| Background and Objectives The gastrointestinal cancer is one of thecommonest clinical malignant tumors. Although the surgical interventions have beenadvancing and radiotherapy, chemotherapy, biotherapy, immunotherapy andChinese traditional medicine been developing all the time, The prognosis andsurvival of the patients with gastrointestinal cancer has not been improved obviouslyso far, for which the main reason is that the regional recurrence and implantaionmetastasis can not be treated effectively.The recurrence and metastasis ofgastrointestinal cancer often occurs in the resection place, peritoneal membranesurface and liver by turns. Intraperitoneal chemotherapy, which aims at thisbiological behaviour and makes the recurrence and metastasis places ofgastrointestinal cancer expose to anti-cancer drug directly for a long time, provides anew adjuvant therapy for intraperitoneal malignant tumors and has been an importantprevention and treatment measure for gastrointestinal cancer especially now.However, there are still two main problems in intraperitoneal chemotherapy: one isthe poor penetration of chemotherapeutic agents, the other is the lack of carriersolutions which can stay in abdominal cavity with high concentration of anti-cancerdrugs. The ideal carrier solutions for intraperitoneal chemotherapy should expose cancerous surfaces or residual tumor cells within the peritoneal cavity to high levelsof cytotoxic agent as long as possible and make the agent distribute in abdominalcavity uniformly. Currently, isotonic micromolecule solutions includingphysiological saline are the commonly used carriers for intraperitonealchemotherapy, However, the low molecular weight of this kind of solutions results inits rapid peritoneal absorption and can not make the systemic toxicity ofintraperitoneal chemotherapy under satisfactory control. According to the reportsfrom foreign scholars, middle molecule and macromolecule carder solutions havemany advantages over micromolecule solutions, but there has not been a carriersolution which is effective for intraperitoneal chemotherapy definitely and can beutilized widespreadly up to now. HAES-steri is a neotype hetastarch with middlemolecule, which is commonly used for clinical volume expansion therapy. On basesof its characteristic that can stay in blood vessel for a long time and the researchabout the solutions of the same kind, HAES-steri is supposed to be an ideal carriersolution for intraperioneal chemotheapy. The objectives of this thesis are to study thehydrodynamics and pharmacokinetics of HAES-steri as carrier solution forintraperitoneal chemotherapy with 5-fluorouracil in rats and compare it with thetraditional carder solutions such as physiological saline, 1.5% dextrose peritonealdialysis solution, to identify the advantages and feasibility of HAES-steri as carriersolution for intraperitoneal chemotherapy.Methods1. A HPLC methods was selected to determine the concentration of5-fluorouacil in the plasma, peritoeal fluid and the main organ tissue of rats, then theconditions of chromatographic analysis and the regression equations of 5-fluorouacilin peritoneal fluid, plasma, stomach, colon, liver, kidney and lung were established.2. The Sprague-Dawley rats were randomized into physiologic saline group, 1.5% dextrose peritoneal dialysis solution group and HAES-steri group, theneach group was further randomized according to the length of the dwell period ofchemotherapy (1, 3, 6, 12, 18 and 24 h) with 5 rats at each time-point.3. Surgical procedure: The cytotoxic agent plus the carrier solution wasadministered intraperitoneally, then rats were returned to their cages to be observedand free access to food and water. At the end of the dwell-time, rats were brieflyanesthetized by inhalation of aether. Through a midline laparotomy the peritonealfluid was withdrawn completely and quantitated, then the samples of portal vein andinferior caval vein blood were taken in a standardized fashion and tissue sampleswere taken from colon, stomach, kidney, liver and lung by turns.4. 5-fluorouacil levels were determined in plasma, peritoneal fluid andtissue samples after pre-disposal.5. Main parameters of hydrodynamics and pharmacokinetics were obtainedand the cures of average drug concentration-time were plotted.6, The pharmacokinetic data was analyzed with DAS 2.0 software, all thestatistical analyses were carried out with SPSS 10.0 software and Mcrosoft Excel,Origin Pro 7.5 were used for plotting.Results1. On chromatographic condition of removing interference of foreignsubstance in biological specimen, the regression equation of 5-fluorouacil in plasmaof rats was: C=26.2180A/Ais-0.09966 (r=0.9998), the linear range is from0.001μg/ml to 10μg/ml; The regression equation of 5-fluorouacil in physiologicalsaline peritoneal fluid is a, c=28.4286A/Ais-2.2667 (r=0.9988), the linearrange is from 0.001μg/ml to 50μg/ml; b, C=65.4911A/Ais-58.7932 (r=0.9989), the linear range is from 50μg/ml to 