KR20040053884A - Use of meloxicam in combination with an antiplatelet agent for treatment of acute coronary syndrome and related conditions - Google Patents

Abstract

PURPOSE: The use of meloxicam in treatment or prevention of acute coronary syndrome or related conditions or reducing the risk of cardiovascular events, in combination with a therapeutically or prophylactically effective amount of an antiplatelet agent is provided. Furthermore, the use of meloxicam is provided 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. CONSTITUTION: For the treatment or prevention of acute coronary syndrome or related conditions or reducing the risk of cardiovascular events, a therapeutically or prophylactically effective amount of meloxicam is administered to a patient in need of such treatment, in combination with a therapeutically or prophylactically effective amount of an antiplatelet agent. The pharmaceutical composition comprising the meloxicam and antiplatelet agent also is added to the standard antiplatelet treatment or applied after the antithrombotic treatment. The antiplatelet agent is selected from glycoprotein IIb/IIIa receptor antagonists, clopidogrel, ticlopidine, dipyridamole, cilostazol and acetyl salicylic acid.

Description

Use of meloxicam in combination with an antiplatelet agent for treatment of acute coronary syndrome and related conditions

The present invention treats or prevents acute coronary syndromes (ACS) and related conditions, including co-administration of an effective amount of COX-2 selective NSAID meloxycam and antiplatelet agents to a person in need thereof, or Methods of reducing the risk of developing relationship problems, such as recurrent angina, percutaneous coronary revascularization, bypass graft and cardiovascular death; Suitable pharmaceutical compositions comprising meloxycam and antiplatelet agents as combination formulations for simultaneous, separate or continuous use in the method; And when used in combination with antiplatelet agents, the use of meloxycam for the treatment or prevention of ACS and related conditions or for the manufacture of pharmaceutical compositions for reducing the risk of developing cardiovascular problems.

Meloxycamp (4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide) is an NSAID (Non-steroidal anti-inflammatory agent) and described in EP-A-0 002 482.

Solid pharmaceutical preparations for oral administration of meloxycamps (WO 99/49867), in which the active substance is rapidly released and absorbed, as well as syrup formulations for oral administration [WO 99/49845] and highly concentrated stable solutions [WO 01/97813 is already described.

In relation to the mechanism of action, meloxycamps have been identified as cyclooxygenase-2 (COX-2) and oxidoreductase inhibitors.

However, the use of meloxicam for the treatment and prevention of ACS has never been described or suggested.

NSAIDs (non-steroidal anti-inflammatory agents) are a class of compounds that are widely used in the treatment of inflammation, eg, rheumatoid arthritis, pain and fever. Acetylsalicylic acid (ASA) and other NSAIDs are well known to block prostaglandin synthesis by exerting pharmacological effects through non-selective inhibition of cyclooxygenase (COX) enzymes [Nature, 231: 232- 235, 1971. There are two types of COX enzymes named COX-1 and COX-2. COX-1 is constitutively expressed in numerous tissues, including the stomach, kidneys and platelets, while COX-2 is expressed only at sites of inflammation (Gastroenterol., 111: 445-454, 1996). Prostaglandins derived from COX-1 are involved in numerous physiological effects, including maintenance of gastric mucosal integrity. Reduction or avoidance of gastrointestinal toxicities has motivated the development of COX-2 selective or more specific NSAIDs.

Because of the antiplatelet effect, ASA, which has been in use for more than 100 years, is still a reference agent included in the group of COX inhibitors for the treatment of acute coronary syndrome (ACS) and its effects are well known [Br. Med. J. 1994, 308: 81-106. ASA has been shown to be effective in patients with unstable angina or non-Q-wave acute myocardial infarction (MI) (ASA significantly reduces the incidence of MI), death of cardiovascular causes, and nonfatal reinfarction. Complications of cardiovascular death, MI and stroke have been reduced by 25% in patients with ACS [N. Engl. J. Med. 1983, 309: 396-403; Lancet 1990: 827-30; N. Engl. J. Med. 1985, 313; 1369-1375; N. Engl. J. Med. 1988, 319: 1105-1111; Lancet 1988: 349-360.

Recently, it has been reported that COX-2 inhibitors may increase the incidence of cardiovascular problems, which requires further research [Seminars in Urologic Oncology, 2001, Nov., 19 (4), 294-. 305]. Studies with first-generation COX-2 inhibitors have shown that arthritis patients treated with rofecoxib are five times more likely to develop a heart attack than patients treated with naproxen. [N. Engl. J. Med. 2000; 284: 1247-1255. Thus, like ASA, non-selective NSAID naproxen appears to exert a cardioprotective effect compared to selective COX-2 inhibitors such as rofecoxib.

An irreversible COX-1 inhibitor, triflusal, which shows little inhibitory activity on COX-2 expression in endothelial cells, has been reported as an effective alternative to ASA in the treatment of unstable angina and acute MI [European Heart Journal Supplements (2001) 3 (Supplement I), 123-130.

In addition, ASA has been reported to exacerbate post-ischemic cardiac dysfunction, but not to the more selective COX-2 inhibitors, meloxicam and SC 58125 [Naunyn-Schimiedebergs Archives of Pharmacology 363 (2), 233-240). (2001). In addition, inhibition of COX-2 has been reported to exacerbate ischemia-induced acute dysfunction in rabbits (British Journal of Pharmacology 135 (6), 1540-1546 (2002)).

