WO2010052828A1 - Agent pharmaceutique destiné à des troubles myocardiques non ischémiques - Google Patents

Agent pharmaceutique destiné à des troubles myocardiques non ischémiques Download PDF

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WO2010052828A1
WO2010052828A1 PCT/JP2009/005264 JP2009005264W WO2010052828A1 WO 2010052828 A1 WO2010052828 A1 WO 2010052828A1 JP 2009005264 W JP2009005264 W JP 2009005264W WO 2010052828 A1 WO2010052828 A1 WO 2010052828A1
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doxorubicin
midkine
drug
protein
amino acid
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PCT/JP2009/005264
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English (en)
Japanese (ja)
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堀場充
門松健治
原田将英
竹中拡晴
石黒久晶
住田有弘
蝶野貴彦
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国立大学法人名古屋大学
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Priority to JP2010536641A priority Critical patent/JP4831551B2/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • the present invention relates to a medicament for non-ischemic myocardial injury and its use.
  • MK Midkine
  • Non-patent documents 1 to 4 Involvement of MK in various diseases such as cancer and inflammatory diseases has been reported (Non-Patent Documents 5 and 6).
  • Patent Document 1 The action / effect of MK on myocardial ischemia / reperfusion injury was examined (Patent Document 1). As a result, it was shown that MK suppresses the suppression of myocardial damage progression in the acute phase by an anti-apoptotic effect. In the chronic phase after ischemia reperfusion, it was proved that the continuous administration of MK protein promotes angiogenesis and contributes to the improvement of cardiac function. Thus, it was shown that MK is effective for myocardial ischemia reperfusion injury.
  • Myocardial damage includes ischemic myocardial damage as well as non-ischemic myocardial damage such as cardiomyopathy, valvular disease, or dilated cardiomyopathy.
  • ischemic myocardial damage As well as non-ischemic myocardial damage such as cardiomyopathy, valvular disease, or dilated cardiomyopathy.
  • pathogenesis As well as the pathological conditions and symptoms of ischemic myocardial injury and non-ischemic myocardial injury.
  • there are many unexplained parts regarding the onset mechanism of non-ischemic myocardial injury and this is a big foot pad that prevents the establishment of an effective treatment for non-ischemic myocardial injury.
  • Non-patent Document 7 it has been reported that when MK is suppressed, activated T cells increase and autoimmune encephalomyelitis is suppressed (Non-patent Document 8). Taken together these two reports, MK suppression is expected to be an effective treatment strategy even in dilated cardiomyopathy.
  • an object of the present invention is to provide an effective medical means (treatment or prevention means) for non-ischemic myocardial injury.
  • the present inventors focused on various physiological activities of MK and examined the action of MK using an animal model of non-ischemic myocardial injury. As a result, administration of MK improved the symptoms of non-ischemic myocardial injury. That is, it has been found that enhancing MK rather than suppressing MK is effective in treating non-ischemic myocardial injury. In other words, an unexpected finding that “suppression of MK is an effective treatment strategy even in dilated cardiomyopathy” was brought forward, and the way to establish a treatment for non-ischemic myocardial injury was opened. It was.
  • MK is effective for drug-induced dilated cardiomyopathy
  • MK for dilated cardiomyopathy caused by arrhythmia Is effective.
  • the present invention is based on the above results and is as follows.
  • a medicament for non-ischemic myocardial injury comprising the following (1) or (2) as an active ingredient: (1) Midkine protein; (2) A vector carrying a midkine gene.
  • Drugs that induce dilated cardiomyopathy are doxorubicin, pharmaceutically acceptable salts of doxorubicin, doxorubicin derivatives (however, those having antitumor activity), pharmaceutically acceptable salts of doxorubicin derivatives
  • the medicament according to [6] which is a drug selected from the group consisting of: [8] A drug selected from the group consisting of doxorubicin, a pharmaceutically acceptable salt of doxorubicin, a doxorubicin derivative (provided that it has an antitumor action), and a pharmaceutically acceptable salt of a doxorubicin derivative is effective.
  • the medicine according to [7] which is used in combination with a medicine as an ingredient.
  • a method for treating non-ischemic myocardial injury comprising a step of administering a drug containing the following (1) or (2) as an active ingredient to a patient with non-ischemic myocardial injury: (1) Midkine protein; (2) A vector carrying a midkine gene.
  • a method for preventing or treating non-ischemic myocardial injury comprising a step of administering a drug containing the following (1) or (2) as an active ingredient to a patient undergoing cancer treatment with a drug as a component: (1) Midkine protein; (2) A vector carrying a midkine gene.
