JPH11246433A - Cardiac infarction medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicine useful for improving ischemic myocardiopathy by including a hepatocyto growth factor(HGF) as an active ingredient. SOLUTION: This cardiac infarction medicine contains HGF as an active ingredient. The HGF includes a commercially available HGF and a HGF obtained by culturing a first stage culture cell or an established cell producing the HGF, separating the HGF from the supernatant of the culture product and subsequently purifying the HGF. The medicine is preferably prepared by processing the HGF into a medicinal composition preparation singly or together with proper additives for the preparation and subsequently parenterally administered (for example, the direct injection of the HGF from a ventricular hollow into cardiac muscle through a catheter). The cardiac infarction medicine is preferably administered at a daily dose of about 1-500 μg/kg of the body weight of an adult patient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a preparation for treating myocardial infarction or angina pectoris which contains hepatocyte growth factor (HGF) as an active ingredient. For more information,
By administering HGF locally to the myocardium,
Myocardial angiogenesis using laser with administration of F (T
MLR) in combination with a preparation for treating myocardial infarction or angina more efficiently.

[0002]

2. Description of the Related Art Conventionally, as a method for treating myocardial infarction or angina, several treatment methods, which are roughly classified into medical treatment and surgical treatment, have been implemented. At present, thrombolytic therapy is mainly used as a medical therapy used in a clinical setting. Tissue plasminogen activator (t-PA), urokinase and urokinase are used to remove thrombus causing myocardial infarction and the like. A fibrinolytic drug such as (UK) has been used. However, because these fibrinolytic drugs are administered in large quantities,
It has been reported that a thrombus required for a living body in a place other than the affected part is dissolved, and serious side effects such as intracerebral hemorrhage are caused. For this reason, a warning has been issued today to warn the use of elderly people over the age of 75. In addition, since these fibrinolytic drugs dissolve fibrin and dissolve thrombus, if the content of thrombus is not derived from fibrin, a sufficient effect may not be obtained depending on the situation. Therefore, at present, the following surgical treatment is more often performed than such medical treatment. Today, percutaneous angioplasty (PTCA) and coronary artery bypass surgery (C) are used as surgical treatments for resolving occlusion and stenosis of blood vessels that cause myocardial infarction and angina.
ABG) and the like. However, each of these methods is a method of dilating or bypassing an obstructed blood vessel or a stenotic portion of a blood vessel, and is a therapy for a main coronary artery in terms of treatment. Therefore, even if these treatment methods are successful, not all myocardial ischemia disappears, but ischemia still remains at local parts of the myocardium,
In some cases, cardiac function did not recover sufficiently. On the other hand, in recent years, since various factors having an angiogenic effect have been known, by using these factors, the above-mentioned purpose, that is, angiogenesis is caused at an ischemic site of myocardium, and collateral circulation is caused. It has been envisioned that fresh blood is supplied to the ischemic myocardium by promoting development. At present, various model experiments on FGF or VEGF have been attempted, but the effectiveness thereof has not been clarified yet. In recent years, new attempts have been made in surgical treatment methods. That is, intramyocardial angiogenesis using laser (TMLR or TMR: transmyocardinal
laser revascularization) (Circulatory T
oday, 1,939-946 (1997)). The TMLR method is a treatment method in which a channel is opened in the myocardium by a laser and the myocardium is perfused directly from the ventricular cavity. As a result of this method, it has been reported that it was effective for coronary stenosis (Horvath KA et al, J. Thoracic and Cardiova)
sc Surg., 111, 1041-1053 (1996), Cooley DA et al, J.
Thoracic and Cardiovasc Surg., 111, 791-799 (199
6)). However, this method has problems such as clogging of open channels, and according to additional tests, results that are not very effective have been obtained (Burkhoff D, Ann
Thrac Surg., 61, 1532-1535 (1996)). Therefore, recently, an improved TMLR method (a method for promoting angiogenesis by making a hole around a coronary artery with a laser) has been developed. In addition, attempts have been made to improve this method by using VEGF, an angiogenic factor, to avoid clogging the laser opened channels. However, the combination therapy with the modified TMLR method was performed using VEGF, but the effect of the combination was not recognized (Annals of Thoracic Surger
y, 62, 1051-1058 (1996)). As described above, in recent years, the FGF, VEGF, and TMLR methods have been known as one of the medical treatments or surgical treatments for myocardial infarction or angina pectoris, but the specific efficacy of these methods has been known. Was not yet revealed.

