JP2004525979A - Use of radical scavenging compounds for the treatment and prevention of NO-dependent microcirculatory disorders - Google Patents

Abstract

Disclosed is a method of treating the body of a human or non-human animal for the treatment of a NO-dependent microcirculatory disorder, the disorder being, for example, a microcirculatory disorder caused by a metabolic disease, such as an increased amount of homocystin. Homocystin inflammatory response or an autoimmune disease, as well as a peripheral microcirculatory disorder or a microcirculatory disorder associated with increased cell division, wherein the method is human or non-human depending on the need for such treatment. Administering to the animal body an effective amount of a pharmaceutical composition comprising a substance that scavenges free radicals, e.g., a pyrimido-pyrimidine selected from dipyridamole, mopidamole and pharmaceutically acceptable salts thereof, and Use of such substances for the manufacture of a pharmaceutical composition in combination with an agent that can increase NO production, if desired It is intended to disclose the theft.

Description

[0001]
The present invention relates to a method of treating microcirculatory disorders, specifically diseases in which insufficient generation of NO appears to cause problems, wherein a substance that scavenges free radicals, such as dipyridamole or mopidamole, is treated with platelet aggregation. Decrease serum lipids, alone or in combination with substances that increase cellular nitric oxide (NO) production, e.g., HMG CoA reductase inhibitors, in amounts less than required to directly inhibit It is used in an amount less than the typical amount to be applied but sufficient to further enhance eNOS in vascular cells.
[0002]
Laboratory models that reflect the complex physiology of blood vessels allow the vascular system to interact deeply with blood through a complex check and balance system, rather than as a passive conduit, and its post-vascular disease. It has been shown to protect integrity. In this way, endothelial cells produce prostacyclin, a potent aggregation inhibitor. Normal endothelial cells are not thrombogenic and block platelet aggregation. Various stimulators trigger the release of endothelial cell-derived relaxing factor (EDRF), which inhibits platelet adhesion and aggregation. At the same time, it was shown that the intracellular increase in cGMP was responsive to smooth muscle cell relaxation following administration of nitrogen compounds. Thus, endothelial cells can provide for the maintenance of local perfusion of blood vessels by a number of separate mechanisms, one of which is mediated by prostacyclin and nitric oxide (NO, also denoted EDRF). Local vasodilation, as well as reduced interactions between blood cells or reduced negative interactions between leukocytes or platelets and cells on the vessel wall. Another is to control local fibrin accumulation by controlling the dissolution of already formed strands, similar to fibrin formation. In larger vessels, aggregation and adhesion of platelets to the site of injury to the vessel wall plays an important role, especially after interventional treatment, and has been shown to be treated with platelet aggregation inhibitors (WO 98/11896; Please see). The advantage of enhancing endothelial cell NO synthesis by HMG CoA reductase inhibitors is described in US Patent Nos. 5,968,983 and WO 00/56403.
[0003]
In the past prevention and treatment of conditions that result in reduced tissue perfusion, the focus has been primarily on mechanical and pharmaceutical revascularization of large arteries that supply blood to large areas of tissue. The focus is either on preventing the accumulation of atherosclerotic plaques (lipid-lowering therapy) or on preventing thromboembolism induced by rupture of plaques and platelet aggregation activation, often leading to occlusive thrombi. I was This is because the main effort was focused on preventing platelet aggregation, which eventually blocks the final common pathway of platelet aggregation, i.e., when forming a platelet-rich thrombus In the final step of binding together, by inhibiting the receptor for fibrinogen in platelets. Thus, it also proceeds directly in the direction of combining lipid-lowering therapy with potent platelet aggregation inhibitors, such combinations being shown in WO 98/11896.
[0004]
In addition, techniques for rapid and safe revascularization of occluded arteries have been developed, for example mechanically by pharmacological dissolution of thrombus with thrombolytic agents such as r-tPA or by percutaneous intravascular balloon angioplasty Was done. Here again, the main problem remaining is acute rethrombosis of the reopened part of the blood vessels, where a potent platelet aggregation inhibitor or inhibitor of fibrin formation in combination with platelet inhibition is effective It was shown.
