Preclinical Drug Safety Analysis by Chemogenomic Profiling in the Liver

The economic hurdles of drug development and the emergence of genomic technologies such as chemogenomics are combining to shift the existing paradigms in preclinical drug development. Today, the information gleaned from high content molecular data has begun to augment traditional approaches to the assessment of drug safety. The optimal approach is a hybrid strategy employing chemogenomic data and gene expression-based biomarkers of drug efficacy and toxicity to supplement low content and insensitive methods for risk assessment and mechanistic evaluation of drug candidates. Large reference databases of chemogenomic data are essential to the derivation and validation of accurate and predictive gene expression biomarkers. An example of the development of a predictive biomarker for hepatic bile duct hyperplasia is described herein. As gene expression technologies improve, biomarkers will achieve higher throughput, and become more cost effective and increasingly accurate. This will elevate the value of chemogenomics in drug development, shift attrition to earlier in the process, and reduce the overall cost of drug development. Over the past 2 to 3 years, the transition of chemogenomics from a research tool to a decision-making tool has begun and regulatory agencies are anxiously awaiting implementation of this technology to make faster and more informed evaluations of potential drugs.     

Genetically Engineered Mouse Models for Drug Development and Preclinical Trials

Drug development and preclinical trials are challenging processes and more than 80% to 90% of drug candidates fail to gain approval from the United States Food and Drug Administration. Predictive and efficient tools are required to discover high quality targets and increase the probability of success in the process of new drug development. One such solution to the challenges faced in the development of new drugs and combination therapies is the use of low-cost and experimentally manageable in vivo animal models. Since the 1980’s, scientists have been able to genetically modify the mouse genome by removing or replacing a specific gene, which has improved the identification and validation of target genes of interest. Now genetically engineered mouse models (GEMMs) are widely used and have proved to be a powerful tool in drug discovery processes. This review particularly covers recent fascinating technologies for drug discovery and preclinical trials, targeted transgenesis and RNAi mouse, including application and combination of inducible system. Improvements in technologies and the development of new GEMMs are expected to guide future applications of these models to drug discovery and preclinical trials.     

Alzheimer's Therapeutics: Translation of Preclinical Science to Clinical Drug Development

Over the past three decades, significant progress has been made in understanding the neurobiology of Alzheimer''s disease. In recent years, the first attempts to implement novel mechanism-based treatments brought rather disappointing results, with low, if any, drug efficacy and significant side effects. A discrepancy between our expectations based on preclinical models and the results of clinical trials calls for a revision of our theoretical views and questions every stage of translation—from how we model the disease to how we run clinical trials. In the following sections, we will use some specific examples of the therapeutics from acetylcholinesterase inhibitors to recent anti-Aβ immunization and γ-secretase inhibition to discuss whether preclinical studies could predict the limitations in efficacy and side effects that we were so disappointed to observe in recent clinical trials. We discuss ways to improve both the predictive validity of mouse models and the translation of knowledge between preclinical and clinical stages of drug development.     

Antibody Drug Conjugates: Preclinical Considerations

The development path for antibody drug conjugates (ADCs) is more complex and challenging than for unmodified antibodies. While many of the preclinical considerations for both unmodified and antibody drug conjugates are shared, special considerations must be taken into account when developing an ADC. Unlike unmodified antibodies, an ADC must preferentially bind to tumor cells, internalize, and traffic to the appropriate intracellular compartment to release the payload. Parameters that can impact the pharmacological properties of this class of therapeutics include the selection of the payload, the type of linker, and the methodology for payload drug conjugation. Despite a plethora of in vitro assays and in vivo models to screen and evaluate ADCs, the challenge remains to develop improved preclinical tools that will be more predictive of clinical outcome. This review will focus on preclinical considerations for clinically validated small molecule ADCs. In addition, the lessons learned from Mylotarg®, the first in class FDA-approved ADC, are highlighted.     

