Method and composition for the prevention and delay of onset of alzheimer's


(57) Abstract:

The invention relates to the field of medicine. The essence of the invention is that the composition for the prevention or delay of Alzheimer's disease includes beta-sitosterol, campesterol and stigmasterol may additionally include campestanol, and the method is characterized by the fact that the person is administered a therapeutically effective amount of this phytosteroles composition. The invention provides improved memory and has no visible side effect. 2 S. and 4 C.p. f-crystals, 4 tab., 4 Il.

This invention relates to the field of study of Alzheimer's disease and the ways of its prevention and delay its onset.

Background of the invention

Alzheimer's disease ("BA") is a relentlessly progressive disorder leading to dementia. Its main distinctive pathological feature is the development of changes of the cytoskeleton in some susceptible neurons. These changes do not occur inevitably in the process of aging, but if the disease is initiated, spontaneous recovery or remission does not occur.

The initial changes of the cerebral cortex, described further below, the RA is th process develops in a predictable type as its spread to other areas of the cerebral cortex. Localization forming a plexus of neurons and the weight changes allow us to provide snow six stages in the progression of the disease from the I-II stages that are not clinically evident until V-VI stages, which indicate the full development of ad. The relatively small number of patients are particularly early changes, which indicates that old age is not a necessary condition for the development of lesions. Accordingly BA is thus associated with age, but not dependent on the age of the disease.

Regarding the causes and mechanism of development of the BA at the present time there are a number of theories, many of which are associated with genetic defects. A very small percentage of patients with BA there was a defect on chromosome 21 that are related to gene responsible for the production of a protein, the amyloid precursor ("RDAs"). The RDA is a large protein involved in the growth and repair of cells, which when splitting into small nevereverever protein beta-amyloid ("B-A") can accumulate in plaques within the brain.

Further interesting studies have focused on the relationship between late start family BA and polymeric gene on chromosome 19, kojirou lipids inside the cells and throughout the body. APO E) plays a key role in the transport and metabolism of lipids, and it is discussed further below. Neurobiological role of APO-E was the result of a series of observations over many years. First, mRNA APO-E in great numbers are present in the brain, where it is synthesized and secreted primarily by astrocytes (Elshourbagy et al., 1985). Secondly, APO-E-containing lipoprotein, found in the spinal fluid and, as it turns out, plays an important role in the transport of lipids in the Central nervous system (Pitas et al., 1987). Thirdly, APO-E in combination with a source of cholesterol causes a pronounced elongation of axons of nerve cells in the cells of the ganglion dorsal root in the culture (Handelmann et al., 1992). Fourth, the content of APO-E increases dramatically after peripheral nerve injury (Muller et al., 1985). Accordingly, as it turns out, APO-E is involved in the utilization of lipids generated after the collapse of the axon, and the redistribution of these lipids in growing axons during regeneration and later in Schwann cells during remyelination of new axons (Boyles et al., 1989).

The implied role of APO-E, which exists in three different isoforms encoded by three separate alleles (E-2, E-3, E-4), to the C connection APO-E with two typical BA patinirovanie lesions in the form of extracellular axonyx plaques (representing deposits B-A) and intracellular neurofibrillary plexus (representing thread associated with the microtubule protein, called "tau"). The review is presented in the work Weisgraber et al., 1994).

In particular, it was discovered a genetic link between isoform of APO E4 and BA. E4-homozygous individuals show a higher risk of ad development than E4-heterozygous individuals, which in turn are higher risk than those with no E4 allele. Although the exact mechanism by which correlation functions remains unclear, researchers presented several possible answers. It may include the biological effects of the protein encoded by this allele, in the same way as reducing the avidity of binding of APO-E2 with the LDL receptor leads to increased cholesterol in plasma E2-homozygotes. Strittmatter et al. (1993) showed that APO-E4 more effectively binds with a peptide B-A, leading to increased formation of senile plaques, in comparison with the other two isoforms, and hence suggested that the increased susceptibility to BA is not the presence of APO-E4, and the absence of other isoforms of APO E (Strittmatter et al., 1994a).

