Composition containing mixed free-ring flavonoids and flavanov used for prevention and treatment of impaired cognition and age-specific amnesia

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and aims at treating the conditions associated with amnesia and impaired cognition. A medically indigent patient is prescribed with the effective amount of a composition containing a mixed extract prepared of Scutellaria plants with high concentration of free V-ring flavonoids, including Baicalin, and an extract of Acacia plants with high concentration of flavanes, including catechine and epicatechin.

EFFECT: methods ensure restoration and preservation of cognition and memory.

44 cl, 15 ex, 2 tbl, 17 dwg

 

The technical field to which the invention relates.

The present invention generally relates to the claimed composition prepared for use for the prevention and treatment of neurodegeneration, neuronophagia and cumulative deterioration of cognitive abilities, disorders, diseases and conditions caused by exposure to reactive oxygen species (ROS), inflammatory proteins and eicosanoids. In particular, the present invention relates to a new claimed composition containing a mixture of representatives of two specific classes of compounds - flavonoids with a free ring and flavanol intended for use for the prevention and treatment of age-related, cognitive, neuropeptidergic and neurodegenerative diseases and conditions mediated oxidative stroke, inflammation, and associated with cyclooxygenase (SOH) and lipoxygenase (LOX) pathways. Diseases and conditions include, but are not limited to, neurodegenerative disorders, stroke, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ABS) and the deterioration of cognitive abilities in old age.

Background of invention

The release and metabolism of arachidonic acid (AA) from the cell membrane results in the formation of Pro-inflammatory metabolites in several different ways. Apparently, the two most important pathway leading to inflammation, mediated by the enzymes 5-lipoxygenase (5-LO) and cyclooxygenase (SOH). These parallel paths lead to the formation of leukotrienes and prostaglandins, respectively, which play an important role in the initiation and development of the inflammatory response. These vasoactive compounds are chemotaxonomy that stimulate the infiltration of inflammatory cells in the tissue and provide a prolonged inflammatory response. Consequently, the enzymes are able to produce these inflammatory mediators were selected as the target for many new drugs intended for the treatment of inflammation, which is involved in the pathogenesis of diseases such as rheumatoid arthritis, osteoarthritis, Alzheimer's disease and some types of cancer.

Enzyme inhibition SOH represents the mechanism of action inherent in the majority of non-steroidal anti-inflammatory drugs (NCPUL). There are two different isoforms of the enzyme MOR (MOR-1 and MOR-2), sequences which are homologous, about 60%, but which differ in the expression profiles and function. MOR-1 is a constitutive form of the enzyme associated with the production of physiologically important prostaglandins, which are involved in the regulation of normal physiologically the ski features such as platelet aggregation, protection of cellular function in the stomach and the maintenance of normal renal function (Dannhardt and Kiefer, Eur. J. Med. Chem., 36, 2001, pp.109-126). The second isoform, SOH-2, is a form of the enzyme induced by proinflammatory cytokines, such as interleukin-1β (IL-1β), and other growth factors (Herschmann, Cancer Metastasis Rev., 134, 1994, SS-256; Xie and others, Drugs Dev. Res., 25, 1992, SS-265). This isoform catalyzes the production of prostaglandin E2 (PGE2from AK. Inhibition of MOR-2 anti-inammatory activity of normal NCPUL.

It is obvious that the inhibitors with dual specificity for both MOR-2 and 5-LO, while maintaining the selectivity in respect of the SOH-2 compared to MOR-1, have an advantage from the viewpoint of inhibiting multiple pathways of metabolism AK. Such inhibitors can block the inflammatory actions of prostaglandins (PG), as well as many of leukotrienes (LT), by limiting their production. This applies to vasodilator, which increases vascular permeability and chemotactic actions of PGE2, LTB4, LTD4 and LTE4, which is also known as having a slow reaction anaphylactic substances. Among them LTB4 has the most powerful chemotactic and chemokinetic actions (Moore, Prostanoids: Pharmacological, Physiological and Clinical Relevance, published by Cambridge University Press, N.Y., 1985, cc.229-230).

N the past the above advantages of dual inhibitors of COX-2/5-LO many dual inhibitors do not cause some side effects, typical NCPUL or inhibitors SOH-2, including gastrointestinal damage and discomfort associated with traditional NCPUL. It has been suggested that induced NCPUL inflammation of the stomach mainly caused by the metabolites of 5-LO, especially LTB4, which attracts cells to the site of gastric damage, causing its further development (Kircher and others, Prostaglandins Leukot. Essent. Fatty Acids, 56, 1997, cc.417-423). Leukotrienes are primary metabolites AK in the gastric mucosa after prostanoid inhibition. Apparently, these compounds contribute significantly to the damage of the epithelium of the stomach arising from the application NCPUL (Celotti and Laufer, Pharmacological Research, 43, 2001, cc.429-436). On the model of arthritis heart in rats also found that dual inhibitors of SOKH and 5-LO inhibit the narrowing of the coronary vessels (Gok and others, Pharmacology, 60, 2000, cc.41-46). Taken together these data suggest that dual inhibitors SOH-2 and 5-LO may have significant advantages in comparison with specific inhibitors SOH-2 and nonspecific NCPUL from the point of view of higher efficiency and reduced side effects.

Because the mechanism of action of inhibitors SOH partly coincides with the mechanism of action of most conventional NCPUL inhibitors SOH is used to treat the same ones which the R symptoms which is treated with NCPUL, such as pain and swelling associated with inflammation in the short-term conditions and chronic diseases in which inflammation plays a crucial role. The short-term treatment of conditions includes the treatment of inflammation associated with minor abrasions, sunburn or contact dermatitis, as well as the pain associated with high blood pressure, migraines and menstrual cramps. For chronic conditions include arthritic diseases such as rheumatoid arthritis and osteoarthritis. Although rheumatoid arthritis is primarily an autoimmune disease, and osteoarthritis is caused by the degradation of cartilage in the joints, reducing inflammation associated with each of these diseases can significantly improve the quality of life of individuals suffering from these diseases (Wienberg, Immunol. Res., 22, 2001, SS-341; Wollhiem, Curr. Opin. Rheum., 13, 2000, SS-201). Because inflammation is a component of rheumatic diseases in General, inhibitors SOKH was extended to include diseases such as systemic lupus erythematosus (SLE) (Goebel and others, Chem. Res. Tox., 12, 1999, SS-500; Patrono and others, J. Clin. Invest., 76, 1985, SS-1018) and rheumatic skin conditions such as scleroderma. Inhibitors SOH is also used to relieve inflammatory skin conditions, not having revelations the CSOs origin, such as psoriasis, in which reduction is caused by overproduction prostaglandins inflammation can have a direct beneficial effect (Fogh and others, Acta Derm. Venereol (Oslo), 73, 1993, SS-193).

Research conducted recently revealed a correlation between the expression of MOR-2, General inflammation and the pathogenesis of Alzheimer's disease (AD) (But also others, Arch. Neurol., 58, 2001, s-492). On models with animals found that in transgenic mice, the body undergoes overexpression of the enzyme SOH-2, neurons are sensitive to damage. The national Institute on aging The National Institute on Aging (NIA)began clinical experience to determine whether NCPUL to slow the progression of Alzheimer's disease. It is planned to conduct an assessment of naproxen (NCPUL indiscriminate effects) and rofecoxib (Vioxx, specific NCPUL with selective action against MOR-2). Previously it was established that inflammation has an effect on Alzheimer's disease. According to the Alzheimer's Association and the NIA from Alzheimer's disease (AD) affects about 4 million people in the United States and it is expected that in the middle of the century, this number will increase to 14 million.

Protective effect SPVL in ad pathogenesis is due to the inhibition With The X-2 and direct prevention of amyloidosis in the brain (Xiang and others, The expression of a gene 10, 2002, SS-278). Due to suppression of the production of Pro-inflammatory prostaglandin PGE2enzyme SOH-2 provides protection of surrounding neurons from oxidative and inflammatory stroke, which can occur when the activation of microglia (Combs and others, Neurochem. Intl., 39, 2001, s-457). This action eliminates the subsequent formation of microglia cytokines and ROS, which nourish the cycle and spread (develop!!) neurodegeneration (Kalaria and others, Neurodegeneration, 5, 1996, SS-503; Combs and others, J. Neurosci., 19, 1999, s-939). NCPUL inhibit the activity of γ-secretase, thus preventing the processing of amyloid protein precursor (APP), increased levels of amyloid-beta (Ab) peptide and the development of neurofibrillary plexus (NFT) and trigeminus plaques (Weggen and others, Nature, 414, 2001, SS-216; Takahashi and others, J. Biol. Chem., 278, 2003, SS-18670).

Progressive nervous exhaustion that occurs when exposed to ROS, cytokines and Pro-inflammatory eicosanoids, manifests itself in many painful conditions, which all have a common cause. These diseases currently treated with NCPUL, which are protective against cognitive and neuroprotective properties due to their multifactorial activity against ROS, cytokines and Pro-inflammatory eicosanoids. Their action consists in the inhibition and Rodnik deposits, reducing the production of thromboxane and prostanoids, reducing the production of cytokines, preventing activation of microglia, reducing the production of ROS and, in some cases, they have high antioxidant activity. All these activities can prevent the deterioration of cognitive abilities and slow cumulative effect against neurodegeneration caused oxidative stress and aging.

Neuroprotective activity NCPUL is the basis of modern theories concerning somatic and neurodegenerative deterioration occurring at various degenerative conditions, aging, inflammation and oxidative stress. Early studies have established that exposure to ionizing radiation simulates some such States, causing similar histopathological changes in exposed organs, and their antioxidant status suggests that the causal factor is the formation of free radicals (Gerschman and other Science, 119, 1954, s-626; Harman, J. Gerontol., 11, 1956, SS-300; Harman, J.Gerontol, 2, 1957, SS-300). Introduction antioxidants prior to exposure to radiation provides the body with a certain protection from its damaging effects. On the basis of these studies it was concluded that prolonged impact is the development of oxidative stress, caused by free radicals that are formed as a result of ionizing radiation or oxidative metabolism, disrupts intracellular oxidation-reduction (REDOX) balance and leads to the damage inside and on the surface of the cell itself, if it is not restrained by antioxidant protection. On the basis of these data were conducted fundamental research on life extension and nerozumite based on the reduced levels of free radicals as a result of exposure to the main exchange by means of caloric restriction (Berg and Simms, J.Nutr., 71, 1960, SS-261; Weindruch and Walford, The retardation of aging and disease by dietary restriction, Izd-vo ..Thomas, Springfield, IL, 1988).

Berg and Simms suggested that the maintenance of somatic function correlates with a limited intake of calories and subsequent reduced production of free radicals due to oxidative metabolism, primarily by calorie restriction (OK) (Berg and Simms, J. Nutr., 71, 1960, SS-261). Harman suggested that such protection was carried out with anti-oxidants, can spread to the nervous system in the prevention of lipid peroxidation (Harman, J.Gerontol., 23, 1969, SS-482). Other researchers have found that damage cells and DNA, apparently correlates with the intensity of the main exchange in the organization is the mechanism (PSI) and demonstrated the higher the PSI, the lower life expectancy and more damage to cells and DNA (Barja, Free Rad. Biol. Med., 33, 2002, s-1172). The explanation lies in the fact that the formation of damaging ROS due to mitochondrial and cytoplasmic oxidative metabolism leads to accumulation induced free radical damage both at the cellular and molecular level and it is one of the causes of many degenerative and age-related disorders. However, the damage caused by ROS can be reduced by suppressing PSI using OK or by enhancing antioxidant defense to compete with the production of ROS. It was repeatedly demonstrated that OK is an effective method of increasing the life expectancy of many animal species (Weindruch and Walford, The retardation of aging and disease by dietary restriction, Izd-vo ..Thomas, Springfield, IL, 1988; Weindruch, Prog. Clin. Biol. Res., 287, 1989, SS-103). This study stimulated the study of the antioxidant status of the organism from the point of view of progressive somatic degradation and neurodegerative that occur during aging, and the subsequent development of a theory of aging based on the role of free radicals (Harman, Ann. NY Acad. Sci., 717, 1994, SS-15).

This theory is supported by other studies that demonstrated neuroprotective activity associated with increased or supplemented who eat antioxidant defenses. It was found that the feed additive for rodents containing micronutrients (Liu and others, Ann. NY Acad. Sci., 959, 2002, SS-166), antioxidants (Floyd and Hensley, Ann. NY Acad. Sci., 899, 2000, SS-237; Joseph and others, Mech. Ageing Dev., 116, 2000, s-153; Galli and others, Ann. NY Acad. Sci., 959, 2002, SS-132) and plant extracts (Bickford and others, Brain. Res., 866, 2000, s-217; Cartford and others, J.Neurosci., 22, 2002, SS-5816), in addition to improving behaviour in tests of cognitive ability (Bickford and others, Mech. Ageing Dev., 111, 1999, SS-154) and recovery of electrophysiological responses of the Central nervous system (Gould and others, Neurosci. Lett., 250, 1998, SS-168; Bickford and others, Free Rad. Biol. Med., 26, 1999, s-824) protects the aging nervous system to ionizing radiation (Lenton and Greenstock, Mech. Ageing Dev., 107, 1999, SS-20) or oxidative stroke (Butterfield and others, Ann. NY Acad. Sci., 854, 1998, SS-462; Cao and others, J. Applied Physiol., 86, 1999, SS-1822). It is assumed that all of these therapeutic interventions alter the antioxidant status of the intracellular environment and protect critical elements of the cytoplasm and mitochondria from degradation under the action of ROS, restoring and/or preserving homeostasis. It was found that as a result of these changes, diet change accordingly indices of antioxidant status. For example, it was found that decreasing the level of lipid peroxide marker, malondialdehyde (MDA) (Gemma and others, J.Neurosci., 22, 2002, SS-6120), hydroquinone the La (WRATH) (Yoshimura and others, Free Rad. Res., 36, 2002, SS-112), reduced levels of isoprostanes (Montine, etc., Biochem. Pharmacol., 65, 2003, s-617), reduced levels of 8-hydroxy-2-deoxyguanosine (Lee and others, Cancer Lett., 132, 1998, SS-227), reduced residue levels proteincalorie (Carney and others, Proc. Natl. Acad. Sci. USA, 88, 1991, SS-3636; Stadtman and Berlett, Drug Metab. Rev., 30, 1998, SS-243) and residues nitrotyrosine (Whiteman and Halliwell, Free Rad. Res., 25, 1996, SS-283) and decreases the reactivity of the acceptor spin (spin trapping) antioxidants (Carney and others, Proc. Natl. Acad. Sci. USA, 88, 1991, SS-3636).

