| 摘要: | 根據衛生署的統計，糖尿病居十大死因的第五位，且近幾年來快速成長，並以非胰島素依賴型糖尿病(NIDDM; type II)為主，約佔罹患率的95%左右。目前雖有胰島素注射劑及口服降血糖藥物，但在臨床上之使用仍未達理想。已有文獻指出糖尿病之高血糖會引發身體的自由基過度增加，而導致諸多糖尿病的慢性合併症。氧化壓力增加亦對許多細胞功能造成損害，並因體內抗氧化防禦系統能力的降低使得糖尿病患者體內的氧化壓力、蛋白質糖化均較正常人嚴重，再加上脂質代謝不良，是引發糖尿病併發症的主因。但是，糖尿病患者若血糖控制良好，可使患者體內的氧化壓力及蛋白質糖化作用降低。西藥Glipizide屬於第二代 Sulfonylurea的降血糖藥物，適用於非胰島素依賴型糖尿病，其作用為刺激胰臟分泌胰島素，但是副作用會造成低血糖、發燒、喉嚨痛，皮膚疹，黃疸症狀等症狀。我國傳統醫學研究指出槐花含有Rutin 和 Quercetin，中醫常用於涼血、止血，現代藥理研究指出其可用於治療腦血管相關疾病及防止DNA 受外來化學物質的破壞，並具有血管舒張、清除自由基、降低血清膽固醇、降血壓、降血脂、抗發炎及抗癌等作用。因此本計畫以常用之降血糖西藥 Glipizide併用藥用植物槐花進行降血糖及氧化壓力探討，並期望Glipizide使用劑量減少，減少Glipizide之副作用，以尋得先導中西藥併用藥物以供醫學研究依據。另一方面，糖尿病患者可能會同時服用Glipizide及槐花，是否引發交互作用值得探討。本計畫以大鼠為動物模式，評估中西藥交互作用發生機會與其機制。以Nicotinamide (180 mg/kg, ip)及STZ (streptozotocin, 65 mg/kg, iv) 誘發糖尿病，當血糖達到200 mg/dL，判定為糖尿病老鼠。實驗分成五組，一組為空白組，不誘發糖尿病，其餘四組則誘發糖尿病，一組給予標準配方飲食，做為控制組，第二組則添加槐花 (2 g/kg, bid)，第三組則給與口服降血糖藥(Glipizide, 1 mg/kg)，第四組則給予槐花及Glipizide。實驗期四週，實驗期間採取血液分析，進行口服葡萄糖耐受度測試(OGTT)，並於實驗期結束犧牲老鼠取血液分析，測定血中之葡萄糖及胰島素含量做為指標，氧化壓力以抗氧化防禦系統中的抗氧化酵素活性做為參考依據。初步研究結果發現，糖尿病鼠之體重、飲水量與尿量均較控制組顯著增加。本研究目的將釐清Glipizide及槐花併用之相關機制，探索其實證，期能規劃研究成果，以利國人用藥安全，並進一步期望能尋找可降低口服醬血糖藥物之中草藥。大黃為掌葉大黃Rheum palmatum L.的乾燥根及根莖，何首烏為Polygonum multiflorum thunb乾燥根莖，二者皆為臨床或保健常用之中草藥。前者常用於清熱泄火潤便，具止痛、消腫、促進血液循環及降血脂之作用，其所含成分主要為蒽醌類，包括aloe-emodin、rhein、emodin及chrysophanol。後者則用於解毒、消癰、腸燥便秘、補肝腎、益精血、烏鬚髮、壯筋骨，其成分含rhein、emodin、chrysophanol及physcion等蒽醌類。Phenytoin (PHT) 用於治療除失神性癲癇外之各型癲癇及心律不整，治療指數狹窄，血中濃度過高易致神經及心血管毒性，長期使用癲癇藥物，往往因產生抗藥性而降低其療效。血腦障壁上分佈的P-glucoprotein (Pgp) 與multidrug resistance proteins (MRPs)之過度表現與其抗藥性有關，另有研究指出MRP1 與MRP2 是其中主要的表現蛋白。先前動力學研究發現蒽醌化合物主要以硫酸及葡萄糖醛酸結合態代謝物循環於血流中，此些結合態代謝物之轉運、外排與MRP1、 MRP2、MRP3等運送蛋白有關，而PHT之轉運、外排則與MRP1、MRP2等運送蛋白有關。吾人推測多酚化合物與PHT併服時會競爭MRP1及 MRP2，可能導致動力學交互作用。因此，本研究以大鼠為模型，探討併服富含蒽醌類之大黃與何首烏對PHT動力學之影響。本計畫擬利用交叉設計，予大鼠分別單獨口服PHT及分別併服大黃(2 g/kg及4 g/kg)與何首烏(2 g/kg及4 g/kg)水煎劑，定時自心臟穿刺採血，PHT之血中濃度以HPLC測定法定量。血中藥物濃度數據以WINNONLIN軟體計算動力學參數，並以 ANOVA 及Scheffe’s事後分析，統計各組間差異。預試驗結果發現無論是高或低計量之大黃或何首烏水煎劑，均可顯著降低PHT之中濃度及AUC，而降低 PHT之暴露量，因此病人若服用PHT，應注意避免與含蒽醌淚衍生物之中草藥併用，以免降低PHT之生可用率。
Sophorae flos, a Chinese herb, contains aboundant flavanol aglycon including rutin and quercetin. There are reports that indicated used for treatment of cerebral vessels associated disease and prevention of DNA dystruction by external chemicals. Oxidative stress, glycation and lipid metabolism have been proposed to be linked and be increasing to tissue damage and the development of pathophysiology in diabetic patients. The purpose of this projected is evaluated the effects of Sophorae flos on oxidative status, insulin and blood glucose in diabetic rats. Diabetic rats were induced by injecting