Similarly, with regard to isoformspecific interaction APO-E protein "tau", phosphorylated forms which are the basic constituents of neurofibrillary plexus, b is th effect led to the emergence of hypotheses, what APO-E3 usually allows the protein "tau" to stabilize microtubules and that the decrease in the content, or the lack of it in patients with one or two alleles of APO-E4 leads to dissociation "tau and microtubules and increased phosphorylation and polymerization in abnormal paired helical filaments (Strittmatter et al., 1994b).

Despite numerous studies in the field of development BA, treatments are few, and ways to prevent and/or delay the beginning of this debilitating disease is virtually absent.

The present invention is to eliminate or reduce the above disadvantages.

The invention

The present invention provides a method of prevention and/or delay the start of Alzheimer's disease ("BA") in animals, which includes the introduction of animal fitosterinov composition.

In addition, the present invention is compositions that are effective in the prevention or delay the onset of ad, which include beta-sitosterol, campesterol and stigmasterol.

Brief description of drawings

The present invention is illustrated by the following non-limiting drawings, in which:

Fig. 1 free time (%), spent in each quadrant, when the platform was in quadrant 1;

Fig. 2 is a graph showing the results of the research in the water maze Morris, expressed as time (%) spent in each quadrant, when the platform was removed from quadrant 1;

Fig. 3 is a graph showing the results of the research in the water maze Morris, expressed as time (%) spent in each quadrant, when the platform was in quadrant 3; and

Fig. 4 is a graph showing the results of the research in the water maze Morris, expressed as time (%) spent in each quadrant, when the platform was removed from quadrant 3.

The preferred embodiment of the invention

Phytosterols are stalinophobia compounds synthesized in plants and have no direct nutritional value for humans. In plants they are necessary for the functioning of cells in the same way that cholesterol is necessary for people. The average Western diet contains up to 360 mg of phytosterols per day. Recently, these dietary plant sterols has attracted great attention due to their possible anti-cancer t is Up to the present time has never been offered or has not investigated the use of plant sterols in the prevention and delay (treatment) BA.

According to the chemical structure of phytosterols is strongly reminiscent of cholesterol. The major phytosterols are beta-sitosterol, campesterol and stigmasterol. Other phytosterols include stigmastanol (beta sitostanol), desmosterol, holenstein, peripherality, clionasterol and brassicasterol. The composition of the present invention includes all natural and synthetic forms of phytosterols, all hydrogenated analogs, i.e., Stanly, and all derivatives thereof, including isomers.

Although phytosterols available in vegetable oils and vegetables, they do not necessarily see a significant enough concentrations or in the form necessary to ensure the benefits of the present invention. In the scope of claims of the present invention is included a method of prevention and/or delay the beginning of the BA with the introduction of animals, in particular humans, fitosterinov composition. As required and described herein below, this composition can be included directly in food additives, oils, vitamins and therapeutic compositions.

It is assumed that phytosterolemia compositions of the present invention can be mixed with regular food for the large-scale distribution among the population, nativitatis by more intensive program aimed at those individuals who have a risk of developing certain forms of BA, i.e., family BA. In the preferred form of the composition is mixed with a vegetable oil selected from the group comprising oil of safflower, sesame oil, corn oil, rice bran oil, olive oil and rapeseed oil. The most preferred additive based on olive oil, as this oil is widely used and is low in phytosterols and fatty acids. Alternatively, the composition can be included in products on the basis of saturated fat (lard) or added to the dough fats such as butter or margarine.

In another implementation, the composition can be included in compositions with other conventional or herbal products for prevention or treatment of ad. These products include cholinesterase inhibitors such as AriceptTM, risperidone (drug for treatment of schizophrenia, which is currently found effective at eliminating aggression associated with BA), and possible strengthening memory herbal preparations such as Ginkgo, but are not limited to.

The basis of the present invention is the use of phytosterols, mainly for the data result they in no way should be interpreted as limiting the broad scope of the claims of the present invention, since the same positive results can be achieved using many of phytosterols individually or in various combinations.

