本文選題：骨化三醇 + 局部應用��； 參考：《南方醫(yī)科大學》2016年碩士論文

【摘要】：研究背景骨缺損的修復一直以來是臨床工作中關注的焦點,口腔種植修復中,也常常會面臨骨量不足的問題,而獲得和長期維持種植體骨結合最重要的先決條件是種植位點存在充足的健康骨量,可用骨高度和厚度允許植入適當長度和直徑的種植體。但是,半數(shù)以上的種植位點存在骨量不足,必須進行與種植體植入同期或分階段的骨量擴增。自體骨被認為是骨修復重建的“金標準”,但由于其來源的局限性,供骨區(qū)術后出現(xiàn)的失血、疼痛及感染等并發(fā)癥,使用具有骨引導能力的人工植骨材料成為臨床修復骨缺損的主要方式。人工植骨材料在骨缺損修復過程中主要起維持成骨空間,穩(wěn)定血凝塊,促進愈合的作用,其促進新骨生長的作用有限,成骨緩慢,成骨效能較差,不能滿足臨床上對早期負重的訴求。為了獲得更好的成骨效果,嘗試復合不同的骨生長因子以提高成骨質量,加快新骨的形成,一直是骨修復研究的熱點。目前應用的骨生長因子多為蛋白質或多肽類分子,如骨形態(tài)發(fā)生蛋白(BMP)、轉化生長因子(TGF-β)等,它們在體內會被蛋白酶降解,或被體液迅速稀釋,半衰期極短,難以維持有效的治療濃度,且均具有一定的免疫原性,可能引起免疫排斥反應。另外,此類大分子藥物無論從何種途徑獲取,都存在價格昂貴的問題,這使得骨生長因子的臨床應用受到了極大的限制。運用非蛋白小分子激活胞內信號傳導通路,促進成骨,是骨缺損修復研究的新方向。近年來,有一些學者注意到一種之前未曾局部應用小分子藥物一骨化三醇[1,25(OH)2D3]。在許多體外實驗中發(fā)現(xiàn),它可以促進成骨細胞及骨細胞的成熟,且與BⅧ-2有協(xié)同作用,促進礦化,進而促進成骨,同時,它能通過下調c-Fos和RANK的表達,抑制破骨細胞的生成。目前,骨化三醇及其類似物的合成已十分成熟,且骨化三醇沒有免疫原性,不會引起機體的排斥反應,是一種理想的骨生長因子。骨化三醇是維生素D生物活性最高的形式,是維生素D在經過肝臟和腎臟的一系列代謝作用后產生的活性成分,最終進入血液循環(huán),在調控骨形成以及骨發(fā)育中起重要作用∞]。目前,有許多動物模型(雞、老鼠、兔子)支持系統(tǒng)性補充維生素D與骨愈合之間的正相關作用,在這些實驗中維生素D的代謝物促進了骨折的愈合,并且增加了骨痂的強度。然而,通過全身循環(huán)到達靶器官的骨化三醇已經寥寥無幾,僅能維持機體基本的骨代謝平衡,尤其在絕經期女性,骨代謝異�；蚬琴|疏松患者中,體內維生素D的含量更會大大下降,促進局部骨缺損修復的效能有限；而大量口服骨化三醇又會產生藥物毒性,引起高血鈣、食欲不振、嘔吐、腹瀉,甚至軟組織異位骨化等。因此,學者們開始研究局部應用骨化三醇類藥物的效果。Salomo等在比格犬下頜骨植入種植體的同時局部應用維生素D2,發(fā)現(xiàn)其可以減少種植體冠方骨喪失并且增加骨結合的面積。但其所用藥物為骨化三醇的前體,且直接對此類藥物進行局部應用,存在易被體液稀釋發(fā)生快速降解,很難在局部達到有效濃度的問題,同時還會因缺乏支架而變得雜亂無序,其促進成骨細胞成熟和促進骨基質礦化的作用無法有效發(fā)揮。而Hsiang-Hsi Hong等學者在以比格犬為動物模型的研究中,為克服直接局部應用骨化三醇易被體液迅速稀釋的問題,采用了每周在下頜骨環(huán)狀骨缺損周圍注射骨化三醇含量較低的成品藥物溉純的方式,研究骨化三醇局部應用的成骨效能。但這種方法仍存在一定問題。首先,這種每周注射一次的給藥方式使到達靶器官的藥物量仍有所損耗,并且增加了手術次數(shù),反復對缺損部位產生刺激,增加了成骨過程中的干擾因素；其次,實驗中所制備的骨缺損并非標準骨缺損,不利于檢驗藥物的成骨效能。為克服以上問題,我們需要尋找另一種局部應用骨化三醇的方式,并制備標準骨缺損以檢驗其成骨效能。大量文獻報道,羥基磷灰石基團如：-OH-NH2,-COOH-,具有非共價吸附生長因子的功能,是良好的生長因子緩釋載體,開放連通的不規(guī)則多孔結構能增加支架的生長因子吸附表面積,有利于生長因子的吸附和緩釋。因此,羥基磷灰石常常作為支架材料攜帶PDGF-BB、 VEGF、BMP-2等生長因子修復各類骨缺損。而無機脫礦小牛骨的主要成分就是羥基磷灰石,它也是目前應用最廣泛、研究最多的異種骨材料。因此,本研究擬以無機脫礦小牛骨粉為載體,復合骨化三醇后修復兔顱骨標準骨缺損,研究局部應用骨化三醇對骨缺損修復中早中期成骨的影響。目的研究局部應用骨化三醇對于早期及中期成骨的影響。方法1.動物模型及分組18只雄性新西蘭大白兔,15-16周齡,體重2.9-3.2kg,由廣東省醫(yī)學動物實驗中心提供,實驗過程中和術后處理均符合動物倫理學標準。適應性喂養(yǎng)一周后,在廣東省動物實驗檢測所進行實驗。本實驗分為3組：空白組(A組)、骨粉組(B組)以及骨化三醇復合骨粉組(C組)。以2、4、6周為研究時點,每一時點6只兔子。每只兔子顱頂制各4個8 mm直徑的圓形骨缺損,每一研究時點有24個圓形骨缺損,隨機分配給A、B、C三組。2.材料制備及處理用無水乙醇溶解骨化三醇(Sigma Chemical Co. 1a 25-Dihydroxyvitamin D3 D1530)后,將含有6μg 1,25(OH)2D3的無水乙醇溶液與5 mg Bio-Oss骨粉(瑞士蓋氏制藥有限公司,注冊證號：國食藥監(jiān)械(進)字2014第3460922號,進口產品標準編號：YZB/SWI8428-2013,0.25-1 mm)混合,真空低溫凍干,鈷60輻照消毒后備用。3.手術過程術前30分鐘肌注慶大霉素(1 mg/kg),預防術中及術后感染,術區(qū)備皮,以速眠新0.2 mL/kg后腿肌肉注射誘導麻醉,待誘導麻醉起效后,3%戊巴比妥鈉注射液30 mg/kg耳緣靜脈注射麻醉,全麻后取俯臥位,術區(qū)以碘伏消毒,鋪一次性孔巾,2%鹽酸利多卡因術區(qū)皮下局部浸潤麻醉。捫及顱骨中縫骨性突起標志,沿中線作垂直切口,直達骨面,沿中縫翻起全厚瓣,前界達額骨的中部,后界至項骨的底部,兩側完全暴露頂骨的側邊緣,充分暴露術區(qū),以外徑為8 mm的環(huán)形骨鉆于顱頂制各4個環(huán)形骨缺損,缺損之間相距大于2 mm,期間以4℃生理鹽水充分冷卻,注意勿傷及硬腦膜。按分組置入相應單純骨粉或骨化三醇復合骨粉,分層嚴密縫合。術后肌肉注射慶大霉素(20萬/d×5d)預防感染,必要時增加肌注青霉素類抗生素如氨芐西林鈉或頭孢拉定0.1 g/kg/d×5d。在動物處死之前的第3天和第4天頸部皮下注射鈣黃綠素6 mg/kg,處死之前的第13天和第14天,在兔子頸部皮下注射四環(huán)素30 mg/kg。所有動物按照觀察時間點2周,4周,6周分批以耳緣靜脈空氣栓塞法處死,取材,10%甲醛溶液固定48 h后,流水沖洗24小時,一半直接制作硬組織切片,一半置于10%EDTA溶液中脫鈣約3個月,制作石蠟切片。4.主要檢測指標大體觀察、組織學觀察、熒光染色鈣沉積觀察、骨計量學檢測。結果1.術中及術后大體觀察手術共制備72個圓形骨缺損,均未損及硬腦膜。術后所有動物精神狀況良好,無死亡,創(chuàng)緣可見略有紅腫,飲食及排泄均正常。術后1周術創(chuàng)區(qū)腫脹基本消退,縫線無松動、脫落,創(chuàng)區(qū)無感染現(xiàn)象,一期愈合。術后2周,術區(qū)完全愈合,縫線自然脫落,A組骨缺損區(qū)為纖維組織覆蓋,邊界清晰可辨,手指輕觸柔軟,B組及C組手指輕觸稍軟,較完全空白組硬實,骨粉顆粒間見纖維組織長入,缺損邊緣較清晰。術后4周,A組骨缺損區(qū)見骨缺損邊緣有少量新骨生成,缺損邊緣分界模糊,缺損中心仍為軟組織,手指輕觸柔軟,B組及C組手指輕觸較硬,骨粉顆粒邊緣較2周時模糊,缺損邊緣模糊。術后6周,A組骨缺損邊緣新生骨組織繼續(xù)向中心長入,仍未完全長滿,B組及C組骨粉間可見明顯骨組織存在,手指觸感極硬,缺損邊界模糊不清,難以辨別。2.組織學觀察術后2周,A組見缺損邊緣有少量類骨質形成,中央為纖維組織,大量炎性細胞廣泛浸潤,結締組織內見少量的骨膠原團塊；B組見缺損中央及邊緣處均可見骨粉顆粒周圍有少量新骨及類骨質形成；C組所見與B組類似,但新骨及類骨質面積更大。術后4周,A組見缺損邊緣新生骨向中央延伸,面積增大,中央仍為纖維組織充填,可見粗大的膠原纖維,散在少量炎性細胞；B組骨粉周圍新生骨質染色加深,更趨成熟,面積增大：C組新生骨質面積較B組大,骨小梁稀疏交織成網狀,周圍環(huán)繞著扁平的呈單層排列的成骨細胞,可見大量尚未發(fā)育成熟的、由成骨細胞轉化而來的骨細胞,包繞在這些骨細胞周圍的骨陷窩間隙較為狹小,成骨細胞呈柵欄狀排列在新生骨周圍。術后6周,A組缺損邊緣新生骨質繼續(xù)向中央延伸,但仍未對接；B組缺損內廣泛可見新生骨質圍繞于骨粉顆粒周圍,骨質成熟；C組較B組新生骨質面積增大,骨質更成熟,見大量的骨小梁融合成片形成板層骨,其間散在著少量形態(tài)不規(guī)則的間隙,間隙周圍排列著均勻且連續(xù)的成骨細胞。3.熒光染色鈣沉積觀察術后2周,A組鈣沉積較少,僅在缺損邊緣有部分亮綠色的鈣沉積；B組較完全空白組鈣沉積范圍擴大,且在骨缺損中央也出現(xiàn)了部分鈣沉積,C組鈣沉積范圍較前兩組又有增加,且亮度更高,表明鈣沉積量較A、B兩組也有一定程度增加。術后4周,三組鈣沉積范圍均較前擴大,鈣沉積量依然顯示出C組B組A組。術后6周,A組骨缺損中央形成骨島,邊緣可見鈣沉積,但缺損中央仍有部分未見鈣沉積,B組及C組缺損范圍內均可見廣泛鈣沉積,C組較B組鈣沉積所占面積更大,亮度更高。4.骨計量學觀察術后2周,A組新生骨面積比為9.58±1.21%,成骨細胞數(shù)為15.2±1.68；B組新生骨面積比為12.52±1.09%,成骨細胞數(shù)為23.8±1.25；C組新生骨面積比為15.12±0.80%,成骨細胞數(shù)為24.8±2.12。術后4周,A組新生骨面積比為12.75±1.13%,成骨細胞數(shù)為20.3±2.15；B組新生骨面積比為15.88±1.04%,成骨細胞數(shù)為24.1±2.23;C組新生骨面積比為20.95±1.34%,成骨細胞數(shù)為23.8±1.79。術后6周,A組新生骨面積比為18.94±1.20%,成骨細胞數(shù)為25.0±2.26；B新生骨面積比為21.37±1.32%,成骨細胞數(shù)為25.8±1.69；C組新生骨面積比為25.10±1.27%,成骨細胞數(shù)為26.6±3.50。結果進行單向方差分析,3個時間點均顯示出新生骨面積比三組組間有顯著差異(P0.05),且C組B組A組,但隨著時間的延長,3組差距呈逐漸縮小的趨勢,而成骨細胞數(shù)量3組并無顯著差異。結論1.15-16周齡,體重2.9-3.2 kg的雄性新西蘭大白兔顱頂骨可制備4個直徑8mm的圓形骨缺損。2.兔顱骨8mm直徑的骨缺損在6周的觀察時間內,可作為標準骨缺損對藥物或骨代用品成骨效能進行相關研究。3.骨化三醇的局部應用,并未使骨缺損內的成骨細胞數(shù)量產生差異。4.骨化三醇的局部應用在骨缺損修復中可以促進早中期成骨,促進鈣鹽的沉積。
[Abstract]:The repair of bone defects has always been a focus of attention in clinical work. In oral implant repair, it often faces the problem of insufficient bone mass, and the most important prerequisite for the long-term maintenance of implant bone union is that there is sufficient healthy bone mass at the implant site, allowing the implantation of appropriate length and thickness with bone height and thickness. The diameter of the implant. However, more than half of the implant sites are deficient in bone mass. Bone mass amplification must be carried out at the same time or in stages of implant implantation. Autogenous bone is considered as a "gold standard" for bone repair and reconstruction, but due to its source limitations, complications such as blood loss, pain and infection after the operation of the bone region are used with bone citation. Artificial bone graft material is the main way to repair bone defect in clinical. Artificial bone grafting material mainly maintains bone space in the process of bone defect repair, stabilizing blood clot, promoting healing, its effect on promoting new bone growth is limited, bone formation is slow, bone formation efficiency is poor, and it can not meet the demands of early load in clinical. In order to obtain better osteogenic effects, it is a hot spot to try to combine different bone growth factors to improve the quality of osteogenesis and accelerate the formation of new bone. The bone growth factors are often used as protein or polypeptide molecules, such as bone morphogenetic protein (BMP), transforming growth factor (TGF- beta), and so on. They will be protein in the body. The enzyme degradation, or the rapid dilution of the body fluid, the half-life is very short, it is difficult to maintain the effective treatment concentration, and it has a certain immunogenicity, which may cause the immune rejection. In addition, this kind of large molecular drug has a high price problem in any way, which makes the clinical application of bone growth factor greatly limited. The use of non protein small molecules to activate the intracellular signal transduction pathway to promote osteogenesis is a new direction in the study of bone defect repair. In recent years, some scholars have noticed that a previously unlocalized small molecule drug, three alcohol [1,25 (OH) 2D3]., has been found in many in vitro experiments, which can promote the maturation of osteoblasts and bone cells. In addition, it has synergistic effect with B VIII -2 to promote mineralization and promote osteogenesis. At the same time, it can inhibit the formation of osteoclasts by downregulating the expression of c-Fos and RANK. At present, the synthesis of ossified three alcohol and its analogues is very mature, and the ossification of three alcohol has no immunogenicity and does not lead to the rejection of the body. It is an ideal bone growth factor. Three alcohol is the highest bioactivity of vitamin D, the active component produced by vitamin D after a series of metabolism through the liver and kidney, and eventually into the blood circulation and plays an important role in regulating bone formation and bone development. At present, many animal models (chicken, mice, rabbits) support systemic vitamin D and vitamin C The positive correlation between bone healing, in these experiments, vitamin D metabolites promote the healing of the fracture and increase the strength of the callus. However, a few of the ossification three alcohol through the systemic circulation to the target organ can only maintain the basic metabolic balance of the body, especially in menopause women, abnormality of bone metabolism, or bone thinning. In pine patients, the content of vitamin D in the body will be greatly reduced, and the efficacy of promoting the repair of local bone defect is limited, and a large number of oral ossification three alcohol will produce drug toxicity, causing hypercalcemia, anorexia, vomiting, diarrhea, and even ectopic ossification of soft tissue. Therefore, the researchers began to study the effect of local application of three alcohols. Salomo and other local application of vitamin D2 to the implant of the mandible of the Beagle dog. It is found that it can reduce the loss of bone and increase the area of bone binding. But the drug used as the precursor of the ossification three alcohol, and the local application of this kind of medicine directly, is easy to be degraded quickly by the humoral dilution, and is difficult to be localized. At the same time, the problem of reaching the effective concentration will also become disorderly and disorderly due to lack of scaffold, which can not effectively play an effective role in promoting osteoblast maturation and promoting bone matrix mineralization. In the study of the animal model of the Beagle dog, Hsiang-Hsi Hong and other scholars have overcome the problem of rapid dilution of the direct local application of ossification of three alcohol by the body fluid. This method was used to study the osteogenesis efficiency of the local application of ossification of three alcohol by injection of a finished product with low three alcohol content around the circumferential bone defect of the mandible every week. In order to overcome the above problems, we need to find another way to overcome the above problems, and to prepare the standard bone defect for the preparation of the standard bone defect for examination. It is reported that the hydroxyapatite group, such as -OH-NH2, -COOH-, has the function of non covalent growth factor, and it is a good growth factor sustained-release carrier. The open connected irregular porous structure can increase the acreage of the growth factor of the scaffold, be beneficial to the adsorption and release of growth factors. Therefore, the hydroxy phosphorus The limestone is often used as a scaffold material to carry PDGF-BB, VEGF, BMP-2 and other growth factors to repair all kinds of bone defects. The main ingredient of the mineral demineralized calf bone is hydroxyapatite. It is also the most widely used and most widely studied bone material. Therefore, this study is to be used as the carrier of the mineral calf bone powder and after the complex ossification of three alcohol. The effect of local application of ossification three alcohol on bone formation in the early and middle period of bone defect repair in rabbit skull defect. Objective to study the effect of local application of ossification of three alcohol on early and mid-term osteogenesis. Method 1. animal model and group 18 male New Zealand white rabbits, 15-16 weeks old, body weight 2.9-3.2kg, from Guangdong Medical Laboratory Center The experimental process and postoperative treatment were all in accordance with the standard of animal ethics. After a week of adaptive feeding, the experiment was carried out in Guangdong animal laboratory. The experiment was divided into 3 groups: blank group (group A), bone powder group (group B) and ossified three alcohol compound bone powder group (group C). At the time point of study, 6 rabbits and each rabbit cranium at every point. 4 round bone defects of each 8 mm diameter were made with 24 circular bone defects at each time point, and randomly assigned to A, B, and C three groups of.2. materials for the preparation and treatment of three alcohol (Sigma Chemical Co. 1a 25-Dihydroxyvitamin D3 D1530) and 5 alcohol solution and 5 bone powder (Switzerland). Gai Pharmaceutical Co., Ltd., registration number: National Food Drug Supervision (Jin) 2014 3460922nd, imported product standard number: YZB/SWI8428-2013,0.25-1 mm) mixed, vacuum cryo freeze dry, cobalt 60 radiation disinfection after.3. operation 30 minutes before the operation of gentamicin (1 mg /kg), prevention of intraoperative and postoperative infection, surgical area preparation, to sleep a new 0. to sleep a new 0. 2 mL/kg hind leg muscle injection induction anesthesia, after the induction of anesthesia, 3% pentobarbital sodium injection 30 mg/kg ear vein injection anesthesia, after general anesthesia, take the prone position, the operation area with Iodophor disinfection, a disposable hole towel, 2% hydrochloric lidocaine area subcutaneous local infiltration anesthesia. Directly to the bone surface, the full thick flap was turned over the middle of the middle of the frontal bone, the posterior border to the bottom of the bone, the side of the parietal bone exposed on both sides, full exposure of the surgical area. The circumferential bone of 8 mm of the outer diameter was drilled on the cranial top to make 4 ring bone defects, the distance between the defect was more than 2 mm, and the physiological saline was cooled fully during the period, and the hard brain was not injured. Membrane. The corresponding bone powder or ossified three alcohol compound bone powder was inserted into the group. The intramuscular injection of gentamicin (200 thousand /d x 5d) to prevent infection after operation, and the increase of the penicillin antibiotics such as ampicillin sodium or Cefradine 0.1 g/kg/d x 5d. for third and fourth day neck subcutaneous injection of calcium yellow green before the death of the animals. 6 mg/kg, thirteenth days and fourteenth days before death, all animals were subcutaneously injected with tetracycline 30 mg/kg. in the neck of the rabbit, and all animals were killed in accordance with the observation time for 2 weeks, 4 weeks, and 6 weeks by ear vein air embolism. After 10% Formaldehyde Solution fixed 48 h, water was washed for 24 hours, half of the hard tissue sections were made directly, half placed in 10%EDTA solution. About 3 months of decalcification, the main detection indexes of paraffin section.4. were made by gross observation, histological observation, fluorescence staining calcium deposition and bone metrology. Results 72 circular bone defects were prepared in 1. operations and after operation. All of them were not damaged by the dura mater. 1 weeks after the operation, the swelling of the wound area basically subsided, the sutures were not loosened, the sutures were not loose, and the wound area had no infection, the first period of healing. The operation area was completely healed and the suture naturally fell off, the bone defect area of group A was covered with fibrous tissue, the boundary was clearly distinguishable, the fingers touch softly, and the fingers in group B and C were slightly soft, and the complete blank group hard. 4 weeks after the operation, a small amount of new bone formation was found on the edge of bone defect in group A, and the edge of the defect was blurred, the defect center was soft tissue, the finger touch was soft, the fingers of B and C were hard, the edge of bone powder particles was blurred at 2 weeks, and the edge of the defect was blurred. 6 weeks after operation, A In group B and group C, the bone tissues of group B and group C were still not fully full. There was obvious bone tissue in the bone powder between group and group. The finger felt very hard and the defect boundary was blurred. It was difficult to distinguish the 2 weeks after the histological observation. In group A, there was a small amount of osteoid formation on the edge of the defect, the center was fibrous tissue, and a large number of inflammatory cells were widely used. In group B, a small amount of bone gelatin was found in the connective tissue. In group B, a small amount of new bone and osteoid formed around bone powder particles were found at the center and edge of the defect. Group C was similar to that in group B, but the area of new bone and osteoid was larger. In group A, the new bone on the edge of the defect was extended to the Central Center, the area was enlarged, and the central area was still filled with fibrous tissue. There was a large amount of collagen fiber and scattered in a small amount of inflammatory cells. In group B, the bone powder surrounding the bone powder was deepened, more mature, and the area increased: the area of the new bone in group C was larger than that of the B group, the trabecular bone was sparsely interwoven into the reticulation, surrounded by a flat single layer of osteoblasts, which showed a large number of undeveloped mature cells, from osteoblasts. The bone cells surrounded by these cells were narrower and narrower around the bone lacunae around these bone cells. Osteoblasts were arranged around the new bone in a palisade. 6 weeks after the operation, the defect margin of the A Group continued to extend to the center, but still did not dock. In group B defects, the new bone mass was widely surrounded by bone powder particles and bone matured; C group was more than B The area of the new bone in the group was increased and the bone was more mature. A large number of small bone Liang Rong synthetic tablets were found to form the lamellar bone, which scattered in a small amount of irregular space. The.3. fluorescent staining calcium deposition was arranged around the space, and the calcium deposition in the A group was less, and the calcium deposition was only partly bright green on the edge of the defect. The extent of calcium deposition in B group was enlarged, and some calcium deposits appeared in the center of bone defect. The range of calcium deposition in group C was higher than that in the first two groups, and the luminance was higher, indicating that calcium deposition was more than A, and B two groups also increased to a certain extent. The three groups of calcium deposits were expanded at 4 weeks after the operation, and the calcium deposition still showed A group in group B group C. 6 weeks after the operation, the bone island in the A group formed bone island with calcium deposition on the edge, but there was still no calcium deposition in the center of the defect. There was extensive calcium deposition in the B and C group. The area C was larger than the B group, the brightness was higher than the.4. bone metrology, the ratio of the bone area of the A group was 9.58 + 1.21% and the number of osteoblasts was 15. .2 + 1.68; B group new bone area ratio was 12.52 + 1.09%, osteoblast number was 23.8 + 1.25; C group new bone area ratio was 15.12 + 0.80%.
【學位授予單位】：南方醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：R683

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