JP2002080395A - Agent for treatment of myocardial lesion - Google Patents
Agent for treatment of myocardial lesionInfo
- Publication number
- JP2002080395A JP2002080395A JP2000264527A JP2000264527A JP2002080395A JP 2002080395 A JP2002080395 A JP 2002080395A JP 2000264527 A JP2000264527 A JP 2000264527A JP 2000264527 A JP2000264527 A JP 2000264527A JP 2002080395 A JP2002080395 A JP 2002080395A
- Authority
- JP
- Japan
- Prior art keywords
- sod
- agent
- group
- administration
- myocardial injury
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、レシチン化スーパ
ーオキシドジスムターゼ（以下、単にＰＣ−ＳＯＤとも
いう）を含有する心筋傷害処置剤に関する。TECHNICAL FIELD The present invention relates to an agent for treating myocardial injury containing lecithinated superoxide dismutase (hereinafter, also simply referred to as PC-SOD).
【０００２】[0002]
【従来の技術】Clin. Exp. Metastasis, 17(3), p239-2
44 (1999)には、アントラサイクリン系抗腫瘍性抗生物
質であるアドリアマイシンと、スーパーオキシドジスム
ターゼ（以下、単にＳＯＤともいう）との併用投与によ
る、癌転移に対する効果についての記載がある。[Prior Art] Clin. Exp. Metastasis, 17 (3), p239-2
44 (1999) describes an effect on cancer metastasis by the combined administration of adriamycin, an anthracycline antitumor antibiotic, and superoxide dismutase (hereinafter, also simply referred to as SOD).
【０００３】しかしながらこの先行技術には、ＰＣ−Ｓ
ＯＤ投与について、およびこれによる心筋傷害に対する
効果については記載されていない。However, this prior art includes PC-S
No mention is made of OD administration and its effect on myocardial injury.
【０００４】[0004]
【発明が解決しようとする課題】本発明は、ＰＣ−ＳＯ
Ｄを含有する、より有効な心筋傷害処置剤を提供するこ
とを課題とする。SUMMARY OF THE INVENTION The present invention relates to a PC-SO
It is an object to provide a more effective agent for treating myocardial injury containing D.
【０００５】[0005]
【課題を解決するための手段】本発明者らは上記課題を
解決するために鋭意検討を行った結果、ＰＣ−ＳＯＤ
が、アドリアマイシンの投与により引き起こされる心筋
傷害を有意に抑制することを見い出し、これにより上記
課題を解決しうる心筋傷害処置剤を提供するに至り、本
発明を完成した。The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that PC-SOD
Found that they significantly suppressed myocardial injury caused by the administration of adriamycin, thereby providing a therapeutic agent for myocardial injury capable of solving the above problems, and completed the present invention.
【０００６】すなわち本発明は、ＰＣ−ＳＯＤを含有す
る心筋傷害処置剤（以下、本発明処置剤という）を提供
する。That is, the present invention provides a therapeutic agent for myocardial injury containing PC-SOD (hereinafter referred to as the therapeutic agent of the present invention).
【０００７】[0007]
【発明の実施の形態】＜１＞ＰＣ−ＳＯＤ 本明細書における「レシチン」とは、フォスファチジル
コリンを意味する通常のレシチンをいい、「リゾレシチ
ン」とは、レシチンのグリセロールの２位に結合してい
る脂肪酸１分子がとれて、２位の炭素原子に水酸基が結
合した化合物をいう。BEST MODE FOR CARRYING OUT THE INVENTION <1> PC-SOD In the present specification, “lecithin” refers to ordinary lecithin meaning phosphatidylcholine, and “lysolecithin” binds to position 2 of glycerol of lecithin. A compound in which one molecule of a fatty acid is removed and a hydroxyl group is bonded to the 2-position carbon atom.
【０００８】本発明に用いられるＰＣ−ＳＯＤは、通
常、リゾレシチンの２位の水酸基に化学的架橋剤を結合
させたレシチン誘導体を、ＳＯＤに１個以上結合させて
得ることができる。このＰＣ−ＳＯＤは一般式（Ｉ）で
表わされる。 ＳＯＤ’ （Ｑ−Ｂ）m （Ｉ） 一般式（Ｉ）中、ＳＯＤ’はスーパーオキシドジスムタ
ーゼの残基を表す。[0008] The PC-SOD used in the present invention can be usually obtained by binding one or more lecithin derivatives in which a chemical crosslinking agent is bonded to the hydroxyl group at the 2-position of lysolecithin to SOD. This PC-SOD is represented by the general formula (I). SOD ′ (QB) m (I) In the general formula (I), SOD ′ represents a residue of superoxide dismutase.
【０００９】ＳＯＤ’は、生体内の活性酸素O2 -の分解
というその本来の機能を発揮し得る限りにおいて、その
起源等は特に限定されるものではなく、各種の動植物又
は微生物に由来するＳＯＤ残基を広く用いることができ
る。しかしながら、医薬品用途においては、生体内での
抗原性をできる限り減らすのが好ましいことから、ＳＯ
Ｄ’は、本発明処置剤を投与する動物種に応じて、適宜
適切なＳＯＤ残基を選択することが好ましい。例えば、
最も本発明処置剤が必要であると考えられるヒトを対象
とする場合のＳＯＤ残基には、ヒト体内における抗原性
をできる限り減らすために、ヒト由来のＳＯＤ残基を用
いることが好ましい。[0009] SOD 'is active oxygen O 2 in vivo - as long as capable of exhibiting its inherent function of decomposition, its origin and the like are not particularly limited, from a variety of animals and plants or microorganisms SOD The residues can be widely used. However, in pharmaceutical applications, it is preferable to reduce antigenicity in vivo as much as possible.
For D ′, it is preferable to appropriately select an appropriate SOD residue depending on the animal species to which the therapeutic agent of the present invention is administered. For example,
It is preferable to use a human-derived SOD residue as the SOD residue for humans who need the therapeutic agent of the present invention most in order to reduce antigenicity in the human body as much as possible.
【００１０】ヒト由来のＳＯＤとしては、ヒト由来のＣ
ｕ／Ｚｎ ＳＯＤ（活性中心に銅と亜鉛を含むヒト由来
のＳＯＤ；以下、ヒトＣｕ／Ｚｎ ＳＯＤと略記するこ
ともある）が、細胞内における発現量が多く、また遺伝
子工学的手法による生産技術が確立しており、大量に調
製することが可能であるため、特に好ましい。Human-derived SOD includes human-derived COD.
u / Zn SOD (human-derived SOD containing copper and zinc in the active center; hereinafter may be abbreviated as human Cu / Zn SOD) has a large amount of expression in cells and is produced by genetic engineering techniques. Is particularly preferable since it can be prepared in large quantities.
【００１１】このヒトＣｕ／Ｚｎ ＳＯＤには、ヒト組
織から製造される天然のヒトＣｕ／Ｚｎ ＳＯＤ；遺伝
子工学的手法により製造されるヒトＣｕ／Ｚｎ ＳＯ
Ｄ；天然のヒトＣｕ／Ｚｎ ＳＯＤと実質上同一のアミ
ノ酸配列を有する組換えヒトＣｕ／Ｚｎ ＳＯＤ、これ
らのヒトＣｕ／Ｚｎ ＳＯＤのアミノ酸配列中の一部の
アミノ酸を化学的に修飾もしくは改変したＳＯＤ等があ
り、いずれのヒトＣｕ／ＺｎＳＯＤであってもよい。The human Cu / Zn SOD includes natural human Cu / Zn SOD produced from human tissue; human Cu / Zn SOD produced by genetic engineering techniques.
D: Recombinant human Cu / Zn SOD having an amino acid sequence substantially identical to natural human Cu / Zn SOD, and some amino acids in the amino acid sequence of these human Cu / Zn SOD were chemically modified or modified. SOD and the like, and any human Cu / Zn SOD may be used.
【００１２】参考のため、この天然のヒトＣｕ／Ｚｎ
ＳＯＤのタンパク質のアミノ酸配列を配列番号１に示
す。なお、実際のヒトＣｕ／Ｚｎ ＳＯＤは、このアミ
ノ酸配列を有するタンパク質が二量体（ダイマー）とな
っている。For reference, this natural human Cu / Zn
The amino acid sequence of the SOD protein is shown in SEQ ID NO: 1. In the actual human Cu / Zn SOD, a protein having this amino acid sequence is a dimer.
【００１３】このタンパク質におけるアミノ酸配列に示
すごとく、天然のヒトＣｕ／ＺｎＳＯＤの１１１位のア
ミノ酸はシステインであるが、蛋白工学的手法、例えば
部位特異的変異法により、この１１１位をセリンに変換
したヒトＣｕ／Ｚｎ ＳＯＤ（特開昭62-130684号公報）
や、化学的にこの１１１位のシステインを修飾したヒト
Ｃｕ／Ｚｎ ＳＯＤ（特開平6-199895号公報）も報告さ
れており、これらのヒトＣｕ／Ｚｎ ＳＯＤを素材とし
て、本発明におけるＰＣ−ＳＯＤを得ることができる。
そして、これらのヒトＣｕ／Ｚｎ ＳＯＤの中でも、電
荷的及び分子量的に均一でかつＳＯＤ活性が安定してい
る、１１１位のシステインを化学的に修飾した、例えば
このシステインをＳ−（２−ヒドロキシエチルチオシス
テイン）としたヒトＣｕ／Ｚｎ ＳＯＤを素材として、
本発明におけるＰＣ−ＳＯＤを得るのが好ましい。As shown in the amino acid sequence of this protein, the amino acid at position 111 in natural human Cu / ZnSOD is cysteine, but this position has been converted to serine by protein engineering techniques such as site-directed mutagenesis. Human Cu / Zn SOD (JP-A-62-130684)
Also, human Cu / Zn SOD in which the cysteine at position 111 is chemically modified (JP-A-6-199895) has been reported, and the PC-SOD in the present invention was prepared using these human Cu / Zn SOD as a material. Can be obtained.
Among these human Cu / Zn SODs, the cysteine at position 111, which is uniform in charge and molecular weight and has stable SOD activity, is chemically modified. For example, this cysteine is S- (2-hydroxy Ethylthiocysteine) using human Cu / Zn SOD as material
It is preferable to obtain PC-SOD in the present invention.
【００１４】なお本明細書においては、このようにヒト
Ｃｕ／Ｚｎ ＳＯＤにおいて部位特異的変異法等により
一部アミノ酸を変換したものや、ヒトＣｕ／Ｚｎ ＳＯ
Ｄの一部のアミノ酸を化学的に修飾して得られるものも
含めて、単にヒトＣｕ／ＺｎＳＯＤという。In this specification, human Cu / Zn SOD obtained by partially converting amino acids by site-directed mutagenesis or the like,
It is simply called human Cu / ZnSOD, including those obtained by chemically modifying some amino acids of D.
【００１５】また、一般式（Ｉ）中のＢで示される「グ
リセロールの２位に水酸基を有するリゾレシチンの、そ
の水酸基の水素原子を除いた残基」は、次式(II)で表さ
れる。The "residue of lysolecithin having a hydroxyl group at the 2-position of glycerol except for the hydrogen atom of the hydroxyl group" represented by B in the general formula (I) is represented by the following formula (II): .
【００１６】 -O-CH(CH2OR)[CH2OP(O)(O-)(OCH2CH2N+(CH3)3)] （II） （式中、Ｒは脂肪酸残基（アシル基）である。） Ｒは、炭素数１０〜２８の飽和又は不飽和の脂肪酸残基
が好ましく、より好ましくはミリストイル基、パルミト
イル基、ステアロイル基、イコサノイル基、ドコサノイ
ル基、その他炭素数が１４〜２２の飽和脂肪酸残基であ
り、特に好ましくは炭素数１６の飽和脂肪酸残基である
パルミトイル基である。[0016] -O-CH (CH 2 OR) [CH 2 OP (O) (O -) (OCH 2 CH 2 N + (CH 3) 3)] (II) ( wherein, R fatty acid residue ( R is preferably a saturated or unsaturated fatty acid residue having 10 to 28 carbon atoms, more preferably a myristoyl group, a palmitoyl group, a stearoyl group, an icosanoyl group, a docosanoyl group, or a group having 14 or more carbon atoms. And a palmitoyl group which is a saturated fatty acid residue having 16 carbon atoms.
【００１７】また一般式（Ｉ）中のＱは化学的架橋を表
す。化学的架橋は、ＳＯＤとレシチンとを架橋して化学
的に結合（共有結合）させ得るものであれば特に限定さ
れない。化学的架橋としては、残基−Ｃ（Ｏ）−(Ｃ
Ｈ2)n−Ｃ（Ｏ）−が好ましい。この残基は、 式ＨＯ−
Ｃ（Ｏ）−(ＣＨ2)n−Ｃ（Ｏ）−ＯＨで表される直鎖状
ジカルボン酸、このジカルボン酸の無水物、このジカル
ボン酸のエステル、このジカルボン酸のハロゲン化物、
又はこのジカルボン酸の他の反応性誘導体等を化学的架
橋剤分子として、該分子の両端に存在する水酸基（無水
物、エステル、ハロゲン化物等の反応性誘導体の場合
は、このジカルボン酸の両端に存在する水酸基に対応す
る部分）を除いた残基である。Q in the general formula (I) represents chemical crosslinking. Chemical cross-linking is not particularly limited as long as it can cross-link SOD and lecithin and chemically bond (covalently bond). Chemical cross-linking includes the residues -C (O)-(C
H 2) n -C (O) - are preferred. This residue has the formula HO-
A linear dicarboxylic acid represented by C (O) — (CH 2 ) n —C (O) —OH, an anhydride of the dicarboxylic acid, an ester of the dicarboxylic acid, a halide of the dicarboxylic acid,
Alternatively, the other reactive derivative of the dicarboxylic acid or the like is used as a chemical crosslinking agent molecule, and a hydroxyl group existing at both ends of the molecule (in the case of a reactive derivative such as an anhydride, an ester, or a halide, is attached to both ends of the dicarboxylic acid) (A portion corresponding to an existing hydroxyl group).
【００１８】一般式（Ｉ）中のＱが上記直鎖状ジカルボ
ン酸の残基である場合、Ｑは、その一端において、前記
式（II）のリゾレシチン残基の水酸基由来の酸素とエス
テル結合により結合している。When Q in the general formula (I) is a residue of the above-mentioned linear dicarboxylic acid, Q is bonded at one end thereof to an oxygen bond derived from a hydroxyl group of the lysolecithin residue of the formula (II) by an ester bond. Are combined.
【００１９】また、この場合、このＱの他端は、ＳＯＤ
のアミノ基とアミド結合などにより直接結合していると
考えられる。従ってこの場合、ＳＯＤ’は、ＳＯＤの結
合に関与するアミノ基から水素原子を除いた残基を示
す。なお前記の化学的架橋において、基−(ＣＨ2)n−に
おけるｎは２以上の整数であり、好ましくは２〜１０の
整数であり、特に好ましくは３である。In this case, the other end of the Q is connected to the SOD
It is considered that the amino group is directly bonded to the amino group by an amide bond or the like. Therefore, in this case, SOD 'indicates a residue obtained by removing a hydrogen atom from an amino group involved in the binding of SOD. In the chemical crosslinking described above, n in the group — (CH 2 ) n — is an integer of 2 or more, preferably an integer of 2 to 10, and particularly preferably 3.
【００２０】また一般式（Ｉ）中のｍは、ＳＯＤ１分子
に対するリゾレシチンの平均結合数を表している。ｍは
１以上の正数であり、１〜１２の範囲の正数が好まし
く、４であることが特に好ましい。In the general formula (I), m represents the average number of lysolecithin bound to one SOD molecule. m is a positive number of 1 or more, preferably a positive number in the range of 1 to 12, and particularly preferably 4.
【００２１】ＰＣ−ＳＯＤの製造方法、すなわち、レシ
チン誘導体とＳＯＤとの結合方法は、公知の方法、例え
ば特開平６−５４６８１号公報に記載された方法が採用
できる。ＰＣ−ＳＯＤの製造については、実施例中に具
体的に記載する。As a method for producing PC-SOD, that is, a method for binding a lecithin derivative to SOD, a known method, for example, a method described in JP-A-6-54681 can be adopted. The production of PC-SOD is specifically described in Examples.
【００２２】また、本発明処置剤に用いるＰＣ−ＳＯＤ
は、医薬として使用できる程度に精製され、医薬として
混入が許されない物質を実質的に含まないものであるこ
とが好ましい。Further, PC-SOD used in the treatment agent of the present invention
Is preferably purified to such an extent that it can be used as a medicament, and is substantially free from substances that are not allowed to be contaminated as medicament.
【００２３】例えばＰＣ−ＳＯＤは、2,500 U/mg(PC-SO
D)以上の比活性を有する精製されたものを用いるのが好
ましく、3,000 U/mg(PC-SOD)以上の比活性を有する精製
されたものがより好ましい。なお、本明細書において１
U(ユニット)とは、pH7.8、30℃下でＮＢＴ(ニトロブル
ーテトラゾリウム)を用いてJ.Biol.Chem. Vol.244, No.
22, 6049-6055(1969)に準じた方法により測定し、ＮＢ
Ｔの還元速度を５０％阻害するＰＣ−ＳＯＤの酵素量を
表す。For example, PC-SOD is 2,500 U / mg (PC-SOD
It is preferable to use a purified product having a specific activity of D) or more, and more preferably a purified product having a specific activity of 3,000 U / mg (PC-SOD) or more. In this specification, 1
U (unit) is defined as J. Biol. Chem. Vol. 244, No. 1 using NBT (nitro blue tetrazolium) at pH 7.8 and 30 ° C.
22, Measured by the method according to 6049-6055 (1969), NB
The amount of PC-SOD enzyme that inhibits the reduction rate of T by 50% is shown.
