Preparation based on mixture of flavonoids with free b-cycle and flavanes, as therapeutic agent

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to composition for prevention and treatment of diseases and states, associated with platelet aggregation and platelet-induced thrombosis, including mixture of at least one flavonoid with free B-cycle, of at least one flavane and at least one agent, selected from group, consisting of injection anticoagulant agent, peroral anticoagulant agent, antiplatelet agent, anti-angina medication, non-steroid anti-inflammatory drug (NSAID) or selective cyclooxygenase-2 (COX-2) inhibitor (versions). Method of composition application.

EFFECT: compositions are efficient for prevention and treatment of diseases and states, associated with platelet aggregation and platelet-induced thrombosis.

32 cl, 14 tbl, 11 ex

 

The scope of the invention

This invention relates to the prevention and treatment of diseases and conditions related to platelet aggregation and thrombosis caused by platelets. In particular, the present invention relates to compositions comprising a mixture of two specific classes of compounds - flavonoids with free In-cycle and flavanol, denoted in this context as UP736 intended for use for the prevention and treatment of diseases and conditions mediated platelet aggregation and thrombosis caused by platelets. This invention also relates to a method of applying UP736 adjuvant, and/or synergistic, and/or potentiating agent in combination with injectable or oral anti-coagulants agents, protivotrematodoznye agents, non-steroidal anti-inflammatory drugs (NSAID) and selective inhibitors SOH-2. Finally, this invention relates to a method of applying UP736 in combination with protivotrematodoznye, prophylactic anticoagulation agents and NSAID as a means of reducing the doses of these agents reduce the side effects associated with acute or permanent use of these agents; counter or antagonistic action against the risk and acute and constant use of these agents and achieve additional and/or numerous clinical advantages.

The level of technology

The release and metabolism of arachidonic acid (AA) from the cell membrane results in the generation of metabolites in several different ways. Probably two of the most important ways mediated by the enzymes 5-lipoxygenase (LOX) and cyclooxygenase (SOH). They represent parallel pathways, resulting in the generation of leukotrienes and prostaglandins, respectively, which play an important role in the initiation and development of the inflammatory response and platelet aggregation. Therefore, the enzymes responsible for generating the data mediators, became a target for many new drugs aimed at the treatment of inflammation and modulation of platelet aggregation, which are involved in the pathogenesis of diseases, such as rheumatoid arthritis, osteoarthritis and atherothrombosis.

Enzyme inhibition SOH is the mechanism of action attributed to most non-steroidal anti-inflammatory drugs (NSAIDS). There are two different isoforms of the enzyme MOR (MOR-1 and MOR-2), which have homology sequences of approximately 60%, but with different expression profiles and functions. MOR-1 is a constitutive form of the enzyme, which is associated with the production of physiologically important prostaglandins, which help regulirovaniya physiological functions, such as platelet aggregation, protection of cellular function in the stomach and the maintenance of normal renal function (see Dannhardt and Kiefer (2001) Eur. J. Med. Chem 36:109-26). The second isoform, COX-2, is a form of the enzyme, which induce Pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and other growth factors (see article Herschmann (1994) Cancer Metastasis Rev. 134:241-56; Xie et al. (1992) Dev Drugs. Res. 25:249-65). This isoform catalyzes the production of prostaglandin E2 (PGE2) from arachidonic acid (AA). Because the mechanism of action of inhibitors MOR covers the mechanism of action of the most accepted NSAID inhibitors SOH is used to treat many of the same symptoms, including aerodromes, pain and swelling associated with inflammation when temporary conditions and chronic diseases.

Platelets play a Central role in normal hemostasis. After vascular injury, platelet-derived extracellular matrix through the damaged endothelial wall, where they are activated by various components of the extracellular matrix, including collagen, proteoglycans, fibronectin and other adhesive glycoproteins. Upon contact with the extracellular matrix with the platelets are numerous and consecutive reactions, including adhesion and shape change, secretion of two types of granules and aggregates. Identifitsirovana strong mediator of platelet aggregation: adeninivorans (ADP) and thromboxane A2 (Tha). ADP released from platelets after they are activated by components of the extracellular matrix. In addition to mediating platelet aggregation ADP also enhances the release of ADP from other platelets, forming a positive feedback loop for platelet aggregation. The is synthesized and released from platelets and also represents an important stimulus for platelet aggregation. Together with ADP The prepares autocatalytically reaction, leading to the construction of the increasing aggregation of platelets. Aggregated platelets is important for the subsequent process of blood clotting. Data activated platelets stimulate local activation of plasma coagulation factors, leading to the generation of a fibrin clot, which strengthens the aggregation of platelets. Recent studies suggest that all associated with the membrane reactions of the coagulation system can be localized on the surface of activated platelets (see Conde et al. (2005) Blood 106:1604-1611).

Although the adhesion and activation of platelets is focused on the restoration of response to sudden vascular damage, uncontrolled development of this process through a series of self-sustaining loops amplification can lead to the formation of a blood clot in the lumen of the vessel, soudi is the occlusion and temporary ischemia or infarction (see article Ruggeri (2002) Nat. Med. 8: 1227-34). The ability of platelets to participate in both the normal processes of hemostasis and atherothrombosis depends on their adhesion properties and their ability to very rapid activation in response to various stimuli.

Natural platelets Express only MOR-1. Platelets ProcessInput PGH2 with the formation of mainly The, which is synthesized and released by platelets in response to collagen, thrombin and other incentives. The causes irreversible platelet aggregation by interaction of G-protein-linked receptor, the receptor Tha. Thus, The provides a mechanism for strengthening the response of platelets in relation to a variety of agonists. In addition, The is a strong vasoconstrictor, induces cell proliferation of smooth muscles of blood vessels and is proatherogenic. As vasoconstrictor Tha promotes proper aggregation of platelets. Inhibiting the enzyme SOH-1, the aspirin will reduce the production Tho, which leads to reduced platelet aggregation (see Patrono et al. (2006) The New England Journal Medicine. 353:22: 237).

Prostacyclins are formed in the endothelial lining of the arteries and heart. The balance between prostacyclin (PGI2), a strong vasodilator, and a representative of thromboxanes, such as The, it is important to maintain an adequate cardio-vessel the stop function (see article Bunting et al. (1983) Br. Med. Bull. 39:271). Both PGI2and TxA2, depend on the products of MOR-1 and MOR-2 in the endothelial lining of the arteries and in cardioscan heart (see Caughey et al. (2001) J Immunol, 167:2831; Ribuot et al. (2003) Cardiovascular Res 58:582). It is shown that the ratio of MOR-1 and MOR-2 affect the balance as PGI2and The. MOR-1 metabolizes arachidonic acid, transforming fatty acid mainly in The, whereas induced MOR-2 acts on arachidonic acid, transforming it into PGE2and PGI2(see article Oh-ishi (1997) Biochem. Biophys. Res. Commun. 230:110; Brock et al. (1999) J. Biol. Chem. 274:11660). PGI2inhibits platelet aggregation in response to all agonists via interaction with the receptor PGI2. The is a prostanoid, largely isolated from the MOR-1 (mainly from platelets), and its biosynthesis is highly sensitive to inhibition by aspirin (see Rocca et al. (2002) Proc. Natl. Acad. Sci. USA 99:7634-9). PGI2on the other hand, emit mainly from MOR-2 (see McAdam et al (1999) Proc. Natl. Acad. Sci. USA 96:272-7), and it is less sensitive to inhibition by aspirin. Highly selective inhibition of MOR-2 may contribute to thrombosis by switching the balance of synthesis of PGI2(path, SOH-2) relatively The (path, SOH-1) by transfer of arachidonic acid on eicosanoid way MOR-1 (see Gaetano (2003) Trends in Pharmacoogical Sciences. 24(5):245-252).

Platelet aggregation plays a very important role in the induction and development of aterotromboza, which is the main cause of deep vein thrombosis, pulmonary embolism, atherosclerosis, myocardial infarction, thrombosis of cerebral vessels and/or embolism of cerebral vessels, leading to cerebrovascular events. Antiplatelet drugs such as aspirin, and anticoagulation medications, such as heparin and warfarin (see Verheugt (2005) Presse Med. 34:1325), a specific thrombin inhibitors such as hirudin, desirudin, bivalirudin, and non-specific thrombin inhibitors, such as statins (see Shen (2006) Front Biosci. 11:113), are currently the standard drugs used for the treatment of thromboembolism. However, complications arising from severe bleeding are the main side effect of anticoagulant drugs and high-dose short-term antiplatelet therapy. The use of lower doses of anticoagulant drugs in combination with moderate-to-low-dose antiplatelet compounds, such as aspirin, as shown, has significant therapeutic value in reducing the threat of bleeding in patients from high risk groups (see Harrington et al. (2004) hest. 126.3 Suppl. 513S).

Due to the irreversible inhibition of platelet cyclooxygenase and prevent the formation of The drugs such as aspirin is also used for a long period of time to reduce the risk of cardiovascular diseases, for the prevention of acute myocardial infarction and prevention of acute occlusive stroke (see Hennekens (2002) Am. J. Manag. Care 8 (22 Suppl.):S691). The most common side effect caused by the prolonged use of aspirin and other antiplatelet salicylates, is local erosion of the gastric mucosa by inhibiting SOH-1, which is important to maintain the integrity of the lining of the mucous membrane. This damage of the gastric mucosa may lead from a hidden blood loss to acute gastrointestinal bleeding due to serious gastroduodenal damage. Short-term high-dose use of antiplatelet drugs is also associated with its own risks, such as significantly increased risk of stroke and bleeding after surgical procedures. Selection of the optimal dose represents one possibility to reduce these side effects (see Kong (2004) Am. J. Cardiovasc. Drugs 4(3):151). Daily dose, lying in the range of 75 mg to 150 mg recommended for the extreme prophylactic use. Of course, any compounds that can enhance the antiplatelet effect of aspirenow without increasing their side effects, will have a significant therapeutic advantage (see Patrono et al. (2005) New Eng. J. Med. 353:22; 2373). Unfortunately, currently there is no possibility, whereby it is possible by use of antisecretory agents such as proton pump inhibitor, to reduce the risk of bleeding in the upper part of the gastrointestinal tract in patients taking antiplatelet drugs.

In terms of toxicity of aspirin and other classical NSAID, especially the formation of ulcers of the gastrointestinal tract and bleeding due to selective inhibition of MOR-1, in the process of drug development using two strategies. The first strategy includes the search for selective inhibitors SOH-2, which reduce gastrointestinal side effects by creating a reserve of protective functions MOR-1 in the gastric mucosa (see DeWitt (1999) Mol. Pharmac. 4:625-631). This effort led to the successful implementation of a number of commercial drugs, such as celecoxib and rofecoksib that show selectivity against SOH-2. In clinical trials of selective inhibitors SOH-2 showed significant activity is in relation to pain and other symptoms of inflammation with reduced likelihood of gastrointestinal events. Gradually, however, receive a number of side effects associated with the use of selective inhibitors SOH-2. For example, we discovered that these compounds stimulate allergies and asthma attacks, cause acute renal failure, congestive heart failure, exacerbate coronary and cerebrovascular disease, slow the growth of broken bones and healing of ulcers, suppress the immune system, making a person susceptible to infection viral meningitis, and contribute to the development of ulcers in patients with erosions of the stomach or infection of Helicobacter pylori (see Rainsford (2001) J. Physiol. Paris 95: 11-19). Recent reports suggest that a significant anti-inflammatory effect of some highly selective inhibitors SOH-2 see only after the dose will reach levels at which there is also inhibition of the activity of MOR-1 (see Wallace et al.91999) Br. J. Pharmac. 126:1200-1204.) together with the generation of anti-inflammatory prostanoids by enzyme SOH-2 at a later phase of the inflammatory process (see Gilroy et al. (1999) Nature Med. 5:698-701), put, in addition, the question about the effectiveness of selective inhibitors SOH-2.

In 2004, the drug Vioxx (rofecoksib) was voluntarily withdrawn from the market after clinical trials showed that over time this wysockis the electoral inhibitor SOH-2 increases the risk of heart attack more than twice in comparison with other NSAID, naproxen. In addition, a clinical trial, including celebrex (celecoxib), funded by the National cancer Institute, showed that long-term high-dose use of this selective inhibitor SOH-2 more than doubles the risk of heart attack. There are also considerations concerning the cardiovascular risks associated with other selective inhibitor SOH-2, Bextra (valdecoxib) (see Meier Century Marketing Intensified Trouble for Pain Pills. The New York Times, December 19, 2004). In fact, a review of the current scientific literature showed that the increased risk of cardiovascular events associated with taking rofecoxib (Vioxx) and other selective inhibitors SOH-2, celebrate with 2000 (see article Juni et al. (2004) Lancet. 364(9450): 2021-2029; Clark (2004) Drug Safety 27(7):427-456). There are additional facts which indicate that the main cause of this concern is the extremely high selectivity SOH-2 this class of drugs (see Neal et al. (2004) J. Pharm Sci. 7(3):332-336).

Recently obtained results show that MOR-2 is expressed in healthy bodies, such as the dense stain kidney/cTALH and medullary interstitial cells (see Harris et al. (August. 2004) Acta Physiol Scand 181(4):543-7); in endothelial cells (see Parente and Perretti (January 2003) Biochem Pharmacol. 65(2): 153-9) and in the head is the mind (see article Hoffmann (November 2000) Curr Med Chem. 7(11): 1113-20). Kidney enzyme SOH-2 is required for the production of PGE2and PGI2(prostacyclin) from arachidonic acid. PGI2in particular, is a key regulator of sodium balance in the body (see Harris (2000) J Am Soc Nephrol 11:2387). Inhibition of PGE2and PGI2through selective inhibitors SOH-2 in the kidney leads to retention of sodium and water and increase blood pressure, because PGE2reduces the re-absorption of sodium, whereas PGI2it is a powerful vasodilator, which maintains the balance between renal blood flow and glomerular filtration rate or, in other words, the amount of urine formed in the body. PGI2also stimulates the release of renin, which causes an increase in release of aldosterone, which then increases the secondary absorption of sodium and secretion of potassium (see Carmichael and Shankel (1985) Am J Med 78:992; Whelton and Hamilton (1991) J Clin Pharmacol 31:588). To maintain adequate renal perfusion kidney enhancing way regulate the synthesis of PGI2to counteract the effects of vasoconstrictors to maintain proper kidney function. In most healthy patients, the appropriate blood pressure is maintained on the basis of their own trim the absorption of liquids and separation is of urine without affecting compounds, causing vasoconstriction or vasodilatation. For these patients are not required effects of vasoconstrictors, balanced PGI2. However, found that patients with high blood pressure Vioxx further increases the blood pressure (see Lamarque (2004) Bulletin du Cancer (Montrouge) 91.SI 17; Whelton et al. (2001) Am J Ther 5:85). This increase in blood pressure may contribute to the increased risk of acute myocardial infarction (AMI) (see Deray (2004) Presse Med 33:483).

