BACKGROUND & AIMS: :Novel treatment strategies for tuberculosis are urgently needed. Many different preclinical models assessing anti-tuberculosis drug activity are available, but it is yet unclear which combination of models is most predictive of clinical treatment efficacy. The aim of this study was to determine the role of our in vitro time kill-kinetics assay as an asset to a predictive preclinical modeling framework assessing anti-tuberculosis drug activity. The concentration- and time-dependent mycobacterial killing capacities of six anti-tuberculosis drugs were determined during exposure as single drugs or in dual, triple and quadruple combinations towards a Mycobacterium tuberculosis Beijing genotype strain and drug resistance was assessed. Streptomycin, rifampicin and isoniazid were most active against fast-growing M. tuberculosis. Isoniazid with rifampicin or high dose ethambutol were the only synergistic drug combinations. The addition of rifampicin or streptomycin to isoniazid prevented isoniazid resistance. In vitro ranking showed agreement with early bactericidal activity in tuberculosis patients for some but not all anti-tuberculosis drugs. The time-kill kinetics assay provides important information on the mycobacterial killing dynamics of anti-tuberculosis drugs during the early phase of drug exposure. As such, this assay is a valuable component of the preclinical modeling framework.

背景与目标： 迫切需要新的结核病治疗策略。有许多不同的评估抗结核药物活性的临床前模型，但尚不清楚哪种模型组合最能预测临床治疗效果。这项研究的目的是确定我们的体外时间杀伤动力学测定法作为评估抗结核药物活性的预测性临床前建模框架的资产的作用。在暴露于结核分枝杆菌北京基因型菌株的过程中，确定了六种抗结核药物的浓度和时间依赖性的分枝杆菌杀伤能力，并评估了耐药性。链霉素，利福平和异烟肼对快速生长的结核分枝杆菌最有效。异烟肼与利福平或高剂量乙胺丁醇是唯一的协同药物组合。在异烟肼中添加利福平或链霉素可防止异烟肼耐药性。体外排名显示，对于某些 (但不是所有) 抗结核药物，结核病患者的早期杀菌活性一致。时间杀伤动力学测定法提供了有关药物暴露早期抗结核药物的分枝杆菌杀伤动力学的重要信息。因此，该测定是临床前建模框架的有价值的组成部分。

BACKGROUND & AIMS: :Achieving 'universal access' to antiretroviral HIV treatment (ART) in lower income and transitional settings is a global target. Yet, access to ART is shaped by local social condition and is by no means universal. Qualitative studies are ideally suited to describing how access to ART is socially situated. We explored systemic barriers to accessing ART among people who inject drugs (PWID) in a Russian city (Ekaterinburg) with a large burden of HIV treatment demand. We undertook 42 in-depth qualitative interviews with people living with HIV with current or recent experience of injecting drug use. Accounts were analysed thematically, and supplemented here with an illustrative case study. Three core themes were identified: 'labyrinthine bureaucracy' governing access to ART; a 'system Catch 22' created by an expectation that access to ART was conditional upon treated drug use in a setting of limited drug treatment opportunity; and 'system verticalization', where a lack of integration across HIV, tuberculosis (TB) and drug treatment compromised access to ART. Taken together, we find that systemic factors play a key role in shaping access to ART with the potential adverse effects of reproducing treatment initiation delay and disengagement from treatment. We argue that meso-level systemic factors affecting access to ART for PWID interact with wider macro-level structural forces, including those related to drug treatment policy and the social marginalization of PWID. We note the urgent need for systemic and structural changes to improve access to ART for PWID in this setting, including to simplify bureaucratic procedures, foster integrated HIV, TB and drug treatment services, and advocate for drug treatment policy reform.

