By using a composition for preventing onset and/or recurrence of stroke which contains ethyl icosapentate as its effective component, onset and/or recurrence of stroke is prevented, or in particular, the onset and/or recurrence of stroke in a hyperlipidemia patient who has been treated with HMG-CoA RI, or in particular the recurrence of stroke in a patient who is beyond six months after the onset of stroke, is prevented.

Description of the Invention

SUMMARY OF THE INVENTION

In view of the situation that the stroke is still a major cause of death and it is a serious problem that many cases of stroke are still impossible to be prevented by the HMG-CoA RI therapy, an object of the present invention is to provide a composition for preventing onset and/or recurrence of the stroke.

In order to solve the problems as described above, the inventors of the present invention made an extensive study and found that EPA-E has an effect of preventing onset and/or recurrence of stroke, and in particular, preventing recurrence of stroke in a patient who is beyond six months after the onset of stroke. The present invention has been completed on the basis of such findings. Accordingly, the present invention includes the followings: (1) A method for preventing recurrence of stroke, including administering ethyl icosapentate orally to a patient with history of stroke at a dose of 0.3 g/day to 6.0 g/day; (2) A method according to (1), in which the patient is beyond six months after the onset of stroke; (3) A method according to (2), in which serum TG/HDL-C ratio of the patient is 3.75 or more; (4) A method according to (3), in which 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor is administered to the patient in combination with the ethyl icosapentate; (5) A method according to (3), in which the administration of the ethyl icosapentate to the patient is continued for at least three years; (6) A method according to (3), in which a composition having the ethyl icosapentate at a proportion of 96.5% by weight or more in the total content of fatty acids and their derivatives is administered to the patient; (7) A method according to (2), in which the patient suffers from hyperlipidemia; (8) A method according to (7), in which 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor is administered to the patient in combination with the ethyl icosapentate; (9) A method according to (7), in which the administration of the ethyl icosapentate to the patient is continued for at least three years; and (10) A method according to (7), in which a composition having the ethyl icosapentate at a proportion of 96.5% by weight or more in the total content of fatty acids and their derivatives is administered to the patient.

DESCRIPTION OF THE PREFERRED EMBODIMENT

Next, the present invention is described in detail.

A first embodiment of the present invention is related to a composition for preventing onset and/or recurrence of stroke, which contains at least EPA-E as its effective component, and a method for administering the composition to a normal individual or a patient with history of stroke. Alternatively, the first embodiment of the present invention is related to a composition for preventing onset and/or recurrence of stroke, which contains at least EPA-E and/or DHA-E as its effective component, and a method for administering the composition to a normal individual or a patient with history of stroke.

The stroke includes all the pathological conditions in which impairment of consciousness and neurologic symptoms is acutely induced by cerebrovascular disorders, and examples include, in particular, intracerebral hemorrhages (hypertensive intracerebral hemorrhage, etc.), cerebral infarction, transient ischemic attack, subarachnoid hemorrhage, cerebral thrombosis (atherothrombotic cerebral infarction, etc.), cerebral embolism (cardiogenic cerebral embolism, etc.), and lacunar infarction. The subjects for the administration include any human who needs prevention of the onset of the stroke, and examples include, in particular, patients of hyperlipidemia.

