目的 研究新型肺靶向多西他赛脂质体(DTX-LP)在原位肺癌模型兔中的药动学行为.方法 采用超高效液相色谱-二级串联质谱(UPLC-MS/MS)法测定DTX在兔血浆中的含量,并进行方法学考察.采用胸腔微创穿刺术制备原位肺癌模型兔,然后随机分为多西他赛注射液(DTX-IN)组和DTX-LP组,耳缘静脉注射给予相应药物,给药剂量均为1.0 mg/kg(以DTX计),然后于5、15、30、60、90、120、240、480 min时取血,测定血浆中DTX浓度.采用DAS 3.3软件进行拟合与分析,并计算药动学参数.结果 本研究所用UPLC-MS/MS法的准确度、精密度良好,符合生物样品分析要求.与DTX-IN组比较,DTX-LP组的药-时曲线趋势较平缓,各时间点的血药浓度更低,cmax、t1/2、AUC0→480 min、AUC0→∞均显著降低(P＜0.05).结论 DTX-LP在血浆中的暴露量较DTX-IN降低,提示其能快速地从体循环中分布到肺靶器官.

目的:研究添加了亲水性聚合物后对多西他赛/磺丁基醚-β-环糊精二元体系的影响.方法:在多西他赛/磺丁基醚-β-环糊精中不加或分别添加1％的3种亲水聚合物,聚乙烯吡咯烷酮(PVP)、聚乙二醇(PEG)和泊洛沙姆(P188).采用相溶解度法,于25℃、37℃和45℃下,绘制相溶解曲线,考察药物溶解度、稳定性常数(K)、络合效率及相关热力学参数.结果:PVP的加入,最有利于增强多西他赛/磺丁基醚-β-环糊精二元体系的稳定性及药物的溶解度.与固有溶解度相比,多西他赛的溶解度提高了75倍,稳定性常数从1922.84 L/mol提高到2449.44 L/mol.结论:在多西他赛/磺丁基醚-β-环糊精中加入适量亲水聚合物后可形成三元体系,提高络合效率,增加多西他赛的溶解度.

借助Discovery Studio软件,以3D和2D图形的方式直观展示ATP敏感钾离子通道、雌激素受体等生物大分子的空间结构,对接模拟格列本脲等药物与相关靶点间的作用方式,进而对药物的结构特征或构效关系进行"可视化"解释,帮助学生更好地理解掌握药物化学课程中的重难点内容.

本研究为了探讨罗格列酮对人肝癌细胞QGY-7701增殖凋亡的影响,阐明其作用机制,以罗格列酮和人肝癌细胞QGY-7701为材料,通过结晶紫染色及CCK8方法,发现罗格列酮对人肝癌细胞QGY-7701有明显的抑制作用,其IC50为83.24 μmol/L;通过RT-PCR,发现罗格列酮上调PTEN基因;通过Western blotting,发现罗格列酮能使PCNA、Bcl-2和p-Akt蛋白表达下调,使Bad、PPARγ和PTEN的蛋白表达上调,经PPARγ抑制剂处理后,PTEN和p-Akt表达下调.结果 表明,罗格列酮可能通过调节PTEN/PI3K/AKT基因的途径,诱导人肝癌细胞QGY-7701凋亡,并抑制癌细胞的进一步增殖.本研究为临床肝癌研究提供理论基础.

为了认真贯彻"停课不停学"精神,文章从前期准备、在线课程教学活动的开展、通过监管和反馈保证教学质量三个方面论述了利用在线课堂实现医用有机化学"停课不停学"的实践.

文章首先阐述了医用化学教学的现状,然后论述了医用化学线上线下混合式教学模式的构建策略,接着分析了医用化学线上线下混合式教学模式的特色,最后提出了医用化学线上线下混合式教学模式构建需要注意的内容.

间变性淋巴瘤激酶(ALK)抑制剂是目前治疗NSCLC伴ALK阳性的有效药物,然而,耐药性的产生严重限制了其临床应用.本文对ALK抑制剂耐药产生的主要机制如二次基因突变、基因扩增、旁路通路激活等进行了简要介绍,并对联合用药、开发新型PROTAC降解剂等逆转耐药策略进行了综述,以期为ALK抑制剂药物的未来发展提供参考.