Treatment of spin acceptor antioxidant N-tert-butyl-α-phenylnitrone (PBN) demonstrated the possibility of reducing by pharmacological means neurodegeneration induced by aging and ROS. PBN is an acceptor of free radicals, which has been found to reduce the formation of ROS (Floyd, Proc Soc Exp Biol Med., 222(3), 1999, SS-245), reduces the formation of proteincalorie on the model of accelerated aging using mice (Butterfield and others, Proc. Nati Acad. Sci. USA, 94, cs-678), protects the brain of gerbils from ischemic reperfusion injury (Floyd and Hensley, Ann. NY Acad. Sci., 899, 2000, SS-237), retains the reactivity of the cerebellum in old rats (Gould and Bickford, Brain Res., 660, 1994, SS-336) and reduces the degree of shortening of telomeres in human fibroblasts (von Zglinicki and other, Free Rad. Biol. Med., 28, 2000, SC-74). It is established that PBN have also efficiency from the Oseni reducing the amount of proteincalorie in old gerbils and improve their ability in behavioral experience with the use of the labyrinth with radial branches (Carney and others, Proc. Natl. Acad. Sci. USA, 88, SS-3636). Thus, it remains expressed the need to develop antioxidant protection of the organism using different approaches based on power.

Aging and oxidative stress lead to a deterioration of information processing in the hippocampus (Barnes, Prog. Brain Res., 86, 1990, SS-104; McGahon and others, Neuroscience, 81, 1997, SS-16; Murray and Lynch, J.Neurosci., 273, 1998a, cc.12161-12168), which is manifested in the form of loss of skills and spatial orientation, memory formation and deterioration of long-term potentiation (LTP), which is necessary for memory consolidation. The composition proposed in the invention, containing the inhibitor SOKH and LOX, as well as a strong antioxidant, can reduce the deterioration carried out in hippocampal information processing due to oxidative stress, inflammation or aging.

Finally, inflammatory prostanoids impair LTP in the increasing regulation of the inflammatory cytokine IL-1β. This cytokine, which has been found to increases with age and oxidative stress, inhibits LTP in area CA1 of the hippocampus and DG (Murray and Lynch, J. Neurosci., 273, 1998a, cc. 12161-12168). With increasing regulation of expression of IL-1β is associated increased perechisleniya lipids in the hippocampus (Murray and others, Gerontology, 45, 1999, cc.136-142). Further study of this process revealed that animals that were given enriched with antioxidants to the RM, was the reversal of age-related changes in the level of IL-1β, perechisleniya lipids and related deficit in LTP (Lynch, Prog. Neurobiol., 56, 1998, s-589). In addition, with the introduction of food supplements containing antioxidant, was also weakening associated with age, reducing the concentration of AK in the membrane (Murray and Lynch, J. Biol. Chem., 273, 1998b, cc.12161-12168). All these data clearly indicate that the decline in cognitive abilities, resulting from the effects of oxidative stress, inflammation and aging can be slowed down or weaken with diet and pharmacological interventions.

Flavonoids, or bioflavonoids are a widespread group of natural products, which according to literature data have antibacterial, anti-inflammatory, antiallergic, antimutagenic, antiviral, antineoplastic, antithrombotic and vasodilator activity. Structural unit common to this group of compounds consists of two benzene rings on either side of the ring containing 3 carbon atoms, as illustrated by the following General structural formulas:

Various combinations of hydroxyl groups, sugars, oxygen and methyl groups attached to this General trehalase structure lead to the formation of different classes of flavonoids, including flavanols, flavones, flavan-3-Ola (catechins, anthocyanins and isoflavones.

It was found that the intake of flavonoids is associated inverse dependence with the risk of dementia. Although the mechanism of action is currently not clear, it has been suggested that it is due to the antioxidant properties of flavonoids (Commenges and others, Eur. J. Epidemiol., 16, 2000, cc.357-363). Polyphenolic flavones induce programmed cell death and inhibition of differentiation and growth (Buckingham, The Combined Chemical Dictionary, published by Chapman & Hall CRC, version 5:2, December 2001).

Phenolic compounds, primarily glavany detected in concentrations ranging from moderate to high in all kinds R. Acacia (Abdulrazak and others, Journal of Animal Sciences, 13, 2000, SS-940). Historically, the majority of plants of the genus Acacia, and extracts from them have been used as binders for the treatment of gastrointestinal disorders, diarrhoea, dyspepsia and as a hemostatic means (Vautrin, Universite Bourgogne (France) European abstract 58-01C:177, 1996; Saleem and others, Hamdard Midicus, 41, 1998, SS-67). The bark and pods of Acacia arabica Willd. contain large amounts of tannins and it was used as a binder, and means salt (Nadkarni, India Materia Medica publishing house, Bombay Popular Prakashan, 1996, cc.9-17). Published evidence that diarylpropionitrile derivatives, isolated from stem bark of Acacia studded landscape, growing in Somalia, have the relaxation is youdim action on the smooth muscle (Hagos and others, Planta Medica, 53, 1987, cc.27-31). There is also evidence that terpenoid saponins isolated from Acacia victoriae, have an inhibitory effect on induced dimethylbenz(a)anthracene carcinogenesis on mouse skin (Hanausek and others, Proceedings American Association for Cancer Research Annual Meeting, 41, 2000, s) and induce apoptosis (Haridas and others, Proceedings American Association for Cancer Research Annual Meeting, 41, 2000, s). Published evidence that plant extracts of Acacia nilotica have spasmogenic, vasoconstrictor and anti-hypertensive activity (Amos and others, Phytotherapy Research, 13, 1999, cc.683-685; Gilani and others, Phytotherapy Research, 13, 1999, cc.665-669) and antiaggregatory activity against platelet (Shah and others, General Pharmacology, 29, 1997, cc.251-255). Published data on anti-inflammatory activity of A. nilotica. It has been suggested that the active components can be flavonoids, polysaccharides and organic acids (Dafallah and Al-Mustafa, the American Journal of Chinese Medicine, 24, 1996, cc.263-269). Currently, data are available only one inhibitor of 5-lipoxygenase isolated from plants R. Acacia, which is monoterpenoids carboxamid (Seikine and other, Chemical and Pharmaceutical Bulletin, 45, 1997, SS-11).

The extract from the bark of plants R. Acacia was patented in Japan as a bleaching agent for external application (Abe, JP 10025238), as an inhibitor glucosyltransferase for use in dentistry (Abe, JP 07242555), as Inga is itora protein synthesis (Fukai, JP 07165598)as an acceptor of active oxygen for preparations for external treatment of skin (Honda, JP 07017847, Bindra, US 61266950) and as the hyaluronidase inhibitor for oral administration for the prevention of inflammation, hay fever and cough (Ogura, JP 07010768).

At present inventors unknown no published data on the composition, in which the United flavonoids with a free ring and floveny intended for use for the prevention and treatment of disorders and diseases associated with neurodegerative, neuronopathies and cumulative impairments of cognitive ability.

Summary of the invention

The present invention relates to a method for the simultaneous inhibition of two enzymes, namely, as cyclooxygenase (SOH)and lipoxygenase (LOX). The method of simultaneous inhibition of the two enzymes SOKH and LOX lies in the fact that the owner is in need of this type of composition that contains a mixture of flavonoids with a free ring and flavanol, synthesized and/or isolated from a single plant or multiple plants. This inventive composition in the present description designated as Lasoperin™. The ratio of flavonoids with a free ring and flavanol in the claimed composition can be adjusted on the basis of the evidence and the specific requirements in respect of the prevention and treatment of a specific disease or condition. Typically, the ratio of flavonoids with a free ring and flavanol in the composition may range from about 99.9:0.1 to 0.1:99,9 (flavonoids with a free ring:floveny). In specific embodiments, the implementation of the present invention, the ratio of flavonoids with a free ring and flavanol chosen from the group of ratios of around 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90. In one of the embodiments of the present invention, the ratio of flavonoids with a free ring:floveny in the inventive composition is 80:20. In a preferred embodiment of the invention, the flavonoids with the free ring separated from the plant or plants of p. Scutellaria, and floveny extracted from plants or plant R. Acacia. The effectiveness of this method was demonstrated in experiments with purified enzymes in various cell lines, many models with animals and eventually in clinical experience in humans.

Specifically, the present invention relates to methods for prevention and treatment mediated MOR and LOX diseases and conditions associated with neural and cognitive functions, and this method lies in the fact that the owner is in need of this, introducing an effective amount of a composition containing a mixture of flavonoids with a free ring and flavanol, synthesized and/or separation of the data from one plant or several plants, and pharmaceutically acceptable carrier. The ratio of flavonoids with a free ring and flavanol in the composition may range from about 99.9:0.1 to 0.1:99,9 (flavonoids with a free ring:floveny). In specific embodiments of the invention, the ratio of flavonoids with a free ring and flavanol you can choose from the group of ratios of around 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90. In one embodiment of the invention the ratio of flavonoids with a free ring:floveny in the inventive composition is about 80:20. In a preferred embodiment of the invention, the flavonoids with the free ring separated from the plant or plants of the genus Scutellaria and floveny separated from the plant or plants of the genus Acacia.

Another variant of implementation of the present invention relates to a method for prevention and treatment of General impairment of cognitive abilities, age-related memory loss, neuropeptidergic and neurodegenerative disorders, and this method lies in the fact that the owner is in need of this, introducing an effective amount of a composition containing a mixture of flavonoids with a free ring and flavanol, synthesized and/or isolated from an individual plant or multiple plants, in combination with a pharmaceutically acceptable carrier. Sootnosheniyami free ring and flavanol in the composition may range from about 99.9:0.1 to 0.1:99,9 (flavonoids with a free ring:floveny). In specific embodiments of the invention, the ratio of flavonoids with a free ring and flavanol chosen from the group of ratios of around 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90. In one embodiment of the invention the ratio of flavonoids with a free ring:floveny in the inventive composition is about 80:20. In a preferred embodiment of the invention, the flavonoids with the free ring separated from the plant or plants of the genus Scutellaria and floveny separated from the plant or plants of the genus Acacia.

The following variant of implementation of the present invention relates to a method of modulating the production of mRNA involved in cognitive impairment and other associated with age-related neurodegeneration and neuronopathies States, and this method lies in the fact that the owner is in need of this, introducing an effective amount of a composition containing a mixture of flavonoids with a free ring and flavanol, synthesized and/or isolated from an individual plant or multiple plants, and a pharmaceutically acceptable carrier. The ratio of flavonoids with a free ring and flavanol in the composition may range from about 99.9:0.1 to 0.1:99,9 (flavonoids with a free ring:floveny). In specific embodiments of the invention, the ratio LAF is monoidov free ring and flavanol chosen from the group of ratios, components about 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90. In one embodiment of the invention the ratio of flavonoids with a free ring:floveny in the inventive composition is about 80:20. In a preferred embodiment of the invention, the flavonoids with the free ring separated from the plant or plants of the genus Scutellaria and floveny separated from the plant or plants of the genus Acacia.

The present invention relates also to a method of modulating the production of transcription factors mRNA, which control the production of mRNA of cytokines involved in cognitive impairment and other associated with age-related neurodegeneration and neuronopathies States, and this method lies in the fact that the owner is in need of this, introducing an effective amount of a composition containing a mixture of flavonoids with a free ring and flavanol, synthesized and/or isolated from a single plant or multiple plants, and a pharmaceutically acceptable carrier. The ratio of flavonoids with a free ring and flavanol in the composition may range from about 99.9:0.1 to 0.1:99,9 (flavonoids with a free ring:floveny). In specific embodiments of the invention, the ratio of flavonoids with a free ring and flavanol chosen from the group of ratios that make up about 90:1, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90. In one embodiment of the invention the ratio of flavonoids with a free ring:floveny in the inventive composition is about 80:20. In a preferred embodiment of the invention, the flavonoids with the free ring separated from the plant or plants of the genus Scutellaria and floveny separated from the plant or plants of the genus Acacia.

Another variant implementation of the present invention relates to a method of modulating the production of transcription factors mRNA, controls the production of mRNA SOH-2, but not mRNA SOH-1, is involved in cognitive impairment and other associated with age-related neurodegeneration and neuronopathies States, and this method lies in the fact that the owner is in need of this, introducing an effective amount of a composition containing a mixture of flavonoids with a free ring and flavanol, synthesized and/or isolated from a single plant or multiple plants, and a pharmaceutically acceptable carrier. The ratio of flavonoids with a free ring and flavanol in the composition may range from about 99.9:0.1 to 0.1:99,9 (flavonoids with a free ring:floveny). In specific embodiments of the invention, the ratio of flavonoids with a free ring and flavanol chosen from the group of ratios, the components of the example is about 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90. In one embodiment of the invention the ratio of flavonoids with a free ring:floveny in the inventive composition is about 80:20. In a preferred embodiment of the invention, the flavonoids with the free ring separated from the plant or plants of the genus Scutellaria and floveny separated from the plant or plants of the genus Acacia.

Without going into theory, we can assume that the composition proposed in the present invention, acts by inhibition of Pro-inflammatory cytokines through down-regulation of the transcription factor nuclear factor Kappa b (NFκB), which controls the gene expression of interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6). It can also be assumed that the composition inhibits the expression of another transcription factor, receptor gamma-activated peroxisome proliferation (PPARγ), which is involved in the control of gene expression of cyclooxygenase-2 (SOH-2). In addition, the composition proposed in the present invention inhibits the activity of MOR-2 and 5-lipoxygenase (5-LO), thereby suppressing the transformation of AK in prostaglandins, thromboxanes and leukotrienes, each of which increases inflammation. The composition has also a pronounced antioxidant ability to neutralize reactive way the s oxygen species (ROS), i.e. molecules that can increase the expression of NFκB and thus increase the gene expression of proinflammatory cytokines.