Preferred phytosterolemia composition according to the present application include beta-sitosterol, campesterol, stigmasterol (sitostanol) and, optionally, campestanol and analogues/derivatives. In one implementation, the composition of the present invention includes at least 10% of campestrini and not more than 75% beta-sitosterol. In another preferred form, the composition includes from 10 to 25% of campestrini, from 10 to 40% of stigmastanol and from 45 to 75% beta-sitosterol. May not be present from 1 to 10%, more preferably 3% campestanol.

In another preferred form of the composition of the present invention include the ratio of phytosterols: beta-sitosterol (1); campesterol (0,2-0,4) and stigmastanol (0.2 to 0.5). More preferably, campestrin and stigmastanol together comprise at least 50% of the total concentrations of beta-sitosterol. The compositions of the present invention include the ratio of three key Richi have distribution (%) of plant sterols, are given in table. 2.

However, it should be understood that in any of these preferred compositions can contain other plant sterols. Similarly, if necessary, a part of the composition can comprise adjuvants or carriers. Depending on the method of delivery of compositions of the present invention, the dosage may change somewhat. Most preferably, the daily was administered from about 1.0 to 3.0,

In the method according to the present invention are prevention of ad and/or delay its start by introducing the individual fitosterinov compositions described in detail above. The exact mechanism by which the introduction of phytosterol dietary increase the capacity for learning and memory, reduced dependent on the age of the reduction in the number of synapses and slow the neurodegenerative processes that are unclear, although the applicants have several theories, which are described in more detail below. These theories have no intention to limit the scope of the claims of the present invention, but rather serve to illustrate the complexity of the role of phytosterols in the lipid homeostasis of animals.

As discussed above in the assumptions of izobreteny the evidences, show the relationship between BA and cardiovascular diseases (Kalaria, 1997). An overview of the functions of APO-E are presented below along with information linking the APO-E with the present invention, from the point of view of understanding of the proposed mechanisms of action of phytosterols.


APO-E is only one of the vectors of lipids called apolipoprotein. These proteins have three main functions. First, they help to solubilisate highly hydrophobic cholesterol and triglycerides by interacting with phospholipids (the core of the complex is a lipid, the outer casing is a apolipoproteida) to allow transport of these lipids. Secondly, apolipoprotein regulate the reaction of lipids with enzymes, such as lipoproteinlipase and lecithincholesterolacyltransferase. Thirdly, apolipoprotein bind to receptors kostchei surface and, thus, determine the sites of capture and decay rate of the other ingredients of lipoproteins, in particular cholesterol.

APO-E is unique among lipoproteins in the fact that it has a specific affinity for nervous tissue. During development or after injury to the peripheral nervous system APO-E is th shell and membranes of neurons (Boyles et al., 1989, supra). Much less is known about the function of APO-E in the Central nervous system, which determines the possibility that APO-E is a marker BA (discussed above in the background of the invention), is even more intriguing.

Mouse APO-E

In several studies in humans and animals has been shown to reduce cholesterol effect of plant sterols, including anti-atherogenic effects fitosterinov compositions in mice with deficiency of APO-E (patent Application PCT PCT/CA95/00555, published April 4, 1996, and incorporated here by reference, and Moghadasian et al., 1996). Later it was shown that mice with a deficiency of APO-E is a suitable experimental model to study the pathophysiology of ad. As in mice with deficiency of APO-E phytosterols prevent atypical distribution of cholesterol (skin, tendons, aorta and major arteries), phytosterols can play an important role in determining the tissue distribution of cholesterol, even in the brain cells, independent of the phenotypes of APO-E (research conducted by the applicant).