WO 99/45913 describes a combination treatment for acute coronary syndrome and related conditions, comprising administering to the patient a therapeutically effective amount of antiplatelet agent in combination with a therapeutically effective amount of a COX-2 selective inhibitor. And preventive measures. The antiplatelet agent may be a glycoprotein IIb / IIIa receptor antagonist, clopidogrel, ticlopidine, dipyridamole or ASA, with glycoprotein IIb / IIIa receptor antagonists being preferred. In addition, a series of specific COX-2 selective inhibitors are described _[RR1] . The method is also described as useful for use with other anticoagulants (e.g., thrombin inhibitors such as heparin, factor Xa inhibitors such as wafarin), and thrombolytics (e.g., streptokinase or tissue plasminogen activator). do. Acute coronary syndrome, especially angina pectoris or first and subsequent Q-wave myocardial infarction, as well as thrombosis, thromboembolism, thrombotic occlusion and reclosure, restenosis, transient ischemic attack, and a first or subsequent stroke Specifically indicated.

Herein, optionally, in combination with standard antithrombotic therapies such as heparin therapy, the combination of COX-2 selective NSAID meloxycamp with an antiplatelet agent acts through the anti-inflammatory effect of meloxycamp, thereby limiting the risk of developing cardiovascular problems. It also provides additional benefits related to cardioprotective effects. For example, in patients with acute coronary syndrome without elevation of the ST-segment, the combined treatment of meloxycampin with aspirin and heparin may result in recurrent angina, myocardial infarction and vascular death, or myocardial infarction, death and coronary revascularization. It has been found to reduce the triple end point of the vascularization process by 60%, indicating that it is particularly suitable for treating patients with ACS.

In addition to optimizing treatment for patients with cardiovascular problems, as well as reducing the risk of developing cardiovascular problems in patients, additional treatment and prevention of ACS (with or without elevation of ST segment) There is a clear need for selective treatment regimens and ameliorations.

Accordingly, it is an object of the present invention to treat and prevent ACS (with or without elevation of ST segment) and related conditions, comprising administering to a patient in need thereof an effective amount of hydroxycam and an effective amount of antiplatelet agents. And methods for reducing the risk of patients at risk of developing cardiovascular problems.

It is a second object of the present invention to treat or prevent ACS and related conditions and to reduce the risk of a patient at risk of developing cardiovascular problems, for simultaneous, individual or continuous use, meloxycam and anti To provide a kit of pharmaceutical compositions or parts as a combination formulation comprising platelets.

A third object of the present invention is to provide meloxycamps and antimicrobial agents for simultaneous, separate or continuous use, for the treatment or prevention of ACS and related conditions and for reducing the risk of patients at risk of developing cardiovascular problems. Use of Meloxycam for the preparation of a kit of pharmaceutical compositions or parts as a combination formulation comprising platelets.

In view of the first aspect, the present invention provides a method of treating ACS, comprising administering to a mammal, and more particularly a human patient, a therapeutically or prophylactically effective amount of meloxycamp in combination with a therapeutically or prophylactically effective amount of an antiplatelet agent. New methods of treating or preventing or reducing the risk of developing related conditions or reducing the risk of developing cardiovascular problems are provided. Thus, treatment is based primarily on the inhibition of platelet aggregation and the inhibition of inflammation in the vessel walls of patients in need of such treatment. Inflammatory wall inflammation is known to affect the development of unstable angina and myocardial infarction, since inflammatory markers such as C-reactive protein represent the prognostic value of primary acute coronary syndromes [N. Engl. J. Med. 2002; 347: 1557-1565.

The method according to the invention comprises standard antithrombotic therapies, preferably administration of standard antithrombotic therapies, eg, low molecular weight heparin or unfractionated heparin, in high-risk patients suffering from acute conditions requiring hospitalization. Standard heparin therapy, or pentasaccharide, ximelagatran, melagatran, hirudin, hirulog, argatroban, lepiudin or non Administration of bivalirudin, as well as oral antiplatelet agents such as warfarin or acenocumarol, or antithrombotic therapies (eg, streptokinase or tissue plasminogen activators and related compounds) Can be applied afterwards.

In patients who do not suffer from an acute condition but are at risk of developing acute coronary syndrome (ACS), related conditions or cardiovascular problems, it is desirable to apply the methods of the present invention without the standard antithrombotic therapies mentioned above. In patients with a history of acute coronary syndrome (ACS), related conditions or myocardial infarction at risk of developing cardiovascular problems, the methods of the present invention may be used with or without anticoagulant (secondary prevention, post-discharge treatment). Applicable

The expression "ACS or related condition" refers to an unstable angile, non-ST-segment elevation myocardial infarction (UA / NSTEMI), ST-segment elevation myocardial infarction (STEMI), occlusion or re-obstruction of the peripheral artery in a non-limiting manner. It should be understood to include acute coronary ischemic syndrome, including cerebral thromboembolism of extraneous origin, transient ischemic attacks, and first or subsequent strokes.

The expression "cardiovascular problem" refers to recurrent angina, percutaneous coronary revascularization, bypass graft, cardiovascular death, coronary thrombotic occlusion, and percutaneous coronary revascularization and coronary artery bypass graft in a non-limiting manner. It should be understood to include reobstruction or restenosis.

What is preferably indicated in connection with the method of the invention,

Acute coronary ischemic syndrome, including unstable angina, non-ST-segment elevation myocardial infarction (UA / NSTEMI), and ST-segment elevation myocardial infarction, and

To reduce the risk of developing cardiovascular problems selected from recurrent angina, percutaneous coronary revascularization, bypass graft and cardiovascular death.

In the methods of the invention, the meloxycamp and antiplatelet agents may be administered simultaneously or separately at different time points, ie continuously. Advantageous effects are preferably achieved when the target plasma level concentrations of each active agent are maintained at substantially the same time point.

