SYNTHESIS AND TESTING OF A NEW CLASS OF HEPARINOIDS

描述(调查人员摘要)：这是中的第一阶段应用程序 其目标是开发一种能够取代 肝素。虽然肝素是治疗血栓栓塞症的最佳药物 疾病，如果口服它是不稳定的，因此要大量使用 通过静脉或皮下途径。此外， 血小板减少以及出血和血栓形成，这可以出现为 这种疗法的并发症，仍然是一个临床问题。 近日，在一份初步报告中，一组磺化双乳仿生 酸性胺已被证明具有抗凝血剂和 反咬合性能可与目前可获得的 商用肝素。首先是麦芽糖和 纤维二糖，二糖被氧化并与短链缩合 二胺，然后磺化。申请人的公司生产的大型 红霉素乳胶仿生剂的用量及给药器官 移植。在一次文献检索中，申请人发现 磺化双乳糖酸胺是一种潜在的抗凝血剂。在……里面 肝素，中糖上的3-0‘-硫酸盐是必需的 抗凝血活性。申请者将生产碳水化合物 可能具有改进的肝素样活性的各种结构。这个 化合物的抗凝血性能将在第一阶段进行初步测试 并且，在稍后的第二阶段，将评估它们的抗血栓活性。 使用麦芽糖作为起始二糖的优点是它可以 不能像其他糖一样被消化。纤维二糖是另一个 不能被哺乳动物消化的起始二糖 酵素。此外，这些化合物相当小，可溶，而且可能很容易 全神贯注。这些小聚合物也是无毒的。抗凝剂 最终生成的化合物的性质将被检查其 能延长活化的部分凝血活酶时间和 凝血酶时间。标准将是肝素，175单位/毫克。托勒夫森博士 其中一位顾问将研究活性化合物对 纯化的抗凝血酶III和肝素对凝血酶的抑制率 辅因子II是在他的实验室里建立的。

DESCRIPTION (Investigator's Abstract): This is a phase I application in which the goal is to develop a therapeutic agent which would replace heparin. Although heparin is the best drug for treatment of thromboembolic disease, it is unstable if administered orally and much therefore be used by the intravenous or subcutaneous route. In addition, the thrombocytopenia and both bleeding and thrombosis, which can emerge as complications of this therapy, remain a clinical problem. Recently, in a preliminary report, a group of sulfonated bislactobionic acid amines have been demonstrated to possess anticoagulant and antiocclusive properties comparable to those currently attainable with commercial heparin. Starting with compounds such as maltose and cellobiose, the disaccharide is oxidized and condensed with short chain diamines and then sulphonated. The applicant's company produces large quantities of lactobionic for stabilization of erythromycin and organs for transplant. During a literature search, the applicant found that sulphonated bis-lactobionic acid amines are potential anticoagulants. In heparin, the 3-0'-sulphate on the middle sugar is essential for anticoagulant activity. The applicants will produce carbohydrates of various structure which may have an improved heparin-like activity. The compounds will be initially tested for anticoagulant properties in phase I and, later in phase II, their antithrombotic activity will be evaluated. The advantage of using maltose as a beginning disaccharide is that it may not be digested to the same degree as other sugars. Cellobiose is another starting disaccharide which may not be cleaved by mammalian digestive enzymes. Also, the compounds are rather small, soluble and may be readily absorbed. These small polymers are also non-toxic. Anticoagulant properties of the final compounds generated will be examined for their ability to prolong the activated partial thromboplastin time and the thrombin time. The standard will be heparin, 175 units/mg. Dr. Tollefsen, one of the consultants, will examine the effects of active compounds on the rate of thrombin inhibition by purified antithrombin III and heparin cofactor II as established in his laboratory.