ヘパリノイド、ヘパリン類縁体

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/10/19 19:15:09」(JST)

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Heparinoids are glycosaminoglycans which are derivatives of heparin.^[1] They include oligosaccharides and sulfated polysaccharides of plant, animal, or synthetic origin.^[2] One study conducted on heparinoids.^[3]

Heparinoids, like heparin, act by interacting with heparin binding proteins, generally through ionic interactions or hydrogen bonding. Some examples of heparin binding proteins include antithrombin III. It is thought that much protein interaction with heparin is not direct, and instead heparin binding protein actually interact with glycosaminoglycan (GAG) side chains or mucins bound to the heparin polymer, so it is possible that heparinoids interact with these proteins in a similar way, acquiring GAG side chains in vivo. One counter example is the protein chymase, which directly binds to heparin.^[2]

Sulfonated Polysaccharides

From Animal Tissues

Dermatan sulfate is one example of a compound that is classified as a heparinoid. It is a naturally-occurring polysaccharide of O-sulfonated N-Acetyl-D-galatosamine, L-induronic acid, and D-glucuronic acid that has been clinically used as an antithrombic agent.^[2]

Chondroitin sulfate shows slightly less biological activity than dermatan sulfate, and is composed of O-sulfonated N-Acetyl-D-galatosamine and D-glucuronic acid. It is theorized that this change in efficacy is related to the absence of L-induronic acid, which affects the flexibility of the polymer chain.^[2]

Acharan sulfate is a heparinoid that is naturally produced by the giant African land snail, Achatina fulica. Keratan sulfate is a heparinoid that is a component of cartilage. It is found in the cornea.^[2]

Chitin, a component of insect shells and fungal structures, can be de-N-acetylated to form chitosan, which when sulfonated has a significant chemical similarity to heparin. In fact, it inhibits thrombin by affecting ATIII.

Lepirudin is a recombinant preparation of the polypeptide anticoagulant secreted by leeches and is used in patients with heparin induced thrombocytopenia.

From Plant Sources

Fucoidin is a polymer composed of sulfated L-fucose.

Carrageenans are isolated from algae.

Hyaluronan functions as a heparinoid when it is sulfonated. Intra-articular injections of hyaluronic acid are used to mitigate pain and treat symptoms of osteoarthritis in the knee, but such injections are correlated with increased risk of serious side effects.^[4]

Alginic acid functions as a heparinoid when it is sulfonated.

Pentosan from the bark of Fagus sylvantica, when sulfonated, acts with 1/10th of the efficacy of heparin.

From Microbial Sources

K5 polysaccharide from E. coli acts as a heparinoid when it is sulfonated.

Small Sulfonated Oligosaccharides

History

Heparin was first isolated from dog liver by medical student Jay McClean in 1916. Jorpes discovered the structure of the heparin polysaccharide in 1935, identifying that it is a highly sulfonated polymer of glycosaminoglycoglycan (GAG) and uronic acid. Around that time, heparin began to be used in the prophylaxis and treatment of post-operative thrombosis.^[5]

Production

There is no industrial process for the complete synthesis of heparin; Heparin is isolated from animal tissue - generally bovine lung, porcine, and intestinal mucosa.^[5] Heparinoids generally are also naturally-occurring polysaccharides, and similarly need to be purified from the plant or animal tissue that produces them.

Regulation

There is no internationally accepted molecular standard for the composition of heparin, as it is a complex polymer of GAG units and uronic acids (including D-glucuronic acid, L-iduronic acid, and D-glucosamine). Position of N-acetyl, N-sulfate, and O-sulfate groups in these uronic acids can vary, as can the branching patterns of the chain. This generates an extraordinary amount of variability between molecules of heparin.^[5] Current USP standards for heparin limit levels of contamination with dermatan, chondroitin, and over-sulfonated chondroitin sulfate, as well as galactosamine levels in the sample, as determined by HPLC, H-NMR, and Strong Anion Exchange Chromatography.^[6]^[7]