While the EPA-E content in the total fatty acids of the composition and the dose of the composition are not particularly limited as long as intended effects of the present invention are attained, high purity of EPA-E is preferable, for example, a proportion of the EPA-E in the total fatty acids and their derivatives is preferably 40% by weight or more, more preferably 90% by weight or more, and still more preferably 96.5% by weight or more. The daily dose of the composition in terms of EPA-E is typically 0.3 to 6.0 g/day, preferably 0.9 to 3.6 g/day, and still more preferably 1.8 to 2.7 g/day. Examples of other fatty acids preferably contained in the composition are the .omega.-3 polyunsaturated fatty acids, in particular, DHA-E. When DHA-E is contained in the composition, while the compositional ratio of EPA-E/DHA-E, the content of EPA-E and DHA-E (hereinafter referred to as (EPA-E+DHA-E)) in the total fatty acids, and the dose of EPA-E+DHA-E, are not particularly limited as long as intended effects of the present invention are attained, the compositional ratio of EPA-E/DHA-E is preferably 0.8 or more, more preferably 1.0 or more, and still more preferably 1.2 or more. High purity of EPA-E and DHA-E is preferable and, for example, the content of EPA-E+DHA-E in the total fatty acids and their derivatives is preferably 40% by weight or more, more preferably 80% by weight or more, and still more preferably 90% by weight or more. The daily dose in terms of EPA-E+DHA-E is typically 0.3 to 10 g/day, preferably 0.5 to 6 g/day, and still more preferably 1 to 4 g/day. The content of other long chain saturated fatty acids is preferably low, and the content of .omega.-6 fatty acids, and in particular, the content of arachidonic acid, among the long chain unsaturated fatty acids, is preferably as low as less than 2% by weight, and more preferably less than 1% by weight.

A second embodiment of the present invention is related to a composition for preventing onset and/or recurrence of stroke in a hyperlipidemia patient, which contains at least EPA-E, and a method for administering the composition to a hyperlipidemia patient. Alternatively, the second embodiment of the present invention is related to a composition for preventing onset and/or recurrence of stroke in a hyperlipidemia patient, which contains at least EPA-E and/or DHA-E, and a method for administering the composition to a hyperlipidemia patient.

A third embodiment of the present invention is related to a composition for preventing recurrence of stroke in a patient with history of stroke, which contains at least EPA-E as its effective component, and a method for administering the composition to a patient with history of stroke. Alternatively, the third embodiment of the present invention is related to a composition for preventing recurrence of stroke in a patient with history of stroke, which contains at least EPA-E and/or DHA-E as its effective component, and a method for administering the composition to a patient with history of stroke.

In the second and third embodiments of the present invention, and also in the forth to thirteenth embodiments of the present invention described later, preferable representatives regarding the type of stroke, the proportion of the EPA-E in the total fatty acids, the proportion of the EPA-E+DHA-E in the total fatty acids, the compositional ratio of EPA-E/DHA-E, the daily dose, and the proportion of the other long chain fatty acids etc., are the same as those in the first embodiment of the present invention as described above.

A fourth embodiment of the present invention is related to a composition for preventing recurrence of stroke in a patient who is beyond six months after the onset of stroke, which contains at least EPA-E as its effective component, and a method for administering the composition to a patient who is beyond six months after the onset of stroke. Alternatively, the fourth embodiment of the present invention is related to a composition for preventing recurrence of stroke in a patient who is beyond six months after the onset of stroke, which contains at least EPA-E and/or DHA-E as its effective component, and a method for administering the composition. In this embodiment, the preferable representatives regarding the type of stroke, the proportion of the EPA-E in the total fatty acids, the proportion of the EPA-E+DHA-E in the total fatty acids, the compositional ratio of EPA-E/DHA-E, the daily dose, and the proportion of the other long chain fatty acids etc. are the same as those in the first embodiment of the present invention. The subject for the administration is a patient who is beyond six months after the latest onset of stroke and has passed the acute period of the stroke.

A fifth embodiment of the present invention is related to a composition having an excellent effect of preventing recurrence of stroke after 3 years from the start of its administration, which contains at least EPA-E as its effective component, and a method for administering the composition to a patient with history of stroke. In fact, continuous administration of the composition containing at least EPA-E as its effective component to a patient with history of stroke for at least 3 years reduces the incidence rate of the stroke by at least 15% at 3 years from the start of the administration, and by at least 30% at 4 or 5 years from the start of the administration, compared with the control group with no administration of the EPA-E. In particular, when the subject is a patient whose serum TG/HDL-C ratio is 3.75 or more, a continuous administration of the composition containing at least EPA-E as its effective component for at least 3 years reduces the incidence rate of the stroke by at least 20% at 3 years from the start of the administration, and by at least 40% at 4 or 5 years from the start of the administration, compared with the control group with no administration of the EPA-E. Alternatively, the fifth embodiment of the present invention is related to a composition having an excellent effect of preventing recurrence of stroke after 3 years from the start of its administration, which contains at least EPA-E and/or DHA-E as its effective component, and a method for administering the composition to a patient with history of stroke.

