WO2010021385A1 - Anca関連血管炎治療薬 - Google Patents
Anca関連血管炎治療薬 Download PDFInfo
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- WO2010021385A1 WO2010021385A1 PCT/JP2009/064669 JP2009064669W WO2010021385A1 WO 2010021385 A1 WO2010021385 A1 WO 2010021385A1 JP 2009064669 W JP2009064669 W JP 2009064669W WO 2010021385 A1 WO2010021385 A1 WO 2010021385A1
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- the present invention relates to a prophylactic / therapeutic and / or relapse-suppressing drug for diseases involving anti-neutrophil cytoplasmic antibody (ANCA), particularly ANCA-related vasculitis, and a therapeutic method using the same.
- ANCA anti-neutrophil cytoplasmic antibody
- Anti-neutrophil cytoplasmic antibody is an IgG-type neutrophil cytoplasm found at a high rate in cases showing small vasculitis centering on the kidney and lung found recently.
- Autoantibodies against ANCA is divided into two types, cytoplasmic (C) ANCA and perinuclear (P), depending on the fluorescence staining pattern.
- C-ANCA cytoplasmic
- P perinuclear
- the typical corresponding antigen of C-ANCA is proteinase-3 (PR-3), For P-ANCA, it is myeloperoxidase (MPO).
- ANCA-associated vasculitis is found in serum with ANCA, rapid progressive glomerulonephritis syndrome (RPGN) due to necrotic or granulomatous vasculitis of renal and pulmonary microvessels, or hematuria, chronic nephritis This is a case of high incidence of pulmonary kidney syndrome with syndrome and pulmonary findings (pulmonary hemorrhage, interstitial pneumonia).
- C-ANCA is found at a high rate in Wegener's granulomatosis
- P-ANCA is found at a high rate in microscopic polyangiitis, Churg-Strauss syndrome (allergic granulomatous vasculitis), and the like.
- the treatment of ANCA-related vasculitis is performed by evaluating the activity of systemic vasculitis and dividing it into initial remission induction therapy, remission maintenance (relapse suppression) therapy, and relapse therapy. Treatments that suppress antibody levels are needed.
- initial remission induction therapy mainly plasma exchange, use of a large amount of corticosteroids, cyclophosphamide, etc.
- Immunosuppressive therapy is performed. Later, even after the disease activity has improved and the ANCA titer has decreased, ANCA-related vasculitis often recurs.
- An inhibitor is administered. Treatment at the time of relapse is based on the initial remission induction therapy.
- Non-Patent Document 1 Patients with chronic ANCA-related vasculitis who have relatively low ANCA titer, chronic nephritis and chronic renal failure as nephropathy, and pulmonary fibrosis as pulmonary symptoms or moderate corticosteroid administration alone or Treatment with a small amount of an immunosuppressant is performed (see Non-Patent Document 1).
- drugs that can suppress the ANCA antibody titer such as steroids and immunosuppressants, are used.
- Infection can be one of the triggers of ANCA swaying, and can cause serious symptoms, particularly in subjects who are susceptible to decreased immunity, such as elderly people and cancer-bearing patients.
- Suppressed ANCA antibody titer and combined with infectious disease subjects and infectious diseases, especially in remission maintenance (relapse suppression) therapy requiring long-term use as a therapeutic agent for fundamental ANCA-related vasculitis Drugs that can be used by subjects for a long period of time and can suppress the recurrence of ANCA-related vasculitis have not been known so far, and the development of new treatment methods is eagerly desired.
- a method for treating ANCA-related vasculitis by administration of an antagonist that binds to a ⁇ -cell surface marker such as CD20 antibody see Patent Document 1
- an antagonist that binds to a ⁇ -cell surface marker such as CD20 antibody
- Patent Document 2 As a medicine for preventing and / or treating vasculitis syndrome such as ANCA-related arthritis based on suppression of inflammation associated with macrophage infiltration and inflammation on vascular endothelium based on suppression of expression level of Mac-1 gene and VCAM-1 gene Diacylglycerol (see Patent Document 2), benzimidazole drugs known to have an inhibitory action on NF ⁇ -B involved in inflammation, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, interferons, and the like Combination with drugs (see Patent Document 3) has been proposed .
- EPA-E icosapentoic acid ethyl ester
- anticoagulation / antiplatelet therapy may be performed in combination with steroids and immunosuppressive drugs for RPGN, and subject to ANCA-related nephritis complicated with IgA nephropathy after steroid pulse therapy,
- antiplatelet therapy with eicosapentaic acid and dipyridamole was performed in combination with oral treatment with prednisolone 35 mg (see Non-Patent Document 2).
- Non-Patent Document 3 Non-Patent Document 3
- EPA has been confirmed to induce regulatory T cell production through the activation of PPAR ⁇ and to suppress CD80 and CD86 whose expression was enhanced in splenic dendritic cells (dendritic cells).
- EPA has not been used for the maintenance of remission (relapse suppression) therapy for ANCA-related vasculitis, and the effect of lowering the ANCA antibody titer has not been known. It has not been used as a fundamental remedy for vasculitis.
- a therapeutic agent and a therapeutic method that are suitable for a fundamental therapeutic agent for ANCA-related vasculitis that suppresses the activity of ANCA, particularly a long-term remission maintenance (relapse suppression) therapy.
- a drug that suppresses the production of ANCA and a treatment method that overcomes the problems of conventional ANCA lowering therapy such as steroids and immunosuppressants has few side effects, and can be used safely in a wide range of subjects. is there.
- EPA has both a direct action against ANCA-related vasculitis that suppresses the production of ANCA and an action that regulates autoimmunity, and in particular, the acute phase of ANCA-related vasculitis that requires long-term use. It was found that the subject was suitable for maintaining remission (suppression of recurrence) after remission of symptoms, and the present invention was completed.
- the following pharmaceutical composition is provided.
- a pharmaceutical composition for suppressing recurrence of ANCA-related vasculitis containing as an active ingredient at least one selected from the group consisting of icosapentic acid, pharmaceutically acceptable salts and esters thereof.
- the pharmaceutical composition is preferably administered to the subject after completing the induction therapy for ANCA-related vasculitis.
- a pharmaceutical composition for treating chronic ANCA-related vasculitis comprising as an active ingredient at least one selected from the group consisting of icosapentic acid, pharmaceutically acceptable salts and esters thereof.
- Patients with chronic ANCA-related vasculitis and subjects after remission of acute symptoms of ANCA-related vasculitis may have negative or low ANCA antibody titers as described below.
- the embodiment in which the pharmaceutical composition of the present invention is administered to a subject with decreased renal function is preferred.
- An embodiment in which the pharmaceutical composition of the present invention is administered to a subject who has developed rapid progressive nephritis syndrome (RPGN) is also preferred.
- RPGN rapid progressive nephritis syndrome
- the aspect used together with aspirin is also preferable for the pharmaceutical composition of this invention.
- an ANCA-positive subject containing, as an active ingredient, at least one selected from the group consisting of icosapentic acid, pharmaceutically acceptable salts and esters thereof.
- a pharmaceutical composition for the prevention of rapid progressive nephritis syndrome (RPGN) that is administered.
- RPGN rapid progressive nephritis syndrome
- the present invention provides the following pharmaceutical composition and treatment method.
- a pharmaceutical composition for preventing / treating / suppressing recurrence of ANCA-related vasculitis in a subject comprising as an active ingredient at least one selected from the group consisting of icosapentic acid, pharmaceutically acceptable salts and esters thereof.
- the pharmaceutical composition is used to suppress ANCA production in the subject and / or to lower ANCA and / or to keep ANCA low or negative, (1) or (2 ).
- RPGN rapid progressive nephritis syndrome
- RPGN rapid progressive nephritis syndrome
- the subject is selected from the group consisting of reduced immunity, complications of infectious disease, elderly people, cancer-bearing patients, history of tuberculosis, not using steroid drugs, and not using immunosuppressants.
- the pharmaceutical composition according to any one of (1) to (16), wherein the pharmaceutical composition is administered for 6 months or more.
- the present invention also provides a method for preventing, treating, or suppressing recurrence of ANCA-related vasculitis using the pharmaceutical composition of the present invention.
- the subject is administered with at least one selected from the group consisting of icosapentic acid, pharmaceutically acceptable salts and esters thereof, and prevents, treats, or suppresses recurrence of ANCA-related vasculitis.
- Method. The subject is administered with at least one selected from the group consisting of icosapentic acid, pharmaceutically acceptable salts and esters thereof, suppresses the subject's ANCA production, and / or is negative for ANCA, or A method of maintaining a low value and / or reducing ANCA in ANCA positive subjects.
- the subject is a subject having an ANCA positive and / or ANCA antibody titer to which a corticosteroid is administered, and the dose of the corticosteroid is decreased at an early stage and / or early withdrawal.
- (23) Administer at least one selected from the group consisting of icosapentic acid, a pharmaceutically acceptable salt and ester thereof, to a subject having an ANCA positive and / or high ANCA antibody titer to which a corticosteroid is administered To reduce the dose of corticosteroids and / or withdraw early.