[0005]
In the prevention of myocardial infarction (MI) recurrence, long-term administration of mild platelet inhibitors, such as aspirin, has shown only limited efficacy (public meta-analysis agrees with an 18% reduction in incidence) ing). However, the use of more potent platelet inhibitors, such as various orally available inhibitors of the platelet fibrinogen receptor, has shown no improvement over the effects achieved by ASA. More than 37,000 patients have been the subjects of primary studies looking at the long-term benefits of long-term administration of oral fibrinogen receptor antagonists in preventing the phenomena associated with cardiovascular disease. All studies were negative, in fact, the treatment arm showed a higher risk of bleeding and increased mortality.
From this it is concluded that long-term benefits cannot be inferred from the apparent short-term benefits of very potent platelet aggregation inhibition, either due to the accumulation of atherosclerotic plaques or the plasma lipid content as is achieved by lipid-lowering treatment. Even when combined with treatments designed to reduce the risk of rising relative to the increase.
[0006]
DETAILED DESCRIPTION OF THE INVENTION Tissue perfusion is crucial for health and survival and the function of every organ, especially those with high oxygen and high nutrient requirements. Even after successful epicardial revascularization, tissue perfusion, i.e., microcirculatory properties, showed a significant effect on mortality 90 days after MI (Gibbson et al., Circulation 2000, 101: 125-130). If tissue perfusion was not reduced, ie, microcirculation was not impaired, the mortality rate consequently dropped from 4.6% to 0.8%.
The present invention focuses on the importance of tissue perfusion at the small vascular level downstream of large blood vessels, which supplies oxygen and nutrients to tissues by improving microcirculation. Microcirculatory disorders, ie, circulatory disorders caused by microvascular dysfunction, are caused by metabolic or oxidative stress, and lead to diseases that include vascular dysfunction or damage.
[0007]
The present invention provides a novel approach to improve microcirculation by treating and / or preventing such microcirculatory disorders, wherein the microcirculatory disorders are caused by a decrease in endogenous NO production by cells, Are required for local prevention of vasospasm or reduced delayed responsiveness and for prevention of cell-mediated damage. Improvement of NO-dependent microvascular dysfunction is particularly important in small blood vessels or capillaries where the surface area of the vascular wall is high relative to blood volume, and also a novel approach for the treatment and prevention of the disease of NO I will provide a. Therefore, radical scavengers alone or in combination with substances capable of increasing NO production, such as dipyridamole and mopidamole, have therapeutic potential in a variety of diseases, including progressive dysfunction of medium and small sized vessels. There will be.
[0008]
Thus, the microcirculatory disorder of the present invention means that cells of the vascular system can no longer produce a sufficient amount of NO due to metabolic or genetic effects, i.e., a strong local regulator of homeostasis in the vasculature. Means that. Such diseases are referred to herein as "NO-dependent microcirculatory disorders." Examples of such diseases include:
Diabetic vascular disorders, specifically, diabetic microangiopathies, for example, diabetic gangrene, diabetic retinopathy, diabetic neuropathy, or, for example, hyperhomocysteinemia, homocystinuria, homocystinuria, pulmonary hypertension , Mucovisidosis, neurodegenerative disease, ulcus cruris, atrophic gastritis, ulcerative colitis, or microcirculatory disturbances following partial resection of the stomach and / or intestine;
In addition, insufficient tissue perfusion following revascularization of the large artery, e.g., after acute MI or stroke, or acute antiplatelet therapy to prevent acute reinfarction or peripheral arterial disease in addition to or following such therapy Restoration of blood flow upon insufficient tissue perfusion in, for example, those disclosed in WO 98/11896;
The same condition as when dysfunction occurs after revascularization or re-perfusion injury in transplant recipients;
Microcirculatory disorders caused by inflammatory reactions, such as morbus crohn, ulcerative colitis or acute respiratory distress syndrome (ARDS);
Microcirculatory disorders caused by autoimmune diseases, such as autoimmune chronic active hepatitis (sudden hepatitis), primary biliary cirrhosis, or (autoimmune-related) multiple sclerosis;
Peripheral microcirculatory disorders, such as Raynaud's disease, tinnitus or sudden hearing loss;
Microcirculatory disorders associated with increased cell division,
For example, a neoplastic disease or thrombotic thrombocytopenic purpura (TTP);
And renal sclerosis,
Prerenal hypertension,
Hemolytic uremic syndrome (HUS),
Arterial hypertension,
Vascular dementia,
Alzheimer's disease,
Sudeck's disease,
Central-veneous thrombosis of the eye,
Ischemic optic neuropathy,
Homocystin-induced vasculopathy,
Ischemic or coronary heart disease,
Prevention of myocardial infarction or re-infarction,
Treatment or prevention of atherosclerosis, osteoarthritis, such as arthritis.