Remnants of chylomicrons

Chylomicrons are the largest lipoprotein particles, consisting mainly of triglycerides with lower amounts of tsvetelin, coming from the food fall into the mesenteric lymph and the thoracic duct, where they combine with APO-E. Enzyme lipoproteinlipase ("LL") catalyzes the hydrolysis of triglycerides of chylomicrons, which generated free fatty acids are absorbed primarily by adipocytes, and the remaining smaller pieces of lipoprotein (cholesterol-enriched) are referred to as the remnants of chylomicrons ("CR"). CR rapidly eliminated from plasma with election-dependent APO-E liver mechanism (receptor belonging to the low-density lipoprotein, receptor "LRP"), where cholesterol is used in the biosynthesis of the membrane or lipoprotein, or released as free cholesterol or metabolized into bile acids. The presence of APO-E is considered to be the key for particles that must internalservice. Liver cells and brain is particularly rich in this receptor LRP.

The very low density lipoprotein

Lipoprotein very low density ("VLDL") is similar in structure to chylomicrons, but smaller and contains fewer triglycerides, but relatively more cholesterol, fosfolipida and protein (a mixture of APO-E, APO-C and APO-B100). VLDL is synthesized mainly in the liver, and its main function is pepper lipase ("HL") gives even smaller particles: VLDL remnants (also known as lipoprotein, intermediate-density and low-density lipoprotein ("LDL").


There are at least two different trigliceridos. Extrahepatic or lipotidae ("LL") is found mainly in adipose tissue and skeletal muscle. Hepatic lipase ("HL") is located on the endothelium of the hepatic cells. And LL, and HL are involved in the catabolism of CR and VLDL.

Receptors APO-E

There are four known receptor, involved in the transport of APO-E/lipoprotein (chylomicron, VLDL or LDL) in cells from plasma: receptor low-density lipoprotein (LDL receptor), receptor LRP (defined above), a newly described receptor lipoprotein very low density (VLDL receptor") and the receptor epithelial glikoproteid 330 ("receptor GP330"). All four receptor found in the brain. The discovery that the receptor for activated form of A2-macroglobulin ("A2/M) is identical to the receptor, LRP, is proof that the receptor LRP is a multi-factor receptor protein called receptor alpha 2M/LRP. This receptor is expressed in almost every cell of the body, especially in the liver and brain, the target enzymes, proteins, CR and LDL cholesterol and, it seems, plays a complex role in proteolysis, immunity, cellular poolco, neurons that are very rich surface receptors LRP and that the immunoreactivity of LRP receptors was higher in plaques in ad (Rebeck et al., 1993), but also that the complexes of APO-E/LRP also localized in the plaques in the brain (Ikeda et al., unpublished data). LRP is not only binds residues containing APO-E, but also interacts with important enzymes of metabolism chylomicrons, such as LL. This latter binding regardless of APO-E (Beisiegel et al., 1991). Noteworthy is the ability of phytosterols to prevent the formation of atherosclerotic plaques in mice with deficiency of APO-E.

Inside the liver CR catabolized LL or mechanism that is dependent on APO-E, namely LRP or A2 receptor/LRP.

The proposed mechanisms for the effect of phytosterols on for BA

There are three interrelated main mechanism by which phytosterols have a beneficial effect on prevention and early BA:

1) phytosterols increase independent of APO-E clearance CR in the liver through the hepatic LRP through a complex (and not yet fully understood) mechanism, including allosteric activation LL and education complex LL CR; and/or

2) phytosterols reduce the Zirl, but brain cells, in particular; and/or

3) phytosterols reduce the "peeling" of endothelial cells and protect endothelial function of blood-brain barrier.

Phytosterols are associated with circulating chylomicrons and lipoproteins and have a modifying effect on these particles in the plasma and on the physico-chemical properties of enzymes, such as LL and HL. In other words, the applicants suggest that phytosterols function as apoprotein, changing the structure, composition and function of circulating chylomicrons and lipoproteins and, in addition, indirectly affect many other key cellular functions through receptor LRP.

Simplifying, we can say that from the point of view of the first mechanism, phytosterols associated with lipoproteins, i.e. chylomicrons, and prevent the binding of these particles to receptors allfam/LRP and subsequent penetration of the particles through the cell barrier in the brain. Accordingly, the amount of APO-E in neural cells would be reduced, which is especially important for those who are APO-E4-homozygotes.

