WO1998033526A1

WO1998033526A1 - Remedies for cardiomyopathy

Info

Publication number: WO1998033526A1
Application number: PCT/JP1998/000426
Authority: WO
Inventors: Hiroaki Shimokawa
Original assignee: Sumitomo Pharmaceuticals Company, Limited
Priority date: 1997-02-03
Filing date: 1998-02-02
Publication date: 1998-08-06

Abstract

Preventives/remedies for cardiomyopathy or myocarditis containing selecting inihibitors, e.g., preventives/remedies for cardiomyopathy or myocarditis containing antiselectin antibodies or sialyl Lewis X derivatives as the selectin inhibitor.

Description

Description Cardiomyopathy therapeutic agent Technical field

The present invention relates to an agent for preventing or treating cardiomyopathy or myocarditis. More specifically, the present invention relates to a preventive / therapeutic agent for cardiomyopathy or myocarditis comprising a selectin inhibitor as an active ingredient. Background art

(Definition of cardiomyopathy)

Types of heart disease include 1) congenital heart disease, 2) valvular heart disease, 3) ischemic heart disease, and 4) hypertensive heart disease. However, cardiac hypertrophy and heart failure have been clinically recognized since 1960, despite not being such a disease. Such cases were called cardiomyopathy or muscular disease because they were thought to have caused cardiac lesions due to abnormalities in the myocardium itself. In 1995, a new proposal by the WH0 / ISFC Joint Committee defined “cardiomyopathy as a group of cardiomyopathy with cardiac dysfunction” (HEART nursing 9, 961-967 (1996), 32 cycles of latest internal medicine). Organ disease 4 "Cardiomyopathy and myocarditis" (1991)). In this application, this definition is also followed. (Classification of cardiomyopathy)

Cardiomyopathy can be broadly classified into the following two disease states based on clinical features and cardiac morphology. (1) Hypertrophic cardiomyopathy: Asymmetric hypertrophy of the ventricular wall, especially the ventricular septum. (2) Dilated cardiomyopathy: The main lesion is expansion of the ventricular cavity (HEAET nursing 9, 961-967 (1996), latest cardiology 32 cardiovascular disease 4 “Cardiomyopathy and myocarditis” (1991)). About half of patients with hypertrophic cardiomyopathy are familial. Genetic abnormalities such as muscle myosin heavy chain, cardiac topolonin T, cardiac α-tropomyosin, and cardiac myosin binding protein C have been discovered one after another, and it is becoming clear that this disease is sarcomer's disease caused by abnormal contractile proteins. . The characteristic condition is hypertrophy of the left and / or right ventricular myocardium, typically asymmetric hypertrophy of the ventricular septum. In some cases, abnormal hypertrophy extends to the apex and right ventricle. In terms of cardiac function, the inflow of blood from the atrium into the ventricle during diastole is impaired, and the lumen of the ventricle is narrowed. As a result, blood in the lungs from the left atrium becomes stagnant, causing heart failure symptoms such as shortness of breath and dyspnea (HEART nursing 9, 975-978 (1996). And myocarditis "(1991)).

The basic pathology of dilated cardiomyopathy is ventricular dilation and insufficiency, resulting in 75-95% of patients with heart failure symptoms, arrhythmic death (sudden death), thrombosis / embolism during the course. Are often merged. Patients with heart failure have a poor prognosis, with recent reports reporting a 5-year mortality rate of 20-30%. Although the etiology is unknown, familial inheritance, viral immunity, alcoholic toxicity, etc. are considered (HEAET nursing 9, 968 -974 (1996); 4 “Cardiomyopathy and Myocarditis” (1991)).

(Myocarditis as a basic disease of cardiomyopathy)

Recent studies suggest that myocarditis is the etiology of dilated cardiomyopathy. It has been reported that myocarditis caused by viruses, bacteria, parasites, etc. may have a long-term course and progress to dilated cardiomyopathy (HEART nursing 9, 979-983 (1996)).

