PENTOSAN POLYSULFATE IN TREATMENT OF CHRONIC VASCULAR DISEASE

平滑肌细胞被认为是主要的损伤部位， 慢性血管疾病，包括动脉粥样硬化和慢性进行性 肾小球疾病我们最初发现肝素降低了肾小球系膜 细胞-肾小球中的平滑肌细胞-增殖和 以剂量依赖性方式抑制细胞外基质产生。此外 非抗凝肝素减少小鼠肾小球损伤 具有非常严重形式的肾小球硬化症的GH转基因。 这使我们测试肝素类似物在几种形式的渐进 血管疾病口服复方戊聚糖的可行性 多硫酸盐与肝素有一些共同的性质，这使我们提出 这种药在治疗血管疾病中的应用。 开发了一个CRADA 并与贝克-诺顿公司签署了协议，以调查 这种药物在慢性小血 血管（肾小球硬化）和大血管 （动脉粥样硬化）疾病的实验动物，并最终， 伙计 肾小球硬化症的研究最初集中在bGH小鼠，因为 这些小鼠发生尿毒症肾小球疾病。 药物是在 在饮用水中持续6周， 已建立的损伤。治疗后，我们观察到一个显着的 肾小球系膜基质的数量减少， 编码基底膜和间质的基因的表达 胶原蛋白 在糖尿病小鼠身上进行了类似的实验， 没有肾小球硬化症的遗传倾向 大幅 在硬化倾向的糖尿病小鼠中观察到改善， 血糖水平。 当然，没有病变存在于 抗硬化小鼠。 动脉粥样硬化的评价， 用胆固醇喂养的渡边兔， 在LDL受体中。 用自来水喂养的动物出现严重的主动脉 动脉粥样硬化，而动物喂养戊聚糖多硫酸酯在 饮用水平均减少了50%的病变。

Smooth muscle cells are thought to be the major site of injury in chronic vascular diseases including atheroma and chronic progressive glomerular diseases. We initially found that heparin decreased mesangial cell- the smooth muscle cell in the glomerulus- proliferation and extracellular matrix production in a dose-dependent manner. Furthermore non-anticoagulant heparin decreased lesions in the glomeruli of mice transgenic for GH which have a very severe form of glomerulosclerosis. This led us to test heparin analogues in several forms of progressive vascular diseases. The availability of an oral compound pentosan polysulfate which shares some properties with heparin led us to propose this drug in the treatment of vascular diseases. A CRADA was developed and signed with Baker-Norton company in order to investigate the possible therapeutic applications of this drug in chronic small blood vessel (glomerulosclerosis) and large blood vessel (atherosclerosis)diseases in experimental animals and, eventually, in man. Studies in glomerulosclerosis initially focused on bGH mice, since these mice develop uremic glomerular disease. The drug was administered in the drinking water for 6 weeks after they already had severe established lesions. Following treatment we observed a significant decrease in the amount of mesangial matrix and a decrease in the expression of genes coding for basement membrane and interstitial collagens. Similar experiments were done with diabetic mice, with and without a genetic predisposition to glomerulosclerosis. A sharp improvement was observed in sclerosis-prone diabetic mice irrespective of the glycemic level. Of course, no lesions were present in sclerosis-resistant mice. Atherosclerosis was evaluated in cholesterol-fed Watanabe rabbits, animals which have a genetic defect in the LDL receptor. Animals fed with tap water developed severe aortic atherosclerosis, whereas animals fed pentosan polysulfate in the drinking water had a 50% reduction in lesions, on average.