Enzymes SOH-2 also induce the expression of PGE2and PGI2in the heart, which protects against acute myocardial infarction (AMI) (see Dai and Kloner (2004) J Cardiovascul Pharmacol Therapeutics 9:51). Recent studies on rabbits and mice have shown that when called AMI MOR-2 significantly regulated on the rise, acting to stop the event as a mediator against heart attack (see article Shinmura et al. (2000) PNAS 97: 10197; Guo et al. (2000) Basic Res Cardiol 95:479). This activity against a heart attack prevents further relative to the existing damage, thereby preserving cardiac function (see Bolli et al. (2002) Am J Physiol 282:H1943). In animal models, researchers have shown that the levels of PGI2do not apply when rats administered selective inhibitor SOH-2 compared with placebo. This lack PGI2prevents that the hearts of the rats counteract induced is obitu AMI (see article Bolli et al. (2002) Am J Physiol 282:H1943; Shinmura et al. (2002) Am. J Physiol 283:H2534). At selective inhibition of MOR-2 Tha is formed at a much higher level compared to PGI2. Vasoconstriction through The balanced PGb-induced vasodilation, which reduces the blood flow in the arteries in the heart. This decrease blood flow and limiting the delivery of nutrients and oxygen may tip the balance in sensitive patients towards AMI (see Bing and Lomnicka (2002) J. Am Coll. Cardiol 39:521).

A recent evaluation of the isoforms of cyclooxygenase and their functions demonstrated that the lack of significant inhibition of MOR-1 is a convincing explanation of the observed increase in cardiovascular side effects associated with Vioxx (rofecoksib) and other highly selective inhibitors SOH-2. Recommend even to avoid the application of highly selective against SOH-2 NSAID without the use of suitable inhibitors MOR-1 (e.g., dose of aspirin), (see Neal et al. (2004) J. Pharm. Pharmaceut. Sci. 7(3):332-336).

Modern attempts to combat inflammation focused on the search for agents that inhibit both cyclooxygenase and lipoxygenase ( see Parente (2001) J. Rheumatol. 28:2375-2382; Bertolini / Marian Fisher et al. (2001) Pharmac. Res. 44:437-450). Inhibitors that exhibit dual specificity against MOR and LOX, they who would have the obvious advantage in terms of inhibition of multiple pathways of arachidonic acid metabolism. These inhibitors would block the inflammatory effects of prostaglandins (PG), as well as the effects of many of leukotrienes (LT) by limiting their production. This includes vasodilation, vascular permeability and chemotactic effects of PGE2, LTB4, LTD4 and LTE4, also known as the slow reacting substance of anaphylaxis. Among them LTB4 has the most powerful chemotactic and geokinetics.com effects (see Moore (1985) monograph Prostanoids: pharmacological, physiological and clinical relevance, Cambridge University Press, N.Y., pp. 229-230).

The importance of blocking the inflammatory effects of PGE2and effects of many of leukotrienes (LT) is based on the fact that recently it was discovered that significant shortcomings in the election inhibitors SOH-2 are associated with the switching path of arachidonic acid on the path lipoxygenase, thereby causing overproduction proinflammatory, chemotactic, damaging the stomach and bronchoconstricting leukotrienes (see Celotti and Laufer (2001) Pharmac. Res. 43:429-436).

It is shown that the called NSAID inflammation of the stomach is largely due to the LOX metabolites, in particular LTC4 and LTB4 (see Kirchner et al. (1997) Prostaglandins Leukot. Essent. Fatty Acids 56:417-423). Leukotrienes contribute in a significant number of damaged gastric epithelium by stimulating the infiltration of leukocytes, occlusion of the vessels, reducing blood flow in the mucosa of the release of mediators, proteases and free radicals. Selective inhibitors of LOX showed a significant reduction in the severity or prevention of the formation of ulcers induced by indomethacin (see Fosslien (1998) Annals Clin. Lab. Sci. 28:67-81). Found that by inhibiting ways SOH aspirin and other inhibitors SOH switch metabolites of arachidonic acid on the path LOX, causing increased release bronchospastic leukotriene along with increasing levels of containerisation, which leads to chronic rhinoconjunctivitis, nose polyps and asthma, similar to prolonged viral respiratory infection. The prevalence of aspirin-induced asthma (AIA) in the asthmatic population is approximately from 10 to 20%, and for the treatment of patients with AIA used antileukotriene drugs (see Babu and Salvi (2000) Chest 118: 1470-1476).

Dual inhibitors also exhibit other therapeutic benefits. They have been shown to reduce coronary vasoconstriction in heart affected by arthritis model in rats (see Gok et al. (2000) Pharmac. 60:41-46) and significantly decrease caused by angiotensin II abbreviations in the internal artery of the human mammary gland (see Stanke-Labesque et al. (2000) Cardiovascular Res. 47:376-383). Activation of opioid receptors may cause presynaptic inhibition of visvobodi the Oia neuromediator, mediated by LOX metabolites of arachidonic acid in neurons of the mid-brain. The effectiveness of opioids synergistically improve the treatment of brain neurons dual inhibitors SOKH and LOX. This can lead to the creation of anesthetic drugs for the Central nervous system, including the combination of low doses of opioids and dual inhibitors of COX/LOX (see Christie et al. (1999) Infiamm. Res. 48:1-4). Dual inhibitors of SOKH and LOX can also warn caused by the protein of the lens of eye inflammation in both the early and late phases (see Chang et al. J. Ocular Pharmac. 5:353-360).

Dual inhibitors of SOKH and LOX not only inhibit prostaglandins, which contribute to acute inflammatory States, but are also involved in the accumulation of phagocytic leukotrienes, which are directly associated with symptoms of chronic inflammation. In addition, dual inhibitors also protect the heart from the activity of inhibition of MOR-1. These properties suggest that dual inhibitors SOKH and LOX can have clear advantages relatively selective inhibitors SOH-2 and NSAID. This statement, as shown, is grounded on models in vivo using the potential of synthetic drugs (see Fiorucci et al. (2001) Biochem. Pharmac. 62:1433-1438).

Disclosure of inventions

The present invention relates mainly to the composition and, obtained for use for the prevention and treatment of diseases and conditions associated with platelet aggregation, and produced by platelets thrombosis. This composition in this context refers both to UP736. The composition consists of a mixture of two specific classes of compounds - flavonoids with free In-cycle and flavanol. Compositions comprising flavonoids with free In-cycle, flavanol and mixtures thereof described in patent application U.S. No. 10/091362, filed on March 1, 2002, entitled "Identification of Free-B-ring Flavonoids as Potent COX-2 Inhibitors" (Identification of flavonoids with free In-cycle as strong inhibitors MOR-2), in the patent application U.S. No. 10/104477 filed March 22, 2002, entitled "Isolation of and Dual SOH-2 and 5-Lipoxygenase Inhibitor from Acacia" (Emphasis dual inhibitor SOH-2 and 5-lipoxygenase from Acacia) and in the patent application U.S. No. 10/427746 filed July 22, 2003, entitled "Formulation with Dual SOH-2 and 5-Lipoxygenase Inhibitory Activity (Drug active dual inhibitor SOH-2 and 5-lipoxygenase). Each of these references is included in this context by reference in its entirety.

In the present invention include a composition consisting of a mixture of at least one flavonoid with a free In-cycle, at least one flavan and at least one agent selected from the group consisting of injectable anticoagulation Agay is the selected from the group including, but not limited to, heparin, dalteparin, enoxaparin and Tinzaparin, oral anticoagulation agent selected from the group including, but not limited to, warfarin, vitamin K antagonists and inhibitors of the reductase vitamin K; antiplatelet agent selected from the group including, but not limited to, aspirin, clopidogrel and dipyridamole, a drug against angina selected from the group including, but not limited to, nitrates, β-blockers, blockers of calcium, inhibitors of the angiotensin converting enzyme activators potassium channels; non-steroidal anti-inflammatory drug (NSAID)selected from the group including, but not limited to, acetaminophen, ibuprofen, naproxen, diclofenac, salicylates and indomethacin or selective inhibitor SOH-2, selected from the group including, but not limited to, rofecoksib, celecoxib, etodolac and meloxicam.

The ratio of flavonoids with free In-cycle and flavanol in the composition can be brought on the basis of indicators and specific requirements regarding the prevention and treatment of a specific disease or condition. Mainly the relationship of flavonoids with free In-cycle and Levanov may lie in the range from about 99:1 of flavonoids with free In-cycle:flavanol to about 1:99 flavonoids with free In-cycle:flavanol. In specific embodiments, the implementation of the present invention, the ratio of flavonoids with free In-cycle to flavianum selected from the group consisting of approximately 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90. In a preferred embodiment of the invention, the ratio of flavonoids with free In-cycle to flavianum in the proposed composition of approximately 85:15. Flavonoids with free In-cycle and floveny possible to synthesize and/or isolate from a single plant or multiple plants. In a preferred embodiment, the flavonoids with free In-cycle extracted from the plant or plants of the genus Scutellaria and floveny isolated from the plant or plants of the genus Acacia and Uncaria.

The present invention further includes methods of treating and preventing diseases and conditions related to platelet aggregation and induced platelet thrombosis. The method consists in the introduction to the needy in this master composition, comprising a mixture of flavonoids with free In-cycle and flavanol, synthesized and/or isolated from a single plant or multiple plants. The effectiveness of this method is demonstrated using purified enzymes in various cell lines and a variety of animal models.

Diseases and conditions associated with platelet aggregation and induced platelet thrombosis is om, which can be prevented and treated according to the method presented in the invention include, but are not limited to, deep vein thrombosis, pulmonary embolism, atherosclerosis, myocardial infarction, thrombosis of cerebral vessels and/or embolism of cerebral vessels, leading to cerebrovascular events, thrombosis of peripheral circulation and/or microcirculation, leading to ischemia and infarction, atrial fibrillation, which is associated with stasis of blood and the formation of clots in the left atrium, thrombogenic centers, including artificial implants, such as mechanical heart valves, defibrillators, surgical implants for drug delivery and artificial hips, joints and other exogenous bodies.

The present invention further includes methods of application UP736 adjuvant, and/or synergistic, and/or potentiating agent, which consist in the introduction to the needy in the host an effective amount of the presented composition comprising a mixture of at least one flavonoid with a free In-cycle, at least one flavan and at least one agent selected from the group consisting of injectable anticoagulant agent, an oral anticoagulant agent, an antiplatelet agent, agent shall Rotel angina, non-steroidal anti-inflammatory drug (NSAID) or a selective inhibitor SOH-2. Examples of injectable anticoagulant agents include, but are not limited to, heparin, dalteparin, enoxaparin and Tinzaparin. Examples of oral anticoagulation agents include, but are not limited to, warfarin, vitamin K antagonists and inhibitors of the reductase vitamin K. Examples of antiplatelet agents include, but are not limited to, aspirin, clopidogrel and dipyridamole. Examples of medication for angina include, but are not limited to, nitrates, β-blockers, blockers of calcium, inhibitors of the angiotensin converting enzyme activators potassium channels. Nonsteroidal anti-inflammatory drugs (NSAID) include, but are not limited to, acetaminophen, ibuprofen, naproxen, diclofenac, salicylates and indomethacin. Finally, examples of selective inhibitors SOH-2 include, but are not limited to, rofecoksib, celecoxib, etodolac and meloxicam.

The present invention also includes a method of reducing the standard dose of antiplatelet, anticoagulant, prophylactic agents, NSAID and selective inhibitors SOH-2 to achieve either equal to, or superior is liricheskogo result. The method consists in the introduction to the needy in the host an effective amount of a composition comprising a mixture of at least one flavonoid with a free In-cycle and at least one flavan in combination with the specified antiplatelet, anticoagulant, a prophylactic agent, NSAID or selective inhibitor SOH-2.

The present invention further includes a composition and method of application UP736 to adjuvant, and/or synergistic, and/or potentiating agent in combination with at least one non-steroidal anti-inflammatory drug (NSAID)selected from the group including, but not limited to, acetaminophen, ibuprofen, naproxen, diclofenac, salicylates, indomethacin, and at least one selective inhibitor SOH-2, selected from the group including, but not limited to, rofecoksib, celecoxib, etodolac and meloxicam. This composition and method allow you to reduce the dose of NSAID required to achieve either equal to, or superior clinical outcome, resulting in reduction of side effects associated with acute or permanent use of these agents, and the opposition or antagonistic action against the risks of acute or persistent use of NSAID. This method is also a means of access is the supply of additional and/or multiple clinical advantages as described in detail below. The method consists in the introduction to the needy in the host an effective amount of a composition comprising a mixture of flavonoids with free In-cycle and flavanol in combination with at least one NSAID and at least one selective inhibitor SOH-2 and a pharmaceutically acceptable carrier.

The present invention also includes a composition and method of reducing or eliminating side effects associated with acute or permanent use of antiplatelet, anticoagulant, prophylactic agents, NSAID and selective inhibitors SOH-2, through the introduction of a specified agent in combination with UP736. The method consists in the introduction to the needy in the host an effective amount of a composition comprising a mixture of flavonoids with free In-cycle and flavanol in combination with at least antiplatelet, anticoagulant, a prophylactic agent, NSAID or selective inhibitor SOH-2 and a pharmaceutically acceptable carrier.

The present invention also includes a method of combating or antagonistic actions against the risks associated with acute or permanent use of antiplatelet, anticoagulant, prophylactic agents, NSAID or selective inhibitors SOH-2, through the joint introduction of the decree of the aqueous agent UP736. The method consists in the introduction to the needy in the host an effective amount of a composition comprising a mixture of flavonoids with free In-cycle and flavanol in combination with the specified antiplatelet, anticoagulant, a prophylactic agent, or NSAID, and a pharmaceutically acceptable carrier.