Myocarditis is the presence of inflammation centered on the myocardium. Myocarditis due to infectious diseases is a common cause, and viral infections are particularly important. The mechanism of myocarditis caused by the virus is as follows: (1) cardiomyocyte injury due to an immune complex formed by binding of virus antigen and antibody; (2) in the presence of complement; Complement-dependent cardiomyocyte damage caused by binding of virus antigens to antibodies; ③ antibody-dependent cell-mediated cell damage by K cells and NK cells; ④ cardiomyocyte damage by macrophages and monocytes; ⑤ cell damage Cardiomyocyte damage by sex T lymphocytes is known.

(Myocarditis and sitekines)

In patients with myocarditis, an increase in plasma IL-1 and IL-1 / S and TNF-P was observed at a high rate, and TNF- was high in dilated and hypertrophic cardiomyopathy. Many (Brit. Heart J. 72, 561 (1994)). It has been strongly suggested that these site proteins have an important role in the pathogenesis of myocardial injury. In fact, in a myocarditis model in mice, after virus infection, 3-7 said that blood TNF-hi had risen, cardiac dysfunction was confirmed on 7-10, and 5-8 said about 75% Dies. In this myocarditis model, anti-TNF-α antibody improved survival rates, indicating the importance of cytokines in myocarditis (Internal Medicine 35, 60-63 (1996)).

However, it is not clear whether or not selectin is involved in cardiomyopathy or myocarditis, and the effect of selectin inhibitors on cardiomyopathy or myocarditis was not known. Summary of the Invention

An object of the present invention is to provide a therapeutic or prophylactic agent for cardiomyopathy or myocarditis.

The present inventors have conducted intensive studies to find a therapeutic or preventive agent for cardiomyopathy or myocarditis, and as a result, a selectin inhibitor is effective for cardiomyopathy induced by cytokines, that is, for cardiomyopathy or myocarditis. Thus, the present invention was completed. More specifically, in a cardiomyopathy or myocarditis model induced by administering IL-1 into the canine coronary artery, a selectin inhibitor suppresses the accumulation of leukocytes in cardiac tissues such as myocardium, resulting in cardiac function. Was found to improve. This indicates that the selectin inhibitor is effective in preventing or treating cardiomyopathy induced by cytokines.

That is, the present invention relates to a therapeutic or preventive agent for cardiomyopathy or myocarditis comprising a selectin inhibitor as an active ingredient. Further, the present invention relates to a prophylactic / therapeutic agent for cardiomyopathy or cardiomyositis, which comprises as an active ingredient a substance that suppresses infiltration of leukocytes into a lesion of cardiomyopathy or myocarditis. BRIEF DESCRIPTION OF THE FIGURES

The present invention will now be described by way of example with reference to the accompanying drawings. The drawings are as follows.

FIG. 1 is a graph showing the effect of an SLeX derivative or an anti-P-selectin antibody PB1.3 on leukocyte infiltration after administration of IL-1 / 3 microspheres.

FIG. 2 shows the effect of the SLeX derivative on left ventricular ejection fraction after IL-13 microsphere administration.

FIG. 3 shows the effect of the anti-P-selectin antibody PB1.3 on left ventricular ejection fraction after IL-1S microsphere administration. Detailed description

Cardiomyopathy contemplated by the present invention includes dilated cardiomyopathy. Myocarditis is an underlying disease of dilated cardiomyopathy.

The selectin inhibitor used in the present invention may be any as long as it inhibits the action of selectin. As selectins, for example, P -Selectin and E-selectin. Selectin inhibitors include, for example, agents containing the following four substances depending on the mode of inhibition.

① Substances that bind to selectin

This substance inhibits the binding between selectin and ligand by binding to selectin. Inhibitors of this type include, for example, anti-selectin antibodies, selectin ligands, derivatives of selectin ligands or non-sugar small molecule compounds.

② Substances that bind to selectin ligand

This substance inhibits the binding between selectin and ligand by binding to selectin ligand. Inhibitors of this type include, for example, antibodies specific for selectin ligands, selectin proteins and fragments thereof.

③Selectin expression inhibitor

This substance inhibits selectin expression. Examples of the present expression inhibitor include a selectin gene transcription inhibitor.

④Selectin ligand biosynthesis inhibitor

This substance inhibits the biosynthesis of selectin ligand. Inhibitors of this type include, for example, enzyme inhibitors involved in the biosynthesis of sialyl Lewis X.

Preferred among these are substances that bind to selectin. However, the selectin inhibitor used in the present invention may be a high-molecular compound or a low-molecular compound as long as it inhibits the action of selectin. It is not limited to the above inhibition mode.

An anti-selectin antibody refers to an immunoglobulin that recognizes selectin and selectively binds to selectin, thereby suppressing adhesion between cells. An example An example is an anti-P-selectin antibody. This antibody may be a polyclonal antibody or a monoclonal antibody. The origin of the antibody is not limited, and examples thereof include an antibody of mouse or human origin, a chimeric antibody in which both human and mouse antibodies are bound, or a humanized antibody. In particular,

PB1.3 described in W093 / 21956 is exemplified.

Selectin ligands include glycoproteins and glycolipids on the surface of leukocytes, as well as the sugar chains that are their terminal structures. PSGL-1 (Sako et al., Cell, 75, 1179-1186 (1993)) as a ligand that is a glycoprotein, and ESL-KSteegmaier et al., Nature, 373, 615-620 (() as a ligand for Ε-selectin. 1995)), glycoproteins GlyCAM-KLasky et al., Cell, 69, 927-938 (1992)) and MAdCAM-l (He mad erich et al., Biol. Chem., 270, 12035-) as ligands for L-selectin. 12047 (1995)), CD34 (Baumhueter et al., Science, 262, 436-438 (1993)), etc. Examples of sugar chain ligands include sialyl Lewis X (SL e X), Lewis X, sulfated sugar and the like. SL e X is a sugar chain present at the sugar chain end of the glycoprotein.

Derivatives of selectin ligands include glycoproteins, glycolipids, and sugar chain derivatives that are selectin ligands. Of these, sugar chain derivatives are preferred. Here, the sugar chain derivative also includes a mimetic (mimetics) which is a compound in which another sugar chain is substituted with a non-sugar structure while leaving a part of the sugar chain structure. Many compounds reported as derivatives of sugar chain ligands

(For example, WO911950K W09222565. WO9426760, 0952968K Orchid 31205, EP0671408, etc.)

Non-sugar low molecular weight compounds are low molecular weight compounds that do not contain a sugar chain structure. The compounds include, for example, compounds obtained by performing random screening, or the stereochemical interaction between selectin and sialyl Lewis X. Compounds obtained by analyzing the effects with a computer are included. Specific examples include compounds described in JP-A-7-330595 and JP-A-8-325285.

The antibody specific to a selectin ligand means an antibody specific to the above-mentioned ligand. This antibody may be a polyclonal antibody or a monoclonal antibody. The origin of the antibody is not limited, and examples thereof include an antibody of mouse or human origin, a chimeric antibody in which a part of both human and mouse antibodies are bound, or a humanized antibody. Specific examples include anti-Sialyl Lewis X antibody, anti-Sialyl Lewis a antibody, anti-Lewis X antibody, anti-Lewis a antibody and the like (for example, Fukushima et al., Cancer Res., 44, 5279 (1984). Shitara et al.) ., Cancer Res., 47, 1267 (1987), Takada et al., Biochem. Biophys. Res. Commun., 179, 713 (1991)).

Selectin proteins and fragments thereof include, for example, membrane-bound P-selectin, soluble P-selectin, P-selectin partial peptide, and the like. Selectin and its fragments adhere to cells, for example, the selectin adheres to the ligand or its derivative immobilized on a plastic well (or the selectin or its derivative adheres to the selectin immobilized on a plastic well). Derivative adheres). Examples of selectin partial peptides include those described in Japanese Patent Publication No. 7-501828.

