TW201223532A - Novel acetylsalicylic acid salts - Google Patents

Abstract

Novel betaine salts of acetylsalicylic acid, namely 4-trimethylammoniobutanoate acetylsalicylic acid addition salt (gamma-butyrobetaine acetylsalicylate), L-carnitine acetylsalicylic acid addition salt and 3-(trimethylammonioamino)propanoate (meldonium) acetylsalicylic acid addition salt. Use of meldonium acetylsalicylate as antiplatelet agent for treating various pathologies induced by platelet aggregation, anti-inflammatory and antihyperlipidemic agent.

Description

201223532. VI. Description of the Invention: [Technical Field to Which the Invention Is Applicable] The present invention is substantially affixed with _卩_, _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ B-acid is one of the most widely used drugs and is mainly known for its analgesic properties. Its application range has been greatly reduced by the low water solubility (about 0.3%) of salt, sodium salt, magnesium salt and foreign matter, and it has been disclosed that it has been disclosed (U.S. Patent No. 4,265,888). These faces all have certain advantages and disadvantages, and it is therefore advantageous to have a new salt of salicylic acid which is potentially more advantageous. Since the novel betatosine compounds contained in the novel acetaminophens have various medicinal activities, the novel acetalic acid salts may have more beneficial properties than the characteristics of salicylic acid or betaine, including Novel pharmaceutical activity. [Prior Art] Acetyl sulphate is one of the most widely used drugs, and is mainly known for its anti-inflammatory, analgesic, antipyretic and anti-rheumatic properties. It has also been used as an antiplatelet agent in patients with high risk of cardiovascular disease with a small amount of daily dose (Eidelman RS et al., Qiao Yixue. 2003; 163: pp. 2006 - 2〇1〇). During coronary heart disease, platelets play a key role in the development of atherosclerosis and fatal thrombosis. Antiplatelet agents have become the first choice for the prevention and management of a variety of diseases associated with cardiovascular, cerebrovascular, and peripheral arterial systems (Meadows et al., Acoustics ¢5 mouth 2007; 100(9): Page 1261-75 ). Although ASA has been known for many years as an anti-201223532 platelet preparation' today in cardiology, ASA is better known for its anti-inflammatory properties (Ridker PM et al., Dance Nostalgia, 1997); 336 Page 973 - 979). According to this, the clinical measurement of this inflammatory marker as C-reactive protein (crp) can partially reflect the index of atherosclerosis (Buckley DI et al., Leng Cun Xue Yang Po 2009; 151: page 483~495) ). Evidence today points to a reduction in the concentration of CRP to prevent chd events (Ridker PM et al., Life Scythe 2009; 373: pp. 1175-82). Ross hypothesized that atherosclerosis is an inflammatory disease (and (10) Λ, new nasal snorkeling, 1999; 340: pp. 115_126). ASA not only treats the inflammatory aspects of atherosclerosis, but also directly contributes to the induction of hypolipidemia (KourounakisAP et al., Journal of Molecular Divorce 2002, 73: 135-138). NA is an effective lipid-modifying agent that prevents atherosclerosis and reduces cardiovascular events. NA has a variety of lipoproteins and anti-atherosclerotic effects, which improve endothelial function, reduce inflammation, increase plaque stability' and reduce thrombosis (Rosenson RS, sneakers D. Hardy, 2003; 171) : Page 87-96). NA almost completely prevents intravascular coagulation induced by thrombin and cerule vasopressin, which shows its effect of dissolving thrombus (BalU (ja vp, Heart Anema 1974; 14(11): Page 105-7) (Russian)). Several authors describe the antithrombotic properties of NA (Shestakov VA, 1977; 22(8): pp. 29-35 °Chekalina SI ' MM 1982, 5: pp. 105-8) Nicotinic acid reduces the risk of blood clots (Chesney CM et al., #激心腐游, 2000; 201223532 140: 631-36). NA inhibits the accumulation of gray platelets (Lakin KM, Farmakol Toksikd 'Diagnosis; 43 (5): Page 5). NA in the wild by gently inhibiting blood ^ (, silk set (four) ring, plate sputum, and stabbed serotonin release 'and most of the major primary platelet receptors. NA is unique, unlike other known antiplatelet agents, and offers potential opportunities for pharmaceutical compositions (Serebmany, etc.戽ϋ, 2〇1〇 (in press)) ΝΑ is an effective lipid-modifying agent that prevents atherosclerosis and Know the blood officials incident. (Dfexd squatting, suspected side ^ tender ^ 2006; 8 period 'Supplement F: Page F23-F29. Savd, ev ΑΑ and Shershevskii MG, Xi _ (10) j 1996; 74: Pages 48-52) NA can be formulated in three formulations (immediate release, extended release, and long-acting effect). Immediate release of NA is associated with poor flushing and elevated blood glucose levels. Long-acting NA is associated with reduced flushing, but There is a risk of hepatotoxicity. Prolonged release is associated with less flushing and low risk of hepatotoxicity (McKenney) '痄荇学义蔚' 2004; 164(7): 697-705). Clinical use of NA has been Limited to skin flushing. Extended release from acid testing can help control flushing events (Guyton JR et al., jc/z > 2 • also /, 2009; 3: pages 101-108). It has been suggested that ASA And other NSAIDs can control flushing with different pharmaceutical compositions, confirming the beneficial application of NSAIDs after NA dosing (patent W09632942, W09906052, W02009142731) 〇201223532 曰Previously proposed a specific antagonist of prostaglandin D25 (Parhofer KG , if Chuguang table 琢俭#座2009 Phase 5: Page 901-908) Receptor subtype 1, laropiprant, as a drug used to reduce flushing induced by NA (Lai E et al., plucking Qin and Hezhi #游泞2007, Issue 81: Page 849-857. Davidson MH, 4 Strictly minded 1 disease 爹 爹 2008; 1 〇 1 [Supplement]: Page 14B_19B). Although the addition of lauropirin will reduce the frequency of flushing, it does not completely eliminate this side effect. Lauropirin does not alter the effect of niacin on lipids or other side effects of niacin. Therefore, the combination of acid test and lauropirin can be used at high doses for acid detection' thus the full potential of this drug has been developed (ParhofcrKG, if Jianguang 1 room style 俭 理 2009; 5: page 901 -908, Olsson AG, Sai 莩 莩 彦 2010 2010 2010; 11 (10): 1715-1726). The MD system has certain drugs that have beneficial effects on the heart and blood vessels. Some desirable MS activities have been found in animal models of atherosclerosis (Veveris Μ, Smilsaraja B, violent ginseng participation in the laboratory of 2000; 10 issues 'pages 194-199. Veveris Μ Waiting for others, Polo is a brother-in-law to teach and practice in 2002; 12: page 116-122°OkunevichIV,

Ryzhenkov VE, V. Cut: :Ter 2002; (2): Page 24-7) 'And clinically observed (Karpov RS et al., 1991; 63(4): Page 90-3 ). It has been noted that MD inhibits platelet aggregation (Tsirkin VI, and 〇 5ΖΛ 2002; Phase 1: Pages 45-52). The MD medical use of oral administration to rabbits and dogs for two weeks after experimental arterial thrombosis showed the effect of dissolving the plug (Logunova L et al., five r/?erz>w C/plus 1991; : Page 91-9 (Russian 7 201223532 text)). There is no known data on the preventive effect of MD in controlling or preventing thrombosis. SUMMARY OF THE INVENTION The object of the present invention is to find a novel type of etherosate having certain betaine compounds. Unexpected and surprisingly discovered, the sulphate salt with certain beet tests (which are themselves hygroscopic) produces stable water-soluble crystalline salts. A slave κ 曰 曰 提供 提供 提供 提供 提供 提供 提供 提供 提供 提供 提供 提供 提供 提供 提供 提供 提供 提供 。 。 A further object of the invention is to provide a process for the manufacture of the salts. Another object of the present invention is to provide a kojikitosine (3-(trimethylhydrazinium)propionate salicylate addition salt) for use as a medicament. The object of the present invention is to provide a medicine, that is, 3_(trimethylhydrazine)propionate acetalic acid (Gu scale B), which has anti-inflammatory, analgesic antipyretic, anti-rheumatic, anti-high Lipemia, anti-atherosclerosis, anti-aggregation and anti-A sputum. Another object of the present invention is a method which requires anti-inflammatory, analgesic, antipyretic, anti-rheumatic, anti-hyperlipidemic, anti-atherosclerotic, anti-aggregation and anti-thrombotic treatments. Another object of the invention is a medical composition comprising MASA as described above. The objects of the present invention will become more apparent hereinafter, and other objects will be apparent to those skilled in the art. An illustrative embodiment of a preferred embodiment. The following characteristics of Linfa Ke's bribes and branches and materials 201223532

fExample J Xuan Xuan 1.4-trimethylammonium butyl sulphate plus life m dissolved γ-butyl beet test dihydrate (1.81 g, 〗 〇亳 Mo Er) and eucalyptus acid (1.80 g, 10 Millol) in ethanol (20 ml). The solution was concentrated in vacuo at about 40 C until a crystalline syrup concentration formed upon cooling. The crystal agglomerate was triturated with acetone (50 ml), filtered, washed with acetone, and dried at room temperature under vacuum. The yield of colorless crystals having a melting point of 120-122 ° C was 3.04 g (yield 93.5%). This material is water soluble & is stable under ambient conditions. HNMR spectrum (d2〇' tms) chemical shift δ : 1.93-2 12 (2Η 'multiple sound, CH2〇H2CH2); 2.33 (3Η, single peak, c〇CH3); 2.40 (2H, three 4 peaks' J value = 7 〇 Hertz, Ch2C〇〇- ); 3 〇9 , single bee ' Me3N), 3.24 - 3.37 (2H, multiplet, CH2N); 7.16 (1H, two double peaks 'j value = u and 8 J Hz, H_3) ; 738 (m, triplet peak, J = 1.1, 7.6 and 7.6 Hz, H-5); 7.56 (1H, triplet peak 'J value - 1.8, 7.6 and 8.1 Hz 'H-4); 7·79 millionth

25.80, 27.05, 27.91, 3〇25±〇2„. The structure of the novel salt is confirmed by X-ray radiation with 15.02, 15.17, 17.89, 19.33, 23.92, 24.75, 25.55, optical single crystal structure analysis ( Figure 9 3 201223532 U. Crystalline monoclinic crystals, cell parameters at experimental temperature T = -85 °C System: a = 13.2154 (6) A, b = 7.5092 (3) A ' c = 17.6451 (9) A, /3 = 104.728 (2), cell volume V = 1693.5 (1) A3 'Cryptolite group P2!/a. _&-grade_2. £>-·Meat·Essence of eucalyptus and vinegar to dissolve carnitine (1 · 61 grams, 1 〇 millimolar) and eucalyptus acid (1.80 gram '10 millimoles) in ethanol (20 ml). In a vacuum at about 4 (TC shrinks the solution until it cools down The syrup concentration of the crystal was formed. The crystal lumps were ground in acetone (50 ml), filtered, and washed with acetone and dried at room temperature in vacuo. The yield of colorless crystals having a melting point of 90-94 was 3.17 g. (Yield 93%). This material is water soluble and stable under ambient conditions. Single peak, COCH3); 2.53 (2H' double peak, J value = 6.6 Hz, CH2COO), 3·18 (9H 'Single peak, Me3N); 3.38-3.45 (2H 'multiple sound 'CH2N) ' 4_59 (1H 'five peaks, j value = 61 Hz, Qi〇H), 7.15 (1H, two double peaks, j value =! ] and 8] Hertzian); 7·37 (1H, triple peak, J value = U, 7._76 Hz, , H-5);

