TW200409638A - Use of MELOXICAM in combination with an antiplatelet agent for treatment of acute coronary syndrome and related conditions - Google Patents

Abstract

The invention relates to a method of treatment or prevention of acute coronary syndrome or related conditions or reducing the risk of cardiovascular events comprising the administration of a therapeutically or prophylactically effective amount of meloxicam in combination with a therapeutically or prophylactically effective amount of an antiplatelet agent to a patient in need of such treatment. The invention also provides pharmaceutical compositions comprising meloxicam and an antiplatelet agent as a combined preparation suitable for use in these indications. Furthermore, the invention provides the use of meloxicam for manufacture of a pharmaceutical composition for treatment or prevention of acute coronary syndrome and related conditions when used in combination with an antiplatelet agent.

Description

200409638 • »⑴ 、, 玖, description of the invention (the description of the invention should state: the technical field to which the invention belongs, the prior art, the content, the embodiment and the simple description of the drawings) The field of life The present invention relates to a treatment or prevention of acute coronary syndromes Disease (ACy and related disorders or reducing the risk of cardiovascular disease (such as recurrent angina pectoris, percutaneous coronary angioplasty, vascular bypass grafting, and cardiovascular disease deaths) risks and methods, which involves co-administering an effective amount of COX -2 Selective NSAIDs for Rosicken and antiplatelet agents for patients in need of such treatment. Appropriate medicinal composition comprising Milosekine and antiplatelet agents in a combined preparation for simultaneous, separate or sequential use in these methods, And when used in combination with anti-platelet agents, the use of mirosikine is for the manufacture of pharmaceutical compositions for the treatment or prevention of ACS and related disorders or for reducing the risk of cardiovascular disease. 4-Hydroxy-2-methyl-N- (5-methyl-2- ° Seryl) -2H-1,2-benzothiazol-3-carboxamide-1,1-dioxide ) Belongs to NS AID (non-solid Anti-inflammatory drugs), described in EP-A-0 002 482. Oral administration of solid pharmaceutical preparations of Milosikine releases active substances from them and is rapidly absorbed, which has previously been disclosed (WO 99/49867), and has previously been Reveals oral administration of syrup formulations (WO 99/49845) and highly concentrated stable solutions (WO 01/97813). Regarding the mechanism of action, Milosikine is COX-2 and COX-2 Oxidoreductase inhibitors. There is no disclosure or suggestion of the use of mirosicen for the treatment and prevention of ACS. NSAIDs (non-steroidal anti-inflammatory drugs) belong to a wide range of treatments for inflammation such as (2) (2) 200409638 rheumatoid arthritis , Pain and fever compounds. Acetosalicylic acid (ASA) and other NSAIDs have been known to exert pharmacological effects through the non-selective inhibition of non-selective inhibition of cyclooxygenase (COX), thus blocking the synthesis of prostaglandins ( Nature '231: 232-2 35, 1971). There are two types of cox enzymes, namely COX-1 and COX-2. COX-1 manifests in many tissues including stomach, kidney and platelets, while COX-2 is only found in Inflammatory site manifestations (Gastroenterology, hi: 445-454, 19 96). Prostate derived from COX-1 Responsible for a number of physiological functions, including maintaining the integrity of the gastric mucosa. In order to reduce or avoid gastrointestinal toxicity stimuli stimulate the exhibition of COX-2 selective or even specific NSAIDs. ASA has been in the market for more than 100 years, hitting ASA with anti-platelet 'Efficacy' Therefore, ASA is still a reference drug for the cox inhibitor group in the treatment of acute coronary syndrome (ACS), and its efficacy is well documented (UK Medical Journal 1994 '3 08: 8 1-106). A SA has been shown to be effective in patients with unstable angina pectoris or non-Q-wave acute myocardial infarction (MI). A SA significantly reduces the incidence of MI, cardiovascular-cause-related mortality, and non-fatal reinfarction attacks. Cardiovascular death, myocardial infarction, and stroke combined incidence in patients with ACS showed a 25% reduction (New England Journal of Medicine 19 83, 3 09: 3 96-403; Stinger 1990: 827-30; New England Medicine Journal 1 9 8 5 '3 1 3: 13 6 9 -1 3 7 5; New England Journal of Medicine 1 98 8, 3 1 9: 1105-1111; thorn needle 1988: 349-360). Recent reports of COx-2 inhibitors may increase the risk of cardiovascular disease and require further study (Urological Oncology Symposium, November 2001, 19 (4), 294-305). First-generation COX-2 inhibitor study shows that arthritic patients treated with rofecoxib are five times more likely to have a heart attack than patients treated with naproxen (New England) Medical Journal 2000; 284: 1247-125 5). Thus, similar to ASA, non-selective NSAID NAPSON appears to have a cardioprotective effect compared to selective COX-2 inhibitors such as lofixi. An irreversible cox-ι inhibitor triflusal shows very low inhibitory activity on endothelial COX-2. This irreversible cox_i inhibitor has been reported for the treatment of unknowing angina pectoris and acute myocardium. Effective alternative to ASA at infarct (European Heart Journal Supplement (2001) 3 (Addendum Worker), 123-130). In addition, it is reported that ASA can aggravate cardiac insufficiency after ischemia, but the more selective COX-2 inhibitors Mirosicen and sc 58 1 25 do not (Naunyn-Schmiedebergs