  • Protocol of experiment using drug-induced dilated cardiomyopathy model Echocardiographic findings in doxorubicin-induced dilated cardiomyopathy model mice.
  • MK protein was intraperitoneally administered with an osmotic pump to doxorubicin-induced dilated cardiomyopathy model mice, and the progress was observed by echocardiography.
  • the upper row shows M mode findings 4 weeks after the start of treatment. There is a clear difference between the findings in the control group and those in the MK treatment group.
  • the lower row shows the measurement results of EF (left ventricular ejection fraction) and FS (functional shortening rate) 4 weeks after the start of treatment.
  • the expression level of the MK treatment group was evaluated by the ratio to the expression level of the control group.
  • Results of experiments using rabbit tachycardia model Heart morphology (upper left), HE staining results (upper middle), pleural leakage and ascites retention (upper right), heart, lung, liver weight ratio (lower). Results of experiments using rabbit tachycardia model.
  • the upper graph compares echocardiograms
  • the lower graph compares ventricular septal wall thickness (IVSWT), left ventricular end-diastolic diameter (LVDd), left ventricular posterior wall thickness (PWT), and left ventricular ejection fraction (EF).
  • IVSWT ventricular septal wall thickness
  • LDDd left ventricular end-diastolic diameter
  • PWT left ventricular posterior wall thickness
  • EF left ventricular ejection fraction
  • the first aspect of the present invention relates to a medicament for non-ischemic myocardial injury.
  • “Non-ischemic myocardial injury” is a term opposite to ischemic myocardial injury and refers to myocardial injury caused by causes other than ischemia.
  • the “medicine for non-ischemic myocardial injury” refers to a drug used for the prevention or treatment of non-ischemic myocardial injury.
  • Representative examples of non-ischemic myocardial injury are dilated cardiomyopathy, hypertrophic cardiomyopathy, and valvular disease. Except as otherwise noted, “non-ischemic myocardial injury” in the present invention is as described above. It is a myocardial injury caused by causes other than ischemia, and is not limited to these three diseases (pathological conditions).
  • the medicament of the present invention contains (1) midkine protein or (2) a vector carrying the midkine gene as an active ingredient.
  • the pharmaceutical of this invention contains only either (1) and (2) normally, it does not prevent containing these both.
  • MK Midkine protein Midkine
  • MK is a growth and differentiation factor discovered as a product of a retinoic acid responsive gene and consists of a 13 kDa polypeptide rich in basic amino acids and cysteine (Kadomatsu, K. et al : Biochem. Biophys. Res. Commun., 151: 1312-1318; Tomomura, M. et al .: J. Biol. Chem., 265: 10765-10770, 1990). MK has many physiological activities as described above.
  • MK protein The amino acid sequence of MK (GenPept (NCBI), ACCESSION: NP_001012333, DEFINITION: midkine [Homo sapiens]) registered in a public database is shown in SEQ ID NO: 1 in the sequence listing.
  • the midkine protein (hereinafter referred to as “MK protein”), which is an active ingredient of the present invention, is preferably a polypeptide containing the amino acid sequence.
  • a polypeptide containing an amino acid sequence equivalent to the amino acid sequence can also be used as the MK protein.
  • the “equivalent amino acid sequence” here is partially different from the reference amino acid sequence (SEQ ID NO: 1), but this difference is related to the function of the protein (effective action against non-ischemic myocardial injury).
  • mouse MK protein is shown in SEQ ID NO: 5 (GenPept (NCBI), ACCESSION: NP_034914, DEFINITION: midkine [Mus musculus]), and the amino acid sequence of rat MK protein is shown in SEQ ID NO: 9 (GenPept (NCBI) ), ACCESSION: NP_110486, DEFINITION: midkine [Rattus norvegicus]).
  • “Different in part of amino acid sequence” typically means deletion or substitution of 1 to several amino acids (upper limit is 3, 5, 7, 10) constituting the amino acid sequence. Alternatively, it means that a mutation (change) has occurred in the amino acid sequence due to addition, insertion, or a combination of 1 to several amino acids (the upper limit is, for example, 3, 5, 7, 10). Differences in amino acid sequences here are allowed as long as there is no significant decrease in the above functions. As long as this condition is satisfied, the positions where the amino acid sequences are different are not particularly limited, and differences may occur at a plurality of positions.
  • plural refers to, for example, a number corresponding to less than about 30% of all amino acids, preferably a number corresponding to less than about 20%, and more preferably a number corresponding to less than about 10%.
