药物中间体3-噻吩丙二酸的合成研究

利用铜锂试剂在酯基存在下选择性发生亲核取代反应的特征,将溴代丙二酸二乙酯引入噻吩环的3-位,设计了合成3-噻吩丙二酸(TM A)的新路线。     

雷替曲塞反注射用无菌粉末

（Raltitrexed）化学药品二类 一、新药名称及结构 通用名：雷替曲塞 化学名：N-[5-[N-[（3，4-二氢-2-甲基-4-氧-6-喹唑啉基）-甲基]-N-甲氨基]-2-噻吩基]-L-谷氨酸英文名（INN）：Raltitrexed     

二氢哒嗪酮类化合物的合成及其抗血小板聚集活性研究

目的：合成新的哒嗪酮类化合物，并研究其抗血小板聚集活性。方法：在6-（4-氯乙酰氨基苯基）-4，5-二氢-3（2H）-哒嗪酮侧链引入不同取代的哌嗪，合成了一系列化合物，采用^1H-NMR、IR及元素分析等方法确证其结构。采用Born比浊法进行体外抗血小板聚集药理实验。结杲：合成的10个化合物都具有一定的抗血小板凝集的活性，其中化合物4的抗血小板聚集活性明显优于先导化合物MCI-154。结论：4-位取代哌嗪环基的引入对哒嗪酮类化合物抗血小板聚集的活性有显著影响。     

噻洛芬酸的合成

噻吩经丙酰化得到2-丙酰噻吩，在碘和氧化亚铜催化下进行噻吩基1，2-迁移后水解制得关键中间体2-（2-噻吩基）丙酸，再与苯甲酰氯经Friedel-Crafts反应制得非甾体消炎镇痛药噻洛芬酸，总收率44．6％。     

4-取代-5-苯基-3-吡唑烷酮类化合物的合成及抗惊构效关系的研究

本文研究了4-取代-5-苯基-3-吡唑烷酮类化合物的结构与抗惊活性关系。共合成了6个3-吡唑烷酮类衍生物。其中,3-吡唑烷酮类化合物的4位引入取代基后,均使抗惊活性降低。这可能是因为3-吡唑烷酮类化合物结构中,羰基是生物活性中心,羰基的4位引入取代基会阻碍与受体的结合,使活性降低。     

青霉烯类抗生素Men-10700的合成

目的：合成新型青霉烯类抗生素Men-10700。方法：以4-乙酰氧基氮杂环丁-2-酮为起始原料，经取代、关环、生成目标侧链、脱保护基等8步合成目标化合物。结果与讨论：经。H—NMR，MS证明得到了Men-10700；其中改用对硝基苄基保护羧基，简化了后处理过程，对引入侧链和脱硅氧保护基2个步骤作了改进。     

抗抑郁药盐酸度洛西汀的合成工艺改进

目的：改进盐酸度洛西汀合成工艺。方法：以乙酰噻吩、盐酸二甲胺和多聚甲醛为起始原料，经Mannich反应、还原、拆分、成醚、去甲基、重结晶等6步，改进文献报道的工艺过程，更换部分反应试剂，合成盐酸度洛西汀。结果：所得目标化合物的结构经元素分析、质谱、核磁共振氢谱以及红外光谱确证，总收率由文献报道的7％提高到19．4％。结论：该工艺可降低成本，操作简化，收率高，适合工业化生产。     

舒芬太尼注射液

[通用名称]sufentanil，舒芬太尼[商品名]舒芬尼[化学名称]N-{4-甲氧甲基-1-[2-（2-噻吩基）乙基]4-哌啶基}-N-苯基丙酰胺     

新青霉素羧噻吩甲氧青霉素体外活性的比较

欲作为非胃肠道使用的羧噻吩甲氧青霉素(Temocillin,BRL17421)是一种在其分子结构中的6α位上引入了一个甲氧基的半合成β-内酰胺类抗生素。具体结构为6β(2-羧基-2-噻嗯基-3-乙酰胺基)-6α-甲氧基青霉素酸双钠盐。据已有的报道表明,它对许多革蓝氏阴性菌有抗菌活性,而且对这些菌株产生的β-内酰胺酶具有良好的稳定性。因此作者将羧噻吩甲氧青霉素与其他β-内酰胺类抗生素对新近由临床分离的201株菌进行了体外抗菌活性的比较。作为一起被比较的药物除了氨苄青霉素、羧噻吩青霉素(Ticarcillin)、噻吩甲氧头孢菌素(Cefoxitin)外,     