Pharmacology File 363 (2), 233-240 ( 2001)). Inhibition of COX-2 has also been reported to aggravate ischemia-induced acute dysfunction in rabbits (UK Pharmacology 135 (6), 1540-1546 (2002)). WO 99/459 13 discloses a combined method for treating or preventing acute coronary syndromes and related disorders, comprising administering to the patient a therapeutically effective amount of an antiplatelet agent in combination with a therapeutically effective amount of a COX-2 selective inhibitor. Anti-jk platelets can be glycoprotein Ilb / IIIa receptor antagonists, clopidogrel, ticlopidine, dipyridamole or ASA, but glycoprotein Ilb / IIIa receptor antagonists are preferred. In addition, a series of specific COX-2 selective inhibitors are revealed. Methods of combining other anticoagulants (e.g., thrombin inhibitors such as heparin, factor Xa inhibitors (e.g. rodentin)), and thrombolytic agents (e.g., streptokinase or tissue cytosinogen activator) are also disclosed. Indications include particularly acute coronary ischemic syndrome, especially angina pectoris or initial or recurrence (4), · · · (4), · · · 204096038 Q-wave myocardial infarction and thrombus, thromboembolism, thromboembolism and re-obstruction, and revascularization Stenosis, transient ischemic attack, and initial or recurrent stroke. It was discovered today that C OX-2 selective NS AID Mirosicen combination antiplatelet agents can be combined with standard antithrombotic therapy (such as heparin treatment) as needed to provide additional benefits related to the risk of cardiovascular disease and cardioprotective effects. These effects and benefits are exerted through the anti-inflammatory effects of Milosik. For example, Milosiken combined with aspirin and heparin for patients with acute coronary syndrome but without elevated ST segment, found to reduce the triple endpoint (recurrent angina, myocardial infarction and vascular death; or myocardial infarction, death and coronary Vascular reconstruction surgery) reached 60%, indicating that this combination therapy is particularly suitable for treating ACS patients. SUMMARY OF THE INVENTION It is clear that there is a need for other alternative treatment plans and improved methods of treatment and prevention of ACS (with / without ST segment elevation), to obtain optimal treatment for specific patients, and to reduce cardiovascular disease in patients at risk Seizure risk. Therefore, it is an object of the present invention to provide a method for treating and preventing ACS (with / without ST segment elevation) and related conditions, and reducing the risk of cardiovascular disease in patients at risk, including This treated patient is administered an effective amount of mirosicon and an effective amount of an antiplatelet agent. A second object of the present invention is to provide a medicinal composition as a combined preparation or a kit of parts, which comprises mirosicon and antiplatelet agents for simultaneous, separate or sequential use in the treatment or prevention of ACS and related disorders or for reducing Risk of cardiovascular disease in risk patients. A third object of the present invention is the use of Milosikine for the manufacture of a pharmaceutical composition (5) (5) 200409638. The pharmaceutical composition is a combination preparation or a component kit comprising Milosikine and antiplatelet Agents are intended for simultaneous, separate or sequential use in the treatment or prevention of ACS and related conditions or to reduce the risk of cardiovascular disease in at-risk patients. Implementation In view of the first feature, the present invention provides a novel method for treating, preventing or reducing the risk of AC s or related disorders or reducing the risk of cardiovascular disease, comprising administering a therapeutic or preventive amount of mirosi to mammals and special human patients Ken combines a therapeutically or prophylactically effective amount of an antiplatelet agent. In this way, the therapeutic agent itself is used in patients in need of such treatment to suppress blood micropolar agglutination and to suppress inflammation of blood vessel walls. Inflammation of the blood vessel wall is known to affect the etiology of unstable angina pectoris and myocardial infarction, because inflammation markers such as c-reactive protein are prognostic values for primary acute coronary syndromes (Xin Yinglan Medical Journal 2002; 347: 1557 -1565). The method according to the present invention can be added to standard antithrombotic therapy, preferably for high-risk patients with acute illness who need to be hospitalized. For example, standard heparin therapy includes the administration of low molecular weight heparin or unsorted heparin, or the administration of pentasaccharides, Ximelagatran, melagatran, water insects, hirulog, argatroban, lepirudin, or bivalirudin As well as oral anticoagulants such as warfarin or acenocumarol; or can be administered after standard thrombolytic therapy (such as bond kinase or histone cytoplasmin active agent and related compounds). For patients who are not suffering from an acute condition but who have developed acute coronary syndrome (AeS> (6) 200409638, related conditions or risk of cardiovascular disease onset, the method of the present invention is preferably administered without the aforementioned standard antithrombotic treatment. In the myocardium Patients with a history of infarction are at risk of developing acute coronary syndrome (ACS), related conditions, or cardiovascular disease. The method of the present invention can be administered with or without an oral anticoagulant (recurrent prevention, post-hospital treatment).