背景与目标： : 在低收入和过渡环境中实现抗逆转录病毒艾滋病毒治疗的 “普遍获得” 是一个全球目标。然而，获得艺术的途径是受当地社会条件的影响，绝不是普遍的。定性研究非常适合描述获得艺术的社会地位。我们探讨了在俄罗斯城市 (叶卡捷琳堡) 中注射毒品 (PWID) 的人获得ART的系统性障碍，该城市的HIV治疗需求负担很大。我们对目前或最近有注射吸毒经验的艾滋病毒感染者进行了42次深入的定性访谈。对帐户进行了主题分析，并在此处进行了说明性案例研究。确定了三个核心主题: “迷宫式官僚” 管理获得ART的机会; 由于期望在有限的药物治疗机会中获得ART的条件下以治疗药物的使用为条件而创建的 “系统Catch 22”; 和 “系统垂直化”，其中缺乏艾滋病毒之间的融合，结核病 (TB) 和药物治疗损害了获得ART的机会。综上所述，我们发现系统性因素在塑造获得ART的途径方面起着关键作用，并具有重现治疗开始延迟和脱离治疗的潜在不利影响。我们认为，影响PWID获得ART的中观系统因素与更广泛的宏观结构力量相互作用，包括与药物治疗政策和PWID的社会边缘化有关的力量。我们注意到，在这种情况下，迫切需要进行系统性和结构性改革，以改善PWID获得抗逆转录病毒疗法的机会，包括简化官僚程序，促进艾滋病毒，结核病和药物治疗综合服务，并倡导药物治疗政策改革。

BACKGROUND & AIMS: :Rheumatoid arthritis (RA) is characterized by inflammation and an increased risk for cardiovascular disease (CVD). This study investigates possible associations between CVD and the use of conventional disease-modifying antirheumatic drugs (DMARDs) in RA. Using a case control design, 613 RA patients (5,649 patient-years) were studied, 72 with CVD and 541 without CVD. Data on RA, CVD and drug treatment were evaluated from time of RA diagnosis up to the first cardiovascular event or the end of the follow-up period. The dataset was categorized according to DMARD use: sulfasalazine (SSZ), hydroxychloroquine (HCQ) or methotrexate (MTX). Odds ratios (ORs) for CVD, corrected for age, gender, smoking and RA duration, were calculated per DMARD group. Patients who never used SSZ, HCQ or MTX were used as a reference group. MTX treatment was associated with a significant CVD risk reduction, with ORs (95% CI): 'MTX only', 0.16 (0.04 to 0.66); 'MTX and SSZ ever', 0.20 (0.08 to 0.51); and 'MTX, SSZ and HCQ ever', 0.20 (0.08 to 0.54). The risk reductions remained significant after additional correction for the presence of rheumatoid factor and erosions. After correction for hypertension, diabetes and hypercholesterolemia, 'MTX or SSZ ever' and 'MTX, SSZ and HCQ ever' showed significant CVD risk reduction. Rheumatoid factor positivity and erosions both increased CVD risk, with ORs of 2.04 (1.02 to 4.07) and 2.36 (0.92 to 6.08), respectively. MTX and, to a lesser extent, SSZ were associated with significantly lower CVD risk compared to RA patients who never used SSZ, HCQ or MTX. We hypothesize that DMARD use, in particular MTX use, results in powerful suppression of inflammation, thereby reducing the development of atherosclerosis and subsequently clinically overt CVD.

背景与目标： 类风湿性关节炎 (RA) 的特征是炎症和心血管疾病 (CVD) 的风险增加。这项研究调查了CVD与RA中常规缓解疾病的抗风湿药 (DMARDs) 的使用之间的可能关联。使用病例对照设计，研究了613例RA患者 (5,649患者年)，72例CVD患者和541例无CVD患者。从RA诊断到第一次心血管事件或随访期结束，评估RA，CVD和药物治疗的数据。根据DMARD用途对数据集进行分类: 柳氮磺吡啶 (SSZ)，羟基氯喹 (HCQ) 或甲氨蝶呤 (MTX)。每个DMARD组计算CVD的比值比 (ORs)，校正年龄，性别，吸烟和RA持续时间。从未使用SSZ，HCQ或MTX的患者被用作参考组。MTX治疗与显著降低CVD风险相关，ORs (95% CI): “仅MTX”，0.16 (0.04至0.66); “MTX和SSZ”，0.20 (0.08至0.51); 和 “MTX，SSZ和HCQ”，0.20 (0.08至0.54)。在对类风湿因子和侵蚀的存在进行进一步校正后，风险降低仍然显着。校正高血压，糖尿病和高胆固醇血症后，'MTX或SSZ ever' 和 'MTX，SSZ和HCQ ever' 显示出明显的CVD风险降低。类风湿因子阳性和糜烂均增加了CVD风险，or分别为2.04 (1.02至4.07) 和2.36 (0.92至6.08)。与从未使用SSZ，HCQ或MTX的RA患者相比，MTX和SSZ在较小程度上与CVD风险显着降低相关。我们假设使用DMARD，特别是使用MTX，可以有效抑制炎症，从而减少动脉粥样硬化的发展，并随后在临床上明显减少CVD。

