JP2007008845A - Chronic heart failure treatment and / or prevention drug - Google Patents

Abstract

Disclosed is a drug having an effect of reducing the size of acute myocardial infarction, which is useful as an effective therapeutic and preventive agent for chronic heart failure.
A therapeutic and / or prophylactic agent for chronic heart failure comprising, as an active ingredient, a drug having a histamine H2 receptor blocking effect such as famotidine, cimetidine, ranitidine, roxatidine acetate, nizatidine, or lafutidine.
[Selection figure] None

Description

  The present invention relates to a therapeutic and / or prophylactic agent for chronic heart failure comprising a histamine H2 receptor blocker as an active ingredient.

  Current treatments for patients with chronic heart failure (CHF) use angiotensin converting enzyme (ACE) inhibitors, b-adrenergic receptor blockers, and diuretics (Non-Patent Document 1). However, despite aggressive medical care, CHF remains the leading cause of morbidity and mortality worldwide. In addition, reducing the size of myocardial infarction at the onset of myocardial infarction causing ischemic heart failure leads to the prevention of the onset of heart failure, but there are few known drugs having a myocardial protective effect in the acute phase.

The present inventors previously demonstrated the possibility that a histamine H2 receptor blocker has a cardioprotective effect in patients with chronic heart failure (CHF) by a novel data mining method (Non-patent Document 2).
Braunwald E, Bristow MR. Congestive heart failure: fifty years of progress. Circulation. 2000; 102: 14-23 Kim J, Washio T, Yamagishi M, Yasumura Y, 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.Cardiovasc Drugs Ther 2004; 18: 483-9.

  However, exacerbation factors for ischemic heart failure and non-ischemic heart failure have not been fully elucidated, and effective therapeutic and preventive drugs for chronic heart failure including ischemic heart failure and non-ischemic heart failure and myocardial protection during acute myocardial infarction The drug was still in short supply. The suggestion of the possibility in Non-Patent Document 2 is based on the data excavation method to the last, and has not been demonstrated using an actual drug.

  Accordingly, 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.

  In order to achieve the above object, the present inventors have found that famotidine, a histamine H2 receptor blocker, improves chronic heart failure and reduces myocardial infarction size in patients with actual chronic heart failure (CHF). The present inventors have found that a therapeutic agent for peptic ulcer such as an H2 receptor blocker having a histamine receptor blocking action becomes a new therapeutic and preventive agent for chronic heart failure and a myocardial protective agent during myocardial infarction. Completed.

  The present invention relates to a therapeutic and / or prophylactic agent for chronic heart failure comprising a drug having a histamine H2 receptor blocking effect as an active ingredient.

  According to the present invention, a therapeutic and prophylactic agent for chronic heart failure can be provided.

  The present invention relates to a therapeutic and / or prophylactic 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 condition 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 expressed absolutely or relatively. Most chronic heart failure is based on systolic dysfunction of the left ventricle of the heart, and the cause is roughly classified into non-ischemic dilated cardiomyopathy and ischemic heart disease. In these diseases, neuroendocrine factors typified by the sympathetic nervous system and renin-angiotensin system are markedly increased, resulting in progressive expansion and decreased contraction of the left ventricle, that is, remodeling, resulting in death and worsening heart failure. It is thought to lead to events such as. 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 chronic heart failure treatment.

  In contrast, the present invention provides a therapeutic and prophylactic agent for chronic heart failure containing 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, and particularly includes a drug having a histamine H2 receptor blocking effect.

  A drug having a histamine H2 receptor blocking effect is a drug that competitively binds 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, ranitidine, famotidine, loxatidine acetate, nizatidine, and lafutidine.

  The therapeutic agent for chronic heart failure according to the present invention can be composed of, for example, a drug having the above-mentioned histamine H2 receptor blocking effect and an excipient or the like usually used as a therapeutic drug for peptic ulcer. An appropriate amount of a drug having an H2 receptor blocking effect 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 (combination with other drugs, etc.). Usually, about 1-1000 mg per day is divided into one or several times. Administer.