H-6) 〇 C16H23N07. Calculated '%: c 56·30 ; H6.79 ; N4.10. Found: % : C 55.67 ; Η 6.85 ; Ν 4.12 〇 This novel salt is characterized by an X-ray powder spectrum (CuKa _radiation) having peaks 2Θ angles of 5.09, 12.62, 13.48, 13, 84, 15.04, 17.82, 19 15 19.77, 21.84, 22.56, 23.33, 23.92, 24.40, 25.17, 25 43, 26.14, 27.24, 29.50, 30.36 ± 0.2. . The structural filaments of this novel salt were confirmed by X-ray single crystal structure analysis (Fig. 2). Crystalline monoclinic crystals, cell parameters at experimental temperature T = _ 85 〇 C system: a = 13.1342 (6) A ' b = 7.6396 (3) human ' c = 17 737 into ' stone = 104.535 (2) ' cells Volume V = 1722.8 (2) A3, crystal frame group Ρ 2ι.璧 醯 醯 加 加 加 瞳 朵 朵 朵 朵 朵 溶解 溶解 溶解 3- 3- 3- 3- 3- 3- 3- 3- 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 6 gram gram, % millimolar) in hot propanol-2 (30 ml) and heated at 5 〇 _55 〇 c for 2 。 minutes. Stop heating and stir the solution for 3 hours at room temperature. The second slurry was caked at 0 °C for another 3 hours, passed through the scales and washed with cold propanol (2 x 15 ml). The desired salt was recrystallized from propanol-2 to obtain a melting point of 104-106 °. Colorless crystal of C. Yield 412 g (yield 63%) 〇WNMR spectrum (D2〇, TMS) chemical shift δ: 2.34 (3η, unimodal, COCH3); 2.51 (2Η ' triplet, j = 64 Hz , CH2COO ), 3.26 (2H 'triplet, J = 6 4 Hz, CH2n); 3.33 (9H' unimodal, Me3N); 7.17 (1H, two doublet, j = u and 7.8 Hz, H-3) ;7.39 (1H, triplet peak,] value=1", 76 201223532 and 7.6 Hz paper 'H-5); 7.58 (1H, triplet peak, J = 17,7 6 and 7.8 Hz, called); 7.81 Million points - (1H, two double peaks, j value = 1·7 and 7.6 Hz H-6). C15H22N2〇6. Calculated,% :. 5521 ; h679 ; N858. Found % ' C 55.25 ; Η 6.79 ; N 8.53. The 'X-ray powder map (CuKa _radiation) has peaks 2 5 angles 5.^3.22, 1182, 14, 20, 14.95, 15, 36, 18.11, 18.97, 19.74, 21.02, 22.15, 23.15, 23.65, 24.31, 25.28, 26.18, 26.58, 27.73, 28.36 ± 0.2. . The structure of the new I-member salt was confirmed by the analysis of the structure of the neon single crystal (Fig. 3). Crystalline monoclinic crystals, cell parameters at experimental temperature Τ = - 85 °C System: a = 19.3399 (8) A, b = 7.2400 (3) person, c = 35.237 (2) A ' /5 = 90.758 (2 ), cell volume v = 4933.5 (4) A3, crystal frame group ρ2ι / η. The X-ray single crystal diffraction data clearly shows that the carboxyl group is protonated in the crystal structure of 3,3,3·trimercaptoic acid, L-meat and 3-(trimethylhydrazine)-propionic acid. Therefore, it shows the proton transfer from salt and the formation of salts. The crystal structure of the addition salt of 3,3,3-trimethyl-succinic acid succinic acid, the bond length values of the carboxyl group C=0 and C-0 are 215 and 1.305, respectively, on the L_ meat. The crystal structure of the alkali acid osmectic acid addition salt is 1.219A for the U94 human and 1.308 person's and for the crystal structure of the 3-(dimethyl succinylamine) propionic acid addition salt. 1.321 people. Correspondingly, the carboxyl groups c=〇 and C-0 linkages of the three crystal structures of the bisulfate fragment are all identical and have a value of about 12 201223532 1.26 A. Pharmacological characteristics of 3-(dimethylindole)-propionyl-ethyl sulphate-salt salt (salvage sulphate sulphate) It is envisaged that the novel substance disclosed in the case of '(4) can present a variety of morphological forms The crystalline form and the lysate, preferably a hydrate, which has similar biological impurities, are thus included in the present invention as a variation of the compound described. We have first established a delay in the koji sulphate and significantly reduced the skin vasodilation caused by the secret acid. The further step-by-step experiment proved the surprisingly improved pharmacological activity of the rice sulphate. Abbreviations used For the sake of simplicity, the following abbreviations are further used in this description:

AdA Adjuvant Arthritis ASA ~ Hepatic Acid C ~ Cholesterol CHD - Coronary Heart Disease CIC - Circulating Immune Complex CL ~ Chlorine * 1 vs. Gray CRP - C-Reactive Protein DI ~ Double ^ Big MoDL ~ High Density Lipoprotein-Cholesterol LA ~ Laropipant *=> a 13 201223532 LDL - Low Density Lipoprotein-Cholesterol MASA - Metrexil Acetylate (Chemical Representation: 3_(Trimethylammonium Amine) _Acetyl sulphate to form salt) MD - mitre (INN) NA - nicotinic acid, niacin (blood) RA - rheumatoid arthritis TG - triglyceride - Four Ding Awakening {Triton) WR1339 WBC - White Blood Cell

(Acros chemicals), MD (Grüders Grindex) 'ASA (Akuros Fukuoka Chemicals), LA (MK 0524 'Cayman Chemicals cayman Chemicals), for pilates (piavixTM) CL (Sanofi Anvante San〇fi_Aventis), m (Sikma Erdi Sigma Sigma-Aldrich). Yikui 4-measured MASA Year of the Year The acute toxicity of MASA was determined in the Weiss rats and ICR mice by the oral introduction method (p.o. introduction). Methods - Male irc mice weighing 20-22 grams and Weiss rats weighing 2 〇〇 230 230 grams were used. For the determination of acute toxicity, each of the 6 animals was administered in one dose amount - each increased by 500 mg / kg. After the 寇法法细(四), by the literature Akhila JS et al., #代代学2〇〇7年; 93期. Page 9Π·92〇 method to calculate LD5〇' and modified to determine the letter 201223532 Lai Interval (TumerR, The Popularity of the Law, Academic Press, New York City, 1965, pp. 61_63). The LD50 is calculated as follows: !Α〇=the minimum lethal dose to all members of the group-^(a X b)/NN _ the number of animals in each group a - dose variation b - mean mortality (2 adjacent groups The number of deaths in the group/2) MASA immediately (Hyun 叩0 yang) was dissolved in 〇2% of the lipid and introduced into the stomach by a catheter. The amount of liquid introduced should not exceed 〇 5 ml in mice and not more than 2 ml in rats. Animals were observed until the first day after introduction. Ziki: The results of the acute toxicity of MASA to mice are shown in Tables 1 and 2. Table 1 Acute toxicity of MASA to mice (oral introduction) Group Wm~~~ mg/kg (oral introduction) Number of animals in the group (N) Number of deaths (η) Mean mortality (b) Probability unit (a X b ) 1 1000 6 0 2 15 0 0 6 1 0.5 250 3 2000 6 2 1.5 750 4 Γ 2 5 0 0 6 4 —— 3 1500 3 0 0 0 6 6 5 - 2500 LD5〇= 3000 - ( 5000/6) = 2167 The coefficient of this experiment / is P = 〇. 〇 5 is U2, so LD5. The confidence interval is 1642-2860 (mg/kg). After the introduction of MASA, toxic effects appeared in the first few hours, and some of the animals died within the first 2 days. The toxic symptoms of the surviving animals gradually subsided' and these animals did not differ from the same age group of control animals after 5-8 days. Therefore, oral introduction was found to be 2167 (1642+2860) mg/kg for J LD50. The results of oral toxicity of MASA to rats are shown in Table 2 and Table 3. Table 2 Acute toxicity of MASA to rats (oral introduction) Number of animals in the group dose mg/kg group (N) Number of deaths (η) Mean mortality (b) Bits (a X b) 1 1500 6 0 ------ 2 2000 ~ 6 2 1 5 0 0 3 2 5 00 6 4 3 15 00 4 3 0 0 0 6 6 5 2500 LD5〇= 3000 - (4500/6) = 2250 The coefficient of this experiment / at P = 0.05 is 1.308, so the confidence interval of ID% is 1720 + 2944 (mg / kg). Oral introduction of MASA at a dose of 1500 mg/kg to rats resulted in transient disturbances in eating habits and exercise, but all animals survived. The symptoms of toxicity began to disappear after 3 days of introduction. Therefore, it was found that the oral introduction of MASA to the LD5 of the rat was 2250 (1720 + 2944) mg/kg. Summary - This acute toxicity study indicated that MASA is a low toxicity substance (LD5 经 > 2000 mg/kg administered orally to mice and rats). In view of the acute toxicity of ASA, it was taken from Böehringer Ingelheim Pharmaceuticals (Inc.), Acros Chemicals and Sikma Eldi (Sigma). Aldrich), oral introduction of 250 mg/kg for mice, 200 mg/kg 201223532 kg for the atmosphere, and LD% given by Bayer AG, oral introduction to rat language > 1100 mg / kg 'so MASA is less toxic than ASA. Table 3 Acute toxicity of MASA to mice and rats; n=6. Animal mouse LD50 mg/kg (oral introduction) (trust interval) 2 1 67 (1 642 + 2860) ~- Rat 2250 (1 720 + 2944) -—~———

The study of MASA's analgesic, anti-inflammatory and antipyretic effects uses a widely used method for assessing NSAIDs. The experiment used hybrid white laboratory mice and Weiss rats. At 22 ± 1 ° C, relative humidity of 60 ± 5 〇 /. Animals were placed in appropriate cages in groups of 7-8 in the climate chamber, giving 12/12_hour light/night cycles and free access to food and water. To compare the effects of MASA with ASA and MD oral introduction, the following groups were formed: Group treatment ASA50 ASA 50 mg/kg ASA100 ASA 100 mg/kg MD100 MD 100 mg/kg MASA 75 MASA 75 mg/kg MASA150 Accept MASA 150 mg / kg MASA300 Accept MASA 300 mg / kg ex tempore Prepare an aqueous solution of the test substance. In each of the 17 series, a control group was used which received the same amount of water orally. Blanket It analyzed data by software Microsoft Excel 2007 and the results were expressed as mean ± standard deviation (Mean soil SEM). The average results of the different groups were compared according to ANOVA using single factor analysis and repeated comparisons (tower assays). P < 0.05 was considered significant. Jj.. analgesic activity 2% 3⁄4 rat writhing test evaluation 铠 铠, 茌 克 涤 涤 二 evaluation of pain response to chemical stimulation method - writhing test (Charaborty A and others, life degree Guangxue You Ting 2004; 36 ( 3) Period: Pages 148-150). After intraperitoneal injection (z>), the animals obtained 0. 25 ml of a 75% aqueous acetic acid solution. After the injection, the animals were placed separately in a special box and observed for 10 minutes. Record the number of abdominal contractions. Analgesic activity was demonstrated by the number of abdominal contractions reduced over a 10 minute period. Introduce the test substance in the month of the stimulant for 3 minutes. The degree of analgesic effect The analgesic index calculated by the following formula indicates: A = (Cc - Ct) / Cc · 100%, where A - analgesic index

Cc ''the number of shrinks in the control group,

Ct ''The number of contractions in the experimental group. The results are shown in Table 4. 201223532 Table 4 writhing test nuclear second test pain effect; N=8; average New Zealand standard deviation group bingtao Ί ± R should be the animal / total 8 ΤΓ ~ - the number of contraction 2 ^ Τ〇ΤΤ 鎭 鎭 pain index control group MD 1 0 0 8/8 22.1〇± 1.47 -0.4 ASA 5 0 6/8 5. / !>±] , 32***sss 7.1 MASA 7 5 8/8 ~〇. 6 1 * * 5 5 ~ 4.5 MASA 1 5 0 7/8 ~ "〇· : ] 〇* *5 5 ~ 5.2 MASA 3 0 0 5/8 6.〇〇±i 39***sss 7.3 _ I_____— 7 3 **Ρ< 0.005 w control group - ***ρ<〇.〇0〇5 financial control group _$$ρ<〇〇〇5 埒

$$$Ρ<0.0005 V5 MD MASA shows a dose-dependent positive effect. The best results were observed for the ASA5〇 and MASA300 (P<0.0005) groups, while the Na system was ineffective. The analgesic index of the MASA300 group was 7 3 (only 5 out of 8 animals had a pain response). 5.1.2. Evaluation of bell pain by mouse hot plate test* Method - Perform a hot plate test on 52 mice weighing P - 26 grams, as described in the literature (Belyakov VA and Solov'ev IK. wide,