BACKGROUND & AIMS: :The intricate problems associated with the delivery and various unnecessary in vivo transitions of proteins and drugs needs to be tackled soon to be able to exploit the myriad of putative therapeutics created by the biotechnology boom. Nanomedicine is one of the most promising applications of nanotechnology in the field of medicine. It has been defined as the monitoring, repair, construction and control of human biological systems at the molecular level using engineered nanodevices and nanostructures. These nanostructured medicines will eventually turn the world of drug delivery upside down. PEGylation (i.e. the attachment of polyethylene glycol to proteins and drugs) is an upcoming methodology for drug development and it has the potential to revolutionise medicine by drastically improving the pharmacokinetic and pharmacodynamic properties of the administered drug. This article provides a total strategy for improving the therapeutic efficacy of various biotechnological products in drug delivery. This article also presents an extensive analysis of most of the PEGylated proteins, peptides and drugs, together with extensive clinical data. Nanomedicines and PEGylation, the latest offshoots of nanotechnology will definitely pave a way in the field of drug delivery where targeted delivery, formulation, in vivo stability and retention are the major challenges.

背景与目标： : 与蛋白质和药物的递送和各种不必要的体内转化相关的复杂问题需要尽快解决，以便能够利用生物技术繁荣带来的无数推定疗法。纳米医学是纳米技术在医学领域最有前途的应用之一。它被定义为使用工程纳米设备和纳米结构在分子水平上监视，修复，构建和控制人类生物系统。这些纳米结构的药物最终将颠覆药物输送的世界。聚乙二醇化 (即聚乙二醇与蛋白质和药物的结合) 是药物开发的一种即将到来的方法，它有可能通过大幅改善所给药药物的药代动力学和药效学特性来彻底改变药物。本文提供了提高各种生物技术产品在药物输送中的治疗效果的总体策略。本文还对大多数聚乙二醇化蛋白，肽和药物进行了广泛的分析，并提供了广泛的临床数据。纳米药物和聚乙二醇化是纳米技术的最新分支，无疑将在药物递送领域铺平道路，其中靶向递送，配方，体内稳定性和保留是主要挑战。

BACKGROUND & AIMS: :The purpose of the present research is to establish a novel nanosizing technique starting from wet nano-milling, named "dry nanosuspension" technique for poorly water-soluble drugs. The spray freeze-drying (SFD) method was applied instead of the spray-drying one previously developed. Drug particles were milled in the aqueous solution of dispersing agents using an oscillating beads-milling apparatus. The milled nanosuspension was sprayed to the surface of liquid nitrogen, and the resultant iced droplets were freeze-dried to obtain the powdery product. The loading ratio of a dispersing agent was investigated to enhance its redispersing property. Dry nanosuspension, which could be spontaneously dispersed into original nanosuspension in water, was obtained by SFD process. It was assumed that self dispersion property would be attributed to its structure with porous network, in which the primary milled drug crystals were embedded. Such unique structure contributed greatly to immediate release behaviors of the drug in gastrointestinal buffered media. These pharmaceutical properties were enhanced by increasing the ratio of the dispersing agent to the drug and the solid content in suspension to be sprayed. The present technique via wet milling and spray freeze-drying processes would be a novel dissolution-enhanced technology for poorly water-soluble drugs.