References

^ Heparinoids at the US National Library of Medicine Medical Subject Headings (MeSH)
^ ^a ^b ^c ^d ^e Gunay NS, Linhardt RJ (1999). "Heparinoids: structure, biological activities and therapeutic applications". Planta Medica. 65 (4): 301–6. doi:10.1055/s-1999-13990. PMID 10364832.
^ Mehta PP, Sagar S, Kakkar VV (1975). "Treatment of superficial thrombophlebitis: a randomized, bouble-blind trial of heparinoid cream". British Medical Journal. 3 (5984): 614–6. doi:10.1136/bmj.3.5984.614. JSTOR 20406780. PMC 1674425. PMID 51664.
^ Rutjes AW, Jüni P, da Costa BR, Trelle S, Nüesch E, Reichenbach S (2012). "Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis". Ann. Intern. Med. 157 (3): 180–91. doi:10.7326/0003-4819-157-3-201208070-00473. PMID 22868835.
^ ^a ^b ^c Template:Nieforth, Karl A., and Zbigniew J. Witczak. 1997. "Heparin Oligosaccharides: New Analogues Development and Applications." Carbohydrates in Drug Design. New York: M. Dekker, 1997. eBook Collection (EBSCOhost), EBSCOhost (accessed November 30, 2015).
^ {{U.S. Pharmacopeia Heparin Stage Two Monograph Revisions Open Microphone Web Meeting March 3, 2009 Powerpoint Presentation. Morris, Tina S.; Szajeck, Anita; Wahab, Samir; Ambrose, Michael; Jameison, Fabian A.; <http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/key-issues/2009-03-09-HeparinMeeting.pdf> }}
^ USP Safety Data Sheet: Heparin Sodium with Oversulfated Chondroitin Sulfate. http://static.usp.org/pdf/EN/referenceStandards/msds/1304050.pdf Accessed on 11/30/2015.

External links

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UpToDate Contents

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1. 血液透析中の抗凝固療法 hemodialysis anticoagulation
2. 急性脳出血または脳出血既往歴のある患者における抗血栓療法の利用 the use of antithrombotic therapy in patients with an acute or prior intracerebral hemorrhage
3. ヘパリン起因性血小板減少症のマネージメント management of heparin induced thrombocytopenia
4. 急性虚血性脳卒中および一過性脳虚血発作に対する抗血栓治療 antithrombotic treatment of acute ischemic stroke and transient ischemic attack
5. 血管内皮機能および血栓溶解療法の基本的メカニズム vascular endothelial function and fundamental mechanisms of fibrinolysis thrombolysis

English Journal

Large-scale synthesis of 6-deoxy-6-sulfonatomethyl glycosides and their application for novel synthesis of a heparinoid pentasaccharide trisulfonic acid of anticoagulant activity.

Mező E1, Herczeg M2, Eszenyi D1, Borbás A3.Author information 1Department of Pharmaceutical Chemistry, Medical and Health Science Center, University of Debrecen, PO Box 70, H-4010 Debrecen, Hungary; Department of Organic Chemistry, University of Debrecen, PO Box 20, H-4010 Debrecen, Hungary.2Department of Organic Chemistry, University of Debrecen, PO Box 20, H-4010 Debrecen, Hungary.3Department of Pharmaceutical Chemistry, Medical and Health Science Center, University of Debrecen, PO Box 70, H-4010 Debrecen, Hungary. Electronic address: borbas.aniko@pharm.unideb.hu.AbstractMultigram-scale syntheses of three 6-deoxy-6-sulfonatomethyl α-glucosides were accomplished via reactions of the corresponding primary triflate derivatives with the lithiated ethyl methanesulfonate. Chemoselective glycosylation reactions of different 6-C-sulfonatomethyl glucoside donors were studied. The sulfonic acid-containing building blocks were utilised in a novel [2+3] block synthesis of a trisulfonic acid isoster of the anticoagulant pentasaccharide idraparinux.
Carbohydrate research.Carbohydr Res.2014 Feb 18;388C:19-29. doi: 10.1016/j.carres.2014.02.012. [Epub ahead of print]
Multigram-scale syntheses of three 6-deoxy-6-sulfonatomethyl α-glucosides were accomplished via reactions of the corresponding primary triflate derivatives with the lithiated ethyl methanesulfonate. Chemoselective glycosylation reactions of different 6-C-sulfonatomethyl glucoside donors were studie
PMID 24607537

Heparinoids Activate a Protease, Secreted by Mucosa and Tumors, via Tethering Supplemented by Allostery.

