注射用脱氧氟尿苷临床验证报告

目的验证和比较5'-DFUR(注射用脱氧氟尿苷)和5-FU(5-氟尿嘧啶)抗肿瘤疗效和安全性.方法解放军总医院抗肿瘤临床药理基地组织国内三家医院进行临床验证研究,从1999年12月至2001年2月对121例晚期恶性肿瘤患者进行5'-DFUR单药或联合化疗.结果119例病人可评价疗效,单药有效率13.6%(3/22),各病种之间未见到差异.联合化疗中,对照组有效率为11.6%(5/43),治疗组有效率为20.4%(11/54),两组之间未见到差异,既往治疗与否与疗效无明显相关性.单药主要不良反应为白细胞下降、恶心呕吐、乏力、腹泻、口腔溃疡等.联合化疗不良反应主要为骨髓抑制,恶心呕吐、乏力、神经毒性及口腔粘膜损伤等,治疗组和对照组无明显差别.结论注射用脱氧氟尿苷(5'-DFUR)单药对乳腺癌、胃肠道肿瘤具有一定的疗效,联合其它化疗药物对于乳腺癌、胃肠道肿瘤也具有一定的疗效,但与5-FU对照组之间无明显差异,不良反应主要为白细胞下降、恶心呕吐、乏力、腹泻、口腔溃疡等.     

注射用脱氧氟尿苷临床验证报告

目的:验证和比较5‘-DFUR(注射用脱氧氟尿苷)和5-FU(5-氟尿嘧啶)抗肿瘤疗效和安全性.方法:解放军总医院抗肿瘤临床药理基地组织国内三家医院进行临床验证研究,从1999年12月至2001年2月对121例晚期恶性肿瘤患者进行5‘-DFUR单药或联合化疗.结果:119例病人可评价疗效,单药有效率13.6%(3/22),各病种之间未见到差异.联合化疗中,对照组有效率为11.6%(5/43),治疗组有效率为20.4%(11/54),两组之间未见到差异,既往治疗与否与疗效无明显相关性.单药主要不良反应为白细胞下降、恶心呕吐、乏力、腹泻、口腔溃疡等.联合化疗不良反应主要为骨髓抑制,恶心呕吐、乏力、神经毒性及口腔粘膜损伤等,治疗组和对照组无明显差别.结论:注射用脱氧氟尿苷(5‘-DFUR)单药对乳腺癌、胃肠道肿瘤具有一定的疗效,联合其它化疗药物对于乳腺癌、胃肠道肿瘤也具有一定的疗效,但与5-FU对照组之间无明显差异,不良反应主要为白细胞下降、恶心呕吐、乏力、腹泻、口腔溃疡等.     

奈达铂联合氟尿嘧啶治疗晚期鼻咽癌的临床观察

目的:观察奈达铂(NDP)联合氟尿嘧啶(5-FU)治疗晚期鼻咽癌的近期疗效和安全性。方法:将我院2005年-2011年42例晚期鼻咽癌患者随机均分为治疗组和对照组,治疗组采用NDP80～100mg·m-2,静脉滴注,d1;5-FU600mg·m-2,d1～5。对照组采用顺铂(CDDP)30mg·m-2,静脉滴注,d1～3;5-FU600mg·m-2,d1～5。2组均3周为1个周期,治疗2个周期后评价近期疗效及不良反应。结果:治疗组与对照组的有效率分别为61.90%和38.10%,治疗组明显优于对照组,差异有统计学意义(P<0.05)。与对照组比较,治疗组消化道不良反应、肝肾毒性轻微,差异有统计学意义(P<0.05)。结论:NDP联合5-FU治疗晚期鼻咽癌近期疗效及安全性较好。     