背景与目标： : 本研究的目的是建立一种从湿法纳米研磨开始的新型纳米上浆技术，称为水溶性差的药物的 “干法纳米悬浮液” 技术。采用喷雾冷冻干燥 (SFD) 方法代替了先前开发的喷雾干燥方法。使用振荡珠磨设备在分散剂水溶液中研磨药物颗粒。将研磨的纳米悬浮液喷洒到液氮表面，并将所得的冰滴冷冻干燥以获得粉末状产品。研究了分散剂的负载比，以提高其再分散性能。通过SFD工艺获得了干燥的纳米悬浮液，该悬浮液可以自发地分散到水中的原始纳米悬浮液中。假定自分散特性归因于其具有多孔网络的结构，其中嵌入了初级研磨的药物晶体。这种独特的结构极大地促进了药物在胃肠道缓冲介质中的立即释放行为。通过增加分散剂与药物的比例以及要喷洒的悬浮液中的固体含量，可以增强这些药物性能。本技术通过湿法研磨和喷雾冷冻干燥工艺将是一种新型的水溶性药物溶出增强技术。

BACKGROUND & AIMS: :Little evidence or advice exists in the medical literature on 'medical kit' that could be usefully carried by physicians to prepare them for unexpected emergencies. The aim of this study was to establish what, in the opinion of Emergency Physicians, is an appropriate medical kit for doctors to carry to prepare them for 'Good Samaritan' acts. A telephone survey, using a proforma, of United Kingdom Emergency Physicians was conducted. Of the responders to the survey, 10% routinely undertook prehospital work. Seventy-two percent thought it appropriate to carry equipment, but only 43% thought it appropriate to carry medications. Over 80% considered basic airway equipment useful to carry, whereas other items of medical kit were considered appropriate much less commonly. A large proportion of emergency physicians consider it appropriate to carry some medical kit for 'Good Samaritan' acts and, in general, the consensus of opinion as to what medical kit should be carried agreed with the evidence-base for prehospital interventions.

背景与目标： : 医学文献中关于 “医疗包” 的证据或建议很少，医生可以有效地携带这些证据或建议，以使他们为意外的紧急情况做好准备。这项研究的目的是确定急诊医生认为是合适的医疗包，供医生携带以准备 “好撒玛利亚人” 的行为。使用形式形式对英国急诊医生进行了电话调查。在调查的响应者中，10% 经常进行院前工作。72% 的人认为携带设备是合适的，但只有43% 的人认为携带药物是合适的。超过80% 的人认为基本的气道设备可用于携带，而其他医疗套件则被认为不太合适。很大一部分急诊医生认为携带一些用于 “好撒玛利亚人” 行为的医疗工具包是适当的，并且通常，关于应携带哪种医疗工具包的意见共识与院前干预的证据基础一致。

BACKGROUND & AIMS: PURPOSE OF REVIEW:This paper updates the treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis supported by relevant views about the pathogenesis. RECENT FINDINGS:Building on the thesis that Stevens-Johnson syndrome and toxic epidermal necrolysis are due to dermal cell apoptosis, molecular pathways that may lead to this have been proposed. Intravenous immunoglobulin is postulated to block apoptosis via the Fas pathway. Most series on the use of intravenous immunoglobulin in toxic epidermal necrolysis have been favourable. Tumour necrosis factor is also thought to be an important mediator of cell death in toxic epidermal necrolysis. There was impressive control of the progression of toxic epidermal necrolysis with intravenous anti-tumour necrosis factor antibody infliximab in two cases. Strong associations between human leukocyte antigen subtypes and severe cutaneous reactions due to allopurinol and carbamazepine have been described. SUMMARY:To date, there is no established treatment of Stevens-Johnson syndrome/toxic epidermal necrolysis. With advancing knowledge of the pathogenesis, it is hoped that better forms of treatment may result.

