A Pharmacovigilance Approach for Post-Marketing in Japan Using the Japanese Adverse Drug Event Report (JADER) Database and Association Analysis

BackgroundRapid dissemination of information regarding adverse drug reactions is a key aspect for improving pharmacovigilance. There is a possibility that unknown adverse drug reactions will become apparent through post-marketing administration. Currently, although there have been studies evaluating the relationships between a drug and adverse drug reactions using the JADER database which collects reported spontaneous adverse drug reactions, an efficient approach to assess the association between adverse drug reactions of drugs with the same indications as well as the influence of demographics (e.g. gender) has not been proposed.ConclusionsDifferent combinations of adverse drug reactions were noted between the antidepressants. In addition, the reported adverse drug reactions differed by gender. This approach using a large database for examining the associations can improve safety monitoring during the post-marketing phase.     

HIV as a surrogate marker for drug use: A re-analysis of the San Francisco Men's Health Study

Our analysis of drug use and morbidity data from a cohort of 1034 men yields the following results: 1) HIV infection is a strong indicator of drug use — HIV-positive respondents reported an average lifetime dose of recreational drugs (excluding marijuana) 2.3 times higher than HIV-negative respondents. 2) Homosexuality is a strong indicator of drug use — homosexual respondents reported an average lifetime dose 2.0 times higher than heterosexual respondents. 3) The incidence of AIDS-defining diseases was not limited to respondents infected with HIV, but was almost completely limited (98%) to respondents who reported using drugs. We also address a previous report (Ascheret al., 1993) that was based on the same database and purported to show that HIV alone correlates with the development of AIDS. Specifically, we show that the relationship between HIV infection and CD4+ T Cell loss is weaker than reported by Ascheret al., and provides little evidence for a causative relationship. These results support the hypothesis that long-term, habitual drug use can cause the conditions known as AIDS (independent of the presence of HIV), and refute the hypothesis that HIV alone causes these conditions independent of drug use.     

Receptor alterations and drug tolerance.

A brief review of studies which have employed chronic administration of anticholinesterases, benzodiazepines, amphetamine, antidepressants, neuroleptics and opiates is presented to illustrate the deficiencies in our current knowledge about the degree to which alterations in neurotransmitter receptors can account for tolerance development to these agents. Although numerous investigators have reported alterations in receptor binding following chronic drug treatment and others have reported tolerance development, these two phenomena have seldom been studied in the same experiment. It is argued that a multidisciplinary approach is required to elucidate the role of receptor alterations in drug tolerance.     

Pediatric Drug Safety Surveillance in FDA-AERS: A Description of Adverse Events from GRiP Project

Individual case safety reports (ICSRs) are a cornerstone in drug safety surveillance. The knowledge on using these data specifically for children is limited. We studied characteristics of pediatric ICSRs reported to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Public available ICSRs reported in children (0–18 years) to FAERS were downloaded from the FDA-website for the period Jan 2004-Dec 2011. Characteristics of these ICSRs, including the reported drugs and events, were described and stratified by age-groups. We included 106,122 pediatric ICSRs (55% boys and 58% from United States) with a median of 1 drug [range 1–3] and 1 event [1–2] per ICSR. Mean age was 9.1 years. 90% was submitted through expedited (15-days) (65%) or periodic reporting (25%) and 10% by non-manufacturers. The proportion and type of pediatric ICSRs reported were relatively stable over time. Most commonly reported drug classes by decreasing frequency were ‘nervous system drugs’ (58%), ‘antineoplastics’ (32%) and ‘anti-infectives’ (25%). Most commonly reported system organ classes were ‘general’ (13%), ‘nervous system’ (12%) and ‘psychiatric’ (11%) disorders. Duration of use could be calculated for 19.7% of the reported drugs, of which 14.5% concerned drugs being used long-term (>6 months). Knowledge on the distribution of the drug classes and events within FAERS is a key first step in developing pediatric specific methods for drug safety surveillance. Because of several differences in terms of drugs and events among age-categories, drug safety signal detection analysis in children needs to be stratified by each age group.     

