JP2006298815A - Rare element cerium and its derivatives having anticoagulant action - Google Patents
Rare element cerium and its derivatives having anticoagulant action Download PDFInfo
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- 229910052684 Cerium Inorganic materials 0.000 title claims abstract description 12
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 230000002429 anti-coagulating effect Effects 0.000 title description 2
- 239000003146 anticoagulant agent Substances 0.000 claims abstract description 29
- 229940127219 anticoagulant drug Drugs 0.000 claims abstract description 28
- 210000004369 blood Anatomy 0.000 claims abstract description 5
- 239000008280 blood Substances 0.000 claims abstract description 5
- 239000000701 coagulant Substances 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims abstract 2
- 208000007536 Thrombosis Diseases 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 abstract description 11
- 229960002897 heparin Drugs 0.000 abstract description 11
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- 238000009534 blood test Methods 0.000 abstract description 3
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- YKYOUMDCQGMQQO-UHFFFAOYSA-L cadmium dichloride Chemical compound Cl[Cd]Cl YKYOUMDCQGMQQO-UHFFFAOYSA-L 0.000 description 10
- 230000023555 blood coagulation Effects 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 7
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
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- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 3
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- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
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- 150000002500 ions Chemical class 0.000 description 2
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
【課題】本発明は抗血液凝固剤に関する。血栓症状の予防および治療、あるいは医療用具の表面処理に使用できる、安価で安全な抗血液凝固剤、そしてこの抗血液凝固剤を含む抗血栓症剤、また、この抗血液凝固剤を含む医療用具の血液接触面処理剤を提供する。容易に入手することができ、かつ優れた抗血液凝固性を示し、しかも多方面にわたる血液検査に対しても悪影響を与えない抗血液凝固剤を提供する。
【解決手段】本発明は、ヘパリン抗血液凝固剤の代替となる優れた安全性を備える抗血液凝固剤および、従来のヘパリン系抗血液凝固剤に比べ、生産性が高く、安価に使用できる希少元素セリウム及びその誘導体を用いたヒト抗血液凝固剤を提供することにある。
【選択図】なし
The present invention relates to an anticoagulant. An inexpensive and safe anticoagulant that can be used for the prevention and treatment of thrombotic symptoms or surface treatment of medical devices, and an antithrombotic agent containing the anticoagulant, and a medical device containing the anticoagulant A blood contact surface treating agent is provided. Provided is an anticoagulant that can be easily obtained and exhibits excellent anticoagulability and does not adversely affect various blood tests.
The present invention relates to an anti-blood coagulant with excellent safety, which is an alternative to a heparin anti-blood coagulant, and a rare product which is more productive and can be used at a lower cost than conventional heparin anti-coagulants. The object is to provide a human anticoagulant using elemental cerium and its derivatives.
[Selection figure] None
Description
本発明は希少元素セリウム及びその誘導体を用いた抗血液凝固剤・医療用具の血液接触面処理剤・血栓形成防止剤に関する。
The present invention relates to an anti-blood coagulant, a blood contact surface treatment agent for a medical device, and a thrombus formation inhibitor using rare element cerium and its derivatives.
様々なCa2+結合蛋白質(例えば要因Xおよびトリプシン)に関する研究は、これまで知られている。結晶学に基づいて、ランタニド元素イオンがこれらの蛋白質の金属結合部位へ、化学量論的に、その部位のCa2+より用量的にしっかりと結合するように見える。カルシウムイオンは、内因系と外因系による血液凝固カスケードおよびフイブリン生成にとって重要である。 Studies on various Ca 2+ binding proteins (eg factor X and trypsin) are known to date. Based on crystallography, it appears that lanthanide element ions bind more stoichiometrically to the metal binding sites of these proteins than do Ca2 + at that site. Calcium ions are important for the blood clotting cascade and fibrin production by the intrinsic and extrinsic systems.
Furie等は、活性化第X要因 (第Xa要因)によって、プロトロンビンからトロンビンの生成に必要なカルシウムイオンにランタニド元素イオンが代用されるかもしれないと報告した。さらに、第XIII要因が、その蛋白質を分解されて活性化される間のCa2+の存在は、活性化された第XIII要因の生成および最適な酵素活性の発現の両方に重要であると報告されている Furie et al. Reported that activation factor X (factor Xa) may substitute lanthanide element ions for the calcium ions required for thrombin generation from prothrombin. Furthermore, the presence of Ca 2+ while factor XIII is activated by degrading its protein is reported to be important for both the generation of activated factor XIII and the expression of optimal enzyme activity. Has been
近年の医療技術の進歩に対する臨床検査の果す役割は極めて大きく、特に、血液検査は疾病診断や治療の経過判断、或いは予防医学に関して非常に重要なものであり、そのための抗血液凝固剤の重要性が認識されている。 The role of clinical tests for the advancement of medical technology in recent years is extremely large. In particular, blood tests are very important for disease diagnosis, treatment progress judgment, and preventive medicine, and the importance of anticoagulants for that purpose. Is recognized.
