5-Fu腹腔气雾化疗的药代动力学及组织分布
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摘要
研究背景和目的随着人民生活水平的不断提高,胃肠道恶性肿瘤已成为严重威胁人类健康的主要疾病之一,发病率及死亡率均较高,并且有年轻化的趋势。目前对胃肠道恶性肿瘤的治疗仍是以外科手术为主的综合治疗,从Billroth医生第一例胃大部切除至今已有120年余,胃肠道肿瘤外科已从只重视切除肿瘤到以切除原发肿瘤及受侵器官、彻底清除区域淋巴结及杀灭腹腔脱落癌细胞的外科治疗；从单一的手术进入以围手术期治疗加规范化手术的新的治疗模式中来。但患者白就医被发现胃肠道恶性肿瘤时大多已处于进展晚期,经过根治术后仍约有半数病人5年内出现局部复发和／或远处转移。腹腔内游离癌细胞(free cancer cell,FCC)和不能完全手术切除的微小癌灶的存在是造成胃肠道恶性肿瘤术后腹腔内复发和／或远处转移的主要因素,成为影响长期生存率的直接原因。国内外学者为此进行了不懈的努力,包括术前的动脉灌注化疗、术中肠腔内化疗、术前放化疗相结合、围手术期的辅助化疗等。近年来腹腔化疗(intraperitoneal chemotherapy,IPC)特别是腹腔内温热灌注化疗(continuous hyperthermic peritoneal perfusion chemotherapy, CHPPC)因其独特的药代动力学特征及其他基础特点而备受重视。研究表明腹腔化疗可以有效的预防和治疗胃肠道恶性肿瘤术后手术区域、腹膜及肝脏的复发,并且大样本病例研究发现胃肠道恶性肿瘤术后复发最常见的解剖部位是手术区域、腹主动脉旁淋巴结、腹膜表面、盆底和卵巢等,术后最常见的转移部位是肝脏。由于“腹腔-血浆屏障”的存在,腹腔内化疗的药物浓度可以为血管内给药浓度的数倍乃至数十倍,在腹腔内提供了恒定持久的高浓度,大大加强了抗肿瘤药物的作用,相关的文献报道指出,腹腔内化疗特别是腹腔内温热灌注化疗能对3-5mm的肿瘤结节具有疗效。腹腔镜在胃肠道肿瘤治疗中的应用是近年来开展的一项新技术,自Jacob等最早报道了应用腹腔镜行结直肠手术以来,国内外在此领域的报道日益增多,形成了胃肠道肿瘤外科的一种发展趋势。腹腔镜手术需要建立气腹以显露术野,气腹的涡流作用可将腹腔脱落的癌细胞播散开来,从而造成戳孔及腹膜的种植转移,并且早在1978年,Dobronnate等首次提出恶性肿瘤的C02气腹腹腔镜手术会造成恶性肿瘤细胞的扩散及转移。因此如何采取合理的治疗措施来防止腹腔镜胃肠道恶性肿瘤手术后腹腔内复发和／或远处转移对改善患者的预后和生存率具有极其重要的意义。本课题运用自行研制的气雾化疗仪将5-Fu气雾化后,对动物腹腔实行灌注,研究在活体动物体内气雾状态下的5-Fu在血液及组织中的分布规律,建立药代动力学数学模型,为其临床开发与应用提供实验室依据和理论基础。
目的
1、研制出可将液态5-Fu雾化成气态的动物实验气雾化疗仪,且不改变化疗药物的化学性质。
2、建立色谱分析条件及5-Fu在腹腔液、门静脉血、下腔静脉血、胃、结肠、肝脏、肾、肺组织中的标准曲线。
3、用高效液相色谱法(HPLC)测定腹腔液、门静脉血、下腔静脉血、胃、结肠、肝脏、肾、肺组织中的5-Fu浓度。
4、计算药代动力学参数,并绘制出平均药时浓度拟合曲线。
方法
1、腹腔镜手术需要建立气腹以显露术野,CO2气体对机体理化、免疫和分子生物学方面的影响使得腹腔游离癌细胞更易于脱落种植于腹腔。因此我们设想可否通过将雾化的化疗药物注入腹腔以达到杀灭游离癌细胞的作用,既符合传统腹腔化疗的原理,又可更广泛的接触腹膜,并边手术边化疗,简化治疗过程。根据此设想我们设计并研制了可与气腹机相连接的简易超声气雾化疗仪。