[0009]
Furthermore, the indication "NO-dependent microcirculatory disorders" includes the corresponding diseases of the myocardium. Accordingly, the present invention provides methods for improving myocardial blood supply and preventing myocardial infarction or re-infarction in humans in need of such treatment, for example, those suffering from ischemic or coronary heart disease. This is especially the case after successful reperfusion by mechanical or pharmacological revascularization and in parallel with or after prevention of acute rethrombosis / reinfarction by potent platelet aggregation inhibitors.
Furthermore, treatment of “NO-dependent microcirculatory disorders” within the scope of the present invention also includes treatment or prevention of atherosclerosis by improving perfusion through the vasculature of large blood vessels (vasa vasorum). .
[0010]
Either increased local production of NO or, preferably, a combination of increased NO and reduced local destruction of NO can result in a NO-dependent disorder of the microcirculation.
Preference is given to pulmonary hypertension; inadequate tissue perfusion after revascularization of the aorta, eg after MI or stroke, or peripheral anti-platelet therapy in addition to or after acute anti-platelet therapy to prevent acute re-infarction Restoration of blood flow in inadequate tissue perfusion in disease, for example as disclosed in WO 98/11896; condition in which dysfunction is caused by reperfusion injury after revascularization or in transplant recipients; peripheral microcirculation Disorders such as Raynaud's disease, tinnitus or sudden hearing loss; vascular dementia, Alzheimer's disease; homocystinuria and homocystin-induced vascular disorders;
Ischemic or coronary heart disease; prevention of myocardial infarction or reinfarction; and treatment or prevention of atherosclerosis.
[0011]
The most preferred indications to be treated according to the invention are inadequate tissue perfusion after revascularization of the aorta, such as after MI or stroke, or in addition to or after acute antiplatelet therapy to prevent acute reinfarction. Restoration of blood flow due to insufficient tissue perfusion in peripheral artery disease; homocystinuria and homocystin-induced vasculopathy and vascular dementia.
Substances that scavenge free radicals have been found to increase local production of NO. Accordingly, NO-dependent microcirculatory disorders can be treated according to the present invention by therapeutics involving substances that scavenge free radicals.
Preferred are substances that scavenge free oxy and / or peroxy radicals.
Even more preferred are materials that are films that bind to and remove oxy and peroxy radicals.
[0012]
Compounds acting as scavengers of the present invention include, for example,
Probucol,
Ascorbic acid,
α-tocopherol dipyridamole or mopidamole;
The preferred ones are
Dipyridamole and mopidamole;
Most preferred is dipyridamole.
[0013]
The above substances may be applied in combination with an agent capable of increasing NO production. Compounds of the present invention that can increase NO production include, for example,
acetylcholine,
estrogen,
Or
HMG CoA reductase inhibitor,
For example,
Lovastatin pravastatin,
Simvastatin,
Fluvastatin,
Dalvastatin,
Compactin, mevastatin
HR 780,
BMY 22,089,
BMY 22,566,
SQ 33,600,
GR 95,030 or
CI 981;
The preferred ones are
Lovastatin,
Pravastatin,
Simvastatin,
Fluvastatin,
Dalvastatin,
Compactin, mevastatin,
HR 780,
BMY 22,089,
BMY 22,566,
SQ 33,600,
GR 95,030 or
CI 981;
More preferred are
Lovastatin,
Pravastatin,
Simvastatin,
Fluvastatin,
Dalvastatin,
Compactin and mevastatin.
[0014]
Preferred are combinations with mopidamole, more preferred are combinations of dipyridamole with an agent selected from the class of HMG CoA reductase inhibitors. An HMG CoA reductase inhibitor known to up-regulate the expression of eNOS (endothelial nitric oxide synthase), which is a sub-therapeutic amount or less than a lipid-lowering amount with clinical benefit A combination of an amount and a dose of dipyridamole or mopidamole that inhibits the destruction of NO.
