Pharmaceutical composition (variants) no containing proteins and peptides for neutralization and/or removing endotoxins from body

FIELD: medicine, toxicology, pharmacy.

SUBSTANCE: according with the first variant the composition contains neutral lipid and therapeutically effective amount of cholanic acid or cholanic acid salt and phospholipid. Neutral lipid presents in the amount from 3% to 50% by mass relatively to the total amount of lipid. According with the second variant the composition contains from 3% to 30% by mass of bile acid or bile acid salt, from 3% to 50% by mass of neutral lipid and from 10% to 95% by mass of phospholipid. Composition is designated for treatment in poisoning with endotoxins. Composition no containing peptides and proteins but containing the combination of phospholipid with cholanic acid proves effective relief or prophylaxis of endotoxemia.

EFFECT: enhanced effectiveness and valuable medicinal properties of composition.

23 cl, 10 dwg, 2 tbl, 10 ex

 

The technical field

The invention relates to the treatment of endotoxemia caused by endotoxins, in particular to the treatment of poisoning endotoxins introduction into the organism of various compounds that neutralize and/or remove endotoxins from the body, and also to prevent using these compositions.

The level of technology

Bacterial endotoxin-toxic shock syndrome is a condition that is often fatal, caused by release of lipopolysaccharide (LPS) from the outer membrane of most gram-negative bacteria (e.g. Escherichia coli: Salmonella tymphimurium). The structure of bacterial LPS is pretty well explained, and the only molecule, called lipid A, is associated with acyl chains through its glucosamine chain (see Paetz, Ann. Pev. Biochem. 59: 129-170 (1990)).

The lipid molecule And serves as a membrane retainer structure of lipopolysaccharide (LPS), which is involved in the development of endotoxin shock. Should indicate that LPS molecules are characterized by the structure of lipid a and a part of the polysaccharide. This part may differ in detail from different LPS molecules, but it retains the common structural basis of endotoxins. It would be incorrect to say that the LPS molecule is similar in all bacteria (see Raetz, above). Experts usually called different LPS molecules "endotoxins", and this term will be used hereinafter for about the values of LPS molecules.

In U.S. patent No. 5128318, the description of which is used by reference, indicates that the reconstructed particles containing as apolipoproteida associated with HDL cholesterol and a lipid capable of binding endotoxin for its inactivation, can be used as effective materials to reduce toxicity caused by endotoxins.

In previous applications, which are used in the present description by reference, it was stated that to suppress the toxicity caused by endotoxins, you can use other materials. In particular, it was found that apolipoprotein not required in the reconstructed particles and that of the reconstructed particle can contain a peptide and a lipid, where the peptide is not apolipoproteida.

The inventors also found that the toxicity caused by endotoxins, you can fight sequential introduction apolipoproteida or peptide, and then lipid. Successively introduced components form a reconstructed particle and become active in the removal of endotoxins.

It was also discovered that at least some patients have natural levels apolipoproteida that are higher than normal and allow effective treatment of endotoxemia introduction of reconstructed particles that do not contain apolipoproteida or PEP is ID, but containing the described lipid.

In addition, the invention disclosed in these applications involves the use of reconstructed particles and the above-mentioned components for the prevention of toxicitiy caused by endotoxins, by introducing a prophylactically effective amount of the subjects of prevention. Such subjects include patients infected or recovering after surgery. These patients sometimes have very low levels of HDL in the blood plasma, declining to 20% of normal levels. In these cases, desirable early prevention using HDL to offset these declines.

It was unexpectedly found that phospholipids can be used alone or in combination with additional materials such as neutral lipids, holty and the like, as an effective means to mitigate and/or prevent endotoxemia. In particular, prefer to use phosphatidylcholine (hereafter PF) both separately and in combination with other phospholipids, such as sphingolipids, in compositions that are essentially free of peptides and proteins, such as apolipoprotein or derived peptides. Neutral lipids, such as mono-, di-, and triglycerides, can be mixed with phospholipids, while the total number of natural lipids will not be below the opredelennog the mass content in percent when using these compositions in the form of balls for intravenous injection. In other ways, for example by continuous intravenous infusion, the percentage by weight is not so important, but it is desirable.

Particularly preferred examples of embodiments of the invention involve the use of emulsions, in which the bile acid or its salt is used together with a phospholipid or a neutral lipid.

The efficiency of bile acids and their salts - Khalatov in the treatment of endotoxemia. These bile acids can be used alone or in combination with one or more phospholipid and/or a neutral lipid, such as phosphatidylcholine and/or triglyceride.

In more detail, the invention is described next.

A brief description of the illustrations.

Figure 1 and 2 shows the results obtained when testing different formulations of the model, where neutralization of endotoxin was determined by identifying the allocation of UNFPA in the model of whole human blood. Figure 1 shows the value of protein, and figure 2 is a phospholipid. The tested compounds included natural lipoproteins lipoproteins (VLDL, LDL, HDL), reconstructed HDL(R-HDL) and formulations INTPALIPID ®, as well as emulsions containing phospholipid and protein.