2、由南方医科大学南方医院实验动物中心提供清洁级实验Sprague-Dawley(SD)大鼠,体重200-300g,共30只,雌雄各半,随机分为1h、3 h、6 h、12h、18h、24 h时间点组,每一时间点随机分给5只。
3、通过乙醚吸入性麻醉后,将大鼠固定于手术操作台上,并内置有乙醚棉球的50ml注射器追加麻醉(针孔固定于大鼠鼻孔处)。腹腔穿刺针分别置入大鼠左、右下腹,左下腹穿刺处连接气雾化疗仪,利用STROZ气雾机维持气腹压约8mmHg,气体流量约5L／min,右下腹导管置于水面以下。待5-Fu(0.1ml/g)气雾灌注结束后,每组分别在1h、3h、6h、12h、18h、24h采用腹正中切口剖腹取腹腔液、门静脉和下腔静脉血样各2ml,依次取出肝、胃、结肠、肾、肺组织备测5-Fu浓度。
4、建立色谱分析条件及5-Fu在腹腔液、门静脉血、下腔静脉血、胃、结肠、肝脏、肾、肺组织中的标准曲线。
5、所取样品经预处理后,用高效液相色谱法测定其中5-Fu浓度。
6、计算药代动力学参数,并绘制出平均药时浓度曲线。
7、5-Fu浓度一时间数据用Drug and Statistics (DAS)2.0软件智能化计算,以确定合适的模型、权重选择,依据程序自动运算后给出的参数选择最佳拟合条件,不同组织及体液中5-Fu分布的最佳房室、非房室模型及其相应的药代动力学参数；用DAS 2.0软件绘制出各组织及体液中5-Fu平均药时拟和曲线,若数据过少,该软件不能拟和时,则用OriginPro 7.5绘制出5-Fu浓度随时间变化趋势图。
结果
1、腹腔液、门静脉及下腔静脉血,结肠、胃、肝、肾及肺脏组织中的药物浓度峰值均出现在1h组,均随时间推移药物浓度呈递减趋势；腹腔液中的药物浓度在1h组中达到峰值(259.7730ug／ml)；门静脉(PV)血中药物浓度较高,在1h组中其浓度(7.4933ug／ml)是下腔静脉(ICV)血(5.5930ug/ml)的约1.3倍；组织中肾中浓度最高,1h组浓度为(2.4030ug/ml),肺、胃浓度次之,结肠、肝组织中浓度依次最低。
2、在排除生物样品杂质干扰的色谱条件下,得5-Fu血浆标准曲线为c=26.2180A/Ais-0.09966,r=0.9998,线性范围：0.001μg／ml-10μg/ml.得5-Fu腹腔液标准曲线为①c=28.4286A/Ais-2.2667,r=0.9988,线性范围：0.001μg/ml-50μg/ml；②c=65.4911A/Ais-58.7932,r=0.9989,线性范围：50μg/ml-2000μg/ml.得5-Fu胃组织标准曲线为c29.0487A/Ais-3.2353,r=0.9991,线性范围：0.001μg/ml-50μg/ml.得5-Fu结肠组织标准曲线为c=24.9276A／Ais-1.2175,r=0.9997,线性范围：0.001μg/ml-50μg/ml.得5-Fu肝脏组织标准曲线为c=25.4524A/Ais-0.0135,r=0.9999,线性范围：0.001μg/ml-50μg/ml.得5-Fu肾组织标准曲线为c=25.7613A/Ais-0.3486,r=0.9994,线性范围：0.001μg/ml-50μg/ml.得5-Fu肺组织标准曲线为c=28.1921A/Ais-0.2214,r=0.9998,线性范围：0.001μg/ml-50μg/ml.