Immune Suppression During Preclinical Drug Development Mitigates Immunogenicity-Mediated Impact on Therapeutic Exposure

In the clinical setting, anti-drug antibodies (ADA) against biotherapeutics can influence patient safety and interfere with product efficacy. High immunogenicity has been addressed in clinic by concomitant immune suppression, such as co-administration of methotrexate with enzyme replacement therapy (ERT) and combination tacrolimus/sirolimus treatment for prophylaxis against organ transplant rejection. This study investigates the use of such immune suppressants in mitigating ADA responses to a fully human monoclonal antibody (mAb1) in preclinical animal studies. Three groups of Sprague Dawley rats (n?=?18) were treated with low (0.01 mg/kg), moderate (50 mg/kg), or high (300 mg/kg) doses of mAb1. Experimental groups also received either methotrexate or tacrolimus/sirolimus immune suppressive regimens. ELISA-based methods were utilized to measure and characterize ADA and mAb1 pharmacokinetics (PK). Results demonstrated a stepwise increase in immunogenicity with mAb1 dosage. Methotrexate significantly lowered incidence of anti-variable region antibodies at moderate mAb1 dose (P?<?0.05), while tacrolimus/sirolimus did likewise at moderate and high doses (P?<?0.01) of mAb1. Except for low-dose mAb1 + methotrexate, all immunosuppressed groups displayed more than a 70-fold decrease in ADA magnitude (P?<?0.05). This abrogation in ADA response correlated with more mAb1 in circulation by week 4 for moderate- and high-dosed mAb1 groups. These data provide an approach to mitigate preclinical immunogenicity by the use of immunosuppressant regimens. Such preconditioning can support preclinical drug development of human therapeutics that are antigenic to animals. Similar approaches could be investigated for wider application to novel therapeutics.     

纳米载体在非酒精性脂肪肝药物治疗中的研究进展

非酒精性脂肪肝(non-alcohol fatty liver disease,NAFLD)已成为当前全球最常见的肝病之一,临床表现为肝脂肪变性,并逐步恶化为非酒精性脂肪肝炎(nonalcoholic steatohepatitis,NASH)、肝硬化、肝癌等末期肝病.目前治疗NAFLD的药物主要包括保肝药物、胰岛素增...     

抗体偶联药物临床前安全性评价考虑要点

抗体偶联药物（Antibody Drug Conjugate,ADC）,是通过连接子将高细胞毒性化合物连接到靶向肿瘤抗原的抗体上,利用抗体靶向识别将化合物递呈至肿瘤细胞表面,杀死肿瘤细胞。ADC药物同时具有抗体和化学药物属性,是将两者的优势结合,极大地提高了药物安全有效性。ADC药物结构复杂,在抗原识别表位、连接位点、连接子以及小分子药物各组分均存在特异性,所以在开展安全性评价研究时有一定的特殊性。本文将从动物种属选择、一般毒性研究、毒代动力学研究、组织交叉反应、免疫原性检测、安全药理研究、遗传毒性研究等方面,阐述ADC药物临床前安全性评价的考虑要点和研究策略。     

Tyrosine Kinase Inhibitors in Preclinical Development

Due to the limited efficacy of cytotoxic chemotherapy in the treatment of advanced malignancy and its excessive toxicity precluding its use in chemoprevention, new therapeutic and preventive strategies have been sought. One of the most interesting of these new approaches is the manipulation of signal transduction pathways. Among the approaches being considered to eventuate such a strategy is the inhibition of autophosphorylation, a critical first step in the signal transduction pathways of many cell surface receptor tyrosine kinases, as well as of non-receptor tyrosine kinases. This article is intended to review those tyrosine kinase inhibitors that are currently in preclinical development, for which there are data to support consideration for their use in chemoprevention or cancer treatment. We will focus upon those agents that have received attention in the past several years.     