Figure 3 and 4 show the comparative value of triglyceride (neutral lipid) and phosphatidylcholine, a phospholipid in the same model.

Figure 5 presents information on the toxicity with the introduction of various PF and PF/TG to the positions in the mouse model, using the model infected with E.coli LPS. fatal 55 %.

Figure 6 shows the data comparable with the data obtained above, the test model of whole human blood, but when using phospholipid with neeterificirovannah cholesterol, sphingomyelin or a mixture of the latter instead of triglycerides.

7 and 8 shows the results comparable with that shown in figures 1 and 2, and in this case, a phospholipid, neeterificirovannah cholesterol and/or sphingomyelin mixed with triglycerides or esterified cholesterol as a neutral lipid.

Figure 9 presents a comparison of the results obtained from the injection of emulsions containing ester of cholesterol and triglyceride in mice in vivo.

Figure 10 shows a graph of theoretical amount of triglycerides released into the blood after administration of various TG-containing compounds, with thresholds of toxicity. The abbreviation "OPP" means "total parenteral nutrition", and "C" - the compositions according to the invention.

Detailed description of examples of embodiment of the invention

Example 1

Factors that affect the stimulation of the UNFPA-α by LPS, while preserving the integrity of the interaction of plasma proteins and cellular elements of blood, can be properly investigated in vitro on the system of whole human blood. This system used the La determine what lipoproteine components important in the neutralization of LPS.

Experienced the following materials:

the reconstructed high-density lipoprotein (R-HDL), natural lipoproteins lipoproteins (VLDL, LDL, HDL) in the blood plasma, serum deficiency of lipoprotein (SNLP) and saturated triglyceride emulsion 20% INTPALIPID ® (a mixture of triglycerides and phospholipids).

Blood was collected in heparinized test tube, diluted with balanced salt solution Hank (hereinafter SSR) or filled in the test material dissolved in SRH. The resulting material was poured in a test tube of Sarstedt (250 ál/vial). LPS was dissolved in pyrogen-free saline containing 10 mm Hepesbuffered and added to 2.5 μl) to a final concentration of 10 ng/ml After incubation for 4 hours at 37°the tubes were cooled to 4°S, and then centrifuged at 10000×g for 5 minutes. The supernatant was decanted and using a known enzyme immunosorbent assay (ELISA) was determined UNFPA-α.

Table 1 shows the comparative data of the compositions of the materials tested. Figure 1 and 2 presents the results. The data presented in the graphs according to the number of manufactured UNFPA-α on the concentration of added protein (figure 1) and phospholipid (figure 2). To show the wide range of concentrations used, were used logari the economic scale, where 10° correspond to 1 mg/ml. All incubated system of whole blood contained 10 ng/ml E. coli 0111:B4 LPS, supplemented by one of the trains, as the explication to figures 1 and 2.

That the effectiveness of various materials in the case of drawing the graph of the protein (figure 1) and the like when applied to the content of phospholipid (figure 2), suggests that the phospholipid is an important component. This was confirmed by the fact that do not contain protein lipid emulsion is more effective than natural HDL, but less effective than R-HDL. Protein is not as important for neutralization.

Table 1

The composition of the natural lipoproteins and reconstructed HDL

LipoproteinCTTGPFProtein
ClassDensity (g/ml)Weight (%)
Lonp<1,0062253187
LDL1,007-1,06348112220,9
LHP1,063-1,211882252
R-HDL1,063-1,21--7921/td>
SNLP<1,2100298
Intralipid-19360

Example 2

In this example do not contain protein lipid emulsions containing different amounts of neutral lipid, was tested on whole human blood. Used the same analysis as in the in vitro study of whole human blood in example 1.

All these particles were obtained according to the same procedure, which involves mixing the phospholipid, sphingomyelin or phosphatidylcholine, triolein and/or ether neeterificirovannah cholesterol dissolved in chloroform, and weighing them before being placed in the flask. Vitamin E (0,02% weight/volume) was added as an antioxidant. Then prepared the dry lipid film, blowing nitrogen gas or argon over the sample. Then the flask was added pyrogen-free saline, and then the contents of the flask was stirred in a vortex mixer until the suspension of the total lipid. Then the solution is homogenized in the homogenizer high pressure. Samples containing phosphatidylcholine (PC), triolein or without loop was passed through the homogenizer 10 times at a pressure of 137895 kPa (20000 psi). Samples, soda is containing cholesterol ester with one or more other lipids, cyclically missed 15-20 times when the pressure 206842 kPa (30000 psi). Homogenized solution was filtered with a syringe with filter-nozzle having pores of 0.45 μm, the filtrate was left at room temperature (3 days) prior to use. Figure 3 and 4 shows the results of these studies, where data about the production of FSC-dependent UNFPA-α depend on the concentration of added triglycerides (figure 3) or phospholipid (figure 4). The compositions, as shown in the explication, contained 7% of the triglyceride (TG), 45% TG, 89% TG, 94% TG, R-HDL cholesterol or phospholipid without TG (shown only in figure 4). The composition of 89% TG contains 10% INTPALIPID ®, and 94%TG - 20% INTPALIPID. In all other experiments used egg phosphatidylcholine (PC) and triolein.

