JPS6087221A - Remedy and preventive for cardiac disease - Google Patents

Abstract

PURPOSE:To provide a drug containing L-lysine or its salt as an active component, having positively inotropic activity and high safety, and useful for the remedy and prevention of cardiac diseases such as ischemic cardiopathy, metabolic cardiopathy, etc. CONSTITUTION:The objective drug contains L-lysine or its salt as an active component. It has been found by the investigation of the pharmacological activity of lysine, that the administration of lysine does not cause the increase in the pulse rate in spite of the positively inotropic activity of lysine. Furthermore, lysine can be utilized sufficiently as an energy source of the cardiac muscle to protect the cardiac muscle from the change caused by ischemia. The positively inotropic activity of lysine has been found to be independent of the calcium and beta-receptor activity. Accordingly, the present composition is expected to be effective to ischemic cardiopathy, metabolic cardiopathy (diabetic or thyrocardiac diseases), and myocardial disorder caused by a carcinostatic agent or psychotropic agent. Dose: 10mg-10g, preferably 100mg-5g daily for adult by oral or parenteral administration. The non-toxic nature of the compound enables continuous administration over a long period.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an agent for treating and preventing heart diseases. More specifically, the present invention relates to a heart disease treatment/prevention agent containing L-lysine or a salt thereof as an active ingredient.

There are various therapeutic agents on the market for treating heart diseases such as angina pectoris, myocardial infarction, ischemic heart disease, arrhythmia, congestive heart failure, cardiomyopathy, and drug-induced myocardial damage. It can be classified into three types.

■p-brooker (β-receptor blocker)■
Calcium antagonist ■ Metabolic drugs Regarding the functional metabolism of the myocardium, the above five groups of drugs greatly contribute to the treatment of heart disease.

From the perspective of heart metabolism, there are still many unresolved issues.

Therefore, the present inventor has conducted extensive research on the effects of individual amino acids on cardiac function.

Namely, 1. The present inventors have investigated the pharmacological effects of various essential abanoic acids on the heart.

It has surprisingly been found that L-lysine or a salt thereof has a positive inotropic effect. Taking this discovery as an opportunity, we further investigated myocardial metabolism and cardiac function, and as a result, we discovered new effects in the following points.

■ Has a positive inotropic effect. However, it does not cause an increase in heart rate (poaitiya 1notropio a
otion but ohronotropio ao
tion is not involved).

■ Can be fully utilized as an energy source for the myocardium.

■ Protects myocardial changes caused by ischemia.

■ Positive inotropy occurs independently of calcium and beta receptor action.

In view of the pharmacological effects of L-lysine as described above.

It can be said to be an effective drug for ischemic heart disease 1 metabolic heart disease (diabetes and thyroid heart disease) and myocardial damage caused by anticancer drugs and psychotropic drugs.

In the present invention, L-lysine or a salt thereof is used for the treatment and prevention of heart disease.
Pharmacologically acceptable salts such as salt, salt, Oa salt, 1Mg salt, etc. can be mentioned.

Next, in order to explain the effects of the present invention in detail, examples of pharmacological experiments on animals will be given.

Experimental Example 1 Male rice rats weighing 350 to 370 I were used.
A heart-lung specimen was prepared according to the method described in 1). Perfuse blood into allogeneic rat red blood cells suspended in Madritt 25% Krebs-Ringer sodium bicarbonate buffer p) 17
．． 4.30- was used. Cardiac function: aortic pressure 80 M
Hg was kept constant, right atrial central venous pressure (using a pressure transducer), cardiac output (using an electromagnetic flow meter), and heart rate.

And electromotive force was observed in the first lead of the electrocardiogram.

# (Group 0) that does not contain all substances that should become an energy source in the perfused blood, and a group that contains 10 m Mol of glucose (G
), 1 rn of L-lysine 0.8 molar pH 7.4 solution
A group containing l/10 ml wave blood (L group) and a group containing both glucose and L-lysine at the same time (G+
For the 4 groups of L, group), 4! After perfusion for 40 minutes, Warren gel (Nol!/enbe) cooled with liquid nitrogen was added.
The heart was flash-frozen using forceps, and intramyocardial creatine phosphate (CP)% adenosif-3-phosphate [(ATP)
Glycoin and lactate were measured.

The results are shown in Table 1.

Table 1 Table 1 shows that the lysine of the present invention is metabolized in the cardiac muscle.

It is often used in the synthesis of high-energy phosphoric acids OP and ATP, and it is clear that it plays a role in maintaining cardiac function. On the other hand, unlike glucose.

It is not used for glycogen synthesis or lactic acid production.

Experimental Example 2 The experimental system was the same as Experimental Example 1, and groups G, G+L, 0, and L were created, and cardiac function before and after administration was measured over time. Furthermore, I, -! No decrease in aortic pressure was observed even with the administration of J-lysine, and other parameters were observed under conditions of 801 isHg during the entire course. The results are shown in Table 2. The unit of numerical values in Table 2 is ml/min, and the numerical values in brackets are %.
shows.

