COLON-SPECIFIC DRUG DELIVERY

结肠特异性给药

• 批准号: 2177764
• 负责人: DAVID R FRIEND
• 金额: $ 25.17万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2177764
• 关键词: colon; corticosteroid analog; dexamethasone; disease /disorder model; dosage; drug delivery systems; drug design /synthesis /production; drug metabolism; eicosanoid metabolism; feces; germ free condition; glucuronides; human tissue; inflammatory bowel diseases; laboratory rat; myeloperoxidase; nonhuman therapy evaluation; pharmacokinetics; prodrugs

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.

拟议研究的长期目标是开发新的、 临床上有用的治疗方法，用于治疗大范围的疾病 肠道，例如炎症性肠病（IBD）。 方法是 基于通过前药传递抗炎（或其他）药物 大肠的载体。 活性药物通过酶释放 由肠道微生物群产生，主要存在于大 肠。 一旦释放，药物被吸收，导致盲肠升高 和结肠组织水平比使用相同药物时可能的水平 以等摩尔剂量全身给药。 具体目标 建议的工作是（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 在大鼠体外条件下（正常、无菌和有缺陷的大鼠） 结肠炎）肠道内容物和组织以及人类粪便样本 正常人和 IBD 患者，(3) 研究正常和无菌条件下的药物输送 大鼠处于或接近药理学相关剂量。 (4)行为效能 研究[评估总体形态学损伤、组织学损伤、 体内液体和电解质吸收、体外溶质跨壁通量 测量、髓过氧化物酶活性和类二十烷酸（PGE2 和 LTB4） 结肠炎诱导的大鼠（正常和 无菌）并将结果与​​特定目标 2 中获得的结果联系起来 3、(5) 测量前药和药物中的血清 ACTH 水平 特定目标 4 中接受治疗的动物。特定目标 1 旨在提供 足够的前药用于体外和体内测试。 具体目标2 和 3 旨在确定细菌和哺乳动物的作用 结肠特异性酶，以及前药的能力 限制药物在胃肠道中的吸收。 具体目标 4 旨在 建立药物递送的药代动力学之间的关系 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中具有选择性优势 相对于通过静脉内递送的活性剂而言，获得了时间 行政。 根据药代动力学和药代动力学结果 功效研究中，所提出系统的主要优点是 能够递送治疗有效量的地塞米松或 氟尼缩松，通过糖苷前药，到达大肠粘膜 使用比全身治疗所需的剂量更低的剂量 行政。 这一发现表明，副作用 相对于全身用药，皮质类固醇可以显着减少 行政。 结肠特异性递送系统的开发将有助于 全世界有许多人患有 IBD。 患有 IBD 的个人位于 患结肠癌的风险显着增加。 交付 放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所帮助 减轻辐射引起的结肠炎的影响。 其他潜力 应用包括 5-氟尿嘧啶 (5-FU) 的局部递送 治疗结肠癌，将5-FU缓慢注入肝门 系统帮助控制继发性肝肿瘤并将药物输送到 下肠有助于控制痉挛性结肠和肠易激 使用抗胆碱能药物或抗痉挛药物的综合征。