JP2005060359A - Use of dipyridamole, acetyl salicylic acid and angiotensin ii antagonist for treatment and prevention of vascular morbidity - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new method for treating and preventing vascular morbidity. <P>SOLUTION: The method for treating and preventing the vascular morbidity comprises the administration of effective amount of a medicinal composition containing dipyridamole or its medicinally acceptable salts in combination with acetyl salicylic acid and an angiotensin II antagonist to a person who requires such treatment. Also, the medicinal compositions containing the dipyridamole or its salts acceptable as a medicine, acetyl salicylic acid or the angiotensin II antagonist for simultaneous, separate use, or sequential use are provided. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

The present invention relates to:
Indication (A) treatment and prevention method, wherein the indication is selected from acute myocardial infarction, secondary myocardial infarction and cardiovascular death,
Used in humans in need thereof, particularly those at high risk of cardiovascular events, such as hypertensive patients;
A method for treating and preventing an indication (B), wherein the indication is pulmonary embolism, retinal vascular disease, deep vein thrombosis, peripheral artery occlusion, transient cerebral ischemic attack (TIA), ischemic Selected from peripheral circulatory disease, myocardial ischemia (angina), thrombotic thrombocytopenic purpura and progressive heart failure after myocardial infarction,
Those used in patients in need thereof, specifically in humans who are generally at increased risk of vascular pathologies, including arterial, venous and central and peripheral vascular events; for example, in patients with diabetes, obesity and hypertension;

A method for the prevention or treatment of indication (C), which can be clearly influenced by the organprotective, tissue-protective and vasculoprotective action of the drugs used;
The indication is renoprotection, such as renal failure or diabetic nephropathy,
Left ventricular hypertrophy, vascular hypertrophy, for example prevention of vascular wall thickening after vascular surgery, prevention of arterial recurrence stenosis after angioplasty, prevention or treatment of atherosclerosis, diabetic vasculopathy and diabetic retinopathy Selected from the prevention of;
A method for preventing or treating an indication (D), wherein the indication is obstructive airway disease, chronic obstructive pulmonary disease such as bronchitis or chronic bronchitis, emphysema, asthma, cystic fibrosis, Interstitial lung disease, lung cancer, pulmonary vascular disease, and increased resistance to air flow during deep breathing,
Adult respiratory distress syndrome (ARDS), reduced ability to grow epithelial tissue in lung and breast cancer, treatment of sepsis syndrome, lung damage forms such as aspiration pneumonia of stomach contents, chest trauma, shock, burn, Selected from fat embolia, cardiopulmonary bypass, O ₂ toxicity, hemorrhagic pancreatitis, interstitial and bronchial pneumonia, epithelial and interstitial cell proliferation, collagen accumulation or fibrosis;

Here, the methods include co-administering an effective amount of dipyridamole (DIP) to a human in need of such treatment in combination with an acetylsalicylic acid (ASA) and an angiotensin (ANG) II antagonist. Including:
And a suitable pharmaceutical composition comprising DIP in combination with ASA and ANGII antagonist as a combination formulation for simultaneous, separate or sequential use in the treatment of the above indications; and in combination with ASA, Use of an ANGII antagonist for the manufacture of a pharmaceutical composition for the treatment of the above indications when used in combination with DIP.
It is to be understood that the above indication prevention methods reduce the risk associated with the indication or reduce the incidence of the indication in a patient population at high risk for the indication.

Dipyridamole, {2,6-bis (diethanolamino) -4,8-dipiperidino-pyrimido [5,4-d] pyrimidine} and methods for their preparation closely related to substituted pyrimido-pyrimidines are described, for example, in the United States This is described in Japanese Patent No. 3,031,450. DIP was introduced as a coronary dilator in the early 1960s. It is also known to have platelet aggregation inhibitory activity by inhibiting adenosine uptake. Later, DIP was shown to reduce thrombus formation in a rabbit model brain arterial circulation study. These studies have led to their use as antithrombotic agents, which can quickly be applied to applications such as stroke prevention, patency maintenance of coronary artery bypass and valve replacement, and pre-coronary angioplasty procedures. Was the optimal treatment.
In addition, European Stroke Prevention Study 2 (ESPS-2; J Neurol Sci. 1996; 143: 1-13; Neurology 1998; 51: 17-19) shows that treatment with DIP alone reduces the risk of stroke. It was shown to be as effective as low-dose aspirin, and the combination therapy of DIP and aspirin was more than twice as effective as aspirin alone.
DIP appears to inhibit thrombosis through a number of mechanisms. Early studies have shown that it inhibits adenosine uptake, and adenosine was found to be a potent endogenous antithrombotic compound. DIP has also been shown to inhibit cyclic AMP phosphodiesterase, thereby increasing intracellular c-AMP.

