154例药品不良反应监测报告分析

目的:分析我院2009和2010年收集的154例药品不良反应(ADR)报告,以期了解不良反应发生的特点和规律,减少或避免不良反应的重复发生,为临床科室合理用药提供参考。方法:采用回顾性分类统计方法,对我院2009和2010两年上报的154例报告就ADR分布与年龄、给药途径、药物分类、累及系统及器官等方面的关系进行统计分析。结果:154例不良反应报告中以抗微生物药物和中药注射剂为主,分别占44.81%和20.78%。ADR临床表现以变态反应为主,其中儿童和老年患者居多(33.12%和48.05%),以静脉滴注方式为主(91.55%),临床表现主要以皮肤及其附件损伤最常见(75.97%)。结论:应加强ADR监测上报工作,并及时向临床科室反馈,提高临床安全用药意识,确保临床用药安全。     

154例药品不良反应监测报告分析

目的：分析我院2009和2010年收集的154例药品不良反应（ADR）报告,以期了解不良反应发生的特点和规律,减少或避免不良反应的重复发生,为临床科室合理用药提供参考。方法：采用回顾性分类统计方法,对我院2009和2010两年上报的154例报告就ADR分布与年龄、给药途径、药物分类、累及系统及器官等方面的关系进行统计分析。结果：154例不良反应报告中以抗微生物药物和中药注射剂为主,分别占44．81％和20．78％。ADR临床表现以变态反应为主,其中儿童和老年患者居多（33．12％和48．05％）,以静脉滴注方式为主（91．55％）,临床表现主要以皮肤及其附件损伤最常见（75．97％）。结论：应加强ADR监测上报工作,并及时向临床科室反馈,提高临床安全用药意识,确保临床用药安全。     

2009 年-2010 年我院212 例不良反应报告分析

目的:总结医院药品不良反应(ADR)发生的特点。方法:通过ADR网上检索工具统计2009年1月～2010年12月不良反应报告表,采用回顾性分析全院不良反应分布情况。结果:60岁以上老年人ADR发生率较高(27.36%);静脉滴注方式导致的不良反应例数最多(75.00%);导致不良反应的药品以抗微生物药物最多(45.28%);临床表现以皮肤及其附件损害和全身性损害为主(44.35%)。结论:全院不良反应工作有所提高,但仍应加强全院用药监测工作,确保患者用药安全。     

我院2010年度药物不良反应分析

目的分析药物不良反应(ADR)发生的特点与规律,促进临床合理用药。方法回顾性分析2010年1~12月我院上报的401份ADR报告,按患者年龄、性别、给药途径、引起ADR的药品种类、涉及器官或系统以及临床表现等进行统计、分析。结果静脉给药较其他给药途径更易发生ADR(336例,占83.89%);抗感染药物引发ADR的比例最高(159例,占39.65%),其次为营养药、消化系统药物及抗肿瘤药物;头孢菌素类药物是引发ADR的主要抗菌药物(15种,28.85%),其次为青霉素类(10种,19.23%)。ADR主要累及皮肤及附件损害为主,其次涉及到消化系统以及神经系统损害。结论临床科室应重视ADR监测,减少ADR的发生,提高合理用药水平。     

Adverse Drug Reaction Prediction Using Scores Produced by Large-Scale Drug-Protein Target Docking on High-Performance Computing Machines

Late-stage or post-market identification of adverse drug reactions (ADRs) is a significant public health issue and a source of major economic liability for drug development. Thus, reliable in silico screening of drug candidates for possible ADRs would be advantageous. In this work, we introduce a computational approach that predicts ADRs by combining the results of molecular docking and leverages known ADR information from DrugBank and SIDER. We employed a recently parallelized version of AutoDock Vina (VinaLC) to dock 906 small molecule drugs to a virtual panel of 409 DrugBank protein targets. L1-regularized logistic regression models were trained on the resulting docking scores of a 560 compound subset from the initial 906 compounds to predict 85 side effects, grouped into 10 ADR phenotype groups. Only 21% (87 out of 409) of the drug-protein binding features involve known targets of the drug subset, providing a significant probe of off-target effects. As a control, associations of this drug subset with the 555 annotated targets of these compounds, as reported in DrugBank, were used as features to train a separate group of models. The Vina off-target models and the DrugBank on-target models yielded comparable median area-under-the-receiver-operating-characteristic-curves (AUCs) during 10-fold cross-validation (0.60–0.69 and 0.61–0.74, respectively). Evidence was found in the PubMed literature to support several putative ADR-protein associations identified by our analysis. Among them, several associations between neoplasm-related ADRs and known tumor suppressor and tumor invasiveness marker proteins were found. A dual role for interstitial collagenase in both neoplasms and aneurysm formation was also identified. These associations all involve off-target proteins and could not have been found using available drug/on-target interaction data. This study illustrates a path forward to comprehensive ADR virtual screening that can potentially scale with increasing number of CPUs to tens of thousands of protein targets and millions of potential drug candidates.     

