COLON-SPECIFIC DRUG DELIVERY

拟议研究的长期目标是开发新的， 临床上有用的，治疗性的治疗方法， 肠，如炎症性肠病（IBD）。 该方法是 基于通过前药递送抗肿瘤（或其它）药物 携带者进入大肠。 活性药物被酶释放出来 由肠道微生物群产生，主要存在于大的 肠子 一旦释放，药物被吸收，导致更高的盲肠 和结肠组织的水平比当相同的药剂 以等摩尔剂量全身给药。 的具体目标 拟开展的工作是：（1）合成β-D-葡萄糖醛酸苷， 地塞米松和氟尼缩松，（2）研究前药的水解 在体外条件下，在大鼠（正常、无菌和 结肠炎）肠内容物和组织中以及来自 正常和IBD患者，（3）正常和无菌的研究药物递送 大鼠在或接近剂量相关。(4)行为效能 研究[评估大体形态学损伤、组织学损伤， 体内液体和电解质吸收，体外溶质透壁通量 测量、髓过氧化物酶活性和类花生酸（PGE 2和LTB 4） 结肠炎诱导的大鼠（正常和 无菌），并将结果与特定目标2中获得的结果相关联 和（5）测量前药和药物中的血清ACTH水平 具体目标中的治疗动物4. 具体目标1旨在提供 用于体外和体内测试的足够的前药。 具体目标2 和3的目的是确定细菌和哺乳动物的作用， 酶在结肠特异性，以及前药的能力， 限制药物在GIT中的吸收。 具体目标4旨在 建立药物释放的药代动力学关系 以及在豚鼠中观察到的功效。 具体目标5旨在 评估输送系统减少副作用的潜力 通常与长期服用皮质类固醇有关。 目前的研究表明，使用前药地塞米松β-D- 葡萄糖苷，在盲肠和结肠组织水平的选择性优势， 相对于通过静脉内递送的活性剂， 局 根据药代动力学和 有效性研究，所提出的系统的主要优点是 递送治疗有效量的地塞米松的能力，或 氟尼缩松，通过糖苷前药，到大肠粘膜 使用比全身用药所需剂量更低的给药剂量 局 这一发现表明， 皮质类固醇可以显着减少相对于全身 局 结肠特异性递送系统的开发将有助于 全世界有很多人患有IBD。 IBD患者在 患结肠癌的风险显著增加。 提供 放射治疗后患者结肠局部皮质类固醇 治疗子宫癌和前列腺癌的疗法将有助于 减轻辐射引起的结肠炎的影响。 其他潜在 应用包括5-氟尿嘧啶（5-FU）的局部递送， 结肠癌的治疗，5-FU缓慢输注到肝门 系统，以帮助控制继发性肝肿瘤和药物输送， 下肠道，以帮助控制痉挛结肠和肠易激惹 使用抗胆碱能药或解痉药的综合征。

The long-term objective of the proposed research is to develop new, clinically useful, therapeutic treatments for diseases of the large intestine, such as inflammatory bowel disease (IBD). The approach is based on delivery of antiinflammatory (or other) agents via a prodrug carrier to the large intestine. The active drug is liberated by enzymes produced by gut microflora, which reside primarily in the large intestine. Once released, the drug is absorbed, leading to higher cecal and colon tissue levels than are possible when the same agent is administered systemically at an equal molar dose. The specific aims of the proposed work are to (1)synthesize the beta-D-glucuronides of dexamethasone and flunisolide, (2) study the hydrolysis of the prodrugs under in vitro conditions in rat (normal, germfree, and rats with colitis) intestinal contents and tissues and in human fecal samples from normal and IBD patients, (3) study drug delivery in normal and germfree rats at or near pharmacologically relevant doses. (4) conduct efficacy studies [assessment of gross morphologic injury, histologic injury, in vivo fluid and electrolyte absorption, in vitro solute transmural flux measurements, myeloperoxidase activity, and eicosanoid (PGE2 and LTB4) levels in the colonic lumen] in colitis-induced rats (normal and germfree) and relate the results with those obtained in specific aims 2 and 3, and (5) measure serum ACTH levels in both prodrug and drug treated animal in specific aim 4. Specific aim 1 is designed to provide sufficient prodrug for testing in vitro and in vivo. Specific aims 2 and 3 are designed to determine the role of bacterial and mammalian enzymes in colon specificity, as well as the ability of the prodrug to limit absorption of the drug in the GIT. Specific aim 4 is designed to establish the relationship between the pharmacokinetics of drug delivery and the efficacy observed in guinea pigs. Specific aim 5 is designed to assess the potential of the delivery system to reduce side effects commonly associated with chronic administration of corticosteroids. Current studies indicate that, using the prodrug dexamethasone beta-D- glucoside, a selective advantage in cecal and colon tissue levels over time is gained relative to the active agent delivered by intravenous administration. On the basis of results from pharmacokinetic and efficacy studies, the primary advantage of the proposed system is the ability to deliver therapeutically effective amounts of dexamethasone or flunisolide, via a glycoside prodrug, to the large intestinal mucosa using lower administered doses than required with systemic administration. This finding suggests that the side effects of corticosteroids could be markedly reduced relative to systemic administration. The development of a colon-specific delivery system will be useful to many people worldwide who suffer from IBD. Individuals with IBD are at a significantly greater risk of developing colon cancer. Delivering corticosteroids locally to the colon of patients following radiation therapy for treatment of uterine and prostate cancers would help alleviate the effects of radiation-induced colitis. Other potential applications include localized delivery of 5-fluorouracil (5-FU) for treatment of colon cancer, slow infusion of 5-FU into the hepatic portal system to help control secondary hepatic tumors and delivery of drugs to the lower intestine to help control spastic colon and irritable bowel syndrome using anticholinergics or antispasmotics.