The term "AC S or related condition" must be understood to indicate in a non-limiting manner the inclusion of acute coronary ischemic syndromes including unstable angina pectoris, non-ST segment elevation myocardial infarction (UA / NSTEMI), and ST segment elevation Myocardial infarction (STEMI), peripheral arterial obstruction or re-obstruction, cerebral thromboembolism from extracranial origin, transient ischemic attack, and initial or recurrent stroke. The term "cardiovascular attack" must be understood to include, in a non-limiting manner, recurrent angina pectoris, percutaneous coronary angioplasty, vascular bypass grafting, death from cardiovascular disease, coronary obstruction and reobstruction, or percutaneous coronary Vessel stenosis again after remodeling and coronary artery bypass grafting. Preferred indications related to the method of the invention include

Acute coronary ischemic syndrome includes unstable angina pectoris, non-s T segment elevation myocardial infarction (UA / NSTEMI), and ST segment elevation myocardial infarction (STEMI), as well as reducing the risk of cardiovascular disease. Vascular disease is selected from recurrent angina pectoris, percutaneous coronary angioplasty, coronary artery bypass grafting, and death from cardiovascular disease. In the method of the present invention, mirosicken and antiplatelet agents can be administered simultaneously or separately at staggered times such as sequentially. When the target plasma concentration of each active drug can be maintained substantially simultaneously, a better advantageous effect can be achieved. -10- (7) 200409638

The term "acute coronary ischemia" refers to local anemia due to mechanical obstruction of the blood supply such as arterial stenosis. This disease is called myocardial ischemia and is characterized by insufficient myocardial blood circulation, usually as a result of coronary artery disease. Myocardial ischemia is chest pain, which often passes from the front of the heart to the left shoulder and down to the left arm (angina). Myocardial ischemia is caused by coronary artery disease. Blood loss also includes myocardial infarction, which is caused by a blocked coronary artery. As used herein, the term “myocardial infarction” is intended to include unstable angina pectoris and ST segment elevation myocardial infarction (UA / NSTEMI) and ST segment elevation myocardial infarction (STEMI) (unless otherwise indicated). "Cerebrovascular ischemic attack" refers to the reduction of cerebral blood flow supply, including but not limited to primary or recurrent thrombotic stroke or transient ischemic attack. A “therapeutically effective amount” means the amount of a drug or agent that a veterinarian, physician, or other clinical therapist can elicit in a tissue, system, animal, or human that elicits a biological or medical response.