3、得出不同组织及体液中5-Fu分布的最佳房室、非房室模型及其相应的药代动力学参数,并绘制出平均药时拟合浓度曲线。
结论
1、本课题从腹腔镜气腹的角度研究腹腔化疗,将化疗药物气雾化后行动物腹腔内灌注,研究其药代动力学,并建立其药代动力学数学模型,使腹腔气雾化疗有望成为腹腔镜手术围手术期腹腔化疗的新的治疗模式,在提供治疗胃肠道恶性肿瘤乃至整个腹腔恶性肿瘤的腹腔内复发和／或远处转移方面具有一定的应用前景。
2、本研究建立的测定SD大鼠血浆、腹腔液及主要脏器组织中5-Fu含量的高效液相色谱法,血清和组织中杂质峰不干扰5-Fu的测定；提取回收率较高、敏感度高、特异性强,预处理简单省时,适于研究5-Fu药代动力学。
Background and Objectives With the continuous improvement of living standards, gastrointestinal cancer has become a serious threat to human health, one of the major diseases, morbidity and mortality are high, and has been dropping.At present the treatment of gastrointestinal cancer surgery is still dominated by the comprehensive treatment of the first cases of doctors from Billroth gastrectomy has been more than 120 years, gastrointestinal tumor surgery to remove the tumor from only concerned with removal of the primary tumor and the invaded organ, the elimination of regional lymph nodes and kill off cancer cells in the surgical treatment of abdominal cavity; from a single surgical access to standardized perioperative therapy plus surgery to new treatment modalities. However, since medical treatment was found in patients with gastrointestinal cancer is already in progress when the most advanced, after a radical mastectomy is still about half of the patients had local recurrence within 5 years and/or distant metastasis.Intraperitoneal free cancer cells (free cancer cell, FCC), and can not be completely resected the existence of small foci caused by intraperitoneal gastrointestinal tumor recurrence and/or distant metastasis of the main factors, affects the long-term survival the direct cause. Scholars have made unremitting efforts to this end, including preoperative arterial infusion chemotherapy, the intestine surgery chemotherapy, preoperative chemotherapy combined with perioperative adjuvant chemotherapy, etc..In recent years, intraperitoneal chemotherapy (intraperitoneal chemotherapy, IPC) in particular, intraperitoneal hyperthermic chemotherapy (continuous hyperthermic peritoneal perfusion chemotherapy, CHPPC) because of its unique pharmacokinetic characteristics, and other basic characteristics of much attention. The results show that abdominal chemotherapy could be effective prevention and treatment of gastrointestinal cancer after surgery area, peritoneal and hepatic recurrence, and the large sample case study found that recurrence of gastrointestinal cancer the most common anatomic site surgery, regional,abdominal aortic lymph nodes, peritoneal surfaces, ovaries and other pelvic floor and, after the most common sites of metastasis is the liver. Because "peritoneal-plasma screens,"the existence of the concentration of intraperitoneal chemotherapy drugs can be several times the concentration of intravascular administration or even several times, in the abdominal cavity to provide a constant sustained high concentrations, greatly strengthened the role of anticancer drugs,the relevant literature reported that intraperitoneal chemotherapy in particular, intraperitoneal hyperthermic perfusion chemotherapy on 3-5mm of tumor nodules is effective.Laparoscope in gastrointestinal cancer therapy is carried out in recent years, a new technology, such as self-Jacob reported the first application of laparoscopic colorectal surgery has been reported in this field at home and abroad increased, the formation of the gastrointestinal Road surgery in a trend.Need to establish pneumoperitoneum in laparoscopic surgery in order to reveal the operative field, the eddy current effect of pneumoperitoneum can be open abdominal spread of cancer cells to fall off, resulting in puncture and peritoneal metastasis, and early in 1978, Dobronnate so the first time Cancer CO2 pneumoperitoneum laparoscopic surgery can cause the spread of cancer cells and metastasis. Therefore, how to take reasonable measures to prevent the laparoscopic treatment of gastrointestinal cancer recurrence after surgery within the abdominal cavity and/or distant metastasis for improving the prognosis and survival of great importance.The subject of the use of chemotherapy instrument developed by the aerosol mist of the 5-Fu after the implementation of animal peritoneal perfusion to study the aerosol in vivo state of 5-Fu in the blood and tissue distribution of the drug on behalf of the establishment mathematical model of the development and applications for the clinical laboratory and theoretical basis.
Purpose
1.Developed 5-Fu can be atomized liquid into gas in animals aerosol chemotherapy device, without changing the chemical nature of chemotherapy drugs.
2.Chromatographic analysis of conditions and the establishment of 5-Fu in the peritoneal fluid, portal vein, inferior vena venous blood, stomach, colon, liver, kidney, lung tissue standard curve.