  The administration target is a patient suffering from chronic heart failure, and any patient suffering from non-ischemic dilated cardiomyopathy or a patient suffering from ischemic heart disease is also a subject.

  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 terms of dosage form, administration form, administration subject and the like.

  Hereinafter, the present invention will be described in more detail with reference to examples.

Example 1
Clinical retrospective study We studied 1104 consecutive heart failure cases admitted to the National Cardiovascular Center. All cases had 1) heart failure symptoms, and 2) left ventricular shortening rate was less than 30%, even though conventional medication for heart failure was administered. All patients were heart failure cases classified as II or III in the New York Heart Association (NYHA) cardiac function machine classification II versus III, and this condition was stable for 2 months. Among these cases we selected patients who were prescribed famotidine (159 cases, famotidine group). As control, 159 cases were randomly selected from other cases of heart failure that matched the age, sex and cause of heart failure of the famotidine group. Among 159 patients in each group, 71, 11 and 39 were dilated cardiomyopathy (DCM), hypertensive heart disease (HHD), virtual heart cardiomyopathy (ICM) and valvular heart disease, respectively And 38 people. We compared blood brain sodium excretion peptide (BNP) levels, clinical parameters of echocardiography, and NYHA cardiac function classification. The results are shown in Table 1.

Values are any number, range, or mean 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-diastole diameter, LV; left ventricle, LA; left atrium, ACE; angiotensin converting enzyme, ARB; angiotensin receptor blocker
* P <0.05 vs. control group

  From the results in the above table, there is no difference in age, gender and medication content in both groups, but in the famotidine group, a decrease in left ventricular diameter and blood BNP levels, which are indicators of heart failure, was observed in addition to blood pressure and heart rate. Improvement was observed.

Example 2
A prospective drug intervention study was conducted on 50 cases of heart failure showing symptoms similar to those in the retrospective study shown in Clinical Prospective Study Example 1. The average age was 65 years, 32 were male and 18 were female. The causes of heart failure were DCM, HHD, ICM, and vulvular heart disease in each group: 17, 2, 4, and 2, respectively. All patients were treated with an optimal and stable dose of b-blockers and ACE inhibitors for at least 3 months before obstructing echocardiography and randomization. Patients were arbitrarily divided into two treatment groups: famotidine (n = 25, famotidine group) and teprenone (n = 25, control group). The doses of famotidine and teprenone were 30 mg and 150 mg per day, respectively. The results are shown in Table 2.

Values are any number, range, or mean 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-diastole diameter, LV; left ventricle, LA; left atrium, ACE; angiotensin converting enzyme, ARB; angiotensin receptor blocker

  From the results in the above table, there was no difference between the famotidine group and the control group in terms of age, medication content, etc. before the start of medication. Furthermore, the BNP and NYHA cardiac function classification in blood before and after 24 weeks is shown in FIG. As shown in FIG. 1A, in the control group, there was no change in BNP in the blood around 24 weeks. In contrast, in the famotidine group, improvement in BNP in the blood was observed before and after the administration of famotidine for 24 weeks. Furthermore, even with regard to the NYHA cardiac function classification, as shown in FIG. 1B, the famotidine group showed improvement. These improved functions in the famotidine group are associated with improved cardiac function. As shown in FIG. 2, in the famotidine group, LVDd and LVDs are decreased without changing FS in the famotidine group. The frequency of lead missions due to CHF deterioration was lower in the famotidine group than in the control group. (4% and 24%, P <0.05)