Novgorod City’ 2001 (Russian). A hot plate test was used to screen for central analgesia (Osterberg A et al., 痹礼身^1958; 122: p. 59). An aqueous solution of the substance to be tested is introduced through the mouth of 30 or 60 octaves/~w knives before the test. The standard for recording the time-to-door pain activity from the beginning until the addition of the paw is a delay in responding to thermal stimuli. ^ The results are shown in Table 5. 201223532 Table 5 Reaction time of mice in hot plate test; N = 8-10; mean ± standard deviation group latency, s~~' After introduction of test substance for 30 minutes after introduction of test substance for 6 minutes Control group 4.5±0.42 5.0±0.27 MD 1 00 9.5±0.68***λλ 8.3 Soil 0.53* ** AS· A 5' 0 5.4 ± 0.4 6 9 -7±1.05** MAS A75 5.4±0.3 8 4.6±0.26 MASA150 9.5±0.53***“& 7.1±0.55** MAS A300 9.6± 1. 1 2* ** 8.6±0.60*** **P<0.005 w Control Group-***P<0.0005 vs Control Group -&p<〇.〇5 vs ASA (30 minutes) *^<0.005 vsASA (30 minutes)-*^<0.0005 vsASA (30 minutes) Experimental data indicates that after 30 and 60 minutes MASA150 and MASA300 and The MD group showed significant analgesic effects. ASA significantly increased the pain threshold only after 60 minutes', indicating that the effect was slower (Table 5). Comparison of the withdrawal activity of the 符 皙 注射 注射 注射Rat's preventive talks and livelihood legislation--Testing 48 Weiss rats weighing 165-182 grams, intramuscular injection of heat source (Gflmfl/ez·Biejiage to transfer, Moss City, Russia) 'Dose is 100 micrograms (Shwarz GY and Syubaev RD, Vedomosti NCEG lekarstvenr^yh sredstv MZ RF 2QQQ year., I: page 44-50 (Russian)). One hour before the pyrolysis source injection Oral administration of the test substance 20 201223532. Before the injection of the heat source (reference) and 3 hours after the injection, the electronic body temperature «10 TERMG33 rectal temperature. The decrease of the high temperature reaction 2 hours after the injection of the pyrogen source was evaluated. The data of the anti-Linlin silk (ι〇) has a good correlation (Table 6). The ambient temperature is maintained at 2〇_21〇c. As the data obtained, the body temperature of the control group gradually increased, at 2 small and · Internal arrival table value ' and continue to be higher than the normal range in the next hour. Table 6 Changes in rectal temperature of the control group under the influence of the heat source; N = 8; mean ± standard deviation group basis (°C) rectal temperature (°C) After 60 minutes, after 60 minutes, after 120 minutes, after 180 minutes, control group 36.16 ± 0.16 & 6.25 ± 0.21 36.75 ± 0.12 ## 36.90 ± 〇.1〇 ### 36.70±〇.17# #P< 0.05 W benchmark-^PO.OOS Viy benchmark-_p<〇〇〇〇5 ν·ϊ benchmark to be tested The substance did not substantially affect the normal body temperature of the animal, but substantially reduced the hyperthermia induced by the heat source (Table 7). Table 7 Effect of substance to be tested on hyperthermia induced by intramuscular heat source; Ν=8; mean±standard deviation group reference rectal dissection (°C) rectal temperature (.C) control group 36 minutes after injection 2±0.12 36·9±0·16 will MD 1 00 35.9±0.18 36.2±0.16* AS A50 35·8±0·17 35.6i0.19***31 MAS A75 36.1±0·18 36.3±0·20 * MASA 1 50 35.8 ± 0.15 36 ± 0.21** MAS A300 35.9 Soil 0.14 35.8 ± 0.16 *** 1 * P < 0.05 w Control group - ** P < 0.005 w Control group - *** P < 0.0005 w 21 201223532 Control group

^¥<0.005 v·? Benchmark-$Ρ<0·05 Still MD In the hyperthermia model, the increase in body temperature induced by injection of heat source was completely prevented in the ASA50 group and the MASA300 group (Table 7). The antipyretic effect in the MD100 group, MASA75 group and MASA150 group was less obvious. Lack._2.2·Evaluate the prophylactic antispasmodic activity of rats by injection of pyrogen (treatment mode) 3: Method - for 48 Weiss rats weighing 182-205 g, study the substance to be tested in medical treatment The antipyretic effect of the model is to inject 1 〇〇 microgram dose (Shwarz GY and Syubaev RD, μ shape 2000; 1 : page 44-50 (Russian)). The heat source induces excessive heat. , Moscow City, Russia). The test substance was orally administered 2 hours after the injection of the heat source and immediately after the increase in body temperature was recorded. The rectal temperature was measured with a forceps TERM〇 before the intramuscular injection of the heat source (reference temperature), excessive heat peak (heat source control), and 3 minutes after the substance to be tested (and 21⁄2 hours after the injection of the heat source). The experimental to ambient temperature was maintained at 2〇_22〇c. The results are shown in Table 8. 22 201223532 Table 8 Effect of substance to be tested on her sister's heat-induced hair (treatment mode); N=8; mean ± standard deviation group ~ Wm rectal m (°C) Rectal brewing after injection of heat source (°C) (heat source control) rectal release after 30 minutes of treatment (〇c) control group 36.10±0.15 36.90±0.2 (Γ 37.00i0.181* MD 1 0 0 36.41±0.14 3T.06±0A3m 37__·14 A. S A. j 0 36.39±0.13 37.04±0.25# 36.5^0.15=^ MASA 7 5 36.23±0.12 37.0^0.11^ 36.90i0.071® MASA 1 5 0 36.25±0.20 36.96±0.15# 36.75±0.09#* MASA 3 0 0 36.11±〇.14 Γ 3610.11- ~36.40±0.11*thief~~ 叩<0.05 w control group-#p<〇.05 v>s benchmark _ ##p<〇〇〇5 still benchmark ° /οΡ<0.05 ν·5 Heat source control group _ $p<〇〇5 VJ md _ $$p<〇(8)5 w md For all animals in the experiment, the heat source induces a significant and similar increase in body temperature (compared to the heat source control VS Benchmarks, Table 8). Treatment with the substance to be tested, except for MD, resulted in a decrease in body temperature relative to the baseline and heat source control. Relatively low temperatures were observed in the MASA300 group and the ASA5 group, where body temperature The reduction was significant compared to the control group and the MD100 group. It is worth noting that in the MASA300 group, contrary to the ASA50, the body temperature control for the heat source was also significantly reduced. This indicates a fairly rapid antipyretic effect of MASA. It may be clinically valuable. 5.3. Comparison of anti-inflammatory activity of the substance to be tested 511. Acute inflammation of the edema model. Method - using red algae test (Winter C and others, real 1 splash To #学舜磬学之拉# Public abandonment 1962; ΠΙ (3): 544-547. Wei Jia et al.

S 23 201223532, 'The School of Science, 2003 (89): 139_141; Suth_n 箸, Journal of Traditional, Complementary and Alternative Medicines, · Year's: Page 411_416) in 42 rats weighing 226-274 grams To experiment. Single-injection difficult to dilute 1 ml) Red algae knee (Sigma) solution (1%) was introduced into the hind paw of rats. After the injection of the red algae gel, the test substance was introduced orally (via the catheter to the purchase). The volume of the foot was measured at the reference time and 4* after the injection of red algae by the instrument B volume measurer. Calculate the ratio of prevention (inhibition of edema) according to the following formula: p(%) = (1 - Vo/Vc) X 100, where percentage of p_prevention (inhibition of edema)

Vo - the difference in the volume of the foot between the baseline and the experimental conditions;

The analogy difference Q of Vc' in the control group is shown in Table 9. Table 9 Anti-bleeding activity of the test substance in the red algae inflammation model; N=7, average standard deviation

Control group - & P < 0.05 Vly ASA100 - $p < 0.05 VS 24 201223532 In the acute inflammatory edema model, the volume of the affected limb in the control group increased approximately 1.6 times. The most significant effect on the inflammatory process was observed in the MASA 150 group, where the prophylactic index was 93% relative to the control group. In the ^8-8 group, the activity was slightly lower _ edema was reduced by 91%. A decrease in edema was also observed in the MD100 group and the ASA50 group. Nothing to be tested 皙 皙 皙 皙 之 之 之 之 之 之 之 之 之 赭 赭 赭 赭 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (Russian)) Red algae edema was studied in 42 rats weighing 178-220 grams. The test substance was introduced orally through the mouth over a period of 5 days. On the sixth day, immediately after the introduction of the test substance into the rat, immediately, 0.1 ml of a 1% red algae solution was administered to the hind paw. The paw volume was measured at baseline and after 4 hours of injection of red algae. Calculate the prevention index as described in the previous section. Prophylactic introduction of the test substance for 6 times resulted in a reduction in edema compared to untreated animals (Table 10). Table 1 预防 Preventive anti-seepage activity of the substance to be tested on red algae edema; N=7, mean ± standard deviation group foot volume (ml) After injection of red algae gum volume (ml) ml reduction % control Group 1 · 43 ± 〇. 1 2 1.93 ± 0.11 0 MD 1 00 1 .33 ± 0.09 1.66 ± 0.1 0 34 _ AS A50 1 · 40 ± 〇. 〇 6 1 · 5 5 〇 〇 04 * 7 0 A MASA 15 0 1 ·3 7±〇· 1 1 1 .40±〇·〇9* 94 A MAS A3 00 1 .34 土〇.〇7 ~1 .41±0 04* **~ 86

*Ρ<0.05 w control group-**p<〇.〇〇5 w control group-¥<0.05 w MD 25 201223532 In this inflamed model, a significant preventive effect was observed in the MASA 150 group and the MASA 300 group. Activity (94%), which was higher in the mdioo group (34%) and the ASA50 group (70%) (Table 10). To assess the strength of the inflammatory process 'at the end of the experiment (5 hours after injection of red algae)', the tender concentration was determined by a standard method on an analyzer "INTEGRA 4〇〇+>>. The results of CRP measurement in blood are shown in Table u. Table 11 In rat model of red algae inflammation, CRP concentration in rat blood; N=7, mean soil standard deviation group CRP mg/L CRP increase % i group 〇·17±0.015 0 red algae gel control group 0.23±0.016* * 100 ~MD 1 00 0.22±0.01 4* 83 AS A 100 0.20±0.01 8 50 MAS A 1 50 0.1 9±0.009” 33 MASA 3 0 0 0.21±〇.〇14* 67

*P<0.05 still control group-**p<0.005 w control group-#p<〇〇5 still red algae control group ¥<0.05 vsMD As data obtained, red algae gel leads to increased CRP in rat blood . In the ASA100 group, the CRP concentration was reduced by 50% (Table 11). Unexpectedly, in the MASA 150 group, the significantly increased CRC concentration was less significant (only 33% relative to the control group). It supports the theory that MASA can have a positive effect on the inflammatory process in the clinic. Example 6 - Study of the anti-rheumatic activity of MASA against ASA deduction MD 26 201223532 Clinical evidence shows that patients with rheumatoid arthritis (RA) have previously had atherosclerosis and cardiovascular disease (Nas〇n 〇v EL, 2003 (7 issues): Page 6_1〇). Patients with long-term follow-up have more atherosclerosis than patients with more recent age of the same age. Secret inflammation can increase the risk of vascular disease of the age of the dysfunction (Del Rincon I et al. 'Study of Difficulty for 2 years 7 years; 196 (7): pp. 354-360). Rheumatoid arthritis ranks first in rheumatoid arthritis. The experimental animal lion that turned the most for human wet arthritis was the adjuvant arthritis model, which was injected into Freund's hind paw by injection of Freund's adjuvant. It is widely used to screen anti-arthritis agents (Wei Jia et al., pp. 2003 (89) item 139_(4); minus (four) ^ fine coffee, etc., traditional, complementary and alternative medicine African journals, said (7) years, From »Hot.. see 411-416) 〇越: We arranged the experiment to test the effect of ancestral recognition on the adjuvant arthritis process, compared with MD and ASA ^ in Weiss rats with a starting weight of 153_185 grams. experiment. The rats were placed in a climate chamber of 22 ± 1, m humidity 6 〇 soil 5%, Xuan 12 / called, time light / night cycle. Seven 4 rats were placed in each standard cage, and there were no peaks and no granular standards. All experiments were carried out according to the European Community Council Directive __EC on November 24, 1986. All efforts are made to minimize the pain of the animal; to minimize the amount of animal use and to reduce the amount of animal use. 0 27 § 201223532 Use a modified calibration procedure to guide and evaluate the process of chronic adjuvant arthritis (Bellavite P, Ortolani R and Conforti A, Immunology and Homeopathic 3 Animal Model Experimental Study, Admnce

Access 2·05 ’ 2006, pp. 171-186). A complete Freund's adjuvant solution was injected 1 ml to the rat's paw and sputum 5 ml to the abdominal cavity of the rat. A solution of the substance to be thanked is prepared on the spot. The amounts used are ASA 〇 1% and 1%, MD 1% ’ and maSA 〇 25%, 1% and 2% aqueous solutions. The solution to be tested is introduced into the stomach of the animal through a catheter. The following animal groups were formed (N=7): Group treatment group 1 intact animals used as control group (control group); Group 2 animals with induced arthritis (AdA); Group 3 After induction of adjuvant arthritis, animals received an ASA dose of 1 mg/kg per day for 28 days (ASA 10); Group 4 After induction of adjuvant arthritis, animals received an ASA dose of 1 mg/kg per day. 28 days (ASA100); Group 5 After induction of adjuvant arthritis, 'animals received an MD dose of 1 mg/kg per day for 28 days (MDl〇〇); Group 6 after induction of adjuvant arthritis, Animals received a daily dose of MASA 25 mg/kg for 28 days (MASA25); Group 7 After induction of adjuvant arthritis, animals received a daily dose of MMA of 1 mg/kg for 28 days (MASA100); Group 8 After induction of adjuvant arthritis, the animals received a daily dose of MASA 200 mg/kg for 28 days (MASA200); 28 201223532 Animals in the control group and animals in the AdA group did not receive the test substance, but in the same way as the test group. The watch accepts water by mouth. The blanket was analyzed by software Microsoft Excel 2007 and the results were expressed as mean soil standard deviation (Mean soil SEM). The average results of the different groups were compared according to ANOVA using single factor analysis and repeated comparisons (tower assays). Ρ <0·05 is considered to be significant. Shame: Study the kinetics of clinical manifestations of arthritis on days 14 and 28. Use the following criteria to assess the effects of the substance to be tested: 1. Assessment of arthritis in the area - foot volume and ankle joint circumference. 2. Assessment of the blood count (WBC). 3. Evaluation of biochemical tests (CRP). 4. Evaluation of the immune index (CIC concentration). The edema is measured by the organ volume measurer, which is the volume of the hind paw. Percentage of prevention (inhibition of edema) was calculated according to the following formula: P(%) = (Vc - Vt) / Vc X 100, where Vc - the volume of the foot in the control group Vt - the volume of the foot in the test group P - prevention (inhibition of edema) percentage. The blood index was measured on a blood analyzer <<PENTRA 12>> by a standard method, and CRP was measured on "INTEGRA400+>>. The CIC concentration in the serum was measured by spectrometry, and ethylene glycol was used. After the / main shot of Freund's adjuvant, all animals in the experimental group developed chronic inflammation, and the rats were fatigued, aggressive, and unkempt. However, healthy food