  • the number is preferably less than about 5%, and most preferably less than about 1%. That is, the equivalent amino acid sequence is, for example, about 70% or more, preferably about 80% or more, more preferably about 90% or more, even more preferably about 95% or more, and most preferably about 99% or more with the amino acid sequence of SEQ ID NO: 1. Sequence identity.
  • conservative amino acid substitution refers to substitution of a certain amino acid residue with an amino acid residue having a side chain having the same properties.
  • a basic side chain eg lysine, arginine, histidine
  • an acidic side chain eg aspartic acid, glutamic acid
  • an uncharged polar side chain eg glycine, asparagine, glutamine, serine, threonine, tyrosine
  • Cysteine eg alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan
  • ⁇ -branched side chains eg threonine, valine, isoleucine
  • aromatic side chains eg tyrosine, phenylalanine, Like tryptophan and histidine.
  • a conservative amino acid substitution is preferably a substitution between amino acid residues within the same family.
  • sequence identity % of two amino acid sequences or two nucleic acid sequences (hereinafter, “two sequences” is used as a term including them) can be determined, for example, by the following procedure.
  • two sequences are aligned for optimal comparison (eg, a gap may be introduced into the first sequence to optimize alignment with the second sequence).
  • a molecule amino acid residue or nucleotide
  • Gapped BLAST described in Altschul et al. (1997) Amino Acids Research 25 (17): 3389-3402 can be used.
  • MK proteins can be easily prepared by using standard genetic engineering techniques, molecular biological techniques, biochemical techniques, etc. with reference to the sequence information disclosed in this specification or the attached sequence listing. Can do. For example, it can be prepared by transforming a suitable host cell (for example, E. coli or yeast) with DNA encoding MK protein and recovering the protein expressed in the transformant. The recovered protein is appropriately purified according to the purpose. Thus, various modifications are possible if the MK protein is obtained as a recombinant protein. For example, if a DNA encoding MK protein and other appropriate DNA are inserted into the same vector and a recombinant protein is produced using the vector, the peptide consists of a recombinant protein linked to any peptide or protein.
  • MK protein can be obtained.
  • modification may be performed so that addition of sugar chain and / or lipid, or processing of N-terminal or C-terminal may occur.
  • extraction of recombinant protein, simplification of purification, addition of biological function, and the like are possible.
  • MK protein can be prepared by a genetic engineering technique.
  • the method for preparing the MK protein is not limited to genetic engineering.
  • MK protein can also be prepared from natural materials by standard techniques (crushing, extraction, purification, etc.).
  • a vector holding a midkine gene (hereinafter referred to as “MK gene”) is used as an active ingredient.
  • a “vector” is a carrier for carrying a target gene to a target cell.
  • the MK gene is the target gene.
  • the type of vector is not particularly limited as long as the MK gene can be introduced into the target cell and expressed in the target cell.
  • the “vector” herein includes viral vectors and non-viral vectors. The gene transfer method using a virus vector skillfully utilizes the phenomenon that a virus infects cells, and high gene transfer efficiency can be obtained.
  • Adenovirus vectors, adeno-associated virus vectors, retrovirus vectors, lentivirus vectors, herpes virus vectors, Sendai virus vectors and the like have been developed as virus vectors.
  • Non-viral vectors include liposomes, positively charged liposomes (Felgner, PL, Gadek, TR, Holm, M. et al., Proc. Natl. Acad. Sci., 84: 7413-7417, 1987), HVJ (Hemagglutinating virus of Japan) -Liposome (Dzau, VJ, Mann, M., Morishita, R. et al., Proc. Natl. Acad. Sci., 93: 11421-11425, 1996, Kaneda, Y., Saeki, Y. & Morishita , R., Molecular Med. Today, 5: 298-303, 1999).
  • the vector in the present invention may be constructed as such a non-viral vector.
  • Retroviral vectors are not suitable for gene transfer into non-dividing cells because cell division is required for integration of the viral genome into the host chromosome.
  • lentivirus vectors and adeno-associated virus vectors cause integration of foreign genes into the host chromosome after infection even in non-dividing cells. Therefore, these vectors are effective for stably and long-term expressing foreign genes in non-dividing cells.
  • Each virus vector can be prepared according to a previously reported method or using a commercially available dedicated kit.
  • an adenovirus vector can be prepared by the COS-TPC method or full-length DNA introduction method.
  • the COS-TPC method is a homologous recombination that occurs in 293 cells by co-transfecting a recombinant cosmid incorporating the target cDNA or expression cassette and a parent virus DNA-terminal protein complex (DNA-TPC) into 293 cells.
