JP2005513148A - 女性の有効な分娩を確立するための硫酸化グリコサミノグリカンの使用 - Google Patents
女性の有効な分娩を確立するための硫酸化グリコサミノグリカンの使用 Download PDFInfo
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Abstract
Description
K.Shakerら、British Medical Journal 16(1974年11月)により、ヘパリンに起因する子宮収縮が、妊娠32週の32歳の経妊婦への、静脈血栓症を処置するための高用量のヘパリンの静脈内投与の副作用として記載されている。ヘパリンは、動物組織から商業ベースで単離され、そして抗血栓薬として臨床使用されているグリコサミノグリカンである。
ヘパラン硫酸プロテオグリカンの発現は、妊娠および分娩の間の子宮の再構築の間に変化することが最近見出された。従って、これらは、分娩において中枢的な役割を果たすと考えられている。硫酸化グリコサミノグリカンでのヒト子宮細片の処理がその収縮活性を増強することも見出されている。
実施例1.ヘパラン硫酸の調製
10gのヘパリン副産物である、TB 001−91 SVCM 950130(Kabi−Pharmacia、Sweden)を、1lの5%酢酸カルシウム−0.5M酢酸中に溶解した。この溶液をろ過した。次いで、ろ過した溶液を、18%のエタノール濃度に調整した。次いで、遠心分離後の上清を、36%のエタノール濃度に調整した。沈殿物を、遠心分離により集めた。以下のヘパラン硫酸を、Franssonら、Structural studies on heparan sulphates、Eur.J.Biochem.106、59−69(1980)に従い調製した。
18〜36%エタノールの得られた沈殿物を、1.2MのNaCl中に溶解した。18gの塩化セチルピリジニウム(CPC)を添加し、そして沈殿物を、24時間にわたり生じさせた。沈殿物をろ過により回収し、そして2MのNaCl中に再溶解した。ろ液を、HS5の調製のために用いた。溶解した沈殿物に3倍容量のエタノールを添加した。得られた沈殿物を16時間にわたり生じさせ、そして遠心分離により集めた。最後に、それを、水中に再溶解させ、そして3倍容量のエタノール−0.4%酢酸ナトリウムを用いて再沈殿させた。沈殿物を遠心分離により集め、そして乾燥した。収量は、 4.34gであった。
次いで、HS6の調製からのろ液を、0.1% CPCを用いて、1.0M NaClの最終濃度まで希釈した。次いで、それを、HS6と同様に処理した。ろ液を、HS4の調製のために用いた。収量は、0.82gであった。
次いで、HS5の調製からのろ液を、0.1% CPCを用いて、0.8M NaClの最終濃度まで希釈した。次いで、それを、HS6と同様に処理した。ろ液を、HS3の調製のために用いた。収量は、0.51gであった。
次いで、HS4の調製からのろ液を、0.1% CPCを用いて、0.6M NaClの最終濃度まで希釈した。次いで、それを、HS6と同様に処理した。ろ液を、HS2の調製のために用いた。収量は、0.17gであった。
次いで、HS3の調製からのろ液を、0.1% CPCを用いて、0.4M NaClの最終濃度まで希釈した。次いで、それを、HS6と同様に処理した。収量は、0.09gであった。
1kgの乾燥したブタの皮膚を、5lの0.5M NaCl、0.01M EDTAおよび0.01Mの塩酸システイン、pH6.5中に懸濁した。500mgの結晶パパインを添加し、そして50時間消化を進行させた。この消化物をろ過し、次いで75mlのCPCの10%溶液を用いて沈殿させた。得られたピリジニウム複合体を、ろ過により集め、そして15%エタノールを含む2M NaCl中に再溶解した。この溶液を、3倍容量の0.5% CPCで希釈した。沈殿物を集め、そして200mlの1MのNaClおよび40mlのエタノール中に溶解した。この材料を100mlの水に再溶解し、次いで3倍容量のエタノール−0.4%酢酸ナトリウムを用いて沈殿させた。得られた沈殿物を集め、そして乾燥した。最終的な収量は2.32gであった。Franssonら、Structure of pig skin dermatan sulfate.1.Distribution of D−glucuronic acid residues.(1971)Eur.J.Biochem.18、422−430を参照のこと。
2.2gの上記で得られた物質を、220mlの5%酢酸カルシウム−0.5M酢酸中に溶解した。この溶液を、エタノールと混合し、そしてそれぞれ0−18%エタノール(DS−18)、18−36%エタノール(DS−36)、および36−50%エタノール(DS−50)の間で形成された沈殿物を集めた。これらの材料を、水に再溶解し、そして3倍容量のエタノール−0.4%酢酸ナトリウムを用いて再沈殿した。乾燥後、最終収量は、DS−18について0.9g;DS−36について1.02g;DS−50について0.28gであった。
試験1.収縮アッセイ
以下の試験において、ヘパリンサイドフラクションTB 001−91 SVCM 950130(Kabi−Pharmacia、Sweden)から得られたヘパラン硫酸HS2およびHS6を試験した。HS6は、より高度に硫酸化されておりかつより多いL−イズロン酸残基を有することによりHS2とは異なる(上記表1を参照のこと)。