培美曲塞联合顺铂对晚期非小细胞肺癌的临床效果比较

目的观察多西紫杉醇、培美曲塞单药或联合顺铂治疗晚期非小细胞肺癌(NSCLC)的近期疗效和毒性反应。方法选择85例入我院治疗的经病理学或细胞学确诊为晚期非小细胞肺癌的患者,随机分为四组并分别按以下方案进行化疗。PM组:培美曲塞500mg.m-2,第1天静脉滴注,21天为一周期;PC组:培美曲塞500mg.m-2第1天静脉滴注,顺铂75mg.m-2,第1～3天,21天为一周期;DC组:多西紫杉醇75mg.m-2,第1天、第8天,静脉滴注1h;DP组:多西紫杉醇75mg.m-2,第1天、第8天,静脉滴注1h,顺铂75mg.m-2分3天于第1～3天静脉滴注,21天为一周期。结果比较各组治疗有效率、疾病控制率、一年生存率无显著统计学差异(P>0.05)。比较DC组与DP组、PM组与PC组、DP组与PC组之间的无进展生存期差异有显著性(P<0.05);DC组与PM组比较两组差异无显著性(P>0.05)。DC组与DP组、PM组与PC组之间白细胞数减少发生率差异有统计学意义(P<0.05);各组间其他毒副反应的发生率差异无统计学意义(P>0.05)。结论多西紫杉醇、培美曲塞单药或联合化疗治疗进展或晚期NSCLC均有疗效,联合用药较单药化疗方案治疗晚期NSCLC的临床疗效更好,且不良反应轻。     

紫杉醇联合顺铂、5-FU治疗宫颈癌的临床效果观察

目的探讨紫杉醇联合顺铂、5-FU方案化疗治疗宫颈癌的疗效及安全性。方法选择2009年6月至2012年6月间于我院治疗的患者95例,随机分为对照组(48例)和观察组(47例),观察组给予紫杉醇联合顺铂、5-FU方案化疗治疗,对照组给予顺铂、5-FU方案治疗,治疗结束后评价近期疗效及患者的不良反应发生率。结果观察组化疗方案的总有效率达到55.3%,明显优于对照组(37.5%),比较差异有统计学意义(Z=2.07,P=0.04);观察组的不良反应发生率高于对照组,但比较差异无统计学意义(P>0.05)。结论紫杉醇联合顺铂、5-FU方案治疗宫颈癌患者的疗效确切,可延长患者的生存率,不良反应无明显增加,是一种治疗宫颈癌的有效方案。     

国产盐酸拓扑替康治疗小细胞肺癌Ⅱ期临床试验

目的评价国产注射用盐酸拓扑替康(TPT)治疗小细胞肺癌的疗效和不良反应,并与卡铂加依托泊苷进行比较.方法入组小细胞肺癌.47例,随机分为TPT单药组32例和对照组15例(卡铂加依托泊苷).单药组,用TPT 1.25mg·m-2·d,静滴＞30min,d1～d5;每3周重复1次.对照组用卡铂300mg·m-2,静滴,d1;依托泊苷60mg·m-2·d-1,静滴＞60min,d1～d5;每3周重复1次.治疗2周期后评价疗效,有效病例4周后确认疗效.结果单药组有效率37.9%,对照组有效率66.7%,对照组高于单药组,但无显著性差异(P＞0.05).主要不良反应为中性粒细胞减少,二者Ⅲ/Ⅳ度毒性单药组为43.8%,对照组为20.0%,无显著性差异(P＞0.05).2组非血液学毒性均轻微.结论国产注射用TPT单用和卡铂加依托泊苷比较治疗小细胞肺癌疗效相似,特别对复发小细胞肺癌疗效较好,耐受性良好,值得进一步深入临床研究.     

复方苦参注射液联合化疗治疗晚期结肠癌临床观察

目的：评价复方苦参注射液联合化疗治疗晚期结肠癌的临床疗效、生活质量及其不良作用。方法：对56例晚期大肠癌患者分为治疗组和对照组,每组28例。治疗组静脉滴注复方苦参注射液15mL,d1～14,加用化疗,即用OXA130mg·（m2）-1静脉滴注2h,d1,CF300mg·（m2）-1静脉滴注2h,d1,5-FU400mg·（m2）-1静脉滴,d1,5-FU2400mg·（m2）-1静脉滴注46h,3周为1个周期;对照组单用化疗,3周为1个周期。均连用2周期后评定疗效。结果：治疗组部分缓解17例,有效率为60.7%,对照组部分缓解12例,有效率为42.8%,差异有显著性（P〈0.05）;治疗组生活质量Karnofsky评分高于对照组,差异有显著性（P〈0.05）;治疗组血液不良反应、胃肠道反应明显低于对照组,差异有显著性。结论：复方苦参注射液联合化疗治疗晚期结肠癌,可提高疗效,改善患者生活质量,降低化疗不良反应。     