3.High performance liquid chromatography (HPLC) determination of peritoneal fluid, portal vein, inferior vena venous blood, stomach, colon, liver, kidney, lung tissue concentrations of 5-Fu.
4.Pharmacokinetic parameters were calculated, and plotted the average concentration of drug when the fitting curve.
Methods
1.Need to establish pneumoperitoneum in laparoscopic surgery in order to reveal the operative field, CO2 gas on the body chemical, immunological and molecular biology of peritoneal free cancer cells makes it easier to grow in the abdominal cavity off. Therefore, we envisage the possibility of chemotherapy drugs by spray into the abdominal cavity in order to achieve free to kill cancer cells, is consistent with traditional principles of intraperitoneal chemotherapy, but also more extensive contacts peritoneum, and side edge surgery chemotherapy, simplifying the treatment process.According to this idea we designed and developed that can be connected with pneumoperitoneum simple ultrasound instrument aerosol chemotherapy.
2.Nanfang Hospital, Southern Medical University Experimental Animal Center of the clean laboratory Sprague-Dawley (SD) rats weighing 200-300g, a total of 30 rats were randomly divided into 1h,3h,6h,12h,18h,24h time point group, each time point were randomly divided to five.
3.By ether inhalation anesthesia, the rats were fixed on the operative table, and built a cotton ball in 50ml syringe additional ether anesthesia (needle fixed on the rat nostril).Rats were placed in abdominal needle left, right lower quadrant, left lower quadrant puncture aerosol chemotherapy connected device,, using STROZ aerosol machine to maintain pressure of pneumoperitoneum about 8mmHg, gas flow rate of about 5L/min, catheters placed in the right lower abdomen, below the water surface. When 5-Fu (0.1ml/g) aerosol after reperfusion in each group at 1h,3h,6h,12h,18h, 24h with abdominal midline incision laparotomy, peritoneal fluid, portal vein and blood samples from the inferior vena 2ml,followed by Remove the liver, stomach, colon, kidney, lung 5-Fu concentration measurement equipment.
4.Chromatographic analysis of conditions and the establishment of 5-Fu in the peritoneal fluid, portal vein, inferior vena venous blood, stomach, colon, liver, kidney, lung tissue standard curve.
5.The samples were obtained after pretreatment with high performance liquid chromatography in which the concentration of 5-Fu.
6.Pharmacokinetic parameters were calculated, and plotted the average drug concentration curve time.
7.5-Fu concentration-time data with the Drug and Statistics (DAS) 2.0 software, intelligent calculation to determine the appropriate model,weight selection, based upon automatically computing the best fit parameters given conditions, in different tissues and body fluids 5-Fu distributed the best AV, non-compartment model and the corresponding pharmacokinetic parameters;using DAS 2.0 software to map out the organization and the body fluid 5-Fu and the average concentration-time curve to be, if the data is too small, The software can not be and when, is mapped using OriginPro 7.5 5-Fu concentration trends over time.
Result
1.Peritoneal fluid, portal vein and inferior vena cava blood, colon, stomach, liver, kidney and lung tissue concentration peak in 1h group, all drug concentrations over time showed a decreasing trend; peritoneal fluid drug concentration in the 1h group in the peak (259.7730ug/ml);portal vein (PV), blood level higher concentration in the 1h group (7.4933ug/ml) is the inferior vena cava (ICV) blood (5.5930ug/ml) of about 1.3 times;the highest concentration of renal tissue,1h group concentration (2.4030ug/ml),lung, stomach concentration of the second, colon, liver tissue concentration of the lowest order.