In addition, phytosterols'LL increase the activity through allosteric modification so that obog lacienega channel independent of APO-E hepatocytolysis receptor CR, which is identical to the LRP receptors. As discussed above, LL is the main enzyme involved in the metabolism of triglyceride (chylomicron and VLRL) having carboxyl (C) or nitrogen (N) ends. Its regulation, structural and functional relationship and the C-terminal domain of lipoproteinlipase (by induction of catabolism CR through receptor LRP) has been well studied by researchers, and it is concentrated applicants on the opportunities catabolism of lipoproteins, independent of APO-E.

It is believed that phytosterolemia compositions of the present invention alter the physico-chemical properties of lipoproteins using allosteric modification. Therefore, the activity of LL under the influence of phytosterols may be more efficient to use a lot of the enzyme for the catabolism of triglycerides N-terminal catalytic site, whereas the C-terminal domain may serve as a ligand for CR. The complexes of the C-domain of LL-CR with low intake of fatty acids in the liver then internalisers receptor, utilizing identical receptors (alfam/LRP), and then catabolized hepatic lipase expressed further collapse of the ether fatty acids CR.

In other words, it is possible that the phytosterol is processes independent of APO-E, they should not lead to stimulation of the LDL receptor.

From the point of view of the third, but complementary mechanism that phytosterols reduce the desquamation of cells (endothelial effect), the applicants have found that in normal rats and rats with hypercholesterolemia introduction with food fitosterinov composition has reduced the "shedding" of endothelial cells, respectively, at 50 and 70%. This is a fundamental finding, given the role of the endothelium in the blood-brain barrier and the passage of undesirable damaging particles in the brain, which can lead to the development of ad. In addition, integrins, a diverse class of receptors are glycoproteins that are involved in the interaction of cells with extracellular matrix ("ECM"). Violation of the expression of integrins in the brain may be associated with an increase subendothelial infiltration of APO-E. ECM directs the growth, differentiation and function of the lining epithelium (Getlenburg et al., 1990).

Moreover, applicants believe that plant sterols modify membranes, including the blood-brain barrier. Respectively may be impaired transport of potentially toxic substances, such as the precursor of beta-amyloid through this membrane, which leads to a delay al. , 1996). This may be due to BA. In ongoing research, the applicants have shown that plant sterols may have antioxidant activity. Accordingly, these sterols can protect the brain from oxidative stress, leading to delay or even prevent AD.

Below is a summary of the possible mechanisms of action of phytosterols.

1) Enzymatic effect

allosteric modification of LL and changes the molecular configuration lipoproteine complexes

2) Chylomicrons and CR

stimulation of LL ---> CR enriched LL

inhibition of HL

CR ---> independent of APO-E capture VLDL receptors or LRP using the C-Terminus of the monomer LL as ligand binding and/or internalization of receptors. Inhibition of the monomer HL capture CR via LDL receptor

occurrence in the smooth endoplasmic network of hepatocytes

stimulation of 7-alpha-hydroxylase ---> increased synthesis of bile acids

the increase cholesterol levels in bile and decrease cholesterol in the liver, independent of LDL metabolism increased activity of HMG-CoA, i.e., CR can inhibit the receptor VLDL or LDL

reduced "peeling" andate is in the present invention provided with the following non-limiting examples. In particular, the study shows that the acceleration of atherosclerosis in mice with deficiency of APO-E is delayed by the introduction of fitosterinov composition and has improved with the development of atherosclerotic lesions. "FCP-3PI" means the preferred composition within the range of the claims of the present invention.

Example 1

Improvement using FCP-3PI learning ability and memory of mice with deficiency of APO-E


Mice with deficiency of APO-E (APO E-KO) is known as a model of atherosclerosis, xanthomatosis and Alzheimer's disease (16-18). Mice with deficiency of APO-E was used as a useful system for studying values apoliprotein E in brain function. Some of these studies have focused on learning and working and reference memory in mice with deficiency of APO-E (19-20). These mice had reduced the density of synapses in the hippocampus and the regenerative capacity after lesions of the hippocampus (21, 22). The authors of the invention have been effectively delayed/prevented the first two of the above disorders by nutritional supplements in the form of fitosterinov mixture FCP-3PI (11, 23). The purpose of this study is to evaluate the effects of adding in food FC">


Add in food FCP-3PI improves learning ability and memory in mice with deficiency of APO-E.

