多功能纳米载体

目前所用药物纳米载体（如脂质体，胶束，纳米乳，聚合物纳米粒）有很多有益特性，如血液循环时间延长，使药物在痛灶聚集；靶向作用；增强细胞内渗透作用；体内载体造影；生理环境敏感的药物释放。但多功能纳米载体仍很少，如长循环免疫脂质体。多功能药物纳米载体可显著增强许多治疗和诊断试剂的效果。本文论述了多功能纳米载体的当前状况和发展方向，主要关注结合长循环性、靶向性、胞内渗透性和造影能力的多功能纳米载体。     

乳剂的缓释和控释作用研究进展

乳剂药物转运系统的某些独特性质，使其具有淋巴输送和靶向定位及缓释作用。影响乳剂稳定性和药物缓释作用遥因素较多，主要有药物性质，油相性质、相体积比、乳化剂、ＰＨ值、粘度、添加剂、制备工艺等。本文主要叙述了乳剂的缓释和控释作用，释药机制及其影响因素。     

生物芯片技术在药物研究与开发中的应用

近年来，以DNA芯片为代表的生物芯片技术，得到了迅猛发展，已有多种不同功用的生物芯片问世。目前生物芯片技术已应用于分子生物学、疾病的预防、诊断和治疗、新药开发、司法鉴定和食品卫生监督等诸多领域，已成为各国学术界和工业界所瞩目并研究的一个热点。生物芯片技术的飞速发展，引起了制药业的极大兴趣，使得生物芯片技术在药物研究与开发领域得到越来越广泛的应用，已逐渐渗入到药物研发过程中的各个步骤。目前，生物芯片技术已经应用于药物靶点发现与药物作用机制研究、超高通量药物筛选、毒理学研究、药物基础组学研究以及药物分析等药物研发环节。可以预见，随着生物芯片技术的不断发展，生物芯片技术将在药物研究与开发领域，尤其是在中药现代化研究中得到更广泛更深入的应用。     

全国主要医药期刊有关药物流行病学题录选载(上)

选载说明：①收录范围：主要收录药物流行病学有关理论、方法、药物不良反应、药物利用、药物经济学等方面的重点论文；②选栽途径：通过中华医学系列刊物和国内主要药学期刊选录；③刊登时间：选录前一年的重点文题，以半年为一阶段，分别在本年第1、2期上刊载，供读者参考，并望提出意见。     

抗栓药物研究进展

抗栓药物可进一步分抗凝、抗血小板和溶栓这三类药物，它们广泛用于预防和治疗各种缺血性事件，具体适应证则包括急性冠脉综合征、心肌梗塞、中风、静脉血栓栓塞和外周动脉闭塞症等。     

神经系统用药市场前景看好

中枢神经系统药物的市场有多方面，包括：抗抑郁症药物、抗老年性痴呆（AD）药物、注意力缺陷与多动障碍（ADHD）药物、失眠药物、抗癫痫药物、神经性疼痛药物、抗精神病药物和抗精神分裂症药物市场。其中以抗抑郁药物、抗癫痫药、抗精神病药物和抗精神分裂症药物的市场为主，近年来人们对老年性痴呆的认识增多和生活工作压力的增大，抗老年性痴呆药物和失眠药物的市场规模亦有所上升。     

INH、RFP致药物热32例临床分析

目的分析INH、RFP所致药物热的发生情况。方法由结核专科医师提供病程记录，医嘱单，实验室检查结果，回顾性分析和总结32例INH、RFP所致药物热的发生情况。结果32例药物热患者中，INH所致者3例，RFP所致者26例，INH和RFP共同所致者3例，85％的药物热发生在服药后30d之内。结论应重视INH，RFP所致的药物热，提高对药物热的认识。     