抗血液凝固剤としてはヘパリン塩系の抗血液凝固剤がよく知られており、人工透析や体外循環時の血液凝固防止のために患者の血液中に投与がなされ、また、検査或いは治療時に血液が接触する医療用材料の表面処理用として多量に用いられている。 Heparin-based anticoagulants are well known as anticoagulants and are administered into the patient's blood to prevent blood clotting during artificial dialysis or extracorporeal circulation. It is used in a large amount for surface treatment of medical materials that come into contact.
また、血液検査を目的とした抗血液凝固剤としてはエチレンジアミン四酢酸やクエン酸の金属塩系の抗血液凝固剤が知られている。
抗血液凝固剤のうち、ヘパリン系抗血液凝結剤の場合は、その原料であるヘパリンは現在では各種動物の臓器からの抽出によってのみ得られるため、生産性が悪く、生産コストも高く、患者の経済性に大きな負担となっている。また、原料を各種動物の臓器に依存しているので、病原菌等の不純物の混入の危険性も否定出来ず、安全性の面でも問題がある。 Among the anticoagulants, in the case of heparin anticoagulants, the raw material heparin is currently obtained only by extraction from various organs of animals, resulting in poor productivity and high production costs. It is a great burden on the economy. In addition, since the raw material depends on various organs of animals, the risk of contamination with impurities such as pathogenic bacteria cannot be denied, and there is a problem in terms of safety.
また、エチレンジアミン四酢酸やクエン酸の金属塩系の抗血液凝固剤の場合は、血液形態検査や凝固・線溶系検査として日常用いられているが、これら抗血液凝固剤は生体系への悪影響のために生体内への投与は不可能であるので、ヘパリン系抗血液凝固剤の代替とはならないという問題がある。 In addition, ethylenediaminetetraacetic acid and citric acid metal salt-based anticoagulants are routinely used for blood morphology testing and coagulation / fibrinolysis testing, but these anticoagulants have an adverse effect on biological systems. Therefore, since administration to a living body is impossible, there is a problem that it cannot be a substitute for a heparin anticoagulant.
そこで、従来のヘパリン系抗血液凝固剤の代替となり、優れた安全性を有し、かつ生産性が高くて、生産コストの安い抗血液凝固剤の出現が望まれていた。 Therefore, there has been a demand for the appearance of an anti-blood coagulant that is an alternative to the conventional heparin-based anti-coagulant and has excellent safety, high productivity, and low production cost.
本発明の目的は、ヘパリン抗血液凝固剤の代替となる優れた安全性を備える抗血液凝固剤および、従来のヘパリン系抗血液凝固剤に比べ、生産性が高く、安価に製造することが出来る製造方法を提供することにある。 The object of the present invention is to produce an anti-coagulant with excellent safety, which is an alternative to a heparin anti-coagulant, and has a higher productivity and can be manufactured at a lower cost than conventional heparin anti-coagulants. It is to provide a manufacturing method.
本発明の抗血液凝固剤は、抗血液凝固作用を有する希少元素セリウム及びその誘導体
から成ることを特徴とする。
The anticoagulant of the present invention is characterized by comprising the rare element cerium having an anticoagulant action and derivatives thereof.
発明の抗血液凝固剤は、従来の合成高分子を利用した抗血液凝固剤では使用不可能であった人工透析や体外循環治療用等の抗血液凝固剤としてヘパリン系抗血液凝固剤の代替品として使用することが出来ると共に、従来のヘパリン系抗血液凝固剤に比較して病原菌等の不純物の混入の危険性がなく、生体に対して優れた安全性を有する等の効果がある。 The anticoagulant of the invention is a substitute for a heparin-based anticoagulant as an anticoagulant for artificial dialysis or extracorporeal circulation treatment that cannot be used with conventional anticoagulants using synthetic polymers As compared with conventional heparin-based anticoagulants, there is no risk of contamination with pathogenic bacteria and the like, and there is an effect such as excellent safety for a living body.
