氟比洛芬酯用于宫颈癌手术镇痛以及对宫颈癌肿瘤生长的影响

发布时间：2018-05-18 20:49

本文选题：氟比洛芬酯 + 手术镇痛　；参考：《山东大学》2016年博士论文

【摘要】：研究目的：观察非甾类抗炎药氟比洛芬脂用于宫颈癌手术病人围术期镇痛效果,并探讨对宫颈癌患者的免疫系统和肿瘤细胞生长的影响。一、选择75例ASAⅠ-Ⅱ级病人,年龄50-60岁,拟在全麻下行宫颈癌根治手术。随机分为三组,对照组、术前组、术后组,每组25例。对照组(C)：手术前30分钟及手术结束前30分钟静脉均静脉注射安慰剂；术前组(Pr)：手术前30分钟和手术结束前30分钟静脉分别注射1mg/kg氟比洛酚脂和安慰剂；术后组(Po)：手术前30分钟和手术结束前30分钟分别静脉注射安慰剂和1mg/kg氟比洛芬脂。监测拔管后咽喉痛、恶心、呕吐发生率、拔管后躁动评分、拔管后10分钟测定全麻后身体舒适度评分(BCS)和Ramsay镇静评分；用放射免疫法检测术前和拔管后即刻肾上腺糖皮质激素水平、用氧化酶法检测术前和拔管后血糖水平采用法。二、选取ASAI-Ⅱ级拟行根治性手术的宫颈癌患者,随机分为3组,每组20例,Ⅰ组为多模式镇痛组(氟比洛芬酯复合舒芬太尼),Ⅱ组为舒芬太尼组,Ⅱ组为芬太尼组。Ⅰ组患者术前30分钟静脉注射氟比洛芬酯,舒芬太尼0.4ug／kg诱导、0.2ug／L靶控输注(target-infusion,TCI),术毕连接自控静脉镇痛泵(patient—controlled invenous analgesia,PCIA),镇痛药物为舒芬太尼50ug+氟比洛芬150 mg+盐酸昂丹司琼8 mg+生理盐水共100 m1。Ⅱ组患者镇痛不用氟比洛芬酯,其余同工组；术毕PCIA镇痛药物为舒芬太尼100 ug+盐酸昂丹司琼8ug+生理盐水共100 m1。Ⅲ组患者使用芬太尼4ug/kg诱导、2ug/LTCI维持,术毕PCIA镇痛药物为芬太尼1.0 mg+盐酸昂丹司琼8 mg+生理盐水共100m1。拔除气管导管后10分钟测定全身麻醉后身体舒适度评分(BCS)和不良反应,监测麻醉前及术后24、48、72 h时血浆白细胞介素(IL)1、IL-6、CD4、CD8、CD4 /CD8比值和PGE2含量。三、选择雌性BALB/c裸鼠50只,4～6周龄,将实验动物随机分为空白对照组(C)、肿瘤+生理盐水组(T)、肿瘤+氟比洛芬酯10mg/kg(Cf10)组、肿瘤+氟比洛芬酯25mg/kg(Cf25)组、肿瘤+氟比洛芬酯50mg/kg(Cf50)组,每组10只,建立人宫颈癌动物模型。空白对照组连续15天给予腹腔注射生理盐水,实验组分别于造模前一天开始腹腔注射相应剂量的氟比洛芬酯和生理盐水,连续15天,测量肿瘤相对体积(RTV),相对肿瘤增殖率(T/C),抑瘤率。实验组在第15天全部处死,将裸鼠瘤组织匀浆,取上清液采用酶联免疫吸附法测定肿瘤组织的PGE：含量。结果一、Pr、Po两组术后躁动评分均低于C组(P0.05),Pr组术后躁动评分明显低于Po组(P0.05)；Pr、Po两组身体舒适度评分和镇静评分明显高于C组(P0.05),Pr组身体舒适度评分又明显高于Po组(P0.05),Pr、Po两组镇静评分比较差异无统计学意义；三组患者均未发现恶心、呕吐不良反应。Pr、 Po两组拔管后肾上腺皮质激素、血糖增高值明显低于C组(P0.05),且Pr组苏醒期肾上腺皮质激素、血糖增高值又明显低于Po组(P0.05)。