1997年我院抗菌药物利用和费用分析

目的：对住院病人病历抗菌药物利用和费用进行分析，以提高该类药物应用合理性。方法：随机抽查1997年第1次住院病历1000份并查阅药库1997年药品使用目录，采用DDD分析方法和药物经济学方法，分析合理用药、用药频度和药物费用。结果：应用的抗菌药物主要为头孢菌素类、喹诺酮类和青霉素类；不合理用药病历占抗菌药物病历总数的20％；在全部抗菌药物病历中，头孢菌素类药物占30．9％，DDDs排序前10位中有3种，并且该类药物支出占购药金额的40％以上。结论：头孢菌素类药物应用欠合理，喹诺酮类剂量偏大，其它药物基本合理．     

对“药物警戒”的认知和探讨(续三)

在震惊全球的“反应停事件”水落石出之后，世界各国于20世纪70年代中期先后开展了药物不良反应监测工作。20世纪80年代初，世界上少数几个国家将临床药理学和流行病学相互渗透形成了一门新的学科药物流行病学，将上市后的药物不良反应监测工作纳入其中。然而，在上市前的临床试验中还会涉及到安全性问题和许多非预期的药物不良事件，甚至暴露出不少有关伦埋学的问题；其次，在药物不良反应监测中会进一步察觉到其监测的范围不应仅限于临床治疗药物，而应扩大到所有应用于广大公众的传统药(包括中草药和其他民族药物)、营养品、血液制品、生物制品(包括疫苗)和医疗器械(材)等。因此，有人于20世纪末提出了“药物警戒”这个新术语。它把监测的范围扩大到所有与预防和治疗有关的物质，并将医疗器械也纳入其中，从而将被动的监测转变为主动的警戒，以防患于未然。笔者通过学习世界卫生组织发布的《The Importance ofPharmacovigilance Safety Monitoring of Medical Products》所获得的肤浅认识结合我国国情试作探讨。     

基层医院开展临床药学服务的实践

药学信息（pharmaceutical information）：包含药学领域所有知识数据，这是由信息的系统性决定的，既包括与药物直接相关的药物信息，如药物作用机制、药物不良反应、药物相互作用等，也包括与药物间接相关的信息，如疾病变化、耐药性、生理病理状态、健康保健信息等。药物信息（drug information）是药物的自然属性，是物质、疾病和人3方面的知识和信息的集合。药学服务自始至终均离不开药学信息的收集和整理分析。临床药师要直接面向患，要充分利用各种信息资源，整和、分析和优化各种信息嘲，直接为患提供专业的药学服务。     

Challenges Facing Antitubercular Therapy: New Drugs and Delivery Systems

Tuberculosis (TB) has again emerged as a challenging disease, victimizing a large section of the world population. Long duration of therapy, drug resistance, side effects associated with large doses of number of drugs, and economic reasons have resulted in poor patient compliance and in ineffective anti-TB therapy. In addition, drug-resistant strains of tubercle bacilli have further compounded the problem. In this article challenges facing present therapy, the mode of tuberculosis infection, challenges facing fixed-dose combination (FDC) formulation, new anti-TB molecules from the modification of existing anti-TB drugs for better activity, new molecules acting on the novel targets for reducing bacterial pathogenicity, antibiotics and nonantibiotics exhibiting anti-TB activity, and new drug delivery systems are discussed.     

Fluoroquinolones and tuberculosis

Tuberculosis (TB) remains one of the main causes of morbidity worldwide, and the emergence of multi-drug resistant (MDR) Mycobacterium tuberculosis strains in some parts of the world has become a major concern. The decrease in activity of the major anti-TB drugs, such as isoniazid and rifampicin, is an important threat and alternative therapies are urgently required. The anti-TB activity of the fluoroquinolones has been under investigation since the 1980s. Many are active in vitro but only a few, including ofloxacin, ciprofloxacin, sparfloxacin, levofloxacin and lomefloxacin, have been clinically tested. Fluoroquinolones can be used in co-therapy with the available anti-TB drugs. However, the choice of fluoroquinolone should be based not only on the in vitro activity, but also on the long-term tolerance. Fluoroquinolones are novel anti-TB drugs to be used when a patient is infected with a MDR-TB strain.     