A “prophylactically effective amount” means the amount of a drug or agent intended by a veterinarian, physician, or other clinical therapist to seek to prevent or reduce the risk of a biological or medical condition in a tissue, system, animal, or human. "Reducing the risk of A CS or related conditions" means reducing the risk of developing these diseases in patients at risk. Patients at risk for these conditions include a history of heart disease, a genetic predisposition to these conditions, diabetes with hyperlipidemia, high blood pressure, and withdrawal from the patient. The oral dose of Milosikine for indications is about 0.01 mg / kg / day to about 1.0 mg / kg / day, preferably 0.05 to 0.75 -11-(8) (8) 200409638 mg / kg / day, and optimally 0.1 to 0.4 mg / kg / day. For example, individual patients can take a dose of 15 grams per day. Tablets, capsules or suspensions (syrups) formulations or suppositories suitable for oral administration contain 2.5 mg to 30 mg, preferably 5 to 20 mg, and most preferably 7.5 to 15 mg such as 2.5 mg, 5 mg , 7.5 mg, 10 mg, 15 g, 20 mg, or 30 mg of Mirosicon. Any commercially available Milosikine formulation can be used in the method of the invention. For example, Rote Liste® 2002, Editio Cantor Verlag Aulendorf, Germany. Oral administration can be divided into two, three, three, four, five, or six times per day or equally. A single dose per day is preferred. Milosikine can also be administered intravenously in large doses of about 10 to 20 grams per day, and preferably about 15 milligrams per day. For parenteral administration, 'Mirosicken can be intravenously infused slowly over a period of 24 hours from 0.1 to 0.4 mg / kg body weight, and preferably from 0.2 to 03 mg / kg body weight. Antiplatelet agents suitable for use in the present invention include glycoprotein (Gp) nb / nia receptor antagonists, copidolide, ticopidine, dipilidamo, cilostazol, and ASA. With respect to aspects of the invention herein, the term "antiplatelet agent" is intended to include all pharmaceutically acceptable salt, ester, and solvate forms, including hydrates with platelet aggregation inhibitory active compounds and prodrug forms. Compounds with one or more palm centers can be racemic isomers, racemic mixtures, and individual diastereomers or enantiomers, all such isomers and mixtures Included in the scope of the present invention. The crystalline form of any polymorphic compound formed by any antiplatelet agent is intended to include -12-(9) (9) 200409638 within the scope of the present invention. GP Ilb / IIIa receptor antagonists inhibit fibrinogen binding to the nb / IIIa platelet receptor site, thereby inhibiting platelet aggregation. Suitable GP Ilb / IIIa receptor antagonists are disclosed in WO 99/459 1 3, page 22, line 35 to page 27, line 5 and incorporated herein by reference. Appropriate GP Ilb / IIIa receptor #antibiotics are selected from DMP 754, silbraHban, xemlofiban, fradafiban, and orbofiban. Antiplatelet agents which are preferably suitable for use in the present invention are selected from the group consisting of copidolide, dipilidamo and ASA. Particularly good is ASA. Any of the Copidory, Dipilidamo, Silotazo and ASA formulations available on the market can be used in the method of the invention. References Rothrist 2002, Editio Cantor Verlag Aulendorf, Germany, and a physician's desktop reference manual, 56th edition, 2002. The oral dose of the GP Ilb / IIIa receptor antagonist for the indication effect is about 0.001 mg / kg / day to about 50 mg / kg / day, and preferably 0.005-20 mg / kg per kilogram of body weight. / Day, and preferably 0.005-10 mg / kg / day. Suitable oral tablets and capsules contain 0.1 mg to 5 g, preferably 0.5 mg to 2 g, and most preferably 0.5 mg to 1 mg, such as 0.5 mg, 1 g, 5 mg, 10 mg , 150 mg, 250 mg, or 500 mg GPIIb / IIIa receptor antagonist. Oral administration can be taken once daily, or an average of two, three, or four times daily. A single dose per day is preferred. When administered intravenously, the optimal dose of the GP Ilb / IIIa receptor antagonist is about 0.5 μg to about 5 μg / kg / min during the strange infusion period, reaching 0.1 nanogram / ml to 1 μg during the period of administration. / Ml of plasma concentration. -13- (10) (10) 200409638 Copidori can be administered daily at a dose of about 25 mg to 5 ο 0 mg, preferably 75 to 3 75 mg, and optimally 75 to 150 mg orally Medication. For example, the formulation or dosage unit contains 25 mg, 50 mg, 75 mg, 150 mg, 250 mg or 500 g of copidory. Oral administration can be divided into two, two or four times per day. It is better to take it once a day. Ticosidine can be administered orally at a daily dose of about 50 mg to 10 mg, preferably 100 to 7500 mg, and most preferably 200 to 500 mg. For example, the formulation or dosage unit contains 50 mg, 100 mg, 200 mg, 250 mg, or 500 mg of Ticopidine. Oral administration can be divided into two, three or four times a day. It is better to administer once a day. Cilotazo may be administered orally at a dose of about 50 mg to 500 mg, preferably 100 to 300 mg, and most preferably 150 to 250 mg per day. For example, the formulation or dosage unit contains 50 mg, 100 mg, 200 mg, 250 mg, or 500 mg of cilostazol. Oral administration can be divided into two, three or four times a day. It is better to administer once a day. Dipilidamo can be administered orally at a daily dose of about 25 to 500 mg, preferably 75 to 375 mg, and most preferably 75 to 150 mg. For long-term treatment, it is preferred to administer repeated