Flavonoids with a free ring, also indicated in the present description as flavones with a free ring and flavonols, which can be used according to the present invention include compounds having the following General structure:

in which

R1, R2, R3, R4and R5independently of one another selected from the series comprising-H, -OH, -SH, OR, -SR, -NH2, -Other, -NR2, -NR3+X-containing atoms of carbon, oxygen, nitrogen or sulfur glycoside of a single or a combination of multiple sugars including, but not limited to) aldopentose, metalldetektor, hexoses, ketohexose and their chemical derivatives;

where

R denotes an alkyl group having 1-10 carbon atoms; and

X is selected from a number of pharmaceutically acceptable counterions, including (but not limited to hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride, carbonate, etc.

Flavonoids with a free ring proposed in the present invention, can be obtained by methods synthetase or extraction from a family of plants, including (but not limited to, Annonaceae, Asteraceae, Bignoniaceae, Combretaceae, Compositae, Euphorbiaceae, Labiatae, Lauranceae, Leguminosae, Moraceae, few Pinaceae, teridaceae, Sinopteridaceae, Ulmaceae and Zingiberacea. Flavonoids with a free ring can be extracted, concentrated and clear of the following genera of higher plants, including (but not limited to) Desmos, Achyrocline, Oroxylum, Buchenavia, Anaphalis, Cotula, Gnaphalium, Helichrysum, Centaurea, Eupatorium, Baccharis, Sapium, Scutellaria, Molsa, Colebrookea, Stachys, Origanum, Ziziphora, Lindera, Actinodaphne, Acacia, Derris, Glycyrrhiza, Millettia, Pongamia, Tephrosia, Artocarpus, Ficus, Pityrogramma, Notholaena, Pinus, Ulmus and Alpinia.

Glavany, which can be used according to the present invention include compounds which generally describe using the following General structure:

in which

R1, R2, R3, R4and R5independently of one another selected from the series comprising-H, -OH, -SH, -och3, -SCH3, -OR, -SR, -NH2, -NRH, -NR2, -NR3+X-, esters of the above alternative groups, including (but not limited to) complex gallate, acetate, cinnamoyloxy and hydroxycinnamic esters, complex trihydroxybenzoate esters and complex cafeology esters and their chemical derivatives; containing atoms of carbon, oxygen, nitrogen or sulfur glycoside of a single or several sugars, including (but not limited to) aldopentose, metalldetektor, hexoses, ketohexose and their chemical derivatives, dimeric, trimeric and other cured glavany;

where

R of the mean alkyl group, having 1-10 carbon atoms; and

X is selected from a number of pharmaceutically acceptable counterions, including (but not limited to hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride and carbonate etc.

Glavany proposed in the present invention, can be obtained from a plant or plants belonging to the genus Acacia. In a preferred embodiment of the invention, the plant is selected from a range that includes Acacia catechu, Acacia concinna, Acacia farnesiana, Acacia senegal, Acacia speciosa, Acacia arabica, A. caesia, A. pennata, A. sinuata, A. mearnsii, A. picnantha, A. dealbata, A. auriculiformis, A. holoserecia and A. mangium.

One of the embodiments of the invention relates to a method for prevention and treatment of many mediated MOR and LOX diseases and conditions associated with neural and cognitive functions, including (but not limited to) General deterioration of cognitive abilities associated with age, memory loss, neirolepticalkie and neurodegenerative disorders and other conditions associated with neural and cognitive functions. Another variant of implementation of the present invention relates to a method of modulating the production of mRNA involved in the deterioration of cognitive abilities and other associated with age-related neurodegeneration and neuronopathies States.

Method of prevention and treatment proposed in the present invention, is that the owner, n is gaudemus, enter a therapeutically effective amount of a combination containing flavonoids with a free ring and floveny isolated from one source or multiple sources. The purity of individual flavonoids with a free ring and flavanol and/or mixtures of several such compounds are (but are not limited to specified parameters) from 0.01 to 100% depending on the method of obtaining the compound(s). In a preferred embodiment of the invention the magnitude of the dose of a mixture of flavonoids with a free ring and flavanol, is an effective non-toxic amount that generally ranges from 0.001 to 100% based on the total weight of the composition. Specialists in this field can use standard clinical tests to determine the optimal dosages for specific ailments to be treated.

Under the scope of the present invention is subject to evaluation of different compositions of flavonoids with a free ring and flavanol using enzymatic methods and experiments in vivo models for the optimization of the composition and the desired physiological activity. The efficacy and safety of these compositions demonstrated in clinical trials in humans. Thus, under the scope of the present invention also includes therapeutic compositions containing therapeuti the mini-agents proposed in the present invention. The composition proposed in the present invention, can be entered using any of the methods known to the person skilled in the art. Routes of administration include, but are not limited to, enteral (oral) administration, parenteral (intravenous, subcutaneous and intramuscular) administration and local application.

It should be borne in mind that as the previous summary and the following detailed description are given only as examples and with the purpose of explanation and do not limit the scope of the claimed invention.

Brief description of drawings

In the drawings shown:

On figa-1B is a graphical depiction of the steps Lasoperin™, administered daily for 13-week test using the water maze radial branches (RAWM), old male rats of the line Fisher 344, which received standard food and feed with the addition of 3, 7 or 34 mg/kg Lasoperin™, respectively, as described in example 2. Composition Lasoperin™ (80:20) was obtained as described in example 1 method using two standardized extracts, isolated from the bark of Acacia catechu and roots of Scutellaria baicalensis. As a control in evaluating normal age-related changes in behavior used young male rats Fisher 344 treated with standard food. Data are presented as zavisimost and average total errors from the number of experiments (each day of the experiment was performed on four of the experience). On figa illustrate the results obtained before the experiment during the 1st and 2nd weeks (baseline). On figb results after 5 weeks (session II), and figv presents the results after week 11 (session III).

Figure 2 - effect Lasoperin™, administered daily for 12 weeks prior experience in the context of the formation of the conditioned reflex of fear (CFC) old rats Fisher 344 fed standard feed or feeds, supplemented 3, 7, or 34 mg/kg Lasoperin™, as described in example 3. Composition Lasoperin™ (80:20) was obtained as described in example 1 method using two standardized extracts, isolated from the bark of Acacia catechu and roots of Scutellaria baicalensis. As a control in evaluating normal age-related changes in behavior used young male rats Fisher 344 treated with standard food. Data are presented as the average percentage of "fading" for groups exposed to various treatments.

Figure 3 - graphical representation of the steps Lasoperin™ reaction time under difficult choice, obtained according to the method described in example 4. Lasoperin™ was administered daily 40 individuals during the 4-week clinical experience. Comparison of results with the results obtained for a group of 46 individuals who received placebo during the same time period. is the song Lasoperin™ (80:20) was obtained as described in example 1 method using two standardized extracts, isolated from the bark of Acacia catechu and roots of Scutellaria baicalensis. Data are presented as percentage change compared to baseline levels. This drawing illustrates that Lasoperin™ (300 mg/day) increased the speed of processing in patients faced with a difficult choice and information.

Figure 4 is a graphical illustration of Lasoperin™ standard deviation of reaction time (RTSD) in the experiment described in example 5. Lasoperin™ was administered daily 40 individuals during the 4-week clinical experience. Comparison of results with the results obtained for a group of 46 individuals who received placebo during the same time period. Composition Lasoperin™ (80:20) was obtained as described in example 1 method using two standardized extracts, isolated from the bark of Acacia catechu and roots of Scutellaria baicalensis. Data are presented as percentage change compared to baseline levels. This drawing illustrates that Lasoperin™ (300 mg/day) increased the standard deviation of the reaction time during the experience that demonstrates the ability to stay focused and more attentive during the proposed tasks on cognitive ability.

Figure 5 is a graph of inhibition of MOR-1 and MOR-2 using Lasoperin™. Composition Lasoperin™ (50:50) was obtained as described in example 1 method with COI is whether the two standardized extracts, isolated from the bark of Acacia catechu and roots of Scutellaria baicalensis. Lasoperin™ was investigated with respect to its ability to inhibit peroxidase activity of recombinant Ovine MOR-1 (♦) and sheep MOR-2 (■). Data are presented as the dependence of percentage inhibition against the concentration of inhibitor (μg/ml). The value of the IC50for MOR-1 was 0.38 µg/ml/unit of enzyme, while IC50for MOR-2 ranged from 0.84 μg/ml/unit.

Figure 6 is a graph of the profile of inhibition of 5-LO purified flavan-catechin isolated from A. catechu. The connection is explored in relation to its ability to inhibit the activity of recombinant 5-lipoxygenase from potato (♦). Data are presented as the dependence of the percentage inhibition of the sample without inhibitor concentration of inhibitor (μg/ml). The value of the IC50for 5-LO amounted to 1.38 μg/ml/unit of enzyme.

Figure 7 - comparison of levels of LTB4stored in reinducing cell line HT-29 after treatment 3 µg/ml Lasoperin™ and 3 μg/ml of ibuprofen, which were obtained using ELISA in the experiment described in example 8. Composition Lasoperin™ (80:20) was obtained as described in example 1 method using two standardized extracts, isolated from the bark of Acacia catechu and roots of Scutellaria baicalensis.

On Fig - chart of steps of a mixture of flavonoids with a free ring and flavanol (80:20) is as induced by lipopolysaccharide (LPS) level of TNFα in monocytes of peripheral blood (RVMS) after treatment for 1 h with lipopolysaccharide in combination with different concentrations of a mixture of flavonoid with a free ring and flavan. The level of TNFα is expressed in PG/ml.

Figure 9 - graph of the action of a mixture of flavonoids with a free ring and flavanol (80:20) induced by lipopolysaccharide (LPS) levels of IL-1β in monocytes of peripheral blood (RVMS) after treatment for 4 h with lipopolysaccharide in combination with different concentrations of a mixture of flavonoid with a free ring and flavan. The level of IL-1β is expressed in PG/ml.

Figure 10 - graph of the action of a mixture of flavonoids with a free ring and flavanol (80:20) induced by lipopolysaccharide (LPS) levels of IL-6β in peripheral blood monocytes (RVMS) after treatment for 4 h with lipopolysaccharide in combination with different concentrations of a mixture of flavonoid with a free ring and flavan. The level of IL-6 is expressed in PG/ml For each experimental point are given standard deviation.

Figure 11 - effect of different concentrations Lasoperin™ gene expression of Mor-1 and Mor-2. The expression levels were standardized with respect to the levels of expression of 18S-pPHK (internal control), and then standardized relative to the variant without treatment, without FSC. This drawing illustrates that LPS-stimulation and processing Lasoperin™ led to a decrease in gene expression of Mor-2, but not gene Mor-1.

On Fig - comparison steps 3 µg/ml Lasoperin™ and the same concentration of another NCPUL on gene expression of Mor-1 and Mor-2. Ur the PBR expression was standardized in relation to the levels of expression of 18S-pPHK (internal control), and then standardized relative to the variant without treatment, without FSC.

On figa and 13B - effect of different concentrations Lasoperin™ gene expression in tnfα-1 (figa) and il-1β (figb). The expression levels were standardized with respect to the levels of expression of 18S-pPHK (internal control), and then standardized relative to the variant without treatment, without FSC. These drawings demonstrate the reduction of tnfα gene expression-1 and il-1β after LPS-stimulation and processing Lasoperin™.

On Fig - action Lasoperin™ induced by lipopolysaccharide (LPS) levels of Mor-1 and Mor-2, il-1β, tnfα, il-6, nfκb and pparγ in peripheral blood monocytes (RVMS)taken from the body of three patients after treatment for 4 h, according to the method described in example 11.

On Fig - promoters of genes tnfα, il-1β, il-6 and Mor-2, which are down-regulation results in a decrease in nfκb gene expression and pparγ.

On Fig - chromatogram of a mixture of flavonoids with a free ring and flavanol obtained using liquid chromatography high pressure (ghvd), under the conditions described in example 14. In these conditions, the flavonoids with the free ring was loirevalley in the time period from the 11th to the 14th minute and floveny was loirevalley in the time period from the 3rd to the 5th minute.

On Fig - the chromatogram obtained with Ehud, a mixture of flavonoids with a free ring and Levanov, under the conditions described in example 14. Under these conditions two flavan (catechins and epicatechin) loirevalley in the period of time from 4.5 to 5.5 minutes, and flavonoids with a free ring (baicalein and bakalin) loirevalley in the time period from 12 to 13.5 minutes. Under the conditions described in example 15, the separation occurred on the basis of differences in molar absorptivity of flavonoids with a free ring and flavanol.

Detailed description of the invention

The present invention suggests ways to effectively inhibit both enzymes cyclooxygenase (SOH) and lipoxygenase (LOX), which are intended for use for the prevention and treatment of diseases and conditions associated with neural and cognitive functions. The method of simultaneous inhibition of the two enzymes SOKH and LOX lies in the fact that the owner is in need of this type of composition that contains a mixture of flavonoids with a free ring and flavanol, synthesized and/or isolated from a single plant or multiple plants. This inventive composition is indicated in the present description as Lasoperin™. The ratio of flavonoids with a free ring and flavanol in the claimed composition can be adjusted on the basis of the evidence and the specific requirements in relation to the prevention and treatment of certain diseases or with the situation.

To denote elements of the present invention used in the description of various concepts. To clarify the description of the components of the present invention, the following definition.

Unless specified otherwise, all technical and scientific terms used in the present description, have a common value, well known to the ordinary skilled in the art to which the present invention relates.

It should be noted that in the present description a single or plural refers to one or more of these elements; for example, the term "flavonoid" refers to one or more flavonoids. In the present description, the notion of singular or the plural, "one or more" and "at least one" are used interchangeably.

"Flavonoids with a free ring" in the present description denotes a specific class of flavonoids, which have no substitute groups on the aromatic ring, as illustrated by the following General structure:

in which

R1, R2, R3, R4and R5independently of one another selected from the series comprising-H, -OH, -SH, OR, -SR, -NH2, -Other, -NR2, -NR3+X-containing atoms of carbon, oxygen, nitrogen or sulfur glycoside of a single or combination the several sugars, including (but not limited to) aldopentose, metalldetektor, hexoses, ketohexose and their chemical derivatives;

where

R denotes an alkyl group having 1-10 carbon atoms; and

X is selected from a number of pharmaceutically acceptable counterions, including (but not limited to hydroxyl, chloride, iodide, fluoride, sulfate, phosphate, acetate, carbonate, etc.

