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    Please use this identifier to cite or link to this item: http://ir.cnu.edu.tw/handle/310902800/29348


    標題: 開發腸道葡萄醣醛酸脢專一性抑制劑57以降低化療誘導腹瀉及提高化療療效(I)
    Development of the Intestinal Beta-Glucuronidase Inhibitor 57 Reducing Chemotherapy-Induced Diarrhea and Enhancing Chemotherapeutic Efficacy
    作者: 呂玉玲
    貢獻者: 嘉南藥理大學藥學系(含碩士班)
    日期: 2014
    上傳時間: 2015-11-06 16:09:42 (UTC+8)
    摘要: 葡萄醣醛酸化(glucuronidation)是肝臟藥物解毒的主要路徑;然而,當化療藥物進入腸道後會被腸道菌所分泌的葡萄醣醛酸酶(-glucuronidase;G)再活化而造成腸道損傷及誘發腹瀉 (chemotherapy-induced diarrhea)。有50-80%的化療藥物會誘發腹瀉,其中大腸癌第一線化療藥物 Irinotecan (CPT-11)在臨床上有60-80%的病人有腹瀉的副作用,嚴重的腹瀉會影響病人生活品質,甚至停藥而降低治療效果。目前抗腹瀉劑或抗生素雖可降低腹瀉,但是不是針對G,無法有效改善腹 瀉現象。為了有效改善化療藥物誘導腹瀉,我們將開發一細菌葡萄醣醛酸酶(eG)專一抑制劑做為化療口服佐劑,以保護腸道而降低化療誘發腹瀉,並增加療效。我們先前已證實了口服eG 專一性抑制性57 可抑制腸道eG 活性而降低CPT-11 所引起的小鼠體重流失及腹瀉。基於此結果,我們將開發eG 專一性抑制性57 成為化療口服佐劑。同時參照先前構想書審查意見及Gap analysis 分析,設計以下實驗:(1)檢測CPT-11 合併eG 專一性抑制性57 之腫瘤治療效率。(2)最佳化eG 專一性抑制性57 劑型開發成為化療口服佐劑57。(3)對口服佐劑57 進行藥物動力學及毒理測試以朝向臨床試驗檢測。此計畫成功,將可有效降低化療誘發腹瀉並且提高化療療果及改善病人生活品質,以解決目前臨床上化療藥物治療之困境。
    Glucuronidation represents a major route of drug detoxification. However, deconjuation of the drug-glucuronide by intestinal microflora -glucuronidase (eG) can reactivate the detoxified drugs and induce intestinal injury and chemotherapy-induced diarrhea (CID). CID is the main drawback for cancer patients, which can occur in 50-80% of patients depending on the chemotherapy regimen, especially in patients with advanced cancers. For example, Irinotecan (CPT-11), a first-line therapeutic drug mainly used for the treatment of metastatic colorectal cancer, has been clinically demonstrated to induce diarrhea varies 60-80% depending on treatment regime. Currently, the antidiarrheal agents or antibiotics were used to reduce the CID. However, these treatments are not specific to the eG, thus they only have palliative effects to relieve symptoms. To overcome these problems, we will develop an eG specific inhibitor as oral adjuvant to protect intestine against chemically-induced toxicity and reduce CID, thus enhancing chemotherapeutic efficiency. In our previously result, we have identified a lead compound 57 which can effectively inhibit eG activity but have no effect on human G (hG). The inhibition ability of the compound 57 (IC50 = 0.15 M) is better than -GInh (a Science-published compound 1, IC50 = 2 M). Importantly, oral administration of the inhibitor 57 can inhibit CPT-11 induced weight loss and diarrhea by blocking intestinal eG activity. Based on these results, we will promote eβG specific inhibitor 57 (lead compound) to be oral adjuvant 57 (candidate) against CID. Toward this goal, we have the following aims based on the suggestion of NRPB and the Gap Analysis report. (1) Examine the in vivo anti-tumor efficacy of CPT-11 combined with the eβG specific inhibitor 57. (2) Optimal formulation of the eβG specific inhibitor 57 as oral adjuvant for chemotherapy. (3) Examine the pharmacokinetics and toxicity of the oral adjuvant 57 towards IND enabling studies. We believe, upon completion, the eβG specific inhibitor 57 as an oral adjuvant will reduce chemotherapy-induced toxicity and improve patients’ quality of life.
    關聯: 計畫編號:MOST103-2325-B041-001
    計畫年度:103;起迄日期:2014-05-01~2015-04-30
    Appears in Collections:[藥學系(所)] 科技部計畫

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