doses such as 25 mg dipilidamo long-acting agent or any other instant release formulation three or four times daily. For example, the formulation or dosage unit contains 25 mg, 50 mg, 75 mg, 150 mg, 250 mg, or 500 mg dipilidamo. Oral administration can be divided into two, three or four times per day. It is better to administer once a day. For oral administration, Dipilidamo can be infused slowly over a 24-hour period (not higher than 0.2 mg / min) at 0.5 to 5 mg / kg / body weight, and preferably 1 -14- (11) (11) 200409638 to 3.5 Mg / kg / weight. The oral dose of A SA for indications is about 10 mg to about 325 mg per day. For example, a formulation or unit dose containing 10 mg, 20 mg, 50 mg, 75 mg, 80 mg, 100 mg, 150 mg, 250 mg, or 325 mg of ASA. Standard heparin treatment that can be used in combination with the methods of the invention includes administration Low-molecular-weight heparin (LMWH), unsorted heparin (UFH), hirudin, Hailuo Luo, Yagdoben, melagchuan, repyrudin or bivalirudin, such as subcutaneous injection of LMWH (e.g. sodium Doparin (nadroparin) 87 IU / kg twice daily or enoxaparin (lmg / kg twice daily), or intravenous administration of UFH, the first large dose to 5000 IU, This was followed by a continuous infusion of 1,000 international units per hour for 7 days. Activated partial clotting time (APTT) can be used to assess the extent of anticoagulation in patients receiving intravenous UFH. Patients were administered every 12 hours on the first day and then every 24 hours. APTT is maintained in the range of 45 to 87 seconds (normally 30 to 5 seconds). In view of the second feature, the present invention provides a medicinal composition comprising a therapeutically or prophylactically effective amount of mirosicken and a therapeutically or prophylactically effective amount of an antiplatelet agent for treating, preventing or reducing the risk or reducing the occurrence of ACS or related disorders Cardiovascular disease risk. The pharmaceutical composition includes a single pharmaceutical formulation, containing both mirosicon and an anti-platelet agent in the pharmaceutical formulation for simultaneous use, and a combined preparation or component set kit comprising mirosikine in a pharmaceutical formulation and Antiplatelet agents are used in another pharmaceutical formulation for simultaneous, separate, or sequential use. -15- (12) (12) 200409638 For example, the specific embodiment of the component kit group may be a Milosikine oral dosage form formulation and an ASA oral dosage form formulation. Kit packs can be designed and manufactured in a variety of ways. Preferably, for example, the vesicles are packaged on the same vesicle card and contain rows of Mirosicon tablets and ASA tablets arranged side by side. The two tablets are each inside the vesicle of the vesicle, and the card has a calendar or other Similar labels inform users to take a "pair" of lozenges daily. The active compound for administration can be formulated in one or more conventional inert carriers and / or diluents known in the industry, for example, with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidine Ketones, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose, or fatty substances such as stearin or its appropriate Mixtures are formulated into conventional pharmaceutical formulations such as ordinary lozenges or coated lozenges, diamond-shaped lozenges, hard or soft capsules, dispersible powders or granules, sugar or brewing agents, solutions for injection, ampoules , Aqueous or oily suspensions, emulsions or suppositories. Any commercially available Milosikine formulation can be used in the pharmaceutical composition of the present invention. See Rotrist 2002, Editio Cantor Verlag Aulendorf, Germany. Suitable formulations for oral administration, capsules or suspensions (syrups) contain 2.5 mg to 30 mg ', preferably 5 to 20 mg, and optimally 7.5 to 15 mg, such as 2.5 Milligram, 5 milligram, 7.5 milligram, 10 milligram, 15 milligram, 20 milligram, or 30 milligram. GP Ilb / IIIa receptor antagonists can be used as oral platelets or capsules as antiplatelet agents, containing 0.1 mg to 5 g, preferably 0.5 mg to 2 g, and most preferably 0.5 mg to 1 mg. 0.5 mg, 1 g, 5 mg, 10 mg • 16-(13) (20) 200409638, 150 mg, 250 mg or 500 mg of active compound. Suitable lozenges and intravenous formulations containing GP Ilb / IIIa receptor antagonists are disclosed in WO 99/459 13 as in Examples 1 and 2. Any commercially available Milosikine formulation can be used in the pharmaceutical composition of the present invention. Reference is made to Verister 2002, Editio Cantor Verlag Aulendorf, Germany, and the Physician's Desktop Reference Manual, 56th edition, 2002. Copidogrel can be used, for example, as an antiplatelet agent in oral tablets or capsules containing 25 mg, 50 mg, 75 mg, 150 mg, 250 mg or 500 mg of the active compound. Ticopitine can be used, for example, as an antiplatelet agent for oral tablets or capsules containing 50 mg, 100 mg, 200 mg, 250 mg, or 500 mg of the active compound. Sillotazone can be used, for example, as an antiplatelet agent in oral tablets or capsules containing 50 mg, 100 mg, 200 mg, 250 mg or 500 mg of the active compound. Dipilidamo can be used, for example, as an antiplatelet agent in oral tablets or capsules containing 25 mg, 50 mg, 75 mg, 150 mg, 250 mg or 500 mg of the active compound. ASA as an antiplatelet agent can be used, for example, in oral tablets or capsules containing 10 mg, 20 mg, 50 mg, 75 mg, 80 mg, 100 mg, 150 mg, 250 mg or 325 mg of active compound.

