本文選題：5-氨基乙酰丙酸 + 光動力治療　； 參考：《第三軍醫(yī)大學》2015年碩士論文

【摘要】：背景與目的甲狀旁腺功能亢進癥(hyperparathyroidism)一般分為原發(fā)性(Primary hyperparathyroidism,PHPT)、繼發(fā)性(secondary hyperparathyroidism,SHPT)、三發(fā)性(tertiary hyperparathyroidism,3HPT)三種類型,其共同特征是甲狀旁腺激素(parathyroid hormone,PTH)的合成和分泌過多。對大部分繼發(fā)于甲狀旁腺(parathyroid gland,PTG)增生所致的甲狀旁腺功能亢進癥來說,其治療以甲狀旁腺切除術(shù)(parathyroidectomy)最為有效。手術(shù)治療往往需要比較嚴格的適應癥或部分患者不愿意接受手術(shù)而使其應用受到限制。對于多發(fā)或非典型腺瘤者,術(shù)中被遺漏或切除相對不足等時有發(fā)生,而切除過多則可導致術(shù)后持久性的低鈣血癥,甚至發(fā)生永久性甲狀旁腺功能減低(hypoparathyroidism)的可能。近年來發(fā)展起來的微創(chuàng)手術(shù),雖然具有創(chuàng)傷性小、耐受性好、術(shù)后甲旁減發(fā)生率低等優(yōu)點,但其適應人群僅限于單個腺瘤的患者。光動力治療(photodynamic therapy,PDT)是近年來興起的一種基于光化學反應的新療法。其基本原理是利用光敏劑在某些特定組織中的差異性高濃度蓄積,在氧的存在下,經(jīng)特定波長(630nm)光的照射后,生成活性氧(reactive oxygen species,ROS),進而產(chǎn)生一系列氧化產(chǎn)物誘導細胞死亡,從而達到治療腫瘤等病變組織的目的。其相比于傳統(tǒng)手術(shù)、放療或化療,具有適應癥廣、特異性高、副作用少等優(yōu)點,目前已廣泛應用于各種腫瘤、皮膚病、甚至感染性疾病的治療當中。已有研究表明,將光敏劑5-氨基乙酰丙酸(5-aminolevulinic acid,5-ALA)注射入大鼠或人體內(nèi)后,其中間代謝產(chǎn)物原卟啉IX(Protoporphyrin IX,Pp IX)(光敏物質(zhì))在正�；蛟錾募谞钆韵俳M織中具有與周圍組織相比更高濃度的蓄積。但是否能產(chǎn)生光動力效應,目前仍不清楚。本研究旨在分析5-ALA介導PpIX在大鼠甲狀旁腺及其周圍組織當中的分布特點,明確5-ALA所介導的光動力療法(5-ALA PDT)作用于正常大鼠甲狀旁腺的安全性與有效性,并嘗試將5-ALA PDT應用于繼發(fā)性甲狀旁腺功能亢進癥(SHPT)大鼠模型的治療中。方法1、將5-ALA注射入大鼠腹腔后切取甲狀旁腺(PTG)、甲狀腺(TG)及周圍肌肉組織,分別測定其內(nèi)的Pp IX濃度進行比較,同時明確Pp IX濃度與5-ALA注射劑量及作用時間之間的關(guān)系;2、按光敏劑劑量和光照時間進行隨機分組,手術(shù)暴露PTG及其周圍組織后行光動力照射,檢測照射前后血清甲狀旁腺激素(PTH)、總鈣(Ca)、三碘甲狀腺原氨酸(T3)、甲狀腺素(T4)、促甲狀腺素(TSH)水平,并觀察各組織形態(tài)學上的變化。3、通過5/6腎切除結(jié)合高磷飼養(yǎng)制備SHPT大鼠模型后分多次對其行PDT照射,并比較每次照射前后血清PTH水平的變化。結(jié)果1、在各時間點上檢測到PTG內(nèi)PpIX濃度均高于TG及周圍肌肉組織(p0.05);PTG內(nèi)PpIX濃度隨5-ALA作用時間逐漸升高,在1.5h檢測到最大值(77.38±8.92)ug/g,之后開始逐漸下降,PTG內(nèi)Pp IX濃度隨5-ALA注射劑量增加而逐漸升高(p0.05),當5-ALA注射劑量由400mg/kg增加到600mg/kg時,PTG內(nèi)PpIX含量仍有所上升,但差異已無統(tǒng)計學意義(p0.05);2、單獨使用光敏劑或光照對PTG功能無影響,在PDT照射0.25d后即檢測到血清PTH、總Ca顯著下降(p0.05),而照射前后血清T3、T4、TSH始終無明顯改變(p0.05)。PDT照射后血清PTH水平隨5-ALA注射劑量的增加、光照時間延長而降低,與對照組(0mg/kg,0min)相比差異顯著(p0.05);組織學檢查顯示PDT照射后PTG組織包膜仍完整,但主細胞明顯減少,脂肪細胞增多,TG與周圍肌肉組織未見到明顯變化。3、5/6腎切除結(jié)合高磷飼養(yǎng)28天后大鼠血清Cr、PTH水平明顯高于手術(shù)前(p0.05),SHPT模型大鼠經(jīng)多次PDT照射后的血清PTH水平隨照射次數(shù)的增加而降低,經(jīng)PDT(100mg/kg,10min)照射3次后的PTH水平與手術(shù)前比較已無顯著差異(p0.05)。結(jié)論1、5-ALA介導PpIX在大鼠PTG內(nèi)的蓄積濃度明顯高于周圍組織,并與5-ALA注射劑量及作用時間相關(guān);2、5-ALA PDT可對正常大鼠PTG的組織形態(tài)和功能產(chǎn)生特異性破壞作用,有效性、安全性良好;3、5-ALA PDT對SHPT模型大鼠的治療效果明顯,多次照射療效可疊加。
[Abstract]:Background and objective hyperparathyroidism (hyperparathyroidism) is generally divided into three types, primary (Primary hyperparathyroidism, PHPT), secondary (secondary hyperparathyroidism, SHPT), and three types of tertiary hyperparathyroidism (3HPT). The common feature is the synthesis and differentiation of parathyroid hormone (parathyroid hormone). Hyperparathyroidism is the most effective treatment for most hyperparathyroidism secondary to hyperparathyroid (parathyroid gland, PTG) hyperplasia. Surgical treatment often requires stricter indications or some patients are not willing to undergo surgery to restrict their application. Patients with multiple or atypical adenomas may be missed or excised during operation, and excision may lead to postoperative persistent hypocalcemia, or even permanent hypoparathyroidism (hypoparathyroidism). The minimally invasive surgery in recent years has a small traumatic, tolerable tolerance, and a postoperative one. Photodynamic therapy (PDT) is a new therapy based on photochemical reaction in recent years. The basic principle is to use photosensitizer to accumulate differential high concentration in certain tissues, in the presence of oxygen, by specific wavelengths ( 630nm) after light irradiation, it generates active oxygen (reactive oxygen species, ROS), and then produces a series of oxidation products to induce cell death, thus achieving the purpose of treating tumor and other pathological tissues. Compared with traditional surgery, radiotherapy