Example 3
Anesthetized Open-chest Dog Model The experimental protocol for the anesthetized open-chest dog model is shown in FIG. In an anesthetized / thoracotomy dog, the anterior descending coronary artery was ligated for 90 minutes and reperfused for 360 minutes, and then myocardial infarction size was examined. In the famotidine group, famotidine was administered intracoronary for 10 minutes before ligation and 60 minutes during reperfusion (15 μg / kg / min). In the control group, physiological saline containing no drug was administered intracoronary as in the famotidine group. The results are shown in FIGS. FIG. 3 is a representative example of each group of myocardial infarction size evaluation, and it can be seen that the faint skin group significantly reduces the light-skinned portion that has fallen into myocardial infarction. FIG. 4 shows comparison data of myocardial infarction size and collateral circulation. No difference in collateral circulation between the two groups was observed, and myocardial infarct size was significantly lower in the famotidine group. These results indicate that famotidine acts myocardially during ischemic myocardial injury and reduces myocardial infarct size.

Example 4
Animal experiments (experiments using heart failure model mice)
According to the method described in Yulin Liao et al. (Circulation Research October 17, 2003, p759-766), a heart failure model mouse was prepared by aortic constriction.
Cimetidine was forcibly administered to the prepared aortic constriction model (TAC + Cimetide), and blood glucose levels were measured as needed after 4 weeks. As controls, a Sham group in which only thoracotomy was performed and aortic constriction was not performed, and a group that did not receive cimetidine after aortic constriction (TAC) group were used. The results are shown in FIG.

  From the results shown in FIG. 6, in the mouse aortic constriction model (TAC group), the heart weight / body weight ratio (HW / BW), which is an index of cardiac hypertrophy, was significantly increased compared to the Sham group. (TAC + Cimetide) shows that the increase is suppressed. That is, it can be seen that cimetidine has an effect of suppressing cardiac hypertrophy.

  Furthermore, from the results shown in FIG. 6, in the mouse aortic constriction model (TAC group), the left ventricular wall thickness (LVPWd) at 4 weeks after constriction was significantly increased, and it was affected by cimetidine (TAC + Cimetide). It can be seen that the index of heart failure improves. That is, it can be seen that cimetidine has an effect of suppressing cardiac remodeling.

  Further, from the results shown in FIG. 6, in the mouse aortic constriction model (TAC group), the left ventricular shortening rate (LVFS) indicating the lung weight and left ventricular contractility at 4 weeks after the constriction was significantly decreased. It can be seen that cimetidine improves the index of such heart failure (TAC + Cimetide). That is, it can be seen that cimetidine has an effect of improving heart failure.

  From these effects of cimetidine in the mouse pressure load model (results shown in FIG. 4), it was possible to suppress cardiac hypertrophy due to the effects of cimetidine. In the pressure overload model, cimetidine suppressed cardiac hypertrophy / expansion and obtained the same results as those observed in humans.

  In this example, it was shown that cimetidine has cardiac hypertrophy / 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.

  The present invention is useful in the pharmaceutical field.

Results of blood BNP (A) and NYHA cardiac function classification (B) in Example 2. * P <0.01, ** P <0.05 vs. control group Results of various cardiac functions in Example 2 [(A) Left ventricular end expansion volume (LVDd), (B) Left ventricular end contraction capacity (LVDs), (C) LV function shortened (FS), (D) LA diameter (LAD ) And (E) Pressure differential cusp value (TR dPmax). 2 shows the experimental protocol of the anesthetized open chest dog model of Example 3. The representative example of each group of myocardial infarction size evaluation obtained in Example 3 is shown. The comparison data of the myocardial infarction size and collateral circulation obtained in Example 3 are shown. 4 is a result showing the effect of cimetidine in the mouse pressure load model obtained in Example 4. FIG.

Claims (2)

A therapeutic and / or prophylactic agent for chronic heart failure comprising a drug having a histamine H2 receptor blocking effect as an active ingredient. The therapeutic and / or prophylactic agent for chronic heart failure according to claim 1, wherein the drug having a histamine H2 receptor blocking effect is famotidine, cimetidine, ranitidine, roxatidine acetate, nizatidine, or lafutidine.