背景与目标：

BACKGROUND & AIMS: OBJECTIVES:The objectives of this study were 1) to obtain information regarding the prescribing pattern of nonsteroidal anti-inflammatory drugs (NSAIDs) in the primary care setting at a Malaysian university, 2) to determine the prevalence and types of potential NSAID prescription related problems (PRPs), and 3) to identify patient characteristics associated with exposure to these potential PRPs. METHODS:We retrospectively collected data from 1 academic year using the electronic medical records of patients in the University Sains Malaysia (USM) primary care system. The defined daily dose (DDD) methodology and the anatomical therapeutic chemical (ATC) drug classification system were used in the analysis and comparison of the data. Statements representing potential NSAID PRPs were developed from authoritative drug information sources. Then, algorithms were developed to screen the databases for these potential PRPs. Descriptive and comparative statistics were used to characterize DRPs. RESULTS:During the study period, 12,470 NSAID prescriptions were prescribed for 6,509 patients (mean ± SD = 1.92 ± 1.83). This represented a prevalence of 35,944 per 100,000 patients, or 36%. Based on their DDDs, mefenamic acid and diclofenac were the most prescribed NSAIDs. 573 potential NSAID-related PRPs were observed in a cohort of 432 patients, representing a prevalence of 6,640 per 100,000 NSAIDs users, or 6.6% of all NSAID users. Multivariate logistic regression analysis revealed that patients with a Malay ethnic background (p < 0.001), members of the staff (p < 0.001), having 4 or more prescribers (p < 0.001) or having 2 - 3 prescribers (p = 0.02), and representing 4 or more long-term therapeutic groups (LTTGs) (p < 0.001) or 2 - 3 LTTGs (p < 0.001) were significantly associated with an increased chance of exposure to potential NSAID related PRPs. CONCLUSIONS:This is the first study in Malaysia that presents data on the prescribing pattern of NSAIDs and the characteristics of potential NSAID-related PRPs. The prevalence of potential NSAID-related PRPs is frequent in the primary care setting. Exposure to these PRPs is associated with specific sociodemographic and health status factors. These results should help to raise the awareness of clinicians and patients about serious NSAID PRPs.

背景与目标：

BACKGROUND & AIMS: :We have used combinatorial chemistry with amino acid mixtures (X) at positions 6 to 23 in vasoactive intestinal peptide (VIP) to optimize binding affinity and selectivity to the rat VPAC(1) receptor. The most efficient amino acid replacement was a substitution of alanine at position 18 to diphenylalanine (Dip), increasing the displacement efficiency of (125)I-VIP by 370-fold. The [Dip(18)]VIP(6-23) was subsequently used to find a second replacement, employing the same approach. Tyrosine at position 9 was selected and the resulting [Tyr(9),Dip(18)]VIP(6-23) analog has a K(i) value of 90 nM. This analog was unable to stimulate cAMP production at 10(-6) M but was able to inhibit VIP-induced cAMP stimulation (K(b) = 79 nM). The K(i) values of [Tyr(9),Dip(18)]VIP(6-23) using the rat VPAC(2) and PAC(1) receptors were 3,000 nM and >10,000 nM, respectively. Thus, [Tyr(9),Dip(18)]VIP(6-23) is a selective VPAC(1) receptor antagonist. The C-terminally extended form, [Tyr(9),Dip(18)]VIP(6-28), displays improved antagonistic properties having a K(i) and K(b) values of 18 nM and 16 nM, respectively. On the contrary, the fully extended form, [Tyr(9),Dip(18)]VIP(1-28), was a potent agonist with improved binding affinity (K(i) = 0.11 nM) and ability to stimulate cAMP (EC(50) = 0.23 nM) compared with VIP (K(i) = 1.7 nM, EC(50) = 1.12 nM). Furthermore, the specificity of this agonist to the VPAC(1) receptor was high, the K(i) values for the VPAC(2) and PAC(1) receptors were 53 nM and 3,100 nM, respectively. Seven other analogs with the [Tyr(9),Dip(18)] replacement combined with previously published VIP modifications have been synthesized and described in this work.

背景与目标： : 我们已使用血管活性肠肽 (VIP) 中6至23位氨基酸混合物 (X) 的组合化学来优化对大鼠VPAC(1) 受体的结合亲和力和选择性。最有效的氨基酸置换是将第18位的丙氨酸替换为二苯丙氨酸 (Dip)，将 (125)I-VIP的置换效率提高了370倍。随后使用 [Dip(18)]VIP(6-23) 来寻找第二种替代品，采用相同的方法。选择位置9的酪氨酸，所得 [Tyr(9)，Dip(18)]VIP(6-23) 类似物的K(i) 值为90 nM。该类似物无法刺激10(-6) M的cAMP产生，但能够抑制VIP诱导的cAMP刺激 (K(b) = 79 nM)。使用大鼠VPAC(2) 和PAC(1) 受体的 [Tyr(9)，Dip(18)]VIP(6-23) 的K(i) 值分别为3,000 nM和> 10,000 nM。因此，[Tyr(9)，Dip(18)]VIP(6-23) 是选择性VPAC(1) 受体拮抗剂。C端扩展形式 [Tyr(9)，Dip(18)]VIP(6-28) 显示出改善的拮抗特性，其K(i) 和K(b) 值分别为18 nM和16 nM。相反，完全扩展的形式，[Tyr(9)，Dip(18)]VIP(1-28)，与VIP (K(i) = 0.11纳米，EC(50) = 1.12纳米) 相比，是一种有效的激动剂，具有改善的结合亲和力 (K(i) = 纳米) 和刺激cAMP的能力 (EC(50) = 0.23纳米)。此外，该激动剂对VPAC(1) 受体的特异性高，VPAC(2) 和PAC(1) 受体的K(i) 值分别为53 nm和3,100 nM。在这项工作中，已经合成并描述了与先前发布的VIP修饰相结合的 [Tyr(9)，Dip(18)] 替换的其他七个类似物。

