TW201223530A - Novel therapeutic combinations of nicotinic acid and meldonium - Google Patents

Abstract

The present invention comprises a synergistic combination of nicotinic acid and meldonium characterized by increased efficiency in treating disorders, including platelet aggregation, dyslipidemia, hyperlipidemia, atherosclerosis, coronary heart disease as chosen from the group of angina pectoris and myocardial infarction, transient and permanent ischemic attack including cerebrovascular accident and stroke and peripheral arterial occlusive disease, and by reduced flushing effect and/or increase of blood glucose levels, comprising as active ingredients nicotinic acid or pharmaceutically acceptable salt thereof and meldonium or pharmaceutically acceptable salt thereof, effective for said purpose.

Description

201223530 τ VI. Description of the Invention: [Technical Field to Which the Invention Is Applicable] The present invention is a combination of 卿 卿 秘 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和Sclerosis, coronary heart disease selected from the group consisting of angina pectoris and myocardial infarction, cerebrovascular accident with transient or permanent ischemic attack, and diseases such as stroke and peripheral arterial occlusive disease, prevention of platelet aggregation and The method of embolism. More specifically & 'The present invention relates to a novel therapeutic combination comprising niacin, nicotinic acid and rice koji, which synergistically enhances the therapeutic effect of nicotinic acid and improves some undesirable side effects of niacin In particular, peripheral vasodilatation (flushing) and an increase in blood glucose concentration. The present invention also relates to a pharmaceutical composition comprising the pharmaceutical product, and to the use thereof for the manufacture of a medicament for preventing and/or treating the aforementioned diseases. Abbreviations used For the sake of simplicity, the following abbreviations are further used in the present description: ATP - adenosine tri-acid C-cholesterol GL - glucose HDL-C-high density lipoprotein _ cholesterol I / R - ischemia / reperfusion LDL -C -Low density lipoprotein_cholesterol MD-metequinidine (inn) 201223530 NA'nicotinic acid NAMg - nicotinic acid money salt PI-0 compared to acetamide (piracetam) RPP-heart rate blood pressure product = mean blood_pressure & x, rate X 1000·1 SI · simvastatin TG - triglyceride s top - town 瞧 division (four) side 339 (Tylosa pogo 1) VF - ventricular fibrillation VT - ventricular beat Overspeed [Prior Art] NA series - an important agent for the treatment of abnormal morbidity, is also the only available drug for the positive blood-clearing age of the sputum, which reduces the total gallbladder _, TG and LDL_C in the blood. Slave, and has the most enhanced activity of HDL_C in the folklore lipid agent (PiepefIA, Yan Fe Yin#/Shenzhen 2002; 8 (12 Supplement): Page S308_14). As early as 1955 (Altshul R, Hoffer A, and Stephen JD, to the body of Towon, 1955; 54: 558, 559) and 1959 (Parsons Jr WB and Flinn JH, Jiang Yumeng) Zi #存学文广 1959, · 103: Page 783-790), has been reported to treat abnormal dyslipidemia.

Because ΝΑ effectively increases HDL-C concentration (McKenney J, 绔邦黄文#2004; 164(7): 697-705. Carlson LA, 2005; 258 pp. 94-114), current NA system In combination with other moon modifiers, most of them act on LDL-C concentration in order to increase HDL-C

S 5 concentration (Rosenson RS, 4 iron shovel / 2005; 118 (10): page 1067-77).

NA-effectively alters lipids that prevent progression of atherosclerosis and reduce cardiovascular events (Savel, evAA and shershevskiiMG's ' ♦ 存 #学 游文》 1996; 74: Page 48-52 Drexel squats, breaks the heart and sorrows to run the office in 2006; 8th, supplement F: page F23_F29.

Brown BG and Zhao XQ ’ 4 Heart Condensation Learning Touring 2008; 1〇1 (8Α) period. Page 58B-62B. ) by increasing the concentration. NA reduces morbidity and mortality in patients with dyslipidemia (CannerPL et al., American Journal of Cardiology Journals; 8: pp. 1245-55). In the case of treatment of hyperlipidemia, NA is the most effective agent for increasing (Ellingworth DR et al., Internal Medicine, ι 994; 154: pp. 1586-95. Schectman G et al., American Journal of Cardiology i993 Year; 71: page 758-65). NA attenuates the golden suppository, reduces blood viscosity and has a cardioprotective effect, which can limit the damage of ischemia/reperfusion (LampmgKA et al., 痹遂 丝 实 ^ 1984; 231 (3): 532-538 °Tmebl〇〇dNA et al., 4 Logic learning should be and Xinhuan in the Grid of the Year 2000; 279 (2), page H764-H771. Rosenson RS, sneak peeks in 2003; 171(1): Pages 87-96) 〇 Because of the low risk factor of HDL-C stroke (she drinks,

Shaper AG, Ebrahim S, Hu Li 2000; 31: page 1882.

Sacco RL, Benson RT, Kargman DE, Learning / y 2001; 285: page 2729-2735. Rizos E, Mikhailidis DP, heart cover 13⁄4 mouth 2001; 52(2), pp. 199-207. SanossianN, Tarlov NE, heart cover f doctor's treatment #斋洽疗select 2〇〇8年;1〇(3)期, pp. 195-206) 'NA as a medicament to improve HDL-C (Carlson LA, heart new name 2006; 21(4): pp. 336-344) 'Used to prevent stroke and stroke sequelae (Koniukov SG, Liberzon SP, Museum to School (Mosk) 1975; 53(9): Page 38-41). Has been recognized

In the case of acute ischemic stroke, the concentration of HDL-C is decreased (Russman AN et al., Journal of Transfusion and Respiratory Medicine, 2009; 279 (1-2): pp. 53-56). NA has been shown to improve functional recovery after stroke (chen J et al., Cheng Xuexue, 2007; 62(1): pp. 49-58). HDL-C itself has been proposed for the treatment of stroke and other symptoms of jk deficiency (KapurNK et al., 盖 杂 杂 2008 ; 2008; 4 (1): pp. 39-57. European Patent No. EP 1 425 031). NA is available in 3 formulations (immediate release, extended release and long-acting effects). 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 also a risk of hepatotoxicity. The extended release type is associated with less flushing and low risk of hepatotoxicity (pieper JA, body-strengthed shoulder-shouldered tour 2003; 60 (13 supplement 2): page S9-14. McKenney J, cold存学文虡2〇〇4年;164(7)期: Page 697-705. Knopp RH, the beautiful darts are reduced to 2_ years; 86 (supplement) period; page 51L-56L). The use of sodium, potassium and magnesium salts of NA is also described. A major disadvantage of NA is that large doses must be administered to substantially alter blood lipid concentrations. Almost 100%/〇 of the subjects treated with NA will experience discomfort 201223530 = Lake, 'Working in the field', which hinders the treatment with NA. The release of the skin from the prostate was determined to be the direct cause of the induced flushing (Morrow JD et al., 'Wonder's disease, W1992; 98: 812-5). Because of the relationship between NA and the tidal system of the erythropoietin, the result is that the saponin is used as a surface for the former straits. NSAiDS is also effective (Oberwittler Η and Baccara-Dinet Μ, strict basket to Zitai fine ^ 2006, 6G (6): stomach 7G7-715). However, NSAIDS itself does not have a total of 5 ’ side and can cause gastrointestinal irritation and ulceration. Before the sputum, a specific antagonist of prostaglandin D2 was proposed (Parhofer KG, 'Colourful 胗 遂 遂 2009; 5: 901-908) Stylistic first subtype 'laropiprant, as a use In order to reduce the flushing induced by na, _j(5)e et al., Recordings, 2007, 81, 849-857. Davidson MH, for the School of Thin Heart Rotology 2008; 101 [Supplement]: Page 14B-19B). Although the addition of lauropirin will reduce the frequency of flushing, it does not completely eliminate this side effect. Larox does not alter the effect of niacin on lipids or other side effects of niacin. Therefore, the combination of acid testing and laroipine can be used at high doses for acid testing, thus developing the full potential of this drug (Parhofer KG, Vascular Recording 胗#座 2009; 5: 901-908, Olsson AG, Qin Yuzhi #专家彦名 2010; 11 (1〇) period: 1715-1726). Patients with type 2 diabetes often have altered lipid abnormalities characterized by an increase in TG concentration and a decrease in HDL-C concentration. Thinking about the effect of NA on lipid metabolism, 'NA should offset the abnormal change of lipid in patients with type 2 diabetes 201223530

change. However, several reports indicated that NA increased the resistance of Tenjinsu (post A and Grundy SM, 4, Meng Xuewen, 1990; 264: page 723-6).