29 S 201223532 The habit of weight in all groups is not different from the control group in all groups. ^2 and 13 represent data for day 14 and 28: foot volume (characterized by edema of soft tissue = current volume (arthritic organ damage characterized by joint tissue). 12 on the 14th day of injection of Freund's light and Effect of M) on day 28; N=7; mean number of days difference ml ml prevention % ml ΗΗ 预防 % % % control group 1 · 〇 3 ± 0. 12### Λ 1 · 08±0.1 - A d A 2.42 ±0.1 7 AS A 1 0 2.5 3 ±0 l〇U η 2.23±0.24 0 ASA100 "Κ/Γ ΙΛ 1 Λ A -/ Γ 2.〇8±〇.12 7 z . j ;> 士0 · 1 4 Γ 3 1 ”±0.07^ 3 2 MUIUU "MA~SA25~~ MAS A 1 00 ” 2.60±0·21 ^2.20±〇T2l~~~2 .〇7±〇Γΐ 7^~ ClfZ ~Γ5 — 1·93土013 mj Λλ 13 1 · 32±0.12 ~ 41 1 ·22±〇.〇8 45 JV1 A 〇A ^ l) U 2 · 1 3±〇. 1 1 & 12 1 . 7 ± 0 · 0 9ff * 24 V5 ASA10 P<0.0005 vs ASA10 - ®Ρ<〇.〇5 vs ASA100 - ^<0.05 vs MD As shown in Table 12, all animals in the experimental group developed significant soft tissue on day 14 Edema. Treatment during the 14-day period has minimal impact on the development of edema. However, MASA100 group and MASA Animals in the 200 group had significantly less edema than the animals in the ASA10 group. On day 14, the MD and ASA10 groups not only did not prevent the development of edema, but had a larger volume than the AdA group (negative protection). _7%). All doses of 30 201223532 masa on day 28 and ASA100 significantly prevented edema development (% of protection, 41, 45, 24 and 32% each). It is worth noting that ^sAioo is compared to ASA10, ASA100 and MD' showed significantly better protection. On the 14th and 28th day after the injection of Freund's adjuvant, the test substance was turned on.

'P<0.05 AdA - ><0.005 AdA - *P<a〇5^ASAl〇T ^<0.05 ASA100 $P<0.05wMD Analysis of the joint data (Table 13) shows that on the 14th day Only MASA200 significantly prevented the progression of arthritic damage. At day π, MASA25, MASA100 and ASA100 showed significant protection. In this experimental setup, 'MASA100 showed relatively best protection. We have established that on the 28th day, the degree of leeches (Table 12) and arthritic changes in the joints (Table 13) were all attenuated. MASA 100 is significantly more effective than ASA or md. The evaluation of wbc showed an increase (apoptosis) under the influence of Freund's adjuvant (Table 14). Leukocytosis is a characteristic of the inflammatory process. 31 s 201223532 Table 14 Changes in WBC in the blood of rats under the influence of the test substance on the 14th day and the 28th day after the injection of Freund's adjuvant. 1SK7 ;mean ^ standard deviation group control group

Ad A AS A 1 Ο AS A 1 〇 MD 1 〇〇 M AS^A2 5 M ASXl 〇〇~

TiTiirmT TTT〇7±l .43 """" Day 14 15. 1 7±0.76 ΤΓΤδΤΓΤΤ

6/68^17^2^ 14.42± 1.4 1

5 · 5 5± 1.26 1 6.77±1 .78 14.72±1.63 14.lfi0.53~ 1 5.42± 1.40 ^4^5±Τ.8 4 # M ASA200 *P<_5 v^T^<0_05 One phase Compared with the AdA group, the substance to be tested caused a decrease in the amount of the treasure, and Ting indicated anti-inflammatory activity. The effect of the substance to be tested on the increase of white blood cell concentration ^Wei Wei on the last day _ on the 14th day, the brain flat = relatively high activity, but on the 28th day is the genus (table ^ for · inflammation In the abundance, the (10) wave was measured on day 14 and day. It is known that the CRp concentration is co-administered during the inflammatory process. 32 201223532 Table 15 On the 14th and 28th day after the injection of Freund's adjuvant, in the test The change of CRP concentration in the blood of rats under the condition of plastic film formation. N=7; the average number of standard deviation group CRP, halo T^j:~—the 14th day of the control group 0.1 9±0·0 1 〇 .16±〇.〇2 ## A d A 0.30±0·02*** 0.24±〇.〇2* * AS A 1 0 0.26±0.01** 0.1 9±〇.〇ι # ASA 100 0.29士0.01 *** 0.1 8±〇.〇2 MD 1 〇〇0.26士0.02* * Γ 〇.17±〇.〇2 # ' MAS A25 0.29士0.02* * 0.15±〇.〇2 MAS A 1 00 0.29±0 ·02** 0.1 6±0.〇1 mas A200 0·25±0.01*# ® 〇.19±〇.〇ι # *P<0.05 vs Control Group-**p<〇.〇〇5 v>s Control group _ ***P<〇〇〇〇5 still control group P<0.05 w AdA - ^<0.005 vj AdA - ·Ρ<〇.〇〇〇5 w AdA - &p< 〇5 w ASA10 ®Ρ<0.05 vj ASA 100 As shown in the data in Table 15, all the test groups showed an increase in CRP concentration on day 14 indicating the process of inflammation. In our experimental setup, at 14th Only masmoo showed obvious protection against the increase of CRp. It should be noted that MASA200 had a better effect than MASA100 on the 14th day. On the 28th day, maSA25 and MASA100 showed a significant comparison with the eight 1 Excellent protection (Table 15). Determination of CIC concentration by standard spectrophotometric method (Baranovskii PV and RudykBI, Wirework 1982; 12: pp. 35-39 (Russian)). Day and day 28 immune factors. Changes in concentration are shown in Table 16. £ 33 201223532 Table 16 Number of CICs (units) on days 14 and 28 after injection of Freund's adjuvant. N=7; Number ± standard deviation CIC unit, 14th day CIC unit, 28th day control group 9·4± 1 .〇5(1) 7.8±0.49## AdA 17-4 ±1,29** 1 3,4± 1.25 * * AS A 1 〇10.8±〇.74s s 8.2±0.53ff AS A 1 〇〇1 5 · 0士1 · 2 3 * 14.4±1.66* MD 1 〇〇1 1 8±2.22 8.6±0.93s MAS A25 12.6±〇76F 1 1 ,8±1 .53 MASAI〇〇20·8±2·99* 5.8± 0 · 7 4&@@s MASA200 2 1.6 ± 3.2 6 * 6_2 Soil 1.02"®*

*P<0.05 vs control group-**P<〇.〇〇5 ViS control group_#p<〇.〇5 w AdA - Office<0·005 vs AdA $P<0.05 MD - &P>0.05 Vs ASA10 - ^<0.05 ASA100 -_P<0.005 v·? ASA100 On day 14 and day 28, the CIC concentration of the test group was higher than that of the control group. On day 14, only the ASA10 and MASA25 groups had lower CIC concentrations than the AdA group. On day 28, the CIC line in the group receiving the test substance was close to the control group, except for the ASA100 group. During the experiment, on day 14, an increase in CIC concentration was observed in the ASA100, MASA100, and MASA200 groups. At day 28, the CIC concentrations in the MASA100 and MASA200 groups were normalized. An increase in serum CIC concentration can be observed in a variety of immunopathological conditions. In the process of inflammation (including the symptoms of the system), a substantial increase in CIC can be observed, and the concentration of CIC indicates the strength of the pathological process (Bier Ο et al., Di Ji Long Ling #, New York, Hai 34 201223532 Debao 'Berlin, page 442). Long-term treatment with different doses of MASA reduces the CIC concentration to the normal range. Under adequate active immunization, the major portion of CIC is removed by Copernic cells and a reduction in CIC concentration is understood to be a positive benefit. On day 28, in the MASA100 and MASA200 groups, the use of MASA demonstrated the benefit of normalizing CIC concentrations. This fact indicates that 'long-term use of different doses of MASA can clinically treat arthritis, more than increase ASA dose hope. Example 7. Study of anti-hyperlipidemic properties Atherosclerosis is a multifactorial process (Berliner JA et al., Trilogy of the Rings 1995; 91: pp. 2488-2495) 'has a coronary artery with an increase The clinical impact of an increase in heart disease symptoms. Inflammation and the reaction of organic tissues have played a substantial role in the process of atherosclerosis (Ross R, Tao Sheng, Cao Pan/〆 1999; 138; page S419-S420). Clinical observations indicate that anti-inflammatory treatment reduces the occurrence of atherosclerosis (Stoller DK et al., 1993); 54: pages 7-11. Experimental data confirms a significant association between anti-inflammatory activity and hypolipidemic activity, at least between cox-i inhibitors (Kourounakis AP et al. 'Realization as Molecular Reduction of Sexuality 2002; 73: 135-138) . We compared the activity of ASA and MASA at the same dose. Z.I. Comparison of lipid concentrations in the model of acute dyslipidemia in Datun. Effect Fang Fen I used male Weiss rats weighing 250-270 grams. In a climate chamber with 22 ± 1 35 201223532 C relative humidity of 60 ± 5 〇 / 将, the animals were placed in appropriate cages with 6 8 __ miscellaneous, giving 12/12 hr light/black fore ring, and $ Free access to food and water. Acute experimental hyperlipidemia/hypercholesterolemia induced by Trid〇n (Trit〇n) ^1339 (TR), as evidenced by κ〇(10)AP et al., 'Success and Molecular Sterilology 2002; 73 Period: Pages 135-138. Rats were orally treated with an isotonic saline solution at a dose of 25 mg/kg after overnight fasting. The solution or water of the test substance was orally introduced into the control group and the TR group animals 2 hours before, after, and 2 hours after the introduction of the TR, as described below. On the next day (24 hours after the injection of TR), blood was collected for biochemical analysis by cardiac puncture under B-anesthesia. Serum was separated by centrifugation and analyzed for total cholesterol, HDL, LDL and TG concentrations using a commercially available kit. Perform three series of experiments. Charmitz analyzes the data by software Microsoft Excel, and the results are expressed as the mean +/· average standard deviation. Single factor analysis and repeated comparisons (tower assays) were used to compare the average results of the different groups according to ANOVA and Student's t-test. P < 0.05 was considered significant.