- (24) Provided is at least one use selected from the group consisting of icosapentic acid, pharmaceutically acceptable salts and esters thereof for the manufacture of a medicament for the prevention / treatment / recurrence suppression of ANCA-related vasculitis in a subject.
- (25) At least one selected from the group consisting of icosapentic acid, pharmaceutically acceptable salts and esters thereof for preventing / treating / suppressing recurrence of ANCA-related vasculitis in a subject.
- An ANCA production inhibitor containing, as an active ingredient, at least one selected from the group consisting of icosapentic acid, pharmaceutically acceptable salts and esters thereof.
- An ANCA lowering agent comprising as an active ingredient at least one selected from the group consisting of icosapentic acid, pharmaceutically acceptable salts and esters thereof.
- a therapeutic agent for vasculitis and a method of treatment are provided.
- it is useful as a relapse inhibitory agent, a chronic ANCA-related vasculitis therapeutic agent, and a preventive agent for ANCA-related vasculitis after remission of acute symptoms of ANCA-related vasculitis requiring long-term use of drugs.
- the pharmaceutical composition of the present invention exhibits a particularly excellent effect when used in combination with aspirin.
- mouth is shown.
- the test result about the influence of EPA on ANCA production in SCG / Kj mice is shown.
- 2 shows the evaluation results of PD-1, PD-L1, PD-L2, Foxp3, and CTLA4 mRNA expression levels in the kidneys of SCG / Kj mice.
- the evaluation results of the expression levels of PD-1, PD-L1, PD-L2, Foxp3, and CTLA4 mRNA in the spleen of SCG / Kj mice are shown.
- icosapentic acid is all-cis-5,8,11,14,17-icosapentaenoic acid.
- EPA in the present invention is used to mean not only icosapentic acid, but also pharmaceutically acceptable salts thereof, or EPA derivatives such as esters, amides, phospholipids, and glycerides.
- EPA-E icosapentic acid ethyl ester
- the EPA content ratio and dose in the total fatty acids in the pharmaceutical composition of the present invention are not particularly limited, but EPA is of high purity, for example, the EPA content ratio in total fatty acids and derivatives thereof. Is preferably 40% by mass or more, more preferably 90% by mass or more, and still more preferably 96.5% by mass or more.
- Epadale TM and Epadale STM (trade names, both manufactured by Mochida Pharmaceutical Co., Ltd.), which are marketed as therapeutic agents for obstructive arteriosclerosis and hyperlipidemia in Japan, are soft capsules containing high-purity EPA-E, The EPA-E content ratio in the total fatty acids is 96.5% by mass or more. These can be used for the pharmaceutical composition of the present invention.
- ANCA-related vasculitis is recognized by autoantibodies against neutrophil cytoplasm (anti-neutrophil cytoplasmic antibody: ANCA) in the serum, and is rapidly caused by necrotic or granulomatous vasculitis of small blood vessels and capillaries Progressive glomerulonephritis syndrome (RPGN) or pulmonary kidney syndrome with hematuria, chronic nephritis syndrome, and pulmonary findings (pulmonary hemorrhage, interstitial pneumonia). Those who have developed nephritis are also referred to as ANCA-associated nephritis.
- ANCA-related vasculitis is positive in one or more of C-ANCA and P-ANCA measured by the indirect fluorescent antibody method, and PR-3ANCA and MPO-ANCA measured by ELISA.
- ANCA is positive
- ANCA antibody titer exceeds the reference value
- ANCA is negative means that the ANCA antibody titer is within the reference value range.
- the reference value may vary depending on the diagnostic criteria, each facility, and the measurement method, it is not particularly limited, but in one example, for MPO-ANCA by ELISA method, less than 10 IU / mL is negative, and 10 IU / mL or more Is positive.
- the unit of ANCA measurement is not particularly limited, and EU, U / mL, etc. are also used.
- the pharmaceutical composition of the present invention is not particularly limited, but is effective for the following diseases, for example.
- C-ANCA, PR-3ANCA mainly related to vasculitis / nephritis (1) idiopathic (renal localized type), (2) Wegener's granulomatosis (WG), P-ANCA and MPO-ANCA are mainly related to vasculitis and nephritis (1) idiopathic (renal localized type), (2) microscopic polyangiitis (MPA), (3) Churg-Strauss syndrome (Allergic granulomatous vasculitis: AGA), (4) non-hypertensive scleroderma kidney crisis, (5) drug-induced (propylthiouracil, hydralazine, zylolic, anti-rheumatic agents, etc.), (6) silicosis-induced, It is preferably used for things resulting from special environmental / life factors.
- ANCA-associated vasculitis may present with rapid progressive glomerulonephritis syndrome (RPGN), chronic nephritis syndrome, and pulmonary kidney syndrome with pulmonary symptoms (pulmonary hemorrhage, interstitial pneumonia).
- RPGN rapid progressive glomerulonephritis syndrome
- chronic nephritis syndrome chronic nephritis syndrome
- pulmonary kidney syndrome with pulmonary symptoms (pulmonary hemorrhage, interstitial pneumonia).
- the pharmaceutical composition of the present invention is preferably used. Rapidly progressive glomerulonephritis is a clinical syndrome in which renal function deteriorates rapidly over a period of several weeks to several months, even among nephritis, but the pharmaceutical composition of the present invention is as described in this example, Effectiveness against autoimmune diseases in kidney disease is suggested, and particularly effective.
- the pharmaceutical composition of the present invention is, for example, a subject who developed rapid progressive glomerulonephritis syndrome (RPGN), and is a steroid pulse therapy, a corticosteroid, or a cyclophosphamide, or It is preferably used for suppressing recurrence of a subject after performing induction therapy such as plasma exchange.
- RPGN rapid progressive glomerulonephritis syndrome
- diseases that develop rapidly progressive glomerulonephritis syndrome (RPGN) include meniscal glomerulonephritis (anti-GBM antibody type, immune complex type, Pauci-immune type, mixed type, etc.), and meniscal formation.
- the pharmaceutical composition of the present invention can be expected to have a therapeutic effect on subjects who are positive for ANCA.
- the pharmaceutical composition of the present invention is preferably used for subjects with Pauci-immune type lupus nephritis or microscopic polyangiitis with a high ANCA positive rate.
- the pharmaceutical composition of the present invention can be used for the prevention of ANCA-related vasculitis.
- the use for the prevention of ANCA-related vasculitis refers to a period in which ANCA is negative, or ANCA is positive but no other symptoms (signs) are observed, and ANCA-related vasculitis cannot be diagnosed.
- ANCA-related vasculitis refers to medication.
- “prevention” refers to any one or more selected from suppressing, reducing or delaying the onset of a disease or symptom, or reducing the onset rate of the disease.
- ANCA antibody titers There are subjects with high ANCA antibody titers but no other physical symptoms (for example, symptoms associated with inflammation, vasculitis, etc.) and easily develop severe ANCA-related vasculitis due to some stimulus or infection There is a high possibility of In particular, when the ANCA antibody titer is extremely high, for example, active treatment by plasma exchange or the like is performed.
- the pharmaceutical composition of the present invention is administered to a subject with a high ANCA antibody titer but no other symptoms (signs), and by reducing ANCA, it is possible to fundamentally prevent the onset of ANCA-related vasculitis It becomes.
- one of the preferable embodiments of the pharmaceutical composition of the present invention is a composition for preventing ANCA-related vasculitis for a subject who has a high ANCA antibody titer but does not develop physical symptoms.
- one of the preferable aspects of the pharmaceutical composition of this invention is a pharmaceutical composition for reducing ANCA of the subject who is positive for ANCA but does not develop physical symptoms.
- “high ANCA antibody titer” is not limited because it varies depending on the measurement method. However, in the case of MPO-ANCA, it is 50 IU / mL or more, more preferably 100 IU / mL or more, and even more preferably 200 IU / mL or more. Particularly desirable is 500 IU / mL or more.
- the pharmaceutical composition of the present invention is preferably used for humans who are highly likely to develop ANCA-related vasculitis (genetic factors, administration of drugs that induce disease, environmental factors such as silicon), and the like. Prevent the onset of fire. Desirably, rapid progressive glomerulonephritis, chronic nephritis syndrome, pulmonary kidney syndrome and the like are prevented.
- the pharmaceutical composition of the present invention is administered to a subject having ANCA-related vasculitis during a period in which ANCA is positive and abnormal laboratory values or clinical symptoms of ANCA-related vasculitis are observed.
- ANCA ANCA-related vasculitis
- Abnormal laboratory values include, for example, increased red sediment, increased acute phase reactants (CRP, SAA, alpha2, beta globulin fraction, fibrinogen), leukocytosis, anemia, urinary occult blood, appearance of erythrocyte cast, appearance of urine protein And elevation of serum creatinine.
- CRP acute phase reactants
- SAA alpha2, beta globulin fraction, fibrinogen
- leukocytosis anemia
- urinary occult blood appearance of erythrocyte cast
- appearance of urine protein And elevation of serum creatinine.
