KR20050018330A - Use of dipyridamole, acetylsalicylic acid and an angiotensin II antagonist for treatment and prevention of vascular events - Google Patents

Abstract

PURPOSE: Provided is the use of dipyridamole, acetylsalicylic acid and angiotensin II antagonist for treatment and prevention of vascular and circulatory disorder. And provided is pharmaceutical composition containing the dipyridamole, acetylsalicylic acid and angiotensin II antagonist. CONSTITUTION: The dipyridamole or its pharmaceutically acceptable salt, acetylsalicylic acid and angiotensin II antagonist are administered into patients suffering from vascular and circulatory disorders. The angiotensin II antagonist is telmisartan.

Description

Use of dipyridamole, acetylsalicylic acid and an angiotensin II antagonist for treatment and prevention of vascular events}

The present invention comprises administering an effective amount of dipyridamole (DIP) in combination with acetylsalicylic acid (ASA) and angiotensin (ANG) II antagonist,

Those in need of treatment or prevention of symptoms (A) selected from acute myocardial infarction, secondary myocardial infarction and cardiovascular disease, especially those at high risk of cardiovascular disorders (e.g., hypertensive patients),

Pulmonary embolism, retinal vascular accident, deep vein thrombosis, peripheral arterial occlusion, transient ischemic attack (TIA), ischemic peripheral circulation disorder, myocardial ischemia (angina), thrombotic thrombocytopenic purpura and selected symptoms during heart failure after myocardial infarction (B ) Patients in need of treatment or prevention, especially those who are at high risk of vascular disorders, including arterial, venous, central and peripheral vascular disorders (e.g., diabetes, obesity and hypertension),

It can be positively affected by the organoprotective, tissue protective and vascular protective effects of the drug used, prevention of vascular wall thickening after angioplasty, prevention of arterial restenosis after angioplasty, prevention or treatment of atherosclerosis, diabetic blood vessels A person in need of treatment or prevention of a condition (C) selected from nephropathy (eg, renal failure or diabetic nephropathy), left ventricular hypertrophy, vascular thickening, including the prevention of conditions and diabetic retinopathy, or

Obstructive airway disease, chronic obstructive pulmonary disease (eg bronchitis or chronic bronchitis), emphysema, asthma, cystic fibrosis, interstitial lung disease, lung cancer, pulmonary vascular disease and increased resistance to airflow during deep periods, adult respiratory distress syndrome (ARDS), decreased proliferative capacity of epithelium in lung and breast cancer, pneumonia, lung damage, eg pneumonia by aspiration of gastric contents, chest trauma, shock, burns, fatty embolism, cardiopulmonary tract, O ₂ toxicity, hemorrhagic pancreatitis, epilepsy A method of treating or preventing said disease in a person in need of treatment or prevention of a condition (D) selected from sexual and bronchial alveolar inflammation, proliferation of epithelial and stromal cells, collagen accumulation or fibrosis;

Suitable pharmaceutical compositions comprising DIP in combination with ASA and ANG II antagonists, as a combination formulation for simultaneous, separate or continuous use in the treatment of the condition; And

The use of an ANG II antagonist in combination with DIP and ASA in the manufacture of a pharmaceutical composition for the treatment of the above symptoms.

It is to be understood that the above mentioned methods of preventing symptoms reduce the risk of the symptoms or reduce the incidence of the symptoms in a group of patients with an increased risk of the symptoms.

Dipyridamole {2,6-bis (diethanolamino) -4,8-dipiperidino-pyrimido [5,4-d] pyrimidine} and the substituted pyrimido-pyrimidines closely related thereto The preparation is described, for example, in US Pat. No. 3,031,450. DIP was introduced as a coronary vasodilator in the early 1960s. In addition, DIP is well known to have platelet aggregation inhibitor properties due to the inhibition of adenosine uptake. Later, DIP has been shown to reduce thrombus formation in cerebral arterial circulation studies in rabbit models. As a result of this study, DIP was used as an antithrombotic agent, and was soon selected for application before coronary angioplasty, as well as for application therapies such as stroke prevention, maintenance of patency of coronary circuitry and valve replacement.