Finally, the present invention includes methods to achieve additional and/or multiple clinical advantages through co-injection of antiplatelet, anticoagulant, prophylactic agents, NSAID and selective inhibitors SOH-2 in combination with UP736. As discussed below, UP736 is a strong antioxidant, which regulates the production of the messenger RNA NFκB and PPAR-γ, leading to specific down-regulation of TNFα, IL-1β, IL-6 and other proinflammatory cytokines at levels as gene expression and production of proteins. The method consists in the introduction to the needy in the host an effective amount of a composition comprising a mixture of flavonoids with free In-cycle and flavanol, synthesized and/or isolated from a single plant or multiple plants, in combination with antiplatelet, anticoagulant, a prophylactic agent, NSAID or selective inhibitor SOH-2 and a pharmaceutically acceptable carrier.

Flavonoids with free In-cycle, also known as Yes in the context of the flavones and flavonols with a free In-cycle, which can be used in accordance with the next invention, include the compounds illustrated in the following General formula:

in which

R1, R2, R3, R4and R5independently from each other selected from the group consisting of-H, -OH, -SH, OR, -SR, -NH2, -Other, -NR2, -NR3+X-carbon, oxygen, nitrogen or sulfur, glycoside of a single or combination of multiple sugars including, but without limitation, aldopentose, metalldetektor, hexoses, ketohexose and their chemical derivatives;

in which

R represents an alkyl group containing from 1 to 10 carbon atoms, and

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

Glavany, which can be used in accordance with the next invention, include the compounds illustrated in the following General formula:

in which

R1, R2, R3, R4and R5independently from each other selected from the group consisting of-H, -OH, -SH, -och3, -SCH3, -OR, -SR, -NH2, -NRH, -NR2, -NR3+X-, esters mentioned alternative groups, including names limitation, esters of gallate, acetate, cynnamoyl and hydroxycinnamic, trihydroxybenzoate esters and cafeology esters and their chemical derivatives; carbon, oxygen, nitrogen or sulfur, glycoside of a single or combination of multiple sugars including, but without limitation, aldopentose, metalldetektor, hexoses, ketohexose and their chemical derivatives, dimeric, trimeric and other cured glavany,

in which

R represents an alkyl group containing from 1 to 10 carbon atoms, and

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

Flavonoids with free In-cycle, presented in this invention can be obtained by the methods of synthesis and/or extracted from a plant or plants of the families of plants, including, but not limited to, Annonaceae, Asteraceae, Bignoniaceae, Combretaceae, Compositae, Euphorbiaceae, Lahiatae, Lanranceae, Leguminosae, Moraceae, few Pinaceae, Pteridaceae, Sinopteridaceae, Ulmaceae and Zingiberaceae. Flavonoids with free In-cycle can be extracted, concentrated and purified from the genera of higher plants, including, but not limited to, Desmos, Achyrocline, Oroxyhim, Buchenavia, Anaphalis, Cotula, Gnaphalium, Helichrysum, Centaurea, Eupatorium, Baccharis, Sapium, Scutellaria, Molsa, Colebrookea, Stachys, Origanum, Ziziphoa, Lindera, Actinodaphne, Acacia, Denis, Glycyrrhiza, Millettia, Pongamia, Tephrosia, Artocarpus, Ficus, Pityrogramma, Notholaena, Pinus, Ulmus and Alpinia.

Biologically active glavany presented in this invention can be obtained by the methods of synthesis and/or extracted from a plant or plants selected from the genus Acacia and/or Uncaria. In a preferred embodiment, the plant Acacia selected from the group including, but not limited to, A. 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 and A. mangium. In a preferred embodiment, the plant Uncaria selected from the group consisting of Uncaria gambir, U. lanosa, U. hirsute, U. africana, into U., U. orientalis, U. attenuate, U. acida, U. homomalla, U. sessilifructus, U. sterrophylla, U. bernaysii, U. sinensis, U. callophylla, U. rhychophylla, U. tomentosa and U. longiflora, U. hirsute, U. cordata and U. borneensis.

In a preferred embodiment, the flavonoids with free In-cycle extracted from plants or plants of the genus Scutellaria and floveny separated from the plant or plants of the genera Acacia and Uncaria.

As noted above, the ratio of flavonoids with free In-cycle to flavianum may lie in the range from about 99:1 of flavonoids with free In-cycle:flavanol to about 1:99 flavonoids with free In-cycle:flavanol. In specific embodiments, the implementation of the present invention, the ratio of flavonoids with free In-cycle to flavianum selected isgroup, consisting of approximately 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90. In a preferred embodiment of the invention, the ratio of flavonoids with free In-cycle:flavanol in the present compositions is about 85:15.

It should be borne in mind that as the preceding General description and the subsequent detailed description are only illustrative and explanatory and are not restrictive of the invention as it is claimed.

Brief description of drawings

In Fig. 1 shows a HPLC chromatogram standardized extract, isolated from the roots of S. baicalensis (party # RM052302-01)having a content of flavonoids with free In-cycle and 82.2%. As you can see in the drawing, when using HPLC/PDA/MC presents data on the following ten compounds: baicalin, wogonin-7-glucuronide, oroxylin And 7-glucuronide, norwegain-7-glucuronide, scutellarin, Netzer and oroxylin A.

Figure 2 presents the HPLC chromatogram of flavanol extracted from A. catechu with 80% Meon in the water.

In Fig. 3 graphically presents the bleeding time and the percentage increase in bleeding time in treatment groups relative to control media using the combined results from example 11 (n=9-10). The average bleeding time and the percentage increase in bleeding time in treatment groups relative to control what the media represent and analyze using t-student test. The prolonged bleeding time in the treatment groups is expressed as the percentage increase in bleeding time relative to control media.

In Fig. 4 graphically presents the results obtained in example 12. In this example, UP736 orally administered in a dose of 100 mg/kg or monocomponent or in combination with aspirin at a concentration of 3, 10 and 30 mg/kg to groups of 5 male mice obtained from ICR, weighing 22±2 g 1 hour before transfection in the end (0.3 mm) of the tail of each animal. In addition, mice similarly injected with aspirin monotherapy at a dose of 3, 10, 30 and 100 mg/kg Increase bleeding time by 50 percent or more (50%) compared to the control group of animals is considered significant.

A detailed description of the preferred embodiments

In this context, use different terms for consideration of aspects of the present invention. The following definitions are presented to assist in understanding the description of the components of the present invention.

It should be noted that the term "any" or "undefined" object refers to one or more of the data objects, such as the flavonoid refers to one or more flavonoids. In this case, the terms "any" or "uncertain", "one or more" and "at least one" in this context use the form interchangeably.

"Flavonoids with free In-cycle", as used in this context, constitute a specific class of flavonoids, which have no substitute groups on the aromatic B-cycle, as illustrated by the following General structure:

in which

R1, R2, R3, R4and R5independently from each other selected from the group consisting of-H, -OH, -SH, OR, -SR, -NH2, -Other, -NR2, -NR3+X-, carbon, oxygen, nitrogen or sulfur, glycoside of a single or combination of multiple sugars including, but without limitation, aldopentose, metalldetektor, hexoses, ketohexose and their chemical derivatives;

in which

R represents an alkyl group containing from 1 to 10 carbon atoms, and

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

"Glavany", as used in this context, pertain to a specific class of flavonoids, which can basically submit the following General structure:

in which

R1, R2, R3, R4and R5independently from each other selected from the group consisting of-H, -OH, -SH, -och3, -SCH3, -OR,-SR, -NH2, -NRH, -NR2, -NR3+X-, esters mentioned alternative groups, including, but not limited to, esters of gallate, acetate, cynnamoyl and hydroxycinnamic, trihydroxybenzoate esters and cafeology esters and their chemical derivatives; carbon, oxygen, nitrogen or sulfur, glycoside of a single or combination of multiple sugars including, but without limitation, aldopentose, metalldetektor, hexoses, ketohexose and their chemical derivatives, dimeric, trimeric and other cured glavany, in which

R represents an alkyl group containing from 1 to 10 carbon atoms, and

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

The term "therapeutic"as used in this context, includes the treatment and/or prevention. When using therapeutic refers to man and animals.

The term "pharmaceutically or therapeutically effective dose or amount" refers to the level of a dose sufficient to induce a desired biological result. This result may be the relief of signs, symptoms or causes of disease, or any other ISM is out of the biological system, want.

The term "placebo" refers to the replacement of pharmaceutically or therapeutically effective dose or quantitative dose sufficient to induce the desired biological response, which can ease the signs, symptoms or causes of disease, inactive substance.

"Owner" or "patient" is a living subject, human or animal, which enter the composition described in this context. Thus, the invention described in this context, can be used in veterinary medicine, but also in relation to the person, and the terms "patient" or "owner" should not be interpreted in a limiting way. In the case of veterinary applications, the spacing of the doses can be defined, as described below, whereas the body weight of the animal.

The term "gene expression" refers to transcription of a gene into mRNA.

The term "protein expression" refers to the translation of mRNA into protein.

The present invention relates, generally, to compositions obtained for use for the prevention and treatment of diseases and conditions related to platelet aggregation and induced platelet thrombosis. This song is called in this context UP736. The composition includes a single or a mixture of two specific classes of compounds - flavonoids with free In-cycle and flavanol.

ACCOR is osenia flavonoids with free In-cycle and flavanol in the composition can be brought on the basis of indicators and specific requirements regarding the prevention and treatment of a specific disease or condition. Mainly the relationship of flavonoids with free In-cycle and flavanol may lie in the range from about 99:1 of flavonoids with free In-cycle:flavanol to about 1:99 flavonoids with free In-cycle:flavanol. In specific embodiments, the implementation of the present invention, the ratio of flavonoids with free In-cycle to flavianum selected from the group consisting of approximately 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90. In a preferred embodiment of the invention, the ratio of flavonoids with free In-cycle to flavianum in the proposed composition of approximately 85:15.

In one embodiment, the present invention standardized extract of flavonoids with free In-cycle includes active compound purity 1-99% by weight of the total content of flavonoids with free In-cycle, as defined in examples 3, 4 and 8. Baicalin is the main active component in the extract, which is approximately 50-90% (by weight) of the total flavonoids from free-cycle. In a preferred embodiment, the standardized extract includes >70% of flavonoids with free In-cycle, of which >75% of flavonoids with free In-cycle is baicalin.

In one embodiment, the standardized extract of flavanol includes active is soedineniya purity 1-99% (by weight) of the total flavanol, as defined in examples 5, 6 and 7. Catechin is the main active component in the extract and is 50-90% by weight of the total flavanol. In a preferred embodiment, the standardized extract of flavanol includes >50% of the total flavanol in which >70% of flavanol is catechin.

In one embodiment, UP736 obtained by mixing or plant extracts, as described in detail above, or their synthetic equivalents ratio of from 99:1 to 1:99 (flavonoids with free In-cycle:floveny). The preferred ratio of flavonoids with free In-cycle to flavianum is 85:15 flavonoids with free In-cycle:flavanol as defined in example 9. The concentration of flavonoids with free In-cycle in UP736 may range from 1% to 99%, and the concentration of flavanol in UP736 can range from 99% to 1%. In a preferred embodiment of the invention the concentration of total flavonoids with free In-cycle in UP736 approximately 75% when the content of baicalin approximately 60% of the total mass UP736, and the concentration of total flavanol in UP736 is approximately 10% for catechin content of about 9%. In this embodiment, the total active ingredients (flavonoids with free In-cycle and floveny) in UP736 form >80% of the total mass.

This izobreteny which includes the evaluation of different compositions of flavonoids with free In-cycle and flavanol using enzymatic and in vivo models to optimize the composition and obtain the desired physiological activity. Currently, the applicant of the present invention not aware of any reports of drug, which includes a combination only of flavonoids with free In-cycle and flavanol as the main biologically active ingredients for the treatment of diseases and conditions. No substitution of one aromatic cycles flavonoid with a free In-cycle plays a very important role in ensuring the effectiveness of these compounds. Unlike other non-steroidal anti-inflammatory drugs (NSAID) and natural compounds flavonoids with free In-cycle, such as baicalin have aromatic cycle with low polarity on one side of the molecule and a highly polar glucuronide and two hydroxyl groups on the other side. This structural configuration allows data connections to be directed to tissues and cells. The combination of flavonoids with free In-cycle flavanone to obtain the presented composition, called in this context UP736, results in a synergistic and powerful modulator of ways as SOH and LOX eicosanoides system.

In this context, clearly demonstrated that the combination of flavonoids with free In-cycle and flavanol provides a more balanced modulation of enzymes MOR-1 and MOR-2. For example, aspirin, selective inhibitor of MOR-1, which is more che is 150 times of election in respect of MOR-1, causes gastrointestinal side effects. On the contrary, Vioxx, celebrex and Bextra, which are selective inhibitors SOH-2, with between 50 and 200 times greater activity against enzyme SOH-2, do not cause such a significant gastro-intestinal damage, however, the data polling against SOH-2 drugs increase the risks of cardiovascular events.

The profile of inhibition of MOR-1 and MOR-2 purified component of baculinum, which is isolated from S. baicalensis, shows almost two-fold selectivity for MOR-2 (determines that the IC50for MOR-1 is of 0.44 μg/ml/unit of enzyme, and the IC50for MOR-2, as determined, is to 0.28 μg/ml/unit). While the profile of inhibition of MOR-1 and MOR-2 presents the composition comprising more than 90% catechins isolated from A. catechu, is almost three times more selective in relation to MOR-1. For catechin IC50inhibition of MOR-1 calculated as of 0.11 μg/ml/unit of enzyme, and the IC50for MOR-2 count as of 0.42 μg/ml/unit

The combination of a mixture of flavonoids with free In-cycle, extracted from the roots of S. baicalensis, and flavanol, isolated from the bark of A. catechu in the ratio of 80:20 intended to receive presents compositions, hereinafter referred to UP736, provides a balanced selectivity MOR-1 regarding MOR-22:1. This drug, which provides a balance between the higher activity of baicalin against SOH-2 and higher activity of catechin against SOH-1, gives the optimal modulation path eicosanoids without gastrointestinal side effects associated with selective about MOR-1 NSAID, and risk of cardiovascular system associated with selective inhibitors SOH-2.

It is also important that the mechanism of action is completely different from currently available drugs and natural formula UP736. Aspirin, Vioxx, celebrex and bextra irreversibly bound to the enzyme through SOKH covalent bonds with the formation of closely related complexes of the enzyme-inhibitor. This dramatic interaction completely changes the active center of the enzyme and a side pocket and destroys the enzyme (see Walker et al. (2001) Biochem. 357:709-718). The flavonoids in UP736, on the other hand, inhibit the enzyme through SOKH weaker and reversible binding due to their antioxidant properties. In this interaction process is not irreversible changes in the structure and function of the enzyme SOKH, which results in superior to a large extent tolerability and safety profile UP736.