- ANCA exceeds a normal value, and systemic symptoms (fever, weight loss, easy fatigue, etc.), rapid progressive glomerular syndrome (RPGN), pulmonary hemorrhage, interstitial pneumonia, It is administered to a subject who develops acute phase symptoms such as pulmonary kidney syndrome, and the symptoms are ameliorated or alleviated.
- Remission induction therapy for ANCA-related vasculitis is usually treated over 3-6 months by corticosteroids, steroid pulse therapy, immunosuppressive therapy with cyclophosphamide, plasma exchange, etc.
- the pharmaceutical composition can additionally be used for this treatment. It is also desirable to use aspirin in combination.
- the pharmaceutical composition of the present invention is, for example, a so-called refractory subject such as a subject who does not become negative of ANCA even after completing remission induction therapy, a subject whose ANCA becomes positive immediately and becomes unstable even if it is negative once. It is preferably used for a subject.
- ANCA immediately turns positive means that ANCA becomes negative within 1 year after becoming negative, but for example, within 6 months, within 3 months, within 1 month, within 10 days Including cases that turn to positive. Since it is thought that an effect
- one of the preferred embodiments of the pharmaceutical composition of the present invention is the implementation of remission induction therapy containing as an active ingredient at least one selected from the group consisting of icosapentic acid, pharmaceutically acceptable salts and esters thereof.
- a pharmaceutical composition for keeping ANCA negative or low in subjects who do not become ANCA negative after completion, or subjects who have ANCA negative but immediately turn positive in ANCA after completing remission induction therapy is there.
- a subject with chronic ANCA-related vasculitis who has a relatively low ANCA antibody titer and presents with chronic nephritis, chronic renal failure as a renal symptom, and pulmonary fibrosis as a pulmonary symptom, preferably for long-term treatment used.
- the pharmaceutical composition of the present invention can be used in remission maintenance (relapse suppression) therapy after completion of the induction therapy for ANCA-related vasculitis.
- ANCA-related vasculitis is likely to recur, and it is said that remission maintenance (relapse suppression) therapy is required for about 5 to 7 years after the initial treatment.
- the pharmaceutical composition of the present invention is preferably used as a recurrence inhibitor of ANCA-related vasculitis.
- the use as a recurrence inhibitor of ANCA-related vasculitis means that it is administered during the period after the completion of the induction therapy for ANCA-related vasculitis, and preferably the induction therapy is completed.
- “suppressing recurrence of ANCA-related vasculitis” means that the incidence of ANCA-related vasculitis is reduced in subjects who have completed the induction therapy for ANCA-related vasculitis, or ANCA-related vasculitis. Including delaying the onset of.
- ANCA is low
- the ANCA antibody titer is in the range of about 3 times the standard value.
- the reference value for MPO-ANCA is 10 IU / mL
- it is preferably administered to a subject of 30 IU / mL or less, more preferably 20 IU / mL or less.
- the pharmaceutical composition of the present invention desirably exhibits any effect of suppressing, reducing or delaying the recurrence of symptoms associated with ANCA-related vasculitis.
- One preferred embodiment of the pharmaceutical composition of the present invention is an induction therapy for ANCA-related vasculitis, comprising as an active ingredient at least one selected from the group consisting of icosapentic acid, pharmaceutically acceptable salts and esters thereof. It is a pharmaceutical composition for keeping ANCA negative or low, which is administered to a subject after completing the above.
- the pharmaceutical composition of the present invention may be used as a remission maintenance (relapse suppression) therapy after completing the induction therapy for ANCA-related vasculitis, such as a subject with poor immune status, such as an elderly person, a cancer-bearing patient, Suitable for long-term use for subjects with infectious diseases and those with a history of tuberculosis.
- the elderly is not particularly limited, but preferably refers to those 65 years of age or older using the standards of the World Health Organization (WHO) of the United Nations.
- WHO World Health Organization
- the pharmaceutical composition of the present invention is preferably used for a subject who has been negative for ANCA by remission induction therapy but tends to be positive for ANCA, for example.
- the pharmaceutical composition for prevention / treatment / recurrence suppression of ANCA-related vasculitis is preferably administered to an ANCA-positive subject and / or a subject with a high ANCA antibody titer to suppress ANCA production in the subject.
- / or lower ANCA and / or keep ANCA low or negative are desirable to keep the subject's ANCA low or negative for a long period of time by administering to the subject the pharmaceutical composition of the present invention, where the long term is at least 6 months or more, preferably 1 year or more, More preferably, it is 3 years or more, More preferably, it is 5 years or more, Especially preferably, it is 7 years or more.
- the pharmaceutical composition of the present invention induces regulatory T cells in ANCA model animals, particularly in the kidney, and participates in an autoimmune regulatory mechanism.
- the number of regulatory T cells and / or Or it is preferably used for a subject whose function is reduced.
- the decrease in the number or function of regulatory T cells may be determined, for example, by comparison with the average value of healthy subjects, or may be determined by comparison with, for example, past numerical values of the subject.
- regulatory T cells have been reported to suppress CD80 and CD86 (Proc Natl Acad Sci USA 2008 Jul 22; 105 (29): 10113-8. Onishi et al.). CD80 and CD86 are known as co-stimulatory molecules for antigen-presenting cells.
- the pharmaceutical composition of the present invention includes, for example, a subject in which expression of CD80 and / or CD86 is increased (up-regulated), or antigen-presenting cells present in, for example, peripheral blood or lymphoid tissues such as lymph nodes and spleen
- the above CD80 / CD86 expression is preferably used for subjects whose expression is enhanced as compared with healthy subjects, and an effect of controlling excessive autoimmunity by suppressing enhanced CD80 and CD86 can be expected.
- CD80 and / or CD86 up-regulation may be determined by comparison with the average value of healthy subjects, or may be determined by comparison with the past numerical values of the subject, for example. .
- the pharmaceutical composition of the present invention may be used in combination with conventional corticosteroids such as oral corticosteroids, azathioprine, cyclosporine, mizoribine, etc., but the pharmaceutical composition of the present invention directly increases the ANCA antibody titer. Because it has a reducing effect, it is possible to reduce or discontinue the dose of other drugs. For example, it is also desirable to discontinue the immunosuppressant, set a low dose of oral corticosteroids, or discontinue.
- conventional corticosteroids such as oral corticosteroids, azathioprine, cyclosporine, mizoribine, etc.
- the dosage and administration period of the EPA used for the pharmaceutical composition or therapeutic agent of the present invention are an amount and a period sufficient to exhibit the intended effect, but its dosage form, administration method, number of administrations per day
- the dosage may be adjusted according to the degree of symptoms, weight, age, etc.
- EPA-E is 0.1 to 10 g / day, preferably 0.3 to 6 g / day, more preferably 0.6 to 4 g / day, still more preferably 0.9 to 2.
- 7 g / day is administered in 1 to 3 divided doses, the total amount may be administered once or in several divided doses as necessary.
- the amount is preferably 1.8 to 2.7 g / day, particularly preferably 2.4 g. It is also possible to reduce the dose according to the dose of other drugs.
- the administration time is preferably during or after meals, more preferably immediately after meals (within 30 minutes).
- the administration period is not particularly limited, but for example, 6 months or more, 1 year or more, preferably 2 years or more, more preferably 3.5 years or more, more preferably 5 years or more, especially Preferably, it is 7 years or more, but the state of high risk of developing and / or recurrence of ANCA-related vasculitis continues while the pathological condition or biochemical index related to ANCA-related vasculitis continues. It is desirable to continue administration during this period. In addition, for example, administration every other day, administration for 2-3 days per week, and in some cases, a drug holiday of about 1 day to 3 months, preferably about 1 week to 1 month, can be provided.
- fatty acids contained in the pharmaceutical composition of the present invention include ⁇ 3 polyunsaturated fatty acids other than EPA such as docosahexaenoic acid, docosapentaenoic acid, and ⁇ -linolenic acid, and their pharmaceutically acceptable products.
- docosahexaenoic acid ethyl ester hereinafter referred to as DHA-E.
- EPA-E + DHA-E is highly pure, for example, the content ratio of EPA-E + DHA-E in all fatty acids and derivatives thereof is preferably 40% by mass or more, and 80% by mass or more Is more preferable, and 90% by mass or more is more preferable.
- the daily dosage is 0.3 to 20 g / day, preferably 0.5 to 12 g / day, more preferably 1 to 8 g / day as EPA-E + DHA-E.
- Other preferred daily doses are exemplified by 0.3-6 g / day, 0.3-4 g / day, and 0.3-1 g / day.
- the content of other long-chain saturated fatty acids is preferably low, and even long-chain unsaturated fatty acids are desired to have a low ⁇ 6 type, particularly arachidonic acid content, preferably less than 2% by mass, and more preferably less than 1% by mass.
- a commercial preparation containing EPA-E and DHA-E for example, a soft capsule containing about 46% by mass of EPA-E and about 38% by mass of DHA-E (Lovaza, Lovaza TM (Reliant; Reliant; Pronova, Pronova), etc. are marketed in the United States, Europe, etc. for the indication of anti-TG treatment. These can be used for the pharmaceutical composition of the present invention.