Series I - 鲛 ASA, MD and MASA cohort control group treated animals 6 TR TR 250 mg / kg 8 ASA45 TR 250 mg / kg + ASA 45 mg / mg 6 ASA90 TR250 mg / kg + ASA 90 mg / mg 8 36 201223532 MD150 TR250亳克/kg+MD150mg/kg8 MASA75 TR250mg/kg+MASA75mg/kg6 MASA150 TR250mg/kg+MASA150mg/kg8 MASA300 TR250mg/kg+MASA300mg/kg8 Blue hang Z accepts TR Rats developed significant hypercholesterolemia and hyperlipidemia. The total cholesterol, LDL and TG concentrations were significantly different from those in the control group (total C increased by 6-7 times, TG 30 times - more see Table 17). «>ASA treatment', especially at a dose of 90 mg/kg, limits the increase in total c, LDL and TG, but does not significantly alter HDL concentration. MD did not significantly prevent changes in lipid concentration caused by TR in our experimental settings. Treatment with MASA caused a dose-dependent inhibition of hyperimmune hyperlipidemia/hypercholesterolemia. The dose of 75 mg/kg MASA is no different from ASA45, but the rejection of TR is more effective than ASA45 and MD150. In terms of reducing total C, LDL and TG, it is far better than ASA45 and ASA90. This indicates that MASA can be used to prevent and/or treat hypercholesterolemia and hyperlipemia, and its anti-inflammatory activity can be used to prevent and/or treat atherosclerosis and promote dysregulation and inflammation of lipid metabolism. Other illnesses. 37 201223532 Table 17 Comparison of lipid concentrations in rat hyperlipidemia model by MD, ASA and MASA; n=6-8; mean±standard deviation group C mg/dl HDL mg/dl ldl mg/min TG MG / dl control group 8 (K7 ± 4.7 ... 56.5 2.8 2 2 · 1 2.6 *** 44.0 ± 6.9 *** TR 453.6 ± 40.0 6 0.3 soil 9.6 386.0 ± 36.5 1399 ± 129.7 ASA45 3 « 1.0士30.3 62.8±10.9 307.4±37.8 973±82.7* ASA90 288·1±23.5* 60.0±7.4 219·1±23·9* 791±73·9** MD1 50 345·6±34·1 63.8±9.3 273.9 ±31.6* 1022±80.7* MASA75 341 _9±16·3* 68.1±8.7 270.l±l2.8* 861±105·7* MASA150 249.6±22.2 ♦本$ & 58.2±8· 1 182.4 士19.6&quot ;u 668±104.4**s& MASA300 219.0±16.7 56·3±8·6 1 58.6±19.4**s#& 548±73.2 ... *P<0.05 TR - **P<0.005 V5 TR - ** *P<〇.〇〇〇5 vs TR -$P<0.05 ASA45 #P<0.05 V5 ASA90 - &P<0.05 v5 MD150 Series ΰ _ Compare ASA, MASA, NA and ASA+NA, MASA+NA compositions Group treatment animal number control group 6 TR TR250 mg / kg 8 ASA45 TR250 mg / kg + ASA45 毫g/mg 6 MASA TR 250 mg/kg + MASA 150 mg/kg 6 NA TR 250 mg/kg + NA 50 mg/kg ASA ASA+NA TR 250 mg/kg + ASA 45 mg/kg 7 +NA50 mg/mg 38 201223532 MASA +NA TR 250 mg/kg+MASA 15〇mg/kg 7+NA50mg/kg Zyu: In our experimental setup, 'NA provides significant changes in xr-induced lipid (C, LDL and TG) concentrations. Confrontation protection (see Table 18). The combination of ASA and NA did not significantly alter the effect on lipid concentration. Surprisingly, the combination of MASA and NA considerably enhanced the effect of NA50 and was superior to MASA's protective effect on TR-induced TG concentration increase (Table 18 > MASA and NA combination use, compared to ASA45+NA50 The normalization effect of LDL and TG concentrations was also significantly more effective. Table 18 Lipid concentrations of MD, ASA and MASA in the rat hyperlipidemia model and the effects of the composition; n = 6-8; mean ± Standard deviation group c mg / deciliter HDL mg / deciliter LDL mg / deciliter TG mg / deciliter control group 80 · 7 ± 4 · 7 *** 56.5 soil 2.8 21.1 ± 2.6 *** 44 soil 6.9 ** * TR 60.3±9.6 3 8 6.0±3 6.5 1399 Earth 129,7 ASA45 381.0±30.3 62·8±1 0.9 307.4±37.8 973±82·7* MASA150 249.6±22.2**4 58.2 8.1 182.4±19.6** * 668±70.9**s NA50 327.5±38.4* 66.5±14.6 246.3±32·5* 591士43.3** ASA45+NA50 3 16.0±43.1 * 57.9 Soil 14.3 251·2±33.8* 618±42.8** MASA150+ NA50 226.3±24.9**#ϊ 63.1±10.2 163.2土 19.3* « $#% 468土34.7** $ # % @ *P<0.05 vi TR - **<0.005 v,s TR - ***P< 0.0005 TR - ¥<0.05 V5 ASA45 @P<0.05 V5 MASA150 - #P&lt ;0.05 vs NA50 - 〇/〇P<0.05 v5 ASA45+NA50 39 201223532 Series πι -Compare one _, j^Masa and si+j^, SI+MASA Composition group treatment animal number control group 6 TR TR250 mg /kg8 top movemg/kg+SI5mg/kg7 MD TR250mg/kg+md 150mg/kg6 MASA TR250mg/kg+MASA150mg/kg6 SI+MD TR250mg/kg+SI5亳g/kg +MD ? 150 mg / kg SI + MASA TR 250 mg / kg + SI 5 g / kg + MASA 7 150 mg / kg Ιέ to: In our experimental settings 'SI at the dose of 5 mg / kg provides a clear Counter-protection of changes in TR-induced lipid (c, LDL, and TG) concentrations (see Table 19). The combination of SI and the substance to be tested increases the effect of normalizing the lipid concentration. The combination of MASA and SI was significantly more effective than md+SI for countering the increase in xr-induced LDL and TG concentrations (Table 19). The combination of MD and Stade has been proposed by the patents w〇2〇〇6〇99244, which does not contain any data. The combination of Striding and ASA requires additional pharmaceutical compositions because these materials are pharmacologically and chemically incompatible (Patent US 6,235,311) so there is no synergy. 201223532 Table 19 Lipid concentrations of MD, MASA and SI in the rat model of hyperactivity and the effects of the composition; n = 6_8; mean ± standard deviation group C mg / dl HDL mg / dl LDL mg / Split TG mg/dl control group 80.7±4.7*** 56.5±2.8 21.1±2.6 ... 44±6.9 ... TR 453.6±40.0 60.3±9.6 386.0±36.5 1399±129_7 SI 321.3±32.3* 53.7±12.4 259.3±30.1 * 826±44.1** MD 345.6±34.1 63_8±9.3 273.9±31.6* 1022±80.7* MASA 249.6±22.2**& 58.2±8.1 182.4±19.6**&668±70.9**& SI + MD 281.5 ±3 59·5±14·9 217.1±26.2* 690±32.6**&* SI + MASA 230.7±28.6^* 62.8±14.6 153.4±28.0** &%u 512±40.2** &%

*P<0.05 vs TR - **<〇.〇〇5 vs TR - ***P<0.0005 vs TR - &P<〇.〇5 vs MD -$P<0.05 SI - #P<〇. 〇5 V5 MEH-SI Summary - Results indicate the potential of MASA to prevent and/or treat southern cholesterol and hyperlipidemia. Consider the anti-inflammatory activity of MASA, which is more effective than ASA or MD in the prevention and/or treatment of atherosclerosis and other conditions promoted by inflammation. The combination of MASA and NA enhances the positive effect of increasing the lipid concentration experimentally over ASA plus NA. The combination of MASA and SI is not only more effective than SI alone, but is also significantly more effective than MD+SI for countering the increase in TR-induced LDL and TG concentrations. The effects of NA and MASA on the lipids of rats with chronic hyperlipidemia and the effects of the composition were compared with male Weiss rats. Animals were placed in appropriate cages in groups of 7-8 in a climate control chamber with 22 ± 1 sense and relative humidity of 6 〇 ± 5%, giving 12/12-hour light/night cycle ' and free access to water With food. The 201223532 animal has an initial weight of 220-240 grams. Using the method described by Levine and Saltzman (Levine S and Saltzman A, 襄座 and Qin^才法势^2〇〇7年'55, 224-226) induce experimental chronic (subchronic) with TR Lipidemia / hypercholesterolemia. Animals received a 250 mg/kg TR solution via the tail vein for a total of three weeks a week. The solution of the test substance for the experimental group or the water for the control group was orally introduced once a day before the injection of the solution or the blood collection sample, according to the following calculations: Group treatment animal number control group 10 TR TR250 mg/kg 14 TR+NA TR 250 mg/kg+NA 50 mg/kg/day 14 TR+MASA Tetraphenol (Triton) 250 mg/kg+150 mg/kg/day 14 TR+NA+MASA Tetrabutylphenol 250 mg/ Kg + NA 50 mg / kg + MASA 150 mg / kg / day 14 After 1, 2, 3 weeks (from the next day after TR injection), blood for biochemical analysis was obtained by cardiac puncture under acetaminophen anesthesia. The bleeding was separated by centrifugation and the total c, HDL, LDL and TG concentrations were analyzed in a commercially available kit. 0 42 201223532 Charisma Itz analyzed the data by software] VticrosoftExcel and the results were expressed as mean +/_ mean standard deviation. Single factor analysis and repeated comparisons (tower assays) were used to compare the average results of the different groups according to ANOVA and Student's t-test. P < 0.05 was considered significant. Suspension = Repeated injection of TR developed significant and stable hypercholesterolemia and hyperlipidemia, which was characterized by a significant increase in total c, LDL, and TG concentrations compared to the control group (total c increased by 6-7 fold, TG to 30 and more, see Table 21). The NA therapy' particularly markedly increased the total c, ldl and TG increase in the first week but significantly increased the HDL concentration only at 2 and 3 weeks. MASA reduced the total C and LDL concentrations and increased the HDL concentration almost as in NA, but it was less than NA in terms of preventing the increase in TG caused by tr (see Table 20). Surprisingly, the combination of Na+MASA was substantially better after 3 weeks compared to NA or MASA alone in reducing total C, LDL and TG concentrations and increasing HDL concentrations. Therefore, the composition of NA + MASA is expected to be useful in the prevention and/or treatment of hypercholesterolemia and hyperlipidemia. 43 g 201223532 Table 20 Lipid concentrations of sputum and MASA in rat chronic hyperlipidemia model and effects of composition; n=9-14; mean ± standard deviation group total C after 1, 2, 3 weeks , mg/dl Cl C2 C3 control group 77·6±4·9# 75”±5.1# 72.7±2.5ff TR 487·6±25.4 501±16.7 5 1 3±41. 1 TR + NA 345± 1 5.7 * 401.1±25· 1 * * 405.5 soil 25.9* TR+MASA 375.9±25.8* 4 0 6.7 ± 1 9.8 * * 409±39.4 TR+NA+MASA 33 1.7±28.4* * 379.1±24.7** 3 75·8 ±31 * Table 20 continued group HDL after 1, 2, 3 weeks, mg / dl HDL1 HDL2 HDL3 control group 54.6 ± 1 · 9 * 54.1 ± 1. 3 53.7 ± 1 · 0 * TR 76.3 ± 6.9 76.2 ± 1 1.4 77±10.2 TR + NA 1 1 1 _3±9· 1 * 144.7±13·5β 1 27·3± 1 0.9* TR+MASA 100.1 ± 9.4 1 1 3.8 ± 1 3 . 1 128.3 ± 18.5* TR+ NA+MASA 112.3士10.9* 1 29.2± 1 3 . 1 * 154.1±1 Table 20 continued group LDL After 1, 2, 3 weeks, mg/dl LDL 1 LDL2 LDL3 control group 1 8.7±3·8* 1 9.7±4.4ff 1 6.3±2.0ff TR 3 8 8.7 Soil 26.7 402.1± 19.2 405.1±4 1.7 TR + NA 216.3 ± 14.0 25 0.3±20.6* 265·1±18·4* TR+M ASA 263.3士1 9.4 287.6 soil 18.5* 261.9±12·6** TR+NA+MASA 205.7± 1 8. 222.4±16.5ΒΛ 214.4±15.1 Table 20 continued group TG after 1, 2, 3 weeks, mg/ Split TGI TG2 TG3 control group 38±2.9ff 37±3.2ff 3 8±4.4ff TR 1 240±80- 1 1 297±78.3 1 234± 1 14.1 TR + NA 734±8 1.6ff 860±73.8 * * 828士44.7* TR+MASA 964±94.9* 1 079±84 982±72.7 TR+NA+MASA 72 1.6±52.4&ff 807·6±80·1 714±27.3...

*P<0.05 vs TR - **<0.005 V5 TR - #<0.0005 TR - $P<0.05 NA 44 201223532

&P<0.05 vi MASA The combination of MASA and NA is significantly more effective than the substance alone.

1D.1. Platelet aggregation ASA is one of the most widely used anti-platelet preparations for prevention (Miner J et al., the name of the production of the heart and the rot of the poor test 2 years 7 years; 34 (2) period: 179-186). ASA has been combined with NA as an anti-inflammatory agent (patent US 3,312,593) and an anti-platelet agent (patent w〇 9632942). Many other agents and combinations thereof are known. It has been established that MD normalizes vascular tone, inhibits platelet aggregation and fatty acid oxidation, and optimizes oxygen consumption during myocardial ischemia (Tsirkin VI, and 2002, No. 1: pp. 45-52). Slightly inhibit platelet aggregation (Lakin KM et al., F is like //, 1980, 43(5): pp. 581-5 (Russian)). A typical anti-platelet formulation, sputum, is used alone (patent US 4,529,596, US 4,847,265, US 5,576,328) or in combination with Sterding (patent W098〇4259) or in combination with ASA (patent W09729753). The anti-platelet preparation double η ratio can also be combined with asa (Halkes PH et al., 襄 襄 2006 2006, 367 (9523): pp. 1665-73). Clinical experience points to a higher versatility of multiple pharmaceutical compositions. Stand up! Use whole blood impedance agglutination on multiplates to study platelet aggregation (multiple platelet function analyzers, Dynabyte Medical, Germany) (Toth Ο et al., 'Lishe Formation Shame 2006 2006; 96 Period: pp. 781-788. Velik-Salchner C et al., Yan Jing Free ^ Tibetan Education Office 2008; 107: Page 1798-1806). A health donor who has never used ASA or 2 45 201223532 any other antiplatelet agent. B. (37 years old) collects the blood used in the in vitro experiment (4) the company's plastics tube covered by the money It is used to measure between 30 minutes and 4 hours. In the ex vivo (exviv. Indignation, the blood of the rat from the hemp, which has been treated with the substance to be tested for 3 days, to the plastic tube covered with hirudin (Dynabyte Medicai, Germany). The modified scientific laboratory of Dynabyte Medical is used for straightening. Isotonic sodium solution (〇3 ml, or saline with the compound to be studied (each to a final concentration of 1σ4 mmol/ml)) Pre-heated to 37 C and pipetted to the test cells, then add 3 ml of water-stained whole blood sample for antibiotics. After 5 minutes of incubation, stir at 37 ° C to add appropriate promotion. The solution (obtained from Dynabyte Medical, Germany) was used to start the measurement: 1) Di-glycolic acid (ADP) - ADP-test. ADP stimulates platelet activation by the ADP receptor (P2Y12 and others). 2) Arachidonic acid (AA) - ASPI-test: The matrix of AA-reactive cyclooxygenase forms thromboplastin A2 (TXA2), which is a potent platelet agonist. 3) ADP HS test (combination of prostaglandin E! and ADP) Adding the endogenous inhibitor PG&, making the ADPHS test more sensitive to the effect of clobarrel and related drugs than the ADP test. Record aggregation curve ό min Using Dynabyte Medical's software analysis, we calculated the following platelet aggregation parameters: l) Amax, the maximum platelet aggregation in arbitrary units (AU) of 46 201223532; 2) AUC 'under the aggregation curve Total area (AU*min). This is affected by the total twist of the aggregation curve and its slope, and is best suited to represent the overall platelet activity. Blanket ib results are expressed as mean ± standard deviation (Mean ± SEM). To assess the significance of the differences, one-way ANOVA analysis was used. If the null hypothesis is ruled out, then the student Newman Muller check is used after the fact. As shown in Table 21, 'masa provides significant contrast to the concentration of ισ4, especially for platelet aggregation induced by sputum and ADP+PGE (significant reduction in AUC and Amax, Table 21)« > ΝΑ (in the 1〇^ pen Moer 35 liter group) also reduces the aggregation caused by ADP (see, Table 21). The binding activity of the two substances provided a significantly greater and significant decrease in platelet aggregation caused by ADP or ADP + PGE], which is shown in both the A and Amax data (Table 21). Table 21, NA, and their combinations also affect the induction by ADP, AA, and PGEfADP; mean ± standard deviation; N = 5-8.

