ヘパリン 化学特性,用途語,生産方法
解説
ヘパリン,L-イズロン酸2-硫酸が(α1→4)結合で2-デオキシ-2-スルファミド-D-グルコース 6-硫酸に結合した(a)とD-グルクロン酸が(β1→4)結合で同様に結合した(b)の2種類の二糖の繰返し構造が主成分になったムコ多糖．小腸や肺に多く，皮膚や胸腺，そのほかにも分布している．工業的には，ウシやブタの肺や腸からアルカリ性飽和硫酸アンモニウム溶液で抽出し，エタノールでタンパク質との複合体を沈殿させ，除タンパク後金属塩として精製する．分子量1万～2万5千．[α]D＋45～＋53°．臨床的には抗血液凝固活性と脂血清澄活性が利用されている．前者は血液中のアンチトロンビンⅢによる各種の血液凝固因を阻害するもので，活性発現には，最低，図の五糖が必要とされている．後者は毛細血管内皮表面に存在するリポタンパク質リパーゼを，血流中に放出する活性である．
効能
抗凝固薬, アンチトロンビンIII活性化薬, 血小板凝集抑制薬
臨床作用
ヘパリンはマスト細胞（肥満細胞ともいう。ヘパリンやヒスタミンなどの分泌顆粒(かりゅう)を含み、血管周囲に多く存在する）中でプロテオヘパリン（ヘパリンの前駆体で分子量100万の巨大分子）として生合成され、エンド-β(ベータ)-グルクロニダーゼの作用で、分子量6000～2万となり、ヒスタミンなどと結合してマスト細胞の顆粒中に貯蔵される。ヘパリンはアンチトロンビンⅢ（血液凝固に関与するトロンビンなどの働きを阻害する糖タンパク質）の血液凝固阻害作用を促進する。臨床的には、播種(はしゅ)性血管内凝固症候群および血栓塞栓(そくせん)症の治療、血液体外循環時における還流血液の凝固防止などに用いられる。
説明
Parnaparin sodium is a low molecular weight heparin obtained from bovine mucosal
heparin by chemical depolymerization. It has more potent antithrombotic and profibrinolytic
activity than heparin evidenced by its higher activity in inhibiting factor Xa and in reducing
plasma activity of platelet activator inhibitor. It is effective in improving the venous blood
outflow of lower limbs in deep vein thrombosis (DVT) patients in addition to preventing DVT
following orthopaedic surgery, reportedly without causing bleeding complications. Parnaparin
has also shown efficacy in inflammatory occlusive complications of postphlebitic syndrome
and in acute myocardial infarction.
化学的特性
White or pale-colored amorphous powder; nearly odorless; hygroscopic. Soluble in water;
insoluble in alcohol, benzene, acetone, chloroform,
and ether; pH in 17% solution between 5.0 and 7.5.
天然物の起源
Heparin is a complex organic acid (mucopolysaccharide) present in mammalian tissues and a strong inhibitor of blood coagulation. Although the precise formula and structure of heparin are uncertain, it has been suggested that the formula for sodium heparinate, generally the form of the drug used in anticoagulant therapy, is (C12H16N2Na3)20 with a molecular weight of about 12,000. The commercial drug is derived from animal livers or lungs.
使用
Medicine (anticoagulant), biochemical
research, rodenticides.
定義
heparin: A glycosaminoglycan (mucopolysaccharide)with anticoagulantproperties, occurring in vertebratetissues, especially the lungs andblood vessels.
生物学の機能
Heparin (heparin sodium) is a mixture of highly electronegative
acidic mucopolysaccharides that contain
numerous N- and O-sulfate linkages. It is produced by
and can be released from mast cells and is abundant in
liver, lungs, and intestines.
危険性
May cause internal bleeding.
作用機序
The anticoagulation action of heparin depends on
the presence of a specific serine protease inhibitor (serpin)
of thrombin, antithrombin III, in normal blood.
Heparin binds to antithrombin III and induces a conformational
change that accelerates the interaction of
antithrombin III with the coagulation factors. Heparin
also catalyzes the inhibition of thrombin by heparin cofactor
II, a circulating inhibitor. Smaller amounts of
heparin are needed to prevent the formation of free
thrombin than are needed to inhibit the protease activity
of clot-bound thrombin. Inhibition of free thrombin
is the basis of low-dose prophylactic therapy.