肺癌是威胁人类生命健康的重大疾病之一,近年来临床上抗肺癌药物的研究发展迅速,但目前抗肺癌药物靶向性较弱,在攻击肺瘤细胞的同时也杀死了正常的组织细胞,毒副作用大是研究抗肺癌药物的难点.肺靶向抗癌药物的研究与开发成为攻克这一难题的重要途径.目前各国对于肺靶向抗癌药物的研究主要集中在靶向药物的载体方面,脂质体作为靶向给药载体,是广大医药研发人员的研究热点.本文综述了近年来肺靶向抗癌药物的研究现状及发展的趋势,并在此基础上对肺靶向抗癌药物脂质体在研发中存在的问题提出自己的一点见解.

To choose a method for the determination of encapsulation efficiency of lung-targeted docetaxel liposomes(DTX-LP), DTX-LP was prepared by solid dispersion method combining with effervescent technology, and its size distribution and Zeta charge were determined by Malvern Zeta-sizer. HPLC method was established to measure the content of DTX. The solubility of DTX in different solutions was tested. High speed centrifugation method and protamine-induced aggregation method were used to determine the encapsulation efficiency of DTX-LP. The research showed that the average size of obtained DTX-LP was (0.72±0.23) μm while Zeta potential was -27.5 mV with negatively charged surface. A good linear relationship was found between the peak area and the concentration of DTX ranging from 0.5 μg/mL to 100 μg/mL (r=0.999 9). Intra-day and inter-day precision RSD were both less than 2.00％. The stability RSD stored in ambient temperature within 8 h was no more than 2.00％. The recovery rate of DTX was in a range of 99.96％～108.05％. Using normal saline, 0.2％ tween 80-normal saline,0.5％ tween 80-normal saline as solvents, the encapsulation efficienc y of DTX-LP determined by high speed centrifugation method were (91.15±1.07)％, (85.28±3.75)％ and (79.76±2.71)％ (n=3), respectively; while those determined by protamine-induced aggregation method were (95.46±0.29)％, (93.61±2.75)％ and (87.83±1.23)％ (n=3), respectively. A small amount of non-encapsulated drugs could be completely dissolved by normal saline. Through analyzing and comparing, protamine-induced aggregation method might be more applicable to determine the encapsulation efficiency of negatively charged DTX-LP with normal saline as the solvent. It could avoid the influence of surfactant and high centrifugation to the membrane structure of DTX-LP. The proposed method could be simple, rapid, feasible and with high accuracy.

The important pharmaceutical intermediate, ethyl-(5-amino-1,3,4-thiadiazol-2-yl) propio-nate with yield of 70%,was synthesized by one-pot method,using succinic anhydride and thiosemicar-bazide as starting materials. The structure was confirmed by 1H NMR,IR and MS. The reaction condi-tions were optimized by orthogonal test. The results showed that the optimal reaction conditions were as follows n(thiosemicarbazide) :n(succinic anhydride) :n(concentrated sulfuric acid) =1:2:3,reac-tion at 80 ℃ for 6 h.

色瑞替尼（ceritinib,1）,又名LDK378,化学名5-氯-N4-[（2-异丙基磺酰基）苯基]-N2-[2-异丙氧基-5-甲基-4-（哌啶-4-基）苯基]-2,4-嘧啶二胺,商品名Zykadia,是由瑞士诺华公司（Novartis）研制的新型间变性淋巴瘤激酶（anaplastic lymphoma kinase,ALK）靶向抑制剂,于2014年4月经美国FDA批准上市,用于对克唑替尼治疗后已进展或不能耐受的ALK阳性转移性非小细胞肺癌（NSCLC）