[0015]
If the substance that scavenges free radicals is selected from dipyridamole or mopidamole, the plasma level of dipyridamole or mopidamole is about 0.2-5 μmol / L, preferably about 0.4-5 μmol / L, more preferably 0.5-2 μmol / L. It is particularly convenient to maintain the concentration at about 0.8 to 1.5 μmol / L, or to use it together with the HMO CoA reductase inhibitor 0.2 to 2.0 μmol / L. This can be achieved using any of the commercially available oral retard, instant or parenteral formulations of dipyridamole, with slow-acting formulations being preferred, e.g. (Trademark), or as low-dose acetylsalicylic acid (ASA) and optionally as an additional combination treatment, under the trade name Asasantin® (Asasantin®) or Aglenox® ) (Aggrenox®) may be used. Slow-acting dipyridamole formulations are described in EP-A-0032562, rapid-acting formulations are described in EP-A-0068191, and combinations of dipyridamole and ASA are described in EP-A-0257344. These documents are included in the present specification. Also in the case of mopidamole, oral slow-acting, fast-acting or parenteral preparations can be used, such as those disclosed in GB 1,051,218 or EP-A-0,108,898. These documents are included in the present specification. Slow release formulations are preferred.
[0016]
Dipyridamole or mopidamole may be administered orally in a daily dose of 25-450 mg, preferably 50-240 mg, most preferably 75-200 mg. For long-term treatment, it may be advantageous to administer a dose, for example, 25 mg of either a slow-release or other immediate-release formulation of dipyridamole, three to four times daily. For parenteral administration, dipyridamole is given as a slow intravenous injection (not faster than 0.2 mg / min) in a dose of 0.5-5 mg / kg body weight, preferably 1-3.5 mg / kg body weight, over a 24 hour period be able to.
[0017]
Closely related to substituted pyrimido-pyrimidines, dipidamole {2,6-bis (diethanolamino) -4,8-dipiperidino-pyrimido [5,4d] pyrimidine} and methods for their production are described, for example, in US Patent 3,031,450. Has been described. Furthermore, related substituted pyrimido-pyrimidines and methods for their preparation are described, for example, in GB 1,051,218, and in particular the compound mopidamole {2,6bis (diethanolamino) 4piperidinopyrimido [5,4d] Pyrimidine}. Dipyridamole was introduced as a crown expander in the early 1960s. It is also well known for its ability to inhibit platelet aggregation by inhibiting adenosine uptake. However, it is at the above dosage ranges and therapeutic dosages in the Agrenox® formulation. Although the activities of dipyridamole and mopidamole are well known, directly as platelet aggregation inhibitors at high concentrations and indirectly as platelet aggregation inhibitors via inhibition of adenosine reuptake at therapeutic plasma levels, these agents are further It is newly discovered that it is a NO destruction inhibitor through its ability to scavenge oxy and peroxy radicals while bound to the cell membrane of the vessel wall.
[0018]
Previous studies have led to its use as an antithrombotic agent, which soon became the treatment of choice for stroke prevention, maintaining patency of coronary artery bypass and valve replacement, and treatment before coronary angioplasty. became.
In addition, the European Stroke Prevention Study 2 (ESPS-2; J Neurol Sci. 1996; 143: 1-13; Neurology 1998; 51: 17-19) indicated that dipyridamole alone was associated with lower doses of aspirin in reducing stroke risk. It was equally effective, and the combination of dipyridamole and aspirin was more than twice as effective as aspirin alone.
[0019]
Dipyridamole appears to block thrombosis by a multi-step mechanism. Early studies have shown that adenosine uptake is inhibited, and adenosine was found to be a potent endogenous antithrombotic compound. Dipyridamole was also shown to inhibit cyclic AMP phosphodiesterase, thereby increasing intracellular c-AMP.
Dipyridamole exhibits, in addition to its adenosine-sparing effects, enhanced anti-thrombotic mechanisms of the vascular wall (increased cAMP, increased cGMP-). It stimulates prostacyclin production by increasing intracellular levels of cAMP and enhances the potent nitric oxide system by increasing cGMP. It also prevents topical fibrin formation.
[0020]
Dipyridamole also has antioxidant properties (Free Radic. Biol. Med. 1995; 18: 239-247), which may contribute to antiatherosclerotic effects. When oxidized, low-density lipoprotein becomes recognized by scavenger receptors on macrophages, which has been postulated to be an essential step in the progression of atherosclerosis (Ann. Rev. Med. 1992). ; 43: 219-25).