In the present description the term "glavany" refers to a specific class of flavonoids, which, in General, can be described using the following General structure:

in which

R1, R2, R3, R4and R5independently of one another selected from the series comprising-H, -OH, -SH, -och3, -SCH3, -OR, -SR, -NH2, -NRH, -NR2, -NR3+X-, esters of the above alternative groups, including (but not limited to) complex gallate, acetate, cinnamoyloxy and hydroxycinnamic esters, complex trihydroxybenzoate esters and complex cafeology esters and their chemical derivatives; containing atoms of carbon, oxygen, nitrogen or sulfur glycoside of a single or several sugars, including (but not limited to) aldopentose, metalldetektor, hexoses, ketohexose and their chemical derivatives, dimeric, trimeric and other cured glavany;

where

R appears the t alkyl group, having 1-10 carbon atoms; and

X is selected from a number of pharmaceutically acceptable counterions, including (but not limited to hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride and carbonate etc.

The concept of "therapeutic" in the present description refers to the treatment and/or prevention. When you use the term "therapeutic"as it relates to humans and to other animals.

"Pharmaceutically or therapeutically effective dose or amount" means the dose sufficient to achieve the desired biological result. This result may be a relief of signs, symptoms or causes of disease, or any other desired alteration of a biological system. The exact dose will vary depending on various factors, including (but not limited to) the age and size of the individual, the disease and provide treatment.

The concept of "placebo" refers to the replacement of a pharmaceutically or therapeutically effective dose or amount, sufficient to achieve the desired biological effect, which can ease the signs, symptoms or causes of disease, inactive substance.

The term "owner" or "patient"or "individual" means a living mammal, human or animal, for which treatment is required. The concept of "x is Zain", "patient" or "individual"generally refers to the recipient treated according to the method proposed in the invention.

In the present description the term "pharmaceutically acceptable carrier" refers to any media that does not affect the biological activity of the active substance and which is not toxic to the host to which it is administered. Examples of "pharmaceutically acceptable carriers" include (but are not limited to) any of the standard pharmaceutical carriers, such as saline solution, i.e. the ringer's solution, buffered saline solution, water, dextrose solution, serum albumin and other excipients and preservatives for tablets and encapsulated compositions.

"Gene expression" refers to transcription of a gene with the formation of mRNA.

"Protein expression" refers to the translation of mRNA to protein.

FROM-qPCR" in the present description denotes a realization method of reverse transcription FROM the mRNA molecules in the cDNA molecule and then quantifying the expression level of the gene using polymerase chain reaction (PCR) using fluorescent reporter.

It should be noted that in the present description cited various documents. Each of these documents specifically included in the present description to the operation reference in its entirety.

The present invention relates to methods to effectively inhibit both enzymes SOKH and LOX, which are intended for use for the prevention and treatment of diseases and conditions associated with neural and cognitive functions. The method of simultaneous inhibition of the two enzymes SOKH and LOX lies in the fact that the owner is in need of this type of composition that contains a mixture of flavonoids with a free ring and flavanol, synthesized and/or isolated from a single plant or multiple plants. This inventive composition is indicated in the present description as Lasoperin™ and is sold under the trademark Univestin™ and described in the patent application US serial number 10/427746, filed April 30, 2003, entitled "Composition with dual inhibitory activity against SOH-2 and 5-lipoxygenase" ("Formulation with Dual Cox-2 and 5-Lipoxygenase Inhibitory Activity"), which is incorporated into this description by reference in its entirety. The ratio of flavonoids with a free ring and flavanol can be from about 99.9:0.1 to 0.1:99,9 (flavonoids with a free ring:floveny). In specific embodiments, the implementation of the present invention, the ratio of flavonoids with a free ring and flavonol selected from a range of ratios of around 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 � 10:90. In one of the embodiments of the invention the ratio of flavonoids with a free ring:floveny in the inventive composition is about 80:20.

Isolation and identification of flavonoids with a free ring from plants of the genus Scutellaria described in the patent application US 10/091362, filed on March 1, 2002, entitled "Identification of flavonoids with a free ring In as strong Cox-2 inhibitors" ("Identification of Free-B-Ring Flavonoids as Potent Cox-2 Inhibitors"), which is incorporated into this description by reference in its entirety. Isolation and identification of flavonol from plants of the genus Acacia is described in the patent application US serial number 10/104477 filed March 22, 2002, entitled "Allocation of dual inhibitor SOH-2 and 5-lipoxygenase from plants R. Acacia" "Isolation of a Dual Cox-2 and 5-Lipoxygenase Inhubitor from Acacia", which is incorporated into this description by reference in its entirety.

The present invention relates to a method that has efficacy in prevention and treatment of age-related deterioration of cognitive abilities, neurodegeneration and neuronopathies diseases and conditions. The way to prevent and treat these cognitive and neural diseases and conditions lies in the fact that the owner is in need of this type of composition that contains a mixture of flavonoids with a free ring and flavanol, sintezirovannyh and/or isolated from a single plant or multiple plants. The ratio of flavonoids with a free ring and flavanol can be from about 99.9:0.1 to 0.1:99,9 (flavonoids with a free ring:floveny). In specific embodiments, the implementation of the present invention, the ratio of flavonoids with a free ring and flavonol selected from a range of ratios of around 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90. In one of the embodiments of the invention the ratio of flavonoids with a free ring:floveny in the inventive composition is about 80:20.

In addition, the present invention relates to methods for prevention and treatment mediated by proinflammatory cytokines neural and cognitive diseases and conditions, and this method lies in the fact that the owner is in need of this, introducing an effective amount of a composition containing a mixture of flavonoids with a free ring and flavanol, synthesized and/or isolated from a single plant or multiple plants, and a pharmaceutically acceptable carrier. The ratio of flavonoids with a free ring and flavanol in the composition may range from about 99.9:0.1 to 0.1:99,9 (flavonoids with a free ring:floveny). In specific embodiments of the invention, the ratio of flavonoids with a free ring and flavanol you can choose from a group of ratios that make up about 90:10, 8020, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90. In one embodiment of the invention the ratio of flavonoids with a free ring:floveny in the inventive composition is about 80:20.

The present invention relates also to a method of reducing the levels of TNFα and IL-1β, two components that play a crucial role in age-related, cognitive, neurodegenerative, and neuropeptidergic diseases and conditions. The way to reduce the levels of TNFα and IL-1β is that the owner, who needs this, introducing an effective amount of a composition containing a mixture of flavonoids with a free ring and flavanol, synthesized and/or isolated from a single plant or multiple plants, and a pharmaceutically acceptable carrier. The ratio of flavonoids with a free ring and flavanol in the composition may range from about 99.9:0.1 to 0.1:99,9 (flavonoids with a free ring:floveny). In specific embodiments of the invention, the ratio of flavonoids with a free ring and flavanol you can choose from the group of ratios of around 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90. In one embodiment of the invention the ratio of flavonoids with a free ring:floveny in the inventive composition is about 80:20.

The present invention relates to a method for prevention and treatment of disease is the third and conditions mediated ROS, by reducing ROS. ROS is a critical product of oxidative stress and lipid metabolism, and its level can be increased substantially with age-related, cognitive ability, neurodegeneration and neuronopathies diseases and conditions. The method of treatment mediated ROS diseases and conditions is that the owner, who needs this, introducing an effective amount of a composition containing a mixture of flavonoids with a free ring and flavanol, synthesized and/or isolated from an individual plant or multiple plants, and a pharmaceutically acceptable carrier. The ratio of flavonoids with a free ring and flavanol in the composition may range from about 99.9:0.1 to 0.1:99,9 (flavonoids with a free ring:floveny). In specific embodiments of the invention, the ratio of flavonoids with a free ring and flavanol you can choose from the group of ratios of around 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90. In one embodiment of the invention the ratio of flavonoids with a free ring:floveny in the inventive composition is about 80:20.

Finally, the present invention relates to a method of modulating the production of mRNA involved in cognitive impairment and other related reluctant is that the neurodegeneration and neuronopathies conditions, including the modulation method for the production of mRNA of transcription factors that control the production of mRNA of cytokines, and the modulation method for the production of mRNA of transcription factors that control the production of mRNA SOH-2, but not Mor-1. The modulation method for the production of mRNA involved in cognitive impairment and other associated with age-related neurodegeneration and neuronopathies States, lies in the fact that the owner is in need of this, introducing an effective amount of a composition containing a mixture of flavonoids with a free ring and flavanol, synthesized and/or isolated from a single plant or multiple plants, and a pharmaceutically acceptable carrier. The ratio of flavonoids with a free ring and flavanol in the composition may range from about 99.9:0.1 to 0.1:99,9 (flavonoids with a free ring:floveny). In specific embodiments of the invention, the ratio of flavonoids with a free ring and flavanol you can choose from the group of ratios of around 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90. In one embodiment of the invention the ratio of flavonoids with a free ring:floveny in the inventive composition is about 80:20.

Flavonoids with a free ring, which can be used in the accordance with the foregoing, include compounds having the above General structure. Flavonoids with a free ring proposed in the present invention, can be obtained by the methods of synthesis or can be isolated from plant families, including (but not limited to, Annonaceae, Asteraceae, Bignoniaceae, Combretaceae, Compositae, Euphorbiaceae, Labiatae, Lauranceae, Leguminosae, Moraceae, few Pinaceae, Pteridaceae, Sinopteridaceae, Ulmaceae and Zingiberaceae. Flavonoids with a free ring you can select from the following genera of higher plants, including (but not limited to) Desmos, Achyrocline, Oroxylum, Buchenavia, Anaphalis, Cotula, Gnaphalium, Helichrysum, Centaurea, Eupatorium, Baccharis, Sapium, Scutellaria, Molsa, Colebrookea, Stachys, Origanum, Ziziphora, Lindera, Actinodaphne, Acacia, Derris, Glycyrrhiza, Millettia, Pongamia, Tephrosia, Artocarpus, Ficus, Pityrogramma, Notholaena, Pinus, Ulmus and Alpinia.

Flavonoids with a free ring may be present in various plant parts, including but not limited to, stems, bark, stalks, stems, trunks, branches, tubers, roots, bark, roots, young shoots, seeds, rhizomes, flowers and other reproductive organs, leaves and other aerial parts. Methods for isolation and purification of flavonoids with a free ring described in the patent application US serial number 10/091362, filed on March 1, 2002, entitled "Identification of flavonoids with a free ring In as strong COX-2 inhibitors" ("Identification of Free-B-Ring Flavonoids as Potent COX-2 Inhibitors"), and the patent application US serial number 10/427746, filed April 30, 2003, zegavlenas "Composition, with dual inhibitory activity against SOH-2 and 5-lipooxygenase" ("Formulation with Dual Cox-2 and 5-Lipoxygenase Inhibitory Activity"), each of which is incorporated into this description by reference in its entirety.

Glavany that can be applied according to the method proposed in the present invention include compounds illustrated by the above General structure. Glavany proposed in the present invention, can be obtained by the methods of synthesis or they can be distinguished from a plant selected from a range including (but not limited to, Acacia catechu, A. concinna, A. farnesiana, A. senegal, A. speciosa, A. arabica, A. caesia, A. pennata, A. sinuata. A. mearnsii, A. picnantha, A. dealbata, A. auriculiformis, A. holoserecia, A. mangium, Uncaria gambir, Uncaria tomentosa, Uncaria africana and Uncaria qabir.

Glavany may be present in various plant parts, including but not limited to, stems, bark, stalks, stems, trunks, branches, tubers, roots, bark, roots, young shoots, seeds, rhizomes, flowers and other reproductive organs, leaves and other aerial parts. Methods for isolation and purification of flavanol described in patent application US serial number 10/104477 filed March 22, 2002, entitled "Allocation of dual inhibitor SOH-2 and 5-lipoxygenase from plants R. Acacia" ("Isolation of a Dual COX-2 and 5-Lipoxygenase Inhibitor from Acacia"), which is incorporated into this description in its entirety.

In one specific embodiment, the wasp is estline invention flavonoids with a free ring separated from the plant or plants of the genus Scutellaria and floveny separated from the plant or plants of the genus Acacia.

The present invention provides an implementation strategy that combines several tasks on cognitive ability in vivo, as well as carry out in vitro biochemical, cellular screening and screening of gene expression to identify active plant extracts, which have the ability to specifically inhibit the enzymatic activity of SOKH and LOX, reduce the level of proinflammatory cytokines through down-regulation of critical transcription factors, which stimulate the production of mRNA of these cytokines, and production of ROS, support antioxidant properties that affect the prevention and treatment of neurodegeneration, neuronophagia and cumulative deterioration of cognitive abilities, disorders, diseases and conditions that occur when exposed to reactive capable oxygen species (ROS), inflammatory proteins and eicosanoids. In addition, the extracts evaluated for their effect on gene expression mRNA. Flavonoids with a free ring and floveny tested for their ability to prevent age-related deterioration of cognitive abilities in oral introduction in the form of an extension component to the meal.

Example 1 describes the General method of obtaining Lasoperin™ using two standardized extracts, separation is the R from plants R. Acacia and p. Scutellaria, respectively, in combination with one or more excipients(AMI). As indicated in table 1, this particular party Lasoperin™ contains 86% of active substances, including 75.7% of flavonoids with a free ring and 10.3% of flavanol. In the inventive composition, you can add one or several excipient(s). The number of added excipient can be adjusted based on the actual content of each of the desired active substance.

To assess impacts Lasoperin™ on cognitive function were conducted by two specific behavioral test models using animals, namely the test using the water maze radial branches (RAWM) and test in the context of the formation of the conditioned reflex of fear (CFC), which allow us to estimate the dependent hippocampal working memory. Example 2 illustrates the effect Lasoperin™ - dependent hippocampal cognitive function, which was evaluated using a test using the water maze radial branches (RAWM). The results are presented on figa-1B, which graphically shows the impact Lasoperin™, administered daily for 13-week test using the water maze radial branch (RAWM), old male rats of the line Fisher 344, which received standard food and food with added on the m 3, 7 or 34 mg/kg Lasoperin™, respectively. As a control in evaluating normal age-related changes in behavior used young male rats Fisher 344 treated with standard food. Data are presented as the dependence of the average total error on the number of experiments (each day of the experiment was performed on four of the experience). On figa illustrate the results obtained before testing for 1st and 2nd weeks (baseline). On figb results after 5 weeks (session II), and figv presents the results after week 11 (session III). The data presented in figa-1B, indicate that Lasoperin™ (in the groups that were administered doses of 7 and 34 mg/kg) prevented age-related memory impairment.