These results show that does not contain protein composition to influence the content of the triglyceride are very different, but they are very similar in the study of the influence of content of phospholipid (PC). This confirms the role of phospholipid, as only the phospholipid effective, although to a lesser extent than emulsions containing up to 45% TG.

Example 3

Further experiments were conducted in vivo in mouse model, which was chosen as a reliable system for predicting the effectiveness of actions on people.

In these experiments, the mice were injected, in the form of balls, a sufficient amount of the composition described in example 2, and the other compositions (pure phosphatidylcholine, 7% TG, 25% TG, 45% TG, 71% TG, 81% TG, 94% TG) or control saline solution, with doses of phospholipid (200 mg/kg or 400 mg/kg), together with 25 mg/kg .li 0111:B4 LPS. The control group was injected intravenously with saline in a volume corresponding to the volume of the emulsion. Survival after 72 hours is shown in figure 5. Of the 344 animals of the control group survived 155.

Use only PF gave a moderate protective effect is statistically insignificant at the 95 percent confidence level, while formulations containing 7%, 45% and 71% TG significantly increased the survival rate. Formulations containing 80% and 89% TG, ensured minimal effect, and containing 94% TG survival reduced.

When the dose was increased to 400 mg/kg PF, emulsions with a content of 89% and 94% TG significantly reduced life time, likely due to the poisonous effect of the TG, the explanation of which follows.

Example 4

In examples 1-3 found that phospholipids are an active tool of suppression of endotoxemia. The fact that non-polar lipids, instead of triglycerides, can form an emulsion with phospholipids, but not with PF, suggests that it is possible to use other substances, such as sphingomyelin (another phospholipid), neeterificirovannah cholesterol (polar and neutral lipid) and mixtures thereof. Can also be used esterified cholesterol (non-polar ether), squalene (carbohydrate the genus) and vitamin E (non-polar antioxidant). To test these substances was conducted a number of experiments with model analysis of whole human blood in example 1 and survival of mice in example 3.

Were prepared emulsion, as described above, of pure phosphatidylcholine, phosphatidylcholine with 10% (mass ratio) neeterificirovannah cholesterol, 10% (mass ratio) of sphingomyelin or just 10% of the mixture neeterificirovannah cholesterol and sphingomyelin. The emulsion was added to whole blood at a concentration of 100 mg/DL in respect of PF and 10 ng/ml LPS. The mixture is incubated and measured allocated UNFPA-α.

The results of the experiments shown in Fig.6. The allocation of UNFPA-α was significantly reduced when using only PF. Emulsions containing neeterificirovannah cholesterol, sphingomyelin, or their mixture, also inhibited the allocation of UNFPA-α.

Example 5

Analysis of whole blood was also used to determine the effect of neeterificirovannah cholesterol and/or sphingomyelin on emulsion containing a neutral lipid. In addition, the used emulsion at 100 mg/DL PF. Various compositions (in mass ratio) shown in table 2.

Table 2

EmulsionComposition
PF 45% TG55:45
PF+TG+54,4:45,3:0,3
PF+TG+SF 51,6:43,3:5,4
PF+TG+With+SF51,4:42,9:0,3:5,4
PF+OH54,5:45,5
FH+EH+54,4:45,3:0,3
FH+EH+SF51,6:43,0: 5,4
FH+EH+WITH+SF51,5:42,9:0,3:5,4

Figure 7 and 8 presents the results of the experiment. The PF emulsion prepared with a neutral lipid in the presence of polar lipids or without them, showed inhibitory ability. In addition, the LPS concentration was 10 ng/ml, i.e. clinically relevant concentration of endotoxin. Emulsions containing ester of cholesterol, were less effective than emulsion comprising triglycerides, whereas emulsion containing neeterificirovannah cholesterol, did not suppress the UNFPA-αas well as emulsions that do not contain cholesterol. Add sphingomyelin in the emulsion resulted in greater suppression of the production of UNFPA-α.

Example 6

Emulsions containing ester cholesterol was tested in vivo on the model used in example 3, with a lethal dose of endotoxin. Were prepared emulsion of FG and TG or PC and ester cholesterol (OH)introduced a single dose of 200 mg/kg PF in the form of a ball with 25 mg/kg E. coli 0111:B4 LPS (lethal dose) in the vein of the tail. The control group was injected intravenously with saline in a volume corresponding to the volume of the emulsion.

the and Fig.9 are the comparative effects of emulsions, containing FG and TG. One and the other emulsion was tested in two experiments using 16 or more animals.

As can be seen in Fig.9, the emulsion containing 7% or 45% of OH by weight, significantly increased the survival rate. These results, taken together with the results of example 5 show that EH can be replacement for TG when creating emulsions, which neutralize endotoxins.