【００２４】ＰＣ−ＳＯＤは、例えば注射（静脈内、筋
肉内、皮下、皮内等）、経口、吸入等の投与方法によっ
て、経口あるいは非経口的に投与することができる。投
与方法に応じてＰＣ−ＳＯＤを適宜製剤化して、本発明
処置剤とすることができる。剤形としては、注射剤（溶
液、懸濁液、乳濁液、用時溶解用固形剤等）、錠剤、カ
プセル剤、顆粒剤、散剤、液剤、リポ化剤、ゲル剤、外
用散剤、スプレー剤、吸入散剤等が挙げられるが、注射
剤が好ましい。The PC-SOD can be administered orally or parenterally, for example, by an injection (intravenous, intramuscular, subcutaneous, intradermal, etc.), oral, inhalation or other administration method. The treatment agent of the present invention can be appropriately formulated into PC-SOD according to the administration method. Dosage forms include injections (solutions, suspensions, emulsions, solids for dissolution before use, etc.), tablets, capsules, granules, powders, solutions, lipoagents, gels, external powders, sprays Preparations, inhalation powders and the like, but injections are preferred.
【００２５】本発明処置剤を注射剤として提供する場
合、その形態は、溶液状、凍結状、または凍結乾燥状の
いずれであっても良い。これをアンプル、バイアル、注
射用シリンジ等の適当な容器に充填・密封し、そのまま
流通させあるいは保存して、注射剤として投与できる。When the therapeutic agent of the present invention is provided as an injection, it may be in the form of a solution, a frozen form, or a lyophilized form. This can be filled and sealed in a suitable container such as an ampoule, a vial, or a syringe for injection, and then distributed or stored as it is, and administered as an injection.
【００２６】本発明処置剤の製剤化は、公知の方法を用
いることができる。また製剤化にあたり、ＰＣ−ＳＯＤ
に悪影響を与えず、かつ本発明の効果に悪影響を与えな
い限りにおいて、他の医薬活性成分や、慣用の賦形剤、
安定化剤、結合剤、滑沢剤、乳化剤、浸透圧調整剤、緩
衝剤、等張化剤、保存剤、無痛化剤、着色剤、崩壊剤
等、通常医薬に用いられる成分を使用できる。The treatment agent of the present invention can be formulated by a known method. Also, when formulating PC-SOD
As long as it does not adversely affect the effects of the present invention, other pharmaceutically active ingredients and conventional excipients,
Components usually used in medicine such as a stabilizer, a binder, a lubricant, an emulsifier, an osmotic agent, a buffer, a tonicity agent, a preservative, a soothing agent, a coloring agent and a disintegrant can be used.
【００２７】＜３＞本発明処置剤の投与対象等本発明処
置剤が投与される動物は、脊椎動物、特に哺乳動物が好
ましく、とりわけヒトが好ましい。本発明処置剤は、こ
れら動物における心筋傷害の処置のために投与されるも
のであるが、心筋傷害の抑制又は予防のために投与され
ることが好ましい。本発明にいう心筋傷害は、当分野に
おいてこれらの用語により理解される意味を有し、例え
ば心電図でモニターした場合にＳＴ部分の間隔の有意な
延長が認められる状態が該当する。本発明処置剤は、自
然発症する心筋傷害、薬剤投与により引き起こされる心
筋傷害のいずれにも適用できる。<3> Animals to which the therapeutic agent of the present invention is administered, such as subjects to which the therapeutic agent of the present invention is administered, are preferably vertebrates, particularly mammals, and particularly preferably humans. The therapeutic agent of the present invention is administered for treating myocardial injury in these animals, but is preferably administered for suppressing or preventing myocardial injury. The myocardial injury referred to in the present invention has a meaning understood by these terms in the art, and corresponds to, for example, a state in which the interval between ST portions is significantly prolonged when monitored by an electrocardiogram. The therapeutic agent of the present invention can be applied to both spontaneously occurring myocardial injury and myocardial injury caused by drug administration.
【００２８】心筋傷害を引き起こす可能性がある薬剤と
しては抗腫瘍剤が例示され、本発明処置剤は、抗腫瘍剤
投与により引き起こされる心筋傷害を抑制するために、
より好ましく適用することができる。抗腫瘍剤のなかで
も抗腫瘍性抗生物質が好ましく、アントラサイクリン系
抗腫瘍性抗生物質が好ましい。アントラサイクリン系抗
腫瘍性抗生物質とは、7,8,9,10-テトラヒドロ-5,12-ナ
フタセンキノンをアグリコンとする配糖体からなる抗腫
瘍性抗生物質であり、アドリアマイシン（ドキソルビシ
ン）、ダウノマイシン（ダウノルビシン、ルビドマイシ
ン、ルボマイシンＣ）、アクラルビシン（アクラシノマ
イシンンＡ）、ピラルビシン、エピルビシン等が例示さ
れるが、これらに限定されない。本発明処置剤の特に好
ましい適用疾患は、特にアントラサイクリン系抗腫瘍性
抗生物質の投与により引き起こされる心筋傷害、特に心
筋症、うっ血性心不全等である。ただし本発明処置剤の
適用疾患の範囲はこれらに限定されない。本発明処置剤
は、上記薬剤の投与により引き起こされる副作用(心筋
傷害)に対して、顕著な予防・抑制効果を有することか
ら、これらの副作用の予防剤としても適用できる。よっ
て本発明処置剤の投与は、このような副作用(心筋傷害)
を惹起する可能性がある薬剤の投与後だけでなく、その
投与前、あるいは該薬剤の投与と同時であってもよい。Examples of the drug that may cause myocardial injury include antitumor agents. The therapeutic agent of the present invention is intended to suppress myocardial injury caused by administration of an antitumor agent.
It can be more preferably applied. Among the antitumor agents, antitumor antibiotics are preferable, and anthracycline antitumor antibiotics are preferable. Anthracycline antitumor antibiotics are antitumor antibiotics consisting of glycosides containing 7,8,9,10-tetrahydro-5,12-naphthacenequinone as aglycone, and include adriamycin (doxorubicin), daunomycin ( Examples include, but are not limited to, daunorubicin, rubidomycin, rubomycin C), aclarubicin (acracinomycin A), pirarubicin, epirubicin, and the like. Particularly preferred diseases to which the therapeutic agent of the present invention is applied are myocardial injury caused by administration of an anthracycline antitumor antibiotic, particularly cardiomyopathy, congestive heart failure and the like. However, the range of diseases to which the therapeutic agent of the present invention is applied is not limited to these. The therapeutic agent of the present invention has a remarkable preventive / suppressive effect on side effects (myocardial injury) caused by the administration of the above-mentioned drugs, and thus can be applied as a preventive agent for these side effects. Therefore, administration of the treatment agent of the present invention may cause such side effects (myocardial injury).
