WO2015012338A1 - Utilisation combinée d'aspirine et d'acide folique pour le traitement ou la prévention de l'artériosclérose - Google Patents

Utilisation combinée d'aspirine et d'acide folique pour le traitement ou la prévention de l'artériosclérose Download PDF

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Publication number
WO2015012338A1
WO2015012338A1 PCT/JP2014/069524 JP2014069524W WO2015012338A1 WO 2015012338 A1 WO2015012338 A1 WO 2015012338A1 JP 2014069524 W JP2014069524 W JP 2014069524W WO 2015012338 A1 WO2015012338 A1 WO 2015012338A1
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WO
WIPO (PCT)
Prior art keywords
aspirin
folic acid
pharmaceutical composition
arteriosclerosis
administered
Prior art date
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PCT/JP2014/069524
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English (en)
Japanese (ja)
Inventor
研太郎 山田
佐藤　秀一
祐司 田尻
Original Assignee
学校法人 久留米大学
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Application filed by 学校法人 久留米大学 filed Critical 学校法人 久留米大学
Priority to JP2015528324A priority Critical patent/JP6443935B2/ja
Publication of WO2015012338A1 publication Critical patent/WO2015012338A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a combination of aspirin and folic acid for the treatment or prevention of arteriosclerosis.
  • Arteriosclerosis causes serious diseases such as cardiovascular diseases such as myocardial infarction and cerebral infarction, and foot gangrene due to peripheral artery occlusion.
  • cardiovascular diseases such as myocardial infarction and cerebral infarction
  • foot gangrene due to peripheral artery occlusion.
  • administration of low-dose aspirin is recommended except for the management of hypertension, dyslipidemia and diabetes, which are the exacerbating factors.
  • the effect of aspirin on preventing arteriosclerosis is relatively weak, and its effect is limited in preventing the onset of cardiovascular disease and peripheral artery occlusion.
  • An object of the present invention is to provide a medicine effective for the treatment and prevention of arteriosclerosis.
  • the present invention provides a pharmaceutical composition containing folic acid for the treatment or prevention of arteriosclerosis for use in combination with aspirin.
  • the present invention provides a pharmaceutical composition containing aspirin and folic acid for the treatment or prevention of arteriosclerosis.
  • the present invention provides a kit for treating or preventing arteriosclerosis comprising a pharmaceutical composition containing aspirin and a pharmaceutical composition containing folic acid.
  • the present invention provides a novel and effective therapeutic and prophylactic agent for arteriosclerosis.
  • Aspirin exhibits antipyretic, analgesic and anti-inflammatory effects at high doses, and inhibits platelet aggregation at low doses.
  • aspirin is administered in an amount generally used in low-dose aspirin therapy for suppressing thrombus / embolization.
  • the dose of aspirin varies depending on the subject's age, sex, weight, and symptoms, and administration method, administration timing, administration interval, dosage form, etc., and is not particularly limited, but is usually 10 to 400 mg per day for adults, preferably Is in the range of 50 to 325 mg, more preferably 50 to 200 mg.
  • the number of administrations per day is not particularly limited, but is usually 1 to 3 times, preferably 1 time.
  • the dosage of folic acid varies depending on the subject's age, sex, weight, and symptoms, and administration method, administration timing, administration interval, dosage form, etc., and is not particularly limited, but is usually 0.4 to 40 mg per day for adults, preferably Is in the range of 5-20 mg.
  • the number of administrations per day is not particularly limited, but is usually 1 to 3 times, preferably 1 time.
  • the pharmaceutical composition of the present invention can be a pharmaceutical composition containing aspirin for use in combination with folic acid, a pharmaceutical composition containing folic acid for use in combination with aspirin, or a pharmaceutical composition containing aspirin and folic acid.
  • the pharmaceutical composition of the present invention can also be provided as a kit.
  • the kit of the present invention includes a pharmaceutical composition containing aspirin and a pharmaceutical composition containing folic acid.
  • the pharmaceutical composition and kit of the present invention can be provided together with a package insert, a packaging container, an instruction manual, etc. describing the usage / dosage etc. in the combined use of aspirin and folic acid.
  • aspirin and folic acid may be administered simultaneously or separately.
  • “administered at the same time” means that aspirin and folic acid are administered in the same administration schedule, and aspirin and folic acid are contained in a single preparation, but are contained in another preparation. Also good.
  • “Separate administration” means that aspirin and folic acid are administered on different administration schedules, one is administered, and then the other is administered at regular intervals, either of which can be administered first. Well, the interval is also arbitrary.
  • the number of administrations of aspirin and folic acid may be the same or different. For example, one may be administered once a day and the other may be administered twice or more a day.