Because the test using RAWM includes a component of motor function, there is a possibility that the improvement shown in this test may be due to the fact that the introduced composition reduces the pain and discomfort. To test this was also CFC-test, because this test did not require movement of the animal and therefore served to confirm the cognitive aspect of both tasks (due to the analgesic properties of the composition when evaluating the results of CFC-test used the threshold of pain of the shock). Example 3 illustrates the effect Lasoperin™ hung on the total from the hippocampal cognitive function, obtained in the test in the context of the formation of the conditioned reflex of fear (CFC). As described in example 2, this experience is used 60 male rats Fisher 344. The results presented in figure 2, illustrate the impact Lasoperin™, which was administered daily for 12 weeks before conducting the test in the context of the formation of the conditioned reflex of fear of old male rats of the line Fisher 344 in the form of an additive to the feed, component 3, 7, or 34 mg/kg Lasoperin™. As a control in the evaluation of age-related changes in behavior, used of young male rats Fisher 344 treated with standard food. Data are presented as the average percentage of "fading" for different groups of treatment. The data shown in figure 2, demonstrate that Lasoperin™ (in the groups that were administered doses of 7 and 34 mg/kg) facilitated the age-related deterioration.

In examples 4 and 5 shows the results of the impact assessment Lasoperin™, which was administered daily at a dose of 300 mg/day over a 4-week period of 40 individuals received conducted in a randomized double blind using placebo control clinical experience in studies of cognitive function. The results were compared with the results obtained for 46 individuals who were treated with placebo. Measuring cognitive abilities was performed using a series of tests on SOH is Annie cognitive abilities based on the principle of "obfuscation" (web-based), to assess psychomotor speed, speed, working memory (executable acceptance decisions, speed and flexibility) and immediate memory (processing of verbal and spatial information in memory). Before the beginning of the experiment, participants were required to complete an internship for two consecutive days to establish a baseline ability. The data analysis was to compare the original abilities with abilities after treatment.

A test of psychomotor speed or physical reflexes is a simple test of reaction time, which requires the individual as quickly as possible, press when you see the figures on the computer screen.

In the test for speed of working memory at the same time the word appears and the picture and an individual may be required to decide whether they match each other or not. Randomly occurs a change of signal values on the opposite and an individual may be required to answer, the opposite is correct, so the answer to the correct pair must be "no", and Vice versa. This job requires suppression or inhibition of learned response" and the subsequent abolition of change"tasks") response. The rate of switching from one task or one form of response to another often equivalent mental flexibility and cognitive clicks the processing information of a higher order, as well as a higher ability to make a decision.

Test direct memory similar to the classical problem of Sternberg, in which a number of items-stimuli, "targets"that you want to remember, you must "check" the item. The individual must determine was whether a test item in the previous list of targets. The list length can be varied to assess short-term memory capacity of the individual. In this task, use as a literal elements and spatial location.

The results are shown in figure 3, which graphically illustrated the impact Lasoperin™ on the reaction time of difficult choices, and figure 4, which graphically illustrated the impact Lasoperin™ standard deviation of reaction time (RTSD). The standard deviation of the reaction time represents a variation during the experiment. The results presented in figure 3 and 4, indicate that Lasoperin™ increases the speed of information processing in individuals, faced with a difficult choice and information.

Example 6 describes the analysis of inhibition of MOR conducted using Lasoperin™. Method of biochemical analysis, used to measure inhibition of MOR is based on the estimation of peroxidase activity of the protein in the presence of heme and arachidonic acid. The measurement results for the W ill of the dose-response and the values of the IC 50Lasoperin™ is shown in figure 5. The value of the IC50for MOR-1 was 0.38 µg/ml/unit of enzyme, and the value of the IC50for MOR-2 ranged from 0.84 μg/ml/unit of enzyme.

Example 7 describes the analysis of the inhibition of LOX using flavan catechin isolated from A. catechu. Inhibition of LOX activity was assessed by using analysis of screening lipoxygenase in vitro. The results of this analysis are shown in Fig.6. The value of the IC50for inhibition of the catechin 5-LO amounted to 1.38 μg/ml/unit of enzyme.

In example 8 described stem cell analysis aimed at evaluating the inhibition of the compounds produced during the cleavage of arachidonic acid in LOX-path, namely LTB4. The results are shown in Fig.7. From the data shown in Fig.7, we can see that Lasoperin™ inhibits 80% of the formation of new LTB4synthesized in the cell line HT-29. Ibuprofen caused only a 20%decrease in the number of LTB4during the same period of time.

In example 9 describes the measurement of the impact Lasoperin™ on LPS induced levels of TNFα, IL-1β and IL-6 in peripheral blood monocytes. The results are shown in Fig-10. From the data shown in Fig, you can see that the extract in a wide range of concentrations from 2 to 100 μg/ml resulted in a decrease in the levels of TNFα secreted in the supernatant of cell culture. From the results, p is iudenich on these drawings, you can see that the concentration of LPS 10 μg/ml induced the highest level of TNFα and IL-1β after co-incubation with Lasoperin™ for 1 h and 4 h, respectively. The extract reduced the levels of TNFα and IL-1β secreted in the supernatant of cell culture in almost all of the wide range of concentrations from 2 to 100 µg/ml (see Fig and 9). Since the levels of TNFα, IL-1β and IL-6 are elevated in inflammation and age-related diseases, by reducing the levels of these proinflammatory cytokines and transcription factors in premirovany inflammatory cells Lasoperin™ can have a significant impact on these violations.

In example 10 describes an experiment conducted to determine the difference between the inhibition of gene Mor-1 using Lasoperin™ and other NCPUL. Data on gene expression were obtained using semiquantitative FROM qPCR analysis of inhibition of mRNA production Mor-1 and Mor-1. The results are shown figure 11-13. From the data presented figure 11, you can see that Lasoperin™ inhibited the production of mRNA SOH-1, without affecting the expression of Mor-1. In addition, comparison with other drugs-inhibitors Mor-1 shows that Lasoperin™ possessed the ability to reduce LPS-stimulated increase in gene expression of Mor-1 and Mor-1. It is important to note that both celecoxib and ibuprofen increased gene expression with the -1 (Fig). Finally, from the data shown in figa and 13B, it can be seen that the processing Lasoperin™ led to a decrease in production as tnfα-1, and il-1 αβ.

In example 11 describes an experiment conducted to determine the effects of Lasoperin™ on LPS induced the level of Mor-1 and Mor-2, il-1β, tnfα, il-6, nfκb and pparγ in peripheral blood monocytes (RVMS)obtained from the organism of three individuals, after described in example 11 treatment within 4 hours the Results are shown in Fig. From the data shown in Fig, you can see that the extract Lasoperin™ significantly reduced the expression of genes for all species of mRNA.

In example 12 described downward regulation of promoter elements inflammatory genes using Lasoperin™. These promoter elements are presented on Fig.

In example 13 describes a method of evaluating the effectiveness Lasoperin™ as an antioxidant by using a test to measure the ability to absorb oxygen radicals (ORAC). ORAC analysis, in which the fluorescent probe using fluorescein allows to measure the ability of antioxidants to absorb peroxyl radicals, which are one of the most common reactive oxygen species, found in the body. The results are shown in table 2 as relative absorption capacity compared with concentrates of several Shi is the eye of the known antioxidants from food. Lasoperin™ had a high ORAC score. Indeed, for Lasoperin™ ORAC-score is comparable to the score of the antioxidant vitamin C and so it must effectively reduce the levels of ROS in the body.

In examples 14 and 15 described two methods used to determine the amount of flavonoids with a free ring and flavanol in a standardized extract. The results are shown in Fig and 17.

The following examples are only for illustration purposes and are not intended to limit the scope of the invention.

Examples

Example 1. Getting Lasoperin™ from extracts obtained from plants of R. Acacia and p. Scutellaria

Preparative form Lasoperin™ were prepared using two standardized extracts isolated from plants R. Acacia and p. Scutellaria, respectively, in combination with one or more excipient(s).

Used the extract of Acacia contained >60% of the total flavanol representing catechin and epicatechin, and extract of Scutellaria contained >70% of flavonoids with a free ring, which mainly represented baicalin. Extract of Scutellaria contain minor quantities of other flavonoids with a free ring shown in table 1. In the inventive composition is added one or more excipients. The ratio of flavanol and flavonoids with a free ring can be adjusted in the light of evidence and specific requirements in the compared the inhibition of MOR-2 compared with 5-LO and performance requirements of the product. The number of excipient(s) can be adjusted based on the actual content of each active ingredient. Table of mixing proportions for each individual batch of product should be developed on the basis of product specifications and results of quality control (QC). To match the specifications of the product it is recommended to use additional quantities of active ingredients (2-5%).

Table 1 is a table of the proportions of the mixture, developed for one of the parties Lasoperin™ (lot # G1702-COX-2). In General, the combined extract of roots of Scutellaria baicalensis (38,5 kg) (lot # RM052302-01)having a content of flavonoids with a free ring and 82.2% (baicalin); the extract of the bark of Acacia catechu (6.9 kg) (lot # RM052902-01) with a total content of flavanol 80,4% and excipient index (Candex) (5,0 kg) to obtain the composition Lasoperin™ (50,4 kg), with the ratio of components in a mixture of 85:15. Table 1 shows the number of active substances, flavonoids with the free ring and flavanol, in this particular party Lasoperin™ (lot # G1702-COX-2), determined using the methods described in the patent application US serial number 10/427746, filed April 30, 2003, entitled "Composition with dual inhibitory activity against SOH-2 and 5-lipoxygenase" ("Formulation With Dual Cox-2 And 5-Lipoxygenase Inhibitory Activity"), which is incorporated into this description in its entirety.

Table 1The content of flavonoids with a free ring and flavanol in the composition Lasoperin™Active ingredientsContent (%)FlavonoidsBaicalin62,5%Minor flavonoidswogonin-7-glucuronide6,7%oroxylin And 7-glucuronide2,0%baicalein1,5%wogonin1,1%chrysin-7-glucuronide0,8%5-metallogeny-7-glucuronide0,5%scutellarin0,3%norwegain0,3%chrysin<0,2%oroxylin And<0,2%The total content is of flavonoids with a free ring 75,7%Glavanycatechin9,9%epicatechin0,4%The total content of flavanol10,3%The total content of the active substance86%

As can be seen from table 1, this particular party Lasoperin™ contains a total of 86% of active substances, including 75.7% of flavonoids with a free ring and 10.3% of flavanol. From this party Lasoperin™ (50,0 kg) to prepare a final product in the form of capsules with two dose levels of 125 mg/dose (60 capsules) and 250 mg/dose (60 capsules). Using a similar approach, prepare two additional party Lasoperin™ with ratios of components in a mixture of 50:50 and 20:80, respectively.

Example 2. Impact Lasoperin™ - dependent hippocampal cognitive function (RAWM)

Composition Lasoperin™ (80:20) was obtained according to the method described in example 1 (see also example 14 the patent application US serial number 10/427746, filed April 30, 2003, entitled "Composition with dual inhibitory activity against SOH-2 and 5-lipoxygenase" ("Formulation With Dual COX-2 And 5-Lipoxygenase Inhibitory Activity"), which is included in the crust is ASEE description by reference in its entirety) by combining standardized extract flavonoid with a free ring, isolated from the roots of Scutellaria baicalensis, and standardized flavan extract, isolated bark of Acacia catechu, with the ratio of components in a mixture of 80:20. To study the effects Lasoperin™ - dependent hippocampal cognitive function was assessed by the ability of 60 male rats Fisher 344 (below age) using a test using labyrinth with radial branches (RAWM). This test allows to assess changes in learning and memory during processing of the medicinal product. Before the experiment started with the addition of the feed of the test compounds (experimental feeding) was performed to estimate the baseline and the test was repeated at 5 and 11 weeks after the start of the experimental feeding. Mode "without delay" is intended to demonstrate the ability of the animal to perform a task and serves as a control in evaluating differences in the ability to perform a task (e.g., associated with movement, vision, motivation, etc). In the "delayed" entered the 4-hour delay between experiments 3 and 4, which complicates the task. Mode "delay" is intended to demonstrate associated with age memory loss.

Animals. Male rats of the Fischer 344 (colony created under contract by the National Institute on aging (National Institute on Aging contract colony); firm Harlan Sprague Dawley, Indianapolis, Indiana) (who the AST 6 months, n=12, age 17 months, n=48) were kept in pairs in chambers with controlled environmental conditions with a light cycle of 12 h light/12 h dark at 21±1°C and had free access to feed and water. Young and old control animals were given food for rodents NIH-31 (TD 00365; firm Harlan Teklab, Madison, Wisconsin). Experimental groups were given food for rodents NIH-31 with the addition of Lasoperin™ (3, 7, or 34 mg/kg). Control food and experimental song she would cook a kind firm Harlan Teklab, and supplied in the form of extruded pellets for animals. The rats were embedded microchips to ensure the proper identification during all stages of experience. Due to the large number of animals the experiment was performed in parallel for two cohorts of 30 rats, divided into groups of 6 animals each. To obtain the source level of the animals was estimated using RAWM before the start of the experimental feeding. After completing the initial RAWM test old rats were divided into four groups (control group aged rats (old control animals), 3, 7, and 34 mg/kg Lasoperin™) balanced way, so that each group had an uncertain characteristics according to the RAWM test. Conducted weekly monitoring of animal weight and absorption of feed to determine General health and feed intake. Between groups was not detected by the network of differences in these parameters.

Water maze radial branches (RAWM). RAWM consisted of 12 branches (width 15 cm, length 43 cm)originating from the circular "region of choice" (60 cm in diameter)filled with water tank 1.5 m Rescue platform (10 cm × 13 cm) was placed at the end of one of the branches 2 cm below the water surface. Rats previously trained in the maze for 5 days. Prior practice has been to build up in animals by successive approximation to the ultimate goal of the conditioned reflex of the search target of the branch, which initially was not closed all the target branch and gradually increased the number of available branches until then, until you have opened all 12 branches. Then rats were trained for two periods of five days each. Full training process took three weeks. The initial (starting) branch in each experiment was appointed pseudorandom, 11 branches. This branch is used only once a day, so every day there were four different starting branches. In order to avoid a preferred location and position, the starting and target branches for each animal in the group for each day has been different, but the same in all groups. In day four of the experience (with a maximum continue what eTelestia at 180 C) with 30-second intervals between experiments. If the rat could not find the escape platform within 180 with its gently guided in the right branch. Registered number of branches, which included animal as long as it was not included in the branch, which was the saving platform (number of errors). Between experiments 3 and 4 during days 6-10 introduced a 3-hour delay. During the delay, the rats were returned to their cage in which they were held. The results are shown in figa-1 C. Data are presented as the dependence of the mean values for each experiment the number of experiments.