or chemotherapy, it has many advantages, such as wide adaptation, high specificity, less side effects and so on. It has been widely used in various kinds of tumors at present. In the treatment of dermatoses and even infectious diseases, studies have shown that the photosensitizer 5- aminolevulinic acid (5-aminolevulinic acid, 5-ALA) is injected into the rat or human body, in which the metabolic product protoporphyrin IX (Protoporphyrin IX, Pp IX) is compared with the surrounding tissue in normal or hyperplastic parathyroid tissue. The aim of this study is to analyze the distribution characteristics of 5-ALA mediated PpIX in the parathyroid and surrounding tissues of rats, and to clarify the safety and effectiveness of 5-ALA mediated photodynamic therapy (5-ALA PDT) in the parathyroid glands of normal rats and try to make 5-ALA PD. T was used in the treatment of rat model of secondary hyperparathyroidism (SHPT). Method 1, the 5-ALA was injected into the abdominal cavity of the rat and the parathyroid gland (PTG), the thyroid (TG) and the surrounding muscle tissue were measured. The concentration of Pp IX in the rat was compared. At the same time, the relationship between the IX concentration of Pp and the dose of 5-ALA and the time of action and the time of action were determined. 2, According to the dose of photosensitizer and light time, the PTG and its surrounding tissue were exposed to photodynamic irradiation. The serum parathyroid hormone (PTH), total calcium (Ca), three iodine thyroxine (T3), thyroxine (T4) and thyrotropin (TSH) were detected before and after irradiation, and the morphological changes of each tissue were observed and.3 was observed by 5/6 nephrectomy. The SHPT rat model was irradiated with PDT with high phosphorus feeding, and the changes of serum PTH level before and after each time were compared. Results 1, the concentration of PpIX in PTG was higher than TG and the surrounding muscle tissue (P0.05) at each time point. The concentration of PpIX in PTG increased with the 5-ALA action time, and the maximum value (77.38 + 8.9) was detected in 1.5h. 2) ug/g, then began to decrease gradually, and the concentration of Pp IX in PTG gradually increased with the increase of 5-ALA injection dose (P0.05). When 5-ALA injection dose increased from 400mg/kg to 600mg/kg, PpIX content in PTG was still up, but the difference had no statistical significance (P0.05). Serum PTH, total Ca decreased significantly (P0.05), but the serum T3, T4, TSH before and after irradiation had no significant changes (P0.05).PDT irradiation, the serum PTH levels were increased with the increase of 5-ALA injection dose and light time prolonged, compared with the control group (0mg/kg, 0min). But the main cells decreased obviously, the fat cells increased, and the TG and the surrounding muscle tissue did not see obvious changes in the serum Cr, PTH level was significantly higher than that before the operation (P0.05) after 28 days of.3,5/6 nephrectomy combined with high phosphorus. The serum PTH level of SHPT model rats decreased with the increase of the number of shots after PDT irradiation, and was irradiated by PDT (100mg/kg, 10min). There was no significant difference in the level of PTH after 3 times (P0.05). Conclusion the accumulation of PpIX in PTG was significantly higher than that of peripheral tissue, and it was related to the dose and time of 5-ALA injection; 2,5-ALA PDT could produce specific damage to the morphology and function of PTG in normal rats. The effectiveness and safety of 2,5-ALA PDT were good; 3,5 is good. 3,5 The effect of -ALA PDT on SHPT model rats was obvious, and the effect of multiple irradiation could be superposed.

【學位授予單位】：第三軍醫(yī)大學
【學位級別】：碩士
【學位授予年份】：2015
【分類號】：R582.1

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