Feed supplement for aids patients (versions)

FIELD: medicine.

SUBSTANCE: invention is related to a food product for AIDS patients. Proposed is a food composition containing one or more acidic oligosaccharide(s) and one or more neutral oligosaccharide(s) and cysteine and/or a cysteine source. The acidic oligosaccharides are produced from pectin, pectate, alginate, chondroitin, hyaluronic acids, heparin, heparan, sialoglycanes, fucoidan, fucooligosaccharides or carageenan. The neutral oligosaccharides are selected from a group consisting of galactooligosaccharide, fructooligosaccharide, transgalactooligosaccharide, xylooligosaccharide, lactosucrose and arabinooligosaccharide where the said cysteine source is represented by N-acetylcysteine and/or diacetylcysteine, whey, beestings, egg whites or combination thereof.

EFFECT: invention enables preclusion and prevention of AIDS-related disfunctions.

12 cl, 1 tbl, 7 ex

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to a nutritional product for patients with HIV. More specifically, the invention relates to a food composition, which provides carefully selected nourishing ingredients, specifically supporting HIV patients with symptoms related to nutrition. This invention also relates to the production of nutritional supplements for patients with HIV.

PRIOR art

Infection with human immunodeficiency virus (HIV) and the development of acquired immunodeficiency syndrome (AIDS) have a significant impact on domestic and global health, social, political and economic consequences. Globally, the number of HIV-1 infected individuals exceeds 40 million, most of whom live in Asia, Africa (sub-Saharan and South America. Despite all therapeutic benefits achieved in the last decade, including the development of highly active antiretroviral therapy (“HAART”), once an individual becomes infected, the destruction of the virus still remains impossible.

It is now recognized the importance of nutritional support for HIV-infected people. Infected patients may have an increased need for primary energy, protein, and is microelement due to metabolic stress, which they carry. This stress, combined with anorexia and malabsorption associated with disease, contributes to the development of malnutrition. Malnutrition in General effect, for example, on immunocompetent, (working) performance and perception. The extra power helps these patients to improve their overall nutritional status.

Currently, the market offers several products for nutritional support of patients with HIV. Various commercial vendors have several clinical nutritional products on the market, listed below.

1. Advera, Ross Abbott

The distribution of calories:

Protein: 18,7% (hydrolyzed soy protein, sodium Caseinate)

Carbohydrates: 65,5% (maltodextrin, sucrose, cellulose soybean)

Fat: 15.8 percent (Canola, MCT, refined Devdariani oil sardines 1,5 e%)

Calories: 1,28 kcal/ml

2.Resource, Novartis

The distribution of calories:

Protein: 14% (Caseinates sodium and calcium, soy protein isolate)

Carbohydrates: 64% (corn syrup, sugar)

Fat: 22% (sunflower oil with high oleic acid corn oil)

Calorie: the 1.06 kcal/ml

3.Benecalorie, Novartis

The distribution of calories:

Protein: 9% (calcium Caseinate)

Carbohydrate: 0%

Fat: 91% (sunflower oil with high oleic acid, mono-and diglycerides)

Calories: 7 kcal/ml

4.Boost, Mead Johnson, at this time the product is delivered Novartis

The distribution of calories:

Protein: 24% (milk protein concentrate, Caseinates Ca & Na)

Carbohydrates: 55% (solids corn syrup, sugar)

Fat: 21% (canola, sunflower oil and corn with high oleic acid content)

Calories: 1,01 kcal/ml

However, despite the availability of products that support the General nutritional requirements of HIV-infected patients, there are no available food, which further significantly reduce or prevent specific symptoms related to HIV infection, particularly of the immune dysfunction, intestinal dysfunction and/or status of glutathione in patients.

The INVENTION

Current dietary requirements of patients with HIV have the disadvantage that they do not provide a General solution for all the power-related medical problems of patients with HIV, especially those related to infection immune dysfunction, intestinal dysfunction and/or status of glutathione. In one embodiment, the present invention relates to the use of oligosaccharides and cysteine and/or source of cysteine in the manufacture of a composition for use in the method of treatment and/or prevention of HIV or AIDS, and the method including the et in the introduction to the specified mammal specified composition, containing a therapeutically effective amount of the oligosaccharide and cysteine and/or source of cysteine. In yet another embodiment, the composition additionally contains one or more polyunsaturated fatty acids (PUFA) and/or one or more biologically active compounds, particularly compounds produced from milk.

The present invention provides a complete food additives, suitable for food treat patients with HIV. Food additives of the present invention contain at least 2, preferably at least 3 component supports bowel function in a patient, the status of glutathione (GSH) and/or immune function. It has been unexpectedly discovered that by careful selection of the combinations of food ingredients some of the power-related side effects of HIV infection (i.e., the symptoms related to the infection) can be prevented and/or reduced significantly. Found that the effect is much better when a few of the symptoms related to the disease, were selected as the target than when the patient received only one of the individual ingredients, as practiced before.

A healthy gut and a healthy intestinal flora complex way connected with healthy immune function. The potential immunomodulatory effects through specificscondition/oligosaccharides may be mediated by effects on the composition of the intestinal flora (documented immune effects types of bifidobacteria and lactic acid bacteria) and/or function (fermentation kletchatki produces compounds such as fatty acids with short-chain that affect General and immunological function of intestinal cells). Unexpectedly, the inventors have discovered that a molecule DC-SIGN, dendritic cells may be blocked by some oligosaccharides. Because blocking this molecule can potentially prevent transmission of HIV, the use of these oligosaccharides to block receptor DC-SIGN and for the production of compositions for the prevention and/or treatment of diseases mediated by DC-SIGN (especially HIV and AIDS), provided in one embodiment of the invention.

DETAILED description of the INVENTION

Common definitions

“Oligosaccharide” refers to the carbohydrate chains of monosaccharide units with chain length between 1 and 5000, more preferably between 2 and 250, more preferably between 2 and 50, most preferably between 2 and 10.

“Degree of polymerization” or “SP” refers to the total number sharidny units in the oligosaccharide chain. “The average SP” refers to the average SP oligosaccharide chains in the composition, without taking into the account the possible mono - or disaccharides (which are preferably removed in case of presence). The average SP of the composition used to distinguish between songs. Preferably, the average degree of polymerization of the oligosaccharide chains is between the 2 and 100, more preferably between 3 and 250, for example between 3 and 50.

“Simultaneous introduction of two or more substances refers to the introduction of these substances to a single person or in a single composition or in separate compositions (set of parts; as a combined composition), which are one and the same time (simultaneously) or within a small time interval (separate or sequential use, for example, within minutes or hours).

The term “containing” are to be interpreted as indicating the presence of installed parts, stages or components but does not preclude the presence of one or more additional parts, stages or components.

“Percentage” or “average” in General refers to the percentage or the average of the mass until otherwise indicated or until until it becomes clear that imply a different basis.

“GOS” or “galactooligosaccharide” or “TRANS - galactooligosaccharide” or “TOS” refers to oligosaccharides, composed of galactose units.

“The treatment and/or prevention of HIV” refers to a significant reduction or prevention of one or more symptoms/dysfunction related to HIV infection selected from immune dysfunction, intestinal dysfunction and/or low status of glutathione. In one embodiment, Uchenie or prevention of HIV refers to a significant reduction (or prevention) HIV due to the blockade of the receptor DC-SIGN, as will be clear from the context.

“A significant reduction or prevention” refers to the reduction of the symptom (or HIV), at least, 5, 10, 15, 30, 50 or even 100% compared with control patients who do not enter the composition in accordance with the invention. The symptoms can be measured, as is known in the technical field, such as immune dysfunction can be assessed by measuring the accounts of CD4+. Blocking receptor DC-SIGN can be determined, as in Example 1.

The problem to which the present invention is directed, is to provide food compositions suitable for the treatment of HIV patients, to improve their nutritional status and at least two, preferably at least three symptoms related to HIV. Compositions in accordance with the invention are particularly applicable for patients with a score of CD4+T cells, which is below the critical level of approximately 700 cells/μl blood, when in the General case HAART therapy is not necessary, but when patients are already or are experiencing one or more of the immune, intestinal and/or related to glutathione dysfunction.

Thus, these compositions are suitable for preventing and/or treating one or more disorders related to HIV, in particular the military:

1. Immune dysfunction, i.e. reduction of accounts CD4+T cells, leading to impaired immune function;

2. Intestinal dysfunction, i.e. problems with the intestines, specifically HIV-induced impaired absorption and diarrhea; and/or

3. Low status of glutathione, especially low levels of glutathione in the blood and intracellular T-cells.

In a preferred embodiment, the compositions are suitable for treating or preventing at least, immune dysfunction, and low status of glutathione. These compositions contain suitable quantities of both oligosaccharides and cysteine and/or source of cysteine. In yet another embodiment, the compositions additionally contain a suitable amount of one or more polyunsaturated fatty acids and/or one or more biologically active compounds and are suitable for the treatment or prevention of all three of the above dysfunctions.