In addition, European Stroke Prevention Study 2 (ESPS-2; J Neurol Sci. 1996; 143: 1-13; Neurology 1998; 51: 17-19) showed that treatment with DIP alone was as effective as low dose aspirin in reducing the risk of stroke. Combination therapy with DIP and aspirin proved twice as effective as aspirin alone.

DIP is believed to inhibit thrombosis through multiple mechanisms. Initial studies have shown that DIP inhibits the absorption of adenosine, which is known to be a potent endogenous anti-thrombotic compound. In addition, DIP has been shown to inhibit cyclic AMP, increasing intracellular c-AMP.

DIP also has antioxidant properties that may contribute to antithrombotic effects (Free Radic. Biol. Med. 1995; 18: 239-247). Low density lipoproteins are recognized by scavenger receptors on macrophages when oxidized, which is believed to be an essential step in the progression of atherosclerosis (Ann. Rev. Med. 1992; 43: 219-25).

Inhibition of free radical formation by DIP inhibits fibrinogen production in experimental liver fibrosis (Hepatology 1996; 24: 855-864) and inhibits oxygen radicals and proteinuria in experimental animals suffering from aminonucleoside nephropathy. (Eur. J. Clin. Invest. 1998; 28: 877-883; Renal Physiol. 1984; 7: 218-226). Inhibition of lipid peroxidation has also been observed in human non-neoplastic lung tissue (Gen. Pharmacol. 1996; 27: 855-859).

ANG II plays an important role as the most effective blood pressure booster in pathophysiology, especially in humans. Thus, ANG II antagonists are suitable for treating elevated blood pressure and congestive heart failure in mammals. Examples of ANG II antagonists are described in EP-A-0 502 314, EP-A-0 253 310, EP-A-0 323 841, EP-A-0 324 377, US-A-4,355,040 and US-A-4,880,804. Described. Specific ANG II antagonists include sartans such as candesartan, eprosartan, irbesartan, rosartan, telmisartan or balsatan, as well as olmesartan and tasosartan.

ANG II is known to be a cause of left ventricular hypertrophy, vascular thickening, atherosclerosis, kidney failure and stroke in addition to the blood pressure increase effect. On the other hand, bradykinin is described, for example, in W. Wienen et al .: Antihypertinsive and renoprotective effects of telmisartan after long term treatment in hypertensive diabetic (D) rats, 2nd. Int. Symposium on Angiotensin II Antagonism, February 15-18, 1999, The Queen Elizabeth II Conference Center, London, UK, Book of Abstracts, Abstract No. 50, exerts vasodilation and tissue protective action.

Losartan and Irbesartan are described, for example, in S. Andersen et al .: Renopotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy, Kidney int 57 (2), 601-606 (2000). Turned out.

ANG II antagonists selectively block only the AT ₁ receptor, leaving the AT ₂ receptor intact, which means that it plays a role in anti-growth and tissue regeneration.

Clinical trials terminated using ANG II antagonists are described, for example, in D.H.G. Smith et al .: Once-daily telmisartan compared with enalapril in the treatment of hypertension, Adv. Ther 1998, 15: 229-240 and B.E. Karlberg et al .: Efficacy and safety of telmisartan, a selective AT1 receptor antagonist, compared with enalapril in elderly patients with primary hypertension, J Hypertens 1999, 17: 293-302, as described in similar blood pressure drops as ACE inhibitors. And tissue protective effects.

EP-A-1 013 273 discloses AT ₁ receptor antagonists or AT ₂ receptor modulators for the treatment of diseases associated with an increase in AT ₁ receptor in the subepithelial region or an increase in AT ₂ receptor in the epithelium, in particular for the treatment of some lung diseases. The use is described.

Surprisingly, the combination of ASA and ANG II antagonists with DIP has been found to provide unexpected efficacy in preventing or treating the aforementioned symptoms (A) to (D).

ASA acts directly on platelets and, in more detail, inhibits aggregation by irreversibly acetylating platelet cyclooxygenase to inhibit the production of thromboxanes that exhibit potent thrombogenicity. However, high doses of aspirin penetrate into endothelial cells (N. Eng. J. Med. 1984; 311: 1206-1211) where there is a potent natural inhibitor of platelet aggregation and a byproduct of the "arachidonic acid cascade" of prostacyclin Block production (N. Engl. J. Med. 1979; 300: 1142-1147). This observation led to the concept of low dose antiplatelet therapy with ASA to maximize inhibition of thromboxane while minimizing loss of prostacyclin (Lancet 1981; 1: 969-971). In the prophylactic method according to the invention, the combination of DIP and ANG II antagonists with low dose ASA is preferred.

