Cationic Lipid-Based Gene Delivery Systems: Pharmaceutical Perspectives

Gene delivery systems are designed to control the location of administered therapeutic genes within a patient's body. Successful in vivo gene transfer may require (i) the condensation of plasmid and its protection from nuclease degradation, (ii) cellular interaction and internalization of condensed plasmid, (iii) escape of plasmid from endosomes (if endocytosis is involved), and (iv) plasmid entry into cell nuclei. Expression plasmids encoding a therapeutic protein can be, for instance, complexed with cationic liposomes or micelles in order to achieve effective in vivo gene transfer. A thorough knowledge of pharmaceutics and drug delivery, bio-engineering, as well as cell and molecular biology is required to design optimal systems for gene therapy. This mini-review provides a critical discussion on cationic lipid-based gene delivery systems and their possible uses as pharmaceuticals.     

复方18甲基炔诺酮透皮控释传递系统的LNG人体药物动力学与药效学评价

复方18甲基炔诺酮/雌二醇透皮控释传递系统(LNG/E_2 TCDS)能同时恒速释放低剂量的LNG和E_2,在1周内维持一个平稳而有效的LNG血药浓度。药动学与药效学研究证明,该系统释放的LNG能达到血清LNG目标水平,产生有效的排卵抑制(6/6)。LNG/E_2 TCDS可望发展成为一种安全、有效、非侵入性的新型生育调节避孕制剂。     

Cholera Toxin B-Mediated Targeting of Lipid Vesicles Containing Ganglioside GM1 to Mucosal Epithelial Cells

Purpose. To determine whether the non-toxic pentameric B subunit of Cholera toxin (CTB) binding to ganglioside GM1 on both the lipid vesicles and epithelial cells may provide a means to target lipid vesicles to mucosal cells expressing surface GM1. Methods. Sonicated lipid vesicles containing ganglioside GM1 were prepared. Inter-vesicle cross-linking due to pentameric CTB binding to these GM1 vesicles was determined with a sub-micron particle analyzer. Association of CTB to GM1 vesicles was analyzed with continuous sucrose gradient centrifugation. CTB-mediated binding of GM1 vesicles to human mucosal epithelial cells (Caco-2 and HT-29), mucous membranes of mouse trachea, and nasal tissues were detected with fluorescent labeled vesicles. Results. An increase in lipid particle size due to binding of CTB to lipid vesicles and inter-vesicles cross-linking was detected. At a 30-to-1 mole ratio of membrane-bound GMl-to-CTB, optimum increase in GM1 vesicle aggregation, was detected. Under such conditions, all the added CTB molecules were associated with GM1 vesicles. Time course analysis showed that inter-vesicles cross linking by CTB was detectable within 10 min. and reached a maximum value at 60 min. CTB associated GM1-vesicles bind to mucosal epithelial cells HT-29 and Caco-2 with similar affinity [K_d = 7.8 × 10^–4 M lipid (Caco-2) and 7.6 × 10^–4 M lipid (HT-29)]. GM1 mediated binding specificity was demonstrated by blocking with anti-GMl antibody and the insignificant degree of CTB-associated GM1 vesicle binding to GM1 deficient C6 cells. Conclusions. The CTB-mediated GM1 binding to multiple membrane surfaces provides selective localization of GM1 vesicles to GM1 expressing mucosal cells and tissues. The strategy may be useful in localizing drugs and proteins to gut and respiratory tract mucosa.     

新生儿窒息124例临床分析

目的探讨预防新生儿窒息的措施，以降低新生儿窒息的发生率。方法收集我院124例新生儿窒息的临床资料，分析发病的相关高危因素。结果窒息的相关因素依次为：早产因素34例居首位，占27．4％；羊水过少占14．5％；胎位异常占10．5％；产程异常占9．7％；脐带因素（缠绕、脱垂及过短）占8．9％；巨大儿占8．9％；胎盘早剥及前置胎盘占6．5％；妊娠高血压综合征占5．6％；宫内生长迟缓（IUGR）占3．2％。结论加大孕产妇分级管理的力度，加强孕期保健和产前检查，适时纠正臀位，尽量减少早产，及早发现和正确处理胎儿宫内窘迫，是降低新生儿重度窒息的有效措施。     

RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature

During the past decade, RGD-peptides have become a popular tool for the targeting of drugs and imaging agents to alphavbeta3-integrin expressing tumour vasculature. RGD-peptides have been introduced by recombinant means into therapeutic proteins and viruses. Chemical means have been applied to couple RGD-peptides and RGD-mimetics to liposomes, polymers, peptides, small molecule drugs and radiotracers. Some of these products show impressive results in preclinical animal models and a RGD targeted radiotracer has already successfully been tested in humans for the visualization of alphavbeta3-integrin, which demonstrates the feasibility of this approach. This review will summarize the structural requirements for RGD-peptides and RGD-mimetics as ligands for alphavbeta3. We will show how they have been introduced in the various types of constructs by chemical and recombinant techniques. The importance of multivalent RGD-constructs for high affinity binding and internalization will be highlighted. Furthermore the in vitro and in vivo efficacy of RGD-targeted therapeutics and diagnostics reported in recent years will be reviewed.     

Proposed diagnostic thresholds for gestational diabetes mellitus according to a 75-g oral glucose tolerance test. Maternal and perinatal outcomes in 3260 Danish women.

AIMS: To study if established diagnostic threshold values for gestational diabetes based on a 75-g, 2-h oral glucose tolerance test can be supported by maternal and perinatal outcomes. METHODS: Historical cohort study of 3260 pregnant women examined for gestational diabetes on the basis of risk indicators. Information on oral glucose tolerance test results and clinical outcomes were collected from medical records. RESULTS: There was an increased risk of delivering a macrosomic infant in women with 2-h capillary blood glucose of 7.8-8.9 mmol/l compared with women with 2-h glucose < 7.8 mmol/l. Despite treatment, 2-h glucose of 9.0-11.0 mmol/l and > or = 11.1 mmol/l were both associated with increased rates of macrosomia, spontaneous preterm delivery, hypertensive complications, and neonatal hypoglycaemia. Adverse outcomes tended to be more frequent in women with 2-h glucose > or = 11.1 mmol/l than in women with 2-h glucose of 9.0-11.0 mmol/l. CONCLUSIONS: The risk for several maternal and perinatal complications increased with the diagnostic threshold for 2-h glucose. Large-scale blinded studies are needed to clarify the question of a clinically meaningful diagnosis of gestational diabetes mellitus. Until these results are available, a 2-h threshold level of 9.0 mmol/l after a 75-g oral glucose tolerance test seems acceptable.     

Prenatal lead exposure in relation to gestational age and birth weight: A review of epidemiologic studies

Although the adverse effect on pregnancy outcomes at high levels of lead exposure in the workplace has been recognized for years, there is uncertainty regarding the impact of exposure at the lower community exposure levels commonly encountered today. This review summarizes the epidemiologic literature and discusses pertinent methodologic issues and possible sources of interstudy variation. The authors conclude that prenatal lead exposure is unlikely to increase the risk of premature membrane rupture but does appear to increase the risk of preterm delivery. Whether prenatal lead exposure decreases gestational age in terms of infants is unclear. Prenatal lead exposure also appears to be associated with reduced birth weight, but results vary in relation to study design and degree of control for confounding. Adjustment for gestational age, a possible confounder of the birth weight-lead exposure association, did not yield clearer results.     

早产胎膜早破65例妊娠结局分析

目的　探讨早产胎膜早破 (pretermprematureruptureofmembranes ,PPROM)的妊娠结局。方法　对 6 5例PPROM进行回顾性分析。结果　 6 5例PPROM中以流产引产史、感染及胎位不正多见。孕 2 8～ 34+ 6w 与孕35～ 36 + 6wPPROM比较 ,前者剖官产率明显低于后者 (P <0 .0 1) ,而新生儿发病率明显高于后者 (P <0 .0 1)。结论　对孕 2 8～ 34+ 6w 的PPROM宜采用期待疗法 ,以减少新生儿的并发症 ,降低新生儿的发病率及死亡率     

无痛麻醉在拔牙术中的临床应用

目的：评价无痛麻醉技术的临床麻醉效果，寻求一种更有利于手术进行的局麻技术。方法：选择120例就诊于齿槽外科门诊需要拔牙的患者，将其随机分为对照组和实验组，每组60例。对照组施常规局麻，实施组施无痛麻醉技术，观察每组麻醉结束、术中及术后的血压、心率变化。结果：对照组与实验组对比，术中、术后观测指标的变化无显著性差异，麻醉结束后的观测指标15以下者无显著性差异，15岁以上者有显著性差异。结论：无痛麻醉技术与常规的局麻技术一样可以达到麻醉的目的，无痛麻醉可减少麻醉注射中因疼痛所引起的血压、心率的变化。