From the data shown in figa-1B, it is seen that in all sessions was a significant decrease in the total error when the number of experiments that demonstrates the ability of rats to learn to perform a task. The task "without delay" was not found age-related or drug use differences in abilities. The task "delay" was identified significant age effect in all three sessions held with delay (baseline, session II and session III; see figa, 1B and 1C, respectively). In experiment 4 old animals performed the task significantly worse than the young control animals. In tests "delay"with the definition of the original level (figure 1) and the session II (figb), found no effect, depending on the drug. However, there was significant due to the drug effect in session III test "latency" (pigv). Groups treated with doses of 7 and 34 mg/kg, made significantly fewer errors than the old group control animals. They did not differ significantly from groups of young control animals, suggesting that Lasoperin™ prevents age-related memory impairment. Analysis of the results was performed using 2-directed analysis of variance (ANOVA) for repeated measurements.

Example 3. Impact Lasoperin™ - dependent hippocampal cognitive function (CFC)

This experience is used 60 male rats Fisher 344 that described in example 2.

In the context of the formation of the conditioned reflex (CFC). After 1 week after completion of the RAWM test rats were placed in a box (30.5 cm x 24,1 cm × 21 cm; Med Associates, St. Albans, Vermont) with mesh floor (rods with a diameter of 4.8 mm at a distance of 1.6 cm from each other), along with the Shocker, the current from the constant current (Med Associates). Before placing each rat in the mailbox, it was washed 3%acetic acid, which served the function of a specific flavor to the original context. Carried out two consecutive series of trainings. Each series trenirovochka duration 180 sec and included a conditional stimulus (the stimulus for the development of the conditioned reflex, CA)in the form of a white noise levels of 85 dB, 30 s and the effect of electric shock on the paw (2 s, 0.5 mA) (unconditional stimulus, BS). Action MOUSTACHE and BS stopped simultaneously at the end of the series of trainings. All rats responded to the effect of electric shock on the foot by jumping. Rats remained in the drawer for training within 30 s after the second series of workouts. The memory was tested 2 days after a workout, which initially animals were placed in the same device, using 3%acetic acid as a flavoring in which training for 5 min without MOUSTACHE or BS. After 2-3 h, the rats were placed in the same camera except that the mesh floor was covered with a piece of black plastic (Formica) and the cell was rinsed 3%ammonium hydroxide (firm Novel Context) for 6 min, during the last 3 min was used by US. "Sinking" was evaluated visually by hand every 10 s, the experimenter, who had no information about which group processing refers rat. The experimenter was evaluated with 10-second intervals "froze" whether rat or not. The percentage of "fading" was calculated using the following formula: the number of intervals in which the rat was assessed as being in a state of "awe"/total number of intervals × 100. The results are shown in Fig..

"Sinking" in the context of training. When analyzed by this method revealed a statistically significant reduction of "fading" the old control animals compared to young control animals (see figure 2). Dose 7 and 34 mg/kg Lasoperin™ facilitated this age-related deterioration. For a dose of 3 mg/kg revealed a statistically insignificant trend toward easing associated with age deterioration. None of the treated Lasoperin™ rats did not reveal statistically significant differences from young control animals.

"Sinking" in response to noise conditional stimulus (US) allows us to estimate the memory which is not dependent on the hippocampus. The results obtained in this experiment indicate that there are no statistically significant differences in the "sinking" between any of the groups of animals (data not shown).

"Sinking" in response to a new context is a control assessment when determining the initial level of "fading". To obtain this characteristic, the number of "zastawanyi", registered in the context of training and under the action CONDITION, compared with the initial level of "fading" to determine whether there is learning. Between any groups of animals was not statistically significant difference in the "sinking" (data not shown).

Nociceptive threshold. the device was a camera for experiments by 30.5×25.4mm×30.5 cm (firm Coulbourn Instruments, Allentown, Pennsylvania). The ceiling and two walls of the chamber were made of aluminium. The other two walls were made of transparent plastic. The box was poorly lit (XX LK). The floor was made of rods of stainless steel (diameter 5 mm, the distance between the rods 1,68 cm). Electric shock (shock) were created using precisely controlled Shocker (Precision Regulated Shocker, model Model H12-16, the company Coulbourn Instruments). Rats were placed in a cage with metal slatted floor (size of the lattice). On the opposite the experimenter's side of the camera to set the mirror to facilitate observation. All rats were allowed to adapt for 2 minutes before starting the experiment. Each rat was placed in the chamber for 2 min before the start of a series of electric shocks and then the floor of the cell was cleaned with steel wool for cleaning utensils and water. The duration of each electrical pulse was 0.5 s and electric shocks were applied with an interval of about 10 C. the intensity of the electric shock can be adjusted in a manner that is logarithmic law in the range from 0.05 to 4.0 mA. When you define a threshold, the full range is not used. Border intensities within which ought to search for a threshold, determined on the basis of previous measurements. Midpoints between these boundaries is luili as the source intensities in the experiments. "Jerk" was defined as raising one paw, and "jump" - as a fast moving three or four legs, both reactions was assessed by separation of the legs from the floor. To determine the order of application of the intensities of electric shock in each series electric strikes used a modification of the method of "up-and-down ("up-and-down") as applied to small samples.

The procedure involved the following stages: 1) the first series began with the intensity of electric shock, as close to the threshold for "wince" or "jump" for the processing; 2) conducted a series of experiments as follows: in the case of reactions ("wince" or "jump") in the following experience reduced the intensity of the electric shock (0.1 log10units), and in the absence of reactions in the following experience increased the intensity of the electric shock (0.1 log10units). In each series of experiments were continued up until there was no change in behavior and in four of the experience after this, the series continued. Estimation of the average effective intensity (EI50) was calculated by the formula EI50=Xf+kd, where Xf= last used intensity, k is the value from table 1 of the publication Dixon (Dixon, J. Am. Stat. Assoc., 60, 1965, SS-55) and d is the logarithm of the interval between the intensities of electric shock. DL the assessment thresholds for "wince" carried out two series of electric shocks, then conducted two series of electric shocks to define the threshold values for "jump". These tests on the determination of the intensities of electric shock created the paradigm of behavior in the context of the formation of the conditioned reflex of fear and was not associated with a particular group of results.

Example 4. Impact Lasoperin™ on the speed of information processing

To assess the impact Lasoperin™ on cognitive function was carried out during the 4-week period a series of tests on intact cognitive (unprepared) individuals aged 35-65 years. Individuals were treated with 300 mg/day of the composition Lasoperin™ (80:20), which were prepared according to the method described in example 1. Measurement of cognitive abilities was performed using a series of tests on the preservation of cognitive abilities based on the principle of "obfuscation", which allow to assess psychomotor speed, speed, working memory (executable acceptance decisions, speed and flexibility) and immediate memory (processing of verbal and spatial information in memory). Before the beginning of the experiment, participants were required to practice the test for two consecutive days to determine initial skills. The data analysis was to compare the original abilities with what sposobnostyami after treatment. Individuals exposed to processing, weekly, were examined to determine what caused whether a food additive to changes in cognitive function. In the analysis of data was performed by comparison of the initial abilities of individuals exposed to processing, with the individuals who received placebo during the same time period. Analyzed the data only for those individuals who passed all the tests, starting with the definition of baseline and during weeks when they were injected dose of the drug. Cast loose the results of having more than 2 standard deviations from the mean value in the experience, and the data is not internally consistent with the other obtained in experiment estimates. In order to avoid anomalous results which could be due to distraction or failure ("glitches") of the "entanglement" of the computer, which could lead to unreliable results of the session, the data were analysed using the method of analysis of variance (ANOVA) for repeated measurements in the days of the experiment, and by comparing the reference level with the level of cognitive abilities in the last week of testing using the corresponding postexperimental tests.

A test of psychomotor speed or physical reflex is a simple test on BP the two reactions, which requires the individual as quickly as possible, press when you see the figures on the computer screen. General ability perform psychomotor tasks for all ages was very stable and was not characterized by any significant differences of average, median or standard deviation between the groups (p>0,05). Thus, a test of psychomotor speed revealed no differences between groups exposed to the treatment and control groups. However, it was found overall improvement in capabilities for all groups during the testing period.

In the test for speed working memory task on reaction time difficult of choice at the same time the word appears and the picture and an individual may be required to decide whether they match each other or not. Randomly occurs a change of signal values on the opposite and an individual may be required to answer, the opposite is correct, so the answer to the correct pair must be "no", and Vice versa. This job requires suppression or inhibition of learned response and subsequent changes ("change task") response. The rate of switching from one task or one form of response to another often equivalent mental flexibility and cognitive information processing higher order the ka, as well as a higher ability to make a decision. Cognitive elements of this test allow the assessment of Executive cognitive function, including speed of information processing, long-term attention, cognitive flexibility and the ability to make quick decisions in complex and demanding cognitive ability tasks.

Test direct memory similar to the classical problem of Sternberg, in which a number of items-stimuli, "targets"that you want to remember, you must "check" the item. The individual must determine was whether a test item in the previous list of targets. The list length can be varied to assess short-term memory capacity of the individual. In this task, use as a literal elements and spatial location.

The results are shown in figure 3, which demonstrated that Lasoperin™ can increase the speed of cognitive processing of information (decision making), without compromising the accuracy of selection, i.e. to increase the speed of response to cognitive task or situation with a difficult choice.

Example 5. Impact Lasoperin™ on the ability to focus and attention by measuring the standard deviation of the reaction time

To assess the impact Lasoperin™ on cognitive function was performed within 4 weeks of the series t the experts with the participation of cognitively intact individuals aged 35-65 years, according to the method described in example 4. The standard deviation of reaction time (RTSD) are often used as a criterion of attention in the study of cognitive abilities and, as a rule, believe that it reflects the efficiency of information processing and related to the nervous system noise (Jensen). The data presented in figure 4, one can see that during the 4-week test was significant improvement RTSD. This means that starting from the moment of determination of the initial level was a decrease in the standard deviation during the 4-week period of introduction individuals Lasoperin™. The subjects who were given a placebo, there were improvements, but not to the same extent. This suggests that the effect is due to improvement in the consistency of the task, which was increased when processing using Lasoperin™, not just learning, leading to better task performance. These results suggest that Lasoperin™ may lead to higher long-term attention, improving consistency requires cognitive response to the task or situation with a difficult choice.

Example 6. Inhibition of MOR-1 and MOR-2 using Lasoperin™

Measurement IC50Lasoperin™ was performed using the following method. The analysis used the cleaved chromophore, predstavljajushej a peroxide, for visual estimation of peroxidase activity of each enzyme in the presence of arachidonic acid as a cofactor. Typically, the assays were performed in 96-well format. Each inhibitor, taken from a 10 mg/ml stock solution in 100%DMSO, was tested in triplicate at room temperature using the following concentrations: 0, 0,1, 1, 5, 10, 20, 50, 100 and 500 µg/ml In each well was made in 150 μl of 100 mm Tris·HCl, pH 7.5, combined with 10 µl of 22 µm hematin diluted in Tris-buffer, 10 μl of inhibitor dissolved in DMSO and 25% or enzyme COX-1, or enzyme MOR-2. The components were mixed for 10 s on a rotating platform, and then added 20 μl of 2 mm dihydrochloride of N,N,N, N'-tetramethyl-para-phenylenediamine (TMPD) and 20 μl of 1.1 mm AK to initiate the reaction. The tablet was shaken for 10 s and then incubated for 5 min before registering absorbance at 570 nm. Build a graph of percent inhibition on the concentration of the inhibitor and determined the value of the IC50from a series of increasing concentrations pending on the X-axis as the corresponding point on the half maximum isotherms. Then the values of the IC50were standardized in relation to the number of units of enzyme used in the analysis. The results of measurement of dependence of dose-response and the values of the IC50for Lasoperin™ presents the and 5.

Example 7. Inhibition of 5-lipoxygenase (5-LO) - catechin isolated from A. catechu

One of the most important pathways involved in the inflammatory response, mediated curtain heme iron lipooxygenase (5-LO, 12-LO and 15-LO), which catalyze the joining of molecular oxygen to fatty acids such as arachidonic acid (AA), with the formation of hydroxyperoxides 5-, 12 - and 15-WRITE, which are then converted into leukotrienes. There is evidence that flavonovy extract of A. catechu may to a certain extent, to inhibit 5-LO, thus preventing the formation of 5-WRITE. To determine whether purified flavan catechin from A. catechu directly inhibit 5-LO in vitro, was used kit for screening inhibitors of lipoxygenase (A Lipoxygenase Inhibitor Screening Assay Kit) (company Cayman Chemical, Inc., catalogue number 760700). After replacing with microfiltration phosphate buffer at Trio-the buffer was replaced with 15-LO from soy, which is usually used in the set of 5-LO from potatoes. This analysis allows to detect the formation of peroxides using chromagen sensitive to oxygen. In General, the analysis was performed in triplicate by adding 90 μl of 0.17 units/μl of 5-LO from potatoes, 20 μl of 1.1 mm AK, 100 μl sensitive to oxygen chromagen and 1 µl of the purified inhibitor of flavan to the final concentrations are in d is apatone from 0 to 500 µg/ml The results are shown in Fig.6. It was found that the value of the IC50for inhibition of 5-LO by catechin amounted to 1.38 μg/ml/unit of enzyme.

