Pharmaceutical composition containing no proteins and peptides, a method of treating humans or animals suffering from endotoxemia, and the way to prevent disease

 

(57) Abstract:

Farmacevticheskaja composition includes an effective amount of at least one phospholipid. The phospholipid can be represented by a phosphatidylcholine or sphingolipids. The composition may further contain up to 70% by weight of a neutral lipid and a therapeutic amount of holonovel acid or its salts. The neutral lipid can be represented by a triglyceride or cholesterol ester. Galanova acid or its salt represented by the bile acid or bile acid salt. Salt of the bile acid is selected from cholate sodium, desoxycholate sodium and hendezoksiholeva sodium. Method for the treatment or prevention of endotoxemia in humans or animals, or neutralization of endotoxemia in humans or animals, or neutralization of endotoxins is the introduction of a specified pharmaceutical composition. This provides a level of phospholipid to approximately 400 mg per 1 kg of body weight of the specified person or animal. The technical result consists in suppressing the toxicity caused by endotoxins and endotoxin removal from the body in case of poisoning. 5 C. and 23 C.p. f-crystals, 10 ill., 5 table.

The invention relates to the treatment end of different compositions, that neutralize and/or remove endotoxins from the body, and also to prevent using these compositions.

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 skeleton (see Paetz, Ann. Pev. Biochem. 59: 129 - 170 (1990)).

The lipid molecule is 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 to refer to molecules LPS.

In U.S. patent N 5128318, the description of which ispolzovat, 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 an apolipoprotein.

These inventors also found that the toxicity caused by endotoxins, you can fight sequential introduction apolipoprotein 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 of apolipoprotein that is higher than normal and allow effective treatment of endotoxemia introduction of reconstructed particles containing apolipoprotein or a peptide described but containing avannah 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.

Now it was unexpectedly found that phospholipids can be used alone or in combination with additional materials such as neutral lipids, holty and so on, 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 combined with phospholipids, so that the total amount of neutral lipids was below a certain mass content in percent when using these compositions is aqueous 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.

In Fig. 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 TNF in the model of whole human blood. In Fig. 1 shows the value of protein, and Fig. 2 - phospholipid. The tested compounds included natural lipoproteins lipoproteins (VLDL, LDL, HDL), reconstructed HDL(R-HDL) and formulations INTPALIPID, and emulsions containing phospholipid and protein.

In Fig. 3 and 4 show the comparative value of triglyceride (neutral lipid) and phosphatidylcholine (phospholipid) in the same model.

In Fig. 5 presents information on the toxicity when the PTO 55%.

In Fig. 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.

In Fig. 7 and 8 show results comparable to the one shown in Fig. 1 and 2, and in this case, a phospholipid, neeterificirovannah cholesterol and/or sphingomyelin mixed with triglycerides or esterified cholesterol as a neutral lipid.

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

In Fig. 10 shows a diagram of theoretical amount of triglycerides is 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.

Example 1

Factors that affect the stimulation of TNF - a 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 si the ASS="ptx2">

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 37oC the tubes were cooled to 4oC, and then centrifuged at 10,000 g for 5 minutes. The supernatant was decanted and using a known enzyme immunosorbent assay (ELISA) was determined by TNF-.

Table 1 shows the comparative data of the compositions of the materials tested. In Fig. 1 and 2 presents the results. Data are presented as graphs of the dependence of the amount of TNF - on the concentration of added protein (Fig. 1) and phospholipid (Fig. 2). To show the wide range ispolnenie system of whole blood contained 10 ng/ml E. coli 0111:B4 LPS, supplemented by one of the trains, as the explication to Fig. 1 and 2.

That the effectiveness of various materials in the case of drawing the graph of the protein (Fig. 1) and such when applying the content of phospholipid (Fig. 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.