As shown in Table 2, cardiac output/n+in increased immediately after L-lysine administration, and the increase continued during the 40 minute observation period. In addition, a particularly remarkable finding is that when L-lysine is administered alone (L#), it is better when administered in combination with glucose (1,
+G group), its positive inotropic effect was stronger.

Experimental Example 5 Analysis of the positive inotropic effect of L-lysine In the above-mentioned Experimental Example 2, it was revealed that l, -IJ lysine had a positive inotropic effect.

In order to elucidate the mechanism by which this occurs, we investigated using verabacul (vera hydrochloride/(') as a calcium antagonist and glopranolol as a β-blocker. In this experimental example, Experimental Example 10 Using the heart S specimen of the G group, perfusion was first performed for 10 minutes, and then 1 μl/ml of verapail hydrochloride was added to the perfusion solution to reduce cardiac function.After this condition occurred, L- Lysine 0.8
Mo/l/PI (7,4 solution, 1.0 ml/10
By adding verapamil to the all fluid, the cardiac output suppressed by verapamil was able to recover to the pre-suppression value (see Figure 1). In Figure 1, (A) shows verapamil before administration; (BJ is when verapamil 1 μl/ml liquid was administered (↓ in the figure indicates the time point of administration).

(0) is added with L-lysine 0.8 m Mol /at
* (When 9g of fluid was administered (↓ in the figure indicates the time of administration).

Figure 1 shows the average cardiac output i', cardiac output (one stroke), venous pressure, and electrocardiogram in each case.

Next, instead of verapamil hydrochloride, the β-blocker propranolol was administered to reduce cardiac output, and the effect of L-lysine on this was observed (see Figure 2). ztL-U gin showed the effect of restoring the cardiac function to the normal state again due to the blocker.

In FIG. 2, (A) is before administration of propranolol.

(B) shows the case where propranolol 0.01 Da/η·overflow fluid was administered (↓ in the figure indicates the time point of administration).

(0) was added with 0.8 m Mop/ILl of L-lysine.
e (7i means when fluid is administered (↓ in the figure indicates the time of administration). 1 Figure 2 shows the average cardiac output, cardiac output (one time), venous pressure, and Showing an electrocardiogram.

Experimental Example 4 Membrane protective effect on ischemic myocardium Cardiopulmonary specimens were prepared in the same manner as in Experimental Example 1. A circulatory system with a one-way valve with a bypass was installed just below the aortic valve, and 5 minutes after the start of M flow, the bypass was ligated to block coronary blood flow during diastole, causing ischemia, for 25 minutes. After ischemia, the bypass is opened again and reperfusion is performed for an additional 30 minutes.

Starting 5 minutes after the start of perfusion, creatine phosphokinase (OPK) flowing into the perfused blood was measured every 5 minutes. The perfused blood was Group G, which contained 10 mMo1'it of glucose in the same manner as in Experimental Example 1, and Group G ()+L, in which I, -lysine was added from the start of perfusion. L-lysine is present in perfused blood at 0.8 mol-7,4
The solution was added at a rate of 1/1011 tl. Also for rats.

15 minutes into the experiment, 0.8 mol L-lysine was added. Od/
Intravenous administration was performed at a ratio of 10011/body weight. The results are shown in Table 4.

+9- Soha (The values in Table 4 are creatine phosphokinase COPK)
Mu7'tnl is shown. The group with one mark among the groups is
It means a case of ischemia, and no mark means a case of no ischemia. ) As is clear from Table 4 above, even in group 0 without ischemia, there is a certain amount of OPK outflow from the myocardium after 60 minutes of perfusion. When ischemia occurs (group G*), the outflow becomes larger; however, in contrast to this outflow, the L-lysine administration group (
G:+□LIM''), the outflow of OPK is significantly suppressed.

Furthermore, when L-lysine was administered during normal perfusion without ischemia (G+L group), OPK outflow was significantly suppressed.

Experimental Example 5 A heart-lung specimen was prepared in the same manner as in Experimental Example 1. As experimental groups, Group G and Group G-1-L were created in the same manner as in Experimental Example 1, but L-! J resin was administered intravenously to rats 15 minutes before the start of the experiment.

Ischemia occurred 10 minutes after the start of perfusion, and the aortic pressure of the cardiopulmonary specimen was 8011.
Remove peripheral resistance by using Hg as OjllHg.

At the same time, an inflow volume of Y O was prepared which was laminarly flowed into the right atrium at a pressure of 20/yJH20.

There is no blood in the heart chambers (the heart has ``karauchi'',
Early development develops into atrioventricular (h-v) block. Reperfusion was started 10 minutes after ischemia. Peripheral resistance and drained blood volume are gradually increased to restore the pre-ischemic circulatory state. Heart rate, atrioventricular block status, and cardiac output during ischemia and reperfusion.

The effect of L-lysine on the time required for recovery is shown in Figure 3.

In FIG. 3, the horizontal axis indicates elapsed time (minutes).

11- The vertical axis shows the change in heart rate, with pre-ischemia being 100%,
Shown as % change after ischemia and during reperfusion.

