WO2007000928A1 - Remedy and/or preventive for chronic heart failure - Google Patents

Abstract

A preventive and/or a remedy for chronic heart failure which contains, as the active ingredient, a drug having an effect as a histamine H2 receptor blocker such as famotidine, cimetidine, ranitidine, roxatidine acetate, nizatidine or lafutidine. Namely, it is intended to provide a drug having an effect of reducing acute cardiac infarction size which is useful as preventive and a remedy for chronic heart failure.

Description

 Specification

 Chronic heart failure treatment and Z or prophylaxis

 Technical field

 [0001] 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.

 Background art

 [0002] Current treatments for patients with chronic heart failure (CHF) use angiotensin converting enzyme (ACE) inhibitors, b-adrenergic receptor blockers, and diuretics (Braunwald E, Bnstow MR. Congestive heart failure: fifty years of progress. And lrculation. 2000; 10 2: 14-23 (Reference 1)). However, despite aggressive medical care, CHF remains the leading cause of morbidity and mortality worldwide. In addition, reducing myocardial infarct size at the onset of myocardial infarction, which causes ischemic heart failure, leads to prevention of the onset of heart failure, but there are few known drugs that have a myocardial protective effect in the acute phase.

 [0003] The present inventors have previously shown that 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)).

 [0004] However, exacerbation factors for ischemic heart failure and non-ischemic heart failure have not been fully elucidated, and effective therapeutic and preventive drugs for acute heart failure including ischemic heart failure and non-ischemic heart failure and acute myocardium Myocardial protective drugs at the time of infarction were still in short supply. The suggestion of the possibility in Reference 2 is based on the data excavation method to the last, and has not been proven by using actual drugs.

 [0005] 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.

[0006] In order to achieve the above-mentioned object, the present inventors have been able to obtain a pharmacologic agent, 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 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.

 Disclosure of the invention

 [0007] 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.

[0008] According to the present invention, a therapeutic and prophylactic agent for chronic heart failure can be provided.

 BEST MODE FOR CARRYING OUT THE INVENTION

 [0009] 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.

 [0010] 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. In these diseases, 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.

 [0011] In contrast, 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

Mention may be made of drugs having an H2 receptor blocking effect.

[0012] 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.

 [0013] 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.

 [0014] The subjects of administration are patients suffering from chronic heart failure, suffering from nonischemic dilated cardiomyopathy !, and suffering from ischemic heart disease! Of no!

 [0015] 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.

 Example

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

[0017] Example 1

 Maroki Lab

 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. 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 ultrasonic cardiac screening, and NYHA cardiac function classification. The results are shown in Table 1.

[0018] [Table 1] Control group (159) Famotidine group (/ F159) Age (years) 66 Sat 1 66 Sat 1

 M / F (%) 97/62 (61/39) 97/62 (61/39) Hypertension (¾) 11 (7) 11 (7)

 CHF period, y 8.7 ± 0.7 8.5 Sat 0.8

 Cardiac systolic blood pressure (mmHg) 112 6 9 105 ± 8 *

 Dilated blood pressure (mmHg) 67 ± 4 62 Sat 5 Thu

 Heart rate (bpm) 73 Saturday 5 66 people 5 *

 Function shortening (%) 24 Sat 1 23 Sat 1

 LV expansion diameter (mm) 58 ± 2 54 Sat 1 *

 LV cardiac contraction diameter (mm) 44 Sat 1 41 Sat 1 *

 LA diameter (mm) 40 ± 3 39 ± 3

 Pressure width cusp value (mmHg) 30 ± 2 28 ± 2

 rfn—Width BNP level (pg./mL) 259 25 25 182 Sat 21 *

 NYHA function class: 丄 丄 / 丄 丄 丄 () 75/84 (47/53) 97/62 (61/39)

NYHA functional class (average) 2.53 Sat 0.04 2.38 Shi 0.04 * Concomitant medications (numerical value) (%)

 Digoxin 丄 26 (80) 134 (84)

 Diuretic 140 (88) 137 (86)

 Nitrate other than spironolacton 80 (25) 32 (20)

 β-blocker 143 (90) 137 (86)

 ACE inhibitor 127 (80) 121 (76)

 ARB 118 (20) 38 (24)

 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

 * P <0.05 vs. control group

[0019] From the results in the above table, there is no difference in age and gender and medication content in both groups, but in the famotidine group, a decrease in left ventricular diameter * blood BNP level, which is an indicator of heart failure, in addition to blood pressure and heart rate was observed Improved heart failure.

[0020] Example 2

Sincerity A prospective drug intervention study was conducted on 50 patients with heart failure who showed symptoms similar to those in the retrospective study shown in 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 people, 2 people, 4 people and 2 people, respectively. All patients were treated with optimal and stable doses of b-blockers and ACE inhibitors for at least 3 months before interrupting ultrasound heart screening 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.