A substance that binds to selectin or a substance that binds to a selectin ligand is selected by evaluating the activity of inhibiting the adhesion between selectin and one ligand. For example, a method for measuring the adhesion inhibitory activity between E, P-selectin and HL-60 cells having a ligand on the cell surface (Glycobiology, 5, 583-588 (1995)), E, P-selectin and SL e X The adhesion inhibitory activity with (JCI, 91, 1157-1166 (1993)) and a method for measuring the adhesion inhibitory activity of L-selectin and its ligand GlyCAM-1 (Biochemistry, 34, 14271-14277 (1995)). Can be

Selectin expression inhibitors include, for example, selectin gene transcription inhibitors. Examples of selectin gene transcription inhibitors include inhibitors of the activation of NF-κB, a transcription factor involved in the expression of E-selectin. Selectin expression inhibitors have the ability to inhibit selectin expression in cells or selectin gene expression (eg, Ferran et al., Biochem. Biophys. Res. Commun. 214, 212 (1995)).

The term “selectin ligand biosynthesis inhibitor” means an inhibitor such as glycosyltransferase used in the biosynthesis of the selectin ligand described above. Specific examples include an inhibitor for sialyltransferase for transferring sialic acid to the oligosaccharide force receptor, and an inhibitor for fucosyltransferase for transferring fucose. For example, a sialyltransferase inhibitor described in JP-A-5-247078 and a fucosyltransferase described in Chi-Huey Wong et al., J. Am. Chem. Soc. 114, 7321 (1992). And the like.

Examples of the substance used in the present invention that suppresses infiltration of leukocytes into a lesion of cardiomyopathy or myocarditis include a selectin inhibitor.

The prophylactic / therapeutic agent of the present invention is administered parenterally, topically, orally, or transdermally, and can be administered in various unit dosage forms depending on the administration method. For example, unit dosage forms suitable for oral administration include powders, tablets, pills, capsules and dragees.

Preferably, the prophylactic / therapeutic agent of the present invention is administered intravenously. For intravenous administration, dissolution in a pharmaceutically acceptable carrier, preferably an aqueous carrier Or use it suspended. As the aqueous carrier, for example, water, buffered water, physiological saline and the like can be used. The resulting aqueous solutions can be packaged as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous solution prior to administration. The prophylactic / therapeutic agent of the present invention may be a pharmaceutically acceptable auxiliary such as a pH adjusting and buffering agent, a tonicity adjusting agent, an infiltrating agent, and the like, for example, sodium acetate, sodium lactate, chloride, so as to approximate a physiological condition. It can contain concrete, calcium chloride, sorbitan monolaurate, triethanolamine, and the like.

The prophylactic / therapeutic agent of the present invention is administered for prophylactic and / or therapeutic treatment.

In therapeutic applications, the prophylactic / therapeutic agents of the invention may be used in patients already afflicted with a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Is administered. The dosage in such uses will, for example, vary according to the particular active ingredient, the mode of administration, the extent of the disease to be treated, the overall health of the patient, and the prescribing physician, but will generally vary for patients weighing 70 kg. The daily dose of the prophylactic / therapeutic agent of the present invention is in the range of about 0.5 mg to about 2000 mg, and preferably, for a patient weighing 70 kg, about 5 mg of the active ingredient of the present invention per day. Administer in the range of about 500 rag. In prophylactic applications, the prophylactic and therapeutic agents of the invention are administered to patients who are susceptible to, or otherwise at risk of, a particular disease. The dosage in such uses will, for example, vary according to the particular active ingredient, the mode of administration, the degree of the disease to be treated, the overall health of the patient, and the prescribing physician, but will generally vary for a patient weighing .70 kg. The daily dosage of the prophylactic and / or therapeutic agent of the present invention is in the range of about 0.5 mg to about 2000 mg, and preferably, for a patient weighing 70 kg, the active ingredient of the present invention is administered in a daily amount of about 5 mg to about 5 mg. 500 Administer in the mg range.

