100 wt.% prebiotic carbohydrates/saccharides of the carbohydrate component And belong to the group of galactooligosaccharides and at least 60 wt.% and, particularly, from 80 to 100 wt.% prebiotic carbohydrates/saccharides of the carbohydrate component In belong to the group of fructooligosacharides.

If this kind of prebiotic mixture of carbohydrates present in the proposed drug, the weight ratio of antiadhesive carbohydrate or antiadhesive carbohydrates to prebiotic carbohydrate mixture is preferably from 1:99 to 99:1 and in particular from 1:10 to 10:1 and then in particular about 1:1.

Additionally, the proposed remedy along with antiadhesive carbohydrates and present, if necessary, prebiotic mixture of carbohydrates can also be added other common carbohydrates of any kind. This may IDT is about insoluble carbohydrates, about soluble and digestible carbohydrates on a regular basic, suitable for food purposes carbohydrates (e.g. starch, maltodextrins, lactose and sucrose), or mixtures of one or more of these carbohydrates. Antiadhesive carbohydrate in this case is preferably from 0.1 to 30 and in particular from 1 to 10 wt.%.

With antiadhesive oligosaccharides reach that pathogenic substances not bound to mammalian cells or already associated pathogens dissolved. The addition of prebiotic oligosaccharides are overcome often vorochalsja in connection with pathogens violations of bowel flora. Moreover due to the systemic effect of balanced intestinal flora compete with pathogens in other places than the gastrointestinal tract, such as in the urogenital tract, respiratory tract, circulatory system and the skin.

Since the adhesion of pathogens is a prerequisite for infection or toxicity in all cells of mammals used according to the invention antiadhesive carbohydrate can be implemented to prevent or reduce infections or disorders not only in the gastrointestinal tract, but also in all cells.

Thus, the subject invention is also the use of the proposed drug and its right to use the education antiadhesive carbohydrate to prevent or impede the adhesion of pathogens in eukaryotic cells, and in particular, mammalian cells. Preferably, these carbohydrates are used to treat infections of the gastrointestinal tract, circulatory system, respiratory tract, urinary tract, nasopharynx, and for treating disorders in the cells of the gastrointestinal tract, circulatory system, respiratory tract, urinary tract and nasopharynx caused by toxins or heavy metal cations. The subject of the invention, therefore, is appropriate for use antiadhesive carbohydrate to obtain dietary or pharmaceutical product named for therapeutic purposes.

The application usually is not limited suitable for enteral application of food products or pharmaceutical drugs. Rather, the proposed antiadhesive carbohydrates can also be used as active substances unfit for enteral introduction farmacevticheskih drugs. In the case of the proposed remedies it may go thus not only suitable for enteral use of pharmaceutical drugs.

Enter amount (doses) used according to the invention antiadhesive carbohydrate, and thereby the amount of carbohydrates that contain terminal structural unit of uronic acids without double bonds, and carbohydrates, which are equally soda is RATM end structural unit of uronic acids with a double bond (unsaturated carbohydrates), and from 10 to 100% present limit of structural units of uronic acids contain such a double bond, amount to at least 8 mg/kg of body weight per day, preferably from 8 to 20 mg/kg of body weight per day and, in particular, about 10 mg/kg / day. Such data, in particular, is preferable to one unsaturated antiadhesive carbohydrate.

If the scope of the present invention are talking about intervals, for example,- percentage intervals or intervals in mg, at such intervals include all intermediate values and thus all values between final values, as well as all narrow area covered by the intervals. The indication from 8 to 20 mg/kg thus covers all intermediate values and, in particular, an integer value, for example, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 mg/kg indicating the interval from 10 to 100%, thus, represents only a brief indication valid for all intermediate values and, in particular, for integer values 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99%. This applies, for example, to %the instructions on the number of structural units of uronic acids with one double bond. These instructions are also covered all sorts of narrow intervals. Similarly this applies to the instructions on the intervals that belong to the wt.%, DP or other units.