Kahn SE et al., County Disease 1989; 38 issues · page 562_8) and increased glucose concentration (Elam, MB, etc., Yan Medicine shot 2 years; 284 (10) · Page 1263-1270) . Therefore, it is recommended to give only a limited dose of NA (<2 g/day) for patients with necrotizing disease (Shepher j, Betteridge, and VanGaalL) # #梦学号杂彦名2〇〇5年;21(7)期·页665_682 ). Obviously, there is a need to improve the blood sugar control of diabetic patients who use NA. Clinically, there is a Wei-like curve to lower blood sugar (StatsenkoME et al. 'Tangluo shoots') 2〇〇7 years;%(7)期·39.42) 'So it is expected that this agent can bind NA as another clinical advantage During coronary heart disease, platelets play an acidic horny & antiplatelet agent in the development of atherosclerosis and fatal thrombosis, which has become a lion and manages more than vascular, brain, and peripheral arteries. The first choice for system-related diseases (Mead〇wsTA et al., Ritual 2007; 1〇〇(9): page-75). NA is an effective lipid-changing agent that prevents atherosclerosis Symptoms and reduce cardiovascular events. Na has a variety of white and anti-aortic thrombosis effects, which improve endothelial function, reduce inflammation, increase plaque stability, and reduce blood test (__ RS, mine fiber disease 2 〇〇 3 years; 171: page 87_96) NA inhibits the aggregation of gray plate a. Intestine, f Toksikd, _ year; 43 (5): page 58i_5 > na in vitro by gently inhibiting platelet aggregation And affects platelet miscellaneous and stimulates prostaglandins significantly 5 9 201223530 Release, and most intact primary platelet receptor expression. The potency of NA is unique, unlike other known anti-gold platelet formulations, and offers potential opportunities for therapeutic combinations (Serebruany yl et al. This, 2010 (in press)) ΝΑ almost completely prevent intravascular coagulation induced by thrombin and pituitrin-shows its effect of dissolving thrombosis (BaludaVP, Heart Rotology 1974; 14 (11 Period: Page 1〇5_7 (Russian). Several authors have described the antithrombotic properties of NA (Shestakov VA, Pro6/ Corpse-V, 1977; 22(8): pp. 29-35 ChekalinaSI,

Sov Afedl 982, 5: p. 105-8). Acid testing reduces the risk of blood clots (Chesney CM and others, the United States and the United States, 2 years; 14〇: Page 631-36). The MD system has certain drugs that have beneficial effects on the heart and blood vessels. Some desirable MD activities have been found in animal models of atherosclerosis (Veveris Μ, Smilsaraja B, Poser's Lian Seng Le Xue School 2000; 1 ,, pp. 194-199. Veveris Μ等等人, Polo's Brotherhood 2002; 12 issues: pp. 116-122. OkunevichlV and Ryzhenkov VE, Huga / and / 0 / Wu Xihe, 2002; (2): Page 24-7 'and as observed clinically (Karpov RS et al., AM 1991; 63(4): pp. 90-3) 'It is therefore expected that this agent can bind NA as an additional clinical advantage. It has also been noted that 'MD inhibits platelet aggregation (Tsirkin VI, Z/z 2002; Phase 1: pages 45-52). After the experimental arterial thrombosis, oral administration to rabbits and dogs for two weeks of MD medical use showed the effect of lysing 201223530 dialysis test (L〇gUnova L et al., Hu Jing·Zhejiang 1991; 19: page 91_9 (Russian)). There is no known data on the prevention or prevention of thrombosis.

The development of pharmaceutical compositions to treat urethral metabolism-related diseases/diseases is currently improving the efficiency of clinical care (Black DM, #代液麦呀震2003年五期. Page 39-32). Because fibrates, να, and stellin can each modulate serum lipids according to different mechanisms, monotherapy offers a particularly desirable benefit to others. As the development of novel agents for lowering the concentration of B has progressed slowly, research has turned to developing better agents for increasing the concentration of HDL-C. Increasingly, a combination of sputum, fibrate, stellin, and bile acid sequestrants is used to treat lipid metabolism-related diseases because of the additive traits of these combined products (Miller Μ, #欧梦Rotology Jt 褰 2003; 78 (; 6): 735-42. Backes JM et al. 'If Chu Guangdian belongs to 2005; 1 (4): 317-331. Belsey L et al. ' #券#学母粟库彦名 2008; 24(9), pp. 2703-9. R〇sensonRS and PittB, 泠涝心i camp should live in 2009; 6(2): page 98 - Reed). Increasingly, a combination of να and other agents such as acetaminophen and other NSAIDs as platelet inhibitors has been used (U.S. Patent No. 5,981,555). However, these compositions did not increase the activity of NA', i.e., no synergistic effect was reported. Therefore, any agent which enhances the therapeutic effect of NA in a lipid metabolism-related disease without increasing the adverse side effects of NA will have an excellent clinical effect. SUMMARY OF THE INVENTION One object of the present invention is to provide a method for preventing and/or treating a therapeutic combination of lipid generation 201223530 ==, and a method for preventing and/or treating a lipid-related disease in need of such prevention. By using na: mouth, "there is a further beneficial effect of alleviating the adverse side effects of NA. The treatment of Yuhe Han has the effect of treating facial dysplasia or lion green, including abnormal dyslipidemia and hyperlipidemia. The sclerosis sign is selected from the group consisting of angina pectoris and myocardial infarction. The coronal stimuli of the group consisting of angina pectoris and catenary occlusive disease are temporarily mixed with blood, lion platelet aggregation and jk suppository. (10) According to The present day and month 'if the treatment combination is better to treat the effect of NA or MD alone' is a synergistic effect. Since the treatment combination used herein means simultaneous, sequential or separate WORKING COMPOSITION AGENTS. A further object of the present invention is to provide a pharmaceutical composition comprising both NA and _ for the aforementioned purposes. Further objects of the invention will become more apparent hereinafter, and other objects are in the art. It will be apparent to those skilled in the art. Description of the Invention The present invention comprises a combination of NA and MD which provides the result of an effective synergistic combination for the treatment of diseases associated with lipid metabolism, preferably in the form of a single dosage unit. Alternatively, the second The ingredients may be administered separately, simultaneously or sequentially in any order. The exact form of administration of the active ingredient is not critical as long as the desired effect of the invention is obtained. The active ingredient may be in the form of capsules, suspensions, dispersions, Elixir, saccharide, or the like can be administered separately or in a single composition. 12 201223530 We have now surprisingly found that να and md have a slanting side and other beneficial filaments for diseases associated with lipid metabolism. Unexpectedly discovered, MD is the first beneficial agent for NA, which is to reduce the concentration of TG and LDL-C and increase the concentration of h〇l_c, enhance the anti-polymerization effect of NA' and improve NA. Poor side effects, especially flushing and increased blood glucose levels. t Therefore, the above composition is preferred for the treatment of abnormal dyslipidemia in diabetic patients. We are also surprisingly Now, the composition of the present invention improves the effects of experimental infarction and stroke. Now we have surprisingly found that NA and MD have a synergistic effect on platelet aggregation. Unexpected findings are that the first line of MD can be enhanced. An anti-platelet effect agent. The composition of the present invention may be in a form suitable for oral administration (for example, as a tablet, a capsule, a sap suspension or a dispersible powder or difficult), and is administered parenterally (for example, as an intravenous injection). a sterile aqueous solution for subcutaneous administration, or as a suppository for rectal administration. Preferably, the treatment of the present invention is in the form of a capsule, for example, as a medicine capsule. The treatment according to the present invention The combination also includes a separate pharmaceutical composition of the active agent, which comprises - a first bismuth composition or a pharmaceutically acceptable salt thereof and - a pharmaceutically acceptable excipient or carrier, and a second A composition comprising MD or a pharmaceutically acceptable fine and pharmaceutically acceptable skin or carrier thereof. The composition of the pharmaceutical composition provides for the simultaneous or sequential use of the therapeutic combination of the present invention. The advantage of this composition is that

13 S 201223530 Physicians can be difficult for a job. The present invention comprises a pharmaceutically acceptable salt of NA and NA (the therapeutic combination of the invention is also formulated (sodium, potassium or magnesium) and sustained release or extended release of MD and its salts. Heke includes other known scales crane related diseases, known as Shide, which is simvastatin. The medical field of the present invention can be obtained by using traditional (four) acceptable excipients or carriers. Obtained from the traditional procedures of the technology. The following aspects of the invention are provided, but the invention is not directed to the invention. [Embodiment] The example of the face L can be studied by using (4) fresh green to study the medical activity of the substance. In the climate control room with 22±1 〇C and relative humidity of 6〇±5%, the animals were placed in appropriate cages in groups of 6 to 12 hours/days and freely available. Food and water. All experiments were carried out in accordance with the provisions of the European Community Council Directive (86/609/EEC) on the care of experimental animals on June 24, 1986. All efforts were made to minimize animal worms and reduce animals. Do the amount of use.

Hjjt sterol (Akuros Fukuoka Organic A_ 〇rganics), rice koji (Grenders Grindex), animal nutrition (R7 〇Lactamin), cream (commercially possible), choline (Akuros Fukuoka organic), NA (Akuros Fukuoka Organic), La Ropinin (la^pipit) (MK 〇 524, Cayman Chemicals). Other chemicals are commercially available.