"Acute coronary ischemia" means local anemia due to mechanical obstruction of the blood supply, eg, artery narrowing. This condition is referred to as myocardial ischemia and is generally characterized as inappropriate blood circulation to the myocardium as a result of coronary artery disease. Myocardial ischemia is evidenced by pain in the chest (angina) that radially spreads from the anterior chest to the left shoulder and under the arm and is caused by coronary artery disease. Ischemia also includes myocardial infarction, which results from occlusion of the coronary arteries. As used herein, the term “myocardial infarction” refers to both unstable angina and non-ST-segment elevation myocardial infarction (UA / NSTEMI) as well as ST-segment elevation myocardial infarction (STEMI) unless otherwise noted. It is intended to be included.

A "cerebrovascular ischemic problem" relates to a reduced blood supply to the brain and includes, but is not limited to, a first or subsequent thrombotic stroke, or a transient ischemic attack.

A "therapeutically effective amount" means an amount of a medicament or pharmaceutical agent that induces a biological or medical response in a tissue, systemic, animal or human, as sought by a veterinarian, physician or other clinician.

A “prophylactically effective amount” means an amount of a medicament or pharmaceutical agent that prevents or reduces the risk of developing a biological or medical problem to be prevented in a tissue, systemic, animal or human, as sought by a veterinarian, physician or other clinician. .

The occurrence of ACS or related conditions "reducing the risk" means lowering the risk of developing in patients at risk of developing the condition. Patients at risk of developing the condition include those who have a history of heart disease, the condition, diabetes, hyperlipidemia, genetic predisposition to develop hypertension, and are smokers.

When used for the indicated effect the oral dosage of meloxycamp is from about 0.01 mg / kg body weight / day (mg / kg / day) to about 1.0 mg / kg / day, preferably 0.05 to 0.75 mg / kg / Days, most preferably 0.1 to 0.4 mg / kg / day. For example, an oral dose of 15 mg can be given to an individual patient once a day. Suitable tablet, capsule or suspension (syrup) formulations, or suppositories for oral use, are from 2.5 mg to 30 mg, preferably from 5 mg to 20 mg, most preferably from 7.5 mg to 15 mg, eg For example, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, or 30 mg. All commercially available meloxycam formulations can be used in the methods of the present invention. Rote Liste 2002, Editio Cantor Verlag Aulendorf, Germany. Oral administration can be in a daily dose or in divided doses of 2, 3, 4, 5 or 6 times. A single daily dose is preferred.

Meloxycam can also be provided in a bolus iv dose of about 10-20 mg per day, preferably in a bolus iv dose of about 15 mg per day.

For parenteral administration, meloxycamps can be given for 24 hours, such as slow intravenous infusion, at a dose of 0.1 to 0.4 mg / kg body weight, preferably 0.2 to 0.3 mg / kg body weight.

Antiplatelet agents suitable for use in the present invention include glycoprotein (GP) IIb / IIIa receptor antagonists, clopidogrel, ticlopidine, dipyridamole, cilostazol and ASA.

As used herein, with respect to all aspects of the invention, the term “antiplatelet agent” includes solvate forms, including prodrug forms of compounds having platelet aggregation inhibitory activity, as well as all pharmaceutically acceptable salts, esters, and hydrates. It is intended to be. Compounds having one or more chiral centers may be produced as racemates, racemic mixtures and individual diastereomers or enantiomers having all such isomeric forms included within the scope of the invention, and mixtures thereof. All crystalline forms of antiplatelet agents taking polymorphisms are intended to be included in the present invention.

GP IIb / IIIa receptor antagonists inhibit the binding of fibrinogen to the IIb / IIIa platelet receptor site, thereby inhibiting platelet aggregation. Suitable GP IIb / IIIa receptor antagonists are described in WO 99/45913, page 22, line 35 to page 27, line 5, which is incorporated herein by reference. Suitable GP IIb / IIIa receptor antagonists are selected from DMP 754, sibrafiban, xemlofiban, pradafiban and orbofiban.

Preferred antiplatelet agents suitable for use in the present invention are selected from clopidogrel, dipyridamole and ASA. Especially preferred is ASA. All formulations of commercial clopidogrel, dipyridamole, cilostazol and ASA can be used in the methods of the invention. Rote Liste 2002, Editio Cantor Verlag Aulendorf, Germany, and Physicians Desk Reference, 56 ^th edition, 2002.

When used for the indicated effect, oral dosages of GP IIb / IIIa receptor antagonists range from about 0.001 mg / kg body weight / day (mg / kg / day) to about 50 mg / kg / day, preferably 0.005 to 20 Mg / kg / day, and most 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, most preferably 0.5 mg to 1 mg, for example 0.5 mg, 1 mg, 5 mg, of the GP IIb / IIIa receptor antagonist, 10 mg, 150 mg, 250 mg or 500 mg. Oral administration may be in a daily dose or in divided doses of two, three or four times. A single daily dose is preferred.

For intravenous injection, the most preferred dose for the GP IIb / IIIa receptor antagonist is from about 0.5 μg to about 5 during a constant rate infusion to achieve plasma level concentrations of 0.1 ng / ml to 1 μg / ml during the time of administration. Will be in the mg / kg / min range.

Clopidogrel may be administered orally in a daily dosage of about 25 mg to 500 mg, preferably 75 to 375 mg, and most preferably 75 to 150 mg. For example, the dosage form or dosage unit may contain clopidogrel 25 mg, 50 mg, 75 mg, 150 mg, 250 mg or 500 mg. Oral administration may be in a daily dose or in divided doses of two, three or four times. A single daily dose is preferred.