In the following examples describe preferred preparations according to the invention. Examples 1 through 7 describe the receipt of antiadhesive carbohydrates, and at least 10% of the present structural units of uronic acids contain double bond. The products are drugs which consist exclusively of antiadhesive carbohydrates. In examples 8 through 13 described mixture antiadhesive carbohydrates and prebiotic mixture of carbohydrates in various weight ratios.

Example 1 (enzymatic cleavage)

10 g GENU pectin USP/100 (Fa. Hercules, Copenhagen, Denmark) was dissolved in 1 l of 50 mm NaOAc buffer solution (pH 5.0). To this solution was added 10 ml of pectinase (Sigma, Deisenhofen). The transformation was carried out at 40°C for 24 h the Reaction was interrupted by heating to 100°10 min Enzyme and unreacted pectin was separated by filtration through a 50 kDa membrane. The filtrate is then dried by freezing.

Example 2 (chemical decomposition)

10 g GENU pectin USP/100 (Fa. Hercules, Copenhagen, Denmark) was dissolved in 1 l of 0.2 M NH3-carbonate buffer solution (pH 6.8) and heated for 8 h at 80°C. the Resulting oligosaccaride besieged metal salt (for example, barium salt), filtered, washed, su is or translated in free acid N+the ion exchanger Dowex-50 and was dried by freezing.

Example 3 (enzymatic cleavage)

10 g Laboron pectin X-77 And (..A.Klimmeck, Bad Zwischennahn) was dissolved in 1 l of 50 mm nitroacetate buffer solution (pH 4.5). The digestion was carried out with 1 ml of a solution of pectinase (Fa. Gist-Brocades, Seclin, France) at 45°C for 24 h the Reaction was interrupted by heating to 95°s for 5 min Enzyme and unreacted pectin was removed by gelfiltration through BioGel P2 or TosoHaas HW 40 S. oligosaccharide Fraction was then dried by freezing.

Example 4 (enzymatic cleavage)

10 g Gruenband-pectin (Obipektin, Bischofszell, Switzerland) was dissolved in 1 l of 50 mm nitroacetate buffer solution (pH=4,5). Thereto was added 2 ml of Pectinex 3 XL (Fa. Novo Nordisk, Dittingen, Switzerland). The solution was heated for 24 h to 50°C. termination reaction was performed by heating to 95°With in 5 minutes the Resulting oligosaccaride precipitated with ethanol, washed and dried.

Example 5 (chemical decomposition)

10 g Gruenband-pectin (Obipektin, Bischofscell, Switzerland) was dissolved in 1 l of 0.1 M nutrifaster buffer solution (pH 6.8) and heated for 1 h to 90°C. the Released oligosaccaride precipitated with ethanol, washed and dried.

Example 6 (chemical decomposition)

10 g GENU pectin USP/100 (Fa. Hercules, Copenhagen, Denmark) was dissolved in 1 l of 0.1 M nutrifaster buffer solution (pH 6.8) and heated for 1 h to° C. long-chain polymer besieged hydrochloric acid at pH 2 and centrifuged. Balance oligosaccaride was liofilizovane.

Example 7 (enzymatic cleavage)

10 g of alginate was dissolved in 1 l of 50 mm NaAc buffer solution. To this solution was added 10 ml of alginates. Cleavage was carried out at 40°C for 24 h the Reaction was interrupted by heating to 100°10 min Enzyme and reacted alginate was removed by filtration through a membrane 50 kDa. The filtrate is then dried by freezing.

Examples 8 through 13

To obtain the drug, which, along with antiadhesive carbohydrates also contains prebiotic carbohydrates, did the following.

10 g of oligosaccaride who received either by enzymatic cleavage according to one of examples 1, 3, 4 and/or 1, or a chemical cleavage according to one of examples 2, 5 and/or 6, before drying was mixed and stirred with 10 g of prebiotic mixture of carbohydrates of 9 parts of galactooligosaccharides (for example, Elixor Fa. Borculo und Oligomate Fa. Yakult) and 1 part of a high molecular weight inulin (for example, Raftiline HP Fa. Orafti or Frutafit or EXL. Fa Sensus or Fibruline LC HAT Fa. Cosucra) according to the quantitative proportions shown in the following table.