希罗达联合铂类用于中晚期宫颈癌新辅助化疗方案的疗效观察

目的 评价希罗达联合铂类治疗中晚期宫颈癌的近期临床疗效和安全性.方法 将120例FIGO分期为IB2期及以上的宫颈鳞癌患者随机分为4组:①组:30例,卡铂+希罗达;②组:30例,顺铂+希罗达;③组:30例,卡铂+5-FU;④组:30例,顺铂+5-FU;经3周期化疗,评价4组疗效及毒副反应.结果 ①组临床有效率( CR+PR)为83.33％,②组有效率(CR+PR)为93.33％,③组有效率(CR+PR)为76.67％,④组有效率(CR+PR)为90.00％;4组有效率比较,差异无显著性(P＞0.05).希罗达组(①+②组)总有效率( CR+PR)为88.33％,5-FU组(③+④组)总有效率(CR+PR)为83.33％;两组有效率比较,差异无显著性(P＞0.05),认为希罗达和5-FU 2种化疗药物对宫颈癌的疗效无差异(P＞0.05). 4组患者均无严重的化疗相关不良反应.4组患者骨髓抑制、胃肠道反应、肝功能损害和脱发发生率间差异无显著性(P＞0.05).希罗达组与5-FU组相比,静脉炎发生率低,而手足综合症发生率高,差异有显著性(尸＜ 0.05).结论 希罗达联合铂类作为中晚期宫颈癌的新辅助化疗方案,疗效确切,用药方便,优于5-FU,且毒副反应轻、安全性好,具有临床应用价值.     

复方苦参注射液联合同步放化疗治疗中晚期食道癌的临床观察

目的:观察复方苦参注射液联合同步放化疗治疗中晚期食道癌的近期疗效和放化疗不良反应。方法:将72例中晚期食道癌患者随机分为对照组和试验组各36例,2组均采用同步放化疗:放疗总量为64～68 Gy(6～7周),且在放疗d1、d29予以2次FP方案化疗,为DDP 20 mg·m-2,d1～4和5-FU 500 mg·m-2,d1～5。试验组在上述给药基础上再静脉注射复方苦参注射液20 mL,d1～10、d29～39。结果:试验组的近期有效率为81%,对照组为75%,2组无明显差异;试验组放化疗不良反应明显减轻,2组有显著差异(P<0.05)。结论:复方苦参注射液联合同步放化疗治疗中晚期食道癌可减轻放化疗的不良反应。     

紫杉醇与顺铂联合治疗晚期食道癌的临床疗效观察及安全性评估

目的探讨紫杉醇联合顺铂治疗晚期食道癌(advanc edesophageal cancer,AEC)的临床疗效及安全性。方法选择我院2007年9月～2011年2月收治并诊断为晚期食道癌患者160例,随机分为观察组和对照组,每组80例。观察组患者采用紫杉醇联合顺铂化疗方案治疗,TAX170mg.m-2d1+DDP30mg.m-2d1～d3,静脉滴注;对照组采用顺铂联合氟尿嘧啶方案,DDP30mg.m-2d1～d3+5-FU0.5g.m-2d1～d5。化疗结束后,评定治疗效果,并按照Kamofsky分级标准评价患者生活质量的改善情况。结果观察组治疗有效率为60.0%,明显高于对照组(P<0.05);平均生存时间为9.4±5.1个月,明显长于对照组(P<0.05);主要毒副作用为骨髓抑制和消化道反应,其发生率与对照组相比显著降低。化疗结束后,观察组患者生活质量改善的总体有效率78.8%,明显高于对照组(P<0.05)。结论紫杉醇与顺铂联合治疗AEC不仅临床疗效显著优于顺铂联合氟尿嘧啶,且不良反应小,并明显改善患者的生活质量。     

抗肿瘤药物2′-脱氧-5-氟尿苷合成研究

目的:合成抗肿瘤药物2′-脱氧-5-氟尿苷。方法:以5-氟尿嘧啶核苷为原料,经丙酰溴酰化溴代得2′-溴代-3,′5′-O-二丙酰基-5-氟尿嘧啶核苷,然后氢化得产物2′-脱氧-3,′5′-O-二丙酰基-5-氟尿嘧啶核苷,最后经皂化合成2′-脱氧-5-氟尿苷。结果:以5-氟尿嘧啶核苷为起始原料经3步反应合成了2′-脱氧-5-氟尿苷。结论:本合成方法工艺简便,原料易得,条件温和,总收率为72.0%,适于工业制备。     