2.Biological samples in the impurity exclusion chromatographic conditions, was 5-Fu plasma standard curve for the c=26.2180A/Ais-0.09966, r=0.9998,linear range:0.001μg/ml-10μg/ml.5-Fu peritoneal fluid obtained standard curve①c =28.4286A/Ais-2.2667, r=0.9988,linear range:0.001μg/ml-50μg/ml;②c= 65.491 lA/Ais-58.7932, r=0.9989 linear range:50μg/ml-2000μg/ml.5-Fu gastric tissue was standard curve for the c=29.0487A/Ais-3.2353,r=0.9991,linear range:0.001μg/ml-50μg/ml.5-Fu colon was standard curve for the c 24.9276A/Ais-1.2175,r=0.9997, linear range:0.001μg/ml-50μg/ml.Was 5-Fu liver standard curve for the c=25.4524A/Ais-0.0135, r=0.9999, linear range:0.001μg/ml-50μg/ml. Was 5-Fu kidney standard curve for the c 25.7613A/Ais-0.3486, r=0.9994,linear range:0.001μg/ml-50μg/ml.5-Fu in lung tissue obtained standard curve for the c=28.1921A/Ais-0.2214, r=0.9998, linear range:0.001μg/ml-50μg/ml.
3. Come to different tissue and body fluid distribution of 5-Fu in the best AV, non-compartment model and the corresponding pharmacokinetic parameters, and drawing the average drug concentration time curve fitting.
Conclusion
1.The issue from the perspective laparoscopic cholecystectomy intraperitoneal chemotherapy, the animals underwent chemotherapy drug aerosolization intraperitoneal perfusion study the pharmacokinetics and to establish the pharmacokinetic model, so that abdominal chemotherapy could become aerosol Laparoscopic surgery perioperative intraperitoneal chemotherapy for the treatment of the new model, the treatment of gastrointestinal cancer and the whole abdominal cavity abdominal cancer recurrence and/or distant metastasis has a certain application.
2.This study established the determination of SD plasma, peritoneal fluid and the major tissues of 5-Fu content of high performance liquid chromatography, serum and tissue of impurities do not interfere with the determination of 5-Fu; extraction recovery of high-sensitive high specificity, pretreatment simple time-saving,5-Fu is suitable for studying the pharmacokinetics.
目的
1、研制出可将液态5-Fu雾化成气态的动物实验气雾化疗仪,且不改变化疗药物的化学性质。
2、建立色谱分析条件及5-Fu在腹腔液、门静脉血、下腔静脉血、胃、结肠、肝脏、肾、肺组织中的标准曲线。
3、用高效液相色谱法(HPLC)测定腹腔液、门静脉血、下腔静脉血、胃、结肠、肝脏、肾、肺组织中的5-Fu浓度。
4、计算药代动力学参数,并绘制出平均药时浓度拟合曲线。
方法
1、腹腔镜手术需要建立气腹以显露术野,CO2气体对机体理化、免疫和分子生物学方面的影响使得腹腔游离癌细胞更易于脱落种植于腹腔。因此我们设想可否通过将雾化的化疗药物注入腹腔以达到杀灭游离癌细胞的作用,既符合传统腹腔化疗的原理,又可更广泛的接触腹膜,并边手术边化疗,简化治疗过程。根据此设想我们设计并研制了可与气腹机相连接的简易超声气雾化疗仪。
2、由南方医科大学南方医院实验动物中心提供清洁级实验Sprague-Dawley(SD)大鼠,体重200-300g,共30只,雌雄各半,随机分为1h、3 h、6 h、12h、18h、24 h时间点组,每一时间点随机分给5只。
3、通过乙醚吸入性麻醉后,将大鼠固定于手术操作台上,并内置有乙醚棉球的50ml注射器追加麻醉(针孔固定于大鼠鼻孔处)。腹腔穿刺针分别置入大鼠左、右下腹,左下腹穿刺处连接气雾化疗仪,利用STROZ气雾机维持气腹压约8mmHg,气体流量约5L／min,右下腹导管置于水面以下。待5-Fu(0.1ml/g)气雾灌注结束后,每组分别在1h、3h、6h、12h、18h、24h采用腹正中切口剖腹取腹腔液、门静脉和下腔静脉血样各2ml,依次取出肝、胃、结肠、肾、肺组织备测5-Fu浓度。
4、建立色谱分析条件及5-Fu在腹腔液、门静脉血、下腔静脉血、胃、结肠、肝脏、肾、肺组织中的标准曲线。
5、所取样品经预处理后,用高效液相色谱法测定其中5-Fu浓度。
6、计算药代动力学参数,并绘制出平均药时浓度曲线。
7、5-Fu浓度一时间数据用Drug and Statistics (DAS)2.0软件智能化计算,以确定合适的模型、权重选择,依据程序自动运算后给出的参数选择最佳拟合条件,不同组织及体液中5-Fu分布的最佳房室、非房室模型及其相应的药代动力学参数；用DAS 2.0软件绘制出各组织及体液中5-Fu平均药时拟和曲线,若数据过少,该软件不能拟和时,则用OriginPro 7.5绘制出5-Fu浓度随时间变化趋势图。
结果
1、腹腔液、门静脉及下腔静脉血,结肠、胃、肝、肾及肺脏组织中的药物浓度峰值均出现在1h组,均随时间推移药物浓度呈递减趋势；腹腔液中的药物浓度在1h组中达到峰值(259.7730ug／ml)；门静脉(PV)血中药物浓度较高,在1h组中其浓度(7.4933ug／ml)是下腔静脉(ICV)血(5.5930ug/ml)的约1.3倍；组织中肾中浓度最高,1h组浓度为(2.4030ug/ml),肺、胃浓度次之,结肠、肝组织中浓度依次最低。