Comparative Molecular docking analysis of DNA Gyrase subunit A in Pseudomonas aeruginosaPAO1

Pseudomonas aeruginosa is an opportunistic bacterium known for causing chronic infections in cystic fibrosis and chronic obstructive pulmonary disease (COPD) patients. Recently, several drug targets in Pseudomonas aeruginosa PAO1 have been reported using network biology approaches on the basis of essentiality and topology and further ranked on network measures viz. degree and centrality. Till date no drug/ligand molecule has been reported against this targets.In our work we have identified the ligand /drug molecules, through Orthologous gene mapping against Bacillus subtilis subsp. subtilis str. 168 and performed modelling and docking analysis. From the predicted drug targets in PA PAO1, we selected those drug targets which show statistically significant orthology with a model organism and whose orthologs are present in all the selected drug targets of PA PAO1.Modeling of their structure has been done using I-Tasser web server. Orthologous gene mapping has been performed using Cluster of Orthologs (COGs) and based on orthology; drugs available for Bacillus sp. have been docked with PA PAO1 protein drug targets using MoleGro virtual docker version 4.0.2.Orthologous gene for PA3168 gyrA is BS gyrAfound in Bacillus subtilis subsp. subtilis str. 168. The drugs cited for Bacillus sp. have been docked with PA genes and energy analyses have been made. Based on Orthologous gene mapping andin-silico studies, Nalidixic acid is reported as an effective drug against PA3168 gyrA for the treatment of CF and COPD.     

Effect of intravenous drug administration mode on drug distribution in a tumor slab: a finite Fourier transform analysis

Cancer therapy using chemotherapeutic drugs frequently involves injection of the drug into the body through some intravenous mode of administration, viz, continuous (drip) infusion or single/multiple bolus injection(s). An understanding of the effect of the various modes of administration upon tumor penetration of drug is essential to rational design of drug therapy. This paper investigates drug penetration into a model tumor of slab geometry (between two capillaries) in which the overall transport rate of drug is limited by intra-tumor transport characterized by an effective diffusion coefficient. Employing the method of Finite Fourier Transforms (FFT), analytical solutions have been obtained for transient drug distribution in both the plasma and the tumor following three modes of administration, viz, continuous infusion, single bolus injection and equally-spaced equal-dose multiple bolus injections, of a given amount of drug. The qualitative trends exhibited by the plasma drug distribution profiles are consistent with reported experimental studies. Two concepts, viz, the dimensionless decay constant and the plasma/tumor drug concentration trajectories, are found to be particularly useful in the rational design of drug therapy. The dimensionless decay constant provides a measure of the rate of drug decay in the plasma relative to the rate of drug diffusion into the tumor and is thus characteristic of the tumor/drug system. The magnitude of this parameter dictates the choice of drug administration mode for minimizing drug decay in the plasma while simultaneously maximizing drug transport into the tumor. The concentration trajectories provide a measure of the plasma drug concentration relative to the tumor drug concentration at various times following injection. When the tumor drug concentration exceeds the plasma drug concentration, the drug will begin to diffuse out of the tumor. Knowledge of the time at which this diffusion reversal occurs is especially useful for optimum scheduling of subsequent bolus injections in a multiple bolus dosing regimen. There are no reported applications of the FFT method to solve repeated input functions in either the chemical engineering or pharmaceutical science literature. Thus, the application of FFT method to solve multiple bolus injections is a unique one. Use of this FFT based analysis as a predictor tool can limit the number of costly experiments which are being done now to achieve this purpose. Even though the model in its present form is simplified, the analysis thereof has nevertheless led to a better understanding of the various factors that must be taken into account for rational design of drug therapy.     

时间分辨荧光免疫分析在兽药残留检测中的应用

近年来,兽药残留引起食物中毒的报道日益增多,兽药残留检测的意义重大。传统的气相色谱法、液相色谱法存在前处理复杂、仪器成本昂贵等缺陷,酶联免疫吸附分析(enzyme-linked immunosorbent assay,ELISA)灵敏度也不高,而时间分辨荧光免疫分析(time-resolved fluoroimmunoassay,TRFIA)操作简便、灵敏度高,已在兽药残留检测领域引起重视。介绍了TRFIA的原理和优势,综述了其在促生长繁殖类、瘦肉增产类和杀菌驱虫类兽药残留检测中的应用,并与传统方法进行了对比,TRFIA有望取代传统的检测方法成为兽药残留检测的常规方法。     

