2016-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/649383摘要：全球每年有數以百萬的人死於創傷，而嚴重創傷會導致三分之一的患者發生出血性休克，並導致高達30-50%患者死亡 。vasopressin 無疑是目前效果最好的升壓劑，許多的臨床與動物 研究顯示休克時內源性的 vasopressin 缺乏和休克死亡率高度相關。但是受限於 vasopressin 的短效性，臨床使用 vasopressin 必須採取連續性輸液方式，大幅減少實用性 。 脂質體 (liposome) 可以保護 peptide 藥物免受酶降解，並可作為“microreservoir”緩慢釋放 peptide 藥物。我們最近在PLOS ONE 期刊證實535奈米微脂體可以用來包覆 (encapsulated) vasopressin 並延長血液中的半衰期達到2倍。 可是535 奈米微脂體包覆的 vasopressin 在 4 種常使用的急救功效指標上(平均動脈壓（mean artery pressure, MAP）、血清乳酸值、發炎因子和肺水腫)並沒有比傳統的 vasopressin 有較好的療效。 所以，這個計劃我們想要測試幾個假設。第一，不同大小的微脂體可能會影響 vasopressin 在血液中的輸送速度；所以，我們要測試用比535 奈米小的微脂體包覆 vasopressin。第二，我們要把微脂體攜帶在 vasopressin上而不是用包覆的技術；微脂體攜帶的 vasopressin 不需要花時間解封裝，可以直接結合到 receptor 上，但其還是有可能受到酶的降解，故以此模式來了解急救之功效。最後，我們要在出血性休克動物模式上比較微奈米微脂體包覆 vasopressin（第一年尋找到的最佳奈米大小)、 微脂體分別攜帶vasopressin 和 terlipressin，探討這兩種不同急救升壓劑在急救之功效，以作為之後臨床上急救的參考。Terlipressin 是一種化學合成的 vasopressin，之前我們已經證明在出血性休克動物模式上比傳統的vasopressin 有較好的療效。<br> Abstract: Millions of people died from traumatic injuries every year. It has been estimated that aboutone-third of those with severe traumatic injuries suffer from trauma-associatedhemorrhagic shock (HS). Using a vasopressor early may avoid the detrimental effectsassociated with aggressive fluid resuscitation, while maintaining a level of adequate tissueperfusion for a short period of time. Vasopressin deficiency can contribute to hypotensionobserved in patients with catecholamine-resistant septic shock, postcardiotomy shock andcardiac arrest. The short-term survival benefits of vasopressin in hemorrhagic shock havebeen shown in animal studies and human case. Clinical administration of vasopressin forpatients with refractive shock may require continuous infusion due to its short half-life.This may preclude their use in the pre-hospital setting where severe hemorrhagic shockoccurs. Liposomes have been shown to improve delivery of peptide drugs by protectingencapsulated peptide from enzymatic degradation and act as a “microreservoir” to releasethe peptide slowly at the site of injection. Our recently published study at PLOS ONEsuggested that we have successfully encapsulate vasopressin with liposome at a diameterof 535 nm. The liposome encapsulated vasopressin can prolong the serum concentration ofvasopressin in an animal model of uncontrolled hemorrhagic shock by 2 fold. However,animals treated with vasopressin or liposomal vasopressin has no significant difference in4 common prognostic tests of hemorrhagic shock: mean arterial pressure (MAP), serumlactate level, inflammatory profile and pulmonary edema. It is unclear what are the reasonsfor 535 nm liposome vasopressin being able to prolong the serum concentration ofvasopressin but not improve the values of 4 common prognostic tests. We have differenthypotheses that we will like to test. In the first year, we will like to make liposomalvasopressin with a smaller diameter and test it in an animal model of uncontrolledhemorrhagic shock. This is because a particle’s size can affect it’s circulation rate in theblood. In the second year, we will like to use a different approach to increase the serumhalf-life of vasopressin. Instead of encapsulation, vasopressin will be tagged to liposomevia a lipid linker. Although this liposome tagging approach can only partially protectvasopressin from protease, this approach offers the advantage that vasopressin can bind tothe receptor without the need of decapsulation. In the third year, we will like to comparethe effects of liposomal encapsulated vasopressin (the size with the best result), liposometagged vasopressin, vasopressin and terlipressin in an uncontrolled model of hemorrhagicshock. Terlipressin is an analogue of vasopressin that we have demonstrated to have betteroutcome than vasopressin in an animal model of uncontrolled hemorrhagic shock.