2000μg/ml. The regression equation of5-fluorouacil in peritoneal fluid of 1.5% dextrose peritoneal dialysis solution is a, C =29.3152A/Ais-3.4561 (r=0.9988), the linear range is from 0.001μg/ml to 50μg/ml; b, C=65.68472A/Ais-67.9876 (r=0.9994), the linear range is from 50μg/ml to 2000μg/ml. The regression equation of 5-fluorouacil in HAES-steriperitoneal fluid is a, C=29.5754A/Ais-3.7976 (r=0.9994), the linear range isfrom 0.001μg/ml to 50μg/ml; b, C=66.5292A/Ais-89.8926, (r=0.9995), thelinear range is from 50μg/ml to 2000μg/ml. The regression equation of5-fluorouacil in gastric tissue of rats is C=29.0487A/Ais-3.2353(r=0.9991),the linear range is from 0.001μg/ml to 50μg/ml. The regression equation of5-fluorouacil in colon tissue is C=24.9276A/Ais-1.2175 (r=0.9997), the linearrange is from 0.001μg/ml to 50μg/ml. The regression equation of 5-fluorouacil inliver tissue is C=25.4524A/Ais-0.0135 (r=0.9999), the linear range is from0.001μg/ml to 50μg/ml. The regression equation of 5-fluorouacil in kidney tissue isC=25.7613A/Ais-0.3486 (r=0.9994), the linear range is from 0.001μg/ml to50μg/ml. The regression equation of 5-fluorouacil in lung tissue is C=28.1921A/Ais-0.2214 (r=0.9998), the linear range is from 0.001μg/ml to 50μg/ml.2. There are no significant differences in behaviours of rats among thethree gorups (P=0.843).3. The main parameters of hydrodynamics and pharmacokinetics of eachcarrier solution were obtained.4. The clearance rates of peritoneal fluid of HAES-steri group weresignificantly lower than those of 1.5% dextrose peritoneal dialysis solution group (pvalue is 0.009, 0.009 and 0.009 respectively) at 3 h, 6 h and 12 h and were lowerthan those of physiologic saline group at 1 h and 6 h (P=0.047,0.009); thepercentages of remaining peritoneal fluid volume of HAES-steri group weresignificantly higher than those of 1.5% dextrose peritoneal dialysis solution group at 1 h, 3 h, 6 h (p value is 0.047, 0.028 and 0.009) and than those of physiologic salinegroup at 1 h, 6 h, 12 h, 18 h ( p value is 0.047, 0.009, 0.005 and 0.005) and noexccss peritoneal fluid remained in peritoneal dialysis solution group at 12 h and inphysiologic saline group at 18 h; At 24 h, the percentage of remaining peritonealfluid volume of HAES-steri group was 4.2%.5. Mean peritoneal fluid 5-fluorouacil concentration was significantlyhigher in HAES-steri group than that in physiologic saline group at 3 h, 6 h and 18 h(P=0.009, 0.009 and 0.005) and than that in 1.5% dextrose peritoneal dialysissolution group at 3 h and 6 h (P=0.009 and 0.009); Mean plasma 5-fluorouacilconcentration in portal vein was significantly higher in HAES-steri group than thatin physiologic saline group at 3 h, 12 h, 18 h and 24 h (p=0.009, 0.034, 0.005 and0.019 respectively) and than that in 1.5% dextrose peritoneal dialysis solution group(p=0.047 and 0.019); Mean 5-fluorouacil concentration in gastric tissue wassignificantly higher in HAES-steri group than that in dialysis solution group (p=0.028 and 0.016 respectively) at 3 h, 18 h and than that in physiologic saline group at18 h (p=0.016); At 18h and 24h, Mean drug concentration in colon tissue wassignificantly higher in HAES-steri group than that in dialysis solution group (p valueis 0.028 and 0.05 respectively) and than that in physiologic saline group (P=0.009)at 18h; Mean 5-fluorouacil concentration in liver tissue was significantly higher inHAES-steri group than that in physiologic saline group at 3 h, 6 h, 12 h and 24 h (p=0.009, 0.013, 0.034 and 0.013 respectively) and than that in 1.5% dextroseperitoneal dialysis solution group at 3 h, 6 h, 18 h and 24 h (p=0.009, 0.013, 0.007and 0.005); There are no significant differences regarding plasma drugconcentrations of inferior caval vein and drug concentration in kidney tissue betweenthe three groups; At 18 h, mean 5-fluorouacil concentration in lung tissue wassignificantly higher in HAES-steri group than that in physiologic saline group (p= 0.009).Conclusion1. The HPLC methods established in this experiment can determine the5-fluorouacil in plasma, peritoneal fluid and main organ tissue of rats with highextraction recovery, sensitivity and specificity, without the intervention of foreignsubstance, which is convenient and suitable for the pharmacokinetics studies of5-fluorouacil.2. HAES-steri can be used as carder solution for intraperitonealchemotherapy in rats as safe as the traditional carrier solutions including physiologicsaline and 1.5% dextrose peritoneal dialysis solution and might be feasible forclinical application.3. HAES-steri has significant advantages in hydrodynamics andpharmacokinetics compared to physiologic saline and 1.5% dextrose peritonealdialysis solution as the carrier solution for intraperitoneal chemotherapy with5-fluorouacil, can make the systemic toxicity under satisfactory control theoretically.So, HAES-steri might be a promising carrier solution for intraperitonealchemotherapy.
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