Inhibition of LOX activity extract flavonol isolated from A. catechu, ocenivaut using in vitro assays, aimed at screening lipoxygenase. Due to the addition of flavanol to flavonoids with free In-cycle UP736 inhibits the activity of 5-lipoxygenase (LOX). The LOX inhibition results in reduced accumulation of phagocytic leukotrienes, which are directly associated with symptoms of chronic inflammation, also reduces the potential gastrointestinal side effects. It is obvious that the combination of flavonoids with free In-cycle flavanone provides the additional benefit of significantly reducing the production of leukotrienes. This decrease production of leukotrienes is much higher than the conventional non-steroidal anti-inflammatory drugs such as ibuprofen, to increase activity and reduce side effects, discussed in the section on prior art.

The benefits of the drug, comprising a mixture of extracts of flavonoid with a free In-cycle and flavan also demonstrated in two animal studies, which showed that the new composition exhibits an unexpected synergistic effects. The composition used in these two studies, includes a mixture of flavonoids with free In-cycle, obtained from the extract of the seeds of Oroxylum indicum (10.0 g) (party # 040723)with the content of the flavonoid with a free In-cycle Chris is in 62,3%, and flavanol, isolated from an extract of the whole plant Urticaria gambir (40,0) (party # UG0407-050420) with the total catechin content of 32.5%. The combination of the two extracts in the mixing ratio of 80:20 is a drug called UP736 (50.0 g, batch #EXT-283-14-1). Extract individual flavonoid with a free In-cycle from the seeds of Oroxylum indicum, flavan extract from the whole plant Unicaria gambir and the combination of these extracts (UP736) administered orally in a dose of 100 mg/kg, using indomethacin as a control in a model of acute inflammation in animals, the Test ear swelling in mice. Suppression of ear swelling (suppression 50.8%) when using UP736 significantly higher than when the same dose of the individual components of 36.5% when using the extract of Uncaria gambir and 31,7% when using extract of Oroxylum indicum, respectively.

In another analysis of in vivo suppression of ear swelling in mice caused by arachidonic acid, also see synergistic effects when using the drug, called UP736-K, which was mixed in a ratio of 9:1 extract flavonoid with a free In-cycle from the roots of S. baicalensis, including 25% baicalin, and 40% extract catechin from the whole plant Uncaria gambir. UP736-K includes 24% of baicalin and 4% catechins. Extract individual flavonoid with a free In-cycle from the roots of S. baicalensis, flavan extract from the whole plant Unicaria gambir and it is minciu data extracts (UP736-K) administered orally in a dose of 100 mg/kg, using indomethacin as a control. UP736-K demonstrates a statistically significant improvement in reducing swelling on each of the individual extracts.

In addition, due to the different biological availability, i.e. the speed and the percentage of biologically active compounds, penetrating through the membrane of epithelial cells, and local concentrations of biologically active compounds, a combination of two different types of compounds (flavanol with higher polarity relative to the flavonoids with free In-cycle with a lower polarity) gives as a fast local suppression of COX/LOX biologically active flavanone in conjunction with a more long lasting modulation path COX/LOX physiologically active flavonoids with free In-cycle. For flavonoids with free In-cycle in UP736 need about two hours after oral administration to achieve effective concentrations. However, serum concentrations of flavonoids with free In-cycle will remain above therapeutic levels for about 10 hours after oral administration. To compensate for the lack of a quick bioavailability of flavonoids with free In-cycle drug flavanol type of catechin gives complementary advantage. The investigation of bioavailability of catechins, quercetin and epigallocatechin-3-ha is the lats (see article Kao et al. (2000) Endocrinology 1410): 980-987; Koga and Meydani (2001) Am. J. Clin. Nutr. 73:941-948; Lee et al. (2002) Cancer Epidemiol. Biomarker Prevention 11:1025-1032) show that Cmaxand Tmaxcatechin appears quickly (approximately 45 minutes), and the period of existence is, as reported, 2 hours. Consequently, by combining flavonoids with free In-cycle flavanone, quickly penetrating catechins, achieve effective serum concentrations within about 0.5 hours after oral administration. When the concentration of catechin falls, the second active component, flavonoids with free In-cycle, reach bioactive concentrations that will last up to 12 hours after oral administration. In conclusion, developing the drug UP736, which has a fast local effects of COX/LOX due flavanone, such as catechin, and more long-term effects caused by flavonoids with free In-cycle, such as baicalin. Data is synergistic and complementary effects will also be implemented through local delivery structure.

Finally, in the preferred embodiment, the drug that has significant amounts of flavonoids with free In-cycle (80% by weight) at a relatively lower concentration of flavanol (20 mass%), a stronger antioxidant glavany will be abott as natural preservatives against oxidative destruction of flavonoids with free In-cycle and to neutralize and tebufelone composition, delivering the main active components of flavonoids with free In-cycle - at the optimum pH and ionization conditions. Catechin includes four phenolic hydroxyl groups, which make the connection more acidic and sensitive to oxidative stress. Extremely high capacity for the absorption of oxygen radicals (ORAC at 20000) catechin demonstrates its antioxidant properties. Based on the stress test of pure catechin in various conditions, such as pH, the existence of H2About2and metal ions, determine (not shown)that catechin stable and neutral conditions at 4°C and at 40°C, but not in the basic conditions or under the influence of metal ions, such as Fe3+. Catechin is decomposed even in slightly alkaline conditions (pH=7,5). However, it can be saved with the help of a number of preservatives, including but not limited to, tin chloride (SnCl2), sodium bisulfate/metabisulfite (SBS) and other preservatives.

In the present invention include a composition comprising a mixture of at least one flavonoid with a free In-cycle, at least one flavan and at least one agent selected from the group consisting of injectable anticoagulant agent is selected from the group including, but without limiting arecoline, heparin, dalteparin, enoxaparin and Tinzaparin; oral anticoagulation agent selected from the group including, but not limited to, warfarin, vitamin K antagonists and inhibitors of the reductase vitamin K; antiplatelet agent selected from the group including, but not limited to, aspirin, clopidogrel and dipyridamole; drug against angina selected from the group including, but not limited to, nitrates, β-blockers, blockers of calcium, inhibitors of the angiotensin converting enzyme activators potassium channels; non-steroidal anti-inflammatory drug (NSAID)selected from the group including, but not limited to, acetaminophen, ibuprofen, naproxen, diclofenac, salicylates and indomethacin, or a selective inhibitor SOH-2, selected from the group including, but not limited to, rofecoksib, celecoxib, etodolac and meloxicam.

The present invention further includes methods of treating and preventing diseases and conditions associated with platelet aggregation and induced platelet thrombosis. Thrombosis is an unwanted blood clots that can be venous or arterial. UP736 can be used as antidromically, protivosvertavath the speaker and prophylactic agent for the prevention and treatment of the aforementioned diseases and conditions. The method consists in the introduction to the needy in the host an effective amount of a composition comprising a mixture of flavonoids with free In-cycle and flavanol, synthesized and/or isolated from a single plant or multiple plants.

Diseases and conditions associated with platelet aggregation and induced platelet thrombosis, which can be prevented and treated according to the method presented in this invention include, but are not limited to, deep vein thrombosis, pulmonary embolism, atherosclerosis, myocardial infarction, thrombosis of cerebral vessels and/or embolism of cerebral vessels, leading to cerebrovascular events, thrombosis of peripheral circulation and/or microcirculation, leading to ischemia and infarction, atrial fibrillation, which is associated with stasis of blood and the formation of clots in the left atrium, thrombogenic centers, including artificial implants, such as mechanical heart valves, defibrillators, surgical implants for drug delivery, and artificial hip joints and other exogenous bodies.

The present invention further includes methods of application UP736 adjuvant, and/or synergistic, and/or potentiating agent, which consist in the introduction to the needy in this master EF is an objective quantity presents the composition, comprising a mixture of at least one flavonoid with a free In-cycle, at least one flavan and at least one agent selected from the group consisting of injectable anticoagulant agent, an oral anticoagulant agent, an antiplatelet agent, the agent against angina, non-steroidal anti-inflammatory drug (NSAID) or a selective inhibitor SOH-2. Examples of injectable anticoagulant agents include, but are not limited to, heparin, dalteparin, enoxaparin and Tinzaparin. Examples of oral anticoagulation agents include, but are not limited to, warfarin, vitamin K antagonists and inhibitors of the reductase vitamin K. Examples of antiplatelet agents include, but are not limited to, aspirin, clopidogrel and dipyridamole. Examples of medication for angina include, but are not limited to, nitrates, β-blockers, blockers of calcium, inhibitors of the angiotensin converting enzyme activators potassium channels. Nonsteroidal anti-inflammatory drugs (NSAID) include, but are not limited to, acetaminophen, ibuprofen, naproxen, diclofenac, salicylates and indomethacin. Finally, examples of selective inhibitors SOH-2 include,but are not limited to, rofecoksib, celecoxib, etodolac and meloxicam.

The present invention also includes a method of reducing the standard dose of antiplatelet, anticoagulant, prophylactic agents, NSAID and selective inhibitors SOH-2 to achieve either equal to, or superior clinical outcome. The method consists in the introduction to the needy in the host an effective amount of a composition comprising a mixture of at least one flavonoid with a free In-cycle and at least one flavan or synthesized and/or isolated from a single plant or multiple plants, and a pharmaceutically acceptable carrier in combination with the specified antiplatelet, anticoagulant, a prophylactic agent, NSAID or selective inhibitor SOH-2.

UP736 is a natural product isolated from the two traditional plants, which include antioxidants and other natural food compounds that support the body in different ways. UP736 is not selective inhibitor SOH-2, but he 2.25 times more selective in relation to MOR-1 compared with MOR-2 and, in addition, really inhibits 5-lipoxygenase (LOX), which regulates the path that leads to the formation of many of vasodilating and chemotactic leukotrienes. Natural inhibitory activity of the UP736 against SOH-2, as judged by enzyme inhibition, approximately 50-400 times less effective than highly selective against SOH-2 drugs by rofecoksib and celecoxib, as shown in the table. 1.

Table 1.
Activity UP736 against SOH-2 in comparison with the known inhibitors SOH-2
ConnectionThe selectivity in respect of the SOH-2 compared to MOR-1
Rofecoksib250
Celecoxib30
Licofelone1
UP7360,44
Indometacin0,016
Aspirin0,006

UP736 is a strong antioxidant, which naturally regulates the formation of the RNA NFκB and PPAR-γ, resulting in the specific down-regulation of TNFα, IL-1β, IL-6 and other proinflammatory cytokines at levels as gene expression and production of proteins.

The present invention further is clucalc composition and method of application UP736 adjuvant, and/or synergistic, and/or potentiating agent in combination with at least one non-steroidal anti-inflammatory drug (NSAID), including, but not limited to, acetaminophen, ibuprofen, naproxen, diclofenac, salicylates, indomethacin, and at least one selective inhibitors SOH-2, including, but not limited to, rofecoksib, celecoxib, etodolac and meloxicam. This composition and method reduce the dose of NSAID required to achieve either equal to, or superior clinical outcome, resulting in reduction of side effects associated with acute or regular use of NSAID, and opposition or antagonistic action against the risks of acute or persistent use of NSAID. This method is also a means of achieving additional and/or multiple clinical advantages, due to the specific down-regulation of TNFα, IL-1β, IL-6 and other proinflammatory cytokines as described above.

The present invention also includes a composition and method of reducing or eliminating side effects associated with acute or permanent use of antiplatelet, anticoagulant, prophylactic agents, NSAID and selective inhibitors SOH-2, through the introduction of a specified agent in the combination is UP736. The method consists in the introduction to the needy in the host an effective amount of a composition comprising a mixture of flavonoids with free In-cycle and flavanol, synthesized and/or isolated from a single plant or multiple plants, in combination with the specified antiplatelet, anticoagulant, a prophylactic agent, NSAID or selective inhibitor SOH-2 and a pharmaceutically acceptable carrier.

The present invention also includes a method of combating or antagonistic actions against the risks associated with acute or permanent use of antiplatelet, anticoagulant, prophylactic agents, NSAID or selective inhibitors SOH-2, through the joint introduction of the specified agent UP736. The method consists in the introduction to the needy in the host an effective amount of a composition comprising a mixture of flavonoids with free In-cycle and flavanol, synthesized and/or isolated from a single plant or multiple plants, in combination with the specified antiplatelet, anticoagulant, a prophylactic agent, or NSAID, and a pharmaceutically acceptable carrier.

Finally, the present invention includes methods to achieve additional and/or multiple clinical advantages through co-injection of antiplatelet about epowermanager, preventive agents, NSAID and selective inhibitors SOH-2 in combination with UP736. As noted above, UP736 is a strong antioxidant, which regulates the production of the messenger RNA NFκB and PPAR-γ, leading to specific down-regulation of TNFα, IL-1β, IL-6 and other proinflammatory cytokines at levels as gene expression and production of proteins. The method consists in the introduction to the needy in the host an effective amount of a composition comprising a mixture of flavonoids with free In-cycle and flavanol, synthesized and/or isolated from a single plant or multiple plants, in combination with antiplatelet, anticoagulant, a prophylactic agent, NSAID or selective inhibitor SOH-2 and a pharmaceutically acceptable carrier.

The present invention is directed to therapeutic compositions comprising therapeutic agents described in this invention. Therapeutic agents presented in this invention, can be entered by any suitable means, including parenteral, outdoor, oral or local injection, such as intradermal, by injection or spray. The specific route of administration will depend on the condition being treated. Assume that the introduction of agents in the present invention, it is possible ASU is actvity through the liquid body or any target or any tissue available for the passage through it of the body. In a preferred embodiment of the invention, the agent is administered in an oral dose. This delivery can be done locally in any affected area. therapeutic composition can be introduced in several standardized dosage forms depending on the method of introduction. For example, standardized dosage forms suitable for oral administration to an animal, include powder, tablets, pills and capsules. Preferred methods of delivery of therapeutic compositions presented in the present invention include intravenous and local injection, for example by injection or local administration. Therapeutic reagent in the present invention, there may be any animal, preferably mammalian and more preferably human.