Example 7

Does not contain protein emulsion phospholipid to triglyceride effectively block the production of UNFPA-α in whole blood activated with LPS. Theoretically, these emulsions can be effective also on live objects if they can be administered safely in doses that provide a protective concentration of phospholipid in the plasma. Our previous experiments with R-HDL suggest that the minimum dose of phospholipid - about 200 mg/kg Using this dose and plasma volume of 4.5% of body weight, you can calculate the concentration of triglyceride, expected in plasma after injection of emulsions with successively higher content of triglycerides. The result is shown in figure 10 in the form of a smooth line that curves upwards with increasing TG content (% by weight). The concentration of TG in plasma rarely exceed 1000 mg/DL in healthy adults even after ingestion of fatty foods. Clinical data pancreatitis occurs in p the patients with TG concentration in plasma above 2000 mg/DL (Farmer et al., Amer. J. Med. 54: 161-164 (1973); Krauses et al., Amer. J.

Med. 62: 144-149 (1977); Glueck et al., J. lab. Clin. Med. 123: 59-61). The concentration of TG in plasma above 4000 mg/DL very infrequent and becomes a cause of serious concern. Figure 10 the last two threshold shown by horizontal lines. With the introduction of 10% or 20% INTPALIPID ® for a dose containing 200 mg/kg phospholipid is expected a significant increase in concentrations of triglycerides in plasma (see two contour mug) beyond safe limits. In contrast, injection of emulsions containing 7%, 45%, 71%, or 78% (solid squares from left to right) increases the concentration of TG in plasma, respectively, to 136, 477, 1300 or 2000 mg/DL. It is expected that emulsions with a content of triglycerides by up to 50% will not be toxic due to the presence of TG.

Example 8

The effectiveness of combinations of phospholipid and bile acids, i.e. cholate sodium, tested in an experiment similar to that described in the previous examples. However, the method by which to prepare the compositions entered for animal testing, had the honors. In this and subsequent examples, compositions were prepared using a homogenizer high pressure

"Microfluidizer". This device facilitates scaling.

Liquid triolein or liquid soybean triglyceride was dissolved in the appropriate mass amount of water or water with 9 mm, 18 mm or 36 mm cholate sodium. Solid granular f is statically weighed on paper, and then slowly added to the solution while stirring. When this takes about 3-5 minutes for dispersion of lipid. After dispersing the resulting material was poured into a high-pressure homogenizer. This device uses hydraulic pressure to activate the pump, which in turn counter sends two opposite jets samples. The pressure can reach 172,4 kPa (25000 psi). When the collision jet pressure is held in the cross-shaped hole, thus homogenizing the sample.

The sample was passed through the homogenizer several times, while the "single pass" is the time required for pumping the entire sample through the device. The samples were passed 20 times to achieve the required level of homogenization. Dextrose was added to a final 5%concentration.

Endotoxin purified from E. coli 0111:B4 (40 mg/kg), and the emulsion described below (200 mg phosphatidylcholine/kg), mixed at room temperature and immediately injected into mice C57BL6/J (mass 19-30 g) by intravenous injection in the tail vein. Those mice that received only Holt, introduced volumetric dose cholate sodium, equal to the dose of the drug Holt/EML (emulsion)at the same concentration holata. Control mice were injected the same dose of a 5%solution of dextrose to match the osmolality of plasma.

The results of the experience is Imanta are shown in table 3. In this case, the used emulsion containing phosphatidylcholine and 7% of triglyceride, described in the previous examples. Holt sodium was added at the indicated concentrations of starting materials to obtain the emulsion.

Table 3

Protection of mice from lethal doses of endotoxin

Time (hours)Control7% TG7% TG+HC18 MMHG
9 mm18 mm36 mmno PF or TG+PF
The number of surviving mice (N)
02828816888
24912415888
48510215888
7225115888
96101 15878

The content of the emulsion by weight was as follows. When using 9 mm cholate the percentage by weight in the emulsion was as follows: 7 % cholate, 6.1% of the triglyceride and 86.9% of phosphatidylcholine; 18 mm cholate: 13,1% cholate, 5.7% of the triglyceride and 81,2% phosphatidylcholine; 36 mm cholate: 23,2% cholate, 5% triglycerides and 71.8% of phosphatidylcholine.

It should be noted that the number of LPS injected in these experiments (40 mg/kg), significantly higher than the number used in the study of mortality in the previous examples. The purpose of the introduction of these high doses was to suppress any protective effect of phosphatidylcholine and/or triglycerides. Thus, from these experiments we conclude that the salt of the bile acid, i.e. Holt sodium, have a protective property.

Not here described experiments with other salts of bile acids and taurine containing bile salts. Among bile acids should be noted, for example, allogenically, lithocholic, hyodesoxycholic, geoholiday acid, α- β- and ω-marihoeve acid, Murtazaliyeva, ursodeoxycholic, arseholery acids and their salts such as sodium salt or taurine, or a conjugate glycine. Cm. Hoffmann below.

