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WO2007000928A1 - Remede et/ou agent de prevention pour l'insuffisance cardiaque chronique - Google Patents

Remede et/ou agent de prevention pour l'insuffisance cardiaque chronique Download PDF

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Publication number
WO2007000928A1
WO2007000928A1 PCT/JP2006/312486 JP2006312486W WO2007000928A1 WO 2007000928 A1 WO2007000928 A1 WO 2007000928A1 JP 2006312486 W JP2006312486 W JP 2006312486W WO 2007000928 A1 WO2007000928 A1 WO 2007000928A1
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WO
WIPO (PCT)
Prior art keywords
heart failure
drug
chronic heart
histamine
preventive
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2006/312486
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English (en)
Japanese (ja)
Inventor
Masafumi Kitakaze
Jiyoong Kim
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Japan Health Sciences Foundation
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Japan Health Sciences Foundation
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Filing date
Publication date
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Publication of WO2007000928A1 publication Critical patent/WO2007000928A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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 therapeutic and Z or preventive agent for chronic heart failure comprising a histamine H2 receptor blocker as an active ingredient.
  • CHF chronic heart failure
  • ACE angiotensin converting enzyme
  • histamine H2 receptor blockers may have a cardioprotective effect in patients with chronic heart failure (CHF) by a novel data mining method (Kim J, Wa Shio T, Yamagishi M, Yasumura Y, et al. A Novel Data Mining Approacn to the I den tification of Effective Drugs or Combinations for Targeted Endpoints— Application to Chronic Heart Failure as a New Form of Evidence-based Medicine.Cardiovasc Drugs Ther. 2004; 18 : 483- 9. (Reference 2)).
  • an object of the present invention is to provide a drug having an effect of reducing the size of acute myocardial infarction, which is useful as an effective therapeutic and preventive drug for chronic heart failure.
  • the present inventors have been able to obtain a pharmacologic agent, a histamine H2 receptor blocker.
  • a histamine H2 receptor blocker Using tidine to improve chronic heart failure in patients with actual chronic heart failure (CHF) 'found to reduce myocardial infarct size and treat peptic ulcer like H2 receptor blocker with histamine receptor blocking action
  • CHF chronic heart failure
  • the present invention was completed by discovering that the drug is a novel and therapeutic agent for chronic heart failure and a myocardial protective agent for myocardial infarction.
  • the present invention relates to a therapeutic and / or preventive agent for chronic heart failure comprising a drug having a histamine H2 receptor blocking effect as an active ingredient.
  • a therapeutic and prophylactic agent for chronic heart failure can be provided.
  • the present invention relates to a therapeutic and Z or preventive agent for chronic heart failure comprising a drug having a therapeutic effect for peptic ulcer as an active ingredient.
  • Chronic heart failure refers to a state in which the heart's pumping function is reduced due to chronic myocardial injury, and the amount of blood that can meet the oxygen demand of the peripheral major organs cannot be pumped absolutely or relatively.
  • the majority of chronic heart failure is based on systolic dysfunction of the left ventricle of the heart, which is roughly classified into non-ischemic dilated cardiomyopathy and ischemic heart disease.
  • neuroendocrine factors such as the sympathetic nervous system, renin-angiotensin system, are markedly increased, resulting in progressive expansion of the left ventricle and decreased contraction, that is, remodeling. It is thought to lead to events such as death and heart failure. Therefore, conventionally, the inhibition of left ventricular remodeling by inhibiting such a neuroendocrine system and improving the prognosis of heart failure have been the center of treatment for chronic heart failure.
  • the present invention provides a therapeutic and prophylactic agent for chronic heart failure comprising a drug having a therapeutic effect for peptic ulcer as an active ingredient.
  • a drug having a therapeutic effect on peptic ulcer is literally a drug used as a therapeutic drug for peptic ulcer, particularly histamine
  • a drug having a histamine H2 receptor blocking effect is a drug that binds competitively to the H2 receptor of histamine and has an action of suppressing secretion of gastric acid and pepsin. It is usually used as a treatment for gastroduodenal ulcer and Zollinger-Ellison syndrome.
  • examples of drugs having a histamine H2 receptor blocking effect include cimetidine, latidine, famotidine, Examples include oral xanthidine acetate, nizatidine, and lafutidine.
  • the therapeutic agent for chronic heart failure of the present invention can be composed of, for example, the above-mentioned drug having a histamine H2 receptor blocking effect and an excipient ordinarily used as a therapeutic agent for peptic ulcer.
  • An appropriate amount of a drug having an histamine H2 receptor blocking effect, which is an active ingredient, can be administered to a patient, for example, once to several times.
  • the dose is determined by the patient's symptoms, age, sex, drug efficacy, and other conditions (such as concomitant use with other drugs). Usually, about 1 to 1000 mg per day is divided into 1 to several times. Administer.
  • the subjects of administration are patients suffering from chronic heart failure, suffering from nonischemic dilated cardiomyopathy !, and suffering from ischemic heart disease! Of no!
  • the therapeutic agent for chronic heart failure of the present invention can be the same as the therapeutic agent for chronic heart failure of the present invention in dosage form, administration form, administration subject, and the like.
  • a total of 1104 heart failure cases admitted to the National Cardiovascular Center were included. All patients had 1) heart failure symptoms, and 2) left ventricular shortening rate was less than 30%, even though they had been treated with conventional heart failure drugs. All patients were cases of heart failure classified as III-III or New York Heart Association (NYHA) heart function machine classification III or III, and this condition was stable for 2 months. Among these cases, patients who were prescribed famotidine (159 cases, famotidine group) were selected. As a control group, 159 cases were randomly selected from other heart failure cases that matched the age, sex and cause of heart failure of the famotidine group.
  • famotidine 159 cases, famotidine group
  • DCM dilated cardiomyopathy
  • HHD hypertensive heart disease
  • ICM virtual heart cardiomyopathy
  • valvular heart disease 38 people.
  • BNP blood brain sodium excretion peptide
  • NYHA function class ⁇ ⁇ / ⁇ ⁇ ⁇ () 75/84 (47/53) 97/62 (61/39)
  • Spinolepinolaton 25 (20) 25 (20) Values are any number, range, or average of each group SEM, NYHA; New York Heart Association, CHF; chronic heart failure, shortened function (%) (Left ventricular end—diastolic diameter—left atrial end—systolic diameter) / left ventricular end—diastolic diameter, LV; left ventricle, LA; left atrium, ACE; angiotensin converting enzyme, ARB; angiotensin Receptor blocker
  • FIG. 1 shows the BNP and NYHA cardiac function classification in blood around 24 weeks.
  • Fig. 1 (A) in the control group, there was no significant change in BNP in the blood around 24 weeks.
  • famotidine group blood BNP was improved around 24 weeks after the administration of famotidine.
  • Figure 1 (B) improvement was seen in the famotidine group, as shown in Figure 1 (B).
  • Figure 3 shows the experimental protocol for the anesthetized open-chest dog model.
  • the anterior descending coronary artery was ligated for 90 minutes and reperfused for 360 minutes, and then myocardial infarct size was examined.
  • famotidine famotidine was administered intracoronary for 10 minutes before ligation and 60 minutes during reperfusion (15 g / kg / min).
  • physiological saline containing no drug was administered intracoronary as in the famotidine group. The results are shown in Figs.
  • Figure 3 is a representative example of each group for myocardial infarction size assessment, and it can be seen that the faint skin group with faint skin color significantly decreased in the famotidine group.
  • Figure 4 shows comparison data of myocardial infarction size and collateral circulation. There was no difference in collateral circulation between the two groups, and myocardial infarct size was significantly lower in the famotidine group. These results indicate that famotidine acts as a myocardial protectant during ischemic myocardial injury and reduces myocardial infarction size.
  • Cimetidine was forcibly administered to the prepared aortic constriction model (TAC + Cimetide), and blood glucose levels were measured as needed after 4 weeks.
  • TAC + Cimetide prepared aortic constriction model
  • cimetidine has cardiac hypertrophy 'heart expansion. That is, it was shown that a drug having a histamine H2 receptor blocking effect such as cimetidine has a therapeutic and preventive effect on chronic heart failure.
  • FIG. 1 shows the results of BNP (A) and NYHA cardiac function classification (B) in the blood of Example 2. * P ⁇ 0.01, * * P ⁇ 0.05 vs. control group
  • FIG.2 Shows the results of various cardiac functions in Example 2 [(A) Left ventricular end dilation capacity (LVDd), (B) Left ventricular end contraction capacity (LVDs), (C) LV function shortening (FS), ( D) LA diameter (LAD) and (E) Pressure differential cusp value (TR dPmax)] 0
  • FIG. 3 shows the experimental protocol of the anesthetized thoracotomy dog model of Example 3.
  • FIG. 4 shows a representative example of each group for myocardial infarction size evaluation obtained in Example 3.
  • FIG. 5 shows the comparative data of (A) myocardial infarction size obtained in Example 3 and (B) endocardial collateral blood flow during ischemia (effect of reducing the size of myocardial infarction by fatimidine).
  • FIG. 6 is a result showing the effect of cimetidine in the mouse pressure load model obtained in Example 4 (inhibition effect of cimetidine on cardiac hypertrophy under mouse pressure load).