A C57BL/6J small 201223530 rat atherosclerosis model that is susceptible to atherosclerosis genes, as suggested by the literature (Smith (7) and Breslow JL, 戌抒 shoulder ^ 1997; 242: page 99 〇〇9). The control team receives fresh laboratory secret nutrition. Experimental atherosclerosis was induced by the use of 25% cholesterol, 15% cream and 〇.5% bile acid to standard nutrition (Nishina P et al., Ministry of Public Welfare, 1993; 34 issues : Page 1413-1422). The experimental group received the materials of the divided formulas and combinations of the effective doses established by the lead experiments. Add the substance to be tested to drinking water. The preparation of the dose was corrected based on the amount of water actually consumed during the experiment. On average, mice drink about 12% of body weight of water a day. At 2 weeks, the concentration of atherosclerotic changes was assessed by morphological, biochemical, and histological criteria by standard methods and criteria (Paigen) B et al., 1987, 1989; Pages 231-240.) Total C, HDL-C, LDL-C and TG in serum were determined using a commercially available test kit. The LDL-C/HDL-C ratio was accepted as a standard tool for assessing cardiovascular risk (Fernandez ML and Webb D, Jiang Yanxue, Qin Guang^, 2〇〇8 years; 27(1): 1-5) . The atherosclerosis index (which reflects coronary atherosclerosis and is differentially identified from peripheral atherosclerosis) is calculated by the following formula: index = LDL-C/HDL-C coefficient of atherosclerosis (reflecting coronary atherosclerosis) is calculated by the following formula: coefficient = total C/HDL-C. The data of the respective animals/quantities of 7 to 10 of the charm tL丄 are expressed by the mean soil standard deviation (Mean soil SEM). One-way ANOVA analysis and repeated comparison (stranding assay) were used to compare the differences between the experimental groups. P<〇.〇5 is considered significant 201223530. Arrange the effects of different ratios and doses of the test-aggregate composition of the first-_. As shown in Table 1, after 22 weeks, the C-controlled group of animals receiving C nutrition developed a change in atherosclerosis in the aorta, particularly the aortic arch. NA and _, when used separately, show the _ to reduce the damage area. Surprisingly, the combination of NA and the combination has a higher quality and a protective effect on the atherosclerotic damage, that is, it has a synergistic effect. Table 1 Effect of NA and MD on atherosclerotic lesions of aorta; η=7·10; mean standard deviation group lesion area, mkm2, aortic arch trigeminal area, % of aortic area Control group 44 ± 25.8* * 〇.02±〇.〇1 * * c control group 6076±1282 5 -44± 1. 1 2 NA 50 mg/kg 5867 975 5.2 1 ± 1 . 〇7 NA 200 mg/kg 4153 742 3 · 3 9±〇.6 9 MD50 mg/kg 4741 786 3.8 7±0.64 MD 150 mg/kg 3 8 0 1 ± 5 7 3 3 · 3 0± 〇.4 9 MD 200 mg/kg 3098±547 2_74± 0.47* NA50 + MD50 3 1 06±3 6 8* 2 · 5 8± 0·3 1 * s NA50 + MD150 2231士390*i& 1.93±0.40**s NA200 + MD200 1 602±404 *i4t 1 · 29 ± 〇 · 38** & NA50 + MD50 = ΝΑ 50 mg / kg + MD 50 mg / kg NA5 〇 fMDl 50 = ΝΑ 50 mg / kg + MD 150 mg / kg NA200 + MD200 = NA 200 mg / Kg + MD 200 mg / kg * Ρ < 0 · 05 v * s C control group ** P < 0.005 usC control group SP < 0.05 w ΝΑ same dose & P < 0.05wMD The same dose as shown in Table 2, NA and MD composition exhibits a reduction in LDL-C and TG concentration Degree and increase in HDL-C concentration, a statistically significant effect. At a dose of the composition NA50 + MD150, wherein the NA system was used at a dose which did not have a significant effect on the lipid concentration, the summary effect (summary 201223530 effect) was surprisingly higher than that of the individual substances. This is particularly evident in the atherosclerosis and total C/HDL-C ratio, and the synergistic effect of να and MD is observable. Table 2 Group fliri irO Total c mg/dl HDL - C mg/dl ldl-c mg/dl index, ^ LDL-C/HDL-C i total c/ hdl-c ratio TG mg/dl control Group 66·5±4.5# 57±3.4 9.7±2.2# ο. 17±0.〇4* 1.17±0·04# 22·1±2.19** L control group χτ λ c η 161±10.4 50±5· 0 11〇±9.9 2·22±0.25 3.23±0·25 48.8±4.93 IN A OU mg/kg 156±9.4 56±5.2 100±6.9 1 ·78±0·19 2.77±〇.l8 37.8±4.56 IN AZ UU mg/kg 153±11.1 59±4.7 93±8.3 1.63±0.15* 2.60±0.2* 31_7±4·21“ M JJ j U mg/kg 157±9.5 54±5.0 1〇2±7.5 1.97±0.20 2.94 0.2 44.3 soil 4.84 MU I j U mg / kg 153 士 11 · 8 59 soil 5.0 94 ± 9.1 1 · 65 ± 0 · 18 * 2.63 ± 0.18 * 42.9 ± 4.62 ML; 2U0 mg / kg 151 ± 11 · 2 56 3.9 95±1〇.〇1.72±0.20 2.70±0.2 42.2 ±3.35 NA50 + MD 50 156±10·2 58 ±5.5 97±7.9 1.7U0.23 2.72±〇.23 40·1±3.75 N A5U + MD 150 148±8.9 65±5.7 83±4.4*s 1.31±0.09*s&2·30±〇.〇8**& 36.1 Soil 2.23* NA200 + MD200 152±7_1 67 5.2* 85±5.1* 1.29±0.11 *s&2·31±〇.12*&33.6±2.45*& NA5〇fMD150 = NA50 mg/kg+MD 15〇mg/kg NA20 (KMD200 = NA 200 mg/md 200 m^/kg of substance to be tested) Effect of lipids in serum; η=7_10; mean±standard deviation NA5〇+MD50 = ΝΑ 50 mg/kg+ md 50 mg/kg*P<0.05wC control group*=*^<0.005 vulgar<:Control Group #P<0.0005wC Control Group¥<0.05 vsNA Same dose&P<0.05wMD Same dose In another series of experiments, the anti-atherosclerotic activity of the composition of the present invention was evaluated in more detail, and further added The anti-lipid agent si is known to be in the composition. NA and MD', when used separately, showed a tendency to reduce the damage area (Table 3). Surprisingly, the combination of NA+MD resulted in a fairly high and statistically significant protective effect on atherosclerotic damage compared to a different substance. The addition of the compositions of the invention to si further increases its protective effect against atherosclerotic damage.

The effect of the substance to be tested on atherosclerotic damage of the aorta; n=7_9; mean soil standard deviation

ΝΑ5(Η·Μ0150 = ΝΑ5〇mg/kg+MD 15〇mg/kg a5g milligram side w(four) milligrams **Ρ<0·005 still C control group

#P<0.0005wC Control group ^^.05 vj NA &P<0.05 vjMD Total, LDL-C and TG in serum were also determined in the same series of experiments. As shown in Table 4 below, NA and md, when slightly used, were only slightly improved in the ratio of cholesterol content and the atherosclerosis index' without any statistical significance. Surprisingly, the combination of NA and (d) considerably improved the ratio of bile-content and statistically significantly reduced the atherosclerosis index and total C/HDL_C ratio. This composition also prevents an increase in serum LDL-C and TG. Thus, the compositions of the present invention have a higher protective effect against the SI compound when compared to when the _' pair is modified to alter lipid metabolism. 18 201223530 Effect of substance to be tested on serum towel lipids; n=7-9; mean±standard deviation Table 4

Group total C mg/dl HDL-C mg/dl TdlTc ~~ mg/dl control group 66.8±3.7# 58±3.4 8.7±1.94* C control group 167±8.64 54±4.7 113±8.4 NA 50 mg /kg158±9.9 57±5.2 100±7.6 MD 150 mg/kg 159±7.8 62 soil 4.1 95±8.2 S1 10 mg/kg 132±9.9* 55±5.0 77±6·7* N A50+MD 150 139± 7.5* 60±6.1 79±6·2* NA50 + MD 50+SI10 141±7.3* 61±5.5 8〇±5.7* 〇.15±0.034 2.24 士 ‧ ·76±0·21 .58 ± 0.2 1 4 0.08* 1.32±0_20*s -31±0.16*J Total C/ HDL-C rate 1-15±〇.〇3( 3·23±〇·24 2·75±〇·ΐ9 2·60±0.2 1 2.30 ±〇.2〇" 2.30±〇.ΐ6*$ TG mg/dl 22.8 soil 1.82* 52.2±3.98 41.0±4.62 44.2±4·05 39.5±3·96* 42.2±3.65 NA5〇fMDl50 = NA50 毫- 10 gram / kg) = 5 (^MD5_10 = NA50 攸 攸 + hall 〇 公 gong * p < a 〇 5wc control group '<0.0005 w C control group ^^, 05 vs ΝΑ another series of experiments The NAMg and NA+SI compositions were included in the comparative evaluation (Table 5). The NAMg and NA of the cock have been compared (Burstem J and TelkkaA with 'Youhuan Huanhua Syndrome 962, 56: 261-265). The composition of the clinically based experiments, NA (50 mg / kg) and md 〇 5 〇 mg / kg) have the most aortic Significant beneficial effects, better than ^ and ^^^, and better than the combination of SI and NA (PandianA et al., if Chu Guanghui 琢縻 淫 2008; 4 (5): Page 1001-1009) . Table 5 Effect of test substance on atherosclerotic damage of aorta; n=7_9; mean standard deviation 19 201223530 Group damage area, halo square kilometers, aortic arch lesion area, aortic area% Control group 35 soil 19.8 *** 0.02i〇, 〇1 * * * C control group 62 1 6 839 5 · 7 5 ± 0.8 2 NA 50 mg / kg 4978 688 4.2 3 ± 0.6 7 NAMg 60 mg / kg 4053 518 * 3 .3 9±0.44 * MD 1 50 mg/kg 3904 489* 3 ·47±0.45 * NA50 + MD1 50 2 1 05±2 1 5 * 1.95±0.30*·*(9ΪΛ NA50+SI2 3068±297* 2.67 ±0.48* NA5 (WV丨D150 = NA50 mg/kg+MD 150 mg/kg NA5 (HSI2 = NA50 mg/kg+SI2 mg/kg*P<0.05 w C control group**P<0.005v5C control group** *P<〇.〇〇〇5 w C control group

