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Kyoto University (京都大学) / 0048 / 新制・課程博士 / 博士(工学) / 甲第16393号 / 工博第3474号 / 新制||工||1525(附属図書館) / 29024 / 京都大学大学院工学研究科機械理工学専攻 / (主査)教授 松久 寛, 教授 富田 直秀, 教授 安達 泰治 / 学位規則第4条第1項該当

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在本實驗室之前的研究中顯示在發炎狀態的大白鼠上以intrathecal (i.t.) 方式給予angiotensin IV (Ang IV) ，Ang IV 是insulin-regulated aminopeptidase (IRAP) inhibitor，可以減少腳掌發炎之大白鼠的疼痛過敏化。然而，這個由Ang IV所產生之效果背後的機制還未被完全釐清。 在這次的實驗中，我們利用由carrageenan引起腳掌腫脹之大鼠進行plantar test來研究Ang IV所產生之抗疼痛過敏化其中可能機制。由於有文獻指出，在發炎狀態的大白鼠上以intrathecal (i.t.) 方式給予oxytocin可產生一劑量相關性的抗疼痛過敏化作用，因此我們推測在大白鼠的脊髓層次上由oxytocin以及Ang IV所個別誘導的抗疼痛過敏化之間可能有關聯性。利用 i.t.單獨給予atosiban (selective oxytocin receptor antagonist) 可以觀察到一個較強烈的疼痛過敏化現象，然而合併給予atosiban，可使Ang IV所產生的抗疼痛過敏化完全被阻斷掉。因此我們推測oxytocin在以intrathecal (i.t.) 方式給予Ang IV而阻斷IRAP的活性，進而產生抗疼痛過敏化作用的過程中是一個主要的IRAP受質。 當我們在carrageenan誘導疼痛過敏化的大白鼠上單獨給予低劑量之oxytocin並沒有產生統計上顯著之抗疼痛過敏作用。然而合併給予oxytocin和Ang IV後，則可以有觀察到Ang IV 能增加並且延長oxytocin所引起的抗疼痛過敏化作用。 就內生性oxytocin來看，電刺激paraventricular hypothalamic nucleus (PVN)已被證實可以增加內生性的oxytocin分泌到脊髓。而這樣的一個神經路徑被發現和疼痛的調節具有很密切的關聯性。從我們的結果中，我們發現在carrageenan誘導疼痛過敏化的大白鼠上，i.t.給予Ang IV可以延長PVN電刺激產生的抗疼痛過敏化作用，由此推測 Ang IV可能可以保護內生性oxytocin不被分解或失去活性。 除了oxytocin之外，IRAP在體外的實驗中被證實可以分解數種具生理活性之peptides 的N-terminal amino acid，其中包括vasopressin, bradykinin 以及 enkephalin等。在這些物質中，bradykinin已被證實在週邊發炎的過程中具有重要的調控效果，若IRAP在週邊組織扮演了一個分解促發炎物質的角色，利用Ang IV也許可以去阻斷IRAP之活性進而增加這些促發炎物質。因此，我們在由carrageenan誘導疼痛過敏化的動物模式上利用腳掌局部注射 Ang IV來探討在發炎部位Ang IV可能的作用。我們猜測Ang IV 可能可以調控不同物質(例如：bradykinin)而在發炎部位產生局部之作用， 但結果顯示在疼痛過敏化以及腫脹程度上，Ang IV並不具有調控週邊組織發炎過程的能力。所以推測Ang IV在週邊發炎位置可能並沒有扮演非常重要的角色。 總而言之，本實驗結果證實了Ang IV以及 oxytocin在發炎大白鼠的脊髓層次上所個別引起之抗疼痛過敏化作用之間具有相關性，其中的機制可能是Ang IV在發炎大白鼠的脊髓層次上藉由抑制IRAP降解oxytocin的活性，進而產生抗疼痛過敏化的效果。 / In our previous study, we showed that intrathecal (i.t.) administration of angiotensin IV (Ang IV), an insulin-regulated aminopeptidase (IRAP) inhibitor, could attenuate hyperalgesia in rats with inflammation. However, the underlying mechanism(s) for this effect of Ang IV was not clarified yet. Using the plantar test in rats with carrageenan-induced paw inflammation, we attempted to investigate the possible mechanism(s) of Ang IV in the present study. Because it has been reported that i.t. administration of oxytocin produced a dose-dependent anti-hyperalgesia effect in rats with inflammation, we speculate that there is a possible correlation between the oxytocin-induced and angiotensin IV-induced anti-hyperalgesia at the spinal level in rats. Using i.t. co-administered atosiban (a selective oxytocin receptor antagonist), the anti-hyperalgesia effect of Ang IV was completely abolished, although a severer hyperalgesia was observed in rats receiving atosiban alone. This indicates that oxytocin could be the major substrate of IRAP responsible for the anti-hyperalgesia caused by intrathecal administration of Ang IV, which blocked the activity of IRAP. Using i.t. administration of oxytocin in rats with carrageenan-induced hyperalgesia, the anti-hyperalgesia effect of oxytocin was potent and significant. When Ang IV was co-administered with the low dose of oxytocin, a significant enhancing effect of Ang IV on anti-hyperalgesia of oxytocin was observed. In view of the endogenous oxytocin, electrical stimulation of the paraventricular hypothalamic nucleus (PVN) has been proved to cause the increase of oxytocin release at the spinal cord. This neural pathway has been found to be highly related to the modulation of pain. In our results, we found that i.t. administration of Ang IV could prolong the anti-hyperalgesia induced by PVN stimulation. This suggests a possible protective effect of Ang IV on endogenous oxytocin degradation/dysfunctioning. In addition to oxytocin, it was well known that IRAP is able to cleave the N-terminal amino acid from several bioactive peptides in vitro, including vasopressin, bradykinin and enkephalin. Among these substrates, bradykinin has been demonstrated to be an important mediator in peripheral inflammation. It is a pro-inflammatory substance that can be enhanced by Ang IV, if the peripheral IRAP plays a role in its degradation. Therefore, we examined the possible local effect of intraplantarly injected Ang IV on the carrageenan-induced hyperalgesia in the same model. However, our results showed no effect of local Ang IV on hyperalgesia and paw edema, indicating that Ang IV may not be able to regulate the peripheral inflammatory process. Overall, the present study verified the possible interaction between the oxytocin-induced and angiotensin IV-induced anti-hyperalgesia at the spinal level in rats with inflammation. It suggests that Ang IV may act though the inhibition of the activity of IRAP to reduce the degradation of oxytocin, thereby lead to anti-hyperalgesia in rats with inflammation.