In one aspect, the invention includes administering an effective amount of dipyridamole (DIP) in combination with acetylsalicylic acid (ASA) and angiotensin (ANG) II antagonist,

Those in need of treatment or prevention of symptoms (A) selected from acute myocardial infarction, secondary myocardial infarction and cardiovascular disease, especially those at high risk of cardiovascular disorders (e.g., hypertensive patients),

Pulmonary embolism, retinal vascular accident, deep vein thrombosis, peripheral arterial occlusion, transient ischemic attack (TIA), ischemic peripheral circulation disorder, myocardial ischemia (angina), thrombotic thrombocytopenic purpura and selected symptoms during heart failure after myocardial infarction (B ) Patients in need of treatment or prevention, especially those who are at high risk of vascular disorders, including arterial, venous, central and peripheral vascular disorders (e.g., diabetes, obesity and hypertension),

It can be positively affected by the organoprotective, tissue protective and vascular protective effects of the drug used, prevention of vascular wall thickening after angioplasty, prevention of arterial restenosis after angioplasty, prevention or treatment of atherosclerosis, diabetic blood vessels A person in need of treatment or prevention of a condition (C) selected from nephropathy (eg, renal failure or diabetic nephropathy), left ventricular hypertrophy and vascular thickening, including the prevention of conditions and diabetic retinopathy, or

Obstructive airway disease, chronic obstructive pulmonary disease (eg bronchitis or chronic bronchitis), emphysema, asthma, cystic fibrosis, interstitial lung disease, lung cancer, pulmonary vascular disease and increased resistance to airflow during deep periods, adult respiratory distress syndrome (ARDS), decreased proliferative capacity of epithelium in lung and breast cancer, pneumonia, lung damage, eg pneumonia by aspiration of gastric contents, chest trauma, shock, burns, fatty embolism, cardiopulmonary tract, O ₂ toxicity, hemorrhagic pancreatitis, epilepsy Provided are methods for treating or preventing such diseases in persons in need of treatment or prevention of conditions (D) selected from sexual and bronchial alveolar inflammation, proliferation of epithelial and stromal cells, collagen accumulation or fibrosis.

As a second aspect, the present invention provides a pharmaceutical composition comprising DIP or a pharmaceutically acceptable salt thereof and ASA and an ANG II antagonist, suitable for simultaneous, separate or continuous administration.

A pharmaceutical composition according to the present invention comprises a first container containing a pharmaceutical composition comprising a therapeutically effective amount of DIP, as well as a fixed dose combination comprising the active ingredient in one formulation, (b) ASA And a second container containing a pharmaceutical composition comprising a pharmaceutically acceptable carrier and (c) a third container containing a pharmaceutical composition comprising an ANG II antagonist.

In another aspect, the present invention provides ASA and ANG II antagonists in the manufacture of pharmaceutical compositions for such prophylaxis and / or treatment in patients in need of the prophylaxis and / or treatment of the aforementioned symptoms (A) to (D). It provides the use of DIP or a pharmaceutically acceptable salt thereof in combination with.

The present invention relates to the above-mentioned symptoms (A) to (D), comprising administering to a patient an effective amount of a pharmaceutical composition containing DIP or a pharmaceutically acceptable salt thereof as an active ingredient together with ASA and ANG II antagonists. New and improved methods for preventing and / or treating).

In the method of the present invention, any of the commercially available oral DIP sustained release, immediate release or parenteral formulations may be used, but sustained release formulations are preferred, for example formulations marketed under the trademark Persantin ^® , already in combination with ASA. Formulations sold under the trade names Asasantin ^® or Aggrenox ^® . Suitable DIP sustained release formulations are described in EP-A-0032562, immediate release formulations are described in EP-A-0068191, and combinations of DIP and ASA are described in EP-A-0257344. These patent documents are incorporated herein by reference. All ANG II antagonists known in the art can be used in the prophylactic methods of the invention, examples of which are candesartan, eprosartan, irbesartan, losartan, telmisartan (trademark Micardis ^® ), Sartan and salts or isomers thereof, such as valsartan, olmesartan or tasosartan, are for example described in Rote Liste ^® 2003, Editio Cantor Verlag Aulendorf, Germany or Physician's Desk Reference, 57 edition, 2003].