DIP also has antioxidant properties (Free Radic. Biol. Med. 1995; 18: 239-247), which may be due to its antithrombotic activity. When oxidized, low density lipoprotein becomes recognized by the scavenger receptor on macrophages, which is postulated to be an inevitable step in the progression of atherosclerosis (Ann. Rev. Med. 1992 Year; 43: 219-25).
Inhibition of free radical formation by DIP inhibits fibrinogenesis in experimental liver fibrosis (Hepatolgy 1996; 24: 855-864) and oxygen radicals and proteinuria in experimental animals with aminonucleoside nephropathy. It was found to suppress (Eur. J. Clin. Invest. 1998; 28: 877-883; Renal Physiol. 1984; 7: 218-226). Inhibition of lipid peroxidation was also observed in human non-neoplastic lung tissue (Gen. Pharmacol. 1996; 27: 855-859).

ANGII plays a major role in pathophysiology, specifically as the most potent blood pressure raising agent in humans. Therefore, ANGII antagonists are suitable for the treatment of hypertension and congestive heart failure in mammals. Examples of ANGII antagonists are 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. It is described in. Specific ANGII antagonists include sultans such as candesartan, eprosartan, irbesartan, losartan, telmisartan or valsartan, as well as olmesartan and tasosartan.
In addition to its blood pressure-increasing action, ANGII is known to have a further characteristic growth promoting action, which contributes to left ventricular hypertrophy, vascular hypertrophy, atherosclerosis, renal failure and stroke. Bradykinin, on the other hand, exerts vasodilatory and tissue protective effects such as, for example, W. Wienen et al., “Antihypertensive 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.

Losartan and irbesartan exhibit a renoprotective effect, which was found in a first clinical trial, for example, S. Andersen et al., `` Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy "Kidney Int 57 (2), 601-606 (2000).
ANG II antagonists selectively inhibit the AT ₁ receptor but leave the AT ₂ receptor intact, where the AT ₂ receptor plays a role in anti-growth and tissue regeneration and is uncompetitive. (unopposed).
Completed clinical trials with ANGII antagonists appear to show blood pressure lowering and tissue protective effects similar to those with ACE inhibitors, for example, DHG Smith et al., “Once -daily telmisartan compared with enalapril in the treatment of hypertension ”, Adv. Ther 1998, 15: 229-240 and BE Karlberg et al.“ Efficacy and safety of telmisartan, a selective AT ₁ receptor antagonist, compared with enalapril in elderly patients with primary hypertension ", J Hypertens 1999, 17: 293-302.
EP-A-1 013 273 is for the treatment of diseases associated with an increase of AT ₂ receptors in increase or epithelium of AT ₁ receptors in subepithelial area, in particular, for the treatment of several pulmonary disorders, AT ₁ Disclose the use of receptor antagonists or AT ₂ receptor modulators.

Surprisingly, it has been found that administration of DIP in combination with ASA and ANGII antagonists provides an unexpected effect in the prevention or treatment of the above indications (A) to (D).
ASA acts directly on platelets to inhibit aggregation, and more specifically, it irreversibly acetylates platelet cyclooxygenase, thus inhibiting the production of thromboxanes with strong thrombogenicity. However, at high doses, aspirin crosses over endothelial cells (N. Eng. J. Med. 1984; 311: 1206-1211), where prostacyclin (a potent natural inhibitor of platelet aggregation) And which is a byproduct of the “arachidonic acid cascade” (N. Engl. J. Med. 1979; 300: 1142-1147). These observations led to the concept of low-dose antiplatelet therapy with ASA, maximizing thromboxane inhibition while minimizing loss of prostacyclin (Lancet 1981; 1: 969-971) . In the prevention method of the present invention, a combination of low dose ASA and DIP and ANGII antagonists is preferred.