For specific delivery of therapeutic composition in the present invention can be obtained so that it included other components such as pharmaceutically acceptable excipient, adjuvant and/or carrier. For example, the compositions presented in the present invention, can be obtained in the filler, which can carry an animal, which is supposed to treat. Examples of fillers include, but are without the exhaust gas is anichini listed, cellulose, silicon dioxide, dextrans, sucrose, starch glycolate, sodium, calcium phosphate, calcium sulfate, water, saline, ringer's solution, dextrose, mannitol, solution, Henk and other aqueous physiologically balanced salt solutions. You can also use non-aqueous media, such as fatty oils, sesame oil, etiloleat or triglycerides. Other effective drugs include suspension containing agents that increase viscosity, such as carboxymethylcellulose sodium, sorbitol, or dextran. Fillers may also include a minimum number of additives such as substances that enhance isotonicity and chemical stability. Examples of buffers include phosphate buffer, bicarbonate buffer, Tris buffer, histidine, citrate, and glycine or mixtures thereof, while examples of preservatives include thimerosal, m - or o-cresol, formalin and benzyl alcohol. Standard drugs can be either liquid injection, or solid, which can be introduced into a suitable liquid in the form of a suspension or solution for injection. Thus in non-liquid product, the filler can include dextrose, human serum albumin, preservatives, etc. that before the introduction of add sterile water or saline solution.

In one embodiment of the present invention to notice may also include adjuvant or carrier. Adjuvants, as a rule, are substances that basically enhance the effect of the drug in the prevention and treatment of indications associated with paths SOKH and LOX. Suitable adjuvants include, but are not limited to, beta-blockers, other components of the bacterial cell wall, salt, albumin, calcium salts, alum; Bor, histidine, glucosinolate, chondroitin sulfate, copper gluconate, polynucleotide, vitamin D, vitamin K, toxoid, shark cartilage and bovine serum proteins, viral envelope proteins, other bacterial preparations, γ-interferon, adjuvants based on block copolymers, such as adjuvant hunter (Vaxcel™, Inc. Norcross, Ga.); adjuvants, Ribi (available in the firm ImmunoChern Research, Inc., Hamilton, Mont.) and saponins and their derivatives, such as Quil A (available in the company Superfos Biosector A/S, Denmark). The media, as a rule, are compounds that increase the half-period of the existence of therapeutic composition in the animal body that is treated. Suitable carrier materials include, but are not limited to, polymeric drugs controlled release, biodegradable implants, liposomes, bacteria, viruses, oils, esters and glycols.

One variant of implementation of the present invention is a drug controlled release, which ways the Yong slow release of the composition, in the present invention, in the body of the animal. As used in this context, the drug controlled release composition includes, in the present invention, the carrier of controlled release. Suitable carrier materials with controlled release include, but are not limited to, biocompatible polymers, other polymeric matrices, capsules, microcapsules, bolus preparations, osmotic pumps, diffusion devices, liposomes, liposphere and percutaneous delivering system. Other drugs controlled release, presented in this invention include liquids that, when the introduction of the animal form a solid or a gel in situ. Preferred drugs controlled release are biorazlagaemykh (i.e. biodegradable).

After the production of therapeutic composition can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or digidratirovannogo or lyophilized powder or directly encapsulated and/or tablets with other inert carriers for oral administration. These drugs can be stored in a form ready for use or needs repair just before the introduction. The introduction paragraph is aparatow, includes compositions for systemic delivery may be oral, subcutaneous, intramuscular, intravenous, intranasal or vaginal or using the rectal suppository.

The amount of a composition which will be effective in the treatment of specific disorders or condition will depend on the nature of the violation or condition, which can be set to standard clinical methods. In addition, in vitro or in vivo optional can be used as an auxiliary when determining optimal spacing of doses. The exact dose intended for the use of the drug, will also depend on the route of administration and the severity or extent of the disease or condition, and should be determined in accordance with the opinion of the attending physician and the situation for each patient. Effective doses may be extrapolated on the basis of the curves dose-response obtained in test systems in vitro or in animal models. For example, the effective amount of the composition can easily be determined by introducing a graded doses of the composition and monitoring of the desired effect.

The treatment method proposed in this invention, includes an inner or outer introduction to the needy in this patient a therapeutically effective amount of a composition comprising a mixture of flavonoids with free In-qi is scrap and flavanol or a mixture of at least one flavonoid with a free In-cycle, one flavan and one agent selected from the group consisting of injectable anticoagulant agent, an oral anticoagulant agent, an antiplatelet agent, a medicinal product against angina, non-steroidal anti-inflammatory drug (NSAID) or a selective inhibitor SOH-2. The purity of the mixture includes, but is not limited to, 0.01 to 100%, depending on the method of obtaining the compound(s). In a preferred embodiment, the dose of a mixture of flavonoids with free In-cycle and flavanol containing pharmaceutical compositions are effective, nontoxic quantity generally selected interval of 0.01-200 mg/kg of body weight. Competent specialists in this field, using routine clinical testing that can determine the optimal dose for a particular disease that can be cured.

Common method of extraction described in Example 1. The extraction process ensures the obtaining of organic and aqueous extract for each of the studied species. The results of extraction of various kinds of lead in table 2. For effective identification of active compounds from plant extracts using the method efficient fractionation as described in example 2. Briefly, the active organic the Chia and water extracts fractionary, using two different methods, respectively. Fractions are collected in 96-well tablets with deep holes. Then each of the fractions are tested for biological activity.

Separation, purification and identification of active flavonoids with free In-cycle present in the organic extract of Scutellaria orthocalyx described in example 3. With reference to figure 1 shows ten connections, and baicalin identified as the main active component.

In example 4 and table 3 give the content and number of flavonoids with free In-cycle in five active plant extracts from three different plant species. Flavonoids with free In-cycle are present in much greater quantities in organic extracts compared to water extracts.

Separation, purification and identification of active constituents present in the organic extract of Acacia catechu described in example 5. Using the method described in example 5, catechin and epicatechin identify two of the main active compound in an organic extract from the roots of Acacia catechu, having values IC505-7 µg/ml quantification using HPLC active extracts from Acacia catechu and Urticaria gambit described in example 6. The results are shown in table 4, which shows that the content of flavanol in organic and aqueous extracts of A. catechu, as the definition is collected using HPLC, is 30.4% and 1.0%, respectively. Example 7 describes a General method of obtaining a standardized extract of Acacia. In this example, glavany of A. catechu extracted with different solvent system. The results in table 5. The improved method proposed in this invention, includes: extraction of the crushed biomass plants containing glavany, organic solvent or combination of organic solvent(s) and/or water; neutralization and concentration of the neutralized extract and purification of the extract by recrystallization and/or chromatography. From table 5 we can see that 80% methanol in water is one of the most preferred solvents for the extraction of flavanol from plants Acacia. As shown above, these glavany can be isolated from plants of the genera Acacia and Urticaria. The method presented in this invention can be extended to the selection of these compounds from any plant source including connection information.

Example 8 describes a General method of obtaining a standardized extract from various species of Scutellaria. In example 8 flavonoids with free In-cycle of two species of Scutellaria extracted with different solvent system. The results in table 6 and 7. The method presented in this invention, includes the extraction ismelin the th biomass plants, contains flavonoids with free In-cycle, one or a combination of the organic solvent(s) and/or water; neutralization and concentration of the neutralized extract and purification of the extract by recrystallization and/or chromatography. As shown above, these flavonoids with free In-cycle can be distinguished from the genera more than twenty families of plants. The method presented in this invention can be extended to the selection of these compounds from any plant source including connection information.

Example 9 describes a General method of obtaining a composition UP736, which includes a proprietary blend of two standardized extracts containing flavonoids with free In-cycle and floveny respectively. In the General method shown in example 9, the composition of gain, using two standardized extract isolated from Acacia and Scutellaria, respectively, together with fillers or without them. The extract of Acacia, used in example 9, includes >60% of the total flavanol, such as catechol and epicatechin, and an extract of Scutellaria includes >70% of flavonoids with free In-cycle, the main of which is baicalin. Extract of Scutellaria includes other minor quantities of flavonoids with free In-cycle, as shown in table 8. One or more optional fillers added to presented the military composition. The amount of added filler can be made on the basis of the actual content of each required ingredient in the active form. Table mix for each batch of product must be created on the basis of the description of the product and QC results for separate batches of ingredients. Recommended the introduction of additional quantities of the active ingredients in the range of 2-5% to match the product description. Example 9 illustrates a table of mixing, which is designed for one party UP736 (party #G1702). Get a different ratio mixtures of cooked product UP736 tested for biological activity.

Example 10 demonstrates a synergistic effect, which has a composition that includes a mixture of UP736 and aspirin in respect of platelet aggregation caused by arachidonic acid. The results are shown in table and 10, which show that, although UP736 as monocomponent has low antiaggregatory activity at concentrations of 10 μm, antiaggregatory effect of aspirin significantly increased at such low doses UP736 how to 0.007 μm.

The lower dose of aspirin could theoretically reduce the risk of complications associated with bleeding. However, a very low dose of aspirin may be effective in the treatment or prevention of a number of diseases and conditions. For example the EP, for long-term treatment of acute myocardial infarction effect of doses less than 75 mg per day is not expressed (see Hennekens (2002) Am j Manag. Care 8(22 Suppl):S691-700). In addition, patients who do not respond to low-dose aspirin appears resistant to aspirin (see Patrono (2005) Thromb. Haemost. S: 1597-602). The present invention solves the problem by using UP736 for potentiation activity against platelet aggregation, largely associated with low doses of aspirin.

Example 11 illustrates that UP736 as monocomponent and in combination with aspirin has little effect on bleeding time. The results are shown in table-14.

Note that throughout this application describes the various links. Each material specifically included in this context in its entirety by reference.

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

Examples

The following examples are provided only for illustrative purposes and do not allow the limitation of the scope of the invention.

Example 1. Obtaining organic and aqueous extracts from the plant Acacia, Uncaria and Scutellaria

Plant material the bark of Acacia catechu (L.) WMd., the aerial parts of Uncaria hirsute, above-ground parts of Uncaria sinensis, the bark of Uncaria tomentosa roots of Scutellaria orthocalyx, the roots of Scutellaria baicaensis or the whole plant of Scutellaria lateriflora milled to obtain a particle size of not more than 2 mm. Then the dried powdered plant material (60 g) is transferred into a flask of Erlenmeyer and add methanol:dichloromethane (1:1) (600 ml). The mixture is shaken for one hour, filtered and the biomass is again extracted with a mixture of methanol:dichloromethane (1:1) (600 ml). The organic extracts are combined and evaporated under vacuum to obtain an organic extract (see table 2 below). After organic extraction biomass air-dried and extracted once with ultrapure water (600 ml). The aqueous solution is filtered and lyophilizers, receiving aqueous extract (see table 2 below).

Table 2.
The output of organic and aqueous extracts of Acacia species, Uncaria and Scutellaria
Vegetable sourceNumberThe organic extractAqueous extract
Acacia catechu, bark60 g27,2 g10.8 g
Scutellaria orthocalyx, roots60 gAndroid 4.04 gof 8.95 g
Scutellaria baicalensis roots60g 9,18 g7,18 g
Scutellaria lateriflora (whole plant)60 g6,54 g4,08
Uncaria hirsute, aerial parts60 g2,41 g0,90 g
Uncaria sinensis, aerial parts60 g3.94 g1,81 g
Uncaria tomentosa bark60 g6,47 g2,31 g

Example 2. STD-fractionation of active extracts

The organic extract (400 mg) of active plants load on pre-Packed rapid column (2 cm ID×8.2 cm, 10 g of silica gel). Column elute using a highly efficient cleaning system (STD) Hitachi with a gradient mobile phase of (a) 50:50 EtOAc:hexane and (B) methanol from 100% a And 100% b for 30 minutes at a flow rate of 5 ml/min. Separation monitorium using UV detector broadband waves, and fractions are collected in a 96-well plate with a deep hole in 1.9 ml/well, using the collector fractions of Gilson. Tablet for samples dried under low vacuum and centrifugation. DMSO (dimetilformamid) (1.5 ml) is used for dilution of samples in each cell and a portion (100 μl) are taken for biological analysis of inhibition.

Aqueous extract (750 mg) of active plants is dissolved in water (5 ml), filtered through a syringe filter 1 micron and transferred into a container with a volume of 4 ml for liquid chromatography high pressure (HPLC). Then the solution is injected into the automatic sampler on pre-Packed reversed-phase column (C-18, particle size 15 μm, 2.5 cm ID×10 cm using insert). Column elute using a highly efficient cleaning system (NTR) with a gradient mobile phase of (a) water and (B) methanol from 100% a And 100% b for 20 min, followed by 100% methanol for 5 minutes at a flow rate of 10 ml/min. Separation monitorium using UV detector broadband waves, and fractions are collected in a 96-well plate with a deep hole in 1.9 ml/well, using the collector fractions of Gilson. Tablet for samples lyophilizer. Ultrapure water (1.5 ml) is used for dilution of samples in each cell and a portion (100 μl) are taken for biological analysis of inhibition.

Example 3. Isolation and purification of active flavonoids with free In-cycle of the organic extract of Scutellaria

The organic extract (5 g) from the roots of Scutellaria orthocalyx allocated as described in example 1, the load on the pre-Packed rapid column (120 g silica gel, 40 micron particle size 32-69 μm, 25 cm ID×4 cm, 10 g of silica gel and elute using gradi the HT mobile phase (A) 50:50 EtOAc:hexane and (B) methanol from 100% And 100% In for 60 minutes at a flow rate of 15 ml/min Fractions are collected in a test tube (10 ml/fraction. The solvent is evaporated under vacuum and the sample in each fraction was dissolved in 1 ml DMSO and an aliquot of 20 μl is transferred to a 96-well plate with small holes and tested for biological activity (data not shown). Based on the results of biological analysis, active fraction #31-#39 combined and evaporated. Analysis by HPLC/PDA and LC/MS provides the primary connection with the retention time of 8.9 minutes and MC-peak at 272 m/E. the Product is further purified on prepreparation C18 column (25 cm×1 cm) and a gradient mobile phase of (a) water and (C) methanol for 45 minutes at a flow rate of 5 ml/minute. Collect 88 factions, gaining 5.6 mg solid light yellow color. The purity was determined by HPLC/PDA and LC/MS and comparison with standards and data NMR spectroscopy. Data1H NMR: δ ppm (DMSO-d6) 8,088 (2H, m, H-3',5'), 7,577 (3H, m, H-2',4',6'), 6,932 (1H, s, H-8), 6,613 (1H, s, H-3). MS: [M+1]+= 271 m/E. the Connection identify as baicalein.