谷氨酸受体与药物成瘾的相关研究

谷氨酸是中枢神经系统中最重要的兴奋性神经递质,其受体分为离子型和代谢型,受体激活后通过对Na+、K+、Ca2+等阳离子调节或通过与G蛋白偶联,从而激活一系列信号转导途径,参与记忆形成。药物成瘾是一种慢性、复发性脑疾病,以强迫性药物寻求以及丧失对药物使用控制能力为主要特征。研究表明谷氨酸受体与药物成瘾的发生发展有关,就谷氨酸受体在药物成瘾中作用的研究做一综述。     

Genotoxic effects of niclosamide in Aspergillus nidulans

A 2-5-month treatment with niclosamide, a widely used drug in developing countries, has been reported to induce lymphosarcomas in toad liver and kidney. The genotoxic effects of this drug have also been evaluated in Salmonella typhimurium, in somatic and germinal cells of mice and in human lymphocytes exposed in vitro and in vivo. The present study shows that niclosamide is also capable of inducing mitotic crossing-over and non-disjunction in Aspergillus nidulans, which points to the wide potential of this drug as a genotoxic agent.     

Potent competitive inhibition of drug binding to the Saccharomyces cerevisiae ABC exporter Pdr5p by the hydrophobic estradiol-derivative RU49953

The hydrophobic estradiol-derivative RU49953 inhibits the energy-dependent interaction of yeast multidrug-transporter Pdr5p with its fluorescent drug-substrate rhodamine 6G. The potent inhibition is competitive towards drug binding (Ki=23+/-6 nM), whereas nucleoside-triphosphate hydrolysis is two-orders-of-magnitude less sensitive. RU49953 constitutes the most efficient inhibitor of drug binding to a yeast multidrug ABC exporter reported so far.     

Proficiency testing of conventional drug susceptibility tests of Mycobacterium tuberculosis

Proficiency testing of indirect drug susceptibility tests of Mycobacterium tuberculosis was begun in 1985 by the Laboratory Centre for Disease Control (LCDC) with the participation of Provincial Public Health Laboratories in Canada. Comparable sets of 60 cultures of Mycobacterium tuberculosis representing 30 strains were distributed by LCDC to the participating laboratories to be tested for drug susceptibility against isoniazid, streptomycin, rifampin, and ethambutol using conventional methodologies. Intralaboratory agreement values determined by comparing results obtained on sets of duplicate cultures were high and were found to vary little from drug to drug and from laboratory to laboratory. Interlaboratory agreement was determined by comparing results reported by participating laboratories to those obtained by the Reference Laboratory. Agreement percentages were found to be lower for drug-resistant cultures than for drug-susceptible cultures. The reliability of drug susceptibility testing results was higher for isoniazid and rifampin, than for ethambutol and streptomycin. This study shows that the higher subsidiary drug concentrations do not compare well with main drug concentrations, especially in the case of streptomycin and ethambutol. The significance of the higher subsidiary concentrations in in vitro susceptibility testing is therefore in need of clarification. The proficiency testing results obtained in this study compare favorably with those reported in other developed countries despite the fact that a variety of testing procedures are used throughout the country.     

In-line assessment of pulmonary drug delivery using light obscuration

A candidate optical technology for characterisation of the value and quality of the drug dose delivered to a patient from an inhaler is examined. The theoretical reasoning behind the design of this technology is presented with reference to the optical scattering of the drug cloud. A technical implementation is presented; based upon the light obscuration signature, observed in the delivery path during drug delivery. Dose evaluation studies are reported, performed on different types of drug formulations using regulatory testing procedures and the proposed optical sensing system. Further applications of this technology are discussed in relation to the identification and evaluation of inhaler-drug formulation combinations, which are most suitable for particular patients.     

Injection drug use and HIV/AIDS transmission in China

After nearly three decades of being virtually drug free, use of heroin and other illicit drugs has re-emerged in China as a major public health problem. One result is that drug abuse, particularly heroin injection, has come to play a predominant role in fueling China's AIDS epidemic. The first outbreak of HIV among China's IDUs was reported in the border area of Yunnan province between China and Myanmar where drug trafficking is heavy. Since then drug-related HIV has spread to all 31 provinces, autonomous regions and municipalities. This paper provides an overview to HIV/AIDS transmission through injection drug use in China. It begins with a brief history of the illicit drug trade in China, followed by a discussion of the emergence of drug related AIDS, and a profile of drug users and their sexual partners who have contracted the virus or who are vulnerable to infection. It ends by summarizing three national strategies being used by China to address both drug use and AIDS as major health threats.     

