Quantitation of dolastatin-10 using HPLC/electrospray ionization mass spectrometry: application in a phase I clinical trial

A highly sensitive and specific assay for the quantitation of the anticancer agent dolastatin-10 (DOL-10) in human plasma is described. The method was based on the use of electrospray ionization-high-performance liquid chromatography/mass spectrometry (ESP-LC/MS). The analytical procedure involved extraction of plasma samples containing DOL-10 and the internal standard (DOL-15) with n-butyl chloride, which was then evaporated under nitrogen. The residue was dissolved in 50 μl mobile phase and 10 μl was subjected to ESP-LC/MS analysis using a C₁₈ microbore column. A linear gradient using water/acetonitrile was used to keep the retention times of the analytes of interest under 5 min. The method exhibited a linear range from 0.005 to 50 ng/ml with a lower limit of quantitation (LLQ) at 0.005 ng/ml. Absolute recoveries of extracted samples in the 85–90% range were obtained. The method's accuracy (≤5% relative error) and precision (≤10% CV) were well within industry standards. The analytical procedure was applied to extract DOL-10 metabolites from samples obtained following incubation of the drug with an activated S9 rat liver preparation. Two metabolic products were detected and were tentatively identified as a N-demethyl-DOL-10 and hydroxy-DOL-10. Structural assignments were made based on the fragmentation patterns obtained using the electrospray source to produce collision-induced dissociation (CID). The method was also applied to the measurement of DOL-10 in the plasma of patients treated with this drug. Preliminary investigation of the pharmacokinetics suggested that drug distribution and elimination may be best described by a three-compartment model with t_1/2α = 0.087 h, t_1/2β = 0.69 h and t_1/2γ = 8.0 h. Plasma clearance was 3.7 l/h per m². Received: 17 March 1997 / Accepted: 13 June 1997     

开展全程化药学服务,促进抗菌药物合理应用

目的探讨促进抗菌药物合理应用的有效途径。方法分析和评价全程化药学服务在促进抗菌药物合理应用中的作用。结果全程化药学服务是促进抗菌药物合理应用的有效途径。结论医院药学应积极开展全程化药学服务,以促进抗菌药物合理应用,使有限的抗菌药物资源得到最大限度的利用。     

应用相位测量轮廓技术重建面部睁眼三维数字化模型

目的：建立活体睁眼状态下的面部三维数字化模型,为颌面缺损的仿真修复奠定基础。方法：采用3D CaMaga人体三维彩色数字化系统对面部进行活体测量,获得三维点云数据,运用CloudForm反求工程软件对数据进行处理后,转化为相应的数字化文件格式,在Geomagic实体构造软件中重建面部三维数字化模型。结果：成功建立了面部睁眼状态下的三维数字化模型。结论：应用相位测量轮廓术可快速准确安全的重建真实的面部三维形态,该方法在颜面赝复、口腔颌面外科、正畸科、整形外科都将有广阔的应用前景。     

Phase II study of bevacizumab and pemetrexed for recurrent or persistent epithelial ovarian,fallopian tube or primary peritoneal cancer

Objective

We aimed to evaluate the efficacy and safety of combination bevacizumab/pemetrexed for the treatment of recurrent epithelial ovarian cancer (EOC).

Methods

Platinum-sensitive or -resistant patients with recurrent or persistent EOC were eligible if they had received up to 2 prior chemotherapy regimens, including a platinum/taxane regimen without prior bevacizumab. Pemetrexed 500 mg/m² IV and bevacizumab 15 mg/kg IV were administered every 3 weeks. The primary endpoint was 6-month progression-free survival (PFS); other endpoints included toxicities, PFS and overall survival (OS).

Results

Thirty-four patients received a median of 7 treatment cycles (range, 2–26). Median follow-up was 25.7 months (range, 3.0–47.2). Six month progression-free survival (PFS) was 56% (95% CI: 38–71). The following response rates were documented (%; 95% CI): 0 complete response, 14 partial responses (41%; 25–59), 18 stable disease (53%; 35–70) and 2 progressive disease (6%; 1–20). Median PFS was 7.9 months (95% CI, 4.6–10.9), with a median OS of 25.7 months (95% CI, 15.4–29.8). Twenty-two patients (64.7%) had a platinum-free interval (PFI) of > 6 months prior to enrollment. Grade 3–4 hematologic toxicities included neutropenia (50%), leukopenia (26%), thrombocytopenia (12%) and anemia (9%). Non-hematologic grade 3–4 toxicities included metabolic (29%), constitutional (18%), pain (18%) and gastrointestinal (15%). Two patients developed hematologic malignancies within one year of treatment.

Conclusions

Combination bevacizumab/pemetrexed is an active option for both platinum-sensitive and -resistant recurrent EOC. Further investigation of cost and novel toxicities associated with this regimen may be warranted.     