[Table 2]

Values can be any number, range, or average for each group SEM, NYHA; New York Heart New York Heart Association, CHF: Chronic heart failure, shortened function (%) = (left ventricular end-to-heart expansion diameter left atrial end-to-heart contraction diameter) / left ventricular end-to-heart expansion diameter, LV; left ventricle, LA; left atrium , ACE; angiotensin converting enzyme, ARB; angiotensin receptor blocker

 [0022] From the results in the above table, there was no difference in age 'content of administration between the famotidine group and the control group before the start of the injection. In addition, Figure 1 shows the BNP and NYHA cardiac function classification in blood around 24 weeks. As shown in Fig. 1 (A), in the control group, there was no significant change in BNP in the blood around 24 weeks. On the other hand, in the famotidine group, blood BNP was improved around 24 weeks after the administration of famotidine. In addition, regarding the NYHA cardiac function classification, improvement was seen in the famotidine group, as shown in Figure 1 (B). These improvements in the famotidine group are associated with improved cardiac function. As shown in Fig. 2, the FSD did not change and the LVDd and LVDs decreased in the famotidine group compared to the control group. The frequency of lead missions due to CHF deterioration was lower in the famotidine group than in the control group. (4% and 2 4%, P 0. 05)

 [0023] Example 3

 Anesthesia open chest dog model

 Figure 3 shows the experimental protocol for the anesthetized open-chest dog model. In the anesthetized thoracotomy, the anterior descending coronary artery was ligated for 90 minutes and reperfused for 360 minutes, and then myocardial infarct size was examined. In the famotidine group, famotidine was administered intracoronary for 10 minutes before ligation and 60 minutes during reperfusion (15 g / 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. 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.

[0024] Example 4 Animal experiment (experiment using heart failure model mouse)

 In accordance with 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 the aortic constriction was strong and a strong group (TAC) in which cimetidine was administered after aortic constriction were used. The result is shown in Fig. 6.

[0025] From the results shown in Fig. 6, in the mouse aortic constriction model (TAC group), the heart-weight-Z-weight ratio (HW / BW), which is an indicator of cardiac hypertrophy, increased significantly compared to the Sham group. The increase is suppressed by cimetidine (TAC + Cimetide). That is, it is understood that cimetidine has an effect of suppressing cardiac hypertrophy.

 Further, 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 increased significantly, and cimetidine (TAC + Cimetide) It can be seen that the index of strong heart failure improves. In other words, cimetidine has the effect of suppressing cardiac remodeling.

 [0027] Furthermore, from the results shown in FIG. 6, in the mouse aortic constriction model (TAC group), lung weight at 4 weeks after constriction 'left ventricular contraction rate (LVFS), which indicates left ventricular contractility, significantly decreased. It can be seen that cimetidine improves the index of heart failure (TAC + Cimetide). That is, it can be seen that cimetidine has an effect of improving heart failure.

 [0028] From these effects of cimetidine in the mouse pressure load model (results shown in Fig. 4), it was possible to suppress cardiac hypertrophy by the effects of cimetidine. In the pressure overload model, cimetidine suppressed cardiac hypertrophy and cardiac expansion, and obtained results similar to those observed in humans.

 [0029] In this example, it was shown that 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.

 Industrial applicability

[0030] The present invention is useful in the pharmaceutical field. Brief Description of Drawings

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).

Replacement paper (Rule ²⁶ )

Claims

The scope of the claims  [1] Chronic heart failure treatment and Z or preventive agent containing a drug having a histamine H2 receptor blocking effect as an active ingredient. [2] The chronic heart failure treatment and Z or prophylactic agent according to claim 1, wherein the drug having a histamine H2 receptor blocking effect is famotidine, cimetidine, latidine, oral xanthidine acetate, -zatidine, or lafutidine. [3] 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. [4] The chronic heart failure treatment and Z or prevention drug according to claim 1, wherein the drug having a histamine H2 receptor blocking effect is cimetidine. [5] The therapeutic and / or preventive drug for chronic heart failure according to claim 1, wherein the drug having a histamine H2 receptor blocking effect is latidine. 6. The chronic heart failure treatment and Z or prevention drug according to claim 1, wherein the drug having a histamine H2 receptor blocking effect is oral xanthidine acetate. [7] The therapeutic and / or preventive drug for chronic heart failure according to claim 1, wherein the drug having a histamine H2 receptor blocking effect is -zatidine. [8] The chronic heart failure treatment and Z or prevention drug according to claim 1, wherein the drug having a histamine H2 receptor blocking effect is lafutidine.