5,7-异丙亚基-哥纳三醇与叠氮化钠的反应

目的：改造哥纳三醇的8位的取代基。方法：将5，7-异丙亚基-哥纳三醇与甲磺酰氯反应，其产物再与叠氮化钠发生反应。结果：得到5，7-异丙亚基哥纳三醇4-位，及4位、8-位同时取代的2个化合物。结论：叠氮化钠能与5，7-异丙亚基-哥纳三醇的双健发生亲核取代反应。     

氟罗沙星和阿奇霉素治疗非淋菌性尿道(宫颈)炎的临床对照研究

目的 比较注射用氟罗沙星和注射用阿奇霉素治疗非淋茵性尿道(宫颈)炎的疗效与安全性。方法 74例非淋菌性尿道(宫颈)炎患者分成2组：A组38例。每天静脉滴注氟罗沙星0．4g，连用7d；B组36例，第1d静脉滴注阿奇霉素0．5g．以后每天静脉滴注阿奇霉素0．25g．连用6d，观察疗效与安全性。结果 A组临床总有效率、细菌清除率、不良反应率依次为92．1％、92．1％、7．9％，B组依次为94．4％、94．4％、5．6％，无统计学差异。结论 氟罗沙星与阿奇霉素都是安全、有效的治疗非淋菌性尿道(宫颈)炎的抗菌药物。     

头孢地嗪钠体内、外抗菌活性研究

目的:评价国产及进口头孢地嗪钠(CDZ)体内、外抗菌活性。方法:采用琼脂平皿稀释法及试管稀释法测定国产CDZ及其进口制剂、头孢氨噻肟钠对300株临床分离致病菌的最低抑菌浓度( MIC) ;采用小鼠腹腔感染模型,观察CDZ对大肠杆菌、克雷伯氏肺炎杆菌及金黄色葡萄球菌感染小鼠的体内抗菌作用,按Bliss法计算半数有效剂量(ED50)值。结果:国产和进口CDZ对大部分革兰阴性菌,革兰阳性菌中的肺炎球菌、乙型链球菌等具有显著的抗菌活性,MIC90大多为0.012～1.0μg·mL-1。对阴沟杆菌、产气杆菌和沙雷氏菌具有中度抗菌活性,对甲氧西林敏感金黄色葡萄球菌、表皮葡萄球菌抗菌活性较差,MIC50为4μg·mL-1。对本实验所试绿脓杆菌、不动杆菌、肠球菌、甲氧西林耐药金黄色葡萄球菌耐药。对敏感大肠杆菌、克雷伯氏肺炎杆菌及金黄色葡萄球菌感染模型小鼠均具有较好保护作用,两者疗效相近。结论:国产与进口CDZ具有较强和相同的抗菌活性。     

利妥昔单抗及其生物类似药的杂质分析

目的  对利妥昔单抗原研药和类似药的产品相关杂质和工艺相关杂质进行分析。方法 用分子排阻高效液相色谱法（size-exclusion high-performance liquid chromatography,SE-HPLC）、毛细管电泳和离子交换高效液相色谱法（ion-exchange high-performance liquid chromatography,IEX-HPLC）对原研药和类似药的产品相关杂质进行分析。同时对类似药的电荷异质体进行纯度和生物活性鉴定。采用ELISA和定量PCR对原研药和类似药的工艺相关杂质进行分析。结果 SE-HPLC分析表明,原研药和类似药中抗体单体分别占98.9%和99.9%,聚合体分别占1.0%和0.1%。毛细管电泳显示,原研药中相对分子质量低的杂质占5.6%,类似药中占3.3%;原研药和类似药中非糖基化重链均占0.6%。IEX-HPLC分析表明,原研药酸性峰和碱性峰含量分别为21.0%和10.0%,类似药分别为17.7%和9.1%。类似药主峰组分的纯度和补体依赖的细胞毒性均高于酸性峰组分和碱性峰组分。原研药和类似药中的宿主细胞蛋白、宿主细胞DNA及蛋白A的残留量相似,且大多低于检测限。结论 利妥昔单抗原研药和类似药产品相关杂质和工艺相关杂质的类别和水平相似。     