  • DNA-TPC parent virus DNA-terminal protein complex
  • the full-length DNA introduction method is a method for producing a recombinant adenovirus by subjecting a recombinant cosmid inserted with a target gene to restriction digestion and then transfecting 293 cells (Miho Terashima, Koki Kondo). Hiromi Kanegae, Izumi Saito (2003) Experimental Medicine 21 (7) 931.).
  • the COS-TPC method can be performed using Adenovirus® Expression® Vector® Kit® (Dual® Version) (Takara Bio Inc.) and Adenovirus® genome® DNA-TPC (Takara Bio Inc.).
  • the full-length DNA introduction method can be performed using Adenovirus® Expression® Vector® Kit® (Dual® Version) (Takara Bio Inc.).
  • retroviral vectors can be prepared by the following procedure. First, the virus genome (gag, pol, env gene) other than the packaging signal sequence between the LTRs (Long Terminal Repeat) existing at both ends of the virus genome is removed, and the target gene is inserted therein. The viral DNA thus constructed is introduced into a packaging cell that constitutively expresses the gag, pol, and env genes. Thereby, only the vector RNA having the packaging signal sequence is incorporated into the viral particle, and a retroviral vector is produced.
  • the virus genome gag, pol, env gene
  • LTRs Long Terminal Repeat
  • the recombinant vector of the present invention may be constructed as such a viral vector.
  • the midkine gene inserted into the vector is preferably SEQ ID NO: 2 (GenBank (NCBI), ACCESSION: NM_001012334, DEFINITION: Homo sapiens midkine (neurite growth-promoting factor 2) (MDK), transcript variant 1, mRNA), SEQ ID NO: 3 (GenBank (NCBI), ACCESSION: NM_001012333, DEFINITION: Homo sapiens midkine (neurite growth-promoting factor 2) (MDK), transcript variant 2, mRNA), or SEQ ID NO: 4 (GenBank (NCBI), ACCESSION: NM_002391, DEFINITION: Homo sapiens midkine (neurite growth-promoting factor 2) (MDK), transcript variant 3, mRNA).
  • DNA having a base sequence equivalent to the base sequence can also be used as the MK gene.
  • the “equivalent base sequence” here is partly different from the standard base sequence, but the function of the protein encoded by the difference (effective action against non-ischemic myocardial injury) is substantial. This means a base sequence that is not affected by any significant influence.
  • a specific example of equivalent DNA is DNA that hybridizes under stringent conditions to a base sequence complementary to a reference base sequence (any one of SEQ ID NOs: 2 to 4).
  • the “stringent conditions” here are conditions under which so-called specific hybrids are formed and non-specific hybrids are not formed.
  • hybridization solution 50% formamide, 10 ⁇ SSC (0.15M NaCl, 15 mM sodium citrate, pH 7.0), 5 ⁇ Denhardt solution, 1% SDS, 10% dextran sulfate, 10 ⁇ g / ml denaturation
  • 5 ⁇ Denhardt solution 1% SDS
  • 10% dextran sulfate 10 ⁇ g / ml denaturation
  • incubation at about 42 ° C to about 50 ° C using salmon sperm DNA, 50 mM phosphate buffer (pH 7.5), followed by washing at about 65 ° C to about 70 ° C using 0.1 x SSC, 0.1% SDS can be mentioned.
  • Further preferable stringent conditions include, for example, 50% formamide, 5 ⁇ SSC (0.15M NaCl, 15 mM sodium citrate, pH 7.0), 1 ⁇ Denhardt solution, 1% SDS, 10% dextran sulfate, 10 ⁇ g / ml as a hybridization solution. Of denatured salmon sperm DNA, 50 mM phosphate buffer (pH 7.5)).
  • equivalent DNA it consists of a base sequence including substitution, deletion, insertion, addition, or inversion of one or more bases with respect to a reference base sequence (any one of SEQ ID NOs: 2 to 4). And a DNA encoding a protein effective against non-ischemic myocardial injury. Base substitution or deletion may occur at a plurality of sites.
  • the term “plurality” as used herein refers to, for example, 2 to 40 bases, preferably 2 to 20 bases, more preferably 2 to 10 bases, although it varies depending on the position and type of amino acid residues in the three-dimensional structure of the protein encoded by the DNA. It is.
  • Such equivalent DNAs include, for example, restriction enzyme treatment, treatment with exonuclease and DNA ligase, position-directed mutagenesis (MolecularMCloning, Third Edition, Chapter 13, Cold Spring Harbor Laboratory Press, New York) Includes substitutions, deletions, insertions, additions, and / or inversions of bases using mutation introduction methods (Molecular Cloning, ingThird Edition, Chapterhap13, Cold Spring Harbor Laboratory Press, New York) Thus, it can obtain by modifying DNA which has a standard base sequence.