- the pharmaceutical composition for ANCA-related vasculitis of the present invention can be prepared by administering the compound (which may contain other components inevitably contained during purification), or a suitable carrier or vehicle generally used.
- Additives include, for example, lactose, partially pregelatinized starch, hydroxypropylcellulose, macrogol, tocopherol, hydrogenated oil, sucrose fatty acid ester, hydroxypropylmethylcellulose, titanium oxide, talc, dimethylpolysiloxane, silicon dioxide, carnauba wax, etc. sell.
- antioxidants such as butyrated hydroxytoluene, breached hydroxyanisole, propyl gallate, gallic acid, pharmaceutically acceptable quinones and ⁇ -tocopherol It is desirable to contain an effective amount of at least one selected as an antioxidant.
- the dosage form of the formulation varies depending on the combined form of the active ingredient of the present invention and is not particularly limited.
- oral formulations include tablets, film-coated tablets, capsules, microcapsules, granules, fine granules,
- oral liquid preparations, syrups, jellies, inhalants parenteral preparations include, for example, ointments, suppositories, injections (emulsifying, suspending, non-aqueous) or milk for use. It is a topical preparation such as a solid injection, infusion preparation, transdermal absorption agent, etc.
- a simple oral formulation is desirable, especially in capsules such as soft capsules and microcapsules, or in tablets and film-coated tablets. Masui.
- it may be orally administered as an enteric preparation or sustained-release preparation, and it is also preferable to orally administer as a jelly agent to dialysis patients or subjects who have difficulty swallowing.
- the pharmaceutical composition and the treatment method of the present invention may be used in combination with other drugs or treatment methods.
- Concomitant use with other drugs means administration as a combination drug containing both EPA-E and other drugs, and separate preparations of EPA-E and other drugs at the same time or with a time difference. To be administered.
- Other drugs in the present invention are not particularly limited, but preferably do not diminish the effects of the present invention.
- corticosteroids methylprednisolone pulse therapy, oral prednisolone, etc.
- immunosuppressants cyclophosphamide in large quantities
- Intravenous therapy oral cyclophosphamide, methotrexate, mizoribine, etc.
- immunoglobulin azathioprine, TNF ⁇ inhibitor (infliximab, etanercept, etc.)
- anti-IL-5 antibody SCH55700
- anti-IgE antibody omalizumab
- antibiotics examples include antibacterial agents (such as ST mixtures).
- a PPAR ⁇ agonist may be mentioned as one of other preferable drugs to be used in combination.
- the combined use of the pharmaceutical composition of the present invention and a PPAR ⁇ agonist can be expected to have a synergistic effect on the regulation of excessive autoimmunity associated with ANCA-related vasculitis.
- the PPAR ⁇ agonist is not particularly limited, and examples thereof include thiazolidinedione derivatives (such as pioglitazone hydrochloride and rosiglitazone maleate) and angiotensin receptor blockers (such as ARB: telmisartan).
- anticoagulant therapy (warfarin), vasodilator (prostaglandin preparation), antiplatelet agent (dipyridamole, etc.) may be used for vascular stenosis and thrombus formation.
- the pharmaceutical composition has a direct action on ANCA, which is not found in these drugs, and may act to regulate autoimmunity, and is useful as a fundamental therapeutic agent for ANCA-related vasculitis. High nature.
- One of the preferred embodiments of the pharmaceutical composition and treatment method of the present invention is the combined use of EPA-E and aspirin.
- the preferred dosage and administration of EPA-E are as described above.
- the usage / dose of aspirin is not particularly limited. For example, it can be administered at 50 to 200 mg / day, preferably 100 mg / day.
- Aspirin is commercially available, for example, Biaspirin (registered trademark): (Bayer Pharmaceutical Co., Ltd.).
- EPA exerts a very significant effect on ANCA vasculitis when used in combination with aspirin. Easy to use because it has fewer side effects than steroids and immunosuppressants.
- combination therapy with EPA and aspirin exerts the surprising effect of restoring reduced renal function. Recovery of renal function can be confirmed by various tests such as a decrease in creatinine level.
- One of the preferred embodiments of the pharmaceutical composition and treatment method of the invention is the combined use of EPA-E and oral corticosteroid.
- the usage / dose of the corticosteroid is not particularly limited, but the dose of the corticosteroid can be set low due to the effect of the pharmaceutical composition of the present invention.
- the low-dose corticosteroid refers to, for example, 20 mg / day or less, preferably 15 mg / day or less, more preferably 10 mg / day or less, still more preferably 5 mg / day or less, and particularly preferably 2.5 mg. / Day or less may be set.
- the administration of corticosteroids has the side effect that arteriosclerosis is likely to occur, but the pharmaceutical composition of the present invention preferably has an advantageous effect of suppressing the progress of arteriosclerosis, preferably in combination with aspirin. .
- the second aspect of the present invention is a method for preventing, treating, or preventing recurrence of ANCA-related vasculitis using the pharmaceutical composition of the present invention. That is, it is a method for preventing / treating / relapses of ANCA-related vasculitis, in which at least one selected from the group consisting of icosapentic acid, pharmaceutically acceptable salts and esters thereof is administered to a subject.
- the method of the present invention desirably suppresses ANCA production in a subject and / or keeps ANCA negative or low and / or reduces ANCA in a subject positive for ANCA.
- the method of the present invention is preferably performed by administering the subject pharmaceutical composition of the present invention to at least 6 months, preferably 1 year or more, more preferably 3 years or more, and even more preferably 5 years or more. Particularly preferred is a method of keeping the subject's ANCA low or negative for more than 7 years.
- the subject to be targeted in the prevention method of the present invention is preferably a subject who is negative for ANCA or a subject who is positive for ANCA but has no other clinical symptoms and cannot be diagnosed with ANCA-related vasculitis.
- subjects are highly likely to develop ANCA-related vasculitis (genetic factors, taking drugs that induce disease, environmental factors such as exposure to silicon, etc.), and preferably, renal examination, genetic
- the subject is highly likely to develop kidney disease due to factors.
- the usage, dosage and dosing period are in accordance with the first aspect of the invention.
- the subject's ANCA is kept negative or low, or even if ANCA is positive, the clinical symptoms associated with ANCA-related vasculitis, rapidly progressive glomerulonephritis, or the development of pulmonary kidney syndrome are suppressed, It is administered for either reducing or delaying purposes.
- One of the preferred embodiments of the prevention method of the present invention is that at least selected from the group consisting of icosapentic acid, pharmaceutically acceptable salts and esters thereof for subjects who are positive for ANCA but have not developed physical symptoms.
- One is a method of reducing the incidence of ANCA-related vasculitis.
- the test subject used in the treatment method of the present invention is a test subject who is positive for ANCA and has clinical values associated with abnormal test values and ANCA-related vasculitis.
- the usage, dosage, and dosing period are not particularly limited according to the first aspect of the present invention, but one desirable treatment method is, for example, ANCA-related vasculitis and rapidly developing glomerulonephritis
- ANCA-related vasculitis and rapidly developing glomerulonephritis
- the administration of the pharmaceutical composition of the present invention is started to switch the therapeutic agent, and there is a risk of recurrence. The method of continuing dosing until it disappears is mentioned.
- a method of administering the pharmaceutical composition of the present invention to a subject who does not become negative of ANCA even after the completion of remission induction therapy is preferable. That is, one of the preferred embodiments of the treatment method of the present invention is a subject in which ANCA does not become negative after completing the induction therapy for ANCA-related vasculitis, or ANCA becomes negative after completing the induction therapy.
- a method for maintaining ANCA in a subject at a negative or low level comprising administering at least one selected from the group consisting of icosapentic acid, a pharmaceutically acceptable salt and ester thereof to a subject who immediately becomes positive for ANCA. It is.
- the subject to be targeted in the method for suppressing recurrence of the present invention is a subject after the completion of the induction therapy for ANCA-related vasculitis, preferably a subject whose ANCA is negative or low.
- the usage, dose, and dosing period are not particularly limited according to the first aspect of the present invention, but the dosing period is particularly long, for example, 1 year or more, preferably 3 years or more, more preferably 5 years or more. It is desirable.
- EPA-E EPA-E is used for subjects who have become negative for ANCA or subjects who have become negative for CRP.
- Steroid pulse therapy is a treatment method in which a steroid is administered intensively for a short period of time and then a drug holiday is provided.
- methylprednisolone 500-1000 mg / day may be administered continuously for 3-4 days and repeated every 1-3 weeks while observing the therapeutic effect.
- corticosteroids are often administered, starting from about 40 mg, gradually reducing the dose and maintaining about 10 mg for about 1 to 2 years.
- the amount of the corticosteroid can be reduced at a relatively fast pace (for example, up to about 5 mg in half a year), so that it is also effective as a method for early withdrawal of the corticosteroid. It is.
- one of the preferred methods of the present invention is to administer EPA-E and aspirin to a subject who has received remission induction therapy for ANCA-related vasculitis and is administered a corticosteroid,
- it is a method for suppressing recurrence of ANCA-related vasculitis by gradually reducing the dose to about 5 mg within one year.