Because CD4+T cells are infected and destroyed by HIV, the HIV virus can be routinely and regularly recorded by measuring the account of CD4+T-lymphocytes in the circulation. The initial period after HIV infection, which can last from three to more than ten years, is characterized by a slow but gradual decline in the General account of CD4+T cells, without apparent symptoms, reduced soprotivlenie and infections. The first signs of infectious complications usually occur when scores of CD4+T cells is lower than 700 cells/μl blood. At this point, HIV-seropositive man can endure respiratory (cough, chills, fever) and/or gastro-intestinal (intestinal discomfort, diarrhea) symptoms. These symptoms are relatively mild and can be considered as subclinical; although annoying person, they are usually not severe enough to lead to hospitalization or early highly active antiretroviral treatment (HAART).

One of the types of cells initially colliding with the human immunodeficiency virus type 1 (HIV-1) after the sexual transmission method are dendritic cells (DC). DC capture HIV-1 through latinovich receptor With a-type, of which the most studied example is the DC-SIGN, which mediates the internalization of HIV-1. DC can withstand a viral infection in a few days and are able to transmit HIV-1 to CD4(+) T cells. As described in Example 1, the authors present invention unexpectedly found that oligosaccharides can contact DC-SIGN.

Composition and application in accordance with the invention

Compositions in accordance with the invention are suitable for treatment and/or prevention of HIV and/or AIDS in a mammal. Patients who predstavlyaet preferably a people, HIV and containing an account of CD4+approximately 700 cells per µl of blood or less, more preferably in the range of between approximately 200 and 700 cells / µl of blood, for example, between approximately 200 and 500 cells or approximately 200 and 600 or 500 and 700 cells / μl blood. In one embodiment, patients have a score of CD4+equal to 700 or less, but not those who are undergoing highly active antiretroviral therapy (HAART).

In one embodiment, the nutritional compositions are preferably food additives and contain oligosaccharides and cysteine and/or source of cysteine.

Oligosaccharides

Compositions in accordance with the invention contain a therapeutically effective amount of the oligosaccharide, preferably acidic oligosaccharides and/or neutral oligosaccharides, as described below.

Acidic oligosaccharides contain at least one acid group, while the neutral oligosaccharides do not have such acid groups. Developed dietary fiber largely to provide their impacts, are conducive to health. Some of cellulose are insoluble and are not exposed to enzymes and pass unchanged through the intestines. Other types of kletchatki can serve as prebiotics, i.e. on the and used by the bacteria of the intestine and stimulate their growth. Thus, documented that fiber, such as inulin or oligosaccharides, such as galactooligosaccharide (GOS) and fructo-oligosaccharides (FOS) stimulate the growth of bifidobacteria and lactic acid bacteria, which are important for healthy intestinal flora.

Acidic oligosaccharides

The term “acidic oligosaccharide(s)” refers to oligosaccharides containing at least one acid group selected from the group consisting of N-acetylneuraminic acid, N-glycolylneuraminic acid, free or esterified carboxylic acid group, sulfuric acid group and phosphoric acid. In one embodiment, the acidic oligosaccharide preferably represents polyhexes. Preferably, at least one of the above-mentioned acid group located on the terminal unit hexose acidic oligosaccharide. Preferably, the acidic oligosaccharide has the structure as depicted in figure 1, where the end hexose (left) preferably contains a double bond. Preferably, the acidic oligosaccharide contains a carboxylic acid on the terminal unit hexose where the specified carboxylic acid group can be free or esterified. Methods of production of esterified pectin hydrolysates, which can suitably be used in the crust is the yaschih method and compositions provided in WO 01/60378 and/or WO 02/42484, which are included in this description by reference. Unit hexose other than terminal units(s) hexose may preferably be units of uronic acids, even more preferably units of the galacturonic acid. The carboxylic acid group on these units can be free or partially esterified and preferably at least 10% methylated (see below).

Figure 1. Polymeric acidic oligosaccharide

where:

R is preferably selected from the group consisting of hydrogen, hydroxy or acid groups, preferably hydroxy; and

at least one Deputy, selected from the group consisting of R2, R3, R4and R5represents N-acetylneuraminic acid, N-glycolylneuraminic acid, free or esterified carboxylic acid group, sulfuric acid group and phosphoric acid, and the remaining R2, R3, R4and R5represent hydroxy and/or hydrogen. Preferably one Deputy selected from the group consisting of R2, R3, R4and R5represents N-acetylneuraminic acid, N-glycolylneuraminic acid, free or esterified carboxylic acid group, sulfuric acid group and FOS who priori acid, and the remaining represent hydroxy and/or hydrogen. Even more preferably one Deputy selected from the group consisting of R2, R3, R4and R5represents a free or esterified carboxylic acid, and the remaining R2, R3, R4and R5represent hydroxy and/or hydrogen; and

n is an integer and refers to the number of units of hexose (see also Degree of Polymerization below), which can be any unit of hexose. Suitably, n is an integer in the range of 1-5000. Preferably the unit (unit) hexose are the unit of uronic acid.

Most preferably R1, R2and R3represent hydroxy, R4is hydrogen, R5represents carboxylic acid, n is a number between 1 and 250, preferably between 1 and 10 and a unit of hexose is a galacturonic acid.

Detection, measurement and analysis of acidic oligosaccharides as used in the present method, are given in an earlier patent application of the applicant, related to the acidic oligosaccharides, i.e. WO 01/60378, which is incorporated in this description by reference.

Preferably, the acidic oligosaccharide has one, preferably two end units of uronic acid, which can be free or this is aficionada. Preferably, end unit uronic acid selected from the group consisting of a galacturonic acid, glucuronic acid, guluronic acid, iduronovoy acid, mannurone acid, Rybarikova acid and alternova acid. These units can be free or esterified. In one embodiment, end unit hexose has a double bond, which is preferably located between the provisions of the4and C5end unit hexose. Preferably one of the end units hexose contains a double bond. End hexose (e.g., uronic acid) preferably has a structure in accordance with Figure 2.

Figure 2. The preferred acid end group hexose

where:

R is preferably selected from the group consisting of hydrogen, hydroxy or acid groups, preferably hydroxy (see above); and

at least one Deputy, selected from the group consisting of R2, R3, R4and R5represents N-acetylneuraminic acid, N-glycolylneuraminic acid, free or esterified carboxylic acid group, sulfuric acid group and phosphoric acid, and the remaining R2, R3, R4and R5represent hydroxy and/or hydrogen. Preferably one Deputy shall stitely, selected from the group consisting of R2, R3, R4and R5represents N-acetylneuraminic acid, N-glycolylneuraminic acid, free or esterified carboxylic acid group, sulfuric acid group and phosphoric acid, and the remaining of R2, R3, R4and R5represent hydroxy and/or hydrogen. Even more preferably one Deputy selected from the group consisting of R2, R3, R4and R5represents a free or esterified carboxylic acid, and the remaining R2, R3, R4and R5represent hydroxy and/or hydrogen; and n is an integer and refers to the number of units of hexose (see also Degree of Polymerization below), which can be any unit of hexose. Suitably, n is an integer in the range of 1-5000, representing the number of units of hexose, and these units hexose preferably are units of uronic acids, even more preferably units of the galacturonic acid. The carboxylic acid group on these units can be free or partially esterified and preferably at least partially methylated.

Most preferably R2and R3represent hydroxy, R4before the hat hydrogen and R 5represents a free or esterified carboxylic acid.

In one embodiment, the compositions contain a single type of acid oligosaccharide (having a uniform degree of polymerization), while in another embodiment, the compositions contain a mixture of acidic oligosaccharides, which have different Degrees of Polymerization (SP) and/or contain both saturated and unsaturated end unit hexose. Preferably, at least 5%, more preferably at least 10%, even more preferably at least 25% of the limit of units of glucose acidic oligosaccharide is unsaturated unit hexose (see, e.g., Figure 2). Because each individual acidic oligosaccharide preferably contains only one unsaturated end unit hexose, preferably not more than 50% of end units hexose is unsaturated unit hexose (i.e. contains a double bond).

A mixture of acidic oligosaccharides preferably contains between 2 and 50% unsaturated units hexose in the calculation of the total number of units hexose, preferably between 10 and 40%.

Acidic oligosaccharide as used in the present method has a degree of polymerization (SP) from 1 to 5000, preferably from 1 to 1000, more preferably from 2 to 250, even more preferably from 2 to 50, most preferably from 2 to 10. If you use a mixture of acid oligosaccharides with different degrees of polymerization, average SP of a mixture of acidic oligosaccharide preferably equal to from 2 to 1000, more preferably from 3 to 250, even more preferably from 3 to 50. Cm. also Figure 1, where the sum of “n” and the terminal units (i.e. n+1) represents the degree of polymerization. It was found that lower SP oligosaccharide improves palatability and leads to reduced viscosity of the product, if the acidic oligosaccharide is administered in liquid form. Acidic oligosaccharide may be a homogeneous or heterogeneous carbohydrate.

Acidic oligosaccharides used in the invention, preferably derived from pectin, pectate, alginate, chondroitin, hyaluronic acid, heparin, heparan, bacterial carbohydrates, sialogogues, fucoidan, followsamerican or carrageenan, preferably from pectin and/or alginate. Acidic oligosaccharides can be obtained by methods described in WO 01/60378, such as chemical or enzymatic hydrolysis or partial hydrolysis, see page 8 and 9, which is incorporated herein by reference.

Alginates are linear unbranched polymers containing residues of β-(1→4)-linked D-mannurone acid and α-(1→4)-linked L-guluronic acid with sorokiniana average molecular masses (100-100000 residues). Suitable sources of alginate include algae and bacterial alginates.

Pectin is divided into two main categories: vysokomehanizirovannyh pectin, which is characterized by a degree of methoxylation above 50%, and nizkokaloriyny pectin having a degree of methoxylation below 50%. As used here, implies that “the degree of methoxylation (also referred to as SCS or “degree of esterification”) means the degree to which group of free carboxylic acid contained in the circuit polygalacturonic acid were tarifitsirovana (e.g., by methylation). Presents acid oligosaccharide is preferably obtained from vysokomehanizirovannogo pectin.

Acid(e) oligosaccharides preferably characterized by a degree of methoxylation above 20%, preferably above 50%, even more preferably above 70%. Preferably acidic oligosaccharides have a degree of methylation above 20%, preferably above 50%, even more preferably above 70%.

Acidic oligosaccharide(s) is preferably introduced in an amount of from about 10 mg to 100 grams per day, preferably from about 100 mg to 50 grams per day, even more preferably from about 0.5 to 20 grams per day.

Neutral oligosaccharides

As mentioned above, the composition may also contain od is n or more neutral oligosaccharides, either instead of or in addition to one or more of the acidic oligosaccharides. One or more neutral oligosaccharide selected from the group consisting of cellobiose, allocstring,-cyclodextrin, neperebrodivsego dextrin, gentiopicroside, glucooligosaccharides, isomaltooligosaccharides, isomaltose, isomaltulose, Panoz, lacrose, palatinose, tenderoni, D-agatz, D-lyxo-hexulose, lactosucrose, α-galactooligosaccharides, β-galactooligosaccharides, transplantationfollow, lactulose, 4'-galatosidase, synthetic galactooligosaccharide, fructans - Levan-type fructans - Inulin-type 1 f-β-fructofuranosidase, lacto-N-tetraaza, lacto-N-neoteroi, xylooligosaccharide, Latinos, lactosucrose and arabinopyranoside.

Preferably the neutral oligosaccharide selected from the group consisting of galactooligosaccharide, fructooligosaccharide, transplantologiia, xylooligosaccharide, lactosucrose and arabinopyranoside. Even more preferably neutral oligosaccharide selected from the group consisting of galactooligosaccharide, fructooligosaccharide and transplantologiia.

Preferably the composition contains two chemically different neutral oligosaccharide, one of which is selected from the group consisting of neutral oligosaccharide-based gala is cozy, and the other is chosen from the group of the oligosaccharide on the basis of fructose and/or glucose.

More preferably the composition contains fructooligosaccharide and at least one oligosaccharide selected from translatological and galactooligosaccharide.

The preferred daily amount of neutral oligosaccharides comprise from about 10 mg to 100 grams per day, preferably from about 100 mg to 50 grams per day, even more preferably from about 0.5 to 20 grams per day.

Preferably using a composition containing neutral and acidic oligosaccharides, where at least 15% of the total oligosaccharides consist of acidic oligosaccharides, more preferably from 10 to 90%, and most preferably from 25 to 75%. Preferably using a composition where at least 25% of the oligosaccharides are acidic oligosaccharides containing at least one terminal unit of uronic acid.

Cysteine or source of cysteine

The provided compositions contain in addition to one or more oligosaccharides, as described above, a suitable amount of cysteine and/or source of cysteine. The phrase “source of cysteine” refers here to all compounds that contain bioavailable cysteine, in any form, and is calculated as the number of amino acids qi is Thein, which is present in the compound or can be produced from a compound in the body after ingestion, on a molar basis.

Below here cysteine equivalent” refers to the number of cysteine per se or the number of cysteine, which is present in the source of cysteine. For example, 100 mg NAC (N-acetylcysteine; MM=163,2) is equivalent to 74 mg cysteine (MM 121,15). Thus, 100 mg of NAC is 74 mg cysteine equivalent. Similarly, it can be applied to proteins or peptides. When peptide (MM = kdalton) contains 3 amino acids cysteine (Walton), then 100 mg of this peptide equivalent Hu/X mg of cysteine. Thus, 100 mg of this peptide is 300 u/x mg cysteine equivalent.

Suitable sources of cysteine in accordance with the invention are, for example, proteins in denatured and/or Undenatured form, such as milk proteins, proteins such as whey or casein. Egg whites are rich in cysteine and, therefore, are also applicable. Vegetable proteins, such as peas, potatoes, soybeans and rice can also be used to provide cysteine. Can also be used hydrolysates of these protein sources or fractions enriched in proteins or peptides rich in cysteine (e.g., as described in ER). In addition, there may be used synthetic cysteine is equivalent, for example, derivatives of cysteine, such as cysteine, salts of cysteine, N-acetylcysteine and/or deacetylation.

HIV-infected patients appropriately administered a daily dose equal to at least about 100 mg cysteine equivalent, preferably at least about 200, 400 or 600 mg cysteine equivalent per day. Understand that the daily dosage may be divided into 2, 3 or more dosage units taken several times a day.

In yet another embodiment, the compositions according to the invention contain one or more compounds that stimulate the levels of glutathione, such as lipoic acid, pyruvate, oxaloacetate, oxaloacetic have the ability to boost levels of glutathione. Such compounds that stimulate glutathione levels, can be used in addition to cysteine, but also instead of cysteine. In yet another embodiment, the composition containing one or more oligosaccharides and cysteine and/or source of cysteine optionally contain one or more fatty acids and/or one or more biologically active compounds, such as compounds found in milk or probiotic microorganisms.

Probiotic microorganism

Probiotic micro-organism means an organism that has a positive effect on The H patient by improving its intestinal microbial balance (Fuller, R. J. Applied Bacteriology, 1989; 66:365-378). The probiotic microorganism may be selected from one or more microorganisms that are suitable for human consumption and which have the ability to improve the microbial balance in the gut. Preferably, the present composition contains from 104up to 1012more preferably from 105up to 1011most preferably from 107up to 5×1010kolonialismus units (CFU) of probiotic bacteria per gram of oligosaccharide with uronic acid with JV between 2 and 100. The present composition preferably contains from 102up to 1013kolonialismus units (CFU) of probiotic bacteria per gram dry weight of the present composition, preferably from 104up to 1012more preferably from 105up to 1010most preferably from 105up to 1×109some. Dosage of probiotic bacteria in accordance with the present invention is preferably between 102up to 1013more preferably from 105up to 1011most preferably from 108up to 5×1010kolonialismus units (CFU) per day. Preferably use a live or viable bacteria, but can also be applied dead bacteria or bacterial fragments.

Preferably the present composition comprises bacteria of the genus Lactobaillus and/or Bifidobacterium. Preferably the composition contains Bifidobacterium selected from the group consisting ofB. longum,B. breveandB.bifidumand/or Lactobacillus selected from theL. casei,L. paracasei,L. rhamnosus,L. acidophilisandL. plantarum. Most preferably the present composition containsBifidobacterium breveand/orLactobacillus paracasei.

Bifidobacterium breveis a gram-positive anaerobic, rod-shaped bacterium. ThisB. brevepreferably has at least 95% identity to the sequence of the nucleic acid sequence of the 16 S grnc when compared with the type strain ofB. breveADS 15700, more preferably at least 97%, 98%, 99% or more sequence identity, as defined in Stackebrandt &Goebel, 1994, Int. J. Syst. Bacteriol. 44:846-849. The identity of the nucleic acid sequence count for two nucleotide sequences, when they are optimally aligned using the programs GAP or BESTFIT using default parameters. Use the default parameters of GAP c is fine for creating gap = 50 (nucleotides)/ 8 (proteins) and the penalty for creating a gap = 3 (nucleotide)/ 2 (protein). For nucleotides one used by the matrix calculation is the default nwsgapdna (Henikoff &Henikoff, 1992, PNAS 89, 915-919). Obviously, when they say that RNA sequences are essentially similar or have a certain step is ery sequence identity with the DNA sequence thymine (T) in the DNA sequence is considered equal to uracil (U) in RNA sequences. Sequence alignment and evaluation of the percent sequence identity may be determined using computer programs such as the GCG Wisconsin Package, Version 10.3, available from Accelrys Inc., 9685 Scranton Road, San Diego, CA 92121-3752, USA or EMBOSSwin. v. 2.10.0.Bifidobacteriumused in the present invention it is preferable's hybrid probeB. breveand gives the signal in the method of analysis with the 5'-nuclease, as described in the considered simultaneously with the present application of international patent application PCT/NL2004/000748 and European patent application 05075486.0 the present applicant. In accordance with a preferred embodiment the present composition contains at least oneB. breveselected from the group consisting ofB. breveBb-03 (Rhodia),B. breveM16-V (Morinaga),B. breveR0070 (Institute Rosell, Lallemand), DSM 20091 and LMG 11613. Most preferably,B. breverepresents aB. breveM16-V (Morinaga).

In a preferred embodiment, the present composition containsLactobacillus paracasei. Preferably this strain ofL. paracaseihas at least 95%, more preferably at least 97%, 98%, 99% or more sequence identity of the nucleic acid sequence of the 16 S grnc when compared with the type strain ofL. paracaseiADS, as specified above.Lactobacillusused in the present invention, it is preferable's hybrid probeL. paracaseiand gives the signal in the method of analysis with the 5'-nuclease, as described in the considered simultaneously with the present application European patent application 05075486.0 the present applicant. In accordance with the preferred embodiment, the present composition contains at leastL. paracaseiselected from the groupL. paracaseiF19 (Arla, Sweden),L. paracaseiLAFTI L26 (DSM Food Specialties, the Netherlands) andL. paracaseiCRL 431 (Chr. Hansen, Denmark), LMG 12165 and LMG 11407.

Polyunsaturated fatty acids:

The authors of the present invention found that eicosapentaenoic acid (EPA, n-3) and gamma-linolenic acid (GLA, n-6) effectively reduce inflammatory mediated intestinal permeability in tight contact. Therefore, provided a composition suitable for improving the integrity of the intestinal barrier, which contains (in addition to oligosaccharides and cysteine and/or source of cysteine) EPA and/or GLA. Based on the biochemical pathways, we propose the hypothesis that other combinations of fatty acids are also effective. Thus, also provided is a composition containing one or more other polyunsaturated fatty acids or mixtures thereof. For example, there may be used a mixture of any of the EPA, docosahexaenoic acid (DHA, n3), di-Homo-gammalinolenic acid (DPC, C20:3n-6), stearidonic acid (STK, C18:4n-4), alpha-linolenic acid (ALA, C18:3n-3), docosapentaenoic acid (KDP, C22:5n-3), eicosatetraenoic acid (C20:4n-3) and/or arachidonic acid (AA, n-6).

Appropriately apply a relatively high daily dose of polyunsaturated fatty acids. In one embodiment, use of at least approximately 25 EN%, preferably at least about 30 EN%, more preferably at least about 35 EN% fat mixture containing n-3 and/or n-6 fatty acids (EN% is a brief expression of interest energy distribution and represents the relative amount that each component contributes to the total caloric content of the product). The preferred daily amount is at least 1 gram polyunsaturated fatty acids, more preferably between 1-50 grams of DHA, more preferably between 5 and 25 grams of polyunsaturated fatty acids and most preferred is a number between 7.5 and 15 grams of DHA.

Optimal fat mixture may, for example, contain 40% oil borrajo and 60% of fish oil. Then the ratio of acids n-3/n-6 is between 1-2 and the mass percentage of n-3 is between 20-40, and n-6 is between 15-35 of the total content of fatty acids. Oil of borrajo may be partially or completely replaced by m the scrapping of evening primrose.

Therefore, the preferred daily amount is at least 0.1 grams of EPA and 0.05 grams of GLA, more preferably from 0.1 to 5 grams of EPA and from 0.05 to 2.5 grams of GLA, more preferably from 0.5 to 2.5 grams of EPA and from 0.25 to 1.25 grams of GLA and most preferred is a number from 0.75 to 1.5 grams of EPA and from 0.37 to 0.75 grams of GLA.

Biologically active ingredients

Compositions in accordance with the invention can additionally contain one or more biologically active molecules, preferably of components found naturally in milk. These include growth factors, immunoglobulins and other milk components or components made from milk.

A. growth Factors

It was found that milk growth factors are favorable for intestinal health. Transforming growth factor-beta, insulin-like growth factor and growth factors keratinocytes are the most important examples of mammary growth factors. Therefore, in one embodiment, the compositions optionally contain one or more growth factors, for example approximately 1-500 μg of growth factors in the day.

Century Immunoglobulins

It is shown that immunoglobulins serve as protection against intestinal infections, and compositions in accordance with the invention suitably contain d is Chou dose of from 0.1 to 10 g immunoglobulins.

C. Other ingredients

Also found that other bioactive ingredients derived from milk, such as nucleotides, fatty acids, oligosaccharides have a favorable effect on the barrier function of the intestine and can therefore appropriately be used in the production of compositions.

D. Colostrum

In one embodiment, the compositions contain colostrum. Colostrum is a pre-milk fluid secreterial Breasts mammalian mothers after childbirth, in particular cows after calving. Colostrum contains many biologically active ingredients of milk and, therefore, is an excellent source of biologically active molecules. Colostrum as a source of protein, has the additional advantage of providing cysteine. To provide favorable effects on patients with HIV, at least about 5 grams of colostrum provide on a daily basis, preferably at least about 10 grams, more preferably at least about 20 grams per day or more.

Extracts of milk proteins, such as the extract of growth factor serum, as described in ER, extract or casein, as described in WO02083164, concentrates immunoglobulins, lactoferrin or other concentrated fractions of serum also mo is ut be used to improve the barrier function of the intestine of patients with HIV.

It is clear that biologically active molecules or components can be obtained using a number of ways. Many are commercially available or can be produced synthetically, by recombinant DNA technology or they can be (partially) purified or extracted from natural sources such as milk. Can also be used a mixture of any biologically active molecules or components containing these molecules.

Compositions suitable for blocking DC-sign receptor

In yet another embodiment, provided compositions suitable for the treatment and/or prevention of diseases mediated by DC-sign, such as HIV or AIDS. Such compositions contain a suitable amount of oligosaccharides, especially acidic oligosaccharides, as described herein above in Example 1. Preferred are oligosaccharides, which have an IC50 value of approximately 1000, 600, 400, more preferably 200 μg/ml or less, such as 150, 100, 50, 25 μg/ml or less. The IC50 value can be determined using methods known in the art (see example 1).

These compositions may optionally further contain cysteine and/or source of cysteine, polyunsaturated fatty acids, etc. as described herein elsewhere. Oligosaccharides can be obtained in the form of finished form in the form of pharmaceutical compositions or the AK composition of the food or food additive (as described here below for songs, containing oligosaccharides and cysteine and/or source of cysteine).

The guide finished pharmaceutical forms which are suitable for different types of introduction, can be found in Remington''s Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17thed. (1985).

Food composition and dietary supplements

It was found that oligosaccharides and cysteine and/or source of cysteine can be favorably used in food, such as food for infants and clinical food. Such food preferably contains lipids, proteins and carbohydrates and may be in liquid or solid form. The term “liquid food”, as used in the present invention, includes dry food (e.g., powders), which are accompanied by instructions on how to mix the specified dry food mixture with a suitable liquid (e.g. water). Solid food includes food in the form of a bar of the additive with the water activity of 0.2 to 0.4. Water activity can be defined as the ratio of the pressure of the water vapor product to the vapor pressure of pure water at the same temperature. The solid product should meet the requirement of water activity, otherwise the product will be unstable during storage. Also provided semi-solid foods and dietary supplements.

Therefore, the present invention also relates to a food composition, which in addition to this oligos is haredim and cysteine and/or source of cysteine preferably contains from 5 to 50 EN% lipid, from 10 to 60 EN% protein, between 15 to 85 EN% carbohydrate. In the context of this invention it should be understood that the oligosaccharides in the compositions of the present invention does not supply calories and, therefore, are not included in the CN%mentioned here. All proteins, peptides, amino acids do not contribute calories and, therefore, are not included in the CN%mentioned here. In one embodiment, the food composition contains from 15 to 50 EN% lipid, between 25 and 60 EN% protein and 15 to 45 EN% carbohydrate. In yet another embodiment, nastasha food composition contains from 15 to 50 EN% lipid, between 35 and 60 EN% protein and 15 to 45 EN% carbohydrate.

Preferably used lipids, which have a high content of EPA or GLA. Fish oil and the oil borrajo or evening primrose are the preferred sources of these fatty acids.

The source of digestible carbohydrate can be added to food formula. It preferably provides from about 25 to 40% of the energy of the food composition. Can be used with any suitable source of carbohydrate, such as sucrose, lactose, glucose, fructose, solids corn syrup and maltodextrins, and mixtures thereof.

Preferably the vitamins and minerals present in quantities as required by regulations FSMP.

Diarrhea is a major problem in many HIV patients who are square-liquid food. It was found that stool be reduced with the introduction of these oligosaccharides in dry food compositions or liquid food composition, which has osmollnosti from 50 to 500 mOsm/kg, more preferably from 100 to 400 mOsm/kg

With this in mind, the food composition preferably does not supply excess calories. Therefore, the nutritional composition preferably does not contain more than 500 kcal/daily dose, more preferably from 200 to 400 kcal/daily dose and more preferably from 250 to 350 kcal/daily dose.

In accordance with the above, the present invention relates to food compositions containing:

a) oligosaccharides, preferably oligosaccharides contain, at least, acidic oligosaccharides, preferably in such amounts that provide a daily dose of from 10 mg to 100 grams per day, preferably from about 100 mg to 50 grams per day, even more preferably from about 0.5 to 20 grams; and

b) cysteine and/or source of cysteine, where preferably at least 0.1 g cysteine equivalent is provided in a daily dose; and optional

C) one or more biologically active ingredients (for example, colostrum) and/or polyunsaturated fatty acids (such as EPA and/or GLA), preferably where at least 1 gram polyunsaturated fatty acids, more preferably 1-50 grams of the NLC, more preferably, from 5 to 25 grams of polyunsaturated fatty acids and even more preferably from 7.5 to 15 grams of DHA comes in a daily dose, also preferably at least 0.1 grams of EPA and 0.05 grams of GLA, more preferably from 0.1 to 5 grams of EPA and from 0.05 to 2.5 grams of GLA, more preferably from 0.5 to 2.5 grams of EPA and from 0.25 to 1.25 grams of GLA and even more preferably from 0.75 to 1.5 grams of EPA and from 0.37 to 0.75 grams of GLA comes in a daily dose.

In one embodiment, the food composition contains from 5 to 50 EN% lipid, between 35 and 60 EN% protein, between 15 and 60 EN% carbohydrates, acidic oligosaccharides and cysteine and/or source of cysteine, where the source of cysteine selected from the group consisting of NAC, whey, colostrum, egg proteins, or mixtures thereof.

In yet another embodiment, the food composition contains from 15 to 50 EN% lipid, between 35 and 60 EN% protein, between 15 and 45 EN% carbohydrates, acidic and neutral oligosaccharide oligosaccharide and cysteine and/or source of cysteine, where the source of cysteine selected from the group consisting of NAC, colostrum, egg proteins or combinations thereof.

The food composition preferably is or are introduced in the form of a dietary Supplement. This food composition or food additive may preferably be used in the treatment of patients with HIV, where the method includes the introduction of a specified composition or additive mammalian what usamu, preferably the person infected with HIV.

Also provided is a method of production of a composition for use in treating and/or preventing HIV infection, where the method includes:

- providing a suitable number of one or more oligosaccharides;

- provision of an adequate supply of cysteine and/or source of cysteine;

- getting ready form both of the above components in a suitable composition of the food or food additive or pharmaceutical compositions.

The following examples illustrate the invention. Until not differently stated, in the practice of the present invention will be used standard methods of molecular biology, pharmacology, immunology, Virology, Microbiology or biochemistry. Such methods are described in Sambrook and Russel (2001) Molecular Cloning: A Laboratory Manual, Third Edition, Cold Spring Harbor Laboratory Press, NY, Volumes 1 and 2 of Ausubel et al. (1994) Current Protocols in Molecular Biology, Current Protocols, USA and Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17th ed. (1985), Microbiology: A Laboratory Manual (6th Edition) by James Cappuccino, Laboratory Methods in Food Microbiology (3rd edition) by W. Harrigan (Author) Academic Press, all incorporated herein by reference.

EXAMPLES

Example 1. Blocking the binding of DC-SIGN - Fc acidic oligosaccharides and GOS

It is shown that blocking DC-SIGN prevents viral translocation from dendritic cells to CD4 T cells. The authors and is gaining unexpectedly discovered, that oligosaccharides can block DC-SIGN with different efficiency. Acidic oligosaccharides (KOS), like hydrolyzed pectin, are the most active, as shown in Table 1. These results show that KOS can prevent the binding of the Fc fragments with DC-SIGN at the lowest concentration.

TABLE 1
The EFFICIENCY of binding of DC-sign a OLIGOSACCHARIDES
OligosaccharideI.C. 50 (µg/ml)
Acidic oligosaccharide (hydrolyzed pectin)200
Galactooligosaccharide (Transplantological)600
Fructooligosaccharides (Inulin HP)>1000

Materials and methods:

Oligosaccharide preparations applied on the plate ELISA in serial dilutions. Binding of DC-SIGN - Fc was measured in ELISA using anti-DC-SIGN-Fc, and visualize adding a labeled secondary antibodies. OD was measured with a spectrophotometer (Becton Dickinson) after 20 minutes of incubation. The results are presented as the inhibitory concentration at 50% inhibition.

Example 2. The composition of the food bar

The original substancecodeg/dayproteing/100g
ColostrumSR20,0015,0027,38
Oil of borrajo (Ropufa 25 n-6)20003424,000,005,48
Oil EPA-DHA (Maruha)20012926,000,008,21
Galactooligosaccharide (elixir or syrup)200118915,380,0021,06
Inulin (Raftiline HP)20011900,790,001,08
Acidic Oligosaccharides (gidrol. pectin)SR8,540,11of 11.69
N-acetyl-CysteineSR 1,83of 1.342,50
Fructose syrupJJ13,200,0018,07
GlycerinJJ3,300,00to 4.52

Per day
KcalEN.%
Energy protein6626,9
Energy carbohydrates82the 33.4
Energy fat9739,7
245

Example 3. The composition of the food bar

The original substancecodeg/dayBel. UHL.fatg/100g
ColostrumSR20,0015,002,100,8021,04
Oil of borrajo (Ropufa 25 n-6)20003424,000,000,004,004,21
Oil EPA-DHA (Maruha)20012926,000,000,006,00of 6.31
Galactooligosaccharide (elixir or syrup)200118915,380,004,780,0016,18
Inulin (Raftiline HP)20011900,790,000,000,000,83
Acidic Oligosaccharides (gidrol. pectin) SR8,540,110,090,008,98
The powder of eggshell membrane21,0916,870,000,0022,19
Fructose syrupJJ15,400,0011,920,0016,20
GlycerinJJ3,850,003,830,004,05
AMOUNT95,0531,9822,7210,80100,00

Per day100 g
Kcal EN.%Kcal
Energy protein12840,5135
Energy carbohydrates9128,896
Energy fat9730,8102
AMOUNT316332

Example 4. Composition powder

The original substancecodeg/dayBel.UHL.fatg/100g
ColostrumSR20,0015,002,100,8029,39
Oil of borrajo (Ropufa 25 n-6)20003424,000,000,00 4,005,88
Oil EPA-DHA (Maruha)20012926,000,000,006,008,82
STATE/MD DE2 powder200118914,780,007,660,0021,72
Inulin (Raftiline HP)20011900,790,000,000,001,16
Acidic Oligosaccharides (gidrol. pectin)SR8,540,110,090,0012,55
N-acetyl-CysteineSR1,83of 1.340,000,002,69
MD DE47MM7,000,01 6,750,0210,29
MD DE47MM5,000,014,820,017,35
SSL (emulsifier)SHS0,110,000,000,110,17
AMOUNT68,0516,4621,4110,94100,00

Per day100 g
KcalEN.%Kcal
Energy protein6626,397
Energy carbohydrates8634,3 126
Energy fat9839,4145
AMOUNT250367

Example 5. Composition powder

The original substancecodeg/dayBel.UHL.fatg/100g
ColostrumSR20,0015,002,100,8019,95
Oil of borrajo (Ropufa 25 n-6)20003424,000,000,004,003,99
Oil EPA-DHA (Maruha)20012926,000,000,006,005,98
STATE/MaltoDex(DE2 powder) 200118914,780,007,660,0014,74
Inulin (Raftiline HP)20011900,790,000,000,000,79
Acidic Oligosaccharides (gidrol. pectin)SR8,540,110,090,00charged 8.52
Alpha-lactalbumin (Davisco)34,0331,210,170,1733,94
MaltoDex DE47MM7,000,016,750,026,98
MaltoDex DE47MM5,000,014,820,01 4,99
SSL (emulsifier)SHS0,110,000,000,110,11
AMOUNTto 100.2546,3321,58to 11.11100,00

Per day100 g
KcalEN.%Kcal
Energy protein185to 49.9185
Energy carbohydrates8623,286
Energy fat10026,9100
AMOUNT372371

Example 6. W is DCA food composition

The original substancecodeg/dayBel.UHL.fatg/100g
Oil of borrajo (Ropufa 25 n-6)20003424,000,000,004,0010,67
Oil EPA-DHA (Maruha)20012926,000,000,006,0016,00
Galactooligosaccharide (elixir or syrup)200118915,380,004,780,0041,01
Inulin (Raftiline HP)20011900,790,000,000,002,11
Acidic Oligosaccharides (gidrol. pectin) SR8,540,110,090,0022,77
The powder of eggshell membraneSR21,0916,870,000,0056,24
WPH (cysteine peptide)SR0,000,000,000,00
MaltoDextrin DE47MM18,800,0218,120,0550,13
AMOUNT74,6017,0022,99of 10.05198,93

Per day100 g
Kcal EN.%Kcal
Energy protein6827,2181
Energy carbohydrates9236,7245
Energy fat9036,1241
AMOUNT250668

Example 7. Liquid food composition

6,00
The original substancecodeg/dayBel.UHL.fatg/100g
Oil of borrajo (Ropufa 25 n-6)20003424,000,000,004,0010,67
Maruha oil EPA-DHA20012926,000,000,0016,00
Galactooligosaccharide (elixir or syrup)200118915,380,004,780,0041,01
Raftiline HP (inulin)20011900,790,000,000,002,11
KOS (gidrol. pectin)SR8,540,110,090,0022,77
WPH (cysteine peptide)SR24,1920,830,920,0264,51
MD DE47MM13,500,0213,010,0336,00
AMOUNT72,4020,5 18,8010,06193,07

Per day100 g
KcalEN.%Kcal
Energy protein8433,6223
Energy carbohydrates7530,1201
Energy fat9136,3241
AMOUNT250665

1. The application of one or more acidic and one or more neutral oligosaccharides and cysteine and/or source of cysteine in the manufacture of a composition for treatment and/or prevention of HIV or AIDS in humans, and this composition contains a therapeutically effective amount of acidic and neutral oligosaccharides, where acidic oligosaccharides derived from pectin is estate, alginate, chondroitin, hyaluronic acid, heparin, heparan, sialogogues, fucoidan, focalisation or carrageenan, and neutral oligosaccharide selected from the group consisting of galactooligosaccharide, fructooligosaccharide, transplantologiia, xylooligosaccharide, lactosucrose and arabinopyranoside, and where the specified source of cysteine is an N-acetylcysteine and/or deacetylation, whey, colostrum, egg whites or a combination thereof.

2. The use according to claim 1, where the serum, colostrum or egg whites are at least partially gidrolizovannykh.

3. The use according to claim 1 or 2, where cysteine and/or source of cysteine provide at least 100 mg cysteine equivalent daily dose.

4. The use according to claim 3, where the cysteine and/or source of cysteine provides at least 600, preferably at least 1000 mg, cysteine equivalent daily dose.

5. The use according to claim 1 or 2, where the acidic oligosaccharides are hydrolyzed pectin.

6. The use according to claim 1 or 2, where the neutral oligosaccharide is a mixture of fructooligosaccharide and galactooligosaccharide.

7. The use according to claim 1 or 2, where at least 15% and not more than 90% of the total oligosaccharides consist of acidic oligosaccharides.

8. The use according to claim 1 or 2, where the composition additionally contains what it polyunsaturated fatty acids (Pufas).

9. Food composition containing from 15 to 50 EN.% lipid, from 25 to 60 EN.% protein, 15 to 45 EN.% carbohydrates, acidic oligosaccharide derived from pectin, pectate, alginate, chondroitin, hyaluronic acid, heparin, heparan, sialogogues, fucoidan, focalisation or carrageenan, preferably hydrolyzed pectin and neutral oligosaccharide selected from the group consisting of galactooligosaccharide, fructooligosaccharide, transplantologiia, xylooligosaccharide, lactosucrose and arabinopyranoside, and cysteine or NAC and/or deacetylation, whey, colostrum, egg whites or a combination thereof.

10. The food composition according to claim 9, where the specified lipid contains eykozapentaenovuyu acid (EPA) and/or gamma-linolenic acid (GLA).

11. Food composition containing from 15 to 50 EN.% lipid, from 35 to 60 EN.% protein, 15 to 45 EN.% carbohydrates, acidic oligosaccharide derived from pectin, pectate, alginate, chondroitin, hyaluronic acid, heparin, heparan, sialogogues, fucoidan, focalisation or carrageenan, preferably hydrolyzed pectin and neutral oligosaccharide selected from the group consisting of galactooligosaccharide, fructooligosaccharide, transplantologiia, xylooligosaccharide, lactosucrose and arabinopyranoside, and cysteine or NAC and/or deacetylation, whey, colostrum, Yaya is the major proteins or combinations thereof.

12. The food composition according to claim 11, where the specified lipid contains EPA and/or GLA.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to (5H-pyrazolo[1,5-c][1,3]benzoxazin-5-yl)phenylmethanone derivatives (I), useful as HIV viral replication inhibitors, as well as pharmaceutical compositions, use thereof as medicinal agents.

EFFECT: disclosed compounds are meant for preventing or treating HIV infection and treating AIDS.

7 cl, 2 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds described by a structural formula wherein: R1 is chosen from a group including R9-phenyl, and R2 is chosen from a group including H and (C1-C6)-alkyl; R3 is chosen from a group including (C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl- and R9-(C6-C10)-aryl; R4, R5, R6 and R7 are independently chosen from a group including H and (C1-C6)-alkyl; R8 is chosen from a group including и ; R9 means 1, 2 or 3 substitutes independently chosen from a group, including H, halogen and -CF3; R10 is chosen from a group including H and (C1-C6)-alkyl; R11 is (C3-C10)-cycloalkyl-S (O2)-; R15 and R16 are independently (C1-C6)-alkyl; R17 is R20O-; R20 is chosen from a group including H, and (C1-C6)-alkyl-(C6-C10)-aryl; Q is N; Z is CH; n is equal to 0; s is equal to 2; and t is equal to 2. Also, the invention concerns a pharmaceutical composition exhibiting properties of a chemokine receptor inhibitor, based on these compounds.

EFFECT: produced are the new compounds and based pharmaceutical composition can find application in medicine for treating human immunodeficiency virus (HIV) infection.

8 cl, 2 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel 5-substituted pyrimidines of general formula (I), their pharmaceutically acceptable additive salts probably in form of their stereochemically isomeric form. In general formula (I), A represents -CH2-CH2-, -CH=CH-; each of R1 independently represents hydrogen; R2 represents cyano; X1 represents -NR1-; R3 represents H, C1-6-alkyl, halogen; R4 represents H, C1-6-alkyl, halogen; R5 represents nitro, amino, mono- and di(C1-4-alkyl)amino, phenyl, probably substituted by halogen, halogen, -CO-H-, -COOR7, -NH-C(=O)H, -NH-C(=O)R6, -CH=N-O-R8; R6 represents C1-4-alkyl, amino, mono- or di(C1-4-alkyl)amino or polyhalogen-C1-6-alkyl; R7represents hydrogen, C1-6-alkyl; R8 represents hydrogen, C1-6-alkyl. Invention also relates to pharmaceutical composition based on novel compounds.

EFFECT: elaborated are compounds which possess antiviral activity with respect to HIV infection.

7 cl, 2 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: compounds have formula (lb) in which R1 denotes (1) -N(R1A)SO2-R1B, (2) -SO2NR1CR1D, (3) -COOR1E, (4) -OR1F, (5) -S(O)mR1G; (6) -CONR1HR1J, (7) -NR1K COR1L, or (8) cyano, where m equals 0, 1 or 2;X denote a bond or a spacer which contains 1-3 atoms as the backbone chain; ; R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1K and R1L each independently denotes (1) a hydrogen atom, (2) a C1-8alkyl group which can have a substitute (substitutes) selected from a group comprising [1] a hydroxy group, [2] a carboxy group, [3] a C1-6alkoxy group which can be substituted with a halogen and [4] a mono- or disubstituted amino substituted C1-8alkyl group or (3) tetrahydropyran, piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl, and where R1C and R1D, or R1H and R1J together with a nitrogen atom to which they are bonded can form piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl; ring A is a benzene ring or a pyridine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl, nitro, C1-6alkoxy and halogen; ring B is a benzene ring, a pyridine ring or a pyrazine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl; R51 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (2) benzene, pyrazole, pyridine, isoxazole, thiophene, benzothiazole, each of which can have a substitute (substitutes) selected from a group comprising C1-4alkokyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylthionyl, C1-6alkylsulphonyl and halogen; R52 denotes a hydrogen atom; R53 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (3) benzene, pyrazole, pyridine, thiophene, benzodioxane, cyclohexan or tetrahydropyran, each of which can have a substitute (substitutes) selected from a group comprising [1] hydroxy group, [2] cyano, [3] carbamoyl, [4] aminocarbonyl, substituted with one or two substitutes selected from (a) hydroxy group, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group, (e) carboxyl and (f) C1-6alkoxycarbonyl, [5] carboxy, [6] halogen, [7] C1-6alkoxy, [8] C1-6alkylsulphonyl, [9] amino, [10] C1-6acylamino, [11] alkyl-sulphonylamino, [12] cyclic aminocarbonyl and [13] C1-8 hydrocarbon group substituted with 1 or 2 substitutes selected from (a) hydroxy, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group and (e) aminocarbonyl, substituted with a C1-8 hydrocarbon group; to salts thereof, N-oxide thereof and solvate thereof. The invention also relates to a pharmaceutical composition based on said compound, having antagonistic activity towards CCR5, to use of formula (1b) compound to produce an agent for preventing or treating CCR5 related diseases. Novel compounds which have anti CCR5 activity are obtained and described. Said compounds are therefore useful in preventing and/or treating CCR5 related diseases, for example various inflammatory diseases, immunological diseases etc.

EFFECT: wider field of use of the compounds.

7 cl, 11 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention discloses pharmaceutical composition for controlled release regarding toxic active compounds, in particular, bioactive proteins from class of interferons. Composition contains bio-degradable block-copolymer made of poly(ethyleneglycol)terephthalate (PEGT) in amount from 50 to 95%, and poly(butyleneterephthalate) (PBT). Agent may be represented as injection microparticles, injection liquid, capable of independent gel or solid implant formation. Besides, invention provides a pharmaceutical set, including specified composition, methods of composition making and pharmaceutical versions of its application.

EFFECT: invention provides for initial release within 4 hours of not more than approximately 10% of included amount of one or more alpha-interferons and at least 80% of one or more alpha-interferons are released in monomer non-aggregated form.

31 cl, 8 ex, 2 dwg

FIELD: medicine.

SUBSTANCE: present invention refers to a spray drying production process of a solid pharmaceutical powder containing microcrystalline cellulose in a solid dispersion of the anti-HIV compound etravirine (TMC125) in a water-soluble polymer. In a parent mixture, the relation of the water-soluble polymer to TMC 125 makes 10:1 to 1:1, and of microcrystalline cellulose to TMC 125 - 1:1 to 1:3. Said parent mixture of microcrystalline cellulose, a solution of the water-soluble polymer and etravirine is sprayed in the form of drops into a drying chamber by atomisers to form a solid dispersion of TMC 125 powder.

EFFECT: better solubility and bioavailability of the antiviral compound etravirine.

10 cl, 9 dwg, 2 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to heterocyclic compounds of formula I or their stereo isomer, tautomer or pharmaceutically acceptable salt or solvate, where W denotes -C(=S)- or -C(=O); X denotes -N(R5)-; U denotes a bond or -(C(R6)(R7))b- where b equals 1; R1, R2 and R5 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-7 carbon atoms and other radicals given in claim 1 of the formula of invention; R3, R4, R6 and R7 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; R15, R16 and R17 indicated below are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; or R15, R16 and R17 denote ; , where R23 denotes 0-2 substitutes, m equals 0 and n equals 1 or 2, and where all alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R6, R7 can be independently substituted with 1-3 R21 groups independently selected from alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, halogen, aryl with 6-10 carbon atoms; -CN, -OR15, -C(O)R15, -C(O)OR15, - C(O)N(R15)(R16), -S(O)2N(R15)(R16), -N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, - CH2-R15; -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, -NO2 and -S(O)2R15; and where alkyl with 1-6 carbon atoms and cycloalkyl with 3-7 carbon atoms are independently substituted or contain substitutes in form of 1-5 R22 groups, independently selected from a group comprising halogen, -CN or -OR15; R23 denotes alkyl with 1-6 carbon atoms; provided that if W denotes -C(O)- and U denotes a bond, then R1 does not denote, if needed, a substituted phenyl, provided that neither R1 nor R5 denotes alkyl disubstituted with -CO(O)R15 or -C(O)N(R15)(R16)) and (-N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17) or -N(R15)C(O)OR16) groups; provided that if R1 denotes methyl, R2 denotes H, W denotes C(O)- and U denotes a bond, then (R3, R4) does not denote (H, H), (phenyl, phenyl), (H, phenyl), (benzl, H), (benzyl, phenyl), (isobutyl, H), (isobutyl, phenyl), (OH-phenyl, phenyl), (halogenphenyl, phenyl) or (CH3O-phenyl, NO2-phenyl);provided that if R1 and R5 both denote H, W denotes -C(O)- and U denotes a bond, then (R3, R4) does not denote (substituted phenyl if needed, substituted benzyl if needed), (substituted phenyl if needed, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); provided that if R1 denotes R21-aryl or R21 arylalkyl, where R21 denotes -OCF3, -S(O)2CF3, -S(O)2alkyl, -S(O)2CHF2, -S(O)2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3 or -S(O)2NR15R16; where R15 and R16 are independently selected from a group comprising H, said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heterocycloalkyl and R18 -aryl, and U denotes a bond; then R5 denotes H, where R18 is as defined in claim 1 of the formula of invention. The present invention also relates to a pharmaceutical composition based on the compound of formula , use of the formula I compound in preparing a medicinal agent.

EFFECT: novel heterocyclic derivatives of formula I, having aspartyl protease inhibiting properties, are obtained.

16 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds, which have anti HIV-1 activity, of general formula (I) , where X stands for NH, as well as their pharmaceutically acceptable additive salt. Invention also relates to pharmaceutical composition, method of obtaining pharmaceutical composition and method of obtaining compound.

EFFECT: novel compounds possessing anti-HIV-1 activity.

5 cl, 7 dwg, 1 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds, which possess properties inhibiting HIV replication, of general formula (I) , in form of E-isomer, in which -a1=a2-a3=a4- represents bivalent radical of formula -CH=CH-CH=CH- (a-1); -b1=b2-b3=b4. Represents bivalent radical of formula -CH=CH-CH=CH- (b-1); n equals 0; m equals 2; each of R1 radicals independently on each other stands for hydrogen atom; C1-6alkyl; R2a stands for cyanogroup; X1 stands for -NR1-; R3 represents C2-6alkenyl, substituted with cyanogroup; R4 stands for C1-6alkyl; R5 represents radical of formula -Y-Alk-L, -Alk'-Y-L or -Alk'-Y-Alk-L; each of radicals Alk or Alk' independently represents bivalent C1-6alkyl or C2-6 alkenyl group; L stands for aryl or Het; Y stands for NR1; -CH=N-O-; Het stands for 5- or 6-member fully saturated ring system, in which one, two or three ring elements represent heteroatoms, each of which is independently selected from group, including nitrogen, oxygen and sulphur, and in which other ring elements represent carbon atoms; and, if possible, any nitrogen ring element can be optionally substituted with C1-6alkyl; and ring system can be optionally bound with benzene ring; and in which any carbon atom of ring, including any carbon atom of optionally bound benzene ring, each independently can be substituted with substituent selected from such groups as halogen atom, C1-6alkyl, hydroxyC1-4alkyl, carboxyC1-4alkyl, C1-4 alkylcarbonyloxyC1-4alkyl, di(C1-4alkyl)aminoC1-4alkyl, aryloxy, morpholinyl, aryl, Het1; Het1 stands for thienyl, isoxazolyl, thiadiazolyl, each of which can be optionally substituted with one or two C1-4alkyl radicals; Q stands for hydrogen atom; each aryl represents phenyl or phenyl, substituted with one, two substituents, each of which is independently selected from such groups as halogen atom, C1-6alkyl, C2-6alkinyl, cyano, polyhalogen C1-6alkyl or Het1, as well as to its pharmaceutically acceptable additive salts Invention also relates to pharmaceutical composition.

EFFECT: creation of novel compounds, which possess properties inhibiting HIV replication

5 cl, 7 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmacology and medicine and represents application of composition, which contains probiotic bacteria of genus Lactobacillus or Bifidobacterium or both and from 25 to 100 wt % of uronic acid oligosaccharide, in which, at least, 50% of residues are selected from group consistsing of guluronic acid, mannuronic acid, galacturonic acid and glucuronic acid with DP from 2 to 250 on the basis of total mass of uronic acid in composition, for manufacturing nutritional composition for treatment and/prevention of infection with pathogen in person.

EFFECT: invention ensures synergic inhibiting of pathogens.

17 cl, 1 ex

FIELD: food industry.

SUBSTANCE: invention relates to low-glycemic affordable carbohydrate composition. Carbohydrate composition in compliance with invention contains the following components: (i) 5-60 wt %, one or more monosaccharides, selected from monosaccharides that differ from glucose and fructose, in particular, galactose, ribose and mannose; (ii) 10-75 wt % oligosaccharides, having length of 2-20 anhydromonose units, at least half of which represents anhydroglucose remains bound in alpha-1-position with 1-, 3-, 5- or 6 positions of another anhydromonose unit, besides, component (ii) contains 10-60 wt % of one or more oligosaccharides selected from trehalulose, palatinose, turanose and leucrose; (iii) 0-75 wt %, other affordable carbohydrates. Invention also relates to food composition, containing low-glycemic carbohydrate composition and proteins and/or lipids, besides, carbohydrate composition makes 35-70 en.% of food composition. Food composition is used to treat diabetes, obesity, resistance to insulin, or for postprandial reaction to glucose.

EFFECT: carbohydrate composition makes it possible to maintain low level of glucose in blood and tissues after consumption for a long period of time and does not result in undesirable high concentrations of glucose in blood in people, who became resistant to insulin.

12 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to oligosaccharide, suitable for vaccine against meningitis A, which includes first mannose unit, which has spacer in alfa-configuration in C-1, where said spacer is able to conjugate with protein, and bound to second mannose unit by 1,6-bond, which binds C-6 of first unit with C-1 of second unit, 1,6-bond including phosphonate. Invention also relates to methods of obtaining oligosaccharide and improved methods of obtaining mannose derivative, suitable for obtaining immunogenic oligosaccharide. Invention also relates to pharmaceutical composition for induction of immune response, immunogenic composition, capable of inducing formation of protective antibodies against meningitis A and vaccine against meningitis A, which include oligosaccharide.

EFFECT: obtained glycoconjugates have C-phosphonate bond, which is much more stable than natural phosphodiester bonds, as well as higher immunologic activity.

51 cl, 4 dwg, 3 tbl, 16 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to surgical dentistry and maxillofacial surgery, and aims at treating alveolitis. After local anaesthesia, pharmacological treatment and curettage, an alveolar socket is 2/3 filled with a mixture of the osteoplastic material 'Bialgin' of granule size 1 mm and 30 % lincomycin hydrochloride gel in ratio 1:2, covered with the biologically resorbed membrane 'Collost' and a trapezoid mucoperiosteal flap cut out of a transitory fold of a cheek with its base turned to a buccal wall of the socket so that edges of the flap overlap membrane by 2 mm.

EFFECT: method allows to prevent development of inflammatory complications, atrophy of an alveolar process, to reduce convalescence of patients.

4 ex

FIELD: food industry.

SUBSTANCE: method for production of a nanocomposition based on a biologically active substance with particle size up to 300 nm and an accessory substance taken in specific quantities including preparation of a solution of the biologically active substance in an organic solvent (Solution A); preparation of a solution of the accessory substance in water (Solution B); mixture of Solution A with an equivalent quantity of water, organic solvent recovery, mixture with Solution B, solvent recovery;suspension drying.

EFFECT: nanocomposition produced in accordance with the above method possesses enhanced bioavailability, is suitable for peroral and inhalation application and stable in the course of storage.

3 cl, 4 dwg, 17 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical composition for treating gastric and duodenal ulcers contains a proton pump inhibitor (PPI) in amount 0.05-25 wt %, and a prebiotic in amount 40-95 wt % specified in aliphatic alcohols, di-, tri-, oligo- or polysaccharides. A method of treating gastric and duodenal ulcers implies enteral administration of said pharmaceutical composition once a day for 14 days.

EFFECT: synergetic action of the proton pump inhibitor and prebiotic provides faster repair of gastric mucosal ulcers, effective stable eradication of Hpylori without using antibacterial therapy, the absence of side effects and recurrences.

14 cl, 8 tbl

Infant food // 2404785

FIELD: food industry.

SUBSTANCE: invention relates to food and pharmaceutical industry. Infant food composition, containing protein, fats, carbohydrates, nucleotides, nucleosides and nonprotein negatively charged polygalacturonic acid taken at in certain amounts. Application of composition for production of composition for infant feeding. Application of nutrient composition to produce composition for treatment and/or prophylactics of inflammatory disease, diarrhea, eczema and/or atopic dermatitis of a baby.

EFFECT: nutrient composition efficiently imitates protective action of human milk, in particular, against allergies and infections.

9 cl, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to pharmacology and medicine. Pharmaceutical composition for reduction of excess sugar levels in blood of type 2 diabetes mellitus patients, containing at least one cyanogenic glycoside from bitter almond kernels as active ingredient.

EFFECT: invention provides for use of natural source in composition for reduction of sugar in blood.

4 cl, 7 ex, 2 tbl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to antithrombotic compound of formula (I) (oligisaccaride-spacer-A(I)), where oligosaccharide is negatively charged pentasaccharide residue of formula given lower, where R5 - OCH3 or OSO3-, charge is compensated by positively charged counterions, and where pentasaccharide residue is obtained from pentasaccharide which has AT-III mediated anti-Xa activity per se; spacer is, in fact, pharmacologically inactive movably bound residue, which has from 10 to 50 atoms long chain; A is residue of -CH[NH-SO2-R1] [CO-NR2-CH(4-benzamidin)-CO-NR3R4], where R1 - 4-methoxy-2,3,6-trimethyphenyl; R2 - H; NR3R4 is piperidinyl group or its pharmaceutically acceptable salt or derivative, where amino group of amidin residue is protected by hydroxyl or (1-6C) alcoxycarbonyl group; where spacer of formula I compound contains one covalent bond with biotin residue of formula -(CH2)4-NR-BT, where R - H or (1-4C)alkyl and BT is residue . Invention also relates to pharmaceutical composition based on formula I compounds for treatment or prevention of thrombosis or other connected with thrombin diseases.

EFFECT: elaboration of antithrombotic compound for treatment or prevention of thrombosis or other, connected with thrombin diseases.

6 cl, 3 tbl, 2 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to endocrinology, and concerns treatment and/or prevention of obesity or excessive body weight. For this purpose, causes of excessive weight are specified by analysing polymorphism of genes selected from line: LPL, GREL, INS, FABP2, ADRb3. Selection of diet and pharmacotherapy is carried out depending on versions of detected polymorphism.

EFFECT: method ensures efficient treatment of excessive body weight due to selection of adequate pharmaco- and diet-therapy for each individual patient.

9 cl, 24 dwg, 1 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology, and can be used for treating patients with recurrent nasopharynx cancer. The method involves administration of chemopreparations and gamma-ray teletherapy; the first therapeutic day involves intravenous drop infusion of an automyelosuspension ex temporae incubated with cisplatin at 50 mg/m2 with underlying excessive hydration and forced diuresis; 5-fluorouracil dissolved in normal saline 200 ml is infused the same day at 500 mg/m2. After one day of a pause, gamma-ray teletherapy is performed in a hyperfractionation mode taking into account a residual dose 1.5 Gy of single basic dose twice a day every 5 hours to at 5 o'clock to 65 isoGy of total basic dose. After one week of a pause, the second course of automyelochemotherapy with cisplatin at 100 mg/m2 with underlying excessive hydration and forced diuresis is performed; 5-fluorouracil 500 mg/m2, bleomycine 30 mg/m2 and adriamycin 35 mg/m2 are infused the same day.

EFFECT: use of the invention allows higher clinical effectiveness ensured by combined anticancer effect of the chemopreparations and additional stimulation of immune cells by the factors contained in the bone marrow.

2 tbl, 1 ex

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