Viewed from a first aspect, the present invention provides the following:
Indication (A) prevention and treatment method, wherein the indication is selected from acute myocardial infarction, secondary myocardial infarction and cardiovascular death,
Used in humans in need thereof, specifically in humans at high risk of cardiovascular events, such as hypertensive patients;
A method of preventing and treating an indication (B), wherein the indication is pulmonary embolism, retinal vascular disease, deep vein thrombosis, peripheral artery occlusion, transient cerebral ischemic attack (TIA), ischemic Peripheral circulatory disease, myocardial ischemia (angina), thrombotic thrombocytopenic purpura and progressive heart failure after myocardial infarction, the method described above being used in patients in need thereof, specifically arteries, Used in humans who are generally at increased risk of vascular events including venous and central and peripheral vascular events, such as patients with diabetes, obesity and hypertension;
A method for the prevention and treatment of indication (C), which can be clearly influenced by the organ-protection, tissue-protection and vascular-protective action of the drugs used, the indication being renoprotective, eg renal Failure or diabetic nephropathy,
Left ventricular hypertrophy, vascular hypertrophy, for example prevention of vascular wall thickening after vascular surgery, prevention of arterial restenosis after angioplasty, prevention or treatment of atherosclerosis, diabetic vasculopathy and diabetic retina Chosen from the prevention of illness;
Indication (D) prevention and treatment method, wherein the indication is obstructive airway disease, chronic obstructive pulmonary disease such as bronchitis or chronic bronchitis, emphysema, asthma, cystic fibrosis, Interstitial lung disease, lung cancer, pulmonary vascular disease, and increased resistance to air flow during deep breathing,
Adult respiratory distress syndrome (ARDS), reduced ability to grow epithelial tissue in lung and breast cancer, treatment of sepsis syndrome, lung damage forms such as aspiration pneumonia of stomach contents, chest trauma, shock, burns, fat embolism, Selected from cardiopulmonary bypass, O ₂ toxicity, hemorrhagic pancreatitis, interstitial and bronchial pneumonia, proliferation of epithelial and interstitial cells, collagen accumulation or fibrosis;
Here, the above method administers to a human in need of such treatment an effective amount of a pharmaceutical composition comprising DIP or a pharmaceutically acceptable salt thereof in combination with an ASA and ANGII antagonist. Including that.

Viewed from a second aspect, the present invention provides a pharmaceutical composition comprising DIP or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential administration in combination with ASA and ANGII antagonists. Provide an adapted one.
The pharmaceutical composition according to the invention is intended to include a fixed dose combination containing the active ingredients in one formulation and a kit of parts including the following:
A first containment comprising a pharmaceutical composition comprising a therapeutically effective DIP; and a second containment comprising a pharmaceutical composition comprising ASA and a pharmaceutically acceptable carrier.
(c) A third containment comprising a pharmaceutical composition comprising an ANGII antagonist.
Viewed from different aspects, the present invention relates to ASA and ANGII antagonists for the manufacture of a pharmaceutical composition for the prevention and / or treatment of the above indications (A) to (D) in patients in need thereof. Use of DIP or a pharmaceutically acceptable salt thereof in combination.

The present invention provides a new and improved approach for the prevention and / or treatment of the above (A) to (D), which is an effective amount of a pharmaceutical composition, as an active ingredient DIP or medicament. Including administering to a patient those acceptable salts thereof in combination with ASA and ANGII antagonists.
In the method of the present invention, any of commercially available oral DIP delayed, instant or parenteral preparations may be used, but delayed preparations are preferred, for example, the trade name Persantin (Registered trademark) or those already available in combination with ASA under the trade name Asasantin (registered trademark) or Aggrenox (registered trademark). Suitable DIP slow release formulations are disclosed in EP-A-0032562, fast release formulations are described in EP-A-O068191 and combinations of ASA and DIP are described in EP-A-0257344, Are hereby included as references. Any ANGII antagonist known in the art may be used in the methods of the present invention, for example, sultans such as candesartan, eprosartan, irbesartan, losartan, telmisartan (trade name Micardis®), Valsartan, Olmesartan, or Tasosartan, including their salts or polymorphs thereof, for example, Rote Liste® 2003, Editio Cantor Verlag Aulendorf, Germany or Physician's Desk Reference, 57th edition, 2003 The doses disclosed in may be used.