Example 9

Further experiments were conducted, the first of which is followed survival rate of mice, used as experimental animals. Thus they were divided into 4 groups. The first group is the control and introduced a 5%solution of dextrose. The second introduced the emulsion containing 93% by weight of phosphatidylcholine and 7% (by weight) of triglyceride and prepared as described above. This emulsion contained 5% dextrose and soy phospholipids from about 50 mg/ml lipid. The third and fourth groups of animals were injected emulsion, this emulsion entered the second group, with the addition of 18 mm cholate sodium or 18 mm desoxycholate sodium. In this experiment used the same procedure as in example 8. Survival was determined after 72 hours after infection; the data are summarized in table 4.

Table 4

The effect of the addition of bile acids to 7%emulsion of triglyceride on the survival of mice after 72 hours
GroupNo.Survival (%)Value

R/group
  123
15 % dextrose284---
27 % TG648NS*--
Holt sodium + 7 % TG16940,000010,00001-
4Deoxycholate sodium + 7 % TG8750,00010,00001NS
* NS - not acceptable

Note that the statistical significance of comparisons of survival of groups of animals were tested according to the method of Wilcox using a computer program. Comparative data with the control group 1 placed under the index "1", comparison with group 2, animals which have introduced a 7%-emulsion - "2", and comparison with group 3 animals, which introduced the emulsion with Holtom sodium - "3".

As survival (%)and statistical analysis reflect a certain, unexpected advantage of the compositions containing salts of bile acids.

Example 10

The second group of experiments tested on the model of the rabbit. In this model, it was determined the allocation of UNFPA-α (necrosis factor neoplasm).

Rabbits were divided into 3 groups and injected with 5%dextrose, emulsion phospholipid and triglyceride (93%/7%)described above, or the same emulsion, but with 18 mm holeva acid. All of the emulsion was adjusted to 5%increase dextrose, as in example 9. Rabbits have previously entered the ball of the emulsion and after 2 hours of 100 μg of E. coli 0111:B4 LPS. In addition to Shari is the intravenous emulsion was continuously injected composition at the rate of 50 mg of lipid per kilogram of body weight per hour. Intravenous infusion was performed for 3 hours after control of infection.

Blood was taken from the rabbits in the field line between the arch and the base of the skull, through the 30 minutes after the introduction of the ball and every hour for 5 hours after injection.

Table 5 presents the maximum values of the UNFPA-α. They are registered through 2 hours after injection of endotoxin.

The statistical significance of results was determined using the well-known criterion Student. As can be seen from table 5, the indicators UNFPA-α dropped significantly after the introduction of 18 mm holeva acid.

Table 5

The effect of the emulsion on the production of UNFPA-α in rabbits
EmulsionUNFPA-αSignificance
 (ng/ml)NP
5%dextrose, control134±709 
7% TG emulsion68 ±55<0,05
7% TG emulsion + 18 mm holeva acid39 ±204<0,01

These examples explore in detail the invention, which involves one of the goals of weakening or prevent the giving of endotoxemia by introducing the patient an effective amount of phospholipid, with whom are associated endotoxins. Association of phospholipid and endotoxins then removed from the patient's body due to normal biological processes, are well known to those familiar with the processes of removal of lipoprotein particles. The phospholipid suppresses endotoxin in Association with him.

From these examples it is seen that the introduction of any of holanovich acids or salts holanovich acids, such as bile acid or its salt, can also be used instead of phospholipids to achieve the same effect, i.e. reduce or prevent endotoxemia. Thus, the compositions not containing peptides and proteins, but contains only a bile acid or bile salt acid, or both, as well as the phospholipid, can be used for the treatment of endotoxemia. Description holanovich acids (see, for example, article Hofmann, Hepatology 4(S): 4S-14S (1984)) entered in this text by reference, in particular, page 5, figure 1 and 2, which shows characteristic patterns holanovich acids.

The invention can be used preferably for the treatment of humans, but it is possible its use in veterinary medicine.

The term "attenuation"is used here, means a treatment to reduce the severity of the symptoms of endotoxemia caused by any of the endotoxins produced, for example, gram-negative bacteria (S.tymphimirium, E.coli, etc.). Profile the tick can be carried out by introduction of the appropriate funds at the moment when there is or is suspected of poisoning with endotoxins. A classic example of a surgical operation. So, the patient is prepared for surgery, you can enter the active ingredient.

An effective amount of phospholipid and bile acids needed to treat the patient, may be different. Usually the dose is the total mass of approximately 200-800 mg phospholipid per kilogram of body weight is preferred, although this number may be more or less depending on the severity of endotoxemia or risk prevention. The dose applied holanovich acids and salts, such as bile acids and their salts, contains approximately 10-300 mg per kilogram of body weight, more preferably about 275 mg per kilogram of body weight.

It is advisable to enter the bile acid/her salt and phospholipids, neutral lipids, but not necessarily, as provided by the introduction and also emulsion of phospholipids that do not contain neutral lipids. The feasibility of the combined introduction of phospholipids due to the fact that neutral lipids and phospholipids are combined into particles, which are similar to lipoproteins, but differ in that they do not contain protein peptide components, which of course always present in lipoproteins.