Substrate properties of 5-fluorouridine diphospho sugars detected in hepatoma cells

Nucleotide sugars derived from 5-fluorouridine were studied in cultured AS-30D hepatoma cells as well as in kinetic enzyme assays in vitro in comparison with the physiologic uridine diphospho sugars. Hepatoma cells converted 5-fluoro [¹⁴C]uridine to 5-fluorouridine diphospho (FUDP) glucose, FUDP-galactose, FUDP-N-acetylglucosamine, FUDP-N-acetylgalactosamine, and trace amounts of FUDP-glucuronate, as analyzed by different systems of high-performance liquid chromatography. 5-Fluoro[¹⁴C]uridine and [¹⁴C]uridine, at concentrations of 5 μM in the culture medium, were phosphorylated by the cells during 60 min to similar amounts of FUTP and UTP, respectively, while the synthesis of [¹⁴]FUDP-sugars was reduced to 14% as compared to that of [¹⁴C]UDP-sugars.FUDP-sugars, synthesized by chemical and enzymatic procedures, were assayed in vitro as substrates for enzymes of UDP-sugar metabolism. K_m and V values in a range comparable to that of the respective UDP-sugars were determined for FUDP-sugars in the reactions catalyzed by UDP-glucose pyrophosphorylase, galactose-1-phosphate uridylyltransferase, UDP-glucose 4-epimerase, UDP-N-acetylglucosamine 2-epimerase, glycogen synthase, and UDP-glucose dehydrogenase.Our experiments in hepatoma cells and with enzymes in vitro have revealed additional reactions of FUDP-sugar metabolism demonstrating a metabolite pattern analogous to that of UDP-sugars. The amounts of FUDP-sugars formed relative to UDP-sugars in intact cells were smaller than suggested on the basis of their kinetic comparison in vitro.     

去氧氟尿苷胶囊的人体药物动力学及相对生物利用度

目的:了解国产去氧氟尿苷胶囊在人体的药物动力学及相对生物利用度.方法:采用随机交叉试验设计,10例男性健康志愿者单剂量po试验品与参比品去氧氟尿苷胶囊400mg,以HPLC法测定血药浓度.结果:试验品与参比胶囊各项动力学参数为T_1/2:(19.35±3.69)与(17.50±3.06)min,t_(max):(38.5±14.7)与(33.5±8.5)min.c_(max):(3.35±0.93)与(3.42±0.98)μg/ml;AUC(o-T):(157.58±41.90)与(154.20±45.36)(μg·min)/ml .经交叉试验方差分析,上述药物动力学参数无统计学显著差异(P>0.05).结论:试验品与参比胶囊生物等效,试验品的相对生物利用度为(104.05±13.97)%.     

RP-LC determination of 5-fluorouridine in nanoparticulate formulations

5-fluorouridine (5-FUrd) is an anticancerous drug with a number of side effects due to its high toxicity. One possibility to overcome these drawbacks may consist on the use of polymeric nanoparticles to increase the therapeutic index of this drug. The objective of this study was to develop an analytical high performance liquid chromatography (HPLC) method for the determination of (i) the 5-FUrd content in poly (methyl vinyl ether-co-maleic anhydride) nanoparticles, (ii) its release from these carriers and, its eventual degradation during preparation, storage or release in 5-fluorouracil (5-FU). The chromatography was performed on a reversed-phase encapped column (LiChrospher Select B C8) with a mobile phase of 0.05 M ammonium acetate (pH 6.5). Ganciclovir (GCV) was used as internal standard and the detection wavelength was 268 nm. The limits of quantification of 5-FUrd and 5-FU were 12 and 5 ng/ml, respectively. Similarly, precision did not exceed 7%. Under our experimental conditions, the maximal drug loading capacity of 5-FUrd was around 105 microg/mg nanoparticle and the drug was released in a biphasic way from these particles. In addition, no degradation of 5-FUrd to 5-FU during either the preparative process or the release studies was observed. In summary, this HPLC method is selective, sensitive, specific and reproducible for the quantification of 5-FUrd in polymeric nanoparticles and release mediums.     