May be administered not only after the administration of the drug that may cause the above, but also before the administration or simultaneously with the administration of the drug.
【００２９】本発明処置剤におけるＰＣ−ＳＯＤの配合
量、１回あたりの投与量、投与間隔等は、本発明処置剤
の投与方法、投与形態、使用目的等、患者の具体的症
状、年齢、性別、体重等に応じて個別に決定されるべき
事項であり、特に限定されないが、ＰＣ−ＳＯＤの臨床
量として成人１人１回当り1〜100 mg（3,000〜300,000
Ｕ）が例示される。The compounding amount of PC-SOD in the treatment agent of the present invention, the dose per administration, the administration interval, etc. are determined based on the specific symptoms, age, It is a matter to be determined individually according to gender, body weight, etc., and is not particularly limited. However, the clinical dose of PC-SOD is 1 to 100 mg per adult (3,000 to 300,000 per dose).
U) is exemplified.
【００３０】[0030]
【実施例】以下に、本発明を製造例及び実施例により具
体的に説明する。しかしながら、これらにより本発明の
技術的範囲は限定されない。The present invention will be described below in more detail with reference to production examples and examples. However, these do not limit the technical scope of the present invention.
【００３１】〔製造例〕 ＜１＞ヒトＣｕ／Ｚｎ ＳＯＤの調製 該ＳＯＤは、特開平6-199895号公報に記載された方法で
調製したものを用いた。このヒトＣｕ／Ｚｎ ＳＯＤの1
11 位のアミノ酸はＳ−（２−ヒドロキシエチルチオ）
システインとなっている。[Production Example] <1> Preparation of Human Cu / Zn SOD The SOD used was prepared by the method described in JP-A-6-199895. This human Cu / Zn SOD
The amino acid at position 11 is S- (2-hydroxyethylthio)
Has become cysteine.
【００３２】＜２＞ＰＣ−ＳＯＤの調製 ＰＣ−ＳＯＤは、特開平6-54681号公報に記載された方
法によって、２−（４−ヒドロキシカルボニルブチロイ
ル）リゾレシチンの活性エステル体を調製し、これと上
記＜１＞のＳＯＤとを反応させることによって調製し
た。精製・濃縮後、蛋白質濃度をローリー法(Lowry, O.
h.ら、J. Biol. Chem., 193 巻, 265 頁 (1951年))、Ｓ
ＯＤの残存アミノ基をＴＮＢＳ法（トリニトロベンゼン
スルホン酸塩、Goodwin, J. F.ら、Clin. Chem., 16
巻, 24頁 (1970年))で分析することにより、ＳＯＤ１分
子あたりのレシチン誘導体の結合数を求めたところ、平
均４．０個であった。このＰＣ−ＳＯＤの水溶液は青緑
色〜緑色を呈し、ｐＨは７〜８であった。また、分子量
をＳＤＳ−ポリアクリルアミドゲル電気泳動法により測
定したところ、ＰＣ−ＳＯＤサブユニットのモノマー
（ＰＣ−ＳＯＤはサブユニットのホモダイマーである）
あたり約１８０００であった。<2> Preparation of PC-SOD PC-SOD was prepared by preparing an active ester of 2- (4-hydroxycarbonylbutyroyl) lysolecithin by the method described in JP-A-6-54681. And SOD of the above <1>. After purification and concentration, the protein concentration was determined by the Lowry method (Lowry, O.
H. et al., J. Biol. Chem., 193, 265 (1951)), S.
The remaining amino groups of the OD were determined by the TNBS method (trinitrobenzene sulfonate, Goodwin, JF et al., Clin. Chem., 16
Vol. 24, 1970 (1970)), the number of lecithin derivatives bound per SOD molecule was determined to be 4.0 on average. This aqueous solution of PC-SOD exhibited a bluish green to green color, and had a pH of 7 to 8. When the molecular weight was measured by SDS-polyacrylamide gel electrophoresis, a monomer of PC-SOD subunit (PC-SOD is a homodimer of subunit)
It was about 18,000.
【００３３】〔実施例〕アドリアマイシン惹起マウス心
筋傷害モデルに対する効果の検討 (1)以下の本実施例で用いた薬剤 塩酸ドキソルビシン（ファルマシア） 塩酸ドキソルビシンを生理食塩水に溶解し、2mg/ml溶液
として用いた。ＰＣ−ＳＯＤは、前記製造例で製造した
もの(比活性：3000U/mg)を、５％マンニトールで希釈し
て用いた。[Examples] Examination of effects on adriamycin-induced mouse myocardial injury model (1) Drugs used in the following Examples Doxorubicin hydrochloride (Pharmacia) Doxorubicin hydrochloride was dissolved in physiological saline to prepare a 2 mg / ml solution. Was. As the PC-SOD, the one produced in the above Production Example (specific activity: 3000 U / mg) was used after being diluted with 5% mannitol.
【００３４】(2)本実施例で用いた実験動物 Balb/cマウス（雄、体重24〜28g） マウスを、ペントバルビタール(pentobarbital)-ナトリ
ウムの腹腔内注射(110mg/kg体重)、およびブプレノルフ
ィン(buprenorfine)の皮下注射(2mg/kg体重)によって麻
酔した後、マウスの皮下にトランスミッター TA10ETA-F
20 (Data Sciences International社製)を移植した。移
植は、同社のマニュアルに従って行った。(2) Experimental animals used in this Example Balb / c mice (male, weight: 24-28 g) Mice were intraperitoneally injected with pentobarbital-sodium (110 mg / kg body weight) and buprenorphine ( After anesthesia by subcutaneous injection (2 mg / kg body weight) of buprenorfine), the transmitter TA10ETA-F was subcutaneously injected into the mouse.
20 (manufactured by Data Sciences International) was transplanted. The transplant was performed according to the company's manual.
【００３５】(3)薬効薬理試験 マウスを以下の通り群分けし、薬効薬理試験を行った。 第１群：生理食塩水投与群 (n=3) 第２群：ドキソルビシン投与群 (n=6) 第３群：PC-SOD 5,000U/kg＋ドキソルビシン投与群 (n=
6) 第４群：PC-SOD 20,000U/kg＋ドキソルビシン投与群 (n
=6) 第５群：PC-SOD 80,000U/kg＋ドキソルビシン投与群 (n
=6) 第６群：マンニトール＋ドキソルビシン投与群 (n=6) 第３〜５群のマウスには、所定の投与量となるように濃
度を調整したPC-SOD溶液を、体重１ｇあたり３μl尾静
脈に注射した。第６群のマウスには、PC-SOD溶液の代わ
りに５％マンニトールを同様に注射した。その１５分後
に、第１群のマウスには体重１ｇあたり２μlの生理食
塩水を、第２〜６群のマウスには、体重１ｇあたり２μ
lのドキソルビシン溶液をそれぞれ尾静脈に注射した。
第１回目の心電図のモニターは上記物質を投与した日の
午後12:00に行い、このデータを「第１週目」のデータ
とした。その１週間後の午後12:00に「第２回目」(第２
週目)のデータを取得し、その後同様に第８週目までデ
ータを取得した。なお、上記投与の１週間前にも同様に
心電図をモニターしておき、このデータを「第０週目」
のデータとした。心電図のモニターは、マウスに移植さ
れたトランスミッターからの情報をテレメトリー受信機
RPC-1 (Data Sciences International社製)で受信する
ことにより行った。心電図のモニターは２分間行い、サ
ンプリング速度は10,000秒-1（0.1m秒まで解析可能）で
行った。記録された心電図にマウスの動作等による干渉
ノイズが入った場合には、さらに２分間測定を行った。
それぞれのマウスについて得られた心電図において９回
連続して同様の形を有する部分を選択し、それぞれ、Ｓ
-ピークからＴ-ピークの末端までの間隔(ＳＴ時間；ミ
リ秒)を測定し、その平均値を算出した。算出されたＳ
Ｔ時間の平均値から、そのマウスの「第０週目」におけ
るＳＴ時間の平均値を差し引いて、ＳＴ時間の増減値を
求めた。心筋傷害が起きるとＳＴ時間が増加することか
ら、ＳＴ時間の増減値を心筋傷害の程度の指標とした。
ＳＴ時間の増減値について、第１、２及び６群の結果を
図１に、第３、４、５及び６群の結果を図２に、第１、
３、４及び５群の結果を図３にそれぞれ示す。なお、図
１中のａは、第２群の値が第１群の値に比して有意に増
加していることを(p<0.05)、ｂは第６群の値が第１群の
値に比して有意差に増加していることを示す(p<0.05)。
また、図２中のａは、第３群の値が第６群の値に比して
有意に減少していることを(p<0.05)、ｂは第４群の値が
第６群の値に比して有意に減少していることを(p<0.0
5)、ｃは第５群の値が第６群の値に比して有意に減少し
ていることを示す(p<0.05)。図３中のｂは、第４群の値
が第１群の値に比して有意に増加していることを示す(p
<0.05)。なお統計解析は、多重比較(ＬＳＤ法)により行
った。(3) Pharmacological pharmacology test The mice were divided into groups as follows, and pharmacodynamic pharmacology tests were performed. Group 1: saline administration group (n = 3) Group 2: doxorubicin administration group (n = 6) Group 3: PC-SOD 5,000U / kg + doxorubicin administration group (n =
6) Group 4: PC-SOD 20,000U / kg + doxorubicin administration group (n
= 6) Group 5: PC-SOD 80,000U / kg + Doxorubicin administration group (n
= 6) Group 6: Mannitol + doxorubicin administration group (n = 6) The mice of Groups 3 to 5 were given 3 μl of PC-SOD solution adjusted to a predetermined dose at a concentration of 3 μl / g body weight. It was injected intravenously. Group 6 mice were similarly injected with 5% mannitol instead of the PC-SOD solution. Fifteen minutes later, mice in the first group received 2 μl of physiological saline per gram of body weight, and mice in the second to sixth groups received 2 μl of physiological saline per gram of body weight.
l of doxorubicin solution were each injected into the tail vein.
The first monitoring of the electrocardiogram was performed at 12:00 pm on the day when the substance was administered, and this data was used as the data of "the first week". One week later at 12:00 pm, the "second time" (second
Week 8), and then data until the eighth week. One week before the above administration, the electrocardiogram was monitored in the same manner, and this data was referred to as “week 0”.
Data. The ECG monitor is a telemetry receiver that uses information from the transmitter implanted in the mouse.
This was performed by receiving with RPC-1 (manufactured by Data Sciences International). The monitoring of the electrocardiogram was performed for 2 minutes, and the sampling rate was 10,000 seconds −1 (analysis can be performed up to 0.1 ms). If the recorded electrocardiogram contained interference noise due to mouse operation or the like, the measurement was performed for another 2 minutes.
In the electrocardiogram obtained for each mouse, nine consecutive portions having the same shape were selected, and
The interval from the peak to the end of the T-peak (ST time; millisecond) was measured, and the average value was calculated. Calculated S
From the average value of the T time, the average value of the ST time in “the 0th week” of the mouse was subtracted to obtain the increase / decrease value of the ST time. Since the ST time increases when the myocardial injury occurs, the increase / decrease value of the ST time was used as an index of the degree of the myocardial injury.
Regarding the increase / decrease value of the ST time, the results of the first, second and sixth groups are shown in FIG.
The results for Groups 3, 4, and 5 are shown in FIG. 3, respectively. In addition, a in FIG. 1 indicates that the value of the second group was significantly increased as compared with the value of the first group (p <0.05), and b indicates that the value of the sixth group was higher than that of the first group. It indicates that the value is significantly different from the value (p <0.05).
In addition, a in FIG. 2 indicates that the value of the third group was significantly reduced as compared with the value of the sixth group (p <0.05), and b indicates that the value of the fourth group was less than that of the sixth group. (P <0.0
5) and c show that the value of group 5 is significantly reduced as compared with the value of group 6 (p <0.05). B in FIG. 3 indicates that the value of the fourth group is significantly increased as compared with the value of the first group (p
<0.05). The statistical analysis was performed by multiple comparison (LSD method).
【００３６】図１より、ドキソルビシンを投与すると、
生理食塩水の投与（第１群）に比してＳＴ時間が増加す
ることが示された（第２群）。またドキソルビシン投与
前に５％マンニトールを投与しても、ＳＴ時間の増加に
対して何ら影響がなかった（第６群）。よって、ＰＣ−
ＳＯＤの溶媒であるマンニトールは、ドキソルビシンの
心筋傷害に対して効果がないことが示された。図２よ
り、ドキソルビシン投与前にＰＣ−ＳＯＤを投与するこ
とにより、ドキソルビシンにより誘発されるＳＴ時間の
増加が抑制されることが示された（第３〜５群）。図３
より、ドキソルビシン投与前にＰＣ―ＳＯＤを投与した
場合（第３〜５群）、生理食塩水のみの投与（第１群）
に比して大幅なＳＴ時間の増加は見られなかった。な
お、移植されたトランスミッターは、マウスの動作や行
動に影響を及ぼさず、移植部位の皮膚の修復も特に影響
は見られなかった。以上の結果より、ドキソルビシンの
投与前にＰＣ―ＳＯＤを投与することにより、ドキソル
ビシンによる心筋傷害を有効に抑制できることが示され
た。この効果は、今回実験したいずれの投与量(5,000、
20,000または80,000 U/kg体重)においても確認された。
このことから、本発明処置剤は心筋傷害処置剤、特にド
キソルビシン等のアントラサイクリン系抗腫瘍性抗生物
質の投与による心筋傷害抑制剤（副作用抑制剤）として
有用であることが確認された。また本発明処置剤は、ド
キソルビシンの投与前に投与することにより優れた効果
を発揮することから、このような心筋傷害の予防剤（副
作用予防剤）としても利用できることが示された。According to FIG. 1, when doxorubicin was administered,
It was shown that the ST time was increased as compared to administration of physiological saline (Group 1) (Group 2). Also, administration of 5% mannitol before doxorubicin administration had no effect on the increase in ST time (Group 6). Therefore, PC-
Mannitol, a solvent for SOD, was shown to be ineffective against doxorubicin myocardial injury. FIG. 2 showed that administration of PC-SOD before doxorubicin administration suppressed the increase in ST time induced by doxorubicin (Groups 3 to 5). FIG.
Thus, when PC-SOD was administered before doxorubicin administration (groups 3 to 5), administration of physiological saline alone (group 1)
No significant increase in ST time was observed. The implanted transmitter had no effect on the movement or behavior of the mouse, and there was no particular effect on the repair of the skin at the implantation site. The above results indicate that administration of PC-SOD before administration of doxorubicin can effectively suppress myocardial injury caused by doxorubicin. This effect was observed at any dose tested in this study (5,000,
20,000 or 80,000 U / kg body weight).
From this, it was confirmed that the therapeutic agent of the present invention is useful as a therapeutic agent for myocardial injury, in particular, a myocardial injury inhibitor (an inhibitor of side effects) by administration of an anthracycline antitumor antibiotic such as doxorubicin. In addition, since the therapeutic agent of the present invention exerts an excellent effect when administered before the administration of doxorubicin, it has been shown that it can also be used as an agent for preventing such myocardial injury (agent for preventing side effects).
【００３７】[0037]
【発明の効果】本発明処置剤は、ＰＣ−ＳＯＤを含有さ
せることにより、レシチン化していないＳＯＤ(フリー
のＳＯＤ)を投与した場合に比して顕著な心筋傷害抑制
作用を発揮することから、心筋傷害処置剤として有用で
あり、特にアドリアマイシン等のアントラサイクリン系
抗腫瘍性抗生物質の投与による心筋傷害抑制剤（副作用
抑制剤）として有用である。また本発明処置剤は、アン
トラサイクリン系抗腫瘍性抗生物質の投与前に投与する
ことにより優れた効果を発揮することから、このような
心筋傷害の予防剤（副作用予防剤）としても有用であ
る。The treatment agent of the present invention, by containing PC-SOD, exerts a remarkable inhibitory action on myocardial injury as compared with the case where non-lecitinated SOD (free SOD) is administered. It is useful as an agent for treating myocardial injury, and particularly useful as an agent for suppressing myocardial injury (an inhibitor of side effects) by administration of an anthracycline antitumor antibiotic such as adriamycin. Further, the therapeutic agent of the present invention exerts an excellent effect when administered before administration of an anthracycline antitumor antibiotic, and is therefore useful as a preventive agent for such myocardial injury (agent for preventing side effects). .
