Plasma pharmacokinetics,tissue disposition,excretion and metabolism of vinorelbine in mice as determined by high performance liquid chromatography

Summary We have investigated the pharmacokinetics of the investigational semi-synthetic vinca alkaloid vinorelbine (navelbine, NVB). The analyses have been performed by using a sensitive and selective method based on ionexchange normal phase high-performance liquid chromatography with fluorescence detection combined with liquid-liquid extraction for sample clean-up. Pharmacokinetic studies were performed in male FVB mice receiving 12 mg/kg NVB through intravenous injection. The results have been compared to those obtained for vinblastine (VBL). The plasma pharmacokinetics of NVB can be described by a three compartment model. The elimination half-life is significantly longer and the plasma AUC values higher for NVB compared to VBL. This is reflected in tissues, where, 24 hr after drug administration, the concentration of NVB is 5 to 10-fold higher compared to VBL. Qualitatively, the tissue distribution and retention of the drugs is very similar. The drug concentrations in most tissues decline parallel with the circulating plasma levels, whereas prolonged retention is found in tissues of lymphatic and testicular origin. Deacetylation yielding deacetylnavelbine (DNVB) is the primary metabolic route for NVB. This cytotoxic metabolite accounts for a substantial part of the overall disposition of drug. Only 58% of the administered dose is excreted in the urine (17%) and faeces (41%) as NVB or DNVB. No other metabolites have been detected.     

异长春花碱加顺铂治疗晚期非小细胞肺癌23例疗效观察

目的 观察异长春花碱（NVB）加顺铂（DDP）治疗晚期非小细胞肺癌（NSCLC）的近期疗效和毒副反应。方法 NVB DDP治疗晚期NSCLC23例，采用NVB25mg/m^2静注，第1、8天，DDP30mg/m^2静滴，第3、4、5天，每21天为一周期，连用2-3周期。结果 全组总有效率为43.5%；主要毒副反应是白细胞下降和局部静脉炎，白细胞下降占100.0%，其中Ⅲ、Ⅳ度占56.5%。静脉炎发生率为39.1%。结论 NVB DDP方案治疗NSCLC有较好疗效，毒副反应可以耐受，是一个较好的联合化疗方案。     

Paclitaxel, vinorelbine and 5-fluorouracil in breast cancer patients pretreated with adjuvant anthracyclines

We investigated the activity and toxicity of a combination of vinorelbine (VNB), paclitaxel (PTX) and 5-fluorouracil (5-FU) continuous infusion administered as first-line chemotherapy in metastatic breast cancer patients pretreated with adjuvant anthracyclines. A total of 61 patients received a regimen consisting of VNB 25 mg m(-2) on days 1 and 15, PTX 60 mg m(-2) on days 1, 8 and 15 and continuous infusion of 5-FU at 200 mg m(-2) every day. Cycles were repeated every 28 days. Disease response was evaluated by both RECIST and World Health Organization (WHO) criteria. Objective responses were recorded in 39 of 61 patients (64.0%) assessed by WHO and in 36 of 50 patients (72.0%) assessable by RECIST criteria. Complete remission occurred in 15 (24.6%) and 14 patients (28.0%), respectively. The median time to progression and overall survival of entire population was 10.6 and 27.3 months, respectively, and median duration of complete response was 14.8 months. The dose-limiting toxicity was myelosuppression (leucopenia grade 3/4 in 52.5% of patients). Grade 3/4 nonhaematologic toxicities included mucositis/diarrhoea in 13.1%, skin in 3.3% and cardiac in 1.6% of patients. Grade 2/3 neurotoxicity was observed in five patients (7.2%). The VNB, PTX and 5-FU continuous infusion combination regimen was active and manageable. Complete responses were frequent and durable.     