马齿苋总黄酮微乳的制备及经皮渗透研究

目的：以马齿苋总黄酮为模型药物,制备治疗湿疹的经皮给药中药有效组分微乳。方法：通过单因素试验及伪三元相图的绘制筛选微乳组分,并以药物体外经皮渗透速率进一步优化微乳处方。结果：优选处方为肉豆蔻酸异丙酯-Cremophor EL-丙三醇-水（6.5：29.25：29.25：35）,平均粒径为24.54nm;马齿苋总黄酮稳态透皮速率为114.70μg·cm^-2·h^-1,比原湿疹搽剂的透皮速率提高了17倍。结论：马齿苋总黄酮微乳性状均一,澄清透明,质量稳定,透皮性能好。     

Preparation of bovine serum albumin loaded poly (D,L-lactic-co-glycolic acid) microspheres by a modified phase separation technique

BSA-loaded mcirospheres were prepared by a modified phase separation method, in which petroleum ether (PE) containing a certain amount of Span 80 rather than poly (dimethylsiloxane) (PDMS) was adopted as coacervating agent. Process parameters such as Span 80 concentration, the volume and addition rate of coacervating agent, polymer concentration, agitation rate during the phase separation process and PE type were evaluated to optimize the protein encapsulation. It was found microspheres with high yield (>80.0%) and entrapment efficiency (>90%) could be obtained using PE containing 5.0% Span 80 as the coacervating agent. Microspheres with small particle size (<10?µm) could be produced successfully with appropriate process parameters. In vitro release study suggested that burst release was significantly influenced by Span 80 concentration, polymer concentration and PE type and the burst release could be reduced to <20% with optimized formulation. A biphasic release behavior in vitro test was observed for the microspheres prepared by this method. GC analysis demonstrated that residual solvent of DCM and petroleum ether was decreased dramatically in comparison with PDMS used as a conventional coacervating agent.     

用差示扫描量热法及激光拉曼光谱研究足叶乙甙对二棕榈酰磷脂酰胆碱脂质体膜流动性影响

本文用DSC和激光拉曼光谱研究抗癌药物足叶乙甙(4-去甲基表鬼臼毒素-β-D-乙叉吡喃葡萄糖甙,简称VP 16-213)与二棕榈酰磷脂酰胆碱(DPPC)脂质体的作用。VP 16-213分子掺入DPPC脂质体双层中,不但使相转变温度向高温移动,而且吸热峰的半高宽度随VP 16-213浓度增加而变宽。其Raman光谱在频率2850 cm~(-1)处的C-H键对称伸缩振动亦随着药物浓度增加而减弱。这些结果表明VP 16-213分子是定域在脂双层中DPPC分子链的C_1～C_9亚甲基区域,使脂质体的有序性提高而流动性降低。     

相转移催化法合成对氯苯乙腈

本文介绍了用新洁尔灭作相转移催化剂,使对氯苄氯和氰化钠溶液反应制备对氯苯乙腈的操作方法。并讨论了影响反应的因素。     

蒲元胃康胶囊治疗消化性溃疡的临床研究

目的评价蒲元胃康胶囊治疗消化性溃疡(气滞证)的有效性和安全性。方法采用随机、双盲、阳性对照、多中心研究方法,进行蒲元胃康胶囊的Ⅱ期临床试验。受试者288例,分为试验组144例,对照组144例,分别口服蒲元胃康胶囊和溃疡灵胶囊,疗程6周。结果治疗后两组间胃镜疗效比较:试验组胃溃疡胃镜检查总有效率98.59%,对照组90.14%,两组比较有显著性差异(P<0.05);十二指肠溃疡胃镜检查,试验组总有效率94.03%,对照组82.86%,两组比较有显著性差异(P<0.05)。中医证候疗效比较:胃溃疡和十二指肠溃疡,试验组治疗后证候积分均低于对照组(P<0.05);幽门螺杆菌(HP)感染治愈率比较,试验组高于对照组(P<0.05)。治疗6周后,血、尿、便常规、便潜血、肝肾功能和心电图检查未见异常改变,亦未出现明显不良反应。结论蒲元胃康胶囊可用于治疗消化性溃疡(气滞证),临床应用安全有效。     

蛇胆川贝液和蛇胆汁中牛磺胆酸的SPE-HPLC法测定

目的 :建立蛇胆川贝液和蛇胆汁中牛磺胆酸含量的测定方法。方法 :含磷酸二氢钾的样品与甲醇的混合溶液流过Sep PakC18固相萃取微柱。固相萃取微柱吸附溶液中强保留物质以保护分析柱 ,牛磺胆酸被固相萃取微柱饱和吸附后的流出液作反相高效液相色谱法测定用的供试液。色谱条件 :SupelcosilLC 8色谱柱 (15 0mm× 4 .6nm ,5 μm)为分析柱 ,甲醇 0 .4 %磷酸二氢钾溶液 (5 6∶4 4 ,V/V)为流动相 ,检测波长 2 0 3nm ,进样体积为 5 0 μL。 结果 :在 0 .0 2 5 3～0 .2 5 3mg·mL-1浓度范围内 ,牛磺胆酸钠进样浓度与峰面积响应值呈良好的线性关系 ,r =0 .9999;平均回收率为10 1.3% ,RSD为 0 .4 0 % (n =6 )。结论 :本法简便实用 ,分析结果准确可靠 ,可作为中成药蛇胆川贝液和蛇胆汁的质量控制方法