BACKGROUND & AIMS: OBJECTIVES:Dysthymia is a depressive disorder of chronic nature but of less severity than major depression, which depressive symptoms are more or less continuous for at least two years. The aim of this review was to conduct a systematic review of all RCTs comparing drugs and placebo for dysthymia. SEARCH STRATEGY:Electronic searches of Cochrane Library, EMBASE, MEDLINE, PsycLIT, Biological Abstracts and LILACS; reference searching; personal communication; conference abstracts; unpublished trials from the pharmaceutical industry; book chapters on the treatment of depression. SELECTION CRITERIA:The inclusion criteria for all randomised controlled trials were that they should focus on the use of drugs versus placebo for dysthymic patients. Exclusion criteria were: non randomised, mixed major depression/ dysthymia (trials not providing separate data) and depression secondary to other disorders (e.g. substance abuse). DATA COLLECTION AND ANALYSIS:The reviewers extracted the data independently. In order to achieve an intention-to-treat analysis, when trials failed to report it was assumed that people who died or dropped out had no improvement. Authors of relevant trials were contacted for additional and missing data. Absence of treatment response as defined by authors was the main measure of outcome used. Relative Risks (RR) and 95% confidence intervals (CI) of dichotomous data were calculated with the Random Effects Model. Where possible, number needed to treat (NNT) and number needed to harm (NNH) were estimated, taking the reciprocal of the absolute risk reduction. MAIN RESULTS:Currently the review includes 15 trials. Similar results were obtained in terms of efficacy for different groups of drugs, such as tricyclic (TCA), selective serotonin reuptake inhibitors (SSRI), monoamine oxidase inhibitors (MAOI) and other drugs (sulpiride, amineptine, and ritanserin). The pooled RR for absence of treatment response was 0.68 (95% CI 0.59-0.78) for TCA and the NNT was 4.3 (95% CI 3.2-6.5). SSRIs showed similar RR for this outcome: 0.64 (95% CI 0.55-0.74), the NNT being 4.7 (95% CI 3.5-6.9). Concerning MAOIs, the RR was 0.59 (95% CI 0.48-0.71) and the NNT was 2.9 (95% CI 2.2-4.3). Other drugs (amisulpride, amineptine and ritanserin) showed similar results in terms of absence of treatment response. Using more stringent criteria for improvement - full remission - the results were unchanged. Patients treated on TCA were more likely to report adverse events, compared with placebo. REVIEWER'S CONCLUSIONS:Drugs are effective in the treatment of dysthymia with no differences between and within class of drugs. Tricyclic antidepressants are more likely to cause adverse events and dropouts. As dysthymia is a chronic condition, there remains little information on quality of life and medium or long-term outcome.

背景与目标：

BACKGROUND & AIMS: :The present paper reviews evidence on the effect of antidepressant treatments on dopamine transmission. Chronic treatment with antidepressant drugs potentiates the behavioural stimulant responses elicited by the stimulation of dopamine receptors, including reward-related behaviours. Moreover, antidepressants affect dopamine release in several brain areas. The reviewed literature is discussed in terms of the possible mechanisms underlying antidepressant-induced supersensitivity to dopamine-mediated behavioural responses, and of the possible implications for the therapeutic effect of these drugs. It is concluded that the potentiation of dopaminergic neurotransmission induced by chronic antidepressant treatments might contribute to their therapeutic effect.