A sixth embodiment of the present invention is related to a composition for preventing onset and/or recurrence of stroke, which contains at least EPA-E as its effective component, and is continuously administered to a normal individual or a patient with history of stroke for at least 3 years, in combination with HMG-CoA RI. When the subject is a patient with history of stroke, such combined use reduces the incidence rate of the stroke by at least 15% at 3 years from the start of the administration, and by at least 30% at 4 or 5 years from the start of the administration, compared with the control group with no administration of the EPA-E. In particular, when the subject is a patient whose serum TG/HDL-C ratio is 3.75 or more, a continuous administration of the composition containing at least EPA-E as its effective component in combination with HMG-CoA RI for at least 3 years reduces the incidence rate of the stroke by at least 20% at 3 years from the start of the administration, and by at least 40% at 4 or 5 years from the start of the administration, compared with the control group with no administration of the EPA-E. Alternatively, the sixth embodiment of the present invention is related to a composition for preventing onset and/or recurrence of stroke, which contains at least EPA-E and/or DHA-E as its effective component, and is continuously administered to a normal individual or a patient with history of stroke for at least 3 years, in combination with HMG-CoA RI.

A seventh embodiment of the present invention is related to a method for preventing onset and/or recurrence of stroke, which includes continuously administering a composition containing at least EPA-E as its effective component to a normal individual or a patient with history of stroke for at least 3 years. Alternatively, the seventh embodiment of the present invention is related to a method for preventing onset and/or recurrence of stroke, which includes continuously administering a composition containing at least EPA-E and/or DHA-E as its effective component to a normal individual or a patient with history of stroke for at least 3 years.

A eighth embodiment of the present invention is related to a composition for preventing onset and/or recurrence of stroke which contains at least EPA-E as its effective component, and a method for administering the composition to a subject of a patient whose serum TG/HDL-C ratio is 1 or more, preferably 2 or more, and more preferably 3.75 or more. Alternatively, the eighth embodiment of the present invention is related to a composition for preventing onset and/or recurrence of stroke which contains at least EPA-E and/or DHA-E as its effective component, and a method for administering the composition to a subject of a patient whose serum TG/HDL-C ratio is 1 or more, preferably 2 or more, and more preferably 3.75 or more.

A ninth embodiment of the present invention is related to a composition for preventing recurrence of stroke in a hyperlipidemia patient, which contains at least EPA-E as its effective component, and a method for administering the composition. Alternatively, the ninth embodiment of the present invention is related to a composition for preventing recurrence of stroke in a hyperlipidemia patient, which contains at least EPA-E and/or DHA-E as its effective component, and a method for administering the composition to a hyperlipidemia patient. The preferable representatives regarding the type of stroke, the proportion of the EPA-E in the total fatty acids, the proportion of the EPA-E+DHA-E in the total fatty acids, the compositional ratio of EPA-E/DHA-E, the daily dose, and the proportion of the other long chain fatty acids etc. in the ninth embodiment of the present invention, are the same as those in the first embodiment of the present invention.

A tenth embodiment of the present invention is related to a composition for preventing recurrence of stroke, which contains at least EPA-E as its effective component, and is used in combination with HMG-CoA RI; in other words, a composition to be used in combination with HMG-CoA RI for preventing recurrence of stroke in a patient requiring HMG-CoA RI, which contains at least EPA-E as its effective component, and a method for administering the composition to a patient with history of stroke. Alternatively, the tenth embodiment of the present invention is related to a composition for preventing recurrence of stroke, which contains at least EPA-E and/or DHA-E as its effective component, and is used in combination with HMG-CoA RI; in other words, a composition to be used in combination with HMG-CoA RI for preventing recurrence of stroke in a patient requiring HMG-CoA RI, which contains at least EPA-E and/or DHA-E as its effective component, and a method for administering the composition to a patient with history of stroke.