对我国药物临床前研究实验室管理的思考

目的对我国药物临床前研究实验室管理现状进行研究,完善药物研发监管体系。方法采用问卷调研、实地调研和文献比对等方法。结果与结论制定药物临床前研究实验室管理规范,是加强药物研究监管的重要基础工作,对保证药品质量具有重要意义。     

Dexamethasone Megadoses Stabilize Rat Liver Lysosomal Membranes by Non-Genomic and Genomic Effects

Purpose. Membrane-stabilizing effects may be part of glucocorticoid action during high-dose glucocorticoid therapy. The present study investigates the mode of action of dexamethasone megadoses on rat liver lysosomal membranes. Methods. Following intravenous administration of dexamethasone in rats, the release of -glucuronidase from liver lysosomes was assessed ex vivo as a marker for lysosomal membrane integrity. Results. Dexamethasone megadoses significantly inhibited -glucuronidase release 10 min post-administration by 38% (3 mg/kg dexamethasone) and 33% (10 mg/kg dexamethasone) at corresponding dexamethasone liver concentrations of 3.9 × 10^–5 mol/kg and 15.1 × 10^–5 mol/kg, respectively. Comparable inhibition of -glucuronidase release (34% for 3 mg/kg and 38% for 10 mg/kg) was observed 24 h after administration of dexamethasone, although dexamethasone liver concentrations had already declined to 0.09 × 10^–5 mol/kg and 0.19 × 10^–5 mol/kg, respectively. A 2-h oral pretreatment of rats with the glucocorticoid receptor antagonist RU 486 (10 mg/kg) did not alter immediate (10 min) stabilization by dexamethasone (3 mg/kg), but almost completely prevented lysosomal membrane protection 24 h after dexamethasone injection. Conclusions. Dexamethasone megadoses may preserve lysosomal membrane integrity by a dual action involving both rapid nongenomic effects occurring instantaneously after administration and long-term receptor-dependent genomic events.     

Preclinical Drug Metabolism in the Age of High-Throughput Screening: An Industrial Perspective

With the advent of genomics, combinatorial paradigms and high-throughput screen (HTS)-based pharmacological testing, the number of compounds flowing through the discovery pipeline is likely to escalate. At the same time, with increased knowledge of the human drug-metabolizing enzymes and the availability of in vitro absorption-metabolism (AM) models, Preclinical Drug Metabolism is poised to meet the challenges of HTS. In order to be successful, however, a rational HTS strategy (vs. serendipitous HTS) has to be employed. Such a strategy is based on automation, validation and integration of in vitroAM models and database management (AVID). A generalized strategy for rational (AVID-based) HTS in Preclinical Drug Metabolism is described briefly.     

二级及以下医疗机构开展药品不良反应监测工作的探讨

目的:为二级及以下医疗机构做好药品不良反应(ADR)监测工作提供借鉴。方法:分析二级及以下医疗机构ADR监测工作存在的主要问题,以我院为二级医疗机构模型,探讨二级及以下医疗机构如何加强ADR监测工作。结果与结论:二级及以下医疗机构ADR监测工作存在总体技术水平落后、缺乏先进信息网络、医院领导重视不够、医护人员意识不强、药学部门不能充分发挥作用等一些问题,对此应当引起重视,可通过扩大宣传、提高认识、完善组织结构和相关工作制度、发挥临床药师和护理人员的作用、建立奖惩机制等措施促进此项工作开展。     

Drug Use in a Rural Secondary School in Kenya

ABSTRACT

Alcohol abuse and alcohol-related use problems among adolescents are highly prevalent and are a major concern worldwide. This study estimated the prevalence of drug abuse, knowledge about drug abuse and its effect on psychosocial well-being and induced behavioral problems among students of a public rural secondary school that admitted both girls and boys which offered both boarding and day school facilities. The students filled out a self-reporting substance use tool which measures the prevalence, frequency, and general patterns of substance use. Alcohol, tobacco, khat (catha edulis) and bhang (cannabis) were the most commonly reported substance of use, with user prevalence rates of 5.2%, 3.8%, 3.2%, and 1.7%, respectively. Tobacco use was initiated at 10 years, while cannabis, hard drugs, khat, and alcohol were initiated at 11, 12, 13, and 15 years of age, respectively. Among the students 71% were aware that their schoolmates were on drugs and it was known by 49.8%, 41.7%, 37.6%, 44.3%, and 32.4% of these students that using alcohol, tobacco, khat, cannabis, and hard drugs, respectively was a behavioral problem in the school. Three quarters of the students were aware that use of drugs was harmful to their health, with majority (78.6%) indicating that drug users need help to stop the drug use behavior. However most (73.6%) of the students suggested drug users in school should be punished. The drug use behavioral problems included school dropout, poor scholastic attainment, drunken driving, delinquency, and adolescence pregnancy which threaten the stability of the education system, family as an institution (family difficulties) and society at large. Therefore, teachers have an added burden of playing an active role in guidance and counselling the survivors of drug abuse, a pandemic facing teaching institutions apart from instilling knowledge.     

