JP2003267888A - Cardiac arrest fluid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a cardiac arrest fluid mitigating a damage on the myocardium and having excellent cardiac function-retaining effect. <P>SOLUTION: The cardiac arrest fluid contains a poly-ADP ribose synthetase inhibitor and metal ions such as Na<SP>+</SP>, K<SP>+</SP>, Mg<SP>++</SP>and Ca<SP>++</SP>. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to cardioplegia.

[0002]

2. Description of the Related Art Cardiac surgery is performed in a state in which cardiac arrest is artificially performed by perfusing a cardiac arrest fluid into the heart. Heretofore, as this type of liquid drug, a drug having a high potassium ion concentration and being close to an extracellular liquid has been used, as typified by a St. Thomas liquid. However, when these solutions were used, the myocardium was in an ischemic state during cardiac arrest, which often led to a decline in cardiac function due to lack of oxygen.

[0003]

Therefore, it cannot be said that the conventional cardioplegic solution has a sufficient cardioprotective action. In particular, after the ischemic state, there was a case where the reperfusion caused a large damage to the myocardium (referred to as reperfusion injury). This reperfusion injury can be fatal to the patient,
It's a big problem.

Therefore, it has been desired to provide a cardioplegic solution having a sufficient myocardial protective effect, particularly a preventive / preventive effect on reperfusion injury.

[0005]

The present inventors have completed the present invention as a result of intensive studies to solve the above problems.

That is, the present invention is a cardioplegia solution containing a poly ADP ribose synthetase inhibitor (also referred to as PARP inhibitor) and a metal ion.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Examples of PARP inhibitors include 3-aminobenzamide, 4-hydroxyquinazoline, 3-aminobenzoic acid and 1,5-dihydroxyisoquinoline, but preferably 3-aminobenzamide or 4 -Hydroxyquinazoline.

The content of the PARP inhibitor in the cardioplegic solution of the present invention is about 0.01 to 1000 μM,
Since there are some variations depending on the individual PARP inhibitor,
It is not limited to this. For example, in the case of 3-aminobenzamide, its content is preferably 1
˜500 μM, particularly preferably 10 to 300 μM, for example 100 μM, in the case of 4-hydroxyquinazoline, its content is preferably 0.1 to 50 μM,
Particularly preferred is 1 to 30 μM, for example 10 μM.

As metal ions in the cardioplegia solution of the present invention,
Na⁺, K⁺, Mg⁺⁺, Ca⁺⁺, Zn ⁺⁺Such as metal io
N, preferably Na⁺, K⁺, Mg⁺⁺, Ca⁺⁺Metal Io
Contains one or more The content of metal ions is 0.1
~ 300 mmol / l, depending on the type of metal ion
However, the concentration is not limited to this concentration.

The cardioplegic solution of the present invention is particularly preferably used as a metal ion because it induces a rapid cardiac arrest, maintains a balance with extracellular fluid, and prevents inflow of extracellular metal ions into cells. , Na ⁺ , K ⁺ , Mg ⁺⁺ and Ca ⁺⁺ . The preferable concentration of each metal ion is Na ⁺ : 100
~ 140 mmol / l, K ⁺ : 10-20 mmol / l, Mg ⁺ : 5-
40 mmol / l and Ca ⁺ : 0.5 to 3 mmol / l.

In order to contain these metal ions, salts of each metal (for example, NaCl, KCl, MgC) are used.
l ₂ · 6H ₂ O, adding CaCl ₂ · 2H ₂ O chloride, etc.) cardioplegic solution.

The cardioplegia solution of the present invention is preferably 7.3.
PH of ~ 8.2, especially around pH 7.4 around the extracellular fluid
Have. The pH can be adjusted, for example, by adding an appropriate amount of NaHCO ₃ .