  • the pharmaceutical composition and kit of the present invention are administered to a subject who has developed or is likely to develop arteriosclerosis.
  • Subjects include patients with diabetes, hypertension, dyslipidemia, and metabolic syndrome.
  • the subject is a type 2 diabetic patient.
  • the pharmaceutical composition of the present invention can be administered by a general oral or parenteral method (intravenous, intramuscular, subcutaneous, transdermal, nasal, other transmucosal, enteral, etc.).
  • the dosage form of the pharmaceutical composition of the present invention is not particularly limited, and examples thereof include tablets, granules, capsules, powders, solutions, suspensions, emulsions, injections, drops, and the like.
  • the pharmaceutical composition of the present invention comprises, in addition to aspirin and / or folic acid, excipients, stabilizers, preservatives, buffers, taste-masking agents, suspending agents, emulsifiers, flavoring agents, solubilizing agents, and coloring agents. Suitable additives such as thickeners can be included.
  • the pharmaceutical composition of the present invention is an injection or infusion, it may contain distilled water for injection, physiological saline, aqueous glucose solution, and the like.
  • Aspirin is Biaspyrin (registered trademark) tablet (Bayer Co., Ltd.), Bufferin combination tablet A81 (Eisai Co., Ltd.), etc. It is marketed as San (Nippon Pharmaceutical Co., Ltd.).
  • the therapeutic or preventive effect of arteriosclerosis can be examined, for example, by a blood flow-dependent vasodilator response test (FMD (Flow-mediated dilatation) test).
  • FMD Flow-mediated dilatation
  • the present invention provides a method for treating or preventing arteriosclerosis comprising administering aspirin and folic acid to a patient.
  • the present invention relates to the use of aspirin for the manufacture of a medicament for the treatment or prevention of arteriosclerosis in combination with folic acid; the manufacture of a medicament for the treatment or prevention of arteriosclerosis in combination with aspirin.
  • Method 1.1 Subjects From December 2010 to December 2012, 32 patients with type 2 diabetes who were admitted to Kurume University Hospital for blood glucose control participated in the study. Nine patients were treated with sulfonylurea, five with metformin, four with pioglitazone, nine with a DPP-4 inhibitor, and three with insulin (Table 1).
  • Exclusion criteria include HbA1c> 11.0%, use of antiplatelet drugs, pregnancy and lactation, chronic inflammatory disease, recent acute infection, serum creatinine level> 88.4 ⁇ mol / L, liver dysfunction (AST> 40 IU / L Or ALT> 40 IU / L), known malignancy, smoking, aspirin allergy, history of cerebrovascular disorder, proliferative diabetic retinopathy, urinary albumin level defined as urinary albumin level> 300 mg / day (macro- albuminuria), and painful diabetic polyneuropathy. Appropriate dietary management continued during the study period. Subject was instructed to avoid intense exercise. Written written consent was obtained from all subjects. The study plan was approved by the Ethics Committee of Kurume University School of Medicine and implemented in accordance with the guidelines of the Declaration of Helsinki.
  • Glucose, HbA1c, triglycerides (TG), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C) were measured according to standard protocols.
  • Folic acid and interleukin-6 (IL-6) levels were measured by chemiluminescent enzyme immunoassay.
  • Homocysteine (Hcy) levels were measured by HPLC (Hitachi High-Technologies Corporation).
  • Serum high sensitivity CRP (hsCRP) levels were significantly reduced in both groups after aspirin monotherapy and after combination therapy.
  • Serum IL-6 levels tended to decrease after both aspirin monotherapy and combination therapy in both groups, but this decrease was not statistically significant, except for values after group B combination therapy (Table 2).
  • Example 1 Method In the same manner as in Example 1, in addition to the patient analyzed in Example 1, the patient who received folic acid monotherapy (group C) was analyzed. The subjects of the analysis were type 2 diabetic patients admitted to Kurume University Hospital for blood glucose control. There were 46 patients in groups A to C, 15 patients were sulfonylurea, 11 were metformin, and 4 were pioglitazone 14 were treated with DPP-4 inhibitors and 4 were treated with insulin (Table 3). Group C subjects were administered folic acid 20 mg for 7 days (1 week) (FIG. 1).
  • L-Arginine improves vascular function by overcoming deleterious effects of ADMA, a novel cardiovascular risk factor. Altern Med Rev 2005; 10: 14-23.
  • Sciacqua A Grillo N, Quero M, Sesti G, Perticone F. Asymmetric dimethylarginine plasma levels and endothelial function in newly diagnosed type 2 diabetic patients. Int J Mol Sci 2012; 13: 13804-15.
  • Razmara M Hjemdahl P, Ostenson CG, Li N. Platelet hyperprocoagulant activity in Type 2 diabetes mellitus: attenuation by glycoprotein IIb / IIIa inhibition. J Thromb Haemost 2008; 6: 2186-92.
  • Colwell JA Colwell JA.
  • McCully KS Chemical pathology of homocysteine. IV. Excitotoxicity, oxidative stress, endothelial dysfunction, and inflammation. Ann Clin Lab Sci 2009; 39: 219-32.
  • Lawrence VA Loewenstein JE, Eichner ER.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