Patterns of childhood trauma and psychological distress among injecting heroin users in China

Background

Childhood trauma has been reported as a possible cause of future substance abuse in some countries. This study reports the prevalence of childhood trauma and examines its association with psychological distress among injecting drug users from mainland China.

Methodology

The study was conducted in three government-operated drug rehabilitation facilities in Shanghai, China in 2007. The Early Trauma Inventory Self Report-Short Form (ETISR-SF) was used to evaluate 4 types (general, emotional, physical and sexual) and severity of childhood trauma, and the Symptom Checklist-90-Revised (SCL-90-R) to evaluate psychological distress.

Principal Findings

Among 341 injecting drug users who completed the study, about 80% reported one or more types of childhood trauma, specifically 53% general trauma, 56% physical abuse, 36% emotional abuse and 26% sexual abuse. Compared to female injecting drug users, males reported significantly higher scores of general trauma and physical abuse, but lower sexual abuse scores. Hierarchical linear regression analyses showed that greater physical and emotional abuse in childhood predict greater current psychopathological distress among these injecting drug users in China.

Conclusions

The results reveal a high prevalence of childhood trauma among injecting drug users in China, and it is comparable to other similar studies in Western countries. It is important to consider the role of childhood trauma in the prevention and treatment of substance abuse.     

Epidemiology of Drug Use and HIV-Related Risk Behaviors among People Who Inject Drugs in Mwanza,Tanzania

Heroin trafficking and consumption has increased steadily over the past decade in Tanzania, but limited information regarding HIV and drug use exists for the city of Mwanza. Our study investigates the epidemiology of drug use, and HIV risk behaviors among drug users in the northwestern city of Mwanza. Using a combination of targeted sampling and participant referral, we recruited 480 participants in Mwanza between June and August 2014. The sample was 92% male. Seventy-nine (16.4%) participants reported injecting heroin, while 434 (90.4%) reported smoking heroin. Unstable housing and cohabitation status were the only socioeconomic characteristics significantly associated with heroin injection. More than half of heroin injectors left syringes in common locations, and half reported sharing needles and syringes. Other risk behaviors such as lack of condom use during sex, and the use of illicit drugs during sex was widely reported as well. Among the study sample, there was poor awareness of health risks posed by needle/syringe sharing and drug use. Our results show that heroin use and HIV risk related behaviors are pressing problems that should not be ignored in Mwanza. Harm reduction programs are urgently needed in this population.     

Efflux as a mechanism for drug resistance in Mycobacterium tuberculosis

Tuberculosis remains an important global public health problem, with an estimated prevalence of 14 million individuals with tuberculosis worldwide in 2007. Because antibiotic treatment is one of the main tools for tuberculosis control, knowledge of Mycobacterium tuberculosis drug resistance is an important component for the disease control strategy. Although several gene mutations in specific loci of the M. tuberculosis genome have been reported as the basis for drug resistance, additional resistance mechanisms are now believed to exist. Efflux is a ubiquitous mechanism responsible for intrinsic and acquired drug resistance in prokaryotic and eukaryotic cells. Mycobacterium tuberculosis presents one of the largest numbers of putative drug efflux pumps compared with its genome size. Bioinformatics as well as direct and indirect evidence have established relationships among drug efflux with intrinsic or acquired resistance in M. tuberculosis. This minireview describes the current knowledge on drug efflux in M. tuberculosis.     

Strategic genome-scale prioritization of unique drug targets: A case study of Streptococcus gordonii

The current reach of genomics extends facilitated identification of microbial virulence factors, a primary objective for antimicrobial drug and vaccine design. Many putative proteins are yet to be identified which can act as potent drug targets. There is lack and limitation of methods which appropriately combine several omics ways for putative and new drug target identification. The study emphasizes a combined bioinformatic and theoretical method of screening unique and putative drug targets, lacking similarity with experimentally reported essential genes and drug targets. Synteny based comparison was carried out with 11 streptococci considering S. gordonii as reference genome. It revealed 534 non-homologous genes of which 334 were putative. Similarity search against host proteome, metabolic pathway annotation and subcellular localization predication identified 16 potent drug targets. This is a first attempt of several combinational approaches of similarity search with target protein structural features for screening drug targets, yielding a pipeline which can be substantiated to other human pathogens.