¥<0.05 wNA ®P<0.05 vj NAMg

&P<0.05 V5 MD #P<0.05 w NA50+SI2 Similar to morphological data, the biochemical test confirmed that the NA+MD composition is significantly better than NA or NAMg in normalizing lipid concentration (Table) 6) 〇 Table 6 The effect of the substance to be tested on lipids in serum; n=7-9; mean ± standard deviation group total C mg / dl HDL-C mg / dl LDL-C mg / dl, LDL-C/H DL-C Total C/HDL-C TG mg/dl control group 57 soil 3.9... 56±3.0 7.8 soil 1.83 this* * 3.14 ± 0.03 ... 1.19 ± 0.04 ... 26.5 soil 2.13** c control group 164 soil 9.2 50±3.8 107±7.4 2.21±0.18 3.33±0.19 54.8 ±5.56 ΝΑ 50 mg/kg 158 soil 8.7 57±4·7 96±6.2 1·74±0·15 2.82±0.16* 40.8± 3.46* NAMg 60 mg/kg 151±9.6 55±4.0 91 soil 7.7 1·67±0.12* 2.73±0.14* 41.4 soil 1.06* MD 150 mg/kg 154 soil 8·1 55±3.3 95 soil 5.5 1.75 ± 0.14 2.74 ± 0.11 * 43.2 Soil 1.25 NA50 + MD 150 148 soil 7.4 63±3.9* 81士4·1* 1_31 土0·Η*_ 2.35 士〇1〇** s@& 37.5 士0. 97 & NA50 + SI2 144 ±4.7 58±4.4 82 soil 4.8* 1.49±0.12&q Uot; 2.52±〇·12** 42.4± 1.74 NA5〇fMD150 = NA50 mg/kg+MD 150 mg/kg20 201223530 NA50+SI2 = ΝΑ 50 kWh kg+SI2 mAh*Ρ<0·05ν·ϊί: Control group **Ρ<0·005 w C control group **叩<0.0005 wC control group ¥<0.05 ΝΑ @P<0.05 wNAMg

&P<0.05viMD The composition of NA+MD is similar to the composition of NA+SI in reducing total C and LDL-C, but in effect on the beneficial effects of hdl-c and TG concentrations, it is substantially more Excellent, and has a more significant effect on the index of atherosclerosis and the total C/HDL-C ratio. This series of tests confirmed that the compositions of 'NA and MD' in experimental atherosclerosis have significantly better beneficial effects than NA or NAMg and are also superior to the clinically used compositions of NA and SI. Examples of the effects of 2-NA and ]V1D on lipid rafts in a rat hyperlipidemia model, methods of influencing and composition: using the method described by Levine and Saltzman (Levine S and Saltzman A) The drug-induced genital warfare regimen 2007; 55: 224-226) induces experimental chronic hyperlipidemia/hypercholesterolemia with TR. Animals received 250 g/kg TR solution via the tail vein three times a week for three weeks. The solution of the test substance for the experimental group or the water for the control group was orally introduced one hour before the injection of the TR solution or the blood sample. Male Weiss rats weighing 220-240 grams were assigned to the following 8 groups (group 'number of animals): 1. Control group 1 () 2. TR (TR 250 mg / kg)

S 21 201223530 3· ΝΑ (TR250 mg/kg+NA5〇mg/kg/day) ^

4. MD (TR250 mg/kg+MD15〇mmol/kg/day) R 5. NA+MD (four diced 250 mg/kg + ΝΑ 50+MD 150 mg/kg/day) 14 6· SI10 ( TR250 mg/kg+ SI1〇mg/kg/day) ^ 7. NA+SI2 (TR 250 mg/kg+ si 2 + NA 50 mg/kg/day) 12 persons. NA+SI2+ catch 3 (TR 250 mg/ Kg + SI 2 + NA 50 + MD 150 mg / kg / day) 12

After 1, 2, and 3 weeks (from the next day after the TR injection), blood for biochemical analysis was obtained by cardiac puncture under ether anesthesia. The bleeding was removed by centrifugation and total C, HDL-C, LDL-C and TG concentrations were analyzed in a commercially available kit. The chain was mathematically processed using software Microsoft Excel and the results were expressed as mean ± mean standard deviation (SEM). ANOVA one-way analysis and Student's t-test were used to compare the average results of different groups. At p < 0, the difference in results is considered significant. Build 1 repeated injection of TR developed a significant and stable hypercholesterolemia and hyperlipidemia 'characterized by a significant increase in total C, LDL-C and TG concentrations compared to the control group. NA therapy, more significantly In the first week, the increase in total C, LDL-C, and TG was limited, but the HDL-C concentration was significantly increased only at 2 and 3 weeks. MD is slightly weaker in reducing total C and LDL-C concentrations and increasing HDL-C concentration, but does not prevent an increase in TG concentration. Surprisingly, the combination of NA+MD is more effective than the individual components in reducing the LDL-C and TG concentrations and further increasing the HDL-C concentration. Furthermore, the use of extended NA+MD (2 or 3 weeks in our experiments) demonstrates that it is substantially more significant in terms of reduction and TG concentration and increase in hdl-c concentration compared to the use of NA+SI. (see below). Therefore, it is expected that the composition of NA + MD is useful in the prevention and/or treatment of hypercholesterolemia and hyperlipidemia.

The use of SI at a dose of 10 mg/kg significantly reduced the increase in total C and LDL-C induced by TR, but only slightly affected the concentration of hdl-c and TG. The combination of SI and NA in a clinically acceptable ratio demonstrates significant protection against the increase in total C, LDL-C and TG in serum and increases HDL-C concentration. Surprisingly, the combination of na, SI and MD, compared to the individual use of each component, still demonstrates better protection against changes induced by Han, and significantly lowers the concentration of TG and LDL-C compared to NA. +SI is better. Of particular importance for clinical practice is that the combination of NA, SI, and _ is substantially better than SI or NA in terms of increasing HDL-C concentration. Therefore, a combination of NA + MD and NA + SI + MD is expected to be useful in clinically preventing and/or treating hypercholesterolemia and hyperlipidemia. Table 7 Effects of NA, SI, and MD on the lipids of the rat hyperlipidemia model and the effects of the composition; n = 9-14; mean number standard strike group 1, 2, and total C after 3 weeks, Mg/dl Cl C2 C3 control group 77.6±4.9*** 75.1±5.1*** 72_7 soil 2.5*** IR 487.6±25.4 5〇1± 1 6.7 5 1 3 soil 4 1 . 1 NA 345±15.7* ** 40 1.1 ±25.1 * * 405·5±25.9* MD 412±24.7 414.7±23.2* 401 soil 22·8 * NA + MD 340.5±19.5***& 3 60±2 1.7 * ♦ * 346.4 soil 32.8 ** IS 1 314±29_6*** 329.5±36.2** 335.7±31.6**

S 23 201223530 NA + SI 345.9士27.5** 3 8 8.7 士 32_3* 384.5士33.9* NA + Sl + MD 333.5±26·2***& 376.4 士23_ 1 *** 333.4±19.3***s&amp Table (continued)

HDL-C after group 1, 2 and 3 weeks, mg/dl HDL-C 1 HDL-C2 HDL-C3 control group 54.6 ± 1.9* 54. 1 ± 1 .3 5 3·7±1 · 0 * TR 76·3±6·9 76.2± 1 1 .4 7 7 soil 1 0.2 ΝΑ 1 1 1 .3±9· 1 * 1 44 · 7 士 1 3 .5 * * 127.3±1〇.9** Μ D 11) 7.3 it .4* 1 TS . 6 ± 1 〇. 3 Ϋ Τ 1 5.9 ± 9.6 » Ν A + MD 126.2±11.1** 150.4±11.2***&# 1 36.9± 1 8. 1 * SI 84.5±12.5 98·5±20.5 94·4±1 0.2 Ν A + SI 99± 1 2.9 1 1 6.2±1 1 .7* 114·9±11-9* NA + SI + MD 124.8±18.2* 1 57.3±15**&# 143.2±9.Ί*** Table 7 (continued) LDL-C, mg/dl LDL-C 1 LDL-C2 LDL-C3 control after group 1, 2 and 3 weeks Group 1 8_7±3 .8". 19.7±4.4'” 1 6.3±2.0··· TR 3 8 8.7±26.7 402.1±19.2 405.1 ±4 1 .7 ΝΑ 216.3±14_0*** 2 5 0·3±20 ·6 ... 265·1±18.4* MD 290.8±21 * 2 7 5 ± 22.3” 2 7 0± 1 6.9 * Ν A + MD 209,6±16.7"*s 197.6±15.4***λι# 203.3± 20.3** ... SI 2 1 2±24. 1 * * * 228.9±20.6 ... 232.1±22.%* * NA + SI 227.2±26.1*** 272·5±21·3** 2 6 8±23.2 * NA + SI + MD 193·2±16·5***~ 216.6 Soil 17 ... said 197.1±16.6**ia:ff Table 7 (continued) TG, mg/dl TGI TG2 TG3 after groups 1, 2 and 3 weeks Control group 38士2_9... 37 土3.2·*' 3 8±4·4 ... TR 1240±80,1 1 297士78.3 1 2 3 4± 1 14.1 ΝΑ 734±8 1 .6”' 860士 73.8* * 82 8±44·7 * MD 1 040 soil 9 1 1081±63.2 1 〇1 〇±72.5 Ν A + MD 7 8 5 ± 6 2 · 9 * * * & 792±73.8**** Π Α±39.2 * SI ' 849 士 96.8 * 879 ± 72.1 * * 891 ± 1 29.1 NA + SI Ί 69 ± 69.2* * * 868 土 36.1 *** 8 79 ± 3 1 * NA + SI + MD 734·4±95·7&quot ;" — 763±3 6* * 692±45 * **" *P<0.05 w TR **P<〇.〇〇5 v^TR