重症乙型肝炎病史患者抗结核治疗方案的制定与药学监护

目的 探讨临床药师参与特殊结核患者个体化药物治疗方案制定及抗结核药物药学监护.方法 通过对1例重症乙型肝炎病史患者抗结核治疗方案制定与药学监护,临床药师从药物的选择、给药剂量、疗程、药物相互作用、不良反应监测等多方面给予药学服务.结果 临床药师在保证疗效的基础上,制定了最大限度减少肝功能损伤的治疗方案:①肌内注射硫酸链霉素针0.75 g,1次/d;②口服异烟肼片0.3g,1次/d;③口服盐酸乙胺丁醇片0.75 g,1次/d;④口服左氧氟沙星片0.5g,1次/d.抗结核治疗第19天,患者体温37℃,无咳嗽、气短等不适.肝功能检查结果:总蛋白71.0g/L,AST 105 U/L,ALT123 U/L,AST/ALT 0.85.转氨酶虽仍在升高,但患者无肝损害征象,继续抗结核和保肝治疗.第26天患者无咳嗽、气短,病情好转,复查血常规正常,转氨酶正常:总蛋白59.5 g/L,白蛋白37.1 g/L,AST 28 U/L,ALT 33 U/L,AST/ALT 0.8.第27天患者出院.结论 临床药师的参与使药物治疗个体化,更趋合理,有利于临床治疗的连续完整性,提高药物治疗水平.     

NAT2 and CYP2E1 polymorphisms associated with antituberculosis drug-induced hepatotoxicity in Chinese patients

1. The present study investigated the relationship between antituberculosis (anti-TB) drug-induced hepatotoxicity and genetic polymorphisms of two important drug-metabolizing enzymes involved in the metabolism of isoniazid, namely N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1). 2. A polymerase chain reaction direct sequencing approach was used to detect genetic polymorphisms of the NAT2 and CYP2E1 genes in tuberculosis (TB) patients with (n = 101) or without (n = 107) anti-TB drug-induced hepatotoxicity. Associations between various genetic polymorphisms and anti-TB drug-induced hepatotoxicity were then determined. 3. Patients with NAT2 (282TT , 590AA and 857GA) alleles had an increased susceptibility to anti-TB drug-induced hepatotoxicity. The slow acetylator NAT2 genotypes (especially NAT2*6A/7B and NAT2*6A/6A) were risk factors for hepatotoxicity (odds ratio (OR) 9.57 (P < 0.001) for NAT2*6A/7B; OR 5.24 (P = 0.02) for NAT2*6A/6A). 4. The CYP2E1 genotype per se was not significantly associated with the development of anti-TB drug-induced hepatotoxicity. However, the combination of the CYP2E1 C1/C1 genotype with a slow acetylator NAT2 genotype increased the risk of anti-TB drug-induced hepatotoxicity (OR 5.33; P = 0.003) compared with the combination of a rapid acetylator NAT2 genotype with either a C1/C2 or C2/C2 genotype. 5. Thus, slow acetylators with the NAT2*6A/7B and NAT2*6A/6A genotypes combined with the C1/C1 CYP2E1 genotype may be involved in the pathogenesis of anti-TB drug-induced hepatotoxicity. 6. The present findings may be explained, in part, by changes in the metabolism of the anti-TB drug isoniazid induced via NAT2 and CYP2E1, a metabolic process known to produce hepatotoxic intermediates.     

Fluoroquinolones and tuberculosis

Tuberculosis (TB) remains one of the main causes of morbidity worldwide, and the emergence of multi-drug resistant (MDR) Mycobacterium tuberculosis strains in some parts of the world has become a major concern. The decrease in activity of the major anti-TB drugs, such as isoniazid and rifampicin, is an important threat and alternative therapies are urgently required. The anti-TB activity of the fluoroquinolones has been under investigation since the 1980s. Many are active in vitro but only a few, including ofloxacin, ciprofloxacin, sparfloxacin, levofloxacin and lomefloxacin, have been clinically tested. Fluoroquinolones can be used in co-therapy with the available anti-TB drugs. However, the choice of fluoroquinolone should be based not only on the in vitro activity, but also on the long-term tolerance. Fluoroquinolones are novel anti-TB drugs to be used when a patient is infected with a MDR-TB strain.     

