- 學位論文
探討含有甲基培尼皮質醇的溫感性聚合物應用於巴豆油誘發之小鼠直腸炎
The Study of Methylprednisolone with Thermosensitive Polymer on Croton Oil-Induced Proctitis in Mice
摘要
本研究製備含有甲基培尼皮質醇 (Methylprednisolone, MP)的溫感性聚合物直腸投與劑型，並評估其對於巴豆油誘發的的小鼠直腸炎治療之可能性。 在測定溫感性聚合物劑型的物化特性實驗中，得知此聚合物隨著濃度增加，其凝膠化溫度會隨之下降；同時，此聚合物的凝膠化溫度也會受到MP的添加而使凝膠化溫度下降，同時在螢光物質評估下，此凝膠可以在直腸1小時內有聚集現象。而含有MP的17%聚合物在纖維素膜的24小時累積釋放藥量約為20%。17%聚合物也能將MP的4℃溶解度從157.8 ± 3.3 ug/ml提升至626.6 ± 0.4 ug/ml。 小鼠的直腸道在接受巴豆油的12小時後，組織有明顯的水腫(edema)，同時蘇木紫染色的結果也顯示出白血球細胞(White blood cells, WBCs)的浸潤。在分生層面觀察到傷害後顆粒性球群落刺激因子(granulocyte-colony stimulating factor, G-CSF)、環氧合酶-2 (cyclooxygenase-2, COX-2)與抑制細胞凋亡 (anti-apoptotic)蛋白Bcl-xL的mRNA在傷害後12小時皆有明顯上升。同時，磷酸活化態的磷脂酶A2 (phospho-cytosolic phospholipase A2, p-cPLA2)和骨髓過氧化酶 (myeloperoxidase, MPO)的蛋白質表現皆在傷害後的早期即有明顯的增加，而COX-2和G-CSF的蛋白質表現量則是在12~48小時才有明顯的上升，推測上述發炎現象是巴豆油在小鼠腸道內活化cPLA2訊息傳遞路徑所引起的反應。 目前結果顯示，投與含有5 mg/kg MP的17%溫感性聚合物至老鼠直腸道內，治療後12小時，雖然腸道組織的外觀還無法恢復至正常型態，但與市售栓劑 (抑痣寧®)抑制組織水腫的有相同效果，同時在p-cPLA2、MPO及COX-2的蛋白質有明顯下降表現，並且對於COX-2和G-CSF的mRNA表現均有降低效果。
並列摘要
The main purpose of this study was to evaluate the inhibition of inflammatory with thermosensitive polymer and methylprednisolone(MP) on croton oil-induced proctitis in mice. The gelation temperature of thermosensitive polymer was decreased with increasing concentration of the polymer solution. In addition, the present of MP also decreased the gelling temperature of the polymer solution. Using sodium fluorescein, the retention of gel polymer could observe around rectal area with 1 hr under fluorescence microscopy. The accumulative release amount of MP with 17% polymer was about 20% at 24 hr. The solubility of MP with 17% polymer was found from 157.8 ± 3.3 ug/ml to 626.6 ± 0.4 ug/ml. The inflammatory phenomena in mice shows that infiltration of white blood cells (WBCs) in the tissue is increasing, as well as edema phenomena in rectal area. The mRNA expression of pro-inflammatory cytokine(granulocyte-colony stimulating factor, G-CSF), enzyme(cyclooxygenase-2, COX-2) and anti-apoptotic member (Bcl-xL) are all significantly increasing at 12 hr after damage. Furthermore, phospho-cytosolic phospholipase A2 (p-cPLA2) and myeloperoxidase(MPO) protein expression levels increased at early time point following with COX-2 and G-CSF increased at 12~48 hr. Therefore, the inflammatory effect induced by croton oil in mice rectum was suggested by cPLA2 signal pathway. Although under 17% polymer with MP (5 mg/kg) can not improve the morphology of rectal tissue at 12 hr after treatment, similarity of decreasing edema was observed after MP 5 mg/kg with 17% polymer delivery compared with proctosedyl® administration. The biomarkers revealed that the protein expression of p-cPLA2, MPO and COX-2 can be reduced. The mRNA expression of COX-2, G-CSF were also decreased with 12hr rectum tissue.
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