Materials and methods

24 male mice at the age of 2 weeks. with deficiency of APO-E and 24 similar matched wild-type mice with feeding their mothers were purchased from Jackson Laboratory. At the age of 4 weeks. mice were weaned and were divided into 4 groups, matched for body weight and total cholesterol in the plasma. Group for 33 weeks. fed the following diets.

Group 1 (n = 10) Mice with deficiency of APO-E, fed normal food for mice, containing 4.5% (wt./wt.) fat (normal food, OK) with the addition of 2% (wt./wt.) FCP-3PI.

Group 2 (n = 10) Mice wild-type, fed OK with the addition of 2% (wt./wt.) FCP/3PI

Group 3 (n = 10) Mice with deficiency of APO-E, fed OK

Group 4 (n = 10) Mice wild-type, fed OK

Animals were kept separately (each mouse was given an empty bottle with a large opening for the game), conducted daily monitoring to assess their physical activity and behavior, and weekly register the weight of their bodies. At 0, 4, 17 and 29 weeks. research from the tail vein took the blood and carried out the enzymatic determination of cholesterol in plasma. Through the and Morris, as described previously. The procedure was recorded using a video camera, and the results were analyzed using computerized systems. At the end of the study, the mice were scored, and their brains were fixed in 10% formalin and used for histochemical evaluation. Paraffin sections of mouse brain were stained with (a) hematoxylin and eosin (D and e) as the standard method of staining for histological study, (b) Congo red for educational evaluation amyloid plaques, c) Bielchowsky to assess axonal and (d) Do fast blue for the study of myelin. Moreover, in cooperation with the University, Miami mice brain were stained (immunohistochemically) on potential markers of neurodegenerative diseases, including glial fibrillar acidic protein (GFA), the precursor protein of amyloid (APP), neurofilament (NF) and ubiquitin. One mouse from group 1 and one mouse from group 3 were euthanized at an early stage of the experiment due to loss of body weight and reduced food consumption. For consistency with other experimental groups were removed one mouse from group 2 and one mouse from group 4. During the experiment, one mouse from group 1 was filled at 17 weeks. due to skin lesions and one of Mysovaya in the water maze Morris one control mouse APO E-KO (# 15 from group 3) twice during the first day of training was observed seizures.


A: body Weight

Body weight of mice were recorded weekly. The results are summarized in table. 3. As can be seen, in the course of the experiment, all animals gained weight. It shows that among all 4 groups of mice growth and development were the same. Adding FCP-3PI in murine feed had no effect on body weight.

B: the Level of cholesterol in plasma

Total cholesterol in plasma was determined at the beginning and in the course of the experiment. The results are summarized in table. 4. Adding FCP-3PI in mouse food was associated with a significant decrease in the concentration of total cholesterol in plasma in mice APO E-KO, which is consistent with our previous data. On the other hand, adding FCP-3PI in mouse food had little effect on the concentration of total cholesterol in plasma from wild-type mice.

C: a review of research in water maze Morris

All 4 groups of mice were subjected to behavioral test using established techniques in the water maze Morris. Computerized analysis of the data revealed no significant differences in terms of learning ability and memory among groups of mice. In Fig. 1-4 summarizes the results obtained in each group of mice. In Fig. 1 shows the percentage of time to the. shows the percentage of time that each group of mice spent in each quadrant of the pool to find the platform after completion of training. It shows the spatial memory of mice. In this regard, mouse wild-type, fed food FCP-3PI, tend to have a better memory than other groups of animals. As can be seen from Fig. 2, mouse wild-type receiving food FCP-3PI, in search of a platform to spend more time in quadrant 1 (the location of the platform during training). It is also apparent in Fig. 3, showing some of the best training on positioning platform (quadrant 3) wild-type mice that received food FCP-3PI. In Fig. 4 shows the absence of differences among groups of mice, when they investigated the preferences of quadrant 3 (reverse studied the way) that shows poor retention among all four groups of mice.