In the prevention method according to the present invention, the plasma concentration of DIP is maintained at about 0.2-5 μmol / L, preferably about 0.5-2 μmol / L, or in particular about 0.8-1.5 μmol / L. May be. DIP can be orally administered at 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.
With regard to ASA, this component of a ternary drug therapy may be administered orally at a daily dose of 10-200 mg, preferably 25-100 mg, most preferably 30-75 mg, eg 25 mg twice a day.

  For the third component, the ANGII antagonist telmisartan is preferred. This component may be administered at a daily dose of 10 to 200 mg, such as a daily dose of 20, 40, 80 or 160 mg, preferably a daily dose of 40 to 160 mg, most preferably 60 to 100 mg, such as 20 times a day. Or 40 mg can be administered orally.

Specific prevention methods according to the present invention include DIP orally administered 200 mg twice daily, ASA orally administered 25 mg twice daily, and telmisartan orally administered 20, 40 or 80 mg once daily Including a combination of
For all aspects of the present invention, a combination of DIP, ASA and telmisartan is preferred, specifically at the above oral dosage.

Claims (6)

Indication (A) treatment and prevention method, wherein the indication is selected from acute myocardial infarction, secondary myocardial infarction and cardiovascular death,
Those used in humans where they are needed;
A method for treating and preventing an indication (B), wherein the indication is pulmonary embolism, retinal vascular disease, deep vein thrombosis, peripheral artery occlusion, transient cerebral ischemic attack (TIA), ischemic Selected from peripheral circulatory disease, myocardial ischemia (angina), thrombotic thrombocytopenic purpura and progressive heart failure after myocardial infarction,
Those used in patients in need thereof;
A method for the prevention or treatment of indication (C), which can be clearly influenced by the organ-protection, tissue-protection and vascular-protective action of the drugs used;
The indication is nephroprotective, such as renal failure or diabetic nephropathy,
Left ventricular hypertrophy, vascular hypertrophy, for example prevention of vascular wall thickening after vascular surgery, prevention of arterial recurrence stenosis after angioplasty, prevention or treatment of atherosclerosis, diabetic vasculopathy and diabetic retinopathy Selected from the prevention of;
A method for preventing or treating an indication (D), wherein the indication is obstructive airway disease, chronic obstructive pulmonary disease such as bronchitis or chronic bronchitis, emphysema, asthma, cystic fibrosis, Interstitial lung disease, lung cancer, pulmonary vascular disease, and increased resistance to air flow during deep breathing,
Adult respiratory distress syndrome (ARDS), reduced ability to grow epithelial tissue in lung and breast cancer, treatment of sepsis syndrome, lung damage forms such as aspiration pneumonia of stomach contents, chest trauma, shock, burns, fat embolism, Selected from cardiopulmonary bypass, O ₂ toxicity, hemorrhagic pancreatitis, interstitial and bronchial pneumonia, proliferation of epithelial and interstitial cells, collagen accumulation or fibrosis;
Here, the method comprises administering to a human in need of such treatment an effective amount of a pharmaceutical composition comprising dipyridamole or a pharmaceutically acceptable salt thereof in combination with acetylsalicylic acid and an angiotensin II antagonist. Including the above method.   2. The method of claim 1, wherein the angiotensin II antagonist is telmisartan.   A pharmaceutical composition for simultaneous, separate or sequential use comprising dipyridamole or a pharmaceutically acceptable salt thereof, acetylsalicylic acid and an angiotensin II antagonist.   4. The pharmaceutical composition according to claim 3, wherein the angiotensin II antagonist is telmisartan.   A dipyridamole in combination with acetylsalicylic acid and an angiotensin II antagonist for producing the pharmaceutical composition for prevention or treatment of the indications (A) to (D) according to claim 1, or a pharmaceutically acceptable product thereof Use of salt.   6. Use according to claim 5, wherein the angiotensin II antagonist is telmisartan.