二、(1)Ⅲ组患者中,发生恶心10例(50%,10／20),呕吐2例,头晕1例,嗜睡2例,皮肤瘙痒2例,咽喉痛3例；Ⅱ组分别为6(30%,6／20)、1、2、0、0、4例；Ⅰ组分别为1(5%,1／20)、0、1、0,0、3例；Ⅲ、Ⅱ组患者恶心的发生率明显高于Ⅰ组(P均0.05),Ⅲ组最高。3组患者均没有发现呼吸抑制。(2)、3组患者IL-1、IL-6、CD4、CDB、CD4/CD8比值、PGE2的测定结果：麻醉前3组患者血浆中IL-1、IL-6、CD4、CD8、CD4/CD8比值、PGE2水平分别比较,差异均无统计学意义(P0.05)。3组患者术后24、48 h IL-1、IL-6水平均明显高于麻醉前(P0.05),24 h升高最多。Ⅲ组在24、48 h时间点IL-1、IL-6水平均明显高于Ⅰ、Ⅱ组(P0.05)；Ⅰ、Ⅱ组之间比较,差异无统计学意义(P0.05)。3组患者在72 h时 IL-1、IL-6水平均恢复到麻醉前水平。与麻醉前比较,三组的CD4/CD8在术后都呈下降趋势,其中Ⅱ、Ⅲ组在T2时间点下降显著(P0.05),在T2时间点Ⅲ组CD4/CD8显著低于Ⅱ组(P0.05),工组术后各时间点与麻醉前比较差异无统计学意义。与麻醉前比较,三组PGE2在T1、T2时间点都呈增加趋势,其中Ⅱ、Ⅲ组在T1时间点增加显著(P0.05),Ⅱ、Ⅲ组之间在各时间点差异无统计学意义。Ⅰ组术后各时间点与麻醉前比较差异无统计学意义。三、(1)、C组没有成瘤,其余各组成瘤时间差异无统计学意义；(2)、Cf50组RVT值均低于其他各组,Cf10和Cf25组RVT值较T组均有减小趋势,但组间差异无统计学意义;(3)、肿瘤生长曲线显示,T组瘤重均明显高于给药组(P0.01),cf50组瘤重明显低于Cf10和Cf25组(P0.01),Cf10和Cf25组间比较差异无统计学意义(P0.05)。cf10、cf25、cf50三组的抑瘤率分别是16.8%、19.6%、36%,肿瘤相对增值率分别是85%、91%、72%。cf50组的抑瘤率明显高于cf10和cf25组(P0.05),cf10和cf25组间比较差异无统计学意义(P0.05)。各组动物在整个实验过程未见不良反应。结果4：对照组T组肿瘤组织的PGE2水平明显高于实验组,cf50组PGE2水平明显低于Cf10和Cf25组(P0.01),Cf10和Cf25组间比较差异无统计学意义(P0.05)。结论1、术前30分钟使用氟比洛芬脂1mg/kg可增加宫颈癌患者术后舒适度,提高苏醒质量；2、氟比洛芬复合舒芬太尼用于宫颈癌患者围手术期镇痛能较好地抑制炎性介质的释放,术后不良反应少,细胞免疫功能的影响最小；3、氟比洛芬酯能抑制裸鼠宫颈癌移植瘤的生长,cf50组效果最佳；裸鼠宫颈癌移植瘤组织中PGE2含量明显增高,氟比洛芬酯能抑制裸鼠宫颈癌移植瘤组织PGE2的产生。意义：本课题研究结果提示,氟比洛芬酯属于非选择性环氧化酶2抑制剂,由于其靶向镇痛的特点,其超前镇痛和围术期持续镇痛效果良好,不良反应少。并对宫颈癌患者的免疫系统有一定保护作用。通过动物实验进一步证实可抑制宫颈恶性肿瘤生长,其机制可能与PGE2的抑制有关。本课题从临床实践到动物实验进一步提高了非甾类抗炎药在癌症病人中的应用价值,为癌症病人的镇痛和预防肿瘤复发开拓了新的思路。
[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.
【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R614;R737.33

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