Synthesis of Ethyl 2-[5-(3-Hydroxybenzamido)-1,3,4-thiadiazol-2-yl]acetateZHU Fei, LI Xin, CHEN Yu-hang, CHEN Huan, WANG Wu, WAN Chun-mei, GAN Zong-jie, YU Yu*College of Pharmaceutical Sciences, Chongqing Medical University, Chongqing 400016, ChinaEthyl 2-[5-(3-hydroxybenzamido)-1,3,4-thiadiazol-2-yl]acetate(1), with total yield of 37.2%, was synthesized by the reactions of saponification, acidification, chlorination, cyclization and amidation from diethyl malonate.The structure was confirmed by 1H NMR, 13C NMR, IR and LC-MS(ESI).The amidation conditions were optimized by orthogonal experiment[L9(34)].The results showed that under the optimum conditions{n[ethyl-(5-amino-1,3,4-thiadiazol-2-yl)acetate] ∶n(NEt3) ∶n(3-hydroxybenzoyl chloride)=1 ∶2 ∶3, reaction at 20 ℃ for 8 h}, the yield of 1 was 75.5%.

In order to cultivate clinical pharmacy undergraduates to have better quality, Chongqing Medical University collaborated with The University of Chicago and University of Cincinnati in the reform of the course of pharmacotherapeutics. We build pharmacotherapeutics series curriculum with the center of disease, construct department of clinical pharmacy for transnational departments, build course leader and teaching team of pharmacotherapeutics series curriculum , compile teaching program and its material of pharmacotherapeutics series curriculum, build pharmacotherapeutics series curriculum and teaching model in line with the current direction of China's education system of clinical pharmacy training, reform teaching methods, and strengthen clinical pharmacy practice and community clinical pharmacy education.

Objective To evaluate the long-term efficacy and safety of docetaxel liposome(DTX-LP) in a rabbit model of lung cancer.Methods Thirty rabbit models of lung cancer established by orthotopic transplantation of VX2 tumor tissues were randomized in 5 equal groups to receive intravenous injections of blank liposome (BLA-LP),docetaxel (DTX-IN,2.7 mg/kg),or DTX-LP at high (0.9 mg/kg),moderate (0.3 mg/kg) or low (0.1 mg/kg) doses once a week for 4 consecutive weeks,and the survival time of the rabbits was recorded.The survival of the rabbits in each group was estimated using Kaplan-Meier analysis and analyzed with Log-rank test.The changes in body weight and leukocyte count of the rabbits were observed,and the incidence of anorexia,diarrhea and intestinal bleeding were evaluated.After the rabbits died,the heart,liver,spleen,lungs and kidneys were dissected for histopathological examinations.Restlts The median survival time of the rabbits was 28 d in BLA-LP group,35 d in DTX-IN group,49 d in high-dose DTX-LP group,34 d in moderate-dose DTX-LP group and 32 d in low-dose DTX-LP group.The survival rate of the rabbits was significantly higher in high-dose DTX-LP group than in BLA-LP group (P =0.001) and DTX-IN group (P =0.005).The percent change in the body weight in the 5 groups was (-23.03 ± 7.99) ％,(-11.25 ±9.67)％,(-1.48 ±6.36)％,(-2.08 ±14.39)％ and (-17.27 ±18.41)％,respectively,and that of leukocyte count was (-3.53 ±18.17)％,(-52.78 ±12.50)％,(-16.56±10.21)％,(-22.19 ± 10.70) ％ and (-15.37 ± 14.14％),respectively.The incidence of anorexia was 83.3％ in DTX-IN group and 50.0％ in high-dose DTX-LP group.The incidence of diarrhea was 16.7％,66.7％,33.3％,16.7％ and 16.7％ in the 5 groups,respectively,and intestinal bleeding occurred in DTX-IN group was 83.3％.Histological examination revealed obvious pathological changes in the heart,liver,spleen,lungs and kidneys in DTX-IN group but not in high-dose DTX-LP group.Conclusion Treatment with high-dose DTX-LP significantly prolongs the survival of tumor-bearing rabbits with only mild adverse effects.

Succinic acid monoethyl ester chloride (3) was prepared by alcoholysis , acetylation reaction from succinic anhydride.The important intermediate, (5-amino-[1,3,4] thiadiazol-2-yl)-propionic acid ethyl ester , was synthesized by cyclization of 3 with thiosemicarbazide catalyzed by methane sulfo-nic acid.The structure was confirmed by 1 H NMR, IR and MS.The reaction conditions for cyclizating reaction was investigated by the orthogonal design .The results showed that the optimal reaction condi-tions were as followed:3 132 mmol, n(thiosemicarbazide) ∶n(3) ∶n(methane sulfonic acid)=1∶3∶3, reaction at 110 ℃for 3 h, the total yield was 51.3%.

