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系統識別號 U0026-0812200913431315
論文名稱(中文) 藥物對糖尿病鼠胃部出血性潰瘍保護作用之探討
論文名稱(英文) Protective effects of several drugs on gastric hemorrhagic ulcer in diabetic rats
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 95
學期 2
出版年 96
研究生(中文) 林佳慧
研究生(英文) Chia-hui Lin
電子信箱 s2694406@mail.ncku.edu.tw
學號 s2694406
學位類別 碩士
語文別 中文
論文頁數 98頁
口試委員 指導教授-洪正路
口試委員-簡伯武
口試委員-鄭瑞棠
中文關鍵字 發炎細胞激素  胃酸逆擴散機制  糖尿病  出血性潰瘍  胃氧化性壓力  溶菌酶素  褪黑激素 
英文關鍵字 gastric oxidative stress  acid back-diffusion  inflammatory cytokines  melatonin  hemorrhagic ulcer  diabetes mellitus  lysozyme 
學科別分類
中文摘要 文獻指出長期患有糖尿病的患者常會遭受到如胃部、腹部疼痛,噁心,嘔吐,腹瀉,便秘等腸胃症狀方面之苦。通常,胃部本身即具有破壞與防禦的機轉。胃酸的逆擴散和自由基大量產生會破壞胃黏膜的完整性,形成出血性潰瘍,而麩胺基硫和胃部黏液產量的增加則防禦胃黏膜被破壞。糖尿病鼠的胃黏膜容易受損傷,但對於在糖尿病的狀態的胃部出血性潰瘍研究目前尚未被探討。
本篇研究主要想探討糖尿病鼠胃部出血性潰瘍可能生理機轉與投與傳統潰瘍治療性藥物如famotidine、sucralfate、lansoprazole以及抗氧化藥物如溶菌酶素、蒜油、褪黑激素的潰瘍保護效果比較。本研究經由靜脈注射Wistar大白鼠streptozotocin(65mg/kg)以誘導糖尿病。經由藥物處理的糖尿病鼠經胃部及迷走神經截斷手術,鼠胃以人工胃液灌流三小時後,將胃部分離取出做觀察並測定胃黏膜各種的參數分析。實驗結果顯示,各種潰瘍參數(如:胃潰瘍面積、胃酸逆擴散現象,血紅素含量、脂質過氧化物濃度和組織氨濃度等)的惡化,以及防禦物質(包括麩胺基硫濃度,黏液含量等)的減少,也都能在糖尿病鼠中被觀察到。糖尿病鼠胃的參數變化與胃部出血性潰瘍間存在呈現相關關係。並且投與傳統潰瘍治療性藥物和抗氧化藥物都可以觀察到隨著劑量增加而增加防止傷害的能力。
胃黏膜抵禦傷害的系統是很複雜的其中的前列腺素也扮演了一個重要的角色。前列腺素已知也會參予在發炎機制裡,而本研究使用的糖尿病鼠其胃黏膜發現在發炎反應中重要的細胞激素如IL-1β,TNF-α, i-NOS有顯著性的增加。因此利用口服的方式投與糖尿病鼠抗發炎藥物,如TNF-α inhibitor – Pentoxifylline; i-NOS inhibitor – Aminoguanidin; COX inhibitor – Indomethacin 以及COX-2 inhibitor – celicoxib試圖辨別糖尿病鼠胃部潰瘍與發炎反應之間的關係。研究發現,pentoxifylline和aminoguanidin可以減輕糖尿病鼠胃部潰瘍情況,然而糖尿病鼠合併Indomethacin 和celicoxib處理則是會造成相較於單獨糖尿病鼠胃部潰瘍更嚴重的損傷。此可能機轉將以COX酵素作用機轉作進一步的討論。
綜合以上結果,糖尿病確實可導致胃部潰瘍,並且推論機制與氧化壓力,黏液減少及發炎反應有關;若增加血中胰島素則會抑制糖尿病所造成的胃部潰瘍情況。
英文摘要 Patients with diabetes mellitus may suffer from gastrointestinal disturbances, such as dysphagia, abdominal pain, nausea, vomiting, diarrhea and fecal incontinence. The integrity of gastric mucosa is greatly affected by offensive factors, such as increased gastric acid-back diffusion and free radicals generation as well as by decreased defensive substances, including glutathione and mucus production. Gastric mucosa of diabetic rats is highly vulnerable to injury, but little is known about the influence of diabetic conditions on the gastric hemorrhagic ulcers. Therefore, we investigated the pathophysiological mechanisms and several drug protective effects on hemorrhagic ulcer in diabetic rats.
The aim is to study hemorrhagic ulcer induced by diabetes mellitus and protective effects of lysozyme, melatonin and garlic oil ,and compared them with traditional drugs famotidine, sucralfate and lansoprazole in diabetic rats. Intravenous streptozotocin (65mg/kg) was used to induced DM in rats. DM caused aggravation of various gastric offensive and defensive parameters in DM rat stomachs irrigated for 3hs with gastric juice. Aggravation of gastric parameters that associated with gastric oxidative stress such as acid back diffusion, hemoglobin content, and lipid peroxide, as well as decreased concentration of defensive substances, including glutathione and mucus content were observed in these DM rats. An increased gastric hemorrhagic ulcer also achieved in DM rats. These ulcerogenic parameters were doses-dependant effectively inhibited by daily administrated lansoprazole, fomatidine, sucralfate, melatonin, lysozyme and garlic oil in those DM rats.
A complex system of interacting mediators exists in the gastric mucosa to strengthen its resistance against injury. In this system prostaglandins play an important role. Initially the concept was prostaglandins involved in pathophysiological reactions such as inflammation. Inflammatory cytokines (TNF-alpha, IL-1beta and i-NOS) significantly elevated in gastric mucosa of DM rats. Oral administrated anti-inflammatory drugs(TNF-α inhibitor – Pentoxifylline 20mg/kg; i-NOS inhibitor – Aminoguanidin 20mg/kg; COX inhibitor – Indomethacin 2.5mg/kg and COX-2 inhibitor - celicoxib;5mg/kg)to investigate the pathophysiological mechanisms on hemorrhagic ulcer in diabetic rats. These ulcerogenic parameters were effectively inhibited by daily administrated pentoxifylline and aminoguanidin decreased gastric hemorrhagic ulcer in DM rats. COX inhibitor and a selective COX-2 inhibitor when given added to DM rats the severe gastric damage develops. With the views of mechanisms of COX enzyme was discussed in the present.
In conclusion, Indomethacin and celicoxib could produce deeper and more extensive mucosal hemorrhagic ulcer in DM rats than normal rats that is associated with oxidative stress, decreased mucus and inflammation. Exogenous insulin leading to hyperinsulinemia could decreased ulcer produced in DM rats.
論文目次 考試合格證明
誌謝……………………………………………………………………I
目錄……………………………………………………………………II
圖目錄…………………………………………………………………III
中文摘要………………………………………………………………1
英文摘要………………………………………………………………3
第一章緒論……………………………………………………………5
第二章實驗方法和材料………………………………………………25
第三章實驗結果………………………………………………………37
第四章討論……………………………………………………………43
第五章結論……………………………………………………………60
參考文獻………………………………………………………………61
圖表及附錄……………………………………………………………70
作者簡歷………………………………………………………………98
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