A high performance liquid chromatography method for vinorelbine and 4-O-deacetyl vinorelbine: a decade of routine analysis in human blood

A sensitive high performance liquid chromatographic method was developed and validated for the simultaneous quantification of vinorelbine and its active metabolite, 4-O-deacetyl vinorelbine, in human biological fluids. These two compounds together with vinblastine, used as internal standard, were extracted from blood and urine by a liquid-liquid process using diethyl ether, and followed by a back-extraction in acidic conditions. Then, they were analysed through a cyano column and detected in ultraviolet at 268 nm. The assay linearity was validated up to 2000 ng/ml. The lower limit of quantification was set at 2.5 ng/ml. The between-run precision and accuracy were always higher than 94%. Biological samples were stable when stored at -80 degrees C over 2 years. The long-term reproducibility and the suitability of this analytical method were demonstrated within the last decade through the analysis of about 7000 samples during the clinical development of i.v. and oral formulations of vinorelbine. Because vinorelbine binds mainly to platelets and blood cells and because this binding is rapidly reversible and highly influenced by environmental conditions, drug concentration in plasma may be highly influenced by the sampling conditions and the centrifugation process used to separate blood cells from plasma. Therefore, this method was developed in blood and then used for sample analyses in routine. The major benefit was that it was easy for nurses to directly collect blood instead of plasma and that reduced volume of sampling could be withdrawn from frail patients. Furthermore, the analysis in blood enabled to quantify vinorelbine and 4-O-deacetyl vinorelbine concentrations for a longer period of time, which resulted in a more accurate evaluation of pharmacokinetic parameters.     

马铃薯外敷对长春瑞滨所致的兔耳缘静脉炎的防治作用

目的探讨马铃薯对长春瑞滨实验性静脉炎的防治作用。方法将36只日本大耳白兔按数字随机法分为A组（模型对照纽）、B组（33％硫酸镁溶液湿敷组）和C组（马铃薯片外敷组）．每一兔耳经耳缘静脉缓慢输注长春瑞滨1．0mg·kg^-1（20mL生理盐水溶解。分别于输液后24h、72h、7d观察并比较各组静脉炎发生严重程度。结果与模型组比较,马铃薯和硫酸镁外敷组的静脉炎较轻（P〈0．05）,而马铃薯外敷组72h的静脉炎轻于硫酸镁组（P〈0．05）。结论马铃薯外敷对长春瑞滨所致的兔耳缘静脉炎有一定的防治作用。     

长春瑞滨加醛氢叶酸和大剂量氟尿嘧啶治疗晚期三阴性乳腺癌

目的 探讨长春瑞滨（NVB）加醛氢叶酸（CF）和大剂量氟尿嘧啶（5-FU）治疗晚期三阴性乳腺癌（TNBC）的疗效.方法 选择2010年4月～2012年4月我院收治的35例晚期TNBC患者作为观察对象,给予NVB联合CF、大剂量5-FU进行治疗,观察患者化疗后的有效率、毒副反应、疾病进展时间（TTP）、1年生存率.结果 治疗总有效率为74.29%,其中CR为5例,PR为21例,SD为5例,PD为4例,RP为26例.绝经前后有效率分别为40.00%、34.29%;浸润性导管癌和小叶癌有效率分别为42.85%、31.43%;转移灶单个和多个有效率分别为62.85%、8.57%;既往治疗包含紫杉类和不含紫杉类有效率均为37.14%.主要副作用有白细胞下降和口腔溃疡,其中白细胞下降总发生率为60.00%,口腔溃疡总发生率为74.29%,毒副反应大多为Ⅱ～Ⅲ级,在病患可承受范围内,疾病进展时间为（9.5±2.3）个月、1年生存率为（76.36±8.21）%.结论 NVB联合CF、大剂量5-FU治疗TNBC能提高有效率以及患者生存率,安全性较高,值得临床推广应用.     

盖诺联合顺铂治疗晚期非小细胞肺癌近期疗效分析

目的观察国产去甲长春花碱(盖诺)与顺铂联合治疗晚期非小细胞肺癌疗效.方法 NP方案第1、8 天盖诺25 mg/m2、第1 ～ 3 天加顺铂40～50 mg 治疗Ⅲ～Ⅳ期非小细胞肺癌24例.结果 CR 1例,PR 15例,SD 11例,PD 9 例,总有效率为44.4%.初治有效率为56.7%,复治有效率为30.8%.主要毒副作用为白细胞减少.结论盖诺与顺铂联合治疗晚期非小细胞肺癌疗效确切,易于耐受,可作为晚期非小细胞肺癌的首选方案.     

Efficacy of Aidi Injection (艾迪注射液) on Overexpression of P-Glycoprotein Induced by Vinorelbine and Cisplatin Regimen in Patients with Non-Small Cell Lung Cancer

Objective:To investigate the efficacy of Aidi Injection(艾迪注射液) on overexpression of P-glycoprotein(P-gp) induced by vinorelbine and cisplatin(NP) regimen in patients with non-small cell lung cancer(NSCLC), and study the difference between intravenous administration and targeting intratumor administration of Aidi Injection with thoracoscope. Methods:Totally 150 patients with NSCLC were randomly assigned to the control group, the intravenous group and the intratumor group by the random envelope method, 50 cases in each group. The patients were treated with NP regimen(2 cycles), NP regimen(2 cycles) plus Aidi intravenous injection, or NP regimen(2 cycles) plus Aidi intratumor injection with thoracoscope, respectively for 6 weeks. The clinical efficacy was observed based on Response Evaluation Criteria in Solid Tumors(RECIST) rules, the expression of P-gp in the tumor tissue was tested before, 3 and 6 weeks after treatment, the safety was evaluated by monitoring the toxicity in the process of treatment, and the progressionfree survival(PFS) was measured. Results:Fifteen cases dropped out because of the irreconcilable conditions which had no relationship with the treatment, 4 in the control group, 5 in the intravenous group, and 6 in the intratumor group, respectively. Compared with the control group, the response rates(complete remission + partial response) and the disease control rates(complete remission + partial response + stable disease) were significantly higher, the P-gp expressions were significantly decreased after 3 and 6 weeks of treatment, and the Kaplan-Meier survival curves of PFS were significantly longer in the intravenous and intratumor groups(P0.05 or P0.01), and the intratumor group showed better effects than the intravenous group(P0.05 or P0.01). Compared with the control group, the occurrences of rash, nausea and leukocytopenia were significantly decreased in the intravenous and intratumor groups(P0.05), but without significant difference between the intravenous and intratumor groups(P0.05). Conclusion:Aidi Injection not only improves the efficacy of NP regime, but also has the function of reducing adverse events and preventing against overexpression of P-gp induced by chemotherapy of NP regimen.     

rh-Apo2L联合长春瑞滨对诱导肺鳞癌细胞凋亡作用及机制的研究

目的 晚期肺鳞癌治疗方式相对有限.Ⅲ期临床试验提示,rh-Apo2L有望为其提供一种新颖、有效的治疗方法.本研究旨在观察rh-Apo2L、长春瑞滨及两药联合对人肺鳞癌细胞SK-MES-1的抑制增殖和促进凋亡作用,并探讨其机制.方法 将不同质量浓度的rh-Apo2L、长春瑞滨干预人肺鳞癌SK-MES-1细胞,采用CCK8法检测细胞增殖;Annexin Ⅴ-FITC/PI流式细胞术检测细胞凋亡;蛋白质印迹法检测细胞凋亡相关蛋白DR4、DR5和Caspase-3的表达.结果 通过CCK8检测发现,rh-Apo2L对人肺鳞癌细胞SK-MES-1的体外增殖具有抑制作用,24和48 h的IC50分别为28.57和8.97 μg/mL;长春瑞滨对人肺鳞癌细胞SK-MES-1的体外增殖具有抑制作用,24和48 h的IC50分别为27.30和7.87 μg/mL.其中,1μg/mL rh-Apo2L组、1 μg/mL长春瑞滨组和两药联合组(rh-Apo2L和长春瑞滨质量浓度均为1 μg/mL)的24 h细胞增殖抑制率分别为(15.03±1.54)％、(21.88±2.75)％和(65.11±4.09)％;0.1 μg/mL rh-Apo2L组、0.5 μg/mL长春瑞滨组和两药联合组(rh-Apo2L质量浓度为0.1μg/mL,长春瑞滨为0.5 μg/mL)的48 h细胞增殖抑制率分别为(19.01±1.12)％、(19.97±1.23)％和(84.81±3.99)％;24和48 h联合组两药相互作用指数(q值)分别为1.94和2.40.细胞凋亡实验结果显示,1 μg/mL rh-Ap02L组、1μg/mL长春瑞滨组和两药联合组(rh-Ap02L和长春瑞滨质量浓度均为1 μg/mL)干预细胞24 h的凋亡率分别为(21.76±3.13)％、(37.31±2.21)％和(74.88±3.63)％;与单药组相比较,两药联合组对SK-MES-1细胞增殖的抑制作用明显增强(P＜0.001),两药联合干预24 h的凋亡指数显著升高,P＜0.001.蛋白印迹法检测结果发现,rh-Ap02L联合长春瑞滨在上调DR4(P=0.026)和DR5(P=0.001)表达方面具有交互作用,在增加Caspase-3活性片段表达亦具有交互作用,P=0.011.结论 rh-Apo2L与长春瑞滨均能协同抑制人肺鳞癌SK-MES-1细胞增殖并诱导细胞凋亡,其机制可能与上调SK-MES-1细胞表面的DR4、DR5蛋白表达和活化Caspase-3相关.     