***P<O.O005wTR ¥<0.05 νί ΝΑ &P<0.05 wMD 24 201223530

#P<0.05wNA+SI f Example 3 - Determination of cardiac preservation characteristics The male and female male Weiss rats were assigned into 6 groups (12 to 16 animals per group): 1) The control group received oral 〇.9 〇/◦ brine; 2) NA50 group received 50 mg/kg/day NA; 3) MD50 group received 50 mg/kg/day md; 4) NA50+MD50 group received 50 mg/kg orally / Day of NA plus 5 〇 mg / kg of MD; 5) MD150 group received 15 〇 mg / kg / day touch); 6) NA50 + MD150 group orally received 50 mg / kg / day of NA plus On the 150 mg / kg / day md. At 48, 24 and 1 hour before the experiment, the animals of the test group received an aqueous solution of the test substance via the gastric catheter. Animals in the control group received an equal amount of saline. Animals were anesthetized (intraperitoneal injection of pentobarbital sodium 6 mg/kg) and placed under mechanical ventilation to prepare for obstruction of the left coronary artery. Experimental arterial infarction was induced by occlusion of the coronal 45 minutes long followed by reperfusion for 2 hours. 5 The following data were recorded: VT, VF, number of dead animals, mean arterial pressure, Rpp, functional status of the RPP myocardium, reflect the production of Ajp in the myocardium, and widely used index for clinical and experimental data analysis (Br〇 Derick TL, Qinshen Department completed the 2008; 9 (2): Page 83_91). After the experiment, the ischemic and necrotic areas were detected by the diphenyltetrazine Evans blue perfusion staining method. The left ventricle was incised and weighed, and the criteria for the morphology were calculated: the ratio of the ischemic area of the left ventricle, the proportion of the necrotic area of the left ventricle, and the ratio of the necrotic area to the ischemic area (necrosis index). 5 25 201223530 The results of each group are expressed as mean ± standard deviation (Mean ± SEM). The analysis of the lining in the group is a test. The animal towel that survived the blood-reperfusion-reperfusion experiment was counted as data obtained from the recorded blood pressure and heart and pulse rate. The number of episodes of arrhythmia (VT^w) and the number of deaths were calculated for all animals. One-way ANOVA analysis and repeated comparisons (tower assays) were used to compare the differences between the various groups. ρ<·Lin is significant.

Mil was in control of the I6 secret towel and called for ischemia and reperfusion to cause severe heart rhythm. There were 7 deaths. The NA group was not significantly different in terms of heart rhythm compared to the control group. The jyQ) and NA+MD groups had less significant life-threatening filaments (w and ντ) relative to the control group, but the number of deaths was significantly lower in the NA50+MD50 group and the STA50+MD150 group (Table 8 below). )〇" Coronary artery reperfusion, the substance to be tested is on Table 8

*P<0.05 vi Ι/R During control group reperfusion, mean arterial pressure and heart rate were similar in all experimental groups, but the decrease in RPP observed in the control group was only in the intestine 0+MD5G _ NA5G +mD15() _ Lin Shanglin was prevented (Table 9). It is pointed out that the treatment of the composition of the present invention for a short period of time (3 days 26 201223530 long) has been provided with protection against functional depletion caused by infarction. Table 9 = 9-12; ancestry ’ 翻 material, c rate blood ^ green 呀 1 ")effect; group ι / R control group

NA MD50 MD 1 50 NA50 + MD50 N A50 + MD 1 50 Initial 44.2±3.0 43 . 1±2. 44·8±1 · 7 44.3± 1. 42·7±3. 4 3.9±2 *P<0.05 v&lt ;s Ι/R control group “Ρ<0·005 wI/R control group &P<0.05 vs initial #Ρ<0·01 vs initial occlusion 4 5 minutes reperfusion 1 20 minutes 3 97±2.3 4 0.4± 2.7 4 1 . 5 ±2.9 40.3±2,5 4 0 · 5 ± 1 . 9 4 1 .2± 1 34.2±2.1 3 6.0±1 · 3 3 7.6±1.91 3 7,9± 1 . 8 3 8.6± 1 8 * 40.1 ± 1.6 This is also a statistically significant reduction in the percentage of necrotic areas to the left ventricle and to the ischemic area by the composition of the present invention (NA+MD for both dose combinations) (Table 10), confirmed KSf occlusion and reperfusion during the 'test substance versus heart type group left ventricle, milligrams of necrotic area / left ventricle, % necrosis index, %

*P<0.05 vs Ι/R control group **P<0.005 vs Ι/R control group #P<0.0005 vs Ι/R control group Table 10 Academic effect; η=9·12 ; 5 27 1

P<0.05 vs MD same dose $P<0.05 NA necrosis index=necrotic area/ischemic area x 100 201223530 Therefore, we have surprisingly found that the synergy of sputum and MD drugs against the onset of myocardial infarction High degree of protection. The NA+MD composition significantly maintained myocardial function and increased animal survival (Tables 8, 9)' and compared with NA and MD alone, it significantly prevented myocardial necrosis due to ischemia and reperfusion (Table) 10). Example 4 - Further experiments on the determination of brain anti-hypoxia and anti-hypoxic ischemic sputum' to determine the composition of 'NA and MD' in the experimental 局部^ ischemia, hypoxia and stroke models The utility of the utility of individual ingredients. 4.1· Mouse brain circulation deficiency model. Induction of experimental circulatory hypoxia by introducing MgCl2 (2% MgCl2, dose 200 g/kg) into the tail vein of male ICR mice within 3 seconds (Berga P et al. People, Guangshen found 1986; 36 (9): page nmo). Animals received a test substance for a total of 7 days per day in a single-dose dose. The test substance is introduced through a gastric catheter. Animals were randomly divided into 7 groups (a group of 6 to 10 animals): The control group received water 0.01 ml/g gluten (active control) at a dose of 5 mg/kg where the ethylamine NA50 group received 50 mg. /kg dose of na

The decapitation group received a dose of 50 mg / kg of MD

Shun 50 group received 15G mg / kg dose of MD NA50 + MD50 group received 5 〇 Natsen house / a kg NA plus 50 mg / kg 28 201223530 MD dose NA50 + MD150 group received 50 gram / kg take plus 15 The dose of 〇mg/kg MD is administered to the last dose of the test substance one hour before the start of the test. From

The period from the end of the injection of MgCl2 to the end of the last respiratory action is recorded as the survival time. The results of each group in the blanket were expressed as an average; t standard deviation system 6211 ± 8 £] ^. Statistical analysis within the group was performed by Student's t test. One-way terrestrial analysis and repeated comparisons (tower assays) were used to compare the differences between the experimental groups. p<〇〇5 is considered significant. The pot results are summarized in Table 11. When repeatedly introduced, the clinically used ρι and MD demonstrated protective anti-hypoxia effects (Table n). Unexpectedly, the composition of NA+MD has been shown to have a protective effect of the syllabus after the transfer, especially the dose NA50 + hall 150, where the effect is superior to individual substances. Repeated use of this composition has a more pronounced effect. The results known in this test indicate that the composition of NA + MD is clinically useful for the treatment of hypoxia. The effect of the substance to be tested on the cerebral circulation of the mouse; the mean number of 卞 + the group between the necks of the leap year, the second. The treatment of the single-agent 7 7 days control fine _2 5.7 5 ± 1 . 〇 1 2 5 · 4 ± 1 . 〇7 _p I 5 0 〇2 8.5 ± 1 η 4 29.8± 1 .32* _NA5 0 _2 7.3 ±〇.6 8 27·8±0·86 MD 5 0 26.5± 1 ,〇7 2 8 · 9 Earth 1 2 0 * MD 1 5 0 2 7.0 ± 〇q ^ 29.8±1 .19* NA5 0 + MD5 0 .. 30.8 soil 1 44*$ 32.6± 1 18#&s _NA50 + MDl<:n 3 1 . ± 1 1 ^ * S & 34.4 ± 1 , 50@s§ ----1

S 29 201223530 *P<0.05 vs control group #Ρ<0.005 ν·ϊ Control group @Ρ<0·0005 νί Control group $Ρ<0·05 νί MD Same dose &Ρ<0·05 V5 ΝΑ §Ρ< 0.005 V5 ΝΑ 4.2. Middle cerebral artery occlusion mode scraping method: use male body ICR small I 体重 from body weight 21 to 25 gram according to Zhang Q et al. (Behavioura 丨 Brain Research 2QQ6; 169: pp. 66-74) A known method of occlusion of the middle cerebral artery (MCA) source by intraluminal filament technique (Longa EZ et al., 1989; 20: pp. 84-91). Scientific trials were performed using prophylactic (7 days a day for permanent MCA occlusion models) and therapeutic (starting treatment after temporary MCA occlusion). Control group animals received only saline. This test is a good model for a true clinical brain injury and stroke (which often encounters occlusion of the middle cerebral artery). The experiment was further continued according to two scientific experiments. In the first case, the occlusion was permanent. In the second case, the occlusion of the intraluminal filaments was temporary and the filament was removed after 2 hours and introduced into the refill. The neurological status of the animals was assessed 24 hours after occlusion. On a one-level scale, animals with no pathology were given a point of 4 points for animals that were unable to spontaneously move (LongaEZ et al., Family 1989; 20: page 84-91). After assessing neurological deficits, the animals received an excess of sodium pentobarbital and the brain was isolated and sliced into 6 layers of approximately 15 mm each. The sections were stained with 2% sodium triphenyltetrazate at 37 ° C for 3 minutes and photographed. The brain was selected as the third slice in the cross-stratification of the nerve, which is best for calculating the cerebral deficiencies and also the injury 30 201223530 because it is completely supplied by blood from the middle cerebral artery. Passing _17 9 t points lion secret number _ average number ± standard deviation purchase post SEM) said. One-way ANOVA analysis and repeated comparisons (tower assays) were used to compare the differences between the experimental groups. Student's t test was used to analyze differences in neurological function scores between groups. Ρ<〇·〇5 is considered to be significant. After 24 hours of occlusion, all 8 control animals exhibited an average of 2 63 points of neurological disorder (Table 12 below). The hiding of the material to be tested hides the secret of the new fabric; η=7 9 ; Ping touch + Yanghu 丨 々 々 α --rr^~~:------- ' Test the group nerve state, point Control group 2.63±0.38 sham operation group 0.14±0.14 * NA 5 0 X 7 2·25±〇·25 MD 1 5 0 χ 7 “I .63±0.29 NA :> U + MD 1 5 0 χ 7 1 .3 8±〇.26*&*P<0.05 vs accused 丨NEW#Ρ<0·0005 vs control group &P<0.05 vs ΝΑ In the sham operation group, only 1 animal showed a slight Disorders. Repeated use of MD for a total of 7 days partially prevented the deterioration of the neurological state of the MCA turtle. Surprisingly, the NA+MD composition exhibited a clear defense against neurological disorders, superior to the effect of NA (Table 12). In the control group, middle cerebral artery occlusion resulted in ischemic injury, which accounted for 222% of the brain tissue in the optic nerve crossing layer (Table 13). The application of NA+MD composition for 7 days showed the duck (four) inspection and weaving The defense of damage is also superior to the effect of NA alone. 31 201223530 Table 13 Effect of substance f on the size of cerebral ischemic thief injury area in permanent occlusion animals; 7-9, mean + 姮 * * m 3Φ in ~ _ ischemia Sexual injury area, % control group 22.2±2.21 NA '~ 19.0±1.75 MD ΓΤ6.9±1 .82 NA50 + MD150 12.9±1.54*& * corpse<1).1)1)5 vs control group P< 0.05 vs ΝΑ In the next experiment, the middle cerebral artery was temporarily occluded for 2 hours, followed by reperfusion, which resulted in severe brain functioning in the control group of animals 24 hours after the test (Table 14 below). The test substance was introduced at 3 and 6 hours, and neither the NA25 (25 mg/kg χ3) group nor the MD75 (75 mg/kgx3) group provided significant protection. Surprisingly, only the test combination NA25+MD75 The group (25 mg/kg + 75 mg/kg) was introduced 3 times after occlusion, and the brain function was substantially protected, which was significantly better than NA and MD alone (Table 14 below).