Ticlopidine may be administered orally in a daily dosage of about 50 mg to 1000 mg, preferably 100 to 750 mg, and most preferably 200 to 500 mg. For example, the dosage form or dosage unit may contain 50 mg, 100 mg, 200 mg, 250 mg, or 500 mg of ticlopidine. Oral administration may be in a daily dose or in divided doses of two, three or four times. A single daily dose is preferred.

Cilostazol may be administered orally in a daily dosage of about 50 mg to 500 mg, preferably 100 to 300 mg, and most preferably 150 to 250 mg. For example, the formulation or dosage unit may contain 50 mg, 100 mg, 200 mg, 250 mg or 500 mg of cilostazol. Oral administration may be in a daily dose or in divided doses of two, three or four times. A single daily dose is preferred.

Dipyridamole can be administered orally in a daily dosage of about 25 mg to 500 mg, preferably 75 to 375 mg, and most preferably 75 to 150 mg. For long term treatment, one dose of delayed 25 mg dipyridamole or repeated administration of another immediate release formulation 3 or 4 times daily is advantageous. For example, the dosage form or dosage unit may contain 25 mg, 50 mg, 75 mg, 150 mg, 250 mg or 500 mg dipyridamole. Oral administration may be in a daily dose or in divided doses of two, three or four times daily. A single daily dose is preferred.

For parenteral administration, dipyridamole can be given for 24 hours, such as slow intravenous infusion (0.2 mg / min or less), at a dose of 0.5 to 5 mg / kg body weight, preferably 1 to 3.5 mg / kg body weight. .

Oral dosages of ASA for the indicated effects generally range from about 10 mg to about 325 mg per day. For example, the formulation or dosage unit may contain 10 mg, 20 mg, 50 mg, 75 mg, 80 mg, 100 mg, 150 mg, 250 mg or 325 mg ASA.

Standard heparin therapies that may be used in combination with the treatment methods according to the invention include low molecular weight heparin (LMWH), unfractionated heparin (UFH), hirudin, hirulog, argatroban, melagatran, repyrudine or b. Initial bolus injection of subcutaneous LMWH (e.g., nadroparin 87 IU / kg BID or enoxaparin 1 mg / kg BID) or 5000 IU Then presented intravenous UFH such as continuous infusion at 1000 IU per hour for 7 hours. Activated partial thromboplastin time (APTT) can be used to assess the degree of anticoagulation in patients receiving intravenous UFH. Patients may test every 12 hours on the first day and every 24 hours thereafter. APTT should be maintained within 45 to 87 seconds (normal value, 30 ± 5 seconds).

In view of the second aspect, the present invention provides a therapeutically or prophylactically effective amount of meloxycamp for use in treating, preventing or reducing the risk of developing ACS or related conditions, or for reducing the risk of developing cardiovascular problems and Provided is a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of an antiplatelet agent. The pharmaceutical composition of the present invention is a single pharmaceutical dosage form containing both meloxycam and antiplatelet agent in a pharmaceutical dosage form for simultaneous use, as well as pharmaceutical dosage forms for simultaneous, separate or continuous use. Kits of combination formulations or moieties comprising the anti-platelet agent in the meloxycampin and separate pharmaceutical dosage forms.

For example, a specific embodiment of the kit of parts may be an oral dosage form of meloxycam and an oral dosage form of ASA. The packaging of the kits can be designed and manufactured in a variety of ways. Preferred examples contain ASA tablets in several rows and sides of Meloxycham tablets on the same blister card, with a similar form of indication on the card or card for a user that a "pair" of tablets is consumed for 1 day. Is a blister package, and each of the two tablets is in its own blister foam.

For administration, the active compounds may be simple tablets or tablets, lozenges, hard or soft capsules, dispersible powders or granules, syrups or elixirs, injectable solvents, ampoules, aqueous or oily suspensions, emulsions, solvents or suppositories Among conventional gallene pharmaceutical formulations such as one or more conventional inert carriers and / or diluents as known in the art, for example corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrroly Formulated with fatty substances such as don, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or hard fats, or a suitable mixture thereof Can be.

All commercially available meloxycam formulations can be used in the pharmaceutical compositions according to the invention. Rote Liste 2002, Editio Cantor Verlag Aulendorf, Germany. Suitable tablet, capsule or suspension (syrup) formulations, or suppositories for oral use, meloxam 2.5 mg to 30 mg, preferably 5 mg to 20 mg, and most preferably 7.5 mg to 15 mg, eg For example, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, or 30 mg.

As antiplatelet agents, GP IIb / IIIa receptor antagonists are present in the active compound of 0.1 mg to 5 g, preferably 0.5 mg to 2 g, and most preferably 0.5 mg to 1 mg, for example 0.5 mg, 1 mg, 5 mg, 10 Oral tablets or capsules containing mg, 150 mg, 250 mg or 500 mg. Suitable tablets and intravenous formulations containing GP IIb / IIIa receptor antagonists are described in WO 99/45913, Examples 1 and 2.

All formulations of commercial clopidogrel, dipyridamole, cilostazol and ASA can be used in the pharmaceutical compositions according to the invention. Rote Liste 2002, Editio Cantor Verlag Aulendorf, Germany, and Physicians Desk Reference, 56 ^th edition, 2002.

Clopidogrel as an antiplatelet agent can be used, for example, in oral tablets or capsules containing the active compound 25 mg, 50 mg, 75 mg, 150 mg, 250 mg or 500 mg.

Ticlopidine as an antiplatelet agent can be used, for example, in oral tablets or capsules containing 50 mg, 100 mg, 200 mg, 250 mg or 500 mg of the active compound.