背景与目标： : 本文回顾了抗抑郁药治疗对多巴胺传播影响的证据。抗抑郁药物的长期治疗增强了多巴胺受体刺激引起的行为刺激反应，包括奖励相关行为。此外，抗抑郁药会影响几个大脑区域的多巴胺释放。讨论了抗抑郁药诱导的对多巴胺介导的行为反应超敏的可能机制，以及对这些药物的治疗作用的可能影响。结论是，慢性抗抑郁药治疗引起的多巴胺能神经传递的增强可能有助于其治疗效果。

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: Class I antiarrhythmic drugs do not decrease, but increase, the risk of ventricular fibrillation in the ischemic myocardium. On the contrary, vulnerability to fibrillation related to ischemia appears to be substantially reduced by calcium antagonists. We assessed whether the calcium antagonist diltiazem (0.50 mg/kg bolus plus 0.02 mg/kg/min infusion) could prevent the profibrillatory effect or even partially restore the antifibrillatory effect of a class I antiarrhythmic drug, flecainide (1 mg/kg bolus plus 0.04 mg/kg/min infusion) in the ischemic myocardium of anesthetized, open-chest pigs. Ischemia was obtained by completely occluding the left anterior descending coronary artery near its origin. Vulnerability to fibrillation was assessed by electrical fibrillation threshold (EFT), measured with diastolic impulses of 100 msec duration delivered at a rate of 180 beats/minute. Diltiazem did not oppose the rise in EFT induced by flecainide in the absence of ischemia (6.8 +/- 1.2 to 9.9 +/- 0.9 mA, p<0.001). It limited the fall in EFT observed under the dual influence of ischemia and flecainide (4.2 +/- 0.9 vs 1.3 +/- 0.6 mA, p<0.001). By reducing calcium entry into myocardial fibers, diltiazem delayed ischemic depolarization, as evidenced by reduced shortening of the monophasic action potential duration from 215 +/- 7 to 200 +/- 4 msec, instead of 178 +/- 6 (p<0.001), and reduced lengthening of intraventricular conduction time from 33 +/- 5 to 43 +/- 4 msec, instead of 53 +/- 4 (p<0.01). Therefore, diltiazem is likely to prevent the loss and even the reversal of the antifibrillatory properties of flecainide due to myocardial ischemia in dosages that do not adversely affect myocardial contractility or atrioventricular conduction to a large extent.

背景与目标： I类抗心律失常药物不会降低，但会增加缺血性心肌中室颤的风险。相反，钙拮抗剂似乎大大降低了与缺血相关的纤颤的脆弱性。我们评估了钙拮抗剂地尔硫卓 (0.50 mg/kg推注加0.02 mg/kg/min输注) 是否可以预防I类抗心律失常药物的抗纤颤作用或甚至部分恢复抗纤颤作用，在麻醉的开胸猪的缺血心肌中 (1 mg/kg推注加0.04 mg/kg/min输注)。缺血是通过完全阻塞左前降支冠状动脉起源附近而获得的。通过电颤动阈值 (EFT) 评估对颤动的脆弱性，该阈值用以180次/分钟的速率递送的100毫秒持续时间的舒张期脉冲来测量。地尔硫卓不反对在没有缺血的情况下由氟卡尼诱导的EFT升高 (6.8 +/- 1.2 9.9 +/- 0.9 mA，p<0.001)。它限制了在缺血和氟卡宁的双重影响下观察到的EFT下降 (4.2 +/- 0.9 vs 1.3 +/- 0.6 mA，p<0.001)。通过减少钙进入心肌纤维，地尔硫卓可延迟缺血去极化，这表现为单相动作电位持续时间从215 +/- 7缩短至200 +/- 4毫秒，而不是178 +/- 6 (p<0.001)，并将脑室内传导时间从33 +/- 5缩短到43 +/- 4毫秒，而不是53 +/- 4毫秒 (p<0.01)。因此，地尔硫卓很可能以不会在很大程度上不利影响心肌收缩力或房室传导的剂量防止氟卡尼因心肌缺血而丧失甚至逆转抗纤颤特性。