The plasma level of DIP in the method according to the invention can be maintained at about 0.2 to 5 μmol / L, preferably about 0.5 to 2 μmol / L, in particular about 0.8 to 1.5 μmol / L. DIP can be administered orally in a daily dose of 50 to 750 mg, preferably 100 to 500 mg, most preferably 200 to 450 mg, for example 200 mg twice a day.

The ASA component of the above three drugs can be administered orally in a daily dose of 10 to 200 mg, preferably 25 to 100 mg, most preferably 30 to 75 mg, for example, 25 mg twice a day. .

As a third component, the ANG II antagonist is preferably telmisartan. This component is in a daily dose of 10 to 200 mg, for example in a daily dose of 20, 40, 80 or 160 mg, preferably in a daily dose of 40 to 160 mg, most preferably in a daily dose of 60 to 100 mg. For example, 20 mg or 40 mg can be orally administered once a day.

Specific preventive method according to the invention, DIP 200 mg orally administered twice a day, ASA 25 mg orally administered twice a day, Telmisartan 20, 40 or 80 mg orally administered once a day Concomitant administration.

In all aspects of the invention, combinations of DIP, ASA and telmisartan are preferred, particularly when the oral dose indicated above as most preferred.

The present invention is useful for patients in need of treatment and prevention of vascular and circulatory disorders, especially in patients at risk of such symptoms.

Claims (6)

An effective amount of a pharmaceutical composition comprising dipyridamole or a pharmaceutically acceptable salt thereof in combination with acetylsalicylic acid and angiotensin (ANG) II antagonist, Those in need of treatment or prevention of selected symptoms (A) among acute myocardial infarction, secondary myocardial infarction and cardiovascular disease, Pulmonary embolism, retinal vascular accident, deep vein thrombosis, peripheral arterial occlusion, transient ischemic attack (TIA), ischemic peripheral circulatory disorder, myocardial ischemia (angina), thrombotic thrombocytopenic purpura and selected symptoms during heart failure following myocardial infarction (B ) Who need treatment or prevention It can be positively affected by the organoprotective, tissue protective and vascular protective effects of the drug used, prevention of vascular wall thickening after angioplasty, prevention of arterial restenosis after angioplasty, prevention or treatment of atherosclerosis, diabetic blood vessels A person in need of treatment or prevention of a condition (C) selected from renal protection (eg, renal failure or diabetic nephropathy), left ventricular hypertrophy and vascular thickening, including the prevention of symptoms and diabetic retinopathy, or Obstructive airway disease, chronic obstructive pulmonary disease (eg bronchitis or chronic bronchitis), emphysema, asthma, cystic fibrosis, interstitial lung disease, lung cancer, pulmonary vascular disease and increased resistance to airflow during deep periods, adult respiratory distress syndrome (ARDS), decreased proliferative capacity of epithelium in lung and breast cancer, pneumonia, lung damage, eg pneumonia by aspiration of gastric contents, chest trauma, shock, burns, fatty embolism, cardiopulmonary tract, O ₂ toxicity, hemorrhagic pancreatitis, epilepsy A method of treating or preventing said disease, comprising administering to a person in need of treatment or prevention of a condition (D) selected from sexual and bronchial alveolar inflammation, proliferation of epithelial and stromal cells, collagen accumulation or fibrosis. The method of claim 1, wherein the angiotensin II antagonist is telmisartan. A pharmaceutical composition comprising dipyridamole or a pharmaceutically acceptable salt thereof, acetyl salicylic acid and angiotensin II antagonist for simultaneous, separate or continuous use. The pharmaceutical composition of claim 3, wherein the angiotensin II antagonist is telmisartan. Use of dipyridamole or a pharmaceutically acceptable salt thereof in combination with acetylsalicylic acid and angiotensin II antagonist in the preparation of a pharmaceutical composition for the prophylaxis or treatment of the symptoms (A) to (D) mentioned in claim 1. Use according to claim 5, wherein the angiotensin II antagonist is telmisartan.