- the corticosteroid dose is reduced to, for example, about 5 mg within 6 months, more preferably within 3 months.
- One of the preferable methods of the present invention is selected from the group consisting of icosapentic acid, pharmaceutically acceptable salts and esters thereof for ANCA positive and / or high antibody titers administered with corticosteroids.
- a method of reducing the dose of corticosteroids at an early stage and / or a method for early withdrawal is not particularly limited, but it is preferably 5 mg or less, more preferably 3 mg or less, still more preferably 1 mg or less, and particularly preferably 0.5 mg or less. Desirably, the dose of corticosteroids should be gradually reduced, and finally the corticosteroids should be stopped.
- EPA-E for example, 1.8 to 2.7 g / day
- aspirin for example, 50 to 100 mg
- Aspirin may be 150 to 200 mg according to the symptoms of the subject. In this case, it may also be desirable to use a low dose corticosteroid.
- corticosteroids for example, corticosteroids, immunosuppressive agents, aspirin, etc.
- aspirin for example, it is desirable to administer corticosteroids, immunosuppressive agents, aspirin, etc. in a short period of time when the condition of the subject deteriorates for some reason during treatment with the pharmaceutical composition of the present invention.
- Example 1 ANCA model Effect of EPA on survival rate of SCG / Kj mice ⁇ Method> SCG / Kj mice (7-week-old) (Nippon Kayaku Co., Ltd.), a spontaneous model of ANCA vasculitis / nephritis, were divided into 3 groups of 6-7 mice per group, and (1) Fish meal-free feed F1 (Funakoshi Co., Ltd.
- control group (2) 5% corn oil mixed diet (manufactured by Sigma) (corn oil group), (3) 5% EPA-E mixed diet (EPA-E to be 5% in F1) (EPA group), each was reared by free feeding and the survival rate was observed.
- Example 2 Effect of EPA on ANCA production in SCG / Kj mice ⁇ Method> Three groups of SCG / Kj mice (7 weeks old) were divided into 3 groups of 6 to 7 animals per group, and were raised to 11 weeks of age under the same conditions as in Example 1. In five groups of B6 mice (2 mice) and SCG / Kj mice (3 mice at 15 weeks of age), the absorbance of MPO-ANCA in the serum was measured by ELISA. MPO-ANCA antibody titers were measured according to previously reported methods. (Ishida-Okawara A, Ito-Ihara T, Muso E et al. Neutrophil contribution to the crescentic glomerulonephritis in SCG / Kj mice.
- Example 3 Evaluation of PD-1, PD-L1, PD-L2, Foxp3, and CTLA4 mRNA expression levels in kidney, lung and spleen of SCG / Kj mice ⁇ Method> Three groups of SCG / Kj mice (7 weeks old) were divided into 3 groups of 6 to 7 animals per group, and were raised to 11 weeks of age under the same conditions as in Example 1, and PD-1 in the kidney, lung and spleen PD-L1, PD-L2, Foxp3, and CTLA4 mRNA expression levels were evaluated. Frozen kidneys were homogenized in TRIzol® reagent (Invitrogen, Carlsbad, Calif.).
- Total RNA was prepared from the homogenate and purified using the PureLink Micro-to-Midi Total RNA Purification System (Invitrogen). CDNA was prepared from the purified total RNA using the SuperScript TM III first-strand synthesis system (Invitrogen), and quantitative real-time PCR using ABI Prism (registered trademark) 7000 (Applied Biosystems, Foster City, Calif.) Was performed. TaqMan (registered trademark) gene expression assays (Applied Biosystems) were used as PCR primers and probes.
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Abstract
Description
ANCA力価が高く、RPGN、肺出血などを認める急性型のANCA関連血管炎の症例には、初期寛解導入療法として、血漿交換、大量の副腎皮質ステロイド薬の使用、シクロホスファミドを中心とする免疫抑制療法などが行われる。その後、疾患活動が軽快し、ANCA力価が低下した後も、ANCA関連血管炎は再発することが多いため、寛解維持療法として、投薬量を調節してステロイド薬やシクロホスファミドなどの免疫抑制剤が投与される。再発時療法は初期寛解導入療法に準じた治療方法がとられる。
ANCA抗体価を抑制し、根本的なANCA関連血管炎の治療薬として、特に、長期的な使用が必要とされる寛解維持(再発抑制)療法において、免疫の低下した被験者、感染症を合併した被験者でも長期に使用でき、ANCA関連血管炎の再発を抑制することができる薬剤はこれまで知られておらず、新たな治療方法の策定が切望されている。
ステロイドや免疫抑制剤等、従来のANCA低下療法が抱える問題点を克服する、副作用が少なく、広い範囲の被験者に安心して使用できる、ANCA産生を抑制する薬剤、及び、治療方法を提供することである。
また、モデル動物の各臓器における遺伝子レベルの解析(Foxp3,PD-1,PD-L1,L2,CTLA4)から、EPAが特に腎臓において過剰な自己免疫に対して抑制的に作用する可能性が示唆された。
これらのことから、EPAは、ANCA産生を抑制するというANCA関連血管炎に対する直接的な作用と自己免疫を調整する作用とを併せ持ち、特に、長期的な使用が必要なANCA関連血管炎の急性期症状が寛解した後の被験者の寛解維持(再発抑制)に適することが分かり、本発明を完成した。
1つの態様例として、イコサペント酸、その製薬学上許容しうる塩及びエステルからなる群から選ばれる少なくとも1つを有効成分として含有する、ANCA関連血管炎の再発抑制用医薬組成物を提供する。
この態様において、医薬組成物が、ANCA関連血管炎の寛解導入療法の実施を終えた後の被験者に投与されることが好ましい。
慢性型ANCA関連血管炎患者およびANCA関連血管炎の急性期症状が寛解した後の被験者は、後述するようなANCA抗体価が陰性または低値を示すことがある。
本発明の医薬組成物は、急速性進行性腎炎症候群(RPGN)を発症した被験者に投与される態様も好ましい。
また、本発明の医薬組成物は、アスピリンと併用される態様も好ましい。
具体的に、本発明では、以下のような医薬組成物、及び治療方法が提供される。
(2)前記被験者が、ANCA陽性、及び/又はANCA抗体価が高い被験者である、(1)に記載の医薬組成物。
(3)前記医薬組成物が、前記被験者のANCA産生を抑制する、及び/又は、ANCAを低下させる、及び/又は、ANCAを低値若しくは陰性に保つために用いられる、(1)又は(2)に記載の医薬組成物。
(5)前記被験者が、寛解導入療法の実施を終えた後にANCAが陰性化しない被験者、又は、寛解導入療法の実施を終えた後にANCAが陰性化したがすぐにANCAが陽性に転じる被験者である、(4)に記載の医薬組成物。