Using chromatography on a preparative column (C-18 isolate and identify other flavonoids with free In-cycle when using standardized extract, isolated from the roots of Scutellaria baicalensis (party # RM052302-01)having a content of flavonoids with free In-cycle and 82.2%. Using HPLC/PDA/MC represent eleven structures as produced by lusterous in figure 1. With reference to figure 1 eleven identified compounds are baicalin, wogonin-7-glucuronide, oroxylin And 7-glucuronide, baicalein, wogonin, Christine-7-glucuronide, 5-methyl-wogonin-7-glucuronide, scullery, norwegain, Christine and oroxylin A.

Example 4. Quantification HPLC flavonoids with free In-loop in the active extracts isolated from Scutellaria orthocalyx (root), Scutellaria baicalensis (root) and Oroxylum indicum (seeds)

Confirm the presence and quantity of flavonoids with free In-cycle in five active extracts obtained from three different plant species, and lead the data in the table. 3. Flavonoids with free In-cycle is subjected to quantitative analysis using HPLC, using a column Luna C-18 (250×4.5 mm, 5 μm) using 1% phosphoric acid and a gradient of acetonitrile from 80% to 20% within 22 minutes. Flavonoids with free In-cycle determines when using a UV detector at a wavelength of 254 nm and identified based on retention time by comparison with standards of flavonoids with free In-cycle.

Table 3.
The content of flavonoids with free In-loop in the active plant extracts
Active extracts Mass extract%extracted from biomassThe total number of flavonoids with free In-cycle% flavonoids with free In-cycle extract
Scutellaria orthocalyx (aqueous extract)of 8.95 g14,9%0.2 mg0,6%
S. orthocalyx (organic
extract)
3,43 g5,7%1,95 mg6,4%
S. baicalensis (water
extract)
7,18 g12,0%0.03 mg0,07%
S. baicalensis (organic extract)9,18 g15,3%20,3 mg35,5%
Oroxylum indicum (organic
extract)
to 6.58 g11,0%0.4 mg2,2%

Example 5. Isolation and purification of active compounds from the organic extract of Acacia catechu

The organic extract (5 g) from the roots of A. catehu, allocated as described in example 1, the load on the pre-Packed column for the Express chromatography (120 g silica, 40 μm particle size 32-60 μm, 25 cm×4 cm) and elute with a gradient mobile phase of (a) 50:50 EtOAc:hexane and (B) methanol from 100% a to 100% b for 60 minutes at a flow rate of 15 ml/min Fractions collected from the test tube (10 ml/fraction. The solvent is evaporated under vacuum and the sample from each fraction was dissolved in DMSO (1 ml) and an aliquot of 20 μl is transferred to a 96-well plate with small holes and tested for biological activity (data not lead). Based on the results of biological analysis, active fraction #32-#41 are combined and evaporated, obtaining 2.6 g of a solid substance. Analysis of the HPLC/PDA and LC/MS showed the two main compounds with retention time of 15.8 and 16.1 minutes respectively. The product is further purified on prepreparation C18 column (25 cm×1 cm), which load 212,4 mg product and elute with a gradient mobile phase of (a) water and (B) acetonitrile (ACN) for 60 minutes at a flow rate of 5 ml/minute. Collect 88 factions and there are two active connections, connection 1 in (11.5 mg) and compound 2 (16.6 mg). Purity is determined by comparing the data of HPLC/PDA LC/MS standards (catechin and epicatechin) and according to NMR spectroscopy.

Connection 1. Data13With NMR: δ ppm (DMSO-d6) of 27.84 (C4), 66,27 (C3, 80,96 (C2), 93,78 (C9), 95,05 (C7), To 99.00 (C5), 114,48 (C12), 115,01 (C15), 118,36 (C16), 130,55 (C11), 144,79 (C14), 155,31 (C6), 156,12 (C10), 156,41 (C8). Data1H NMR: δ ppm (DMSO-d6) 9,150 (1H, s, OH), 8,911 (1H, s, OH), 8,835 (1H, s, OH), 8,788 (1H, s, OH), 6,706 (1H, d, J=2 Hz, H2'), 6,670 (1H, d, J=8.0 Hz, H-6'), 6,578 (1H, dd, J=2, 8 Hz, H-5'), 5,873 (1H, d, J=2 Hz, H8), 5,670 (1H, d, J=2 Hz, h6), 4,839 (1H, d, J=4 Hz, HE), 4,461 (1H, d, J=7,3 Hz, H2)3,798 (1H, m, H3), 2,625 (1H, m, H4b), 2,490 (1H, m, Na), MS: [M+1]+= 291 m/E. This compound identified as catechin.

Compound 2. Data13With NMR: δ ppm (DMSO-d6) 28,17 (C4), 64,87 (C3), 78,02 (C2), 94,03 (C9), 95,02 (C7), 98,44 (C5), 114,70 (C12), 114,85 (C15), 117,90 (C16), 130,56 (C11), 144,39 (C14), 155,72 (C6), 156,19 (C10), 156,48 (C8). Data1H NMR: δ ppm (DMSO-d6) 9,083 (1H, s, OH), 8,873 (1H, s, OH), 8,777 (1H, s, OH), 8,694 (1H, s, OH), 6,876 (1H, d, 3=2 Hz, H2'), 6,646 (2H, s, H-5', G)5,876 (1H, d, J =2 Hz, H8), 5,700 (1H, d, J =2 Hz, h6), 4,718 (1H, s, OH), 4,640 (1H, d, J=4.5 Hz, H2)3,987 (1H, d, J=4.5 Hz, H3), 2,663 (1H, dd, J=4,6, and 6.3 Hz, H4b), 2,463 (1H, dd, J=4,6, and 6.3 Hz, H4a), MS: [M+1]+= 291 m/e. This connection is identified as epicatechin.

Example 6. Quantification using HPLC active extracts from Acacia catechu and Unicaria gambir

The content of flavanol in organic and aqueous extracts obtained from the core wood of Acacia catechu, quantitatively determined by HPLC, using a detector PhotoDiode Array (HPLC/PDA) and column Luna C18 (250 mm×4.6 mm). Glavany elute from the column using a gradient of acetonitrile from 10% to 30% atsn for 20 min, then 60% atsn for the of five minutes. The results in table 4. Profile cleanup HPLC is shown in figure 2. Glavany quantitatively determined on the basis of retention time and PDA data when using catechol and epicatechin as standard. The retention time for two main flavanol is of 12.73 minutes and 15,76 minutes respectively.

Table 4.
The content of flavanol in active plant extracts
Active extracts from the core wood of Acacia catechuMass extract%extracted from biomass% flavonol extract
Aqueous extract10.8 g18,0%is 0.998%
The organic extract27,2 g45,3%30.37 per cent

The content of flavanol in a standardized extract (batch #UG0407-050420), isolated from the whole plants Urticaria gambir, quantitatively determined by HPLC, using a detector PhotoDiode Array (HPLC/PDA) and column Luna C18 (250 mm×4.6 mm). Glavany elute from the column using a gradient of acetonitrile from 10% to 30% of the TSN for 20 min, and then 60% atsn within five minutes. Glavany quantitatively determined on the basis of retention time and PDA data when using catechin as standard 28,6% catechin and 3.9% epicatechin.

Example 7. Obtaining a standardized extract of Acacia catechu

Acacia catechu (500 mg shredded bark) with the following solvent system: (1) 100% water, (2) 80:20 water: methanol, (3) 60:40 water:methanol, (4) 40:60 water:methanol, (5) 20:80 water:methanol, (6) 100% methanol, (7) 80:20 methanol:THF (tetrahydrofuran), (8) 60:40 methanol:THF. The extracts are concentrated and dried under low vacuum. Identification of chemical components in each extract carry out HPLC using detector PhotoDiode Array (HPLC/PDA) and C18 column 250 mm×4,6 mm Chemical components quantitatively determined on the basis of retention time and PDA data when using catechin and epicatechin as standard. The results in table 5. As shown in table 5, the extract flavanol obtained from the extract solvents using 80% methanol/water gives the highest concentration flavanoid components.

Table 5.
The solvents to obtain standardized flavanoid extracts from Acacia catechu
The solvent for
extraction
Weight
extract
%extractable
biomass
General
number
catechins
% catechins in the extract
100% of the water292,8 mg58,56%13 mg12,02%
Water:methanol (80:20)282,9 mg56,58%13 mg11,19%
Water:methanol (60:40)287,6 mg57,52%15 mg13,54%
Water:methanol (40:60)264,8 mg52,96%19 mg13,70%
Water:methanol (20:80)222,8 mg44,56%15 mg14,83%
100% methanol215,0 mg43,00%15 mgof 12.73%
Methanol:THF (80:20)264,4 mg52,88%11 mg8,81%
Methanol:TTF (60:40)259,9 mg51,98%15 mg9,05%

Example 8. Obtaining standardized extracts of flavonoids with free In-cycle of Scutellaria species

Scutellaria orthocalyx (500 mg crushed roots) twice extracted with 25 ml of the following solvent systems: (1) 100% water, (2) 80:20 water:methanol, (3) 60:40 water:methanol, (4) 40:60 water:methanol, (5) 20:80 water:methanol, (6) 100% methanol, (7) 80:20 methanol:THF, (8) 60:40 methanol:THF. Extracts combine, concentrate, and dried under low vacuum. Identification of chemical components is carried out using HPLC, using a detector PhotoDiode Array (HPLC/PDA) and C18 column 250 mm×4,6 mm Chemical components quantitatively evaluated on the basis of retention time and PDA data using baicalein, baicalin, scutellarein and wogonin as standards. The results in table 6.

Table 6.
Quantitative determination of flavonoids with free In-cycle extracted from Scutellaria orthocalyx
The solvent for extractionMass extract%,
extracted from biomass
General
number
flavonoids
% flavonoids in extract
100% of the water96 mg19,2%0.02 mg0,20%
Water:methanol (80:20)138,3 mg27,7%0,38 mg0,38%
Water:methanol (60:40)169, 5mm mg33,9%0,78 mg8,39%
Water:methanol (40:60)142,2 mg28,4%1,14 mgof 11.26%
Water:methanol (20:80)104,5 mg20,9%0,94 mg7,99%
100% methanolof 57.5 mg11,5%0,99 mg10,42%
Methanol:THF (80:20)to 59.6 mg11,9%0,89 mg8,76%
Methanol:THF (60:40)to 58.8 mg11,8%1,10 mg10,71%

Scutellaria baicalensis (1000 mg crushed roots) extracted twice using 50 ml of a mixture of methanol and water, as follows: (1) 100% water, (2) 70:30 water:methanol, (3) 50:50 water:methanol, (4) 30:70 water:methanol, (5) 100% methanol. Extracts combine, concentrate, and dried under low vacuum. Identification of chemical components is carried out using HPLC, using a detector PhotoDiode Array (HPLC/PDA) and C18 column 250 mm×4,6 mm Chemical components in each extract was quantitatively assessed on the basis of retention time and PDA data 10 using baicalein, baicalin, scutellarein and wogonin as standards. The results in table 7.

Table 7.
Quantitative determination of flavonoids with free β-cycle extracted from Scutellaria baicalensis
The solvent for extractionMass extract% extracted from biomass The total number of
flavonoids
% flavonoids in extract
100% of the water277,5 mg27,8%1 mg0,09%
Water:methanol (70:30)338,6 mg33,9%1,19 mg11,48%
Water:methanol (50:50)304,3 mg30,4%1,99 mg18,93%
Water:methanol (30:70)293,9 mg29,4%to 2.29 mg19,61%
100% methanol204,2 mg20,4%2,73 mg24,51%

Example 9. Receiving medication with the standardised extract of flavonoids with free In-cycle from the roots of Scutellaria baicalensis and standardized extract flavanol from the bark of Acacia catechu

Presents a new song, called in this context UP736, get, using two standardized extract isolated from Acacia and Sutellaria respectively, together with one or more fillers. A common example for this song below. The extract of Acacia, used in this example, includes >60% of the total flavanol, such as catechol and epicatechin, and an extract of Scutellaria includes >70% of flavonoids with free In-cycle, which mainly represented by biolinum. Extract of Scutellaria includes minor quantities of other flavonoids with free In-cycle, as shown in table 8. It presents the composition add one or more fillers. The ratio of flavan and flavonoids with a free In-cycle can be brought on the basis of the evidence and the specific requirements in terms of biological activity of the product. The amount of fillers can be brought based on the actual active content of each ingredient. Table mix for each batch of product must be created on the basis of the description of the product and QC results for separate batches of ingredients. Recommended the introduction of additional quantities of the active ingredients in the range of 2-5% to match the product description. Table 8 illustrates a table of mixing, which is designed for one party UP736 (party #G1702).

The extract from the roots of Scutellaria baicalensis (38,5 kg) (party # RM052302-01) with the content of flavonoids with free In-cycle and 82.2% (baicalin); the extract of the bark of Acacia catechu (6.9 kg) (party # RM052902-01) with the content of flavanol 80,4%) and a filler (5,0 kg Candex) mix, receiving the drug UP736 (50,4 kg)having a mixing ratio of 85:15. In table 8 represent the quantification of active flavonoids with free In-cycle and flavanol this special party UP736 (party #G1702), set by using methods proposed in Examples 4 and 6.

According to table 8, this special party UP736 includes 86% of the total active ingredients, including 75.7% of flavonoids with free In-cycle and 10.3% of flavanol. This party UP736 (50,0 kg) get the final product with two different dose levels in the form of capsules: 125 mg/dose (60 capsules) and 250 mg/dose (60 capsules).

Using the same approach get two other party UP736, using a combination of standardized extract flavonoid with a free In-cycle from the roots of Scutellaria baicalensis and standardized flavan extract from the bark of Acacia catechu, having a mixing ratio of 50:50 and 20:80, respectively.