Example 8. Measurement of the levels of LTB4after processing Lasoperin™

Composition Lasoperin™ were prepared according to the method described in example 1, using standardized extract flavonoid with a free ring from the roots of S. baicalensis and standardized flavan extract from the bark of A. catechu with the ratio of components in a mixture of 80:20 (Lasoperin™). Lasoperin™ and ibuprofen, another known inhibitor of 5-LO, was added at a concentration of 3 μg/ml to the cell line HT-29, which is a cell line of monocytes expressing MOR-1 AND MOR-2 and 5-LO, and incubated for 48 h at 37°C in humidified atmosphere containing 5% CO2. Then each processed line cells were collected by centrifugation and cells were carefully destroyed with dual homogenization in physiological buffer for lysis. To assess the impact Lasoperin™ new levels synthesized LTB4present in each cell line, which reflect the inhibitory effect of Lasoperin™ 5-LO path that was used by competitive ELISA for LTB4(LTB4; firm Neogen, Inc., catalogue number 406110). The analysis was carried out with duplicate by adding 160000-180000 cells per well in 6-well plates. The results are shown is figure 7. As can be seen from the results shown in Fig.7, Lasoperin™ inhibited by 80% the level of newly synthesized LTB4in the cell line HT-29. Ibuprofen has only led to 20%increase decrease amount of LTB4during the same period of time.

Example 9. Impact Lasoperin™ on LPS induced levels of TNFα and IL-1β in monocytes peripheral blood

Monocytes peripheral blood (RVMS) from human blood donors were isolated using gradient histopaque (Histopaque, the company Sigma). Then cells were cultured for approximately 12 h in RPMI medium 1640, supplemented with 1% bovine serum albumin, and then for the induction of inflammation were processed by lipopolysaccharide (LPS) in increasing concentrations in the presence of different concentrations Lasoperin™ (80:20). The results are shown in Fig-10.

Example 10. Comparison of selective inhibition of gene expression of Mor-2 relative inhibition of gene expression of Mor-1 using Lasoperin™ and other NCPUL

To assess whether Lasoperin™ impact on genomic level, isolated monocytes in human peripheral blood (RVMS) stimulated by lipopolysaccharide (LPS), were treated Lasoperin™, celecoxib, ibuprofen or acetaminophen, and then the obtained total RNA was collected and analyzed using semiquantitative FROM qPCR. Specifically, the analysis consisted in the fact that the AC is blowing a hole 6-hole tablet was added 130,000 cells. The cells are then stimulated with 10 ng/ml LPS and incubated together with Lasoperin™ at a concentration of 1, 3, 10, 30 and 100 μg/ml and celecoxib, ibuprofen and acetaminophen at a concentration of 3 μg/ml for 18 h at 37°C in humidified atmosphere containing 5% CO2. Then each processed batch of cells were collected by centrifugation and the obtained total RNA was isolated using TRIzol reagent®(firm Invitrogen™ Life Technologies, catalogue number 15596-026) according to the Protocol recommended by the manufacturer of the reagent TRIzol®. Was carried out by reverse transcription of total RNA using the reverse transcriptase of the virus murine leukemia, Malone (M-MLV RT; firm Promega Corp., catalogue number M1701) using random hexamers (firm Promega Corp., catalogue number With 1181). q experiments were performed using a detection system sequence type ABI Prism®7700 using pre-generated certified products used for analysis on demand (Assays-on-Demand, AOD, the company Applied Biosystems, Inc., catalogue number 4331182), as an internal standard 18S-pPHK and specific for a gene analysis method. The levels of specific gene expression was standardized with respect to their corresponding values in the gene expression of 18S-pPHK (internal control) and then the data obtained in the condition without LPS treatment and medication is authorized means, was standardized to 100. Data obtained under conditions of processing, was represented by a relative value compared with the data obtained in these "zero" conditions (without processing). Lasoperin™ reduced the standardized gene expression SOH-2 is more than 100 times, while the standardized gene expression of Mor-1 has undergone only minor change. Under the same treatment conditions standardized TNFα gene expression was decreased in 6 times, and standardized gene expression of IL-1β was decreased more than 100-fold. When RWMS was treated with 3 μg/ml Lasoperin™, celecoxib, ibuprofen or acetaminophen, only Lasoperin™ has not led to an increase in gene expression of Mor-2. This study was performed in conjunction with tests using ELISA method to assess changes in the levels of protein, as well as analyses of enzymatic functions to estimate changes the function of the protein. The results of these studies have been shown as associated with the genome and proteomic effects processing using Lasoperin™. In other cited publications used for specific protein methods in order to conclude about the presence of gene expression, and not to demonstrate it directly. The results are shown figure 11-13.

Example 11. Downward regulation of mRNA crucial inflammatory proteins with what omashu Lasoperin™

RUMS from human donor blood (obtained from a local blood Bank) were isolated using gradient histopaque (Histopaque, the company Sigma). Then cells were cultured for approximately 24 h in medium RPMI 1640, supplemented with 1% bovine serum albumin, and then was treated with LPS (10 μg/ml) and increasing concentrations Lasoperin™ (80:20). Specifically, the analysis consisted in the fact that each well of a 6-hole tablet was added 130,000 cells. The cells are then stimulated with 10 ng/ml LPS and incubated together with Lasoperin™ at a concentration of 100 μg/ml for 18 h at 37°C in humidified atmosphere containing 5% CO2. Then each processed batch of cells were collected by centrifugation and the obtained total RNA was isolated using TRIzol reagent®(firm Invitrogen™ Life Technologies, catalogue number 15596-026) according to the Protocol recommended by the manufacturer of the reagent TRIzol®. Was carried out by reverse transcription of total RNA using the reverse transcriptase of the virus murine leukemia, Malone (M-MLV; firm Promega Corp., catalogue number M) using random hexamers (firm Promega Corp., catalogue number With 1181). qPCR experiments were performed using a detection system sequence type ABI Prism®7700 using pre-generated certified products used for analysis on demand Assays-on-Demand, AOD, the company Applied Biosystems, Inc., catalogue number 4331182)as an internal standard for 18S-rRNA and specific for a gene analysis method. The levels of specific gene expression was standardized with respect to their corresponding levels of mRNA gene expression of cyclophilin And (internal control) and then the data obtained in the condition without LPS treatment and drug were standardized to 100. Data obtained under conditions of processing are relative values compared with the data obtained in these "zero" condition (without processing). The results are shown in Fig.

From the data shown in Fig, you can see that Lasoperin™ reduced the standardized gene expression SOH-2 average 3 times, while the normalized gene expression of Mor-1 has undergone only minor change. Under the same treatment conditions standardized gene expression infα decreased in average 3 times, standardized gene expression of il-1β was decreased on average 45 times, and standardized gene expression of il-6 was decreased on average 37 times. In other cited publications used for specific protein methods in order to conclude about the presence of gene expression, and not to demonstrate it directly. The results are shown in Fig.

Example 12. Decreasing R is galacia promoter elements inflammatory genes using Lasoperin™

The promoter region of each of inflammatory genes tnfα, il-1β, il-6 and Mor-2 contain NFκB binding sites, which may have an impact on reducing the regulation of gene expression when cells are treated Lasoperin™. The promotor region of the gene SOH-2 also contains a reactive element PPARγ (PPRE), which interacts with the transcriptional protein retinoid X receptor. Lasoperin™ provides lower regulation of gene expression of pparγ, which, obviously, leads to a decrease of PPARγ protein level, with the result that he cannot perform the action, stimulating gene expression of Mor-2. In addition, Lasoperin™ has a lower regulation on the expression of nfκb. Thus, the connection operates on two transcription factors, which affect gene expression SOH-2 and, apparently, the production of a protein SOH-2. These promoter elements shown in Fig.

Example 13. Measurement of the ability Lasoperin™ to absorb oxygen radicals (ORAC)

Lasoperin™ was tested against its ability to absorb oxygen radicals (ORAC) compared to some well-known antioxidants from food using the experimental methods described in Cao and others, Free It. Biol. Med., 16, 1994, cs-137 and Prior and Cao, Proc. Soc. Exp. Biol. Med., 220, 1999, SS-261. ORAC analysis, which is used as a fluorescent probe fluorescein, allows smarati the ability of antioxidants to absorb peroxyl radicals, which is one of the most common reactive oxygen species, found in the body. ORAChydrocharacterizes the absorption capacity of the water-soluble antioxidants and ORAClipothe ability of fat-soluble antioxidants. As the calibration standard used trolox, a water-soluble analogue of vitamin E, the results were expressed as an equivalent amount of micromol trolox (TE) per gram. Lasoperin™ had an ORAC value ofhydroconstituting 5,517 µmol of TE/g, and the amount of ORAClipoconstituting 87 mcmole TE/g, while ORACtotalwas 5,604 µmol of TE/g the Results are shown in table 2, from which it follows that Lasoperin™ had an ORAC value, comparable with the value ORAC of vitamin C and, thus, should reduce the levels of ROS in the body.

Table 2
The relative ORAC value Lasoperin™ compared to conventional antioxidants
Designation sampleORAC (mcmli TE/g)
Vitamin C (water soluble)5,000
Vitamin E (fat-soluble)1,100
Powdered Lasoperin5,517
Grape concentrate133
Cherry concentrate79
Cranberry concentrate90
Blueberry concentrate125

Example 14. Quantitative assessment of the composition of the mixture of flavonoids with a free ring and flavanol using liquid chromatography high pressure (ghvd) with reversed phase (method 1)

A mixture of flavonoids with a free ring and flavanol (20 μl of a standardized extract with a concentration of 1.13 mg/ml) in a mixture of 80% methanol:20% of tetrahydrofuran was introduced Phenomenex Luna C-18 column (250×4.6 mm, grain size 5 μm) and suirable for 19 min at a speed of 1.0 ml/min using a linear gradient from 80% a to 20% And (eluent And of 0.1% (vol./about.) phosphoric acid; eluent B-acetonitrile) at 35°C. As can be seen from the data shown in Fig, under these conditions, the flavonoids with a free ring (baicalein and bakalin) loirevalley in the form of a main peak in the period between the 11th and 14th minutes, and glavany (catechins and epicatechin) loirevalley as a minor peak in the period between about 3 and 5 minutes. The amount of flavonoids with a free ring and Livanov was determined by measuring the area under each curve and comparison with known standards.

Example 15. Quantitative assessment of the composition of the mixture of flavonoids with a free ring and flavanol using isocratic jhud with reversed phase (method 2)

A mixture of flavonoids with a free ring and flavanol (20 ml standardized extract with a concentration of 3.55 mg/ml) in a mixture of 80% methanol: 20% water was made on a Phenomenex Luna C-18 column (250×4.6 mm, grain size 5 mm) and were suirable in isocratic conditions at 35°C with 80% And (eluent And of 0.1% (vol./about.) phosphoric acid; eluent B-acetonitrile). As can be seen from the data shown in Fig, under these conditions, two flavan (catechins and epicatechin) loirevalley in flush in the period between 4.5 and 5.5 minutes, and flavonoids with a free ring (baicalein and bakalin) loirevalley between 12 and 13.5 minutes. Quantification of the peaks of flavanol carried out according to the method described in example 14.

1. The method of treatment mediated by cyclooxygenase (SOH) and lipoxygenase (LOX) diseases and conditions related to memory and cognitive functions, namely, that the owner, who needs this, introducing an effective amount of a composition comprising a mixture of extracts obtained from plants of the genus Scutellaria with a high content of flavonoids with free In-ring including baicalin, and extracts derived from plants of the genus Acacia, with a high content of flavanol, including utechin and epicatechin.

2. The method according to claim 1, in which the ratio of flavonoid with a free ring and flavan in the composition is about 80:20.

3. The method according to claim 1, wherein the flavonoid with a free ring and flavan isolated from a plant part selected from a range, including stems, bark, stalks, stems, stem bark, branches, tubers, roots, bark, roots, young shoots, seeds, rhizomes, flowers and other reproductive organs, leaves and other aerial parts.

4. The method according to claim 1, wherein the flavan isolated from plants belonging to the species, selected from a range that includes Acacia catechu, Acacia concinna, Acacia fornesiana, Acacia Senegal, Acacia speciosa, Acacia arabica, A. caesia, A. pennata, A. sinuata, A. mearnsii, A. picnantha, A. dealbata, A. auriculiformis, A. holoserecia, A. mangium, Uncaria gambir, Uncaria tomentosa, Uncaria africana and Uncaria qabir.

5. The method according to claim 1, wherein the flavonoid free ring isolated from the plant Scutellaria baicalensis, and flavan isolated from Acacia catechu.

6. The method according to claim 1, wherein the composition is administered in a dose comprising from 0.001 to 200 mg/kg body weight.

7. The method according to claim 1, wherein the route of administration selected from the range, including oral, topical introduction introduction using the suppository, intravenous, and intradermal, intragastric, intramuscular, intraperitoneal and intravenous administration.

8. The method according to claim 1, wherein the pharmaceutical composition contains, in addition, normal excipient, which is suitable with pharmaceutical, dermatologist the character and beauty of viewpoints for local use, and optional adjuvant and/or excipient and/or carrier for conventional or controlled release.

9. The method according to claim 1, where the specified mediated by cyclooxygenase (SOH) and lipoxygenase (LOX) diseases and conditions selected from the group including stroke, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ABS) and the deterioration of cognitive abilities in old age.

10. Method of recovery of cognitive processes associated with inflammation, which is that the owner, who needs this, introducing an effective amount of a composition comprising a mixture of an extract obtained from a plant of the genus Scutellaria with a high content of flavonoids with free In-ring including baicalin, and extract derived from a plant of the genus Acacia, with a high content of flavanol, including catechin or epicatechin.

11. The method according to claim 10, in which the ratio of flavonoids with a free ring and flavan in the composition is about 80:20.

12. The method according to claim 10, in which the flavonoid with a free ring and flavan isolated from a plant part selected from a range, including stems, bark, stalks, stems, stem bark, branches, tubers, roots, bark, roots, young shoots, seeds, rhizomes, flowers and other reproductive organs, leaves and other nazem the s part.

13. The method according to claim 10, in which the flavan isolated from plants belonging to the species, selected from a range that includes Acacia catechu, Acacia concinna, Acacia fornesiana, Acacia Senegal, Acacia speciosa, Acacia arabica, A. caesia, A. pennata, A. sinuata, A. mearnsii, A. picnantha, A. dealbata, A. auriculiformis, A. holoserecia, A. mangium, Uncaria gambir, Uncaria tomentosa, Uncaria africana and Uncaria qabir.

14. The method according to claim 10, in which the flavonoid free ring isolated from the plant Scutellaria baicalensis, and flavan isolated from Acacia catechu.

15. The method according to claim 10, in which the composition is administered in a dose comprising from 0.001 to 200 mg/kg body weight.

16. The method according to claim 10, wherein the route of administration selected from the range, including oral, topical introduction introduction using the suppository, intravenous, and intradermal, intragastric, intramuscular, intraperitoneal and intravenous administration.