INP和AP方案三线治疗晚期非小细胞肺癌的近期疗效观察

目的 肺癌是全世界发病率及死亡率最高的恶性肿瘤.非小细胞肺癌(non-small cell lung cancer,NSCLC)约占肺癌的85％,＞2/3患者临床确诊时已处于中晚期.近年来晚期NSCLC治疗方法进步很大,但晚期NSCLC的三线治疗尚无标准方案.本研究回顾性分析比较异环磷酰胺(ifosfamide,IFO)、长春瑞滨(vinorelbine,NVB)及顺铂(cisplatin,DDP)组合的INP方案和培美曲塞(pemetrexed,PEM)联合DDP的AP方案三线治疗不可切除的局部晚期或Ⅳ期NSCLC的近期疗效及不良反应.方法 2013-04-01-2015-04-01江门市中心医院肿瘤科共收治经一、二线治疗失败的ⅢB期或Ⅳ期NSCLC患者158例,简单随机分配至INP组78例和AP组80例.2组患者的性别、年龄、ECOG评分、分期、吸烟状况及既往治疗方面均具有良好的可比性.INP组应用IFO 1.2 g/m2,静脉滴入,d1～d2;NVB 20 mg/m2,静脉推注,d1、d8;DDP 25 mg/m2,静脉滴入,d1～d3.AP组应用PEM 500 mg/m2,静脉滴入,d1;DDP 25 mg/m2,静脉滴入,d1～d3.治疗周期为21 d,共4个周期.每2及4个周期后复查CT,按RECIST标准评价疗效.无进展生存期(progression free survival,PFS)定义为首次治疗开始之日到疾病进展或患者死亡.结果 158例患者均可评价,中位随访期13个月.INP和AP组的客观缓解率分别为12.8％(10/78)和17.5％(14/80),x2=0.671,P=0.413;疾病控制率分别为53.8％(42/78)和57.5％(46/80),x2=0.214,P=0.644.PFS分别为153和189 d,差异有统计学意义,P=0.027.不良反应可耐受.INP组和AP组的白细胞减少分别为74.4％ (58/78)和37.5％ (30/80),差异有统计学意义,P＜0.001;中性粒细胞减少分别为64.1％ (50/78)和37.5％ (30/80),差异有统计学意义,P=0.001;血小板减少分别为30.8 ％(24/78)和40.0％(32/80),P=0.225;贫血分别为59.0％(46/78)和52.5％(42/80),P=0.413;恶心呕吐分别为79.5％(62/78)和55.0％ (44/80),差异有统计学意义,P=0.001;周围神经毒性分别为64.1％ (50/78)和37.5％(30/80),差异有统计学意义,P=0.001;静脉炎分别为25.6％(20/78)和2.5％(2/80),差异有统计学意义,P＜0.001.INP组独有的不良反应尿路刺激征发生率为12.8％(10/78).血液学及非血液学毒性INP方案明显高于AP方案,P＜0.05.结论 INP组和AP组三线治疗晚期NSCLC的疗效相似;但后者的中位PFS较长,且不良反应明显减轻.患者经济奈件允许的情况下,三线化疗,尤其是肺腺癌患者,推荐AP方案.