11
Example

Oligosaccaride
89101213
enzymatic cleavage10 g10 g90 g
chemical cleavage10 g10 g90 g
prebiotic. mixture10 g10 g90 g90 g10 g10 g

Instead mentioned prebiotic mixture of carbohydrates of galacto-oligosaccharides and inulin can also be used a mixture of carbohydrates, which consists of the following components:

α-galactooligosaccharide and inulin, β-galactooligosaccharide and galactomannan, fructo-oligosaccharides, and galactomannan, fructo-oligosaccharides and arabinogalactane, β-galactooligosaccharide and arabinogalactan and xylooligosaccharide and galactomannan.

1. The drug is to reduce and/or block the adhesion of pathogenic substances and organisms in eukaryotic cells, particularly mammalian cells, which contains the antiadhesive carbohydrate or more antiadhesive carbohydrates with a structural unit of uronic acids located at its end or ends, wherein the antiadhesive carbohydrates have a Maxim is inuu degree of polymerization DP 100, from 10 to 100% present limit of structural units of uronic acid antiadhesive carbohydrates have a double bond and from 50 to 100% of the double bonds are located between the C4and C5atoms, the end links of the uronic acid.

2. The preparation according to claim 1, characterized in that it is a pharmaceutical drug.

3. The preparation according to claim 1, characterized in that it is a diet drug.

4. Preparation according to one of claims 1 to 3, characterized in that from 10 to 100% of the antiadhesive carbohydrates end link uronic acids are restoring an end group, and at the other end contain trailing link uronic acid.

5. Preparation according to one of claims 1 to 4, characterized in that from 10 to 50% of the attendees end links uronic acid antiadhesive carbohydrates contain a double bond.

6. Preparation according to one of the preceding paragraphs, characterized in that it contains several antiadhesive carbohydrates with terminal link uronic acids, which have different degrees of polymerization.

7. Preparation according to one of the preceding paragraphs, wherein the antiadhesive carbohydrates have a degree of polymerization from DP 2 to DP 40 and, in particular, from DP 2 to DP 10.

8. Preparation according to one of the preceding paragraphs, wherein the antiadhesive carbohydrates with terminal link uronic the acid obtained from the containing uronic acid carbohydrates, which chemically or enzymatically broken down in such a way that it turns out the specified number of trailing units of uronic acids with double bonds.

9. Preparation according to one of the preceding paragraphs, characterized in that the amount described in the preceding paragraphs antiadhesive carbohydrates per neutral sacharine links is a maximum of 50% and in particular from 0 to 30%.

10. Preparation according to one of the preceding paragraphs, characterized in that the degree of esterification described in the preceding paragraphs antiadhesive carbohydrates methanol up to 75% and in particular from 20 to 50%.

11. Preparation according to one of the preceding paragraphs, characterized in that, along with the antiadhesive carbohydrate or carbohydrates it contains prebiotic mixture of carbohydrates from two different, mainly soluble carbohydrate components a and b, which remain undigested in the gastrointestinal tract and not rezorbiruetsa up to the large intestine, the carbohydrate component And constructed of at least one monosaccharide, or at least one oligosaccharide (from disaccharide to hexasaccharide), or from a mixture of two or more of these sugars, carbohydrate component built In from the polysaccharide (from Gateshead) or from a mixture of two or several polysaccharides, carbohydrate component And sostavlayut 5 to 95 wt.% and a carbohydrate component In from 5 to 95 wt.% from the amount of carbohydrate components a+b (=100 wt.%) and at least 80 wt.% carbohydrates/saccharides of the carbohydrate components a and b are prebiotics, and carbohydrates, which correspond to the carbohydrate component and the carbohydrate component b are not antiadhesive carbohydrates according to claim 1.

12. The drug in claim 11, characterized in that the weight ratio antiadhesive carbohydrate or carbohydrates to prebiotic mixture of carbohydrates is from 1:99 to 99:1 and in particular from 1:10 to 10:1, and hereinafter, in particular about 1:1.