Insights into the pharmacokinetic properties of antitubercular drugs

Introduction: The furiously advancing cases of multidrug-resistant tuberculosis (TB) along with the recent emergence of total drug resistant TB and TB-AIDS comorbidity present an increased threat to global public health. Knowledge of pharmacokinetic properties helps in selecting an appropriate anti-TB dosage regimen to achieve optimal results in patients.

Areas covered: This article provides a brief compilation of the information available regarding published pharmacokinetic data for anti-TB drugs and may act as a single window for investigators/medical practitioners in this field. The information regarding absorption, tissue distribution, elimination and pharmacokinetic interactions of the first- and second-line anti-TB drugs and candidate drugs under clinical trials is discussed.

Expert opinion: Pharmacokinetic properties such as poor absorption, too short biological half-life, extensive first-pass metabolism, drug-food and drug-drug related interactions are not attractive for prospective anti-TB drugs and significantly contribute to treatment failure and further resistance. The long duration, monotonous and multidrug treatment plan leads to poor patient compliance and resulted in a greater occurrence of anti-TB drug resistance worldwide. Few new agents, which are in development phase, are considering the aspect of shortening duration of the treatment regimen and provide a boost in therapy that is sorely needed.     

化疗对结核病大鼠T细胞亚群变化的影响

目的探讨CD4^＋CD8^＋双阳（DP）T细胞与结核病相关性。方法60只PPD皮试阴性SD大鼠随机分成（1）结核病化疗组、（2）感染对照组、（3）健康对照组。化疗组和感染组大鼠均于观察开始接受结核菌标准株H37Rv（TB）攻击，攻毒1个月后化疗组接受抗TB化疗；三组动物均于感染结核分枝杆菌前和感染后1、2、3、5个月末检测外周血中CD3^＋、CD4^＋．CD8^＋,DPT细胞含量。结果5个月全程观察中，感染后1个月内化疗组、感染对照组各死亡2例（10％）；2—5个月内化疗组死亡率5．6％（1／18），不化疗组同期死亡率38．9％（7／18），P〈0．05；健康对照组动物无死亡。开始观察时3组之间各对应参数对比差异无显著性，P〉0．05；对照组观察期内各参数的改变差异亦无显著性，乃O．05：感染1个月后，化疗组、感染对照CD4^＋单阳（SP）细胞数、CD4^＋/CD8^＋T细胞比率降低，而CD8^＋、DPT细胞数升高。P〈0．05或P〈0．01。不化疗的感染对照组在感染后1个月时与其后2—5个月各参数差异无显著性。P〉0．05。化疗组化疗1个月后各参数恢复到结核感染前相近水平，与对照组各对应参数差异已无显著性，P〉0．05。TB感染后．CD4^＋单阳、CD4^＋／CD8＋比率降低，而DP、CD8^＋T细胞升高呈负相关。结论CD4^＋CD8^＋双阳（DP）T细胞是抗结核保护性免疫相关细胞。     

Increased rifampicin resistance in blood isolates of meticillin-resistant Staphylococcus aureus (MRSA) amongst patients exposed to rifampicin-containing antituberculous treatment