In view of the third feature, the present invention provides the use of a Milosikin combination antiplatelet agent for the manufacture of a pharmaceutical composition for treating ACS (14) 200409638 or related conditions for preventing or reducing the occurrence of ACS or related conditions Risk, or reduce the risk of cardiovascular attacks. The antiplatelet agents and their preferred embodiments, indications and preferred embodiments, and pharmaceutical compositions are described in the first and second features of the foregoing invention. The best feature of the present invention is the combination of Mirosikken and A S A.

The composition and method of the present invention can be used to treat, prevent or reduce the risk of thrombosis and thromboembolism, and thus can be used to treat, prevent or reduce the risk of thromboembolism and re-occlusion. It can be used in peripheral arterial surgery (arterial transplantation, carotid endarterectomy) and cardiovascular surgery. This operation deals with the interaction of arteries and organs and / or platelets with the surface of the arteries. As a result, platelets are formed and blood clots may form embolism. For example, combination therapy can be used to prevent or reduce the risk of platelet thrombosis, thromboembolism, and reocclusion after emergency surgery such as endarterectomy, angioplasty, coronary artery bypass surgery, or cardiac membrane replacement. Combination therapy can also be used to prevent or reduce the risk of platelet thrombosis, thromboembolism, and reocclusion during and after thrombolytic therapy. Because the blood vessels may be chronically damaged due to the pathophysiological process of atherosclerosis, patients with atherosclerosis also use this combination treatment to prevent or reduce the risk of obstructive emboli formation. This combination therapy can be used to treat, prevent or reduce the risk of intermittent claudication and clinical characterization of peripheral vascular disease with intermittent claudication. This combination therapy can also be used to treat, prevent or reduce the risk of primary or secondary myocardial infarction in patients at risk, and to prevent or reduce the risk of vascular restenosis in patients at risk for restenosis. In addition, this combination therapy can be used to treat, prevent, or reduce the risk of acute cardiovascular ischemic attacks (eg, primary -18 · (15) 200409638 or secondary thrombotic stroke, or transient ischemic attacks). Usually this combination therapy can be used for patients who need antiplatelet therapy or inhibit platelet aggregation. Example 1 Efficacy rating of the Milosikine / ASA combination for acute coronary syndrome (A C S) without elevated ST segments

BACKGROUND: Despite the use of heparin, aspirin, and other antiplatelet agents, patients with ACS without elevated ST segments are still at risk for cardiovascular thrombosis. It has been tested whether the combination of Milosikine and A SA is superior to ASA alone in ACS patients receiving standard antithrombotic heparin therapy.

Abstract: Patients with acute coronary syndrome but without ST-segment elevation in a prospective single-blind pilot study before randomization of open-label fibers were randomly divided into aspirin and treatment groups during indwelling in the coronary intensive care unit. (N = 60) or aspirin, heparin, and mirosicken treatment groups (n = 60). The patient then received aspirin or aspirin Gamirosicken for 30 days. During the indwelling period of the coronary artery intensive care unit, the major outcome variables such as recurrent angina pectoris, myocardial infarction, or death were significantly lower in the patients receiving the Mirosiken group (15.0% vs. 3 8.3%, P = 0.07). The second composite variable (coronary artery angioplasty, myocardial infarction, and death) was also significantly lower in the patients receiving the Mirosiken group (10.0% vs. 26.7%, P = 0.034). At 90, the primary focus was still significantly lower in the Mirosikian group (2.7% vs. 48.3%, P = 0.004), and the secondary endpoint was also the same (13.3% vs. 33.3%, P = 0.015). Angioplasty also had the same variables (11.7% vs. 30.0%, P = 0.025). No adverse complications were seen with mirosicken treatment. -19- (16) (16) 200409638 Methods Milosikine was used in an open randomized prospective single-blind pilot study of ACS patients without ST-segment elevation. Patients must be from Argentina, Centro de Salud and Centro Modelo de Cardiologia Medical Center in Tucaman. The criteria for the test patients were suppression of chest pain with ST segment (20.5 mm) in the previous 24 hours, and evidence of electrocardiogram ischemia or previous history of coronary artery disease. Excluded from the trial were persistently elevated ST segments and elevated sarcosine kinase MB isoenzyme (CK-MB) concentrations consistent with acute myocardial infarction, who had undergone revascularization within the previous 6 months Contraindications to surgery, malignancy, pregnancy, kidney or liver disease, anticoagulant therapy, anti-inflammatory drug treatment or research medication. Patients were randomized into the aspirin plus heparin group (n == 60) or the aspirin, heparin, or mirosicon group (n = 60). In the active treatment group, just 15 mg of mirosticon was injected intravenously after randomization, followed by oral administration of 15 mg per day during hospitalization, and continuous administration of 30 mg after discharge. Both groups received aspirin 30 days. At the clinician's discretion, the dosage is in the range of 100 to 300 mg per day. CK-MB concentration was measured before random grouping. Additional dK-MB concentrations were measured at the onset of chest pain to confirm the diagnosis of acute myocardial infarction. All patients received subcutaneous LMWH (nadoparin 87 IU / kg twice daily or inoxaparin 1 mg / kg twice daily), or intravenously administered UFH, with an initial high dose of 5000 IU , Followed by a continuous infusion of 1,000 international units per hour for a total of 7 days, or until the discharge. The activated partial clotting time (APTT) is used to evaluate the degree of anticoagulation in patients receiving intravenous unsorted heparin. Patients are tested every 12 hours and every 24 hours thereafter. APTT dimension (17) (17) 200409638 is in the range of 45 to 87 seconds (normal value, 30 ± 5 seconds). Study endpoints The primary outcome was Θ during the coronary intensive care unit and the combined variables that tracked recurrence of cardiac pain, myocardial infarction, or death during the 90th day. Secondary combination variables were also measured: myocardial infarction, death, and total angioplasty (transcatheter coronary angioplasty [PTCA] or coronary artery transplantation [CABG]). Each component of the primary and secondary consequences variables is also recorded separately. According to Degner et al., Today's drug 1 998,34 (Addendum A): Bu 22 _, after a large dose of 15 mg mirosicen intravenously, was 3.0 mg / L and tmax was 0.05 hours. These data are expected to have an immediate anti-inflammatory effect with intravenous administration of mirosicken, and any outbreak of disease after randomization is considered an endpoint. Cardiac catheterization was performed at the discretion of the clinician, but only the urgent PTCA and CABG (bone chanting Φ τ τ Vk now after recurrent angina pectoris and myocardial infarction) were considered as the end point. The blood camp belongs to _selection, and another %% surgery is suitable for relapse chest pain of stubborn medication. During the stay in prn * long LCU and after discharge, all patients were checked for clinical status by studies that did not understand / σ treatment allocation. Instruct the patient to report any disease outbreaks to researchers immediately. The diagnostic criteria for myocardial infarction are chest pain that lasts for 20 minutes or more, accompanied by changes in the electrocardiogram and CK-MB at least ancient. & ^ ^ Μ _ 1 Ah 2 times. Recurring palpitation of the palate means recurrent chest pain, accompanied by stubborn electrocardiogram changes to medications (aspirin, heparin, nitroglycerin, and blockers). Statistical analysis ^ y ν 77 lineage was evaluated by Shapiro-Wilk test. 2 The difference between treatments was borrowed by the student's t test (independent sample; A fork whit-21-(18) (18) 200409638) test, which was analyzed based on distribution. Activated partial coagulation after receiving unsorted heparin The time difference is evaluated in a two-way ANOVA model, and one of the factors is repeated (student Newman-+ _ (Newman-1 ^ 1115) 051: -110 (: test). A single random variable between the quantitative variables Relations were assessed by x2 (Yates correction) and Spearman's ranking correction. Obtained relative risks (RRs) and their 95% CI. RR reduction (RRR) is defined as 1 minus RR and expressed as a percentage .Absolute risk reduction (ARR) is calculated as the difference between the risk reduction of the control group and the risk of the treatment group, and is expressed as a percentage. Multiple logistic regression model is used to determine the 90-day prediction of disease-related variables based on the previous single random variable analysis. Value. The software used is css / statistics 3.1 (StatSoft) and EPI INFO 6ν · 6.04, 1996. Results A total of 120 patients were randomly divided into groups. 60 patients received Miro Siken and aspirin with heparin, right Sixty patients in the control group received only heparin and aspirin. There were no significant differences in baseline clinical characteristics between the two groups of patients (Table 1). Male patients in the control group (37, 61.7%) were more than milosicken. There are more groups (31, 517%), and the average ecu stay time is longer for the control group (4 •… · 6, compared to * 35 ± 1.14), but these differences are not significant. —— benchmark characteristics of humans Rossi control group (n = 60) p sex " --- male 31 (51.7) 37 (61.7) 0.357 female 29 (48.3) 23 (38.3) ··· age, age -22- (19) 200409638 average 61 60.7 1.0 range 38-84 28-81… risk factor smoking current 21 (35.0) 22 (36.7) 1.0 previous * 3 (5.0) 8 (13.3) 0.206 never 36 (60.0) 30 (50.0) 0.359 quality index < 25 17 (28.3) 10 (16.7) 0.19 > 25 43 (71.7) 46 (76.3) • Abnormal fat metabolism 17 (28.3) 1 7 (28.3) 1.0 Diabetes 13 (21.7) 22 (36.7) 0.108 High Blood pressure 22 (36.7) 27 (45.0) 0.458 Previous myocardial infarction 11 (18.3) 11 (18.3) 1.0 Previous angina 2 (3.3) 0… Previous PTCA 4 (6.6) 8 (13.3) 0.361 Previous CABG 3 (5.0) 2 (3.3 ) 1.0