13. Preparation according to one of claims 1, 2, 4-12, characterized in that it contains a customary pharmaceutically acceptable carrier, diluent and/or excipient.

14. Preparation according to one of claims 1, 3 to 12, characterized in that it contains the usual essential nutrients and food components, as well as vitamins and minerals.

15. The application described in claims 1 to 10 antiadhesive carbohydrates with an end link of uronic acid to reduce or impede the adhesion of pathogens in eukaryotic cells.

16. The use of antiadhesive carbohydrates according to 15 in the amount of at least 8 mg/kg of body weight per day and in particular from 8 to 20 mg/kg of body weight per day.

17. Use 15 or 16 for the treatment of infections of the gastrointestinal tract, circulatory system, respiratory tract, urinary tract and nasopharynx and treatment caused by toxins or heavy metal cations violations in the cells of the gastrointestinal tract, circulatory system, respiratory is Uta, urinary tract and nasopharynx.



 

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7 cl, 5 ex

FIELD: medicine.

SUBSTANCE: method involves applying traditional treatment and additionally administering 2 ml of 1% emoxipin solution electrophoresis to epigastric zone at acute stage end daily during 10 days.

EFFECT: accelerated inflammation relief and uterine mucous membrane recovery.

FIELD: medicine, veterinary science.

SUBSTANCE: it is suggested to apply indometophen known previously as a radioprotector. It has been established that application of indometophen at different terms within the first 4 d after irradiation helps to increase survival rate and affect positively the flow of reparative processes in the body at no side effects.

EFFECT: higher efficiency of therapy.

2 tbl

FIELD: biotechnology.

SUBSTANCE: the present innovation deals with obtaining biologically active substances of protein nature out of cereals, moreover it is necessary to isolate a stress separating protein 310 and/or protein being immunochemically similar to that as coarse and/or finely purified extract of the target product. For this purpose one should destruct cellular walls of 3-7-d-aged sprouts due to homogenization to isolate cell-free extract due to centrifuging which should be supplemented with a reagent-precipitator at the first stage under certain conditions to obtain residue followed by isolating a liquid phase which should be subjected to the second of impact with reagent-precipitator under certain conditions, then residue should be separated against a liquid phase due to centrifuging, and an obtained coarsely purified extract of target product should be separated against reagent-precipitator due to dialysis due to the impact of fine purification by gel filtration, if necessary. Moreover, one should conduct this procedure at certain temperature mode, and , if necessary, the extract of target product should be freeze dried. The suggested biologically active substance provides efficient regulation of body energy balance.

EFFECT: higher efficiency.

8 cl, 3 ex

FIELD: pharmacology.

SUBSTANCE: invention proposes use of polysorb as drug with membrane-stabilizing efficacy supplementing early known antioxidant and sorption properties of this substance.

EFFECT: enabled use of polysorb for monotherapy to treat a large number of diseases.

1 tbl

FIELD: prophylactic medicine.

SUBSTANCE: the present innovation deals with curative-prophylactic composition including soybean phospholipid complex being 40-88%, where the content of phosphatidyl choline corresponds to 40-80%, and one or several dry extracts of medicinal plants containing substances of phenolic origin, and their weight ratio to phospholipid complex varies within 1:8 to 1:2, and, also, a dietary biologically active additive based upon the above-mentioned composition.

EFFECT: higher efficiency.

6 cl, 2 ex, 6 tbl

FIELD: pharmaceutical industry.

SUBSTANCE: employment of title compounds is based on their ability of inhibiting NF-κB activation cascade. Invention provides compositions with these acids to treat patients suffering from diseases caused by formation of NF-κB.

EFFECT: expanded therapeutical possibilities.

6 cl, 6 dwg

FIELD: medicine.

SUBSTANCE: the present innovation deals with cyclosporin-containing and practically oil-free compositions being of immunosuppressive action. The composition contains a hydrophilic surface-active substance, a lipophilic component, a lipophilic surface-active substance and ethanol. As a hydrophilic surface-active substance this composition contains ether of fatty acid and polyoxyethylene sorbitane and product of either natural or hydrogenised castor oil and ethylenoxide; as a lipophilic component and lipophilic surface-active substance it contains ether of fatty acid and sorbitane. The suggested composition has been designed as a gelatinous capsule with solid covering. The present innovation solves the problem dealing with stability of galena compositions with cyclosporin: at treating with water the composition develops practically stable microemulsion.

