高效液相色谱法测定去氧氟尿苷含量及其有关物质

目的 用高效液相色谱法（HPLC法）测定去氧氟尿苷的含量及其有关物质。方法 采用Diamonsil C—粒（250mm×4．6mm，5μm），流动相为乙腈-水（1：1），检测波长为269nm，流速为0．8mL／min。结果 去氧氟尿苷质量浓度在10．0～200．4μg／mL范围内与峰面积线性关系良好，r：0．9999（n：5），平均回收率为100．2％，RSD=0．14％。结论 HPLC法简便、准确，专属性好，灵敏度高，可用于去氧氟尿苷含量及有关物质的测定。     

The pharmacokinetics of doxifluridine and 5-fluorouracil after single intravenous infusions of doxifluridine to patients with colorectal cancer

Summary The disposition kinetics of a new 5-fluorouracil prodrug, 5-deoxy-5-fluorouridine (5dFUR, doxifluridine), were investigated in six patients with colorectal carcinoma. Each patient randomly received two single intravenous doses of 5dFUR (2 and 4 g · m^–2) on separate days.Plasma concentrations of 5dFUR fell rapidly with terminal half-lives ranging from 16.1 to 27.7 min. A disproportionate increase in the area under the curve with increasing dose was seen in most patients. Doubling the dose resulted in a 40% decrease in nonrenal clearance (0.60 to 0.37 l · min^–1) but no apparent change in renal clearance (0.32 to 0.29 l · min^–1) or steady-state apparent volume of distribution (19.8 to 20.4 l).The mechanism for dose-dependence of 5dFUR appears to be primarily due to nonlinear elimination associated with nonrenal processes rather than nonlinear plasma protein or tissue binding.     

Human urinary excretion of doxifluridine and metabolites during a 5-day chemotherapeutic schedule using fluorine-19 nuclear magnetic resonance spectrometry

The urinary excretion of doxifluridine (5 dFUrd) and its metabolites was determined during five days of chemotherapy using fluorine-19 nuclear magnetic resonance spectrometry. The daily urinary excretion of 5 dFUrd and its metabolites was high (-100% of the 5 dFUrd administered) and nearly constant through out the treatment. By far the major excreted compounds were unchanged 5 dFUrd and -fluoro--alanine which made up respectively -40% and -50% of the total. Neither accumulation of 5 dFUrd nor significant modifications in its metabolism were observed during the treatment.     

The potential for oral combination chemotherapy of 5'-deoxy-5-fluorouridine, a 5-FU prodrug, and cyclophosphamide for metastatic breast cancer

Preclinical studies have demonstrated the synergistic anti-tumour activity of combination therapy with the oral cytostatics, 5'-deoxy-5-fluorouridine (5'-DFUR) and cyclophosphamide (CPA), in human breast cancer xenograft models. This study was performed to evaluate the efficacy and safety of this oral combination chemotherapy in the treatment of metastatic breast cancer. In all, 101 patients with metastatic breast cancer were enrolled in the study, and the data for 94 eligible patients of these were evaluated. The patients received twice daily oral combinations of 5'-DFUR (1200 mg/body/day) and CPA (100 mg/body/day) for 2 weeks, followed by a 1-week rest period. After a median of 19 treatment cycles (range 1-66 cycles), 16 patients (17.0%) had a complete response, and 40 patients (42.6%) had partial responses. The response rate was 59.6% (95% CI, 49.0-69.6%). The median time to progression and overall survival times were 11.7 and 40.3 months, respectively. The toxicity was mild and tolerable, and the related grade 3/4 clinical adverse effects consisted of haematological toxicity in 21 patients (22%) and nonhaematological toxicity in five patients (5%). These results suggest that the oral combination chemotherapy of 5'-DFUR and CPA has low toxicity and is a novel, very convenient and effective treatment for metastatic breast cancer.     

去氧氟尿苷联合放疗治疗中晚期食管癌的临床观察

目的观察去氧氟尿苷联合放疗治疗中晚期食管癌的疗效。方法 50例中晚期食管癌患者分为2组,其中放疗+去氧氟尿苷组25例;单纯放疗组25例。2组放射治疗方法相同,均采用常规设野,常规分割外照射,同步放化疗组在每日放疗的同时口服去氧氟尿苷。结果全组病例随访2年以上,放疗增敏组与对照组。结果放疗+去氧氟尿苷组和单纯放疗组组的近期疗效总有效率分别为72%和44%。1、2年生存率分别为72%、52%和56%、32%,放疗+去氧氟尿苷组明显优于单纯放组(P<0.05)。结论去氧氟尿苷联合放疗可作为提高中晚食管癌疗效的一种重要手段,且毒副反应易于耐受。     