Pharmacogenetics and drug development: the path to safer and more effective drugs

Pharmacogenetics provides opportunities for informed decision-making along the pharmaceutical pipeline. There is a growing literature of retrospective studies of marketed medicines that describe efficacy or safety on the basis of patient genotypes. These studies emphasize the potential prospective use of genome information to enhance success in finding new medicines. An example of a prospective efficacy pharmacogenetic Phase-IIA proof-of-concept study is described. Inserting a rapidly performed efficacy pharmacogenetic step after initial clinical data are obtained can provide confidence for a commitment to full drug development. The rapid identification of adverse events during and after drug development using genomic mapping tools is also reviewed.     

双膦酸盐类药物致不良反应回顾性分析

目的:分析双膦酸盐类药物所致不良反应情况。方法:检索中国期刊全文数据库(CNKI)、万方数据库(Wan Fang)、中文科技期刊数据库(VIP)2004年1月至2013年8月国内有关双膦酸盐致不良反应的个案报道,按年龄、性别、原发病、药物名称、给药途径、不良反应发生时间、临床表现症状、治疗与转归等进行分类统计分析。结果:48例不良反应包括运动系统、消化系统、感官系统、循环系统、神经系统及全身性损害,高年龄段与女性发生率较高。结论:临床上应重视双膦酸盐类药物所致不良反应,坚持合理用药。     

Advances in Molecular Modeling of Human Cytochrome P450 Polymorphism

Cytochrome P450 (CYP) is a supergene family of metabolizing enzymes involved in the phase I metabolism of drugs and endogenous compounds. CYP oxidation often leads to inactive drug metabolites or to highly toxic or carcinogenic metabolites involved in adverse drug reactions (ADR). During the last decade, the impact of CYP polymorphism in various drug responses and ADR has been demonstrated. Of the drugs involved in ADR, 56% are metabolized by polymorphic phase I metabolizing enzymes, 86% among them being CYP. Here, we review the major CYP polymorphic forms, their impact for drug response and current advances in molecular modeling of CYP polymorphism. We focus on recent studies exploring CYP polymorphism performed by the use of sequence-based and/or protein-structure-based computational approaches. The importance of understanding the molecular mechanisms related to CYP polymorphism and drug response at the atomic level is outlined.     

Direct costs and hospital morbimortality impact from preventable adverse drug events

Introduction. Implementing pharmacovigilance activities consists of monitoring and assessment of activities related to medical attention. However, additional data are necessary to identify conditions where care quality can be improved. Therefore, a focus on adverse drug events analysis from a prevention and economic perspective is needed, with emphasis on its local impact. Objective. Preventable adverse drug events were summarized to establishing their impact on morbidity and mortality, as well as to estimate the ensuing economic burden. Materials and methods. The data were gathered from a level 3 hospital (high complexity), located in Bogotá, Colombia, where specific pharmacovigilance activities were recorded in 2007. Patient charts were reviewed to characterize adverse drug events according to their causality, severity and preventability. Direct costs were estimated by grouping diagnostic tests, length of hospitalization, procedures and additional drugs required. Results. The charts of 283 patients and 448 reports were analyzed. These data indicated that 24.8% of adverse drug events were preventable and that an associated mortality of 1.1% had occurred. The associated direct costs were between USD $16,687 and $18,739. Factors more commonly associated with preventability were drug-drug interactions, as well as inappropriate doses and unsuitable frequencies at which the drugs were administrated. Conclusions. The data recommended that actions be taken to decrease preventable adverse drug events, because of negative impact on patient′s health, and unnecessary consumption of healthcare resources.     

Perceptions of doctors to adverse drug reaction reporting in a teaching hospital in Lagos, Nigeria

Background  

Spontaneous adverse drug reaction (ADR) reporting is the cornerstone of pharmacovigilance. ADR reporting with Yellow Cards has tremendously improved pharmacovigilance of drugs in many developed countries and its use is advocated by the World Health Organization (WHO). This study was aimed at investigating the knowledge and attitude of doctors in a teaching hospital in Lagos, Nigeria on spontaneous ADR reporting and to suggest possible ways of improving this method of reporting.     