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

In the following examples, as a selectin inhibitor, an anti-P-selectin antibody PB1.3 (an antibody described in W093 / 21956) and one of derivatives of sialyl Lewis X known as a selectin ligand were used. The compound name of the present sialyl Lewis X derivative (hereinafter referred to as SL e X derivative) is ethyl (5_acetoamide-3,5-didequin-hi-D-glycerol-D-galact-2-nonuloviranosylic acid)-(2 -3)-0- (yS-D-Galactoviranosyl)-(Table 4)-0-[α-L-Fucopyranosyl- (1-3) -0]-(2-acetoamide-2-doxy-SD- Glucopyranosyl)-(1-3) -〇- / 3-D-galactopyranoside sodium salt, which can be produced according to a known method (US Pat. No. 5,576,305).

The specific explanation is given that these selectin inhibitors suppress the accumulation of leukocytes in cardiac tissues such as myocardium and improve cardiac function. Example

Effects of IL-1β coronary artery administration on leukocyte accumulation in the heart and cardiac function in dogs

(experimental method)

Under anesthesia closed chest, a microphone sphere to which IL-l ^ was chemically bound was administered from the left coronary artery of the dog. The negative control group received a microsphere not bound to IL-1 / 3. Daily ventricular ejection fraction (LVEF) was measured by echocardiography and left ventricular angiography until day 7 of microsphere administration. In addition, in order to measure the degree of leukocyte infiltration into the myocardial tissue, the activity of myelinated peroxidase (MP0) in the tissue was measured on the second and seventh days (myeous peroxidase was It is an enzyme that is specifically present in leukocytes. By measuring myeloperoxidase activity in tissues, the infiltration of leukocytes into tissues can be quantitatively measured.) The anti-P-selectin antibody PB1.3 was administered intravenously at a dose of 2 mg / kg 5 minutes before IL-1 / 3 microsphere administration. The SL eX derivative was administered intravenously at a dose of 35 mg / kg, 5 minutes before the administration of IL-1 / 3 microspheres, and then continuously administered intravenously at 1.75 nig / kg / h for 12 hours.

(Experimental result)

In the IL-1 / 3 microsphere administration group, an increase in leukocyte accumulation in myocardial tissue was observed on the 2nd and 7th days as compared to the negative control group (Fig. 1), and the left ventricular ejection fraction Also decreased from 1 to 7 days (Figs. 2 and 3). In the SLeX derivative or PB1.3 administration group, leukocyte accumulation in myocardial tissue was reduced (No. 7) (Fig. 1), and the SLeX derivative (Fig. 2) or PB1.3C administration group was in the left ventricle. Ejection rate also improved to 1-7.

Claims

The scope of the claims

1. A preventive and therapeutic agent for cardiomyopathy containing a selectin inhibitor as an active ingredient.

2. The preventive / therapeutic agent according to claim 1, wherein the selectin inhibitor is a substance that binds to selectin, a substance that binds to selectin ligand, a selectin expression inhibitor, or a selectin ligand biosynthesis inhibitor.

3. The preventive or therapeutic agent according to claim 2, wherein the selectin inhibitor is a substance that binds to selectin.

4. The preventive / therapeutic agent according to claim 3, wherein the substance that binds to selectin is an anti-selectin antibody, a selectin ligand, a derivative of a selectin ligand, or a non-saccharide low molecular weight compound.

5. The preventive / therapeutic agent according to claim 2, wherein the selectin inhibitor is a selectin ligand biosynthesis inhibitor.

6. A preventive and therapeutic agent for myocarditis containing a selectin inhibitor as an active ingredient.

7. The preventive / therapeutic agent according to claim 6, wherein the selectin inhibitor is a substance that binds to selectin, a substance that binds to selectin ligand, a selectin expression inhibitor, or a selectin ligand biosynthesis inhibitor.

8. The preventive / therapeutic agent according to claim 7, wherein the selectin inhibitor is a substance that binds to selectin.

9. The preventive or therapeutic agent according to claim 8, wherein the substance that binds to selectin is an anti-selectin antibody, a selectin ligand, a derivative of a selectin ligand, or a non-saccharide low molecular weight compound.

10. The preventive / therapeutic agent according to claim 7, wherein the selectin inhibitor is a biosynthesis inhibitor of a selectin ligand.

11. Has a substance that suppresses infiltration of leukocytes into lesions of cardiomyopathy or myocarditis. Prevention of cardiomyopathy or myocarditis as an active ingredient.