While the HMG-CoA RI includes everything having inhibitory action on 3-hydroxy-3-methylglutaryl coenzyme A reductase, those pharmaceutically administrable are preferable. An example is preferably selected from the group consisting of pravastatin, simvastatin, lovastatin, fluvastatin, cerivastatin, atorvastatin, pitavastatin, rosuvastatin, and salts and their derivatives, and more preferably, pravastatin, lovastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, or rosuvastatin, and still more preferably, pravastatin or simvastatin. All pharmaceutically administrable salts are included in the scope of the invention, and preferred are sodium and potassium salts such as pravastatin sodium, fluvastatin sodium, cerivastatin sodium, atorvastatin calcium, pitavastatin calcium, and rosuvastatin calcium. In the present disclosure, all compounds may exist in the form of a salt unless otherwise noted, and "pravastatin", for example, also includes a salt of pravastatin.

An eleventh embodiment of the present invention is related to a composition to be used in combination with HMG-CoA RI for preventing onset and/or recurrence of stroke in a subject of a patient whose serum TG/HDL-C ratio is 3.75 or more, which contains at least EPA-E as its effective component; in other words, a composition to be used in combination with HMG-CoA RI for preventing recurrence of stroke in a patient requiring HMG-CoA RI whose serum TG/HDL-C ratio is 3.75 or more, which contains at least EPA-E as its effective component, and a method for administering the composition to a patient with history of stroke. Alternatively, the eleventh embodiment of the present invention is related to a composition to be used in combination with HMG-CoA RI for preventing onset and/or recurrence of stroke in a subject of a patient whose serum TG/HDL-C ratio is 3.75 or more, which contains at least EPA-E and/or DHA-E as its effective component. In other words, the eleventh embodiment of the present invention is related to a composition to be used in combination with HMG-CoA RI for preventing recurrence of stroke in a patient requiring HMG-CoA RI whose serum TG/HDL-C ratio is 3.75 or more, which contains at least EPA-E and/or DHA-E as its effective component, and a method for administering the composition to a patient with history of stroke. Patients requiring HMG-CoA RI suffer from hyperlipidemia in many cases.

The compositions and the methods in the seventh to eleventh embodiments of the present invention are preferably compositions and methods for a patient with history of stroke, and more preferably compositions and methods for a patient beyond six months after the onset of stroke, i.e., a patient who has passed the acute period of stroke.

A twelfth embodiment of the present invention is related to a method for preventing onset and/or recurrence of stroke in a patient whose serum TG/HDL-C ratio is 3.75 or more, which includes administering a composition containing at least EPA-E as its effective component to the patient, until the TG/HDL-C ratio becomes less than 3.75, more preferably less than 1. Alternatively, the twelfth embodiment of the present invention is related to a method for preventing onset and/or recurrence of stroke in a patient whose serum TG/HDL-C ratio is 3.75 or more, which includes administering a composition containing at least EPA-E and/or DHA-E as its effective component to the patient, until the TG/HDL-C ratio becomes less than 3.75, more preferably less than 1.

A thirteenth embodiment of the present invention is related to use of EPA-E in manufacture of a composition for preventing onset and/or recurrence of stroke. Alternatively, the thirteenth embodiment of the present invention is related to use of EPA-E and/or DHA-E in manufacture of a composition for preventing onset and/or recurrence of stroke.

While the EPA-E content in the total fatty acids of the composition and the dose of the composition are not particularly limited as long as intended effects of the present invention are attained, high purity of EPA-E is preferable and, for example, a proportion of the EPA-E in the total fatty acids and their derivatives of the composition is preferably 40% by weight or more, more preferably 90% by weight or more, and still more preferably 96.5% by weight or more. The daily dose of the composition in terms of EPA-E is typically 0.3 to 6 g/day, preferably 0.9 to 3.6 g/day, and still more preferably 1.8 to 2.7 g/day. Examples of other fatty acids preferably contained in the composition are the .omega.-3 polyunsaturated fatty acids, in particular, DHA-E. When DHA-E is contained in the composition, while the compositional ratio of EPA-E/DHA-E, the content of EPA-E+DHA-E in the total fatty acids, and the dose of EPA-E+DHA-E are not particularly limited as long as intended effects of the present invention are attained, the compositional ratio of EPA-E/DHA-E is preferably 0.8 or more, more preferably 1.0 or more, and still more preferably 1.2 or more. High purity of EPA-E and DHA-E is preferable and, for example, the content of the EPA-E+DHA-E in the total fatty acids and their derivatives is preferably 40% by weight or more, more preferably 80% by weight or more, and still more preferably 90% by weight or more. The daily dose of the composition containing DHA-E in terms of EPA-E+DHA-E is typically 0.3 to 10 g/day, preferably 0.5 to 6 g/day, and still more preferably 1 to 4 g/day. The content of other long chain saturated fatty acids is preferably low, and the content of .omega.-6 fatty acids, and in particular, the content of arachidonic acid, among the long chain unsaturated fatty acids, is preferably as low as less than 2% by weight, and more preferably less than 1% by weight.

The composition of the present invention contains EPA-E and/or DHA-E and has the effect of preventing onset and/or recurrence of stroke when orally administered to a normal individual or a patient having the risk factor for stroke such as hyperlipidemia, diabetes, and hypertension. In particular, the composition of the present invention has the effect of preventing onset and/or recurrence of stroke in a hyperlipidemia patient who has been treated with HMG-CoA RI. The composition of the present invention also has a combined effect when used in combination with HMG-CoA RI, and accordingly, onset and/or recurrence of stroke can be even more effectively prevented by the combined use.

The composition of the present invention may be appropriately used in combination with at least a drug commonly used for preventing onset and/or recurrence of stroke, which is, for example, selected from the group including antiplatelets such as aspirin, ticlopidine, clopidogrel, and cilostazol; anticoagulants such as warfarin, heparin, and ximelagatran; antihypertensives such as angiotensin II receptor antagonists (candesartan, losartan, etc.), angiotensin converting enzyme inhibitors, calcium channel antagonists (amlodipine, cilnidipine, etc.), and .alpha.-1 blockers; drugs for diabetes or for improving abnormal glucose tolerance such as .alpha.-glucosidase inhibitors (voglibose, acarbose, etc.), biguanides, thiazolidinediones (pioglitazone, rosiglitazone, rivoglitazone, etc.), and fast-acting insulin secretagogues (mitiglinide, nateglinide, etc.); and antihyperlipidemics such as the HMG-CoA RI described above, fibrates, squalene synthase inhibitors (TAK-475, etc.), and cholesterol absorption inhibitors (ezetimibe, etc.). It is noted that the composition of the present invention can be used in a package together with at least one drug such as HMG-CoA RI and/or others for improving convenience.

The composition of the present invention contains less impurities such as saturated fatty acids and arachidonic acid which are unfavorable for stroke compared to fish oil or fish oil concentrate, and its intended effects can be attained without causing problems such as overnutrition and excessive intake of vitamin A. In addition, since the effective component of the present composition is an ester and thus more stable against oxidation compared to the fish oil etc. which are essentially in the form of triglyceride, a sufficiently stable composition can be produced by adding a conventional antioxidant. Therefore, the use of the EPA-E has enabled production of a composition for preventing onset and/or recurrence of stroke which can be used in clinical practice, for the first time.

In the present specification, the term "icosapentate" designates all-cis-5,8,11,14,17-icosapentaenoic acid.

In the present specification, the term "stroke" is defined as a pathological condition in which impairment of consciousness and neurologic symptom(s) are acutely induced by a cerebrovascular disorder, which includes intracerebral hemorrhages (hypertensive intracerebral hemorrhage, etc.), cerebral infarction, transient ischemic attack, subarachnoid hemorrhage, cerebral thrombosis (atherothrombotic cerebral infarction, etc.), cerebral embolism (cardiogenic cerebral embolism, etc.), and lacunar infarction.