[0003]

An object of the present invention is to provide a remedy for myocardial infarction or angina. The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that ischemic myocardial injury can be improved by using hepatocyte growth factor (HGF). Furthermore, they have found that ischemic myocardial injury can be efficiently improved by using HGF in combination with the TMLR method.
The present invention has been achieved based on these findings. That is, the gist of the present invention is (1) a therapeutic agent for myocardial infarction or angina pectoris containing HGF as an active ingredient, (2) a preparation for local administration to the myocardium, the treatment according to (1) above. (3) The therapeutic agent according to (2), wherein the myocardial local region is a myocardial ischemic site, (4) Intracardiac angiogenesis using laser (TMLR) (1), (2) or (3).

[0004]

BEST MODE FOR CARRYING OUT THE INVENTION The HGF used in the present invention is already commercially available (Toyobo Code No. HGF-101, etc.), but it can be prepared by various methods as long as it is purified to the extent that it can be used as a medicine. Those prepared can be used. HGF
The HGF can also be obtained by culturing primary culture cells or cell lines that produce E. coli, and separating and purifying them from the culture supernatant or the like. Alternatively, a gene encoding HGF is inserted into an appropriate vector by a genetic engineering technique, inserted into an appropriate host, and transformed, and the desired recombinant HGF can be obtained from the culture supernatant of this transformant. (Eg Nat
ure, 342, 440 (1989), JP-A-5-111383, Biochem.
Biophys. Res. Commun. 163, 967 (1989) and the like). The host cells are not particularly limited, and various host cells conventionally used in genetic engineering techniques, for example, E. coli,
Yeast or animal cells can be used. The HGF thus obtained may have one or more amino acids in its amino acid sequence substituted, deleted and / or added, as long as it has substantially the same action as natural HGF.

[0005] It is preferred that the medicament of the present invention is prepared parenterally by preparing the above-mentioned HGF alone or as a pharmaceutical composition in the form of a pharmaceutical preparation together with appropriate pharmaceutical additives. The administration form of such a pharmaceutical composition is not particularly limited as long as it is generally used for parenteral administration.For example, an ampoule for injection or a lyophilized powder for injection may be used. it can. Preparation into various formulation forms can be performed according to a conventional method using well-known formulation additives available to those skilled in the art, for example, diluents and additives. For example, a freeze-dried powder for injection is prepared by dissolving an effective amount of the purified HGF in a diluent such as distilled water for injection, physiological saline, or an aqueous glucose solution, and if necessary, dissolving carboxymethyl sepharose, sodium alginate or the like. Excipients,
Polyethylene glycol, dextran sodium sulfate, amino acids, stabilizers such as human serum albumin, preservatives such as benzyl alcohol, benzalkonium chloride, phenol, soothing agents such as glucose, calcium gluconate, procaine hydrochloride, hydrochloric acid, acetic acid, A pH adjuster such as citric acid and sodium hydroxide is added, and the mixture can be produced by a conventional method. In addition, the ampoule for injection is prepared using the HGF
An effective amount of is dissolved in a diluent such as distilled water for injection, physiological saline, Ringer's solution and the like, and if necessary, a solubilizing agent such as sodium salicylate, mannitol, sodium citrate,
After adding additives such as buffering agents such as glycerin, glucose, isotonic agents such as added sugars, stabilizers, preservatives, soothing agents, and pH adjusting agents, ordinary heat sterilization, sterile filtration, etc. Can be prepared by sterilization. It should be noted that, depending on the type of the active ingredient, the active ingredient may be inactivated in the heat sterilization step, so the sterilization method should be appropriately selected.

The medicament of the present invention may contain an active ingredient of another drug having the same or similar pharmacological action as the HGF of the present invention. Moreover, sulfated other saccharides such as heparin and dextran sulfate or derivatives thereof (JP-A-5-301824), which are known to enhance the hepatocyte proliferation action of HGF which is an active ingredient of the medicament of the present invention, and the like. You may mix an active ingredient.

HGF, which is an active ingredient of the medicament of the present invention, comprises:
It has an angiogenic effect at the ischemic site of myocardial infarction. Furthermore, HGF can make its angiogenic effect more effective by being directly administered from the intraventricular space to the myocardium at the ischemic site. In addition, the effect is more certain when used in combination with the TMLR method. For example, administration of HGF directly to the myocardium in combination with the TMLR method promotes the development of a capillary bed effective for ischemic myocardium in the early postoperative period, improves myocardial contractility to a normal region, and improves other conditions. It can restore the heart function reserve.