2、在排除生物样品杂质干扰的色谱条件下,得5-Fu血浆标准曲线为c=26.2180A/Ais-0.09966,r=0.9998,线性范围：0.001μg／ml-10μg/ml.得5-Fu腹腔液标准曲线为①c=28.4286A/Ais-2.2667,r=0.9988,线性范围：0.001μg/ml-50μg/ml；②c=65.4911A/Ais-58.7932,r=0.9989,线性范围：50μg/ml-2000μg/ml.得5-Fu胃组织标准曲线为c29.0487A/Ais-3.2353,r=0.9991,线性范围：0.001μg/ml-50μg/ml.得5-Fu结肠组织标准曲线为c=24.9276A／Ais-1.2175,r=0.9997,线性范围：0.001μg/ml-50μg/ml.得5-Fu肝脏组织标准曲线为c=25.4524A/Ais-0.0135,r=0.9999,线性范围：0.001μg/ml-50μg/ml.得5-Fu肾组织标准曲线为c=25.7613A/Ais-0.3486,r=0.9994,线性范围：0.001μg/ml-50μg/ml.得5-Fu肺组织标准曲线为c=28.1921A/Ais-0.2214,r=0.9998,线性范围：0.001μg/ml-50μg/ml.
3、得出不同组织及体液中5-Fu分布的最佳房室、非房室模型及其相应的药代动力学参数,并绘制出平均药时拟合浓度曲线。
结论
1、本课题从腹腔镜气腹的角度研究腹腔化疗,将化疗药物气雾化后行动物腹腔内灌注,研究其药代动力学,并建立其药代动力学数学模型,使腹腔气雾化疗有望成为腹腔镜手术围手术期腹腔化疗的新的治疗模式,在提供治疗胃肠道恶性肿瘤乃至整个腹腔恶性肿瘤的腹腔内复发和／或远处转移方面具有一定的应用前景。
2、本研究建立的测定SD大鼠血浆、腹腔液及主要脏器组织中5-Fu含量的高效液相色谱法,血清和组织中杂质峰不干扰5-Fu的测定；提取回收率较高、敏感度高、特异性强,预处理简单省时,适于研究5-Fu药代动力学。
Background and Objectives With the continuous improvement of living standards, gastrointestinal cancer has become a serious threat to human health, one of the major diseases, morbidity and mortality are high, and has been dropping.At present the treatment of gastrointestinal cancer surgery is still dominated by the comprehensive treatment of the first cases of doctors from Billroth gastrectomy has been more than 120 years, gastrointestinal tumor surgery to remove the tumor from only concerned with removal of the primary tumor and the invaded organ, the elimination of regional lymph nodes and kill off cancer cells in the surgical treatment of abdominal cavity; from a single surgical access to standardized perioperative therapy plus surgery to new treatment modalities. However, since medical treatment was found in patients with gastrointestinal cancer is already in progress when the most advanced, after a radical mastectomy is still about half of the patients had local recurrence within 5 years and/or distant metastasis.Intraperitoneal free cancer cells (free cancer cell, FCC), and can not be completely resected the existence of small foci caused by intraperitoneal gastrointestinal tumor recurrence and/or distant metastasis of the main factors, affects the long-term survival the direct cause. Scholars have made unremitting efforts to this end, including preoperative arterial infusion chemotherapy, the intestine surgery chemotherapy, preoperative chemotherapy combined with perioperative adjuvant chemotherapy, etc..In recent years, intraperitoneal chemotherapy (intraperitoneal chemotherapy, IPC) in particular, intraperitoneal hyperthermic chemotherapy (continuous hyperthermic peritoneal perfusion chemotherapy, CHPPC) because of its unique pharmacokinetic characteristics, and other basic characteristics of much attention. The results show that abdominal chemotherapy could be effective prevention and treatment of gastrointestinal cancer after surgery area, peritoneal and hepatic recurrence, and the large sample case study found that recurrence of gastrointestinal cancer the most common anatomic site surgery, regional,abdominal aortic lymph nodes, peritoneal surfaces, ovaries and other pelvic floor and, after the most common sites of metastasis is the liver. Because "peritoneal-plasma screens,"the existence of the concentration of intraperitoneal chemotherapy drugs can be several times the concentration of intravascular administration or even