(6)前記被験者が、副腎皮質ステロイド薬が投与される、ANCA陽性及び/又はANCA抗体価が高い被験者である、(1)ないし(5)のいずれかに記載の医薬組成物。
(7)前記医薬組成物が、副腎皮質ステロイド薬の用量を早期に低下させる、及び/又は、副腎皮質ステロイド薬を早期に離脱するために用いられる、(6)に記載の医薬組成物。
(8)前記被験者が、腎機能の低下した被験者である、(1)ないし(7)のいずれかに記載の医薬組成物。
(9)前記被験者が、慢性型ANCA関連血管炎を発症する被験者である、(1)ないし(8)のいずれかに記載の医薬組成物。
(10)前記被験者が、急速性進行性腎炎症候群(RPGN)を発症した経歴のある被験者である、(1)ないし(9)のいずれかに記載の医薬組成物。
(12)前記医薬組成物が、急速進行性腎炎症候群(RPGN)の予防のために投与される、(1)ないし(11)のいずれかに記載の医薬組成物。
(13)前記被験者が、ANCA関連血管炎発症の可能性が高い被験者である、(1)ないし(12)のいずれかに記載の医薬組成物。
(15)前記被験者が、制御性T細胞の数、及び/又は機能が低下している被験者である、(1)ないし(14)のいずれかに記載の医薬組成物。
(16)前記被験者が、抗原提示細胞上のCD80及び/又はCD86の発現が亢進している被験者である、(1)ないし(15)のいずれかに記載の医薬組成物。
(17)前記医薬組成物が、6ヶ月以上投与される、(1)ないし(16)のいずれかに記載の医薬組成物。
(18)前記医薬組成物が、アスピリンと併用される、(1)ないし(17)のいずれかに記載の医薬組成物。
(19)前記医薬組成物が、PPARγ作用薬と併用される、(1)ないし(18)のいずれかに記載の医薬組成物。
(20)すなわち、被験者に対して、イコサペント酸、その製薬学上許容しうる塩及びエステルからなる群から選ばれる少なくとも1つを投与する、ANCA関連血管炎を予防、治療、又は再発を抑制する方法。
(21)被験者に対して、イコサペント酸、その製薬学上許容しうる塩及びエステルからなる群から選ばれる少なくとも1つを投与する、被験者のANCA産生を抑制する、及び/又は、ANCAを陰性若しくは低値に保つ、及び/又は、ANCA陽性の被験者のANCAを低下させる方法。
(22)前記被験者が、副腎皮質ステロイド薬が投与されるANCA陽性及び/又はANCA抗体価が高い被験者であって、副腎皮質ステロイド薬を早期に用量を低下させる、及び/又は早期に離脱するために用いられる、(20)又は(21)に記載のANCA関連血管炎を予防、治療、又は再発を抑制する方法。
(23)副腎皮質ステロイド薬が投与されるANCA陽性及び/又はANCA抗体価が高い被験者に対して、イコサペント酸、その製薬学上許容しうる塩及びエステルからなる群から選ばれる少なくとも1つを投与する、副腎皮質ステロイド薬を早期に用量を低下させる、及び/又は早期に離脱する方法。
(24)被験者のANCA関連血管炎予防・治療/再発抑制用医薬製造のためのイコサペント酸、その製薬学上許容しうる塩及びエステルからなる群から選ばれる少なくとも1つの使用を提供する。
(25)被験者のANCA関連血管炎を予防・治療/再発抑制するための、イコサペント酸、その製薬学上許容しうる塩及びエステルからなる群から選ばれる少なくとも1つ。
(26)イコサペント酸、その製薬学上許容しうる塩及びエステルからなる群から選ばれる少なくとも1つを有効成分として含有する、ANCA産生抑制剤を提供する。
(27)イコサペント酸、その製薬学上許容しうる塩及びエステルからなる群から選ばれる少なくとも1つを有効成分として含有する、ANCA低下剤を提供する。
また、本発明の医薬組成物は、アスピリンと併用した場合に、特に優れた効果を発揮する。
本発明の第1の態様は、イコサペント酸、その製薬学上許容しうる塩及びエステルからなる群から選ばれる少なくとも1つを有効成分として含有する、ANCA関連血管炎の予防・治療/又は再発抑制用の医薬組成物である。
「イコサペント酸」の語は、全-シス-5,8,11,14,17-イコサペント酸(all-cis-5,8,11,14,17-icosapentaenoic acid)である。本発明における「EPA」の語は、特に断らない限りは、イコサペント酸だけでなく、その製薬上許容される塩、あるいはエステル、アミド、リン脂質、グリセリドなどのEPA誘導体も含む意味で用いられる。これらは全て本発明の医薬組成物の有効成分として使用可能であるが、とりわけ本発明の医薬組成物の有効成分としては「イコサペント酸エチルエステル(以下、EPA-Eと記す)」が望ましい。
本発明において「ANCAが陽性である」とは、ANCA抗体価が基準値を超えることをいい、逆に「ANCAが陰性である」とは、ANCA抗体価が基準値範囲内であることをいう。基準値は診断基準や各施設、測定方法によって異なる可能性があるため、特に制限されるわけではないが、一例では、ELISA法によるMPO-ANCAについて10IU/mL未満を陰性とし、10IU/mL以上を陽性とする。また、本発明においてはANCA測定の単位も特に限定されず、EU,U/mLなども用いられる。
C-ANCA、PR-3ANCAが主に関連する血管炎・腎炎の(1)特発性(腎限局型)、(2)ウェゲナー肉芽腫症(Wegener’s granulomatosis:WG)、
P-ANCA、MPO-ANCAが主に関連する血管炎・腎炎の(1)特発性(腎限局型)、(2)顕微鏡的多発動脈炎(microscopic polyangiitis:MPA)、(3)Churg-Strauss症候群(アレルギー性肉芽腫性血管炎:AGA)、(4)非高血圧型強皮症腎クリーシス、(5)薬剤誘発型(propylthiouracil、ヒドララジン、ザイロリック、抗リウマチ剤など)、(6)珪肺誘発性、特殊な環境・生活因子に起因するもの、などに好ましく用いられる。
急速進行性糸球体腎炎症候群(RPGN)を発症する疾患としては、例えば、半月体形成性糸球体腎炎(抗GBM抗体型、免疫複合体型、Pauci-immune型、混合型など)、半月体形成を伴う糸球体腎炎(膜性増殖性糸球体腎炎、膜性腎症、IgA腎症、非IgA型メサンギウム増殖性糸球体腎炎など)、全身型(Goodpasture症候群、全身性エリテマトーデス、Wegener肉芽腫、顕微鏡的多発血管炎、慢性関節リウマチ、悪性腫瘍など)が挙げられるが、本発明の医薬組成物はANCAが陽性である被験者への治療効果が期待できる。本発明の医薬組成物は、好ましくは、ANCA陽性率の高いPauci-immune型半月体形成性糸球体腎炎、あるいは、顕微鏡的多発血管炎の被験者に用いられる。
本発明においてANCA関連血管炎の予防のための使用とは、ANCAが陰性である、又は、ANCAが陽性であるがその他の症状(兆候)が見られず、ANCA関連血管炎と診断できない期間の投薬をいう。
本発明において「予防」とは、疾患または症状の発症を抑制、軽減、若しくは遅延させる、又は疾患の発症率を低下させる、から選択されるいずれか1以上をいう。
ANCA抗体価は高いが、その他の身体症状(例えば、炎症、血管炎に伴う症状など)が発症していない被験者が存在し、何らかの刺激や感染などによって容易に重篤なANCA関連血管炎を発症する可能性が高い。中でもANCA抗体価が極めて高い場合には、例えば、血漿交換などによる積極的な治療がなされている。本発明の医薬組成物は、ANCA抗体価が高いがその他の症状(兆候)が見られない被験者に対して投与され、ANCAを低下させることにより、ANCA関連血管炎発症の根本的な予防が可能となる。すなわち、本発明の医薬組成物の好ましい態様のひとつは、ANCA抗体価は高いが身体症状を発症していない被験者のためのANCA関連血管炎予防用組成物である。
また、本発明の医薬組成物の好ましい態様のひとつは、ANCAは陽性であるが身体症状を発症していない被験者の、ANCAを低下させるための医薬組成物である。
検査値異常とは、例えば、赤沈亢進、急性相反応物質(CRP、SAA、alpha2、betaグロブリン分画、フィブリノーゲン)の増加、白血球増多、貧血、尿潜血、赤血球円柱の出現、尿蛋白の出現、血清クレアチニンの上昇などが挙げられる。
ANCA関連血管炎の寛解導入療法は、通常、副腎皮質ステロイド薬、ステロイドパルス療法、シクロホスファミドによる免疫抑制療法、血漿交換などにより3~6ヶ月間をかけて治療されるが、本発明の医薬組成物は、この治療に追加的に使用できる。アスピリンを併用することも望ましい。
本発明の医薬組成物は、例えば、寛解導入療法の実施を終えた後にもANCAが陰性化しない被験者、一度陰性化してもすぐにANCAが陽性転じて状態の安定しない被験者、などいわゆる難治性の被験者に対して好ましく用いられる。本発明において「すぐにANCAが陽性に転じる」とは、ANCAが陰性化した後1年以内に陽性に転じることをいうが、例えば、6ヶ月以内、3ヶ月以内、1ヶ月以内、10日以内に陽性に転じる場合を含む。従来のANCAを低下させる薬剤とは異なる機序で作用を発揮すると考えられるため、治療のバリエーションのひとつとして有用である。
すなわち、本発明の医薬組成物の好ましい態様のひとつは、イコサペント酸、その製薬学上許容しうる塩及びエステルからなる群から選ばれる少なくとも1つを有効成分として含有する、寛解導入療法の実施を終えた後にANCAが陰性化しない被験者、又は、寛解導入療法の実施を終えた後にANCAが陰性化したがすぐにANCAが陽性転じる被験者の、ANCAを陰性又は低値に保つための医薬組成物である。
本発明の医薬組成物は、ANCA関連血管炎に伴う症状の再発を抑制、軽減、又は遅延させる、のいずれかの効果を発揮することが望ましい。
本発明の医薬組成物の好ましい態様のひとつは、イコサペント酸、その製薬学上許容しうる塩及びエステルからなる群から選ばれる少なくとも1つを有効成分として含有する、ANCA関連血管炎の寛解導入療法の実施を終えた後の被験者に投与される、ANCAを陰性又は低値に保つための医薬組成物である。
また、本発明の医薬組成物は、例えば、寛解導入療法によりANCAは陰性化したが、ANCAが陽性化する傾向のある被験者に対して好ましく用いられる。
また、制御性T細胞は、CD80,CD86を抑制することが報告されている(Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10113-8.Onishiら)。CD80,CD86は、抗原提示細胞の補助刺激分子として知られており、これらを抑制することにより、過剰な自己免疫を制御し、自己免疫疾患を治療できる可能性がある。本発明の医薬組成物は、例えば、CD80及び/又はCD86の発現が亢進(アップレギュレート)している被験者、あるいは、例えば、末梢血あるいはリンパ節や脾臓などのリンパ組織に存在する抗原提示細胞上のCD80/CD86の発現が健常者と比較して亢進している被験者に対して好ましく用いられ、亢進したCD80,CD86を抑制して過剰な自己免疫を制御する効果が期待できる。ここで、CD80及び/又はCD86の発現亢進(アップレギュレート)は、健常者の平均値と比較して判断されてもよく、また例えば、被験者の過去の数値と比較して判断されてもよい。