Cilostazol as an antiplatelet agent can be used, for example, in oral tablets or capsules containing 50 mg, 100 mg, 200 mg, 250 mg or 500 mg of the active compound.

Dipyridamole as an antiplatelet agent can be used, for example, in oral tablets or capsules containing the active compound 25 mg, 50 mg, 75 mg, 150 mg, 250 mg or 500 mg.

ASA as an antiplatelet agent can be used in oral tablets or capsules containing, for example, 10 mg, 20 mg, 50 mg, 75 mg, 80 mg, 100 mg, 150 mg, 250 mg or 325 mg of the active compound.

In view of the third aspect, the present invention provides an antiplatelet agent for the manufacture of a pharmaceutical composition for treating ACS or related conditions, preventing or reducing the risk of developing ACS or related conditions, or reducing the risk of developing cardiovascular problems. It provides a use of meloxycamp in combination with.

Antiplatelet agents and preferred specific embodiments thereof, guidelines and preferred embodiments thereof, as well as pharmaceutical compositions, are mentioned above in the first and second embodiments of the present invention. Most preferred with respect to all aspects of the invention is a combination of meloxycam and ASA.

The compositions and methods of the present invention can be used to treat, prevent or reduce the risk of thrombotic occlusion and reclosure by treating, preventing or reducing the risk of the formation of thrombosis and thromboembolism. These include cardiovascular system in surgical operations on peripheral arteries (artery graft, carotid artery dissection), and manipulation of arteries and organs and / or the interaction of platelets with arterial surfaces resulting in platelet aggregation and the formation of potential thrombus and thromboembolism. It is useful in relational surgery. For example, combination therapy can be used to prevent or reduce the risk of platelet thrombosis, thromboembolism, and reoccurrence after acute intervention (eg, arteriotomy, angioplasty, coronary artery bypass procedure, or heart valve replacement). Can be. Combination therapy can also be used to prevent or reduce the risk of platelet thrombosis, thromboembolism and re-occlusion during and after thrombolytic therapy. Because blood vessels can be chronically damaged by the pathophysiological process of atherosclerosis, patients with atherosclerosis can also be treated with the combination therapy of the present invention to prevent or reduce the risk of obstructive thrombus formation. The combination therapy of the present invention can be used to treat, prevent or reduce the risk of intermittent claudication, a clinical indication of peripheral vascular disease.

The combination therapy of the present invention may also be used to treat, prevent or reduce the risk from a patient at risk of a first or subsequent myocardial infarction, or to prevent or reduce the risk of restenosis in a patient at risk of restenosis. have. In addition, the combination therapy of the present invention can be used to treat, prevent or reduce the risk of developing acute cerebrovascular ischemic problems (eg, first or subsequent thrombotic stroke, or temporary ischemic attack). In general, the combination therapy of the present invention can be used whenever antiplatelet therapy or inhibition of platelet aggregation is required.

Example 1

Evaluation of Efficacy of Meloxycham / ASA in Combined Acute Coronary Syndrome (ACS) Without ST-segment Elevation

BACKGROUND: Despite the use of heparin, aspirin and other antiplatelet agents, there is a risk of developing cardiovascular thrombosis problems in ACS patients without ST-segment elevation. The combination of meloxycamp and ASA was tested to be superior to ASA alone in ACS patients under standard antithrombotic heparin therapy.

Summary: In an open-labeled, randomized, promising single-blind small-scale study, patients with acute coronary syndrome without ST-segment elevation were treated with aspirin and heparin (n = 60) or aspirin, heparin And randomized to Meloxycham (n = 60) treatment. Patients were then given aspirin or aspirin plus meloxycam for 30 days. During the stay of the coronary treatment unit, the primary outcome variable of recurrent angina, myocardial infarction or death was significantly lower in patients receiving meloxium (15.0% vs. 38.3%, P = 0.007). Secondary composite variables (coronary revascularization process, myocardial infarction and death) were also significantly lower in meloxycam-treated patients (10.0% vs. 26.7%, P = 0.034). On day 90, as with the secondary endpoints (13.3% vs. 30.0%, P = 0.015) and the need for revascularization alone (11.7% vs. 30.0%, P = 0.025), the primary endpoints were Significantly lower (21.7% vs. 48.3%, P = 0.004). No adverse complications associated with meloxycam treatment were observed.

Way

An open, randomized, promising single-blind small-scale study using meloxycam in ACS patients without ST-segment elevation was performed. Patients were recruited from the Centro de Salud and the Centro Modelo de Cardiologia, Tucuman, Argentina. Inclusion criteria are ECG evidence of chest pain and ischemia or previous coronary disease history in relation to ST-segment drop (≧ 0.5 mm). Exclusion criteria include persistent ST-segment elevation consistent with acute myocardial infarction and increased levels of MB isozyme of creatine kinase (CK-MB), revascularization process within the previous 6 months, malignant tumor, pregnancy, kidney or liver disease, Contraindications to the use of anticoagulant therapy, treatment with anti-inflammatory drugs, or research drugs. Patients were randomly given aspirin plus heparin (n = 60) or aspirin, heparin and meloxycamp (n = 60). The active treatment group was fed 15 mg of meloxicam intravenously immediately after randomization and 15 mg once daily orally during hospital stay and 30 days after discharge. Both groups received aspirin for 30 days. The dosage was 100 to 300 mg per day, as judged by the treating physician. CK-MB levels were measured before randomization. Additional analyzes were performed after the onset of chest pain to confirm the diagnosis of acute MI. Subcutaneous LMWH (Nadroparin 87 IU / kg BID or Enoxaparin 1 mg / kg BID) with continuous infusion at 1000 IU per hour for 7 days after the initial bolus injection of 5000 IU or until discharge from hospital Or intravenous UFH. Activated partial thromboplastin time (APTT) was used to assess the degree of anticoagulant in patients fed with unfractionated heparin. Patients were tested every 12 hours and subsequently every 24 hours on the first day. APTT was maintained in the range of 45 to 87 seconds (normal value, 30 ± 5 seconds).