  • the equivalent DNA can also be obtained by other methods such as ultraviolet irradiation.
  • DNA in which a base difference as described above is recognized due to a polymorphism represented by SNP (single nucleotide polymorphism).
  • mouse MK gene (Kadomatsu, K. et al., Biochem. Biophy. Res. Commun., 151, 1312 (1988)) and rat MK gene have been identified.
  • the sequence of the mouse MK gene is shown in SEQ ID NO: 6 (GenBank (NCBI), ACCESSION: NM_010784, DEFINITION: Mus musculus midkine (Mdk), transcript variant 1, mRNA), SEQ ID NO: 7 (GenBank (NCBI), ACCESSION: NM_001012335 , DEFINITION: Mus musculus midkine (Mdk), transcript variant 2, mRNA) and SEQ ID NO: 8 (GenBank (NCBI), ACCESSION: NM_001012336, DEFINITION: Mus musculus midkine (Mdk), transcript variant 3, MKRNA) Is shown in SEQ ID NO: 10 (GenBank (NCBI), ACCESSION: NM_030859, DEFINITION: Rattus
  • the MK gene can be prepared by using standard genetic engineering techniques, molecular biological techniques, biochemical techniques, etc. with reference to the sequence information disclosed in this specification or the attached sequence listing.
  • the MK gene can be isolated (and amplified) from a human cDNA library by appropriately using an oligonucleotide probe / primer that can specifically hybridize to the MK gene.
  • the oligonucleotide probe primer for example, DNA complementary to the base sequence shown in SEQ ID NO: 2 or a continuous part thereof is used. Oligonucleotide probes and primers can be easily synthesized using a commercially available automated DNA synthesizer.
  • Molecular® Cloning • Third • Edition, • Cold®Spring®Harbor®Laboratory®Press, and “New York” are helpful.
  • An equivalent DNA can be prepared by using a cDNA library derived from a non-human mammalian cell (for example, monkey, mouse, rat, pig, bovine) instead of the human cDNA library.
  • a cDNA library derived from a non-human mammalian cell (for example, monkey, mouse, rat, pig, bovine) instead of the human cDNA library.
  • the pharmaceutical preparation of the present invention can be prepared according to a conventional method.
  • other pharmaceutically acceptable ingredients for example, carriers, excipients, disintegrants, buffers, emulsifiers, suspending agents, soothing agents, stabilizers, preservatives, preservatives, physiological Saline solution and the like.
  • excipient lactose, starch, sorbitol, D-mannitol, sucrose and the like can be used.
  • disintegrant starch, carboxymethylcellulose, calcium carbonate and the like can be used. Phosphate, citrate, acetate, etc. can be used as the buffer.
  • emulsifier gum arabic, sodium alginate, tragacanth and the like can be used.
  • suspending agent glyceryl monostearate, aluminum monostearate, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, sodium lauryl sulfate and the like can be used.
  • soothing agent benzyl alcohol, chlorobutanol, sorbitol and the like can be used.
  • stabilizer propylene glycol, ascorbic acid or the like can be used.
  • preservatives phenol, benzalkonium chloride, benzyl alcohol, chlorobutanol, methylparaben, and the like can be used.
  • preservatives benzalkonium chloride, paraoxybenzoic acid, chlorobutanol and the like can be used.
  • a vector holding the MK gene When a vector holding the MK gene is used as an active ingredient, it may be formulated in combination with a pharmaceutically acceptable medium.
  • “Pharmaceutically acceptable medium” refers to a substance that provides advantages or benefits regarding the administration or storage of a vector without substantially affecting the efficacy of the vector (ie, effectiveness against non-ischemic myocardial injury).
  • examples of the “pharmaceutically acceptable medium” include deionized water, ultrapure water, physiological saline, phosphate buffered saline (PBS), and 5% dextrose aqueous solution.
  • the composition of the present invention may contain other components such as a suspending agent, a soothing agent, a stabilizer (albumin, Prionex (registered trademark, Penta Farm Japan), etc.), a preservative, and an antiseptic.
  • the vector carrying the MK gene is in the form of a viral vector
  • a biocompatible polyol for example, poloxamer 407
  • the use of polyol can increase the transduction rate of viral vectors by 10-100 times (March et al., Human Gene Therapy 6: 41-53, 41 1995). Therefore, if a polyol is used in combination, the dose of the viral vector can be kept low.
  • the dosage form for formulation is not particularly limited. Examples of dosage forms are tablets, powders, fine granules, granules, capsules, syrups, injections, external preparations, and suppositories.