Group ADP

47 S 201223532 Table 21 continued group AA AUC (AU*min) Amax (AU) Control group 1 023±46.3 1 78.8±6.9 MASA 10° 832±54.1 148.4 + 5.71 MASA ΙΟ*4 298±25.3 ^ 66. MD 10_4 1 050±3 7.6Λ 1 79.5±7.3& ASA ΙΟ4 45 0±24. 1 03. l±5.9iff(® ΝΑ ΙΟ'4 1.0.10 ± 4 1.7 1 6 Ί . 1' ± 今.4 mdi〇 -4 + nai〇·4 1 1 06±5 5.4 1 73 ·3± 1 2.1 MASA 10'4+NAl〇·4 216±18 ASA+NA 463±35.2“” 99.4±8.22 ... Table 21 continued group PGEi +ADP AUC (AU * min) Amax (AU) Control group 1 〇〇5±46.5 1 75.3±8.9 MASA 10° 5 95±45.3 1 99.3±4.8Z MAS A 1 Ο·4 5 3 3 士20 J 8 7.7 ± 4.6 j && MD 10'4 587 士 37_42&* 1 0 1 A±2.2Z&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& 3 06±35.5JBSa&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&7.22iD&卞<0.05 w control group-2P<〇.〇〇5 w control group-3Ρ<〇.〇〇〇5 ν·ϊ control group-4P<0.00005 w control Group & < 0.05 Houle eight 8 eight _ & amp &; < 0.005 Houle eight 8 eight - ** ^ <?? 0.0005 w ASA - $ < 0.005 w MD 10 " *

^<0.0005 vi MD 10"4 - ^><0.005 νί ΝΑ 10"1 - ^^.0005 ΝΑ 10^ ®P<0.05 vs MASA104 - ^<0.05 vs ASA+NA - ¥<0.05 MD +NA MASA is significantly better at avoiding AA-induced platelet aggregation than ASA or MD (Table 21). The combination of MASA+NA exhibits significantly higher activity on aggregation induced by AA, which is superior to Individual individual 48 201223532 quality, as well as ASA+NA and MD+na (Table 21).

Parallel experiments were performed with platelet aggregation caused by ADP or AA in combination with diterpene (4) and DI and subsequent or MASA (Table 22). ^ Demonstrating anti-I-plugs and recordings (MammenEF (4) year book, page W) is more than aspirin plus aspirin, compared to aspirin itself, cerebral ischemia of arterial origin Effective ((2) PH et al. '##刀 2006, 367 (9523) period: page secret _73). Table 22 Effect of the material on the induction by ADP or AA, the difference between the plate and the composition. Average soil standard deviation; N=5_8. Group Af)P AA AUC (AU*min) Amax (AU) AUC (AU*min) Amax (AU) Control group 942±43.7 169.3±6.4 1023±46.3 1 7 8.8 Soil 6 · 9 MASA 1 0 798 Soil 38_9 298±25·33 “ά 66 ] ±f\ 93aa& ASA 10·4 883±50.3 151.7±9.3 450±24.8Ja@ ^03 1±S o2a@ DI 3xl0'4 665±44.1 2&111_1±6.92&1104±45.5&@@ 173 9土5 2&@@ M AS A 1 0 4+DI 3xl04 465±27.03^* a& 69.7±3.23@Ia & 116 $aaa& 38·5±3.64@@ $$aa& ASA 10'4 + DI 3x10 4 667±39.42A 105.2 soil 6.72 & @ 207.9±27.53 & aa 62.8±6.82&aa ip<0.05 w control group -2ρ<〇.005 νί control group _ 3P<〇〇〇〇5 pairs control group

4P<0.00005 vj control group-&p<〇.〇5 VlS ASA - ^(0.05 w MASA

@^<0.005 V5 MASA - aP<0.05 νί DI - ^0.005 vj DI - ^P^.ooos V5 DI

$P<0.05 w ASA+DI _ *^><0.005 w ASA+DI In this series, MASA+DI exhibited the highest activity, which was significantly higher than the activity of ASA+DI (Table 22). 8.2. Blood loose flow

After the experimental arterial thrombosis, oral administration to rabbits and dogs for two weeks MD 49 201223532 Medical use showed the effect of lysis blood test (Logunova L et al.

Experim ChnPkarmacoter 1991; 19: page 91-9 (Russian)). There is no known data on the preventive effect of MD in controlling or preventing thrombosis. NA reduces blood tests through a variety of mechanisms (R〇sens〇n milk, etc., the more Dianhe/6 disease; 1998; 140: 271-80). We chose an experimental thrombosis model based on rat arterial thrombosis induced by ferric chloride sweat ecy (KurzK et al., Blood Hair Shape 4, Ministry of Poverty 1990) 60: Page 269-280 WangX and Xul, and the formation of the house was broken in 2005 '115: Page 95-100). Tissue damage initiated by the chemical oxidation of Tiezhongsuke causes injury sites that are susceptible to platelet adhesion and aggregation, followed by coagulation activation and fibrin deposition. Male Weiss rats weighing 350-420 grams were used in the experiment. Animals were placed in appropriate cages in groups of 7-8 in a climate chamber with 22 ± 1 〇 c and a relative humidity of 60 ± 5%, giving 12/12-hour light/night cycles, and free access to food and water. All experiments were carried out in accordance with the provisions of the European Community Parliament Directive (86/609/EEC) on the care of laboratory animals on November 24, 1986. All efforts are made to minimize animal suffering and reduce animal use. Rats were randomly divided into experimental groups, each consisting of not less than 7 animals. Administration of vehicle or test chemical MD (25 mg/kg), NA (25 mg/kg), SA (10 mg/kg), ASA (5 mg/kg) by oral route 2 hours before the onset of thrombosis And composition coffee + like (25 + 25 mg / kg), MASA + NA (10 + 25 mg / kg) and ASA + NA (5 + 25 mg / kg). Parallel experiments were performed to compare the effects of a single dose of test substance (administered 2 hours prior to the onset of thrombosis) 50 201223532 and repeated doses (daily-three times total). Groups of 7·8 animals received the following materials: MASA (10 mg/mx, pyridine pyridoxine (5 $g/kg), ASA (5 mg/kg) and composition MASA+CL (1〇+5 mg) /kg) or ASA+CL (5+5 mg/kg). Rats were anesthetized with barbiturate sodium (intraperitoneal injection of 50 mg/kg, and 1 mg/kg/hr) and placed on a thermally controlled operating table. On the whole, the body temperature of 37 C was maintained throughout the experiment. One of the carotid arteries was exposed by a neck incision, separated from the adhered tissue, the vagus nerve, and the first-class probe (electromagnetic blood flow meter MPV 12〇〇, NiconKohden Corporation' Japan Placed on the exposed part of the total carotid artery to record blood flow. After a 15-minute stabilization period, two pieces (2x1 mm) were immersed in ferric chloride (FeCi3) by topical application (contact with the outer surface of the adventitia). ) 15/° solution of Whitman filter paper to induce thrombosis. The time of carotid thrombosis is recorded as the time required to cause a complete stop of blood stasis, here, until the time of obstruction (TM) In the silk treatment group, if the blood flow does not stop within 90 minutes, record TTO as &g t; 90 minutes. In addition, during the thrombosis experiment, the tail bleeding time of the rat was measured. With the scalpel view 5 mm slit, the tail was immediately immersed in a warm 37 °C, and the bleeding was stopped. The bleeding completely stopped and was not reflowed for the next 30 seconds, which was defined as flow ▲ stop. 4 After the thrombosis experiment, the anesthetized animals that received the test substance for 3 days were used for indirect _ (ex called Platelet polygraph test. Open the abdominal cavity 'Collect blood from the inferior vena cava into a plastic tube covered with hirudin (Cai Hua Coffee (4), Germany). Use a blood sample for between 3 minutes and 4 hours after collection. Measurement

S 201223532 quantity. Measurements were made according to the scientific laboratory test of modified Dynabyte Medical (see above for platelet aggregation).

Mltr analyzes the data with software Microsoft Excel 2007. Data are expressed as mean soil standard deviation (Mean ± SEM). ANOVA one-way analysis and repeated comparisons (tower assays) were used to compare the average results of the different experimental groups. Ρ<θ·θ5 is considered to be significant. In the control group, the mean time for vascular blood tests caused by ferric chloride (FeCl3) and the resulting arterial flow arrest was 24.4 minutes (Table 23). Table 23 Effect of test substance on carotid thrombosis caused by FeCl3. Mean ± standard deviation; N = 7-8 groups until occlusion time tail bleeding ~ minutes % minutes % Control group 24.4 ± 1.45 1 00 8.9 ± 1.28 10 0 NA (25 fag / kg) 3 0.3 ± 3. I 2 1 24 1 1 . 5±1.3 9 Tl9~ MD (25 mg/kg) 29.8±2.29 122 1 0.5± 1 . 〇1 118 MD + NA (25 + 25 mg/kg) 34.0±2.78 1 13 9 1 1 .4± 1.42 12 8 MAS A (1 0 mg/kg) 41 .7±3.952# 17 1 1 2.1±2.20 13 6 MAS A+NA ( 1 0 + 25 mg/kg) 53.1 ±4.1 2^labc # 2 18 1 3.5±4· 1 9 TsITM ASA (5 mg/kg) 3 5 ·2±3.02 1 144 1 3 . 8±3.2 7 ~TsJ~ AS A + NA (5 + 25 mg/kg) 4 2 · 5 ± 4 · 2 4 2 * # 174 15.2i2.121 ΤΤΓ 卞<0.05 vs Control Group-2Ρ<〇·〇〇5 vs Control Group-#p<〇.〇5 vs MD - $P<〇 .〇5 vs ΝΑ

^<0.05 vs ASA - ^<0.05 vs ASA+NA - cP<〇.〇5 vs MIXNA The prophylactic treatment with MASA provided a significant extension of TTO (P<0.005 w control group), but contrary to ASA However, it was less effective in bleeding test 52 201223532 (136 vs. 155%) oMASA + ΝΑ (10+25 mg/kg) resulting in a relatively longer thrombosis delay, better than ASA+NA (Table 23). It should be noted that with ASA and ASA+NA, the TTO was added parallel to the bleeding time, while the use of MASA or M^A+NA was significantly higher than the bleeding time (Table 23). In a parallel experiment with general control, the effects of ASA, MASA and CL and their compositions on thrombosis were studied. The test substance was administered in a single dose (2 hours before the test) or once daily for a total of three days. The ASA or CL introduced 2 hours after the thrombosis test significantly prolonged the TTO relative to the control group receiving water (Table 24). Table 24 Effect of a single dose of test substance on TTO and bleeding time in a three-iron iron (FeCl3)-induced carotid thrombosis experiment. Mean ± standard deviation; N = 7-8 group until occlusion time tail bleeding time minutes % minutes % Control group 24.4 ± 1.45 100 8.9 ± 1.28 100 MASA (10 fag / kg) 4 1 .7 ± 3.952b 17 1 12.1±2.20 13 6 ASA (5 mg/kg) 35. 士]^1 144 13.8 士3.27 155 CL (5 克g/kg) 3 1.7±2.401 130 1 1.9 soil 3.62 134 MASA + CL (10 + 5 Mg/kg) 61.5±4.31”abc 25 2 1 5.7 ±3. 1 6 176 ASA + CL (5 + 5 pg/kg) 45 ·4±4·80... 186 1 6.3±2.25 1 183