Study end point

The primary outcome variable was a composite variable of recurrent anxiety, MI or death during and after CCU retention. Additional secondary composite variables were determined: MI, death and all revascularization processes (transcutaneous coronary angioplasty [PTCA] or coronary artery graft [CABG]). Each component of the primary and secondary outcome variables was also recorded separately. According to Degner et al., Drugs Today 1998, 34 (suppl A): 1-22, after bolus intravenous administration of 15 mg of hydroxycampham, C _max was 3.0 mg / l and t _max was 0.05 hours. From these values, intravenous administration of meloxycam was expected to produce an immediate anti-inflammatory effect and all events after randomization were considered as endpoints. Cardiac catheterization was performed at the discretion of the treating physician, but generally only recurrent angina or urgent PTCA and CABG after MI were considered as endpoints. The revascularization process appeared after the recurrence of chest pain, which was resistant to medical treatment. During the CCU stay and after discharge, all patients were tested for clinical problems by researchers not aware of the treatment placement. Patients were also immediately instructed to report any problem occurrences to the study coordinator. Diagnostic criteria for MI were chest pain lasting more than 20 minutes with ECG changes and a doubling of CK-MB. Recurrent angina is defined as the recurrence of chest pain accompanied by ECG changes that are resistant to medical treatment (aspirin, heparin, nitroglycerin and β-blockers).

Statistical analysis

The nature of the quantitative parameter distribution was evaluated by the Shapiro-Wilk test. Differences between the two treatment groups were analyzed by Student's t test (independent sample) or Mann-Whitney test, depending on the distribution characteristics. Repeated measurements in one of the factors (Student Newman-Keuls post-hoc test) differed in terms of partial thromboplastin time activated after unfractionated heparin. Were evaluated using a two-method ANOVA model. The univariate relevance of the qualitative variables was assessed by X ² (Yates corrected) and Spearman rank-order correlations.

Relative risk (RR) and its 95% CI were obtained. RR reduction (RRR) is defined as 1-RR and is expressed as a percentage. Absolute Risk Reduction (ARR) is calculated as the difference between risk in control patients—risk in treated patients and expressed as percentage. The multiple estimate curve regression model was used to measure the prognostic values of the variables associated with problem occurrence on the 90th day in the previous univariate analysis. The software used was CSS / Statistics 3.1 from StatSoft Corp and EPI INFO 6 v.6.04 1996.

result

In total, 120 patients were randomly selected. Sixty patients were fed meloxicamp with aspirin and heparin, and sixty patients were fed only heparin and aspirin. The basic clinical characteristics of the patients in the two groups were not significantly different (Table 1). There were more male patients (37 patients, 61.7%) in the control group than in the Meloxycham group (31 patients, 51.7%), and mean CCU retention was longer than in the control group (4.4 ± 1.6 vs 4.35 ± 1.14). 1), this difference was not significant.

Basic clinical characteristics of patients Meloxycham (n = 60) Control group (n = 60) P gender male 31 (51.7) 37 (61.7) 0.357 female 29 (48.3) 23 (38.3) ... Age (y) Average 61 60.7 1.0 range 38-84 28-81 ... Risk factor smoking Now 21 (35.0) 22 (36.7) 1.0 Past ^* 3 (5.0) 8 (13.3) 0.206 Never 36 (60.0) 30 (50.0) 0.359 Body weight index ≤ 25 17 (28.3) 10 (16.7) 0.19 > 25 43 (71.7) 46 (76.3) ... Dyslipidemia 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 Instability Angena 2 (3.3) 0 ... Former PTCA 4 (6.6) 8 (13.3) 0.361 CABG was 3 (5.0) 2 (3.3) 1.0 The value is n (%) unless otherwise noted. * More than 12 months after quitting smoking.

Partial thromboplastin time activated after unfractionated heparin Activated thromboplastin time, s 1 day 2 days 3 days 4 days ^* Control group (n = 36) Meloxycham (n = 50) Control group (n = 36) Meloxycham (n = 50) Control group (n = 35) Meloxycham (n = 50) Control group (n = 28) Meloxycham (n = 47) Mean ± SD, s 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 Median, s 48 48 63 62 77 86 74 84.5 APTT within the therapeutic range (45-87s),% 56.9 67.7 77.8 79.7 61.2 52.3 88.9 58.3 Less than therapeutic range (<45s) APTT,% 33.3 25.8 4.4 3.6 2.7 0 0 0 Therapeutic range exceeded (> 87s) APTT,% 9.8 6.5 17.8 16 36.1 47.7 11.1 41.7 Meloxam (Melox) represents the Meloxamk group. N is the number of patients treated with unfractionated heparin. * Control and Meloxamk Group, P <0.05 (ANOVA)

Ten patients in the meloxycam group and 24 patients in the control group were treated with LMWH. The remaining patients received UFH. In the Meloxycham group, 10 patients were treated with nadroparin. In the control group, nadroparin was fed to 22 patients and enoxaparin to 2 patients. The ability of unfractionated heparin to maintain APTT within the therapeutic range (45-87 seconds) is shown in Table 2. Within the first 24 hours, 56.9% of patients fed UFH in the control group and 67.7% in the Meloxycham group had APTT within the therapeutic range and 9.8% and 6.5%, respectively, with the APTT above the therapeutic range. 33% and 26% (P = 0.618), respectively, in the control and meloxycam groups of patients had sub-therapeutic APTT for the first 24 hours. After day 1, <5% of patients in each group were below the therapeutic range, and on day 4 all patients were within or above the therapeutic range.