An update on the pharmacoeconomics of antifungal pharmacotherapy

The incidence and severity of invasive fungal infections are on the rise and they pose a risk of significant morbidity and mortality. The cost burden of fungal infections in the United States is high. There are many newer, less toxic antifungal agents to manage these challenging infections; however, these agents also carry a high cost of their own. When considering an antifungal agent for a specific patient, it is important to consider safety, efficacy, and cost, thus making it essential to continually evaluate the antifungal pharmacoeconomic literature to assist in the therapeutic decision-making process for patients with invasive fungal infections. Unfortunately, there is a lack of pharmacoeconomic studies addressing the costs associated with the treatment and prevention of fungal infections. Future large-scale clinical studies should include pharmacoeconomic analyses and end points that encompass all costs associated with antifungal drug use, not solely drug acquisition costs.     

Net efficacy adjusted for risk (NEAR): a simple procedure for measuring risk:benefit balance

Background

Although several mathematical models have been proposed to assess the risk:benefit of drugs in one measure, their use in practice has been rather limited. Our objective was to design a simple, easily applicable model. In this respect, measuring the proportion of patients who respond favorably to treatment without being affected by adverse drug reactions (ADR) could be a suitable endpoint. However, remarkably few published clinical trials report the data required to calculate this proportion. As an approach to the problem, we calculated the expected proportion of this type of patients.

Methodology/Principal Findings

Theoretically, responders without ADR may be obtained by multiplying the total number of responders by the total number of subjects that did not suffer ADR, and dividing the product by the total number of subjects studied. When two drugs are studied, the same calculation may be repeated for the second drug. Then, by constructing a 2×2 table with the expected frequencies of responders with and without ADR, and non-responders with and without ADR, the odds ratio and relative risk with their confidence intervals may be easily calculated and graphically represented on a logarithmic scale. Such measures represent “net efficacy adjusted for risk” (NEAR).We assayed the model with results extracted from several published clinical trials or meta-analyses. On comparing our results with those originally reported by the authors, marked differences were found in some cases, with ADR arising as a relevant factor to balance the clinical benefit obtained. The particular features of the adverse reaction that must be weighed against benefit is discussed in the paper.

Conclusion

NEAR representing overall risk-benefit may contribute to improving knowledge of drug clinical usefulness. As most published clinical trials tend to overestimate benefits and underestimate toxicity, our measure represents an effort to change this trend.     

Explainable detection of adverse drug reaction with imbalanced data distribution

Analysis of health-related texts can be used to detect adverse drug reactions (ADR). The greatest challenge for ADR detection lies in imbalanced data distributions where words related to ADR symptoms are often minority classes. As a result, trained models tend to converge to a point that strongly biases towards the majority class and then ignores the minority class. Since the most used cross-entropy criteria is an approximation to accuracy, the model focuses more readily on the majority class to achieve high accuracy. To address this issue, existing methods apply either oversampling or down-sampling strategies to balance the data distribution and exploit the most difficult samples of the minority class. However, increasing or reducing the number of individual tokens alone in sequence labeling tasks will result in the loss of the syntactic relations of the sentence. This paper proposes a weighted variant of conditional random field (CRF) for data-imbalanced sequence labeling tasks. Such a weighting strategy can alleviate data distribution imbalances between majority and minority classes. Instead of using softmax in the output layer, the CRF can capture the relationship of labels between tokens. The locally interpretable model-agnostic explanations (LIME) algorithm was applied to investigate performance differences between models with and without the weighted loss function. Experimental results on two different ADR tasks show that the proposed model outperforms previously proposed sequence labeling methods.     

临床危急值与药品不良反应的关联性研究分析

目的:通过监测临床危急值提高药品不良反应(ADR)的上报质量。方法:分析临床药物治疗与出现临床危急值之间的联系,确定可疑的ADR病例。结果:调查中共发现23例疑似ADR报告,占调查期间总上报ADR例数的24.73%;主要ADR表现为血小板减少(13例),其次是尿素升高(5例);给药途径主要为静脉滴注(涉及21例),涉及品种以抗菌药物为主。结论:通过加强对临床危急值的监测,可以提高ADR的报告的质量,减少ADR的漏报率。     

Quantitative study of the drug efflux kinetics from sensitive and MDR human breast cancer cells

Cancer multidrug resistance (MDR) is a major impediment to effective chemotherapy in human cancer, in which P-glycoprotein and Multidrug Resistance-Associated protein figure prominently. Design and exploitation of novel clinical MDR inhibitors is greatly hindered by a lack of understanding of drug efflux dynamics in drug-sensitive and resistant cells. The aim of our study was to provide a microelectrode method for measuring the multidrug transporter mediated efflux of doxorubicin as well as a corresponding data analysis method for quantifying the efflux kinetic parameters. We performed experiments using carbon fiber microelectrode to detect doxorubicin efflux from a monolayer of human breast cancer MCF-7 cells and derived MDR cells (MCF-7/ADR), established a material transport model and proposed a novel inverse method to quantitatively characterize the diffusion dynamics. The kinetic parameters of doxorubicin efflux from MCF-7 and MCF-7/ADR cells in the presence or absence of MDR inhibitors were estimated. Our investigations showed the average initial doxorubicin efflux rate of MCF-7/ADR that was 5.2 times faster than of MCF-7. After treatment by tetramethylpyrazine or verapamil, the drug efflux rate of the MCF-7/ADR cells was reduced by about half that of those without inhibitors. The novel methodology presented suggests new and expanded applications for computer-aided reconstruction of the drug efflux process, microelectrode design, and high-throughput drug screening.     