薬理学
The physiological function of heparin is not completely
understood. It is found only in trace amounts in
normal circulating blood. It exerts an antilipemic effect
by releasing lipoprotein lipase from endothelial cells;
heparinlike proteoglycans produced by endothelial
cells have anticoagulant activity. Heparin decreases
platelet and inflammatory cell adhesiveness to endothelial
cells, reduces the release of platelet-derived growth
factor, inhibits tumor cell metastasis, and exerts an antiproliferative
effect on several types of smooth muscle.
Therapy with heparin occurs in an inpatient setting.
Heparin inhibits both in vitro and in vivo clotting of
blood. Whole blood clotting time and activated partial
thromboplastin time (aPTT) are prolonged in proportion
to blood heparin concentrations.
薬物動態学
The pharmacokinetic profiles of heparin and LMWHs are quite different. Whereas heparin is only
30% absorbed following subcutaneous injection, 90% of LMWH is systemically absorbed. The
binding affinity of heparin to various protein receptors, such as those on plasma proteins,
endothelial cells, platelets, platelet factor 4 (PF4), and macrophages, is very high and is related to
the high negative-charged density of heparin. This high nonspecific binding decreases
bioavailability and patient variability. Additionally, heparin's nonspecific binding may account for
heparin's narrow therapeutic window and heparin-induced thrombocytopenia (HIT), a major limitation
of heparin. These same affinities are quite low, however, in the case of LMWHs. These parameters
explain several of the benefits of the LMWH's. The favorable absorption kinetics and low protein
binding affinity of the LMWHs results in a greater bioavailability compared with heparin. The
lowered affinity of LMWHs for PF4 seems to correlate with a reduced incidence of HIT. Heparin is
subject to fast zero-order metabolism in the liver, followed by slower first-order clearance from the
kidneys. The LMWHs are renally cleared and follow first-order kinetics. This makes the
clearance of LMWHs more predictable as well as resulting in a prolonged half-life. Finally, the
incidence of heparin-mediated osteoporosis is significantly diminished with use of LMWHs as opposed to heparin.
副作用
The major adverse reaction resulting from heparin
therapy is hemorrhage. Bleeding can occur in the urinary
or gastrointestinal tract and in the adrenal gland.
Subdural hematoma, acute hemorrhagic pancreatitis,
hemarthrosis, and wound ecchymosis also occur. The
incidence of life-threatening hemorrhage is low but variable. Heparin-induced thrombocytopenia of immediate
and delayed onset may occur in 3 to 30% of patients.
The immediate type is transient and may not involve
platelet destruction, while the delayed reaction
involves the production of heparin-dependent antiplatelet
antibodies and the clearance of platelets from
the blood. Heparin-associated thrombocytopenia may
be associated with irreversible aggregation of platelets
(white clot syndrome). Additional untoward effects of
heparin treatment include hypersensitivity reactions
(e.g., rash, urticaria, pruritus), fever, alopecia, hypoaldosteronism,
osteoporosis, and osteoalgia.
代謝
Heparin is prescribed on a unit (IU) rather than milligram
basis. The dose must be determined on an individual
basis. Heparin is not absorbed after oral administration
and therefore must be given parenterally.
Intravenous administration results in an almost immediate
anticoagulant effect. There is an approximate 2-hour
delay in onset of drug action after subcutaneous administration.
Intramuscular injection of heparin is to be
avoided because of unpredictable absorption rates, local
bleeding, and irritation. Heparin is not bound to
plasma proteins or secreted into breast milk, and it does
not cross the placenta.
Heparin’s action is terminated by uptake and metabolism
by the reticuloendothelial system and liver and
by renal excretion of the unchanged drug and its depolymerized
and desulfated metabolite. The relative
proportion of administered drug that is excreted as unchanged
heparin increases as the dose increases. Renal
insufficiency reduces the rate of heparin clearance from
the blood.
純化方法
Most likely contaminants are mucopolysaccharides including heparin sulfate and dermatan sulfate. Purify heparin by precipitation with cetylpyridinium chloride from saturated solutions of high ionic strength. [Cifonelli & Roden Biochemical Preparations 12 12 1968, Wolfrom et al. J Org Chem 29 540 1946, Huggard Adv Carbohydr Chem 10 336-368 1955]
ヘパリン 上流と下流の製品情報
原材料
準備製品