Table 8
The content of flavanoids with free In-cycle and flavan in UP736
Active componentsContent, %
1. Flavonoids
A. Baicalin62,5%
B. Minor flavonoids
i. Wogonin-7-glucuronide6,7%
ii. Oroxylin And 7-glucuronide2,0%
iii. Baicalein1,5%
iv. Wogonin1,1%
v. Peter Netzer-7-glucuronide0,8%
vi. 5-methyl-wogonin-7-glucuronide0,5%
vii. Scutellarin0,3%
viii. Norwegain0,3%
ix. Peter Netzer<0,2%
X. Oroxylin And<0,2%
century, the Total flavonoids from Svobody In a cycle75,7%
2. Glavany
A. Catechin9,9%
B. Epicatechin0,4%
century Subbie glavany10,3%
3. Common active ingredients 86%

Example 10. Demonstration of the synergistic effect of the composition comprising a mixture of UP736 and aspirin in inhibiting platelet aggregation caused by arachidonic acid

The synergistic effect of the composition comprising a mixture of UP736 and aspirin in inhibiting platelet aggregation caused by arachidonic acid, as demonstrated in the analysis of platelet aggregation using plasma rich in platelets obtained from new Zealand rabbits. For rabbits (2,75±0.25 kg) are affected by sodium citrate (final concentration of 0.13 M). UP736, aspirin, or combinations thereof dissolved in 0.3% DMSO and incubated with plasma at 37°C for 5 minutes. Agonistic or antagonistic effect of the compounds quantitatively assessed by optical density aggregation. The significance test used for agonistic effect is ≥50% of platelet aggregation relative to the response to arachidonic acid. The significance test used for the antagonistic effect is ≥50% inhibition of platelet aggregation caused by arachidonic acid. In this analysis, various concentrations UP736 (10, 2 and 0.2 µm) and aspirin (30 and 3 μm) tested separately, either as an agonist or as an antagonist of platelet aggregation in platelet-rich plasma of rabbits. In table. 9 shows the results of the test (Test#1.

Table 9.
Synergistic effect of mixtures UP736® and aspirin on the inhibition caused by AK platelet aggregation
Concentration
aspirin (µm)
Concentration
UP736 (µm)
NAgonistic effectAntagonistic effect
010,020%3%
02,020%0%
00,220%0%
3,010,020%100%
3,02,020%100%
3,00,2 20%100%
30,0020%100%
3,0020%1%

In another analysis (test#2), conducted in the same experimental conditions, the test mixture UP736 in lower concentrations (0,2, 0,067, and 0.007 to 0.022 μm) and aspirin at a concentration of 3 μm. The results in table 10.

The results of the study of platelet aggregation show that UP736 as monocomponent has a low aggregation activity at concentrations up to 10 μm (table and 10). However, the activity of aspirin against platelet aggregation in a very low dose (3 μm) significantly increased with UP736 even in the lowest of testiruemi concentrations (0,007 μm).

Table 10.
The synergistic effect of the mixture UP736® and aspirin on the inhibition caused by AK platelet aggregation
Concentration
aspirin (µm)
Concentration
UP736 (µm)
Agonistic
effect
Antagonistic
effect
00,220%9%
3,00,220%100%
3,00,06720%100%
3,00,02220%100%
3,00,00720%100%
3,0020%8

Example 11. The effect UP736 and mixtures UP736 and aspirin on bleeding time

Although UP736 shows a synergistic effect with aspirin in inhibiting platelet aggregation (Tables 9 and 10), UP736 either as monotherapy or in combination with aspirin does not show a significant effect at the time cromatica the Oia in mice. Analysis of bleeding time carried out according to the method described in articles Minsker and Kling (1997) Thrombosis Research 10:619-622) and Butler et al. (1982) Thromb Haemostas 47:46-49. The test products are administered to five male ICR mice one hour prior to the standardized cut-off end (1.0 mm) of each tail. Mice, fixed in the holder, immediately hung vertically, with the ends of the tails dipped into a test tube containing saline solution at 37°C. the Maximum time the trim is not set. Measurements begin, when you see the actual bleeding, and finish when the bleeding stops within 15 seconds, or any longer time. Data analyzed using t-student test. In one analysis (test#3) aspirin as monotherapy at a dose of 3, 10, 65, and 100 mg/kg or UP736 at a dose of 100 mg/kg as monotherapy or in combination with aspirin at a dose of 3, 10 and 65 mg/kg administered orally to groups of 5 male mice of ICR. The results lead to table, which shows the average bleeding time and the percentage of excess bleeding time in treatment groups relative to control with the introduction of the media. Referring to table, the results demonstrate that the effect UP736 on bleeding time is not significant, and the effect UP736 in combination with aspirin in high concentrations lying in the range from 3 mg/kg 65 mg/kg, is limited and does not exceed the EF of the project, caused by 100 mg/kg of aspirin in the form of monotherapy. The analysis is repeated in the same experimental conditions (test#4). The results lead to table, which shows the average bleeding time and the percentage of excess bleeding time in treatment groups relative to control with the introduction of the medium (n=5). As you can see in table and 12, in two experiments get very good compatible results. Data from two experiments are combined and presented in table 13 and figure 3 (n= 9-10).

Table 11.
The average bleeding time and % increase in bleeding time test #3 (n=5)
The treatment groupThe average bleeding time ±SD* (C)% change relative to the group receiving media
Media65±1,0-
3 mg/kg of aspirinfor 77.2±13,018,7↑
10 mg/kg of aspirin74,4±15,414,5↑
65 mg/kg of aspirin105±15,1 61,5*↑
100 mg/kg aspirin119±14,083*↑
3 mg/kg of aspirin +82±12,626,2†↑
100 mg/kg UP736
10 mg/kg of aspirin + 100 mg/kg UP73676,5±17,717,7†↑
65 mg/kg of aspirin + 100 mg/kg UP736of 113.2±33,374,2†↑
100 mg/kg UP73676,4±13,017.5↑
* standard deviation

Table 12.
The average bleeding time and % increase in bleeding time test #4 (n=5)
The treatment groupThe average bleeding time ±SD (sec.)% change relative to the group receiving media
Media72,6±13,0 -
3 mg/kg of aspirin89,4±9,723,1↑
10 mg/kg of aspirin84,6±9,016.5↑
65 mg/kg of aspirin96±6,432,2*↑
100 mg/kg aspirin126,2±14,373,8*↑
3 mg/kg of aspirin + 100 mg/kg UP73692±9,326,7*↑
10 mg/kg of aspirin + 100 mg/kg UP736of 92.6±16,427,5*↑
65 mg/kg of aspirin + 100 mg/kg UP736of 112.8±16,055,3*↑
100 mg/kg UP736of 83.4±6,814,9↑
Table 13.
The average bleeding time and % increase in time shelter the flow (test #3 and #4 (n=9-10))
The treatment groupThe average bleeding time ±SD (C)% change relative to the group receiving mediaA value of P
Media68,8±12,0--
3 mg/kg of aspirin83,3±12,621,7↑0,016854
10 mg/kg of aspirin79,5±13,1the 15.6↑0,072734
65 mg/kg of aspirin100,5±11,946,1↑E-05
100 mg/kg aspirin122,6±13,978,2↑E-08
3 mg/kg of aspirin + 100 mg/kg UP736of 87.0±11,726,5↑0,002958
10 mg/kg of aspirin + 100 mg/kg UP73685,4±25,5 24,1↑0,028458
65 mg/kg of aspirin + 100 mg/kg UP736level 113.0±25,564,2↑0,00013
100 mg/kg UP73679,9±10,516,1↑0,041085

To confirm the results in bleeding time UP736 or UP736 in combination with aspirin again tested in an independent study (Test #5) is carried out using a modified method. UP736 administered orally at a dose of 100 mg/kg as monotherapy or in combination with aspirin at a dose of 3, 10 and 30 mg/kg to groups of 5 male ICR mice weighing 22±2 g 1 hour before the cut-off end (0.3 mm) of each tail. In addition, mice similarly give aspirin at a dose of 3, 10, 30 and 100 mg/kg Mice, fixed in the holder, immediately suspend vertically, with 2 cm each end of the tail is dipped into a test tube containing saline solution at 37°C. Set the maximum time clipping 180 C. If the bleeding stops within 15 seconds, or at any time within 180 seconds of the period of observation, measurement and stop any further bleeding do not take into account. The increase in bleeding time by 50% or more(50%) compared to the control group of animals is considered significant. The results are consistent with those obtained in the above experiments (test #3 and #4). The effect UP736 at a dose of 100 mg/kg on bleeding time is not significant, and the effect UP736 at a dose of 100 mg/kg in combination with aspirin at a dose of 30 mg/kg less than the effect caused by aspirin as monotherapy at a dose of 100 mg/kg (see table 14 and figure 4).

Table 14.
The average bleeding time and % increase in bleeding time in test #5 (n=5)
The treatment groupThe average bleeding time ±SD (C)% change relative to the group receiving media
Media44,4±15,0-
3 mg/kg of aspirin42,8±26,20
10 mg/kg of aspirin39,8±22,40
65 mg/kg of aspirinof 56.4±27,327↑
100 mg/kg aspirin75,0±38,870*↑
Wear the ü 2 (20% DMSO) 55,4±32,5-
3 mg/kg of aspirin + 100 mg/kg UP73653,2±27,10↑
10 mg/kg of aspirin + 100 mg/kg UP73669,6±45,427↑
30 mg/kg of aspirin + 100 mg/kg UP73687,2±59,258*↑
100 mg/kg UP73645,4±23,10

1. Composition for the prevention and treatment of diseases and conditions related to platelet aggregation and thrombosis caused by platelets, comprising essentially a mixture of at least one flavonoid with a free In-cycle, at least one flavan and at least one agent selected from the group consisting of injectable anticoagulant agent, an oral anticoagulant agent, an antiplatelet agent, a medicinal product against angina, non-steroidal anti-inflammatory drug (NSAID) or a selective inhibitor of cyclooxygenase-2 (SOH-2).

2. The composition according to claim 1, in which the ratio of flavonoid with a free In-cycle to the flavan at the specified composition selected from a range from approximately the nutrient 99:1 flavonoid with a free In-cycle: flavan to about 1:99 flavonoid with a free In-cycle: flavan.

3. The composition according to claim 2, in which the ratio of flavonoid with a free In-cycle: flavan in the present compositions is about 85:15.

4. The composition according to claim 1, in which the specified flavonoid with a free In-cycle selected from the group of compounds having the following structure:

in which R1, R2, R3, R4and R5independently from each other selected from the group consisting of-H, -OH, -SH, OR, -SR, -NH2, -Other, -NR2, -NR3+X-, carbon, oxygen, nitrogen or sulfur, glycoside of a single or combination of multiple sugars including, but without limitation, aldopentose, metalldetektor, hexoses, ketohexose and their chemical derivatives;
in which R represents an alkyl group containing 1-10 carbon atoms, and
X is selected from the group of pharmaceutically acceptable counterions, including hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride and carbonate.

5. The composition according to claim 1, in which the specified flavan selected from the group of compounds having the following structure:

in which R1, R2, R3, R4and R5independently from each other selected from the group consisting of-H, -OH, -SH, -och3, -SCH3, -OR, -SR, -NH2, -NRH, -NR2, -NR3+X-esters of substitute groups, independently selected from the group consisting of esters of gallate, acetate, cynnamoyl and hydroxycinnamic, trihydroxybenzoate esters and caffeoyl esters; carbon, oxygen, nitrogen or sulfur, glycoside of a single or combination of multiple sugars including, but without limitation, aldopentose, metalldetektor, hexoses, ketohexose and their chemical derivatives, dimeric, trimeric and other cured glavany, in which
R represents an alkyl group containing 1-10 carbon atoms, and
X is selected from the group of pharmaceutically acceptable counterions, including, but not limited to hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride, carbonate.

6. The composition according to claim 1, in which the specified flavonoid with a free In-cycle and the specified flavan get organic synthesis or extracted from plants.

7. The composition according to claim 6, in which the specified flavonoid with a free In-cycle and the specified flavan extracted from a plant part selected from the group consisting of stems, bark, stems, trunks, trunks, branches, tubers, roots, root bark, young shoots, seeds, rhizomes, flowers and other reproductive organs, leaves and other aerial parts.

8. The composition according to claim 6, in which the specified flavonoid with a free In-cycle selected from
a) family of plants, selected from the group consisting of Annonaceae, Asteraceae, Bignoniaceae, Combretaceae, Compositae, Euphorbiaceae, Labiatae, Lauranceae, Leguminosae, Moraceae, few Pinaceae, Pteridaceae, Sinopteridaceae, Ulmaceae and Zingiberacea, or
b) kinds of plants selected from the group consisting of Desmos, Achyrocline, Oroxylum, Buchenavia, Anaphalis, Cotula, Gnaphalium, Helichrysum, Centaur ea, 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.

9. The composition according to claim 6, in which the specified flavan isolated from a plant species selected from the group consisting of Acacia catechu, Acacia concinna, Acacia farnesiana, Acacia Senegal, Acacia speciosa, Acacia arabica, Acacia caesia, Acacia pennata, Acacia sinuate, Acacia mearnsii, Acacia picnantha, Acacia dealbata. Acacia auriculiformis, Acacia holoserecia and Acacia mangium; Uncaria gambir, Uncaria lanosa, Uncaria hirsute, Uncaria africana, Uncaria into, Uncaria orientalis, Uncaria attenuate, Uncaria acida, Uncaria homomalla, Uncaria sessilifructus, Uncaria sterrophylla, Uncaria bernaysii, Uncaria sinensis, Uncaria callophylla, Uncaria rhychophylla, Uncaria tomentosa, Uncaria longiflora, Uncaria hirsute, Uncaria cordata, and Uncaria borneensis.

10. The composition according to claim 6, in which the specified flavonoid with a free In-cycle extracted from the plant or plants of the genus Scutellaria plants and specified flavan isolated from the plant or plants of the genus plants Acacia and Uncaria.

11. The composition according to claim 1, in which the mentioned diseases and conditions related to platelet aggregation and thrombosis caused by platelets selected from the group consisting of deep vein thrombosis, pulmonary embolism, atherosclerosis, myocardial infarction, thrombosis is and cerebral blood vessels and/or embolism of cerebral vessels, leading to cerebrovascular events, thrombosis of peripheral circulation and/or microcirculation, leading to ischemia and infarction, atrial fibrillation, which is associated with stasis of blood and the formation of clots in the left atrium, thrombogenic centers, including artificial implants, such as mechanical heart valves, defibrillators, surgical implants for drug delivery, and artificial hip joints and other exogenous bodies.

12. The composition according to claim 1, in which the specified injectable anticoagulant agent is selected from the group consisting of heparin, dalteparin, enoksaparina and Tinzaparin.

13. The composition according to claim 1, in which the specified oral anticoagulation agent selected from the group consisting of warfarin, vitamin K antagonists and inhibitors of the reductase vitamin K.

14. The composition according to claim 1, in which the specified antiplatelet agent selected from the group consisting of aspirin, clopidogrel and dipyridamole.

15. The composition according to claim 1, in which the specified drug against angina selected from the group consisting of nitrates, β-blockers, blockers of calcium, inhibitors of the angiotensin converting enzyme and potassium channel activators.

16. The composition according to claim 1, in which the specified NSAID selected from the group consisting of azeta is inopina, ibuprofen, naproxen, diclofenac, salicylates and indomethacin.