Ρ Ρ <0·05 w control group-2P<〇.〇〇5 w control group-3P<0.005 w control group P<0.05 vs MASA - *Ρ<0.05 vs ASA - ^^.05 CL - cP<0. 〇5 v5 ASA+CL 53 201223532 A more pronounced increase in TTO is provided compared to the CL 'single dose of MASA. Simultaneous administration of MASA and CL significantly increased ΤΤ0, but only slightly changed the bleeding time (Table 24). It should be noted that the composition of mASA + Cl resulted in a significant increase in ΤΤ0 relative to the combination of the separated material and ASA+CL. Repeated treatment with the test substance resulted in a further increase in sputum and bleeding time (Table 25). Table 25 The effect of repeated treatment of the test substance on TTO and bleeding time in a ferric chloride (FeCl3)-induced carotid thrombosis experiment. Mean soil standard deviation; 7-8 group until occlusion time tail bleeding time minute % min% control group 25.3 ± 1.75 100 8.6 ± 1.37 100 MASA (10 mg / kg / day) 48.4 ± 4.35 ^ 191 13.1 ± 2.63 152 ASA (5 mg/kg/day) 40.^3.251 162 17.8±3.17' 207 CL (5 fag/kg/day) 49.li7.751 194 18.3db3.78* 213 MASA + CL (10 + 5 mg/ Kg/day) 64·6±8·01 “$ 255 20.7i3.881 241 ASA+CL (5+5 mg/kg/day) 61.0±10.322a 241 27.4±4.9823ia 3 19 ><0.05 w Control Group-2Ρ<0.005 νί Control Group-$p<〇.〇5 VlS MASA - ^(0.05

Vs ASA repeated treatment with MASA or CL produced a significantly higher effect on no compared to ASA (corresponding to '191 and 194% vs. 162%), but MASA, in contrast to CL or ASA, did not increase bleeding time (Table 25). Repeated treatment with MASA+CL or ASA+CL produced a considerable and fairly similar increase in TTO' but was less than ASA+CL (241% V·? 319%) in terms of affecting tail bleeding time. Table 25). 54 201223532 Ex vivo (exvzVo) experiment After the thrombosis experiment, the animal blood was collected and the aggregation parameters were measured. Treatment with MASA at a dose of 10 mg/kg for three days' resulted in a significant reduction in platelet aggregation by all of the tested singers (Table 26). Table 26 Effect of MASA, ASA, CL, and the like in ex vivo (with v(d) on platelet aggregation; mean ± standard deviation; ν = 4_7 · group Mrt /f-rl~Λρ ----- -- ADP AUC (AU * mi η) Amax (AU) Control group 794 ± 33.5 149.7 ± 9T4 MASA 10 g / kg / day 528 ± 46.5 * TyJIYTJ2 ASA 5 mg / kg / large 768 ± 53.2 Γ 150.3 ± 13.5 CL 5 mg / kg / day 423 ± 39.42 ά 68.2 ± 1 MASA + CL (10 + 5 mg / kg / day) 140 ± 16.8 increase (10) & aD 35.3 ± 9.4J 唼 * && ab ASA + CL (! >10 5 mg / public order / day) 230 ± 29.8 Like a 53.3 ± 11 ^ T ^ _ Table 26 continued group AA AUC (AU * min) Amax (AU) Control group 935 ± 62.3 167 · 8 ± 11.6 MASA 10 MG/kg/day 232±44.1^a 48.2±9.7J&a ASA 5 Halo/kg/day 550±31.3Z 86.1±6.8Z CL 5mg/kg/day 905 soil 53.5* 160.7±13.5λ® MASA+ CL (10+5 mg/kg/day) 1 87±29.4 jatsa —30.7±9.8J&&a ASA+CL (5+5 mg/kg/day) 239±32.7... 39·8±14.1 ... 55 201223532 Table 26 continued group PGEi+ADP AUC (AU * min) Amax (AU) Control group _ 8 5 5±40” 1 59·5± 1 2.2 MA SA 10 mg / kg / day 195 ± 35.3 J 41.4 ± 14.82 ASA 5 mg / kg / day 794 ± 48.6 147, 2 ± 118 CL 5 mg / kg / day 259i49.3z & 49.7 ± 9.9 J && MASA + CL (10+5 mg / kg / day) 87 ± 15.8 J ® aDie < K * 15.5 ± 4.8 J (a) ab &&& ASA + CL (5 + 5 mg / kg / day) 128 ± 19.4 ®as&&24.6±5.8j(®a&&&

4 (0.05 w control group-2p<〇,〇〇5 νί control group-3ρ<〇·〇〇〇5 V5 control group-®Ρ<0.05 V5 MASA &Ρ<0·05 vs ASA - ^0,005 w ASA - &&&P<〇.〇〇〇5 w ASA _ aP<0.05

Vi CL - ¥ < 0.05 V5 ASA+CL Treatment with CL at a dose of 5 mg/kg/day for three days resulted in a defensive effect comparable to aggregation induced by ADP and PGEi + ADP, but did not prevent aggregation induced by AA. The ASA provided significant protection against AA-induced aggregation but was not effective against ADP and PGEfAJDP (Table 26). The combination of maSA and CL (10+5 mg/kg/day χ3) provides the relatively highest effect of avoiding aggregation induced by multiple agents' clearly superior to those provided by ASA+CL in ADP and PGEfADP tests (Table 26) . Summary MASA is far superior to MD or ASA with similar molar concentrations in combating AA-induced platelet aggregation. The protection of aggregation caused by all inducers of MASA+NA was significantly better than that of _, like and ASA, and the composition was also superior to MD+NA for aggregation induced by AA. 56 201223532 Considering the positive benefits of the combination of MASA and MASA+NA against platelet aggregation and prolongation of TTO in vivo, MASA or MASA+NA compositions can be used to reduce significant atherosclerosis, potential myocardial infarction and Platelet aggregation and thrombosis risk in patients with injuries and peripheral blood circulation disorders. The MASA and MASA+NA compositions do not extend the tail bleeding time'. This fact indicates that this composition is useful for patients with increased risk of bleeding before and during surgery. MASA+DI is far superior to ASA+DI in preventing aggregation induced by ADP and AA. MASA+CL ° in the thrombosis trial 'single dose of MASA+CL provides a better defense against triironized iron (FeCl3)-induced thrombosis compared to ASA+CL. MASA+CL is relatively less than ASA+CL in terms of extending tail bleeding time. In ex vivo (ex v/vo) experiments, significant anti-purple against platelet aggregation was provided that was much greater than CL, ASA or MASA. MASA+CL is better than ASA+CL for defense against platelet aggregation induced by ADP and PGE]+ADP. These facts indicate that 'MASA+CL can be clinically applied to immediately prevent the risk of increased platelet aggregation, impending or ongoing thrombosis. Example 9 · MASA/NA, MD/NA, and LA/NA are combined to induce flushing. The study of nicotinic acid (niacin, NA) effectively lowers serum cholesterol, LDL, and Triglyceride' and increase hdl. However, for the 2012 201223532 patients who received immediate or sustained release from acid testing, a restrictive adverse effect was the apparent rapid development of skin warming and vasodilation, known as "flushing", which severely led to discontinuation (Gupta EK and Ito MK, Heart Congestion, 2002, 4, pp. 124-137). Laropiprant (MK-0524) (LA) has been proposed as one of the most active and forward-looking agents for reducing tidal flushes (Cheng Κ et al., 琢镠 琢镠 学 虎 魔 魔 魔 2006 2006 2006 2006 Year; 1〇3: Page 6682-6687). 9.jjf cutaneous vasospasm caused by nicotinic acid is used as an empty sputum. Male heves rats are anesthetized with sodium pentobarbital (50 mg/kg, ip) and given an additional dose per hour (1 〇mg/kg) is under anesthesia. The blood pressure of the left carotid artery was measured and the ECG was recorded in the standard Π lead. The blood flow to the right ear artery was measured with a laser Doppler flowmeter (OXYFLOW 2000, USA). Blood flow, ECG, and arterial pressure were recorded in an AD instrument PowerLab system and stored in a computer for further processing. After a 1 minute long baseline recording, the test substance was injected into the armor area by subcutaneous injection and continued to record for 30 minutes. Taking into account the mean blood pressure, the mean blood flow data for each animal was calculated' and compared to the starting value and the control group. The results were calculated from 5 to 8 experiments, respectively, and expressed as a percentage as the largest blood flow for the benchmark (Carballo-Jane £ et al., Scorpio Sexuality, Law, and Law, 2007; 56(3): Page 308-316). Shame it: The results for each group are expressed as mean standard deviation (MeardSEM). Statistical analysis within the group was performed by Student's t test. The average results of the different experimental groups were compared using an〇vA one-way analysis and repeated comparisons (tower assays). P < 0.05 was considered significant. 58 201223532 Results ^ In this animal model, the dose of 15 mg/kg for acid-accepting qsja resulted in a significant increase in blood flow in the auricular arteries (Table 27). MASA, similar to the control group (buffered 0.9% NaCl solution), caused insignificant changes in blood flow. NA, together with MASA, resulted in a delay (slow increase) and a statistically less significant increase in blood flow compared to sputum alone (Table 27). Therefore, we have unexpectedly found that MASA significantly reduces peripheral vasodilation caused by sputum. MASA can antagonize peripheral vasodilation caused by sputum, a potential that can be clinically useful to attenuate the effects of niacin on the skin (flushing) and is studied in further detail, as described below. Table 27

A (1 5 mg jin + 45 mg / kg) _ *P < 0.05 still control group - ** p < 〇. 〇〇 5 control group $ ρ < 〇 · 〇 5 ν ^ 碱 alkaline acid _ caused by skin temperature rise High Drying Effects Our research objective is to compare the effects of MASA, MD, and LA on flushing (changes in skin temperature) caused by NA in the experiment. Friendship I used male Weiss rats (280-330 grams). At 22 ± 1 ° C, relative humidity 60 ± 5 〇 /. Animals were placed in appropriate cages in groups of 7-8 in a climate chamber, given a 12/12-hour light/night cycle, and free access to water and food (R3 - Lactamin AB, Sweden). In order to record the whole 59 201223532