Unless otherwise indicated, values are n (%). * Stop smoking time> 1 February.

Table 2. Activated partial coagulation time after receiving unsorted heparin Activated partial coagulation time 36) Seiken (n = 36) Seiken (n = 35) Seiken (n = 28) Seiken (n = 50) (n = 50) (n = 50) (n = 47) Mean soil standard deviation 54.9 ± 22.4 55.8 ± 26.4 70.4 ± 23.0 69.6 ± 19.9 78.9 ± 22.2 89.9 ± 24.4 72.5 ± 18.5 89.3 ± 20.8, the middle value of the second, the second 48 48 63 62 77 86 74 84.5 -23- (20) 200409638 ΑΡΤΤ in the treatment range (45 -87 seconds),% 56.9 67.7 77.8 79.7 61.2 52.3 88.9 58.3 APRI II in > range of treatment (< 45 seconds),% 33.3 25.8 4.4 3.6 2.7 0 0 0 APTT in excess of treatment range (> 87 seconds),% 9.8 6.5 17.8 16 36.1 47.7 11.1 41.7

Mirosikan represents the Mirosikan formation. η is the number of patients receiving unsorted heparin. * Control group and Milosiken group, P < 0.05 (Janova). Ten patients in the Mirosicen group and 24 patients in the control group received LMWH. The remaining patients were treated with UFH. Ten patients in the Mirosicken group were treated with natopalin. In the control group, 22 patients were treated with nadoparin and 2 patients were treated with inoxaparin. The ability of unsorted heparin to maintain APTT in the therapeutic range (45 to 87 seconds) is shown in Table 2. Within the first 24 hours, 56.9% of the UFH received in the control group and 67.7% of the Milosikine group had APTTT in the treatment range, with 9.8% and 6.5% APTTT higher than the treatment range, respectively. During the first 24 hours, 33% and 26% (P = 0.618) of patients in the control group and the Mirosiken group had APTT below the therapeutic range, respectively. After the first day, patients in the two groups were below the treatment range < 5%, and by the fourth day, all patients were within or above the treatment range. Efficacy of primary outcome variables at the time of coronary intensive care center Results The incidence of recurrent angina was significantly lower in the mirosicen-treated group than in the control group (9 of 60 patients = 15 · 0% compared to 60 patients 21 bits in the 24-24 (21), (21), --njy638 3 ::>%; 1> = 0.02). This is equivalent to 1 ^ 11 to 57.1% (95% (: 1, 14 to 79) (J. Among the patients receiving the Mirosiken group, the need for re-angioplasty has a low trend, but it has not reached statistical significance. (P = 0.05). Milosi ok. The incidence of recurrent angina pectoris, myocardial infarction, and death (9 patients; 15%) was higher than that of the control group (23 patients; 38 3). %) Is low. This difference is statistically significant (ρ = 0.07) and is equivalent to rrR = 608%, (95% CI '23 to 80). Coronary angioplasty (pTC a or CAB G), myocardial infarction and death syndrome in 6 patients (ι 0%) in the Mirosicen group and 16 (2 6.7%) in the control group. This difference is also statistically significant (p = (〇〇34), RRR 62 · 5% (95% CI; 11 to 84). During the hospitalization period, 8 patients in the control group and 3 patients in the Mirosicon group discontinued treatment. The reason for stopping the treatment was confrontation,? There were 5 endpoints in the group and 2 patients in Milosikine who had an end point. One patient in each group dropped out of the study. 2 of the patients assigned to the control group discontinued treatment because of discharge. The difference between the mirosicen treatment group and the control group was observed during the period of staying in the 70 years. The progression frequency of the relapsed angina pectoris during the 20 day follow-up period in the Lerosiken group (12 patients; 2 0 %) Is lower than the control group (26 patients; 43.3%). The difference is statistically significant (P = 0.011) and is equivalent to the RRR = 53.8% (9 5% CI, 17 to 74) (Table 4). The number of patients undergoing coronary arthroplasty remodeling in the Milosiken group was significantly lower (7 patients = 11.7% vs. 18 patients = 30%; P = 〇.025, rrr = 61%, 95% (CI, 14 vs. 82). Thirteen patients (21.7%) in the Milosikine group had a progressive composite endpoint of recurrent angina pectoris, myocardial infarction, and death, compared with 29 patients (48.3%) in the control group. This difference was- 25- (22) 200409638 The difference is statistically significant (p = 0.004), which is equivalent to the bile of the Mirosiken group = 1% (95% CI, 22 to 74). Mirosiken group Coronary angioplasty = progressive frequency of secondary outcome variables for degree of angioplasty, myocardial infarction and death (8 patients; 13.3%) was significantly higher than the control group (20 patients; 33.3%) (P = 0.015), And it is equivalent to the ratio of RRR = 60%. 95% ci, 16 to 8 in Table 4). Onset of dwell time in the awkward artery plus intensive care unit Mirosiccan (n = 60) Control (n = 60) RRR (IC 95%) ARR% p * Recurrent angina pectoris, n (%) 9 (15.0) 21 (35.0) 57.1 (14-79) 20.0 0.02 All blood organs are reshaped, n (0 / 〇) 6 (10.0) 15+ (25.0) 60.1 (4.0-83) 15.0 0.055 PTCA, η 2 4 CABG, n 4 10 AMI, η 0 2 vascular death, η 0 1 recurrent angina pectoris + Μ + vascular death, η (%) 9 (15) 23 (38.3) 60.8 (23-80) 23.3 0.007 Ι + death + Revascularization, η (%) 6 (10.0) 16 (26.7) 62.5 (11-84) 16.7 0.034 * × 2 test. + One patient received percutaneous blood; both. Each only considers one episode. Table 4. The results of the 90-day follow-up period. Fen again # 1 shape surgery and hand planting; 90 episodes during the follow-up period. Milosevic (n = 60) control (n = 60). ) RRR (95% Cl) ARR% p * recurrent angina pectoris, n (〇 / 〇) 12 (20.0) 26 (43.3) 53.8 (17-74) 23.3 0.011 revascularization, n (%) 7 (11.7) 18 + (30.0) 61.0 (14-82) 18.3 0.025 -26-(23) 200409638 PTCA, η 3 7 CABG, η 4 12 AMI 5 η 0 3 (5) vascular death, η 0 2 (3.3) recurrent angina pectoris + ΜΙ + Vascular death, η (%) 13 (21.7) 29 (48.3) 55.1 (22-74) 26.6 0.004 Μ + death + vascular reshaping, η (%) 8 (13.3) 20 (33.3) 60.1 (16-81) 20.0 0.015 * X2 test. + One patient underwent both percutaneous angioplasty and bypass surgery. Each episode is considered only once. Table 5. Association of multiple random variables between disease onset and treatment group. Odd ratio 95% CI P. South blood pressure 2.31 1.00-5.38 < 0.05 Diabetes 2.43 1.01-6.36 < 0.05 Treatment group 0.33 0.14-0.77 0.01 Logistic regression (highest probability ). Χ2 = 22 · 36; df: 4, P = 0 · 0002. Temporal Trend During the 8-hour random grouping period, the Mirosiken group had 1.70%. Patients compared with 6.7% of patients in the control group who had reached the primary outcome variable (P = 0.0361). At 30 days, the ratio was significantly lower in patients treated with Milosikine (20.0% compared to 46.7%; P = 0.004). At the 30th day, 11.7% of the Mirosicon group had reached other secondary outcome variables, compared with the control group = 31.7% (P = 0.015). During the 90th follow-up period, the single random variable Spellman ranking interaction showed significant interactions between the onset of each disease, hypertension (rS = 〇24, p = 〇〇〇07), high blood cholesterol (rS = 0.20, (P = 0.002), diabetes (rS = 0.26, P = 0.004), and the treatment group (rS = -0.28, P = 0.002). In the multi-random variable analysis during the 90-day follow-up period (Table 5), only hypertension, diabetes, and the treatment group were significantly associated with the onset of the disease. safety

No patient had observed bleeding complications, side effects, or intolerance during the study period. So consistent with the pharmacological evaluation, no damage to the central nervous system, cardiovascular / pulmonary, kidney, musculoskeletal or autonomic nervous system was observed using a dosing plan that was 3 to 10 times higher than the anti-inflammatory dose of mirosikine. Evidence (Denger et al., Drugs 1998, 34 (Addendum A): 1-22). discuss

