本文選題：硫酸鈣人工骨　切入點(diǎn)：唑來膦酸　出處：《鄭州大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：背景 富含巨細(xì)胞病變中含有豐富的破骨型多核巨細(xì)胞，該種細(xì)胞反應(yīng)活躍、具有低度侵襲性。在良性或惡性骨腫瘤病變中均出現(xiàn)這類細(xì)胞，如繼發(fā)性棕色瘤（Recklinghausen�。⒕藜�(xì)胞修復(fù)性肉芽腫(GCRG)、動(dòng)脈瘤樣骨囊腫（ABC）、軟骨母細(xì)胞瘤、巨細(xì)胞骨肉瘤和良、惡性骨巨細(xì)胞瘤等。骨巨細(xì)胞瘤(GCT)是臨床中常見的原發(fā)性骨腫瘤之一，瘤體主要由破骨型多核巨細(xì)胞和單核基質(zhì)細(xì)胞組成。WHO骨腫瘤分類將GCT描述為“一種侵襲性的潛在惡性病變”。中國的發(fā)病率較西方國家高，占骨腫瘤的14％～16％，發(fā)病高峰在20～50歲，治療不當(dāng)易造成勞動(dòng)資源的浪費(fèi)。病變多侵犯長骨，常見的部位為股骨下端和脛骨上端，其他部位見于橈骨遠(yuǎn)端、腓骨小頭、股骨近端、肱骨近端、脊柱、骨盆、胸骨、肋骨、顱骨及跟骨等。骨巨細(xì)胞瘤的治療原則為治療或控制局部病變，盡量保留患肢功能。幾十年前，廣泛切除是常用術(shù)式，復(fù)發(fā)率較低。然而，廣泛切除后可對臨近關(guān)節(jié)面造成損害，隨之而來的重建也較復(fù)雜，出現(xiàn)較多的并發(fā)癥。目前骨巨細(xì)胞瘤常用囊內(nèi)刮除植骨術(shù)，但單純的刮除植骨術(shù)難以徹底清除腫瘤組織，微量隱藏在病灶陷窩中的腫瘤細(xì)胞即可導(dǎo)致術(shù)后復(fù)發(fā)。多種輔助措施用于處理瘤腔，如液氮、酒精、石碳酸、雙氧水等沖洗，磨鉆打磨等被廣泛研究和應(yīng)用。輔助治療使病灶邊緣產(chǎn)生近似廣泛切除的區(qū)域，同時(shí)未破壞周圍骨性結(jié)構(gòu)，既降低了腫瘤的復(fù)發(fā)率，又極大地保存患肢功能。但目前各種輔助治療措施的效果尚未達(dá)到完全肯定和統(tǒng)一。 二磷酸鹽類藥物具有一定的抗破骨細(xì)胞活性作用，是一種人工合成的焦磷酸鹽類似物。在人體中不能被代謝，對骨骼有較強(qiáng)的吸附作用，能夠抑制破骨細(xì)胞的形成，促進(jìn)凋亡，，抑制骨吸收，同時(shí)可以誘導(dǎo)瘤體中的間質(zhì)細(xì)胞凋亡。二磷酸鹽不僅對破骨細(xì)胞起到調(diào)控作用，同時(shí)對于成骨細(xì)胞有一定的調(diào)節(jié)作用。二磷酸鹽類藥物可誘導(dǎo)GCT中的多核巨細(xì)胞和單核基質(zhì)細(xì)胞凋亡，抑制破骨活性。近年來，該類藥物被應(yīng)用于破骨細(xì)胞介導(dǎo)的骨腫瘤，如骨巨細(xì)胞瘤、溶骨性骨轉(zhuǎn)移瘤、多發(fā)性骨髓瘤、骨肉瘤等引發(fā)的骨相關(guān)事件，同時(shí)臨床用于預(yù)防骨巨細(xì)胞瘤復(fù)發(fā)。目前已經(jīng)發(fā)展了三代藥物，其中第三代代表藥物為唑來膦酸、阿倫膦酸鈉等。靜脈滴注或口服二磷酸鹽類藥物后，可能會(huì)出現(xiàn)一過性流感樣綜合征、下頜骨壞死等諸多副作用，可累及消化、神經(jīng)、骨骼肌肉等系統(tǒng)。二磷酸鹽類藥物在人體內(nèi)不經(jīng)過代謝，以原形經(jīng)腎排出，對藥物造成了一定的浪費(fèi)。假如唑來膦酸能夠局部緩釋，不但能夠減少副作用，同時(shí)可以提高生物利用率。 目的 觀察不同濃度的唑來膦酸/硫酸鈣人工骨復(fù)合物體外釋放規(guī)律。 方法 制備0.0%、1.3%、2.6%、5.2%、10.4%五個(gè)濃度梯度組的唑來膦酸/硫酸鈣人工骨復(fù)合物標(biāo)本，記錄體外凝結(jié)時(shí)間。從每梯度組中隨機(jī)選取重量為0.900±0.012g3個(gè)標(biāo)本，以空白對照組作為A實(shí)驗(yàn)組，其余依據(jù)濃度梯度依次編為B、C、D、E實(shí)驗(yàn)組，使用高效液相色譜法(HPLC)檢測藥物溶出濃度，研究藥物體外的釋放規(guī)律。 結(jié)果 未使用烘干、加強(qiáng)空氣流通等促凝手段，室溫下A~E組的凝固時(shí)間依次為10.6分鐘、20.9分鐘、32.8分鐘，45.5分鐘，58.2分鐘。統(tǒng)計(jì)學(xué)分析凝固時(shí)間的差異具有統(tǒng)計(jì)學(xué)意義（P＜0．05）。體外釋放實(shí)驗(yàn)B～E組0至24h有明顯突釋相，累計(jì)釋放度均值分別達(dá)19.11%、23.45%、35.93%、26.88%，各組釋放度在同一時(shí)間點(diǎn)有統(tǒng)計(jì)學(xué)差異（P＜0．05），48h以后出現(xiàn)緩釋效應(yīng)，C、D、E組3～21d緩釋相溶出率曲線出現(xiàn)波動(dòng)，D、E組波動(dòng)明顯。 結(jié)論 隨著唑來膦酸載藥量的增加，硫酸鈣結(jié)構(gòu)逐漸不穩(wěn)定。載藥量不超過硫酸鈣人工骨最大載藥量時(shí)，唑來膦酸在硫酸鈣人工骨釋放體系中能夠持續(xù)、穩(wěn)定的釋放。
[Abstract]:background
With the broken bone type is rich in giant cell lesions in multinucleated giant cells, the activity is low. This type of invasive cells in benign or malignant bone tumor lesions, such as secondary brown tumor (Recklinghausen disease), giant cell reparative granuloma (GCRG), aneurysmal bone cyst (ABC), chondroblastoma and giant cell osteosarcoma and benign, malignant giant cell tumor of bone. Bone giant cell tumor (GCT) is a common clinical primary bone tumors, tumor type is mainly composed of osteoclast like multinucleated giant cells and mononuclear stromal cells.WHO bone tumor classification described GCT as "malignant potential" an aggressive disease. The incidence rate of China compared with western countries, accounting for 14% ~ 16% of bone tumors, the peak incidence at the age of 20~50, easily lead to improper treatment of labor resources waste. The lesions invaded long bones, common site of distal femur and tibia In the end, other parts of the distal radius, fibula, proximal femur, proximal humerus, spine, pelvis, sternum, ribs, skull and calcaneus. The principle of treatment of giant cell tumor of bone for the treatment or control of local disease, try to keep the limb function. A few decades ago, extensive resection is a common operation, recurrence rate low. However, after extensive resection can cause damage to the adjacent articular surface, the reconstruction is more complex, more complications. The giant cell tumor of bone used intracapsular