In the present specification, the term "hyperlipidemia patient" designates a patient experiencing either an increase in serum T-Cho concentration, an increase in serum LDL-Cho concentration, a decrease in serum HDL-Cho concentration, or an increase in serum TG. In a narrow sense, the term "hyperlipidemia patient" designates a patient who suffers from any one of hypercholesterolemia (with the serum T-Cho concentration of about 220 mg/dl or higher, and in a narrower sense, 250 mg/dl or higher), hyper-LDL cholesterolemia (with the serum LDL-Cho concentration of 140 mg/dl or higher), hypo-HDL cholesterolemia (with the serum HDL-Cho concentration of less than 40 mg/dl) and hypertriglyceridemia (with the serum TG of 150 mg/dl or higher). Serum concentration of each lipid can be measured and calculated by conventional methods, typically using blood samples collected during fasting. The serum TG/HDL-C ratio is a value obtained by dividing the serum concentration of triglyceride (TG) by the serum concentration of high density lipoprotein-cholesterol (HDL-C).

TG/HDL-C ratio is known to have an inverse correlation with particle diameter of LDL according to a report for subjects of normal individuals by Maruyama et al. (J. Atheroscler. Thromb., vol. 10, pp. 186-191, 2003), in which the correlation was so found as the LDL particle diameter is 25.5 nm when TG/HDL-C ratio is 1. Among LDLs, small dense LDL (sdLDL) with the particle diameter of 25.5 nm or less, also known as "super-bad cholesterol" has a strong effect to induce arteriosclerosis, and thus the TG/HDL-C ratio has recently drawn attentions as one of the criteria for the prognosis of arteriosclerotic diseases. According to the correlation mentioned above, the sdLDL starts to appear when the TG/HDL-C ratio becomes 1 or more, whereby increasing the risk for arteriosclerotic diseases. Thus the cut-off value for the serum TG/HDL-C ratio is set to 3.75 in the present invention based on the reference value of 150 mg/dl for the TG and the reference value of 40 mg/dl for HDL-C. Patients whose serum TG/HDL-C ratio are 3.75 or more have high serum sdLDL concentration, and are predicted to have a high risk for onset of stroke. Both the high TG value and the low HDL-C are considered as the risk factors for the arteriosclerotic diseases. However, when the TG is 400 mg/dl or more, chylomicronemia would be suspected, but chylomicronemia is considered not to be arteriosclerotic. In view of this, when the results were analyzed based on the TG/HDL-C ratio in the embodiment of the present invention, those cases where the serum TG value at the time of registration was 400 mg/dL or more were excluded from the subjects for the analysis.

In the present specification, the term "use of EPA-E in combination with HMG-CoA RI" includes both the embodiment in which the EPA-E and the HMG-CoA RI are simultaneously administered and the embodiment in which both agents are separately administered. When they are simultaneously administered, they may be formulated either as a single combination drug, or separate drugs. When they are separately administered, EPA-E may be administered either before or after HMG-CoA RI. The dose and ratio of EPA-E and HMG-CoA RI may be adequately selected.

In the present specification, the term "use of EPA-E and/or DHA-E in combination with HMG-CoA RI" include both the embodiment in which the EPA-E and/or DHA-E and the HMG-CoA RI are simultaneously administered and the embodiment in which both agents are separately administered. When they are simultaneously administered, they may be formulated either as a single combined drug, or separate drugs. When they are separately administered, EPA-E and/or DHA-E may be administered either before or after the HMG-CoA RI. The dose and ratio of EPA-E and/or DHA-E and HMG-CoA RI may be adequately selected.

The composition of the present invention has the action of preventing onset and/or recurrence of the stroke by sole administration of the composition, and in particular, the composition is expected to have the effect of preventing onset and/or recurrence of stroke which cannot be prevented by sole administration of HMG-CoA RI. In addition, EPA-E has not only the action of reducing the serum T-Cho concentration and the serum TG, but also the pharmacological actions such as suppressing platelet aggregation based on inhibition of arachidonic acid cascade, which are different from those of HMG-CoA RI. Therefore, the action as described above can also be exerted by combined administration with HMG-CoA RI.

Since EPA-E and DHA-E are highly unsaturated, inclusion of an effective amount of an antioxidant, such as butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, gallic acid, and pharmaceutically acceptable quinone, and .alpha.-tocopherol, is preferable.

The preparation may be orally administered to a patient in a dosage form such as tablet, capsule, microcapsule, granules, fine granules, powder, oral liquid preparation, syrup, and jelly. Preferably, the preparation is orally administered by filling in a capsule such as soft capsule or microcapsule.