Fulcher YG1, Sanganna Gari RR, Frey NC, Zhang F, Linhardt RJ, King GM, Van Doren SR.Author information 1Department of Biochemistry and ‡Department of Physics and Astronomy, University of Missouri , Columbia, Missouri 65211, United States.AbstractActivation by glycosaminoglycans (GAGs) is an emerging trend among extracellular proteases important in disease. ProMMP-7, the zymogen of a matrix metalloproteinase secreted by mucosal epithelial and tumor cells, is activated at their surfaces by sulfated GAGs, but how? ProMMP-7 is activated in trans by representative heparin oligosaccharides in a length-dependent manner, with a large jump in activation at lengths of 16 monosaccharides. Imaging by atomic force microscopy visualized small complexes of proMMP-7 molecules linked by 8-mer lengths of heparinoids and extended assembles formed with 16-mer lengths of heparin. Complexes of proMMP-7 with polydisperse heparin or heparan sulfate were more diverse. Heparinoids evidently accelerate activation by tethering multiple proMMP-7 molecules together for proteolytic attack among neighbors. Removal of either the prodomain or C-terminal peptide sequence of KRSNSRKK from MMP-7 prevents formation of the long arrays induced by heparin 16-mers or heparan sulfate. The role of the C-terminus in activation assays suggests it contributes to remote, allosteric binding of GAGs. Enhancement of proteolytic velocity of MMP-by GAGs indicates them to be effectors of V-type allostery. GAGs from proteoglycans appear to assemble proMMP-7 molecules for activation, an event preceding its tumorigenic or antibacterial proteolytic activities at cell surfaces.
ACS chemical biology.ACS Chem Biol.2014 Feb 10. [Epub ahead of print]
Activation by glycosaminoglycans (GAGs) is an emerging trend among extracellular proteases important in disease. ProMMP-7, the zymogen of a matrix metalloproteinase secreted by mucosal epithelial and tumor cells, is activated at their surfaces by sulfated GAGs, but how ProMMP-7 is activated in tran
PMID 24495220

Inhaled anticoagulation regimens for the treatment of smoke inhalation-associated acute lung injury: a systematic review.

Miller AC1, Elamin EM, Suffredini AF.Author information 11Department of Critical Care Medicine, Clinical Center, National Institutes of Health, Bethesda, MD. 2Department of Internal Medicine, Division of Pulmonary, Allergy, and Critical Care, University of Pittsburgh Medical Center, Pittsburgh, PA. 3Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, James A. Haley Veteran's Hospital and University of South Florida, Tampa, FL.AbstractOBJECTIVE: Inhaled anticoagulation regimens are increasingly being used to manage smoke inhalation-associated acute lung injury. We systematically reviewed published and unpublished preclinical and clinical trial data to elucidate the effects of these regimens on lung injury severity, airway obstruction, ventilation, oxygenation, pulmonary infections, bleeding complications, and survival.
Critical care medicine.Crit Care Med.2014 Feb;42(2):413-9. doi: 10.1097/CCM.0b013e3182a645e5.
OBJECTIVE: Inhaled anticoagulation regimens are increasingly being used to manage smoke inhalation-associated acute lung injury. We systematically reviewed published and unpublished preclinical and clinical trial data to elucidate the effects of these regimens on lung injury severity, airway obstruc
PMID 24158173

Japanese Journal

Intravenous immunoglobulin therapy for aspirin-heparinoid-resistant antiphospholipid syndrome

SHIMADA Shigeki,YAMADA Hideto,ATSUMI Tatsuya,YAMADA Takashi,SAKURAGI Noriaki,MINAKAMI Hisanori
Reproductive medicine and biology 9(4), 217-221, 2010-12-01
NAID 10027738115

ロコイドクリーム0.1%とデルマクリンクリーム1%の混合外用療法の効果

山本一哉,小栗剛,内田美香,三石知左子,岩松雅子
日本小児皮膚科学会雑誌 = Journal of pediatric dermatology 28(1), 35-40, 2009-05-31
NAID 10024847377

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