17. The composition according to claim 1, in which the specified selective inhibitor SOH-2 selected from the group consisting of rofecoxib, celecoxib, etodolac and meloxicam.

18. Composition for the prevention and treatment of diseases and conditions related to platelet aggregation and thrombosis caused by platelets, comprising essentially a mixture of at least one flavonoid with a free In-cycle, at least one flavan and aspirin.

19. The method of application of a composition comprising essentially a mixture of at least one flavonoid with a free In-cycle and at least one flavan, adjuvant and/or synergistic and/or potentiating agent for use for delivery of an agent selected from the group consisting of injectable anticoagulant agent, an oral anticoagulant agent, an antiplatelet agent, a medicinal product against angina, non-steroidal anti-inflammatory drug (NSAID) or a selective inhibitor of cyclooxygenase-2 (SOH-2).

20. The method according to claim 19, wherein said injectable anticoagulant agent is selected from the group consisting of heparin, dalteparin, enoksaparina and Tinzaparin.

21. The method according to claim 19, wherein said oral anti-Christ. verticali agent selected from the group consisting of warfarin, vitamin K antagonists and inhibitors of the reductase vitamin K.

22. The method according to claim 19, wherein said antiplatelet agent is selected from the group consisting of aspirin, clopidogrel and dipyridamole.

23. The method according to claim 19, wherein said drug against angina selected from the group consisting of nitrates, β-blockers, blockers of calcium, inhibitors of the angiotensin converting enzyme and potassium channel activators.

24. The method according to claim 19, wherein said NSAID is selected from the group consisting of acetaminophen, ibuprofen, naproxen, diclofenac, salicylates and indomethacin.

25. The method according to claim 19, wherein said selective inhibitor SOH-2 selected from the group consisting of rofecoxib, celecoxib, etodolac and meloxicam.

26. The method according to claim 19, in which the composition is administered at a dose selected from 0.01 to 200 mg/kg of body weight.

27. The method according to claim 19, wherein the route of administration selected from the group consisting of oral, local, in the form of a suppository, intravenous, and intradermal, intragastric, intramuscular, intraperitoneal and intravenous administration.

28. Composition comprising essentially a mixture of at least one flavonoid with a free In-cycle and at least one flavan in combination with antiplatelet, anticoagulant, preventive AG is Tom, NSAID or selective inhibitor SOH-2 for use to reduce the standard dose of an agent selected from the group consisting of the above antiplatelet, anticoagulant, prophylactic agent, NSAID and selective inhibitor SOH-2.

29. Composition comprising essentially a mixture of at least one flavonoid with a free In-cycle and at least one flavan in combination with antiplatelet, anticoagulant, a prophylactic agent, NSAID or selective inhibitor SOH-2 for use to reduce or eliminate side effects caused by acute or continuous administration of agents selected from the group consisting of the above antiplatelet, anticoagulant, prophylactic agent, NSAID and selective inhibitor SOH-2.

30. Composition comprising essentially a mixture of at least one flavonoid with a free In-cycle and at least one flavan in combination with antiplatelet, anticoagulant, a prophylactic agent, NSAID or selective inhibitor SOH-2 to be used to counter or antagonistic actions against the risks associated with acute or continuous administration of agents selected from the group consisting of the above antiplatelet, anticoagulant, prophylactic agent, NSAID and selective the th inhibitor SOH-2.

31. Composition according to any one of p-30, where the composition should be administered at a dose selected from 0.01 to 200 mg/kg of body weight.

32. Composition according to any one of p-30, in which the route of administration selected from the group consisting of oral, local, in the form of a suppository, intravenous, and intradermal, intragastric, intramuscular, intraperitoneal and intravenous administration.



 

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Retinoprotector // 2406487

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5 tbl, 2 ex

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Organic compounds // 2411239

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, in which R1 denotes alkyl or cycloalkyl; R2 denotes phenyl-C1-C7-alkyl, di-(phenyl)- C1-C7-alkyl, naphthyl- C1-C7-alkyl, phenyl, naphthyl, pyridyl-C1-C7-alkyl, indolyl- C1-C7-alkyl, 1H-indazolyl- C1-C7-alkyl, quinolyl C1-C7-alkyl, isoquinolyl- C1-C7-alkyl, 1,2,3,4-tetrahydro-1,4-benzoxazinyl- C1-C7-alkyl, 2H-1,4-benzoxazin-3(4H)-onyl-C1-C7-alkyl, 9-xanthenyl-C1-C7-alkyl, 1-benzothiophenyl-C1-C7-alkyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 9-xanthenyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl, where each phenyl, naphthyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl are unsubstituted or contain one or up to 3 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy-C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkoxy-C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkanoyloxy- C1-C7-alkyl, amino- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkylamino- C1-C7-alkyl, C1-C7-alkanoylamino- C1-C7-alkyl, C1-C7-alkylsulphonylamino- C1-C7-alkyl, carboxy- C1-C7-alkyl, C1-C7-alkoxycarbonyl- C1-C7-alkyl, halogen, hydroxy group, C1-C7-alkoxy group, C1-C7-alkoxy- C1-C7-alkoxy group, amino- C1-C7-alkoxy group, N-C1-C7-alkanoylamino-C1-C7-alkoxy group, carbamoyl- C1-C7-alkoxy group, N-C1-C7-alkylcarbamoyl-C1-C7-alkoxy group, C1-C7-alkanoyl, C1-C7-alkoxy-C1-C7-alkanoyl, C1-C7-alkoxy- C1-C7-alkanoyl, carboxyl, carbamoyl and N-C1-C7-alkoxy-C1-C7-alkylcarbamoyl; W denotes a fragment selected from residues of formulae IA, IB and IC, where () indicates the position in which the fragment W is bonded to the carbon atom in position 4 of the piperidine ring in formula I, and where X1, X2, X3, X4 and X5 are independently selected from a group containing carbon and oxygen, where X4 in formula IB and X1 in formula IC can assume one of these values or can be additionally selected from a group comprising S and O, where carbon and nitrogen ring atoms can include a number of hydrogen atoms or substitutes R3 or R4 if contained, taking into account limitations given below, required to bring the number of bonds of the carbon ring atom to 4 and 3 for the nitrogen ring atom; provided that in formula IA at least 2, preferably at least 3 of the atoms X1-X5 denote carbon and in formulae IB and IC at least one of X1-X4 denotes carbon, preferably 2 of the atoms X1-X4 denote carbon; y equals 0 or 1; z equals 0 or 1; R3, which can be bonded with any of the atoms X1, X2, X3 and X4, denotes hydrogen or a C1-C7-alkyloxy-C1-C7-alkyloxy group, phenyloxy-C1-C7-alkyl, phenyl, pyridinyl, phenyl- C1-C7-alkoxy group, phenyloxy group, phenyloxy-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, tetrahydropyranyloxy group, 2H,3H-1,4-benzodioxynyl-C1-C7-alkoxy group, phenylaminocarbonyl or phenylcarbonylamino group, where each phenyl or pyridyl is unsubstituted or contains one or up to 3 substitutes, preferably 1 or 2 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy group, C1-C7-alkoxy group, phenyl-C1-C7-alkoxy group, where phenyl is unsubstituted or substituted with a C1-C7-alkoxy group and/or halogen; carboxy- C1-C7-alkyloxy group, N-mono- or N,N-di-(C1-C7-alkyl)aminocarbonyl-C1-C7-alkyloxy group, halogen, amino group, N-mono- or N,N-di-(C1-C7-alkyl)amino group, C1-C7-alkanoylamino group, morpholino-C1-C7-alkoxy group, thiomorpholino-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, pyrazolyl, 4- C1-C7-alkylpiperidin-1-yl, tetrazolyl, carboxyl, N-mono- or N,N-di-(C1-C7-alkylamino)carbonyl or cyano group; or denotes 2-oxo-3-phenyltetrahydropyrazolidin-1-yl, oxetidin-3-yl-C1-C7-alkyloxy group, 3-C1-C7-alkyloxetidin-3-yl- C1-C7-alkyloxy group or 2-oxotetrahydrofuran-4-yl- C1-C7-alkyloxy group; provided that if R3 denotes hydrogen, then y and z are equal to 0; R4, if contained, denotes a hydroxy group, halogen or C1-C7-alkoxy group; T denotes carbonyl; and R11 denotes hydrogen, or pharmaceutically acceptable salts thereof. The invention also relates to use of formula I compounds, a pharmaceutical composition, as well as a method of treating diseases.

EFFECT: obtaining novel biologically active compounds having activity towards rennin.

11 cl, 338 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and consists in development of a new dosage of the preparation 6-methyl-2-ethyl-3-hydroxypyridine succinate providing modified release of an active substance. A unit dosage form contains 6-methyl-2-ethyl-3-hydroxypyridine succinate in amount 30.0-70.0 wt %, as a release modifier - cellulose derivatives and/or polyacrylic resins in amount 1.0-20.0 wt %, as an excipient - microcrystalline cellulose in amount 20.0-50.0 wt % and lubricants. The unit dosage form represents a tablet or a capsule consisting of a variety of small dense spheroids containing 6-methyl-2-ethyl-3-hydroxypyridine succinate as a major component. A combination of matrix and instant, coated and uncoated spheroids enables preparation of a drug in the various dosage forms with controlled release rate.

EFFECT: invention allows to produce the unit dosage forms of the preparation 6-methyl-2-ethyl-3-hydroxypyridine succinate for certain treatment regimens of various diseases.

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine and can be used for treating body system involvements caused by activated peroxidation. There is a liquid pharmaceutical composition offered therefore containing 2-ethyl-6-methyl-3-hydroxypyridine succinate, surface active substances and a sulphite stabiliser in a certain ratio. The composition is suggested to be introduced sublingually in the form of a spray.

EFFECT: composition is characterised by high storage stability and improved efficacy enabling an effect similar to such provided by an injection formulation, with a substantially smaller dose of an active agent.

9 cl, 6 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to experimental cardiology and can be used for prevention of chronic toxic cardiopathy in experimental animals. For this purpose natural sorbent irlit-1 in form of 6% suspension in amount 2.5% body weight is introduced via probe into stomach every second day. Sorbent is introduced simultaneously with daily introduction via probe into stomach of nickel chloride solution in dose 2.5 mg/100 g during a month.

EFFECT: method provides efficient protection of chronic toxic cardiopathy due to postponing terms and degree of manifestations of hemodynamic cardiac malfunctions developing in case of intoxication.

1 ex, 3 tbl, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of 4-aminocarbonylpyrimidine of formula (I).

EFFECT: invention is applicable as P2Y12 receptor antagonists for treatment and/or prevention of diseases or disease states of peripheral vessels, as well as vessels, supplying internal organs, vessels of liver and kidneys, in treatment and/or prevention of cardiovascular and cerebrovascular diseases and states, associated with aggregation of platelets, including thrombosis in humans and mammals.

26 cl, 500 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of 4-aminocarbonylpyrimidine of formula (I).

EFFECT: invention is applicable as P2Y12 receptor antagonists for treatment and/or prevention of diseases or disease states of peripheral vessels, as well as vessels, supplying internal organs, vessels of liver and kidneys, in treatment and/or prevention of cardiovascular and cerebrovascular diseases and states, associated with aggregation of platelets, including thrombosis in humans and mammals.

26 cl, 500 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel substituted derivatives of urea, which possess properties of selective modulator of cardiac sarcomere, for instance, enhance action of cardiac myosin. Novel compounds are selected from compounds corresponding to structural formulas: .

EFFECT: compounds can be used in treatment for heart failure, in particular in treatment of systolic heart failure and congestive heart failure.

30 cl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds selected from a group comprising amides of peridine carboxylic acid of formula (I) , in which W denotes a phenyl ring or a six-member, non-benzocondensed aromatic ring, having one nitrogen atom, where said rings are substituted in the para-position through V; V denotes a bond; -A-(CH2)S- or -A-(CH2)v-B-; A and B independently denote -O-; U denotes mono-, di-, tri- or tetra-substituted aryl, in which substitutes are independently selected from a group consisting of halogen, alkyl and -CF3; Q denotes methylene; M denotes an aryl group, where the said group can be optionally mono- or di-substituted with substitutes independently selected from a group comprising alkyl; alkoxy; -CF3; halogen; alkyl-O-(CH2)0-4-CH2- and R'2N-(CH2)0-4-CH2-, where R' is independently selected from a group comprising hydrogen, alkyl (optionally substituted with one, two or three fluorine atoms), cyclopropyl, cyclopropylmethyl, -C(=O)-R", where R" denotes C1-C4-alkyl or -CH2-CF3; R1 denotes cycloalkyl; n equals 0 or 1; s equals 3; v equals 2; and substitutes in the ring, -CON(R1)-Q-M and -W-V-U, are in trans-position relative each other if n equals 1, and where configurations in positions 3 and 4 of the piperidine ring of formula (I) are 3R and 4R, respectively, if n equals 0; and optically pure enantiomers, mixture of enantiomers, such as racemates, diastereomers, mixture of diastereomers, diastereomer racemates, mixture of diastereomer racemates, and mesoforms, as well as to salts of such compounds. Invention also relates to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having non-peptide rennin inhibiting activity.

12 cl, 27 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medications and deals with pharmaceutical composition, including (i) pharmacologically efficient amounts of each of active substances: a) neutral endopeptidase inhibitor, b) endogenous endothelin-producing system inhibitor, and c) HMG (hydroxymethylglutaryl) CoA reductase inhibitor, selected from the group including atorvastin and simvastatin or any their physiologically acceptable salts, solvates or ethers, where subcombination of neutral endopeptidase inhibitor a) and endogenous endothelin-producing system inhibitor is combination of double action, which is able to inhibit neutral endopeptidase and human soluble endopeptidase, which is represented by daglutril and (ii) preferably pharmaceutically acceptable auxiliary substances and/or carriers, for prevention or treatment of cardiovascular disorders in mammals and humans. Also described is set for prevention and treatment of cardiovascular in mammals and humans.

EFFECT: composition demonstrates synergetic effect in treatment of cardiovascular diseases.

9 cl, 3 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of 4-aminocarbonylpyrimidine of formula (I).

EFFECT: invention is applicable as P2Y12 receptor antagonists for treatment and/or prevention of diseases or disease states of peripheral vessels, as well as vessels, supplying internal organs, vessels of liver and kidneys, in treatment and/or prevention of cardiovascular and cerebrovascular diseases and states, associated with aggregation of platelets, including thrombosis in humans and mammals.

26 cl, 500 ex

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