BACKGROUND & AIMS: :We investigated the induction of a stress response gene by anticancer drugs that damage and covalently modify DNA and other cellular macromolecules. Two human colon adenocarcinoma cell lines (HT-29 and BE) which differ in sensitivity to chloroethylnitrosoureas were treated with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) or with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). Both of these drugs can alkylate, crosslink and carbamoylate cellular macromolecules. Treated cells were compared to controls for cytoplasmic levels of HSP70 RNA and for synthesis of heat shock proteins. We also tested for induction of stress response gene expression by equitoxic or greater concentrations of other nitrosourea analogues which can alkylate only, alkylate and crosslink only or carbamoylate only, as well as other DNA crosslinking agents (chlorambucil and cis-platinum). Of these, only BCNU and CCNU, the chloroethylnitrosoureas having all three of the macromolecule-modifying activities, strongly induce HSP70 RNA levels in a dose-dependent and time-dependent manner. Induction of HSP70 by BCNU occurred in both cell lines at dose ranges that were cytocidal to the BCNU-resistant HT-29 cells. No induction was seen in BE cells at the lower BCNU concentrations that were equitoxic to that more sensitive cell line. These observations suggest that induction of HSP70 by BCNU and CCNU is neither a direct consequence of DNA crosslinks nor an invariable result of cytocidal drugs.

背景与目标： : 我们研究了破坏和共价修饰DNA和其他细胞大分子的抗癌药物对应激反应基因的诱导。用1,3-双-(2-氯乙基)-1-亚硝基脲 (BCNU) 或用1-(2-氯乙基)-1-亚硝基脲 (CCNU) 处理对氯乙基亚硝基脲敏感性不同的两种人结肠腺癌细胞系 (HT-29和BE)。3-环己基-1-亚硝基脲 (CCNU)。这两种药物都可以烷基化，交联和氨基甲酸的细胞大分子。将处理过的细胞与HSP70 RNA的细胞质水平和热休克蛋白的合成对照进行比较。我们还测试了等氧或更高浓度的其他亚硝基脲类似物 (仅可烷基化，烷基化和交联或仅氨基甲酸酯) 以及其他DNA交联剂 (苯丁酸氮芥和顺铂) 诱导应激反应基因表达的方法。其中，只有BCNU和CCNU，具有所有三种大分子修饰活性的氯乙基亚硝基脲，以剂量依赖性和时间依赖性方式强烈诱导HSP70 RNA水平。BCNU诱导HSP70在对BCNU抗性HT-29细胞具有杀灭作用的剂量范围内发生。在较低的BCNU浓度下的BE细胞中未见诱导，该浓度与该更敏感的细胞系等分。这些观察结果表明，BCNU和CCNU诱导HSP70既不是DNA交联的直接结果，也不是杀细胞药物的不变结果。

BACKGROUND & AIMS: PURPOSE:Upper gastrointestinal bleeding (UGIB) is a severe and frequent drug-related event. In order to enable efficient drug safety alert generation in the French National Healthcare System database (SNDS), we assessed and calibrated empirically case-based designs to identify drug associated with UGIB risk. METHODS:All cases of UGIB were extracted from SNDS (2009-2014) using two definitions. Positive and negative drug controls were used to compare 196 self-controlled case series (SCCS), case-control (CC) and case-population (CP) design variants. Each variant was evaluated in a 1/10th population sample using area under the receiver operating curve (AUC) and mean square error (MSE). Parameters that had major impacts on results were identified through logistic regression. Optimal designs were replicated in the unsampled population. RESULTS:Using a specific UGIB definition, AUCs ranged from 0.64 to 0.80, 0.44 to 0.61 and 0.50 to 0.67, for SCCS, CC and CP, respectively. MSE ranged from 0.07 to 0.39, 0.83 to 1.33 and 1.96 to 4.6, respectively. Univariate regressions showed that high AUCs were achieved with SCCS with multiple drug adjustment and a 30-day risk window starting at exposure. The top-performing SCCS variant in the unsampled population yielded an AUC = 0.84 and MSE = 0.14, with 10/36 negative controls presenting significant estimates. CONCLUSIONS:SCCS adjusting for multiple drugs and using a 30-day risk window has the potential to generate UGIB-related alerts in the SNDS and hypotheses on its potential population impact. Negative control implementation highlighted that low systematic error was generated but that protopathic bias and confounding by indication remained unaddressed issues.

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