EFFECT: higher efficiency of application.

11 cl, 2 ex

FIELD: coordination compounds synthesis.

SUBSTANCE: invention provides complex comprising calcium and [[(4R)-4[bis[carboxy.kappa.O)methyl]amino-.kappa.N]-6,9-bis[carboxy-.kappa.O)methyl]-1-[(4,4-diphenylcyclohexyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-phosphaundecane-11-ylic acid-.kappa.N6,.kappa.N9,-kappa.011]-oxydato(6-)]-,6H, (MS-325) or its salt with physiologically acceptable cation in each case containing essentially no Gf-MS-325. Also described are pharmaceutical agent based on compounds according to claim 1 and a method for preparing galena composition, complex or its salt with physiologically acceptable cation according to claim 1 intended for preparation of pharmaceutical agent reducing effect produced by heavy metals as well as complex or its salt with physiologically acceptable cation according to claim 1 intended for preparation of pharmaceutical agent suitable for NMR diagnostics and/or diagnostic radiology, a method for amplifying patient's image in NMR tomography based on compounds according to claim 1 and above defined complex or its salt with physiologically acceptable cation in each case containing essentially no visualizing metal chelates and MS-325.

EFFECT: increased assortment of complexes with useful medicine-destination properties.

14 cl, 4 dwg, 30 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes a novel pentasaccharide conjugate of the formula (I):

wherein R represents independently -SO-3 or -CH3; insert represents a flexible insert of length 13-25 atoms. Charge of a pentasaccharide residue is equilibrated with positively charged counterions and the total amount of sulfate groups in a pentasaccharide residue is 4, 5 or 6. Also, invention relates to a method of its preparing and pharmaceutical composition based on thereof and used in treatment of diseases mediated or associated with thrombin.

EFFECT: improved preparing method, valuable medicinal properties of conjugate.

9 cl, 2 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes a novel pentasaccharide conjugate of the formula (I):

wherein R represents independently -SO-3 or -CH3; insert represents a flexible insert of length 13-25 atoms. Charge of a pentasaccharide residue is equilibrated with positively charged counterions and the total amount of sulfate groups in a pentasaccharide residue is 4, 5 or 6. Also, invention relates to a method of its preparing and pharmaceutical composition based on thereof and used in treatment of diseases mediated or associated with thrombin.

EFFECT: improved preparing method, valuable medicinal properties of conjugate.

9 cl, 2 ex

FIELD: veterinary science.

SUBSTANCE: as biologically active substances one should apply succinic acid 4-6 mg%, riboxin 4-6 mg%, vitamin B12 0.8-1.0 mcg%, silver 2 x 10-7 M - 2 x 10-9 M; moreover, the mentioned biologically active substances should be applied in balanced soluble form at applying drinking water purified with a filters system: mechanical, ion-exchange, coal and antibacterial Millipore 0.22 μ that contains no foreign admixtures. The present innovation enables to restore hepatic function, normalize urinary pH, restore renal filtration capacity and this, in its turn, enables to prevent renal lithogenesis, restore intestinal microflora, restore animal hairy integument and prolong their active life period.

EFFECT: higher efficiency of normalization.

1 cl, 3 ex

FIELD: organic chemistry, antibiotics, pharmacy.

SUBSTANCE: invention describes crystalline forms A, C and D of erythromycin derivative of the formula (VII): . Crystalline forms are prepared by recrystallization of crude fumarate crystal from an alcoholic solvent (form A) and, additionally, from ethyl acetate (form C) or, additionally, from an aqueous ethyl acetate (form D). Also, invention relates to methods for preparing intermediate compounds. Prepared crystalline forms possess the better quality, in particular, high stability that is important in preparing pharmaceutical preparations.

EFFECT: improved preparing methods.