BACKGROUND:After spinal cord injury, endogenous neural stem cel s are activated to proliferate and migrate to repair damaged tissue. As a clinical medicine, methylprednisolone shows a lot of functions, but its effects on endogenous neural stem cel s are stil unknown. <br> OBJECTIVE:To explore the effects of methylprednisolone on the proliferation and migration of endogenous neural stem cel s after spinal cord injury. <br> METHODS:Seventy-five Sprague-Dawley rats were used to make animal models of T10 complete paraplegia using Al en’s method, and randomized into methylprednisolone, normal saline and model groups. Rats in these three groups were given intraperitoneal injection of 1 g/L methylprednisolone solution at a dose of 30 mg/kg for 10 minutes and at a dose of 5.4 mg/kg/h for 23 hours, given intraperitoneal injection of normal saline at the same dose and given no treatment, respectively. Neurological and motor functions were assessed by somatosensory evoked potential and Basso Beattie Bresnahan scores at 7, 14, 21, 28 days after spinal cord injury. BrdU and Nestin staining of the injured spinal cord segment was conducted. <br> RESULTS AND CONCLUSION:A large amount of BrdU-and Nestin-positive cel s were visible in al the groups, and the number of these cel s reached the peach at 14 days after spinal cord injury. Methylprednisolone was found to inhibit BrdU-, Nestin-or double-positive cel s, indicating methylprednisolone can inhibit the proliferation and migration of endogenous neural stem cel s. The results of Basso Beattie Bresnahan scores showed no notable improvement in the motor function of the limbs. Methylprednisolone also showed no significant effects on the motor evoked potential latency, but promoted nerve conduction recovery. Al these findings indicate that methylprednisolone has some hindering effects on spinal cord repair by inhibiting the proliferation and migration of endogenous neural stem cel s after spinal cord injury.

BACKGROUND:A large number of biomechanical studies and clinical application research showed that unilateral pedicle screw fixation with a single cage can not only make the spine to obtain immediate stability, and also reduces the fixed segment stiffness. However, there is not related research on the change of adjacent segment disc nucleus pulposus volume with unilateral pedicle screw. OBJECTIVE:To evaluate the effects of unilateral pedicle screw fixation with a single cage on adjacent segment degeneration for treating lumbar degenerative disease with MRI measurement of lumbar nucleus pulposus volume. METHODS:A total of 34 patients with lumbar disc herniation were treated by posterior lumbar interbody fusion with unilateral pedicle screw fixation with a single cage insertion. There were L4-5 segment in 16 patients (9 males and 7 females) and L5-S1segment in 18 patients (10 males and 8 females). The fixator was taken out at 18 months after surgery. They were folowed up for 24 to 36 months. With MRI, the transverse diameter and sagittal diameter of the nucleus pulposus were measured by using T2-weighted images at 6, 12, 18, 30 months after treatment, while the nucleus pulposus height was measured by middle sagittal position. Cephalic intervertebral height was measured with angular bisector method on X-ray films. Effects of unilateral pedicle screw fixation on cephalic intervertebral disc degeneration were evaluated according to nucleus pulposus volume and the intervertebral space height. RESULTS AND CONCLUSION:(1) Nucleus pulposus volume at cephalic L3-4 on the fixed L4-5segment was reduced in male patients after 30 months of treatment compared with pre-treatment (P=0.139), but increased in female patients (P=0.143). (2) Nucleus pulposus volume at L4-5 near to fixed L5-S1 segment was slightly reduced in male patients after 30 months of treatment (P=0.096); nucleus pulposus volume was slightly increased in female patients after 6, 12, 18 and 30 months of treatment (P > 0.05). (3) Disc space height at cephalic L3-4 near to L4-5 segment was diminished in male and female patients at 30 months of treatment (P > 0.05). (4) Disc space height at cephalic L4-5 near to L5-S1 segment was slightly reduced in male and female patients compared with pre-treatment (P > 0.05). (5) Unilateral pedicle screw with a single cage could effectively prevent adjacent segment degeneration in treatment of partial lumbar intervertebral degenerative disease.