several times, in the abdominal cavity to provide a constant sustained high concentrations, greatly strengthened the role of anticancer drugs,the relevant literature reported that intraperitoneal chemotherapy in particular, intraperitoneal hyperthermic perfusion chemotherapy on 3-5mm of tumor nodules is effective.Laparoscope in gastrointestinal cancer therapy is carried out in recent years, a new technology, such as self-Jacob reported the first application of laparoscopic colorectal surgery has been reported in this field at home and abroad increased, the formation of the gastrointestinal Road surgery in a trend.Need to establish pneumoperitoneum in laparoscopic surgery in order to reveal the operative field, the eddy current effect of pneumoperitoneum can be open abdominal spread of cancer cells to fall off, resulting in puncture and peritoneal metastasis, and early in 1978, Dobronnate so the first time Cancer CO2 pneumoperitoneum laparoscopic surgery can cause the spread of cancer cells and metastasis. Therefore, how to take reasonable measures to prevent the laparoscopic treatment of gastrointestinal cancer recurrence after surgery within the abdominal cavity and/or distant metastasis for improving the prognosis and survival of great importance.The subject of the use of chemotherapy instrument developed by the aerosol mist of the 5-Fu after the implementation of animal peritoneal perfusion to study the aerosol in vivo state of 5-Fu in the blood and tissue distribution of the drug on behalf of the establishment mathematical model of the development and applications for the clinical laboratory and theoretical basis.
Purpose
1.Developed 5-Fu can be atomized liquid into gas in animals aerosol chemotherapy device, without changing the chemical nature of chemotherapy drugs.
2.Chromatographic analysis of conditions and the establishment of 5-Fu in the peritoneal fluid, portal vein, inferior vena venous blood, stomach, colon, liver, kidney, lung tissue standard curve.
3.High performance liquid chromatography (HPLC) determination of peritoneal fluid, portal vein, inferior vena venous blood, stomach, colon, liver, kidney, lung tissue concentrations of 5-Fu.
4.Pharmacokinetic parameters were calculated, and plotted the average concentration of drug when the fitting curve.
Methods
1.Need to establish pneumoperitoneum in laparoscopic surgery in order to reveal the operative field, CO2 gas on the body chemical, immunological and molecular biology of peritoneal free cancer cells makes it easier to grow in the abdominal cavity off. Therefore, we envisage the possibility of chemotherapy drugs by spray into the abdominal cavity in order to achieve free to kill cancer cells, is consistent with traditional principles of intraperitoneal chemotherapy, but also more extensive contacts peritoneum, and side edge surgery chemotherapy, simplifying the treatment process.According to this idea we designed and developed that can be connected with pneumoperitoneum simple ultrasound instrument aerosol chemotherapy.
2.Nanfang Hospital, Southern Medical University Experimental Animal Center of the clean laboratory Sprague-Dawley (SD) rats weighing 200-300g, a total of 30 rats were randomly divided into 1h,3h,6h,12h,18h,24h time point group, each time point were randomly divided to five.