本発明において、我々は種々の異なるセリウムを用いた実験条件での凝固時間に及ぼす影響を解析し、セリウムによる抗血液凝固抑制効果を発見した。 In the present invention, we analyzed the effect on clotting time under experimental conditions using various different cerium, and found the anticoagulation inhibitory effect of cerium.
以下、実施例により本発明をさらに詳細に説明するが、本発明は実施例によって限定されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited by an Example.
血液凝固時間の測定には(a)カルシウム再加凝固法、(b)活性化部分トロンボプラスチン時間（APTT）、(c)プロトロンビン時間（PT）を用いた。 Blood coagulation time was measured using (a) calcium re-coagulation method, (b) activated partial thromboplastin time (APTT), and (c) prothrombin time (PT).
カルシウム再加凝固法による血液凝固時間の測定結果を図１に示した。ヒト血漿では、塩化セリウム(CeCl3)、塩化カドミウム(CdCl2)を加えた場合に凝固時間の延長が見られたが、塩化鉄(FeCl3)を加えた場合は、対照群との差は見られなかった。統計的に、塩化セリウム(CeCl3)と塩化カドミウム(CdCl2)では対照群と比較して、危険率１％で有意な差が認められた。ただし、塩化カドミウムでは凝固時間が長すぎたために正確な時間は測定できなかった。 The measurement result of the blood coagulation time by the calcium re-coagulation method is shown in FIG. In human plasma, coagulation time was prolonged when cerium chloride (CeCl 3 ) and cadmium chloride (CdCl 2 ) were added, but when iron chloride (FeCl 3 ) was added, the difference from the control group was I couldn't see it. Statistically, a significant difference was observed between cerium chloride (CeCl 3 ) and cadmium chloride (CdCl 2 ) at a risk rate of 1% compared to the control group. However, cadmium chloride could not measure the exact time because the coagulation time was too long.
活性化部分トロンボプラスチン時間（APTT）による血液凝固時間の測定結果を図２に示した。ヒト血漿では、塩化セリウム(CeCl3)、塩化カドミウム(CdCl2)および塩化鉄(FeCl3)を加えた全ての場合に凝固時間の延長が見られた。しかし、統計的に対照群と有意な差が認められたのは、塩化セリウム(CeCl3)と塩化カドミウム(CdCl2)だけで、１％の危険率で有意であった。 The measurement result of the blood coagulation time by the activated partial thromboplastin time (APTT) is shown in FIG. In human plasma, prolonged clotting time was observed in all cases where cerium chloride (CeCl 3 ), cadmium chloride (CdCl 2 ) and iron chloride (FeCl 3 ) were added. However, the only statistically significant differences from the control group were cerium chloride (CeCl 3 ) and cadmium chloride (CdCl 2 ), which was significant at a 1% risk rate.
プロトロンビン時間（ PT ）による血液凝固時間の測定結果を図３に示した。実験結果をFig.5に示した。ヒト血漿では塩化セリウム(CeCl3)と塩化カドミウム(CdCl2)を加えた場合に、凝固時間の延長が見られた。しかし、ＡＰＴＴの時とは違い、塩化鉄(FeCl3)を加えても対照群と比べて凝固時間の差は見られなかった。統計的に塩化セリウム(CeCl3)と塩化カドミウム(CdCl2)は、対照群と比べて危険率１％で有意であった。 The measurement result of the blood coagulation time by prothrombin time (PT) is shown in FIG. The experimental results are shown in Fig.5. In human plasma, prolongation of clotting time was observed when cerium chloride (CeCl 3 ) and cadmium chloride (CdCl 2 ) were added. However, unlike APTT, the addition of iron chloride (FeCl 3 ) showed no difference in coagulation time compared to the control group. Statistically, cerium chloride (CeCl 3 ) and cadmium chloride (CdCl 2 ) were significant at 1% risk compared to the control group.
今回の実験結果をまとめると、ヒト血漿では、希土類元素(塩化セリウム)と重金属(塩化カドミウム)のどちらでもAPTTとPTの延長が見られたことから、共通系凝固因子(第Ｘ因子)活性の阻害が考えられた。 To summarize the results of this experiment, in human plasma, both rare earth elements (cerium chloride) and heavy metals (cadmium chloride) showed an extension of APTT and PT, indicating that the coagulation factor (factor X) activity Inhibition was considered.
Claims (3)
Human thrombus formation inhibitor using rare element cerium and its derivatives
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