Primary Outcome Variable

Efficacy Results in CCU Period

The incidence of recurrent angina was significantly lower in the meloxycam-treated group compared to the control group (9 of 60 patients in the Meloxycham group, 15.0% vs. 21 of 60 patients in the control group, 35%; P = 0.02). This corresponds to an RRR of 57.1% (95% CI, 14-79) (Table 3). Although statistical significance (P = 0.055) was not reached, the need for the revascularization process tended to decrease in patients receiving meloxicam. Less complex problems (recurrent angina, MI and death) occurred in the meloxycam group (9 patients; 15%) compared to the control group (23; 38.3%). The difference is statistically significant (P = 0.007) and corresponds to an RRR of 60.8% (95% CI, 23-80). Multiple outcomes for the coronary revascularization process (PTCA or CABG), MI and death occurred in 6 patients (10%) in the Meloxycham group and 16 patients (26.7%) in the control group. This difference is also statistically significant (P = 0.034) and corresponds to an RRR of 62.5% (95% CI, 11-84). Treatment was discontinued during the hospitalization period for eight patients in the control group and three patients in the meloxycam group. The reason for discontinuation was the incidence of endpoints in 5 patients in the control group and 2 patients in the meloxycam group. One patient in each group withdrew the consent for treatment and discontinuation of treatment for two patients assigned to the control group due to discharge.

Efficacy Results on Day 90

The difference between the meloxycamp-treated group and the control group observed during the hospitalization period was maintained for the subsequent period. The cumulative frequency of recurrent angina during the 90 day period was lower in the Meloxycham group (12 patients; 20%) than in the control group (26 patients; 43.3%). The difference is statistically significant (P = 0.011) and corresponds to an RRR of 53.8% (95% CI, 17-74) (Table 4). Significantly fewer patients in the Meloxycham group needed coronary revascularization (7 patients, 11.7% vs 18 patients, 30%; P = 0.025, RRR 61%, 95% CI, 14-82 ). Cumulative complex endpoints of recurrent angina, MI, and death occurred in 13 patients (21.7%) in the Meloxycham group and 29 patients (48.3%) in the control group. The difference is statistically significant (P = 0.004) and is associated with 55.1% RRR (95% CI, 22-74) for the melocampam group. The cumulative frequency of secondary outcome variables for coronary revascularization, MI and death was significantly lower in the Meloxycham group (8 patients; 13.3%) compared to the control group (20 patients; 33.3%) (P = 0.015), corresponding to 60.1% of the RRR (95% CI, 16-81) (Table 4).

Results during your hospital stay Problems During Coronary Therapy Unit Meloxycham (n = 60) Control group (n = 60) RRR (CI 95%) ARR% P ^* Recurrent angina, n (%) 9 (15.0) 21 (35.0) 57.1 (14-79) 20.0 0.02 All revascularization, n (%) 6 (10.0) 15 † (25.0) 60.1 (4.0-83) 15.0 0.055 PTCA, n 2 4 ... ... ... CABG, n 4 10 ... ... ... AMI, n 0 2 ... ... ... Vascular death, n 0 One ... ... ... Recurrent Angena + MI + Vascular Death, n (%) 9 (15.0) 23 (38.3) 60.8 (23-80) 23.3 0.007 MI + death + revascularization, n (%) 6 (10.0) 16 (26.7) 62.5 (11-84) 16.7 0.034 X ² Trial. † One patient performed both percutaneous revascularization and bypass graft. Only one occurrence of problem per patient was considered.

Results for after 90 days Problems after 90 days Meloxycham (n = 60) Control group (n = 60) RRR (95% CI) ARR% P ^* Recurrent angina, n (%) 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 PTCA, n 3 7 ... ... ... CABG, n 4 12 ... ... ... MI, n 0 3 (5) ... ... ... Vascular death, n 0 2 (3.3) ... ... ... Recurrent Angina + MI + Vascular Death, n (%) 13 (21.7) 29 (48.3) 55.1 (22-74) 26.6 0.004 MI + death + revascularization, n (%) 8 (13.3) 20 (33.3) 60.1 (16-81) 20.0 0.015 X ² Trial. † One patient performed both percutaneous revascularization and bypass graft. Only one occurrence of problem per patient was considered.

Multivariate associations between problem occurrences and treatment groups variable percentage 95% CI P High 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 Calculation curve regression (maximum likelihood). X ² = 22.36; df: 4, P = 0.0002

A temporary tendency

Within 48 hours of randomization, primary outcome variables were achieved in 1.7% of patients in the Meloxycam group and 6.7% of patients in the control group (P = 0.361). On day 30, the ratio was significantly lower in meloxycam-treated patients (20.0% vs. 46.7%; P = 0.004). Additional secondary outcome variables reached 11.7% in the meloxycam group compared to 31.7% in the control group on day 30 (P = 0.015). The univariate spearman rank-order correlation was associated with problem development and hypertension (rS = 0.24, P = 0.007), hypercholesterolemia (rS = 0.20, P = 0.024), and diabetes mellitus (rS = 0.26, P) over 90 days. = 0.004), and between treatment groups (rS = -0.28, P = 0.002). In the multivariate analysis (Table 5), only hypertension, diabetes, and treatment groups were significantly associated with problem development during the 90-day period.

safety

No hemorrhagic complications, side effects or hypersensitivity were observed in any patients throughout the study. This indicates that in the general pharmacological evaluation using a dose regimen 3 to 10 times higher than the anti-inflammatory dose of meloxycamps, no evidence of damage to the central nervous system, cardiovascular system, lung, kidney, skeletal muscle or autonomic nervous system was observed. In Degner et al., Drugs Today 1998, 34 (suppl A): 1-22.

