Fareed J, Hoppensteadt D, Walenga J M, Bick R L
Hemostasis Research Laboratory, Loyola University Medical Center, Maywood, Illinois.
Med Clin North Am. 1994 May;78(3):713-31. doi: 10.1016/s0025-7125(16)30154-7.
Developments in biotechnology, synthetic chemistry, and extraction methods have contributed significantly to provide many newer antithrombotic and anticoagulant drugs. Many of these drugs exhibit mechanisms of actions distinct from heparin and oral anticoagulants. The depolymerization of heparin has resulted in the development of LMWHs. These drugs have now attained the agent of choice status for the prophylaxis of postsurgical and medical thrombotic disorders. LMWHs are now being clinically evaluated for the treatment of established thrombosis and prevention of post-acute angioplasty occlusion and reocclusion. Many newer applications of these agents will be proposed in coming years. Synthetic and recombinant antithrombin agents, such as hirudin and hirulog, have been claimed to exhibit effective anticoagulant and antithrombotic actions. The clinical data, however, are rather limited, and additional validation studies are needed. These agents, however, provide an alternate anticoagulation approach in patients who are refractory to the actions of heparin or who developed heparin-induced thrombocytopenia. Both hirudin and peptide conjugates are undergoing extensive clinical trials throughout the world in various indications. Once validated, their optimized use will provide physicians and surgeons an alternate anticoagulant approach for heparin-compromised patients. Glycosaminoglycans, such as dermatan sulfate, heparan sulfate, and other mixtures, have been developed for various indications. These drugs, however, are relatively inferior to LMWHs for the prophylaxis of thromboembolism. Although these agents have been used for phlebitis and other indications, well-designed objective clinical trials are not available at this time. Because these agents exhibit other effects, such as the effect on smooth muscle cell proliferation, these may be of some value in the control of post-percutaneous transluminal coronary angioplasty restenosis. Several synthetic analogs of heparin and related glycosaminoglycans have also been developed. One of these agents is a synthetic pentasaccharide that represents the AT-III binding site in the heparin molecule. This agent produces a strong anti-Xa effect and is devoid of any antithrombin actions. This agent is currently being developed for the prophylaxis of thromboembolism. The synthetic pentasaccharide is devoid of any effects on platelets and thus does not produce any thrombocytopenic effects. Thus it may be useful in those patients who develop thrombocytopenia and white clot syndrome. A hypersulfated lactobionic acid analog has also been developed as an antithrombotic agent. This agent was initially found to produce its antithrombotic action via HC-II. More recent data, however, show that it also releases TFPI from endogenous sites.(ABSTRACT TRUNCATED AT 400 WORDS)
生物技术、合成化学和提取方法的发展为提供许多更新的抗血栓和抗凝药物做出了重大贡献。这些药物中的许多都具有与肝素和口服抗凝剂不同的作用机制。肝素的解聚导致了低分子量肝素（LMWHs）的开发。这些药物现已成为预防术后和内科血栓形成疾病的首选药物。目前正在对LMWHs进行临床评估，以用于治疗已形成的血栓以及预防急性血管成形术后的闭塞和再闭塞。未来几年将提出这些药物的许多新应用。合成和重组抗凝血酶药物，如水蛭素和比伐卢定，据称具有有效的抗凝和抗血栓作用。然而，临床数据相当有限，还需要更多的验证研究。然而，这些药物为对肝素作用难治或发生肝素诱导的血小板减少症的患者提供了另一种抗凝方法。水蛭素和肽缀合物正在世界各地针对各种适应症进行广泛的临床试验。一旦得到验证，它们的优化使用将为医生和外科医生为肝素使用受限的患者提供另一种抗凝方法。已开发出硫酸皮肤素、硫酸乙酰肝素等糖胺聚糖以及其他混合物用于各种适应症。然而，这些药物在预防血栓栓塞方面相对不如LMWHs。尽管这些药物已用于静脉炎和其他适应症，但目前尚无精心设计的客观临床试验。由于这些药物具有其他作用，如对平滑肌细胞增殖的作用，它们在控制经皮腔内冠状动脉成形术后再狭窄方面可能具有一定价值。还开发了几种肝素和相关糖胺聚糖的合成类似物。其中一种药物是一种合成五糖，它代表肝素分子中的抗凝血酶III结合位点。这种药物产生强烈的抗Xa作用，且没有任何抗凝血酶作用。这种药物目前正在开发用于预防血栓栓塞。合成五糖对血小板没有任何作用，因此不会产生任何血小板减少作用。因此，它可能对发生血小板减少症和白色血栓综合征的患者有用。一种高度硫酸化的乳糖酸类似物也已被开发为抗血栓药物。该药物最初被发现通过肝素辅因子II产生抗血栓作用。然而，最近的数据表明它也能从内源性位点释放组织因子途径抑制物。（摘要截取自400字）