Dipyridamole inhibits fibrinogenesis in experimental liver fibrosis (Hepatology 1996; 24: 855-864) and also suppresses oxygen radicals and proteinuria in experimental animals with aminonucleoside nephropathy (Eur. J. Clin. Invest. 1998; 28: 877-883; Renal Physiol. 1984; 7: 218-226). Also, inhibition of lipid peroxidation was observed in human non-neoplastic lung tissue (Gen. Pharmacol. 1996; 27: 855-859).
[0021]
In one aspect, the present invention relates to a method of treating the body of a human or non-human animal, preferably a mammalian body, wherein the disease state comprises a NO-dependent microcirculatory disorder or such a microcirculatory disorder. Wherein the method comprises administering to the body an effective amount of a pharmaceutical composition comprising a substance that scavenges free radicals according to the present invention. In a preferred embodiment, which may be administered in combination with one or more agents capable of increasing NO production, the present invention provides a pyrimido-pyrimidine selected from dipyridamole, mopidamole and pharmaceutically acceptable salts thereof, Preferably it provides for the use of dipyridamole and is used in combination with one or more agents capable of increasing NO production, preferably those selected from the class of HMG CoA-reductase inhibitors. May be. It produces a pharmaceutical composition for the treatment of a human or non-human animal body, preferably a mammalian body, for the treatment or prevention of NO-dependent microcirculatory disorders or diseases in which such microcirculatory disorders are implicated. Used for
【Example】
[0022]
Experimentally, this condition was tested in an animal model showing a defect in microcirculatory function. The animal model used was an experimental stroke model in non-rodents, including rats and mice, and non-human primates.
In a stroke model, the size of tissue damage following arterial occlusion, which supplies clear regions of brain tissue, was assessed by histology and non-invasive images to determine local perfusion and extent of tissue damage ( MRI, CT).
It has been found that the size of infarcted tissue depends on the ability of the microcirculatory system to provide peripheral blood flow under conditions of antioxidant and metabolic stress. The size of the infarcted tissue decreased after treatment with the combination of dipyridamole and pravastatin. Similar effects were found to be exhibited by other agents selected from the class of HMG CoA reductase inhibitors.
[0023]
Further experiments were performed in other animal models: using genetically engineered NO synthase knockout mice, where NO synthase activity is blocked or partially inhibited, respectively. Study the effect of dipyridamole in preventing NO destruction by using experimental conditions in such a model where NO synthase activity is blocked or reduced and compare the effect of pravastatin to increase NO production did. This showed that the NO sparing effect was an independent effect when the increase in NO production was limited.
Studies in animal models and subsequent clinical trials in volunteers and patients include testing of effective dosage ranges according to appropriate clinical practice.

Claims (17)

A method of treating the body of a human or non-human animal for the treatment or prevention of a NO-dependent microcirculatory disorder or a disease state encompassing such a microcirculatory disorder, wherein the method is free. The above method, which comprises administering to the body an effective amount of a pharmaceutical composition containing a radical scavenging substance. The method according to claim 1, wherein the substance removes free oxy radicals and / or peroxy radicals. 2. The method according to claim 1, wherein the substance acts as a cell membrane binding substance. 2. The method according to claim 1, wherein said substance is a pyrimidino-pyrimidine selected from dipyridamole, mopidamole and pharmaceutically acceptable salts thereof. The method of claim 1, wherein the pyrimido-pyrimidine is dipyridamole. 2. The method according to claim 1, wherein the substance is administered in combination with one or more agents capable of increasing NO production. 2. The method of claim 1, wherein the NO-dependent microcirculatory disorder is selected from the group consisting of:
Microcirculatory disorders caused by metabolic diseases, including vascular injury,
For example, diabetic vascular disorders, specifically, diabetic microangiopathies, for example, diabetic gangrene, diabetic retinopathy, diabetic neuropathy,
Or for example, hyperhomocystinuria, homocystinuria, pulmonary hypertension, mucovisidosis, neurodegenerative disease, ulcerative cullis, atrophic gastritis, ulcerative colitis, partial resection of the stomach and / or intestine,