17. The method according to claim 10, in which the pharmaceutical composition contains, in addition, normal excipient, which is suitable with the pharmaceutical, dermatological and cosmetic perspectives for local use, and optional adjuvant and/or excipient and/or carrier for conventional or controlled release.

18. Method of reducing development mediated by cyclooxygenase (SOH) and lipoxygenase (LOX) inflammatory diseases and conditions related to memory and cognitive function, namely, that the owner, who needs this, introduce effective to icesto composition, comprising a mixture of an extract obtained from a plant of the genus Scutellaria with a high content of flavonoids with free In-ring including baicalin, and extract derived from a plant of the genus Acacia, with a high content of flavanol, including catechin or epicatechin.

19. The method according to p, in which the ratio of flavonoid with a free ring and flavan in the composition is about 80:20.

20. The method according to p in which flavonoid with a free ring and flavan isolated from a plant part selected from a range, including stems, bark, stalks, stems, stem bark, branches, tubers, roots, bark, roots, young shoots, seeds, rhizomes, flowers and other reproductive organs, leaves and other aerial parts.

21. The method according to p in which the flavan isolated from plants belonging to the species, selected from a range that includes Acacia catechu, Acacia concinna, Acacia fornesiana, Acacia Senegal, Acacia speciosa, Acacia arabica, A. caesia, A. pennata, A. sinuata, A. mearnsii, A. picnantha, A. dealbata, A. auriculiformis, A. holoserecia, A. mangium, Uncaria gambir, Uncaria tomentosa, Uncaria africana and Uncaria qabir.

22. The method according to p, in which the composition is administered in a dose comprising from 0.001 to 200 mg/kg body weight.

23. The method according to p, in which the route of administration selected from the range, including oral, topical introduction introduction using the suppository, intravenous, and intradermal, intragastric, intramuscular, intraperitoneal and intravenous administration.

24 a Method according to p, where the pharmaceutical composition comprises, in addition, normal excipient, which is suitable with the pharmaceutical, dermatological and cosmetic perspectives for local use, and optional adjuvant and/or excipient and/or carrier for conventional or controlled release.

25. The method according to p where specified mediated by cyclooxygenase (SOH) and lipoxygenase (LOX) diseases and conditions selected from the group including stroke, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ABS) and the deterioration of cognitive abilities in old age.

26. Method of reducing the development associated with age impaired memory, mediated inflammation, which consists in the fact that the owner is in need of this, introducing an effective amount of a composition comprising a mixture of extracts obtained from plants of the genus Scutellaria with a high content of flavonoids with free In-ring including baicalin, and extract derived from a plant of the genus Acacia, with a high content of flavanol, including catechin or epicatechin.

27. The method according to p, in which the ratio of flavonoids with a free ring and flavan in the composition is about 80:20.

28. The method according to p in which flavonoid with a free ring and flavan selected is from parts of the plant, selected from a range, including stems, bark, stalks, stems, stem bark, branches, tubers, roots, bark, roots, young shoots, seeds, rhizomes, flowers and other reproductive organs, leaves and other aerial parts.

29. The method according to p in which the flavan isolated from plants belonging to the species, selected from a range that includes Acacia catechu, Acacia concinna, Acacia fornesiana, Acacia Senegal, Acacia speciosa, Acacia arabica, A. caesia, A. pennata, A. sinuata, A. mearnsii, A. picnantha, A. dealbata, A. auriculiformis, A. holoserecia, A. mangium, Uncaria gambir, Uncaria tomentosa, Uncaria africana and Uncaria qabir.

30. The method according to p, in which the composition is administered in a dose comprising from 0.001 to 200 mg/kg body weight.

31. The method according to p, in which the pharmaceutical composition contains, in addition, normal excipient, which is suitable with the pharmaceutical, dermatological and cosmetic perspectives for local use, and optional adjuvant and/or excipient and/or carrier, for normal or controlled release.

32. Method for improving cognitive function, namely, that the owner, who needs this, introducing an effective amount of a composition comprising a mixture of extracts obtained from plants of the genus Scutellaria with a high content of flavonoids with free In-ring including baicalin, and extract derived from a plant of the genus Acacia, with a high content of flavanol, including catechin or epicatechin.

34. The method according to p in which flavonoid with a free ring and flavan isolated from a plant part selected from a range, including stems, bark, stalks, stems, trunks, branches, tubers, roots, bark, roots, young shoots, seeds, rhizomes, flowers and other reproductive organs, leaves and other aerial parts.

35. The method according to p in which the flavan isolated from plants belonging to the species, selected from a range that includes Acacia catechu, Acacia concinna, Acacia fornesiana, Acacia Senegal, Acacia speciosa, Acacia arabica, A. caesia, A. pennata, A. sinuata, A. mearnsii, A. picnantha, A. dealbata, A. auriculiformis, A. holoserecia, A. mangium, Uncaria gambir, Uncaria tomentosa, Uncaria africana and Uncaria qabir.

36. The method according to p, in which the composition is administered in a dose comprising from 0.001 to 200 mg/kg body weight.

37. The method according to p, in which the pharmaceutical composition contains, in addition, normal excipient, which is suitable with the pharmaceutical, dermatological and cosmetic perspectives for local use, and optional adjuvant and/or excipient and/or carrier for conventional or controlled release.

38. A method of treating memory disorders, cognitive disorders and neurodegenerative conditions, namely, that the owner, who needs this, introducing an effective amount of comp the positions, comprising a mixture of extracts obtained from plants of the genus Scutellaria with a high content of flavonoids with free In-ring including baicalin, and extract derived from a plant of the genus Acacia, with a high content of flavanol, including catechin or epicatechin.

39. The method according to § 38, in which the ratio of flavonoids with a free ring and flavan in the composition is about 80:20.

40. The method according to § 38, in which the flavonoid with a free ring and flavan isolated from a plant part selected from a range, including stems, bark, stalks, stems, trunks, branches, tubers, roots, bark, roots, young shoots, seeds, rhizomes, flowers and other reproductive organs, leaves and other aerial parts.

41. The method according to § 38, in which the flavan isolated from plants belonging to the species, selected from a range that includes, Acacia catechu, Acacia concinna, Acacia fornesiana, Acacia Senegal, Acacia speciosa, Acacia arabica, A. caesia, A. pennata, A. sinuata, A. mearnsii, A. picnantha, A. dealbata, A. auriculiformis, A. holoserecia, A. mangium, Uncaria gambir, Uncaria tomentosa, Uncaria africana and Uncaria qabir.

42. The method according to § 38, in which the composition is administered in a dose comprising from 0.001 to 200 mg/kg body weight.

43. The method according to § 38, in which the pharmaceutical composition contains, in addition, normal excipient, which is suitable with the pharmaceutical, dermatological and cosmetic perspectives for local use, and optional adjuvant, and/and the and the filler, and/or media for normal or controlled release.

44. The method according to § 38, where these disorders and the condition is selected from the group including stroke, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ABS) and the deterioration of cognitive abilities in old age.



 

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FIELD: chemistry.

SUBSTANCE: invention refers to novel compounds of the general formula (I) , where R1, R2 are independently H or C1-C6-alkyl; R3, R4 are independently H or C1-C6-alkyl; R5 is halogen, CN; n, m or o are 0, 1 or 2; and to pharmaceutically acceptable salts thereof.

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14 cl, 3 dwg, 31 ex

FIELD: chemistry.

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16 cl, 3 tbl, 1 dwg, 10 ex

FIELD: medicine.

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46 cl, 85 ex

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Antihypoxic agent // 2392956

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, namely to preparation of an antihypoxic agent. Said agent is presented with aerial hemp agrimony (Eupatorium cannabinum L.) extract on 40% ethanol.

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3 tbl, 3 ex

FIELD: medicine.

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EFFECT: invention allows implementing specified object matter.

6 cl, 3 tbl, 3 ex

FIELD: medicine.

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EFFECT: invention allows implementing specified object matter.

6 cl, 3 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacy. There are performed 1) provision of defatted cocoa bean pod; (2) extraction of defatted cocoa bean pod with an aqueous solution of acetone containing 30 to 80 percent of acetone, for preparing a substance of liquid cocoa bean pod extract; (3) processing the substance of liquid cocoa bean pod extract for removing suspended solid matters and preparing the substance of processed liquid cocoa bean pod extract; (4) removing acetone from the substance of processed liquid cocoa bean pod extract for preparing a substance of aqueous extract; (5) concentration of the substance of aqueous extract to the solid content 1.5 to 5 percent for preparing a substance of concentrated extract; (6) introduction of the substance of concentrated extract in a gel filtration column containing a gel filtration medium applicable for separating theobromine and polyphenols; (7) watering the gel filtration column to collect a theobromine-enriched composition, and (8) elution of the watered gel filtration column by a polar organic solvent of low molecular weight for collecting a polyphenol-enriched composition where the polyphenol-enriched composition essentially does not contain phytosterols and theobromine. The composition is prepared by the method described above.

EFFECT: invention allows implementing specified object matter.

22 cl, 2 ex, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns pharmaceutical and cosmetic industry. It involves preparation of diffuse shelf fungus juice to be precipitated by adding 20% hydrochloric acid to pH 2.0-2.2. Said diffuse shelf fungus juice is prepared with using an aqueous solution of hyperbranched polymer Boltorn H 30 of concentration 1*10-3-1*10-22% as an extractant.

EFFECT: invention allows decreasing the impurity content, improving yield and activity of the product.

2 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns pharmaceutical and cosmetic industry. It involves preparation of diffuse shelf fungus juice to be precipitated by adding 20% hydrochloric acid to pH 2.0-2.2. Said diffuse shelf fungus juice is prepared with using an aqueous solution dymethylsulphooxide of concentration 1÷1*10-6 %.

EFFECT: invention allows decreasing the impurity content, improving yield and activity of the product.

2 ex, 1 tbl

FIELD: medicine, veterinary science.

SUBSTANCE: method involves application of EVL-Se COMPOSITION solution, which is introduced to animal inside orally by a group method with water (milk or imitation milk) once a day for 10 days in single dosage 1.0 ml per a head.

EFFECT: application of the method allows reducing disease incidence and recovery time, increasing average daily weight gains, ensures more rapid microflora formation and has no by-effects.

2 tbl, 3 ex

FIELD: agriculture.

SUBSTANCE: invention refers to the sphere of poultry keeping. Method includes application of preparation "EVL-Se COMPOSITION" solution, which is administered to chickens once by group method through unrestricted bottle-feeding with water once per day for 10-20 days in a single dose of 0.02 ml per head.

EFFECT: application of method makes it possible to reduce losses, to increase weight gains, to improve immune response in vaccinations.

4 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to gastroenterology, and concerns a reducing diet therapy. A patient takes a saline laxative and stops food intake. Stating from first day of fast, 1.5-2 l of purified water is introduced daily in equal portions, with administering at the end of the day a cleansing enema of 1.5-2 l of purified water with colloidal silver added at 10 drops per 1 l. Psychotherapeutic discussion, walks for 30-40 minutes 2-3 times a day and Nishi gymnastics are practiced. Starting from the second day of fast, for 16 days, daily at 7:30 the patient takes 1/3 teaspoons of a vegetative organic sorbent dissolved in a glass of water with another glass of water taken in half an hour thereafter. At 9:30 and 18:30, an herbal antihelmintic drug is administered; 9:40 and 18:40, 1 capsule of an herbal preparation "Catrel" is taken. At 10:00 and every night at bedtime, colloidal silver is taken in amount 1 teaspoon, held in a mouth for 6 minutes, then swallowed and also instilled 1 drop in each eye and 1 drop in nose. During a day, herbal tea "Pohudey-ka", "Cleansing", and every night at bedtime, 2 tablets of "Senade" are prescribed. On 3rd, 6th, 10th, 13th, 16th days of fast, every night at bedtime, liver and gall bladder flush is performed. The course involves 3-5 procedures of hydrocolonotherapy. The first days of the recovery period, the patient consumes fresh juices, vegetables, fruits, bacterial preparation "Bacteriobalance", with a vegetarian salt-free diet for a month. Starting from the third day, vitamin-mineral and microelement complexes containing organic calcium, selenium, iodine, polyunsaturated fat acids, and essential amino acids are prescribed.

EFFECT: method provides effective complex normalisation of digestive organs activity and thereby health improvement.

4 cl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to gastroenterology, and concerns a reducing diet therapy. A patient takes a saline laxative and stops food intake. Stating from first day of fast, 1.5-2 l of purified water is introduced daily in equal portions, with administering at the end of the day a cleansing enema of 1.5-2 l of purified water with colloidal silver added at 10 drops per 1 l. Psychotherapeutic discussion, walks for 30-40 minutes 2-3 times a day and Nishi gymnastics are practiced. Starting from the second day of fast, for 16 days, daily at 7:30 the patient takes 1/3 teaspoons of a vegetative organic sorbent dissolved in a glass of water with another glass of water taken in half an hour thereafter. At 9:30 and 18:30, an herbal antihelmintic drug is administered; 9:40 and 18:40, 1 capsule of an herbal preparation "Catrel" is taken. At 10:00 and every night at bedtime, colloidal silver is taken in amount 1 teaspoon, held in a mouth for 6 minutes, then swallowed and also instilled 1 drop in each eye and 1 drop in nose. During a day, herbal tea "Pohudey-ka", "Cleansing", and every night at bedtime, 2 tablets of "Senade" are prescribed. On 3rd, 6th, 10th, 13th, 16th days of fast, every night at bedtime, liver and gall bladder flush is performed. The course involves 3-5 procedures of hydrocolonotherapy. The first days of the recovery period, the patient consumes fresh juices, vegetables, fruits, bacterial preparation "Bacteriobalance", with a vegetarian salt-free diet for a month. Starting from the third day, vitamin-mineral and microelement complexes containing organic calcium, selenium, iodine, polyunsaturated fat acids, and essential amino acids are prescribed.

EFFECT: method provides effective complex normalisation of digestive organs activity and thereby health improvement.

4 cl, 4 ex

Antihypoxic agent // 2392956

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, namely to preparation of an antihypoxic agent. Said agent is presented with aerial hemp agrimony (Eupatorium cannabinum L.) extract on 40% ethanol.

EFFECT: agent extends the range of herbal antihypoxic products, prolongs a latent time in the heat-space hypoxia conditions.

3 tbl, 3 ex

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