  • the medicament of the present invention contains an active ingredient in an amount necessary for obtaining an expected therapeutic effect (or preventive effect) (that is, a therapeutically effective amount).
  • the amount of the active ingredient in the medicament of the present invention generally varies depending on the dosage form, but the amount of the active ingredient is set, for example, within the range of about 0.1% by weight to about 95% by weight so as to achieve a desired dose.
  • the medicament of the present invention is administered to the subject by oral administration or parenteral administration (intravenous, intraarterial, subcutaneous, intradermal, intramuscular or intraperitoneal injection, transdermal, nasal, transmucosal, etc.) according to the dosage form.
  • oral administration or parenteral administration intravenous, intraarterial, subcutaneous, intradermal, intramuscular or intraperitoneal injection, transdermal, nasal, transmucosal, etc.
  • parenteral administration intravenous, intraarterial, subcutaneous, intradermal, intramuscular or intraperitoneal injection, transdermal, nasal, transmucosal, etc.
  • administration routes are not mutually exclusive, and two or more arbitrarily selected can be used in combination (for example, intravenous injection or the like is performed simultaneously with oral administration or after a predetermined time has elapsed).
  • the “subject” here is not particularly limited, and includes humans and non-human mammals (including pet animals, domestic animals, laboratory animals. Specifically, for example, mice, rats, guinea pigs, hamsters, monkeys, cows, pigs, goats. , Sheep, dogs, cats, chickens, quails, etc.).
  • the medicament of the present invention is applied to humans.
  • the dosage of the medicine of the present invention is set so as to obtain the expected therapeutic effect.
  • a therapeutically effective dose the patient's symptoms, age, sex, weight, etc. are generally considered.
  • a person skilled in the art can set an appropriate dose in consideration of these matters.
  • the dose is adjusted so that the amount of active ingredient per day is about 0.1 mg to about 500 mg, preferably about 10 mg to about 50 mg.
  • the administration schedule for example, once to several times a day, once every two days, or once every three days can be adopted. In preparing the administration schedule, the patient's symptoms and the duration of effect of the active ingredient can be taken into consideration.
  • non-ischemic cardiomyopathy is a disease concept including dilated cardiomyopathy, hypertrophic cardiomyopathy and valvular disease.
  • dilated cardiomyopathy is cardiomyopathy characterized by a decrease in myocardial contraction of the left ventricle or both left and right ventricles and enlargement of its lumen.
  • Viral infections, genetic predispositions, immune disorders, systemic diseases, metabolic diseases, hypertension, alcohol, drugs, etc. are considered as etiologies. Onset of dilated cardiomyopathy is often observed as a side effect of anthracycline antitumor antibiotics.
  • hypertrophic cardiomyopathy is cardiomyopathy mainly characterized by left ventricular dilatation due to myocardial hypertrophy. Myocardial hypertrophy is not uniform and strong hypertrophy often occurs locally. Hypertrophic cardiomyopathy is roughly classified into obstructive hypertrophic cardiomyopathy due to thickening of the wall near the aortic valve and non-obstructive hypertrophic cardiomyopathy due to thickening of the apical wall.
  • valvular disease is a state in which a heart valve (aortic valve, pulmonary valve, tricuspid valve, mitral valve) has failed and cannot play its original role.
  • Valvular disease is aortic stenosis, aortic regurgitation, pulmonary stenosis, pulmonary regurgitation, tricuspid stenosis, tricuspid regurgitation, tricuspid regurgitation, mitral stenosis and It is roughly divided into mitral regurgitation.
  • congenital and acquired rheumatic fever, arteriosclerosis, myocardial infarction, degeneration, etc.
  • the medicament of the present invention exhibits its effectiveness particularly for dilated cardiomyopathy.
  • the medicament of the present invention is provided as a medicament for dilated cardiomyopathy.
  • MK showed a therapeutic effect in an animal model of drug-induced dilated cardiomyopathy (Example 1).
  • one of the preferred indications for the medicament of the present invention is drug-induced dilated cardiomyopathy.
  • MK showed a therapeutic effect on an animal model of dilated cardiomyopathy caused by arrhythmia (Example 2).
  • dilated cardiomyopathy due to arrhythmia is also a suitable indication for the medicament of the present invention. Therefore, in a preferred embodiment, the medicament of the present invention is provided as a medicament for drug-induced dilated cardiomyopathy and / or dilated cardiomyopathy caused by arrhythmia.
  • the drug here ie, drug that induces dilated cardiomyopathy
  • doxorubicin or a pharmaceutically acceptable salt thereof eg, hydrochloride
  • a drug having the same medicinal effect that is, a doxorubicin derivative (however, limited to those having an antitumor action) or a pharmaceutically acceptable salt thereof also corresponds to the “drug” herein.
  • doxorubicin is an anthracycline antitumor antibiotic and is also called adriamycin (common name).
  • a doxorubicin hydrochloride preparation is commercially available under the name Adriacin (trade name, Kyowa Hakko Kogyo Co., Ltd.).
  • Doxorubicin hydrochloride is a malignant lymphoma (reticulosarcoma, lymphosarcoma, Hodgkin's disease), lung cancer, gastrointestinal cancer (gastric cancer, gallbladder / bile duct cancer, pancreatic cancer, liver cancer, colon / rectal cancer, etc.), breast cancer, bladder tumor, osteosarcoma Used to treat. It is also used in combination with other antineoplastic agents and is also applied to breast cancer, endometrial cancer, malignant bone tumor, multiple myeloma, and childhood malignant solid tumor.
  • doxorubicin derivatives examples include epirubicin, pirarubicin and daunorubicin. All of these compounds have a molecular structure called anthracycline, like doxorubicin.
  • farmorubicin registered trademark, Pfizer Inc.
  • epirubicin hydrochloride Mylan Pharmaceutical Co., Ltd.
  • epirubicin hydrochloride preparations are known as epirubicin hydrochloride preparations.
  • pinorbin (trade name, Mercian Corporation, Nippon Kayaku Co., Ltd.) and terarubicin (Meiji Seika Co., Ltd.) are known as pirarubicin hydrochloride preparations
  • daunomycin (trade name, Meiji Seika Co., Ltd.) is known as a daunomycin hydrochloride preparation. ing.
  • the pharmaceutical of the present invention When administering a drug that may induce myocardial injury such as doxorubicin, the pharmaceutical of the present invention is administered in combination to prevent the occurrence of myocardial injury or to reduce the symptoms of myocardial injury. Also good.
  • the medicament of the present invention can also be used as a countermeasure against the side effects of a specific drug.
  • the following prevention or treatment method is mentioned as a specific example of the said aspect.
  • a drug selected from the group consisting of doxorubicin, a pharmaceutically acceptable salt of doxorubicin, a doxorubicin derivative (provided that it has an antitumor action) and a pharmaceutically acceptable salt of a doxorubicin derivative as an active ingredient A step of administering the medicament of the present invention (that is, a medicament containing (1) a midkine protein or (2) a vector carrying a midkine gene as an active ingredient) to a patient who receives a cancer treatment with said medicament. And a method for preventing or treating non-ischemic myocardial injury.
  • the doxorubicin derivatives epirubicin and pirarubicin have relatively low cardiotoxicity.
  • the medicament of the present invention is also effective when using a medicament (such as farmorubicin or pinorbin) containing these compounds as an active ingredient.
  • doxorubicin-induced dilated myocardium was administered by intraperitoneal administration of doxorubicin (Sigma) 3 mg / kg 6 times every other day (total dose 18 mg / kg) to 7-8 week old mice (C57BL / 6).
  • Disease model mice were prepared.
  • FIG. 2 shows the M mode findings, EF (left ventricular ejection fraction), and FS (functional shortening rate) 4 weeks after the start of treatment.
  • EF and FS are used as indicators of left ventricular contractility. From the M mode findings (upper), significant functional improvement is observed in the MK treatment group. In the MK treatment group, EF and FS also improved (lower row).
  • MK family and receptor The expression state of endogenous MK family protein Pleiotrophin and Syndecan 1, 3 and 4 which are receptors of MK was examined by the following method. MRNA was extracted from the isolated heart 4 weeks after treatment, and RNA expression was measured by quantitative PCR. As a result, the expression of pleiotrophin and syndecans 1, 3, and 4 was clearly enhanced in the MK treatment group ( FIG. 4).
  • Apoptosis-related factor The expression state of the factor Akt1 involved in apoptosis was examined by the following method. MRNA was extracted from the heart removed 4 weeks after treatment, and RNA expression was measured by quantitative PCR in the same manner as described above. As a result, a clear expression enhancement of Akt1 was observed in the MK treatment group (FIG. 5).
  • TIMP-1,2 Myocardial fibrosis-related factor
  • MRNA was extracted from the heart isolated 4 weeks after treatment, and RNA expression was measured by quantitative PCR as described above. As a result, the expression of TIMP-1,2 was clearly enhanced in the MK treatment group (Fig. 6).
  • ⁇ Effect of MK on the tachycardia model> (1) Creation of rabbit tachycardia model A rabbit tachycardia model was created by the following method (FIG. 7). First, anesthetize and intubate the rabbit, expose the heart after thoracotomy, and sew the tip of the pacemaker lead to the right ventricular epicardium. The pacemaker body is implanted subcutaneously in the back of the rabbit. Wait for recovery and stability after surgery for 10 days, and start tachycardia stimulation with a heart rate of 350 times / minute (physiological heart rate: average 185 times / minute) by a programmer. Create myocardial injury by sustaining tachycardia stimulation for 28 days.
  • MK Since MK showed a therapeutic effect in an animal model of non-ischemic myocardial injury (Examples 1 and 2), MK is effective for non-ischemic myocardial injury. (2) Since two animal models (Examples 1 and 2) whose therapeutic effects have been confirmed both reproduce dilated cardiomyopathy, MK is effective for dilated cardiomyopathy. (3) Since MK showed a therapeutic effect in an animal model of drug-induced dilated cardiomyopathy (Example 1), MK is effective for drug-induced dilated cardiomyopathy.
  • doxorubicin or its derivatives used for the production of animal models are frequently used for the treatment of malignant lymphoma, lung cancer, digestive organ cancer, breast cancer, bladder tumor, osteosarcoma, etc.
  • Cardiotoxicity (cause of myocardial injury)” is a problem.
  • MK showed a therapeutic effect on an animal model of dilated cardiomyopathy caused by arrhythmia (Example 2), MK is effective for dilated cardiomyopathy caused by arrhythmia.
  • the medicament of the present invention is effective for treating or preventing non-ischemic myocardial injury.
  • application to dilated cardiomyopathy caused by drug-induced dilated cardiomyopathy or arrhythmia is expected.
  • the medicament of the present invention is used in combination with the anticancer agent.

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Abstract

La présente invention a pour objet un moyen médical (un moyen thérapeutique ou prophylactique) efficace pour les troubles myocardiques non ischémiques.  L’invention concerne spécifiquement : un agent pharmaceutique destiné à des troubles myocardiques non ischémiques qui comprend (1) une protéine midkine ou (2) un vecteur portant un gène midkine en tant que principe actif ; et une méthode prophylactique ou thérapeutique pour des troubles myocardiques non ischémiques, qui utilise l’agent pharmaceutique.
PCT/JP2009/005264 2008-11-06 2009-10-09 Agent pharmaceutique destiné à des troubles myocardiques non ischémiques WO2010052828A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09100240A (ja) * 1995-06-14 1997-04-15 Sanofi Sa 特に心血管系の愁訴の治療に有効な医薬品の製造のためのアンギオテンシンｉｉ拮抗剤及びベンゾフラン誘導体の使用
WO2001026694A1 (fr) * 1999-10-08 2001-04-19 Medgene Bioscience, Inc. Therapie genique pour cardiomyopathie
JP2002241306A (ja) * 2001-02-14 2002-08-28 Junkanki Kenkyusho:Kk 拡張型心筋症治療薬
JP2005068122A (ja) * 2003-08-27 2005-03-17 Mitsuru Horiba ミッドカインによる心筋障害予防および治療への応用。
WO2007098716A1 (fr) * 2006-02-28 2007-09-07 Centro De Ingeniería Genética Y Biotecnología Composés analogues aux sécrétagogues peptidiques de l'hormone de croissance et préparations contenant ceux-ci
WO2008047904A1 (fr) * 2006-10-20 2008-04-24 National University Corporation Nagoya University Agent thérapeutique pour vasculopathie périphérique oblitérante et utilisation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09100240A (ja) * 1995-06-14 1997-04-15 Sanofi Sa 特に心血管系の愁訴の治療に有効な医薬品の製造のためのアンギオテンシンｉｉ拮抗剤及びベンゾフラン誘導体の使用
WO2001026694A1 (fr) * 1999-10-08 2001-04-19 Medgene Bioscience, Inc. Therapie genique pour cardiomyopathie
JP2002241306A (ja) * 2001-02-14 2002-08-28 Junkanki Kenkyusho:Kk 拡張型心筋症治療薬
JP2005068122A (ja) * 2003-08-27 2005-03-17 Mitsuru Horiba ミッドカインによる心筋障害予防および治療への応用。
WO2007098716A1 (fr) * 2006-02-28 2007-09-07 Centro De Ingeniería Genética Y Biotecnología Composés analogues aux sécrétagogues peptidiques de l'hormone de croissance et préparations contenant ceux-ci
WO2008047904A1 (fr) * 2006-10-20 2008-04-24 National University Corporation Nagoya University Agent thérapeutique pour vasculopathie périphérique oblitérante et utilisation

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