目的 考察多西他赛脂质体(DTX-LP)在兔体内的生物分布及其在各主要脏器的靶向参数.方法 通过固体分散与泡腾组合技术,使用放射性同位素锝(99mTC)对DTX-LP进行标记(DTX-LP-99mTC).考察DTX-LP-99m TC的外观、粒径、Zeta电荷、包封率、载药量以及放射化学纯度及稳定性.将DTX-Lp-99mTC或游离锝(99mTC-Free)经耳缘静脉注射入兔体内,经SPECT/CT静态采集数据及计算机融合显像获得DTX-LP-99mTC及99mTC-Free在兔体内的放射性影像.另将注射DTX-Lp-99mTC或99mTC-Free的兔分别于给药后1、2、4、8、12 h处死,使用甲状腺功能测定仪采集兔各离体器官的放射性计数,并计算各脏器的相对摄取率(Re)和靶向效率(Te).结果 DTX-LP-99mTC平均粒径为726 nm,Zeta电荷为-35.6 mV,包封率及载药量分别为(90.27±1.15)％和(1.30±0.20)％.在室温放置或兔血清中37 ℃温育1、4、12 h后,DTX-LP-99m TC的放射化学纯度分别为98.45％、96.32％、94.28％及96.78％、93.45％、91.56％.放射性影像显示DTX-LP-99mTC在兔肺浓聚;每克兔组织的放射性计数由高到低排列,在DTX-LP-99mTC组为肺、脾、肝、肾、心、脑,在99mTC-Free组为肝、脾、肾、心、肺、脑,同一时间点相同脏器的放射性计数在两组之间差异有统计学意义(P＜0.01).Re值表明,DTX-LP-99mTC组在肺、脾和脑的放射性计数分别是99mTC-Free组的64.41、1.62倍和1.57倍,而心、肝、肾的放射性计数较99m TC-Free组明显减少.Te值表明,DTX-Lp-99mTC在兔肺的放射性计数是脑的64.01倍,心的40.73倍,肾的14.01倍,肝的3.22倍.结论 DTX-LP主要浓集在兔肺,具有高度的肺靶向性.

In order to cultivate clinical pharmacy talents with better quality,Chongqing Medical University collaborated with The University of Chicago and University of Cincinnati,to make clinically oriented integration courses,build the new curriculum and teaching model in line with the current direction of China' s education system and the United States as the representative of clinical pharmacy training,strengthen pharmacotherapeutics,reform teaching methods,strengthen clinical pharmacy practice and community clinical pharmacy education,and implement cases discussion and interactive learning,and carry out formative evaluation,which will contribute to the training of clinical pharmacy students' comprehensive ability.

Objective To investigate the recurrent cause of thoracic and lumbar spinal tuberculosis treated by one-staged anterior debridement, bone fusion and spinal reconstruction, and strategies of revision. Methods 136 pa-tients with thoracic and lumbar spinal tuberculosis were undergone one-staged anterior debridement, bone fusion and spinal reconstruction. It was analyzed that the cause of the 15 patients among them with recurrent spinal tuberculosis and sinus tract and conservative treatment were not cured. 15 patients had undergone one-stage anterior sinus clearing and debridement, instrument removal, bone graft and internal fixation by posterior approach. Results All cases were followed up for 12~48 months. 14 patients got cured, the imaging examination showed bone graft fusion. 1 pa-tient got recurrence with the rate of 6. 67%(1/15),cured by anti-tuberculosis treatment for 4 months. Conclusions The recurrent cause of thoracic and lumbar spinal tuberculosis treated by one-staged anterior operation include un-completed debridement, drug-resistant strains of tuberculosis, redundant inactive foreign body, loosening of instru-mentation, chronic malnutrition and irregular chemotherapy. It can reduce the recurrence rate of spinal tuberculosis by revision include anterior radical debridement and satisfactory bone graft, posterior stable internal fixation, which must combine with effective chemotherapy.