Human Jejunal Effective Permeability and Its Correlation with Preclinical Drug Absorption Models

This review focuses on intestinal permeability measurements in humans and various aspects of in-vivo transport mechanisms. In addition, comparisons of human data with preclinical models and the blood-brain barrier is discussed. The regional human jejunal perfusion technique has been validated by several crucial points. One of the most important findings is that there is a good correlation between the measured human effective permeability values and the extent of absorption of drugs in humans determined by pharmacokinetic studies. We have also shown that it is possible to determine the effective permeability (P_eff) for carrier-mediated transported compounds, and to classify them according to the proposed Biopharmaceutical Classification System (BCS). Furthermore, it is possible to predict human in-vivo permeability using precuneal permeability models, such as in-situ perfusion of rat jejunum, the Caco-2 model and excized intestinal segments in the Ussing chamber. The permeability of passively transported compounds can be predicted with a particularly high degree of accuracy. However, special care must be taken for drugs with a carrier-mediated transport mechanism, and a scaling factor has to be used. It is also suggested that it is possible to roughly estimate the permeability of the blood-brain barrier using measurements of intestinal permeability, even if the quantitative role of efflux of P-glycoprotein(s) in-vivo still remains to be clarified. Finally, the data obtained in-vivo in humans emphasize the need for more clinical studies investigating the effect of physiological in-vivo factors and molecular mechanisms influencing the transport of drugs across the intestinal and as well as other membrane barriers. It is also important to study the effect of anti-transport mechanisms, such as efflux by P-glycoprotein(s), and gut wall metabolism, for example CYP 3A4, on the bioavailabaility.     

药物性肝损伤的临床药学监护

摘 要 目的： 探讨临床药师对药物性肝损伤患者开展临床药学监护的方法。方法: 详细介绍临床药师参与3例典型药物性肝损伤病例的治疗过程及分析。结果: 病例1提示在临床用药过程中应警惕新的可能导致药物性肝损的药物并及时发现并采取合理诊治;病例2提示发生药物性肝损伤时,临床药师可利用TDM判断致肝损害的药物;病例3提示应关注特殊患者的肝功能,对于肝功能异常的患者,应避免使用肝毒性的药物或选用肝毒性较小的药物。结论:临床药师应多途径、多环节参与药物性肝损伤的药学实践,关注新的可能导致药物性肝损伤的药物;提供TDM监测,为诊断药物性肝损伤提供客观依据;关注患者的肝肾功能,为患者提供更佳的用药方案。     

药物性肝损害临床流行病学研究进展

摘要 药物性肝损害是最常见的药品不良反应之一,重者会导致黄疸、急性肝功能衰竭甚至死亡。其发病率逐年上升,已越来越受到人们的关注。影响因素包括患者因素（如年龄、性别、妊娠、营养不良和基础疾病等）、药物因素和环境因素。有效利用医院信息系统开展监测预警药物性肝损害的发生至关重要,因此建议国家和政府尽快建立药物性肝损害的监测系统。     

虚拟二级库管理功能与药品的三级管理

在整个医疗活动中，医院药学部(药剂科)除了承担药学服务工作之外，还承担着全院病人治疗所需全部药品的采购入库、管理和发放工作。由于目前药品收入在全院总收入中占有较大比重，因此药品的管理在药学部整个工作中占重要地位。