16 cl, 8 dwg, 13 ex

FIELD: medicine.

SUBSTANCE: method involves introducing sulfatide having 14-18 carbon atoms in fat acid chain to a patient. The sulfatide acts upon sulfatide metabolism in a way that sulfatide quantity grows insulin reserve in Langerhans islets is retained.

EFFECT: enhanced effectiveness of treatment.

10 cl, 6 dwg, 2 tbl

FIELD: medicine, hematology.

SUBSTANCE: invention proposes an agent for reducing blood and plasma viscosity. Agent represents "Reamberin-1.5% for infusion" known early as an antioxidant and detoxifying agent. Invention provides normalization of blood rheological properties expressed as plasma viscosity and blood viscosity indices in patients, among them, in children and elimination of hemodynamic indices and in the absence of undesirable adverse effects.

EFFECT: valuable medicinal properties of preparation.

2 tbl, 2 ex

FIELD: medicine, surgery.

SUBSTANCE: one should apply a polycompositional film onto donor's wounds after autodermoplasty performed. This film contains the following components in weight proportions: chitosan 78.3-89.4; polyvinyl alcohol 9.8-19.8; antibiotic of aminoglycoside group 0.5-2.0; anesthetic 0.1-0.2. It is perforated at tension coefficient being 1:4. The innovation enables to decrease wound's traumatization, improves prophylaxis of suppuration and increases cosmetic effect even at a single application of the film suggested.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine, surgery.

SUBSTANCE: the present innovation deals with treating patients in early post-operational period after interferences in mediastinal and esophageal organs. One should conduct the course of subxyphoidal bolus injection of lymph-stimulating mixture containing 64 U lidase diluted in 1 ml 5%-glucose, 25 mg suspension of hydrocortisone followed by slow drop-by-drop injection of 500 mg metrogil during the first 3 d of post-operational period. The innovation provides high concentration of curative preparations in operation region at decreasing their dosages, decreased toxic effects and risk of purulent-inflammatory complications due to stimulating drainage-detoxication function of lymph system.

EFFECT: higher efficiency.

1 ex

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating malignant tumors of mammary gland in case no tumor penetration into thoracic fasciae. The method suggested includes autohemochemotherapy. Moreover, on the 1st d of therapy it is necessary to sample 30 ml blood out of patient's peripheral vein into the 1st vial to combine its content with 500 mg 5-fluorouracil and 600 mg cyclophosphan; then one should sample 20 ml blood into the 2nd vial to combine its content with 40 mg doxorubicin; both vials should be incubated at 37-37.5 C for 20-30 min, afterwards its necessary to inject the mixtures out of both vials under the tumor and along its circumference. On the 8th d of therapy one should repeat impact procedures at the same dosages of anti-tumor preparations and at the same order. The innovation suggested enables to develop the largest concentration of anti-tumor preparations in lesion focus, divide into fragments, decrease tumor's size and its inflammatory component and border it against surrounding tissues for performing radical surgical treatment.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine, clinical pharmacology.

SUBSTANCE: the present innovation deals with peroral intake of antibacterial and antacidic remedies, omeprasol. Moreover, for introduction one should apply suspended mixture of 1-2 antibacterial preparations with antacidic remedies to be applied onto mucous membrane of the affected organ with possibility for medicinal localization. As antibacterial preparations one should apply clarithromycin at a single dosage of 50 mg, amoxicillin 100 mg. As for course dosages of these preparations they equal to 1600 mg and 3200 mg, correspondingly. As antacidic remedy one should apply almagel. The innovation enables to decrease dosages of medicinal preparations considerably due to preventing the losses of these preparations during absorption into the blood and their delay on mucous membrane of affected organs at entering submucosal layer.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine.

SUBSTANCE: method involves carrying out hernia removal in intralaminar way. Posterior longitudinal ligament defect is covered with Tacho-Comb plate after having done disk cavity curettage. Subcutaneous fat fragment on feeding pedicle is brought to dorsal surface of radix and dural sac.

EFFECT: enhanced effectiveness of treatment; reduced risk of traumatic complications.

1 dwg

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