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un agent de prévention et/ou un remède pour l'insuffisance cardiaque chronique, qui contient, en tant que principe actif, un médicament exerçant un effet d'inhibition des récepteurs histaminiques H2, tel que la famotidine, la cimétidine, la ranitidine, l'acétate de roxatidine, la nizatidine ou la lafutidine. En particulier, la présente invention concerne un médicament réduisant la gravité de l'infarctus aigu du myocarde, qui est utile en tant qu'agent de prévention et en tant que remède pour l'insuffisance cardiaque chronique.
PCT/JP2006/312486 2005-06-29 2006-06-22 Remede et/ou agent de prevention pour l'insuffisance cardiaque chronique Ceased WO2007000928A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2005189970A JP2007008845A (ja) 2005-06-29 2005-06-29 慢性心不全治療および／または予防薬
JP2005-189970 2005-06-29

Publications (1)

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WO2007000928A1 true WO2007000928A1 (fr) 2007-01-04

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JP (1) JP2007008845A (fr)
WO (1) WO2007000928A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12013389B2 (en) 2018-09-20 2024-06-18 National University Corporation Hokkaido University Method of evaluating pathological conditions of heart failure

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004004702A2 (fr) * 2002-07-09 2004-01-15 The Scripps Research Institute Procede pour empecher les lesions par ischemie et reperfusion

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004004702A2 (fr) * 2002-07-09 2004-01-15 The Scripps Research Institute Procede pour empecher les lesions par ischemie et reperfusion

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KIM J. ET AL.: "A Novel Data Mining Approach to the Identification of Effective Drugs or Combinations for Targeted Endpoints-Application to Chronic Heart Failure as a New Form of Evidence-based Medicine", CARDIOVASCULAR DRUGS AND THERAPY, vol. 18, no. 6, 2004, pages 483 - 489, XP019205295 *
KIM J. ET AL.: "Blockade of histamine H2 receptors protects the heart against ischemia and reperfusion injury in dogs", JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, vol. 40, no. 5, May 2006 (2006-05-01), pages 666 - 674, XP005392732 *

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