The aim of this study was to determine the rifampicin (RIF) resistance rate of meticillin-resistant Staphylococcus aureus (MRSA) amongst patients with MRSA bacteraemia who have or have not been exposed to RIF-containing antituberculous (anti-TB) treatment. From 2000 to 2008, patients with MRSA bacteraemia and previous exposure to RIF-containing anti-TB therapy were selected. Patients matched for sex, age and time of culture of MRSA bacteraemia but without exposure to anti-TB therapy were selected as a control group. A total of 139 patients, comprising 49 with RIF exposure and 90 without RIF exposure, were analysed. The RIF resistance rate was higher in patients with previous RIF exposure (61.2% vs. 20.0%; P<0.001). The minimum inhibitory concentration of RIF that inhibited 50% of MRSA isolates (MIC(50)) for the study group was also higher (128 mg/L vs. 0.015 mg/L; P<0.001). The mortality rate was higher in the study group (59.2% vs. 41.1%; P=0.041). MRSA isolates recovered from patients with current usage of a RIF-containing anti-TB regimen were more likely to be resistant to RIF (87.5% vs. 36%; P=0.001), with higher MIC(50) values (256 mg/L vs. 1mg/L; P=0.002), and resulted in a higher mortality rate than isolates from patients with remote usage of an anti-TB regimen (79.2% vs. 40%; P=0.005). Multivariate analysis showed that current anti-TB drug usage was the only risk factor for RIF resistance [odds ratio (OR)=7.457, 95% confidence interval (CI) 1.581-35.167] and mortality (OR=7.201, 95% CI 1.583-32.766). Given the high rate of RIF resistance in patients with prior anti-TB treatment, RIF susceptibility testing should be performed before considering combination treatment of RIF in MRSA infection.     

Adverse reactions of anti-tuberculosis drugs in hospitalized patients: incidence, severity and risk factors

BACKGROUND: Tuberculosis (TB) has been a common chronic infectious disease in human communities. Besides disease-related complications, there could be serious adverse reactions due to anti-tuberculosis (anti-TB) drug therapy. OBJECTIVES: To assess the incidence and severity of adverse drug reactions (ADRs) induced by anti-TB drugs. To determine possible covariates associated with detected ADRs. METHODS: All patients with respiratory TB admitted to a teaching hospital who received anti-TB drugs during the research period entered the study and were monitored for ADRs. Socio-demographic and medical history of patients were used as independent covariates. The relationship between independent covariates with frequency and severity of ADRs was analysed using multivariate logistic regression. Preliminary analyses of the Mann-Whitney, Chi-square, Kruskal-Wallis and the Fisher's exact tests were applied to determine factors unlikely associated with the independent variables. RESULTS: Among 204 patients admitted, there were 92 patients (45.1%) with ADRs induced by anti-TB drugs. Patients with a previous history of anti-TB drugs usage (OR = 5.81, 95% confidence interval [95%CI]: 1.31-25.2), patients with a history of drug allergy (OR = 6.68, CI: 1.28-36.2), those from Afghani ethnic (OR = 4.91, 95%CI: 1.28-18.30) as well as smoker patients with concurrent diseases (OR = 19.67, CI: 1.24-341.51) had a higher rate of ADR incidence. Being female (OR = 1.63, 95%CI: 1.96-36.40) and having previous history of ADR (OR = 17.46, 95%CI: 1.96-20.42) were identified as risk factors. CONCLUSION: Anti-TB drugs could cause severe and frequent adverse effects. Females, those with a previous history of ADRs to anti-TB drugs and Afghani patients, should be considered as high-risk groups.     

Derivatives of 3-isoxazolecarboxylic acid esters: a potent and selective compound class against replicating and nonreplicating Mycobacterium tuberculosis

New antituberculosis (anti-TB) drugs are urgently needed to battle drug-resistant Mycobacterium tuberculosis (Mtb) strains and to shorten the long treatment regimen. A series of isoxazole-based compounds, bearing a carboxy moiety at the C3 position, are highly potent and versatile anti-TB agents. Several members of this compound class exhibit submicromolar in vitro activity against replicating Mtb (R-TB) and thus comparable activity to the current first-line anti-TB drugs. Remarkably, certain compounds also show low micromolar activity in a model for nonreplicating Mtb (NRP-TB) phenotype, which is considered a key to shortening the current long treatment protocol. The series shows excellent selectivity towards Mtb and, in general, shows no cytotoxicity on Vero cells (IC50's > 128 μM). Selected compounds retain their activity against isoniazid (INH), rifampin (RMP), and streptomycin (SM) resistant Mtb strains. The foregoing facts make derivatives of 3- isoxazolecarboxylic acid esters a promising anti-TB chemotype, and as such present attractive lead compounds for TB drug development.