从落实《药品管理法》角度探讨假劣药认定检验的管理

目的：为药品检验机构等相关单位落实《药品管理法》,规范高效开展假劣药认定检验提供参考。方法：通过对比研究、文献研究和政策分析,从假劣药定义、认定依据等方面的变化,分析新修订 《药品管理法》对假劣药认定检验的影响,以及假劣药认定检验实际工作中面临的问题和挑战,提出落实《药品管理法》做好假劣药认定检验的建议。结果：新修订《药品管理法》对假劣药的重新定义缩减了形式而增加了实际内容,对假劣药认定依据仅原则性规定应当载明检验结论,相关行政责任条款实施中要求判断是否属于假劣药,这都为假劣药认定检验带来了挑战。并且,假劣药认定检验实践中存在机构之间衔接协作制度机制不健全、药品检验机构相关功能定位未明确、受技术能力不足和样品不合规等条件限制、检验结论出具及收费和经费保障要求需进一步明确等问题。结论：建议明确药品检验机构关于假劣药认定检验的定位分工,完善药品检验机构之间的协作及与司法机关的衔接机制,明确假劣药认定检验受理、结论出具和使用、收费及经费保障相关要求。     

替硝唑螺内酯乳膏的制备及质量控制

目的制备替硝唑螺内酯乳膏并建立其质量控制方法。方法以平平加O、十六醇、十八醇为混合乳化剂,替硝唑、螺内酯为主药制备乳膏;采用高效液相色谱法分别测定其主药替硝唑、螺内酯的含量,并考察制剂稳定性及刺激性。结果制备的乳膏质地均匀、细腻、黏稠度适宜;替硝唑、螺内酯检测质量浓度的线性范围分别为30．69～245．52μg／mL（r=0．9994,n=6）和2．55—20．40μg／mL（r=0．9996,n=6）;平均回收率分别为99．96％（RSD=1．19％,n=9）和99．47％（RSD=1．27％,n=9）;离心试验和耐热、耐寒试验及留样观察中各项指标无明显变化,对皮肤刺激性小。结论替硝唑螺内酯乳膏制备工艺简便可行,质量稳定可控。     

Acute and sublethal effects of two insecticides on earthworms (Lumbricus terrestris L.) under laboratory conditions

Earthworms (Lumbricus terrestris L.) were exposed to commercial formulations of endosulfan and aldicarb for 2, 7, and 15 days, and the LC(10), LC(25), and LC(50) were determined. Worms were then exposed to LC(10), LC(25), and LC(50) concentrations of endosulfan and LC(10) and LC(25) concentrations of aldicarb. The growth rate and total protein content were determined and related to endosulfan and aldicarb residues in soil and earthworms. Aldicarb was more toxic than endosulfan under the experimental conditions. The residues of endosulfan and aldicarb caused a significant reduction in the growth rate and total protein content of earthworms. The residues of endosulfan and aldicarb were monitored in soil and earthworms after 2, 7, and 15 days of exposure. The residues remaining in the soil after the experiments ranged between 37.75% and 68.54% of the applied concentration for endosulfan and between 10.13% and 67.71% of the applied concentration for aldicarb. Small amounts of both insecticides were detected in worms, and accumulation was more important for endosulfan. This study proposes the use of growth rate and total protein content as biomarkers for contamination by endosulfan and aldicarb.     

Biphenyl hydroxylations and spectrally apparent interactions with liver microsomes from hamsters pre-treated with phenobarbitone and 3-methylcholanthrene.

1. Metabolism of [14-C]biphenyl by hamster liver microsomes has been studied by t.l.c., quantitative fluorimetry and difference absorption spectrophotometry. 2. 4-Hydroxybiphenyl (major metabolite) and 2-hydroxybiphenyl (minor) accounted for at least 83% of total biphenyl metabolism. Small quantities of 2,2'- and 4,4'-dihydroxybiphenyl metabolites were also tentatively identified. 3. Biphenyl 2- and 4-hydroxylations exhibited different NADPH-NADH specificities and pH profiles. 4. Phenobarbitone preferentially induced formation of 4-hydroxybiphenyl, while 3-methylcholanthrene induced 2- and 4-hydroxylation almost equally by affecting both production and further metabolism of 2- and 4-hydroxybiphenyl. 5. Biphenyl, 2- and 4-hydroxy- and 2,2'-dihydroxybiphenyl gave both high- and low-affinity type I spectrally apparent microsomal interactions, whereas 4,4'-dihydroxybiphenyl promoted a reverse type I spectral change. There was an inverse correlation between the spectral dissociation constants (Ks) and lipid solubilities for the low-affinity type I interactions and a possible direct correlation for the high-affinity type I interactions. 6. Phenobarbitone and 3-methylcholanthrene induced cytochrome P-450 and cytochrome P-448 respectively and produced complex changes in the biphenyl type I interaction kinetics. No direct relationship was found in 'control' or 'induced' microsomes between biphenyl 2- or 4-hydroxylation, the type I interaction and cytochrome P-450 concentration. The results are discussed in terms of a 3-methylcholanthrene-inducible biphenyl 2- and 4-hydroxylase and a phenobarbitone-inducible biphenyl 4-hydroxylase.     