経口投与する場合は、例えばEPA-Eとして0.1~10g/日、好ましくは0.3~6g/日、よりに好ましくは0.6~4g/日、さらに好ましくは0.9~2.7g/日を1ないし3回に分けて投与するが、必要に応じて全量を1回あるいは数回に分けて投与してもよい。好ましくは、1.8~2.7g/日、とりわけ好ましくは、2.4gである。また、他の薬剤の投与量に応じて減量することも可能である。投与時間は食中ないし食後が好ましく、食直後(30分以内)投与が更に好ましい。
本発明の効果が得られればEPA-E/DHA-Eの組成比、全脂肪酸中のEPA-EおよびDHA-E(以下、EPA-E+DHA-E)の含量比およびEPA-E+DHA-Eの投与量は特に問わないが、EPA-E+DHA-Eは高純度のもの、例えば、全脂肪酸およびその誘導体中のEPA-E+DHA-E含量比が40質量%以上のものが好ましく、80質量%以上のものが更に好ましく、90質量%以上のものが更に好ましい。
本発明における他の薬剤は、特に限定されないが、本発明の効果を減弱しないことが好ましく、例えば、副腎皮質ステロイド薬(メチルプレドニゾロンパルス療法、経口プレドニゾロンなど)、免疫抑制剤(シクロホスファミド大量静注療法、経口シクロホスファミド、メソトレキセート、ミゾリビンなど)、免疫グロブリン、アザチオプリン、TNFα阻害剤(インフリキシマブ、エタネルセプトなど)、抗IL-5抗体(SCH55700)、抗IgE抗体(omalizumab)、抗生物質、抗菌剤(ST合剤など)などが例示される。また、PPARγ作用薬が制御性T細胞を誘導することが報告されているから、併用されるのに好ましい他の薬剤のひとつとして、PPARγ作用薬が挙げられる。本発明の医薬組成物とPPARγ作用薬の併用により、ANCA関連血管炎に関連する過剰な自己免疫の調節について相乗的な効果が期待できる。PPARγ作用薬は、特に限定されないが、例えば、チアゾリジンジオン誘導体(ピオグリタゾン塩酸塩、マレイン酸ロシグリタゾンなど)、アンジオテンシン受容体ブロッカー(ARB:テルミサルタンなど)が例示できる。
副腎皮質ステロイド薬を投与すると、動脈硬化を起こしやすいという副作用があるが、本願発明の医薬組成物は、好ましくはアスピリンと併用とともに用いて、この動脈硬化の進展を抑制するという有利な効果を有する。
本発明の方法により、望ましくは、被験者のANCA産生を抑制する、及び/又は、ANCAを陰性若しくは低値に保つ、及び/又は、ANCA陽性の被験者のANCAを低下させる。本発明の方法は、被験者に対して、本願発明の医薬組成物を投与することにより、好ましくは、少なくとも6ヶ月以上、好ましくは1年以上、より好ましくは3年以上、さらに好ましくは5年以上、とりわけ好ましくは7年以上、被験者のANCAを低値又は陰性に保つ方法である。
本発明の予防方法において対象とする被験者は、好ましくは、ANCAが陰性である被験者、又は、ANCAが陽性であるがその他の臨床症状が見られず、ANCA関連血管炎と診断できない被験者である。好ましくは、ANCA関連血管炎発症の可能性が高い被験者(遺伝的要因、疾患を誘発する薬剤の服用、珪素への暴露などの環境因子など)であり、また、好ましくは、腎臓検査、遺伝的要因などから、腎臓疾患を発症する可能性の高い被験者である。
用法、用量、投薬期間は、本発明の第1の態様に従う。
望ましくは、被験者のANCAを陰性若しくは低値に保つ、又は、ANCAが陽性であっても、ANCA関連血管炎に伴う臨床症状、急速進行性糸球体腎炎、又は、肺腎症候群の発症を抑制、軽減、又は遅延させる、のいずれかの目的で投与される。
本発明の予防方法の好ましい態様のひとつは、ANCAは陽性であるが身体症状を発症していない被験者に対して、イコサペント酸、その製薬学上許容しうる塩及びエステルからなる群から選ばれる少なくとも1つを投与する、ANCA関連血管炎の発症率を低下させる方法である。
用法、用量、投薬期間は、本発明の第1の態様に従い、特に限定されないが、望ましい治療方法の1つとして、例えば、ANCA関連血管炎であって急速進行性糸球体腎炎を発症している被験者の寛解導入療法中に、副腎皮質ステロイド、免疫抑制剤を段階的に減量するのに併せて、本発明の医薬組成物の投薬を開始して治療薬の切り替えを行い、再発の危険性がなくなるまで投薬を継続する方法が挙げられる。
また、例えば、寛解導入療法の実施を終えた後にもANCAが陰性化しない被験者に対して、本発明の医薬組成物を投与する方法も好ましい。
すなわち、本発明の治療方法の好ましい態様のひとつは、ANCA関連血管炎の寛解導入療法の実施を終えた後にANCAが陰性化しない被験者、又は、寛解導入療法の実施を終えた後にANCAが陰性化したがすぐにANCAが陽性転じる被験者に対して、イコサペント酸、その製薬学上許容しうる塩及びエステルからなる群から選ばれる少なくとも1つを投与する、被験者のANCAを陰性又は低値に保つ方法である。
本発明の好ましい方法のひとつは、ステロイドパルス療法、血漿交換などの寛解導入療法の実施を終え、好ましくは、ANCAが陰性化した被験者、あるいはCRPが陰性化した被験者に対して、EPA-Eとアスピリンとを併用して投与する、ANCA関連血管炎の再発を抑制する方法である。ステロイドパルス療法とは、ステロイド剤を短期集中的に投与し、その後、休薬期間を設ける治療方法である。例えばメチルプレドニゾロン500~1000mg/日を3~4日間連続投与し、治療効果をみながら1~3週間ごとに繰り返す方法がある。
本発明の好ましい方法のひとつは、副腎皮質ステロイド薬が投与されるANCA陽性、及び/又は抗体価が高い被験者に対して、イコサペント酸、その製薬学上許容しうる塩及びエステルからなる群から選ばれる少なくとも1つを投与する、副腎皮質ステロイド薬を早期に用量を低下させる方法、及び/又は早期に離脱するための方法である。副腎皮質ステロイド薬の用量の低下は、特に限定されないが、好ましくは5mg以下、より好ましくは3mg以下、さらに好ましくは1mg以下、とりわけ好ましくは0.5mg以下に低下させることが好ましい。望ましくは副腎皮質ステロイド薬の服用量を段階的に低下させ、最終的に副腎皮質ステロイド薬の服用を中止させることが望ましい。
(実施例1)ANCAモデル SCG/Kjマウスの生存率に及ぼすEPAの影響
<方法>
ANCA血管炎/腎炎の自然発症型モデルであるSCG/Kjマウス(7週齢)(日本化薬(株))を1群6~7匹の3群に分けて、(1)魚粉抜き飼料F1(フナコシ(株)(対照群)、(2)5%コーン油混餌(シグマ社製)(コーン油群)、(3)5%EPA-E混餌(F1に5%となるようにEPA-Eを添加)(EPA群)、それぞれ自由摂食で飼育し、生存率を観察した。
生存率のグラフを図1に示す。
対照群、コーン油群は、ともに10~12週齢ごろから生存率が低下し始め、コーン油に生存延長効果は認められなかった。一方、EPA群では、生存率の低下が見られるのは15週齢ごろからであり、EPA-Eの生存延長効果が認められた。
<方法>
SCG/Kjマウスの3群(7週齢)を1群6~7匹の3群に分けて、実施例1と同じ条件で満11週齢まで飼育した。B6マウス(2匹)、SCG/Kjマウス(15週齢 3匹)の5群において、ELISA法にて血清中のMPO-ANCAを吸光度測定した。
MPO-ANCA抗体価は、これまでに報告された方法に従って測定された。(Ishida-Okawara A, Ito-Ihara T, Muso E et al. Neutrophil contribution to the crescentic glomerulonephritis in SCG/Kj mice. Nephrol Dial Transplant 2004; 19: 1708‐1715)簡単に述べると、リコンビナントのマウスのMPOは、ELISAプレート(Toyoshima Co., Tokyo, Japan)の上に、4℃で一夜、コートされた。プレートは、1% bovine serum albumin (BSA) (Sigma)でブロックされ、その後、マウス血清(50倍希釈)とともに、1.5時間、室温でインキュベートされた。
結合したMPO-ANCAは、アルカリフォスファターゼでラベルされた抗マウスIgG抗体(Cappel)とともに2時間インキュベートすることにより検出された。結合した2次抗体は、その後、1mg/mlのp-ニトロフェニルフォスフェート(p-nitrophenyl phosphate :Sigma)とともにインキュベートした後、405nmでの吸光度を測定することにより定量化された。
結果を図2に示す。
N:SCG/Kjマウス(1)対照群 魚粉抜き飼料
C:SCG/Kjマウス(2)コーン油群 5%コーン油混餌
E:SCG/Kjマウス(3)EPA群 5%EPA-E混餌
B6:通常餌
SCG/Kj:通常餌
EPA群では、対照群及びコーン油群と比較して、明らかにANCAの産生が抑制された。EPA群のANCA測定値は、正常マウス(B6)の値に並ぶ程度まで低下しており、EPA-EのANCA産生抑制効果が認められた。
<方法>
SCG/Kjマウスの3群(7週齢)を1群6~7匹の3群に分けて、実施例1と同じ条件で満11週齢まで飼育し、腎臓、肺及び脾臓におけるPD-1、PD-L1、PD-L2、Foxp3、CTLA4のmRNA発現量を評価した。
凍結した腎臓をTRIzol(登録商標) reagent (Invitrogen, Carlsbad, CA)中でホモジナイズした。 Total RNAをホモジネートから調整し、PureLink Micro-to-Midi Total RNA Purification System (Invitrogen)を用いて精製した。精製したTotal RNAから SuperScriptTM III first-strand synthesis system(Invitrogen)を用いてcDNA を調整し、ABI Prism(登録商標) 7000 (Applied Biosystems, Foster City, CA)による定量的リアルタイムPCRを行った。PCRのプライマーとプローブは、TaqMan(登録商標) gene expression assays (Applied Biosystems)を用いた。
腎臓と脾臓の結果を図3、図4に示す。他の臓器と比較して、腎臓において、EPA群では、対照群と比較して、Foxp3有意に上昇し、その他のPD-1、PD-L1、L2、CTLA4も高い傾向にあったことから、EPAは、T細胞の制御機構に関与し、過剰な自己免疫に対して抑制的に作用している可能性が示唆された。EPAは特に腎臓において、より効果を発揮する可能性が高いことが示唆された。
Claims (8)
- イコサペント酸、その製薬学上許容しうる塩及びエステルからなる群から選ばれる少なくとも1つを有効成分として含有する、被験者のANCA産生を抑制する、ANCA関連血管炎の予防・治療/再発抑制用医薬組成物。