D: Histochemistry

Conducted histological examination of the brain of the mice of all groups. Staining with hematoxylin and eosin revealed mild degenerative changes in the brain of animals in all four groups. The Congo red staining did not reveal data for the formation of amyloid plaques in any animal brain from all 4 groups. Analogichnye mice in the ratio of the characteristic signs of myelin and axon brain. Will conduct immunohistochemical assessments by an independent neurologist in St. Paul's Hospital. The results will be presented as soon as you have finished the assessment.


This study showed that adding FCP-3PI (2% wt./wt.) significantly reduces total cholesterol in plasma in mice APO E-KO. This dose FCP-3PI has no visible side effects and is well tolerated by all groups of animals. Adding FCP-3PI in the diet of wild-type mice was associated with improved learning ability and memory in comparison with other groups.

1. Phytosterolemia composition for the prevention or delay of Alzheimer's disease, comprising a therapeutically effective amount of beta-sitosterol, campesterol of stigmastanol.

2. The composition according to p. 1, where campesterol and stigmasterol together comprise at least 50% of the concentration of beta-sitosterol.

3. The composition according to p. 1, comprising 10 to 25% of campesterol, 10 - 40% of stigmastanol and 45 - 75% beta-sitosterol.

4. The composition according to p. 1, further comprising campestanol.

5. The way to prevent or delay the start of Alzheimer's disease in an animal, comprising the introduction of a specified animal is="ptx2">

6. The method according to p. 5, where a specified animal is man.


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2 cl

Organic compounds // 2292890

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes a medicament comprising separately or as the unit composition (A) a compound of the formula (I) given in the invention description as a free form or a pharmaceutically acceptable salt or solvate, and (B) corticosteroid designated for simultaneous, successive or separate administration in treatment of inflammatory or obstructive diseases of respiratory ways wherein the molar ratio of component (A) to (B) is from 100:1 to 1:300. Proposed medicaments possess high broncholytic and anti-inflammatory properties and used in treatment of inflammatory or obstructive diseases of respiratory ways.

EFFECT: improved and valuable medicinal properties of agent.

17 cl, 245 ex

FIELD: medicine, gastroenterology, medicinal biochemistry.

SUBSTANCE: invention relates to a method for treatment and choice of a pharmaceutical preparation used in treatment of diseases caused and accompanying with disturbance in metabolism of bile acids and cholesterol. Method involves determination of the quantitative composition of short-chain fatty acids of (C2-C4)-fraction in blood serum and feces. Method involves using preparations containing fatty acids and promoting fro dissolving cholesterol bile stones in case when the content of propionic acid is decreased from 5.6% and increasing the content of butyric acid from 3.5%, and in increasing propionic acid from 19.9% to 21.8% and butyric acid from 18.9% to 20.1% in feces. Method involves administration of preparations effecting on activity of intestine anaerobic microorganisms in case when the content of propionic acid is decreased from 5.7% to 6.5% and the content of butyric acid is increased from 2.9% to 3.4% in blood serum, and when the content of propionic acid is increased from 21.8% and that of butyric acid from 20.1% in feces. Method involves the combination of preparations containing fatty acids and promoting to dissolving cholesterol bile stones and preparations effecting on activity intestine anaerobic microorganisms when the content of propionic acid is decreased from 5.6% and less and the content of butyric acid is increased from 3.5% and above. Proposed method provides possibility for differentiating treatment based on assay of leading ethiopathogenetic mechanisms in development of choledocholithiasis.

EFFECT: improved and enhanced method of treatment.

2 tbl, 3 ex

FIELD: organic chemistry, steroids, medicine.

SUBSTANCE: invention describes compounds or their salts of the general formula (I): wherein values C are disclosed in the invention description. These compounds can be used in preparing medicinal agents used in treatment of acute disorders in portal and hepatic venous circulation.

EFFECT: valuable medicinal properties of compounds.

4 cl, 1 tbl, 2 ex