Argument

The first significant decrease in the number of problem occurrences was observed during the CCU period, which persisted for the period after 90 days. Significant differences between the control and meloxycham groups were accompanied by an RRR of 57.1%, an absolute risk reduction of 20% (ARR), and a reduced need for myocardial revascularization process (RRR 60.8%; ARR 15%) during the CCU period. This was caused by a difference in the rate of recurrent chest pain. In recurrent angina, ARR improved by 3.3% during the 30-day treatment period. After 90 days, the difference was maintained with only one additional death in each group.

The methods and pharmaceutical compositions of the invention can be used to treat or prevent acute coronary syndrome (ACS) and related conditions, or to reduce the risk of patients at risk of developing cardiovascular problems.

Claims (16)

Treating or preventing acute coronary syndromes or related conditions comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of Meloxycham in combination with a therapeutically or prophylactically effective amount of antiplatelets; A method for reducing the risk of developing cardiovascular problems. The method of claim 1, wherein the method is added to or applied after standard antithrombotic therapy. The method of claim 1 or 2, wherein the patient is a high risk patient suffering from acute coronary syndrome (ACS) or a related condition requiring hospitalization or a patient at risk for developing coronary syndrome, related conditions or cardiovascular problems. . The method according to any one of claims 1 to 3, wherein the acute coronary syndrome or related condition is unstable angina, non-ST-segment elevation myocardial infarction (UA / NSTEMI), ST-segment elevation myocardial infarction (STEMI), Occlusion or re-closure of peripheral arteries, cerebral thromboembolism of extracranial origin, transient ischemic attack, and acute coronary ischemic syndrome, including a first or subsequent stroke, wherein cardiovascular problem development is associated with recurrent A method, selected from the group consisting of percutaneous coronary revascularization, bypass graft and cardiovascular death, coronary thrombotic occlusion, and percutaneous coronary revascularization and coronary artery bypass graft. The method according to any one of claims 1 to 3, wherein the acute coronary syndrome or related condition is associated with instability, non-ST-segment elevation myocardial infarction (UA / NSTEMI) and ST-segment elevation myocardial infarction (STEMI). And acute coronary ischemic syndrome, wherein the occurrence of cardiovascular problems is selected from the group consisting of recurrent angina, percutaneous coronary revascularization, bypass graft and cardiovascular death. The method of claim 1, wherein the antiplatelet agent is selected from the group consisting of glycoprotein (GP) IIb / IIIa receptor antagonists, clopidogrel, ticlopidine, dipyridamole, cilostazol and acetylsalicylic acid. The method of claim 1, wherein the antiplatelet agent is selected from the group consisting of clopidogrel, ticlopidine, dipyridamole, cilostazol and acetylsalicylic acid. The method according to any one of claims 1 to 5, wherein the antiplatelet agent is selected from the group consisting of ticlopidine, dipyridamole and acetylsalicylic acid, particularly preferably acetylsalicylic acid. A pharmaceutical composition comprising a therapeutically or prophylactically effective amount of meloxycamp and a therapeutically or prophylactically effective amount of antiplatelet agent. 10. The composition of claim 9, wherein the composition is a kit of combination formulations or portions comprising meloxam in a pharmaceutical dosage form and antiplatelet agent in a separate pharmaceutical dosage form for simultaneous, separate or continuous use. Antiplatelet agents in the manufacture of pharmaceutical compositions for the treatment of acute coronary syndromes or related conditions, for preventing or reducing the risk of developing acute coronary syndromes or related conditions, or for reducing the risk of developing cardiovascular problems. Use of combined meloxycam. 12. The method of claim 11, wherein the acute coronary syndrome or related condition is unstable angina, non-ST-segment elevation myocardial infarction (UA / NSTEMI), ST-segment elevation myocardial infarction (STEMI), occlusion or reclosure of the peripheral artery, Selected from the group consisting of cerebral thromboembolism of extracranial origin, transient ischemic attack, and acute coronary ischemic syndrome, including a first or subsequent stroke, and the development of cardiovascular problems is associated with recurrent angina or percutaneous coronary revascularization. , Bypass graft, and cardiovascular death, coronary thrombotic occlusion, and percutaneous coronary revascularization and re-occlusive stenosis after coronary artery bypass graft. The acute coronary ischemic syndrome according to claim 11, wherein the acute coronary syndrome or related condition is an acute coronary ischemic syndrome comprising an unstable angina, non-ST-segment elevation myocardial infarction (UA / NSTEMI) and ST-segment elevation myocardial infarction (STEMI). And wherein the occurrence of cardiovascular problems is selected from the group consisting of recurrent angina, percutaneous coronary revascularization, bypass graft and cardiovascular death. The use according to any one of claims 11 to 13, wherein the antiplatelet agent is selected from the group consisting of glycoprotein (GP) IIb / IIIa receptor antagonists, clopidogrel, ticlopidine, dipyridamole, cilostazol and acetylsalicylic acid. The use according to any one of claims 11 to 13, wherein the antiplatelet agent is selected from the group consisting of clopidogrel, ticlopidine, dipyridamole, cilostazol and acetylsalicylic acid. 14. Use according to any one of claims 11 to 13, wherein the antiplatelet agent is selected from the group consisting of ticlopidine, dipyridamole and acetylsalicylic acid, particularly preferably acetylsalicylic acid.