5-氟尿嘧啶现代给药系统研究进展

5-氟尿嘧啶（5-Fu）是药典收载的抗肿瘤经典药物,作用于DNA合成期,对食道癌、胃癌、结肠癌等消化系统癌症有显著的抑制作用,对卵巢癌、宫颈癌、绒毛膜上皮癌、膀胱癌也有一定疗效。但是,5-Fu口服吸收不规律,且副作用较大,不良反应有胃肠道反应、骨髓抑制、脱发、共济失调等,严重者甚至发生血性下泻而死亡。为降低不良反应发生率,提高疗效,     

抗肿瘤药物2''''-脱氧-5-氟尿苷合成研究

目的合成抗肿瘤药物2'-脱氧-5-氟尿苷.方法以5-氟尿嘧啶核苷为原料,经丙酰澳酰化溴代得2'溴代-3',5'-O-二丙酰基-5-氟尿嘧啶核苷,然后氢化得产物2'-脱氧-3',5'-O-二丙酰基-5-氟尿嘧啶核苷,最后经皂化合成2'-脱氧-5-氟尿苷.结果以5-氟尿嘧啶核苷为起始原料经3步反应合成了2'-脱氧-5-氟尿苷.结论本合成方法工艺简便,原料易得,条件温和,总收率为72.0%,适于工业制备.     

Kinetic model for 5-fluorouridine degradation. Catalytic effect of 5-fluorouracil

The effects of 5-fluorouridine (5-FUR, CAS 316-46-1) degradation products, 5-fluorouracil (5-FU, CAS 51-21-8) and D-ribose (CAS 50-69-1), on its degradation rate was investigated following a 2(3) factorial design. The experimental data fitted to the proposed mathematical model which includes two parallel degradation mechanisms: the first one, a second order bimolecular reaction involving both 5-FUR and 5-FU, and the second, a first order one. Experimental data obtained show a high variability. Both graphic and statistical analysis of the experiments for which a full kinetic model was applied manifested that the degradation mechanism included an autocatalytic route and confirmed the role of the 5-FU on the hydrolysis of 5-FUR.     

Pharmacokinetics and bioavailability of oral 5'-deoxy-5-fluorouridine in cancer patients

AIMS: Oral administration of 5-fluorouracil (FUra), an important cytotoxic agent, is limited by a wide variation in bioavailability. 5'-deoxy-5-fluorouridine (dFUrd), a masked form of FUra, has shown promise clinically when given intravenously or orally as a solution or tablet. This study investigates the efficacy of an oral capsule formulation of dFUrd in generating continuous systemic levels of this compound in cancer patients. METHODS: Six patients with advanced intestinal or ovarian malignancies were given three cycles of dFUrd, days 1-5, at intervals of 4 weeks. The doses of dFUrd were 600 mg m-2 three times daily, 800 mg m-2 three times daily, and 1000 mg m-2 three times daily, on cycles one, two and three, respectively (total dose 36 g m-2 ). The initial dose in each cycle was given as a slow intravenous injection over 10 min, and the remainder orally. Plasma and urine levels of dFUrd and two of its metabolites, FUra and 5,6-dihydro-5-fluorouracil (FUraH2 ), were monitored in six patients at each dose level. RESULTS: All six patients completed the study, receiving three different doses over a 3 month period, following which one had achieved a partial response, one had stable disease, and four had developed progressive disease. Side-effects were negligible, and only two instances of transient diarrhoea WHO grade 1 were seen. Total body clearance (CLtot) of intravenous dFUrd decreased with increasing dose; 2.7, 2.0 and 1.3 l min-1 m-2, following doses of 600, 800 and 1000 mg m-2, respectively. The mean elimination half-life of intravenous dFUrd increased with the dose from 15 to 22 min. Oral dFUrd was rapidly absorbed with a lag time of less than 20 min. The mean elimination half-life (t1/2, z ) of oral dFUrd was 32-45 min in the dose range 600-1000 mg m-2. The AUC of FUra and FUraH2 increased overproportionally with increasing intravenous doses of dFUrd. The mean systemic bioavailability of oral dFUrd was 34-47%. CONCLUSIONS: dFUrd, which selectively releases the antimetabolite FUra in tumour cells, can be given orally at doses of 600-1000 mg m-2 three times daily for 5 days. The systemic levels achieved are equivalent to those seen following continuous infusions of dFUrd or FUra. Toxicity is tolerable, and further clinical investigation of oral dFUrd is warranted.