- 前記被験者が、ANCA関連血管炎の寛解導入療法の実施を終えた後の被験者である、請求項1に記載の医薬組成物。
- 前記被験者が、寛解導入療法の実施を終えた後にANCAが陰性化しない被験者、又は、寛解導入療法の実施を終えた後にANCAが陰性化したがすぐにANCAが陽性に転じる被験者である、請求項1又は2に記載の医薬組成物。
- 前記被験者が、副腎皮質ステロイド薬が投与される、ANCA陽性及び/又はANCA抗体価が高い被験者であって、副腎皮質ステロイド薬の用量を早期に低下させる、及び/又は、副腎皮質ステロイド薬を早期に離脱するために投与される、請求項1ないし3のいずれか1項に記載の医薬組成物。
- 前記被験者が、慢性型ANCA関連血管炎を発症する被験者である、請求項1ないし4のいずれか1項に記載の医薬組成物。
- 前記被験者が、ANCAは陽性であるが身体症状を発症していない被験者である、請求項1ないし4のいずれか1項に記載の医薬組成物。
- アスピリンと併用される請求項1ないし6のいずれか1項に記載の医薬組成物。
- イコサペント酸、その製薬学上許容しうる塩及びエステルからなる群から選ばれる少なくとも1つを有効成分として含有する、ANCA産生抑制剤。
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2734870A CA2734870A1 (en) | 2008-08-22 | 2009-08-21 | Therapeutic agent for anca-related vasculitis |
EP09808321A EP2324827A4 (en) | 2008-08-22 | 2009-08-21 | THERAPEUTIC ACTIVE FOR ANCA-ASSOCIATED VASCULITIDES |
JP2010525718A JPWO2010021385A1 (ja) | 2008-08-22 | 2009-08-21 | Anca関連血管炎治療薬 |
US13/059,789 US20110152223A1 (en) | 2008-08-22 | 2009-08-21 | Therapeutic agent for anca-related vasculitis |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2008214707 | 2008-08-22 | ||
JP2008-214707 | 2008-08-22 |
Publications (1)
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WO2010021385A1 true WO2010021385A1 (ja) | 2010-02-25 |
Family
ID=41707259
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PCT/JP2009/064669 WO2010021385A1 (ja) | 2008-08-22 | 2009-08-21 | Anca関連血管炎治療薬 |
Country Status (5)
Country | Link |
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US (1) | US20110152223A1 (ja) |
EP (1) | EP2324827A4 (ja) |
JP (1) | JPWO2010021385A1 (ja) |
CA (1) | CA2734870A1 (ja) |
WO (1) | WO2010021385A1 (ja) |
Families Citing this family (1)
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EP2902020A4 (en) * | 2012-09-28 | 2016-03-23 | Mochida Pharm Co Ltd | COMPOSITION FOR REDUCING NEW DIABETES APPARITIONS |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2005281283A (ja) | 2004-03-31 | 2005-10-13 | Akira Matsumori | ベンズイミダゾール系薬剤の併用医薬 |
JP2007119387A (ja) | 2005-10-27 | 2007-05-17 | Kao Corp | 血管炎症候群予防・治療剤 |
JP2008515890A (ja) | 2004-10-05 | 2008-05-15 | ジェネンテック・インコーポレーテッド | 血管炎の治療方法 |
WO2008088030A1 (ja) * | 2007-01-17 | 2008-07-24 | Mochida Pharmaceutical Co., Ltd. | 血栓もしくは塞栓に関連する疾患の予防又は治療用組成物 |
Family Cites Families (5)
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DE60124256T3 (de) * | 2000-02-16 | 2012-09-20 | The Brigham And Women's Hospital Inc. | Aspirin-ausgelöste lipidmediatoren |
US7759395B2 (en) * | 2002-08-12 | 2010-07-20 | The Brigham And Women's Hospital, Inc. | Use of docosatrienes, resolvins and their stable analogs in the treatment of airway diseases and asthma |
GB0413730D0 (en) * | 2004-06-18 | 2004-07-21 | Tillotts Pharma Ag | A pharmaceutical composition and its use |
US7652068B2 (en) * | 2005-12-20 | 2010-01-26 | Cenestra Llc | Omega 3 fatty acid formulations |
US20090137527A1 (en) * | 2007-09-14 | 2009-05-28 | Resolvyx Pharmaceuticals, Inc. | Compositions and methods for modulating immune function |
-
2009
- 2009-08-21 CA CA2734870A patent/CA2734870A1/en not_active Abandoned
- 2009-08-21 JP JP2010525718A patent/JPWO2010021385A1/ja active Pending
- 2009-08-21 EP EP09808321A patent/EP2324827A4/en not_active Withdrawn
- 2009-08-21 US US13/059,789 patent/US20110152223A1/en not_active Abandoned
- 2009-08-21 WO PCT/JP2009/064669 patent/WO2010021385A1/ja active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005281283A (ja) | 2004-03-31 | 2005-10-13 | Akira Matsumori | ベンズイミダゾール系薬剤の併用医薬 |
JP2008515890A (ja) | 2004-10-05 | 2008-05-15 | ジェネンテック・インコーポレーテッド | 血管炎の治療方法 |
JP2007119387A (ja) | 2005-10-27 | 2007-05-17 | Kao Corp | 血管炎症候群予防・治療剤 |
WO2008088030A1 (ja) * | 2007-01-17 | 2008-07-24 | Mochida Pharmaceutical Co., Ltd. | 血栓もしくは塞栓に関連する疾患の予防又は治療用組成物 |
Non-Patent Citations (7)
Title |
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AMERICAN JOURNAL OF TRANSPLANTATION, vol. 9, no. 6, 13 May 2009 (2009-05-13), pages 1294 - 1307 |
APMIS, vol. 117, no. SUPPL., June 2009 (2009-06-01), pages 89, XP008143116 * |
ISHIDA-OKAWARA, A.; IHARA, T.; MUSO, E. ET AL.: "Neutrophil contribution to the crescentic glomerulonephritis in SCG/Kj mice", NEPHROL. DIAL. TRANSPLANT., vol. 19, 2004, pages 1708 - 1715 |
KIDNEY AND DIALYSIS, vol. 59, no. 3, September 2005 (2005-09-01), pages 563 - 566 |
MEBIO, vol. 20, no. 10, October 2003 (2003-10-01), pages 21 - 27 |
ONISHI ET AL., PROC. NATL. ACAD. SCI. USA, vol. 105, no. 29, 22 July 2008 (2008-07-22), pages 10113 - 10118 |
See also references of EP2324827A4 |
Also Published As
Publication number | Publication date |
---|---|
EP2324827A1 (en) | 2011-05-25 |
JPWO2010021385A1 (ja) | 2012-01-26 |
CA2734870A1 (en) | 2010-02-25 |
EP2324827A4 (en) | 2012-04-25 |
US20110152223A1 (en) | 2011-06-23 |
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