An initial significant reduction in the number of disease episodes observed during C C U was maintained during the 90-year follow-up period. The significant difference between the control group and the Mirosicon group was the difference in the rate of recurring chest pain, with an RRR = 57.1% absolute risk reduction (ARR) = 20%, and a reduced need for myocardial revascularization during CCU (RRR = 60.8%; ARR = 15%). ARR of recurrent angina was improved by 3.3% during the 30-day treatment period. During the 90th follow-up, this discrepancy was maintained, with only one death case report for each group. -28-

Claims (1)

200409638 Patent application scope 1. A medicinal composition for treating or preventing patients with acute coronary syndrome or related diseases or reducing the risk of cardiovascular disease, comprising a therapeutically effective amount of meloxicam combination treatment Or preventive anti-platelet agents. 2. The pharmaceutical composition according to item 1 of the patent application scope, which is administered during standard antithrombotic therapy or after thrombolytic therapy. 3. If the pharmaceutical composition of item 1 or 2 of the patent application scope, wherein the patient needs to be hospitalized with high-stroke patients with acute coronary syndrome or related conditions, or has coronary syndrome (ACS), related conditions or cardiovascular Patients at risk of seizures. 4. The pharmaceutical composition according to item 1 or 2 of the scope of patent application, wherein the acute syndrome or related disorder is selected from the group consisting of acute coronary ischemic syndrome, including unstable angina pectoris, non-segment elevation Myocardial infarction (UA / NSTEMI), ST segment elevation myocardial infarction (STEMI), peripheral arterial obstruction or reocclusion, cerebral embolism from extracranial origin, transient ischemic attack, and initial or subsequent stroke, and The cardiovascular disease is selected from the group consisting of recurrent angina pectoris, percutaneous coronary angioplasty, bypass grafting, fatal due to cardiovascular disease, coronary thrombus obstruction and re-obstruction, or skin coronary angioplasty, and Coronary artery bypass graft revascularization stenosis. 5. The pharmaceutical composition according to item 1 or 2 of the patent application scope, wherein the acute symptom syndrome or related disorder is selected from the group consisting of the following group of diseases or a blood-risky crown: ST, blood clot, postmenstrual crown, 200409638, acute Coronary ischemic syndrome includes unstable angina pectoris, non-sτ-segment elevation myocardial infarction (UA / NSTEMI) and ST-segment elevation myocardial infarction (STEMI), and wherein the cardiovascular disease line is selected from the following composition Recurrence of angina pectoris, percutaneous coronary angioplasty, bypass grafts, and deaths due to cardiovascular disease occurred in the group. 6. The pharmaceutical composition according to item 1 or 2 of the scope of patent application, wherein the antiplatelet agent is selected from the group consisting of glycoprotein (GP) IIb / IIIa receptor antagonists, clopidogrel, and tikopitin ( ticlopidine), dipyridamole, cilostazol, and ethylsalicylic acid. 7. The pharmaceutical composition according to item 1 or 2 of the patent application scope, wherein the anti-platelet agent is selected from the group consisting of copidolide, ticopidine, dipilidamo, cilostazol, and ethosylsalicylic acid Groups of people. 8. The pharmaceutical composition according to item 1 or 2 of the patent application scope, wherein the anti-platelet agent is selected from the group consisting of Ticopidine, Dipilidamo and Ethyl salicylic acid, the latter being particularly preferred . 9. A pharmaceutical composition comprising a therapeutically or prophylactically effective amount of mirosicken and a therapeutically or prophylactically effective amount of an antiplatelet agent. 10. The composition of item 9 in the scope of the patent application, which is a kit of components or parts, which includes mirosikine in one pharmaceutical formulation and antiplatelet agent in another pharmaceutical formulation for simultaneous and separate preparation. Or use it sequentially. 11. The use of a mirosicen combination antiplatelet agent for the manufacture of a pharmaceutical composition 2004096038, the pharmaceutical composition is used to treat acute coronary syndrome or related disorders, or to prevent or reduce acute coronary syndrome or related disorders The risk of occurrence, or reduce the risk of cardiovascular disease. 12. The use according to item 11 of the scope of patent application, wherein the acute coronary syndrome or related disorder is selected from the group consisting of acute coronary ischemic syndromes, including unstable angina pectoris, non-ST segment elevation myocardial infarction (UA / NSTEMI), ST segment elevation myocardial infarction (STEMI), peripheral arterial obstruction or reocclusion, cerebral thromboembolism from extracranial origin, transient ischemic attack, and initial or subsequent stroke, and Cardiovascular disease is selected from the group consisting of recurrent angina pectoris, percutaneous coronary angioplasty, bypass graft surgery, fatal due to cardiovascular disease, coronary thrombus obstruction and reobstruction, or percutaneous coronary angioplasty, and coronary Vascular stenosis again after arterial bypass surgery. 13. The use according to item 11 of the patent application, wherein the acute coronary syndrome or related disorder is selected from the group consisting of acute coronary ischemic syndrome including unstable angina pectoris, non-ST segment elevation myocardial infarction (UA / NSTEMI) and ST segment elevation myocardial infarction (STEMI), and the cardiovascular disease is selected from the group consisting of recurrent angina pectoris, percutaneous coronary angioplasty, bypass graft surgery, and cardiovascular disease The illness is fatal. 14. The use as claimed in claim 11, 12, or 13, wherein the anti-platelet agent is selected from the group consisting of glycoprotein (GP) IIb / IIIa receptor antagonists, copidori, citrate 40096038 copidine, pipi A group consisting of lidamo, sirota left, and ethinosalicylic acid. 15. For use as claimed in claim 11, 12, or 13, wherein the antiplatelet agent is selected from the group consisting of copidoride, ticopidine, dipilidamo, cillotazone, and ethinosalicylic acid Groups of people. 16. If the application of the scope of patent application No. 11, 12 or 13 is used, wherein the anti-platelet agent is selected from the group consisting of Ticopidine, Dipilidamo and Acetylsalicylic Acid ^ The latter is particularly preferred . -4- 200409638% Lu, (a), the representative representative of the case is: "__ (b)", the representative symbol of the representative diagram is briefly explained: 柒, if there is a chemical formula in this case, please reveal the features that can best show the invention Chemical formula