Insufficient tissue perfusion after revascularization of the aorta, such as after acute MI or stroke, or in addition to acute antiplatelet therapy to prevent acute reinfarction or in peripheral arterial disease after such treatment ,
Dysfunction following revascularization or reperfusion injury in transplant recipients,
Microcirculation disorders caused by inflammatory reactions,
For example, Crohn's disease, ulcerative colitis or acute respiratory distress syndrome (ARDS),
Microcirculatory disorders caused by autoimmune diseases,
For example, autoimmune chronic active hepatitis (sudden hepatitis), primary biliary cirrhosis, or (autoimmune-related) multiple sclerosis,
Peripheral microcirculatory disorders,
For example, Raynaud's disease, tinnitus or sudden hearing loss;
Microcirculatory disorders associated with increased cell division,
For example, a neoplastic disease or thrombotic-thrombocytopenic purpura (TTP);
Or, as a further indication,
Renal sclerosis,
Prerenal hypertension,
Hemolytic uremic syndrome (HUS),
Arterial hypertension,
Vascular dementia,
Alzheimer's disease,
Zudek's disease,
Central venous thrombosis of the eye,
Ischemic optic neuropathy,
Homocystin-induced vasculopathy,
Ischemic or coronary heart disease,
Prevention of myocardial infarction or re-infarction,
Treatment or prevention of atherosclerosis, osteoarthritis, such as arthritis. 5. The method of claim 4, wherein a plasma level of about 0.2-5 μmol / L of the pyrimido-pyrimidine is maintained. 5. The method of claim 4, wherein the pyrimido-pyrimidine is administered using an oral slow-release, immediate-release or parenteral formulation. 5. The method of claim 4, wherein the pyrimido-pyrimidine is administered orally at a daily dose of 25-450 mg or parenterally at 0.5-5 mg / kg body weight over a 24-hour period. 7. The method of claim 6, wherein the agent is a HMG CoA reductase inhibitor. 9. The method of claim 7, wherein a plasma level of about 0.2 to 50 [mu] mol / L dipyridamole or mopidamole is maintained for the treatment of microcirculatory disorders associated with increased cell division. Free radical scavenger for the manufacture of a pharmaceutical composition for the treatment of the human or non-human animal body for the treatment or prevention of NO-dependent microcirculatory disorders or disease states involving such microcirculatory disorders Use of. 14. Use according to claim 13, wherein the substance is a pyrimido-pyrimidine selected from dipyridamole, mopidamole and pharmaceutically acceptable salts thereof. 15. Use according to claim 14, wherein the pyrimido-pyrimidine is dipyridamole. 14. Use according to claim 13, wherein the substance is used in combination with one or more agents capable of increasing NO production. 14. Use according to claim 13, wherein the NO-dependent microcirculatory disorder is selected from the group consisting of:
Microcirculatory disorders caused by metabolic diseases, including vascular injury,
For example, diabetic vascular disorders, specifically, diabetic microangiopathies, for example, diabetic gangrene, diabetic retinopathy, diabetic neuropathy,
Or for example, hyperhomocystinuria, homocystinuria, pulmonary hypertension, mucovisidosis, neurodegenerative disease, ulcerative cullis, atrophic gastritis, ulcerative colitis, partial resection of the stomach and / or intestine,
Insufficient tissue perfusion following revascularization of the aorta, such as after acute MI or stroke, or in addition to acute antiplatelet therapy to prevent acute reinfarction, or in peripheral artery disease following such treatment ,
Dysfunction following revascularization or reperfusion injury in transplant recipients,
Microcirculation disorders caused by inflammatory reactions,
For example, Crohn's disease, ulcerative colitis or acute respiratory distress syndrome (ARDS),
Microcirculatory disorders caused by autoimmune diseases,
For example, autoimmune chronic active hepatitis (sudden hepatitis), primary biliary cirrhosis, or (autoimmune-related) multiple sclerosis,
Peripheral microcirculatory disorders,
For example, Raynaud's disease, tinnitus or sudden hearing loss,
Microcirculatory disorders associated with increased cell division,
For example, a neoplastic disease or thrombotic-thrombocytopenic purpura (TTP);
Or, as a further indication,
Renal sclerosis,
Prerenal hypertension,
Hemolytic uremic syndrome (HUS),
Arterial hypertension,
Vascular dementia,
Alzheimer's disease,
Zudek's disease,
Central venous thrombosis of the eye,
Ischemic optic neuropathy,
Homocystin-induced vasculopathy,
Ischemic or coronary heart disease,
Prevention of myocardial infarction or re-infarction,
Treatment or prevention of atherosclerosis, osteoarthritis, such as arthritis.