[0013]

EXAMPLES The present invention will be described below with reference to examples, but the examples are not intended to limit the present invention. Examples 1 and 2 and Comparative Examples NaCl, KCl, MgCl ₂ .6H ₂ O, CaCl ₂ .2
H ₂ O and PARP inhibitor 3-aminobenzamide (100 μM) or 4-hydroxyquinazoline (10 μM) were dissolved in distilled water, and distilled water was further added to bring the total amount to 100 ml. The content of 3-aminobenzamide or 4-hydroxyquinazoline depends on the PARP inhibition rate (inhibition rate of 100 μM 3-aminobenzamide = 68%; inhibition rate of 100 μM 4-hydroxyquinazoline = 80%). Examination and inhibition rate 60
% Was determined as a guide. A so-called St. Thomas solution was prepared in the same manner except that the PARP inhibitor was not added. By adding 1.2 ml of 8.4% (w / v) NaHCO ₃ aqueous solution thereto, Example 1 shown in Table 1 was added.
And 2 and the cardioplegic solutions of Comparative Example were prepared.

[0014]

[Table 1]

The transmittance is the transmittance of the entire visible light.

Test Example SD rats (male) weighing 350 to 450 g were divided into three groups and subjected to the following cardiac arrest test. As the cardioplegic solution, the group A had a St. Thomas solution (7 animals), the group B had the cardioplegic solution of Example 1 (8 animals), and the group C had the cardioplegic solution of Example 2 (8 animals). It was used.

First, each rat was anesthetized with ether and pentobarbital, and a thoracotomy was performed. The heart was removed and ice-cooled Krebs-Henseleit buffer (100 ml of NaCl: 0.6895 g, KCl: 0.0343).
g, MgSO ₄ : 0.145 g, CaCl ₂ · 2H ₂ O: 0.
368 g, KH ₂ PO ₄ : 0.164 g, NaHCO ₃ :
2.10 g, glucose: 0.188 g). Subsequently, the weight of the excised heart was measured, and then immediately attached to a Langendorff apparatus, and pre-perfused with a Krebs-Henseleit buffer solution saturated with a mixed gas of 95% oxygen and 5% carbon dioxide as a perfusion solution. Then, a latex balloon was connected from the left atrium to the left ventricle via the mitral valve. After 20 minutes of pre-perfusion, collect myocardial perfusate,
The myocardial escape enzyme was measured. At the same time, the balloon inserted into the left chamber was connected to the pressure monitor via the transducer. Thereby, the pressure-time relationship (dP / dt) and the heart rate were measured. Furthermore, the left ventricle balloon was expanded and the pressure-volume relationship at that time was measured.

Next, 20 ml / kg of cardioplegia solution cooled to 4 ° C.
Was perfused and cardiac arrest was achieved. 10 ml of cardioplegia solution every 30 minutes
/ kg was additionally administered, and the cardiac arrest state was continued for a total of 90 minutes. After that, nothing was added to the Krebs-Henseleit buffer in the group A and the group B was treated with 3-aminobenzamide (concentration 100 μm).
M), C group is 4-hydroxyquinazoline (concentration 10μ
M) was added to flush out the cardioplegic solution in the heart in an amount of 10 ml / kg (hot shot), and then Krebs saturated with a mixed gas of 95% oxygen and 5% carbon dioxide was used as in the preperfusion. Reperfusion was performed using Henseleit buffer as a perfusate. At 5 minutes and 20 minutes after the start of reperfusion, the myocardial escape enzyme and the cardiac function (pressure-time relationship, heart rate, pressure-volume relationship) were measured, and the ratio to the value before each cardiac arrest was calculated. The perfusion was terminated 20 minutes after the start of the reperfusion, and the heart weight at that time was measured to determine the weight increase ratio with respect to the initial value. Furthermore, the myocardium was observed pathologically.