curettage and bone grafting, but the simple curettage and bone grafting is difficult to completely remove the tumor tissue, tumor cells can trace hidden in the lesions of lacuna the cause of postoperative recurrence. Various auxiliary measures for the treatment of tumor cavity, such as liquid nitrogen, alcohol, phenol, hydrogen peroxide and other washing, drill grinding is widely researched and applied. The adjuvant treatment of wide excision of the lesion edge approximate area, and not Destruction of the surrounding bony structure not only reduces the recurrence rate of the tumor, but also greatly preserves the function of the affected limb.
Two phosphate drugs has certain anti osteoclast activity, is a synthetic analogue of pyrophosphate. Cannot be metabolized in the body, has the stronger adsorption on bone, can inhibit osteoclast formation, promote apoptosis, inhibit bone resorption and induce tumor stroma cell apoptosis. Two phosphate not only affects osteoclast, also have a regulatory role for osteoblasts. Two phosphate drugs can induce multinucleated giant cells and mononuclear stromal cells apoptosis in GCT, inhibition of osteoclast activity. In recent years, the drugs of bone tumor were used in osteoclasts mediated, such as giant cell tumor of bone, osteolytic bone metastasis, multiple myeloma, bone related events triggered by osteosarcoma, and clinical for the prevention of recurrence of giant cell tumor of bone. There are three generations of drugs, the representative of the third generation The drug for zoledronic acid, Allen alendronate. Intravenous or oral two phosphate drugs, there may be a flu like syndrome, and other side effects of osteonecrosis of the jaw, involving the digestive, nervous, skeletal muscle system. Two phosphate drugs in the human body without metabolism. In order to prototype excreted by kidney caused a waste of drug. If zoledronic acid can local release, not only can reduce the side effect, and can improve the bioavailability.
objective
The external release of zoledronic acid / calcium sulphate artificial bone in different concentrations was observed.
Method
The preparation of 0%, 1.3%, 2.6%, 5.2%, 10.4% and five concentration gradient group zoledronic acid / calcium sulfate artificial bone composite specimens were recorded in vitro. The setting time from each group were randomly selected for gradient weight 0.900 + 0.012g3 specimens, the control group was taken as the experimental group A, the other based on concentration gradient in order for the B, C, D, E in the experimental group, using high performance liquid chromatography (HPLC) detection of the concentration of dissolved drug release of drug in vitro.
Result
Without the use of drying, enhance air circulation to promote coagulation, coagulation time of group A~E at room temperature in 10.6 minutes, 20.9 minutes, 32.8 minutes, 45.5 minutes, 58.2 minutes. The difference between the solidification time was statistically significant (P < 0.05). The in vitro release experiment of B ~ E were 0 to 24h significant burst release phase, cumulative release rate value of 19.11%, respectively, 23.45%, 35.93%, 26.88%, each release at the same time there were significant differences (P < 0.05), 48h after C, D, sustained release effect, E group of 3 ~ 21d release phase dissolution rate curve fluctuations, D, E group fluctuated significantly.
conclusion
With the increase of loading dose of zoledronic acid, the structure of calcium sulfate is gradually unstable. When loading dose is not greater than that of calcium sulfate artificial bone, zoledronic acid can release continuously and steadily in calcium sulfate artificial bone release system.

【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R943

【共引文獻(xiàn)】

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