After temporary occlusion, the neurological status of the test substance on the neurological function test group, the point control group 2.75 ± 0.3 1 tooth surgery group 0.29 ± 0.18 # Ν Α 25 2 · 25 ± 0.16 MD75 2.13 ± 0_23 N A25 + MD75 1.44 ±0"8*&s *P<0.005 Vi Control Group #P<0.0005 vs Control Group SP<0.05 V5 MD &P<0.05 vi NA

Morphological analysis revealed that NA or MD: 7.9; mean ± standard deviation. Early prevention of brain damage caused by MCA transient occlusion and reperfusion (Table Μ below). Surprisingly, the combination of NA+MD (25 mg/kg+mg/kg), which started treatment after occlusion, demonstrated substantial defense against brain tissue damage, significantly better than NA and MD alone (Table 15). U / Xi, Ding Shaoping left test group ischemic injury area, one 'control group 22.3 ± 1. 3 NA 2 5 1 8 · 9 ± 1 · 8 MD 7 5 Bu 1 8_2 ± 1. 3 NA25 + MD75 1 3 . 3 ± 1 . 7 # 41 P<0.005 Vi Control New &

SP<0.05 vi MD P<0.05 vs NA, we have surprisingly found that whether the combination of 'NA plus MD' is used in the medical music before or after MCA occlusion, it provides a significant comparison Good against the brain _ in the defense of Wei Shang and occupational injuries, this also pointed out that the age of the drug can be beneficial in the treatment and / or lion contains NS hypoxia-ischemic conditions, which is also because of its platelets The inhibitory activity of aggregation and thrombosis tests is as follows.

拠L small blood deficiency (4) read); rat thrombus to record changes in skin temperature in vivo. Disease model (in vivo slit 1 from her _ ASA fine _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Germany), in the established method (Toth 〇 et al. 'Qiu Fazhi becomes itchy and shy into the law of the year' 96 issue: page 781-788. Velik-SalchnerC and others, the fresh-keeping place ^ Jiyou Office 2008 Year; 107: page 1798-1806) to study platelet aggregation. Blood samples were collected into plastic tubes covered with hirudin (Dynabyte Medical 'Germany') for between 3 minutes and 4 hours after collection. Measurements. Measurements were performed according to the modified scientific laboratory of Dynabyte Medical. Isotonic sodium solution (0.3 ml, or saline with the compound to be studied (to a final concentration of HT 6 to 104 mmol/ml)) Preheated to 37. <: and pipet to the test cells, then add 3 ml of heparin anticoagulated whole blood sample. After 5 minutes of incubation, stir at 37 °c to add appropriate Agonist solution (taken from Dynabyte Med Ieal, Germany) to start measuring: 1) adenosine diphosphate (ADP) _ ADP-test. ADP stimulates platelet activation by the adp receptor (P2Y12 and others). 2) ADP HS test (combination of prostaglandin El and ADP). The addition of the endogenous inhibitor PGEi made the ADPHS test more sensitive to the effects of gaspiris and related drugs than the ADP test. δ has been recorded for 6 minutes' and used software analysis by Dynabyte Medical. We calculated the following parameters for platelet aggregation: 1) Amax 'maximum value of aggregated platelet aggregation in arbitrary units (AU); 2) Total area of AUC ' under the aggregation curve (AU*min). This will be aggregated 34 201223530 The generality of the curve and its slope are most suitable for expressing the overall platelet activity. The results of Wei 111丄 are expressed as mean ± standard deviation (Mean ± SEM). In order to assess the significance of the difference, the unidirectional bird analysis was performed. If the null hypothesis is ruled out, then the student Newman Muller check is used after the fact. The test of tm' is defined as the effect of different concentrations of the drug. As shown in Table 16, a wide range of concentrations provided a significant anti-purple effect on platelet aggregation induced by ADP + PGE. ^ Shaped from the control group's 100/. Drop to the MD 10 group and the ισ4 group a ·. NA (in the 1〇_4 and 1〇3 house Mohr/ml groups) also reduced the aggregation caused by Na. The combination of the two substances provides a significant comparison with the New Zealand's Μρ or Ship 1 and the plate turn low, which is both in the auc and Α_ data. The effect of MD, ΝΑ and their combination on platelet aggregation induced by ADP and pGP + Δγ^η; Ν = 5-8. 1 mean ± group ADP ----^ — ---- AUC ( AU*min) A max' ~~~~_ PG >E, + ADP AU % AUC ί A Π ^ . Amax control group 942 soil 43.7 169.3±6.4 ~io〇~ ^94- AU % MD 10'6 897 ±23.4 T59T5±4T~ au〇5±465 175.3 8.9 100 MD 10 s 882±26.0 1 5 7.7 士 yh ~~93~ __^4±3l.〇151.8±5.2 87 MD ΙΟ 4 869±36.3 153.2± 6.1 90 ^ /^±48.4** ^ 9 .~ 96.6±48.3** 55 ΝΑ ΙΟ 4 859±62.5 148.0±5.2* 87— •^o /±37.4** -- 101.4±2.2** 58 MD104 + 474 ±34.9** 81±5.7**i~· ------ _^2±51.9 146.7±8.6 84 NAIO4 ^##$$ 4:#$S 48 i〇6±35.5* 54.5±5.8 ... * * Floating ss 3 1 *P<0.05 vs Control Group - **Ρ<0·005 νί Control Group ***Ρ<〇·〇〇〇5 vs Control Group ****Ρ<〇.00005 νί Control Group# P<0.005 vi MD l〇'4 s 35 201223530 ##P<0.0005 Vi MD 10'4 SP<0.005 νί ΝΑ ΙΟ'4 $$P<0_0005 vs NA 10_4 Example 6 _MD and NA on the shadow of 'Xu Zheng Branch &L we choose a kind based Experimental thrombosis model of rat arterial thrombosis induced by ferric chloride (Fed3) (Kurz κ et al., ▲ 遂费成哥龙 1990, 60 issues: 269-280°WangX and XuL , ▲ in the 4 Pingke 2005 '115 period: page 95-100). Tissue damage initiated by the chemical oxidation of Tiezhongjie makes the injured site 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. Rats were randomly divided into experimental groups' each consisting of not less than 7 animals. The vehicle or test chemical _ (25 mg/kg), NA (25 mg/kg) and the composition md+na (25+25 mg/kg) were administered by oral route 2 hours before the onset of thrombosis. The rats were anesthetized with an intraperitoneal injection of 50 mg/kg sodium pentobarbital and placed on a thermally controlled operating table to maintain a body temperature of 37 〇c throughout the experiment. One of the carotid arteries was exposed by a neck incision, and the self-adhesive tissue and the vagus nerve were separated' and a first-class probe (electromagnetic blood flow meter MFV 1200, Nic〇n K〇hden, Japan) was placed at the exposed part of the total carotid artery. To record blood flow. After a 15-minute stabilization period, two pieces (2x1 mm) of Whitman filter paper immersed in a solution of triiron sulphide (peCl3) 2 15 〇/〇 were induced by topical application (contact with the outer surface of the adventitia) to induce thrombosis. . The time to carotid thrombosis is recorded as the time required to completely stop the blood flow, and is described here as the time to block (TTO) until 36 201223530. In addition, during the thrombosis experiment, the tail bleeding time of the rat was measured. The tail was transected 5 mm from the trailing end with a scalpel and the tail was immediately immersed in warm isotonic saline at 37 °C until bleeding was noted. The point at which bleeding completely stopped and no more bleeding occurred in the next 30 seconds was defined as bleeding stopped. The blanket analyzes the data with the software Microsoft Excel 2007. Data for 7 to 8 separate animals/quantities are expressed as mean ± standard deviation (Mean ± SEM). One-way ANOVA analysis and repeated comparisons (tower assays) were used to compare the differences between the experimental groups. p<〇.〇5 is considered to be significant.

In the control group, the mean time for vascular blood tests caused by ferric chloride (FeC13) and the resulting arterial flow was 244 minutes (Table 17).

The effect of MD, sputum and combinations thereof on thrombosis caused by FeCl3.

The MD did not provide a significant increase in ττ〇 at 25 ί: g/kg but was not significant.意 unexpectedly caused by the combination of tail bleeding and sputum

plus. NA causes an increase in a small amount of TTO, and the impact of time is small. MD and NA ΤΤΟ S 啸 ( 39 39 39 39 39 39 39 39 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 The composition can be used to reduce the risk of thrombosis in patients with significant atherosclerosis, possible myocardial infarction and injury, and peripheral blood circulation disorders, and the sputum composition does not prolong the bleeding time. This fact indicates that this composition is used for Possible use of patients with increased risk of bleeding before and during surgery. The combination of the two methods of MP/ΝΑ and LA/NA is used to reduce the flushing ratio. The nicotinic acid (niacin, NA) is effective in lowering serum cholesterol, LDL and triglyceride. And improve HDL. However, a restrictive adverse effect on patients receiving immediate or sustained release from acid testing is the apparent rapid development of skin warming and vasodilation, known as "flushing", which severely leads to discontinuation (Gupta EK and Ito MK) Heart rot, 2002; 4: page I24 - I37). Laropipant (MK-0524) has been proposed as one of the most active and prospective agents for reducing nicotinic acid flushing (Cheng K et al., 4 darts, school, 2006) ;103 issues: page 6682-6687). Our goal was to compare the effects of md and LA on flushing (changes in skin temperature and blood flow) caused by NA in the experiment. 7.1.1. Determination of blood sputum in the skin. Emperor Huang was anesthetized with male pentosine pentobarbital (5 mg/kg, ip) and at an additional dose per hour (10 mg/kg) Make it in the state of hemp 38 201223530 drunk. The blood pressure of the left carotid artery was measured and the ECG was recorded in a standard π lead. The friend's flow of 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 sputum area by subcutaneous injection and continued for 30 minutes. Taking into account the mean blood pressure, the mean blood flow data for each animal was calculated and compared with 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 to the baseline (Carballo-Jane E et al. '襄襄学学房毒礼梦才敎办2007; 56(3): page 308-316). The results of avoiding each group of JL1 are expressed as mean ± standard deviation. Statistical analysis between groups was performed by Student's t-test and chi-square test for unpaired data. One-way AN〇VA analysis and repeated comparison (tower assay) were used to compare the differences between the experimental groups. p<〇 〇5 is considered significant. As can be observed in Table 18 below, in this animal model, a dose of 15 mg/kg of sputum resulted in an apparent increase in blood flow to the auricular arteries. _ similar to the control group' resulted in insignificant changes in blood flow. ΝΑ and MD - compared to ΝΑ alone led to delay (slow increase) and significantly statistically less significant = absolute increase in flow (Table 18). MD can antagonize the peripheral blood swell caused by sputum. This potential can have clinically beneficial effects for attenuating the acid-to-skin (shock), and is therefore further studied in detail (as described below). Table 18 Experimental substance vs. vascular effusion; η=5 8, average standard deviation 39 201223530 Group blood flow change 〇7〇 control group/solvent 2 · 1 5 士 4ΤΤ9 NA (1 5 mg/kg 4 6 . 1 ± 77^2-0 MD (45 mg/kg) 7.15±3Τ72~- NA + MD (15 + 45 mg/kg) 1 9.3 3 soil--- Ρ<0·01 V5 control group $ P<0.05 V5 ΝΑ 7.1.2. _ and LA on the blood of the cockroach 镊 之 之 傅 傅 傅 傅 傅 傅 材料 材料 材料 材料 : : : : 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.1 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 Treatment of solvents for hydrazine and MD ΝΑ 15 mg / kg Solvent for LA LA LA + NA [0] LA + NA [30] LA 0.3 mg / kg LA 0.3 mg / kg + ΝΑ 15 mg / kg LA0. 3 mg / kg + ΝΑ 15 mg / kg MD 45 mg / kg NA + MD [0] ΝΑ 15 mg / kg + MD 45 mg / kg NA + MD [30] ΝΑ 15 mg / kg + MD 45 mg / kg selected rose 丄 group The results of the group are expressed as mean ± standard deviation (Mean ± SEM). Statistical analysis within the group was performed by Student's t test. One-way ajsjovA analysis and repeated comparisons (tower assays) were used to compare the differences between the experimental groups. p<〇 〇5 is considered significant. RESULTS: When MD was administered alone, 'similar to LA, only caused a significant change in blood flow. When both NA and MD were administered simultaneously (advance time = 0), the rise in blood flow slowed down - and was less pronounced than the simultaneous administration of sputum and LA (LA + NA [0], see Table 19). In terms of ear blood flow, between MD+NA [〇] (when MD and ΝΑ are added) and md+na ρ〇] (pre-treatment before MD 3 mg/kg before ΝΑ 3 minutes) There is no obvious difference. In our experiments, pre-LA treatments (NA+LA [30]) 30 minutes before sputum significantly reduced the increase in blood flow induced by NA in the rat ear vessels (Table 19). Table 19 Effect of MD and LA on skin vasodilation induced by NA; N = 5_7, mean soil standard deviation group blood flow change, % 'solvent for sputum and MD 2. 1 2 ± 1.66** NA 52.27±8.5** MD 6.04±2.02, NA + MD [0] 25.1 1±5.25 *$ NA + MD [30] 28.07±5.74*s Solvent for LA 7.31±1.93s* ~ LA NA + LA [ 0] 29.34±7.82* NA + LA [30] 16.32±6.21* *P<0.05 vs Solvent**P<0.005 vj Solvent $P<0.05 vs ΝΑ $$P<0.005 vs ΝΑ MD can antagonize the surrounding area caused by ΝΑ Vasodilation 'This potential may have the beneficial effect of clinically reducing the effects of sputum on the skin (flushing). In our experiments, we were unable to establish the advantages of simultaneous administration of any of the hydrazine and LA compositions compared to the simultaneous administration of hydrazine and MD. 201223530 Evaluation of Nicotinic Acid 诿 由 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾 宾1382_1387). Temperature measurements were made with a hand-held infrared thermometer (Model Proscan 510 'TFA-Dostman). Animals were accustomed to being treated with the infrared probe three days prior to use. Under no anesthesia, three animals were read from the dorsal side of each ear before subcutaneous injection of NA (armor region) or solvent/test compound (tail region). The ear temperature was then measured every 5 minutes for a period of up to 60 minutes. Between measurements, animals are placed back into their cages. Six ear temperature measurements (three per ear) were averaged at each time point. On each day of the experiment, laropiprant (MK 0524, Cayman Chemicals) was first dissolved in dimercaptosulfoxide (dmso), followed by 〇9〇/〇 gasification ( Dilute with NaCl). The ratio of the NA and LA compositions is based on TredaPtive d^Hgn£t(iar(>piprant)) 1 〇〇〇 mg/20 mg modified product profile of the sustained release tablets. Experimental book l_..M test time and solvent on skin temperature 孪 group treatment animal number SolvLA solvent for LA 6 SolvNA solvent for sputum 6 ΝΑ ΝΑ 15 mg / kg (subcutaneous injection) 6 42 201223530 _Π The j^A/L_A and NA/MD compositions have an effect on the temperature of the ancient skin and are simultaneously introduced into LA such as LA+NA [0], or introduced into LA such as LA+NA ρ〇 before 30 minutes of NA, Simultaneously introduce md such as να + MD [0], or introduce it before 30 minutes of ]] Vfl) such as na + MD [30]; also examine the effect of LA and MD alone on skin temperature. Group control group / solvent treated animals 6 NA NA15 mg / kg 6 LA LA 0.3 mg / kg 6 NA + LA NA15 mg / kg + LA 0.3 mg / kg 6 * MD MD 45 mg / kg 6 NA + MD NA15 Mg/kg+MD45 mg/kg 6*# The data was analyzed by software Microsoft Excel in each time group and the results were expressed as mean +/- mean standard deviation. The average results of the different groups were compared according to ANOVA using single factor analysis and student t test. p<〇 〇5 is considered significant. Trend 1 is from 10 AM to 2 PM, and the recorded average mean ear temperature is 28 一 3 〇.2. [. A time-reaction study of NA (15 mg/kg, subcutaneous injection) showed an increase of 2 32 ± 0.37 QC from the baseline maximum temperature at ίο min. The maximum temperature was increased by 2 57 ± 〇 43 compared with the solvent group. (figure 1). It was established that the effect of LA solvent on ear temperature was only substantially different from that of hydrazine and MD solvent at the first 5 minutes after injection of 2012 201223530, so only one control group was used. Subcutaneous injection of MD or LA did not significantly alter the skin temperature of the rat ear (Table 21). Simultaneous administration of NA and MD (NA + MD [〇] group; lead time = 0) caused a decrease in NA flushing, which was similar to the simultaneous application of NA and LA. The temperature increase caused by NA was reduced, correspondingly to 69% and 67% (Table 21). There is no temperature change between MD+NA[0] (when MD is added with NA) and MD+NA [30] (pre-treatment before md 45 mg/kg 30 minutes ago). In our experiments, only pre-LA treatment (when subcutaneously dosed 〇·3 mg/kg, Να 30 minutes earlier) caused significant defense against skin temperature increase due to sputum (Table 21). Table 21 Effect of LA and MD on skin temperature increase caused by sputum; Ν = 6, mean standard deviation group control group / solvent

N A

LA

Starting temperature, DC 29.5 ± 0.29 29.61 ± 0.4

Maximum temperature, 0C 29.62±〇.25iis 32.2±〇.42*** increase, % 00 NA + LA [0] NA + LA [30] 29.43±0.27 29.72±0.3 1 29.51±0.32 29.5±〇T3 5** 1 31,45±0.40** 3 〇-73±〇.34** 6 7 4 7 ^ 9.7 ± 〇.TP11"

Therefore, we have established that the combination of NA and MD not only has unpredictable synergistic anti-gold platelet activity, but also reduces side effects - flushing. 44 201223530 — The test of the effects of blood sugar 澧麿 is well known, even a single large oral dose of να increases the GL concentration in the blood of animals (Thornton JH and Schultz LH, 980 years of dry literacy; 63 issues) Page 262_268), and in the treatment of diabetic patients, the use of NA requires monitoring of sugar concentration (Goldberg RB and Jacobson TA, Hai Qin Meng Xi Wen Wen 2008; 83 (4): page 470-8). Friendship _L used male adult Weiss rats in the experiment. Animals were pre-experimented - late fasted to stabilize the blood sugar concentration. The GL concentration in venous blood was measured before the experiment and 45 minutes after oral administration of the blank control group or the test substance. The GL concentration was determined in a commercially available kit (Optium, Abboit Diabetes Care Ltd, M.). High doses of strontium (300 mg/kg, orally introduced) were used which were known to cause stable and long-term increase in GL concentration in blood. Use the same dose of MD (300 mg/kg). Animals were randomly divided into 4 groups (η=8): 1) Control group (accept 1% sodium chloride (NaCl) solution, dose 2 ml / kg) 2) NA group (accept NA, dose 300 mg / kg) 3 MD group (accepting MD, dose 300 mg/kg) 4) NA+MD group (accepting 300 mg/kg NA and 300 mg/kg MD) Results of box ILL groups by mean ± standard deviation (Mean ± SEM) ) said. Statistical analysis within the group was performed by Student's t test. One-way ANOVA analysis and repeated comparisons (tower assays) were used to compare the differences between the experimental groups. P<〇.〇5 is considered significant. 5 45 201223530 Here is a statistically significant increase in GL concentration compared to the baseline and control groups (Table 21 below). MD caused a significant decrease in gl concentration, and the combination of MA and MD caused a noticeable, less significant increase in GL concentration (27 5% for the benchmark and 61.1% for 对照). This positive benefit points out that the combined combination of NA+MD can have no significant side effects in the unsettled or unrestrained Shaole surplus. The effect of the substance to be tested on the GL concentration in the big mad liquid; (4); the average standard deviation of the table 21 group control group (saline)

N A

M D

ΝΑ + MD experiment to see the change of the benchmark, % 3.8 4±〇.5 1 3·8±0·344 3~92±0.3 4 4.03±0·349 *Ρ<0·05 w control group &Ρ<0 ·01 vj Benchmark 3 _ 9 ± Ο · 5 3 6 · 12±〇.42 * ·72±〇·31 5 · 1 4±〇.5 6 1,6 .6 1 -5 . + 27.5 % for the control group 〇+ 56,9 8 Summary Conclusions Unexpectedly, it was discovered that the composition of the test enhances the therapeutic effect of the disease, including abnormal dyslipidemia, hyperemia, atherosclerosis , selected from the group consisting of angina pectoris and myocardial infarction, coronary heart disease, brain-borne accidents and cap and peripheral arterial deep-thickness disease, temporary cerebral ischemia episodes, changes in the heart of the heart ° the composition has also improved Due to the expansion of the surrounding corporate officials. Thus, the therapeutic combination exhibits improved activity compared to the disorder in the treatment of lipid metabolism side, resulting in a reduced daily dose with less significant adverse side effects. / 46 201223530 Mode for Carrying Out the Invention Herein, the treatment is combined to provide a component for simultaneous, sequential or separate composition of the composition. Accordingly, the present invention provides a therapeutic combination for simultaneous, sequential or separate use comprising NA and (10) or a pharmaceutically acceptable class thereof, lion blood stasis, a deficiency and chlorosis. The present invention provides a form of pharmaceutical composition comprising NA or a pharmaceutically acceptable salt thereof and MD or a pharmaceutically acceptable surface thereof, Mix a pharmaceutically acceptable diluent or carrier. "The pharmaceutical composition according to the present invention also includes a separate composition comprising a first NA composition or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier, and a second inclusion MD or its pharmaceutically acceptable _ and - pharmaceutically acceptable sputum or sputum. This composition provides a sequence or a cheerful one. Because the treatment or facial lipid metabolism-related diseases assume long-term use of drugs, the best implementation The mode of the present invention is to provide a form suitable for oral administration, such as a tablet or a capsule. In a pharmaceutical composition, the amount of each active ingredient in the therapeutic combination will vary depending on the condition to be treated. Patients who are familiar with the treatment of diseases related to lipid metabolism The artist can easily select an appropriate amount of each active ingredient, and a suitable dosage meter. The ratio of the preferred NA and MD or its active ingredient is from 3:1 to 1:3. A further aspect of the invention provides a therapeutic combination as defined above or a pharmaceutical composition as defined above for the manufacture of a medicament for simultaneous, sequential or separate use to prevent platelet aggregation/thrombosis Way. 47201223530 [Brief Description of the drawings FIG. 1 is NA, NA for the solvent (SolvNA) for the LA solvent (SolvLA) Effect of ear skin temperature of the rats. Ί main element 048 None REFERENCE NUMERALS

Claims (1)

201223530. VII. Patent Application Range: 1. A novel nicotinic acid therapeutic combination comprising an effective amount of niacin or a pharmaceutically acceptable salt thereof and an effective amount of mitrequinone or a pharmaceutically acceptable thereof Salt. 2. A combination of the scope of the patent application, wherein the nicotinic acid or a pharmaceutically acceptable salt thereof is in the form of an immediate release, sustained release or extended release formulation. 3. A combination of the scope of the patent application, wherein the rice koji or a pharmaceutically acceptable salt thereof is in the form of an immediate release, sustained release or extended release formulation. 4. The combination of claim 1 of the patent application is characterized by reducing the negative effects of nicotinic acid, i.e., peripheral vasodilatation (flushing), and/or increasing blood glucose concentration. 5. A combination of the first aspect of the patent application for preventing and/or treating a disease comprising abnormal dyslipidemia, which is selected from the group consisting of hyperlipemia, atherosclerosis, peripheral arterial occlusive disease, A group of angina, myocardial infarction, cerebrovascular accident, and stroke with temporary or permanent ischemic attack. 6. A combination of items i of the scope of application for the prevention and/or treatment of diseases contained in platelet aggregation, particularly thrombosis and thrombotic embolism. 7. A pharmaceutical composition that is adapted to prevent and/or treat a disease comprising aberrant fatty acid selected from the group consisting of high-fat-fat, atherosclerosis, peripheral arterial occlusive disease, temporary or The group consisting of red heart pain, myocardial infarction, cerebrovascular accident, and stroke in a permanent ischemic attack, the 49 S 201223530 pharmaceutical composition comprising an effective amount of niacin or a pharmaceutically acceptable salt thereof and effective A pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable agent or carrier. 8. The composition of claim 7, wherein the nicotinic acid or a pharmaceutically acceptable salt thereof is in the form of an immediate release, sustained release or extended release formulation. A composition wherein the (iv) quinone or a pharmaceutically acceptable salt thereof is in the form of an immediate release, sustained release or extended release formulation. 10. The composition of claim 7 of the scope of the patent application comprising about 5 〇 5 (8) milligrams of acid or its pharmaceutically acceptable amount of about 50.500 milligrams of rice koji or a pharmaceutically acceptable salt thereof. class. 11. A composition as claimed in claim i or a pharmaceutical composition according to claim 7 for the treatment and/or prevention of pathological abnormalities contained in diseases or platelet aggregations containing abnormal dyslipidemia. 12. A composition such as the patent application item i or a pharmaceutical composition according to claim 7 in the manufacture of a medicament for simultaneous, sequential or separate administration to a patient, (10) therapy or lion with abnormal dyslipidemia The pathological abnormalities contained in the disease or small plate aggregation. 13. The use of the composition of claim 12, wherein the disease comprising abnormal dyslipidemia is selected from the group consisting of hyperlipidemia, atherosclerosis, coronary artery selected from the group consisting of angina pectoris and myocardial infarction A group consisting of heart disease, a transient cerebral ischemic attack involving a cerebrovascular accident and a towel, and a peripheral arterial occlusive disease. 50 201223530 14. The use of the composition of claim 12, wherein the pathological abnormalities contained in platelet aggregation include thrombosis and thrombotic embolism. 15. A method for testing or treating a disease containing abnormal money, wherein the package s is simultaneously, sequentially or separately administered an effective amount of the therapeutic composition as claimed in claim 1 or as claimed in claim 7 The pharmaceutical composition to a patient in need of such treatment. 16. The method of claim 15, wherein the disease is selected from the group consisting of atherosclerosis of the blood stasis syndrome, a sequelae selected from the group consisting of angina pectoris and myocardial infarction, and a cerebrovascular accident. Temporary or permanent ischemic attack with stroke, and a group of peripheral occlusive diseases. π. The method of preventing and/or treating the pathological abnormality contained in the platelet aggregation, which comprises simultaneously, sequentially or separately applying the aging amount as the combination of the first application of the patent scope or the towel The pharmaceutical composition of item 7 to a patient in need of such treatment. 18. The method of claim 17, wherein the pathological abnormality comprises thrombosis and thrombotic embolism. 19. The method of claim 15 or the method of claim 17 wherein the conjugate is taken as a single-pharmaceutical composition, including the final acid or its medical red, and Mina or its Both medicines can be connected to the dragons of the text, combined with a pharmaceutically acceptable paste or carrier. 20. The composition of claim 7 of the patent scope, wherein the step further comprises a step selected from the group consisting of Atorva, the domain, the fluvastatin, the domain juice, the mevastatin/1, the pitava, Studing of the group consisting of pravastatin, scaled squad and simvadant river 51 201223530. 21. Use of a composition as claimed in claim 20 for the prevention and/or treatment of a disease selected from the group consisting of abnormal dyslipidemia, hyperlipidemia and atherosclerosis. 52