3.By ether inhalation anesthesia, the rats were fixed on the operative table, and built a cotton ball in 50ml syringe additional ether anesthesia (needle fixed on the rat nostril).Rats were placed in abdominal needle left, right lower quadrant, left lower quadrant puncture aerosol chemotherapy connected device,, using STROZ aerosol machine to maintain pressure of pneumoperitoneum about 8mmHg, gas flow rate of about 5L/min, catheters placed in the right lower abdomen, below the water surface. When 5-Fu (0.1ml/g) aerosol after reperfusion in each group at 1h,3h,6h,12h,18h, 24h with abdominal midline incision laparotomy, peritoneal fluid, portal vein and blood samples from the inferior vena 2ml,followed by Remove the liver, stomach, colon, kidney, lung 5-Fu concentration measurement equipment.
4.Chromatographic analysis of conditions and the establishment of 5-Fu in the peritoneal fluid, portal vein, inferior vena venous blood, stomach, colon, liver, kidney, lung tissue standard curve.
5.The samples were obtained after pretreatment with high performance liquid chromatography in which the concentration of 5-Fu.
6.Pharmacokinetic parameters were calculated, and plotted the average drug concentration curve time.
7.5-Fu concentration-time data with the Drug and Statistics (DAS) 2.0 software, intelligent calculation to determine the appropriate model,weight selection, based upon automatically computing the best fit parameters given conditions, in different tissues and body fluids 5-Fu distributed the best AV, non-compartment model and the corresponding pharmacokinetic parameters;using DAS 2.0 software to map out the organization and the body fluid 5-Fu and the average concentration-time curve to be, if the data is too small, The software can not be and when, is mapped using OriginPro 7.5 5-Fu concentration trends over time.
Result
1.Peritoneal fluid, portal vein and inferior vena cava blood, colon, stomach, liver, kidney and lung tissue concentration peak in 1h group, all drug concentrations over time showed a decreasing trend; peritoneal fluid drug concentration in the 1h group in the peak (259.7730ug/ml);portal vein (PV), blood level higher concentration in the 1h group (7.4933ug/ml) is the inferior vena cava (ICV) blood (5.5930ug/ml) of about 1.3 times;the highest concentration of renal tissue,1h group concentration (2.4030ug/ml),lung, stomach concentration of the second, colon, liver tissue concentration of the lowest order.
2.Biological samples in the impurity exclusion chromatographic conditions, was 5-Fu plasma standard curve for the c=26.2180A/Ais-0.09966, r=0.9998,linear range:0.001μg/ml-10μg/ml.5-Fu peritoneal fluid obtained standard curve①c =28.4286A/Ais-2.2667, r=0.9988,linear range:0.001μg/ml-50μg/ml;②c= 65.491 lA/Ais-58.7932, r=0.9989 linear range:50μg/ml-2000μg/ml.5-Fu gastric tissue was standard curve for the c=29.0487A/Ais-3.2353,r=0.9991,linear range:0.001μg/ml-50μg/ml.5-Fu colon was standard curve for the c 24.9276A/Ais-1.2175,r=0.9997, linear range:0.001μg/ml-50μg/ml.Was 5-Fu liver standard curve for the c=25.4524A/Ais-0.0135, r=0.9999, linear range:0.001μg/ml-50μg/ml. Was 5-Fu kidney standard curve for the c 25.7613A/Ais-0.3486, r=0.9994,linear range:0.001μg/ml-50μg/ml.5-Fu in lung tissue obtained standard curve for the c=28.1921A/Ais-0.2214, r=0.9998, linear range:0.001μg/ml-50μg/ml.
3. Come to different tissue and body fluid distribution of 5-Fu in the best AV, non-compartment model and the corresponding pharmacokinetic parameters, and drawing the average drug concentration time curve fitting.
Conclusion
1.The issue from the perspective laparoscopic cholecystectomy intraperitoneal chemotherapy, the animals underwent chemotherapy drug aerosolization intraperitoneal perfusion study the pharmacokinetics and to establish the pharmacokinetic model, so that abdominal chemotherapy could become aerosol Laparoscopic surgery perioperative intraperitoneal chemotherapy for the treatment of the new model, the treatment of gastrointestinal cancer and the whole abdominal cavity abdominal cancer recurrence and/or distant metastasis has a certain application.
2.This study established the determination of SD plasma, peritoneal fluid and the major tissues of 5-Fu content of high performance liquid chromatography, serum and tissue of impurities do not interfere with the determination of 5-Fu; extraction recovery of high-sensitive high specificity, pretreatment simple time-saving,5-Fu is suitable for studying the pharmacokinetics.
引文
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