Changes in skin temperature in rats were performed using a non-contact temperature recording method (Papaliodis D et al., Pod Glyphs for 2 years; 153: 1382-1387). Temperature measurement was performed using a hand-held infrared thermometer (M〇dd pr〇scan 510, TFA-Dostman). In the first three weeks of use, the animal is treated with the mussel and the infrared probe. Under no anesthesia, the temperature read from the back of each ear was recorded at the beginning and throughout the experiment. The ear temperature was measured every 5 minutes for a period of up to 60 minutes. Between measurements, place the animals back into their cages. NA, and M^A were dissolved in saline before use and the pH was corrected. On each day of the experiment, LA (MK 0524 'Caman Chemicals) was first dissolved in DMSO and diluted with 0.9% NaCl. The ratio of the NA and LA compositions is based on the product characteristics of the TredaptiveTM (in the acid/Lalopine (1) (8) mg / 2 〇 mg modified sustained release tablets. 邈社! Six ear temperature measurements (three per ear) The data were averaged at each time point. The data were analyzed by software Microsoft Excel and the results were expressed as mean ± MS. The single factor analysis and repeated comparison (tower verification) were used to compare different groups according to AN0VA and Student's t test. The average result of the group. P < 0.05 is considered to be significant. Interstitial and solvent versus * Skin temperature Tang shadow group treatment Animal number SolvLA Solvent for LA 6 SolvNA Solvent for ΝΑ, MASA and MD 6 ΝΑ 毫克 15 mg / Kg (subcutaneous injection) 6 201223532 22.2. Subcutaneous injection of 丨301 at the same time 丨01 or 30 minutes ago, the study of 猸 ^ ^ ^ 物质 虔 虔 虔 检验 LA LA LA LA LA LA LA LA LA LA LA LA LA LA LA LA LA LA LA LA LA LA LA LA LA LA LA LA LA Each compound studied was injected subcutaneously with NA, such as LA+NA [0], or 30 minutes before NA, such as LA+NA [30]. Number of animals 6 cohort control group / solvent ΝΑ NA15 mg /kg LA LA0.3 mg/kg LA+NA LA 0.3 mg/kg+NA15 mg/kg6 MD MD45 mg/kg6 MD+NA MD45 mg/kg+NA15 mg/kg6 MASA MASA45 mg/kg6 MASA+NA MASA45 mg /kg+NA15mg/kg6 9.2.3. At the same time, 〇1 or 45 minutes before the application of subcutaneous injection, MAqA/Ma and MD/NA compositions for the skin / Solvent NA MD MD+NA MASA150 Number of animals 6 NA40 mg / kg 8 g / kg 6 MD 100 mg / kg + NA40 mg / kg 6 MASA 150 mg / kg MASA75 + NA MASA 75 mg / kg + NA40 mg / kg 6 MASA150 +NA MASA150 mg/kg+NA40 mg/kg6 Results R 9.2.1 Test time and effect of solvent on skin temperature from 1 pm to 2 pm, the recorded mean ear temperature was 28.4-30.6 °C. A time response study of ΝΑ (15 mg/kg, subcutaneous injection) showed that at 10 minutes, the maximum temperature from the baseline was increased by 2.32 ± 0.37 ° C. The maximum temperature was increased by 2 57 ± 〇 43 compared with the solvent group. (P0.005) (Fig. 4). It was established that the effect of LA solvent on ear temperature was only after injection. The initial 5 minutes is essentially different from the NA, masa, and ^ solvents, so only one control group is used to calculate the temperature at 1 minute. R 9.22· At the same time, 1 or 30 minutes before the application of 古3〇1 to the ancient injection, the subcutaneous injection of MASA, MD or LA on the skin temperature is not obvious to the skin temperature of the rat ear. Changes (Table 28). There is no change in temperature between MD+NA[0] (when MD is added with NA) and MD+NA p〇] (when MD is given 30 minutes before NA). 201223532 Table 28 Effect of MASA, LA and MD on skin temperature increase caused by sputum; Ν=6, mean±standard deviation group start temperature °c maximum temperature °C increase, % control group/solvent 29.5±0.29 29.62 ±〇.25^Λ - ΝΑ 29.6 1±0.40 32.2±0.42*** 100 MAS A 29.3±(K35 29·2±0·38 ... - MASA + NA [0] 29.9±0.3 1 3 1.5 ±0.40* * 62 MASA + NA [30] 29.6db〇.32 30.9 ±0.32** 50 LA 29.43±0.27 29.5士0.35 ... - LA + NA [0] 29.72±0.3 1 31.45±0·40** 67 LA + NA [30 ] 29.5 1±0.3 2 3 0.73±0.34〇47 MD 45 29.42±0.3 8 2 9 · 6 Earth 0 · 3 1 (1) - MD+NA [0] 29.53±(K29 3 1 ·33±0·48* 69 MD + NA [30] 29.68±0.26 3 1 .40±0·39* 65 *P<0.05 w Control group-**P<〇_〇〇5 w Control group-***P<0.0005 w Control group $Ρ&lt ;0.05 ΝΑ - $$$Ρ<0.0005 ΝΑ Simultaneous administration of strontium and MASA (NA+MASA [0] group; lead time = 0) caused a decrease in NA flushing, which was similar to simultaneous administration of NA and LA or NA and MD The temperature increase caused by NA is reduced, correspondingly from 100% (NA effect) to 62%, 67 and 69% (Table 28). In the experiments, administration of MASA+NA and LA+NA (30 minutes prior to NA, subcutaneous injection) resulted in a significant and similar increase in skin temperature caused by NA (Table 28). R 9.2.3. Oral NA/MASA And the effect of the ancient skin temperature effect of the NA/MD composition at a dose of 40 mg / kg orally (orally introduced) NA caused a substantial increase in the skin temperature of the rat ear and the delay of 63 201223532 (up to 60 minutes), the highest value was 15 Between 45 minutes and 45 minutes (Table 29). Table 29 MASA or MD for NA-induced skin hyperthermia at the same time [〇] or in advance [4 effects of treatment; N = 6-8, mean ± standard deviation group Starting temperature °C Temperature 15 minutes Temperature 3 〇 Minute temperature 45 minutes Highest - Increase % Control group / Solvent 29.9 ± 〇.32 30.2 ± 0.48 * s 30.0 ± 0.335 ** 30.1 ± 0.37 ss 9 NA 30_0 ± 0.41 32 · 3 ± 0·46** 33_1±0.41*" 32.4±0.48** 100 MASA 15 0 29.7±0.28 29.9±0.33s* 29.5±0.35*s* 29.6±0.39s* 6 MASA75+NA [0] 29.7±0.33 31.9 ±0.51* 32.3±0.37**5 32.1±〇.46* 84 MASAI 50+NA [0] 29_8±0.37 30.9 Soil 0.47s 32.0±0.42*s 31.95±0.38* 70 MD 29_9±0.35 30.1±0.39ss 29. 8±0.38ss* 30.0±0.34*s 6 MD + NA [0] 29.6±0·26 31.3±0.35*s 32.5±〇.42** 32.2±0.40* 96 MD100+NA [45] 29.3±0.35 31.2± 0.33** 32.3±〇.41** Γ32.1±〇,44*~ 95 MASA75+NA [45] 29.4±0.30 31.3±0.53* 3 1.9±0.45* 31.5±0.42*s 80 MASA150+NA[45] 29.7 Soil 0.38 30.7±0.41s 3 1.2±〇.44*# —30.2 ±0.38s— 48 *P<0.05 w Control group-**P<〇.〇〇5 vs control group _ _ρ<〇.〇005 νί Control group $Ρ<0.05 νί ΝΑ - $$Ρ<0.005 vs ΝΑ - mP<〇,〇〇〇5 ΝΑ &Ρ<0·05 w MASA150+NA [0] - ®Ρ<〇.〇5 w MASA75 +NA [45] ^<0.05 νί MD+NA [45] Oral introduction of MASA or MD did not cause a substantial change in skin temperature. A small change was made at a dose of 75 mg/kg while introducing the dishes ^^8 and (9), but the dose of 150 mg/kg substantially prevented the increase in skin temperature induced by ^ (Table 29). Simultaneous introduction of md (1 mg/kg) and NA prevented the temperature from increasing for 15 minutes, but did not significantly prevent the maximum increase in skin temperature induced by NA (see temperature of 3 minutes, 45 minutes). The results of the analysis showed that a dose of 15 mg/kg from 64 201223532 and sputum introduction increased the skin temperature to 70%, which was substantially better than the decrease caused by NA+MD (96%). Those who increase by NA alone are considered to be 100%. Introducing the substance in a prophylactic mode—SNA 45 minutes ago, the activity of temperature decrease was increased by MASA150+NA [45] and was significantly better than MD+NA [45] or MASA75+NA [45] (Table 28). Oral introduction or subcutaneous injection of MASA reduced the skin temperature increase induced by NA. When subcutaneous injection of MASA' is similar to laropiprant, the increase in skin temperature induced by NA is reduced, either simultaneously or prophylactically. When introduced simultaneously with NA or in a prophylactic mode, the substantial anti-flushing activity of MASA indicates the potential for MASA to reduce the adverse skin effects (flushing) of NA. Summary Conclusion Because MASA has anti-inflammatory, anti-hyperlipidemic and anti-platelet effects, it can be considered as a novel therapeutic agent for the treatment of thrombotic diseases. Mode for Carrying Out the Invention The present invention provides a medicine comprising 'MASA for anti-inflammatory, analgesic, antipyretic, anti-rheumatic, anti-hyperlipemia, anti-atherosclerosis, anti-aggregation and anti-thrombotic agents. The medicament of the present invention can be administered in the form of a pharmaceutical composition. According to this aspect of the invention, there is provided a pharmaceutical composition comprising a MASA mixed pharmaceutically acceptable diluent or carrier. For anti-inflammatory, analgesic, antipyretic, anti-rheumatic, anti-hyperlipidemic, anti-atherosclerotic, anti-aggregation and antithrombotic drug uses, it is assumed that long-term use of the 'best practice of the invention' mode is to provide Oral shape 65 201223532 type, such as pills or capsules. «This bribe provides a pharmaceutical composition as defined above or a pharmaceutical composition as defined above for the manufacture of _ in the treatment of inflammation, pain, fever, rheumatism, hyperlipemia, atherosclerosis, Use of a drug for platelet aggregation or gold plug formation. Another aspect of the invention relates to a composition drug comprising an agent selected from the group consisting of NA, Studdin, CL and DI. These products can be based on the N-phase composition of the MASA. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a fragment of a crystal structure of a 4-trimethylammonium butyrate acid addition salt. Figure 2 is a fragment of the crystal structure of the bismuth succinic acid addition salt. Figure 3 is a fragment of the crystal structure of 3-(trimethylhydrazine)propionate acetalic acid addition salt. Figure 4 shows the effect of NA, solvent for NA (SolvNA) and solvent for LA (SolvLA) on skin temperature in rat ears. [Main component symbol description] None. 66

Claims (1)

201223532 VII, the scope of application for patents: 1.4-triammonium ammonium butyrate acid salt. 2. The 4-trimethylammonium butyric acid succinic acid addition salt as described in the first paragraph of the patent application is characterized in that it has an X-ray peak value of 2.10, 13.58, 13.83, 15.02, 15.17, 17.89, 19.33, 19.87. , 21.85, 22.05, 23.32, 23.56, 23.92, 24.75, 25.55, 25.80, 27.05, 27.9, 30.25 ± 0.2〇. 3· Z-meat test B-salt acid addition salt. 4. The plant carnitine salicylic acid addition salt according to item 3 of the patent application is characterized by having X-ray peaks 2 5.0 values of 5.09, 12.62, 13.48, 13.84, 15.04, 17.82, 19.15, 19.77, 21.84, 22.56. , 23.33, 23.92, 24.40, 25.17, 25.43, 26.14, 27.24, 29.50, 30.36 ± 0.2 〇〇5.3-(dimercaptopurine) propionate (metazone) salicylic acid addition salt. 6. The 3-(trimethylhydrazine) propionate (metazone) salicylic acid addition salt of the fifth paragraph of the patent application is characterized by having a calender peak value of 20.9, 13.22, 13.82, 14.20, 14.95, 15.36, 15.93, 18.11, 18.97, 19.74, 21.02, 22.15, 23.15, 23.65, 24.31, 25.28, 26.18, 26.58, 27.73, 28.36 ± 0.2. . 7. The 3-(trimethylhydrazine)propionate (metazone) acetalic acid addition salt of claim 5, which is a solvate or polymorph for pharmaceutical use. 8. A pharmaceutical composition comprising, as described in claim 5, 3((3)thyl)propionate (metrequinone) ethanoic acid addition salt, and a pharmaceutically acceptable carrier. B 67 201223532 ' 9. A pharmaceutical composition according to claim 8 of the patent application as an immediate release, sustained release or extended release formulation. 10. A pharmaceutical composition according to claim 8 which is suitable for oral administration. 11. A method for preventing and/or treating inflammation, pain, fever, rheumatism, hyperlipemia, atherosclerosis, conditions aggravated by platelet aggregation or thrombosis, including The patient is administered a pharmaceutically effective amount such as a towel, and the fifth embodiment of the cultivating osmanthus acid addition salt or the pharmaceutical composition of claim 8 is applied. 12. A pharmaceutical composition according to claim 8 for use in the prevention and/or treatment of inflammation, pain, fever, rheumatism, hyperlipemia, atherosclerosis, aggregation by gold platelets or thrombosis Form the induced condition. 13. The use of a rice koji succinic acid addition salt as claimed in claim 5 or a pharmaceutical composition according to claim 8 for the prevention and/or treatment of inflammation, pain, fever , rheumatic conditions, hyperlipemia and atherosclerosis, conditions induced by platelet aggregation or gold plug formation. 14. The use of the rice koji succinic acid addition salt of claim 13 wherein the condition induced by platelet aggregation comprises an ischemic event such as myocardial infarction or stroke, or a gold test and Thrombotic embolism. 15. A combination drug comprising an effective amount of a rice sulphate succinic acid addition salt as in claim 5 of the patent application and an effective amount of a double alpha ratio to prevent and/or treat platelet aggregation The induced condition, especially in the wind of 68 201223532. 16. A combination drug comprising an effective amount of a schisandine acid addition salt as in claim 5 of the patent application and an effective amount of clopidogrel or a pharmaceutically acceptable salt thereof for prevention And/or treating conditions induced by platelet aggregation. 17. The use of a combination drug as claimed in claim 16, wherein the condition induced by aggregation of the jk platelet comprises an ischemic event such as myocardial infarction or stroke, or a thrombosis and thrombotic embolism, acute Coronary syndrome, sudden cardiac death, and complications after coronary angioplasty or coronary bypass. A combination drug comprising an effective amount of a schisandine acid addition salt as in item 5 of the patent application and an effective amount of a niacin acid or a pharmaceutically acceptable salt thereof. 19. The combination drug of claim 18, wherein the rice koji salicylic acid addition salt is in the form of an immediate release, sustained release or extended release formulation. 20. The combination drug of claim 18, wherein the acid or pharmaceutically acceptable salt is in the form of an immediate release, sustained release or extended release formulation. 21· - A combination of the 18th article of the Cap Patent _ Pinsaki, used to prevent and 7 or treat conditions induced by platelet aggregation. 22. The use of claim 21, wherein the condition induced by platelet aggregation comprises an ischemic event such as myocardial infarction or stroke, or thrombosis and thrombotic embolism. 69 S 201223532 23. The combination drug of claim 18, characterized in that it has an effect of peripheral vasodilatation (flushing) which is less pronounced than nicotinic acid. 24. Use of a combination drug as claimed in claim 18 for the prevention and/or treatment of a disease selected from the group consisting of abnormal dyslipidemia, hyperlipidemia and atherosclerosis. 25. A combination drug comprising an effective amount of a rice sulphate and a sulphate addition salt as claimed in claim No. $ and a selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, Sterling of the group consisting of lovastatin, mevastatin, pitavastat, diced, pravula, rosuvastatin and simvastatin (10). 26. A use of a drug as claimed in claim 25 for the prevention and/or treatment of a disease caused by a group consisting of heteroslipidemia, hyperlipemia and atherosclerosis .