【配列表】 <110> Seikagaku Corporation <120> Suppressing agent for cardiomyopathy <130> <160> 1 <210> 1 <211> 153 <212> PRT <213> Homo sapiens <400> 1 Ala Thr Lys Ala Val Cys Val Leu Lys Gly Asp Gly Pro Val Gln Gly 1 5 10 15 Ile Ile Asn Phe Glu Gln Lys Glu Ser Asn Gly Pro Val Lys Val Trp 20 25 30 Gly Ser Ile Lys Gly Leu Thr Glu Gly Leu His Gly Phe His Val His 35 40 45 Glu Phe Gly Asp Asn Thr Ala Gly Cys Thr Ser Ala Gly Pro His Phe 50 55 60 Asn Pro Leu Ser Arg Lys His Gly Gly Pro Lys Asp Glu Glu Arg His 65 70 75 80 Val Gly Asp Leu Gly Asn Val Thr Ala Asp Lys Asp Gly Val Ala Asp 85 90 95 Val Ser Ile Glu Asp Ser Val Ile Ser Leu Ser Gly Asp His Cys Ile 100 105 110 Ile Gly Arg Thr Leu Val Val His Glu Lys Ala Asp Asp Leu Gly Lys 115 120 125 Gly Gly Asn Glu Glu Ser Thr Lys Thr Gly Asn Ala Gly Ser Arg Leu 130 135 140 Ala Cys Gly Val Ile Gly Ile Ala Gln 145 150[Sequence List] <110> Seikagaku Corporation <120> Suppressing agent for cardiomyopathy <130> <160> 1 <210> 1 <211> 153 <212> PRT <213> Homo sapiens <400> 1 Ala Thr Lys Ala Val Cys Val Leu Lys Gly Asp Gly Pro Val Gln Gly 1 5 10 15 Ile Ile Asn Phe Glu Gln Lys Glu Ser Asn Gly Pro Val Lys Val Trp 20 25 30 Gly Ser Ile Lys Gly Leu Thr Glu Gly Leu His Gly Phe His Val His 35 40 45 Glu Phe Gly Asp Asn Thr Ala Gly Cys Thr Ser Ala Gly Pro His Phe 50 55 60 Asn Pro Leu Ser Arg Lys His Gly Gly Pro Lys Asp Glu Glu Arg His 65 70 75 80 Val Gly Asp Leu Gly Asn Val Thr Ala Asp Lys Asp Gly Val Ala Asp 85 90 95 Val Ser Ile Glu Asp Ser Val Ile Ser Leu Ser Gly Asp His Cys Ile 100 105 110 Ile Gly Arg Thr Leu Val Val His Glu Lys Ala Asp Asp Leu Gly Lys 115 120 125 Gly Gly Asn Glu Glu Ser Thr Lys Thr Gly Asn Ala Gly Ser Arg Leu 130 135 140 Ala Cys Gly Val Ile Gly Ile Ala Gln 145 150
【図１】 ドキソルビシン投与による心電図のＳＴ時間
の増加程度を示す図である。FIG. 1 is a graph showing the degree of increase in ST time of an electrocardiogram due to doxorubicin administration.
【図２】 ドキソルビシン投与前にＰＣ−ＳＯＤを投与
することによるＳＴ時間の増加程度を示す図である。FIG. 2 is a graph showing an increase in ST time by administering PC-SOD before doxorubicin administration.
【図３】 ドキソルビシン投与前にＰＣ―ＳＯＤを投与
した場合のＳＴ時間の増加程度と、生理食塩水のみ投与
した場合のＳＴ時間の増加程度を比較した図である。FIG. 3 is a graph comparing the increase in ST time when PC-SOD is administered before doxorubicin administration and the increase in ST time when only saline is administered.
Claims (6)
ゼを含有する心筋傷害処置剤。1. An agent for treating myocardial injury comprising lecithinated superoxide dismutase.
るものである、請求項１に記載の心筋傷害処置剤。2. The therapeutic agent for myocardial injury according to claim 1, wherein the myocardial injury is caused by drug administration.
るものである、請求項１に記載の心筋傷害処置剤。3. The method according to claim 1, wherein the myocardial injury is caused by an antitumor agent.
求項３に記載の心筋傷害処置剤。4. The method according to claim 3, wherein the antitumor agent is an antitumor antibiotic.
系抗腫瘍性抗生物質である、請求項４に記載の心筋傷害
処置剤。5. The method according to claim 4, wherein the antitumor antibiotic is an anthracycline antitumor antibiotic.
れることを特徴とする、請求項１〜５のいずれか１項に
記載の心筋傷害処置剤。6. The therapeutic agent for myocardial injury according to any one of claims 1 to 5, wherein the agent is administered for suppressing or preventing myocardial injury.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000264527A JP2002080395A (en) | 2000-08-31 | 2000-08-31 | Agent for treatment of myocardial lesion |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000264527A JP2002080395A (en) | 2000-08-31 | 2000-08-31 | Agent for treatment of myocardial lesion |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2002080395A true JP2002080395A (en) | 2002-03-19 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000264527A Pending JP2002080395A (en) | 2000-08-31 | 2000-08-31 | Agent for treatment of myocardial lesion |
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| Country | Link |
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| JP (1) | JP2002080395A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101966334A (en) * | 2010-09-29 | 2011-02-09 | 北京泰德制药股份有限公司 | Application of lecithin superoxide dismutase composite in preparation of medicines for treating and/or preventing cardiac ischemic injury |
| WO2022244757A1 (en) * | 2021-05-18 | 2022-11-24 | 株式会社Ｌｔｔバイオファーマ | Pharmaceutical composition for treating or preventing disorder associated with administration of anticancer agent |
| CN116284437A (en) * | 2022-12-14 | 2023-06-23 | 广州美神生物科技有限公司 | Superoxide dismutase fusion polypeptide, preparation method thereof and application thereof in preparation of anti-aging products |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61194023A (en) * | 1985-02-22 | 1986-08-28 | Eisai Co Ltd | Administration of adriamycin |
| JPH04103538A (en) * | 1990-08-24 | 1992-04-06 | Ajinomoto Co Inc | Inhibitor for side effect of carcinostatic agent |
-
2000
- 2000-08-31 JP JP2000264527A patent/JP2002080395A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61194023A (en) * | 1985-02-22 | 1986-08-28 | Eisai Co Ltd | Administration of adriamycin |
| JPH04103538A (en) * | 1990-08-24 | 1992-04-06 | Ajinomoto Co Inc | Inhibitor for side effect of carcinostatic agent |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101966334A (en) * | 2010-09-29 | 2011-02-09 | 北京泰德制药股份有限公司 | Application of lecithin superoxide dismutase composite in preparation of medicines for treating and/or preventing cardiac ischemic injury |
| WO2022244757A1 (en) * | 2021-05-18 | 2022-11-24 | 株式会社Ｌｔｔバイオファーマ | Pharmaceutical composition for treating or preventing disorder associated with administration of anticancer agent |
| CN116284437A (en) * | 2022-12-14 | 2023-06-23 | 广州美神生物科技有限公司 | Superoxide dismutase fusion polypeptide, preparation method thereof and application thereof in preparation of anti-aging products |
| CN116284437B (en) * | 2022-12-14 | 2023-12-05 | 广州美神生物科技有限公司 | Superoxide dismutase fusion polypeptide, preparation method thereof and application thereof in preparation of anti-aging products |
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