妊娠していない人および正期妊娠(term pregnant)の患者および膣から分娩した女性(分娩後の患者)から繊維芽細胞培養物を確立した。細胞を、10%のドナー仔ウシ血清を有する最小必須培地を用いて単層培養中で培養した。実験のために、これらの細胞をセミコンフルーエントでカバーグラス上にプレートし、そして30分間にわたり、10mMのHEPESを含むリン酸緩衝化生理食塩水中のFluo−4を充填した。最初に、10mMのHEPES(HEPES−緩衝液)を含むリン酸緩衝化生理食塩水を、30分間観察チャンバ中にポンピングし、次いで、同じ緩衝液中のKClを、60秒間ポンピングし、引き続き30秒間HEPES緩衝液をポンピングした。次いで、HEPES−緩衝液中1mlあたり10ngのPDGFを添加した。3分間蛍光を連続的にモニタリングした。他の実験において、PDGFを、100μgのHS6と置き換えた。妊娠していない患者および正期妊娠患者から確立された培養物において蛍光の変化は示されなかった。分娩後に患者から直接得られた培養物において、KCl、PDGFおよびHS6は、全て、蛍光の一過性の4〜8倍の増加を誘導し、これは、細胞内Ca2+の一過性の増加を示す。このことは、分娩後の患者から確立された培養物中の細胞がHS6により活性化されることを示す。この効果は、分娩のための頸部の最終的な準備のために、分娩において重要であると仮定される。
未経産婦における分娩の結果に対する臨床データを研究した。14人の未経産婦に、血栓の危険性の増加に起因して、妊娠期間の間、Fragmin(登録商標)(Pharmacia、Sweden)を皮下投与した。投与した予防用量は、毎日2500IEを投与した4人の女性を除き、毎日5000IEであった。これらの女性のうち8人に、12週間より長く(12〜28週間の範囲)処置をし、そして彼女らのうち6人に、1〜6週間の間、処置をした。女性たちがこの研究に参加した直後に同じ診療所で分娩する、Fragmin(登録商標)投薬療法を行わなかった次の13人の未経産婦が、コントロールとしての役割を果たした。評価項目は、陣痛−分娩期間(時間)ならびに帝王切開の数およびこれらの適応である。
Claims (10)
- 女性の有効な分娩を確立するための頸部および子宮筋層の予防的プライミングまたは治療的処置のための薬学的調製物を製造するための100BP単位/mg以下の抗凝固活性を有する硫酸化グリコサミノグリカンの使用。
- ヘパラン硫酸および脱重合化ヘパラン硫酸からなる群に属する、請求項1に記載のグリコサミノグリカンの使用。
- コンドロイチン硫酸および脱重合化コンドロイチン硫酸からなる群に属する、請求項1に記載のグリコサミノグリカンの使用。
- デルマタン硫酸または脱重合化デルマタン硫酸からなる群に属する、請求項1に記載のグリコサミノグリカンの使用。
- 10000Da未満の、好ましくは6000Da以下の平均分子量を有する脱重合化ヘパリンからなる群に属する、請求項1に記載のグリコサミノグリカンの使用。
- 30BP単位/mg以下の抗凝固活性を有する、請求項1〜5のいずれかに記載のグリコサミノグリカンの使用。
- 1.0未満のスルフェ−ト/ヘキソサミン比および10BP単位/mg以下の抗凝固活性を有する、請求項2または6に記載のグリコサミノグリカンの使用。
- オキシトシンと組み合わせた、請求項1〜7のいずれかに記載のグリコサミノグリカンの使用。
- 局所的薬学的調製物の製造のための請求項1〜7のいずれかに記載のグリコサミノグリカンの使用。
- 非経口的薬学的調製物の製造のための請求項1〜7のいずれかに記載のグリコサミノグリカンの使用。
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PCT/SE2003/000004 WO2003055499A1 (en) | 2002-01-02 | 2003-01-02 | Use of sulfated glycosaminoglycans for establishing effective labor in women |
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Cited By (5)
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KR20140113652A (ko) * | 2011-12-19 | 2014-09-24 | 딜라포 아베 | 반복 다이사카라이드 단위를 포함하는 비-항응고 글리코스아미노글리칸 및 이의 의학적 용도 |
JP2015500388A (ja) * | 2011-12-19 | 2015-01-05 | ディラホア アクチエボラゲット | 二糖繰り返し単位を含んでいる非抗凝固グリコサミノグリカンおよびそれらの医療用途 |
KR102135485B1 (ko) * | 2011-12-19 | 2020-07-17 | 딜라포 아베 | 반복 다이사카라이드 단위를 포함하는 비-항응고 글리코스아미노글리칸 및 이의 의학적 용도 |
JP2015511664A (ja) * | 2012-03-26 | 2015-04-20 | ディラフォール・アクチボラゲットDilafor Ab | 分娩を誘発するための療法 |
JP2015514705A (ja) * | 2012-03-26 | 2015-05-21 | ディラフォール・アクチボラゲットDilafor Ab | 分娩停止の処置のための方法 |
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