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 further machining work: the mixer prior to 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 (20 000 psi). Samples containing ester of cholesterol with one or more other lipids, cyclically missed 15 - 20 times at a pressure of 206842 kPa (30 000 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. On. Fig. 3 and 4 show the results of these studies, where data about the production of FSC-dependent TNF - dependent on the concentration of added triglyceride (Fig. 3) or phospholipid (Fig. 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 Fig. 4). The composition of 89% TG represents 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 when compared to the triglyceride content is very different. They are very similar when tested on the content of effektivnym, 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, mice were injected in the form of balls, a sufficient amount of the composition described in example 2, as well as 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 of E. coli 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 Fig. 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 TG on the main 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 (hydrocarbon) 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 TNF-.

The results of the experiments shown in Fig. 6. The secretion of TNF - a was significantly reduced when using only PF. Emulsions containing neeterificirovannah cholesterol, sphingomyelin, or their mixture, also suppressed Zirovnica cholesterol and/or sphingomyelin on the emulsion, containing a neutral lipid. In addition, the used emulsion at 100 mg/DL PF. Various compositions (in mass ratio) in table 2.

In Fig. 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 concentrations of endotoxin. Emulsions containing ester of cholesterol, were less effective than emulsion comprising triglycerides, whereas emulsion containing neeterificirovannah cholesterol, did not suppress TNF-, as well as emulsions that do not contain cholesterol. Add sphingomyelin of the emulsion was increased to suppress the production of TNF-.

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 of 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.

In Fig. 9 are given with the experiments, using 16 or more animals.

As can be seen in the illustration, 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 TNF 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 Fig. 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. On the Kli is 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. In Fig. 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 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 sootvetstvyy weighed on paper, and then slowly added to the solution while stirring. This requires about 3 to 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, the 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 ptx2">

The results of the experiment 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.

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 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: the Holevo, 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 examined the survival rate of mice, used as experimental animals.

Thus they were divided into 4 groups. The first group, the control, has 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.

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, vividly what I -"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 TNF (tumor necrosis factor)-.

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 ball of the emulsion intravenously continuously poured 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 dosing.

Table 5 presents the maximum values of TNF-. They are registered through 2 hours after injection of endotoxin. The statistical significance of the indicators determined the e introduction 18 mm holeva acid.

These examples explore in detail the invention, which involves one of the goals of the reduction or prevention of endotoxemia by introducing the patient an effective amount of phospholipid, which is 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 Association of endotoxin with phospholipid inactivates it.

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., attenuation or prevention of 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): 43 - 14S (1984)) entered in this text by reference, in particular, page 5, Fig. 1 and 2, which shows characteristic patterns holanovich acids.

The invention can be Fermin "weakening", 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. ). Prevention 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. The usual dose total weight of about 200 to 800 mg of 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 to 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, not with what about the neutral lipids and phospholipids are combined into particles, which is similar to density, but differ in that they do not contain protein peptide components, which of course is always present in the lipoproteins.

Particularly desirable such forms of treatment, where the phospholipid represented by phosphatidylcholine, such as 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 mono - glycerides 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 opasnost what about the neutral lipid should be approximately 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 for intravenous injection, 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 mg/kg to 500 mg/kg body weight and more preferably from about 50 mg/kg to 100 mg/kg of body weight. The preferred dose of phospholipids preferably be from 100 mg/kg to 1000 mg/kg of body weight. Here are the common dosages, but 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. For phospholipids, 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 (such as cholesterol, sitosterol), esterified or oil, 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 (such as 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. Especially the e 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 as those described above specified 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 are clear 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, not beyond his sushenya or prevention of endotoxemia in humans or animal or neutralization of endotoxins, comprising an effective amount of at least one phospholipid with which are associated endotoxins are responsible for groove toxins.

2. The pharmaceutical composition under item 1, characterized in that it additionally contains up to 70% by weight of neutral lipid.

3. The pharmaceutical composition under item 1 or 2, characterized in that it further comprises a therapeutic amount of holonovel acid or salt holonovel acid.

4. The pharmaceutical composition according to p. 3, characterized in that Galanova acid or salt holonovel acid presents bile acid or bile acid salt.

5. The pharmaceutical composition according to p. 4, characterized in that the salt of the bile acid is selected from cholate sodium, desoxycholate sodium and chenodesoxycholic sodium.

6. The pharmaceutical composition according to p. 4, characterized in that the salt of the bile acid presents Holtom sodium.

7. The pharmaceutical composition according to any one of paragraphs.1 - 6, characterized in that the phospholipid represented by phosphatidylcholine.

8. The pharmaceutical composition according to any one of paragraphs.1 - 6, characterized in that the phospholipid represented by sphingolipids.

9. Pharmaceutical >10. The pharmaceutical composition according to any one of paragraphs.2 to 8, wherein the neutral lipid is represented by the ether of cholesterol.

11. The pharmaceutical composition according to any one of paragraphs.2 to 10, characterized in that it contains up to 50% by weight of neutral lipid.

12. The pharmaceutical composition according to any one of paragraphs.2 to 11, characterized in that it contains from about 5% to about 10% by weight of neutral lipid.

13. The pharmaceutical composition according to any one of paragraphs.2 to 12, characterized in that it contains a phospholipid and neutral lipid mass ratio of about 93:7.

14. The pharmaceutical composition according to any one of paragraphs.3 to 13, characterized in that it contains from about 5% to about 30% by weight holonovel acid or salt holonovel acid.

15. The pharmaceutical composition according to any one of paragraphs.3 to 14, characterized in that it contains from about 10% to about 15% by weight holonovel acid or salt holonovel acid.

16. The pharmaceutical composition according to p. 3, characterized in that it contains Holloway acid or salt holonovel acid, phospholipid and neutral lipid in the total mass ratio of approximately 13:81:6 southeasterlies, the neutral lipid is represented by triglyceride and Galanova acid or salt holonovel acid presents Holtom sodium.

18. The pharmaceutical composition according to any one of paragraphs.1 - 17 in the form for intravenous administration.

19. Method for the treatment or prevention of endotoxemia in humans or animal or neutralization of endotoxins, which consists in the introduction of the pharmaceutical composition according to any one of paragraphs.1 - 18 in a quantity sufficient to provide a layer of phospholipid to approximately 400 mg, it is better to 200 mg, preferably up to 100 mg per 1 kg of body weight of the specified person or animal.

20. Not containing proteins and peptides pharmaceutical composition for the treatment or prevention of endotoxemia in humans or animal or neutralize endotoxin, comprising a) at least one neutral lipid in an amount of from about 3% to about 50% by weight of the total lipid content in the specified composition and b) at least one phospholipid.

21. The pharmaceutical composition according to p. 20, wherein the phospholipid represented by phosphatidylcholine.

22. The pharmaceutical composition according to p. 20, wherein the phospholipid represented by sphingolipids is represented by triglyceride.

24. The pharmaceutical composition according to any one of paragraphs.20 to 22, wherein the neutral lipid is represented by the ether of cholesterol.

25. The pharmaceutical composition according to any one of paragraphs.20 to 24, characterized in that it further comprises a sphingosine.

26. The pharmaceutical composition according to any one of paragraphs.20 - 25 in a form for intravenous administration.

27. Method for the treatment or prevention of endotoxemia in humans or animals, which consists in the introduction of no-containing proteins and peptides pharmaceutical composition according to any one of paragraphs.1 - 18.

28. Method for the treatment or prevention of endotoxemia in humans or animals, which consists in the introduction of the pharmaceutical composition according to any one of paragraphs.20 - 26.

Priority points and features:

10.08.1994 on PP.1 and 2;

07.06.1995 on PP.3 - 6, 14 - 17, 20 - 26 and 28;

PP. 7 - 13, 18, 19 and 27 in the absence of symptoms related to holonovel acid or a salt thereof, shall have priority from 07.06.1995, and in other cases have priority from 10.08.1994.

 

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