with nicotinamide (NTA; 230 mg/kg, ip) and 65 mg/kg/day streptozotocin (STZ) in citrate buffer 2 days, continuously. While the blood sugar over 200 mg/dL was defined as the diabetic rats, and then feeding the different experimental diets. Male adult Wistar rats (b.w eq. 125-150 g) were divided into five groups: Blank group was injected with saline and citric buffer, the others groups were injected with NTA and STZ, feeding with standard diet, with or without Sophorae flos and/or Glipizide, respectivelly. Bloods samples were colledted every three days and OGTT was examed on 25th day. Four weeks later, the diabetic rats were sacrificed and sampled. The indicator of oxidative status were individually evaluated the activity of antioxidant enzyme (SOD and GPX). In addition, we also evaluated the plasma insulin and blood glucose of diabetic rats. The results indicated that the body weight , water intake and urine volume of diabetes rats were significantly higher that those of blank rats.. Rhubarb (RP) and Polygonum multiflorum (PM) contain anthraquinones including aloe-emodin, rhein, emodin and chrysophanol. RP was commonly employed for relieving constipation by purgation, clearing away heat and toxins, purgingfire, promoting blood circulation, normalizing functioning of the gallbladder and curing jaundice.PM is used for stroke. Phenytoin (PHT) is used as an antiepileptic drug for generalized tonic-clonic seizure with narrow therapeutic window and supratherapeutic level od PHT often induced neurotoxicity. Drug resistance always caused poor efficacy of antiepileptics and the overexpressions of Pgp and MRPS at BBB were associated to the resistance. In our previous study, polyphenols were found predominantly as sulfates and glucuronides in the bloodstream, instead of their aglycones. The conjugated metabolites were reported as substrates of multidrug resistance proteins (MRPs) and organic anion transporters (OATs). PHT is a substrate of MRPs and Pgp. The sulfates and glucuronides of polyphenols may compete for the transporters with PHT. This study will investigate the effects of RP and PM decoction on the pharmacokinetics of phenytoin in rats. The blood concentration of PHT was determined by a HPLC method and the pharmacokinetic parameters was calculated using noncompatment model of WINNOLIN. The results indicated that the serum concentrations and AUC of PHT were significantly reduced by coadministration with RP or PM. Through this study, it is anticipated to understand the effect and mechanism of RP and PM on the pharmacokinetics of phenytoin. |