高效液相色谱法测定去氧氟尿苷在不同介质中的平衡溶解度和表观油水分配系数

目的测定去氧氟尿苷在不同介质中的平衡溶解度以及在正辛醇-水和正辛醇-缓冲液体系中的表观油水分配系数。方法采用HPLC法测定去氧氟尿苷的浓度,采用摇瓶法测定去氧氟尿苷的表观油水分配系数。结果37℃,pH=7时去氧氟尿苷在水中的平衡溶解度为2.570 1 g.L-1,在pH〈5磷酸盐缓冲液中的平衡溶解度较低;去氧氟尿苷在正辛醇和水相中表观油水分配系数Papp为0.97;当pH〈7时,受pH影响不显著,表现为亲水性。结论去氧氟尿苷在水中的平衡溶解度及油水分配系数与介质的pH值有关,可以通过改变pH值,增加该药物新剂型的稳定性。     

脱氧氟尿苷针剂对小鼠移植性肿瘤的抑制作E用

目的观察脱氧氟尿苷DFUR针剂对动物移植性肿瘤的实验治疗作用.方法选用肉瘤S180、肝癌HepS、白血病L615和艾氏腹水癌ECA等四株小鼠移植性肿瘤,观察注射途径下脱氧氟尿苷DFUR的抗肿瘤作用.结果腹腔、静脉或口服给药,DFUR对S180的抑瘤率均大于80%.腹腔给药对HepS的抑瘤率为78%,对L615和ECA的生命延长率为515%和202%.腹腔给药对S180的化疗指数分别为DFUR2.8,FU1.3,FT207 1.4和FUDR1.5.结论无论是静脉、腹腔或口服给药,脱氧氟尿苷DFUR对多种小鼠肿瘤均有明显的抑制作用.与FU,FT207和FUDR相比,DFUR可在较低的毒性下显示更好的抗肿瘤作用.     

脱氧氟尿苷针剂对小鼠移植性肿瘤的抑制作用

目的 观察脱氧氟尿苷DFUR针剂对动物移植性肿瘤的实验治疗作用。方法 选用肉瘤S180、肝癌HepS、白血病L615和艾氏腹水癌ECA等四株小鼠移植性肿瘤，观察注射途径下脱氧氟尿苷DFUR的抗肿瘤作用。结果 腹腔、静脉或口服给药，DFUR对S180的抑瘤率均大于80％。腹腔给药对HepS的抑瘤率为78％，对L615和ECA的生命延长率为515％和202％。腹腔给药对S180的化疗指数分别为DFUR2．8，FU1．3，FT2071．4和FUDR1．5。结论 无论是静脉、腹腔或口服给药，脱氧氟尿苷DFUR对多种小鼠肿瘤均有明显的抑制作用。与FU，FT207和FUDR相比，DFUR可在较低的毒性下显示更好的抗肿瘤作用。     

Wernicke-Korsakoff-like syndrome in patients with colorectal carcinoma treated with high-dose doxifluridine (5''-dFUrd)

5'-dFUrd (doxifluridine) is a new fluoropyrimidine that may have a higher antitumor effect and less side effects than 5-FU. In this study 15 patients with advanced colorectal carcinoma, one with renal carcinoma, one with carcinoid and one with advanced carcinoma of unknown origin, were randomly assigned to receive 5'-dFUrd 5 g/m2 or 3 g/m2 as a 1-h infusion for 5 days in 3 cycles at intervals of 4 weeks. The patients had repeated neurological and neurophysiological examinations before and during the treatment. Ten patients developed symptoms of toxicity of the central nervous system (CNS), with cerebellopathy and encephalopathy resembling a Wernicke-Korsakoff syndrome. The neurotoxicity was dose related, affecting 7 of 8 patients in the high dosage group and 3 of 9 patients in the low dosage group. The symptoms generally started at the end of the second week of the cycle with unsteadiness and diplopia, and progressed to the fourth week with ataxia, confusion and EEG-changes, becoming more pronounced with increasing number of cycles. After the treatment there was normalisation within 4-8 weeks. Cachectic patients and patients with a pathological EEG before treatment seem to represent a high-risk group for CNS-symptoms. EEG may be helpful in early diagnosis of CNS-toxicity.     

去氧氟尿苷合成工艺改进

以5－氯尿嘧啶为原料经硅醚化、和四乙酰核糖缩合、皂化、酮缩醇形成、碘化、氢解及水解等反应合成了也氧氟尿苷。本法工艺简便、条件缓和、原料易得、成本低，总收率达54．6％。