Adriamycin-induced oxidative mitochondrial cardiotoxicity

The anticancer agent Adriamycin (ADR) has long been recognized to induce a dose-limiting cardiotoxicity. Numerous studies have attempted to characterize and elucidate the mechanism(s) behind its cardiotoxic effect. Despite a wealth of data covering a wide-range of effects mediated by the drug, the definitive mechanism remains a matter of debate. However, there is consensus that this toxicity is related to the induction of reactive oxygen species (ROS). Induction of ROS in the heart by ADR occurs via redox cycling of the drug at complex I of the electron transport chain. Many studies support the theory that mitochondria are a primary target of ADR-induced oxidative stress, both acutely and long-term. This review focuses on the effects of ADR redox cycling on the mitochondrion, which support the hypothesis that these organelles are indeed a major factor in ADR cardiotoxicity. This review has been constructed with particular emphasis on studies utilizing cardiac models with clinically relevant doses or concentrations of ADR in the hope of advancing our understanding of the mechanisms of ADR toxicity. This compilation of current data may reveal valuable insights for the development of therapeutic strategies better tailored to minimizing the dose-limiting effect of ADR.     

熵权法在药品不良反应信号筛选及综合风险评价中的应用

目的：在运用经典方法对药品不良反应信号进行检测后,对信号进行再筛选并评价药品的综合风险。方法：以江苏省药品不良反应监测网络数据库为资料来源,SQL server 为后台数据库,Matlab 为算法主要实现工具,运用熵权法结合专家评分,对BCPNN 方法检测出的信号进行再调整和评级。结果：运用综合权重进行调整后,发现不同药品不良反应信号的强弱发生了一定的变化。其中,氟喹诺酮类药品中的加替沙星导致低血糖、呼吸困难等药品不良反应的风险较信号评级之前有所增加,需要专家在评审时更为留意。结论：将熵权法运用在药品不良反应信号的监测中,可使信号更接近客观筛选和主观判断的平衡值,部分罕发但严重的药品不良反应信号得到发现和重视,并能方便地研究药物引起的多种药品不良反应的综合风险。     

Multidrug resistant HOB1 lymphoma cells express P-glycoprotein that does not play the major role in the development of drug resistance to adriamycin.

Two cell lines resistant to 0.1 microM vincristine (VCR) and 2.0 microM adriamycin (ADR), respectively, (designated HOB1/VCR0.1 and HOB1/ADR2.0) were established from a human immunoblastic B lymphoma cell line. These cell lines showed the typical MDR phenotype with overexpression of P-glycoprotein and decreased [3H]VCR accumulation. The retention amounts of intracellular [3H]VCR in these two cell lines could be augmented by verapamil. However, in spite of the overproduction of P-glycoprotein, both HOB1/VCR1.0 and HOB1/ADR2.0 cells did not exhibit decreased accumulation of intracellular [14C]ADR. And the retention of [14C]ADR was not affected by verapamil. Our data support that P-glycoprotein is a drug transporter more important for the development of drug resistance to VCR than to ADR.     

In vitro evaluation of the chemosensitivity of an experimental murine leukemia rendered resistant in vivo to adriamycin

The results obtained using a rapid assay for in vitro chemosensitivity detection of leukemias are presented. The assay, performed according to the technique already described, involves in vitro incubation of a tumor cell suspension with various concentrations of antitumor drugs for 1 h and evaluation of drug-induced cell damage by addition to the cultured cells of 125I-deoxyuridine 48 h after pharmacological treatment. Results are expressed as percent inhibition of the isotope incorporation with respect to untreated controls. Preliminary results demonstrated that this assay is able to evidence differential chemosensitivity exhibited in vivo by murine leukemias. The present study reports the results obtained using comparatively P388 and P388/ADR, a subline of P388 murine leukemia with acquired resistance to Adriamycin in vivo. We found that P388/ADR exhibited resistance to ADR and DNR at all the concentrations tested, whereas P388 was highly sensitive. Cross-resistance of P388/ADR was also found to some structurally dissimilar agents, i.e. VCR and Act-D. These in vitro results correlate well with much data in the literature concerning the characteristics of resistance and cross-resistance exhibited in vivo by P388/ADR. These results suggest the possibility of using a similar in vitro assay for predicting the in vivo drug resistance of human leukemias.