・The mark means the L-lysine administration group, and the mark X means the control μm group. In the graph of the L-lysine administration group, &
means p<0.05 and b means p<0.01. The following can be said from FIG.

As shown in FIG. 6, when ischemia is induced in group G, P waves gradually decrease along with atrioventricular block, and it takes an average of 4.5 minutes to return to the pre-ischemic state through reperfusion. On the other hand, in the G group (L-lysine addition group), 'N-ventricular block due to ischemia hardly occurred, only a slight decrease in heart rate was observed, and even with reperfusion, L-lysine was eliminated. Heart function recovered significantly earlier than in the supplemented group.

From the above five different experimental results, it was confirmed that L-lysine or its salt of the present invention has the following primary effect on the heart.

■ L-lysine can be used as an energy source in the heart muscle.

■L-1) Jin has the effect of increasing cardiac output.

In other words, positive inotropy (positive inotropy)
opi.

aotion).

■ L-lysine has no effect on heart rate.

■ L-lysine has a protective effect against OPK efflux through the myocardial plasma membrane due to ischemic myocardium.

(2) L-lysine has the effect of preventing the occurrence of atrioventricular block caused by ischemia.

■ Positive inotropy is independent of Oa and β-receptors (occurs).

The above findings were discovered for the first time by the present inventor, and based on these effects, L-lysine or a salt thereof is effective as an agent for treating and preventing various heart diseases. Specifically, these include angina pectoris, ischemic heart disease represented by myocardial infarction, arrhythmia, congestive heart failure, and cardiomyopathy.

It is effective as a therapeutic and preventive agent for heart diseases such as drug-induced myocardial damage. Among these, myocardial damage caused by antitumor agents and psychotropic drugs is difficult to treat and has become a problem in recent years, and the L-lysine of the present invention is effective as a therapeutic agent for this.

The compound of the present invention, lysine, or its salt is an extremely safe substance and has almost no toxicity, so it can be administered with confidence. Therefore, when administered as a therapeutic agent for heart disease, continuous administration for a long period of time is unavoidable due to the nature of the disease, but as mentioned above, there is almost no toxicity, so long-term continuous administration is possible.1 The present invention is also extremely effective in this sense. High value.

When the compound of the present invention, L-lysine or a salt thereof, is used as a therapeutic or preventive agent for heart disease, it is administered orally or parenterally (intravenous infusion, etc.). The dosage varies depending on the disease, the severity of the symptoms, the age and weight of the patient, the type of concurrent treatment, etc., and is not particularly limited, but is usually about 10m9 to 10I per day for adults.
, preferably about 100 Da to sIi, more preferably about 5
It is about 00 to 51 da.

The compounds of the present invention can be formulated into tablets, granules, and the like using conventional methods in the art of formulation.

The dosage form is powder, capsule, injection, etc.

That is, when preparing an oral solid preparation, after adding excipients to the crude drug, and further adding binders, disintegrants, lubricants, coloring agents, flavorings, etc. as necessary, tablets, Coated tablets, granules, powders.

Used in capsules, etc.

Examples of excipients include lactose, cornstarch, sucrose,
Examples of binders include glucose, nruvit, crystalline cellulose, etc., and examples of binders include polyvinyl alcohol, polyvinyl ether, ethylcellulose, methyl heptylulose, and gum arabic.

tragacanth, gelatin, shellac, hydroxyglobil cellulose, hydroxyglobil starch, polyvinylpyrrolid/etc. Disintegrants include starch/
, agar, gelatin powder.

Crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin.

Pectin etc. are lubricants such as magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil etc. Coloring agents are those permitted to be added to pharmaceuticals, and flavoring agents are: Cocoa powder, peppermint, aromatic acid, peppermint oil, cypress, cinnamon powder, etc. are used. These tablets and granules are coated with sugar,
It goes without saying that it may be coated with batter or other coatings as necessary.

When preparing an injection, if necessary, a balmaging agent, buffering agent, stabilizer, preservative, etc. are added to the main drug, and the injection is prepared by a conventional method.

[Brief explanation of the drawing]

Figures 1 and 2 show time and average cardiac output from the top. Cardiac output, venous pressure, and electrocardiogram are shown respectively. In Figure 5, the horizontal axis shows elapsed time (minutes), and the vertical axis shows changes in heart rate.Applicant's agent Kaoru FuruyaFigure 1 (A) (B) (C) ↓ Figure 2 (A) ( B) Average cardiac output (C) ↓ Procedural amendment (method) February 6, 1980 Kazuo Wakasugi, Commissioner of the Japan Patent Office 1 Indication of the case Patent application No. 1987-195773 2 Name of the invention Heart disease treatment and prevention Agent 3 Relationship with the person making the amendment Patent applicant + 0211 Eisai Co., Ltd. 4 Agent Nakai Building, 1-3 Nihonbashi Yokoyama-cho, Chuo-ku, Tokyo 1982
Month 31st (shipping date) 6 Statement subject to amendment 7 Engraving of the statement of contents of the amendment (no change in content) 1-

Claims (1)

[Claims] Heart disease treatment using L-lysine or its salt as an active ingredient 9
Preventive agent.