COLON-SPECIFIC DRUG DELIVERY

结肠特异性给药

• 批准号: 3287361
• 负责人: DAVID R FRIEND
• 金额: $ 25.46万
• 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/3287361
• 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、 对大型疾病的临床有用的治疗性治疗 肠道疾病，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 大肠的携带者。活性药物是由酶释放出来的 由肠道微生物群产生，主要驻留在大型 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相同的药剂 系统地以等摩尔剂量给药。的具体目标 本论文的主要工作是：(1)合成β-D-葡萄糖醛酸苷 地塞米松和氟尼松胺，(2)前药的水解性研究 在体外条件下，大鼠(正常、无菌和 结肠炎)肠道内容物和组织以及来自 正常和IBD患者，(3)正常和无菌药物给药研究 处于或接近药理相关剂量的大鼠。(四)行为效能 研究[评估大体形态损伤，组织损伤，#年 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二十烷类化合物(PGE2和LTB4) 结肠炎诱导的大鼠(正常和 GermFree)，并将结果与在特定目标2中获得的结果相关联 和3，以及(5)测量前药和药物中的血清ACTH水平 在特定目标中处理的动物4.特定目标1旨在提供 足够的前药，可用于体外和体内试验。具体目标2 和3被设计用来确定细菌和哺乳动物的作用 酶在结肠的专一性，以及前药的能力 限制药物在胃内的吸收。专门的目标4旨在 建立药物释放的药代动力学关系 以及在豚鼠身上观察到的疗效。专门的目标5旨在 评估给药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- 糖苷，在盲肠和结肠组织水平上的选择性优势 相对于通过静脉注射的活化剂获得的时间 行政管理。根据药代动力学和药物动力学的结果 功效研究表明，拟议系统的主要优势是 能够提供治疗有效剂量的地塞米松或 氟尼松胺通过糖苷前药对大肠粘膜的作用 使用低于全身所需剂量的给药剂量 行政管理。这一发现表明， 与全身性激素相比，皮质类固醇可以显著减少。 行政管理。 结肠靶向给药系统的开发将有助于 全世界有许多人患有IBD。患有IBD的患者请访问 患结肠癌的风险要大得多。正在交付 放射治疗后患者结肠局部皮质类固醇激素 治疗子宫癌和前列腺癌将有所帮助 减轻辐射引起的结肠炎的影响。其他潜力 应用包括局部递送5-氟尿嘧啶(5-FU)用于 肝门缓慢注入5-FU治疗结肠癌 有助于控制继发性肝脏肿瘤的系统和向 帮助控制结肠痉挛和肠易激的肠道下部 使用抗胆碱类药物或抗痉挛药物的综合征。