Hokkaido University (北海道大学) / 博士 / 医学

University of Macau / Institute of Chinese Medical Sciences

京都大学 / 0048 / 新制・課程博士 / 博士(薬学) / 甲第22404号 / 薬博第842号 / 新制||薬||241(附属図書館) / 京都大学大学院薬学研究科薬学専攻 / (主査)教授 松原 和夫, 教授 金子 周司, 教授 小野 正博 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

當越來越多的藥物被發展出來進而治療人類的疾病，人們使用藥物時只知道該藥物對疾病的療效，卻忽略了其中可能隱藏的危機，不只是西藥，連中藥也隱藏相當大的危機。雖然國內有藥品管制局進行藥物交互作用的控管，但是藥物交互作用真的被有效控管嗎？成效又如何呢？有鑑於此，這成為大家都想知道的問題。 利用健保資料庫中龐大的門診資料，嘗試推估國人藥物交互作用的情形，由國人十大死因中得知，其中尤以慢性病病患的情形更為嚴重，例如：惡性腫瘤、腦血管疾病、心臟疾病、糖尿病、肝病和高血壓，本次研究以心血管病患為討論主體，試瞭解在長期服用心血管藥物時，醫生在已知病患病情之下卻無法避免藥物交互作用的情形為何，利用資料採礦的方法，找出可能造成交互作用發生的原因、族群，進而去提醒醫療機構避免其發生。 研究發現，心血管疾病病患分為一些併發症族群，如：心臟病、心血管疾病糖尿病、關節炎、消化潰瘍，從這些病患用藥中發現許多交互作用的用藥與其併發症也許多相關。高血壓疾病病患大多以強心劑、利尿劑為主的交互作用，心血管疾病併發糖尿病病患大多以口服降血糖為主的交互作用，心血管疾病併發關節炎病患大多以解熱鎮痛劑為主的交互作用，而心血管疾病併發消化潰瘍病患大多以制酸劑為主的交互作用。 健保局應當面對且對交互作用之高危險族群作一共同用藥規則，將用藥危機降到最低，讓心血管病患在治療的過程中，得以享有良好的醫療品質，亦不造成藥物濫用、浪費之情形。 / As more medicines are being developed to cope with diseases, most of the users think of the therapeutic effect of the medicine without thinking of the risk that might have associated with drug interactions. The risk of drug interactions could have set chemical reactions thereby causing drug side effects. Although the National Bureau of Controlled Drugs has set a procedure for controlling drug interactions, the issue of validity and efficiency remains an open question. The trend of people contracting chronic diseases is on the rise, one of which is cardiovascular. The attempt of this paper is to observe for the effect of drug interactions if any for the long term usage of the cardiovascular medications under the supervision of the doctors. We adopt data mining techniques to single out the probable variable causes in triggering negative effect of drug interactions and presented them to related medical personnel so that a tightening measure is adopted when administered the medications. The data used in this research comes from the National Health Insurance Research Database. Our research findings have reviewed that cardiovascular disease patients suffering from the complications, such as diabetes, arthritis, peptic ulcer and hear disease are highly related to the drug interactions. Heart disease patients are at risk of cardiac stimultants and diuretics. Diabetic’s patients taking the Sulfonylureas suffer from its interactions. And arthritis patients are at risk of having the side effects of taking Aspirin. Bureau of National Health Insurance should set a standard procedure in monitoring the prescription given by the medical personnel in an effort to reduce the risk of drug interactions and set off the stage of quality medical treatment to keep off the abuse of drug usages.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23416号 / 医博第4761号 / 新制||医||1052(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 柳田 素子, 教授 木村 剛, 教授 近藤 尚己 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM