本文選題：氟比洛芬酯 + 手術鎮(zhèn)痛　； 參考：《山東大學》2016年博士論文

【摘要】：研究目的：觀察非甾類抗炎藥氟比洛芬脂用于宮頸癌手術病人圍術期鎮(zhèn)痛效果,并探討對宮頸癌患者的免疫系統(tǒng)和腫瘤細胞生長的影響。一、選擇75例ASAⅠ-Ⅱ級病人,年齡50-60歲,擬在全麻下行宮頸癌根治手術。隨機分為三組,對照組、術前組、術后組,每組25例。對照組(C)：手術前30分鐘及手術結束前30分鐘靜脈均靜脈注射安慰劑；術前組(Pr)：手術前30分鐘和手術結束前30分鐘靜脈分別注射1mg/kg氟比洛酚脂和安慰劑；術后組(Po)：手術前30分鐘和手術結束前30分鐘分別靜脈注射安慰劑和1mg/kg氟比洛芬脂。監(jiān)測拔管后咽喉痛、惡心、嘔吐發(fā)生率、拔管后躁動評分、拔管后10分鐘測定全麻后身體舒適度評分(BCS)和Ramsay鎮(zhèn)靜評分；用放射免疫法檢測術前和拔管后即刻腎上腺糖皮質激素水平、用氧化酶法檢測術前和拔管后血糖水平采用法。二、選取ASAI-Ⅱ級擬行根治性手術的宮頸癌患者,隨機分為3組,每組20例,Ⅰ組為多模式鎮(zhèn)痛組(氟比洛芬酯復合舒芬太尼),Ⅱ組為舒芬太尼組,Ⅱ組為芬太尼組。Ⅰ組患者術前30分鐘靜脈注射氟比洛芬酯,舒芬太尼0.4ug／kg誘導、0.2ug／L靶控輸注(target-infusion,TCI),術畢連接自控靜脈鎮(zhèn)痛泵(patient—controlled invenous analgesia,PCIA),鎮(zhèn)痛藥物為舒芬太尼50ug+氟比洛芬150 mg+鹽酸昂丹司瓊8 mg+生理鹽水共100 m1。Ⅱ組患者鎮(zhèn)痛不用氟比洛芬酯,其余同工組；術畢PCIA鎮(zhèn)痛藥物為舒芬太尼100 ug+鹽酸昂丹司瓊8ug+生理鹽水共100 m1。Ⅲ組患者使用芬太尼4ug/kg誘導、2ug/LTCI維持,術畢PCIA鎮(zhèn)痛藥物為芬太尼1.0 mg+鹽酸昂丹司瓊8 mg+生理鹽水共100m1。拔除氣管導管后10分鐘測定全身麻醉后身體舒適度評分(BCS)和不良反應,監(jiān)測麻醉前及術后24、48、72 h時血漿白細胞介素(IL)1、IL-6、CD4、CD8、CD4 /CD8比值和PGE2含量。三、選擇雌性BALB/c裸鼠50只,4～6周齡,將實驗動物隨機分為空白對照組(C)、腫瘤+生理鹽水組(T)、腫瘤+氟比洛芬酯10mg/kg(Cf10)組、腫瘤+氟比洛芬酯25mg/kg(Cf25)組、腫瘤+氟比洛芬酯50mg/kg(Cf50)組,每組10只,建立人宮頸癌動物模型�？瞻讓φ战M連續(xù)15天給予腹腔注射生理鹽水,實驗組分別于造模前一天開始腹腔注射相應劑量的氟比洛芬酯和生理鹽水,連續(xù)15天,測量腫瘤相對體積(RTV),相對腫瘤增殖率(T/C),抑瘤率。實驗組在第15天全部處死,將裸鼠瘤組織勻漿,取上清液采用酶聯(lián)免疫吸附法測定腫瘤組織的PGE：含量。結果一、Pr、Po兩組術后躁動評分均低于C組(P0.05),Pr組術后躁動評分明顯低于Po組(P0.05)；Pr、Po兩組身體舒適度評分和鎮(zhèn)靜評分明顯高于C組(P0.05),Pr組身體舒適度評分又明顯高于Po組(P0.05),Pr、Po兩組鎮(zhèn)靜評分比較差異無統(tǒng)計學意義；三組患者均未發(fā)現惡心、嘔吐不良反應。Pr、 Po兩組拔管后腎上腺皮質激素、血糖增高值明顯低于C組(P0.05),且Pr組蘇醒期腎上腺皮質激素、血糖增高值又明顯低于Po組(P0.05)。二、(1)Ⅲ組患者中,發(fā)生惡心10例(50%,10／20),嘔吐2例,頭暈1例,嗜睡2例,皮膚瘙癢2例,咽喉痛3例；Ⅱ組分別為6(30%,6／20)、1、2、0、0、4例；Ⅰ組分別為1(5%,1／20)、0、1、0,0、3例；Ⅲ、Ⅱ組患者惡心的發(fā)生率明顯高于Ⅰ組(P均0.05),Ⅲ組最高。3組患者均沒有發(fā)現呼吸抑制。(2)、3組患者IL-1、IL-6、CD4、CDB、CD4/CD8比值、PGE2的測定結果：麻醉前3組患者血漿中IL-1、IL-6、CD4、CD8、CD4/CD8比值、PGE2水平分別比較,差異均無統(tǒng)計學意義(P0.05)。3組患者術后24、48 h IL-1、IL-6水平均明顯高于麻醉前(P0.05),24 h升高最多。Ⅲ組在24、48 h時間點IL-1、IL-6水平均明顯高于Ⅰ、Ⅱ組(P0.05)；Ⅰ、Ⅱ組之間比較,差異無統(tǒng)計學意義(P0.05)。3組患者在72 h時 IL-1、IL-6水平均恢復到麻醉前水平。與麻醉前比較,三組的CD4/CD8在術后都呈下降趨勢,其中Ⅱ、Ⅲ組在T2時間點下降顯著(P0.05),在T2時間點Ⅲ組CD4/CD8顯著低于Ⅱ組(P0.05),工組術后各時間點與麻醉前比較差異無統(tǒng)計學意義。與麻醉前比較,三組PGE2在T1、T2時間點都呈增加趨勢,其中Ⅱ、Ⅲ組在T1時間點增加顯著(P0.05),Ⅱ、Ⅲ組之間在各時間點差異無統(tǒng)計學意義。Ⅰ組術后各時間點與麻醉前比較差異無統(tǒng)計學意義。三、(1)、C組沒有成瘤,其余各組成瘤時間差異無統(tǒng)計學意義；(2)、Cf50組RVT值均低于其他各組,Cf10和Cf25組RVT值較T組均有減小趨勢,但組間差異無統(tǒng)計學意義;(3)、腫瘤生長曲線顯示,T組瘤重均明顯高于給藥組(P0.01),cf50組瘤重明顯低于Cf10和Cf25組(P0.01),Cf10和Cf25組間比較差異無統(tǒng)計學意義(P0.05)。cf10、cf25、cf50三組的抑瘤率分別是16.8%、19.6%、36%,腫瘤相對增值率分別是85%、91%、72%。cf50組的抑瘤率明顯高于cf10和cf25組(P0.05),cf10和cf25組間比較差異無統(tǒng)計學意義(P0.05)。各組動物在整個實驗過程未見不良反應。結果4：對照組T組腫瘤組織的PGE2水平明顯高于實驗組,cf50組PGE2水平明顯低于Cf10和Cf25組(P0.01),Cf10和Cf25組間比較差異無統(tǒng)計學意義(P0.05)。結論1、術前30分鐘使用氟比洛芬脂1mg/kg可增加宮頸癌患者術后舒適度,提高蘇醒質量；2、氟比洛芬復合舒芬太尼用于宮頸癌患者圍手術期鎮(zhèn)痛能較好地抑制炎性介質的釋放,術后不良反應少,細胞免疫功能的影響最��；3、氟比洛芬酯能抑制裸鼠宮頸癌移植瘤的生長,cf50組效果最佳；裸鼠宮頸癌移植瘤組織中PGE2含量明顯增高,氟比洛芬酯能抑制裸鼠宮頸癌移植瘤組織PGE2的產生。意義：本課題研究結果提示,氟比洛芬酯屬于非選擇性環(huán)氧化酶2抑制劑,由于其靶向鎮(zhèn)痛的特點,其超前鎮(zhèn)痛和圍術期持續(xù)鎮(zhèn)痛效果良好,不良反應少。并對宮頸癌患者的免疫系統(tǒng)有一定保護作用。通過動物實驗進一步證實可抑制宮頸惡性腫瘤生長,其機制可能與PGE2的抑制有關。本課題從臨床實踐到動物實驗進一步提高了非甾類抗炎藥在癌癥病人中的應用價值,為癌癥病人的鎮(zhèn)痛和預防腫瘤復發(fā)開拓了新的思路。
[Abstract]:Objective: To observe the perioperative analgesic effect of nonsteroidal anti-inflammatory drug flurbiprofen fat in patients with cervical cancer and to explore the effects on the immune system and tumor cell growth of cervical cancer patients. 1, 75 patients with ASA I - II, aged 50-60 years, were treated with radical operation under general anesthesia. The patients were randomly divided into three groups, the control group, and the control group. The anterior group, the postoperative group, 25 cases in each group (C): 30 minutes before the operation and 30 minutes before the end of the operation, intravenous injection of placebo; preoperative group (Pr): 30 minutes before the operation and 30 minutes before the end of the operation, 1mg/kg flurbiolol and placebo were injected respectively; group (Po): 30 minutes before operation and 30 minutes before the end of the operation, respectively, Intravenous injection of placebo and 1mg/kg flurbiprofen fat. Monitoring of sore throat, nausea and vomiting after extubation, agitation score after extubation, 10 minutes after extubation, body comfort score (BCS) and Ramsay sedation score after extubation; radioimmunoassay was used to detect corticosteroid levels of adrenaline before and after extubation, and detected by oxidase method. The blood glucose level was used before and after extubation. Two, select the ASAI- II radical radical operation of cervical cancer patients, randomly divided into 3 groups, 20 cases in each group, group I was a multi mode analgesic group (flurbiprofen compound sufentanil), group II was sufentanil group, group I was fentanyl group. Group I was injected with flurbiprofen in 30 minutes before operation. Fentanyl 0.4ug / kg induction, 0.2ug / L target controlled infusion (target-infusion, TCI), combined auto-controlled intravenous analgesia pump (patient controlled invenous analgesia, PCIA), analgesic drug is sufentanil 50ug+ flurbiprofen, 150 of ondansetron 8 saline (100) patients without flurbiprofen, and the rest of the same work Group (Group), PCIA analgesic was performed by sufentanil 100 ug+ ondansetron 8ug+ saline in a total of 100 m1. III patients with fentanyl 4ug/kg, 2ug/LTCI maintenance, and PCIA analgesics of fentanyl 1 mg+ HCl 8 mg+ normal saline for 10 minutes after the extraction of tracheal tube for 10 minutes after general anesthesia for body comfort. Scores (BCS) and adverse reactions were monitored before and after anesthesia, and the plasma interleukin (IL) 1, IL-6, CD4, CD8, CD4 /CD8 ratio and PGE2 content were measured at 24,48,72 H. Three, 50 female BALB/c nude mice were selected, 4~6 weeks old, and the experimental animals were randomly divided into blank control group (C), tumor + flurbiprofen group, tumor + fluorine The bionprofen 25mg/kg (Cf25) group, the tumor + flurbiprofen 50mg/kg (Cf50) group, 10 rats in each group, established the animal model of human cervical cancer. The blank control group was given intraperitoneal injection of saline for 15 days. The experimental group began to intraperitoneally injected with the corresponding dose of flurbiprofen and saline one day before the model, and the relative body of the tumor was measured for 15 days, and the relative body of the tumor was measured. Product (RTV), relative tumor proliferation rate (T/C) and tumor suppressor rate. The experimental group was killed in fifteenth days, homogenate the tumor tissue of nude mice, and take the supernatant to determine the PGE of tumor tissue by enzyme linked immunosorbent assay. The results 1, Pr, Po two were lower than group C (P0.05), and the postoperative restlessness score of group Pr was significantly lower than that of group Po (P0.05); Pr, Po two groups The body comfort score and the sedative score were significantly higher than that of the C group (P0.05), and the body comfort score of group Pr was significantly higher than that of group Po (P0.05), Pr, Po two groups had no significant difference in sedation score; all the three groups had no nausea, nausea adverse reaction.Pr, and Po two groups after extubation, the increase of blood glucose was significantly lower than the C group (P0.0) 5) and the adrenocortical hormone in group Pr was significantly lower than that in group Po (P0.05). Two, (1) group III patients, 10 cases of nausea (50%, 10 / 20), 2 vomiting, 2 dizziness, 2 sleepy, 2 skin pruritus, 1 cases of larynggia, and group I, 0,1,0,0,3, III, II respectively. The incidence of nausea in the group was significantly higher than that in group I (P 0.05), and no respiratory depression was found in group the highest.3 group of group III. (2), the 3 groups of patients were IL-1, IL-6, CD4, CDB, CD4/CD8 ratio, and PGE2. The levels of IL-1, IL-6, CD4, CD8, etc. were compared in the 3 groups before anesthesia, and the differences were not statistically significant. Postoperative 24,48 h IL-1, IL-6 water was significantly higher than before anesthesia (P0.05), 24 h increased most. Group III at 24,48 h time IL-1, IL-6 water was significantly higher than I, group II (P0.05). The three groups of CD4/CD8 showed a downward trend after operation, of which group II, group III decreased significantly at T2 time point (P0.05), CD4/CD8 in group III of T2 was significantly lower than group II (P0.05), and there was no significant difference between each time point of the group after anesthesia and before anesthesia. Compared with before anesthesia, the PGE2 in the three group was increased in T1 and at the T2 time point, in which group II and group III were in T. 1 time points increased significantly (P0.05), there was no statistical difference between group II and group III at all time points. There was no statistically significant difference between group I and before anesthesia. Three, (1), group C did not have a tumor, and the rest of the composition of the tumor time difference was not statistically significant; (2) the value of RVT in group Cf50 was lower than that of other groups, RVT values in Cf10 and Cf25 groups were more than those of the T group. There was a decreasing trend, but there was no significant difference between groups. (3) the tumor growth curve showed that the tumor weight of group T was significantly higher than that of the administration group (P0.01). The tumor weight of group CF50 was significantly lower than that of group Cf10 and Cf25 (P0.01). There was no significant difference between Cf10 and Cf25 groups (P0.05).Cf10, cf25, the tumor inhibition rates of group three were 16.8%, 19.6%, 36%, and the tumor relative value added, respectively. The rate of tumor inhibition in group 72%.cf50 and group 72%.cf50 was significantly higher than that in group CF10 and cf25 (P0.05), and there was no significant difference between group CF10 and cf25 (P0.05). The results were no adverse reaction in the whole experiment. Results 4: the level of PGE2 in T group of control group was significantly higher than that in experimental group, PGE2 level in CF50 group was significantly lower than that of Cf10 and other groups. 0.01) there was no significant difference between the Cf10 and Cf25 groups (P0.05). Conclusion 1, using flurbiprofen fat 1mg/kg 30 minutes before operation can increase the postoperative comfort of cervical cancer patients and improve the quality of recovery; 2, flurbiprofen combined with sufentanil can better inhibit the release of inflammatory mediators in the perioperative period of cervical cancer patients and the postoperative adverse reaction. 3, flurbiprofen ester can inhibit the growth of cervical cancer in nude mice, and the effect of CF50 group is the best. The content of PGE2 in nude mice cervical cancer tissue is significantly increased. Flurbiprofen ester can inhibit the production of PGE2 in nude mice cervical cancer tissue. Ester is a non selective cyclooxygenase 2 inhibitor. Due to its targeted analgesic characteristics, its super preemptive pain and peri operative sustained analgesic effect is good, and its adverse reaction is less. It has certain protective effects on the immune system of cervical cancer patients. The mechanism of inhibiting the growth of cervical cancer by animal experiments may be inhibited by the inhibition of PGE2. This topic, from clinical practice to animal experiment, has further improved the application value of non steroidal anti-inflammatory drugs in cancer patients, and has opened up a new way of thinking for cancer patients' pain relief and prevention of tumor recurrence.
【學位授予單位】：山東大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R614;R737.33

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