Particularly desirable such forms of treatment, where the phospholipid, not only at the n-phosphatidylcholine, for example, egg yolk phosphatidylcholine, soy phosphatidylcholine or sphingolipids. As bile acids/salts are preferred cholic acid and/or its salts, such as Holt sodium, sodium deoxycholate and chenodesoxycholic sodium. As for neutral lipids, it is preferable to use an ester of cholesterol or triglyceride, but you can also use other neutral lipids, such as squalene or other hydrocarbon oils, di - and monoglycerides and antioxidants such as vitamin E.

Molds for injection can be different, and spherical or other intravenous especially preferred. When using spherical form, for example, triglyceride care must be taken when assigning doses. It is well known that triglycerides are toxic, if you write them in too large quantities. But the specialist can easily find such a composition, to eliminate or reduce the risk of poisoning triglyceride. Usually when using spherical shape mass fraction of triglycerides or other neutral lipid should be approximately no more than 80%, preferably not more than 70%. More preferably, the mass fraction of neutral lipid in the bead should be approximately no more than 50%.

However, when used nelarabine form, for example, other forms within Ivanovo introduction, the risk of poisoning is reduced. However, the limits described above, preferred for intravenous or other routes of administration, although it is obvious that they are not mandatory. Dose of bile acids and their salts preferably comprise from about 25 to 500 mg/kg body weight and more preferably from about 50 to 100 mg/kg of body weight. The preferred dose of phospholipids preferably be from 100 to 1000 mg/kg of body weight. Here are the common dosages, however, they will vary depending on the patient and the method of administration.

As indicated above, the compositions do not contain proteins and peptides required at least one phospholipid or bile acid/her salt. Phospholipid, preferably the presence of at least one neutral lipid, such as a triglyceride, diglyceride or monoglyceride. These compositions may include additional materials, such as sterols (e.g. cholesterol, β-sitosterol), esterified or neeterificirovannah lipids (e.g. cholesterol ester or neeterificirovannah cholesterol), hydrocarbon oils, such as squalene, antioxidants, such as vitamin E, but they are not mandatory. There is no doubt that any such formulation may include more than one phospholipid and/or more than one neutral lipid. When using a combination of neutral lipid and phospholipid, neutral lipid must be present in an amount from about 3% to 50% by weight relative to the total amount of lipid in the composition.

Bile acid or its salts can be used separately or together in combination with phospholipid, neutral lipid. With regard to additional materials (e.g., phospholipids or neutral lipids), preferred species mentioned above.

In particular, according to the invention proposed compositions for the treatment of endotoxemia. One example embodiment of the invention is a composition containing at least one of the bile acids/her salt, phospholipid and neutral lipid, which in General contain the active ingredient in a quantity debilitating manifestation of endotoxemia. This composition mainly contains from about 5% to 30% by weight of bile acid/salt thereof, from about 3% to 50% by weight of neutral lipid and from about 10% to 95% by weight of phospholipid. Particularly preferred compositions contain about 10-15% by weight of bile acid/salt thereof, from about 5% to 10% by weight of a neutral lipid, and the rest is a phospholipid.

It should be noted that these mass fractions are compositions containing three components. When combining the three-component system with, for example, a carrier, adjuvant, optional ingredients, such is described above, these mass fraction relative to the total composition will be lower. It should be borne in mind that in all cases such therapeutic compositions do not contain proteins and peptides.

If the composition does not contain proteins and peptides that do not contain bile acid or its salt, you can enter preferably at least from about 3% to about 50% by weight of a neutral lipid, and the rest - at least one phospholipid. Neutral lipid is mainly triglyceride or any additional neutral lipids described above. In addition, the phospholipid is mainly phosphatidylcholine. Other aspects of the invention clear to the specialist and there is no need to re-quote here.

It is clear that the description and examples serve to illustrate the invention and do not limit the scope, and the specialist may offer other forms of embodiment of the invention, is not beyond the bounds of its nature and scope.

1. Not containing proteins and peptides pharmaceutical composition suitable for the neutralization and/or removal of endotoxins from the body by intravenous injection containing a neutral lipid and a therapeutically effective amount holonovel acid or salt holonovel acid and phospholipid, where the neutral lipid is present in an amount of from about 3 to about 50% of the total the number of lipid.

2. The pharmaceutical composition according to claim 1, where Galanova acid or salt holonovel acid is a bile acid or bile salt acid.

3. The pharmaceutical composition according to claim 1 or 2, where the phospholipid is a phosphatidylcholine.

4. The pharmaceutical composition according to any one of claims 1 and 2, where the phospholipid is sphingolipid.

5. The pharmaceutical composition according to claim 1, where the neutral lipid is a triglyceride.

6. The pharmaceutical composition according to claim 1, where the neutral lipid is an ester of cholesterol.

7. The pharmaceutical composition according to claim 2, where the salt of the bile acid is selected from cholate sodium, desoxycholate sodium and chenodesoxycholic sodium.

8. The pharmaceutical composition according to claim 7, where the salt of the bile acid is Halat sodium.

9. The pharmaceutical composition according to claim 1, containing phosphatidylcholine, triglyceride and Holt sodium.

10. The pharmaceutical composition according to claim 9, containing phosphatidylcholine and triglyceride mass ratio of 93:7.

11. The pharmaceutical composition according to claim 9, where Holt sodium, phosphatidylcholine and triglyceride have a total mass ratio of 13.1:81,2:5,7, respectively.

12. Not containing proteins and peptides pharmaceutical composition suitable for the neutralization and/or removal of endotoxins from the body, containing gelco the acid/salt of the bile acid, the phospholipid and neutral lipid, and the specified composition contains from about 5 to about 30% by weight of bile acids/salts of bile acids, from about 3 to about 50% by weight of neutral lipid and from about 10 to about 95% by weight of phospholipid.

13. The pharmaceutical composition according to item 12, containing about 10-15% by weight of bile acids/salts of bile acids, from about 5 to about 10% by weight of neutral lipid and the rest is a phospholipid.

14. The pharmaceutical composition according to item 12 or 13, which is suitable for intravenous administration.

15. The pharmaceutical composition according to item 12, where the phospholipid is a phosphatidylcholine.

16. The pharmaceutical composition according to item 12, where the phospholipid is sphingolipid.

17. The pharmaceutical composition according to item 12, where the neutral lipid is a triglyceride.

18. The pharmaceutical composition according to item 12, where the neutral lipid is an ester of cholesterol.

19. The pharmaceutical composition according to item 12, where the salt of the bile acid is selected from cholate sodium, desoxycholate sodium and chenodesoxycholic sodium.

20. The pharmaceutical composition according to claim 19, where the salt of the bile acid is Halat sodium.

21. The pharmaceutical composition according to item 12, containing phosphatidylcholine, triglyceride and Holt sodium.

22. The pharmaceutical composition p is item 21, containing phosphatidylcholine and triglyceride mass ratio of 93:7.

23. The pharmaceutical composition according to item 21, where Holt sodium, phosphatidylcholine and triglyceride have a total mass ratio of 13.1:81,2:5,7, respectively.



 

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EFFECT: enhanced effectiveness of treatment; increased sensitivity to antibiotics; reduced drug consumption.

FIELD: medicine, surgery, transplantology.

SUBSTANCE: embryonic spleen should be sampled, washed in nutritive medium № 199 to be placed into fresh medium № 199 to obtain homogenate in teflon homogenizer followed by centrifuging; then one should isolate the upper, medium and inferior layers, suck off medium layer and the upper part of inferior layer; the cell mixture obtained should be diluted in nutritive medium № 199 to be then introduced by injections into mesentery of small intestine or rectus muscle of abdomen. The present innovation favors the activation of immune system in patients undergone splenectomic operation and in those in case of surgical immunodefficient state due to high functional and regenerating activity of transferred embryonic splenic cells.

EFFECT: higher efficiency of prophylaxis.

6 dwg, 2 tbl

FIELD: medicine, operative gynecology.

SUBSTANCE: at final stage of laparoscopic operation for 5-7 min one should introduce 16 U lidase in 1 ml 2%-lidocaine solution into uterine mesentery from both sides, and then, by not removing a needle - a half of single dose of antimicrobial preparation in 1 ml 2%-lidocaine solution, then in postoperational period - an antimicrobial preparation applied during laparoscopy lymphotropically under mucosa of lateral vaginal arch from both sides for 5-7 d once daily and one antimicrobial preparation - intravenously for 5-7 d, moreover, as antimicrobial preparations one should apply gentamicin, metrogyl and other preparations permitted for intravenous application. The present innovation stimulates lymphatic drainage in area of inflammation and activates interstitial humoral transport of antimicrobial preparations that, in its turn, favors complete sanitation of inflammation foci and prophylaxis of disease relapses.

EFFECT: higher efficiency of therapy.

1 cl, 1 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a new growth/differentiation factor of TGF-β-family representing the amino acid sequence SEQ ID NO.2 or, if necessary, its functionally active moieties and to pharmaceutical composition based on thereof that can be used for inducing angiogenesis. Invention provides the enhancement of biological activity of preparation.

EFFECT: valuable biological properties of factor.

4 cl, 3 tbl, 4 dwg, 3 ex

FIELD: medicine, thoracic surgery, anesthesiology.

SUBSTANCE: as non-narcotic medicinal preparation one should apply heparin to be introduced intratracheally at the dosage of 300-500 IU/kg, moreover, heparin should be introduced during the first 30 min after the operation is over. The present innovation enables to create prolonged anesthetizing effect in combination with prophylaxis of postoperational thrombohemorrhagic complications due to heparin capacity to be kept in the body due to its accumulation by mast cells at blockade of their fermentative activity followed by its gradual release into the blood.

EFFECT: higher efficiency.

1 cl, 1 ex, 3 tbl

FIELD: veterinary science.