It is noted that the soft capsule containing high purity EPA-E (Epadel and Epadel S) are commercially available in Japan as safe therapeutic agents for arteriosclerosis obliterans and hyperlipidemia with reduced side effects, and in these products, the proportion of the EPA-E in the total fatty acids is at least 96.5% by weight. Soft capsule (Omacor, Ross products) containing about 46% by weight of EPA-E and about 38% by weight of DHA-E is commercially available in the U.S. and other countries as a therapeutic agent for hypertriglyceridemia. These commercial drugs may be obtained for use in the present invention.

The dose and the period of administration of the composition for preventing onset and/or recurrence of stroke according to the present invention should be sufficient for the expression of the intended action, and may be adequately adjusted depending on, for example, the dosage form, administration route, number of doses per day, severity of the symptom, body weight, age, and the like. When orally administered, the composition may be administered at a dose in terms of EPA-E of 0.3 to 6 g/day, preferably 0.9 to 3.6 g/day, and more preferably 1.8 to 2.7 g/day, and while the composition is typically administered in 3 divided doses a day, if necessary, the composition may be administered in a single dose or in several divided doses. The composition is preferably administered during or after the meal, and more preferably, immediately (within 30 minutes) after the meal. When the composition is orally administered, the administration period is typically at least 1 year, preferably at least 2 years, more preferably at least 3 years, and most preferably at least 5 years. The administration is preferably continued as long as there is a high risk of onset and/or recurrence of stroke. If desired, drug holidays of about 1 day to 3 months, preferably about 1 week to 1 month, may be given.

The HMG-CoA RI to be used in combination is preferably administered according to the recommended dosage regimen, and the dose may be adequately adjusted depending on, for example, its type, dosage form, administration route, number of doses per day, severity of the symptoms, body weight, sex, age, and the like. When orally administered, the HMG-CoA RI is typically administered at a dose of 0.05 to 200 mg/day, and preferably 0.1 to 100 mg/day in 2 to 3 divided doses a day, but if desired, it may be administered in a single dose or in several divided doses. The dose of the HMG-CoA RI may be reduced depending on the dose of the EPA-E.

It is noted that pravastatin sodium (Mevalotin.TM. tablets and fine granules, Sankyo Co., Ltd.), simvastatin (Lipovas.TM. tablets, Banyu Pharmaceutical Co., Ltd.), fluvastatin sodium (Lochol.TM. tablets, Novartis Pharma K.K. and Tanabe Seiyaku Co., Ltd.), atorvastatin calcium hydrate (Lipitor.TM. tablets, Astellas Pharma Inc. and Pfizer), pitavastatin calcium (Livalo.TM. tablets, Kowa Company, Ltd. and Sankyo Co., Ltd., and rosuvastatin calcium (Crestor.TM. tablets, AstraZeneca K.K. and Shionogi & Co., Ltd.) are commercially available in Japan as antihyperlipidemics, and lovastatin (Mevacor.TM. tablets, Merck) is commercially available in the U.S. as a antihyperlipidemic. At least one of these commercial drugs may be obtained and appropriately combined for administration according to the directions recommended for them.

The preferable daily doses of these drugs are, for example, 5-60 mg or preferably 10-20 mg for pravastatin sodium, 2.5-60 mg or preferably 5-20 mg for simvastatin, 10-180 mg or preferably 20-60 mg for fluvastatin sodium, 5-120 mg or preferably 10-40 mg for atorvastatin calcium hydrate, 0.5-12 mg or preferably 1-4 mg for pitavastatin calcium, 1.25-60 mg or preferably 2.5-20 mg for rosuvastatin calcium, 5-160 mg or preferably 10-80 mg for lovastatin, and 0.075-0.9 mg or preferably 0.15-0.3 mg for cerivastatin, but not limited to them.
 

Claim 1 of 5 Claims

1. A method for reducing recurrence of stroke, comprising administering ethyl icosapentate orally to a patient that has had at least one stroke at a dose of 0.3 g/day to 6.0 g/day in combination with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.

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