小叶榕叶总黄酮的抗炎镇痛作用研究

目的:研究小叶榕叶中总黄酮的抗炎镇痛作用。方法:通过二甲苯诱导小鼠耳肿胀模型、角叉菜胶诱导的大鼠足跖肿胀模型、小鼠扭体实验、小鼠热板实验的观察和对小鼠毛细血管通透性的测定研究小叶榕叶总黄酮的抗炎镇痛作用。在小鼠实验中小叶榕叶总黄酮所用高、低剂量均为0.8、0.4g.kg-1;在大鼠实验中所用剂量为1.2、0.6g.kg-1,均为灌胃给药,每天1次,连续7d。结果:0.8、0.4g.kg-1小叶榕叶总黄酮可显著增加二甲苯诱导的小鼠耳肿胀度抑制率,减少醋酸注射小鼠扭体次数,延长热板刺激小鼠痛域值,减少小鼠毛细血管通透性;1.2、0.6g.kg-1小叶榕叶总黄酮可减少角叉菜胶诱导的大鼠足跖肿胀度。结论:小叶榕叶总黄酮具有抗炎镇痛作用。     

The pharmacology of orally administered ciprofloxacin

Ciprofloxacin pharmacokinetics were studied in 6 volunteers after 250 and 500 mg single oral doses. Mean peak serum levels were 1.45 micrograms/ml and 2.5 micrograms/ml for 250 and 500 mg doses. The 12-h levels were 0.12 micrograms and 0.22 micrograms. T1/2 alpha values were 0.32 and 0.43 h; T1/2 beta was 4 h and Vd (area) values were 80L and 90L for the two doses respectively. AUC was 5.65 h. micrograms/ml and 10.37 h. micrograms/ml. Serum clearance was 23L for both doses. Approximately 49% of the 250 mg dose and 43% of the 500 mg dose was recovered in the urine. Ciprofloxacin's in vitro activity and human pharmacology should permit a twice or once-daily dosing schedule for systemic infections due to most Enterobacteriaceae, Haemophilus, Branhamella and Pseudomonas and S. aureus, and once-daily doses for urinary and gastrointestinal infections.     

The influence of co-morbid IBS and psychological distress on outcomes and quality of life following PPI therapy in patients with gastro-oesophageal reflux disease

Background  A subset of patients with gastro-oesophageal reflux disease (GERD) does not achieve complete symptom resolution with proton pump inhibitor (PPI) therapy. The factors which affect response to PPI therapy in GERD patients remain unclear.
Aims  To determine the prevalence and impact of irritable bowel syndrome (IBS) and psychological distress (PD) on GERD symptoms and disease-specific quality of life (QoL) before and after PPI therapy and to assess the same outcomes before and after PPI therapy in non-erosive reflux disease (NERD) and erosive oesophagitis (EO) GERD patients.
Methods  Patients undergoing oesophago-gastroduodenoscopy (OGD) for heartburn were recruited. Participants completed validated surveys: Digestive Health Symptom Index, Reflux Disease Questionnaire, Quality of Life in Reflux and Dyspepsia and Brief Symptom Inventory (BSI). IBS was defined as >3 Manning criteria and PD as BSI score >63. At OGD, patients were classified as NERD or EO. Patients were treated with rabeprazole 20 mg/day for 8 weeks before completing follow-up surveys.
Results  Of 132 GERD patients enrolled, 101 completed the study. The prevalence rates of IBS and PD were 36% and 41%, respectively. IBS independently predicted worse QoL before and after PPI therapy. PD independently predicted worse GERD symptoms and QoL before and after PPI therapy. There were no differences in symptoms or QoL between NERD and EO patients before or after PPI therapy.
Conclusions  IBS and PD impacted GERD symptoms and QoL before and after PPI therapy. Symptoms and QoL before and after PPI therapy were similar in NERD and EO patients.