　La présente invention concerne une composition pharmaceutique contenant de l'aspirine pour le traitement ou la prévention de l'artériosclérose, la composition pharmaceutique étant destinée à être utilisée en combinaison avec de l'acide folique ; une composition pharmaceutique contenant de l'acide folique pour le traitement ou la prévention de l'artériosclérose, la composition pharmaceutique étant destinée à être utilisée en combinaison avec de l'aspirine ; une composition pharmaceutique contenant de l'aspirine et de l'acide folique pour le traitement ou la prévention de l'artériosclérose ; et un kit de traitement ou de prévention de l'artériosclérose, le kit contenant une composition pharmaceutique contenant de l'aspirine et une composition pharmaceutique contenant de l'acide folique.
PCT/JP2014/069524 2013-07-26 2014-07-24 Utilisation combinée d'aspirine et d'acide folique pour le traitement ou la prévention de l'artériosclérose WO2015012338A1 (fr)

Priority Applications (1)

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JP2015528324A JP6443935B2 (ja) 2013-07-26 2014-07-24 動脈硬化の治療または予防のためのアスピリンおよび葉酸の併用

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JP2013-155604 2013-07-26

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000508659A (ja) * 1996-04-17 2000-07-11 メルク エンド カンパニー インコーポレーテッド 心血管疾患関連の危険性を低減する組み合わせ療法
US6121249A (en) * 1998-07-01 2000-09-19 Donald L. Weissman Treatment and prevention of cardiovascular diseases with help of aspirin, antioxidants, niacin, and certain B vitamins
JP2007106703A (ja) * 2005-10-14 2007-04-26 Nutri Kk 血管障害の予防および治療組成物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000508659A (ja) * 1996-04-17 2000-07-11 メルク エンド カンパニー インコーポレーテッド 心血管疾患関連の危険性を低減する組み合わせ療法
US6121249A (en) * 1998-07-01 2000-09-19 Donald L. Weissman Treatment and prevention of cardiovascular diseases with help of aspirin, antioxidants, niacin, and certain B vitamins
JP2007106703A (ja) * 2005-10-14 2007-04-26 Nutri Kk 血管障害の予防および治療組成物

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ATSUHIRO ICHIHARA ET AL.: "Heiyo Ryoho to Haigozai polypill no Shorai", JOURNAL OF BLOOD PRESSURE, vol. 15, no. 7, 2008, pages 631 - 633 *
BROWN N. ET AL.: "Comparison of antiplatelet activity of microencapsulated aspirin 162.5 mg (Caspac XL), with enteric coated aspirin 75 mg and 150 mg in patients with atherosclerosis.", BR. J. CLIN. PHARMACOL., vol. 48, no. 1, 1999, pages 57 - 62 *
OSAMU YAMAMURA ET AL.: "Domyaku Koka to Shikkan Domyaku Kokasho Byohen no Chiryo Nokosoku", GEKKAN THE JOURNAL OF MEDICINE, vol. 49, no. 2, 2003, pages 180 - 187 *
RANGA G.S. ET AL.: "Effect of aspirin on lipoprotein(a) in patients with ischemic stroke.", J. STROKE CEREBROVASC. DIS., vol. 16, no. 5, 2007, pages 220 - 224, XP022225324, DOI: doi:10.1016/j.jstrokecerebrovasdis.2007.05.003 *
SHUNSUKE OTSUKI ET AL.: "No . Shinkekkan Event Yobo ni Taisuru Aspirin no Rinshoteki Yuyosei (EBM) to Arata na Kanosei 8. No Socchu Kyuseiki ni Okeru Aspirin", PROG. MED., vol. 25, no. 2, 2005, pages 389 - 393 *
VRABLIK M. ET AL.: "Folic acid does not improve surrogate markers of early atherosclerosis in atorvastatin-treated patients.", NUTR. RES., vol. 27, no. 3, 2007, pages 181 - 185, XP005929085, DOI: doi:10.1016/j.nutres.2007.01.004 *

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JP6443935B2 (ja) 2018-12-26
JPWO2015012338A1 (ja) 2017-03-02

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