[0008] The medicament of the present invention can be generally administered parenterally, more specifically by subcutaneous, intramuscular or intravenous injection, for the treatment of myocardial infarction or angina. A more preferred embodiment includes injecting HGF directly into the myocardium from the intraventricular cavity using a catheter. The myocardial localization into which the HGF is injected is preferably an ischemic site in the myocardium. Further, in order to promote angiogenesis or development of collateral circulation in a stenosis or occlusion in a coronary artery, an HGF solution can be locally released and applied using a catheter. In general, a predetermined amount can be administered once or divided into a plurality of doses, or can be continuously administered by infusion or the like. The dosage may include patient symptoms,
Adult patient's weight 1k, depending on age, gender, etc.
g, the daily dose is selected from the range of about 1 to about 500 μg, preferably about 1 to about 50 μg.

[0009]

EXAMPLES The present invention will be described below in more detail with reference to examples, but the present invention is not limited to these examples.

Experimental Materials and Methods Preparation of Myocardial Infarction Model and Administration of Drugs The left coronary artery and the left anterior descending branch of 18 beagle dogs with an average body weight of 10 kg were ligated immediately after the first diagonal branch to produce a cardiac ischemia model. . One month later, TMLR was performed on the ischemic myocardial border LAD region using a CO2 laser on six of the animals (T group).
Similarly, to 6 mice subjected to TMLR, 50 μg of HGF was administered twice to each channel created by laser (TH
group). The other six animals served as a control group without TMLR (C
group). Evaluation method Two months and five months after the ligation model was prepared, the LAD region (ischemic myocardial boundary region) and the LCX region (normal region) were col
The local myocardial blood flow (% F) was measured by the ored microsphere method. In addition, dobutamine was loaded at 15 μg / kg / min for 10 min, and changes in the longitudinal direction of myocardium (% S
S) and changes in myocardial wall thickness (% T) were measured. % F,% SS,% T
Were evaluated with the LCX region as 100%. Histological examination with an optical microscope was also added.

Example 1 As shown in Table 1, the ratio of the local myocardial blood flow in the LAD region to the normal region (LCX region) in the two months after the preparation of the ligation model was determined in the TMLR-treated group (T group) and the control group. Compared to the group (Group C), an increasing trend was observed in the group that underwent TMLR and administered HGF (TH group). As shown in Table 1, 5
At month, the TH group tended to increase over time.

[0012]

[Table 1]

Example 2 Regarding the cardiac mechanics, as shown in Tables 2 and 3, two months after the preparation of the ligated model,%
Both SS and% T showed low values. On the other hand,% SS and% T in the TH group showed a recovery to almost the steady region. These parameters of the T group and the TH group were further improved 5 months after the preparation of the ligation model, but were not improved in the control group (C group).

[0014]

[Table 2]

[0015]

[Table 3]

Example 3 In histological examination with an optical microscope two months after the preparation of the ligation model, the development of capillaries was recognized in the TH group as compared with the T group.

[0017]

EFFECT OF THE INVENTION HGF which is an active ingredient of the medicament of the present invention
Is useful for treating myocardial infarction or angina to promote the development of a capillary bed effective for ischemic myocardium.
More preferably, it can be used more effectively by directly administering HGF directly to the myocardium locally, or by directly injecting and applying it to the affected part (occlusion or stenosis) in the coronary artery. In addition, HGF can be used in combination with the TMLR method.
Directly in the myocardium to promote the development of an effective capillary bed for ischemic myocardium in the early postoperative period, improve myocardial contractility to the normal region, and restore other cardiac function reserves It is useful for treating myocardial infarction or angina.

Claims (4)

[Claims] 1. A therapeutic agent for myocardial infarction or angina pectoris comprising hepatocyte growth factor (HGF) as an active ingredient. 2. The therapeutic agent according to claim 1, which is a preparation for local administration to a myocardium. 3. The therapeutic agent according to claim 2, wherein the myocardial local region is a myocardial ischemia site. 4. Intramyocardial angiogenesis using a laser (T
4. The therapeutic agent according to claim 1, 2 or 3, which is used in combination with MLR).