As a result, in the value of myocardial deviation enzyme, G
OT (5-minute value A: 25.2 ± 12.2, B: 12.0
± 5.7, C: 11.0 ± 4.8 IU / l; 20-minute value
A: 9.7 ± 7.6, B: 1.9 ± 1.6, C: 2.6
± 1.9 IU / l), LDH (5-minute value A: 80.3 ±)
42.7, B: 36.6 ± 12.9, C: 26.0 ± 1
3.8 IU / l; 20-minute value A: 37.7 ± 34.9,
B: 7.7 ± 5.4, C: 7.3 ± 5.4 IU / l),
CPK (5-minute value A: 260.0 ± 139.3, B: 1
03.9 ± 37.0, C: 85.1 ± 47.5 IU /
l; 20-minute value A: 119.8 ± 100.1, B: 1
7.0 ± 8.0, C: 20.7 ± 20.6 IU / l),
The PARP inhibitor group showed a significantly low value. From this, it was found that the cardioplegic solutions of Examples 1 and 2 reduce the damage to the myocardium. Also, in the pressure-time relationship (dP / dt), the 5-minute value A:
1.00 ± 0.41, B: 1.85 ± 0.46, C:
1.68 ± 0.30; 20-minute value A: 0.97 ± 0.0
5, B: 1.33 ± 0.22, C: 1.23 ± 0.31
And the PARP inhibitor group showed significantly good values. From this, it was found that the cardioplegic solutions of Examples 1 and 2 were excellent in the action of maintaining the myocardial contractility.

On the other hand, in heart rate and pressure-volume relationship, no significant difference was observed between the groups. Also,
The heart weight increase ratio is A group: 1.32 ± 0.07, B group:
1.32 ± 0.07, C group: 1.29 ± 0.09, which were almost the same.

Upon pathological observation, when PARP was stained with a fluorescent antibody, nuclear PARP tended to be strongly stained in the St. Thomas group.

From the above results, it became clear that the cardioplegic solutions of Examples 1 and 2 to which the PARP inhibitor was added were superior to the St. Thomas solution (Comparative Example) in myocardial protection. The composition of the St. Thomas solution and the solution of Example 1 or 2 is basically only the difference between whether or not a PARP inhibitor is contained, and from the results of pathological examination, it is shown that PARP inhibition It is considered that myocardial protection was obtained.

[0023]

The cardioplegic solution of the present invention has an action of remarkably reducing myocardial damage and maintaining an extremely good cardiac function. Therefore, it is useful in cardiac arrest and myocardial protection.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 9/00 A61P 9/00 41/00 41/00 (71) Applicant 502093302 Marek Yacht Banashik Kyoto Prefecture Kyoto Prefecture Sakyo-ku Shimogamo Higashitsukamotocho 7-7 Corp Takagi Room 12 (72) Inventor Masayuki Yoneda Kyoto Prefecture Kyoto City Kamigyo-ku Muromachi Tsuburagicho Shimodaimoncho 256 Gosho Nishi Urban Life 303 (72) Inventor Kunihiro Ueda Kyoto Prefecture 61 Shimomogishi Honcho, Sakyo-ku, Kyoto (72) Inventor Kazuhiro Yamazaki 92-1 Takano Shimizu-cho, Sakyo-ku, Kyoto-shi, Kyoto Shimogamo East River Stage 402 F term (reference) 4C084 AA16 MA17 MA66 NA14 ZA36 ZC54 4C086 AA01 AA02 BC46 MA02 MA04 MA17 MA66 NA14 ZA36 ZC54 4C206 AA01 AA02 GA09 MA02 MA04 MA37 MA86

Claims (7)

[Claims] 1. A cardioplegia solution containing a polyADP ribose synthetase inhibitor and a metal ion. 2. The cardioplegia solution according to claim 1, wherein the poly ADP ribose synthetase inhibitor is 3-aminobenzamide or 4-hydroxyquinazoline. 3. The content of 3-aminobenzamide is 1
The cardioplegia solution of claim 2, which is ˜500 μM. 4. The content of 4-hydroxyquinazoline is
The cardioplegia solution according to claim 2, which is 0.1 to 50 μM. 5. Na ⁺ , K ⁺ , Mg ⁺⁺ as metal ions
The cardioplegia solution according to any one of claims 1 to 4, containing Ca ⁺⁺ and Ca ⁺⁺ . 6. The concentration of each metal ion is Na ⁺ : 100.
~ 140 mmol / l, K ⁺ : 10-20 mmol / l, Mg ⁺⁺ : 5
~ 40 mmol / l and Ca ⁺⁺ : 0.5-3 mmol / l, cardioplegia solution according to claim 5. 7. The cardioplegia solution according to claim 1, which has a pH of 7.3 to 8.2.