SUBSTANCE: one should introduce mineral additives into the diet of animals in postoperational period for 15-17 d at 4.0-5.0 g, zinc sulfate 0.75-1.5 g, cobalt chloride 30-35 mg, manganese sulfate 40-45 mg, potassium iodide 10-15 mg, monopotassium phosphate 80-100 per 100 kg body weight, moreover, elemental sulfur and monocalcium phosphate should be introduced in combination with concentrates, and zinc sulfate, cobalt chloride, manganese sulfate and potassium iodide should be introduced in dissolved form in the mixture with feedstuffs. The present method enables to decrease the terms for wounds healing.

EFFECT: higher efficiency.

3 tbl

FIELD: medicine, obstetrics, gynecology.

SUBSTANCE: rehabilitation should be carried out in the third trimester of pregnancy based upon dispensary situated in ecologically safe region, as an enterosorbent one should apply "Carbopect" preparation per 0.5-0.6 g once daily for 3 wk; as an iodine preparation it is necessary to prescribe "Potassium iodide" 200 mcg once daily till the end of pregnancy period and during the whole period of lactation; as adaptogens one should additionally prescribe "Revit" per 2 lozenges thrice daily for 2 wk; vitamin-containing tea; one should, also, apply aerotherapy named "mountain air" per 15-40 min, 15 procedures, totally. The present innovation enables to improve anthropometric parameters in neonatals, decrease the percentage of complications in babies in early neonatal period, among them those that require antibioticotherapy.

EFFECT: higher efficiency of rehabilitation.

2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I):

as a free form or salt wherein Ar means group of the formula (II):

wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.

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

13 cl, 3 tbl, 35 ex

The invention relates to new imidazole compounds of the formula I:

where R1represents hydrogen, hydroxy, protected hydroxy, or aryl, optionally substituted with a suitable(and) substituent(s) selected from the group consisting of halogen(lower)alkyl, halogen, hydroxy, protected carboxy, carbamoyl, lower alkylenedioxy, lower alkoxy, optionally substituted aryl, and lower alkyl, optionally substituted by hydroxy or protected carboxy; R2represents hydrogen or lower alkyl; R3is hydroxy or protected hydroxy; R4represents cyano, (hydroxy)minamino(lower)alkyl, carboxy, protected carboxy, N-containing heterocyclic group, optionally substituted amino, or carbarnoyl, optionally substituted with a suitable(s) of the substituent(s) selected from the group consisting of amino, hydroxy, lower alkyl, lower alkylsulfonyl, amidoamine(lower)alkyl, optionally substituted by hydroxy; and-And - is-Q -, or-O-Q-, where Q is a single bond or lower alkylene, or its salt, provided when R2is the lowest Ala the substituent(s), the above, and also provided that the compound of formula I is not 1-(hydroxyethyl)-4-(etoxycarbonyl)imidazole or anilide 1-(2-hydroxyethyl)imidazole-4-carboxylic acid

The invention relates to medicine, in particular to cancer, and can be used in radiation therapy of malignant tumors of the pelvic organs
The invention relates to chemical-pharmaceutical industry, medicine and relates to a composition comprising immunoglobulins

The invention relates to the field of pharmacology, and relates to powder compositions stabilized liposomes unilamellar

The invention relates to the field of medicine and for the application of hydrogenated soy phosphatidylcholine (Phospholipon-N) as an active ingredient, providing a surface-active properties of drugs for substitution of the surfactant therapy

A therapeutic agent // 2207851

The invention relates to medicine and relates to means for the treatment of chronic dermatoses and method of treatment
The invention relates to medicine, in particular to novel solid pharmaceutical compositions containing hexadecylphosphocholine (miltefosine) for oral administration in the treatment of leishmaniasis, to a method for the production of specified pharmaceutical compositions for the treatment of leishmaniasis specified pharmaceutical composition to a combination that includes the specified solid pharmaceutical composition, an antiemetic and/or antidiarrheal agent

The invention relates to the treatment of endotoxemia caused by endotoxins, in particular to the treatment of poisoning endotoxins introduction into the organism of various compounds that neutralize and/or remove endotoxins from the body, and also to prevent using these compositions

The invention relates to the field of biochemical pharmacology and medicinal chemistry

The invention relates to medicine, in particular to pharmacology relates to liposomal pharmaceutical composition for intravenous administration containing insoluble lipophilic active substance in the form of liposomes, at least one phospholipid, distilled water, and targeted supplements, and additionally contains at least one cretaceou fatty acid formula: H3C-(CH2)n-COOH, where n = 4-8, or its salt, at a certain ratio of components

FIELD: medicine, hepatology.

SUBSTANCE: at achieving alkaline phosphatase of 580 U and more one should introduce ursodesoxycholic acid at the dosage of 15-20 mg/kg and orlistate at the dosage of 90-100 mg twice or thrice daily for patients with steatohepatitis. According to normalization of clinical and biochemical values of blood analyses it is possible to conclude upon successfulness of therapy performed. The method provides clinic-laboratory remission of the disease.

EFFECT: higher efficiency of therapy.

3 ex

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